Institute of Pathology
Medical Faculty
University of P. J. Šafárik
Andrej Böőr, Ivan Jurkovič, Marián Benický
and Zuzana Havierová
Practical lessons in histopathology and
methods in pathology
Košice, 2004
1
CONTENTS
Introduction
……………………………………………………………………………….......……7
A.
Methods in pathology
1. Autopsy…………………………………………………………………..………………...................8
2. Surgical pathology…………………………………………………………………....11
3.
Cytopathology………………………………………...…………………………....…15
4.
Immunohistochemistry………………………………...……………………………...17
5.
Electron microscopy……………………………………..………………………..….20
6.
Enzyme histochemistry……………………………………...…………………….….22
7.
Diagnostic molecular pathology……………………………………………..…….…23
8.
Cytogenetics…………………………………………………………...………….…..25
9.
Informatics……………………………………………………..……………………..26
10. Quantitative methods (histometry)……………………………………………...…….29
11. Microscopic technique………………………………………………………………..29
B.
Practical lessons in histopathology
1.
Cell necrosis of renal tubules………………….……………...……………………..31
2.
Caseous necrosis of the lymph node…………………………...………………........31
3.
Liquefaction necrosis of the brain...............................................................................32
4.
Atrophy of the liver (brown atrophy)..........................................................................33
5.
Fatty infiltration of the heart.......................................................................................34
6.
Extracellular hyaline changes (hyaline arteriolosclerosis of the kidney)....................34
7.
Hyaline droplets in the renal tubules...........................................................................35
8.
Hyaline changes in splenic capsule.............................................................................35
9.
Fibrinoid necrosis (degeneration) in rheumatoid nodule.............................................36
10. Amyloidosis of the kidney...........................................................................................36
11. Fatty change of the liver (fatty liver)...........................................................................37
12. Virus-induced cell injury (molluscum contagiosum)..................................................38
13. Dystrophic calcifications in the heart..........................................................................39
14. Cholesterol crystals in the epidermal cyst...................................................................39
15. Exogenous pigmentation (anthracosis of the lung)......................................................40
16. Hemosiderosis of the liver...........................................................................................41
17. Silicosis of the lung......................................................................................................41
18. Hypertrophy of the heart..............................................................................................42
19. Chronic passive congestion of the liver (”nutmeg liver”)...........................................42
20. Chronic passive congestion of the lung (brown induration of lung)...........................43
21. Thrombosis (mural thrombosis in aorta).....................................................................44
22. White infarct of the kidney..........................................................................................44
23. Red infarct of the lung.................................................................................................45
24. Pulmonary edema........................................................................................................46
25. Acute serous inflammation of small intestine..............................................................46
26. Chronic inflammation of the nasal cavities.................................................................47
27. Acute purulent (suppurative) meningitis.....................................................................48
28. Acute purulent appendicitis.........................................................................................48
29. Chronic granulomatous inflammation (tuberculosis of the lung)................................49
30. Chronic granulomatous inflammation (sarcoidosis of lymph node)...........................50
31. Granulation tissue (inflammation in the (sub)chronic stages, connective tissue
repair)...........................................................................................................................51
32. Organized and recanalized thrombus...........................................................................52
33. Chronic granulomatous inflammation around foreign bodies (foreign body
granuloma)…………………………………………………………………………...52
34. Squamous metaplasia of cylindrical epithelium..........................................................53
35. Pseudotumor (epidermoid cyst)...................................................................................54
36. Preneoplastic disorder (cervical dysplasia)..................................................................54
37. Carcinoma in situ (intraductal carcinoma of the breast)..............................................56
38. Metastasis of carcinoma in the lymph node.............................…................................56
39. Characteristics of malignant neoplasms (parenchyma and stroma, anaplasia, and
atypical mitoses)..........................................................................................................57
40. Fibroma........................................................................................................................58
41. Fibrosarcoma...............................................................................................................59
42. Lipoma.........................................................................................................................59
43. Chondroma...................................................................................................................60
44. Osteoma.......................................................................................................................60
45. Chondrosarcoma..........................................................................................................60
46. Cavernous hemangioma...............................................................................................61
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47. Leiomyoma..................................................................................................................61
48. Malignant fibrous histiocytoma...................................................................................62
49. Squamous cell papilloma of the oral cavity.................................................................63
50. Papillary carcinoma of the thyroid gland.....................................................................63
51. Squamous cell carcinoma of the lip.............................................................................64
52. Basal cell carcinoma of the skin (basalioma)..............................................................65
53. Transitional (urothelial) cell carcinoma of the bladder...............................................65
54. Adenocarcinoma of the colon......................................................................................66
55. Neurinoma...................................................................................................................67
56. Pigmented nevus of the skin (nevocellular nevus)......................................................67
57. Malignant melanoma of the skin.................................................................................68
58. Benign teratoma (adult cystic type) of the ovary.........................................................68
59. Fibroadenoma of the breast..........................................................................................69
60. Seminoma of the testis.................................................................................................70
61. Choriocarcinoma..........................................................................................................70
62. Infective (bacterial) endocarditis.................................................................................71
63. Acute myocardial infarction........................................................................................72
64. Healing myocardial infarction.....................................................................................72
65. Myocarditis..................................................................................................................73
66. Atherosclerosis of the aorta.........................................................................................73
67. Polyarteritis nodosa......................................................................................................74
68. Acute purulent bronchitis.............................................................................................75
69. Bronchial asthma.........................................................................................................75
70. Bronchopneumonia......................................................................................................75
71. Lobar pneumonia.........................................................................................................76
72. Primary atypical pneumonia........................................................................................77
73. Fibroplastic pleuritis (pleurisy)....................................................................................78
74. Squamous cell carcinoma of the lung..........................................................................79
75. Small cell carcinoma of the lung.................................................................................80
76. Extramedullary hematopoiesis.....................................................................................80
77. Chronic lymphocytic leukaemia (CLL) in the liver.....................................................81
78. Chronic myeloid leukaemia (CML) in the liver..........................................................82
79. Non-hodgkin´s lymphoma in lymph node...................................................................83
80. Multiple myeloma (plasmacytoma).............................................................................83
81. Pleomorphic adenoma of the salivary gland................................................................84
82. Esophageal varices.......................................................................................................85
83. Chronic peptic ulcer of the stomach............................................................................86
84. Chronic gastritis...........................................................................................................87
85. Transmural infarction of small bowel (infarsatio hemorrhagica intestini tenuis).......88
86. Carcinoma of the stomach..............................................................….........................89
87. Subacute hepatic necrosis............................................................................................89
88. Micronodular hepatic cirrhosis....................................................................................90
89. Hepatocellular carcinoma in cirrhosis.........................................................................90
90. Chronic cholecystitis....................................................................................................91
91. Acute hemorrhagic pancreatitis...................................................................................91
92. Polycystic kidney disease............................................................................................92
93. Benign nephrosclerosis (arterionephrosclerosis).........................................................92
94. Membranoproliferative (mesangiocapillary) glomerulonephritis................................93
95. Acute pyelonephritis....................................................................................................94
96. Nephroblastoma (Wilm´s tumor).................................................................................94
97. Renal cell carcinoma (adenocarcinoma of kidney)......................................................95
98. Hydronephrosis............................................................................................................95
99. Benign prostatic hyperplasia (”hypertrophy”).............................................................96
100.
Mucinous cystadenoma of the ovary.................................................................96
101.
Serous cystadenocarcinoma of the ovary..........................................................97
102.
Ectropion of the cervix......................................................................................97
103.
Cystic glandular hyperplasia of the endometrium.............................................98
104.
