Undergraduate Pathology Series
Refresh
Pathology
3rd Edition (2022)
High-Yield Exam Oriented Review for MBBS
Dr. Shiva M.D.
Undergraduate Pathology Series
Refresh Pathology
3rd Edition; Nov. 2022
Dr. Shiva M.D. (Pathology)
Associate Professor
ASRAM – Eluru, A.P. (INDIA)
Designed for the undergraduates from Andhra
Pradesh and Telangana (India)
Dedicated to Dr. G. Taraka Rajaram MS
E-mail: drshivav@gmail.com
Facebook: https://www.facebook.com/DrShivaMD
Twitter: https://www.twitter.com/Dr_Shiva_MD
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Refresh Pathology, 3rd Edition – Dr. Shiva M.D.
Contents
Dr. NTR UHS, Andhra Pradesh
Paper I (General Pathology & Hematology)
1) Cell injury, Cell Death, and Adaptations, 6
2) Inflammation and Repair, 14
3) Hemodynamic Disorders, Thromboembolic Disease, and Shock, 25
4) Genetic Disorders, 35
5) Diseases of the Immune System, 41
6) Neoplasia, 52
7) Infectious Diseases, 62
8) Environmental and Nutritional Diseases, 70
9) Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus, 75
10) Red Blood Cell Disorders, 87
11) Bleeding Disorders, 97
** Miscellaneous, 103
Paper II (Systemic Pathology)
12) Blood Vessels, 106
13) The Heart, 111
14) The Lung, 119
15) Head and Neck, 129
16) The Gastrointestinal Tract, 132
17) Liver and Gallbladder, 143
18) The Pancreas, 152
19) The Kidney, 154
20) The Lower Urinary Tract and Male Genital System, 164
21) The Female Genital Tract, 168
22) The Breast, 177
23) The Endocrine System, 184
24) The Skin, 194
25) Bones, Joints, and Soft Tissue Tumors, 198
26) The Central Nervous System, 205
** Miscellaneous, 211
KNRUHS, Telangana
Paper I – II (2019, 2020, 2021, 2022), 213
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Undergraduate Pathology Series
Waiting for the teacher is the first step to failure in
education !!
Dr. Shiva M.D.
Refresh Pathology, 3rd Edition – Dr. Shiva M.D.
PAPER I
GENERAL PATHOLOGY
& HEMATOLOGY
5
Undergraduate Pathology Series
1. Cell injury, Cell Death, and Adaptations
MCQs
1) Caspases are seen in which of the following. (May, 2022)
a) Cell division b) Apoptosis c) Necrosis d) Inflammation
2) Example of atrophy is. (May, 2022)
a) Breast in puberty
b) Uterus during pregnancy
c) Ovary after menopause d) Liver after resection
3) Brown atrophy is due to. (May, 2022)
a) Fat necrosis b) Hemosiderin c) Lipofuscin d) Ceruloplasmin
4) Which of the following is antiapoptotic gene. (May, 2022)
a) BAX b) BAD c) Bcl – XL D) BIM
5) Which of the following stains is used to detect lipid in frozen section biopsy in
histopathology. (Feb. 2022)
a) PAS b) Oil Red O c) NSE d) Silver methenamine
6) Alizarin Red S is for demonstrating. (Feb. 2022)
a) Iron b) Calcium c) Copper d) Selenium
15 Marks
1) a. Define apoptosis.
b. Enumerate in detail about the pathways of apoptosis.
c. What are the other methods of death. (Feb. 2022)
5 Marks
1)
2)
3)
4)
Various types of necrosis. (May, 2022)
Different types of calcifications. (May, 2022)
Define necrosis. Explain in detail on various types of necrosis. (Feb. 2022)
Explain briefly on intracellular accumulations and pigments. (Feb. 2022)
4 Marks
1)
2)
3)
4)
5)
6)
Different types of necrosis with examples. (Oct. 2023)
Apoptosis. (May, 2022)
Metaplasia. (March, 2021)
Tabulate differences between necrosis and degeneration. (Feb. 2017)
Mechanisms of apoptosis. (Jan. 2015)
Tabulate the differentiating features of Necrosis and Apoptosis. (Jan. 2014)
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7) Free radicles. (July, 2013)
8) Contrasting features of apoptosis and necrosis. (March, 2010)
9) Metaplasia. (Aug. 2009)
10) Necrosis. (Feb. 2009)
11) Gangrene. (Oct. 2008)
12) Fatty Liver. (Sep/Oct. 2007)
13) Free radicles and cell injury. (May, 2007)
14) Role of free radicles in cell injury. (Oct. 2004)
15) Apoptosis. (April/May, 2004)
16) Pathological calcification. (Sep. 2003)
2 Marks
1) List four free radicles that mediate cell injury. (Oct. 2023)
2) Define pathological calcification and give two examples. (Nov. 2020)
3) Give four types of tissue necrosis with examples. (July, 2019)
4) Morphological changes in apoptosis. (Feb. 2019)
5) List any four types of necrosis with one example for each. (Feb. 2018)
6) Name four types of necrosis with one example each. (July, 2016)
7) List any four types of necrosis with one example each. (Jan. 2016)
8) What are the special stains for fat? (Jan. 2016)
9) Define apoptosis and mention any two morphological features. (July, 2015)
10) Four examples of hyperplasia. (Jan. 2015)
11) Lipofuscin. (July, 2013)
12) Name 4 morphologic changes (cytoplasmic & nuclear) in necrotic cell. (Jan. 2013)
13) Name four (4) types of necrosis with examples. (July, 2012)
14) Name four (4) fat stains. (July, 2012)
15) Autophagy. (Jan. 2012)
16) Hypertrophy and hyperplasia. (July, 2011)
17) Pathogenesis of dystrophic calcification. (Jan. 2011)
18) Taby cat appearance of heart (Tigered effect). (March. 2010)
19) Metaplasia. (Feb. 2009)
20) Metaplasia. (May, 2006)
21) Atrophy. (March/April, 2005)
22) Role of free radicles in cell injury. (Oct. 2004)
High-Yield Topics
Hyperplasia
Free radical ions
Apoptosis
Lipofuscin
Metaplasia
Necrosis
Fatty change
Pathologic calcification
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Hypertrophy
“An increase in the size of cells, causing an increase in the size of the affected organ.”
Mechanisms: Increased production of cellular proteins.
Associations: May coexist with hyperplasia.
Types with e.g.,: I) Physiologic hypertrophy: Hypertrophy of skeletal muscle with increased
work load in bodybuilders; Hypertrophy of smooth muscle of uterus during pregnancy.
II) Pathologic hypertrophy: Hypertrophy of cardiac muscle due to chronic hemodynamic
overload with hypertension.
Hyperplasia
“An increase in the number of cells in an organ or tissue, causing their enlargement.”
Mechanisms: Growth factor driven proliferation.
Associations: May coexist with hypertrophy.
Types with e.g.,: I) Physiologic hyperplasia: Hyperplasia of glandular epithelium of female
breast during puberty and pregnancy; Hyperplasia of hepatocytes following hepatic damage
or resection.
II) Pathologic hyperplasia: Endometrial hyperplasia; Benign prostatic hyperplasia.
Comp.: Pathologic hyperplasia may progress to cancer.
Atrophy
“Decrease in cell size causing a reduction in the size of tissue or organ.”
Mechanisms: Decreased protein synthesis and increased protein degradation in cells.
Types with e.g.,: I) Physiologic atrophy: Atrophy of embryonic structures like notochord
during fetal development; Atrophy of endometrium and breast after menopause.
II) Pathologic atrophy:
1) Atrophy of disuse: Skeletal muscle atrophy following immobilization.
2) Denervation atrophy: Atrophy of skeletal muscle due to damage to nerve supply.
3) Ischemic atrophy: Tissue atrophy with diminished blood supply.
4) Pressure atrophy: Tissue compression can cause atrophy.
Metaplasia
“Replacement of one differentiated cell type with another cell type.”
Mechanisms: Reprogramming of stem cells that exist in normal tissues, or of
undifferentiated mesenchymal cells present in connective tissue.
Types with e.g.,:
I) Epithelial metaplasia:
1) Squamous metaplasia (MC): With cigarette smoking, normal ciliated columnar
epithelium of airways is replaced with stratified squamous epithelium. With stones in
excretory ducts of salivary glands or pancreas, normal columnar epithelium is replaced with
stratified squamous epithelium.
2) Columnar metaplasia: With chronic GERD, stratified squamous epithelium of esophagus
is replaced with intestinal-like columnar epithelium (Barrett esophagus).
Comp.: Dysplasia and malignant transformation.
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II) Connective tissue metaplasia: Formation of mesenchymal elements (cartilage, bone or
adipose tissue) in tissues that do not contain them.
E.g., Bone formation in muscle (myositis ossificans) following intramuscular hemorrhage.
Free Radicals
Source: Oxygen derived (reactive oxygen species) or nitrogen oxide derived.
Reactive oxygen species (ROS): Hydrogen peroxide, superoxide anion and hydroxyl ions.
Generation of free radicals:
1) Reduction-oxidation reactions that occur during normal metabolic processes.
2) Absorption of radiant energy (UV light; X-rays).
3) Activated leukocytes during inflammation.
4) Transition metals (iron and copper) during intracellular reactions.
Removal of free radicals:
1) Antioxidants either block free radical formation or inactivate them. e.g., Vit. A, E and C.
2) Enzymes such as catalase, superoxidase dismutase, and glutathione peroxidase break down
hydrogen peroxide and superoxide anions.
Oxidative stress: State of excess free radicles with increased production or decreased
removal of ROS.
Pathologic effects:
1) Lipid peroxidation in membranes, causing extensive membrane damage.
2) Oxidative modification of proteins, causing cellular damage.
3) Damage to DNA, may promote cell aging and malignant transformation.
Necrosis
“Spectrum of the morphologic changes that follow cell death in living tissue or organs.”
Mechanisms: 1) Denaturation of intracellular proteins.
2) Enzymatic digestion of the injured cell.
Morphology:
Cytoplasm: Increased eosinophilia and glassy or vacuolated appearance.
Nuclear changes: 1) Pyknosis: Small, dense nucleus.
2) Karyorrhexis: Fragmented nucleus.
3) Karyolysis: Faint, dissolved nucleus.
Types
I) Coagulative necrosis
Cause: Ischemia involving all the organs except brain.
Morphology: Preserved tissue architecture with eosinophilic, anucleate cells.
E.g.,: Renal infarct, spleen infarct, and pulmonary infarct.
Fate: Phagocytosis with inflammatory response.
II) Liquefactive necrosis
Cause: Ischemia involving brain and bacterial infections.
Morphology: Formation of liquid viscous mass with inflammatory response.
E.g.,: Cerebral ischemia and lung abscess.
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III) Gangrenous necrosis
Cause: Loss of blood supply.
Sites: Limbs (MC: Lower limb).
Morphology Coagulative necrosis (dry gangrene) or liquefactive necrosis with superimposed
bacterial infections (wet gangrene).
E.g.,: Cerebral infarct and abscess.
IV) Caseous necrosis
Cause: Tuberculosis.
Morphology: Gross: Friable white appearance.
Micro.: Collection of fragmented cells and amorphous granular debris with granulomatous
inflammatory response.
E.g.,: Pulmonary tuberculosis, Pott disease and renal tuberculosis.
V) Fat necrosis
Cause: Destruction of fat.
Morphology: Gross: Chalky-white areas (fat saponification).
Micro.: Foci of necrotic fat cells and deposited calcium salts with inflammatory response.
E.g.,: Acute pancreatitis.
VI) Fibrinoid necrosis
Cause: Immune reactions involving blood vessels and deposition of immune complexes with
fibrin.
Morphology: Wall of arteries show bright pink and amorphous appearance.
E.g.,: Polyarteritis nodosa.
Fate of necrosis: Elimination of necrotic tissue by leukocytes. Dystrophic calcification may
occur with incomplete removal.
Apoptosis
“A pattern of cell death in which cells activate enzymes that degrade the cells own nuclear
DNA and nuclear and cytoplasmic proteins.”
Causes
Physiologic (MC)
1) Programmed destruction of cells during embryogenesis.
2) Hormone-dependent involution of tissues in the adult. e.g., endometrium.
3) Cell loss in proliferating cell populations such as epithelial cells in intestinal crypts.
4) Death of host cells after serving their useful purpose. e.g., neutrophils in an acute
inflammatory response.
Pathologic
1) DNA damage with radiation, cytotoxic drugs and hypoxia.
2) Accumulation of misfolded proteins causing endoplasmic reticulum (ER) stress.
e.g., degenerative diseases of CNS.
3) Cell death with viral infections, such as HIV or adenovirus.
4) Pathologic atrophy of pancreas or parotid gland after duct obstruction.
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Mechanisms: Initiation phase and execution phase.
I) Initiation phase: Activation of enzymes, caspases occur in two distinct pathways.
A) Intrinsic (mitochondrial) pathway: Major pathway.
Activation of sensors of cellular stress and damage (BAD, BIM, and BID), cause antagonism
of anti-apoptotic molecules (BCL-2) and activation of pro-apoptotic molecules (BAX, and
BAK). This results in increased permeability of outer membrane of mitochondria leading to
release of cytochrome c into cytoplasm causing activation of initiator caspases (caspase-9).
B) Extrinsic (death-receptor initiated) pathway: Cross-linking of plasma membrane death
receptors, Type 1 TNF receptor and Fas by external ligands such as TNF and Fas ligand
(FasL) respectively, result in activation of initiator caspases (caspase-8 and caspase-10).
II) Execution phase: Initiator caspases trigger activation of executioner caspases (caspase-3
and caspase-6), which cause disruption of cytoskeleton and fragmentation of nucleus.
Morphology
1) Cell is smaller with dense cytoplasm and tightly packed organelles.
2) Peripheral aggregation of chromatin under the nuclear membrane into dense masses.
3) Nucleus breaks into two or more fragments.
3) Surface blebbing, followed by fragmentation into membrane-bound apoptotic bodies.
4) Plasma membrane remains intact with altered structure.
5) Phagocytosis of apoptotic cells or cell bodies by macrophages.
6) No associated inflammatory response.
Necrosis Vs Apoptosis
Feature
Necrosis
Apoptosis
Cell size
Enlarged
Reduced
Nucleus
Pyknosis, karyorrhexis, karyolysis
Undergo fragmentation
Plasma membrane
Disrupted
Intact
Cellular contents
Enzymatic digestion
Intact
Inflammation
Frequent
Absent
Nature
Pathologic
Physiologic or pathologic
**Other mechanisms of cell death: Necroptosis, pyroptosis, and ferroptosis.
Autophagy
“An adaptive response that is enhanced during nutrient deprivation, allowing the cell to
cannibalize itself to survive.”
Significance:
1) Maintain the integrity of cells by recycling essential metabolites and clearing the cellular
debris under various stress conditions.
2) Turnover of organelles like ER, mitochondria, and lysosomes and the clearance of
intracellular aggregates that accumulate during aging and stress.
Mechanisms:
1) Nucleation and formation of an isolation membrane (phagophore).
2) Formation of a vesicle (autophagosome) from the isolation membrane inside which
intracellular organelles and cytosolic structures are sequestered..
3) Maturation of the autophagosome by fusion with lysosomes, to deliver digestive enzymes
that degrade the contents.
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Associations: Physiologic: Aging and exercise.
Pathologic: Cancer; Alzheimer disease; Inflammatory bowel disease; Infectious diseases
(Mycobacteria, Shigella spp., and HSV-1).
Intracellular Accumulations
1) Lipids: Lipid accumulation can be in the form of triglycerides, cholesterol/cholesterol
esters, and phospholipids.
Steatosis (Fatty Change)
“Abnormal accumulation of triglycerides (TGs) within parenchymal cells.”
Sites: Liver (MC), heart, muscle and kidney.
Fatty liver (Hepatic steatosis)
Causes: Alcohol abuse, nonalcoholic fatty liver disease, toxins, protein malnutrition, diabetes
mellitus, obesity, and anoxia.
Pathogenesis: Excessive entry or defective metabolism or export of lipids.
Morphology: Gross: Liver appears enlarged, bright yellow, soft, and greasy.
Micro.: Initially, small clear cytoplasmic vacuoles are seen around the nucleus. Later, they
coalesce, creating large vacuoles, displacing the nucleus to the periphery of the cell.
Special stains for fat: Sudan IV; Sudan III; Sudan black; Oil Red-O.
*Tigered effect: Within the heart, prolonged moderate hypoxia causes intracellular deposits
of fat, which create grossly apparent bands of yellowed myocardium alternating with bands
of darker, red-brown, uninvolved myocardium.
2) Proteins: Accumulations of proteins can be intracellular, appear as rounded, eosinophilic
droplets, vacuoles, or aggregates in the cytoplasm or extracellular.
Ex: i) Intracellular accumulation: Reabsorption droplets; Russell bodies; Alcoholic hyaline
ii) Extracellular accumulation: Amyloidosis
3) Glycogen: Excessive intracellular deposits appear as clear vacuoles within the cytoplasm
due to abnormality in either glucose or glycogen metabolism.
Causes: Diabetes mellitus; Glycogen storage diseases.
4) Pigments: Colored substances, which can be endogenous or exogenous.
a) Exogenous Pigments: Carbon; Tattooing.
b) Endogenous Pigments: Melanin; Homogentisic acid; Lipofuscin; Hemosiderin.
Lipofuscin (Lipochrome or Wear-and-tear pigment)
“An insoluble endogenous pigment, not injurious to the cell or its functions.”
Source: Lipid peroxidation of polyunsaturated lipids of subcellular membranes.
Composition: Polymers of lipids and phospholipids in complex with protein.
Morphology: Yellow-brown, finely granular cytoplasmic, often perinuclear pigment.
Associations: i) With brown atrophy in large amounts.
ii) Seen in the liver and heart of aging patients or patients with severe malnutrition and cancer
cachexia.
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Pathologic Calcification
“Abnormal deposition of calcium salts, together with smaller amounts of other minerals.”
Types:
I) Dystrophic calcification
i) Deposition of calcium salts occurs locally in dying tissues.
ii) Calcium levels and calcium metabolism are normal.
iii) Sites: E.g.,: Areas of necrosis (coagulative, liquefactive or caseous); Aging or damaged
heart valves; Atherosclerotic plaques.
iv) Comp.: Organ dysfunction.
II) Metastatic calcification
i) Deposition of calcium salts involves normal tissues.
ii) Deranged calcium metabolism with hypercalcemia.
iii) Causes: Hyperparathyroidism; Vitamin D intoxication; Renal failure; Multiple myeloma.
iv) Sites: Interstitial tissues of the gastric mucosa, kidneys, lungs, systemic arteries and
pulmonary veins.
Comp.: Respiratory compromise; Renal damage.
Morphology: Gross: Fine white granules or clumps.
Micro.: i) Calcification appears as intracellular and/or extracellular basophilic deposits.
ii) Psammoma bodies: Laminated, concentric spherules with dystrophic calcification.
**Conditions seen with psammoma bodies: Papillary carcinoma of thyroid; Meningioma;
Malignant mesothelioma; Ovarian serous carcinoma.
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2. Inflammation and Repair
MCQs
1) Endothelium leukocyte interaction with firm adhesion during inflammation is mediated by.
(May, 2023)
a) Selectin b) Integrin c) Defensin d) Endothelin
2) All of the following are signs of inflammation except. (Feb. 2022)
a) Pain b) Swelling c) Redness d) Absence of function loss
3) Counter of tubercular granuloma is formed by. (Feb. 2022)
a) T lymphocytes b) B lymphocytes c) Langhans giant cells d) Necrotic gene
5 Marks
1) Phagocytosis. (May, 2022)
2) Write a note on angiogenesis. (Feb. 2022)
10 Marks
1) 60 years old man was admitted in hospital following a road traffic accident. Wound
closure was done by a surgeon. Answer the following. (Oct. 2022)
a) Differentiate between healing by primary union and secondary union.
b) Describe the stages of cutaneous wound healing in secondary union.
c) Enumerate the factors that delay wound healing.
d) What is keloid?
4 Marks
1) Cellular events in inflammation. (May, 2022)
2) Phagocytosis. (Aug. 2021)
3) Role of prostaglandins in acute inflammation. (Feb. 2020)
4) Role of interleukins in acute inflammation. (July, 2019)
5) Role of vasoactive amines in acute inflammation. (Feb. 2019)
6) Mechanism of wound healing in second intention. (Feb. 2018)
7) Role of complement in inflammation. (July, 2017)
8) Role of prostaglandins in acute inflammation. (Feb. 2017)
9) Phagocytosis. (July, 2015)
10) Mention arachidonic acid metabolites and their role in inflammation. (Jan. 2014)
11) Granuloma. (Jan. 2013)
12) Phagocytosis. (July, 2013)
13) Healing by second intention and complications of wound healing. (July, 2013)
14) Protein derived mediators of acute inflammation. (Jan. 2013)
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15) Phagocytosis. (July, 2012)
16) Role of selectins and integrins involved in the inflammatory response. (Jan. 2012)
17) Chemotaxis. (July, 2011)
18) Growth factors involved in tissue regeneration and repair. (Jan. 2011)
19) Arachidonic acid metabolites and their role in inflammation. (Jan. 2011)
20) Chemokines. (March, 2010)
21) Discuss various processes that participate in the formation of a scar. (March, 2010)
22) Healing by first intention. (Aug. 2009)
23) Phagocytosis. (Feb. 2009)
24) Chemotaxis. (Oct. 2008)
25) Giant cells. (March/April, 2008)
26) Cell derived chemical mediators of inflammation. (Sep/Oct. 2007)
27) Healing by second intention. (May, 2007)
28) Fracture healing. (March/April, 2005)
29) Vascular events of inflammation. (Oct. 2005)
30) Factors influencing wound healing. (Oct. 2004)
31) Phagocytosis. (April/May, 2004)
32) Giant cells. (March/April, 2003)
33) Healing of a bone fracture. (March/April, 2003)
2 Marks
1) List four diseases associated with granulomatous inflammation. (May, 2022)
2) Enumerate four cell derived chemical mediators of inflammation. (Aug. 2021)
3) Lipoxins. (March, 2021)
4) Factors affecting wound healing. (March, 2021)
5) Chemotaxis. (Nov. 2020)
6) Name four cell derived mediators of inflammation. (Nov. 2020)
7) What are the factors affecting healing. (July, 2018)
8) Mention four inflammatory actions of arachidonic acid metabolites. (Feb. 2018)
9) Give four important causes of granulomatous inflammation. (Feb. 2017)
10) Wound healing by first intention. (July, 2015)
11) Fibrinous inflammation. (Jan. 2015)
12) Name four (4) causes of granuloma formation. (July/Aug. 2014)
13) Name any four (4) growth factors involved in regeneration and wound healing. (Jan.
2014)
14) Name 4 main components of extra cellular matrix (ECM). (Jan. 2013)
15) Name four chemical mediators of inflammation. (Aug. 2010)
16) Various types of giant cells. (Aug. 2009)
17) Granuloma. (April, 2009)
18) Cardinal signs of acute inflammation. (April, 2009)
19) Healing by second intension. (Oct. 2008)
20) Complications of wound healing. (Sept/Oct. 2007)
21) Triple response. (May, 2007)
22) Giant cells. (May, 2006)
23) Chemotaxis. (May, 2006)
24) Granuloma. (March/April, 2005)
25) Granuloma. (Sep. 2003)
26) Healing of a wound by second intention. (Sep. 2003)
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High-Yield Topics
Cardinal signs
Chemotaxis
Arachidonic acid metabolites
Complement system
Wound healing – Types & mechanisms
Vascular events
Phagocytosis
Cytokines
Granulomatous inflammation
Abnormalities in tissue repair
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Cardinal Signs of Inflammation
1) Rubor: Redness.
2) Calor: Heat.
3) Tumor: Swelling.
4) Dolor: Pain.
5) Functio laesa: Loss of function.
*Rubor, calor, tumor and dolor are hallmarks of acute inflammation.
Vascular Events of Acute Inflammation
I) Arteriolar vasodilation
Stimulus: Histamine.
Effects: i) Increased volume of blood in flow generates heat (calor).
ii) Increased supply of oxygenated blood makes tissues turn red (rubor or erythema).
iii) Increased hydrostatic pressure.
II) Increased vascular permeability
Mechanisms:
1) Contraction of endothelial cells with increased interendothelial space: Most common.
Stimulus: Histamine (major), bradykinin, and leukotrienes.
Features: Immediate transient response; Reversible; Venules are most commonly involved.
2) Endothelial injury causing necrosis and their detachment:
Stimulus: Severe injury (burns); Microbes.
Features: Immediate sustained response; Irreversible; Arterioles, capillaries and venules are
involved.
Effects: i) Escape of protein rich fluid into interstitial tissues causes edema (tumor).
ii) Decreased plasma oncotic pressure.
iii) Increased viscosity with concentration of blood cells.
iv) Slow or no flow of blood (stasis), disrupts normal laminar flow.
Triple Response
Demonstrated by Lewis experiment with the changes in the skin of inner aspect of forearm by
firm stroking with a blunt point.
Features:
1) Red line: Appears within seconds due to local dilation of capillaries and venules.
2) Flare: Bright reddish appearance surrounding red line with arteriolar vasodilation.
3) Wheal: Swelling of surrounding skin due to edema.
Cellular Events of Acute Inflammation
1) Margination: Leukocytes assume a peripheral position along the endothelium.
2) Rolling: Leukocytes with transient attachment to endothelium, mediated by selectins.
3) Adhesion: Leukocytes with firm attachment to endothelium, mediated by integrins.
4) Transmigration (Diapedesis): Migration of the leukocytes through intact endothelium,
mediated by homotypic interactions between PECAM-1 on leukocytes and endothelial cells.
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5) Chemotaxis: “Locomotion along a chemical gradient within tissues toward the site of
injury mediated by chemoattractants.”
Chemoattractants:
1) Exogenous: Bacterial products (peptides or lipids).
2) Endogenous: Mediators (Leukotriene B4; C5a; Chemokines).
Mechanisms: Chemoattractants bind to leukocyte surface receptors, facilitating
polymerization of actin and cell movement. Leukocytes move by extending pseudopods that
bind the ECM and then pull the cell forward.
Complementary Adhesion Molecules
“Selectins and integrins mediate the attachment of leukocytes to endothelial cells whose
expression is enhanced by cytokines.”
I) Selectins: P-selectin, E-selectin and L-selectin.
P-selectin and E-selectin are expressed on endothelium; L-selectin is expressed on
leukocytes.
Ligands: Sialylated oligosaccharides bound to glycoproteins, expressed on leukocytes and
endothelium.
Interactions:
Molecule
Ligand
P-selectin
Sialyl-Lewis X on leukocytes
E-selectin
Sialyl-Lewis X on leukocytes
L-selectin
Sialyl-Lewis X on endothelium
Functions: Rolling of the leucocytes along the endothelial surface.
II) Integrins: VLA-4, LFA-1 and MAC-1, expressed on leukocytes.
Ligands: ICAM-1, and VCAM-1, expressed on endothelial cells.
Interactions:
Molecule
Ligand
LFA-1
ICAM-1
MAC-1
ICAM-1
VLA-4
VCAM-1
Functions: Firm adhesion of the leukocytes to the endothelium.
Phagocytosis
“Involves recognition and attachment of the particle to be ingested, engulfment of the particle
and killing or degradation of the ingested material by the leukocytes.”
Mechanisms
I) Recognition and attachment of the particle: Mediated by mannose receptors, scavenger
receptors and receptors for opsonins expressed on phagocytes.
II) Engulfment of the particle: Pseudopods form around the receptor bound particle and
encloses it in a phagosome. Phagosome fuses with a lysosomal granule forming
phagolysosome into which discharge of granule’s content occurs.
III) Killing or degradation of the ingested material: Done by reactive oxygen species
(ROS), reactive nitrogen species and lysosomal contents.
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i) ROS are produced in the presence of NADPH oxidase enzyme. Myeloperoxidase mediates
formation of hypochlorite from hydrogen peroxide in the presence of chloride. Hypochlorite
destroys microbes by halogenation or oxidation of proteins and lipids.
ii) Reactive nitrogen species are produced in the presence of nitric oxide synthase enzyme.
Reaction of nitric oxide with superoxide anion forms peroxynitrite.
iii) ROS and peroxynitrite damage proteins, lipids and nucleic acids of microbes.
iv) Lysosomal contents such as acid proteases, elastases, defensins, lysozyme, lactoferrin and
major basic protein are involved in degradation of microbes.
Fibrinous Inflammation
“A morphologic pattern of acute inflammation.”
Mechanism: With marked raise in vascular permeability, fibrinogen may escape and get
converted to fibrin in the extracellular space forming fibrinous exudate.
e.g., Meningitis, pericarditis, and pleuritis.
Microscopy: Eosinophilic meshwork of threads.
Fate: Dissolution or organization.
Mediators of Inflammation
Source: Cell-derived or plasma-derived.
Cell-derived mediators: Vasoactive amines; Arachidonic acid metabolites;
Cytokines and chemokines.
I) Vasoactive amines
“Histamine and serotonin, preformed mediators, are the first to be released during
inflammation.”
Histamine
Stimulus: Physical injury, immediate hypersensitivity reactions and anaphylatoxins.
Source: Mast cells (major), basophils and platelets.
Functions: Arteriolar vasodilation and increased vascular permeability of venules.
II) Arachidonic acid metabolites (Eicosanoids)
“Leukotrienes (LTs) & prostaglandins (PGs) are formed from arachidonic acid present in
membrane phospholipids.”
Stimulus: Mechanical, chemical and physical stimuli.
A) Prostaglandins: Cyclooxygenase enzyme yields prostaglandins like PGE2, PGD2, PGF2a,
thromboxane (TxA2), and prostacyclin (PGI2).
Source: Macrophages, mast cells and endothelial cells.
Functions:
i) Thromboxane A2: Aggregation of platelets and vasoconstriction.
ii) Prostacyclin: Inhibition of platelet aggregation and vasodilation.
iii) PGE2, PGD2: Vasodilation and increased vascular permeability.
iv) PGF2a: Contraction of smooth muscle and small arterioles.
v) PGE2: Pain and fever.
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B) Leukotrienes: Lipoxygenase enzyme yields leukotrienes such as LTB4, LTC4, LTD4, and
LTE4.
Source: Leukocytes and mast cells.
Functions:
i) LTB4: Chemotaxis.
ii) LTC4, LTD4 and LTE4: Vasoconstriction, bronchospasm & increased vascular
permeability.
C) Lipoxins: Lipoxygenase enzyme yields lipoxins such as Lipoxin A4 (LXA4) and Lipoxin
B4 (LXB4).
Functions: Suppress inflammation by inhibiting neutrophil chemotaxis, and adhesion to
endothelium.
III) Cytokines
A) Tumor necrosis factor (TNF) and interleukin-1 (IL-1)
Source: Macrophages and dendritic cells.
Stimulus: Microbial products, immune complexes and physical injury.
Functions:
i) TNF and IL-1 cause endothelial activation which includes increased expression of adhesion
molecules, production of various mediators and increased procoagulant activity.
ii) TNF and IL-1 induce the systemic acute-phase response with fever.
iii) TNF activates leukocytes and IL-1 activates fibroblasts to synthesize collagen.
iv) TNF regulates energy balance by promoting lipid and protein mobilization and by
suppressing appetite.
B) Chemokines
Stimulus: Microbial products.
Groups:
I) C-X-C chemokines: e.g., IL-8.
Function: Activation and chemotaxis of neutrophils.
II) C-C chemokines: e.g., Eotaxin, MCP-1, RANTES, and MIP-1.
Function: Chemotaxis of eosinophils, basophils, lymphocytes, and monocytes.
III) C chemokines: e.g., Lymphotactin.
Function: Chemotaxis of lymphocytes.
IV) CX3C chemokines: e.g., Fractalkine.
Function: Chemotaxis of monocytes and T lymphocytes.
Plasma-derived mediators: Complement proteins; Bradykinin.
I) Complement system
“Consists of soluble plasma proteins in their inactive forms.”
Complement activation: Involves formation of proteolytic enzymes C3 convertase and C5
convertase by 3 pathways.
1) Classical pathway: Triggered by fixation of C1 to antibody combined with antigen.
2) Alternative pathway: Triggered by microbial products (endotoxin) and cobra venom.
3) Lectin pathway: Plasma mannose-binding lectin binds to carbohydrates on microbes and
directly activates C1.
End products
1) C3 convertase splits C3 into C3a and C3b.
2) C5 convertase splits C5 into C5a and C5b.
3) Membrane Attack Complex (MAC) is formed by binding of C5b with C6, C7, C8 and C9.
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Functions
i) C3a and C5a act as anaphylatoxins, stimulate the release of histamine from mast cells and
cause vasodilation and increased vascular permeability.
ii) C5a facilitates chemotaxis and activates the lipoxygenase pathways of arachidonic acid
metabolism.
iii) C3b acts as opsonin and facilitates phagocytosis of microbes.
iv) MAC deposition causes cell death.
II) Bradykinin
Source: High-molecular-weight kininogen by the action of enzyme, kallikrein.
Functions: Increased vascular permeability, vasodilation, contraction of smooth muscle and
pain.
Granulomatous Inflammation
“A form of chronic inflammation characterized by the formation of granulomas.”
Causes: TB; Leprosy; Syphilis; Cat-scratch disease; Sarcoidosis; Crohn disease.
Features
I) Epithelioid cells: “Activated macrophages with pink granular cytoplasm and indistinct
cell boundaries.”
II) Giant cells: Epithelioid cells may fuse to form multinucleate giant cells with abundant
cytoplasm and many nuclei.
Types: 1) Foreign-body type: Nuclei are arranged in a haphazard pattern.
2) Langhans type: Nuclei are arranged in a particular pattern.
III) Granuloma: “Aggregates of epithelioid cells surrounded by a rim of lymphocytes.”
Types: 1) Immune granuloma: i) Associated with persistent microbes in the presence of Tcell mediated immune responses.
ii) Activated Th1 cells produce IFN-γ, which activates macrophages.
2) Foreign body granuloma: i) Seen with relatively inert foreign bodies (talc, sutures) in the
absence of T-cell mediated immune responses.
ii) Foreign material is usually identified in the centre of granuloma with epithelioid cells and
giant cells apposed to its surface.
IV) Caseous necrosis: Caseating granulomas with central caseous necrosis are seen with TB.
Non-caseating granulomas are seen with sarcoidosis, and Crohn disease.
Growth Factors Involved in Regeneration and
Repair
“Growth factors stimulate the activity of genes that are required for cell growth and cell
division.”
1) Epidermal growth factor (EGF)
Source: Macrophages, keratinocytes.
Functions: Mitogenic for keratinocytes and fibroblasts.
2) Vascular Endothelial Growth Factor (VEGF)
Source: Mesenchymal cells.
Stimulus: Hypoxia.
Functions: Angiogenesis by promoting endothelial cell migration and proliferation.
Vasodilation and increased vascular permeability.
Undergraduate Pathology Series
3) Platelet-Derived Growth Factor (PDGF)
Source: Platelets, macrophages, endothelial cells, and smooth muscle cells.
Functions: Proliferation of fibroblasts, endothelial cells and smooth muscle cells.
Chemotactic for neutrophils, macrophages, fibroblasts and smooth muscle cells.
4) Fibroblast Growth Factor (FGF)
Source: Macrophages, mast cells, and endothelial cells.
Functions: Chemotactic and mitogenic for fibroblasts. Stimulates angiogenesis and ECM
protein synthesis.
5) Transforming Growth Factor-β (TGF-β)
Source: Platelets, endothelial cells and mononuclear inflammatory cells.
Functions: Scar formation by stimulating ECM synthesis and preventing break down of
collagen. Limits and terminates inflammatory response as an anti-inflammatory cytokine.
Angiogenesis
“Process of new blood vessel development from existing vessels.”
Physiologic: During development & menstrual cycle.
Pathologic: Sites of injury & ischemia; Tumors.
Mechanisms
1) Vasodilation and increased permeability induced by VEGF.
2) Separation of pericytes from the abluminal surface and breakdown of the basement
membrane to allow formation of a vessel sprout.
3) Migration of endothelial cells toward the area of tissue injury by VEGF.
4) Proliferation of endothelial cells just behind the leading front (tip) of migrating cells by
VEGF, and FGF.
5) Remodeling into capillary tubes.
6) Recruitment of periendothelial cells (pericytes for small capillaries and smooth muscle
cells for larger vessels) to form the mature vessel by PDGF.
7) Suppression of endothelial proliferation and migration and deposition of the basement
membrane by TGF-β.
Healing of Skin Wounds
“Involves both epithelial regeneration and the formation of connective tissue scar.”
Types: Primary union and secondary union.
I) Healing by First Intension or Primary Union
i) Seen with minimal injury to skin, where edges of the wound are approximate.
ii) Healing occurs by regeneration.
iii) Involves small clot formation, minimal necrotic debris, mild inflammatory response,
minimal granulation tissue deposition and insignificant scar formation.
iv) Wound contraction is not seen.
E.g., Healing of a clean, uninfected surgical incision approximated by sutures.
II) Healing by Second Intention or Secondary Union
i) Seen with extensive damage to skin, where edges of the wound are distant.
ii) Healing occurs by regeneration and fibrosis.
iii) Involves larger clot formation, greater necrotic debris, more intense inflammatory
response, abundant granulation tissue deposition and significant scar formation.
iv) Wound contraction is seen.
E.g., Large wounds, abscesses, ulceration and infarction of parenchymal organs.
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Mechanisms
1) Activation of coagulation pathway results in the formation of a clot covering the wound
surface. With dehydration, clot transforms to a scab.
2) Within 24 hrs, neutrophils are recruited and involved in clearing of debris.
3) Within 24 to 48 hrs, epithelial cells from both edges of the wound begin to migrate and
proliferate along the dermis, depositing basement membrane under the scab. Finally, a thin
continuous epithelial layer is formed that closes the wound.
4) By day 3, macrophages replace neutrophils, and clear the debris and fibrin. Deposition of
granulation tissue and collagen follows.
5) By day 5, granulation tissue fills the tissue deficit with prominent neovascularization.
Fibroblast migration and proliferation occur with deposition of abundant collagen. Finally,
Epidermis recovers its normal thickness.
6) During second week, increased collagen deposition and regression of vascular channels
occur with diminished inflammatory response.
7) By the end of first month, formed scar is seen comprising of a cellular connective tissue,
largely devoid of inflammatory cells and covered by an essentially normal epidermis.
8) Wound contraction: In secondary union, formation of a network of myofibroblasts is seen
at the edges of the wound. Their contraction helps to close the wound by decreasing the gap
between its dermal edges and by reducing the surface area of wound.
Healing of Fractures
“Involves reactivating bone formation pathways, regulated by cytokines and growth factors.”
Events:
I) During the first week
1) Hematoma forms immediately after fracture, filling the fracture gap.
2) Clot provides a fibrin meshwork for the influx of inflammatory cells and ingrowth of
fibroblasts and new capillaries.
3) Growth factors (PDGF, TGF-β and FGF) activate osteoprogenitor cells and stimulate
osteoclastic and osteoblastic activity.
4) Finally, uncalcified tissue known as soft tissue callus or procallus is formed providing
some anchorage between the ends of fractured bones.
II) Within 2 weeks
1) Activated osteoprogenitor cells deposit subperiosteal trabeculae of woven bone.
2) Activated mesenchymal cells differentiate into chondrocytes that make cartilage which
undergoes enchondral ossification.
3) Finally, soft tissue callus is transformed into a bony callus which stabilizes the fracture
site.
4) Bony callus is eventually remodelled along lines of weight bearing and the healing process
is complete with lamellar bone having medullary cavity.
Factors that influence healing: Inadequate immobilization, malalignment, infection of the
fracture site, malnutrition and skeletal dysplasia.
Complications: Delayed union or nonunion; Pseudoarthrosis.
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Factors That Influence Tissue Repair
They can be extrinsic or intrinsic to the injured tissue and systemic or local.
1) Infection: Delays healing.
2) Diabetes: Delays healing.
3) Nutritional factors: Protein deficiency and Vitamin C deficiency retard healing.
4) Glucocorticoids: Diminish fibrosis and cause weakness of scar.
5) Mechanical factors: Increased local pressure causes wound dehiscence.
6) Poor perfusion: Arteriosclerosis or diabetes impairs healing.
8) Foreign bodies: Fragments of steel or glass impairs healing.
9) Type of tissue: Labile & stable tissues have better tissue regeneration, whereas permanent
tissues form only scar.
Complications in Tissue Repair
I) Wound dehiscence and ulceration
Mechanisms: Inadequate formation of granulation tissue or formation of a scar.
Causes: Abdominal wounds with vomiting or coughing may undergo dehiscence or rupture;
Atherosclerotic peripheral vascular disease causes wound of lower limb ulcerate.
II) Hypertrophic scar and keloids
Mechanisms: Accumulation of excessive amounts of collagen.
Causes: Thermal or traumatic injuries may cause hypertrophic scar.
Morphology: Hypertrophic scar is a raised scar lying within boundaries of original wound,
but in keloids, scar tissue grows beyond the boundaries and does not regress.
III) Exuberant granulation
Mechanisms: Formation of excessive amounts of granulation tissue.
Causes: Incisional scar or traumatic injuries (rare).
Morphology: Seen as a protrusion above the level of surrounding skin.
IV) Contractures
Mechanisms: Exaggeration of wound contraction.
Causes: Severe burns.
Morphology: Deformities of the wound and surrounding tissues.
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3. Hemodynamic Disorders,
Thromboembolic Disease, and Shock
MCQs
1) Pale infarct is seen in all except. (May, 2022)
a) Lung b) Spleen c) Kidney d) Heart
2) Lines of Zahn are found in. (May, 2022)
a) Thrombus b) Infarct tissue c) Post-mortem clot d) All
3) Transudate is. (Feb. 2022)
a) Protein-rich, cell-poor fluid b) Protein-poor, cell-rich fluid
c) Protein-poor, cell-poor fluid d) Protein-rich, cell-rich fluid
4) Leiden mutation is. (Feb. 2022)
a) Factor III mutation b) Factor VI mutation
c) Factor VII mutation d) Factor V mutation
15 Marks
1) An young male met with a road traffic accident. He sustained multiple injuries, fractures of
femur and tibia. These fractures are stabilized at surgery after admission. He is in a stable
condition. After two days of admission, suddenly became dyspneic and develop tachypnea
and tachycardia, irritability, restlessness and progressed to delirium, coma and on seventh day
death occurred. (May, 2022)
a) What is the provisional diagnosis.
b) Discuss the pathogenesis of the lesion.
c) Microscopic picture of the lungs in the above disease.
d) How the frozen sections of the lung tissue help in the final diagnosis at autopsy and
mention the various stains specific for it.
Ans: Fat embolism.
5 Marks
1) Pathogenesis of thrombus formation. (May, 2022)
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10 Marks
1) A 30 year old man had multiple fractures of the bones of pelvis and lower limbs after a
road traffic accident. He developed sudden onset of tachypnea, dyspnea, tachycardia and
restlessness on the fourth day of hospitalization. There was diffuse petechial rash, anemia and
diffuse opacity of lungs. (May, 2022)
a) What is your diagnosis?
b) Describe in detail the etiology and pathogenesis of the condition.
c) Discuss the autopsy findings of the organs affected in this disorder.
d) What is the cause of petechial rash and anemia in this patient?
Ans: Fat embolism.
2) A 55 year old lady was brought to the emergency room unconscious with history of road
accident. She sustained multiple injuries, fractures of femur and tibia. These fractures are
stabilized at surgery soon after admission. However 2 days after admission, she suddenly
becomes dyspneic and developed tachypnea and tachycardia, irritability, restlessness and it
progressed to delirium, coma and death on 7th day. (March, 2021)
a) What is the provisional diagnosis?
b) Discuss the pathogenesis of the lesion.
c) Describe microscopic picture of the lungs in the above condition.
d) How frozen sections of the lung tissue help in final diagnosis at autopsy and mention
various stains specific for it.
Ans: Fat embolism.
3) A 55 year old lady was brought to the emergency room unconscious. Her blood pressure
was very low, pulse was weak and rapid. Her skin was warm and flushed. Her blood culture
revealed growth of Gram positive bacteria. (Jan. 2015)
a) What is the possible diagnosis?
b) Describe the pathogenesis of this condition.
c) Describe the stages of this disorder.
Ans: Septic shock.
4) Young male met with an accident. Had fracture femur. C/o breathlessness and chest pain,
cough and frothy sputum. (Jan. 2013)
a) What is the provisional diagnosis?
b) What other conditions can produce similar symptoms?
Ans: Fat embolism.
Refresh Pathology, 3rd Edition – Dr. Shiva M.D.
4 Marks
1) Pathogenesis of septic shock. (Oct. 2022)
2) Pathogenesis of septic shock. (Aug. 2021)
3) Pathogenesis of septic shock. (Feb. 2020)
4) Etiopathogenesis of septic shock. (July, 2018)
5) Pathogenesis of septic shock. (Feb. 2018)
6) Pathogenesis of septic shock. (July, 2017)
7) Systemic thromboembolism. (July, 2016)
8) Air embolism. (July, 2015)
9) Pathogenesis of endotoxic shock. (July/Aug. 2014)
10) Etiology and pathogenesis of fat embolism. (Jan. 2014)
11) Systemic thromboembolism. (Jan. 2012)
12) Exudate and transudate. (April, 2009)
13) Thromboembolism. (April, 2009)
14) Fate of thrombus. (Feb. 2009)
15) Thromboembolism. (March/April, 2008)
16) Cardiac edema. (May, 2007)
17) Septic shock. (May, 2006)
18) C.V.C. Liver. (Oct. 2005)
19) Nephrotic edema. (March/April, 2005)
20) Amniotic fluid embolism. (Sep. 2003)
2 Marks
1) Write the components and their inter relationship of Virchow triad. (Oct. 2022)
2) Enumerate four differences between transudate and exudate. (May, 2022)
3) List any four fate of thrombus. (Aug. 2021)
4) Fate of thrombus. (Feb. 2019)
5) List four examples for edema due to reduced plasma oncotic pressure. (Feb. 2018)
6) Fate of thrombus. (Feb. 2017)
7) Fate of thrombus. (July, 2013)
8) Nutmeg liver. (July, 2012)
9) Fate of a thrombus. (July, 2011)
10) Hypovolemic shock. (July, 2011)
11) Phlebothrombosis. (Jan. 2011)
12) Fate of a thrombus. (Aug. 2010)
13) What is paradoxical embolism? Give an example. (March, 2010)
14) Mural thrombus. (Aug. 2009)
15) Exudate and transudate. (April, 2009)
16) Thromboembolism. (April, 2009)
17) Exudate. (Feb. 2009)
18) Cardiac edema. (Oct. 2008)
19) Shock lung. (March/April, 2008)
20) Stages of shock. (Sept/Oct. 2007)
21) Fate of a thrombus. (May, 2006)
22) Amniotic fluid embolism. (May, 2006)
23) Fate of thrombus. (Oct. 2005)
24) Air embolism. (March/April, 2005)
25) Paradoxical embolism. (April/May, 2004)
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26) Nutmeg liver. (April/May, 2004)
27) Brown induration of the lung. (Sep. 2003)
28) Decompensated shock. (March/April, 2003)
High-Yield Topics
Edema – Mechanisms, causes & types
Thrombus – Pathogenesis, types & fate
Fat embolism
Infarct – Types & morphology
Chronic passive congestion of liver
Systemic thromboembolism
Air embolism
Shock – Types, pathogenesis & stages
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Cardiac Edema
Causes: Congestive cardiac failure.
Pathogenesis: Increased capillary hydrostatic pressure and retention of sodium and water
with activated renin-angiotensin system causes development of edema.
Type of edema: Transudate.
Renal Edema
Causes: Nephrotic syndrome; Renal failure.
Pathogenesis:
1) Nephrotic syndrome: Decreased plasma osmotic pressure with massive proteinuria and
retention of sodium and water with activated renin-angiotensin system leads to edema.
2) Renal failure: Retention of sodium and water with activated renin-angiotensin system
causes increased hydrostatic pressure and decreased plasma osmotic pressure leading to
edema.
Type of edema: Transudate.
Transudate Vs Exudate
Feature
Transudate
Exudate
Cause
Increased hydrostatic pressure
or decreased oncotic pressure
Non-inflammatory
Clear
Low (<3 gm/dl)
<1.012
Poor
Absent
Present
Increased vascular permeability
Nature
Appearance
Protein
Specific gravity
Cellularity
Fibrin
Pitting
Inflammatory
Cloudy
High (>3gm/dl)
>1.020
Rich
Present
Absent
Chronic Passive Hepatic Congestion
“Represent increased blood volumes within liver due to impaired outflow for prolonged
duration.”
Causes: Congestive heart failure.
Pathogenesis: 1) Chronic hypoxia leads to ischemic injury of tissues.
2) Capillary rupture causes hemorrhage and formation of hemosiderin-laden macrophages.
Morphology: Gross: Centrilobular regions are red-brown and slightly depressed and are
accentuated against the surrounding zones of uncongested tan liver.
Micro.: Centrilobular hemorrhage, hemosiderin-laden macrophages, and variable degrees of
hepatocyte dropout and necrosis (nutmeg liver).
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Chronic Passive Pulmonary Congestion
“Represent increased blood volumes within lung due to impaired outflow for prolonged
duration.”
Causes: Congestive heart failure.
Pathogenesis: 1) Chronic hypoxia leads to ischemic injury of tissues.
2) Capillary rupture causes hemorrhage and formation of hemosiderin-laden macrophages.
Morphology:
Gross: Lungs are firm and heavy. C/S: Rusty brown (brown induration of lungs).
Micro.: Septa are thickened and fibrotic. Numerous hemosiderin-laden macrophages (heart
failure cells) within the alveoli.
Thrombosis
Thrombus: “Intravascular solid mass attached to the underlying blood vessel wall.”
Pathogenesis:
Virchow triad: Factors may promote thrombosis independently or in combination.
1) Endothelial injury: Injury to endothelial cells can alter local blood flow and affect
coagulability leading to platelet activation.
Causes:
i) Endothelial activation or dysfunction: Hypertension; Smoking; Hypercholesterolemia;
Homocystinemia.
ii) Endothelial damage: Myocardial infarction; Atherosclerosis; Vascular injury.
2) Alterations in normal blood flow: Abnormal blood flow (stasis or turbulence), in turn,
can cause endothelial injury and affect coagulability by disrupting laminar flow and
promoting endothelial activation.
Causes:
i) Stasis: Aneurysms; Hyperviscocity; Sickle cell disease.
ii) Turbulence: Atherosclerosis.
3) Hypercoagulability: Abnormally high tendency of the blood to clot, caused by alterations
in coagulation factors.
Causes:
i) Primary (Genetic): Factor V mutation (Factor V Leiden); Prothrombin mutation.
ii) Secondary (Acquired): Immobilization; Myocardial infarction; Cancer; Tissue injury;
Antiphospholipid antibody syndrome.
Venous Thrombosis (Phlebothrombosis)
Synonyms: Red thrombi or stasis thrombi.
Mechanisms: Stasis or hypercoagulability in the sluggish venous circulation.
Sites: Veins of lower extremity (MC).
Morphology:
1) Firm solid masses, focally attached to the vessel wall and contain lines of Zahn.
2) Appear red with more RBCs and relatively few platelets.
3) Form a long luminal cast and extend in the direction of blood flow.
C/P: Always occlusive causing ischemia.
Fate: Propagation; Embolization; Dissolution; Organization or recanalization.
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Mural Thrombus
“Represent thrombi seen in the heart chambers or in the aortic lumen.”
Mechanisms: Endothelial injury or turbulence.
Causes: Myocardial infarction, dilated cardiomyopathy, myocarditis, arrhythmias,
atherosclerosis, and aneurysms.
Morphology:
1) Firm solid masses, focally attached to the vessel wall and contain lines of Zahn.
2) Consist of a friable meshwork of platelets, fibrin, red cells, and degenerating leukocytes.
C/P: May be occlusive causing ischemia.
Fate: Propagation; Embolization; Dissolution; Organization or recanalization.
Fate of Thrombus
Over a period of time, thrombi are seen undergoing any of the following changes.
1) Propagation: Thrombi accumulate additional platelets and fibrin.
2) Embolization: Thrombi dislodge and travel to other sites in the vasculature.
3) Dissolution: Thrombi may shrink and disappear with fibrinolysis.
4) Organization and Recanalization: Thrombi may organize with ingrowth of endothelial
cells, smooth muscle cells, and fibroblasts. Recanalization involves formation of capillary
lumens.
Thromboembolism
*Most common type of embolism.
“Represent emboli that are dislodged thrombi, carried by the blood from its point of origin to
a distant site.”
Types
I) Systemic thromboembolism
“Represent emboli in the arterial circulation.”
Origin: Intracardiac mural thrombi.
Causes: Left ventricular wall infarcts (MC), aortic aneurysms, atherosclerotic plaques,
vegetations or paradoxical emboli.
Sites of lodgement: Lower extremities (MC); Brain; Kidneys; Intestines.
C/P: Ischemia leads to infarction.
II) Pulmonary embolism
*MC form of thromboembolic disease.
*Mostly, pulmonary emboli are multiple and small.
Origin: Deep veins of lower limb.
Sites of lodgement: Main pulmonary artery, bifurcation of pulmonary artery, or smaller,
branching arteries.
C/P: 1) Asymptomatic (MC): Seen with small emboli being organized with time.