Carcinoma of the uterine cervix........................................................................98
105.
Carcinoma of the endometrium.........................................................................99
106.
Spontaneous abortion........................................................................................99
107.
Hydatidiform mole..........................................................................................100
108.
Suppurative salpingitis....................................................................................101
109.
Tubal pregnancy with abortion........................................................................101
110.
Fibrocystic disease (fibrocystic changes) of the breast...................................102
111.
Invasive lobular carcinoma of the breast.........................................................103
112.
Hashimoto´s thyroiditis...................................................................................103
113.
Colloid goiter of the thyroid............................................................................104
114.
Pituitary adenoma............................................................................................104
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115.
Parathyroid adenoma.......................................................................................105
116.
Fibrous cortical defect (nonossifying fibroma of the bone)............................106
117.
Pyogenic osteomyelitis....................................................................................106
118.
Osteosarcoma..................................................................................................107
119.
Denervation atrophy of skeletal muscle..........................................................107
120.
Nonsuppurative myositis.................................................................................108
121.
Subacute sclerosing panencephalitis...............................................................108
122.
Healed intracerebral hemorrhage....................................................................109
123.
Oligodendroglioma..........................................................................................109
124.
Meningioma.....................................................................................................110
125.
Pilocytic astrocytoma......................................................................................111
126.
Glioblastoma multiforme.................................................................................111
127.
Benign fibrous histiocytoma of the skin..........................................................112
128.
Eczematous dermatitis (Eczema)....................................................................112
129.
Condyloma acuminatum..................................................................................113
130.
Lupus erythematosus of the skin.....................................................................113
131.
Scleroderma (Progressive systemic sclerosis).................................................114
132.
Squamous cell carcinoma of the skin..............................................................115
133.
Hidradenoma...................................................................................................115
134.
Neurofibroma of the skin.................................................................................116
135.
Chorioamnionitis.............................................................................................116
136.
Amniotic fluid aspiration in the lung...............................................................117
137.
Hyaline membrane disease in newborn (Respiratory distress syndrome).......117
138.
Perinatal pneumonia........................................................................................118
139.
Pneumocystis pneumonia................................................................................118
140.
Cystic fibrosis of the pancreas (Mucoviscidosis)............................................119
Introduction
The histopathologic exercises along with demonstrations in the autopsy room play an
important part of the whole teaching course in general and systemic pathology. These
”practical exercises” support the theoretical lectures offering the student the possibility of a
direct contact with histopathological slides for better understanding of many (albeit selected)
pathological processes studied during both semesters of pathology. This manual was prepared
as a study aid supporting the individual in the time of in advance study at home and namely
during the practical exercises and contains basic information about all histopathologic slides,
selected for our students. It is also helpful for those preparing for examination. In spite of the
limited number of described lesions in this manual the students will acquire a basic
knowledge and understanding of all main chapters of general pathology as well as of several
human diseases and their structural features. There is an urgent need at the beginning to call
attention to one of the basic conditions for making a correct histopathologic diagnosis, i.e. to
reasonable knowledge of normal histology. Another condition is the knowledge of the
principles of histopathologic techniques and other complementary methods. In our set of
histopathologic slides practically all specimens with just a few exceptions (requiring special
stains) were stained routinely with hematoxylin and eosin (HE). The most important general
rules for specimen study in the light microscope are reviewed in the Chapter ”Microscopic
Technique”.
Individual themes were grouped according to the traditional course outline and their
finding through the ”Contents” is easy.
The chapter ”Methods in pathology” has been included into the text so that the student
can find modern information about procedures used in daily practice of Institutes of
Pathology.
Authors
Košice, March 2004
7
1. METHODS IN PATHOLOGY
B.
AUTOPSY
The autopsy has served medicine in numerous ways and continues to play evolving
roles in a time when technologies have dramatically improved and when new diseases,
naturally occuring or iatrogenic, continue to arise on the medical horizon. Thus, despite
broad-based appretiation of autopsies as a means of diagnosis and discovery, and of quality
control, support for the autopsy has remained inappropriately low, in the face of increasing
complexity in medical care. For several reasons the autopsy rates have much declined during
the past decades in spite of the fact, that the autopsy remains the singular opportunity for a
comprehensive and indeed final history and physical and laboratory examination.
In ancient times the human disease was attributed to facts related first to animism, later
to naturalism and to solidist theory and human dissections, described as early as 1000 B.C.,
were not systematically performed until the medieval period, when first autopsies have been
documented, mostly when criminal behavior was questioned. Investigations of ”natural”
disease-related deaths had lesser financial, political, and ethical priority (e.g. religious
objections or aversion). During renaissance (16th-17th century) the interest of postmortem
examinations has gradually raised. Publications by Benivieni (1507), Bonetus (1679),
Boerhaave (1668-1738) and especially Morgagni (1682-1771) presented informations on
causes of diseases, on autopsy methodology and activity of clinicopathological correlation.
The premodern period includes the 18th and 19th century, when developments in
anatomy, physiology, and pathology were advanced by many great physicians, namely
Bichat, Laënnec, des Marets and the renowned contemporaries Carl von Rokitansky (born in
Bohemia, lived 1804-1878) and Rudolf Virchow (born in Berlin, lived 1821-1902). They all
made profound contributions to current thinking, approaches, and methodology in pathology
and medicine. The autopsy technique, the individual approach or some variation may be
entirely adequate, depending on the disease, its expression, and the intention of the autopsy.
In the beginning of the twentieth century the autopsy was supposed to be the key
process in medical education. Discovery of cause of death and acquisition of insight into
pathogenesis were foremost on the list of objectives at the autopsy table. The concept of
quality assurance through the autopsy was emerging. Hospital-based medicine saw the
autopsy as an important measure of its general quality.
PURPOSES OF THE AUTOPSY
The autopsy has a pervasive influence on medical care, medical science, society in
general, and the family of the deceased. One may group the points of influence into those
pertinent to medical care (diagnostic-related groups, quality assurance, and total patient care),
the body of medical science (research, education, transplantation, and prostheses), society
(public health, vital statistics, forensic issues), and the family (counseling and understanding
the life cycle). To convince other medical professionals on the importance and meaning of the
highly sophisticated nature of the autopsy approach, a careful conduct of the autopsy by the
pathologist performed with high standard is important and out of discussion. Otherwise, the
reputation of an autopsy as a diagnostic tool suffers.
Fundamental definitions related to terminologies implicit in death and autopsy are
summarized in Fig. 1.
CAUSE
Remote cause: disease process
that provides milieu or substrate
for later accelerated pathologic
◄----- events -----►
Proximate cause: disease or
injury initiating an uninterrupted
Immediate cause: reasonable and
-------►
series of events terminating in death
forseeable complications of the
initiating factor permitting the
development of senous sequelae
MECHANISM
Physiologic derangement or biochemical disturbance
attendant to death
Proximate cause: DISEASE ◄--- MANNER ---►Proximate cause: INJURY
▼
▼
▼
Unintentional
Intentional
▼
NATURAL
ACCIDENTAL
▼
SUICIDE
▼
HOMICIDE
___________________________________________________________________________
DEATH
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THE STANDARD TYPE OF AUTOPSY
The routine autopsy represents a series of steps, which, if seriously performed, enable
a complex insight into the health state of the deceased and serve as the basis for clinicalpathological correlations.