2) Sudden death, acute right heart failure or cardiovascular collapse: Seen with emboli
obstructing 60% or more of pulmonary circulation.
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3) Hemorrhage: Seen with embolic obstruction of medium-sized arteries with subsequent
vascular rupture.
4) Hemorrhage or infarction: Seen with embolic obstruction of small end-arteriolar
pulmonary branches.
5) Pulmonary hypertension and right ventricular failure: Seen with multiple emboli over
time.
Paradoxical Embolism
Def.: Emboli originating in venous circulation, but gain access to the systemic arterial
circulation with interatrial or interventricular defects.
Associations: ASD; VSD.
C/P: Paradoxical emboli lead to systemic thromboembolism.
Fat Embolism
Causes: Fractures of long bones (MC), soft tissue trauma and burns.
Pathogenesis: 1) Rupture of vascular sinusoids in the marrow or small venules will allow
marrow or adipose tissue into the vasculature.
2) Fat microemboli and associated red cell and platelet aggregates can occlude the pulmonary
and cerebral microvasculature.
3) Release of free fatty acids from fat globules cause toxic injury to endothelium.
C/P: 1) 1 to 3 days after injury, sudden onset of tachypnea, dyspnea, and tachycardia.
2) Irritability and restlessness progressing to delirium or coma.
3) A diffuse petechial rash may be seen.
4) Fat Embolism Syndrome: Anemia, thrombocytopenia, pulmonary insufficiency and
neurologic symptoms.
Morphology: Microscopy shows fat microglobules in pulmonary vasculature.
Diagnosis: i) Frozen sections where fat solvents are avoided.
ii) Special stains (Sudan IV; Sudan III; Sudan black; Oil Red-O) for fat.
Amniotic Fluid Embolism
Causes: As a complication of labor and the immediate postpartum period.
Pathogenesis: 1) Tear in the placental membranes or rupture of uterine veins allow infusion
of amniotic fluid or fetal tissue into the maternal circulation.
2) Substances in amniotic fluid activate coagulation factors causing DIC.
Morphology: Maternal lungs show edema, diffuse alveolar damage and the presence of
fibrin thrombi in many vascular beds.
C/P: Sudden onset of severe dyspnea; Cyanosis and shock; Neurologic impairment as
headache, seizures and coma.
Diagnosis: Microscopic demonstration of fetal squamous cells, lanugo hair, fat and mucins in
the maternal pulmonary circulation.
Comp.: Maternal death or permanent neurological deficit.
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Air Embolism
Causes: Obstetric or laparoscopic procedures, chest wall injury, or decompression sickness.
Decompression sickness
Predisposing factors: Deep sea diving or underwater construction.
Pathogenesis: 1) Exposure to sudden decreases in atmospheric pressure causes the nitrogen
comes out of solution in the tissues and the blood.
2) Rapid formation of gas bubbles within skeletal muscles and supporting tissues in and
about joints and pulmonary vasculature causes ischemic injury.
Morphology: Lungs show edema, hemorrhage, and focal atelectasis or emphysema.
C/P: 1) Bends: Painful musculoskeletal condition.
2) Chokes: A form of respiratory distress.
Caisson disease
“Chronic form of decompression sickness.”
Pathogenesis: Persistence of gas emboli in the skeletal system leads to ischemic necrosis
involving bones.
Sites affected: Head of femur, tibia and humerus.
Shock
“A state of circulatory failure that impairs tissue perfusion and leads to cellular hypoxia.”
Types: 1) Cardiogenic shock 2) Hypovolemic shock 3) Septic shock 4) Neurogenic shock
5) Anaphylactic shock
Hypovolemic shock
Causes: Massive hemorrhage or fluid loss from vomiting, diarrhea or severe burns.
Pathogenesis: Low blood volume causes low cardiac output leading to tissue ischemia.
Septic shock
*MC cause of death in ICU.
Causes: Gram +ve bacteria (MC), gram -ve bacteria and fungi.
Pathogenesis: Microbial products mediate various events.
1) Activation of inflammatory cells (neutrophils and monocytes) with the production of
cytokines (IL-1, TNF) causes endothelial activation and systemic effects such as fever,
diminished myocardial contractility and metabolic abnormalities.
2) Activation of complement cascade causes endothelial activation.
3) Endothelial activation results in production of various mediators (IL-6, IL-8, NO, and
PAF) leading to vasodilation, increased permeability and tissue hypoperfusion.
4) Activation of coagulation cascade along with endothelial activation induces a procoagulant
state that causes DIC leading to tissue ischemia.
5) Finally, multiorgan failure is seen.
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Stages of shock
I) Nonprogressive phase
1) Reflex compensatory mechanisms are activated. e.g., Baroreceptor reflexes, catecholamine
release, ADH release, renin-angiotensin activation and generalized sympathetic stimulation.
2) Cardiac output and BP are maintained causing tachycardia, peripheral vasoconstriction,
and renal conservation of fluid.
II) Progressive phase
1) Persistent hypoxia results in anaerobic glycolysis with excessive production of lactic acid.
2) Lactic acidosis blunts the vasomotor response causing arteriolar vasodilation.
3) Pooling of blood in microcirculation worsens cardiac output and causes endothelial
damage.
III) Irreversible phase
1) Irreversible cell injury with lysosomal enzyme leakage, further aggravates the shock state.
2) Survival is not possible even if the hemodynamic defects are corrected.
Morphology: i) Brain: Ischemic encephalopathy with liquefactive necrosis.
ii) Heart: Coagulative necrosis.
iii) Adrenals: Cortical lipid cell depletion.
iv) Kidneys: Acute tubular necrosis (ATN).
v) Lungs: Shock lung with diffuse alveolar damage.
C/P: Hypotension; Weak, rapid pulse; Tachypnea; Cool, clammy cyanotic skin; Decreased
urine output and DIC in later stages.
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35
4. Genetic Disorders
MCQs
1) Number of chromosomes in Turner syndrome. (May, 2022)
a) 47 b) 46 c) 45 d) 44
5 Marks
1) Elucidate lysosomal storage disorders. (Feb. 2022)
2) Write a brief note on Down syndrome. (Feb. 2022)
4 Marks
1) Turner syndrome. (May, 2022)
2) Down syndrome. (Aug. 2021)
3) Klinefelter syndrome. (March, 2021)
4) Down syndrome. (Nov. 2020)
5) Klinefelter syndrome. (Feb. 2017)
6) Name four autosomal dominant diseases. (Jan. 2016)
7) Klinefelter syndrome. (July, 2015)
8) Klinefelter syndrome. (July, 2013)
9) Down syndrome. (Jan. 2013)
10) Turner syndrome. (July, 2012)
11) Klinefelter syndrome. (July, 2011)
12) Klinefelter syndrome. (Aug. 2009)
13) Turners syndrome. (April, 2009)
14) Klinefelter syndrome. (Sept/Oct. 2007)
15) Klinefelter syndrome. (April/May, 2004)
16) Down syndrome. (Sep. 2003)
2 Marks
1) Name four autosomal dominant disorders. (Oct. 2022)
2) Name four autosomal dominant disorders. (Feb. 2020)
3) Give two clinical features and two testicular findings in Klinefelter syndrome. (July,
2019)
4) List four clinical features of Klinefelter syndrome. (Feb. 2019)
5) Name four clinical features of trisomy 21. (July, 2016)
6) Name four autosomal dominant diseases. (Jan. 2016)
7) Name four (4) clinical features of Turner Syndrome. (July/Aug 2014)
8) Name three (3) X-linked recessive and one (1) X-linked dominant disorders. (Jan.
2014)
9) Barr bodies. (Jan. 2012)
10) Clinical features and karyotypes of Turner Syndrome. (Jan. 2011)
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Undergraduate Pathology Series
11) Name two cytogenetic disorders involving sex chromosomes and two involving
autosomes. (March, 2010)
12) Down syndrome. (Oct. 2008)
13) Barr body. (March/April, 2008)
14) Down syndrome. (Oct. 2005)
15) Turner syndrome. (March/April, 2005)
16) Turner syndrome. (March/April, 2003)
High-Yield Topics
Down syndrome
Klinefelter Syndrome
Gaucher disease
Barr body
Turner syndrome
Tay-Sachs disease
Refresh Pathology, 3rd Edition – Dr. Shiva M.D.
37
Autosomal Dominant Disorders
Familial hypercholesterolemia; Marfan syndrome; Hereditary spherocytosis; Von Willebrand
disease; Neurofibromatosis; Adult polycystic kidney disease.
X-Linked Recessive Disorders
Hemophilia A; Hemophilia B; G6PD deficiency; Duchenne muscular dystrophy; WiskottAldrich syndrome; Fragile X syndrome; Diabetes insipidus.
X-Linked Dominant Disorders
Vitamin D-resistant rickets; Rett syndrome; Alport syndrome.
Lysosomal Storage Disorders
1) Gaucher disease
2) Tay-Sachs disease
3) Niemann-Pick Disease Types A and B
4) Niemann-Pick Disease Type C
5) Mucopolysaccharidoses
Pathogenesis: Inherited mutations leading to defective lysosomal enzyme functions gives
rise to accumulation and storage of complex substrates in the lysosomes and defects in
autophagy resulting in cellular injury.
General features
1) Autosomal recessive transmission.
2) Onset of disease in infancy or early childhood.
3) Hepatosplenomegaly.
4) Frequent CNS involvement with associated neuronal damage.
5) Cellular dysfunction.
Gaucher disease
*MC lysosomal storage disorder.
Defect: Autosomal Recessive with deficiency of glucocerebrosidase, resulting in
accumulation of glucocerebrosides in phagocytes.
Subtypes:
i) I (Reduced but detectable levels of glucocerebrosidase).
ii) II (No detectable glucocerebrosidase activity).
iii) III (Intermediate between I & II).
Morphology: Gaucher cells (Distended phagocytic cells with fibrillary cytoplasm resembling
crumpled tissue paper and one or more dark eccentrically placed nuclei) in spleen, liver, bone
marrow, and lymph nodes.
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C/P: i) Type I (MC): Appears in adults.
Chronic nonneuronopathic form with splenomegaly, lymphadenopathy, pathologic fractures
and bone pain.
ii) Type II: Appears during infancy.
Acute neuronopathic form with convulsions and progressive mental deterioration, and
hepatosplenomegaly.
Tay-Sachs disease
*MC form of GM2 gangliosidosis, prevalent among Estern Eropean (Ashkenazic) jews.
Defect: Autosomal Recessive with deficiency of hexosaminidase A, resulting in
accumulation of GM2 gangliosides.
Sites: Neurons in the CNS, ANS, and retina (MC).
Morphology:
i) Ballooning of neurons with cytoplasmic vacuoles.
ii) Destruction of neurons with proliferation of microglia.
iii) Cherry-red spot in the macula.
C/P: Manifestations appear around 6 months.
i) Motor incoordination and mental obtundation.
ii) Muscular flaccidity, blindness and increasing dementia.
Inv.: Enzyme assays and DNA-based analysis.
Cytogenetic Disorders Involving Autosomes
Trisomy 21 (Down syndrome); Trisomy 18 (Edward syndrome); Trisomy 13 (Patau
syndrome).
Cytogenetic Disorders Involving Sex Chromosomes
Turner syndrome; Klinefelter syndrome.
Barr Body (X chromatin)
“The inactive X chromosome can be seen in the interphase nucleus as a darkly staining small
mass in contact with the nuclear membrane knows as the Barr body.”
*The number of Barr bodies in a cell depends upon the number of X chromosomes.
*Number of Barr bodies = Number of X chromosomes – 1
*Normal cells have one Barr body in females (XX) but absent in males (XY).
Lyon hypothesis: Explains the inactivation of X chromosome
1) Only one of the X chromosomes is genetically active.
2) The other X chromosome of either maternal or paternal origin undergoes heteropyknosis
and is rendered inactive.
3) Inactivation of either the maternal or the paternal X chromosome occurs at random among
all the cells of blastocyst on or about day 5.5 of embryonic life.
4) Inactivation of the same X chromosome persists in all the cells derived from each
precursor cell.
Detection of Barr body: Buccal smear; Peripheral blood smear.
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Turner Syndrome
*MC sex chromosome abnormality in females.
Karyotypes: 1) Classic: 45,X (MC).
2) Defective 2nd X chromosome (e.g., an isochromosome of the long arm, 46,X,i(Xq)).
3) Mosaic type (e.g., 45,X/46XX).
Genetic alterations: Partial or complete monosomy of the X chromosome.
Pathogenesis: Absence of second X chromosome causes loss of oocytes leading to
hypogonadism.
Morphology (Ovary): Ovaries are reduced to atrophic fibrous strands, devoid of ova and
follicles (streak ovaries).
C/P: 1) During infancy: Edema of the dorsum of the hand and foot; Swelling of the nape of
neck (cystic hygroma); Bilateral neck webbing.
Associations: Congenital heart disease (preductal coarctation of aorta & bicuspid aortic
valve).
2) Adolescence & adults: Failure to develop normal secondary sex characteristics during
puberty with infantile genitalia, inadequate breast development and little pubic hair;
Shortness of stature; Cubitus valgus; Broad chest and widely placed nipples; Primary
amenorrhea; Infertility.
Associations: Hypothyroidism; Glucose intolerance, obesity & insulin resistance.
Klinefelter Syndrome
“Male hypogonadism that occurs when there are 2 or more X chromosomes & one or more Y
chromosomes.”
Karyotypes: 1) Classic: 47XXY (MC).
2) Mosaic type (e.g., 46,XY/47,XXY).
Genetic alterations: Nondisjunction during the meiotic divisions in the germ cells of one of
the parents.
Risk factors: Increased maternal age with errors in oogenesis.
Pathogenesis: Reduced spermatogenesis leads to hypogonadism.
Morphology (Testis): Gross: Small atrophic testes.
Miro.: Seminiferous tubules may be atrophied and replaced by collagenous ghosts or appear
embryonic, consisting of cords of cells. Leydig cells appear prominent.
C/P: Elongated appearance with an increase in length between the soles and the pubic bone;
Eunuchoid body habitus with abnormally long legs; Small testes; Small penis; Lack of
secondary sex characteristics such as deep voice and beard; Gynecomastia; Infertility.
Associations: Type 2 diabetes & metabolic syndrome; Mitral valve prolapse; Osteoporosis &
fractures; Breast cancer; SLE; Extragonadal germ cell tumors.
Inv.: Elevated plasma gonadotropin (particularly FSH) levels; Variably reduced testosterone
levels; Elevated mean plasma estradiol levels.
Undergraduate Pathology Series
Trisomy 21 (Down Syndrome)
*MC chromosomal disorder.
Karyotypes: 1) Trisomy 21 type: 47,XX, +21 (MC).
2) Translocation type: Robertsonian translocation of the long arm of chromosome 21 to
another acrocentric chromosome (e.g., 22 or 14).
3) Mosaic type: 46,XX/47,XX, +21.
Risk factors: Increased maternal age.
Genetic alterations: Meiotic nondisjunction of chr. 21 in the ovum.
C/P: Flat facial profile; Oblique palpebral fissures; Epicanthic folds; Severe mental
retardation; Gap between first and second toe; Hypotonia; Simian crease; Abundant neck
skin; Brushfield spots (speckeled iris).
Associations: Congenital heart disease (atrioventricular septal defects); Acute leukemias
(ALL & AML); Alzheimer disease; Severe infections.
Diagnostic tests during pregnancy: Triple test (decreased AFP, decreased estriol, and
increased HCG); Chorionic villus sampling and amniocentesis.
40
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5. Diseases of the Immune System
MCQs
1) Granuloma formation involves which type of hypersensitivity. (May, 2022)
a) Type I b) Type II c) Type III d) Type IV
2) Immunoglobulin involved in type I hypersensitivity. (May, 2022)
a) Ig E b) IgM c) Ig A d) Ig G
3) The following interleukin is characteristically produced in Th1 response. (Feb. 2022)
a) IL-2 b) IL-4 c) IL-5 d) IL-10
4) Antigen presenting cells present in skin are called. (Feb. 2022)
a) Kupffer cells b) Microglia c) Langerhans cells d) Melanocytes
5) Birbeck granules are present in. (Feb. 2022)
a) Merkel cell b) Langerhans cell c) Langhans cell d) Melanocyte
6) Immunoglobulin involved in type I hypersensitivity reaction is. (Feb. 2022)
a) Ig G b) Ig D c) Ig E d) Ig M
7) A 40 year old man has chronic cough with fever for several months. The chest radiograph
reveals a diffuse reticulonodular pattern microscopically on transbronchial biopsy, there are
epithelioid granulomas, Langhans giant cells and lymphocytes. The pathogenesis of the
above condition is based on which section pattern. (Feb. 2022)
a) Type I b) Type IV c) Type II d) Type III
8) CD 3 is expressed by. (Feb. 2022)
a) B cells B) T cells c) NK cells d) RBC
15 Marks
1) a. Define hypersensitivity.
b. Explain in detail with examples of each type of hypersensitivity.
c. Explain in detail on type I hypersensitivity. (Feb. 2022)
5 Marks
1) Severe combined immunodeficiency (SCID). (May, 2022)
2) Write in detail the pathogenesis of AIDS. (Feb. 2022)
3) Enumerate and explain the stages of lupus nephritis. (Feb. 2022)
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10 Marks
1) A 25 year lady developed butterfly rash over the face. There was associated fever, pain in
the peripheral joints and photosensitivity. On examination, malar rash and oral ulcers were
observed. (Aug. 2021)
a) Which is your diagnosis.
b) Describe in detail the etiology and pathogenesis of this condition.
c) Discuss the morphological classification of kidney in this disorder.
d) List any two laboratory investigations to be done in this disease.
Ans: Systemic Lupus Erythematosus (SLE).
2) A 60 year old patient long history of rheumatoid arthritis presented with enlarged tongue
and a history of diarrhea. Urine shows positive heat test for proteins and ECG shows
conduction disturbances. (July/Aug. 2014)
a) What is the possible diagnosis and what will be ideal site for biopsy to confirm it?
b) Name the lab technique for definite diagnosis.
c) Write four (4) types of this abnormal substance and their associated diseases.
d) Give the structural details of the substance.
Ans: Amyloidosis.
3) A homosexual individual who is also an intravenous drug abuser with history of persistent
generalized lymphadenopathy (PGL) and chronic diarrhea came to sexually transmitted
diseases (STD) OPD with mucosal candidiasis, fever, oral hairy leukoplakia and loss of more
than 10% body weight. There is a fall in CD4+T cell count. (Jan. 2011)
a) What is the provisional diagnosis?
b) Describe the sequences of events in the pathogenesis of the disease.
c) Discuss various tests used for diagnosis and for monitoring treatment of the same.
Ans: AIDS.
4 Marks
1) Classification of amyloidosis. (Oct. 2022)
2) Type IV hypersensitivity reaction. (May, 2022)
3) Graft versus host disease. (Nov. 2020)
4) Type III hypersensitivity reaction with examples. (July, 2018)
5) Type II hypersensitivity reaction. (Feb. 2018)
6) Pathogenesis of type I hypersensitivity reaction. (July, 2015)
7) Type IV hypersensitivity reaction. (Jan. 2015)
8) Describe the chemical nature of Amyloid. (Jan. 2014)
9) Pathogenesis of amyloidosis. (Jan. 2013)
10) Antinuclear antibodies. (July, 2012)
11) Physical and chemical nature of amyloid. (Jan. 2012)
12) Amyloidosis of spleen. (July, 2011)
13) CNS manifestations of AIDS. (Aug. 2010)
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14) Pathogenesis of amyloidosis. (March, 2010)
15) Nature of amyloid. (March/April, 2008)
2 Marks
1)
2)
3)
4)
List four opportunistic infections seen associated with AIDS. (Oct. 2022)
List four opportunistic infections in AIDS patient. (Aug. 2021)
Stains used to demonstrate amyloid. (March, 2021)
Give four examples of immune complex mediated type II hypersensitivity reaction.
(July, 2019)
5) Describe any four morphologic changes in lupus nephritis. (July, 2019)
6) List four special stains to demonstrate amyloid. (Feb. 2018)
7) Mention four examples of antibody mediated type-II hypersensitivity reaction. (July,
2017)
8) Four special stains for demonstration of amyloid. (Feb. 2017)
9) Give four examples of type II hypersensitivity. (July, 2016)
10) Give four (4) examples of type I hypersensitivity reaction. (July/Aug. 2014)
11) Sago spleen. (July, 2013)
12) Bence-Jones Protein. (Jan. 2013)
13) Sago spleen (Aug. 2009)
14) Lardaceous spleen. (April, 2009)
15) Special stains used in amyloidosis. (Feb. 2009)
16) L.E cell. (Oct. 2008)
17) Antinuclear antibody. (May, 2007)
18) Amyloid spleen. (Oct. 2005)
19) Amyloid spleen. (April/May, 2004)
High-Yield Topics
Hypersensitivity reactions
AIDS
SLE
Amyloidosis
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Hypersensitivity
Def.: Persistent, misdirected or inadequately regulated immune reactions against a variety of
antigens causing tissue injury.
Classification
1) Immediate (type I) hypersensitivity
2) Antibody-mediated (type II) hypersensitivity
3) Immune complex–mediated (type III) hypersensitivity
4) T cell-mediated (type IV) hypersensitivity
Immediate (Type I) Hypersensitivity
“A rapid immunological reaction occurring in a previously sensitized individual.”
*Genetic susceptibility and environmental factors (pollutants, microbes) play an important
role.
*Atopy: An increased propensity to develop allergies.
*Allergen: Antigen involved (pollen, animal dander, house dust and foods).
Pathogenesis
First exposure:
1) Presentation of the antigen (allergen) to naïve CD4+ helper T cells and differentiation of T
cells into Th2 cells.
2) Th2 cells secrete cytokines, IL-4, IL-5, and IL-13.
i) IL-4: Stimulates differentiation of B cells into IgE-secreting plasma cells and T cells into
Th2 cells.
ii) IL-5: Mediates development and activation of eosinophils.
iii) IL-13: Enhances IgE production and stimulates mucus secretion.
3) IgE binds to the Fc receptors on submucosal mast cells (sensitized mast cells).
Repeat exposure:
1) Allergen binds and cross-links adjacent IgE antibodies.
2) Mast cells release granule contents and produce various mediators.
I) Early-phase reaction: Occurs within min. and subsides in a few hrs.
*Involves production of various mediators with edema, mucus secretion and smooth muscle
spasm.
Mediators and effects:
i) Histamine: Increased vascular permeability, smooth muscle contraction and mucus
secretion.
ii) Leukotrienes: C4, and D4: Bronchospasm, and increased vascular permeability;
B4: Chemotaxis.
iii) Prostaglandin D2: Bronchospasm and mucus secretion.
iv) Cytokines (IL-1, TNF and chemokines): Promote leukocyte recruitment.
II) Late-phase reaction: Occurs 2 to 24 hrs. later and lasts for several days.
*Persistent inflammation without more antigen exposure with recruitment of leukocytes and
tissue damage.
*Eosinophils liberate proteolytic enzymes and proteins (major basic protein and eosinophil
cationic protein) which damage tissues.
Associations: Hay fever; Bronchial asthma; Food allergies; Anaphylaxis.
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Antibody-Mediated (Type II) Hypersensitivity
“Antibodies (IgG and IgM) mediate disease upon reaction with antigens present on cell
surfaces or in ECM.”
*Antibodies may be specific for endogenous antigens or for exogenous antigens (chemical or
microbial proteins).
*Antibodies may mediate cell death, inflammation or functional abnormality of cells.
Pathogenesis
I) Opsonization and phagocytosis
i) Phagocytosis of IgG coated cells.
ii) Antibody mediated complement activation and phagocytosis of C3b coated cells.
Associations: Hemolytic disease of the newborn; Autoimmune thrombocytopenic purpura;
Transfusion reactions.
II) Complement and Fc receptor-mediated inflammation
i) Antibodies deposit in fixed tissues and activate complement and recruit leucocytes.
ii) Leukocyte activation with engagement of C3b and Fc receptors.
iii) Tissue damage with lysosomal enzymes and ROS.
Associations: Goodpasture syndrome.
III) Antibody-mediated cellular dysfunction
i) Antibodies directed against cell surface receptors impair or dysregulate receptor function.
ii) No cell injury or inflammation.
Associations: Myasthenia gravis; Graves disease.
Immune Complex-Mediated (Type III) Hypersensitivity
“Antigen-antibody complexes elicit inflammation at the sites of deposition and produce tissue
damage.”
*The antigen may be exogenous or endogenous.
I) Systemic immune complex disease
Pathogenesis:
1) Formation of immune complexes: Antigen combines with antibody in the circulation and
form immune complexes.
2) Deposition of immune complexes: The circulating antigen-antibody complexes are
deposited in vessels. Often affects glomeruli and joints.
3) Inflammation and tissue injury: Once deposited in tissues, immune complexes initiate an
acute inflammatory reaction via complement activation and engagement of leukocyte Fc
receptors.
Morphology:
i) Acute vasculitis associated with necrosis of the vessel wall and neutrophilic infiltration.
ii) Fibrinoid necrosis: Smudgy eosinophilic area of tissue destruction with deposits of ICs,
complement and plasma protein.
C/P: Fever, urticaria, joint pain, lymph node enlargement, and proteinuria.
Associations: Acute serum sickness; SLE; Polyarteritis nodosa; Post streptococcal
glomerulonephritis.
II) Local immune complex disease (Arthus reaction)
i) Produced experimentally by intracutaneous injection of antigen in a previously immunized
animal.
ii) Acute immune complex vasculitis causes localized area of tissue necrosis, usually elicited
in the skin.
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T Cell-Mediated (Type IV) Hypersensitivity
“CD4+ T cells and CD8+ T cells are involved.”
I) CD4+ T Cell-Mediated inflammation
“CD4+ T cells secrete cytokines, which mediate chronic inflammation and tissue damage.”
Pathogenesis:
I) First exposure
i) Naïve CD4+ T cells recognize peptides displayed by antigen presenting cells (APCs) and
secrete IL-2, which stimulate proliferation of the antigen responsive T cells.
ii) APCs produce IL-12, which induces differentiation of CD4+ T cells to the Th1 subset and
IL-1, IL-6 and IL-23, which induces differentiation of CD4+ T cells to Th17 subset.
II) Repeat exposure
i) Th1 cells secrete IFN-g, which mediates macrophage activation. Chronic (granulomatous)
inflammation and tissue damage will follow.
ii) Activated Th17 cells secrete IL-17, IL-22 and chemokines, which recruit neutrophils and
monocytes.
Associations: Delayed-type hypersensitivity (tuberculin reaction, contact dermatitis, and
drug reactions); Rheumatoid arthritis; Multiple sclerosis.
II) CD8+ T Cell-Mediated Cytotoxicity
“CD8+ cytotoxic T lymphocytes (CTLs) mediate killing of antigen-expressing target cells
and tissue destruction.”
Pathogenesis:
1) CTLs secrete preformed mediators, perforins and granzymes into the target cells and
granzymes trigger apoptosis by activating caspases.
2) Activated CTLs express Fas ligand, which can bind to Fas expressed on target cells and
trigger apoptosis.
Associations: Type 1 diabetes; Graft rejection; Viral infections; Tumors.
Systemic Lupus Erythematosus (SLE)
“An autoimmune disease involving multiple organs, characterized by a vast array of
autoantibodies, particularly antinuclear antibodies (ANAs), in which injury is caused mainly
by deposition of immune complexes and binding of antibodies to various cells and tissues.”
Age: 17-55 yrs.
Sex: F>M
Pathogenesis:
i) Exposure to ultraviolet light leads to apoptosis of various cells.
ii) Improper clearance of nuclear fragments combined with failure of B and T cell tolerance
causes activation of lymphocytes specific for self nuclear antigens.
iii) High-affinity antibodies produced against these antigens form immune complexes, which
are endocytosed by dendritic cells and B lymphocytes.
iv) The nuclear DNA and RNA stimulate production of type I interferons, which activate
lymphocytes and APCs, setting up a cycle of persistent autoantibody production.
v) The antibodies form complexes with released antigens, and the complexes deposit in the
kidneys and other organs (type III hypersensitivity).
vi) Antibodies also bind to and opsonize blood cells, leading to their destruction by
phagocytes (type II hypersensitivity).
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LE cell (Lupus Erythematosus Cell)
“Any phagocytic cell (neutrophil or macrophage) that has engulfed the denatured nucleus of
an injured cell.”
Association: Systemic lupus erythematosus (SLE).
Pathogenesis: In tissues, nuclei of damaged cells react with ANAs, lose their chromatin
pattern, and become homogenous forming LE bodies or hematoxylin bodies. Engulfment of
these denatured nuclei by phagocytic cells form LE cells.
Location: Blood, pericardial or pleural effusions.
Detection methods: LE cell demonstration on buffy coat smears; Cytology of body fluids.
Lupus nephritis
*Renal involvement in SLE is mainly in the form of glomerulonephritis and tubulointerstitial
nephritis.
*Six patterns of glomerular disease are seen. Class I is the least common and class IV is the
most common pattern.
Pathogenesis: The glomerular lesions are the result of deposition of immune complexes on
the glomerular basement membrane, in the mesangium, and sometimes throughout the
glomerulus.
Morphology:
1) Minimal mesangial lupus nephritis (class I): Immune complex deposition in the
mesangium with no structural changes on light microscopy.
2) Mesangial proliferative lupus nephritis (class II): Mesangial cell proliferation, often
accompanied by accumulation of mesangial matrix, and granular mesangial deposits of
immunoglobulin and complement without involvement of glomerular capillaries.
3) Focal lupus nephritis (class III): Fewer than 50% of glomeruli are involved and the
lesions may be segmental or global. Affected glomeruli may exhibit swelling and
proliferation of endothelial and mesangial cells, leukocyte accumulation, capillary necrosis,
and hyaline thrombi. Extracapillary proliferation with focal necrosis and crescent formation
is often seen.
4) Diffuse lupus nephritis (class IV): Half or more of the glomeruli are affected and the
lesions may be segmental or global. Involved glomeruli show proliferation of endothelial,
mesangial, and epithelial cells with cellular crescents filling Bowman’s space. Subendothelial
immune complex deposits may cause circumferential thickening of the capillary wall,
forming ‘wire loop’ structures on light microscopy.
5) Membranous lupus nephritis (class V): Diffuse thickening of the capillary walls due to
deposition of subepithelial immune complexes.
6) Advanced sclerosing lupus nephritis (class VI): Sclerosis of more than 90% of the
glomeruli and represents end-stage renal disease.
C/P: Recurrent microscopic or gross hematuria, nephritic syndrome, RPGN, nephrotic
syndrome, acute and chronic renal failure, and hypertension.
Inv.: i) Blood: Hemolytic anemia; Leukopenia or lymphopenia; Thrombocytopenia.
ii) Urine: Persistent proteinuria or red cell casts.
iii) Serology: Abnormal titer of ANA; Low complement; Positive direct Coombs test.
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Antinuclear antibodies (ANAs)
“Antibodies directed against nuclear antigens.”
Significance: 1) Aid in diagnosis and management of various systemic autoimmune diseases.
2) Play a role in the pathogenesis of their associated diseases.
Associated disorders: SLE (antibodies to double-stranded DNA and Smith (Sm) antigen are
diagnostic); Systemic sclerosis; Sjogren syndrome.
Categories:
1) Antibodies to DNA.
2) Antibodies to histone.
3) Antibodies to nonhistone proteins bound to RNA.
4) Antibodies to nucleolar antigens.
Detection methods: Indirect immunofluorescence; ELISA.
Graft-Versus-Host Disease (GVHD)
*Most commonly seen in the setting of hematopoietic stem cell (HSC) transplantation.
Pathogenesis: When immune-compromised recipients receive HSC preparations from
allogeneic donors, the immunocompetent T cells present in the donor inoculum recognize the
recipient’s HLA antigens as foreign and react against them mediating injury.
Manifestations:
1) Acute GVHD: Occurs within days to weeks after allogeneic HSC transplantation.
C/P: Generalized rash, jaundice, and bloody diarrhea.
2) Chronic GVHD: May follow the acute syndrome or may occur insidiously.
C/P: Fibrosis of the skin, cholestatic jaundice, esophageal strictures, and recurrent and lifethreatening infections.
Severe combined immunodeficiency (SCID)
Defect: Often resides in the T-cell compartment, with a secondary impairment of humoral
immunity.
Mode of inheritance:
i) X-linked (MC): Mutation in the common γ-chain (γc) subunit of cytokine receptors with
defective IL-7 receptor signaling.
ii) Autosomal recessive: Deficiency of the enzyme adenosine deaminase (ADA)-MC.
Morphology: Thymus is small and devoid of lymphoid cells.
C/P:
i) Affected infants present with prominent thrush, extensive diaper rash, and failure to thrive.
ii) Extreme susceptibility to recurrent, severe infections with Candida albicans, Pneumocystis
jirovecii, Pseudomonas, cytomegalovirus, varicella, and a host of bacteria.
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AIDS
“A disease characterized by profound immunosuppression with opportunistic infections,
secondary neoplasms, and neurologic manifestations.”
Cause: HIV (HIV-1 and HIV-2).
Major target systems: Immune system and CNS.
Major cellular targets: CD4+ T lymphocytes, macrophages and dendritic cells.
Major routes of transmission: Sexual transmission, parenteral transmission, and mother-toinfant transmission.
Pathogenesis:
I) Immune system: Cell mediated immunity is primarily affected with infection of CD4+ T
lymphocytes by binding of the viral gp120 envelop glycoprotein to CD4 molecules.
A) Mechanisms of loss of CD4+ T lymphocytes
i) Increased plasma membrane permeability.
ii) Virus replication interfering with protein synthesis.
iii) Apoptosis and pyroptosis.
iv) Loss of immature precursors.
v) Fusion of infected and uninfected cells.
B) Qualitative defects of CD4+ T lymphocytes:
i) Reduced antigen-induced T-cell proliferation.
ii) Defects in intracellular signaling.
iii) Decreased Th1-type responses.
II) CNS: Macrophages and microglia are infected. Neurologic deficit is believed to be
indirectly caused by viral products and by soluble factors (IL-1, TNF, and IL-6) produced by
infected microglia.
Manifestations:
1) Acute retroviral syndrome: Occurs 3-6 wks. after infection.
C/P: Sore throat, myalgias, fever, weight loss and fatigue. Diarrhea, vomiting or cervical
adenopathy may occur.
2) Chronic phase (clinical latency period): May last from 7-10 yrs.
C/P: Asymptomatic or develop infections such as candidiasis or herpes zoster.
3) Acquired immunodeficiency syndrome (AIDS):
C/P: i) Long-lasting fever, fatigue, weight loss, diarrhea and generalized lymphadenopathy.
ii) Opportunistic infections: Viral (JC virus, HSV, CMV, and HZV); Bacterial (Salmonella,
Nocardiosis, and Mycobacteriosis); Fungal (Candidiasis, Cryptococcosis, and
Histoplasmosis); Protozoal and Helminthic (Toxoplasmosis, Pneumocystosis, and
Cryptosporidiosis).
iii) Secondary neoplasms: Kaposi sarcoma (MC), cervical carcinoma, anal carcinoma in
males and B-cell lymphomas.
iv) CNS: Meningoencephalitis, aseptic meningitis, peripheral neuropathies, and HIVassociated neurocognitive disorder.
Inv.:
1) Raised HIV-1 RNA levels in the blood.
2) Low CD4+ T lymphocyte counts.
3) Antibody tests: ELISA and Western blot.
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Amyloidosis
“Represents a group of disorders having in common, deposition of similar appearing
proteins.”
Properties of amyloid
a) General: Pathological proteinaceous substance which is amorphous, eosinophilic and
hyaline deposited extracellularly.
b) Physical nature: Electron microscopy reveals continuous, nonbranching fibrils. X-ray
crystallography and infrared spectroscopy demonstrate a characteristic cross-b-pleated sheet
conformation.
c) Chemical nature: Fibril proteins (95%).
Types of amyloid
I) Most common forms
1) AL (amyloid light chain): Mostly composed of l immunoglobulin light chains or their
fragments derived from plasma cells.
2) AA (amyloid-associated): Derived from SAA (serum amyloid-associated) protein that is
synthesized in the liver.
3) Ab (b-amyloid): Derived from amyloid precursor protein. Seen with Alzheimer disease.
II) Less common forms
1) TTR (transthyretin): Normal or mutant forms are seen as amyloid deposits.
2) b2-microglobulin: Identified as the major component of Ab2m.
3) Prion proteins: Misfolded prion proteins are seen as amyloid deposits.
Pathogenesis:
1) Failure of mechanisms involved in clearing of misfolded proteins.
2) Insoluble misfolded proteins aggregate and deposit as fibrils in extracellular tissues.
3) Categories of protein:
a) Normal proteins that have an inherent tendency to fold improperly, associate and form
fibrils, when they are produced in excessive amounts.
b) Mutant proteins tend to get misfolded and then aggregate.
Classification
I) Systemic (generalized) amyloidosis
A) Primary amyloidosis (Immunocyte dyscrasias with amyloidosis): Most common.
Type of amyloid: AL
Associated disorder: Multiple myeloma.
Pathogenesis: Malignant plasma cells secrete abnormal amounts of monoclonal Ig and free,
unpaired light chains (Bence-Jones protein). Bence-Jones proteins are seen in serum, excreted
in urine and deposited in tissues as amyloid.
B) Reactive systemic amyloidosis (Secondary amyloidosis)
Type of amyloid: AA
Associated disorders: Rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel
disease, heroin abuse, renal cell carcinoma and Hodgkin lymphoma.
II) Localized amyloidosis
Amyloid deposits are limited to a single organ or tissue without involvement of any other site
in the body. E.g., lungs, larynx, skin, urinary bladder or tongue.
Other types
1) Hemodialysis-associated amyloidosis
Associated disease: Chronic renal failure with hemodialysis.
Type of amyloid: Ab2m
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2) Endocrine amyloid
Associated diseases: Medullary carcinoma of thyroid and type 2 diabetes mellitus.
3) Amyloid of aging
Senile systemic amyloidosis (Senile cardiac amyloidosis): Systemic deposition of amyloid in
elderly patients with heart being predominantly involved.
Type of amyloid: TTR (normal).
4) Heredofamilial amyloidosis
i) Familial Mediterranean fever: Autosomal recessive.
Type of amyloid: AA
ii) Familial amyloidotic neuropathies: Autosomal dominant.
Type of amyloid: TTR (mutant).
Morphology
I) Kidney
Gross: May be of normal size and color, or, in advanced cases, may be shrunken.
Micro.: Amyloid is deposited in the glomeruli, interstitial peritubular tissue, arteries, and
arterioles leading to capillary narrowing and distortion of the glomerular vascular tuft.
Eventually, capillary lumens are obliterated and the obsolescent glomerulus is replaced by
confluent masses or interlacing broad ribbons of amyloid.
II) Spleen
Gross: Normal in size or moderate to markedly enlarged. Tapioca-like granules are evident in
sago spleen.
Micro.:
1) Sago spleen: Amyloid deposits are largely limited to the splenic follicles.
2) Lardaceous spleen: Amyloid deposits in the walls of the splenic sinuses and connective
tissue framework in the red pulp. Fusion of the early deposits gives rise to large, maplike
areas.
C/P: 1) Asymptomatic.
2) Non-specific: Weakness, weight loss, light-headedness, or syncope.
3) Specific:
i) Kidney: Nephrotic syndrome; Renal failure and uremia.
ii) Heart: Congestive heart failure; Arrhythmias; Restrictive cardiomyopathy.
iii) GIT: Malabsorption; Diarrhea.
iv) Blood vessels: Bleeding.
Inv.: 1) Biopsy
i) Sites: Kidney or rectal or gingival tissues.
ii) Stains for amyloid: Congo red; Crystal violet; Sirius Red; Thioflavin T.
2) Serum and urine protein electrophoresis and immunoelectrophoresis.
3) Bone marrow aspiration.
4) Scintigraphy with radiolabeled serum amyloid P (SAP) component.
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6. Neoplasia
MCQs
1) Serum marker for ovarian carcinoma is. (May, 2022)
a) CA-125 b) PSS c) CA 19-9 d) CA 72
2) Which of the following is known as guardian of genome. (May, 2022)
a) P 53 b) MDM2 c) P 14 d) ATM
3) Sure sign of malignancy is. (Feb. 2022)
a) Mitosis b) Polycythemia c) Nuclear pleomorphism d) Metastasis
4) Tumor suppressor gene P53 induces cell arrest at. (Feb. 2022)
a) G2-M phase b) S-G2 phase c) G1-S phase d) G0-G1 phase
5) Li Fraumeni syndrome is due to mutation in. (Feb. 2022)
a) P21 b) P53 c) P41 d) P43
6) Skin cancers develop due to sunlight exposure induced by. (Feb. 2022)
a) UVA rays b) UVB rays c) UVC rays d) UVD rays
7) Keratin pearls are seen in. (Feb. 2022)
a) Malignant melanoma
b) Basal cell carcinoma
c) Squamous cell carcinoma d) Histiocytosis
5 Marks
1) Hallmarks of cancer. (May, 2022)
2) Write a note on radiation induced carcinogenesis. (Feb. 2022)
4 Marks
1)
2)
3)
4)
5)
6)
7)
8)
9)
Chemical carcinogenesis. (Oct. 2022)
Pathways of spread of malignant tumors. (Aug. 2021)
Routes of tumor metastasis. (Nov. 2020)
Tumor markers. (Feb. 2020)
Examples of viral carcinogens and mechanisms of cell injury by viruses. (July, 2019)
Role of Rb gene in tumor suppression. (Feb. 2019)
Enumerate oncogenic virus. Give pathogenesis of viral carcinogenesis. (July, 2018)
Characteristics of benign and malignant neoplasms. (Feb. 2018)
Tabulate the differences between lymphatic and vascular spread of tumors. (July,
2017)
10) Differences between benign and malignant tumors. (July, 2016)
11) Tabulate differences between benign and malignant tumors. (Jan. 2016)
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12) Enumerate the chemical carcinogens. Give pathogenesis of chemical carcinogenesis.
(Jan. 2016)
13) Tumor markers. (July, 2015)
14) Describe the steps/events involved in mechanism of tumor invasion and metastasis.
(Jan. 2014)
15) Physical carcinogenesis. (Jan. 2013)
16) Differences between benign and malignant tumors. (July, 2012)
17) Important growth factors modulating tumor growth and biology. (Jan. 2012)
18) Paraneoplastic syndromes. (Jan. 2011)
19) Microbial carcinogenesis. (March, 2010)
20) Chemical carcinogens. (August, 2009)
21) Differences between benign and malignant tumors. (April, 2009)
22) Viral carcinogens. (February, 2009)
23) Tumor markers. (March/April, 2008)
24) Spread of malignant tumors. (Oct. 2008)
25) Chemical carcinogenesis. (Sept/Oct. 2007)
26) Paraneoplastic Syndromes. (May, 2007)
27) Metastasis. (May, 2006)
28) Differences between benign and malignant tumors. (March/April, 2005)
29) Viral oncogenesis. (Sep. 2003)
30) Metastasis. (March/April, 2003)
31) Differences between benign and malignant tumors. (March/April, 2003)
2 Marks
1)
2)
3)
4)
5)
6)
List four oncogenic viruses. (May, 2022)
List four conditions due to DNA repair gene defects. (Aug. 2021)
P53 oncogene. (March, 2021)
What are the viral oncogenes with examples? (Nov. 2020)
Name four viral carcinogens. (Feb. 2020)
Name two tumors which metastasizes to liver and two tumors which metastasizes to
lungs. (July, 2018)
7) Name four tumors caused by various viruses. (July, 2018)
8) Name four tumors caused by various viruses. (Feb. 2017)
9) Name four inherited cancer syndromes. (July, 2016)
10) Name four malignant tumors causing paraneoplastic syndromes. (Jan. 2015)
11) Describe four (4) modes of tumor spread with examples. (July/Aug. 2014)
12) Name one (1) infectious disease and three (3) tumors caused by Epstein-Barr virus
(Jan. 2014)
13) Characteristics of malignant cell. (July, 2013)
14) Pathways of spread of malignant Tumors. (July, 2011)
15) Name four tumor suppressor genes. (Jan. 2011)
16) Grading and staging of cancer. (Sept/Oct. 2007)
17) Anaplasia. (May, 2007)
18) Dysplasia. (March/April, 2005)
19) Spontaneous regression of malignant tumors. (April/May, 2004)
20) Carcinoma-in-situ. (Sep. 2003)
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Undergraduate Pathology Series
High-Yield Topics
Dysplasia
Benign Vs Malignant tumors
Tumor suppressor genes
Microbial carcinogenesis
Paraneoplastic syndromes
Anaplasia
Metastasis
Chemical carcinogenesis
Radiation carcinogenesis
Tumor markers
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Dysplasia
“Represents a premalignant change.”
Sites: Usually encountered with epithelia.
Predisposing conditions: Metaplasia
Morphology
1) Pleomorphism: Epithelial cells vary in their shape and size.
2) Nucleus: Large and hyperchromatic nuclei with increased nuclear-to-cytoplasmic ratio.
3) Mitoses: Mitotic rate is high and mitoses can involve all levels of the epithelium.
4) Loss of polarity: Disordered architecture of the tissue.
Fate: May regress or progress to cancer.
Carcinoma In Situ
“Represents the preinvasive stage of cancer.”
Morphology: In situ epithelial cancers display marked dysplastic changes involving the full
thickness of the epithelium without invasion of the basement membrane.
Associations: Carcinomas of the skin, breast, and cervix.
Fate: May progress to invasive carcinoma.
Anaplasia
“Represents lack of differentiation, which is a hallmark of malignant tumors.”
Morphology
1) Pleomorphism: Tumor cells vary in their shape and size. Tumor giant cells with few large
hyperchromatic nuclei and abundant cytoplasm may be present.
2) Abnormal nuclear morphology: Enlarged nuclei with increased nuclear-to-cytoplasm ratio;
Variable shape and may appear hyperchromatic; Abnormally large nucleoli may be present.
3) Mitoses: Atypical, bizarre mitotic figures and high mitotic rates.
4) Loss of polarity: Sheets or large masses of tumor cells grow in a disorganized fashion.
5) Necrosis: Rapidly growing tumors may develop large central areas of ischemic necrosis .
Hallmarks of Cancer
1) Self-sufficiency in growth signals: The self-sufficiency in cancer growth most often
stems from gain-of-function mutations in signaling proteins (convert protooncogenes into
oncogenes) that reduce or eliminate growth factor dependency.
2) Insensitivity to growth-inhibitory signals: Excessive growth of cancer involves
mutations that inhibit the function of tumor suppressor genes.
3) Altered cellular metabolism: Cancer cells demonstrate cellular metabolism characterised
by high levels of glucose uptake and increased conversion of glucose to lactose via the
glycolytic pathway (Warburg effect or aerobic glycolysis).
4) Evasion of cell death: Mutations provide resistance to regulated cell death (apoptosis)
resulting in accumulation of neoplastic cells.
5) Limitless replicative potential (immortality): Tumor cells develop ways to avoid cellular
senescence and mitotic catastrophe by upregulation of telomerase.
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6) Sustained angiogenesis: Solid tumors induce angiogenesis mediated by proangiogenic
factors (VEGF) and develop their own blood supply facilitating the growth.
7) Invasion and metastasis
8) Evasion of immune surveillance: Tumor cells evade the immune system either by being
invisible to lymphoid cells or by hijacking inhibitory pathways designed for regulation of
immunity.
Metastasis
“Spread of a tumor to sites that are physically discontinuous with the primary tumor.”
*It is the most characteristic feature of malignant tumors.
Pathways of spread
1) Seeding of body cavities and surfaces
i) Malignant tumors penetrate into body cavities such as peritoneal (MC), pleural or
pericardial cavity.
ii) Seen particularly with ovarian cancers.
2) Lymphatic spread:
i) Most common pathway for the initial dissemination of carcinomas. E.g., Breast carcinoma,
lung carcinoma and papillary carcinoma of thyroid.
ii) Lymphatic vessels located at the margins of invading cancer are penetrated.
iii) The pattern of spread follows the natural routes of lymphatic drainage.
iv) Sentinel lymph node: “The first node in a regional lymphatic basin that receives lymph
flow from the primary tumor.”
3) Hematogenous spread:
i) Typically seen with sarcomas. E.g., angiosarcoma, fibrosarcoma.
ii) Small veins are usually penetrated.
iii) Liver and lungs are most frequently involved.
iv) Some carcinomas like renal cell carcinoma, hepatocellular carcinoma and follicular
carcinoma of thyroid show hematogenous spread.
Mechanisms of invasion and metastasis
I) Invasion of the extracellular matrix
i) Detachment: Dissociation of cancer cells from one another with loss of E-cadherin
function.
ii) ECM degradation: Proteases (MMPs) secreted by tumor cells cause degradation of the
basement membrane and interstitial connective tissue.
iii) ECM attachment: Catabolism of the ECM generates novel sites that bind to receptors on
tumor cells and stimulate their migration.
iv) Migration: Tumor cell-derived cytokines facilitate migration of tumor cells by contraction
of actin cytoskeleton.
II) Vascular dissemination and homing of tumor cells
i) Within the circulation, tumor cells form clumps or emboli.
ii) Arrest and extravasation of tumor emboli at distant sites involve adhesion to the
endothelium and egress through the basement membrane.
iii) Many tumors arrest in the first capillary bed they encounter (lung and liver) and some
tumors show organ tropism.
*Tumors metastasize to liver: Adenocarcinoma of colon, gastric adenocarcinoma, pancreatic
carcinoma, esophageal carcinoma, and renal cell carcinoma.
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*Tumors metastasize to lung: Bladder cancer, breast carcinoma, adenocarcinoma of colon,
and renal cell carcinoma.
Benign Tumors Vs Malignant Tumors
Feature
Benign
Malignant
Presentation
Differentiation
Anaplasia
Rate of growth
Mitotic figures
Capsule
Local invasion
Metastasis
Prognosis
Circumscribed mass
Well differentiated
Not seen
Slow
Less and normal
Present
Usually absent
Absent
Good
Usually an irregular mass
Well differentiated to poorly differentiated
Can be seen
Usually rapid
Numerous and can be abnormal
Usually absent
Present
Frequently present
Usually poor
Inherited Cancer Syndromes
Autosomal Dominant
1) Retinoblastoma.
2) Li-Fraumeni syndrome.
3) MEN syndromes.
4) Hereditary non-polyposis colorectal cancer (HNPCC).
5) Familial adenomatous polyposis (FAP).
Autosomal Recessive (DNA repair gene defects)
1) Ataxia-telangiectasia.
2) Bloom syndrome.
3) Xeroderma pigmentosum.
4) Fanconi anemia.
Tumor Suppressor Genes
Role in health: Suppress unwanted cell proliferation.
Role in neoplasia: Loss of function results in unregulated cell growth and genetic instability
leading to tumor formation.
E.g.,
Tumor suppressor gene
Associated disorder
APC
RB
TP53
WT1
BRCA1, BRCA2
Colonic carcinoma
Retinoblastoma and osteosarcoma
Li-Fraumeni syndrome
Wilms tumor
Carcinoma of breast
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RB
“A key negative regulator of the G1/S cell cycle transition.”
Functions:
i) Early in G1, RB is in a hypophosphorylated active form and exerts antiproliferative effects
by binding and inhibiting E2F transcription factors that regulate genes required for cells to
pass through the G1/S phase cell cycle checkpoint.
ii) Normal growth factor signaling upregulates the expression of D cyclins, which form
complexes with CDK4 and CDK6 that hyperphosphorylate and inactivate RB. This releases
RB from E2F factors, permitting cells to express genes that are needed for entry into S phase.
Mechanisms that abrogate the antiproliferative effect of RB in cancers
i) Loss-of-function RB mutations.
ii) Amplifications of the CDK4 and cyclin D genes.
iii) Loss-of-function mutations affecting cyclin-dependent kinase inhibitors (e.g.,
p16/INK4a).
iv) Viral oncoproteins that bind and inhibit RB (E7 protein of HPV).
TP53
“Guardian of the genome.”
Importance
1) >70% of human cancers have defects in TP53.
2) Germline mutation in one TP53 allele causes heritable cancer syndrome Li-Fraumeni
syndrome.
3) Stresses that activate the protein encoded by TP53, p53 include DNA damage,
inappropriate progrowth stimuli and hypoxia.
4) The p53 protein is the target of viral oncoproteins.
Functions
1) Triggering cell cycle arrest: p53-mediated cell cycle arrest is a primordial response to
DNA damage. It occurs late in the G1 phase and is caused mainly by p53-dependent
expression of the CDKI p21. By inhibiting cyclin D–CDK4 complexes, p21 prevents RB
phosphorylation and thereby arrests cells in the G1 phase. This pause in cell cycling provides
time to repair DNA damage. If DNA damage is repaired successfully, the cell is allowed to
proceed through the cell cycle.
2) Inducing cellular senescence: If the DNA damage cannot be repaired, cells with active p53
may undergo senescence, a form of permanent cell cycle arrest.
3) Killing stressed cells through apoptosis: p53 induces apoptosis of cells with irreversible
DNA damage by upregulating several proapoptotic genes.
Chemical Carcinogenesis
“A multistep process involved in mediating development of cancers.”
Mechanisms
I) Initiation: 1) Involves exposure of cells to a sufficient dose of a carcinogenic agent
leading to permanent DNA damage (mutation).
2) Rapid and irreversible process.
3) Alone is not sufficient for tumor formation.
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Types of carcinogens
i) Direct-acting carcinogens: They do not require metabolic conversion to become
carcinogenic.
e.g., Alkylating agents; Acylating agents.
ii) Indirect-acting carcinogens: They require metabolic conversion to become active
carcinogens.
e.g., Benzopyrene; Benzidine; 2-Naphthylamine; Aflatoxin B1.
II) Promotion: 1) Involves proliferation and clonal expansion of initiated cells with the
application of promotors.
2) Promotors are not tumorigenic applied before initiation.
3) Reversible process.
Radiation Carcinogenesis
I) Ultraviolet Rays
*UVB light is considered to be carcinogenic.
Pathogenesis: Formation of pyrimidine dimers in DNA.
Associated tumors
Skin cancers: Basal cell carcinoma, squamous cell carcinoma and melanoma.
II) Ionizing Radiation
Source: X-rays, g rays, a particles, b particles, protons, and neutrons.
Pathogenesis: Chromosome breakage, translocations and point mutations.
Associated tumors
1) Leukemias (myeloid).
2) Thyroid cancer in young individuals.
3) Cancers of the breast, lung and salivary glands.
Microbial Carcinogenesis
I) Viruses and associated tumors
1) Human T-Cell Leukemia Virus Type 1 (HTLV 1): Adult T-cell leukemia/lymphoma.
2) Human Papilloma Virus (HPV)
Benign tumors: Squamous papilloma.
Malignant tumors: Squamous cell carcinomas of the cervix, anogenital region and head, and
neck.
3) Epstein-Barr Virus (EBV)
Burkitt lymphoma; Hodgkin lymphoma; Nasopharyngeal carcinoma; B-cell lymphomas in
immunosuppressed individuals.
4) Hepatitis B and C Viruses (HBV and HCV): Hepatocellular carcinoma.
Viral oncogenes: Responsible for oncogenesis resulting from persistent virus infection.
Virus
Oncogene
HTLV-1
Tax, HBZ
HPV
E6, E7
HBV
HBx
EBV
LMP-1, EBNA2
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II) Bacteria and associated tumors
Helicobacter pylori: Gastric adenocarcinoma and gastric lymphoma.
Paraneoplastic Syndromes
“Represent signs and symptoms that cannot readily be explained by the anatomic distribution
of the tumor or by the elaboration of hormones indigenous to the tissue from which the tumor
arose.”
Significance: 1) Contribute to the diagnosis of tumors.
2) May mimic the metastasis.
3) Affect the prognosis of tumors.
E.g.,
Endocrinopathies
Cushing syndrome
Small-cell carcinoma of lung
SIADH
Small-cell carcinoma of lung
Hypercalcemia
Squamous cell carcinoma of lung; Breast carcinoma
Polycythemia
Renal cell carcinoma
Others
Acanthosis nigricans
Gastric carcinoma
Myasthenia
Carcinoma of lung
Hypertrophic osteoarthropathy Carcinoma of lung
Venous thrombosis
Pancreatic carcinoma
DIC
Acute promyelocytic leukemia
Grading and Staging of Tumors
“Grading and staging give information about the aggressiveness of tumors and their extent
and spread in individual patients.”
Significance: 1) Determine the treatment protocols.
2) Predict the prognosis of tumor.
Grading: Based on the degree of differentiation and the number of mitoses or architecture of
the tumor. Ranges from two to four categories.
Staging: Based on the size of primary tumor, its extent of spread to regional lymph nodes,
and the presence or absence of blood-borne metastases.
TNM system
1) T for primary tumor: T0 for in situ lesion and T1 to T4 on the basis of size of tumor.
2) N for regional lymph node involvement: N0 for no lymph node involvement. N1 to N3 on
the basis of number and range of lymph nodes involved.
3) M for metastases: M0 for no distant metastases. M1 or M2 indicates the presence of distant
metastases.
Refresh Pathology, 3rd Edition – Dr. Shiva M.D.
Tumor Markers
“Represent tumor-associated enzymes, proteins or hormones detected in the blood.”
Significance: 1) Contribute to the diagnosis of tumors.
2) Determine the effectiveness of therapy.
3) Detect tumor recurrence.
E.g.,
Hormones
HCG
Choriocarcinoma
Calcitonin
Medullary carcinoma of thyroid
Catecholamines
Pheochromocytoma
Oncofetal antigens
α-Fetoprotein
Hepatocellular carcinoma
CEA
Carcinomas of the colon, pancreas, and lung
Specific proteins
Immunoglobulins
Multiple myeloma
PSA
Prostate cancer
Mucins
CA-125
Ovarian cancer
CA-19-9
Pancreatic cancer
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7. Infectious Diseases
MCQs
1) Clue cells are seen in which infection. (Feb. 2022)
a) Candida b) Trichomonas c) Genitourinary TB d) Bacterial vaginosis
2) Warthin-Finkeldey cells are seen in. (Feb. 2022)
a) Mumps b) Influenza c) Measles d) Rubella
10 Marks
1) A forty year old man presented with history of persistent cough and evening rise of
temperature over a period of 4 months, with associated loss of appetite and reduction in
weight. Examination revealed matted cervical lymph nodes. An X ray chest done showed a
small radiopaque focus in the apex of the upper lobe of the right lung. (Feb. 2018)
a) What is your diagnosis?
b) Describe in detail the pathogenesis of this disease.
c) Describe the microscopic features associated with this lesion.
d) Enumerate the complications associated with this condition.
Ans: Tuberculosis.
2) A 52 year old beggar is admitted with skin patches and nodules on the face. Skin patches
are hypoesthetic. Few toes on both feet are amputated partly. (July, 2017)
a) What is the possible diagnosis? How will you make the diagnosis?
b) Classify the disease.
c) What special stains will you do on the biopsy to make the diagnosis?
d) Discuss the mode of transmission of the disease.
Ans: Leprosy.
4 Marks
1)
2)
3)
4)
5)
6)
Primary tuberculosis. (Nov. 2020)
Tabulate the differences between tuberculoid and lepromatous leprosy. (July, 2019)
Pathogenesis of primary pulmonary tuberculosis. (Feb. 2019)
Morphology of lepromatous leprosy. (Feb. 2019)
Tabulate differences between lepromatous and tuberculoid leprosy. (July, 2018)
Give the clinical picture and microscopic picture of the lesion in lepromatous leprosy.
(Jan. 2016)
7) Ghon complex. (Jan. 2015)
8) Morphology of lepromatous leprosy. (July, 2012)
9) Primary complex. (July, 2011)
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10) Rhinosporidiosis. (July, 2011)
11) Actinomycosis. (Aug. 2010)
12) Primary complex. (Aug. 2009)
13) Lepromatous leprosy. (Oct. 2008)
14) Primary complex. (May, 2006)
15) Actinomycosis. (Oct. 2005)
16) Opportunistic fungal infection. (March/April, 2005)
17) Tuberculoid leprosy. (April/May, 2004)
18) Lepromatous leprosy. (March/April, 2003)
2 Marks
1) Tuberculoid leprosy – Microscopic picture. (July, 2013)
2) Mention 4 sequelae of Ghon complex. (Jan. 2013)
3) Late manifestations of congenital syphilis. (Jan. 2012)
4) Miliary tuberculosis (Aug. 2010)
5) Morphology of actinomycotic mycetoma. (March, 2010)
6) Rhinosporidiosis. (April, 2009)
7) Rhinosporidiosis. (March/April, 2008)
8) Mycetoma. (Sep/Oct. 2007)
9) Lepromatous leprosy. (May, 2007)
10) Mycetoma. (April/May, 2004)
11) Fate of primary tuberculosis. (Sep. 2003)
12) Maduromycosis. (March/April, 2003)
High-Yield Topics
Tuberculosis
Leprosy
Rhinosporidiosis
Syphilis
Madura foot
Actinomycosis
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Actinomycosis
“A chronic suppurative disease with systemic illness.”
Causative agent: Actinomycetes israelii (a filamentous bacteria).
Sex: M>F
Route of transmission: Endogenous.
Types
1) Cervicofacial: Most common.
Risk factors: Dental caries, periodontal disease and injury to oral mucosa.
Sites: Firm swelling is seen involving lower jaw with abscess and sinus tract formation. May
extend to involve mandible, orbit, cranial bones or CNS.
2) Thoracic:
Risk factors: Aspiration of infectious material or extension from abdominal or hepatic
lesions.
Sites: Lungs are involved commonly, may extend to pleura and chest wall.
3) Abdominal:
Risk factors: Swallowing of infectious material; Extension of a thoracic lesion.
Sites: Ileocecal region is commonly involved.
4) Pelvic:
Risk factors: Usage of IUCD.
Morphology: 1) Suppurative and granulomatous inflammation with the formation of
abscesses, containing one or more sulphur granules.
2) Granules are composed of branched, gram +ve filaments, haphazardly arranged in an
amorphous matrix and surrounded by neutrophils and bordered by eosinophilic, club like
material (Splendore–Hoeppli phenomenon).
Inv.: Biopsy, culture and immunofluorescence.
Mycetoma (Madura Foot or Maduromycosis)
“A chronic infection of the skin, subcutaneous tissue and sometimes bone characterized by
discharging sinuses filled with organisms.”
Sites: Hands or Feet (MC).
Sex: M>F
Age: 20-50 yrs.
Types and Etiology:
1) Actinomycetoma: Caused by bacteria such as Actinomadura madurae, Actinomadura
pelletieri, and Nocardia sps..
2) Eumycetoma: Caused by fungi such as Madurella mycetomatis, Madurella grisea.
Pathogenesis: The organism is inoculated into the skin by a minor injury such as a cut with a
thorn when walking barefoot.
Morphology: Gross: Localised swelling appears initially on an exposed site. The affected
area is often hyperpigmented. Multiple firm nodules appear and start to drain spontaneously
or following pressure. The fluid discharged from sinus tract can contain the
characteristic granular grains.
Micro.: 1) Localized abscesses involve dermis and subcutaneous tissue with one or more
granules in the centre.
2) Granules of actinomycotic mycetomas contain delicate, gram positive, branched filaments.
3) Granules of eumycotic mycetomas contain broad, septate, fungal hyphae.
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Rhinosporidiosis
Causative organism: Rhinosporidium seeberi (a parasite).
Sex: M>F
Age: Children and 15-40 yrs.
Site: Mucus membrane of nasopharynx, oropharynx, conjunctiva and rectum.
Route of transmission: Contact with contaminated water and autoinfection.
Pathogenesis: After inoculation, the organism replicates locally and causes hyperplasia of
the host tissue and localized immune response.
Morphology: Gross: Pink to deep red polyps with strawberry like appearance. Bleeds easily
upon manipulation.
Micro.: Surface epithelium exhibits papillomatous hyperplasia. Stroma is hypervascular
showing acute and chronic inflammatory cells with scattered granulomas and sporangia with
endospores.
C/P: Nasal cavity: Unilateral nasal obstruction, epistaxis, rhinorrhea, and local pruritus.
Eye: Photophobia and increased tearing.
Inv.: Biopsy.
Syphilis
“A chronic sexually transmitted infection (STI).”
Causative agent: Treponema pallidum (a spirochete).
Route of transmission: Sexual and transplacental.
Pathogenesis:
1) Proliferative endarteritis affecting small blood vessels leads to ischemia.
2) Th1 response with production of IFN-g mediates macrophage activation and killing of
bacteria.
2) Treponeme-specific antibodies activate complement and allow opsonization of bacteria by
macrophages.
3) TprK, a protein in the outer membrane of bacteria, facilitates the persistence of infection.
Stages:
I) Primary syphilis: Occurs 3weeks after infection.
Morphology: Chancre is characteristic.
Gross: Single firm, nontender, raised red papular lesion on the penis or scrotum in men and
on the vulva or cervix in women.
Micro.: Proliferative endarteritis with rich infiltrate of plasma cells and plenty of spirochetes.
C/P: Eroded chancre with an adjacent button like mass (hard chancre); Regional
lymphadenopathy.
Morphology:.
II) Secondary syphilis: Occurs 2 to 10 wks. after the primary chancre in untreated patients.
Morphology: Superficial lesions of the skin and mucosal surfaces are characteristic.
Micro.: Proliferative endarteritis with rich infiltrate of plasma cells.
C/P: 1) Red brown macular rash involves palms and soles of the feet.
2) Silvery-gray superficial erosions on the oral, pharyngeal and genital mucus membranes.
3) Condyloma lata: Broad-based elevated plaques on the anogenital region, inner thighs, and
axillae.
4) Systemic manifestations: Weight loss, mild fever, and lymphadenopathy.
III) Latent syphilis: Symptom free interval.
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IV) Tertiary syphilis: Occurs after a latent period of 5 yrs or more in untreated patients.
a) Cardiovascular syphilis: Most common.
Morphology: Syphilitic aortitis is characteristic.
Micro.: Endarteritis of the vasa vasorum of the proximal aorta causes aortitis.
C/P: Aortitis leads to dilation of the aortic root and arch, which causes aortic valve
insufficiency and aneurysms of the proximal aorta.
b) Neurosyphilis: May be asymptomatic or symptomatic.
C/P: Meningovascular syphilis, tabes dorsalis and general paresis.
c) Benign tertiary syphilis:
Morphology: Gummas are characteristic.
Gross: Single or multiple, white-gray and rubbery lesions of varying size occur particularly
in skin, subcutaneous tissue, bone, and joints.
Micro.: Coagulative necrosis in the center with palisading macrophages and fibroblasts in the
periphery, surrounded by plasma cells; Spirochetes are scant.
C/P: Skeleton: Pain, swelling and fractures; Skin & mucus membranes: Nodular lesions;
Liver: Hepar lobatum.
Congenital syphilis
Cause: Maternal primary or secondary syphilis.
Manifestations:
1) Intrauterine death and perinatal death may occur in untreated cases.
2) Infantile syphilis: Manifestations occur in the first 2 yrs of life.
Nose: Nasal discharge and congestion (snuffles).
Rash: Bullous eruption of palms and soles of feet with epidermal sloughing.
Bone: Osteochondritis and periostitis affect all bones.
e.g., Nose: Saddle nose deformity; Tibia: Saber shin.
Liver: Diffuse fibrosis with lymphoplasmacytic infiltrate and vascular changes.
Lungs: Diffuse interstitial fibrosis; Pale and airless (pneumonia alba) lungs in the stillborn.
3) Tardive syphilis: Manifestations occur after first 2 yrs of life.
Triad: Interstitial Keratitis, Hutchinson teeth (small incisors shaped like a peg, often with
notches in the enamel) and eight nerve deafness.
Diagnosis: 1) Biopsy with dark field microscopy and silver stains (Warthin-Starry stain).
2) Immunofluorescence.
3) Serological tests:
i) Non treponemal antibody tests
a) Rapid plasma reagin (RPR) test.
b) Venereal disease research laboratory (VDRL) test.
ii) Treponemal antibody tests
a) Fluorescent treponemal antibody absorption test (FTA-Abs).
b) Treponema pallidum enzyme immunoassay test.
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Leprosy (Hansen Disease)
Causative agent: Mycobacterium leprae (an acid fast bacteria).
Source and Route of transmission: Not known.
Ridley-Jopling Classification: Tuberculoid (TT); Borderline Tuberculoid (BT); Borderline
(BB); Borderline Lepromatous (BL); Lepromatous (LL).
Types
I) Tuberculoid (Paucibacillary) leprosy: Less severe form.
Sites: Skin and large peripheral nerves.
Pathogenesis:
1) Th1 response with the production of IFN-g causes macrophage activation and killing of
bacteria leading to low bacterial burden.
3) Asymmetric neuronal involvement with nerve degeneration causes skin anesthesia with
atrophy of skin and muscle.
Morphology: Gross:
1) Localized flat, red skin lesions with indurated, elevated and hyperpigmented margins and
pale depressed center.
2) Chronic skin ulcers, contractures, paralysis or amputation of digits.
3) Eyelid paralysis, keratitis and corneal ulceration with facial nerve involvement.
Micro.: 1) Granulomatous inflammatory response with less or no bacteria.
2) Grenz zone is absent with inflammatory response encroaching upon the basal layer of
epidermis.
II) Lepromatous (Multibacillary) leprosy: More severe form.
Sites: Skin, peripheral nerves (ulnar and peroneal), anterior eye chamber, upper airways,
testes, hands and feet.
Pathogenesis:
1) Weak Th1 response with lower levels of IL-12 or unresponsiveness of T cells to IL-12.
2) Some cases show relative increase in Th2 response with production of IL-4, IL-5 and IL10, which may suppress macrophage activation.
3) Weak cell mediated immunity presents with heavy bacterial burden.
4) Widespread invasion of schwann cells, endoneural and perineural macrophages causes
damage to the peripheral nervous system.
5) Antibody production with immune complex formation causes erythema nodosum,
vasculitis or glomerulonephritis.
Morphology:
Gross: Hypoesthetic or anesthetic macular, papular or nodular skin lesions. Nodular lesions
coalesce and display facial features similar to that of a lion (leonine facies).
Micro.: 1) Lepra cells: Large aggregates of lipid-laden macrophages, often filled with masses
(globi) of acid-fast bacilli.
2) Grenz zone: Dermal infiltration of lepra cells characteristically does not encroach upon the
basal layer of epidermis and is separated from epidermis by a subepidermal uninvolved clear
zone known as Grenz zone.
Inv.:
1) Skin biopsy: Stains: Ziehl-Neelson, Fite-Faraco and GMS (Gomori Methenamine Silver).
2) Lepromin test: Nonreactive (negative) in lepromatous leprosy; Reactive (positive) in
tuberculoid leprosy.
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Feature
Tuberculoid leprosy
Severity
Spread
Infectivity
Th1 response
Bacterial burden
Granulomatous inflammation
Grenz zone
Leonine facies
Erythema nodosum
Lepromin test
Less
Restricted
Low
Strong
Less
Present
Absent
Absent
Absent
Positive
Lepromatous leprosy
More
Extensive
High
Weak
More
Absent
Present
May be present
May be present
Negative
Tuberculosis
“A chronic pulmonary and systemic disease.”
Causative agent: Mycobacterium tuberculosis (an acid fast bacteria).
Route of transmission: Person to person.
Risk factors: Poverty; Crowding; Chronic debilitating illness.
Predisposing conditions: Diabetes mellitus; Hodgkin lymphoma; Chronic lung disease
(silicosis); Chronic renal failure; Malnutrition; Alcoholism; Immunosuppression (AIDS).
Pathogenesis:
1) Bacteria enters macrophages by phagocytosis.
2) Bacteria inhibits maturation of the phagosome and blocks formation of the
phagolysosome, allowing their replication within macrophages.
3) Th1 response is initiated with the production of IFN-g.
4) IFN-g causes macrophage activation and killing of bacteria by facilitating phagolysosome
maturation, production of NO and autophagy.
Types
1) Primary tuberculosis
Host: Previously unexposed and unsensitized (non-immune) person.
Source: Exogenous.
Site: Lungs (Lower part of the upper lobe; Upper part of the lower lobe).
Morphology: Gross:
1) Ghon focus: 1 - to 1.5-cm gray-white lesion with cheesy white appearing center.
2) Ghon complex: Ghon focus along with lymphadenopathy.
3) Fibrosis with radiologically detectable calcification.
Micro.: Granulomatous inflammatory reaction with caseating and noncaseating tubercles.
C/P: 1) Asymptomatic (MC).
2) Progressive form: Acute bacterial pneumonia with consolidation of the lobe, hilar
adenopathy and pleural effusion.
3) Tuberculous meningitis and miliary TB with lympohematogenous dissemination.
Fate: 1) Healed lesion, where organisms are not visible.
2) Latent lesion, where organisms are dormant.
3) Progressive primary TB, which may progress to miliary TB.
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2) Secondary tuberculosis
Host: Previously sensitized host, many years after primary with weakening of host resistance.
Source: Reactivation of a latent infection or exogenous reinfection.
Site: Apex of upper lobes.
Morphology:
Gross: 1) Small circumscribed firm, gray-white to yellow apical foci with central cheesywhite appearance.
2) Cavitation or erosion into airways is associated.
Micro.: Granulomatous inflammatory reaction with caseating and noncaseating tubercles.
C/P: 1) Asymptomatic.
2) Systemic manifestations: Anorexia, weight loss, fever (low grade), and night sweats.
3) Mucoid or purulent sputum or hemoptysis.
4) Pleuritic pain.
Fate: 1) Fibrocalcific scars in immunocompetent persons.
2) Progressive secondary TB, which may progress to miliary TB.
Other forms of TB
Miliary tuberculosis
1) Miliary pulmonary tuberculosis: Bacteria circulate back to the lung via
lymphohematogenous dissemination. Small (2-mm) foci of yellow-white consolidation are
scattered through the lung parenchyma.
2) Systemic miliary tuberculosis: Bacteria disseminate through the systemic arterial system
with involvement of various organs such as liver, spleen, adrenals or meninges.
Inv.: Biopsy; Cytology; X-ray; Acid fast stain or culture of the sputum; Mantoux or
tuberculin skin test; Polymerase chain reaction.
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8. Environmental and Nutritional Diseases
MCQs
1) Bitot spots are seen in deficiency of vitamin. (Feb. 2022)
a) A b) B c) C d) D
5 Marks
1) Rickets. (May, 2022)
2) Write in detail about lead poisoning. (Feb. 2022)
4 Marks
1)
2)
3)
4)
Morphologic changes in kwashiorkor. (July, 2016)
Bone changes in rickets. (July/Aug. 2014)
Examples of radiation injury and morphological changes induced by them. (July/Aug. 2014)
Ionizing radiation. (Oct. 2005)
2 Marks
1) List any four pathological effects of vitamin A deficiency. (May, 2022)
2) Vitamin A deficiency. (Nov. 2020)
3) Give four examples of deficiency diseases associated with four different components
of vitamin B complex. (July, 2019)
4) Mention four effects of radiation. (July, 2017)
5) Four skeletal abnormalities in rickets. (July, 2015)
6) Four alcohol induced diseases. (Jan. 2015)
7) Name any four (4) pathological changes in vitamin A deficiency. (Jan. 2014)
8) Skeletal changes in rickets. (Jan. 2012)
9) Vitamin A deficiency consequences. (Aug. 2010)
10) Consequences of vitamin A deficiency disease. (Aug. 2009)
11) Vitamin C deficiency. (Feb. 2009)
12) Rickets. (Oct. 2008)
13) Lesions of vitamin A deficiency. (March/April, 2008)
14) Vitamin A deficiency disorders. (March/April, 2003)
High-Yield Topics
Smoking
Ionizing radiation
Vitamin D deficiency
Protein-energy malnutrition
Alcoholism
Vitamin A deficiency
Scurvy
Obesity
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Lead Poisoning
Sources
1) Occupational: Spray painting; Foundry work; Mining and extracting lead; Battery
manufacturing.
2) Nonoccupational: Water supply; Paint dust and flakes; Automotive exhaust; Urban soil.
Pathogenesis: Lead binds to sulfhydryl groups in proteins and interferes with calcium
metabolism, effects that lead to hematologic, skeletal, neurologic, gastrointestinal, and renal
toxicities.
Manifestations
1) Blood and bone marrow: microcytic, hypochromic anemia with mild hemolysis and
punctate basophilic stippling of the red cells. Few ring sideroblasts appear in the marrow.
2) Brain:
i) Adult - Headache, memory loss.
ii) Child - Encephalopathy, mental deterioration.
3) Peripheral nerves: Adult - Demyelination.
4) Gastrointestinal tract: Lead colic with severe, poorly localized abdominal pain.
5) Gingiva: Lead lines.
6) Kidneys: Chronic renal damage leads to interstitial fibrosis and renal failure.
7) Bones: Child - Radiodense deposits in epiphyses.
Inv.: Elevated blood lead and red cell free protoporphyrin levels (greater than 50 μg/dL).
Effects of Alcohol
I) Acute alcoholism
Manifestations:
Liver: Fatty change or hepatic steatosis.
Stomach: Acute gastritis and ulceration.
CNS: Drowsiness; Stupor and coma with higher alcohol levels.
II) Chronic alcoholism
Manifestations:
Liver: Alcoholic hepatitis and cirrhosis with complications such as portal hypertension and
hepatocellular carcinoma.
GIT: Massive bleeding from gastritis, gastric ulcer or esophageal varices.
CVS: Dilated congestive cardiomyopathy, hypertension and coronary heart disease.
CNS: Thiamine deficiency causes peripheral neuropathies, & Wernicke-Korsakoff syndrome.
Pancreas: Acute and chronic pancreatitis.
Fetus (during pregnancy): Fetal alcohol syndrome with microcephaly, growth retardation,
and facial abnormalities in the newborn.
Carcinogenesis: Cancer of the esophagus, oral cavity, and liver.
Nutrition: Malnutrition and nutritional deficiencies.
Injury Produced by Ionizing Radiation
Source: X-rays, g rays, a particles, b particles, protons, and neutrons.
Target tissues: Gonads, bone marrow, lymphoid tissue, and the mucosa of the GIT.
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Pathogenesis:
1) Damage to DNA directly or indirectly by production of ROS leads to cell death or
carcinogenesis.
2) Damage to endothelial cells causes narrowing or occlusion of blood vessels leading to
chronic ischemic atrophy and fibrosis.
Morphology: Changes may be early (hours to weeks) or late (months to years).
Brain (embryonic): Destruction of neurons and glial cells.
Skin: Erythema & edema (early); Atrophy & cancer (late).
Lungs: Edema & ARDS (early); Interstitial fibrosis (late).
GIT: Mucosal damage (early); Fibrosis of wall (late).
Lymph nodes: Acute tissue loss (early); Atrophy & fibrosis (late).
Gonads (testes & ovaries): Sterility (early); Atrophy & fibrosis (late).
Blood & Bone marrow: Anemia, granulocytopenia, lymphopenia & thrombocytopenia
(early).
Cancers: Leukemias; Thyroid cancer; Cancers of thyroid, breast, and lungs.
Kwashiorkor
“Kwashiorkor is a component of severe acute malnutrition (SAM).”
Causes: 1) Protein deprivation, which is relatively greater than the reduction in total calories.
2) Chronic diarrhea, nephrotic syndrome or severe burns.
Pathogenesis:
1) Severe loss of the visceral protein compartment with hypoalbuminemia leads to edema.
2) Relative sparing of the somatic protein compartment and subcutaneous fat.
Morphology: 1) Enlarged fatty liver.
2) Small bowel with mucosal atrophy and loss of villi.
3) Thymic and lymphoid atrophy.
4) Bone marrow may be hypoplastic.
Manifestations:
1) Growth failure with peripheral edema
2) Flaky paint appearance of skin with alternating zones of hyperpigmentation, areas of
desquamation, and hypopigmentation.
3) Hair changes are overall loss of color or alternating bands of pale & darker hair.
4) Development of listlessness and loss of appetite.
5) Anemia, vitamin deficiencies, and secondary infections.
Evaluation: Weight; Skin fold thickness; Mid-arm circumference; Serum albumin levels.
Vitamin A Deficiency
Causes: 1) Decreased intake.
2) Malabsorption syndromes.
Manifestations:
Eye: 1) Night blindness: Impaired vision, particularly in reduced light.
2) Xerosis conjunctivae: Dryness of the conjunctiva.
3) Bitot spots: Small opaque, frothy, triangular plaques on conjunctiva with keratin debris.
4) Keratomalacia: Softening and destruction of cornea.
5) Total blindness.
Skin: Follicular or papular dermatosis.
Respiratory tract: Secondary pulmonary infections.
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Urinary tract: Renal and bladder stones.
Immunity: Increased risk of developing infections such as measles, pneumonia and
infectious diarrhea.
Vitamin D Deficiency
“Concentrations of circulating 25-(OH)-D, less than 20 ng/mL constitute vitamin D
deficiency.”
Causes: 1) Inadequate intake.
2) Limited exposure to sunlight.
3) Renal disorders.
4) Malabsorption syndromes.
Deficiency syndromes: Rickets & osteomalacia
Rickets
“Vitamin D deficiency in growing children causes rickets.”
Age: Most common during first year of life.
Morphology:
1) Overgrowth of epiphyseal cartilage.
2) Persistence of distorted, irregular masses of cartilage.
3) Deposition of osteoid matrix on inadequately mineralized cartilaginous remnants.
4) Disruption of the orderly replacement of cartilage by osteoid matrix.
5) Abnormal overgrowth of capillaries and fibroblasts in the disorganized zone.
6) Deformation of the skeleton.
Manifestations:
1) Nonambulatory stage of infancy:
i) Flattening of occipital bones.
ii) Craniotabes: Parietal bones are soft, and when pressure applied, they will collapse
underneath it.
iv) Frontal bossing and a squared appearance of head.
v) Rachitic rosary: Expansion of the anterior rib ends at the costochondral junctions.
vi) Pigeon breast deformity: Anterior protrusion of sternum.
II) Ambulating child: Lumbar lordosis and bowing of the legs.
Osteomalacia
“Vitamin D deficiency in adults causes osteomalacia.”
Morphology:
1) Deposition of inadequately mineralized osteoid matrix.
2) Presence of excess of persistent osteoid.
C/P: Weak bones with increased risk of fractures, mostly affecting vertebral bodies and
femoral necks.
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Vitamin B Complex Deficiency Syndromes
Vitamin
Deficiency Syndromes
Vitamin B1 (thiamine)
Vitamin B2 (riboflavin)
vascularization
Niacin
Vitamin B6 (pyridoxine)
Vitamin B12
cord tracts
Folate
Dry and wet beriberi, Wernicke-Korsakoff syndrome
Cheilosis, stomatitis, glossitis, dermatitis, corneal
Pellagra (dementia, dermatitis, diarrhea)
Cheilosis, glossitis, dermatitis, peripheral neuropathy
Megaloblastic anemia and degeneration of posterolateral spinal
Megaloblastic anemia, neural tube defects
Vitamin C Deficiency
Causes: 1) Old age.
2) Chronic alcoholism.
3) Erratic & inadequate eating patterns.
Deficiency syndrome: Scurvy.
Manifestations:
Scurvy:
1) Growing children: Bone disease (bowing of limbs and depressed sternum) with inadequate
synthesis of osteoid due to defective collagen.
2) Children & adults: Hemorrhages (bleeding gums, bleeding into skin (perifollicular rash),
periosteum and joints) and healing defects due to defective collagen.
3) Anemia.
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9. Diseases of White Blood Cells, Lymph
Nodes, Spleen, and Thymus
MCQs
1) The anemia associated with leukemia is. (May, 2022)
a) Iron deficiency b) Megaloblastic c) Myelophthisic d) None of the above
15 Marks
1) A 35 year old male patient presented with high fever, fatigue, pallor, skin petechiae,
swollen gums and bone pain. His total WBC count is 1,00,000/mm3. (May, 2022)
a) What is the provisional diagnosis.
b) Describe the blood and bone marrow picture of the above case.
c) Classification of the above condition.
d) Discuss the prognosis of the above disease.
Ans: Acute Myeloid Leukemia (AML).
10 Marks
1) A 35 year old man was admitted with easy fatigability, anorexia, weakness, weight loss,
night sweats and dragging sensation in the abdomen due to massive splenomegaly. His total
WBC count was 2,00,000 cells/mm3. (Nov. 2020)
a) What is the provisional diagnosis?
b) Describe the blood and bone marrow picture.
c) Describe the chromosomal abnormality of the disease.
d) Mention various phases of the disease.
Ans: Chronic Myeloid Leukemia (CML).
2) A 32 year old man is admitted with history of weakness and dragging sensation on left side
of abdomen. On examination, his liver is enlarged to 3cm below costal margin and spleen is
enlarged to 15cm below costal margin. His TLC is increased to 2,30,00/cumm. (Feb. 2020)
a) What is the possible diagnosis? What is likely to be the differential leukocyte count.
b) What is the diagnostic genetic abnormality in this condition?
c) To which group of diseases, does this entity belong to? Name the other diseases.
d) Give the clinical picture of this disease.
Ans: Chronic Myeloid Leukemia (CML).
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3) A 2 year old male presented with fatigue, and breathlessness developing over 1 week. On
examination he had gum bleeding, epistaxis with petechiae, lymphadenopathy and
splenomegaly. CT scan showed presence of mediastinal mass. (July, 2019)
a) Give the possible diagnosis
b) Give the peripheral blood and bone marrow findings
c) Give the cytochemical staining properties
4) What are the prognostic factors
Ans: Acute Lymphoblastic Leukemia (ALL).
4) A 35 year old man admitted with gradual weakness with dragging sensation left side of
abdomen. His liver is 2cm and spleen is 15cm enlarged below costal margin. His Hb is 9.3
gm %, TLC – 2,50,000/cumm and platelet count is 3,80,000/cumm. (July, 2018)
a) What is the probable diagnosis?
b) Give the blood picture and molecular abnormality in this disease.
c) How will you differentiate it from leukemoid reaction?
d) Give five causes of massive splenomegaly.
Ans: Chronic Myeloid Leukemia (CML).
5) A 3 year old child is admitted with fever and petechial hemorrhages for 2 weeks. On
examination child is pale, no liver/spleen enlargement. Cervical lymph nodes are enlarged.
TLC – 50, 000/cumm. Peripheral smear shows blast cells. (Feb. 2017)
a) What is the probable diagnosis?
b) What is the bone marrow picture in this disease?
c) Enumerate the various prognostic factors.
d) Tabulate the differences between lymphoblast and myeloblast.
Ans: Acute Lymphoblastic Leukemia (ALL).
6) A male child aged 8 years presented with fever, fatigue, generalized lymphadenopathy,
bone pain, petechial hemorrhages over the skin, pallor, enlarged testes and features of
meningism. (Jan. 2014)
a) What is the provisional diagnosis?
b) Describe blood and bone marrow picture.
c) Other investigations to confirm the diagnosis.
d) Discuss the prognosis of the same.
Ans: Acute Lymphoblastic Leukemia (ALL).
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7) A 35 year old male was admitted with easy fatigability, anorexia, weakness, weight loss,
night sweats and dragging sensation in the abdomen due to massive splenomegaly. His total
WBC count was 2,00,000 cells/mm3. (July, 2013)
a) What is the provisional diagnosis?
b) Describe the blood and bone marrow picture.
c) Describe the chromosomal abnormality of the disease.
d) Mention various phases of the disease.
Ans: Chronic Myeloid Leukemia (CML).
8) A 4 years old male child presented with fatigue, fever, epistaxis, bleeding gums, bone pain
and CNS manifestations from meningeal involvement. Physical examination revealed
petechiae and ecchymoses of skin and mucous membranes, generalized lymphadenopathy
and testicular enlargement. The Leukocyte and differential counts were abnormal. (Jan. 2012)
a) What is the provisional diagnosis?
b) Discuss various main laboratory investigations to make a final diagnosis.
c) Describe peripheral blood and bone marrow picture.
d) Discuss molecular pathogenesis of the disease.
Ans: Acute Lymphoblastic Leukemia (ALL).
9) A 35 year old male patient presented with high fever, fatigue, pallor, skin petechiae,
swollen gums and bone pains. His total WBC count was 1,00,000/ul. (Aug. 2009)
a) What is the provisional diagnosis?
b) Describe the blood and bone marrow picture of the above case.
c) Discuss the prognosis of this disease.
Ans: Acute Myeloid Leukemia (AML).
10) 45 year old male presented with weakness, fatigue, weight loss, night sweats and
dragging sensation in the abdomen caused by massive splenomegaly. (Feb. 2009)
a) What is the provisional diagnosis?
b) What blood investigations should be done to confirm the diagnosis? Describe the
peripheral smear findings.
c) Which chromosomal abnormality is seen in this condition?
Ans: Chronic Myeloid Leukemia (CML).
11) A 40 year male was admitted with easy fatigability, weakness, weight loss and night
sweats. On examination, massive splenomegaly was noted. Total leukocyte count was 275,
000/ul. (Sep/Oct. 2007)
a) What is the possible diagnosis?
b) Describe the chromosomal abnormality of the disease.
c) Describe the peripheral blood smear and bone marrow findings of the same.
Ans: Chronic Myeloid Leukemia (CML).
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12) A 2 year old child presented with fatigue, fever, epistaxis, bleeding gums and bone pain.
On examination, generalized lymphadenopathy and hepatosplenomegaly was noted. Total
leukocyte count was 150,000/ul. (May, 2007)
a) What is the probable diagnosis?
b) Describe the cytogenetics of the disease.
c) Describe the peripheral blood smear and bone marrow findings of the same.
d) Describe the prognostic factors of the disease.
Ans: Acute Lymphoblastic Leukemia (ALL).
13) 36 year old female came with swollen gums, fatigue and weight loss. She gives history of
repeated upper respiratory tract infections. On examination pallor, fever and
hepatosplenomegaly present. (May, 2006)
a) What is the provisional diagnosis?
b) Mention various investigations to make a final diagnosis.
c) Emphasize on the peripheral blood and bone marrow picture.
Ans: Acute Myeloid Leukemia (AML).
14) A 30 years old male patient came with moderate anemia, easy fatigability, weakness,
weight loss, anorexia, dragging sensation in the abdomen due to extreme splenomegaly.
Chromosomal analysis revealed the presence of Philadelphia chromosome. (April/May 2004)
a) What is the provisional diagnosis?
b) Describe the laboratory investigations to make a final diagnosis.
c) Describe the blood and bone marrow picture of the disease.
Ans: Chronic Myeloid Leukemia (CML).
4 Marks
1)
2)
3)
4)
5)
Lab diagnosis of chronic myeloid leukemia. (Oct. 2023)
Laboratory diagnosis of chronic myeloid leukemia. (May, 2022)
WHO classification of Acute Myeloid Leukemia. (Aug. 2021)
Lab diagnosis of chronic myeloid leukemia. (Feb. 2019)
Classify chronic myeloproliferative disorders. Give blood picture and diagnostic tests
in a case of chronic myeloid leukemia. (July, 2017)
6) Leukemoid reaction. (July, 2016)
7) Cytochemistry in differentiation of acute leukemias. (Jan. 2016)
8) FAB classification of Acute Myeloblastic Leukemia (AML). (Jan. 2015)
9) Tabulate the differences between leukemoid reaction and chronic myeloid leukemia.
(July/Aug. 2014)
10) Blood picture and bone marrow findings in CML. (Aug. 2010)
11) Multiple myeloma. (Oct. 2006)
12) Leukemoid reaction. (March/April 2005)
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2 Marks
1) Russel bodies. (March, 2021)
2) Write four clinical and lab features of multiple myeloma. (Feb. 2020)
3) Variants of Reed Sternberg cell. (Feb. 2019)
4) Mention four clinical features of acute lymphoblastic leukemia. (July, 2017)
5) Name four subtypes of Hodgkin disease. (July, 2016)
6) Name any four myeloproliferative disorders. (July, 2015)
7) Draw a diagram of Reed-Sternberg cell. (July/Aug. 2014)
8) Mention 4 morphologic characteristics of a myeloblast. (Jan. 2013)
9) Myeloblast of AML 3. (March, 2010)
10) Juvenile chronic myeloid leukemia. (March/April, 2008)
High-Yield Topics
Leukemoid reaction
CLL
ALL
Polycythemia Vera
Burkitt lymphoma
CML
AML
Multiple myeloma
Hodgkin lymphoma
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Lymphadenopathy
Causes of generalized lymphadenopathy:
1) Infections: Infectious mononucleosis; Measles; HIV; TB; Syphilis.
2) Malignancies: Leukemias; Lymphomas; Metastatic cancers.
3) Storage disorders: Niemann-Pick disease; Gaucher disease.
4) Autoimmune disorders: SLE; Rheumatoid arthritis.
5) Drug reactions: Phenytoin; Allopurinol.
Splenomegaly
Causes of massive splenomegaly: CML, myelofibrosis, polycythemia vera, essential
thrombocythaemia, indolent lymphomas, hairy cell leukaemia, β-thalassaemia major, malaria,
visceral leishmaniasis, Gaucher disease.
Acute Lymphoblastic Leukemia/Lymphoma (ALL)
*Most common cancer of children.
*Leading cause of cancer deaths in children.
Cell of origin: Precursor B or T cells.
Age: <15 yrs.
Sex: Boys>Girls.
Types: B-ALLs (MC) & T-ALLs.
Genetic alterations: 1) T-ALLs: Gain of function mutations in NOTCH 1 gene.
2) B-ALLs: Loss of function mutations in PAX5, E2A, and EBF genes.
3) Hyperploidy is common.
Pathogenesis: Genetic aberrations block the maturation of lymphoid progenitors with their
proliferation and survival.
C/P: 1) Fatigue and weakness; Recurrent infections with fever; Bleeding manifestations.
2) Bone pain; Generalized lymphadenopathy, splenomegaly, hepatomegaly, and testicular
enlargement.
3) Headache, vomiting and nerve palsies with CNS involvement.
Inv.:
1) Peripheral smear: i) Anemia, neutropenia and thrombocytopenia.
ii) Total leukocyte count is variable with many lymphoblasts.
2) Bone marrow: Hypercellular marrow showing many lymphoblasts with interspersed
macrophages imparts a ‘starry sky’ appearance.
*Lymphoblast: Immature cells having scant agranular basophilic cytoplasm and nuclei with
delicate and finely stippled chromatin and small nucleoli. The nuclear membrane is often
deeply subdivided, imparting a convoluted appearance.
3) Cytochemistry: Lymphoblasts are myeloperoxidase negative and PAS positive.
Prognosis: I) Worse prognosis with 1) Age < 2 yrs.
2) Presentation in adolescence or adulthood. 3) Peripheral blood blast counts >100,000/uL.
II) Favorable prognosis with 1) Age between 2 and 10 yrs. 2) A low white cell count.
3) Hyperdiploidy. 4) Presence of a t(12;21). 5) Trisomy of chromosomes 4, 7, and 10.
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Acute Myeloid Leukemia (AML)
“A tumor of hematopoietic progenitors with the accumulation of immature myeloid blasts in
the marrow.”
Cell of origin: Hematopoietic progenitor cells.
Age: >60yrs (MC).
Genetic alterations:
1) Balanced chromosomal translocations such as t(8;21), inv(16) and t(15;17) are associated
with AML arising de novo in patients with no risk factors.
2) Deletions or monosomies involving chromosomes 5 and 7 are associated with AML that
follow MDS or exposure to DNA-damaging agents.
Pathogenesis: Genetic aberrations block the maturation of myeloid progenitors with their
proliferation and survival.
WHO Classification
I) AML with genetic aberrations (e.g., t(8;21); inv(16))
II) AML with MDS-like features
With prior MDS
AML with multilineage dysplasia
AML with MDS-like cytogenetic aberrations
III) AML, Therapy-related
IV) AML, Not Otherwise Specified
AML, minimally differentiated
AML without maturation
AML with myelocytic maturation
AML with myelomonocytic maturation
AML with monocytic maturation
AML with erythroid maturation
AML with megakaryocytic maturation
French American British (FAB) Classification
M0: AML, minimally differentiated
M1: AML without maturation
M2: AML, with maturation
M3: Acute promyelocytic leukemia
M4: Acute myelomonocytic leukemia
M5: Acute monocytic leukemia
M6: Acute erythroleukemia
M7: Acute megakaryocytic leukemia
C/P: 1) Fatigue and weakness; Recurrent infections with fever; Bleeding manifestations.
2) DIC may be seen in AML with t(15;17).
3) Gingival swelling or skin infiltration (leukemia cutis) may be seen in AML with
monocytic differentiation.
4) Occasionally, a localized soft tissue mass (myeloblastoma, granulocytic sarcoma or
chloroma) may be seen.
Inv.:
1) Peripheral smear: i) Anemia, neutropenia, and thrombocytopenia.
ii) Total WBC count is variable with many myeloid blasts.
iii) Blasts are entirely absent in aleukemic leukemia.
2) Bone marrow: Hypercellular with many myeloid blasts (20% or more is diagnostic).
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*Myeloblast: Immature cells having basophilic cytoplasm with fine azurophilic granules and
nuclei with delicate chromatin, and two to four nucleoli. Auer rods are needle-like
azurophilic granules, seen prominently in AML with the t(/15;17).
*Monoblast: Immature cells having abundant basophilic cytoplasm that may contain vacuoles
or few granules and eccentric and round nucleus with delicate chromatin and prominent one
or more nucleoli.
3) Cytochemistry: i) Myeloblasts are myeloperoxidase positive and PAS negative.
ii) Monoblasts are nonspecific esterase (NSE) positive, myeloperoxidase negative and PAS
negative.
Prognosis: 1) Good for AMLs with the t(15;17).
2) Bad for AMLs following MDS or genotoxic therapy or occur in older adults (>60 yrs).
Myeloproliferative Disorders (MPD)
Chronic myeloid leukemia; Polycythemia vera; Essential thrombocythemia; Primary
myelofibrosis; Systemic mastocytosis.
Chronic Myeloid Leukemia (CML)
“A Myeloproliferative disorder, characterized by the presence of a BCR-ABL fusion gene.”
Origin: Pluripotent hematopoietic stem cell.
Age: 50-60 yrs.
Genetic alterations:
1) Reciprocal t(9;22) translocation, designated as Philadelphia chromosome is most common.
2) t(9;22) leads to fusion of portions of the BCR gene on chromosome 22 and the ABL gene
on chromosome 9 generating BCR-ABL fusion gene.
Pathogenesis: Genetic aberrations drive the proliferation of granulocytic & megakaryocytic
progenitors, and also cause abnormal release of immature granulocytic forms into the blood.
Phases: Chronic (majority), accelerated and blastic.
I) Chronic phase: Remains stable for 3 to 5 yrs and is responsive to chemotherapy.
C/P: 1) Fatigue, weakness, weight loss and anorexia.
2) Splenomegaly, mild hepatomegaly and lymphadenopathy.
Inv.:
1) Peripheral smear:
i) Anemia, leucocytosis (>100,000/μl) with shift to left having few myeloblasts (<10%) and
thrombocytosis.
ii) Eosinophilia and basophilia (<20%) are noted.
2) Bone marrow: i) Hypercellular with elevated myeloid and megakaryocytic series of cells.
Erythroid series is either unaffected or may show mild suppression.
ii) Sea-blue histiocytes (scattered macrophages with abundant wrinkled green-blue
cytoplasm) with increased deposition of reticulin.
3) Karyotyping: Detects the BCR-ABL fusion gene.
.
II) Accelerated phase: Basophils (>20%) and blast cells (10 to 19%) increase in number and
shows no response to therapy.
III) Blast phase: Transformation to an acute leukemia like picture having >20% blasts in
peripheral blood or bone marrow with or without a preceding accelerated phase. In 70% of
cases, blasts are of myeloid origin (myeloid blast crisis) and in the reminder the blasts are of
pre-B cell origin (lymphoid blast crisis).
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Juvenile Myelomonocytic Leukemia (Juvenile
Chronic Myelomonocytic Leukemia)
*Grouped under myelodysplastic/myeloproliferative (MDS/MPD) neoplasms.
Age: <4yrs (MC).
Associations: Neurofibromatosis 1 (NF1).
Genetic alterations: Monosomy 7 may be associated. The Philadelphia (Ph) chromosome
and the BCR―ABL1 fusion gene are absent.
C/P: Failure to thrive, pallor, fever, hepatosplenomegaly, lymphadenopathy, skin rashes and
bleeding manifestations.
Inv.:
i) Peripheral smear: Anemia, leukocytosis with neutrophilia and monocytosis and
thrombocytopenia; Few myeloblasts and nucleated red cells are noted.
ii) Bone marrow: Hypercellular marrow with increased myeloid series of cells.
Leukemoid Reaction
“Refers to the presence of markedly increased total leukocyte count (>50,000/μl) with
immature cells in peripheral blood resembling leukemia.”
Causes: Severe bacterial infections (pneumonia); Severe hemorrhage; Severe acute
hemolysis; Burns; Metastatic tumors of bone marrow.
Bone marrow: Hypercellular with increased myeloid series of cells.
Peripheral smear: Leukocytosis (>50,000/μl) with neutrophilia having shift to left.
Myeloblasts are usually absent. Basophilia is not seen.
C/P: Features of underlying disease.
Differential diagnosis: CML.
Chronic Myelogenous Leukemia Vs Leukemoid
Reaction
Feature
CML
Leukemoid reaction
Nature
Clinical picture
Total leukocyte count
Myeloblasts
Basophilia
Eosinophilia
Toxic granules in neutrophils
LAP Score
Philadelphia chromosome
Neoplastic
Splenomegaly
>100,000/μl
Common
Present
Present
Absent
Low
Present
Reactive
Features of underlying disease
>50,000/μl
Uncommon
Absent
Absent
Present
High
Absent
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Multiple Myeloma (Plasma Cell Myeloma)
*Most common plasma cell neoplasm.
Age: 65-70 yrs.
Sex: M>F
Origin: Post-germinal centre B cell.
Genetic alterations: Chromosomal translocations that fuse the IGH locus on chromosome 14
to proto-oncogenes such as the cyclin D1 gene.
Pathogenesis: Tumor cells and stromal cells of marrow produce cytokines (IL-6) which
mediate proliferation and survival of myeloma cells.
C/P: i) Skeletal: Pathologic fractures and chronic pain.
*Bones affected: Vertebral column (MC), ribs, skull, pelvis, femur, clavicle and scapula.
ii) Neurologic: Confusion, weakness, lethargy, constipation, and polyuria.
iii) Renal dysfunction (myeloma kidney).
iv) Recurrent bacterial infections.
v) Amyloidosis.
Inv.:
i) Peripheral smear: Normocytic normochromic anemia; Rouleaux formation; Moderate
leukopenia; Thrombocytopenia.
*Plasma cell leukemia: Tumor cells within the peripheral circulation (rare).
ii) Bone marrow: a) Increased number of plasma cells.
b) Plasmablasts with vesicular nuclear chromatin and a prominent single nucleolus or bizarre,
multinucleated cells may be found.
c) Flame cells with fiery red cytoplasm or Mott cells with multiple grapelike cytoplasmic
droplets may be seen.
c) Globular inclusions such as Russel bodies or Dutcher bodies may be found in some cells.
**Russel bodies: Large homogeneous eosinophilic inclusions that represent marked
accumulation of newly synthesized immunoglobulins in the RER of some plasma cells.
iii) Blood: Increased levels of immunoglobulins; Hypercalcemia.
iv) Urine: Increased levels of light chains (Bence Jones proteins).
v) Radiology: Punched-out defects.
vi) Serum or urine electrophoresis: Abnormal protein spikes.
*The most common monoclonal Ig (M protein) is IgG.
Hodgkin Lymphoma (HL)
“Arises in a single node or chain of nodes and spreads first to anatomically contiguous
lymphoid tissues.”
WHO Classification: Nodular sclerosis; Mixed cellularity; Lymphocyte-rich; Lymphocyte
depletion; Nodular lymphocyte predominance.
Classic forms: Nodular sclerosis; Mixed cellularity; Lymphocyte-rich; Lymphocyte
depletion.
Genetic alterations: Mutations that activate transcription factor NF-kB in classic forms.
Risk factor: EBV infection in classic forms.
Types
I) Nodular sclerosis: Most common.
Age: Young adults.
Sex: M=F
EBV association: Uncommon.
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Morphology: Lymph node: Circumscribed nodules with bands of collagen; Background with
T cells, eosinophils, plasma cells and macrophages; R-S Cells: Lacunar type.
C/P: Painless lymphadenopathy; No systemic signs.
Stage: I or II
II) Mixed cellularity
Age: Young adults and older adults (>55yrs).
EBV association: 70%
Morphology: Lymph node: Diffuse effacement with T cells, eosinophils, plasma cells and
macrophages; R-S cells: Both diagnostic and mononuclear variants.
C/P: Painless lymphadenopathy with systemic signs (night sweats, fever, and weight loss).
Stage: III or IV
III) Lymphocyte rich
Age: Older adults.
Sex: M>F
EBV association: 40%
Morphology: Lymph node: Diffuse effacement with reactive lymphocytes;
R-S cells: Diagnostic and mononuclear variants.
C/P: Painless lymphadenopathy; No systemic signs.
Stage: I or II
IV) Lymphocyte depletion: Least common.
Age: Older adults.
Sex: M>F
Risk factors: HIV infection.
EBV association: 90%
Morphology: Lymph node: Paucity of lymphocytes and relative abundance of R-S cells;
R-S cells: Diagnostic and pleomorphic types.
C/P: Painless lymphadenopathy with systemic signs (night sweats, fever, and weight loss).
Stage: III or IV
V) Lymphocyte predominant
Age: <35 yrs.
Sex: M>F
Sites: Cervical and axillary lymph nodes.
EBV association: Absent.
Morphology: Lymph node: Nodular infiltration with small lymphocytes and macrophages;
R-S cells: Lymphohistiocytic (L&H) variants (popcorn cells).
C/P: Painless lymphadenopathy; No systemic signs.
Stage: I or II
Spread: Lymph nodes are involved first, then spleen, liver and finally bone marrow and
other tissues.
Reed-Sternberg cells (R-S cells)
“Neoplastic giant cells, essential for the diagnosis of Hodgkin lymphoma.”
Origin: Germinal center or post-germinal center B cells.
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Role: R-S cells of classical forms secrete various factors that induce the accumulation of
reactive lymphocytes, macrophages, and granulocytes.
Morphology:
Diagnostic R-S cells: Large cells having multiple nuclei or a single nucleus with multiple
nuclear lobes, each with a large inclusion-like nucleolus and abundant cytoplasm.