In practice, each autopsy starts with careful study of the clinical report. This
information is extremely important for the whole course of autopsy, starting with external
inspection. After finishing this first step the body cavities are opened and the internal
inspection called ”situs organorum” is done during which all possible lesions, their location
and quantity are registered. After intrathoracic, abdominal and intracranial organs were
carefully taken out (”exenteratio”) all organs are systematically inspected using a
standardized procedure. The next step is dedicated to organ measurement (weight and
dimensions), taking necropsy excisions and laboratory samples (microbiological, virological,
parasitological, mycological, serological, immunological and biochemical, which are
immediately sent to appropriate laboratories). In selected cases, also photographic
documentation and eventually radiography is performed.
All findings seen during autopsy are then described (or dictated) by the pathologist in
the autopsy protocol on the same day and a series of macroscopic diagnoses is incorporated
into four consecutive categories:
1. The main (principal) disease
2. Complications
3. Cause of death
4. Findings (diagnoses) unrelated to the main (principal) disease
At the end of each autopsy protocol a brief epicrisis is added, in which the clinical and
pathological diagnoses are carefully compared and the quality of clinical diagnoses and
treatment is evaluated. The autopsy protocol is definitively released after completed necropsy
histology studies and evaluation of all realized laboratory data. Cases characterized by
relevant diagnostic discrepancies (or extremely important cases for postgradual training of
hospital staff) may be chosen for discussions at the clinical-pathological conferences.
The sooner the autopsy is performed after death the higher quality of histological slides
is obtained, with lower level of disturbing autolysis artifacts.
Additional autopsy rules are used and special procedures are recommended for postmortem examinations of children, fetuses and placenta. Certain special methods are described
in autopsy monographies in relation to some extraordinary types of diseases or for e.g.
conjoined malformations or post-surgery or other post-therapy complications.
For all persons engaged in the post-mortem room and medical visitors during autopsies
it is extremely important to comply with strict safety measures.
WHY AUTOPSY RATES HAVE DECLINED
Over the years, a sharp downturn in the number of autopsies has been evident and it
continues to decline. Reasons most often cited are: attitudes (clinicians, families,
administrators), time constraints and competing responsibilities of pathologists, physician´s
fears of legal liability and of being wrong, costs, modern medical technology building false
confidence, lack of inclusion of autopsy finding in death certificate and inability to request
permission from families. The major consequence of medicine without sufficient autopsies is
that both patient care and progress in medical science will be impeded. Hindered also will be
biomedical and epidemiological research. Organs, tissues, and extracts will be unavailable,
and medical student education will be hampered. The public as a whole and health
professionals must be reeducated, not only as to the value of the autopsy, but also as to the
practical mechanisms for reinstatement of the autopsy in the core of medical practice. The
clinical physicians and pathologists should engage in a continuous dialog regarding diagnostic
discrepancies (their present rate varies widely from 4 to 66%) with a view to improving the
education and for betterment of future care. The most studies use a definition of discrepancy
wherein the observation made at autopsy and not made clinically would have altered
significantly the therapy and possible longevity of the patient.
2. SURGICAL PATHOLOGY
Pathology is a medical specialty, which provides the scientific foundation for medical
practice. The pathologist plays an essential role in patient care as diagnostician, patient
advocate, and clinical teacher. The surgical pathologist examines all tissues and foreign
objects removed from patients to identify disease processes, document surgical procedures,
and release tissue for research. Surgical pathology arises from the autopsy at the beginning of
the 20th century. Original designation for surgical pathology was the biopsy (from Greek
words bios, meaning life, and opsis, meaning appearance).
Specimens submitted for examination include all tissues with exception of materials
removed for cosmetic reasons, all products od conception, all medical devices that were
implanted and all foreign objects removed from body, including objects introduced by trauma.
11
It is the responsibility of all hospital personel involved to ensure that each patient´s
specimen is appropriately and safely handled and processed for the maximum benefit of the
patient and physician involved.
When a pathologic examination is requested, the following must be provided:
1. Identification of the patient,
2. Identification of the individual requesting the examination,
3. Date of procedure,
4. Adequate clinical history with prior diagnoses,
5. Specimen identification,
6. Special handling required,
7. Timely and appropriate transport to laboratory and
8. Instructions for the disposition of gross specimens.
There are five basic techniques for obtaining tissues in surgical pathology:
1. needle biopsy,
2. incisional biopsy,
3. excisional biopsy,
4. curretage, and
5. specimens removed during endoscopic procedures.
Needle biopsy requires the use of a large bore needle and tissue obtained is fixed in
formalin (formaldehyde) in toto (means ”on the whole”) and processed as any other biopsy
specimen. On the contrary, fine needle cytology is performed by aspiration of tissue
compartments and smearing on a glass slide and examined in the same fashion as an
exfoliative cytology.
Incisional biopsy, whether performed with a knife or a punch, is the most common
method for making the diagnosis of cancer. By this method is obtained only a part of
pathological lesion. If a given lesion shows a heterogenous gross appearance, it is advisable to
take two or more biopsies from different areas, because sometimes a single biopsy will not
show the diagnostic pathologic changes. The piece of tissue obtained should be handled with
great care, because pinching of small biopsy with forceps can damage otherwise perfect
material. A ”hot knife” should never be used because the margins of the lesion may be
charred or distorted so that microscopic diagnosis may be impossible.
Excisional biopsy is performed mainly for lesions of smaller size and because
pathological lesion is removed in whole, this form is preferable to incisional biopsy, because
excisional biopsy can be both of diagnostic and therapeutic value, and majority of pigmented
skin lesions will be cured by this procedure. Specimens by excisional biopsy should be
removed in one piece, whenever possible.
Curettage is a procedure for scraping of the skin or internal surface of an organ or body
cavity by special instrument (curette). More commonly it is used for scraping the mucous
membrane from cervical canal and uterine cavity.
All specimens obtained by various techniques should be first identified for all
components. The label of the container must include the patient name, date of birth and
designation of material. The gross evaluation and processing of specimens is the cornerstone
upon which all other pathologic diagnoses rest. During gross examination in each specimen
must be identified all anatomic structures, orientation markers, dimensions, and for some
specimens also weights should be taken prior to dissection. All specimens should be
completely dissected and serially sectioned. Next step in specimen processing is identification
of pathologic processes with brief gross differential diagnoses of common lesion. It is often
important to document the pathological change. Morphologically interesting or important
specimens are to be photographed prior to fixation, if it is possible. Some lesions are best
demonstrated after partial dissection of the specimen. Cross-sections of tumors offer much
more information about their appearance and relationship with normal structures. The section
for histological examination should be taken from area that gives best demonstration of the
feature seen on gross examination, i.e. not simply a random section! For example, the best
section to demonstrate penetration of the bowel wall by a colon carcinoma is the one showing
the deepest extent of tumor. Margins of the specimens must be taken at the sites most likely to
show tumor at the margin.
For routine fixation of all specimens 10% formalin is used. This is the standard fixative
and has been used in many studies including special stains and immunohistochemistry. Tissue
can be preserved in formalin for many months. Some non-formalin fixatives are used for
special purposes (Bouin´s solution, Zenker´s acetic fixative, Helly´s solution, glutaraldehyd,
alcohol). The calcium must be removed from bone and other calcified tissues for the
specimens to be sectioned. This procedure is called decalcification. The histotechnologist and
the histology laboratory are essential for the accurate diagnosis of pathology specimen.
Histological technique consists of tissue processing (dehydration, clearing and paraffin
infiltration, tissue embedding with making blocks, and making glass slides with 4-5 um
sections).
13
The tissue sections after drying are stained and provided with coverslips.
For some types of biopsies, special histological stains are used and may be very helpful
in any tissue, especially from liver, kidney, or bone marrow.