Variants:
1) Mononuclear variants: Contain a single nucleus with a large inclusion like nucleolus.
2) Lacunar variants: Contain folded or multilobate nucleus with abundant pale cytoplasm,
often disrupted during sectioning. Seen with nodular sclerosis type.
3) Lymphohistiocytic (L&H) variants: Contain polypoid nuclei with inconspicuous
nucleoli and moderately abundant cytoplasm. Seen with lymphocyte predominance type.
Mummification: Death of R-S cells in classical forms of Hodgkin lymphoma in which, they
shrink and become pyknotic.
Clinical Staging (Ann Arbor Classification)
*Involves physical examination, radiologic imaging of the abdomen, pelvis, and chest and
biopsy of the bone marrow.
*Important for prognosis and to guide therapy.
Stage I – Involvement of a single lymph node region or a single extralymphatic organ or site.
Stage II – Involvement of two or more lymph node regions on the same side of the
diaphragm alone or localized involvement of an extralymphatic organ or site.
Stage III – Involvement of lymph node regions on both sides of the diaphragm without or
with localized involvement of an extralymphatic organ or site.
Stage IV – Diffuse involvement of one or more extralymphatic organs or sites with or
without lymphatic involvement.
All stages are further divided on the basis of the absence (A) or presence (B) of systemic
manifestations (fever, night sweats and/or weight loss).
Inv.: FNAC and biopsy of involved tissues.
Burkitt Lymphoma
“Very aggressive tumor of mature B cells that usually arises at extranodal sides.”
Cell of origin: Germinal center B-cell.
Types: 1) African (endemic) Burkitt lymphoma.
2) Sporadic (nonendemic) Burkitt lymphoma.
3) HIV-associated Burkitt lymphoma.
Age: Endemic and sporadic: Children or young adults.
Risk factor: EBV infection (Endemic >HIV-associated>Sporadic).
Genetic alterations: Increased MYC protein levels with translocations of the MYC protooncogene on chromosome 8 (MC: t(8;14)), promote growth and division of cells.
Morphology: 1) Affected sites are effaced by a diffuse infiltrate of intermediate sized
lymphoid cells with round to oval nuclei, coarse chromatin, several nucleoli and a moderate
amount of cytoplasm.
2) High mitotic index and numerous apoptotic cells.
3) Interspersed phagocytes with abundant clear cytoplasm give ‘starry sky’ pattern.
C/P: 1) Endemic type: Mass involving the mandible and of abdominal viscera (kidneys,
ovaries and adrenal glands).
2) Sporadic type: Mass involving ileocecum or peritoneum.
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10. Red Blood Cell Disorders
MCQs
1) Bite cells are seen in. (May, 2022)
a) G6PD deficiency b) Sickle cell anemia c) Hereditary spherocytosis d) Thalassemia
2) Increase in MCHC is associated with. (May, 2022)
a) Iron deficiency anemia
b) Megaloblastic anemia
c) Anemia of chronic disease d) Hereditary spherocytosis
3) Pure red cell aplasia is associated with. (May, 2022)
a) Thymoma b) Renal cell carcinoma c) Hepatocellular carcinoma d) Prostate carcinoma
4) Which of the following is associated with an intrinsic defect in the RBC membrane. (May,
2022)
a) Autoimmune hemolytic anemia
b) Hereditary spherocytosis
c) Microangiopathic hemolytic anemia d) Thermal injury causing anemia
5 Marks
1) Pathogenesis of megaloblastic anemia. (May, 2022)
10 Marks
1) A 55 year old lady presented with progressive fatigue and tiredness for last one month. She
also complained of tingling and numbness in the lower limbs. On examination, she had pallor
and her tongue had a glossy appearance. (Feb. 2019)
a) What is your diagnosis?
b) What is the cause for neurological symptoms in this condition?
c) What are the peripheral smear and bone marrow findings in this condition?
d) Which specific tests would you like to do to diagnose this condition?
Ans: Megaloblastic anemia (Vitamin B12 deficiency).
2) One year old child is admitted with increasing pallor since the age of 2 months. On
examination, there is pallor and hepatosplenomegaly, Hb – 7.2 gm%; TLC and DLC are
within normal limits. Platelets are normal. (Jan. 2016)
a) What is the probable diagnosis?
b) How do you classify the disease group?
c) What is the blood picture in this disease?
d) Give the clinical picture of the disease.
Ans: Thalassemia (β-Thalassemia major).
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3) A 48-year-old male presented with pallor and easy fatigability. He complains of a sore
tongue and tingling in hands and feet. His hemoglobin level was 9 gms/dL. He gives history
of undergoing partial gastrectomy 3 years ago for gastric ulcer. (July, 2015)
a) What is your diagnosis?
b) Describe the pathogenesis of this disease.
c) Describe the peripheral blood picture and bone marrow appearance in this patient.
Ans: Megaloblastic anemia (Vitamin B12 deficiency).
4) A 3-year-old child presented with pallor, growth retardation and history of repeated blood
transfusions. The child is having splenomegaly and mild jaundice. Skull X-ray showing “hair
on end (crew cut) appearance”. (July, 2012)
a) What is the most probable diagnosis?
b) Describe various laboratory investigations to establish the diagnosis.
c) Discuss pathogenesis of the disorder.
Ans: Thalassemia (β-Thalassemia major).
5) 35 year old female presented with fatigue, weakness, glossitis and peripheral neuropathy.
(July, 2011)
a) What is the provisional diagnosis?
b) What special investigations we do in this case to confirm the diagnosis?
c) Describe the blood and bone marrow picture.
Ans: Megaloblastic anemia (Vitamin B12 deficiency).
6) A 30-year-old pregnant lady who cherishes to eat food prepared by boiling, steaming and
frying presented with anemia, glossitis, mild icterus, history of diarrhea, loss of appetite and
lack of wellbeing. No evidence of nervous system manifestations. Her serum homocysteine
(HCYS) levels are elevated but not methyl malonic acid (MMA) Levels. (March, 2010)
a) What is the provisional diagnosis?
b) Describe the peripheral blood and bone marrow picture.
c) Discuss the special tests in diagnosis.
Ans: Megaloblastic anemia (Folic acid deficiency).
7) 35-year-old female presented with anemia, glossitis and neurological manifestations.
(April, 2009)
a) What is your provisional diagnosis?
b) What are the laboratory investigations you do in this case?
c) How do you confirm the diagnosis?
Ans: Megaloblastic anemia (Vitamin B12 deficiency).
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8) 40-year-old male presented with weakness, fatigue and dyspnoea, having spoon shaped
nails complaints of recurrent bleeding piles. Hb is 2.5 gm/dl. (Oct. 2008)
a) What is the provisional diagnosis?
b) What blood investigations should be done to confirm the diagnosis?
c) What is the test to be done on the bone marrow smear?
Ans: Iron deficiency anemia.
9) A 30-year-old female presented with anemia, loss of sensation and tingling in the feet.
Examination showed smooth tongue with atrophic papillae. (Oct. 2005)
a) What is the probable diagnosis?
b) What is the deficiency in this condition?
c) Describe the peripheral blood picture and bone marrow picture.
Ans: Megaloblastic anemia (Vitamin B12 deficiency).
10) A 3 years old girl from west Bengal presented with pallor, growth retardation and history
of repeated blood transfusions. There was malocclusion of jaws with skull X ray showing
“hair on end appearance”. There was hepatosplenomegaly. Hemoglobin was 3.5 gm/dl. (Oct.
2004)
1) What is the most probable diagnosis?
2) Describe the laboratory diagnosis of the condition.
3) Describe the pathogenesis of the condition.
Ans: Thalassemia (β-Thalassemia major).
11) 25 years old female with the H/O 4 months amenorrhea (4 M.A) complaining of mild
jaundice, anemia and glossitis. Discuss the causes and investigation to come to a diagnosis.
(March/April, 2003)
Ans: Megaloblastic anemia (Folic acid deficiency).
4 Marks
1) Blood picture in megaloblastic anemia. (March, 2021)
2) Tabulate the differences between iron deficiency anemia and thalassemia major. (Feb.
2020)
3) Classifications of anemias and lab diagnosis of megaloblastic anemia. (July, 2019)
4) Blood and bone marrow picture in iron deficiency anemia. (July, 2018)
5) Laboratory investigations in a case of hereditary spherocytosis. (Feb. 2018)
6) Blood and bone marrow picture in folic acid deficiency anemia. (Feb. 2017)
7) Investigations in a case of hereditary spherocytosis. (Feb. 2017)
8) Bone marrow picture of megaloblastic anemia. (July, 2016)
9) Laboratory diagnosis of iron deficiency anemia. (Jan. 2015)
10) Classification of hemolytic anemia and lab diagnosis of beta thalassemia major.
(July/Aug. 2014)
11) Packed cell volume (PCV). (July, 2013)
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12) Blood and bone marrow findings in aplastic anemia. (Jan. 2013)
13) Peripheral smear and bone marrow picture in megaloblastic anemia. (Jan. 2011)
14) Hematocrit. (Jan. 2011)
15) E.S.R (Aug. 2010)
16) Pathogenesis of sickle cell disease. (March/April, 2008)
17) Lab diagnosis of iron deficiency anemia. (Sep/Oct. 2007)
18) Aplastic anemia. (May, 2006)
19) ESR (April/May, 2004)
20) Packed Cell Volume. (Sep. 2003)
2 Marks
1) List four peripheral smear findings in megaloblastic anemia. (Oct. 2022)
2) Enumerate four laboratory tests in a case of sickle cell anemia. (May, 2022)
3) Write any four laboratory investigations for megaloblastic anemia. (Aug. 2021)
4) Principle of osmotic fragility test. (Feb. 2019)
5) Give four diagnostic tests for sickle cell anemia. (July, 2018)
6) Mention four hemoglobinopathies seen in India. (July, 2017)
7) Classify hemolytic anemias. (July, 2017)
8) What is the blood picture in vit. B12 deficiency anemia? (Jan. 2016)
9) Name four inherited hemolytic anemias. (July, 2015)
10) Laboratory diagnosis of iron deficiency anemia. (Jan. 2015)
11) Name two (2) special stains for reticulocytes and two (2) causes of reticulocytosis.
(Jan. 2014)
12) Sickling test. (Aug. 2009)
13) ESR (April, 2009)
14) Reticulocyte. (Feb. 2009)
15) Megaloblast. (May, 2007)
16) ESR (March/April, 2003)
High-Yield Topics
Anemia – Classification
ESR
Iron deficiency anemia.
Aplastic anemia
Hereditary spherocytosis.
PCV
Reticulocyte count
Megaloblastic anemia
Thalassemia
Sickle cell anemia
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Packed Cell Volume (PCV) or Hematocrit
“PCV is the volume occupied by the red cells when a sample of anticoagulated blood is
centrifuged.”
Uses: 1) Detection of presence or absence of anemia or polycythemia.
2) Estimation of red cell indices.
Methods of estimation: Macro method (Wintrobe method); Micro method.
Causes of low PCV: Anemia; Fluid overload.
Causes of raised PCV: Polycythemia; Dehydration.
Reference ranges: Adult males: 40–50%; Adult females: 38–45%
Erythrocyte Sedimentation Rate (ESR)
“ESR measures the rate of settling of erythrocytes in anticoagulated whole blood.”
Methods of estimation: Westergren method; Wintrobe method.
Factors increasing ESR: Anemia; Elevated fibrinogen; Macrocytosis.
Factors decreasing ESR: Polycythemia; Low fibrinogen; Microcytosis.
Causes of raised ESR: Infections (TB, bacterial endocarditis, osteomyelitis); Inflammatory
diseases (rheumatoid arthritis, temporal arteritis); Acute myocardial infarction; Malignancy.
Causes of low ESR: Congestive cardiac failure; Sickle cell anemia; Hereditary
spherocytosis; Dehydration.
Reference ranges: Males <50yrs: 0–15 mm in 1 hr; Females <50yrs: 0–20 mm in 1 hr.
Reticulocyte Count
“Reticulocytes are young red cells containing remnants of RNA and ribosomes but no
nucleus.”
Site of production: Bone marrow.
Time required for maturation: 4 to 4.5 days.
Stains used: New methylene blue; Brilliant cresyl blue.
Reticulocyte %: Number of reticulocytes counted X100
Number of red cells counted
Reference range: Adults & children: 0.5% - 2.5%
Causes of increased reticulocyte count (Reticulocytosis): Blood loss; Hemolytic anemias;
Hemoglobinopathies (sickle cell anemia).
Causes of decreased reticulocyte count (Reticulocytopenia): Megaloblastic anemia;
Aplastic anemia; Anemia of chronic disease; Thalassemia.
Anemia – Classification
I) Morphological classification
1) Normocytic normochromic anemia e.g., Acute blood loss.
2) Microcytic hypochromic anemia e.g., Iron deficiency anemia; Thalassemia.
3) Macrocytic anemia e.g., Vit.B12 or folic acid deficiency.
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II) Etiological classification
1) Blood loss:
i) Acute blood loss e.g., Trauma.
ii) Chronic blood loss e.g., Peptic ulcer; Menstruation.
2) Hemolysis
i) Hereditary: Hereditary spherocytosis; G6PD deficiency; Pyruvate kinase deficiency;
Hemoglobinopathies (Thalassemia; Structural Hb variants (HbS, HbC, HbD, & HbE)).
ii) Acquired: Autoimmune hemolytic anemia; Paroxysmal nocturnal hemoglobinuria;
Hypersplenism; Hemolytic transfusion reactions.
3) Decreased red cell production: Nutritional deficiencies (Iron deficiency anemia; Vit.B12 or
folic acid deficiency); Inherited defects (Fanconi anemia; Thalassemia); Aplastic anemia;
Renal failure; Anemia of chronic disease.
**Hemoglobinopathies in India: Thalassemia; Structural Hb variants (HbS, HbD, & HbE).
Hereditary Spherocytosis
“Hereditary hemolytic anemia with intrinsic defects in the RBC membrane skeleton.”
Mode of inheritance: Autosomal dominant (MC).
Pathogenesis:
1) Mutations most commonly affect ankyrin, band 3 or spectrin, leading to their deficiency.
2) Destabilized lipid layer with loss of membrane fragments, causes spherocytes formation.
3) Less deformable spherocytes get trapped in splenic cords and undergo lysis.
C/P: Chronic hemolytic anemia with splenomegaly, jaundice or gall stones.
Inv.: 1) CBC: Low Hb; Raised MCHC; Raised reticulocyte count.
2) Peripheral smear: RBC: Spherocytes (small, dark staining red cells lacking the central
zone of pallor) are noted.
3) Bone marrow: Hypercellular with erythroid hyperplasia.
4) Osmotic fragility (OF) test: Increased osmotic fragility.
Principle: Red cells are suspended in decreasing concentrations of hypotonic saline solutions
to determine the ability of the red cells to withstand osmotic stress.
5) Autohemolysis test: Increased autohemolysis.
6) Eosin-5-maleimide (EMA) test by flow cytometry: Highly sensitive and specific.
Comp.: 1) Aplastic crisis with parvovirus B19 infection.
2) Hemolytic crisis with infectious mononucleosis infection.
Sickle Cell Disease
“A hereditary hemoglobinopathy.”
Mode of inheritance: Autosomal recessive.
Genotype: Homozygous form.
Genetic alterations: Substitution of valine for glutamic acid at the 6th position of the βglobin chain forms sickle hemoglobin (HbS).
Predisposing factors: Decreased intracellular pH; Intracellular dehydration; Inflamed
vascular beds; Microvascular beds with slow transit times.
Pathogenesis: 1) Deoxygenation favors HbS formation.
2) HbS polymerizes into long, stiff chains that deform RBCs into sickle or holly-leaf shape.
3) Repeated cycles of deformation cause irreversible damage to membrane leading to nondeformable RBCs with permanent sickle shape.
4) Sickle cells undergo hemolysis causing anemia.
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C/P: 1) Chronic hemolytic anemia with gall stones.
2) Impairment of growth & development.
3) Vaso-occlusive crises (pain crises): Major cause of morbidity & mortality.
Severe pain in the affected regions (bones, lungs, liver, brain or penis) e.g., Acute chest
syndrome; Priapism; Strokes; Hand-foot syndrome.
4) Aplastic crises with parvovirus B19 infection, worsens anemia.
5) Sequestration crises with intact spleen may cause splenomegaly.
6) Splenomegaly is seen in early childhood but adults manifest autosplenectomy.
7) Increased risk of infections with Strep. pneumoniae & H. influenza.
Inv.: 1) CBC: Low Hb; Elevated reticulocyte count.
2) Peripheral smear: RBC: Sickle cells (narrow and elongated red cells with one or both ends
pointed), target cells, and Howell-Jolly bodies (small nuclear remnants) are noted.
3) Bone marrow: Hypercellular with erythroid hyperplasia.
4) Serum bilirubin: Increased.
5) Hb electrophoresis: Mostly HbS with no HbA.
6) Prenatal diagnosis by analysis of fetal DNA.
7) Sickle cell slide test: Positive.
Principle: When red cells containing HbS are deprived of oxygen, they become sickleshaped.
Reagent: 2% sodium metabisulphite is used as a reducing agent.
Positive test: Red cells become sickle-shaped or holly-leaf shaped
False negative test: With usage of outdated reagent or low concentration of HbS.
False positive test: With Excessive concentration of reagent or drying of the wet preparation.
8) Solubility test for HbS: Positive.
9) High performance liquid chromatography (HPLC): Method of choice for detection and
quantification of HbS.
Thalassemia
“Inherited disorders with mutations decreasing the synthesis of α or β globin chains.”
Classification:
1) β-Thalassemia: β-Thalassemia major; β-Thalassemia intermedia; β-Thalassemia minor.
2) α-Thalassemia: Silent carrier; α-Thalassemia trait; HbH disease; Hydrops fetalis.
β-Thalassemia
“Characterized by causative mutations that diminish the synthesis of β-globin chains.”
Genetic alterations: Mostly point mutations involve β-globin gene. Inherited mutations
cause either reduced synthesis (β+ mutations) or no synthesis (β0 mutations) of β-globin
chains.
Pathogenesis:
1) Hb A decreases leading to anemia.
2) Unpaired α-globins increase and form insoluble inclusions causing membrane damage.
This leads to ineffective erythropoiesis and extravascular hemolysis.
3) Anemia results in marrow hyperplasia and extramedullary hematopoiesis (spleen, liver,
and lymph nodes).
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Types
I) β-Thalassemia major (Cooley’s anemia): Severe form.
Major Hb: HbF
Genotype: Homozygous form with two β-thalassemia genes.
C/P: Severe transfusion-dependant anemia; Growth retardation and death;
Hepatosplenomegaly and lymphadenopathy; Enlargement and distortion of cheek bones.
Inv.: 1) CBC: Low Hb, MCV, MCH and MCHC; Elevated reticulocyte count.
2) Peripheral smear: RBC: Microcytic and hypochromic red cells, severe anisopoikilocytosis,
target cells, basophilic stippling, red cell fragments and nucleated red cells are noted.
3) Bone marrow: Hypercellular with erythroid hyperplasia.
4) Hb electrophoresis: Elevated HbF.
5) X-rays of skull: Enlarged and distorted involved bones with ‘crewcut’ appearance.
6) Prenatal diagnosis by analysis of fetal DNA.
Comp.: Cardiac disease with secondary hemochromatosis.
II) β-Thalassemia intermedia: Moderately severe form.
Genotype: Heterogeneous form.
C/P: Moderate anemia and hepatosplenomegaly.
III) β-Thalassemia minor or β-Thalassemia trait: Mild form.
Genotype: Heterozygous form with one β-thalassemia gene and one normal gene.
C/P: Asymptomatic with mild or absent anemia.
Megaloblastic Anemia
“Nutritional anemia with Vitamin B12 or folic acid deficiency.”
Etiology:
I) Vit. B12 deficiency: 1) Inadequate intake with vegetarianism or chronic alcoholism.
2) Malabsorption due to pernicious anemia or distal ileal resection.
3) Increased demand during pregnancy.
II) Folic acid deficiency: 1) Inadequate intake with chronic alcoholism.
2) Increased demand during pregnancy.
3) Impaired utilization with methotrexate.
4) Malabsorption due to anticonvulsant or OCP usage.
Pathogenesis: 1) Vit. B12 or folic acid deficiency causes inadequate DNA synthesis.
Defective nuclear maturation leads to ineffective hematopoiesis.
2) Vit. B12 deficiency also causes abnormal myelin degradation leading to neurologic
complications.
C/P: 1) Anemia, mild jaundice and glossitis.
2) Vit. B12 deficiency causes lower extremity spastic weakness, and paraplegia.
3) Folate deficiency is associated with increased risk of neural tube defects.
Inv.: 1) CBC:. Low Hb; Raised MCV; Normal MCHC; Low reticulocyte count;
Pancytopenia may be seen with low total WBC count and low platelet count.
2) Peripheral smear:
i) RBC: Macro-ovalocytes, marked anisopoikilocytosis, basophilic stippling, Howell-Jolly
bodies, and Cabot rings are noted.
ii) WBC: Leukopenia with hypersegmented neutrophils.
iii) Platelets: Thrombocytopenia.
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3) Bone marrow: i) Hypercellular with erythroid hyperplasia.
ii) Erythroid precursors show megaloblastic changes. Megaloblasts are large precursor cells
having large nuclei with open and sieve-like chromatin and relatively hemoglobinized
abundant cytoplasm.
iii) Giant metamyelocytes and band forms.
iv) Large megakaryocytes with bizarre, multilobate nuclei.
v) Most precursors undergo apoptosis.
4) Serum bilirubin: Increased.
5) Serum lactate dehydrogenase: Increased.
6) Serum antibodies to intrinsic factor: Present in pernicious anemia.
7) Vit. B12 deficiency: Low serum Vit. B12 levels; Elevated serum homocysteine and
methylmalonic acid (MMA) levels.
8) Folic acid deficiency: Low serum or RBC folate levels; Raised serum homocysteine levels.
Iron Deficiency Anemia
“Most common nutritional anemia due to iron deficiency.”
Etiology: 1) Inadequate intake in infants.
2) Malabsorption due to sprue or gastrectomy.
3) Increased demand during pregnancy.
4) Chronic blood loss due to peptic ulcer, colonic cancer or menstruation.
Pathogenesis: Depletion of iron stores results in inadequate synthesis of Hb causing anemia.
C/P: Fatigue, pallor; Alopecia, koilonychia; Pica; Plummer-Vinson syndrome.
Inv.: 1) CBC: Low Hb, PCV, MCV, MCH and MCHC; Increased RDW.
2) Peripheral smear: RBC: Microcytic and hypochromic red cells, poikilocytosis, and
elliptocytes are noted.
3) Bone marrow: i) Hypercellular with erythroid hyperplasia.
ii) Erythroid precursors show micronormoblastic changes. Micronormoblasts are small
precursor cells with reduced amount of cytoplasm that is vacuolated and has ragged cell
borders. Hemoglobinization of cytoplasm is defective.
iii) Lack of stainable iron from macrophages demonstrated with Perl’s stain.
4) Iron studies: Low serum iron and ferritin; Low transferrin saturation; Increased TIBC and
serum soluble transferrin receptor.
5) Free erythrocyte protoporphyrin: Increased.
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Iron Deficiency Anemia Vs β-Thalassemia Major
Feature
Iron deficiency anemia
Defect
Skeletal deformities
Hepatosplenomegaly
Serum iron
Serum ferritin
TIBC
Transferrin saturation.
Storage iron in marrow
Micronormoblasts in marrow
Free erythrocyte protoporphyrin
Hemoglobin electrophoresis
Non-hereditary
Absent
Absent
Low
Low
Increased
Low
Absent
Present
Increased
Normal
β-Thalassemia major
Hereditary
Present
Present
Increased
Increased
Decreased
Increased
Increased
Absent
Normal
Increased HbF
Aplastic Anemia
“A syndrome of chronic primary hematopoietic failure and attendant pancytopenia.”
Etiology: 1) Idiopathic (most common).
2) Chemical agents: Alkylating agents, benzene or chloramphenicol.
3) Physical agents: Viral infections (EBV, CMV or unknown hepatitis virus); Whole body
irradiation.
4) Inherited: Fanconi anemia.
Pathogenesis: 1) Following exposure to environmental insults, stem cells may become
antigenically altered and provoke a cellular immune response.
2) Activated Th1 cells produce IFN-g and TNF that suppress and kill hematopoietic
progenitors.
C/P: Weakness, pallor, dyspnea; Petechiae, ecchymosis; Fever. Splenomegaly is not seen.
Inv.: 1) CBC: Pancytopenia is seen. Low Hb; Low reticulocyte count; Low total WBC count;
Low platelet count.
2) Peripheral smear: RBC: Usually normocytic and normochromic. Sometimes mildly
macrocytic.
WBC: Leukopenia.
Platelets: Thrombocytopenia
3) Bone marrow: Hypocellular with only adipocytes, fibrous stroma and scattered
lymphocytes and plasma cells.
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11. Bleeding Disorders
MCQs
1) Extrinsic pathway of clotting factors is measured by. (May, 2022)
a) Prothrombin time b) Activated partial thromboplastin time
c) Bleeding time
d) Clotting time
2) Hemophilia is associated with. (May, 2022)
a) X chromosome b) Y chromosome c) Chromosome 3 d) Chromosome 16
5 Marks
1) Platelet function disorders. (May, 2022)
2) Explain briefly on disseminated intravascular coagulation. (Feb. 2022)
10 Marks
1) A 20 year old male presented with swelling of both knees and pain for the past one week.
He gives history of similar episodes earlier. He also gives history of excessive bleeding after
minor injuries. His maternal uncle has similar complaints and has been treated by repeated
blood transfusions following excessive bleeding episodes. (July, 2016)
a) What are the possible differential diagnoses?
b) What are the laboratory investigations required for the diagnosis?
c) What is the etiopathogenesis of these disorders?
d) How will you make the final specific diagnosis?
Ans: Hemophilia A.
2) An young boy came with the history of massive hemorrhage after trauma, recurrent
hemarthrosis in large joints, muscle hematomas and progressive deformities leading to
crippling. Some of the family members also suffered with identical clinical manifestations.
(Aug. 2010)
a) What is the provisional diagnosis?
b) Discuss various laboratory investigations to confirm the diagnosis.
Ans: Hemophilia A.
3) A male child presented with recurrent painful hemarthrosis and hematomas. History of
bleeding in male relatives on the maternal side of the family was available. (March/April,
2008)
a) What is the probable diagnosis?
b) Describe the inheritance of the disease.
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c) Describe the lab. diagnosis of the disease.
d) Mention the complications following the therapy.
Ans: Hemophilia A.
4) A 13 year old boy came to the hospital with painful left elbow following mild trauma few
days ago. Past history of bleeding gums given. His elder brother also had similar problem.
(March/April, 2005)
a) What is the probable diagnosis?
b) What important investigations should be done?
c) What is the confirmatory test?
Ans: Hemophilia A.
5) 20 years old young man came with the history of massive hemorrhage after trauma,
recurrent hemarthrosis, progressive deformities leading to crippling with same type
manifestations in some of the family members. What is the probable diagnosis? Mention
various laboratory investigations with findings to make a final diagnosis. (Sep. 2003)
Ans: Hemophilia A.
4 Marks
1)
2)
3)
4)
Immune thrombocytopenia. (March, 2021)
Classify bleeding disorders. Give lab diagnosis of hemophilia A. (Feb. 2020)
Disseminated intravascular coagulation. (July, 2019)
Tabulate the differences between hemophilia A & von Willebrand disease. (July,
2017)
5) Von Willebrand disease. (Jan. 2015)
6) von Willebrand disease. (Jan. 2012)
7) Immune thrombocytopenia. (May, 2007)
2 Marks
1) Give two tests to diagnose von Willebrand disease. (Feb. 2020)
2) Give two tests to diagnose von Willebrand disease. (July, 2018)
3) Laboratory investigations in a case of idiopathic thrombocytopenic purpura (ITP).
(Feb. 2018)
4) Enumerate four causes of disseminated intravascular coagulation (DIC). (Jan. 2016)
5) Prothrombin time. (Sep/Oct. 2007)
6) Bleeding time. (Oct. 2005)
High-Yield Topics
Chronic immune thrombocytopenic purpura
Hemophilia A
Von Willebrand disease
DIC
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99
Prothrombin Time (PT)
Indication: To assess the extrinsic and common coagulation pathways.
Principle: The clotting of plasma after addition of an exogenous source of tissue
thromboplastin and calcium ions is measured.
Causes of prolongation: Liver disease; Vit. K deficiency; Treatment with oral
anticoagulants; DIC.
Reference range: 11-16 sec.
Bleeding Time (BT)
Indication: To assess primary hemostasis.
Principle: A superficial skin incision is made and the time required for bleeding to stop is
measured.
Methods: Ivy’s, Duke’s and template.
Causes of prolongation: Thrombocytopenia; Disorders of platelet function; von Willebrand
disease; Disorders of blood vessels.
Reference range (Ivy’s method): 2-7 min.
Bleeding Disorders: Classification
I) Disorders of blood vessels
Hereditary: Hereditary hemorrhagic telangiectasia; Ehlers-Danlos syndrome.
Acquired: Infections; Scurvy; Senile purpura.
II) Disorders of platelets
A) Defective function
Hereditary: Bernard-Soulier syndrome; Glanzmann thrombasthenia.
Acquired: Drugs (aspirin); Uremia.
B) Thrombocytopenia
i) Decreased production of platelets: Aplastic anemia; Leukemias; Drugs (thiazides);
Megaloblastic anemia; Myelodysplastic syndromes.
ii) Decreased platelet survival:
a) Immunologic destruction (immune thrombocytopenia): ITP; SLE; CLL; Drugs (heparin,
quinidine); Infections (infectious mononucleosis, HIV)
b) Nonimmunologic destruction: TTP; DIC; microangiopathic hemolytic anemia
iii) Sequestration: Hypersplenism.
iv) Dilution: Multiple transfusions.
III) Disorders of coagulation
Hereditary: Hemophilia A; Hemophilia B; von Willebrand disease.
Acquired: DIC; Liver disease; Vitamin K deficiency.
Immune Thrombocytopenic Purpura (ITP)
Subtypes: 1) Acute ITP 2) Chronic ITP
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Chronic Immune Thrombocytopenic Purpura
“Autoantibody mediated destruction of platelets causing thrombocytopenia.”
Age: <40yrs.
Sex: F>M
Types: Primary or secondary.
Etiology: 1) Primary or idiopathic: No known risk factors.
2) Secondary: Seen with SLE, HIV or CLL.
Pathogenesis: Autoantibodies (IgG) are produced against platelet membrane glycoproteins
IIb-IIIa or Ib-IX. Autoantibody coated platelets are phagocytosed and destroyed in spleen.
C/P: Petechiae, ecchymoses; Easy bruising, nosebleeds, and gingival bleeding; Melena,
hematuria or excessive menstrual flow.
Inv.: 1) CBC: Platelets: Decreased.
2) Peripheral smear: Thrombocytopenia with large platelets (megathrombocytes).
3) Bone marrow: Normal or increased megakaryocytes.
4) PT & PTT: Normal
5) Tests for platelet autoantibodies.
Comp.: Subarachnoid hemorrhage and intracerebral hemorrhage.
Platelet function disorders
I) Inherited
1) Defects of adhesion: Bernard-Soulier syndrome.
2) Defects of aggregation: Glanzmann thrombasthenia.
3) Disorders of platelet secretion (release reaction): Storage pool disorders.
II) Acquired: Drugs (aspirin); Uremia.
Bernard-Soulier syndrome
Defect: Autosomal recessive disorder with inherited deficiency of the glycoprotein complex
Ib–IX resulting in defective adhesion of platelets to subendothelial matrix.
C/P: Severe bleeding tendency with purpurpic spots, easy or spontaneous bruising, and
mucosal bleeding.
Inv.: i) Peripheral smear: Giant platelets; mild to moderate thrombocytopenia.
ii) Abnormal platelet function studies: Prolonged bleeding time; impaired platelet
aggregation with ristocetin not corrected by addition of normal plasma.
iii) Flow cytometry: Lack of gpIb–IX complex.
Glanzmann thrombasthenia
Defect: Autosomal recessive disorder with inherited deficiency or dysfunction of
glycoprotein IIb–IIIa leading to defective platelet aggregation.
C/P: Severe bleeding tendency with purpurpic spots, easy or spontaneous bruising, and
mucosal bleeding.
Inv.: i) Peripheral smear: Small and discrete platelets; normal platelet count.
ii) Abnormal platelet function studies: Prolonged bleeding time, poor clot retraction, platelet
aggregation is absent with ADP, epinephrine and collagen and normal with ristocetin.
iii) Flow cytometry: Lack of gpIIb-IIIa complex.
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Von Willebrand Disease
*MC inherited bleeding disorder.
Inheritance: Autosomal dominant (MC).
Types: Three types.
Type 1 (MC) and type 3: Quantitative defects in vWF.
Type 2: Qualitative defects in vWF.
Type 1: Autosomal dominant (AD); Mild to moderate vWF deficiency; Mild disease.
Type 3: Autosomal recessive (AR); Severe deficiency of vWF; Severe disease.
Type 2: Autosomal dominant (AD); Normal levels of vWF; Mild to moderate disease.
C/P: Spontaneous bleeding from mucous membranes (e.g., epistaxis); Excessive bleeding
from wounds or menorrhagia.
Inv.: 1) Platelet count: Normal.
2) vWF ristocetin cofactor activity: Reduced.
3) Factor VIII activity: Low in types 1 and 3.
4) PTT: Prolonged in types 1 and 3.
5) Bleeding time: Prolonged in types 2 and 3.
Hemophilia A (Factor VIII Deficiency)
*Most common hereditary disease associated with life-threatening bleeding.
Inheritance: X-linked recessive (XR).
Sex: Primarily males.
Cause: Sporadic or germ line mutations cause deficiency or dysfunction of factor VIII.
Genetic alterations:
Severe hemophilia: Inversions, deletions, insertions and missense mutations.
Moderate/mild hemophilia: Missense mutations and single nucleotide deletions.
Classification and C/P:
Type
FVIII:C Clinical picture
Mild
>5%
Excess bleeding only after major trauma or surgery
Moderate 1 to 5%
Excess bleeding after mild to moderate trauma; Occasional
hemarthrosis; Spontaneous bleeding infrequent
Severe
<1%
Frequent and spontaneous deep tissue hematomas and hemarthroses
Inv.: 1) PTT: Prolonged.
2) PT, bleeding time and platelet count: Normal.
3) Factor VIII activity: Low.
Differential Diagnosis: Hemophilia B; Von Willebrand disease.
Comp.: Joint deformities.
Therapy related comp.: Development of antibodies against factor VIII following infusions
of recombinant factor VIII.
Hemophilia B (Christmas Disease)
Inheritance: X-linked recessive (XR).
Genetic alterations: Mutations involve the gene that encodes factor IX.
C/P: 1) Easy bruising and massive hemorrhage after trauma or operative procedures.
2) Spontaneous bleeding into joints (hemarthrosis).
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Inv.: 1) PTT: Prolonged.
2) PT, bleeding time, and platelet count: Normal.
3) Factor IX activity: Low.
Hemophilia A Vs Von Willebrand Disease
Feature
Hemophilia A
vWD
Incidence
Inheritance
Sex affected
Defect lies in
Mucocutaneous bleeding
Hemarthrosis
PTT
Bleeding time
Factor VIII levels
Rare
XR
Primarily male
Factor VIII
Rare
Common
Increased
Normal
Reduced
Common
AD or AR
Male or Female
vWF
Present
Rare
Normal or Increased
Increased
Normal or reduced
Disseminated Intravascular Coagulation (DIC)
“An acute, subacute or chronic thrombohemorrhagic disorder.”
Etiology: 1) Obstetric complications: Amniotic fluid embolism; Dead retained fetus.
2) Cancers: Adenocarcinomas of the lung and pancreas; Acute promyelocytic leukemia.
3) Sepsis: Meningococcemia.
4) Tissue injury: Major trauma; Severe burns.
Pathogenesis: 1) Release of procoagulants (tissue factor) into the circulation and widespread
endothelial injury cause pathologic activation of coagulation.
2) Wide spread microvascular thrombosis leads to ischemic tissue damage and
microangiopathic hemolytic anemia.
3) Consumption of platelets and clotting factors and the activation of plasminogen lead to a
hemorrhagic diathesis.
C/P: 1) Microangiopathic hemolytic anemia, dyspnea, cyanosis, and respiratory failure.
2) Convulsions and coma.
3) Oliguria, acute renal failure and shock.
Inv.: 1) Platelet count: Low.
2) PT and PTT: Prolonged.
3) Fibrinogen levels: Reduced.
4) Fibrin degradation products: Elevated.
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Miscellaneous
Cytology
MCQs
1) PAP smear is for screening of. (May, 2022)
a) Endometrial carcinoma b) Vulvar carcinoma c) Cervical carcinoma d) Rectal carcinoma
5 Marks
1) PAP smear and its role in cervical cancer screening. (May, 2020)
4 Marks
1)
2)
3)
4)
Indications for FNAC and its pitfalls. (Jan. 2016)
Exfoliative cytology. (Aug. 2010)
Indications for FNAC and its pitfalls. (Feb. 2009)
Exfoliative cytology. (Oct. 2008)
2 Marks
1) Significance of exfoliative cytology. (July, 2012)
2) Exfoliative cytology. (Oct. 2005)
Transfusion Medicine
2 Marks
1) Enumerate four transfusion reactions. (Feb. 2017)
2) Name 4 blood components separated from whole blood and mention one clinical use
for each. (Jan. 2013)
3) Blood transfusion reactions. (July, 2011)
4) Mode of action of anticoagulants. (Jan. 2011)
Others
4 Marks
1)
2)
3)
4)
Complications of myocardial infarction. (Nov. 2020)
Pleomorphic adenoma. (April, 2009)
Basal cell carcinoma. (May, 2006)
Pleomorphic adenoma. (Oct. 2005)
Undergraduate Pathology Series
2 Marks
1)
2)
3)
4)
Mention four complications of bacterial endocarditis. (Feb. 2020)
Name the tests for detection of proteins in urine. (July, 2012)
Frozen section. (Jan. 2012)
Specific gravity of urine. (Aug. 2010)
104
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105
PAPER II
SYSTEMIC PATHOLOGY
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Undergraduate Pathology Series
12. Blood Vessels
4 Marks
1) Describe the pathogenesis of atherosclerosis. (May, 2022)
2) Atherosclerosis. (Nov. 2020)
3) What are the sequelae of an atheroma. (July, 2018)
4) Morphology and complications of atherosclerosis. (Feb. 2017)
5) Atherosclerotic aneurysm. (July, 2015)
6) Pathology of Aortic dissection. (Jan. 2011)
7) Definition and types of Aneurysm. (Oct. 2008)
8) Syphilitic Aneurysm. (May, 2006)
9) Pathogenesis of Atherosclerosis. (March/April, 2005)
10) Pathogenesis of essential hypertension. (Oct. 2004)
11) Aneurysm. (March/April, 2003)
2 Marks
1)
2)
3)
4)
5)
6)
7)
What is the pathogenesis of dissecting aneurysm. (Aug. 2021)
Risk factors of atherosclerosis and its complications. (July, 2019)
What is the pathogenesis of dissecting aneurysms. (Feb. 2018)
Pathogenesis of dissecting aneurysms. (July, 2017)
Types of aneurysms. (July, 2013)
Complications of atherosclerosis. (Aug. 2009)
Types of aneurysms. (Oct. 2006)
High-Yield Topics
Hypertension
Aneurysms
Atherosclerosis
Aortic dissection
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Hypertensive Vascular Disease
Hypertension: “A resting systolic pressure of 130 mm Hg or greater or a diastolic pressure
of 80 mm Hg or greater.”
Types: Essential and secondary.
I) Essential or primary: Most common.
Etiology: Idiopathic.
Pathogenesis:
1) Genetic factors: Play an important role.
2) Insufficient renal sodium excretion: May lead sequentially to an increase in fluid volume,
increased cardiac output, and peripheral vasoconstriction.
3) Environmental factors: Stress, obesity, smoking, physical inactivity, and heavy salt
consumption are involved.
4) Vasoconstrictive influences: Factors that induce vasoconstriction or stimuli that cause
structural changes in the vessel wall, can lead to an increase in peripheral resistance.
II) Secondary: Rare.
Etiology: Known underlying cause.
1) Renal: Renal artery stenosis; Chronic renal disease.
2) Endocrine: Pheochromocytoma; Cushing syndrome; Conn syndrome.
3) Cardiovascular: Coarctation of aorta; Polyarteritis nodosa.
Morphology: 1) Hyaline arteriolosclerosis: Seen with benign hypertension.
Homogenous, pink, hyaline thickening of arteriolar walls with luminal narrowing.
2) Hyperplastic arteriolosclerosis: Seen with severe hypertension.
Concentric, laminated (onion-skin) thickening of arteriolar walls with luminal narrowing.
C/P: Asymptomatic (MC).
Comp.: Aortic dissection; Atherosclerosis; Stroke; Hypertensive heart disease; Renal failure.
Atherosclerosis
“A form of arteriosclerosis, characterized by intimal lesions such as atheromatous plaques.”
Vessels involved: Large elastic arteries (e.g., aorta, carotid, and iliac arteries) and large- and
medium-sized muscular arteries (e.g., coronary and popliteal arteries).
Major risk factors:
I) Modifiable: Cigarette smoking; Diabetes mellitus; Hypertension; Hyperlipidemia.
II) Non-modifiable (Constitutional): Male gender; Advanced age; Family history (e.g.,
familial hypercholesterolemia).
Others: Inflammation; Hyperhomocystinemia; Metabolic syndrome; Lipoprotein a.
Pathogenesis
1) Endothelial injury and dysfunction causes increased vascular permeability, leukocyte
adhesion, and thrombosis.
2) Lipoproteins, mainly LDL and its oxidized forms accumulate in the vessel wall.
3) Monocytes adhere to the endothelium, followed by migration into the intima and
transformation into macrophages and foam cells.
4) Platelets adhere to the subendothelial matrix.
5) Factor release from activated platelets, macrophages, and vascular wall cells, induces
smooth muscle cell recruitment, either from the media or from circulating precursors.
6) Smooth muscle cells proliferate with production of ECM, and recruitment of T cells.
7) Lipid accumulates both extracellularly and within macrophages & smooth muscle cells.
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Morphology
I) Fatty streak: Earliest stage.
Gross: Flat, yellow intimal elongated streaks.
Micro.: Composed of lipid laden macrophages (foam cells).
II) Atheroma or atheromatous plaque or fibrofatty plaque:
Gross: White or whitish-yellow, eccentric raised lesion.
Micro.:
1) Fibrous cap: Composed of smooth muscle cells, inflammatory cells and dense collagen.
2) Necrotic centre: Composed of dead cells, foam cells, lipid, and plasma proteins.
Fate of atheroma: Calcification; Rupture, ulceration or erosion of the surface; Intra plaque
hemorrhage.
Comp.: Myocardial infarction; Stroke; Atheroembolism; Aortic aneurysm; Mesenteric
occlusion and bowel ischemia; Ischemic encephalopathy; Peripheral vascular disease.
Aneurysms
“Localized abnormal dilation of a blood vessel or the heart.”
True aneurysm: Involves all the layers of an intact arterial wall or the thinned ventricular
wall of the heart. e.g., Atherosclerotic aneurysms and ventricular aneurysms following
myocardial infractions.
False aneurysm (pseudoaneurysm): A defect in the vascular wall leading to an
extravascular hematoma that freely communicates with the intravascular space.
e.g., Ventricular rupture after myocardial infarction.
Classification: 1) Saccular aneurysms: Spherical outpouchings involving only a portion of
the vessel wall. They vary in diameter and often contain thrombus.
2) Fusiform aneurysms: Diffuse, circumferential dilations of a long vascular segment. They
vary in diameter and length.
Etiology: 1) Congenital: Fibromuscular dysplasia; Berry aneurysms.
2) Acquired: Atherosclerosis; Hypertension; Trauma; Smoking; Advanced age; Vasculitis;
Infections (mycotic aneurysms).
Pathogenesis: Sporadic (MC) or hereditary.
1) Poor intrinsic quality of the vascular wall connective tissue. e.g., Vascular form of EhlersDanlos syndrome.
2) Abnormal transforming growth factor-β (TGF-β) signaling. e.g., Marfan syndrome.
3) Altered balance of collagen degradation and synthesis by inflammation and associated
proteases. e.g., Atherosclerosis.
4) Loss of smooth muscle cells or the inappropriate synthesis of noncollagenous or nonelastic
extracellular matrix. e.g., Tertiary syphilis.
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Abdominal Aortic Aneurysm (AAA)
“Saccular or fusiform true aneurysms.”
Age: >50 yrs.
Sex: M>F
Location: Between the renal arteries and the bifurcation of the aorta.
Predisposing factors: Smoking (MC).
Causes: Atherosclerosis (MC).
Pathogenesis:
1) Increased MMP production by macrophages in atherosclerosis causes degradation of
extracellular matrix (ECM) in all layers of the wall.
2) Atherosclerotic thickening of the intima causes ischemia of the inner media that leads to
smooth muscle cell loss, elastic fiber loss, and inadequate or inappropriate ECM synthesis.
Morphology: 1) Severe atherosclerosis with destruction and thinning of underlying media.
2) Bland, laminated, and poorly organized mural thrombus in the aneurysmal sac.
C/P: Asymptomatic (MC); May present as an abdominal mass.
Comp.: Rupture with hemorrhage; Embolism; Impingement on adjacent structures.
Aortic Dissection
“Blood separates the laminar planes of the media to form a blood-filled channel within
the aortic wall.”
Age groups & Etiology
1) Men aged 40 to 60 yrs, with antecedent hypertension (MC).
2) Younger adults with connective tissue disorders e.g., Marfan syndrome.
Pathogenesis:
1) Hypertension (major risk factor): Aortas have medial degenerative changes with smooth
muscle cell loss and altered extracellular matrix content.
2) Inherited or acquired connective tissue disorders: Defective TGF-β signaling or defective
extracellular matrix synthesis or degradation.
3) With intimal tear, blood flow under systemic pressure dissects through the media leading
to progression of the hematoma.
Morphology: 1) Medial degeneration is present at the site of tear in most cases.
2) Intimal tear is transverse with sharp, jagged edges up to 1 to 5 cm in length.
3) The dissecting hematoma spreads characteristically between lamellar units of the outer
third of the media or between media and adventitial layers.
Classification:
1) Type A dissections (MC): Proximal lesions involving the ascending aorta with the
descending aorta (DeBakey type I) or the ascending aorta only (DeBakey type II).
2) Type B dissections: Distal lesions usually beginning distal to the subclavian artery
without the involvement of the ascending aorta (DeBakey type III).
C/P: Sudden pain in the anterior chest, radiating to the back.
Comp.: Rupture; Cardiac tamponade; Aortic insufficiency.
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Syphilitic (Luetic) Aneurysm
“Cardiovascular syphilis may cause syphilitic aortitis, which may result in syphilitic
aneurysm.”
Age: >50yrs.
Sex: M>F
Sites: Ascending aorta and arch of aorta.
Predisposing conditions: Syphilitic aortitis.
Pathogenesis: Endarteritis obliterans causes ischemic injury to the media resulting in
scarring.
Morphology: Gross: 1) Mostly saccular in shape, varying in diameter with wrinkled intimal
surface, showing tree-bark appearance.
2) Aortic valve may show stretching and rolling of the valve-leaflets.
3) Left ventricular hypertrophy may cause cardiomegaly known as cor bovinum.
Micro.: The adventitia shows fibrous thickening with endarteritis obliterans of vasa vasorum.
The fibrous scar tissue may extend into the media and the intima. Mural thrombus may be
found within the aneurysm.
C/P: Rupture with hemorrhage; Compression on adjacent structures; Cardiac dysfunction
with aortic incompetence and cardiac failure.
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13. The Heart
MCQs
1) Libman-Sacks endocarditis is found in. (Feb. 2022)
a) Rheumatoid arthritis b) SLE c) Syphilis d) Lymphoma
2) Which protein is defective in dilated cardiomyopathy. (Feb. 2022)
a) Myosin b) Tropomyosin c) Dystrophin d) Troponin
3) Most common site for myeloma in heart is. (Feb. 2022)
a) Right atrium b) Left ventricle c) Right ventricle d) Left atrium
15 Marks
1) A eight year old boy was brought to clinic by his mother with complaints of shifting joint
pain and swelling involving knee joint, elbow joint etc. and fever since three days. On
enquiry it was found that the child had an attack of sore throat. Based on this information,
(Feb. 2022)
a) What is your probable diagnosis.
b) Enlist the organs which may get affected.
c) What is the pathogenesis of this disease.
d) Enlist the causes of death in this condition.
Ans: Rheumatic fever.
10 Marks
1) 58 years old male, known hypertensive presented in the hospital casualty with sudden
onset of precordial chest pain radiating to shoulders, sweating and breathlessness. There was
no relief with sublingual medication. On examination, pulse was irregular. ECG showed ST
segment elevation. Though treatment was initiated, he died in the hospital on the same day
due to complications. An autopsy was done. Answer the following.
a) What is your diagnosis?
b) Describe the etiopathogenesis of the condition.
c) Write the gross and microscopy changes in heart in post mortem examination.
d) Write four complications associated with the condition.
Ans: Myocardial infarction.
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2) 70 year male presented with dyspnea and sweating of sudden onset. He is a known
hypertensive and diabetic for 15 years. On examination, he has weak pulse. (March, 2021)
a) What is the diagnosis?
b) Write about pathogenesis of the above disorder.
c) Write in detail about the morphological changes that occur.
d) Write its complications.
Ans: Myocardial infarction.
3) A 59-year old man is admitted with history of chest pain of half hour duration. Pain was in
the precordial area with radiation in the left arm. Pain was severe in nature and was
accompanied by vomiting. ECG showed ST segment elevation with T wave inversion. (July,
2017)
a) What is the most likely diagnosis?
b) What biochemical investigations are useful in such a case?
c) What complications can occur?
d) What are the predisposing factors of this disease?
Ans: Myocardial infarction.
4) A 68-year old man presented with left sided chest pain of one hour duration. Pain is
radiating to the left arm. ECG demonstrated ST segment elevation with T wave inversion.
(Jan. 2016)
a) What is the probable diagnosis?
b) Enumerate the tests you will carry out to diagnose.
c) What is the gross and microscopic picture of the lesion?
d) What are its complications?
Ans: Myocardial infarction.
5) 60 year old male presented with substernal pain radiating to the arms, sweating and
dyspnoea. (July, 2011)
a) What is the provisional diagnosis?
b) Discuss the evolution of pathologic changes in this condition?
c) What are the complications?
Ans: Myocardial infarction.
6) An adult male patient having coarctation of the aorta and periodontal infection with habit
of vigorous brushing of teeth came to the hospital with fever and anemia. On examination
there are crops of petechiae over the skin, subungual hemorrhages, small tender cutaneous
nodules, pain in the splenic region and retinal hemorrhages. Urine examination showed
hematuria. (March, 2010)
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a) What is probable diagnosis?
b) Describe etiopathogenesis and morphology of lesions in various organs involved.
c) Mention the complications.
Ans: Infective endocarditis.
7) 35 year old female with history of pharyngitis 1 month back, now presented with
migratory polyarthritis and carditis. (Feb. 2009)
a) What is the provisional diagnosis?
b) What is the pathogenesis & pathology of the lesion?
c) Discuss its sequelae.
Ans: Rheumatic fever.
8) 17 year old female complains of recurrent upper respiratory infection, fever, fatigue. Give
H/O recurrent joint pains and now has both knee swelling. (Oct. 2006)
a) What is the provisional diagnosis?
b) What investigations have to be done?
c) In which organ maximum lesions are seen and describe?
Ans: Rheumatic fever.
9) A 9 year old girl with history of recurrent fever, upper respiratory tract infection, arthritis,
involuntary purposeless movements of limbs was admitted with edema of feet and
breathlessness. (May, 2006)
a) What is the provisional diagnosis?
b) Describe the etiopathogenesis.
c) Describe the morphology of the lesions.
Ans: Rheumatic fever.
10) 10 years old female with the H/O recurrent fever, upper respiratory tract infection,
arthritis, and inter ECG abnormalities. Discuss about the causes and come to correct
diagnosis. (Oct/Nov. 2002)
Ans: Rheumatic fever.
4 Marks
1) Light microscopic changes in the evolution of acute myocardial infarction in the first
14 days. (Feb. 2019)
2) Morphology of myocardial infarction. (Feb. 2018)
3) Valvular lesions in rheumatic heart disease. (Jan. 2015)
4) Types and morphology of cardiac vegetations. (July/Aug. 2014)
5) Cardiac lesions in acute rheumatic fever (Acute RHD). (Jan. 2014)
6) Describe location and macroscopic appearance of vegetations in bacterial endocarditis
(BE). Mention extra cardiac complications of BE. (Jan. 2013)
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7) Aschoff nodules/bodies. (July, 2012)
8) Name the causes of left ventricular hypertrophy. (Jan. 2011)
9) Tetralogy of Fallot. (Aug. 2009)
10) Aschoff nodule. (April, 2009)
11) Bacterial endocarditis. (March/April, 2008)
12) Rheumatic heart disease. (Sep/Oct. 2007)
13) Aschoff bodies. (March/April, 2005)
14) Pathology of Aschoff body. (April/May, 2004)
15) Myocardial infarction. (Sep. 2003)
2 Marks
1)
2)
3)
4)
5)
6)
7)
8)
Morphology of myocardial infarction. (Aug. 2021)
Aschoff bodies. (Nov. 2020)
Mention four complications of bacterial endocarditis. (July, 2017)
Mention four complications of myocardial infarction. (Feb. 2017)
Mac Callum plaques. (Jan. 2012)
Enzyme study in acute myocardial infarction. (April, 2009)
Pancarditis. (Oct. 2008)
Enzyme changes in myocardial infarction. (May, 2007)
High-Yield Topics
Tetralogy of Fallot
Rheumatic heart disease
Myocardial infarction
Infective endocarditis
Cardiac vegetations
Cardiomyopathies
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Tetralogy of Fallot
“MC cyanotic congenital heart disease with right to left shunt.”