The surgical pathology reports serve five main purposes:
1. Provide diagnostic and prognostic information for individual patient,
2. Provide information to guide the treatment,
3. Provide information for clinical databases to be used in both clinical and basic research,
4. Provide quality assurance,
5. Intraoperative consultations represent very special circumstances in the pathologist´s
special expertise. There are three principal reasons to establish consultations in the operating
room:
a. Traditionally, the major justification has been that the surgeon has reached a
point in the procedure where morphologic information is necessary for
immediate operative planning. Surgical pathologist may provide also rapid
gross diagnosis, but most important is the microscopic diagnosis that can
guide intra- and perioperative management of a patient. During this evaluation
the surgical pathologist may identify an unknown pathologic process, evaluate
the adequacy of surgical margins, and identify lymph node metastases. The
microscopic diagnostic information are available from frozen section only
when they are appropriately technically prepared. The diagnostic information
available from frozen section is limited in comparison with definitive biopsy
investigation because only small portion of tissue can be frozen, the
occurence of crystal artifacts, lack of special studies, lack of consultation, and
relatively thick sections are evaluated. The accuracy of frozen section
evaluation is reported to be 94 to 97% as compared to permanent section
evaluation. An acceptable rate of major discrepancies is about 3%. Errors can
be classified into next categories:
1. sampling errors,
2. interpretative errors,
3. technical problems, and
4. incorrect or incomplete clinical history.
b. Tissue can be optimally processed for special studies that will be used for
diagnosis (e.g. cytogenetics or electron microscopy), treatment (e.g. hormone
receptor status analysis), or for research.
c. Specimen can confirm that pathological tissue is present for subsequent
diagnosis based on permanent sections. Most operating room consultations
fall into a few general categories: bone biopsies, dermatopathology, breast
biopsies (reason for consultation is mainly diagnosis of invasive carcinoma),
gastrointestinal specimens (mainly for colon polyps or malignancy), pancreas
(to determine whether malignancy is present), gynecologic pathology (more
frequent reason for consultation is evaluation of an ovarian tumor, or
endometrioid carcinoma), respiratory tract (lung and mediastinal tumors,
staging of carcinoma or to identify malignancy in lung masses), soft tissue
tumors, thyroid nodules (to determine whether a carcinoma is present), and
lymph nodes (for evaluation of metastases or determine whether sufficient
tissue is present for eventual diagnosis and special studies).
Personel in pathology laboratory handles potentionally infectious material every day. It
is estimated that e.g. about 50% of the patients who are HIV positive are undiagnosed at the
time of admission to the hospital. Therefore, it is important to limit the risk of infection by
handling all specimens with the utmost precaution.
3. CYTOPATHOLOGY
Even though isolated cells were visualized in the microscope over 200 years before
histology was born in 1839 by Purkyně´s introduction of the microtome for sectioning
of tissues, cytologic techniques were not developed until the 1920s. In the late 1920s a
procedure was designed for the diagnosis of cancer from exfoliated cells
simultaneously by professor George N. Papanicolaou (1883-1962) in New York, U.S.A.
and professor Aurel A. Babeş (1886-1961) in Bucharest, capital of Romania. Aspirated
material was used to diagnose cancer a century before the technique was popularized as
a routine diagnostic procedure by drs. Ewing, Martin and Stewart in the early 1930s in
New York. Exfoliative cytology is used in diagnosis of lesions of different organs and
tissues, e.g. cervix uteri and endometrium (here an reclassified international
formulation is presently used called ”The Bethesda System (2001)”, oral and nasal
cavity, conjunctiva and cornea or ocular chamber aspirate. Exfoliated cells are studied
in various body cavity fluids, namely from pleural, peritoneal or pericardial cavities and
joints. Cells may also be found in gastrointestinal, bronchoalveolar, urinary and
15
peritoneal washings, in cerebrospinal fluid, in the urine and even prenatally, in the
amniotic fluid (in neural tube closure defects). Frequently the sputum is examined. The
use of a nylon brush and the method of brushing and obtaining mechanically
desquamated cells are practised mostly in bronchi as well as in other mucosal coverings,
e.g. the esophagus, stomach or large intestine. The mostly employed exfoliative
cytology examination refers to cytology of the female reproductive tract, i.e. study of
exocervical and endocervical smears in the frame of a mass-screening programme.
Aspiration cytology using thin needle (called FNAC = Fine Needle Aspiration
Cytology) is widely used in diagnosis of different skin tumors, in certain diffuse or
localized organ pathologic lesions, or in a large spectrum of tissues and organs, namely
in the thyroid, parathyroid and salivary glands, female and much less frequently male
breast, prostate, liver, pancreas, adrenals, kidney, lymph nodes, bones and soft tissues.
Localized lung lesions are aspirated either by transbronchial puctures or by
transthoracic (percutaneous) aspiration cytology. Cytology may also be used for
diagnosis of infections and aspirates.
Touch preparations or imprints serve as an adjunct to surgical (biopsy) or autopsy
histopathology. A touch specimen may also be obtained from the breast nipple and areola in
non-neoplastic and neoplastic disorders.
Indications for cytology according to the late professor Cardozo are: cytology for an
early diagnosis, for early orientation, to help determine therapy or indicate preoperative
radiotherapy, for prevention of major or even risky diagnostic procedures, its use on the
operation room, to prevent hospitalization, as the only possible method, as a check of
histology, for early recognition of relaps, as a check during and after therapy, for mass
screening and as a tool for research.
Acceptance of cytology was slow, requiring over 50 years. In the meantime, eager
clinicians have substituted dubious pathologists. Exfoliative and aspiration techniques are
both valuable and useful diagnostic cytology procedures. They represent an adjunct to
surgical biopsy and may obviate exploratory surgery in many instances but are not to be
misused and thereby discredited. This method is relatively cheap, rapid, safe and well
tolerated by patients, repeatable and enables to obtain a definitive diagnosis in about 70% of
cases in a very short time.
Depending on the type of staining procedure the cytological slides are treated both as
unfixed (”air-dried or freeze-dry method”) or fixed, mostly by concentrated alcohol or other
fixatives (e.g. formalin, mercury salts etc.). As for staining of cells three most popular types
of dye combinations are used all over the world: hematoxilin-eosin, Papanicolaou (”Papstain”) and May-Grűnwald-Giemsa-Romanowski stain (having several modifications). The
cytoplasm accepts acid or basic stains and the nucleus, except of the nucleoli, accepts basic
stain with greater intensity than the cytoplasm. For special purposes and studies also phase
contrast microscopy, polarization and fluorescent microscopy, transmission and scanning
electron microscopy and several other procedures including cytometry may be used. For cell
concentration the use of cytocentrifuge is the preferred method of slide preparation. A part of
the collected and concentrated material may be embedded in paraffin as the ”cell block”
suitable for serial sectioning and application of various staining methods including
immunocytochemistry. First attempts at detection of genes on cytological slides have been
recently published.
An access to obtaining wider range of adequate cytological samples is supported by
several recently developed and available screening techniques (radiographic methods,
computerized tomography, MGR, ultrasonography) and endoscopical examinations.
In recent years advances in technology are used for more efficient analysis of cytology
specimen, e.g. automatization, computerized high resolution scanning and quantitative
measurements of cell components, tele-cytopathology consultation and real-time conferences
even at long distances. There is a tendency to create a computerized automatic analyzer for
cytology with artificial intelligence. Great effort is laid at the standardization and quality
control.
For teaching purposes many cytological monographs covering the whole field of
cytology and monographs dealing with separate chapters of cytology and technology are
published in several languages. Teaching slide sets prepared by expert cytopathologists are
edited by the International Academy of Cytology. At least 10 national and international
journals of cytology are published worldwide: ACTA CYTOLOGICA is the official journal
of clinical cytology and cytopathology. National and international (european, others, and
world) congresses of cytology are held all over the world each year.
4. IMMUNOHISTOCHEMISTRY
Principle
Immunohistochemistry is the marriage of immmunologic and histochemical methods,
allowing phenotypic markers to be detected and interpreted within a morphologic context in
all types of tissue. This method was introduced by Coons in 1941. Due to many technical
17
improvements of the original fluorescent-labelling method the immunohistochemistry
represents an essential element of contemporary daily pathology practice. Its most widespread
application is used in determination of appropriate classification of ”undifferentiated”
neoplasms, the detection of their prognostic markers (oncogene products, hormone receptors,
proliferation and prognostic markers) as well as for detection of infectious agents (e.g. H.
pylori, Chlamydia, CMV, HPV etc.) or identification of physiologic substances in abberant
locations and in inflammation (immunoglobulins, complement, fibrinogen etc.).
Central to the immunohistochemical assay is the specific binding of an antibody to its
corresponding antigen. An antigen is any substance that evokes an antibody response due to
multiple molecular binding sites (epitopes). An antibody is an immunoglobulin (mostly of
IgG class) with a specific binding domain for its corresponding antigen.
During the initial period polyclonal antibodies were raised in particular animals (rabbit,
swine, goat etc.) that have been challenged (immunized) with an antigen. Expressing an
intense signal these antibodies also have a series of disadvantages (e.g. low avidity and
specificity, cross-reacting with other antigens etc.). Monoclonal antibodies were introduced to
the market later through the use of cell fusion technology (hybridoma technique). These
immortalized hybrid cell lines result in the ability to indefinitively produce a unique wellcharacterized immunoglobulin (monoclonal antibody). Despite the higher cost to produce
monoclonal
antibodies,
these
purified
reagents
are
increasingly
used
in
immunohistochemistry. Though they have many advantages, there appear still certain
limitations (e.g. undesired cross-reaction, lower sensitivity etc.). Time, temperature, and pH
during the incubation of antigen and antibody will influence the binding result. Antibody
dilution is a critical factor in the antigen-antibody reaction. Antibody should be always used
as high a dilution as possible to obtain best staining result.
Immunohistochemical assay formats
Direct immunohistochemistry is the original and rapid procedure, in which the detection
system (e.g. fluorochrome – FITC) is covalently linked (conjugated) directly to the
primary antibody. The stained slide is then viewed in the fluorescence microscope.
Indirect immunohistochemistry exploits the natural capacity of immunoglobulin to act
as antigen. The primary antibody is raised in one species, for example, the rabbit, and is not
conjugated. Immunoglobulins from this species are then used as an immunogen in a second
species, for example, the goat, resulting in antibody recognizing immunoglobulin in the
primary serum (in this example, goat anti-rabbit). Immunoglobulin from the secondary serum
is then conjugated to a detection system as described earlier for the direct system. This two-
layer procedure permits higher dilution of the primary antibody, enables signal amplification
and increases the sensitivity.
A more efficient and sensitive method called the ”three-step method” or ”antibody
bridge technique” has been developed as modification of the original indirect method. In
addition to the primary and secondary antibodies a tertiary-labelled antibody is used. The first
and third antibody must be from the same species, and the secondary or bridge antibody is
directed against that species, hence binding both primary and tertiary antibodies as a ”bridge”.
The spectrum of other modern procedures includes affinity labelling methods (AvidinBiotin methods, Protein A Methods, Lectin immunohistochemistry and Immunoelectron
microscopy).
Detection systems, enabling visualization of the antigen-antibody complexes were first
represented by fluorescein (FITC) or other suitable fluorochromes (e.g. rhodamin and several
others). The study of such preparations was only possible in a relatively expensive fluorescent
microscope. For more complex immunohistochemical procedures a group of enzymes is
presently used, especially the horseradish peroxidase, alkaline phosphatase, glucose oxidase
and β-galactosidase. Each of these enzymes is detected by a specific chromogenic substrate,
e.g. diaminobenzidine (DAB), 3-amino-9-ethylcarbazole (AEC), Fast red, Fast blue,
Tetrazolium blue or BCI. Such staining combinations are easily interpreted by means of a
standard light microscope.
A crucial requirement for a valid immunohistochemical assay is to have adequate test
material that will yield valid comparative results.
Methods of tissue fixation
To protect the tissue from autolysis causing decrease and sometimes even loss of
antigenicity the fresh, small pieces of native material must be fixed. Superior preservation of
antigens is obtained by rapid freezing (liquid nitrogen). Alternatively, the fresh tissue may be
fixed in water solution of formaldehyde (1:9) or in several modified formalin fixatives. In
these the formaldehyde forms covalent cross-links with the antigen. This process can result in
direct loss of epitopes and potentially irretrievable antigen loss. Similar antigen masking may
be achieved by fixation in glutaraldehyde.
Disadvantageous is also the use of coagulant fixatives, e.g. absolute alcohol, preserving
better the immunoreactivity especially of filament proteins and does not creating cross-links,
but causing tissue shrinkage and distortion, incomplete protection against autolysis and
unwanted dislocation artifacts.
Recognizing that tissue fixation is often a poorly controlled part of the
19
immunohistochemistry sequence and that tissue antigens may undergo deleterious yet
reversible alteration as a result of excessive or harsh fixation, both enzymatic and
nonenzymatic methods have been used in attempts to retrieve or ”unmask” target antigen.
Enzymes such as trypsin, pepsin, and pronase have been used to digest tissue sections before
incubation with the primary antibody. There are several nonenzymatic methods of antigen
retrieval, for instance immersion of tissue sections in a strong alkaline solution or in antigen
retrieval solutions, but the mostly used procedure is microwave-assisted antigen retrieval, still
having some disadvantages.
Immunohistochemical procedures can also be carried out on previously routinely
stained slides, on decalcified or cytology specimens as well as on previously frozen tissues.
5. ELECTRON MICROSCOPY
The electron microscopy has made enormous contributions, and it continues to provide
new information to our understanding of the structure and function of normal and diseased
tissues. Its role in routine diagnostic pathology is today quite selective, and the application of
electron microscopy is now restricted to selected areas of diagnostic pathology.
Immunohistochemistry has greatly diminished the use of ultrastructural studies in
surgical pathology. Immunohistochemistry has several advantages over electron microscopy
because it is more accessible, a special microscope is not required, immunohistochemical
stains
are
easily
compared
with
routine
hematoxylin-eosin
sections,
and
by
immunohistochemistry may be examined many more cells than are usually studied in electron
microscopic preparation. On the contrary there are some advantages of the electron
microscopy over immunohistochemistry, for example in the evaluation of childhood small
round cell tumors.
The types of electron microscopes used in diagnostic and experimental pathology are
the transmission electron microscopy (TEM), the scanning electron microscopy (SEM), and
the analytical electron microscopy.
Transmission electron microscopy is best known to pathologists. It relies on the passage
of a beam of electrons through ultrathin section of tissue. During ”staining” the sections have
been impregnated with heavy metal atoms (such as osmium and uranium), that bind to
different subcellular organels and structures. The resolution of TEM can be fine as 0.2 nm,
but the most diagnostic electron microscopy is conducted at a relatively low magnification,
which ranges from l000x to 10000x. The scanning electron microscopy provides a threedimensional view of tissue and is largely confined to providing views of surface architecture
and topographic relationship of components of tissue. Analytical electron microscopy
provides
information
on the elemental composition
of material
within tissues.
Immunoelectron microscopy allows the precise location of cellular and subcellular products
in tissues. A marker, conjugated to antibody, serves to identify an antigen within tissue.