Features: 1) VSD 2) Overriding aorta 3) Right ventricular out flow tract obstruction 4) Right
ventricular hypertrophy (RVH).
Morphology: 1) Enlarged boot shaped heart with RVH.
2) Aortic valve at the superior border of large VSD.
3) Subpulmonic stenosis.
4) Hypoplastic pulmonary arteries.
5) Large overriding aorta.
C/P: Early cyanosis; Clubbing of digits; Polycythemia; Paradoxical embolism.
Myocardial Infarction (Heart Attack)
“Death of cardiac muscle with prolonged severe ischemia due to coronary artery occlusion.”
Risk factors: Advancing age; Atherosclerosis; Middle aged males; Post-menopausal women.
Pathogenesis:
1) Coronary artery atheromatous plaque undergoes an acute change with intraplaque
hemorrhage, ulceration or rupture.
2) Platelets on exposure to subendothelial collagen & necrotic plaque contents, mediate
formation of microthrombi.
3) Vasospasm is stimulated with mediators released from platelets.
3) Coagulation pathway is activated with the release of tissue factor.
4) Complete occlusion of vessel lumen results with the expanded thrombus.
Arterial trunks involved:
1) Left anterior descending coronary artery (MC).
2) Right coronary artery.
3) Left circumflex coronary artery.
Patterns of infarction:
1) Transmural infarction:
Necrosis involves a portion of the left ventricular wall in its full thickness.
2) Subendocardial (nontransmural) infarction:
Necrosis involves inner third of the ventricular wall.
3) Multifocal microinfarction: Many intramural small necrotic foci are seen.
Morphology:
I) Reversible injury (within ½ hr): No gross or microscopic changes.
II) Irreversible injury: Gross and microscopic changes begin after 4-12 hrs.
Time
12 – 24hrs
1-3 days
3-7 days
10-14 days
2-8 weeks
> 2 months
Gross
Dark mottling
Yellow-tan infarct
Yellow-tan infarct with hyperemic border
Red-gray infarct with depressed borders
Gray-white scar
Scarring complete
Microscopy
Coagulative necrosis
Neutrophil infiltration
Macrophage infiltration
Granulation tissue deposition
Prominent collagen deposition
Dense collagenous scar
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C/P: Prolonged chest pain ( >30 min), crushing or squeezing in nature; Rapid, weak pulse;
Diaphoresis; Nausea & vomiting; Dyspnea.
Inv.: I) Cardiac markers: Cardiac specific troponins (T & I), CK-MB (mass) & myoglobin.
1) Within 3 to 12 hrs, CK-MB, Troponin T & I are elevated.
2) CK-MB and Troponin I peak at 24 hrs.
3) CK-MB returns to normal in 48-72 hrs, troponin I in 5-10 days and troponin T in 5 to 14
days.
4) Myoglobin rises within 1-3 hrs, peaks at 6-9 hr and returns to normal in 24 hrs.
II) ECG: 1) ST elevation with transmural infarct.
2) No ST elevation with subendocardial infarct.
3) Nonspecific changes with microinfarctions.
Comp.: Cardiogenic shock; Arrhythmias; Myocardial rupture; Ventricular aneurysm;
Pericarditis; Cardiac failure.
Rheumatic Fever and Rheumatic Heart Disease
Rheumatic Fever
“An acute, immunologically mediated, multisystem inflammatory disease.”
Age: 5-15yrs (MC).
Organs affected: Heart, joints, brain, and skin.
Causative agent: Group A streptococcus.
Pathogenesis: 1) With streptococcal infection of the pharynx or skin, antibodies and CD4+ T
cells directed against streptococcal M proteins, cross-react with host cardiac proteins.
2) Antibody binding can activate compliment and recruit inflammatory cells.
3) Cytokines produced by the stimulated T cells cause macrophage activation.
Morphology:
1) Pancarditis: Pericarditis, myocarditis, and endocarditis.
2) Aschoff bodies: “Foci of T lymphocytes, occasional plasma cells and plump activated
macrophages (Anitschkow cells) found in any layer of the heart.”
Evolution: Involves 3 stages.
i) Early (exudative or degenerative) stage: It is apparent by about 4th wk. of illness.
Initially, there is edema of the connective tissue with increased ground substance. Later,
separated collagen fibers undergo fragmentation causing fibrinoid degeneration.
ii) Intermediate (proliferative or granulomatous) stage: It is apparent by 4th to 13th wk. of
illness. Infiltration with T lymphocytes, plasma cells and Anitschkow cells is seen.
Anitschkow cells: Macrophages with abundant cytoplasm and central round to ovoid nucleus
with chromatin condensed into a central, slender, wavy ribbon (caterpillar cells).
iii) Late (healing or fibrous) stage: It is apparent by 12 to 16 wk. after the illness. Lesions
become less cellular with an increase in collagenous tissue, forming a fibrocollagenous scar.
3) Fibrinoid necrosis within the cusps or tendinous cords.
4) Small warty vegetations (verrucae) overlie necrotic foci and along the lines of closure of
the valve leaflets.
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Rheumatic Heart Disease
“Characterized by deforming fibrotic valvular disease.”
Sites: Mitral valve (MC).
Predisposing conditions: Recurrent acute rheumatic carditis.
Morphology: Gross:
1) Mac Callum plaques: Irregular thickenings in left atrium induced by subendocardial
lesions.
2) Mitral valve: Shows leaflet thickening, commissural fusion and shortening, & thickening
and fusion of the corda tendinae.
3) Calcification and fibrous bridging across the valvular commissures in mitral stenosis
create “fish mouth” stenoses.
4) Left atrium shows progressive dilation with mural thrombus formation.
5) Right ventricular hypertrophy in late stages.
Micro.: Valves show post-inflammatory neovascularization and transmural fibrosis.
C/P: 1) Acute rheumatic Carditis: Pericardial friction rubs, tachycardia, and arrhythmias.
2) Chronic RHD: Murmurs; Cardiac hypertrophy & dilation; Heart failure & arrhythmias.
Jones criteria: I) Major: Migratory polyarthritis of the large joints; Pancarditis;
Subcutaneous nodules; Erythema marginatum of the skin; Sydenham chorea.
II) Minor: Fever; Arthralgia; Elevated acute phase reactants in blood.
Diagnosis: Evidence of a preceding Group A streptococcal infection, with two major or one
major and two minor manifestations.
Inv.: Pharyngeal cultures; Antibodies to streptococcal enzymes (streptolysin O & DNase B).
Comp.(causes of death): Thromboembolic complications and infective endocarditis.
Infective Endocarditis (IE)
“Microbial infection of the heart valves or the mural endocardium with the formation of
vegetations.”
Etiology: Bacterial infection (MC).
Risk factors
1) Valvular: RHD with valvular scarring; Mitral valve prolapse; Bicuspid aortic valve.
2) Bacteremia: IVDA; Dental or surgical procedures.
Predisposing conditions: Neutropenia; Malignancy; Immunosuppression; Diabetes mellitus.
Types: Acute IE and subacute IE.
Feature
Onset
Heart valve
Bacteria
Vegetations
Lesions
Embolization
Prognosis
Acute IE
Acute
Normal
Highly virulent (Staph. Aureus)
Large
More destructive
More likely
Poor
Sub acute IE
Insidious
Abnormal
Low virulent (Strep. viridans)
Small
Less destructive
Less likely
Good
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Morphology: 1) Single or multiple, friable, bulky & destructive vegetations involve one or
more valves (MC-Mitral or aortic valves).
2) Vegetations are composed of fibrin, inflammatory cells & microbes.
3) Ring abscesses may be formed in acute IE with myocardial erosion.
4) Subacute IE shows healing with granulation tissue & fibrosis.
C/P: Fever, chills, weakness, fatigue, loss of weight & a flu like syndrome; Murmurs are
present in the majority with left-sided IE.
Comp.: Splinter or subungual hemorrhages;
Janeway lesions (erythematous or hemorrhagic nontender lesions on the palms or soles);
Osler nodes (subcutaneous tender nodules in the pulp of digits);
Roth spots (retinal hemorrhages); Glomerulonephritis; Arrhythmias; Septic infarcts.
Diagnosis: Biopsy; Blood culture; Echocardiography.
Vegetations
“Thrombi on heart valves, which can be infected or sterile.”
Disorders with vegetations:
1) Rheumatic heart disease (RHD)
i) Gross: Small warty vegetations are located along the lines of closure of the valve leaflets.
ii) Micro: Fibrinoid necrosis within the cusps or tendinous cords with the overlying infected
thrombi.
iii) Deforming fibrotic valvular disease is associated.
2) Infective endocarditis (IE)
i) Gross: Large, single or multiple, friable & destructive vegetations are located on the valve
cusps that can extend onto the chordae.
ii) Miro.: Infected thrombi, composed of fibrin, inflammatory cells & microbes.
iii) They are prone to embolization.
3) Nonbacterial thrombotic endocarditis (NBTE)
i) Gross: Small, single or multiple vegetations are located usually along the line of closure of
the valve leaflets.
ii) Micro.: Bland thrombi, loosely attached to the underlying valve.
iii) They are non-invasive & do not elicit any inflammatory reaction.
4) Endocarditis of SLE (Libman-Sacks endocarditis)
i) Gross: Small, single or multiple, pink vegetations with warty appearance are located on
either or both sides of the valve leaflets.
ii) Micro.: Bland thrombi, composed of finely granular fibrinous eosinophilic material.
iii) Valvulitis is associated.
Left Ventricular Hypertrophy
Causes: Hypertension (MC); Aortic valve stenosis; Hypertrophic cardiomyopathy; Athletic
training; Congenital heart disease.
Refresh Pathology, 3rd Edition – Dr. Shiva M.D.
14. The Lung
MCQs
1) The most predominant cell type in alveolar epithelium is. (May, 2022)
a) Type 1 pneumocyte b) Type 2 pneumocyte c) Both equally d) Alveolar macrophages
2) Curschmann spirals and Charcot-Leyden crystals are seen in. (May, 2022)
a) Emphysema b) COPD c) Asthma d) Chronic bronchitis
3) Mesothelioma is associated with exposure to. (May, 2022)
a) Silica b) Asbestosis c) Coal d) Tar
4) All are histological types of mesothelioma except. (May, 2022)
a) Epithelioid b) Sarcomatoid c) Biphasic d) Squamoid
5) Reid index is increased in. (Feb. 2022)
a) Asthma b) Emphysema c) Chronic bronchitis d) Pneumonia
6) Collapse of lung is called. (Feb. 2022)
a) Atelectasis b) Bronchiectasis c) Emphysema d) Bronchitis
7) The tubercular bacilli mostly reside in apical lobe of lung. The reason is. (Feb. 2022)
a) Both ventilation and perfusion/unit by volume is maximum at apex
b) Ventilation perfusion ratio is maximum at apical region
c) Both ventilation and perfusion is maximum at base of lung
d) Ventilation perfusion ratio is maximum at the base of lung
8) All are components of Horner syndrome except. (Feb. 2022)
a) Ptosis b) Miosis c) Corneal ulceration d) Anhidrosis
5 Marks
1)
2)
3)
4)
Pathogenesis of asthma. (May, 2022)
Various manifestations of tuberculosis. (May, 2022)
Write a brief note on coal workers pneumoconiosis. (Feb. 2022)
Write a short note on mesothelioma. (Feb. 2022)
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10 Marks
1) A 50 year old male presents with cough, dyspnea, and intermittent hemoptysis for two
months along with loss of weight and appetite. He is a chronic smoker for the past 3 decades.
CT chest revealed mass lesion in the right lobe of lung. (Nov. 2020)
a) What is your probable diagnosis?
b) Discuss in detail the classification, morphological features of the disease.
c) Paraneoplastic syndromes associated with it.
d) Write four complications of it.
Ans: Lung carcinoma.
2) A 65 year old man, a chronic smoker, presented with history of weight loss, low grade
fever and difficulty in breathing. He gave history of hemoptysis for last month. X ray chest
showed enlarged right tracheobronchial lymph nodes. Bronchoscopy revealed a fungating
growth in the right bronchus. (Feb. 2018)
a) What is the probable diagnosis?
b) Mention the major types (classification).
c) Give the spread of the tumor.
d) What is paraneoplastic syndrome? Give features of paraneoplastic syndrome.
Ans: Lung carcinoma.
3) A 55 year old lady presents with breathlessness and cough for the past 2 weeks. She gives
history of loss of weight and tiredness for past 6 months. X-ray chest revealed a massive
pleural effusion on the left side. CT scan showed a nodular mass which is peripherally
located in the left lung. CT guided biopsy of the mass showed, large cells with pleomorphic
nuclei and prominent nucleoli, arranged in a glandular pattern. (Jan. 2015)
a) What is your diagnosis?
b) Mention the histological types (sub-classification) of this lesion with illustrations.
c) Describe it’s etiopathogenesis.
Ans: Lung carcinoma.
4) A male aged 60 years who is a chronic smoker presented with history of slowly increasing
severe exertional dyspnoea and weight loss. He is barrel-chested and dyspneic with
prolonged expiration, sits forward in a hunched-over position and breaths through pursed
lips. (Jan. 2014)
a) What is the probable diagnosis?
b) Mention the major types (classification) with appropriate diagrams.
c) Discuss the pathogenesis of the lesion.
d) Mention two causes of death in most of these patients.
Ans: Emphysema.
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5) An elderly male, chronic smoker presented with steadily progressive dyspnoea. On
examination he was found to be barrel chested and dyspnoeic with prolonged expiration, sits
forward in a hunched over position and breaths through pursed lips. Chest X-ray revealed
hyperinflation and small heart. (May, 2007)
a) What is the probable diagnosis?
b) Explain the role of smoking in the causation of the disease?
c) Describe the morphology of the organ involved?
d) List the complications.
Ans: Emphysema.
6) 60 years old man habituated to tobacco smoking came with history of cough, hemoptysis,
dyspnoea, loss of weight, severe pain in the distribution of the ulnar nerve and Horner’s
syndrome. Mention various laboratory investigations to make a final diagnosis. Describe the
pathology of the lesion. (Sep. 2003)
Ans: Lung carcinoma.
4 Marks
1) Gross and microscopic subtypes of bronchogenic carcinoma. (Oct. 2022)
2) Describe the stages, gross and microscopic features of lung in lobar pneumonia.
(May, 2022)
3) Classify lung cancers and discuss the associated paraneoplastic syndromes. (Aug.
2021)
4) Pathogenesis and morphology of asbestosis. (March, 2021)
5) Etiopathogenesis and morphology of small cell carcinoma of lung. (July, 2019)
6) Discuss the different types of emphysema. (Feb. 2019)
7) Give the complications of bronchiectasis. (July, 2018)
8) Classify pneumonia. What are the stages of lobar pneumonia? (July, 2017)
9) Pathogenesis of bronchial asthma. (July, 2016)
10) Asbestosis. (Jan. 2016)
11) Morphology of lobar pneumonia and complications. (July, 2015)
12) What are the types of pneumonia; write about the morphology of lobar pneumonia
and its complications. (July/Aug. 2014)
13) Lobar pneumonia. (July, 2013)
14) Etiopathogenesis of emphysema. (Jan. 2013)
15) Morphology of lobar pneumonia. (Jan. 2012)
16) Bronchiectasis. (July, 2011)
17) Gross and microscopic picture of lobar pneumonia. (Aug. 2010)
18) Mesothelioma. (Aug. 2009)
19) Asbestosis. (Feb. 2009)
20) Stages of lobar pneumonia. (Oct. 2008)
21) Bronchiectasis. (March/April, 2008)
22) Emphysema. (Oct. 2006)
23) Asbestosis. (May, 2006)
24) Lung abscess. (May, 2006)
25) Broncho pneumonia. (Oct. 2005)
26) Bronchiectasis. (March/April, 2005)
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27) Emphysema-Definition, types & etiology. (Oct. 2004)
28) Lung abscess. (April/May, 2004)
29) Lung abscess. (March/April, 2003)
30) Emphysema. (Oct/Nov. 2002)
2 Marks
1)
2)
3)
4)
5)
6)
7)
8)
9)
Tabulate the differences between centriacinar and panacinar emphysema. (Feb. 2020)
Name any four causes of carcinoma lung. (Feb. 2017)
Lung cancer-Histological types. (July, 2012)
Name the histologic variants of carcinoma lung. (Jan. 2011)
Lung abscess. (April, 2009)
Stages of lobar pneumonia. (Oct. 2008)
Classification of bronchogenic carcinoma. (Sep/Oct. 2007)
Mesothelioma. (Oct. 2005)
Complications of lobar pneumonia. (March/April, 2005)
High-Yield Topics
Emphysema
Asthma
Bacterial pneumonia
Asbestosis
Malignant mesothelioma
Chronic bronchitis
Bronchiectasis
Lung abscess
Carcinoma of lung
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123
Emphysema
“Irreversible enlargement of the air spaces distal to the terminal bronchiole.”
Classification:
1) Centriacinar (centrilobular): Most common form; Central or proximal parts of acini are
affected. Associated with smoking. Most common in the upper lobes.
2) Panacinar (panlobular): Entire acinus is affected. Associated with α1-antitrypsin
deficiency. Most common in lower zones of lungs.
3) Distal acinar (paraseptal): Distal portion of acinus is affected. Associated with
spontaneous pneumothorax in young adults. Seen adjacent to the pleura, along the lobular
connective tissue septa.
4) Irregular: Irregular involvement of acinus; Associated with scarring.
Etiology: Cigarette smoking and α1-antitrypsin deficiency play important role.
Pathogenesis:
1) Toxic injury and inflammation: Epithelial cells and inflammatory cells release mediators
(LTB4, IL-8, and TNF) which further amplify the inflammatory process and induce structural
changes.
2) Protease-antiprotease imbalance: Release of several proteases from inflammatory cells
and epithelial cells with relative deficiency of antiproteases results in tissue damage.
3) Oxidative stress: Oxidants produced from inflammatory cells, substances in tobacco
smoke and alveolar damage cause tissue damage and inflammation.
4) Infection: Bacterial or viral infections may exacerbate the associated inflammation.
Morphology: Gross: Voluminous lungs that overlap the heart; C/S: Large alveoli.
Micro.: Abnormally large alveoli are separated by thin septa with focal centriacinar fibrosis;
Decrease in the capillary bed area.
C/P: Dyspnea, cough, wheezing, and weight loss; Patient is barrel-chested, sits forward in a
hunched-over position, and breathes through pursed lips.
Comp.: Cor pulmonale; Congestive cardiac failure.
Causes of death: Coronary artery disease; Respiratory failure; Right-sided heart failure.
Asthma
“A chronic relapsing inflammatory disorder, characterized by paroxysmal reversible
bronchospasm.”
Types
I) Atopic asthma: Most common.
Age: Childhood.
Family history: Positive.
Stimuli: Environmental allergens (pollens, dusts, animal dander, and foods).
Evidence of allergen sensitization: Present.
Aggravating factors: Respiratory viral infections.
Associations: Allergic rhinitis and eczema.
Mechanism: Type I hypersensitivity reaction.
Pathogenesis: Immune responses to environmental allergens in genetically predisposed
individuals cause atopic asthma.
1) Genetic susceptibility: Individuals with IL-13 gene polymorphisms are at greater risk.
2) Environmental factors: Exposure to airborne pollutants play a crucial role.
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3) Immune responses:
i) Exaggerated Th2 response is seen with secretion of cytokines (IL-4, IL-5, and IL-13) that
promote inflammation and stimulate IgE production from B cells.
ii) IgE binds to the Fc receptors on submucosal mast cells, and repeat exposure to allergen
triggers the mast cells to release granule contents and produce various mediators.
iii) Early-phase reaction: Bronchoconstriction, increased mucus production, vasodilation
and increased vascular permeability are seen.
Mediators and effects:
a) Leukotrienes C4, D4 and E4: Bronchoconstriction, increased vascular permeability and
increased mucus secretion.
b) Acetylcholine: Constriction of airway smooth muscle.
c) Histamine: Bronchoconstriction.
d) Prostaglandin D2: Bronchoconstriction and vasodilation.
e) Platelet-activating factor: Platelet aggregation.
iv) Late-phase reaction: Recruitment of leukocytes, eosinophils, neutrophils and T
lymphocytes is seen.
II) Non-atopic asthma
i) No evidence of allergen sensitization.
ii) positive family history is rare.
Predisposing factors: Respiratory viral infections (rhinovirus, parainfluenza virus, and RSV),
inhaled air pollutants (tobacco smoke, ozone), exposure to cold and exercise.
Morphology:
Gross: Lungs are overinflated with patchy atelectasis and mucus plugging of airways.
Micro.: 1) Whorled mucus plugs (Curschmann spirals) and crystalloid eosinophil granular
debris (Charcot-Leyden crystals) deposit in airways.
2) Airway remodeling with sub-basement membrane fibrosis, increased vascularity, increase
in the size of submucosal glands and number of airway goblet cells and hypertrophy and/or
hyperplasia of the bronchial muscle.
C/P: 1) Recurrent episodes of chest tightness, wheezing, dyspnoea, and cough particularly at
night and/or in the early morning.
2) Acute severe asthma (status asthmaticus): A state of unremitting attacks which may lead to
cyanosis and death.
Inv.: 1) Eosinophilia.
2) Sputum: Eosinophils, Curschmann spirals, and Charcot-Leyden crystals.
3) High total serum IgE levels in atopic asthma.
Bronchiectasis
“Permanent dilation of bronchi and bronchioles with destruction of smooth muscle and
elastic tissue.”
Site: Lower lobes (B/L).
Etiology: Infections (bacterial, viral or fungal); Bronchial obstruction (tumor, foreign body);
Hereditary conditions (cystic fibrosis, Kartagener syndrome); Idiopathic.
Pathogenesis: Obstruction and infection are the major contributing factors.
i) Obstruction leads to retention of secretions resulting in secondary infections with
inflammation.
ii) Severe infections cause necrosis and destruction of smooth muscle and elastic tissue.
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Morphology: Gross: Cystic dilated airways with mucopurulent secretions.
Micro.: Bronchi and bronchioles show inflammatory exudates with necrosis and fibrosis of
the walls occurs with chronicity.
C/P: Persistent cough with foul smelling sputum; Dyspnea, orthopnea or hemoptysis.
Comp.: Cor pulmonale; Brain abscess; Amyloidosis.
Coal Workers’ Pneumoconiosis
Etiology: Inhalation of coal particles and other admixed forms of dust.
Pathogenesis: Inhaled carbon pigment is engulfed by alveolar or interstitial macrophages,
which accumulate in the connective tissue along the lymphatics with fibrogenic response
Morphology:
1) Anthracosis: Accumulations of carbon blacken the tissues of the lungs.
2) Simple coal workers’ pneumoconiosis: The upper lobes and upper zones of the lower lobes
are heavily involved with coal macules consist of carbon-laden macrophages and
coal nodules contain carbon-laden macrophages with collagen.
3) Complicated coal workers’ pneumoconiosis (progressive massive fibrosis): Multiple
blackened scars with dense collagen and pigment.
C/P: Asymptomatic or pulmonary hypertension, and cor pulmonale.
Associations: Emphysema and chronic bronchitis.
Asbestosis
Asbestos, a family of crystalline hydrated silicates, occurs in two geometric forms, serpentine
chrysotiles (most common) and stiff amphiboles (more pathogenic).
Etiology: Inhalation of asbestos is associated with mining, milling, and insulation works.
Pathogenesis:
1) Direct toxicity to parenchymal cells.
2) Macrophages ingest inhaled fibers, and cause production of mediators (fibrogenic growth
factors and cytokines) leading to generalized interstitial pulmonary inflammation and
interstitial fibrosis.
3) Asbestos can act as a tumor initiator and promoter.
Morphology: Marked by diffuse interstitial fibrosis.
1) Fibrosis begins in the lower lobes and sub pleurally, around respiratory bronchioles and
alveolar ducts and extends to involve adjacent alveolar sacs and alveoli. Distortion of
architecture creates enlarged airspaces enclosed by thick fibrous walls.
2) Asbestos bodies: Golden brown, fusiform or beaded rods with a translucent center and
consist of asbestos fibers coated with an iron-containing proteinaceous material.
3) Ferruginous bodies: Other inorganic particulates encrusted with iron.
C/P: Asymptomatic or dyspnea or pulmonary hypertension, and cor pulmonale.
Inv. (CXR): Irregular linear densities, particularly in both lower lobes, and honey comb
pattern.
Pneumonia
“Any infection of the lung parenchyma is known as pneumonia.”
Classification: Community-acquired acute pneumonia; Health care-associated pneumonia;
Hospital-acquired pneumonia; Aspiration pneumonia; Chronic pneumonia.
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Community acquired Bacterial pneumonia
Predisposing factors: Extremes of age; Chronic disease (COPD, Diabetes);
Immunodeficiency; Dysfunctional spleen.
Causes: Streptococcus pneumoniae (MC); H. influenza; Staph. aureus; Klebsiella
pneumoniae; Pseudomonas aeruginosa.
Types: Bronchopneumonia and lobar pneumonia.
I) Bronchopneumonia
“Patchy consolidation of lung, often multilobar and frequently B/L and basal.”
Morphology: Gross: Lesions are slightly elevated, dry, granular, and gray-red to yellow.
Micro.: Suppurative inflammatory exudate filling bronchi, bronchioles and adjacent alveoli.
II) Lobar pneumonia
“Consolidation of a large portion of lobe or of an entire lobe.”
Stages: 1) Congestion: Gross: Lungs are heavy, boggy, and red.
Micro.: Vascular engorgement and intra alveolar edema fluid with many bacteria.
2) Red hepatization: Gross: Lungs are red, firm and airless with liver-like consistency.
Micro.: Exudate in alveoli with neutrophils, red cells, and fibrin.
3) Gray hepatization: Gross: Lungs look grayish brown.
Micro.: Fibrinosuppurative exudate with disintegration of red cells.
4) Resolution: Clearing of exudates is seen.
C/P: High fever with chills, weight loss, and cough with mucopurulent sputum.
Comp.: Lung abscess; Empyema; Endocarditis; Meningitis.
Lung Abscess
“Local suppurative process that produces necrosis of lung tissue.”
Predisposing conditions: Oropharyngeal surgical or dental procedures; Sinobronchial
infections; Bronchiectasis.
Etiopathogenesis
Organisms: Staphylococci, streptococci, numerous gram-negative species, and anaerobes;
Mixed infections are frequent.
Mechanisms of spread:
i) Aspiration of infective material: Most frequent.
Acute alcoholism, coma, seizure disorders, anesthesia, neurologic deficits and protracted
vomiting may favor postpneumonic abscess following aspiration.
ii) Antecedent primary lung infection: S. aureus, K. pneumoniae and pneumococcus may
favor postpneumonic abscess.
iii) Septic embolism: Infected emboli arising from thrombophlebitis may lodge in the lung.
iv) Tumors: Primary or secondary malignancy may favor postobstructive pneumonia.
v) Miscellaneous: Traumatic penetrations of the lungs; Direct extension of suppurative
infections from the esophagus, spine, subphrenic space, or pleural cavity; Hematogenous
seeding of the lung by pyogenic organisms.
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Morphology:
Gross: Single or multiple abscesses, varying in size.
Micro.: Suppurative inflammation with liquefactive necrosis and a fibrous wall with
fibroblast proliferation in chronic cases.
C/P: Cough with foul smelling sputum, fever, chest pain, weight loss, and clubbing of digits.
Comp.: Brain abscess; Meningitis; Amyloidosis.
Lung Carcinoma
*Most common primary tumor of lung.
*Most common cause of cancer mortality.
Age: 40-70 yrs.
Classification: 1) Adenocarcinoma 2) Squamous cell carcinoma 3) Neuroendocrine tumors
(Small cell carcinoma; Carcinoid tumor) 4) Large cell carcinoma 5) Adenosquamous
carcinoma.
Risk factors: Tobacco smoking (major); Exposure to ionizing radiation, asbestos, and
uranium; Air pollution.
Types:
I) Adenocarcinoma
Age: <45 yrs.
Sex: F>M
Genetic alterations: Gain of function mutations of EGFR and KRAS.
Precursors: Atypical adenomatous hyperplasia; Adenocarcinoma in situ.
Gross: Gray-white, firm peripheral mass.
Micro.: Vary from well-differentiated tumors with obvious glandular elements, to papillary
lesions resembling papillary carcinomas, to solid masses with only occasional mucinproducing glands and cells.
II) Squamous cell carcinoma
Sex: M>F
Genetic alterations: Mutations of TP53 and CDKN2A and 3p deletions.
Precursors: Squamous metaplasia or dysplasia and carcinoma in situ.
Gross: Gray-white, firm centrally located mass. Large tumors may show foci of necrosis or
hemorrhage.
Micro.: Keratinization and/or intercellular bridges are prominent in well-differentiated
tumors but not extensive in moderately differentiated tumors, and are focally seen in poorly
differentiated tumors.
III) Small cell carcinoma: Most aggressive type.
Origin: Neuroendocrine progenitor cells.
Genetic alterations: Loss of function mutations of TP53 and RB.
Gross: Pale gray, centrally located mass.
Micro.: Sheets of small cells with scant cytoplasm, ill-defined borders, and hyperchromatic
nuclei with salt and pepper chromatin. Necrosis and high mitotic rates are associated.
IV) Large cell carcinoma: Undifferentiated tumor.
Gross: Gray-white, firm mass.
Micro.: Large cells having moderate cytoplasm and large nuclei with prominent nucleoli.
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C/P: Cough (MC), weight loss, chest pain, hemoptysis, and dyspnea.
Spread:
Local: Mediastinum, pleura or chest wall.
Metastasis: Lymphatic: Bronchial, tracheal and mediastinal lymph nodes.
Hematogenous: Adrenal glands (MC), liver, brain and bone.
Complications: Pleural effusion, pneumonia, hoarseness, dysphagia, diaphragm paralysis,
SVC syndrome, and Horner syndrome.
Paraneoplastic syndromes:
1) Hypercalcemia with squamous cell carcinoma.
2) SIADH and Cushing syndrome with small cell carcinoma.
3) Trousseau syndrome with adenocarcinoma.
4) Hypertrophic pulmonary osteoarthropathy.
5) Pancoast syndrome with Pancoast tumors.
* Pancoast tumors: Apical lung cancers in the superior pulmonary sulcus with severe pain in
the distribution of the ulnar nerve, and Horner syndrome on the same side as the lesion.
Inv.: Radiology (CXR; CT; PET); Cytology (FNAC; Sputum; Bronchial lavage fluids or
brushings); Biopsy.
Malignant Mesothelioma
“Primary malignant tumor of pleura.”
Origin: Mesothelial cells lining visceral or parietal pleura.
Risk factors: Asbestos exposure.
Genetic alterations: Loss of tumor suppressor gene CDKN2A.
Morphology: Gross: Soft, gelatinous, grayish pink mass ensheaths the lung.
Micro.: 1) Epithelioid type (MC): Cuboidal, columnar or flattened cells form tubular or
papillary structures.
2) Sarcomatoid type: Spindle shaped cells arranged in sheets.
3) Biphasic type: Contains both epithelioid and sarcomatoid patterns.
C/P: Chest pain, dyspnea, and recurrent pleural effusions.
Metastasis: Hilar lymph nodes; Liver.
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15. Head and Neck
MCQs
1) Most common tumor in head and neck is. (May, 2022)
a) Adenocarcinoma
b) Squamous cell carcinoma
c) Basal cell carcinoma d) Malignant melanoma
2) Most common salivary gland neoplasm is. (May, 2022)
a) Warthin tumor
b) Pleomorphic adenoma.
c) Adenoid cystic carcinoma d) Acinic cell carcinoma
5 Marks
1) Pleomorphic adenoma. (May, 2022)
4 Marks
1)
2)
3)
4)
5)
Pleomorphic adenoma. (March, 2021)
Morphology of pleomorphic adenoma of salivary gland. (July, 2015)
Pleomorphic adenoma. (July, 2013)
Pleomorphic adenoma - salivary gland. (Aug. 2010)
Pleomorphic adenoma. (March/April, 2003)
2 Marks
1)
2)
3)
4)
Name the premalignant lesions of the oral cavity. (Oct. 2022)
Name four malignant tumors of salivary glands. (Feb. 2017)
Leukoplakia. (Aug. 2010)
Warthin tumor. (March, 2010)
High-Yield Topics
Premalignant lesions of oral cavity
Pleomorphic adenoma
Leukoplakia
Warthin tumor
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Premalignant Lesions of the Oral Cavity
Leukoplakia; Erythroplakia; Submucous fibrosis; Lichen planus.
Leukoplakia
“A white patch or plaque that cannot be scraped off and cannot be characterized clinically or
pathologically as any other disease.”
* Precancerous lesion of oral cavity.
Age: 40 – 70yrs.
Sex: M>F
Risk factors: Tobacco usage.
Sites: Buccal mucosa, floor of mouth, ventral surface of tongue.
Morphology: Gross: Solitary or multiple white patches or plaques.
Micro.: Spectrum of epithelial changes such as hyperkeratosis, acanthosis, dysplasia or
carcinoma in situ.
Comp.: Squamous cell carcinoma of oral cavity.
Salivary Gland Tumors - Classification
Benign: Pleomorphic adenoma; Warthin tumor; Oncocytoma; Basal cell adenoma.
Malignant: Mucoepidermoid carcinoma; Acinic cell carcinoma; Adenoid cystic carcinoma;
Adenocarcinoma, not otherwise specified.
Pleomorphic Adenoma (Benign Mixed Tumor)
“Benign tumor of salivary glands.”
*MC salivary gland tumor.
Age: 50-70s.
Sex: F>M
Site: Parotid gland (MC).
Risk factors: Radiation exposure.
Genetic alterations: Overexpression of the gene PLAG 1.
Morphology: Gross: Well circumscribed round encapsulated mass of varying size.
C/S: Gray-white with myxoid & blue translucent areas of chondroid stroma.
Micro.: Epithelial (ductal or myoepithelial) elements are arranged as ducts, acini, strands or
sheets of cells. They are dispersed within a background of loose myxoid and hyaline tissue
with islands of cartilage or bone. Islands of squamous epithelium may be present.
C/P: Painless slow-growing mobile discrete mass.
Inv.: FNAC; USG; Biopsy.
Comp.: Recurrence; Malignant transformation.
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Warthin Tumor (Papillary Cystadenoma
Lymphomatosum)
“Benign tumor of salivary glands.”
*2nd MC salivary gland tumor.
Site: Parotid gland (MC).
Sex: M>F
Age: 50-70s.
Risk factors: Smoking.
Morphology: Gross: Round to oval encapsulated mass of varying size. Mostly unifocal.
C/S: Pale gray with cleflike spaces filled with serous or mucinous secretions.
Micro.: The lining epithelium consists of a double layer of oncocytic cells on a lymphoid
stroma. The innermost layer is columnar with dispersed secretory cells and outer layer is
cuboidal. Foci of squamous metaplasia may be present.
C/P: Discrete mass in front of & below the ear.
Inv.: FNAC; USG; Biopsy.
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16. The Gastrointestinal Tract
MCQs
1) A new born child presents with a failure to pass meconium in the immediate neonatal
period and it progressed to ineffective peristalsis. The barium enema study shows constricted
rectum and dilated sigmoid colon. The most probable diagnosis in this case is. (May, 2022)
a) Menetrier disease
b) Meckel diverticulum.
c) Hirschsprung disease d) Necrotizing enterocolitis
2) All components of achalasia, except. (May, 2022)
a) LES relaxation
b) Increased LES tone
c) Aperistalsis of esophagus d) Failure of LES relaxation
3) Linitis plastica is. (May, 2022)
a) Intestinal type adenocarcinoma
b) Diffuse type gastric adenocarcinoma
c) Neuroendocrine carcinoma of stomach d) Carcinoid tumor of stomach
4) A young adult male, aged 30 years after taking gluten rich diet presented with irritability,
abdominal distension, pain and anorexia. The patient underwent intestinal biopsy. All are
expected biopsy findings in the given case except. (May, 2022)
a) Increased villi
b) Increased intraepithelial lymphocytes
c) Increased mitosis d) Crypt elongation
5) Longitudinal ulcers in intestinal wall are seen in. (May, 2022)
a) Tuberculosis b) Shigella dysentery c) Typhoid d) Cholera
6) PAS positive macrophages in lamina propria are seen in. (May, 2022)
a) Celiac disease b) Menetrier disease c) Whipple disease d) Pseudomembranous colitis
7) All are seen in Crohn disease except. (May, 2022)
a) Skin lesions b) Transmural inflammation c) Fissures d) Continuous colonic involvement
15 Marks
1) A 30 year old male presented to OPD clinic with abdominal pain, diarrhea, unexplained
weight loss, bloody stools for the last two years. Biopsy of intestine shows clusters of
inflammatory cells. (May, 2022)
a) What is your diagnosis.
b) What are the types of inflammatory bowel disease.
c) Explain the pathogenesis of the above disease.
d) List the differences between ulcerative colitis and Crohn disease.
Ans: Inflammatory bowel disease.
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2) A 72 years old male presented with changes in the bowel habit, bleeding per rectum, loss
of weight, fatigue and weakness of six months duration. After endoscopic biopsy on colon, a
left sided hemicolectomy was done. Answer the following. (Feb, 2022)
a) What is the probable diagnosis.
b) Describe the etiopathogenesis.
c) Describe the gross and microscopic features of the resected colon.
d) Mention the serological marker which is increased. (Feb. 2022)
Ans: Adenocarcinoma of colon.
5 Marks
1) Pathogenesis and morphological features of celiac disease. (May, 2022)
10 Marks
1) A 30 year old male patient complains of recurring epigastric burning sensation of 5 months
duration. Pain is exacerbated by fasting, intake of spicy food and usually develops 2 – 3
hours after meals and is worse during night from 11.00 pm to 2.00 am. There is associated
bloating, belching, nausea and vomiting. (May, 2022)
a) What is your diagnosis?
b) Describe in detail the etiopathogenesis of this condition.
c) Discuss the gross and microscopy of this disorder.
d) Enumerate two complications due to this disease.
Ans: Peptic ulcer disease.
2) An elderly male presented with history of bleeding per rectum, altered bowel habits, loss
of appetite, loss of weight and crampy lower quadrant discomfort in the abdomen.
Hematological evaluation revealed iron deficiency anemia. What is your diagnosis? (Feb.
2017)
a) Discuss the etiopathogenesis of this disease.
b) Describe the morphology of this lesion.
Ans: Adenocarcinoma of colon.
3) A 58 year old male labourer presented with history of epigastric pain occurring
immediately and sometimes within two hours of taking food. The pain relieved by vomiting.
He had good appetite but afraid to eat and used to take bland diet. There is significant loss of
body weight and deep tenderness present in the midline of epigastrium. (Jan. 2012)
a) What is the provisional diagnosis?
b) Discuss the etiopathogenesis.
c) Describe the morphology of the lesion.
d) Mention the complications.
Ans: Peptic ulcer disease.
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4) A 48 years old male presented with weight loss, anorexia, vomiting and mass in the
epigastric region. On investigation, he was detected to have rigid, thickened leather bottle
stomach and a space occupying lesion in the liver. (Sep/Oct. 2007)
a) What is the probable diagnosis?
b) What are the factors associated with the causation of the condition?
c) Describe the morphology of the organ involved.
d) Describe the mode of spread.
Ans: Gastric adenocarcinoma.
5) A 50 year old businessman complained of burning pain in the upper abdomen and
retrosternal region for a long time. The pain worsened at nights and occurred 3 hours after
meals. Pain was relieved with food. (Oct. 2004)
a) What is the provisional diagnosis?
b) What is the etiopathogenesis?
c) Describe the pathology & complications.
Ans: Peptic ulcer disease.
4 Marks
1) Ulcerative colitis. (May, 2022)
2) Barrett esophagus. (Aug. 2021)
3) Crohn disease. (Nov. 2020)
4) Gastric carcinoma – Location, types, and metastasis. (Feb. 2020)
5) Morphological features and complications of ulcerative colitis. (July, 2019)
6) Hereditary non-polyposis colorectal cancer. (Feb. 2019)
7) Differentiate between Crohn disease and ulcerative colitis. (July, 2018)
8) Give the clinical and biochemical features of carcinoid syndrome. (July, 2018)
9) Helicobacter pylori and peptic ulcer. (Feb. 2018)
10) Pathogenesis of peptic ulcer. (July, 2017)
11) Gastric carcinoma – Location, types and metastasis. (Jan. 2016)
12) Etiopathogenesis of carcinoma stomach. (Jan. 2015)
13) What are the causes of peptic ulcer, write its morphology and complications?
(July/Aug. 2014)
14) Crohn disease – Morphology. (July, 2012)
15) Crohn disease. (Aug. 2009)
16) Ulcerative colitis. (April, 2009)
17) Morphology of chronic gastric ulcer. (Oct. 2008)
18) Ulcerative colitis. (May, 2007)
19) Gross and microscopic picture of gastric carcinoma. (Oct. 2006)
20) Ulcerative colitis. (May, 2006)
21) Amoebiasis. (May, 2006)
22) Ulcerative colitis. (March/April, 2005)
23) Gross and histologic classification of gastric carcinoma. (April/May, 2004)
24) Primary malabsorption syndromes. (Sep. 2003)
25) Precancerous lesions of G.I.T. (Oct./Nov. 2002)
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135
2 Marks
1) What is the pathogenesis of Helicobacter pylori gastritis. (Oct. 2022)
2) Tabulate any four differences between Crohn disease and ulcerative colitis. (Aug.
2021)
3) Barrett esophagus. (Feb. 2019)
4) Complications of peptic ulcer. (July, 2016)
5) What are the four precancerous lesions of large intestine? (Jan. 2016)
6) Microscopic appearance of peptic ulcer. (July, 2015)
7) Four differences between Crohn’s disease and ulcerative colitis. (July, 2015)
8) Morphology of amoebic colitis. (Jan. 2014)
9) Four (4) complications of chronic gastric ulcer. (July, 2013)
10) Cause and histology of Barrett esophagus. (Jan. 2013)
11) Chronic gastric ulcer. (July, 2011)
12) Various sites of chronic peptic ulcer. (March, 2010)
13) Barrett esophagus. (Feb. 2009)
14) Barrett esophagus. (March/April, 2008)
15) Barrett esophagus. (Oct. 2008)
16) What is malabsorption syndrome. (Oct. 2006)
17) What is carcinoid. (Oct. 2006)
18) Barrett esophagus. (May, 2006 )
19) Microscopic picture of chronic gastric ulcer. (May, 2006)
20) Complications of gastric ulcer. (March/April, 2005)
21) Crohn disease. (March/April, 2003)
22) Barrett esophagitis. (March/April, 2003)
High-Yield Topics
Barrett esophagus
Gastric adenocarcinoma
Celiac disease
Premalignant lesions of gastrointestinal tract
Peptic ulcer disease
Carcinoid tumor
Inflammatory bowel disease
Carcinoma of colon
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Barrett Esophagus
Age: 40-60s.
Classification: Long segment (3 cm or more) and short segment (< 3 cm).
Risk factors: Chronic GERD.
Morphology: Gross: One or several patches of red velvety mucosa extends upward from the
grastroesophageal junction.
Micro.: Intestinal type metaplasia above the gastroesophageal junction where squamous
epithelium is replaced by columnar epithelium with goblet cells.
Inv.: Endoscopy; Biopsy.
Comp.: Dysplasia; Esophageal adenocarcinoma.
Helicobacter pylori Gastritis
*MC form of chronic gastritis caused by H. pylori infection with normal or increased acid
production.
Site: Antrum (MC).
Predisposing factors: Poverty, household crowding, limited education, residence in rural
areas, and age over 60 years.
Pathogenesis:
i) Virulence of H. pylori is linked to the following factors.
• Flagella, which allow the bacteria to be motile in viscous mucus.
• Urease, which generates ammonia from endogenous urea and thereby elevates local gastric
pH and enhances bacterial survival.
• Adhesins that enhance bacterial adherence to surface foveolar cells.
• Toxins, such as cytotoxin-associated gene A (CagA).
ii) Inflammation limited to the antrum modestly increases local gastrin production which can
augment parietal cell mass within the gastric body and increases acid secretion that leads to
greater risk of gastric or duodenal peptic ulcer disease.
iii) Long-standing H. pylori gastritis may progress to involve the gastric body and fundus
which may result in atrophic gastritis with reduced parietal cell mass that leads to reduced
acid secretion and intestinal metaplasia with increased risk of gastric adenocarcinoma.
Morphology: i) H. pylori, spiral-shaped or curved bacilli concentrated within the superficial
mucus overlying epithelial cells in the surface and neck regions.
ii) Antral mucosa is usually erythematous and has a coarse or even nodular appearance.
iii) The inflammatory infiltrate includes large numbers of plasma cells, often in clusters or
sheets, within the superficial lamina propria accompanied by increased numbers of
lymphocytes, macrophages, and neutrophils within the lamina propria.
iv) Neutrophils infiltrate across the basement membrane and accumulate in the lumens of
gastric glands, or pits, to create pit abscesses.
v) Lymphoid aggregates, some with germinal centers, are frequently present.
C/P: Nausea and upper abdominal pain, sometimes with vomiting.
Inv.:
i) Gastric biopsy with immunostains or histochemical stains (Warthin-Starry silver stain).
ii) Serology for antibodies to H. pylori, fecal bacterial detection, and the urea breath test.
iii) The rapid urease test, bacterial culture, or PCR-based detection of H. pylori DNA.
Com.: Increased risk of gastric adenocarcinoma and lymphoma.
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Peptic Ulcer Disease (PUD)
“Chronic mucosal ulceration affecting the duodenum or stomach.”
Sites: Stomach (along the lesser curvature near the interface of the body & antrum);
Duodenum (anterior wall of proximal duodenum).
Risk factors: H. pylori; NSAIDs; Cigarette smoking; COPD; Alcoholic cirrhosis;
Drugs (cocaine); Zollinger-Ellison syndrome.
Predisposing conditions: Chronic gastritis.
Pathogenesis: Imbalances between mucosal defense mechanisms (surface mucus secretion,
bicarbonate secretion into mucus & elaboration of prostaglandins) and damaging factors
(gastric acidity & peptic enzymes).
Morphology:
Gross: 1) Round to oval, mostly solitary, shallow or deep ulcers seen as punched-out defects.
2) Margins of ulcer level with surrounding mucosa and base is smooth and clean.
3) Hemorrhage & fibrin deposition on gastric serosa.
Micro.: 1) Active ulcers show neutrophilic infiltrates.
2) Healing involves granulation tissue with mononuclear cells & formation of a fibrous scar.
C/P: Epigastric burning or pain (pain tends to occur 1-3 hrs after meals during the day, is
worse at night, and is relieved by alkali or food); Nausea, vomiting, bloating, & weight loss.
Comp.: Bleeding with iron deficiency anemia; Perforation; Obstruction; Rare malignant
transformation.
Gastric Adenocarcinoma
“MC malignancy of the stomach.”
Site: Antrum (MC).
Types: Intestinal and diffuse.
Sex: Intestinal type – M>F; Diffuse type – M=F
Risk factors: Geographic influences (MC in Japan); Low socioeconomic status; Carcinogens
(Benzopyrene).
Precursor conditions: Gastric dysplasia and adenoma for the intestinal type.
Etiology: Sporadic or hereditary.
Genetic alterations:
1) Diffuse type: Loss of function mutations in gene CDH1, which encodes E-cadherin.
2) Intestinal type: Loss of function mutations involving APC gene & gain of function
mutations involving gene encoding beta-catenin.
3) Both types: Loss of function mutations involving TP53.
Morphology:
1) Intestinal type: Gross: Exophytic mass or ulcerative tumor.
Micro.: Tumor cells often contain apical mucin vacuoles and form glandular structures.
Abundant mucin may be present in gland lumina.
2) Diffuse type: Gross: Thickened, rigid wall with diffuse rugal flattening imparts leather
bottle appearance (linitis plastica).
Micro.: Discohesive tumor cells have signet ring cell morphology and infiltrate the wall.
Desmoplasia is seen with no gland formation.
C/P: Early: Dyspepsia, dysphagia & nausea.
Late: Weight loss, anorexia, early satiety, anemia & hemorrhage.
Spread: i) Local invasion: Duodenum, pancreas & retroperitoneum.
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ii) Metastasis: Supraclavicular sentinel node (Virchow node); Periumbilical lymph nodes
(Sister Mary Joseph nodule); Left axillary lymph node (Irish node); Ovary (Krukenberg
tumor); Pouch of Douglas (Blumer shelf).
Carcinoid Tumor
“Represent well-differentiated neuroendocrine tumors.”
Age: 60s (MC).
Sites: Small intestine (MC), stomach, appendix and colorectum.
Morphology
Gross: Intramural or submucosal masses that create small polypoid lesions. The overlying
mucosa may be intact or ulcerated. C/S: Yellow or tan in color and are very firm.
Micro.: Composed of islands, trabeculae, strands, glands, and sheets of uniform cells with
scant, pink granular cytoplasm and a round to oval nucleus with a ‘salt and pepper’ chromatin
pattern.
C/P
i) Zollinger-Ellison syndrome
ii) Carcinoid syndrome: Caused by vasoactive substances secreted by the tumor into the
systemic circulation.
Features: Cutaneous flushing, sweating, bronchospasm, colicky abdominal pain, diarrhea,
and right-sided cardiac valvular fibrosis.
Celiac Disease (Celiac sprue or Gluten-sensitive
enteropathy)
“An immune-mediated disorder triggered by the ingestion of gluten-containing foods such
as wheat, rye, or barley in genetically predisposed individuals.”
Age: Adults: 30-60 yrs.; Children: 6 – 24 months.
Pathogenesis:
i) Genetic predisposition: Strong association with class II HLA alleles, specifically HLADQ2 and -DQ8.
ii) Gliadin: A peptide derived from the gluten may induce epithelial cells to express IL-15,
which in turn triggers activation and proliferation of CD8+ intraepithelial lymphocytes
resulting in epithelial damage.
iii) Deamidated gliadin peptides interact with HLA-DQ2 or HLA-DQ8 on antigen-presenting
cells and in turn stimulate CD4+ T cells to produce cytokines that exacerbate tissue damage.
Morphology:
i) Increased numbers of intraepithelial CD8+ T lymphocytes (intraepithelial lymphocytosis),
crypt hyperplasia, and villous atrophy.
ii) Increased numbers of plasma cells, mast cells, and eosinophils, especially within the upper
part of the lamina propria.
C/P: Adults: Asymptomatic; Chronic diarrhea, bloating, or chronic Fatigue; Anemia;
Dermatitis herpetiformis
Children: irritability, abdominal distention, anorexia, chronic diarrhea, failure to thrive,
weight loss, or muscle wasting. Arthritis or joint pain, aphthous stomatitis, iron deficiency
anemia, delayed puberty, and short stature.
Inv.: Increased titers of IgA anti–tissue transglutaminase antibodies; Biopsy.
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Comp.: Female infertility, osteoporosis, and cancer (Enteropathy associated T-cell
lymphoma; Small intestinal adenocarcinoma).
Associations: Type 1 diabetes, thyroiditis, Sjögren syndrome, and IgA nephropathy.
Amoebiasis
Causative agent: Entamoeba histolytica (protozoan).
Route of transmission: Fecal-oral.
Sites: Caecum & ascending colon.
Pathogenesis: After reaching the colon, cysts colonize the epithelial surface and release
trophozoites. They attach to the colonic epithelium, invade crypts & burrow laterally into the
lamina propria. Ulcers are formed as a result of tissue damage.
Morphology: Gross: Flask shaped ulcers with narrow neck & broad base.
Micro.: Extensive liquefactive necrosis with few inflammatory cells.
C/P: Abdominal pain, bloody diarrhea & weight loss.
Comp.: Amoebic liver abscess; Acute necrotizing colitis; Megacolon.
Inv.: Intestinal biopsy; Stool exam.
Inflammatory Bowel Disease (IBD)
“A chronic condition resulting from complex interactions between intestinal microbiota and
host immunity in genetically predisposed individuals that leads to inappropriate mucosal
immune activation.”
Components: Crohn disease and ulcerative colitis.
Age: Teens and early 20s (MC).
Pathogenesis i) Inadequate wound repair and epithelial barrier function may allow luminal
bacteria and their products to enter the lamina propria, where immune cells are located.
ii) Inadequate regulation in the activation and function of regulatory T cells or in cytokines
(IL-10) that suppress inflammation.
iii) Changes in the gut microbiome may contribute to the inflammation.
iv) Defective autophagy may contribute to the dysregulated immune response.
Crohn Disease (Regional Enteritis)
Sites: Terminal ileum, ileocecal valve & cecum (any area of GIT).
Morphology:
Gross: 1) Many mucosal aphthous ulcers coalesce & form elongated, serpentine ulcers
oriented along the axis of the bowel.
2) Patchy distribution of disease with depressed diseased mucosa & interspersed normal
mucosa gives cobble stone appearance. Skip lesions are seen.
3) Fissures & fistulous tracts may develop.
4) Intestinal wall is thickened & rubbery.
5) Stricture formation.
Micro.: 1) Transmural involvement with ulceration.
2) Cryptitis, crypt abscess & crypt destruction.
3) Distorted mucosal architecture with pseudopyloric metaplasia.
4) Noncaseating granulomas.
5) Mucosal atrophy with loss of crypts appears late.
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C/P: Intermittent attacks of relatively mild diarrhea, fever, & abdominal pain.
Extraintestinal manifestations: Uveitis; Migratory polyarthritis; Sacroiliitis; Ankylosing
spondylitis; Primary sclerosing cholangitis.
Comp.: Hypoalbuminemia; Malabsorption; Carcinoma of colon.
Ulcerative Colitis
Sites: Colon & rectum.
Morphology:
Gross: 1) Mucosa may appear red & granular or with extensive, broad-based ulcers aligned
along the long axis of intestine.
2) Diffuse involvement with no skip lesions.
3) Isolated islands of regenerating mucosa (pseudopolyps) bulge into the lumen, with their
tips may be joined to form mucosal bridges.
4) Mucosal atrophy appears late, with a flat & smooth surface.
5) Mural thickening is not present & the serosal surface is normal.
6) No stricture formation.
7) Colonic dilation & toxic megacolon may be seen.
Micro.: 1) Inflammatory process is diffuse and limited to mucosa & superficial submucosa.
2) Inflammatory infiltrates, crypt abscesses, crypt distortion, & pseudopyloric epithelial
metaplasia.
3) Ulcers may be seen limited by muscularis.
4) Submucosal fibrosis, mucosal atrophy and distorted mucosal architecture appear late.
5) No granulomas.
C/P: Attacks of bloody diarrhea with stringy, mucoid material, lower abdominal pain, and
cramps.
Extraintestinal manifestations: Migratory polyarthritis; Sacroiliitis; Ankylosing spondylitis;
Uveitis; Primary sclerosing cholangitis.
Comp.: Carcinoma of colon.
Feature
Crohn disease
Ulcerative colitis
Bowel region
Distribution
Stricture
Inflammation
Ulcers
Fibrosis
Serositis
Granulomas
Fistulae/sinuses
Toxic megacolon
Any area of GIT
Skip lesions
Present
Transmural
Deep, knife-like
Marked
Marked
Present
Present
Absent
Colon only
Diffuse
Rare
Limited to mucosa
Superficial, broad-based
Mild to none
Mild to none
Absent
Absent
Present
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Hereditary Non-Polyposis Colorectal Cancer
(HNPCC)
*Also known as Lynch syndrome.
*Increased predisposition to colorectal and other extraintestinal cancers.
*Most common syndromic form of colon cancer.
Transmission: Autosomal dominant.
Age: <50 yrs.
Site: Right colon (common).
Genetic alterations: Inherited mutations in DNA mismatch repair genes, majority in MSH2
or MLH1. Mutations accumulate mostly in microsatellites resulting in microsatellite
instability (MSI).
The Amsterdam criteria for the diagnosis
(1) Colorectal cancer in at least three family members, at least one of which is a first-degree
relative of the other two.
(2) Colorectal cancer in at least two successive generations.
(3) The development of colorectal cancer before the age of 50 years in at least one of the
affected family members.
Morphology: Poorly differentiated or mucinous adenocarcinoma.
Adenocarcinoma of Colon
“MC malignancy of the GIT.”
Risk factors: 1) Advancing age: Peak incidence at 60-70yrs.
2) Geographic influences: High incidence in North America.
3) Dietary factors: Low intake of unabsorbable vegetable fiber & high intake of refined
carbohydrates and fat.
Precursors: Inflammatory bowel disease; Colonic adenoma; Peutz-Jeghers syndrome;
Juvenile polyposis.
Etiology: Sporadic or familial. Familial cases such as familial adenomatous polyposis (FAP)
& HNPCC show autosomal dominant transmission.
Genetic alterations:
I) Adenoma-carcinoma sequence:
1) Mutations in gene APC cause activation of APC/ β-catenin pathway.
2) With loss of APC function, β-catenin accumulates and activates genes MYC and cyclin
D1, which promote proliferation.
3) Alterations of TGF-β signaling with loss of function mutations in genes encoding SMAD2
& SMAD4, may allow unrestrained cell growth.
4) Activating mutations in KRAS promote growth & prevent apoptosis.
5) Loss of function mutations in TP53 cause chromosomal instability.
II) Microsatellite instability (MSI):
1) With DNA mismatch repair deficiency, mutations accumulate in microsatellite repeats.
2) Mutations of genes encoding type II TGF-β receptor lead to uncontrolled cell growth.
3) Mutations of genes encoding pro-apoptotic protein BAX lead to its loss, enhancing the
survival of genetically abnormal clones.
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III) CpG island hypermethylation phenotype (CIMP):
1) Seen with a subset of microsatellite unstable colon cancers without mutations in DNA
mismatch repair enzymes.
2) Hypermethylation of MLH1 promoter region reduces its expression & repair function.
3) Activating mutations in the oncogene BRAF promote cell proliferation.
Morphology
Gross: 1) Right sided or proximal colon cancers form polypoid exophytic masses.
2) Distal colon cancers present as annular lesions, that produce napkin-ring constrictions.
Micro.: 1) Well-differentiated adenocarcinomas form largely glands with elongated tumor
cells having elongated, hyperchromatic nuclei. Necrotic debris is present in the gland lumen.
2) Poorly differentiated adenocarcinoma is largely composed of infiltrating nests of tumor
cells with few glands.
3) Desmoplastic response is associated.
C/P: 1) Right-sided colon cancers: Fatigue and weakness due to iron deficiency anemia.
2) Left-sided colon cancers: Occult bleeding, and changes in bowel habits or cramping.
Inv.: Fecal occult blood test; Tumor markers (CEA, CA 19-9); Endoscopy; MRI; CT scan;
Biopsy.
Metastasis: Regional lymph nodes; Liver (MC); Lung; Bone.
Premalignant Conditions of GIT
Oral cavity: Leukoplakia; Erythroplakia; Lichen planus.
Esophagus: Barrett esophagus.
Stomach: Atrophic gastritis; Gastric adenoma.
Colon: Inflammatory bowel disease; Colonic adenoma; Peutz-Jeghers syndrome; Juvenile
polyposis.
Primary Malabsorption Syndromes
Causes: Celiac disease; Tropical sprue; Whipple disease; Collagenous sprue; Disaccharidase
deficiency.
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17. Liver and Gallbladder
MCQs
1) Nodule size in macronodular cirrhosis is. (May, 2022)
a) >2 mm b) >5 mm c) >3 mm d) >4.5 mm
2) Hemolysis is associated with what type of gall bladder stones. (May, 2022)
a) Cholesterol stones b) Pigment stones c) Struvite stones d) Calcium stones
5 Marks
1)
2)
3)
4)
Pathogenesis of primary biliary cirrhosis. (May, 2022)
Nonalcoholic steatohepatitis. (May, 2022)
Histopathology of cirrhosis of liver. (Feb. 2022)
Elaborate about primary biliary cholangitis. (Feb. 2022)
10 Marks
1) A 45 year old woman presented to the surgical OPD with yellowness in eyes and skin,
passage of dark colored urine and pale stools. She complained of right upper abdominal pain
on and off, nausea and vomiting. On USG, radiopaque shadows were seen in right upper
quadrant of abdomen. (July, 2019)
a) What is the most likely diagnosis?
b) What investigations would be appropriate?
c) What is the etiopathogenesis of this lesion?
d) What are the complications of this disease?
Ans: Cholelithiasis (Pigment stones).
2) A 43 year old male, chronic alcoholic dies after a bout of profuse hematemesis. (Jan. 2011)
a) What is the probable diagnosis?
b) Describe the morphological changes in the target organ involved.
c) Write the sequential events that have led to death.
Ans: Cirrhosis of liver.
3) A 50 year old chronic alcoholic was admitted with distended abdomen and hematemesis.
He appears emaciated and has altered sensorium. (May, 2006)
a) What is the provisional diagnosis?
b) What is the gross and microscopic picture of the involved organ?
c) Mention the complications.
Ans: Cirrhosis of liver.
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4) A 50 year old chronic alcoholic developed ascites with history of repeated bouts of
hematemesis and bleeding from rectum, admitted with coma and died. Scan showed shrunken
liver and splenomegaly. (April/May, 2004)
a) What is the probable diagnosis?
b) Mention the reasons in support of your diagnosis.
c) Describe the pathology of liver and spleen.
Ans: Cirrhosis of liver.
4 Marks
1)
2)
3)
4)
5)
6)
7)
Pathogenesis of cholelithiasis. (Oct. 2022)
Classify and describe the morphology of alcoholic cirrhosis. (May, 2022)
Pathology, morphology of cirrhosis of liver. (March, 2021)
Liver abscess. (Nov. 2020)
Etiopathogenesis of viral hepatitis and its complications. (July, 2019)
Sequence of serologic markers in acute hepatitis B infection. (Feb. 2019)
Classify cirrhosis. Give gross and microscopic picture of alcoholic cirrhosis. (July,
2018)
8) Post necrotic cirrhosis liver. (Feb. 2018)
9) Morphology of acute viral hepatitis and its complications. (July, 2017)
10) Morphology of liver in alcoholic cirrhosis. (Feb. 2017)
11) Morphology of hepatocellular carcinoma. (July, 2016)
12) Chronic active hepatitis – Etiology, microscopic picture and fate. (Jan. 2016)
13) Etiopathogenesis of hepatocellular carcinoma. (Jan. 2015)
14) Etiopathogenesis and morphology of alcoholic liver disease. (July/Aug. 2014)
15) Etiologic and morphologic classification of cirrhosis of liver. (Jan. 2013)
16) Morphology of alcoholic cirrhosis. (Aug. 2010)
17) Pathogenesis of hepatocellular carcinoma. (March, 2010)
18) Liver abscesses. (May, 2006)
19) Alcoholic cirrhosis. (Sep. 2003)
2 Marks
1) Classify cirrhosis of liver. (Feb. 2020)
2) Types of gall stones. (July, 2019)
3) Give four complications of gall stones. (July, 2018)
4) Types of gall stones. (July, 2016)
5) Four causes for cirrhosis of liver. (July, 2015)
6) Types of gall stones and their complications. (July/Aug. 2014)
7) Four major etiologic factors associated with hepatocellular carcinoma. (Jan. 2014)
8) Gall stones-Types and complications. (July, 2012)
9) Alcoholic cirrhosis. (July, 2011)
10) Microscopic picture of alcoholic cirrhosis. (Aug. 2009)
11) Gall stones. (Feb. 2009)
12) Pigment gall stones. (March/April, 2008)
13) Serologic markers of hepatitis B virus (HBV). (Sep/Oct. 2007)
14) Etiology of hepatocellular carcinoma. (May, 2007)
15) Complications of cirrhosis. (Oct. 2005)
16) Etiology of hepatocellular carcinoma. (March/April, 2005)
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17) Effects of gall stones. (Oct. 2004)
18) Hepatoma. (Oct/Nov. 2002)
19) Gall stones. (Oct/Nov. 2002)
High-Yield Topics
Cirrhosis
Alcoholic liver disease
Primary biliary cirrhosis
Cholelithiasis
Viral hepatitis
Wilson disease
Hepatocellular carcinoma
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Cirrhosis
“Represent severe chronic injury to liver with diffuse disruption of hepatic architecture.”
Etiology:
i) Alcoholic cirrhosis (Nutritional cirrhosis or Laennec cirrhosis).
ii) Post-necrotic cirrhosis (Post-hepatitic cirrhosis): Chronic hepatitis B; Chronic hepatitis C.
iii) Biliary cirrhosis.
iv) Pigment cirrhosis in hemochromatosis.
v) Cirrhosis in Wilson disease.
vi) Cirrhosis in α1-antitrypsin deficiency.
vii) Cirrhosis in autoimmune hepatitis.
viii) Cirrhosis in non-alcoholic fatty liver disease.
ix) Indian childhood cirrhosis.
x) Cryptogenic cirrhosis.
Pathogenesis:
1) Loss of hepatocytes with injury either by necrosis or apoptosis.
2) Restoration of lost parenchyma by regeneration, proliferation of residual cells or by stem
cell activation and differentiation to hepatocytes.
3) Scarring with fibrosis mediated by myofibroblasts derived from stellate cells with the role
of PDGF, TGF-β, IL-1 and TNF.
4) Vascular derangement as vascular shunting due to smooth muscle contraction of blood
vessels, contraction of myofibroblasts and compression of sinusoids.
Morphology: Gross: Surface of liver appears with nodules of varying size.
Morphologic classification:
1) Micronodular cirrhosis: Nodules are of <3 mm in diameter.
E.g.: Alcoholic cirrhosis.
2) Macronodular cirrhosis: Nodules are of >3 mm in diameter.
E.g.: Post-necrotic cirrhosis.
3) Mixed cirrhosis: Both micronodular and macronodular patterns are seen.
C/S: Gray-brown nodules are separated from one another by gray-white fibrous septa.
Micro.: Regenerative parenchymal nodules surrounded by fibrous bands and a variable
degree of vascular shunting.
Morphology of alcoholic cirrhosis
Gross: Initially, liver appears enlarged and fatty with micronodular cirrhosis but later, it
shrinks and becomes non-fatty with macronodular cirrhosis.
Micro.: Fibrous septa surround the regenerating parenchymal nodules and extend from
central vein to portal regions, or portal tract to portal tract, or both. The hepatic parenchyma
within the nodules shows extensive fatty change early in the disease but greatly reduced in
advanced disease. The fibrous septa usually contain sparse infiltrate of mononuclear cells
with some bile duct proliferation.
Morphology of post-necrotic cirrhosis
Gross: Liver appears small and shrunken having distorted shape with irregular and coarse
scars and nodules of varying size.
Micro.: Thick fibrous septa surrounding the regenerating parenchymal nodules contain
prominent mononuclear inflammatory cell infiltrate and often there is extensive proliferation
of bile ductules. Liver cells vary considerably in size and multiple large nuclei are common
in regenerative nodules. Fatty change may or may not be present in the hepatocytes.
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C/P: 1) Can be asymptomatic.
2) Non-specific manifestations, such as anorexia, weight loss, and weakness.
3) Jaundice with pruritus, encephalopathy, and coagulopathy.
4) Palmar erythema and spider angiomas of skin in males.
5) Hypogonadism and gynecomastia in males.
Comp.:
1) Portal hypertension with clinical consequences:
i) Ascites.
ii) Portosystemic shunts manifest as hemorrhoids, esophagogastric varices, and caput
medusae.
iii) Congestive splenomegaly with hypersplenism may cause pancytopenia.
iv) Hepatic encephalopathy.
2) Hepatocellular carcinoma.
Cause of death: Hepatic encephalopathy; Bleeding from esophageal varices; Bacterial
infections; Hepatocellular carcinoma.
Viral Hepatitis
I) Acute viral hepatitis
*Most common consequence of all hepatotropic viruses.
Causes: HAV; HBV; HCV; HDV; HEV.
Phases:
1) Incubation period: Asymptomatic period.
2) Pre-icteric phase: Seen with fatigue, anorexia, nausea, vomiting, or headache. Serum
transaminases may be elevated.
3) Icteric phase: Seen with jaundice, pruritus, tender hepatomegaly, and dark-colored urine.
Elevated levels of serum bilirubin, transaminases & alkaline phosphatase.
4) Post-icteric phase: Clinical and biochemical recovery is seen.
Morphology
Gross: Liver may be normal in size, enlarged or shrunken.
Micro.: 1) Portal and lobular inflammatory infiltrate comprised predominantly of
lymphocytes and variably admixed with plasma cells and eosinophils.
2) Hepatocytes may undergo necrosis or apoptosis.
4) Severe cases show confluent necrosis of hepatocytes around central veins leading to
central-portal bridging necrosis and parenchymal collapse.
Diagnosis: 1) HAV: Detection of serum IgM antibodies.
2) HBV: Detection of HBsAg or HBcAg antibodies; PCR for HBV DNA.
3) HCV: ELISA for HCV antibodies; PCR for HCV RNA.
4) HDV: Detection of serum IgM and IgG antibodies; PCR for HDV RNA.
5) HEV: Detection of serum IgM and IgG antibodies; PCR for HEV RNA.
Fate: Recovery; Fulminant hepatitis.
II) Chronic viral hepatitis
“Symptomatic, biochemical or serologic evidence of continuing or relapsing hepatic disease
for more than 6 months.”
Causes: HBV; HCV(MC); HDV.
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Morphology
1) Mononuclear portal infiltration with interface hepatitis at the interface between
hepatocellular parenchyma and portal tract stroma.
2) ‘Ground-glass’ hepatocytes with chronic hepatitis B.
3) Lymphoid aggregates in the portal tracts, and steatosis with chronic hepatitis C.
4) Fibrous septa may be seen extending between portal tracts along with increasing ductular
reaction that lead to development of cirrhosis with scarring and nodule formation.
C/P: Fatigue, loss of appetite or mild jaundice; Mild tender hepatomegaly or splenomegaly.
Inv.: Elevated serum transaminases; Prolonged PT; Hyperglobulinemia; Hyperbilirubinemia;
Elevated alkaline phosphatase.
Diagnosis: 1) HBV: Detection of HBsAg or HBcAg antibodies; PCR for HBV DNA.
2) HCV: ELISA for HCV antibodies; PCR for HCV RNA.
3) HDV: Detection of serum IgM and IgG antibodies; PCR for HDV RNA.
Comp.: Cirrhosis; Hepatocellular carcinoma.
Liver Abscess
Site: Right lobe of liver (MC).
Causative organisms: Most commonly bacteria (e.g., E.coli, Klebsiella, Pseudomonas).
Risk factors: Old age; Immunosuppression (AIDS); Chemotherapy.
Routes of spread:
1) Hematogenous spread.
2) Ascending infection in biliary tract.
3) Direct infection.
4) Iatrogenic.
Morphology: Gross: Hepatomegaly with single or multiple abscesses of varying size.
Micro.: Abscesses have a central liquefied region composed of necrotic leukocytes and tissue
cells. Surrounding area may show vascular dilation and parenchymal and fibroblastic
proliferation, indicating chronic inflammation and repair.
C/P: Pain in the right upper quadrant, fever, tender hepatomegaly and jaundice may be seen.
Inv.: Leukocytosis; Elevated serum alkaline phosphatase; Blood culture.
Comp.: Peritonitis.
Alcoholic Liver Disease
“The threshold for the development of alcoholic liver disease is consumption of 80 g/day of
alcohol.”
Sex: M>F
Risk factors: Female gender; Comorbid conditions (iron overload or viral hepatitis).
Pathogenesis: Exposure to alcohol causes steatosis, dysfunction of mitochondrial and
cellular membranes, hypoxia, and oxidative stress.
Forms of alcoholic liver injury:
I) Hepatic steatosis (Fatty liver): It is reversible.
Morphology: Gross: Enlarged, soft, yellow and greasy liver.
Micro.: Microvesicular and macrovesicular fatty change of hepatocytes.
C/P: Hepatomegaly.
Inv.: Mild elevation of serum bilirubin and alkaline phosphatase.
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II) Alcoholic steatohepatitis
Morphology: Swelling of hepatocytes with Mallory-Denk bodies (eosinophilic cytoplasmic
inclusions made up of tangled skeins of intermediate filaments); Necrosis of hepatocytes with
surrounding neutrophilic infiltrates.
C/P: Tender hepatomegaly, anorexia, weight loss, and upper abdominal discomfort.
Inv.: Neutrophilia; Elevated bilirubin, alkaline phosphatase, and aminotransferases
(AST>ALT).
III) Alcoholic steatofibrosis
Morphology: Fibrosis with chicken wire fence pattern around hepatocytes; Cirrhosis with
nodularity (micronodular or Laennec cirrhosis).
Inv.: Hypoproteinemia; Elevated bilirubin, alkaline phosphatase and aminotransferases.
Cause of death: Hepatic coma; GIT hemorrhage; Hepatorenal syndrome; Hepatocellular
carcinoma.
Nonalcoholic steatohepatitis (NASH)
“Refers to nonalcoholic fatty liver disease (NAFLD) patients who demonstrate steatohepatitic
injury with histologic features similar to those seen with alcoholic hepatitis.”
Pathogenesis:
i) Insulin resistance with excessive accumulation of lipid in hepatocytes.
ii) Hepatocyte injury with pro-inflammatory state.
iii) Release of cytokines such as TNF-α and TGF-β locally from Kupffer cells leads to the
activation of stellate cells, collagen deposition, and scarring.
Morphology:
i) Steatosis (≥5% of hepatocytes), lobular inflammation, and ballooned hepatocytes.
ii) Fibrosis typically develops around the central vein as a fine spider web of pericellular
collagen deposition.
iii) Progression of fibrosis usually manifests as periportal fibrosis, followed by bridging
fibrosis and cirrhosis.
C/P: Asymptomatic; Fatigue, or right-sided abdominal discomfort with hepatomegaly.
Inv.: Serum AST and ALT are elevated; Radiology (USG); Biopsy.
Comp.: Hepatocellular carcinoma; Cardiovascular disease.
Primary Biliary Cholangitis (PBC)
“An autoimmune disease characterized by inflammatory destruction of small- and mediumsized intrahepatic bile ducts.”
Age: 40-50 yrs.
Sex: F>M
Pathogenesis: Exposure to environmental factors like infections and toxic chemicals in
genetically susceptible individuals may lead to expression of auto-antigens on bile duct
epithelial cells and the resultant destruction by T lymphocytes. The retention of bile salts due
to bile duct injury leads to secondary hepatocellular injury.
Morphology:
i) Lymphocytic infiltration and epithelial injury involving the small interlobular bile ducts
leading to their loss (ductopenia).
ii) Poorly formed epithelioid granulomas are often present in the portal tracts.
iii) Portal lymphoplasmacytic inflammation and ductular reaction.
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iv) Cholate stasis: Bile accumulation is seen in periportal/periseptal regions. Stasis of bile
salts leads to swelling of periportal hepatocytes, which have clear cytoplasm with granular
strands (feathery degeneration).
C/P: Fatigue, hypercholesterolemia, pruritus, splenomegaly, jaundice, skin
hyperpigmentation, xanthelasmas, steatorrhea, and osteomalacia.
Inv.: Elevated serum alkaline phosphatase, antimitochondrial antibodies, and IgM antibody.
Comp.: End-stage liver disease; Hepatocellular carcinoma.
Associations: Sjögren syndrome, systemic sclerosis, thyroiditis, and rheumatoid arthritis.
Hepatocellular Carcinoma (Hepatoma)
“Primary malignant tumor of liver.”
Sex: M>F
Etiology: 1) Viral infections: HBV; HCV.
2) Toxins: Alcohol; Aflatoxin.
3) Metabolic diseases: Hereditary hemochromatosis; α1-antitrypsin deficiency.
Precursor lesions: Hepatocellular adenoma; High grade dysplastic nodule; Small cell
change.
Genetic alterations: Activating β-catenin mutations and inactivating p53 mutations.
Morphology: Gross: Hepatomegaly with unifocal large mass or multifocal nodules or
diffusely infiltrative lesion with pale or variegated appearance.
Micro.: Well and moderately differentiated tumors are composed of cells that resemble
normal hepatocytes, while poorly differentiated tumors show marked cytologic atypia. The
tumor cells grow in thick plates or trabeculae, pseudoglandular structures with bile plugs, or
sheets.
C/P: Vague upper abdominal pain, fatigue, weight loss, or an abdominal mass; Jaundice,
fever, or esophageal variceal bleeding may be seen.
Inv.: Elevated serum α-fetoprotein levels; Radiology (USG; CT; MRI).
Cause of death: Cachexia; GIT or esophageal variceal bleeding; Hepatic coma.
Metastasis: Hematogenous spread to the lung.
Cholelithiasis (Gallstones)
*Most common biliary tract disease.
Types: Cholesterol stones and pigment stones.
I) Cholesterol stones: Most common in western nations.
Composition: Predominantly composed of cholesterol monohydrate crystals.
Risk factors: Advancing age; Female sex; Obesity; Metabolic syndrome; Estrogen exposure;
Gall bladder stasis; Hereditary factors.
Pathogenesis:
1) Cholesterol concentrations exceed the solubilizing capacity of bile (supersaturation).
2) Nucleation of cholesterol into solid monohydrate crystals is favoured by hypomotility of
the gall bladder.
3) Hypersecretion of mucus in the gall bladder traps nucleated crystals and facilitates stone
formation.
Morphology: Pure cholesterol stones are pale yellow, round to ovoid, and have a finely
granular, hard external surface. The stones take on a gray-white to black color with
increasing proportions of calcium carbonate, phosphates, and bilirubin.
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II) Pigment stones: Most common in non-western nations.
Composition: Predominantly composed of calcium salts of unconjugated bilirubin.
Causes: Chronic hemolytic anemia; Severe ileal dysfunction; Biliary tract infections (E.coli,
Ascaris lumbricoides or C. sinensis).
Pathogenesis: Increased unconjugated bilirubin favors precipitation of calcium bilirubin
salts. Black stones are found in sterile gall bladder bile, and brown stones are found in
infected large bile ducts.
Morphology:
Black stones: Multiple, friable stones with spiculated and molded contours.
Brown stones: Soft and laminated and may have a soaplike or greasy consistency.
C/P: Asymptomatic (MC); Right upper-quadrant or epigastric pain may be seen.
Comp.: Cholecystitis; Empyema; Cholangitis; Obstructive cholestasis; Pancreatitis;
Carcinoma of gall bladder; Gall stone ileus (Bouveret syndrome).
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18. The Pancreas
MCQs
1) Delta cells of pancreas secrete. (Feb. 2022)
a) Insulin b) Glucagon c) Somatostatin d) Amylin
10 Marks
1) A 48 years old male was admitted with acute abdominal pain following a heavy meal. He
is an alcoholic. (Oct. 2005)
a) What is the probable diagnosis?
b) What important investigations will support your diagnosis?
c) What is the pathology in the organ involved?
Ans: Acute pancreatitis.
4 Marks
1) Acute pancreatitis. (Oct. 2008)
2) Acute pancreatitis. (Sep/Oct. 2007)
3) Acute pancreatitis. (Sep. 2003)
High-Yield Topics
Acute pancreatitis
Pancreatic carcinoma
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Acute Pancreatitis
“Reversible pancreatic parenchymal injury associated with inflammation.”
Etiology: Alcoholism; Gall stones; Hypercalcemia; Trauma; Shock; Mumps; Drugs
(azathioprine); Mutations in trypsinogen gene (PRSS1); Cystic fibrosis.
Pathogenesis:
I) Mechanisms of inappropriate activation of pancreatic enzymes:
1) Pancreatic duct obstruction initiates inflammation and interstitial edema, resulting in
ischemic injury to acinar cells.
2) Primary acinar cell injury causes release of digestive enzymes & inflammation leading to
autodigestion of pancreas.
II) Consequences of inappropriate intrapancreatic activation of trypsin:
1) Activation of prophospholipase & proelastase, which degrade fat cells & damage elastic
fibers of blood vessels, respectively.
2) Activation of kinin, clotting & complement systems causes inflammation & small-vessel
thromboses leading to acinar damage.
Morphology: Gross: Pancreas appears red-black with interspersed foci of yellow-white
chalky fat necrosis.
Microscopy:
1) Acute interstitial pancreatitis: Mild inflammation, interstitial edema, & focal fat necrosis
within the pancreas and the peripancreatic fat.
2) Acute necrotizing pancreatitis: Parenchymal necrosis involves ducts, acini and islets.
3) Hemorrhagic pancreatitis: Intraparenchymal hemorrhage is associated.
C/P: Abdominal pain, anorexia, nausea & vomiting.
Inv.: Elevated serum levels of amylase & lipase; Leukocytosis; Hypocalcemia; CT scan.
Comp.: ARDS; Acute renal failure; Shock; Pancreatic pseudocyst.
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19. The Kidney
MCQs
1) Postinfectious glomerulonephritis is most commonly due to. (May, 2022)
a) Tuberculosis b) Staphylococcus c) Streptococcus d) E.coli
2) Microalbuminuria means daily excretion of which range of albumin. (Feb. 2022)
a) 300-500 mg/24 hours b) 500-1000 mg/24 hours
c) 30-300 mg/24 hours d) 10-30 mg/24 hours
5 Marks
1) Write a note on crescentic glomerulonephritis and its light microscopy findings. (Feb.
2022)
10 Marks
1) An 8 year old boy came with history of puffiness of face with decreased urine output. His
urine examination revealed numerous RBCs with mild proteinuria. Renal biopsy was
performed which showed glomerular hypercellularity with neutrophils. (Feb. 2019)
a) What is your diagnosis?
b) Describe the pathogenesis and laboratory findings in this condition.
c) What are the features on immunofluorescence and electron microscopy?
Ans: Post-streptococcal glomerulonephritis.
2) A 60 year old male having fever and weight loss presented with painless hematuria, flank
pain and palpable mass in the left renal angle. CT scan confirmed a specific organ mass
lesion, regional lymph nodes and renal vein involvement. Chest radiography showed
pulmonary “cannonball” secondaries and his PCV is of 60%. (Jan. 2013)
a) What is the provisional diagnosis?
b) Discuss the etiopathogenesis of the lesion.
c) Describe its morphology.
d) Mention various paraneoplastic syndromes produced by this lesion.
Ans: Renal cell carcinoma.
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3) A 40 year old female patient presented with clinical manifestations of massive proteinuria,
hypoalbuminemia, generalised edema with hyperlipidemia and lipiduria. (Aug. 2009)
a) What is the provisional diagnosis?
b) Mention the causes of this syndrome.
c) Discuss the pathophysiology of the same.
Ans: Nephrotic syndrome.
4) A 8 year old boy was admitted with malaise, fever, oliguria, cocoa-coloured urine 2 weeks
after recovery from sore throat. On examination, he was found to have peri orbital oedema
and moderate hypertension. (March/April, 2008)
a) What is the probable diagnosis?
b) Describe the etiopathogenesis of the condition?
c) What is the morphology of the organ involved?
d) List the urinary findings of the condition?
Ans: Post-streptococcal glomerulonephritis.
4 Marks
1) Etiology and morphology of renal cell carcinoma. (Oct. 2022)
2) Describe the etiopathogenesis and morphology of acute poststreptococcal
glomerulonephritis. (May, 2022)
3) Types and morphology of renal cell carcinoma. (July, 2019)
4) Give causes of crescent formation. Give gross and microscopic picture of rapidly
progressive glomerulonephritis. (Feb. 2018)
5) Give the gross and microscopic findings in a case of chronic pyelonephritis. (July,
2017)
6) Morphology of renal cell carcinoma. (July, 2016)
7) Kidney lesions in hypertension. (Jan. 2016)
8) Etiopathogenesis of chronic pyelonephritis. (Jan. 2015)
9) Name the types of renal lesions in diabetic nephropathy and describe the histology of
glomerular lesions. (Jan. 2014)
10) Wilms tumor. (July, 2013)
11) Renal cell carcinoma. (July, 2012)
12) Chronic pyelonephritis. (July, 2011)
13) Renal dysplasia. (Jan. 2011)
14) Chronic contracted granular kidney. (March, 2010)
15) Chronic pyelonephritis. (Feb. 2009)
16) Kidney changes in hypertension. (Sep/Oct. 2007)
17) Chronic pyelonephritis. (May, 2007)
18) Wilms tumour. (May, 2006)
19) Gross and microscopic picture of chronic pyelonephritis. (May, 2006)
20) Diabetic kidney. (Oct. 2005)
21) Renal changes in diabetes mellitus. (Oct. 2004)
22) Classification of glomerular diseases. (Oct/Nov. 2002)
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Undergraduate Pathology Series
2 Marks
1)
2)
3)
4)
5)
Two congenital syndromes associated with Wilms tumor. (Aug. 2021)
Mention four microscopic features of chronic pyelonephritis. (March, 2021)
Give four microscopic features of diabetic kidney. (July, 2018)
List four causes of chronic glomerulonephritis. (Feb. 2017)
Give the gross and morphologic picture of proliferative glomerulonephritis. (Jan.
2016)
6) Morphology of post streptococcal glomerulonephritis. (July/Aug. 2014)
7) Gross pathology of kidneys in benign and malignant nephrosclerosis. (Jan. 2012)
8) Renal stones. (April, 2009)
9) Wilms tumor. (Oct. 2008)
10) Types of renal calculi. (Oct. 2006)
11) Wilms tumor. (March/April, 2005)
12) Stag horn calculus. (Oct. 2004)
13) Renal stones. (Sep. 2003)
14) Differences between adult and infantile polycystic diseases of the kidney.
(March/April, 2003)
High-Yield Topics
Nephrotic syndrome
Membranous nephropathy
Rapidly progressive glomerulonephritis
Chronic pyelonephritis
Diabetic nephropathy
Wilms tumor
Minimal change disease
Post streptococcal glomerulonephritis
Chronic glomerulonephritis
Urolithiasis
Polycystic kidney disease
Renal cell carcinoma
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Glomerular Diseases – Classification
1) Primary glomerular diseases
Minimal change disease
Acute postinfectious glomerulonephritis
Focal segmental glomerulosclerosis
Membranous nephropathy
Membranous glomerulonephritis
2) Glomerulopathies secondary to systemic diseases
Lupus nephritis
Diabetic nephropathy
Amyloidosis
Goodpasture syndrome
3) Hereditary disorders
Alport syndrome
Fabry disease
Post-Streptococcal Glomerulonephritis
“Characterized by formation of immune complexes with enlarged, hypercellular glomeruli &
development of nephritic syndrome.”
Age: Children (6-10yrs).
Causative agent: Group A β-hemolytic streptococci (types 1,4, & 12).
Pathogenesis: With streptococcal infection of the pharynx or skin, antibodies are formed
against streptococcal antigens (SpeB). Deposited immune complexes in glomeruli initiates
inflammation with compliment activation leading to nephritic syndrome.
Morphology:
1) Light microscopy: Glomeruli show obliteration of capillary lumen due to infiltration with
neutrophils & monocytes, and proliferation of endothelial & mesangial cells. Interstitial
edema & inflammation with RBC casts in tubules.
2) Fluorescence microscopy: Granular deposits of IgG & C3 in the mesangium & along the
glomerular basement membrane.
3) Electron microscopy: Discrete, amorphous electron-dense deposits, mostly subepithelial
(hump-like) in location.
C/P: Features of acute nephritic syndrome (hematuria (smoky or cola-colored urine),
oliguria, hypertension, azotemia) with fever, nausea & periorbital edema.
Inv.: 1) Urine: Mild proteinuria, hematuria with dysmorphic RBCs, and red cell casts.
2) Elevated antistreptococcal antibody (Anti-streptolysin O) titres.
3) Low serum complement (C3) levels.
Comp.: RPGN; Chronic glomerulonephritis.
Crescentic (Rapidly Progressive)
Glomerulonephritis
“A clinical syndrome characterized by relatively rapid and progressive loss of renal function
associated with severe oliguria and signs of nephritic syndrome.”
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Classification
Type I (Anti-GBM Antibody): Renal limited; Goodpasture syndrome.
Type II (Immune Complex): Idiopathic; Postinfectious glomerulonephritis; Lupus nephritis;
IgA nephropathy; Henoch-Schönlein purpura.
Type III (Pauci-Immune): ANCA-associated; Idiopathic; Granulomatosis with polyangiitis;
Microscopic polyangiitis.
Pathogenesis: i) Idiopathic.
ii) Anti-GBM antibody mediated, immune complex mediated or ANCA mediated.
Morphology
Gross: Enlarged and pale kidneys, often with petechial hemorrhages on the cortical surfaces.
Micro.:
1) Light microscopy:
i) Glomeruli often show focal and segmental necrosis, and variably show diffuse or focal
endothelial proliferation, and mesangial proliferation.
ii) Crescents are formed by proliferation of glomerular epithelial cells and by migration of
monocytes and macrophages into the urinary space. They have frequently prominent fibrin
strands between the cellular layers.
iii) In time, most crescents undergo organization and foci of segmental necrosis resolve as
segmental scars.
2) Fluorescence microscopy:
i) Anti-GBM antibody mediated: Linear deposits of IgG and C3 in the GBM.
ii) Immune complex mediated: Granular deposits of Ig and complement.
iii) Pauci-immune: Little or no deposition of immune reactants.
3) Electron microscopy: May show ruptures in the GBM and discloses deposits in immune
complex mediated cases.
C/P: Hematuria, oliguria, variable hypertension and edema.
Inv.: 1) Urine: Hematuria with red blood cell casts and moderate proteinuria.
2) Serum analyses for anti-GBM antibodies, antinuclear antibodies, and ANCAs.
Com.: Renal failure.
Nephrotic Syndrome
Features: Massive proteinuria (3.5gm/day or more); Hypoalbuminemia (<3gm/dl);
Generalized edema; Hyperlipidemia & lipiduria.
Etiology:
I) Primary glomerular diseases: Minimal change disease; Membranous nephropathy;
FSGN; MPGN.
II) Systemic diseases: Diabetes mellitus; Amyloidosis; SLE; Infections (Hepatitis B & C).
Pathogenesis:
I) Edema: Increased permeability of glomerular capillary wall for protein causes massive
proteinuria leading to hypoalbuminemia. Decreased plasma osmotic pressure results in
development of edema (generalised & pitting).
II) Hyperlipidemia: Increased blood cholesterol, TG, VLDL & LDL levels due to increased
synthesis, decreased catabolism or abnormal transport of lipids. Hyperlipidemia leads to
lipiduria.
III) Infections: Loss of immunoglobulins in urine increases the risk of developing
staphylococcal & pneumococcal infections.
IV) Thrombotic complications: Loss of endogenous anticoagulants in urine causes
increased risk for thrombotic complications.
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Chronic Glomerulonephritis
“Represents end-stage glomerular disease.”
Etiology: Membranous nephropathy; MPGN; IgA nephropathy; FSGN.
Morphology: Gross: Symmetrically contracted kidneys with diffuse granular surface.
C/S: Thinned cortex with an increase in peripelvic fat.
Micro.: Obliterated glomeruli form acellular eosinophilic masses; Interstitium shows tubular
atrophy with mononuclear cell infiltration & fibrosis; Arteriolar sclerosis.
C/P: Anorexia, anemia, or vomiting; Hypertension, proteinuria or azotemia may be seen.
Comp.: Renal insufficiency or death.
Diabetic Nephropathy
*MC cause of chronic kidney failure.
*Renal failure is the second MC cause of death in diabetics.
Morphology:
I) Glomerular lesions:
1) Diffuse basement membrane thickening of glomerular capillaries.
2) Diffuse increase in mesangial matrix causes diffuse mesangial sclerosis.
3) Nodular glomerulosclerosis or Kimmelstiel-Wilson disease:
i) Ovoid or spherical, often laminated, nodules of matrix situated in the periphery of the
glomerulus. Nodules lie within the mesangial core of the glomerular lobules and often show
features of mesangiolysis.
ii) Prominent accumulations of hyaline material in capillary loops (fibrin caps) or adherent to
Bowman capsules (capsular drops).
iii) Ischemia leads to tubular atrophy and interstitial fibrosis.
II) Renal vascular lesions: Macrovascular disease manifests as renal atherosclerosis and
hyaline arteriolosclerosis affecting both afferent and efferent arterioles.
III) Pyelonephritis: Presents with inflammation of interstitium and tubules either in acute or
chronic form. Acute pyelonephritis may cause papillary necrosis.
Manifestations: Microalbuminuria (earliest); Overt nephropathy with macroalbuminuria;
Hypertension; End-stage renal disease.
Chronic Pyelonephritis
“Chronic inflammation affecting the tubules, interstitium & renal pelvis.”
Predisposing factors: Vesicoureteral reflux & urinary tract obstruction.
Etiology: Urinary tract infection (E.coli (MC), Proteus, Klebsiella, Enterobacter).
Forms: Reflux nephropathy and chronic obstructive pyelonephritis.
I) Reflux nephropathy: MC form, either U/L or B/L.
Age: Childhood.
Causes: Congenital vesicoureteral reflex & intrarenal reflex with superimposed infection.
II) Chronic obstructive pyelonephritis:
Causes: Diffuse or localized obstructive lesions, superimposed with infections.
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Morphology:
Gross: 1) Irregularly scarred kidneys with asymmetric involvement in B/L cases.
2) Coarse, discrete, corticomedullary scars overlying dilated, blunted or deformed calyces
with flattening of the papillae.
3) Scarring usually involves poles of kidneys.
Micro.: 1) Tubules are either atrophic or hypertrophic. Dilated tubules may be filled with
casts resembling colloid (thyroidisation).
2) Chronic interstitial inflammation & fibrosis in the cortex & medulla.
C/P: Acute episodes present with back pain, fever, pyuria, & bacteriuria. Chronic disease
presents with renal insufficiency & hypertension.
Nephrosclerosis
“Sclerosis of small renal arteries & arterioles with a strong association of hypertension.”
Risk factors: Advancing age; Diabetes mellitus; Hypertension.
Pathogenesis:
1) Luminal narrowing caused by medial & intimal thickening and hyalinization of vascular
walls leads to ischemia.
2) Ischemia results in glomerulosclerosis & chronic tubulointerstitial injury.
Morphology:
Gross: Kidneys are either normal or reduced in size. Cortical surfaces may exhibit fine,
leathery granularity.
Micro.:
1) Hyaline arteriolosclerosis: Thickening & hyalinization of the walls of arterioles and small
arteries.
2) Fibroelastic hyperplasia: Medial hypertrophy, replication of the internal elastic lamina, and
increased myofibroblastic tissue in the intima of interlobular and arcuate arteries.
3) Patchy ischemic atrophy: Foci of tubular atrophy, interstitial fibrosis and glomerular
alterations such as sclerotic glomeruli.
C/P: Mild proteinuria and rarely renal failure.
Malignant Nephrosclerosis
“A renal vascular disorder associated with malignant or accelerated hypertension.”
Risk factors: Preexisting benign essential hypertension, chronic renal disease or
scleroderma.
Pathogenesis:
1) Vascular injury results in fibrinoid necrosis of vascular walls & intravascular thrombosis.
2) Hyperplasia of intimal smooth muscle of vessels causes hyperplastic arteriolosclerosis.
3) Luminal narrowing leads to ischemia.
Morphology: Gross: Flea-bitten appearance of the kidney with small, pinpoint petechial
hemorrhages on cortical surface.
Micro.:
1) Fibrinoid necrosis of arterioles and small arteries: Smudgy eosinophilic appearance of
vessel walls.
2) Hyperplastic arteriolosclerosis: Concentric, laminated (onion-skin) intimal thickening of
interlobular arteries & arterioles.
C/P: Marked proteinuria, hematuria & renal failure.
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Cystic Diseases of the Kidney
Autosomal Dominant (Adult) Polycystic Kidney Disease
Mode of inheritance: Autosomal dominant (AD).
*It is usually bilateral.
Genetic alterations: Mutations involving PKD1 & PKD2 which encode polycystin-1 &
polycystin-2 respectively.
Morphology: Gross: Enlarged kidneys with diffuse cystic external surface.
Micro.: Cysts show variable lining epithelia and are filled with serous or red to brown fluid;
Functioning nephrons dispersed between cysts.
C/P: Asymptomatic; Abdominal pain, hematuria or renal colic may be seen; Polyuria or
hypertension can be associated.
Associations: Polycystic liver disease; Berry aneurysms; Mitral valve prolapse.
Autosomal Recessive (Childhood) Polycystic Kidney
Disease
Subcategories: Perinatal, neonatal, infantine & juvenile.
Mode of inheritance: Autosomal recessive (AR).
Genetic alterations: Mutations of the PKHD1 gene, which encodes fibrocystin.
Morphology: Gross: Enlarged kidneys with smooth external surface. C/S: Spongy with
many cysts involving cortex & medulla.
Micro.: Cylindrical dilation of all collecting tubules, lined with cuboidal epithelium.
C/P: Renal failure.
Associations: Congenital hepatic fibrosis in infantile & juvenile forms.
Feature
Adult PKD
Childhood PKD
Inheritance
Age
Mutated genes
Defective proteins
Surface of kidneys
Origin of cysts
Liver comp.
AD
Adults
PKD1 & PKD 2
Polycystin 1& 2
Cystic surface
Tubules
Polycystic liver disease
AR
Perinatal to Juvenile
PKHD 1
Fibrocystin
Smooth surface
Collecting ducts
Congenital hepatic fibrosis
Multicystic Renal Dysplasia
“A sporadic disorder, either unilateral or bilateral.”
Morphology: Gross: Enlarged, irregular & multicystic kidney.
Micro.: Cysts are lined by flattened epithelium; Islands of undifferentiated mesenchyme,
often with cartilage & immature collecting ducts.
Associations: Ureteropelvic obstruction; Ureteral agenesis or atresia.
Comp.: Renal failure in B/L cases.
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Urolithiasis (Renal Calculi)
Site: Kidney (MC).
Sex: M>F
Age: 20-30yrs (MC).
*Mostly unilateral & multiple.
Predisposing factors: Increased concentration of stone constituents, changes in urinary pH,
decreased urine volume, presence of bacteria, deficiency in inhibitors of crystal formation.
Classification
I) Calcium stones: MC
Composition: Calcium oxalate or calcium oxalate mixed with calcium phosphate.
Causes: Idiopathic hypercalciuria (MC); Hypercalciuria & hypercalcemia seen with
hyperparathyroidism, diffuse bone disease, and sarcoidosis.
II) Magnesium ammonium phosphate stones or triple stones or struvite stones
Causes: Infections by urea-splitting bacteria (proteus) with alkaline urine.
e.g., Staghorn calculi.
III) Uric acid stones
Causes: Hyperuricemia, with gout or leukemia; Acidic urine.
IV) Cystine stones
Causes: Cystinuria; Acidic urine.
Morphology: Stones may have smooth or spiculated surface.
*Staghorn calculi: Massive stones with branching structures, occupying large portions of the
renal pelvis. They are usually composed of magnesium ammonium phosphate.
C/P: Asymptomatic; May cause renal colic, abdominal pain or hematuria.
Comp.: Secondary infections with urinary tract obstruction.
Renal Cell Carcinoma
“Primary malignant tumor of kidney.”
Age: 60-70yrs (MC).
Sex: M>F
Site: Poles of kidney (MC).
Risk factors: Tobacco usage (major); Obesity; Hypertension; Unopposed estrogen therapy;
Asbestos exposure; Chronic kidney disease.
Etiology: Sporadic (MC) or familial. Familial forms are autosomal dominant such as Von
Hippel-Lindau (VHL) syndrome & hereditary papillary carcinoma.
Classification
I) Clear cell carcinoma: MC form.
Genetic alterations: 3p deletions.
Origin: Proximal tubular epithelium.
Morphology: Gross: Solitary, unilateral, and spherical bright yellow-gray-white mass with
areas of hemorrhage & necrosis.
Micro.: Most are well differentiated with delicate branching vasculature. Round or polygonal
shaped cells with abundant clear or granular cytoplasm arranged in solid, trabecular or
tubular patterns.
II) Papillary carcinoma
Genetic alterations: Trisomies 7 & 17 and loss of Y Chr. in males.
Origin: Distal convoluted tubules.
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Morphology: Gross: Large masses with hemorrhagic & cystic areas.
Micro.: Cuboidal or low columnar cells, arranged in papillae with interstitial foam cells in
the cores. Stroma is scant, but highly vascularized.
III) Chromophobe carcinoma
Cell of origin: Intercalated cells of collecting ducts.
Morphology: Pale eosinophilic ells, often with a perinuclear halo, arranged in solid sheets.
IV) Collecting duct (Bellini duct) carcinoma
Cell of origin: Collecting duct cells in the medulla.
Morphology: Irregular channels, lined by highly atypical epithelium with a hobnail pattern.
C/P: Non-specific: Fever, weakness, & weight loss.
Specific: Costovertebral pain, palpable mass, & hematuria.
Paraneoplastic syndromes: Polycythemia; Hypercalcemia; Hypertension; Cushing
syndrome; Eosinophilia; Amyloidosis.
Metastasis: Lung (MC); Bone.
Wilms Tumor (Nephroblastoma)
“Primary malignant tumor of kidney.”
*MC primary renal tumor of childhood.
*Mostly unilateral.
Age: 2-5yrs (MC).
Precursor lesions: Nephrogenic rests.
Etiology: Sporadic (MC) or familial. Familial cases are seen with malformation syndromes
such as WAGR syndrome, Denys-Drash syndrome, and Beckwith-Wiedemann syndrome.
Genetic alterations: Germline mutations of WT1 or WT2 genes.
Morphology: Gross: Large, solitary, well circumscribed mass. C/S: Soft, homogeneous, tan
to gray with occasional foci of necrosis & hemorrhage.
Micro.: Triphasic combination of blastemal, stromal, and epithelial cell types is observed.
1) Blastemal component shows sheets of small blue cells.
2) Epithelial differentiation is seen in the form of abortive tubules or glomeruli.
3) Stromal cells are fibroblastic or myxoid in nature.
C/P: Large abdominal mass is felt. Hematuria, intestinal obstruction or hypertension may be
associated.
Metastasis: Lungs.
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20. The Lower Urinary Tract and Male
Genital System
10 Marks
1) 30 years old man with the H/o painless swelling in the right side of the scrotum for the past
6 months duration. Discuss about the differential diagnosis. (March/April, 2003)
4 Marks
1)
2)
3)
4)
5)
6)
Types and morphology of seminoma testis. (Feb. 2020)
Morphology of seminoma testis. (Feb. 2017)
Etiopathogenesis and morphology of carcinoma prostate. (July/Aug. 2014)
Undescended testes. (July, 2012)
Seminoma. (July, 2011)
Benign prostatic hyperplasia. (Sep/Oct. 2007)
2 Marks
1) Causes of prostatic enlargement with morphology of benign prostatic hyperplasia.
(July, 2019)
2) Four etiopathogenic factors of urinary bladder cancer. (July, 2018)
3) Draw a labelled diagram of seminoma testis and what is the route of spread. (July,
2018)
4) Classification of germ cell tumors of testis. (Jan. 2015)
5) Name three (3) pre-malignant (carcinoma-in-situ) lesions of penis. Mention the
common infective agent associated with these lesions. (Jan. 2014)
6) Microscopic picture in seminoma. (July, 2013)
7) Name one benign tumor and three premalignant (carcinoma in situ) lesions of penis.
(Jan. 2013)
8) Condyloma acuminata. (Aug. 2010)
9) Name the benign and malignant tumors of the penis. (March, 2010)
10) Seminoma. (Oct. 2006)
11) Seminoma testis. (Oct. 2005)
12) Classification of germ cell tumors of testis. (April/May, 2004)
High-Yield Topics
Bladder Cancer
Cryptorchidism
Seminoma
Prostatic carcinoma
Premalignant lesions of penis
Classification of testicular tumors
Benign prostatic hyperplasia
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Bladder Cancer
*MC bladder cancer is urothelial carcinoma.
Etiology:
1) Cigarette smoking.
2) Industrial exposure to aryl amines (2-naphthylamine).
3) Infection with Schistosoma haematobium.
4) Long-term use of analgesics.
5) Heavy long-term exposure to cyclophosphamide.
6) Irradiation.
Tumors of the Penis
Benign: Condyloma acuminatum.
Malignant:
A) Carcinoma in Situ: Bowen disease; Bowenoid papulosis.
** Causative agent: HPV (MC – Type 16).
B) Invasive Carcinoma: Squamous cell carcinoma.
Condyloma Acuminatum
“Benign tumor of penis and a sexually transmitted wart.”
Cause: HPV (Types 6 & 11).
Sites: External genitalia (penis) or perineal areas.
Morphology: Gross: Single or multiple, sessile or pedunculated, red papillary excrescences.
Micro.: Papillary connective tissue stroma is covered by epithelium that exhibit
hyperkeratosis, acanthosis & koilocytosis.
Comp.: Rare transformation to in situ or invasive cancers.
Cryptorchidism (Undescended Testes)
“Complete or partial failure of the intra-abdominal testes to descend into the scrotal sac.”
*Congenital anomaly of testis, mostly unilateral & occurs as an isolated anomaly.
Sites of arrest: Inguinal canal (MC).
Morphology: Gross: Testis is small, and firm.
Micro.: Seminiferous tubules appear as dense cords of hyaline connective tissue outlined by
prominent basement membranes. Leydig cells appear prominent. Interstitial stroma is
increased.
C/P: Asymptomatic; Empty scrotal sac; Sterility.
Comp.: Inguinal hernia; Testicular cancer.
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Testicular Tumors – Classification
I) Germ Cell Tumors Derived From Germ Cell Neoplasia in Situ
a) Tumors of a single histologic type (pure forms): Seminoma.
b) Nonseminomatous germ cell tumors: Embryonal carcinoma; Yolk sac tumor,
postpubertal type; Choriocarcinoma; Teratoma, postpubertal type.
c) Nonseminomatous germ cell tumors of more than one histologic type: Mixed germ cell
tumor.