Electron microscopy, to be properly employed as a diagnostic tool, requires attention to
details so that a clinically relevant report must be provided. A representative sample of tissue
must be selected, correctly fixed and processed, and then examined by a pathologist who is
familiar with the corresponding light microscopy, the clinical information, and differential
diagnosis issues.
As fixatives employed in EM penetrate tissue slowly, only small thin pieces of tissues
should be placed into fixative. Buffered glutaraldehyde is widely used to fix tissues for
electron microscopy, but from practical purposes some pathologists prefer formalin and
glutaraldehyd mixtures. If glutaraldehyde-fixed material was not procured, wet formalin-fixed
tissue or even paraffin-embedded tissue may be used. Specimens for ultrastructural evaluation
are after fixation and dehydration embedded in plastic, the blocks are sectioned by
ultramicrotome at thickness of approximately l m. These so-called thick or semithin sections
are usually stained with methylene blue or toluidine blue. Examination of these sections is
very important, since it verifies the blocks selected are representative of the disease processes.
Once the blocks for ultrastructural examination are selected, thin sections are cut by use of
ultramicrotome.
Results of electron microscopic investigations should not be presented as a separate
report, but should be incorporated into the final surgical report.
Indications for ultrastructural examinations are divided in diagnostics of non-tumor
biopsies and for evaluation of the ultrastructure of tumors. Certain types of specimens require
special processing for electron microscopy and here belong percutaneous renal biopsy, fineneedle aspiration biopsy, bone marrow aspirate, core biopsies of bone and body fluids.
Ultrastructural diagnosis of non tumoral biopsies are more important in renal biopsies,
liver biopsies, by detection of microorganisms (detection of viruses), diagnosis of storage
diseases, respiratory tract biopsies, skeletal muscle biopsies, cardiac biopsies, and brain and
peripheral nerve biopsies.
Ultrastructural investigation plays important but selective role in the diagnostic study of
tumors. The electron microscope will always provide some relevant information on a
21
problematic tumor and it sometimes is the only method whereby a firm diagnosis can be made
(e.g. differential diagnosis of adenocarcinoma versus mesothelioma, differential diagnosis of
poorly differentiated tumors and childhood small round-cell tumors).
6. ENZYME HISTOCHEMISTRY
Histochemistry has been defined by Pearse as ”the identification, localization and
quantification in cells and tissues by chemical or physical tests, of specific substances,
reactive groups, and enzyme-catalyzed substances”. Enzyme histochemistry is based on
conversion of the primary reaction product of an enzyme acting on a substrate to form a
colored precipitate.
Histochemical techniques are used selectively and are absolutely essential only for some
diagnostic tools, e.g. here belongs the diagnostic evaluation of muscle biopsy specimens.
Almost all currently utilized procedures in enzyme histochemistry are carried out on cryostate
sections of fresh frozen tissue. Muscle biopsy must be carefully oriented to obtain cross
section of fibers. Myofibrillar ATPase with acidic and basic preincubation is the most useful
technique for muscle fiber typing. For examination of mitochondria succinate dehydrogenase
(SDH) is the most suitable enzyme, but NADH dehydrogenase can be also utilized.
Myofibrillar ATPase serves as a marker for abnormalities of the myofibrils. Acid phosphatase
or alfa-naphtyl acetate esterases can be useful stain to enumerate phagocytic cells in
inflammed muscle.
Enzyme histochemistry is an alternative to the traditional morphologic approach to the
diagnosis of intestinal malabsorption. Cryostat sections of small bowel mucosa mainly distal
to the duodenum are the best material for diagnosis. The most important part of evaluation is
the examination of brush-border enzymes. A semiquantitative evaluation using histochemical
technique for disaccharidases (lactase, sucrose and trehalase) are usually sufficient for clinical
purposes. These techniques can be utilized to identify disaccharidase defficiencies and to
follow the response of patient with celiac disease to treatment.
Enzyme histochemical procedures are used most extensively in diagnostic
hematopathology. For example FAB classification of acute leukemias relies extensively on
well-performed enzyme cytochemical reaction for classification. Presence or absence of
myeloperoxidase, naphtol AS-D chloracetate esterase as a marker of neutrophilic
differentiation and tartrate-resistant acid phosphatase (TRAP) in hairy cell leukemia
represent the mostly used procedures.
Carbohydrate moieties form important and frequently unique portion of many proteins.
Many of these carbohydrates can be specifically and readily identified by their ability to bind
to lectins. Lectins are carbohydrate-binding proteins of nonimmune origin and mostly of plant
origin. The lectin Ulex europeus (UEA 1) is e.g. very good marker of endothelial cells, and
Peanut agglutinin (PNA) has been shown to be useful marker in Langerhans cell
granulomatosis.
7. DIAGNOSTIC MOLECULAR PATHOLOGY
Molecular pathology is the newest subspecialty in pathology and their findings are
frequently fundamental to both medical diagnoses, by solving problems in clinical practice
and medical research. Molecular pathology incorporates many techniques for investigation
mainly of genetic alterations in cells and microbes. There are three most important
techniques:
1. Southern blotting,
2. Polymerase chain reaction (PCR),
3. Fluorescence in situ hybridization (FISH).
Application of molecular pathology plays role in four main areas:
1. Identification of inherited diseases (e.g. cystic fibrosis, hemochromatosis, fragile X
chromosome),
2. Identification of genes confering susceptibility to disease (e.g. BRCA 1 gene in
familial mammary carcinoma),
3. Detection of organisms in infectious diseases (e.g. many viruses),
4. Identification of specific genetic alteration associated with tumors, identification of
clonality in hematolymphoid proliferations and malignant neoplasms, and detection
of minimal residual disease after treatment of some malignant neoplasms.
Indications for use of molecular genetic pathology technique are as follows:
-
Clonal rearrangements of the immunoglobulin heavy and light chain genes and
translocation in some types of leukemias and malignant lymphomas of B-cell origin,
-
T-cell proliferations with rearrangements of gamma and beta T-cell receptor genes,
-
Posttransplant lymphoproliferative disorders with clonal population of cells infected
with Epstein-Barr virus. These studies are especially helpful for difficulty-to-classify
23
hematologic proliferations. Unlike to cytogenetics, the cells need not be viable, but
Southern blot and RNA-based PCR assays are best performed on fresh or frozen
tissues. Formalin-fixed and paraffin-embedded tissue is amenuable to DNA-based
PCR assays. Cytologic preparations may be used for FISH techniques.
-
Southern blotting can be used to characterize any mixture of DNA, including highmolecular weight genomic DNA from tissue, plasmids grown in bacteria, and
fragments generated in a PCR reaction. The type of DNA to be analyzed will affect the
type and percentage of agarose used in the gel. Blotting technique in general are used
to separate biologic molecules by size and then to transfer them to a solid support that
can be probed for the molecule interest. The blotting of DNA is called Southern
blotting after its inventor E.M. Southern, but RNA blots are called Northern, and
protein blots are called Western, in difference to initial denomination. During this
technique DNA is transfered from agarose gel to a specialized membrane, to which the
DNA binds irreversibly. The membrane here named blot is then placed in a plastic bag
with labelled probe in a hybridization solution.
Polymerase chain reaction (PCR) is used to make large number of copies of a specific
DNA sequence. Normal human genes are present at the level of two copies per cell, and viral
or bacterial pathogens may be present at concentrations, which are unable to detect specific
DNA sequences at such low levels. PCR allows the DNA to be copied over and over again
(this process is called amplification) until it is present in sufficient quantity to be easily
detected. PCR can be used to demonstrate the presence or absence of genes, to detect
mutations, amplifications, or rearrangements of a gene, and to detect viral or bacterial DNA.