II) Germ Cell Tumors Unrelated to Germ Cell Neoplasia in Situ: Spermatocytic tumor;
Yolk sac tumor, prepubertal type; Teratoma, prepubertal type.
III) Sex Cord-Stromal Tumors: Leydig cell tumor; Sertoli cell tumor.
Seminoma
“Malignant tumor of testis.”
*MC germ cell tumor of testis.
Age: 40s.
Precursor: Germ cell neoplasia in situ (GCNIS).
Predisposing conditions: Cryptorchidism.
Genetic alterations: Isochromosome 12p.
Morphology: Gross: Enlargement of testis. C/S: Homogeneous, gray-white & lobulated.
Micro.: 1) Sheets of uniform cells divided into poorly demarcated lobules by delicate fibrous
septa containing a lymphocytic infiltrate.
2) The classic seminoma cell is large and round to polyhedral & has a distinct cell membrane.
Cytoplasm appears clear and nucleus is large and centrally placed with prominent nucleoli.
3) Some tumors contain syncytiotrophoblasts.
C/P: Painless enlargement of testis.
Metastasis: Lymphatic spread involves retroperitoneal para-aortic nodes. Hematogenous
dissemination occurs late to lungs.
Prognosis: Seminoma is radiosensitive & has best prognosis.
Painless Scrotal Mass
Differential diagnosis:
1) Common: Hydrocele; Nonincarcerated inguinal hernia; Varicocele
2) Uncommon: Spermatocele; Hematocele; Fluid overload; Testicular cancers (seminoma,
teratoma, lymphoma, leydig cell tumor)
Benign Prostatic Hyperplasia (BPH)
*MC benign prostatic disease in males aged >50yrs.
Site: Transition zone of prostate (MC).
Risk factors: Advancing age.
Etiopathogenesis: Dihydrotestosterone (DHT) derived from stromal cells mediate the release
of growth factors such as FGF & TGF β. These growth factors are believed to act by
increasing the proliferation of stromal cells & decreasing the death of epithelial cells.
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Morphology: Gross: Prostate is enlarged. C/S: Nodular hyperplasia forms discrete nodules.
Early nodules are pale grey & firm. Late nodules are yellow-pink & soft.
Micro.: Early nodules contain mostly fibromuscular stroma. Late nodules contain mostly
glands. Glands are bilayered (inner-columnar & outer-flattened). Foci of reactive squamous
metaplasia in some cases.
C/P: Increased urinary frequency, nocturia, dysuria, difficulty in starting & stopping the
stream of urine; Distended bladder; Increased risk for urinary tract infection.
Adenocarcinoma of the Prostate
*MC cancer of males.
Age: >50 yrs.
Site: Posterior aspect of peripheral zone (MC).
Etiopathogenesis:
1) Advancing age.
2) Hormonal influences: Androgens play a role.
3) Racial factors: Blacks are frequently affected.
4) Environmental factors: Dietary influences play a role.
5) Geographic factors: Uncommon in Asians.
6) Family history: Increased risk for men with the first-degree relatives with prostate cancer.
Genetic alterations: 1) Germ line mutations involving genes, such as BRCA2 & HOXB13.
2) Acquired mutations, such as overexpression of the gene ETS, amplification of the gene
MYC, deletions involving the genes PTEN, & RB and loss of TP53.
Precursor lesion: Prostatic intraepithelial neoplasia (PIN).
Morphology: Gross: Gritty and firm growth.
Micro.: Well differentiated tumors show uniform round crowded glands, lined by a single
layer of cuboidal or low columnar epithelium. Cytoplasm appears pale-clear to amphophilic
and nuclei are enlarged with large nucleoli. Poorly differentiated tumors show tumor cells
infiltrating the stroma in the form of cords, sheets and nests.
Grading: Gleason system grades prostate cancer from grade 1 (well differentiated) to grade 5
(no glandular differentiation). Gleason score is obtained by adding primary grade assigned to
the dominant pattern with secondary grade given to the second most frequent pattern of the
tumor.
C/P: Asymptomatic; Nodule felt on rectal exam; Late urinary symptoms (difficulty in
starting or stopping the stream, frequency, dysuria or hematuria).
Inv.: Elevated PSA levels; Elevated urine PCA3 scores; Digital rectal exam; Transrectal
USG; Transrectal needle biopsy.
Metastasis: Lymphatic spread involves obturator and para-aortic nodes. Hematogenous
spread involves mainly bones producing osteoblastic secondaries.
**Causes of prostatic enlargement: Benign prostatic hyperplasia and carcinoma of the
prostate.
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21. The Female Genital Tract
MCQs
1) A lady presented with abdominal mass. On surgery she was found to have bilateral ovarian
masses with smooth surface. On microscopy they revealed mucin secreting cells with signet
ring shape. What is the most likely diagnosis. (Feb. 2022)
a) Dysgerminoma b) Mucinous adenocarcinoma of ovaries
c) Dermoid cyst d) Krukenberg tumor
5 Marks
1) Teratoma. (May, 2022)
2) Write a note on screening for cervical cancer. (Feb. 2022)
10 Marks
1) A 54-year old woman noted a 6-month history of progressive vaginal discharge sometimes
blood tinged. She was 2 years post menopausal and earlier took oral contraceptives for 10
years. She complains of right back pain and right leg swelling. The per-speculum
examination showed an unhealthy cervix with ulceration. (July/Aug. 2014)
a) What is the most likely diagnosis?
b) Write two (2) high risk, two (2) low risk microorganism & two (2) social factors
associated with this lesion.
c) Name the screening tests performed for it.
d) Describe the preventive measures.
Ans: Cervical carcinoma.
2) A 40 year old female has 16 weeks amenorrhoea and on examination her uterus size was
larger and corresponds to 21 weeks size gestation. She complaints bleeding and passing grape
like vesicles per vaginum. Her blood and urine hCG levels are elevated and higher than
normal pregnancy. (July, 2013)
a) What is the provisional diagnosis?
b) Mention the two types of this benign non-invasive lesion and discuss their different
pathogenesis.
c) Describe the gross and microscopic picture.
d) Mention the complications.
Ans: Hydatidiform mole.
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3) A 55 year old female presented with post menopausal bleeding and foul swelling vaginal
discharge. P/V examination revealed unhealthy, indurated and ulcerated cervix. (July, 2012)
a) What is the provisional diagnosis?
b) How do you establish the diagnosis?
c) Describe the microscopic picture of the lesion.
Ans: Cervical carcinoma.
4) 35 year old female has 12 weeks amenorrhoea. She is married 1 year ago. On examination
uterus size was larger and corresponding to 20 weeks gestation. She complaints of passing
grape like vesicles. Her blood and urine hCG levels are elevated than normal pregnancy.
(Oct. 2008)
a) What is the provisional diagnosis?
b) Describe gross and microscopic picture of the lesion?
c) Discuss its complications.
Ans: Hydatidiform mole.
5) A 55 years old female presented with bleeding per vaginum and white discharge. P/V
examination revealed unhealthy indurated and ulcerated cervix. (March/April, 2005)
a) What is the probable diagnosis?
b) What laboratory test will confirm the diagnosis?
c) What is the histopathology of the disease?
Ans: Cervical carcinoma.
4 Marks
1) Pathogenesis of cervical carcinoma. (Feb. 2019)
2) Etiology of carcinoma cervix. (July, 2016)
3) What are the pathogenic factors of endometrial cancer? Classify gonadal stromal
tumours of ovary and give the hormone secreted by each. (Jan. 2016)
4) Benign cystic teratoma of the ovary. (July, 2015)
5) Endometriosis – Definition, chief locations and histogenesis. (Jan. 2014)
6) Cervical intraepithelial neoplasia. (Jan. 2012)
7) Dermoid cyst-ovary. (Aug. 2010)
8) Brenner tumor. (March, 2010)
9) Choriocarcinoma. (April, 2009)
10) Dysgerminoma. (Feb. 2009)
11) Carcinoma cervix. (March/April, 2008)
12) Morphology of hydatidiform mole. (May, 2007)
13) Functioning ovarian tumours. (May, 2006)
14) Endometrial hyperplasia. (Oct. 2004)
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2 Marks
1) List four factors associated with endometrial hyperplasia. (Oct. 2022)
2) Classify teratoma of ovary. (May, 2022)
3) Cervical intraepithelial neoplasia. (May, 2022)
4) Microscopic picture of mature teratoma. (March, 2021)
5) Define and write about sites involved in endometriosis. (March, 2021)
6) Name four gestational trophoblastic tumors. (Nov. 2020)
7) Draw neat diagram of teratoma ovary. (Feb. 2020)
8) Four differences between complete and partial mole. (Feb. 2019)
9) Enumerate pathogenic factors of carcinoma cervix. (Feb. 2018)
10) Classify ovarian tumors. (July, 2017)
11) Give the names of four malignant ovarian tumours. (July, 2016)
12) What are the pathogenic factors of endometrial cancer. (Jan. 2016)
13) Classify gonadal stromal tumours of ovary and give the hormone secreted by each.
(Jan. 2016)
14) Morphology of uterine leiomyoma. (Jan. 2015)
15) Name 4 surface epithelial tumors of ovary. (Jan. 2013)
16) Hydatidiform mole. (July, 2011)
17) Adenomyosis. (Jan. 2011)
18) Endometriosis. (Aug. 2010)
19) Endometriosis. (Aug. 2009)
20) Carcinoma in situ. (Feb. 2009)
21) Morphology of hydatidiform mole. (May, 2007)
22) Cervical carcinoma-in-situ. (May, 2006)
23) Cervical intra-epithelial neoplasm (CIN). (Oct. 2005)
24) Etiology of carcinoma cervix. (April/May, 2004).
25) Choriocarcinoma. (Sep. 2003)
26) Dermoid cyst of the ovary. (March/April, 2003)
27) Classification of ovarian tumours. (Oct/Nov. 2002)
High-Yield Topics
Cervical carcinoma
Endometrial carcinoma
Classification of ovarian tumors
Dysgerminoma
Hydatidiform mole
Endometriosis
Leiomyoma
Mature teratoma of ovary
Granulosa cell tumor
Choriocarcinoma
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Cervical Intraepithelial Neoplasia (CIN) or
Squamous Intraepithelial Lesions (SIL)
Causative agent: High-risk HPVs (HPV-16 is most common).
Classification:
1) Low –grade squamous intraepithelial lesion (LSIL) or CIN I: More common.
Most cases regress spontaneously. Few may progress to HSIL but not directly to invasive
carcinoma. Not a premalignant lesion.
2) High-grade squamous intraepithelial lesion (HSIL) or CIN II & III: Less common.
Majority arise from LSIL. High risk of progression to invasive carcinoma. Considered as a
premalignant lesion.
Morphology:
1) LSIL - Immature squamous cells are confined to the lower one-third of the epithelium.
2) HSIL - Immature squamous cells expand to the upper two-thirds of the epithelial thickness
from basal location.
3) Nuclear alterations: Nuclear enlargement, hyperchromasia, coarse chromatin granules,
and variation in nuclear size & shape.
4) Koilocytic atypia: Nuclear alterations associated with perinuclear halos.
Cervical Carcinoma
Risk factors: Early age at first intercourse; Multiple sexual partners; Male partner with
multiple previous sexual partners; Persistent infection by high-risk strains of HPV.
Etiopathogenesis:
1) Persistent infection with high-risk HPVs (HPV-16 is most common) is the major cause.
2) Areas of squamous epithelial trauma and repair are susceptible for infection.
3) Basal cells and immature metaplastic squamous cells are infected.
4) Viral E7 and E6 proteins mediate increased proliferation of cells and cancer development.
i) E7 protein: Binds and promotes the degradation of the hypophosphorylated form of RB;
Binds and inhibits p21 & p27.
ii) E6 protein: Binds & promotes the degradation of p53; Upregulates telomerase expression.
5) Integrated viral DNA into host cell genome increases the expression of E6 and E7 genes.
6) Exposure to co-carcinogens and host immune status influences cancer development.
Age: 45 - 50yrs.
Histologic subtypes: Squamous cell carcinoma (MC); Adenocarcinoma (2nd MC);
Adenosquamous carcinoma; Neuroendocrine carcinoma.
Morphology:
Gross: Fungating or infiltrative mass.
Micro.: 1) Squamous cell carcinoma: Nests and tongues of malignant squamous epithelium,
either keratinizing or nonkeratinizing, invade the underlying cervical stroma.
2) Adenocarcinoma: Proliferation of glandular epithelium with malignant endocervical cells
having large, hyperchromatic nuclei and relatively mucin depleted cytoplasm.
C/P: Abnormal bleeding P/V.
Spread:
1) Direct extension: Urinary bladder, ureters, rectum and vagina.
2) Metastasis: Lymph nodes, liver, lungs and bone marrow.
Inv.: Pap test; Colposcopy; Biopsy.
Comp.: Ureteral obstruction, pyelonephritis and uremia.
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Preventive measures:
1) Screening: Pap test and HPV DNA testing.
i) The first Pap smear should be at 21 years of age or within 3 years of onset of sexual
activity, and thereafter every 3 years.
ii) After 30 years of age, women who have had normal cytology results and are negative for
HPV may be screened every 5 years.
iii) Women who have a normal cytology result but test positive for high-risk HPV DNA
should have cervical cytology repeated every 6 to 12 months.
2) Colposcopy guided biopsy of abnormal mucosa.
3) Vaccination against high-risk oncogenic HPVs.
Endometriosis
“Presence of ectopic endometrial tissue at a site outside of the uterus.”
Age: 30 – 40s (MC).
Sites: Ovaries (MC), uterine ligaments, rectovaginal septum, and cul de sac.
Theories that propose the origin of endometriotic lesions:
1) The regurgitation theory: It proposes that endometrial tissue implants at ectopic sites via
retrograde flow of menstrual endometrium.
2) The benign metastases theory: It states that benign endometrial tissue can spread to
distant sites (lung, brain) from uterus via blood vessels & lymphatic channels.
3) The metaplastic theory: It states that endometrium arises directly from coelomic
epithelium.
4) The extrauterine stem/progenitor cell theory: It proposes that stem/progenitor cells
from the bone marrow differentiate into endometrial tissue.
Pathogenesis: Overproduction of prostaglandins & estrogen enhances the survival and
persistence of endometriotic foci.
Morphology: Gross: Bleeding endometriotic lesions form red-blue to yellow-brown
nodules. Advanced lesions cause fibrous adhesions between tubes, & ovaries and obliterate
the pouch of Douglas.
Micro.: Endometrial glands & stroma with or without the presence of hemosiderin.
Chocolate cysts or endometriomas: Large ovarian cystic masses filled with brown fluid.
C/P: Severe dysmenorrhea, dyspareunia & pelvic pain; Menstrual irregularities; Infertility.
Associations: Ovarian endometrioid & clear cell carcinomas.
Adenomyosis
“Presence of endometrial tissue within the myometrium.”
Morphology: Gross: Small foci of cystic hemorrhagic areas.
Micro.: Irregular nests of endometrial stroma with or without glands within the myometrium,
separated from the basalis by at least 2-3mm.
C/P: Irregular & heavy menses, colicky dysmenorrhoea, dyspareunia & pelvic pain.
Associations: Endometriosis.
Endometrial Hyperplasia
“An increased proliferation of the endometrial glands relative to the stroma, with prolonged
estrogenic stimulation of the endometrium.”
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Etiology: Obesity; Menopause; PCOD; Functioning granulosa cell tumors of the ovary;
Estrogen replacement therapy.
Genetic alterations: Mutations in PTEN gene that increase PI3K / AKT signaling.
WHO Classification: Non-atypical hyperplasia & atypical hyperplasia.
Morphology: 1) Non-atypical hyperplasia: Increase in the gland to stroma ratio with glands
showing variation in size & shape.
2) Atypical hyperplasia (endometrial intraepithelial neoplasia): Proliferative glands are
arranged back to back with complex outlines and nuclear atypia. Individual cells appear
round, with nuclei having open chromatin & conspicuous nucleoli.
C/P: Abnormal bleeding P/V.
Comp.: Atypical hyperplasia may progress to endometrial carcinoma.
Carcinoma of the Endometrium
*MC invasive cancer of the female genital tract.
Categories: Type I and Type II.
I) Endometrioid endometrial carcinoma: Most common type I endometrial carcinoma.
Age: 55-65 yrs.
Precursor lesion: Endometrial hyperplasia.
Risk factors: Obesity; Diabetes; Hypertension; Infertility; Unopposed estrogen stimulation.
Genetic alterations: Mutations that increase PI3K / AKT signaling, such as mutations in the
PTEN, PIK3CA, KRAS or ARID1A.
Morphology: Gross: Localized polypoid mass or diffusely involve the endometrial lining.
Micro.: 1) Well differentiated (grade 1): Composed almost entirely of well-formed glands
with lack of intervening stroma.
2) Moderately differentiated (grade 2): Show well-formed glands mixed with areas
composed of solid sheets of cells up to 50% or less of the tumor.
3) Poorly differentiated (grade 3): Comprise greater than 50% solid growth pattern.
Metastasis: Lymphatic spread involves regional lymph nodes. Hematogenous spread
involves lungs, liver and bones.
II) Serous endometrial carcinoma: Most common type II endometrial carcinoma.
Age: 65-75 yrs.
Risk factors: Endometrial atrophy; Thin physique.
Precursor lesion: Serous endometrial intraepithelial carcinoma.
Genetic alterations: Mutations in the TP53 gene.
Morphology: Gross: Large bulky masses or deeply invasive into the myometrium.
Micro.: Poorly differentiated (grade 3) tumors having a papillary growth pattern composed of
cells with high N-C ratio, atypical mitotic figures, hyperchromasia and prominent nucleoli.
Spread: Lymphatic or transtubal.
C/P: Asymptomatic; Irregular or postmenopausal vaginal bleeding.
Inv.: Ultrasound; Biopsy.
Leiomyoma (Fibroid)
“Benign smooth muscle cell tumor myometrium.”
Site: Myometrium of the corpus (MC), uterine ligaments, lower uterine segment or cervix.
Genetic alterations: Mutations in the MED12 gene.
Types: Intramural (within the myometrium); Sub mucosal (beneath the endometrium); Sub
serosal (beneath the serosa).
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Morphology: Gross: Circumscribed round, gray-white, discrete firm masses of varying size,
often multiple. C/S: Whorled pattern of smooth muscle bundles.
Micro.: 1) Bundles of smooth muscle cells with admixed fibrous connective tissue.
2) Tumor cells show oval nucleus & long, slender bipolar cytoplasmic processes.
C/P: Asymptomatic; Abnormal bleeding, urinary frequency & impaired fertility.
Comp.: Spontaneous abortion; Fetal malpresentation; Post-partum hemorrhage.
Ovarian Tumors - Classification
1) Surface epithelial-stromal tumors:
Serous tumors (benign, borderline & malignant);
Mucinous tumors (benign, borderline & malignant);
Endometrioid tumors (benign, borderline & malignant);
Clear cell tumors (benign, borderline & malignant);
Transitional cell tumors (benign, borderline & malignant);
Epithelial-stromal tumors (Adenosarcoma, malignant mixed mullerian tumor).
2) Sex cord-stromal tumors:
Granulosa cell tumors; Fibromas; Thecomas; Sertoli-Leydig cell tumors.
3) Germ cell tumors: Teratoma; Dysgerminoma; Yolk sac tumor.
4) Metastatic cancers
Functioning Ovarian Tumors
Sex cord-stromal tumors:
1) Estrogen producing tumors: Granulosa cell tumors; Thecomas.
C/P: Precocious pseudopuberty in pediatric patients and postmenopausal bleeding in
postmenopausal patients.
2) Androgen producing tumors: Sertoli-Leydig cell tumors; Leydig cell tumors.
C/P: Virilization.
Transitional Cell Tumors (Brenner Tumors)
“Spectrum of epithelial neoplasms composed of urothelial-type epithelium.”
Types: Benign Brenner tumor (MC), borderline Brenner tumor & malignant Brenner tumor.
*Usually unilateral.
Benign Brenner tumor
Age: 40-80 yrs.
Morphology: Gross: Solid masses of varying in size with a smooth external surface.
C/S: Firm yellow or white containing small cysts.
Micro.: i) Well-demarcated nests of cytologically bland urothelial-type epithelium enmeshed
in prominent fibromatous stroma with frequent luteinization.
ii) The cell nests often show central microcysts, which may contain eosinophilic material.
iii) The constituent cells often have longitudinal nuclear grooves, exhibiting the characteristic
“coffee bean” nuclei.
iv) Dystrophic calcification may be seen.
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C/P: Frequently asymptomatic.
Associations: Mucinous cystadenoma.
Teratoma
Types: 1) Mature (benign) 2) Immature (malignant) 3) Monodermal
Mature Teratoma (Dermoid Cyst)
“MC germ cell tumor of ovary.”
*Mostly unilateral.
Age: Young women.
Origin: Ovum after the 1st meiotic division (majority).
Morphology: Gross: 1) Unilocular cystic masses with hair & sebaceous material.
2) Cyst wall is thin, lined by gray-white, wrinkled epidermis with protruding hair shafts.
3) Tooth structures & areas of calcification may be found within the wall.
Micro.: Cyst wall is lined with stratified squamous epithelium with underlying sebaceous
glands & hair shafts. Cartilage, bone, thyroid & neural tissue may be found.
Comp.: Rare malignant transformation to squamous cell carcinoma.
Paraneoplastic syndromes: Inflammatory limbic encephalitis.
Associations: Mucinous cystadenoma; Dysgerminoma.
**Sites of teratoma: Testis, ovary, mediastinum, retroperitoneum, head and neck
Dysgerminoma
“Malignant germ cell tumor of ovary.”
*Ovarian counterpart of testicular seminoma.
*Mostly unilateral.
Age: 20-30s (MC).
Predisposing conditions: Gonadal dysgenesis.
Morphology: Gross: C/S: Solid yellow-white to gray-pink and soft & fleshy.
Micro.: Tumor cells grow in sheets or cords separated by scant fibrous stroma infiltrated by
lymphocytes. Tumor cells are large with clear cytoplasm, well-defined cell boundaries, &
centrally placed regular nuclei.
Associations: Benign cystic teratoma.
Hydatidiform Mole
“Gestational trophoblastic disease, with proliferation of placental tissue.”
Age: Teenagers & 40-50yrs.
Types: Complete mole & partial mole.
A) Complete mole
1) Pathogenesis: Fertilization of an empty egg by a sperm with duplication of its genetic
material (androgenesis). Genetic material is completely of paternal origin.
2) Karyotype: Diploid (MC – 46XX).
3) Embryo is not identified.
4) Comp.: Risk of development of invasive mole & choriocarcinoma.
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B) Partial mole
1) Pathogenesis: Fertilization of an egg with 2 sperms.
2) Karyotype: Triploid (e.g., 69XXY).
3) Fetal tissues are present.
4) Comp.: Risk of development of invasive mole but rarely choriocarcinoma.
Morphology: Gross: Cystic, thin walled, translucent friable mass of grape like structures.
Micro.: 1) Complete mole: All or most of the villi are enlarged and edematous (hydropic),
and scalloped in shape with central cavitation (cisterns). Trophoblastic hyperplasia is well
marked, covering the entire villous circumference.
2) Partial mole: Only a fraction of villi are enlarged and edematous. Trophoblastic
hyperplasia is focal and less marked.
C/P: Spontaneous miscarriage.
Inv.: Elevated hCG levels (complete>partial); Ultrasound.
Feature
Complete Mole
Partial Mole
Ovum
Androgenesis
Karyotype
Villous edema
Trophoblastic proliferation
Fetal tissues
Serum hCG
Choriocarcinoma risk
Empty
Seen
Diploid
All villi
Circumferential
Absent
More elevated
Seen
Normal
Not seen
Triploid
Some villi
Focal
Present
Less elevated
Rare
Gestational Trophoblastic Tumors
Gestational choriocarcinoma; Placental site trophoblastic tumor (PSTT); Epithelioid
trophoblastic tumor (ETT); Mixed trophoblastic tumor.
Choriocarcinoma
“Malignant tumor of trophoblastic cells.”
Predisposing conditions: Complete mole (MC); Previous abortions; Normal pregnancy;
Ectopic pregnancy.
Morphology: Gross Soft, fleshy, and yellow-white tumor with large areas of necrosis &
extensive hemorrhage.
Micro: 1) Proliferating cytotrophoblasts & syncytiotrophoblasts without villi formation.
2) Abundant mitoses with some atypical forms.
C/P: Irregular vaginal spotting of a bloody, brown fluid.
Inv.: Elevated hCG levels.
Metastasis: Lungs (MC), and vagina.
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22. The Breast
MCQs
1) BRCA 1 gene is located on chromosome. (Feb. 2022)
a) 13 b) 11 c) 17 d) 22
15 Marks
1) A 60 year old postmenopausal woman presenting with hard lump of 8 cm x 8 cm in upper
outer quadrant of left breast. FNAC shows cluster of pleomorphic cells. (May, 2022)
a) What is your diagnosis.
b) Discuss pathogenesis and molecular mechanisms of carcinogenesis of disease.
c) Discuss prognostic factors of disease.
d) Write a note on sentinel lymph node biopsy.
Ans: Breast carcinoma.
5 Marks
1) Prognostic factors in carcinoma breast. (Feb. 2022)
10 Marks
1) A 50 year old lady came to surgical outpatient department with a lump in her left breast
which she had noticed 2 weeks back. On examination, a hard swelling of 4x3 was palpable in
the upper outer quadrant of left breast, which was fixed to chest wall. 3 axillary lymph nodes
were palpable. Mastectomy of left breast based on fine needle aspiration report. (Aug. 2021)
a) Which is your diagnosis?
b) Describe in detail the etiopathogenesis of this condition.
c) Discuss the gross and microscopy of the most common histological type of this lesion.
d) Enumerate any four prognostic factors related to this condition.
Ans: Breast carcinoma.
2) A 20 year old female presented with a painless slowly growing freely mobile solitary lump
in the lower part of her left breast. On examination, the nipple is normal. The lump is not
fixed to the overlying skin. No axillary lymph nodes are palpable. (July, 2016)
a) What is the provisional diagnosis?
b) Discuss various investigations to confirm your final diagnosis.
c) Describe the gross and microscopic picture of the lesion.
Ans: Fibroadenoma.
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3) A 45 year old lady presented with a painless swelling in the left breast for 3 months
duration. On examination the swelling was firm, fixed to the overlying skin. Left axillary
lymph nodes were enlarged. Fine needle aspiration of the swelling showed loosely cohesive
cells with pleomorphic hyperchromatic nuclei and prominent nucleoli. (July, 2015)
a) What is your diagnosis?
b) Describe the etiopathogenesis of this condition.
c) How will you classify this condition?
d) What are prognostic factors for this condition?
Ans: Breast carcinoma.
4) 40 year old female presented with lump in the breast. The lump is hard and adhered to the
underlying structures and axillary lymph nodes are enlarged. (Aug. 2010)
a) What is the provisional diagnosis?
b) How do you classify them?
c) Discuss the etiology and pathogenesis of the lesion.
Ans: Breast carcinoma.
5) A 20 year old female presented with a painless slowly growing freely mobile solitary lump
in the lower part of her left breast. On examination the nipple is normal. The lump is not
fixed to the overlying skin. No axillary lymph nodes are palpable. (April, 2009)
a) What is the provisional diagnosis?
b) Discuss various investigations to confirm your final diagnosis.
c) Describe the gross and microscopic picture of the lesion.
Ans: Fibroadenoma.
4 Marks
1)
2)
3)
4)
5)
6)
7)
Medullary carcinoma breast. (March, 2021)
Microscopic types of breast cancer. (Jan. 2016)
Medullary carcinoma breast. (Jan. 2011)
Cystosarcoma phyllodes. (Aug. 2009)
Prognostic factors of breast carcinoma. (May, 2007)
Classification of breast tumors. (Oct. 2005)
Histological types of breast carcinoma. (Apr/May, 2004)
2 Marks
1)
2)
3)
4)
5)
6)
List four prognostic factors in breast carcinoma. (Oct. 2022)
Microscopic features of phyllodes tumor. (Nov. 2020)
Enlist four major prognostic factors of carcinoma breast. (Feb. 2019)
Name four prognostic factors of breast cancer. (Feb. 2018)
Paget disease of nipple – Gross and microscopic picture. (Jan. 2014)
Diagrammatically illustrate the two microscopic patterns of fibroadenoma breast.
(Jan. 2013)
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7) Name the benign tumors of the breast. (July, 2012)
8) Paget disease of breast. (Jan. 2012)
9) Phyllodes tumor. (Feb. 2009)
10) Paget disease of breast. (Oct. 2008)
11) Fibroadenoma. (Oct. 2008)
12) Phyllodes tumor. (March/April, 2008)
13) Paget disease of the nipple. (Sep/Oct. 2007)
14) Fibrocystic disease of the breast. (March/April, 2003)
High-Yield Topics
Fibrocystic disease
Fibroadenoma
Breast carcinoma
Classification of breast tumors
Phyllodes tumor
Paget disease of the nipple
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Nonproliferative Breast Changes (Fibrocystic
Changes)
“Benign epithelial lesion of the breast, not associated with an increased risk of breast cancer.”
Morphology:
1) Cysts: Lined by flattened atrophic epithelium or metaplastic apocrine cells and contain
turbid, brown or blue colored fluid (blue-dome cysts). Calcifications are common.
2) Fibrosis: Rupture of cysts with the release of cystic contents into the stroma causes
chronic inflammation & fibrosis.
2) Adenosis: Increased no. of acini per lobule, lined by columnar cells.
C/P: Palpable nodularity is felt with fibrosis.
Inv.: FNAC; Mammography; Ultrasound.
Tumors of Breast - Classification
I) Epithelial tumors:
Benign epithelial proliferations: Sclerosing Adenosis; Adenoma.
Epithelial-myoepithelial tumors: Pleomorphic adenoma; Adenoid cystic carcinoma.
Papillary lesions: Intraductal papilloma; Intraductal papillary carcinoma.
Precursor lesions: Ductal carcinoma in situ; Lobular carcinoma in situ.
Invasive breast carcinoma: Invasive ductal carcinoma; Invasive lobular carcinoma; Mucinous
carcinoma; Tubular carcinoma; Metaplastic carcinoma.
II) Mesenchymal tumors: Lipoma; Myofibroblastoma; Angiosarcoma.
III) Fibroepithelial tumors: Fibroadenoma; Phyllodes tumor.
IV) Tumors of the nipple: Nipple adenoma; Paget disease of the nipple.
V) Metastatic tumors
Benign Tumors of Breast
Fibroadenoma; Phyllodes tumor; Adenoma; Intraductal papilloma; Pleomorphic adenoma
Carcinoma of the Breast
*MC non-skin malignancy of women.
*2nd MC cause of cancer deaths in women.
*Mostly unilateral.
Sites: Upper outer quadrant (1st MC); Central portion (2nd MC).
Cell of origin: Cells in the terminal duct lobular unit.
Risk factors: Advancing age (70-80yrs); Female gender; First-degree relatives with breast
cancer; Early menarche; Nulliparity; Absence of breast feeding; Older age at 1st pregnancy;
Radiation to the chest; Postmenopausal obesity; Postmenopausal hormone replacement;
Mammographic density; Alcohol consumption.
Etiology: Sporadic, related to hormonal exposures with de novo mutations or familial with
germ line mutations.
Genetic alterations: Loss of function mutations involving tumor suppressor genes, having a
role in DNA repair & maintenance of genomic integrity.
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Most common: BRCA1 & BRCA2;
Rare: TP53 & CHEK2.
Classification
A. Noninvasive: Ductal carcinoma in situ; Lobular carcinoma in situ.
B. Invasive: Invasive ductal carcinoma; Invasive lobular carcinoma; Carcinoma with
medullary features; Mucinous carcinoma; Tubular carcinoma.
Carcinoma in situ: “Neoplastic proliferation of epithelial cells that is confined to ducts &
lobules by the basement membrane.”
I) Ductal carcinoma in situ (DCIS)
Morphology:
i) Comedo DCIS: Tumor cells with pleomorphic high-grade nuclei & areas of central
necrosis.
ii) Noncomedo DCIS: Seen in cribriform or solid or micropapillary patterns; High-grade
nuclei or central necrosis are not seen.
II) Lobular carcinoma in situ (LCIS)
Morphology: Uniform population of round discohesive cells with oval or round nuclei &
small nucleoli involve ducts & lobules. Mucin-positive signet ring cells are seen.
Invasive (Infiltrating) Carcinoma: “Tumor has penetrated through the basement
membrane and grows within stroma.”
*Majority are invasive carcinomas of ‘no special type’ (invasive ductal carcinomas).
Molecular subtypes
I) Luminal Cancers (ER-positive, HER2-negative): MC
1) MC subtype with germline mutations in BRCA2.
2) Precursors: Flat epithelial atypia; Atypical ductal hyperplasia.
3) Genetic alterations: Gains of chr.1q, losses of chr.16q & activating mutations in PIK3CA.
II) HER2 Cancers (HER2-postive)
1) MC subtype with germline mutations in TP53.
2) Genetic alterations: Amplification of the HER2 gene.
3) Either ER-positive or ER-negative.
III) Triple Negative Breast Cancers (ER-negative, HER2-negative)
*MC subtype with germline mutations in BRCA1.
Morphology
Gross: Hard, irregular breast mass of variable size. Retraction of nipple or dimpling of the
skin may be associated.
Micro.: Almost all are adenocarcinomas.
1) Luminal cancers: Well to poorly differentiated.
2) HER2 Cancers: Majority are poorly differentiated.
3) Triple Negative Breast Cancers: Almost all are poorly differentiated.
Histologic grade: ‘Nottingham Histologic Score’
1) Grade 1 (well differentiated): Tumor grows in a tubular or cribriform pattern with small
round nuclei & low proliferative rate.
2) Grade 2 (moderately differentiated): Tumor grows as solid clusters or single infiltrating
cells with marked nuclear pleomorphism & proliferative rate.
3) Grade 3 (poorly differentiated): Tumor grows as ragged nests or solid sheets having
enlarged irregular nuclei with high proliferative rate & areas of tumor necrosis.
Spread: Local: Regional lymph nodes; Distant: Bone (MC), viscera or brain.
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Special histologic types
1) Lobular carcinoma: ‘ER-positive, HER2-negative tumor’
Genetic alterations: Biallelic loss of expression of CDH1.
Morphology: Gross: Hard irregular mass.
Micro.: Discohesive infiltrating tumor cells, often showing signet ring morphology with
absence of tubule formation.
Metastasis: Peritoneum & retroperitoneum, leptomeninges, GIT, ovaries and uterus.
2) Mucinous (colloid) carcinoma:
Morphology: Gross: Soft or rubbery.
Micro.: Clusters & small islands of tumor cells within large lakes of mucin.
3) Tubular carcinoma: Well-formed tubules are seen with apocrine snouts.
4) Papillary carcinoma: True papillae are lined by tumor cells.
5) Invasive breast carcinoma of no special type with medullary pattern (Medullary
Carcinoma): Triple negative breast cancer (ER-negative, HER2-negative).
Genetic alterations: Many show reduced BRCA1 expression.
Morphology: Gross: Well-circumscribed soft mass.
Micro. i) Solid sheets of large cells with pleomorphic nuclei, and prominent nucleoli.
ii) Frequent mitotic figures.
iii) Moderate to marked lymphoplasmacytic infiltrate surrounding & within the tumor.
iv) A pushing (noninfiltrative) border.
v) Minimal desmoplasia.
vi) DCIS is minimal or absent.
Prognostic and Predictive Factors
I) Related to the extent of tumor:
1) Tumor size: Increased size of primary tumor carries poor prognosis.
2) Lymph node metastases: Absence of axillary LN involvement carries good prognosis.
Sentinel lymph node biopsy: i) Used to assess the presence or absence of metastatic lesions.
ii) With biopsy of the sentinel nodes is negative for metastasis, it is unlikely that other, more
distant nodes will be involved.
iii) It helps to avoid the surgical morbidity associated with a complete axillary dissection.
3) Distant metastases: Carry poor prognosis.
4) Lymphovascular invasion: Carries poor prognosis.
5) Inflammatory carcinoma: Carries poor prognosis.
6) Locally advanced disease: Involvement of skin or skeletal muscle carries poor prognosis.
II) Related to tumor biology:
1) Expression of ER, PR & HER2: Survival is highest for the most favorable combination
(high ER and PR and absent HER2) and is lowest for the least favorable combination (absent
ER, PR, and HER2).
2) Special histologic types: Tubular, and adenoid cystic carcinomas are strongly correlated
with very favorable survival.
3) Histologic grade: Survival diminishes with higher histologic grade.
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Paget Disease of the Nipple
“Rare manifestation of breast cancer.”
Morphology: Gross: Unilateral erythematous scaly lesion.
Micro.: 1) Nipple skin shows malignant cells (Paget cells) extending from DCIS.
2) Underlying invasive poorly differentiated carcinoma may be seen.
C/P: Pruritus; Palpable mass.
Inv.: Biopsy; Cytology of exudate.
Fibroadenoma
“Benign stromal tumor of the breast.”
*MC benign tumor of female breast.
*Frequently bilateral & multiple.
Age: 20 – 30yrs (MC).
Origin: Intralobular stroma.
Risk factors: Use of cyclosporine A.
Genetic alterations: Mutations in MED 12.
Morphology: Gross: Well circumscribed, rubbery, grayish white nodules of varying size.
C/S: Slit-like spaces.
Micro.: 1) Stroma appears often myxoid.
2) Epithelium may be surrounded by stroma (pericanalicular pattern) or compressed &
distorted by it (intracanalicular pattern).
C/P: Firm, freely mobile, discrete mass is felt on palpation.
Inv.: Biopsy; FNAC; Mammography; Ultrasound.
Comp.: Infarction during pregnancy.
Phyllodes Tumor (Cystosarcoma Phyllodes)
“Benign stromal tumor of the breast.”
Origin: Intralobular stroma.
Age: 60s (MC).
Types: Benign (low-grade), borderline & malignant (high-grade).
Genetic alterations: Mutations in MED 12 & TERT.
Morphology: Gross: Round to oval mass of varying size with bosselated surface.
C/S: Gray-white with cystic cavities and areas of hemorrhage & necrosis.
Micro.: 1) The stroma frequently overgrows the epithelial component, creating bulbous
protrusions covered by epithelium.
2) Benign (MC): Mild stromal cellularity with low mitotic activity and well-defined borders.
3) Borderline: Moderate stromal cellularity with frequent mitotic activity; Mild to moderate
stromal atypia with well-defined borders.
4) Malignant: Marked stromal cellularity with abundant mitotic activity; Marked stromal
atypia with permeative borders.
C/P: Palpable breast mass.
Inv.: Ultrasound; Mammography; FNAC; Biopsy.
Comp.: Recurrence is occasional with benign tumors, but often with borderline & malignant
tumors. Hematogenous dissemination may be seen with malignant tumors.
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23. The Endocrine System
MCQs
1) The common cause of painless thyroid is. (Feb. 2022)
a) Hashimoto thyroiditis
b) Riedel thyroiditis
c) Subacute granulomatous thyroiditis d) Graves disease
2) Orphan Annie nuclei are seen in which thyroid carcinoma. (Feb. 2022)
a) Medullary b) Anaplastic c) Papillary d) Follicular
3) Plunging goiter is. (Feb. 2022)
a) Solitary nodule b) Colloid goiter c) Retrosternal goiter d) Medullary carcinoma
5 Marks
1) Write a brief note on Cushing syndrome. (Feb. 2022)
2) Skeletal manifestations of hyperparathyroidism. (Feb. 2022)
4 Marks
1) Etiopathogenesis and morphology of nodular goitre. (Oct. 2022)
2) Discuss in detail about Multiple Endocrine Neoplasia (MEN) syndromes. (Aug. 2021)
3) Write about the pathogenesis and complications of diabetes mellitus. (March, 2021)
4) Pheochromocytoma. (Nov. 2020)
5) Papillary carcinoma of thyroid. (Feb. 2020)
6) Hashimoto thyroiditis. (July, 2013)
7) Pathology of Graves disease. (Jan. 2013)
8) Medullary carcinoma thyroid. (Jan. 2012)
9) Hashimoto thyroiditis. (July, 2011)
10) Morphology of pheochromocytoma. (March, 2010)
11) Hashimoto thyroiditis. (April, 2009)
12) Complications of diabetes mellitus. (Feb. 2009)
13) Medullary carcinoma of thyroid. (Feb. 2009)
14) Pheochromocytoma. (Oct. 2008)
15) Pheochromocytoma. (Sep/Oct. 2007)
16) Graves disease. (May, 2007)
17) Thyroid adenoma. (Oct. 2004)
18) Hashimoto thyroiditis. (March/April, 2003)
19) Toxic goiter. (Oct/Nov. 2002)
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2 Marks
1) Enumerate four complications of diabetes mellitus. (May, 2022)
2) Microscopic pattern of follicular adenoma of thyroid. (July, 2019)
3) Pathogenesis of Hashimoto thyroiditis. (Feb. 2019)
4) Name the thyroid tumors and indicate their route of spread. (July, 2018)
5) Hashimoto thyroiditis. (July, 2017)
6) Name four malignant tumors of thyroid. (Feb. 2017)
7) Microscopic appearance of papillary carcinoma of thyroid. (July, 2016)
8) Microscopic patterns of follicular adenoma thyroid. (Jan. 2016)
9) Name four malignant tumours of the thyroid. (July, 2015)
10) Three causes of primary hyperparathyroidism and one cause of secondary
hyperparathyroidism. (Jan. 2015)
11) Microscopic picture of thyroid in Graves disease. (Jan. 2014)
12) Follicular adenoma thyroid – Gross and histological picture. (July, 2012)
13) Four clinical features of primary hyperparathyroidism. (Jan. 2011)
14) Morphology of Hashimoto thyroiditis. (May, 2006)
15) Hashimoto thyroiditis. (May, 2006)
16) Pheochromocytoma. (May, 2006)
17) Pathogenesis of Graves disease. (April/May, 2004)
18) Papillary carcinoma of thyroid. (Sep. 2003)
High-Yield Topics
Hashimoto thyroiditis
Follicular adenoma
Medullary carcinoma of thyroid
Cushing syndrome
Pheochromocytoma
Multiple Endocrine Neoplasia Syndromes
Graves disease
Papillary carcinoma of thyroid
Hyperparathyroidism
Addison disease
Diabetes mellitus
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Hashimoto Thyroiditis
“Autoimmune thyroid disease.”
*MC cause of hypothyroidism in iodine sufficient world.
Age: 45-65 yrs.
Sex: F>M
Genetic alterations: Polymorphisms in immune function genes, CTLA4 & PTPN22.
Pathogenesis: 1) Breakdown in self-tolerance to thyroid autoantigens with formation of
autoantibodies against thyroglobulin & thyroid peroxidase (TPO).
2) CD8+ cytotoxic T cells may destroy thyroid follicular cells.
3) IFN-γ mediated activation of macrophages may result in damage to follicles.
Morphology: Gross: Diffuse symmetrical enlargement with intact capsule.
C/S: Pale yellow-tan, and firm.
Micro.: 1) Follicles are atrophic and may be lined by Hurthle cells (epithelial cells with
abundant, eosinophilic granular cytoplasm).
2) Extensive mononuclear cell infiltrate with small lymphocytes & plasma cells.
3) Increased interstitial connective tissue.
C/P: 1) Painless goitre with hypothyroidism.
2) Hashitoxicosis: Transient thyrotoxicosis preceding hypothyroidism.
Inv.: TFT: Raised TSH, low free T3, & T4; Antibodies: Anti thyroglobulin & anti TPO
antibodies; Ultrasound; FNAC; Biopsy.
Associations: SLE, Sjogren syndrome, Type 1 DM.
Comp.: Extranodal marginal zone B-cell lymphoma.
Graves Disease
“Autoimmune thyroid disorder.”
*MC cause of endogenous hyperthyroidism.
Age: 20-40yrs.
Sex: F>M
Genetic alterations: Polymorphisms in immune function genes, CTLA4 & PTPN22.
Pathogenesis: “Formation of autoantibodies against TSH receptor.”
1) Thyroid stimulating immunoglobulin (TSI) stimulates TSH receptor causing
hyperthyroidism - Most common.
2) TSH receptor blocking antibodies in some may cause hypothyroidism.
Morphology:
Gross: Diffuse symmetric enlargement. C/S: Soft, and meaty.
Micro.: 1) Hypertrophy & hyperplasia of follicular epithelial cells.
2) Follicles lined by cells appearing tall & crowded, forming small papillae; colloid appears
pale, with scalloped margins.
3) Lymphoid aggregates throughout the interstitium.
C/P: Triad – Hyperthyroidism, infiltrative ophthalmopathy, & infiltrative dermopathy.
1) Goitre with diffuse enlargement of thyroid.
2) Thyrotoxicosis with tachycardia, palpitations, & anxiety.
3) Sympathetic overactivity causes wide staring gaze & lid lag.
4) Ophthalmopathy with exophthalmos.
5) Infiltrative dermopathy (pretibial myxedema): Scaly thickening & induration of skin,
mostly overlying shins.
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Inv.: TFT: Elevated free T3 & T4 and low TSH levels; Ultrasound; FNAC; Biopsy;
Radioiodine scan.
Associations: SLE; Addison disease; Type 1 diabetes.
Multinodular Goiter (MNG)
“Recurrent episodes of hyperplasia and involution combine to produce a more irregular
enlargement of the thyroid known as multinodular goiter.”
Pathogenesis: In long-standing simple goiters, the follicle hyperplasia and accumulation of
colloid produce physical stress that may lead to rupture of follicles and vessels followed by
hemorrhages, scarring, and calcifications. With scarring, nodularity appears.
Morphology: Gross: Multilobulated, asymmetrically enlarged thyroid gland. Goiter may
grow behind the sternum and clavicles to produce the intrathoracic or plunging goiter.
C/S: Irregular nodules containing variable amounts of brown, gelatinous colloid. Older
lesions have areas of hemorrhage, fibrosis, calcification, and cystic change.
Micro.: Colloid-rich follicles lined by flattened, inactive epithelium and areas of follicle
hyperplasia, accompanied by degenerative changes.
C/P: Airway obstruction, dysphagia, and compression of large vessels in the neck and upper
thorax (superior vena cava syndrome). Hyperthyroidism (toxic multinodular goiter), known
as Plummer syndrome may be associated.
Inv.: TFT; FNAC; Radioiodine scan; Biopsy.
Primary Tumors of the Thyroid
Benign: Follicular adenoma.
Malignant:
Papillary carcinoma (Spread via lymphatics to regional lymph nodes)
Follicular carcinoma (Spread via blood to lung and bone)
Medullary carcinoma (Spread via lymphatics to regional lymph nodes)
Anaplastic carcinoma (Spread via lymphatics to regional lymph nodes)
Follicular Adenoma
“Benign tumor of thyroid.”
Origin: Follicular epithelial cells.
Genetic alterations: Somatic mutations of the TSH receptor signaling pathway are found in
toxic adenomas.
Morphology: Gross: 1) Solitary, spherical encapsulated gray-white to red-brown mass.
2) Areas of hemorrhage, fibrosis, calcification & cystic change.
Micro.: 1) Uniform appearing follicles that contain colloid.
2) Occasionally, neoplastic cells exhibit oxyphil or Hurthle cell change.
3) Intact, well-formed capsule encircling the tumor.
4) Architectural patterns: Microfollicular, normofollicular, macrofollicular, solid and
trabecular.
C/P: Unilateral painless mass in the neck. Larger masses may cause dysphagia.
Inv.: Ultrasound; FNAC; Biopsy; Radionuclide scanning.
Comp.: Thyrotoxicosis with toxic adenomas & rare transformation to follicular carcinoma.
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Papillary Carcinoma
“MC malignant tumor of thyroid with excellent prognosis.”
Origin: Follicular epithelial cells.
Age: 25-50yrs.
Risk factors: Ionizing radiation.
Genetic alterations: Chromosomal rearrangements of the RET gene (RET/PTC
translocations) and gain of function mutations in BRAF gene.
Morphology: Gross: Solitary or multifocal; Solid or cystic (MC); Circumscribed or
infiltrative. C/S: Areas of fibrosis, calcification or papillary foci.
Micro.: 1) Papillae with fibrovascular stalks lined by well differentiated single or multilayered cuboidal epithelium.
2) Nuclear features: Ground glass or Orphan Annie eye nuclei (optically clear or empty
appearance with finely dispersed chromatin); Intranuclear inclusions (pseudo-inclusions) or
intranuclear grooves.
3) Psammoma bodies within the cores of papillae.
Variants: Follicular variant (MC); Tall cell variant; Diffuse sclerosing variant; Papillary
microcarcinoma.
C/P: Asymptomatic mass in the neck. Advanced cases present with hoarseness, dysphagia,
dyspnoea or cough.
Inv.: Ultrasound; FNAC; Biopsy; Radionuclide scanning
Metastasis: Lymphatic spread to cervical lymph nodes, & rarely hematogenous
dissemination to lungs.
Medullary Carcinoma
“Malignant neuroendocrine tumor of thyroid.”
Origin: Parafollicular cells or C cells.
Age: 1) Sporadic & familial medullary thyroid carcinoma (FMTC) – Adults (40-50s).
2) MEN 2A or MEN 2B associated – Young.
Etiology: 1) Sporadic (MC).
2) Familial: In association with MEN 2A, MEN 2B or as FMTC.
Genetic alterations: Activating point mutations in RET proto-oncogene.
Morphology: Gross: Pale gray to tan, firm & infiltrative. Areas of necrosis & hemorrhage
are seen in larger masses. Sporadic cases present as a solitary nodule. Bilaterality &
multicentricity are common in familial cases.
Micro.: Polygonal to spindle shaped cells forming nests, trabeculae or follicles. Acellular
amyloid deposits in the stroma. Multicentric C-cell hyperplasia in the surrounding thyroid
may be seen in familial cases.
C/P: 1) Sporadic: Mass in the neck; Dysphagia or hoarseness.
2) Familial: Associated with features of MEN 2A, MEN 2B or FMTC.
Inv.: Raised calcitonin; Raised CEA; In some, raised serotonin, ACTH & VIP.
Paraneoplastic syndromes: Diarrhea; Cushing syndrome.
Metastasis: Spread via lymphatics to regional lymph nodes.
Toxic Goitre
Causes: Graves disease; Toxic multinodular goitre; Toxic adenoma; Subacute thyroiditis.
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Hyperparathyroidism
“Hyperfunctioning of parathyroid glands with elevated PTH levels.”
Types: 1) Primary 2) Secondary 3) Tertiary
Primary Hyperparathyroidism
“An autonomous overproduction of PTH.”
*MC cause of asymptomatic hypercalcemia.
Causes: Adenoma (MC); Primary hyperplasia; Carcinoma.
Age: Adults.
Sex: F>M
Parathyroid adenoma
Etiology: Sporadic (MC) or Familial.
Genetic alterations with sporadic adenomas:
1) Cyclin D1 gene inversions leading to its overexpression.
2) Mutations involving MEN1 tumor suppressor gene.
Familial parathyroid adenomas; Associated with MEN-1 & MEN-2A, caused by germline
mutations of MEN1 & RET genes respectively.
Morphology: Gross: Solitary, well-circumscribed encapsulated tan to reddish-brown nodule.
Micro.: Mostly of uniform polygonal chief cells with few nests of larger oxyphil cells.
Adipose tissue is inconspicuous. A rim of compressed parathyroid tissue is visible at the edge
of adenoma separated by a fibrous capsule.
C/P: 1) Asymptomatic hyperparathyroidism: Symptom free stage.
2) Symptomatic primary hyperparathyroidism:
Bone: Osteoporosis or osteitis fibrosa cystica leading to fractures with bone pain.
GIT: Constipation, nausea, peptic ulcers, & pancreatitis.
Renal: Nephrolithiasis & chronic renal insufficiency.
CNS: Depression, lethargy, & seizures.
Neuromuscular: Weakness & fatigue.
Cardiac: Aortic or mitral valve calcifications.
Inv.: Elevated PTH levels, hypercalcemia, hypophosphatemia, and increased urinary
excretion of both calcium & phosphate.
Secondary Hyperparathyroidism
“Compensatory overactivity of the parathyroid glands due to chronic hypocalcemia.”
Causes: Renal failure (MC); Inadequate intake of calcium; Vit.D deficiency; Steatorrhea.
Morphology: Gross: Hyperplasia of parathyroid glands.
Micro.: Increased no. of chief cells or water-clear cells in a diffuse or multinodular
distribution. Fat cells are decreased in number. Metastatic calcification may involve many
tissues.
C/P: Features of chronic renal failure, milder skeletal abnormalities and ischemic damage to
tissues (calciphylaxis).
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Pheochromocytoma
“Tumor of adrenal medulla, secreting catecholamines.”
Origin: Chromaffin cells.
Rule of 10s: 10% - Malignant; 10% - Bilateral; 10% - Extra adrenal;
10% - Non hypertensive.
Etiology: Sporadic or familial (25%).
Genetic alterations: Some of the familial cases are associated with MEN-2A, and MEN-2B,
caused by germline mutations of RET.
Morphology:
Gross: Lobular tumors of variable size with remnants of the adrenal gland.
C/S: Small tumors appear yellow-tan & large tumors show areas of hemorrhage, necrosis or
cystic change.