This technique allows the amplification of a specific DNA sequence. Sample of DNA is
mixed with polymerase and primers specific to the target DNA sequence. The reaction
mixture is cycled through a series of temperature changes that cause repeated separation of
DNA strands, binding of the primers, and synhesis of new DNA. The process allows the rapid
detection of specific DNA sequences that would not be detected by other means.
In situ hybridization is derived from Latin ”in situ” that means ”in its original place”
and ”hybridization” that means to cause the production of a hybrid, ”across”. The basis for
any hybridization assay is specificity of the interaction of a probe with target nucleic acid.
This interaction shares some similarities to the antibody-antigen reaction that forms the basis
for immunohistochemistry. In both instances the remarkable specificity of the interaction is
caused by many weak noncovalent interactions that will be influenced by assay condition.
During in situ hybridization technique tissues or cells are affixed to a glass slide, then
pretreated with protein digestion, next step is interaction with the probe (known fragment of
nucleic acid with label that can be detected), next step is denaturation of DNA (separation of
double-stranded molecule into two single strand), than is realized hybridization (process of
searching a sample for specific nucleic acid sequences), and finally is technique finished with
washing, detection and interpretation of reaction. By in situ hybridization one can reveal the
genotypic changes as well as oncogen expression, chromosomal mapping, infectious disease
detection, and differentiate metabolic disorders. Through the hybridization process one can
demonstrate not only the presence of a particular piece of genetic information, but also its
specific location within the tissue, cells or chromosomes.
Fluorescent in situ hybridization (FISH) is a method in which fluorescent dye-coupled
nucleotides are incorporated directly into cloned DNA fragments, and after in situ
hybridization to chromosome spreads, the chromosomal location of a given gene can be easily
determined and compared between neoplastic and nonneoplastic cells. In addition, application
of the FISH technique to interphase cells allows chromosomal amplification, deletions, and
rearrangements to be detected with greatly increased sensitivity. FISH is a valuable
complement to traditional cytogenetic analysis in the examination of tumors, e.g. when
material for cytogenetic analysis is sparse or inadequate such as during chemotherapy or after
bone marrow transplantation. FISH can be performed on fresh tumor tissue, exfoliative cells,
and embedded and archival specimens.
8. CYTOGENETICS
Recombinant DNA technology has found application in virtually all areas of medicine.
They have application mainly for five main purposes:
1. Detection of inherited diseases (underlying the development of genetic
abnormalities either prenatally or after birth),
2. Detection of acquired mutations that underlie the development of neoplasms,
3. Karyotypic analysis of pediatric and adult human tumors, considered in the past a
relatively unrewarding exercise because of the seemingly random and secondary
nature of the alterations, has proved to be a powerful tool for the study of these
tumors, both in terms of contributing to the definition of the various entities and in
providing clues to the molecular mechanisms involved in their pathogenesis
(especially the germ cell tumors, bone and soft-tissue tumors, leukemias,
25
lymphomas, other hematopoetic neoplasms, epithelial solid tumors or neoplasms of
unknown primary tumor site),
4. Diagnosis of infectious diseases, including HIV infection,
5. Determinations of relationship and identity in transplantation, paternity testing, and
forensic medicine.
Because of the labor-intensive, time-consuming nature of the conventional karyotypic
analysis, new techniques have been sought for detecting numerical and structural
chromosomal abnormalities in a faster and more efficient fashion. Among these the
interphase
cytogenetics
and
more
recently developed
comparative
genomic
hybridization (CGH) are used for rapid detecting and mapping DNA amplification or
losses. CGH can be applied not only to fresh-frozen specimens, but also to the cell lines,
and DNA extracted from formaldehyd-fixed paraffin-embedded material.
9. INFORMATICS
Informatics describes the combination of basic and applied sciences to the processing of
data and information. When applied to medically related information, the term ”medical or
healthcare informatics” is used, encompassing the expanse of healthcare computing interests.
Its scope includes clinical science, computer science, decision science, aspects of engineering,
library science, and information science.
The practice of pathology produces vast amounts of data, which are communicated to
physicians and others. As these individuals process the data, it becomes information that
guides clinical decisions. The data and their availability influence greatly the decisions made
in the care of the patient. The pathologist in the role as an information officer or manager with
interest in and knowledge of the computer hardware and software systems can provide that
function. A basic condition for this is achievement of computer proficiency (computer
literacy) during the training period.
The so-called decision support representing a new discipline is focused on two areas –
test performance and medical utility. Recent applications of these tests have been performed
especially in cost-effectiveness analysis.
In the future, informatics will be recognized as a distinct discipline in medical practice.
The pathologist is in a unique position to capitalize on the current opportunities because of the
long experience of laboratory computerization.
Features of laboratory information system (LIS)
Advantages
Access to information: in most departments and hospitals repetitive access to tissue
diagnosis or test results is required and improves patient care.
Turnaround time is the elapsed time from specimen collection to the reporting of the result.
A LIS can shorten turnaround time by improving processing, transcription, distribution,
billing, and affecting also other components of the examination.
Productivity and financial management is increasingly important as healthcare resources
become constrained. The LIS may optimize productivity of technologists, transcriptionists,
and pathologists. The ability of the LIS to provide data at several different organizational
levels for analysis by the user is also very important. The ability to extract data into formats
that are easily imported into more sophisticated analysis programs (databases, spreadsheets) is
also useful.
Regulatory compliance: compliance with new official regulations and accreditation agencies
requests for data may be better obtained by the use of information system extracting that
information. Rapid collection of data enables the laboratory to perform quality assurance or
various clinical-pathological correlation studies.
Research support: the value of information systems in conducting medical research cannot
be understated. The ability to analyze large quantities of data, collected over a prolonged
period of time, is of great value. Particularly powerful are systems in which the laboratory
system is linked with clinical information, so that outcome analysis can be performed.
Hardware components include central processing unit, electronic storage of information,
and ”dumb” or ”smart” terminals. Networks of various types connect computers with
terminals, printers, modems, and other devices enabling integration of the whole pathology laboratory
system.
Software: The basic functionality of the software used to automate data and information
handling in pathology includes registration, demographics, order entry, entry of results and
the printing of reports. The anatomic pathology functions usually contain modules or
subsections for surgical pathology, cytology, and autopsy pathology. Anatomic pathology
reports are usually composed of text as narrative descriptions of clinical, gross, microscopic
pathologic diagnosis and, in some cases, diagnostic clinical information.
Coding mechanisms such as SNOMED (Systematized Nomenclature of Medicine) are used to
subclassify or organize cases based upon the key words in their narrative descriptions.
Databases in which diagnoses have been recorded may be searched by standardized code,
27
such as SNOMED or by natural language search to identify key words within the diagnosis.
Depending on the accuracy of SNOMED coding, most objective comparisons will find that
natural language searching techniques are most complete but more time consuming.
INTERFACES
An interface is an electronic or mechanical mechanism for data transfer between information
systems. The most common interfaces are billing interface and an admissions-dischargetransfer between the hospital admitting system or hospital information system and the LIS.
RESULT REPORTING
Is accomplished by either printed reports or by electronic transmission of results to another
LIS. The results are transmitted with a heading that contains information regarding the
specimen and order so that the results may be linked to the patient. The results are sent as
either a single component or a linked list of components that represent test codes as part of a
battery or profile. Intangible benefits of this information system are: decreased turnaround
time, improved report formats, increased access to results, reporting of work load of
laboratory section, and many others.