Micro.: Clusters of polygonal to spindle shaped chromaffin cells or chief cells, surrounded
by sustentacular cells in small nests or alveoli (zellballen) with rich vascular network. Chief
cells show fine granular cytoplasm & round to ovoid nucleus with a stippled salt & pepper
chromatin.
C/P: Hypertension with paroxysmal episodes, associated with tachycardia, palpitations,
headache, sweating & tremors.
Comp.: Catecholamine cardiomyopathy with congestive heart failure, myocardial infarction,
& ventricular fibrillation.
Inv.: Increased urinary excretion of free catecholamines & their metabolites
(vanillylmandelic acid (VMA), & metanephrins); Biopsy.
Metastasis (malignant pheochromocytoma): Regional lymph nodes; Liver, lungs, & bones.
Diabetes Mellitus
“A group of metabolic disorders sharing the common feature of hyperglycemia caused by
defects in insulin secretion, insulin action, or, most commonly, both.”
Diagnostic Criteria
1. A fasting plasma glucose ≥ 126 mg/dL.
2. A random plasma glucose ≥ 200 mg/dL (in a patient with classic hyperglycemic signs).
3. A 2-hour plasma glucose ≥ 200 mg/dL during an oral glucose tolerance test (OGTT) with a
loading dose of 75 g.
4. A glycated hemoglobin (HbA1c) level ≥ 6.5%.
Type 1 diabetes (T1D)
Features
i) 5% to 10% of diabetes.
ii) Onset: Usually childhood & adolescence.
iii) Autoimmune disease with circulating islet autoantibodies (anti-insulin, anti-GAD).
iv) Pancreatic β-cell destruction and an absolute deficiency of insulin in a progressive
manner.
Pathogenesis
1) Genetic susceptibility:
i) Major linkage to MHC class II genes (HLA-DR3 or HLA-DR4).
ii) CTLA4 and PTPN22 genes are associated.
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2) Environmental factors: Antecedent viral infections may play a role.
3) Immune abnormalities:
i) Failure of self-tolerance in T cells specific for islet antigens, may include insulin, glutamic
acid decarboxylase (GAD).
ii) Th1 cells secrete cytokines, IFN-γ and TNF, that injure β cells, and CD8+CTLs, kill β
cells directly.
Type 2 diabetes (T2D)
Features
i) 90% to 95% of diabetes.
ii) Onset: Usually adults, majority are obese.
iii) Insulin resistance and β-cell dysfunction with early hyperinsulinemia and late relative
insulin deficiency.
Pathogenesis
1) Genetic factors: Family history with many genes identified, involved in adipose tissue
function, islet β-cell function, and obesity.
2) Environmental factors: Central or visceral obesity, sedentary life style, sleep disorders
(obstructive sleep apnea) and circadian disruption.
3) Metabolic defects
a) Insulin Resistance: Failure of target tissues (liver, skeletal muscle, and adipose tissue) to
respond normally to insulin due to functional defects in the insulin-signaling pathway.
b) Obesity: Contributes to insulin resistance caused by excess plasma FFAs with their toxic
metabolic products and pro-inflammatory cytokines (IL-1) secreted in response to excess
FFAs and glucose.
c) β-Cell Dysfunction: Early hyperinsulinemia and late relative insulin deficiency seen due
to excess FFAs (lipotoxicity) & chronic hyperglycemia (glucotoxicity) and amyloid
deposition within islets.
C/P
T1D: Triad of polyuria, polydipsia, polyphagia; Weight loss, and muscle weakness.
T2D: Asymptomatic; Unexplained fatigue, dizziness, or blurred vision.
Complications
I) Acute metabolic complications
i) Hypoglycemia: Most common.
C/P: Dizziness, sweating, confusion & palpitations. Loss of consciousness may occur.
ii) Diabetic ketoacidosis: Seen predominantly with type 1 diabetes.
C/P: Fatigue, nausea & vomiting, severe abdominal pain, fruity odor and deep, labored
breathing (Kussmaul breathing). Altered consciousness & coma may be seen.
Inv.: Ketonemia & ketonuria with hyperglycemia.
iii) Hyperosmolar hyperosmotic syndrome (HHS): Seen with type 2 diabetes.
C/P: Severe dehydration & impairment of mental status.
II) Chronic complications: Responsible for majority of the morbidity & mortality.
i) Diabetic macrovascular disease: MC cause of mortality in long standing diabetes.
Sites: Large & medium-sized muscular arteries.
C/P: Accelerated atherosclerosis with increased risk of myocardial infarction, gangrene of
the lower extremities and stroke.
ii) Diabetic microangiopathy:
Sites: Small vessels.
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a) Diabetic nephropathy: Leading cause of end-stage renal disease.
C/P: Microalbuminuria (earliest manifestation), overt nephropathy with macroalbuminuria &
end-stage renal disease.
b) Diabetic retinopathy:
C/P: Increased risk of developing cataracts & glaucoma. Visual impairment or total blindness
may be seen.
c) Diabetic neuropathy:
C/P: Distal symmetric polyneuropathy of the lower extremities affecting both sensory &
motor function, autonomic neuropathy with bowel or bladder dysfunction & diabetic
mononeuropathy with sudden footdrop or wristdrop.
iii) Increased susceptibility to infections: Skin infections, TB, pneumonia & pyelonephritis.
Cushing Syndrome (Hypercortisolism)
“Characterised by elevated glucocorticoid levels.”
Etiopathogenesis
1) Exogenous: Administration of exogeneous glucocorticoids (iatrogenic Cushing
syndrome).
2) Endogenous
i) ACTH dependant:
a) Cushing disease: ACTH-secreting pituitary adenoma.
b) Ectopic ACTH secretion: Small cell carcinoma of lung.
ii) ACTH independent: Adrenal adenoma and carcinoma.
Morphology:
1) Pituitary: Crooke hyaline change with homogeneous and paler appearing ACTHproducing cells (MC alteration).
2) Adrenal: i) B/L cortical atrophy with iatrogenic Cushing syndrome.
ii) Diffuse hyperplasia with Cushing disease.
iii) Macronodular or micronodular hyperplasia.
iv) Adenoma or carcinoma.
C/P: Truncal obesity, moon facies, buffalo hump, hypertension, decreased muscle mass,
proximal limb weakness, hyperglycemia, glycosuria, polydipsia, thin and fragile skin with
poor wound healing and abdominal striae, osteoporosis, mental disturbances, hirsutism and
menstrual abnormalities.
Inv.: 1) The 24-hour urine free-cortisol concentration, which is increased.
2) Loss of normal diurnal pattern of cortisol secretion.
3) Measurement of the serum ACTH and the dexamethasone suppression test:
i) Pituitary Cushing syndrome: ACTH levels are elevated and are not suppressed by the
administration of a low dose of dexamethasone. After higher doses of injected
dexamethasone, the pituitary responds by reducing ACTH secretion.
ii) Ectopic ACTH secretion: Elevated ACTH levels and both low-dose and high-dose
dexamethasone fail to suppress ACTH levels.
iii) Cushing syndrome caused by an adrenal tumor: Low ACTH levels and both low-dose and
high-dose dexamethasone fail to suppress cortisol levels.
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Multiple Endocrine Neoplasia Syndromes
“A group of inherited diseases resulting in proliferative lesions (hyperplasia, adenomas, and
carcinomas) of multiple endocrine organs.”
I) Multiple Endocrine Neoplasia, Type 1 (MEN-1)
II) Multiple Endocrine Neoplasia, Type 2 (MEN-2)
i) MEN-2A
ii) MEN-2B
iii) MEN-4
MEN Type 1 (Wermer Syndrome)
Defect: Germline loss of function mutations in MEN 1 tumor suppressor gene.
Manifestations:
1) Parathyroid: Primary hyperparathyroidism (MC manifestation of MEN-1) with
hypercalcemia and nephrolithiasis.
2) Pituitary: Prolactinoma; Acromegaly.
3) Pancreas: MC cause of morbidity & mortality in MEN-1.
i) Zollinger-Ellison syndrome with gastrinomas.
ii) Hypoglycemia & neurologic manifestations with insulinomas.
4) Duodenum: Gastrinomas.
MEN Type 2
1) MEN-2A (Sipple Syndrome)
Defect: Germline gain of function mutations in RET protooncogene.
Manifestations
1) Thyroid: Medullary carcinoma (MC feature of MEN-2A) with elevated calcitonin levels.
2) Parathyroid: Primary hyperparathyroidism with hypercalcemia or nephrolithiasis.
3) Adrenal medulla: Pheochromocytoma (often bilateral).
2) MEN-2B
Defect: Germline gain of function mutations in RET protooncogene.
Manifestations
1) Thyroid: Medullary carcinoma (multifocal & aggressive).
2) Adrenal medulla: Pheochromocytoma.
3) Others - Neuromas or ganglioneuromas; Marfanoid habitus.
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Undergraduate Pathology Series
24. The Skin
5 Marks
1) Precancerous lesions of skin and oral cavity. (May, 2022)
4 Marks
1)
2)
3)
4)
Describe the etiopathogenesis and morphology of malignant melanoma. (Aug. 2021)
Histological types of malignant melanoma. (Feb. 2020)
Morphology of malignant melanoma. (Jan. 2015)
Malignant melanoma. (March/April, 2008)
2 Marks
1) Lichen planus. (March, 2021)
2) Microscopic features of basal cell carcinoma. (Feb. 2019)
3) Morphology of basal cell carcinoma. (July, 2016)
4) Microscopic picture of malignant melanoma. (Jan. 2012)
5) Name four preneoplastic lesions of skin. (Jan. 2011)
6) Histology of malignant melanoma. (Aug. 2010)
7) Name four variant forms of nevocellular nevi. (March, 2010)
8) Melanoma. (April, 2009)
9) Basal cell carcinoma. (Feb. 2009)
10) Pre malignant conditions of skin. (May, 2007)
11) Vesiculo-bullous lesions of skin. (May, 2006)
12) Rodent ulcer. (Oct. 2004)
High-Yield Topics
Psoriasis
Premalignant lesions of skin
Melanoma
Pemphigus
Basal cell carcinoma
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Variant Forms of Melanocytic Nevi
Congenital nevus; Blue nevus; Spitz nevus; Halo nevus; Dysplastic nevus.
Melanoma
“Malignant tumor of skin.”
Sites: Skin (MC) – Upper back in men and back & legs in women; Esophagus; Uvea;
Meninges; Oral & anogenital mucosal surfaces.
Risk factors: Fair skin; Sun exposure (UV radiation).
Etiology: Sporadic (MC) or genetic.
Pathogenesis: Ultraviolet radiation causes DNA damage.
Genetic alterations: 1) Mutations of the gene CDKN2A.
2) Activating mutations in BRAF.
3) Mutations that activate telomerase enzyme.
Morphology: Gross: 1) Asymmetrical with irregular & notched borders.
2) Increased diameter (>6mm) with variegated color.
Microscopy:
1) Patterns of growth: i) Radial growth: Horizontal spread within the epidermis & superficial
dermis. No metastatic risk. Ex.: Superficial spreading, and lentigo maligna.
ii) Vertical growth: Invasion into the deeper dermis heralded by the appearance of a nodule.
Metastatic risk is associated.
2) Melanoma cells are large with large nuclei having irregular contours, peripheral chromatin
clumping & red nucleoli.
Classification
1) Superficial spreading:
i) Sites: Trunk and extremities (MC).
ii) Age: 20-50 yrs.
iii) May arise de novo or in association with melanocytic nevi.
iv) Micro.: Nests and single cell scatter of melanocytes within the epidermis.
2) Lentigo maligna:
i) Sites: Head & neck and arms (MC).
ii) Age: 65 yrs (mean age at diagnosis).
iii) Usually arises de novo and slowly growing.
iv) Micro.: Predominance of solitary units of melanocytes at the dermal-epidermal junction.
3) Nodular:
i) Sites: Trunk and legs (MC).
ii) May arise de novo or in association with melanocytic nevi with history of rapid growth.
iii) Micro.: Invasive melanoma with no detectable in situ component.
4) Acral lentiginous:
i) Sites: Digits, palms and soles.
ii) Usually arises de novo but may be associated with a melanocytic nevus.
iii) Micro.: Lentiginous pattern with predominance of solitary units of melanocytes along the
dermal-epidermal junction.
C/P: Asymptomatic; Itching or pain may be seen.
Metastasis: Regional lymph nodes.
Prognosis: Favourable prognosis is seen with female gender, thinner tumor depth, no or very
few mitoses, many tumor-infiltrating lymphocytes, absence of regression, lack of ulceration,
and absent lymph node metastasis.
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Pre-malignant Lesions of Skin
Actinic keratosis; Solar keratosis; Bowen disease; Leukoplakia; Xeroderma pigmentosum.
Basal Cell Carcinoma (Rodent Ulcer)
“Malignant tumor of skin.”
*MC invasive carcinoma.
*Locally aggressive, slow-growing & rarely metastasize.
Origin: Epidermis or follicular epithelium.
Risk factors: Sun exposure; Old age; Fair skin; Xeroderma pigmentosum;
Immunosuppression.
Etiology: Sporadic or genetic.
Genetic alterations: Loss of function mutations involving PTCH gene, that activate the
Hedgehog signaling pathway.
Morphology: Gross: 1) Pearly papules with telangiectasias or ulceration.
2) Local invasion of bone or facial sinuses in advanced cases.
Microscopy.:
1) Growth patterns: i) Multifocal lesions involving only epidermis.
ii) Nodular lesions involving dermis.
2) Cords & islands of basophilic cells with hyperchromatic nuclei are embedded in a
mucinous matrix, surrounded by lymphocytes & fibroblasts.
3) Cells exhibit palisading in the periphery of the tumor islands.
4) Stroma retracts away from tumor creating clefts or separation artifacts.
Associations: Nevoid basal cell carcinoma syndrome or Gorlin syndrome
Lichen Planus
“Chronic inflammatory dermatoses.”
Sites: Extremities (about wrist, elbow); Vulva; Glans penis; Oral mucosa.
Age: Middle-aged adults (MC)
Pathogenesis: Not known.
Expression of altered antigens in basal epidermal cells or the dermoepidermal junction elicits
a cell-mediated cytotoxic (CD8+) T-cell response.
Morphology
Gross: 1) Multiple, symmetrically distributed, violaceous, flat-topped papules that may
coalesce to form plaques.
2) Wickham striae: White dots or lines highlighting the papules.
Micro.: 1) Epidermal hyperplasia with hypergranulosis and hyperkeratosis.
2) A dense, continuous infiltrate of lymphocytes along the dermoepidermal junction.
3) Basal keratinocytes show degeneration, and necrosis.
4) Dermoepidermal interface takes on an angulated zigzag contour (sawtoothing).
5) Colloid or Civatte bodies: Anucleate, necrotic basal cells incorporated into the inflamed
papillary dermis.
C/P: Cutaneous lesions are multiple and usually symmetrically distributed “pruritic, purple,
polygonal, planar, papules, and plaques.”
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Fate: 1) Spontaneous resolution within 1-2 yrs. with a residuum of postinflammatory
pigmentation.
2) Squamous cell carcinoma may be associated.
Blistering (Bullous) Diseases
1) Inflammatory blistering Disorders: Pemphigus; Bullous pemphigoid; Dermatitis
herpetiformis.
2) Noninflammatory blistering disorders: Epidermolysis bullosa; Porphyria.
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25. Bones, Joints, and Soft Tissue Tumors
MCQs
1) Dystrophin gene mutation leads to. (Feb. 2022)
a) Myasthenia gravis
b) Duchenne muscular dystrophy
c) Amyotrophic lateral sclerosis d) Multiple sclerosis
2) Defective synthesis of fibrillin protein will leads to. (Feb. 2022)
a) Ehlers-Danlos syndrome b) Loeys-Dietz syndrome
c) Marfan syndrome
d) Osteogenesis imperfecta
5 Marks
1) Write a note on etiology, pathogenesis and clinical features of osteomyelitis. (Feb.
2022)
10 Marks
1) A 25 year old man is admitted with swelling of the upper end of tibia. X-ray shows a
tumor in the metaphyseal area of tibia with evidence of new bone formation. (July, 2018)
a) What is the probable diagnosis?
b) Give the microscopic picture of the turnover with labelled diagram.
c) Name the organs where it metastasizes.
d) Classify bone tumors.
Ans: Osteosarcoma
4 Marks
1) Aneurysmal bone cyst. (Nov. 2020)
2) Give the microscopic picture, X-ray appearance and spread of osteogenic sarcoma.
(Feb. 2018)
3) Classify bone tumors. Give X-ray appearance and microscopic picture of giant cell
tumor. (July, 2017)
4) Morphology of osteoclastoma. (Feb. 2017)
5) Skeletal Ewing sarcoma – common sites, X-ray appearance and microscopic picture.
(Jan. 2014)
6) Giant cell tumor – Bone. (July, 2013)
7) Morphology of common and classic osteosarcoma. (Jan. 2013)
8) Ewing sarcoma. (July, 2012)
9) Morphology of giant cell tumor of bone. (Jan. 2011)
10) Morphology of pyogenic osteomyelitis. (March, 2010)
11) Gouty arthritis. (April, 2009)
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12) Giant cell tumor of bone. (Oct. 2008)
13) Ewing sarcoma. (May, 2007)
14) Osteosarcoma. (May, 2006)
15) Giant cell tumor of bone (Osteoclastoma). (Oct. 2005)
16) Osteomyelitis. (March/April, 2005)
17) Giant cell tumor. (March/April, 2003)
2 Marks
1)
2)
3)
4)
Name four manifestations of fibrous dysplasia bone. (Oct. 2022)
Describe two characteristic radiological features of osteosarcoma. (May, 2022)
Mention four histological sub types of osteosarcoma. (March, 2021)
Osteogenic sarcoma – common sites, radiological and microscopic picture. (Feb.
2020)
5) Osteosarcoma – Its common sites, radiological and microscopic findings. (July, 2019)
6) Gross appearance of osteogenic sarcoma. (July, 2015)
7) Microscopic appearance of giant cell tumor of bone. (Jan. 2015)
8) Giant cell tumor – common sites and its radiological and microscopic picture.
(July/Aug. 2014)
9) Four (4) conditions known to be associated with development of osteosarcoma. (Jan.
2012)
10) Osteoclastoma. (July, 2011)
11) Sequestrum. (Aug. 2010)
12) Osteitis fibrosa cystica. (Aug. 2009)
13) Tuberculous osteomyelitis. (March/April, 2008)
14) Microscopic picture of giant cell tumor of bone. (Oct. 2006)
15) Gouty tophi. (May, 2006)
16) Gout. (May, 2006)
17) Tuberculous osteomyelitis. (Oct. 2004)
18) Ewing sarcoma. (April/May, 2004)
19) Osteosarcoma. (Sep. 2003)
20) Ewing sarcoma. (Oct/Nov. 2002)
High-Yield Topics
Osteomyelitis
Rheumatoid arthritis
Osteoid osteoma
Ewing sarcoma
Gout
Osteoarthritis
Classification of bone tumors
Osteosarcoma
Giant cell tumor
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Generalized Osteitis Fibrosa Cystica (von
Recklinghausen disease of bone)
“Represents the combination of increased osteoclast activity, peritrabecular fibrosis and
cystic brown tumors.”
Causes: Severe primary hyperparathyroidism.
Pathogenesis: Excessive or inappropriate release of PTH causes unrestrained osteoclast
activity leading to skeletal changes.
Morphology:
1) Osteoporosis (generalised)
i) Decreased bone mass severely affects phalanges, vertebrae, & proximal femur.
ii) In the medullary bone, osteoclasts dissect trabeculae centrally along the length causing
dissecting osteitis with an appearance of railroad tracks.
iii) The marrow spaces around the affected surfaces are replaced by fibrovascular tissue.
2) Brown tumor: Microfractures, secondary hemorrhage, and ingrowth of reparative fibrous
tissue form a mass lesion known as brown tumor. Cystic degeneration is common.
Osteomyelitis
“Inflammation of bone & marrow secondary to infection with bacteria (MC), virus, fungi or
parasites.”
Pyogenic Osteomyelitis
Cause: Bacteria – Staph.aureus (MC); H. influenza & Group B streptococci in neonates;
E.coli, Pseudomonas & Klebsiella with genitourinary tract infections or IVDA; Salmonella in
patients with sickle cell anemia.
Routes of spread: Hematogenous; Extension from a contagious site; Direct implantation.
Risk factors: Children: Trivial mucosal injuries occurring during defecation or minor skin
injuries. Adults: Open fractures or surgical procedures.
Site: Neonates – Metaphysis, epiphysis or both; Children – Metaphysis; Adults – Epiphysis
& subchondral region.
Morphology: 1) Acute phase: Neutrophilic infiltration; Necrosis of bone & marrow;
Formation of subperiosteal abscesses & sequestrum (dead bone); Draining sinus with
formation of soft tissue abscess.
2) Chronic phase: Reactive bone deposition (involucrum) around segment of dead bone with
ingrowth of fibrous tissue.
C/P: Severe localized pain, fever and chills.
Inv.: Leucocytosis; Blood culture; Biopsy & bone culture.
X-ray: Lytic lesion with surrounding sclerotic zone.
Comp.: Chronic infection; Pathologic fracture; Secondary amyloidosis; Endocarditis;
Squamous cell carcinoma of the draining sinus tract.
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Tuberculous osteomyelitis
Risk factors: Immunosuppression; Pulmonary or extrapulmonary TB.
Routes of spread: Direct extension or spread via blood vessels and lymphatics.
Morphology: Micro.: Granulomatous inflammation with granulomas & caseous necrosis.
C/P: Asymptomatic; Localized pain, low-grade fever, chills, or weight loss.
Comp.: Pott disease (Tuberculous spondylitis); Tuberculous arthritis; Sinus tract formation;
Psoas abscess; Amyloidosis.
Bone Tumors – Classification
A) Cartilage forming
Benign: Osteochondroma; Chondroma.
Malignant: Chondrosarcoma.
B) Bone forming
Benign: Osteoid osteoma; Osteoblastoma.
Malignant: Osteosarcoma.
C) Unknown origin
Benign: Giant cell tumor.
Malignant: Ewing sarcoma.
D) Metastatic tumors
Osteosarcoma
“Bone forming primary malignant tumor of bone.”
Age: <20 yrs. (MC) & older adults.
Sex: M>F
MC subtype: Primary, intramedullary, osteoblastic & high grade.
Site: Metaphysis.
Bones: Distal femur & proximal tibia (MC).
Predisposing conditions for secondary osteosarcoma in older adults: Paget disease; Bone
infarcts; Prior radiation; Chronic osteomyelitis.
Genetic alterations: Mutations involving genes such as RB, TP53, and INK4a.
Morphology:
Gross: Gritty, gray-white mass with areas of hemorrhage & cystic degeneration.
Micro.: Pleomorphic cells with large hyperchromatic nuclei; Tumor giant cells & atypical
mitotic figures; Formation of neoplastic bone with fine, lace-like architecture.
Histologic sub-types: Osteoblastic; Chondroblastic; Fibroblastic; Telangiectatic; Small cell;
Giant cell rich.
C/P: Painful enlarging mass; Pathologic fracture may be seen.
X-ray: Mixed lytic & blastic mass with infiltrative margins; Reactive periosteal bone
formation; Codman triangle (triangular shadow between the cortex & raised ends of
periosteum).
Metastasis: Spread via blood to lung, bone & brain.
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Ewing Sarcoma
“Malignant bone tumor of unknown origin.”
Age: <20 yrs.
Sex: M>F
Site: Diaphysis.
Bones: Femur, and pelvic bones (MC).
Genetic alterations: (11:22) translocation.
Morphology:
Gross: Soft, tan-white mass with areas of hemorrhage & necrosis.
Micro.: Sheets of uniform small, primitive round cells without obvious differentiation having
scant cytoplasm; Stroma is little; Necrosis may be prominent.
C/P: Painful enlarging mass with fever; Affected site is tender & swollen.
Inv.: Anemia, leukocytosis & raised ESR.
X-ray: Lytic tumor with infiltrative margins; Deposition of reactive bone in an onion-skin
fashion.
Giant Cell Tumor (Osteoclastoma)
“Benign, but locally aggressive bone tumor.”
Age: 30-50 yrs.
Site: Epiphysis (may extend into metaphysis).
Bones: Distal femur & proximal tibia (MC).
Pathogenesis: Primitive osteoblast precursors mediate proliferation & differentiation of
osteoclast precursors into mature osteoclasts. Absence of normal feedback between
osteoblasts and osteoclasts results in destructive bone resorption.
Morphology:
Gross: Solitary large red-brown mass with cystic degeneration.
Micro.: Sheets of uniform oval mononuclear cells & numerous osteoclast-type giant cells;
Nuclei of both cell types are ovoid with prominent nucleoli; Reactive bone may be present at
the periphery.
C/P: Bulging soft tissue mass; Affected site is tender & swollen.
X-ray: Lytic tumor with reactive bone formation.
Comp.: Pathologic fracture; Recurrence; Metastasis to lungs (Rare).
Aneurysmal Bone Cyst (ABC)
“A benign, but locally aggressive tumor.”
Age: Adolescence (MC).
Bones: Femur, tibia and vertebra.
Sites: Metaphysis of long bones and posterior elements of vertebral bodies.
Genetic alterations: Chromosome 17p13 rearrangements and USP6 over expression.
Pathogenesis: Increased expression of matrix metalloproteases causes cystic bone resorption.
Morphology: Multiple blood-filled cystic spaces are separated by thin, tan-white septa. The
septa are composed of plump spindle cells, multinucleated osteoclast-like giant cells, and
reactive woven bone lined by osteoblasts. An unusual densely calcified, basophilic
metaplastic matrix (blue bone) may be seen.
C/P: Localised pain and swelling; Pathological fracture (rare).
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X-ray: Expansile, well-circumscribed lytic lesion with well-defined margins; Central lysis
and a thin sclerotic “eggshell” of reactive bone at the periphery.
Comp.: Recurrence.
Fibrous dysplasia
“A benign tumor that arises during skeletal development.”
Genetic alterations: Somatic gain-of-function mutations in the gene GNAS1.
Morphology: Gross: Intramedullary tan-white and gritty lytic lesions.
Micro.: Curvilinear trabeculae of woven bone that lack conspicuous osteoblastic
rimming are seen surrounded by a moderately cellular fibroblastic proliferation. Cystic
degeneration, hemorrhage, and foamy macrophages are common.
Types
I) Monostotic: Single bone is involved.
Age: Early adolescence.
Bones: Femur, tibia, ribs, jawbones, and calvarium (MC).
C/P: Usually asymptomatic, may cause pain and fracture.
II) Polyostotic: Multiple bone are involved.
Bones: Femur, skull, and tibia (MC).
C/P: Deformities and fractures.
III) Mazabraud syndrome: Fibrous dysplasia (usually polyostotic) and soft tissue
myxomas.
IV) McCune-Albright syndrome: Polyostotic disease, associated with café-au-lait skin
pigmentations and endocrine abnormalities, especially precocious puberty.
Gout
“Crystal-induced arthritis with monosodium urate (MSU) within & around joints.”
Types: 1) Primary (MC): Cause is unknown.
2) Secondary: Known underlying cause.
Age: >30yrs.
Sex: M>F
Risk factors: Obesity, metabolic syndrome, alcoholism & renal failure.
Etiology: “Hyperuricemia is associated.”
1) Primary gout is seen with overproduction of uric acid for unknown reasons.
2) Secondary gout is seen with overproduction (leukemia) or reduced excretion (chronic renal
disease) of uric acid or both (Lesch-Nyhan syndrome).
Pathogenesis: 1) Precipitation of MSU crystals into the joint triggers cytokine &
complement mediated recruitment of leukocytes.
2) Phagocytosis of crystals is followed by production of IL-1, free radicals, proteases &
prostaglandins causing tissue injury & inflammation.
Morphology:
1) Acute arthritis: i) Neutrophilic infiltrates involve synovium & synovial fluid with MSU
crystals in their cytoplasm.
ii) Synovium is edematous & congested with small clusters of MSU crystals.
iii) MSU crystals are long, slender & needle shaped, and are negatively birefringent.
2) Chronic tophaceous arthritis: Crystals encrust the articular surface and form deposits in
the synovium. Synovium becomes hyperplastic, & fibrotic and forms a pannus that destroys
the underlying cartilage leading to juxta-articular bone erosions.
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3) Tophi: Formed by large aggregates of MSU crystals surrounded by an inflammatory
reaction of foreign body giant cells. They may be seen in the articular cartilage, ligaments,
tendons, bursae or soft tissues.
4) Gouty nephropathy: Deposition of MSU crystals or tophi in the renal medullary
interstitium or tubules leads to uric acid nephrolithiasis & pyelonephritis.
C/P: 1) Asymptomatic hyperuricemia
2) Acute arthritis: Most 1st attacks are monoarticular (MC site – 1st metatarsophalangeal
joint). Later, insteps, ankles, heels, & knees are involved. Affected joint presents with severe
pain & erythema.
3) Asymptomatic intercritical period: Symptom free interval.
4) Chronic tophaceous arthritis: Juxta-articular bone erosion & loss of the joint space are
seen on radiographs.
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26. The Central Nervous System
MCQs
1) Tau protein is associated with. (Feb. 2022)
a) Prion disease
b) Parkinson disease
c) Alzheimer disease d) Amyotropic lateral sclerosis
2) Psammoma bodies are seen in. (Feb. 2022)
a) Ependymoma b) Meningioma c) Medulloblastoma d) Glioblastoma multiforme
3) All are true about Dandy Walker syndrome except. (Feb. 2022)
a) Dilated 4th ventricle b) Hydrocephalus
c) Small vermis
d) Agenesis of corpus callosum
5 Marks
1) Glioblastoma. (May, 2022)
4 Marks
1) Laboratory diagnosis of bacterial, tuberculous and viral meningitis. (Oct. 2022)
2) CSF findings in pyogenic meningitis. (Aug. 2021)
3) CSF in tuberculous meningitis. (March, 2021)
4) CSF findings in pyogenic meningitis. (Feb. 2020)
5) Morphological changes in brain in Alzheimer disease. (July, 2019)
6) CSF findings in pyogenic meningitis. (Feb. 2017)
7) CSF changes in meningitis. (July, 2016)
8) Meningioma. (July, 2015)
9) Morphology of meningioma. (July/Aug. 014)
10) Morphology of astrocytoma. (Jan. 2014)
11) Astrocytoma. (Jan. 2012)
12) Glioblastoma. (July, 2011)
13) Astrocytoma. (Jan. 2011)
14) Morphology of meningioma. (Aug. 2010)
15) Astrocytoma. (Aug. 2009)
16) CSF findings in tuberculous meningitis. (Oct. 2006)
17) Astrocytoma. (Oct. 2005)
18) Glioblastoma multiforme. (April/May, 2004)
19) Berry aneurysm. (Oct/Nov. 2002)
2 Marks
1) List four histological types of meningioma. (May, 2022)
2) Mention four common tumors of CNS. (Nov. 2020)
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4)
5)
6)
CSF findings in tuberculous meningitis. (Feb. 2018)
Name four brain tumors. (Jan. 2015)
CSF findings in pyogenic meningitis. (July, 2013)
Mention the site, size, appearance and common complication of Berry Aneurysm.
(Jan. 2013)
7) Pyogenic meningitis – CSF findings. (July, 2012)
8) Various histological types of meningioma. (March, 2010)
9) Name four glial tumors. (April, 2009)
10) Brain abscess. (March/April, 2008)
11) Meningioma. (Sep/Oct. 2007)
12) Meningioma. (May, 2006)
13) Berry aneurysm. (Oct. 2005)
14) Berry aneurysm. (Oct. 2004)
15) Astrocytoma. (Sep. 2003)
High-Yield Topics
Berry aneurysms
Multiple sclerosis
Astrocytoma
Meningitis
Alzheimer disease
Meningioma
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Saccular Aneurysms (Berry Aneurysms)
*MC type of intracranial aneurysm.
Sites: Anterior circulation of circle of Willis, near major arterial branch points.
Risk factors: Cigarette smoking & hypertension.
Etiology: Sporadic (MC) or developmental.
Pathogenesis: Underlying defect in the media of the vessel promotes aneurysm formation.
Associations: Autosomal dominant PCKD; Neurofibromatosis type 1; Marfan syndrome.
Morphology: Gross: 1) Single or multiple saccular, thin walled, bright red translucent
outpouchings of variable size with neck & apex.
2) Atheromatous plaques, calcification, or thrombi in the wall or lumen of aneurysm.
Micro.: 1) Aneurysmal sac is made up of thick hyalinised intima & a covering of adventitia.
2) Absence of media & internal elastic lamina.
Comp.: Rupture results in subarachnoid hemorrhage.
Meningitis
“Inflammation of leptomeninges & CSF within the subarachnoid space.”
Etiology: Infections (MC).
I) Acute meningitis
Acute pyogenic (Bacterial) meningitis
Etiology:
Neonates: E.coli & group B streptococcus.
Young adults: Neisseria meningitidis.
Elderly: Streptococcus pneumoniae & Listeria monocytogenes.
Morphology: Gross: Exudate is evident within the leptomeninges over the surface of the
brain. Meningeal vessels are engorged.
Micro.: Neutrophils may fill subarachnoid space or found around leptomeningeal blood
vessels.
C/P: Headache, photophobia, neck stiffness, fever, irritability, & clouding of consciousness.
Inv.: CSF analysis: Appears cloudy with increased no. of neutrophils, increased protein &
low glucose; Gram stain & culture.
Comp.: Cerebritis; Ventriculitis; Venous thrombosis; Hydrocephalus.
Acute aseptic (Viral) meningitis
Etiology: Viral infection by enteroviruses (MC).
C/P: Headache, photophobia, neck stiffness, fever, irritability & altered consciousness.
Inv.: CSF analysis: Appears clear with increased no. of lymphocytes, increased protein &
normal glucose; Negative bacterial cultures; PCR.
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II) Chronic Meningitis
Tuberculous Meningitis
Etiology: Mycobacterium tuberculosis.
C/P: Headache, mental confusion, & vomiting.
Inv.: CSF analysis: Appears cloudy with increased no. of mononuclear cells or a mixture of
neutrophils & mononuclear cells, elevated protein & moderately reduced or normal glucose;
AFB stain & culture; PCR.
Comp.: Meningoencephalitis; Hydrocephalus; Brain infarction.
Brain Abscess
“Localized focus of liquefactive necrosis of brain tissue with accompanying inflammation.”
Etiology: Bacteria – Streptococci & staphylococci (MC).
Routes of spread: Direct implantation, local extension from adjacent foci or hematogenous
spread.
Predisposing conditions: Acute bacterial endocarditis; Bronchiectasis; Immunosuppression.
Morphology: Discrete lesions with central liquefactive necrosis, surrounded by exuberant
granulation tissue and brain swelling. Later, a collagenous capsule forms with an outer zone
of reactive gliosis.
C/P: Progressive focal neurologic deficits; Features of increased intracranial pressure.
Inv.: CSF analysis: Increased WBCs, increased protein and normal glucose.
Comp.: Meningitis; Venous sinus thrombosis; Herniation of brain.
Alzheimer Disease (AD)
*Most common cause of dementia in older adults.
Age: >50 yrs (MC).
Pathogenesis:
i) Accumulation of two proteins (Aβ and tau) in specific brain regions, likely
as a result of excessive production and defective removal.
ii) Deposits of aggregated Aβ peptides in the neuropil form amyloid plaques, and aggregates
of the microtubule binding protein tau form neurofibrillary tangles.
iii) Both amyloid plaques and neurofibrillary tangles appear to contribute to the neural
dysfunction, neuronal death, and inflammation.
Morphology
Gross: Variable cortical atrophy of the brain marked by gyral narrowing and sulcal widening,
most pronounced in the frontal, temporal, and parietal lobes. With significant atrophy, there
is compensatory ventricular enlargement (hydrocephalus ex vacuo).
Microscopy:
i) Neuritic (senile) plaques: “Focal, spherical collections of dilated, tortuous, axonal or
dendritic processes (dystrophic neurites) often around a central amyloid core.” Found in the
hippocampus, amygdala, and neocortex. Microglial cells and reactive astrocytes are present
at the periphery. The dominant component of the amyloid plaque core is Aβ.
ii) Diffuse plaques: “Lesions with deposition of Aβ peptides in the absence of the
surrounding dystrophic neurites.”
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iii) Neurofibrillary tangles: “Tau-containing bundles of filaments in the cytoplasm of the
neurons that displace or encircle the nucleus.” Commonly found in cortical neurons,
especially in the entorhinal cortex, pyramidal cells of the hippocampus, the amygdala, and
the basal forebrain. Ultrastructurally, composed predominantly of paired helical filaments
along with some straight filaments.
iv) Cerebral amyloid angiopathy (CAA) is associated.
v) Severe neuronal loss and reactive gliosis in late stages.
C/P: Forgetfulness, language deficits, loss of mathematical skills, and loss of learned motor
skills. In the final stages, patient may become incontinent, mute, and unable to walk.
Primary Tumors of Brain – Classification
1) Gliomas: Astrocytoma; Oligodendroglioma; Ependymoma; Angiocentric glioma.
2) Neuronal Tumors: Ganglioglioma; Central neurocytoma.
3) Poorly differentiated tumors: Medulloblastoma.
Astrocytoma
Types: Diffuse infiltrating or localized.
I) Diffuse infiltrating Astrocytoma
Sites: Cerebral hemispheres (MC).
Age: 40 – 60yrs (MC).
Types:
1) Diffuse astrocytoma: ‘WHO grade - Grade 2’
Morphology: Gross: Poorly defined, gray, infiltrative tumor of variable size.
C/S: Firm or soft and gelatinous.
Micro.: Increased cellular density with fibrillary background and variable nuclear
pleomorphism.
2) Anaplastic astrocytoma: ‘WHO grade - Grade 3’
Micro.: Greater cellular density and nuclear pleomorphism with frequent mitoses.
3) Glioblastoma (glioblastoma multiforme): ‘WHO grade - Grade 4’
Types:
A) Primary glioblastoma: Most common.
i) Occurs in older individuals as a new onset disease.
ii) IDH status: Wild-type.
B) Secondary glioblastoma:
i) Occurs in younger individuals due to progression of a low-grade astrocytoma.
ii) IDH status: Mutant.
Morphology:
Gross: Firm and gray-white to soft and yellow or red with foci of necrosis or hemorrhage.
Micro.: 1) Densely cellular with prominent nuclear pleomorphism.
2) Necrosis often in a serpentine pattern.
3) Tumor hypercellularity along the edges of the necrotic regions (palisading).
4) Microvascular cell proliferation that bulges into the lumen of small blood vessels.
C/P: Seizures, headaches and focal neurologic deficits.
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II) Localized Astrocytoma
Pilocytic astrocytoma
“Very slow growing and relatively benign localized astrocytoma.”
*MC localized astrocytoma.
Age: Children and young adults.
Site: Cerebellum (MC).
Genetic alterations: Alterations of the MAP kinase pathway.
WHO grade: ‘Grade 1’
Morphology: Gross: Well demarcated and cystic with a mural nodule.
Micro.: 1) Biphasic architecture with loose microcystic and compact, densely fibrillar areas.
2) Bipolar cells with long, thin hairlike processes form dense fibrillary meshwork.
3) Rosenthal fibers and eosinophilic granular bodies.
Comp.: Recurrence.
Meningioma
“Predominantly benign tumors arising from the meningothelial cells of the arachnoid.”
Age: Adults (MC).
Sex: F>M
Sites: Parasagittal aspect of the brain convexity, dura over the lateral convexity, wing of
sphenoid, olfactory groove.
Risk factor: Radiation to the head & neck.
Etiology: Sporadic or genetic.
Genetic alterations: 1) Sporadic – Mutations of NF2 gene on chr.22.
2) Genetic - 22q deletion, including the loss of NF2 gene.
Morphology: Gross: Solitary, rubbery, and rounded dural based encapsulated masses with
bosselated or polypoid appearance.
Micro.: ‘WHO Grade 1 to 4’
Grade 1 – Relatively low risk of recurrence or aggressive growth.
1) Meningothelial meningioma: Whorled clusters of epithelioid cells in syncytial pattern.
2) Fibroblastic meningioma: Fascicles of spindled cells & abundant collagen deposition.
3) Transitional meningioma: Features of both meningothelial & fibroblastic types.
4) Psammomatous meningioma: Psammoma bodies are predominant.
Grade 2 – Higher rate of recurrence & more aggressive local growth.
Atypical meningioma: Atypical features (increased cellularity, small cells with a high
nuclear-to-cytoplasmic ratio or necrosis) & increased no. of mitoses.
Grade 3 – Highly aggressive & high propensity to recur.
1) Anaplastic (malignant) meningioma: Pleomorphic cells with high mitotic rates.
2) Papillary meningioma: Pleomorphic cells are arranged around fibrovascular cores.
C/P: Vague nonlocalizing symptoms or features of compression of underlying brain.
Associations: Neurofibromatosis type 2.
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Miscellaneous
Diseases of White Blood Cells, Lymph Nodes, Spleen and Thymus
4 Marks
1) Burkitt lymphoma. (Jan. 2014)
2) Reed-Sternberg (R-S) cell. (March/April, 2008)
3) Morphology of Hodgkin lymphoma. (Sep. 2003)
2 Marks
1) Classify Hodgkin disease. (Feb. 2020)
2) Nodular sclerosing type of Hodgkin disease. (Feb. 2018)
3) Staging of Hodgkin disease. (July, 2017)
4) Burkitt lymphoma. (July/Aug. 2014)
5) Hodgkin lymphoma – WHO classification. (July, 2013)
6) Reed-Sternberg giant cells. (July, 2011)
7) Variants of Reed-Sternberg cell. (Aug. 2009)
8) Causes of lymphadenopathy. (Sep/Oct. 2007)
9) Nodular sclerosis type of Hodgkin lymphoma. (May, 2007)
10) Microscopic picture of Hodgkin lymphoma. (March/April, 2005)
11) Reed-Sternberg cell. (April/May, 2004)
12) Hodgkin disease. (Oct/Nov. 2002)
Others
MCQs
1) The size of the red blood cell is measured by. (May, 2022)
a) MCV b) MCHC c) ESR d) MCH
2) Reticulocytosis is seen in all except. (May, 2022)
a) Paroxysmal nocturnal hemoglobinuria b) Hemolysis
c) Nutritional anemia
d) Dyserythropoietic syndrome
3) Storage form of iron. (May, 2022)
a) Ferritin b) Transferrin c) Hepcidin d) Ferroportin
4) Anemia which is associated with pancytopenia. (May, 2022)
a) Hemolytic b) Iron deficiency c) Megaloblastic d) Anemia of chronic disease
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5 Marks
1) Significance of Coombs test. (May, 2020)
10 Marks
1) A 56 year old male patient is admitted with swelling of eye lids and puffiness of face. He
is a known case of chronic bronchiectasis for last 6 years. He has advised a kidney biopsy.
(Feb. 2020)
a) What is the most likely diagnosis?
b) What are the gross and microscopic findings in kidney in this disease?
c) Classify the disease.
d) Name the special stains for diagnosis.
Ans: Amyloidosis.
2 Marks
1) Define psammoma body and write two conditions where it occurs. (Aug. 2021)
2) Four sites of teratoma. (Nov. 2020)
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KNRUHS, Telangana
Paper-I (General Pathology and Hematology)
January/February 2019
10 Marks
1) A 36 year old male presents with weakness, pallor and bleeding gums. His Hb was 7 gm%.
Total leukocyte count 1,10,000/cumm., platelet count 22,000/cumm. Smear showed many
immature blasts which were positive for myeloperoxidase.
a. What is your diagnosis? Justify.
b. How do you classify this condition.
c. Write on the blood and bone marrow findings.
Ans: Chronic Myeloid Leukemia (CML).
4 Marks
1) Paraneoplastic syndromes.
2) Pernicious anemia.
3) Cellular events in inflammation.
4) Differences between exudate and transudate.
5) Explain metaplasia with examples.
2 Marks
1) Indications for Coomb’s test.
2) Name four childhood tumors.
3) Complications of wound healing.
4) Define apoptosis and give examples.
5) List four autoimmune diseases.
July/August 2019
10 Marks
1) Define and classify leukemia. Discuss the peripheral smear, bone marrow findings and the
characteristic chromosomal abnormality associated with chronic myeloid leukemia.
4 Marks
1) Physical and chemical nature of amyloid.
2) Etiopathogenesis of edema.
3) Discuss phagocytosis.
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4) Discuss idiopathic thrombocytopenic purpura.
5) Klinefelter syndrome.
2 Marks
1) Two examples each of hypertrophy and hyperplasia.
2) List four differences between benign and malignant tumors.
3) List four sites where squamous cell carcinoma can occur.
4) Name four absolute indications for bone marrow aspiration.
5) Name four childhood malignant tumors.
January/February 2020
10 Marks
1) Define and classify amyloidosis. Explain the gross and microscopic features of organs
involved in secondary amyloidosis.
4 Marks
1) Dystrophic calcification.
2) FAB (French-American-British) classification of acute leukemia.
3) Etiopathogenesis of septic shock.
4) Chemical carcinogenesis.
5) Vascular events in acute inflammation.
2 Marks
1) Four features of megaloblastic anemia.
2) Bone marrow findings in ITP.
3) Importance of Bence Jones protein.
4) Special stains for fat in tissues and result.
5) Four indications of FNAC.
August 2021
10 Marks
1) A 50 year old female, known diabetic with irregular treatment presented in semiconscious
state with high grade fever, cold clammy extremities. On examination, extensive cellulitis of
right lower limb is seen. Her BP was 70/50 mm Hg. Heart rate is 102 beats per minute with
weak rapid pulse, and temp 103 F.
a. What is your diagnosis? Justify.
b. Discuss the stage of this condition.
c. Write etiopathogenesis of this condition.
Ans: Septic shock.
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4 Marks
1) Factors affecting wound healing.
2) Idiopathic thrombocytopenic purpura (ITP).
3) Differences between lepromatous leprosy and tuberculoid leprosy.
4) Routes of metastasis.
5) Type I hypersensitivity reaction.
2 Marks
1) Types of necrosis with examples.
2) Acute phase reactant.
3) Down syndrome.
4) Stains to demonstrate amyloid.
5) Causes of aplastic anemia.
April/May 2022
15 Marks
1) Define and classify necrosis. Discuss the etiopathogenesis, alterations in different types of
necrosis.
2) Define anemia, classify anemia. Discuss the lab diagnosis of megaloblastic anemia.
5 Marks
1) Etiopathogenesis and pathology of fatty liver.
2) Turner syndrome.
3) Leukemoid reaction.
4) Factors influencing wound healing.
5) Classification of acute leukemias.
6) Differences between benign and malignant tumors.
7) Tumor suppressor gene.
8) Physical and chemical nature of amyloid.
3 Marks
1) Differences between transudate and exudate.
2) Delayed hypersensitivity.
3) Peripheral smear examination in the thalassemia.
4) Hamartoma.
5) Graft versus host disease.
6) Actinomycosis.
7) Microscopy in tuberculoid leprosy.
8) Morphology of megaloblast.
9) Reticulocyte count.
10) Sickling test.
Undergraduate Pathology Series
September 2022
15 Marks
1) Define granuloma. Describe the etiopathogenesis, morphology and fate of tuberculous
granuloma.
2) Define and classify leukemia. Discuss the lab diagnosis of chronic myeloid leukemia.
5 Marks
1) Chemical mediators of inflammation.
2) Complications of blood transfusion.
3) Lab diagnosis of megaloblastic anemia.
4) Pathophysiology of shock.
5) Etiopathogenesis of systemic lupus erythematosus.
6) Chemical carcinogens.
7) Phagocytosis.
8) Idiopathic thrombocytopenic purpura.
3 Marks
1) Exfoliative cytology.
2) Schilling test.
3) Demonstration of amyloid.
4) Down syndrome.
5) Types of infarction.
6) Exogenous pigments.
7) Examples of hyaline degeneration.
8) Target cells.
9) Apoptosis.
10) Barr body.
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Paper-II (Systemic Pathology)
January/February 2019
10 Marks
1) A 52 year old female presented with lump in the upper outer quadrant of right breast,
which was noticed 6 months back. The lump on examination was hard and fixed to the
underlying structures.
a. What is the probable diagnosis?
b. Describe the etiopathogenesis of the condition.
c. Write the morphology of the lesion in the breast.
Ans: Breast carcinoma.
4 Marks
1) Emphysema-Definition, types and etiology.
2) Etiopathogenesis of rheumatic carditis.
3) Etiology of carcinoma cervix.
4) Alcoholic liver disease.
5) Hashimoto thyroiditis.
2 Marks
1) Gross pathology of renal cell carcinoma.
2) Microscopy of basal cell carcinoma.
3) Premalignant lesions of carcinoma colon.
4) List the subtypes of Hodgkin lymphoma.
5) Morphology of osteogenic sarcoma.
July/August 2019
1) An otherwise healthy 65 year old man develops severe chest pain radiating down his left
arm, sweating and nausea. The patient is hospitalized, progresses to congestive cardiac failure
and expires after 12 days.
a. What is your diagnosis.
b. Write the laboratory investigations in this case.
c. Mention the etiological factors.
Ans: Myocardial infarction.
4 Marks
1) Classification of cirrhosis.
2) Bronchiectasis.
3) Gall stones.
4) Pathogenesis and complications of peptic ulcer.
5) Ovarian teratoma.
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2 Marks
1) List causes of nephrotic syndrome.
2) Sequestrum and involucrum.
3) Paget disease of nipple.
4) Diabetic microangiopathy.
5) Types of Hodgkin lymphoma.
January/February 2020
10 Marks
1) A 40 year old male reported to the hospital with a history of painless enlargement of left
testis. Examination revealed a solid mass in his testis. His serum LDH level was raised and
AFP level was normal.
a. What is your differential diagnosis?
b. Describe the gross and microscopic features of any one type.
c. Routes of spread of testicular tumors.
4 Marks
1) Ulcerative colitis.
2) Alcoholic liver disease.
3) Dilated cardiomyopathy.
4) Renal stones.
5) Papillary thyroid carcinoma.
2 Marks
1) Complications of asbestosis.
2) CSF findings in pyogenic meningitis.
3) Sites of atherosclerosis.
4) Pancoast tumor.
5) Cardiac vegetations.
August 2021
10 Marks
1) A man develops gradual loss of weight, abdominal pain, anorexia and hematemesis. A
mass was detected in epigastric region. A firm lymph nodal mass in the supraclavicular
region and another nodule in the periumbilical region.
a. What is your probable diagnosis?
b. Discuss the etiopathogenesis.
c. Describe in detail morphology of the lesion.
Ans: Gastric carcinoma.
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4 Marks
1) Giant cell tumor of bone-Clinical features, etiopathogenesis, morphology, radiologic
findings.
2) Etiopathogenesis and morphology of benign prostatic hyperplasia.
3) Morphology and complications of atheroma.
4) Discuss the stages in the evolution of lobar pneumonia and list the complications.
5) Acute poststreptococcal proliferative glomerulonephritis.
2 Marks
1) What are Verocay bodies?
2) List four complications of cirrhosis.
3) Classification of breast carcinoma.
4) Krukenberg tumor.
5) CSF findings in pyogenic meningitis.
April/May 2022
15 Marks
1) Discuss the etiopathogenesis of cholelithiasis. Describe the morphology of different types
of gall stones. List investigations required. Mention complications of cholelithiasis.
2) A 60-year-old lady presented with an ill-defined hard breast mass that was fixed to the
underlying muscle.
a. What is your diagnosis and why? Explain.
b. What are the histologic types of this lesion?
c. What are the investigations required for diagnosis?
d. Write a note on prognostic factors for this lesion.
Ans: Breast carcinoma.
5 Marks
1) Multinodular goitre.
2) Kidney changes in hypertension.
3) Meningioma.
4) Nephrotic syndrome.
5) Etiopathogenesis of gastric carcinoma.
6) Pathogenesis of bronchial asthma.
7) Pyogenic osteomyelitis.
8) Etiopathogenesis of infective endocarditis.
3 Marks
1) Meckel diverticulum.
2) Fibrolamellar variant of hepatocellular carcinoma.
3) Gross features of adult polycystic kidney.
4) Microscopy of squamous cell carcinoma of skin.
5) Microscopy of osteoclastoma of bone.
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6) Gross and microscopy of osteochondroma.
7) Cervical intraepithelial neoplasia. (CIN).
8) Microscopy of schwannoma.
9) Leukoplakia of oral cavity.
10) Complications of portal hypertension.
September 2022
15 Marks
1) Classify emphysema. Discuss the etiopathogenesis and types of emphysema with a note on
gross and microscopy of emphysema.
2) What is nephrotic syndrome? List four causes of nephrotic syndrome. Write a note on its
pathophysiology.
5 Marks
1) Basal cell carcinoma.
2) List differences between ulcerative colitis and Crohn disease.
3) Ewing sarcoma.
4) Pleomorphic adenoma.
5) Grave disease.
6) Etiopathogenesis of alcoholic liver disease.
7) Hydatidiform mole.
8) Morphology and complications of atheroma.
3 Marks
1) Morphology of benign prostatic hyperplasia.
2) Microscopy of papillary carcinoma thyroid.
3) CSF findings in tubercular meningitis.
4) Barrett esophagus.
5) Morphology of osteoclastoma.
6) List the laboratory markers of acute myocardial infarction.
7) Dermoid cyst of ovary.
8) Morphology of peptic ulcer.
9) Endometriosis.
10) Risk factors for gall stones.