The information system is best implemented when physical plant and the layout of the
network, training (a very important issue), and system support are well linked together. The
pathologist assuming a leadership role in implementing the system is the most effective way
to achieve desired results.
EMERGING TECHOLOGIES
Speech recognition allows computers to transform the spoken word into the text even in the
form of continuous speech. This has been demonstrated to function also in pathology, as
continuous speech systems permit dictation at rates equivalent to that obtained by a tape
recorder. Shorter turnaround times and savings of secretarial staffing have been observed.
Image management. Pathology, similar to radiology, depends on imaging technology to
diagnose disease. Digital images can be now captured by different techniques and there is
concentrated effort underway to move toward ”filmless” environment. The advantage of
digitally stored material is that it consumes far less space, is more rapidly accessible and
permanent and can be transmitted either within the own hospital or to remote viewing sites
either for distant real-time consultation or educational purposes.
Pathologist´s workstation integrates diverse clinical information from clinical, hospital,
laboratory and radiology information system, so that with each specimen for study a complete
clinical profile could be obtained, and at the same time access to hypertext modules, image
archives of images, and online access to literature databases.
These technologies and their use are rapidly expanding.
10. QUANTITATIVE METHODS (HISTOMETRY)
Objective measurement of microscopic features has been advocated for decades as a
method to make more reproducible and ”scientific” the practice of histopathology. It is
only recently that technical advances in computing have rendered this procedure
suitable for diagnostic and prognostic determinations in pathology.
Traditionally the time-consuming measurements have been made from photographs,
from projected images, or by use of a planimeter or eyepiece graticules followed by
mathematical and statistical calculations. Most of the original contributions employing these
techniques have been in the evaluation of non-neoplastic diseases of different organs
including the human placenta. By means of histometry (stereology) data on the relative
volume of different tissue components or surface area could be obtained (the mathematical
principle was proposed as early as in 1846 by Delesse).
Currently, semiautomatic or fully automated image analyzers are employed. At present,
the method is also applied with increasing frequency to various aspects of tumor pathology,
such as determination of DNA ploidy, proliferative index, nuclear grading and hormone
receptor status.
Needless to say, image analysis can be also applied to cytological preparations.
Actually, a specimen composed of isolated cells in a clear background represents the
technically ideal situation on which to employ this method.
11. MICROSCOPIC TECHNIQUE
Speaking about the most convenient way of specimen study certain rules and
recommendations should be carefully followed.
Firstly, each specimen should be observed with a naked eye. This step helps assaying
mainly the dimensions, shape, structure, composition and color of the given specimen. In a
lesser degree this helps appreciate certain macroscopic properties or deviations from normal
structure of the diseased tissue or organ (e.g. in a lymph node). Inserting the slide on the
microscope stage it is very important to determine the location of the thin cover glass as this
helps preventing of breaking the whole glass slide or damage the lens when installing and
29
using the high-power objective (x40) with the histological slide placed downwards on the
microscope stage.
During microscopic study it is principally important to proceed gradually from lowpower objective magnification (x4) through medium-power magnification (x10) to highpower magnification (x40). The low-power magnification offers the student a general
introductory view of the whole specimen. It should be also learned, that the definitive
diagnostic decision is sometimes made by means of the low-power magnification.
Clean lenses of microscopic objectives and oculars as well as a correct illumination (
based on the so-called Koehler principle) is a prerequisite for successful and technically
undisturbed microscopic observation.
We suggest to make schematic drawings ( a general view and certain most important
details) from all specimens in the time of practical exercises which together with descriptive
remarks related to the theoretical description of each slide should help recall individual
details important for the diagnosis during the time of final examination.
B.
PRACTICAL LESSONS IN HISTOPATHOLOGY
1. CELL NECROSIS OF RENAL TUBULES
Necrosis is the sum of the morphologic changes that follow cell death in living tissues
or organs. Necrosis is recognized histologically by changes of cell nuclei and cytoplasm.
Nuclear destruction in necrotic cells includes pyknosis (nuclear shrinkage with increased
density), karyolysis (dissolution) and karyorrhexis (fragmentation of nucleus). Eventually, the
nucleus disappears completely. The cytoplasm of the necrotic cell is homogenized with
distinctly increased eosinophilia and occasionally may be vacuolated. Cell necrosis should be
distinguished from the apoptosis (distinctive pattern of individual cell death occuring in
various physiological and pathological conditions). There are several types of necrosis.
Coagulative necrosis is the most common form and occurs in almost all organs. Necrosis of
the epithelium of the renal tubules also known as acute tubular necrosis (ATN) is associated
with shock (ischemic ATN) or some chemicals (nephrotoxic ATN). The clinical consequence is
sudden onset of anuria or severe oliguria and acute renal failure.
Microscopically, there is no nuclear staining in the devitalized cells in coagulation
necrosis, the cytoplasm is deeply eosinophilic (intensive pink-red), but the cell outlines are
preserved. Ischemic ATN is characterized by focal tubular necrosis at multiple points along
the nephron. Eosinophilic hyaline casts, as well as pigmented granular casts, are very
common, particularly in distal tubules and collecting ducts. Other findings involve interstitial
edema and accumulations of mononuclear leukocytes within dilated vasa recta. These changes
may be reversible and during the recovery phase, epithelial regeneration is seen as the
presence of flattened epithelial cells with hyperchromatic nuclei and mitotic figures. Toxic
ATN is manifested by necrosis of proximal tubular epithelium and may be nonspecific in
poisoning with the various chemical agents. Cell necrosis in ATN must be differentiated from
anemic infarct that is caused by obstruction of the branch of the renal artery resulting in a
grossly manifested area of coagulation necrosis.
2. CASEOUS NECROSIS OF THE LYMPH NODE
Caseous necrosis is characteristic of tuberculous lesions and grossly appears as soft,
31
friable, cheesy map-like, yellow area. Tuberculosis is a chronic, communicable disease
caused by Mycobacterium tuberculosis. Infection of lymph nodes is a consequence of spread
of Koch bacilli to the draining one from the primary site. With the unaided eye, large
homogeneous amorphous eosinophilic masses, i.e. caseificated tissues are seen to have
replaced the originally presented lymphoid tissue.
Microscopically, caseous necrosis is seen as amorphous eosinophilic material focally
with small particles of blue-staining (basically with hematoxylin) nuclear debris. Necrotic
tissue lacks any structure and may completely dominate the histologic picture. A special
Ziehl-Neelsen stain would reveal tubercle bacilli in necrotic areas. Peripherally to the focuses
of caseation there are noncaseating or caseating granulomas composed of epithelioid cells
(modified macrophages with epithelial-like appearance) that form tubercle. Surrounding zone
of fibroblasts and lymfocytes usually contains Langhans’ multinucleated giant cells.
Numerous nuclei of the latter are arranged in a horseshoe pattern. This so-called specific
granulation tissue may be visible only as a narrow border, or in some cases, caseous necrosis
may be bordered by only a fibrous capsule.
3. LIQUEFACTION NECROSIS OF THE BRAIN
Liquefaction necrosis is macroscopically characterized by softening and colliquation of
the tissue. This type occurs when autolysis (enzymatic digestion by lysosomes of the dead cells
themselves) and heterolysis (enzymatic digestion by lysosomes of immigrant leukocytes)
prevail over protein denaturation of tissue constituents. Liquefaction necrosis occurs in the
brain and in localized bacterial infections. This type of necrosis in the brain tissue named
formerly
encephalomalacia, contemporarily is termed infarction of the brain. Most
commonly it is caused by a sudden reduction in the blood flow (vascular obstruction).
Infarcted brain tissue in first 6 - 12 hours becomes anemic and by 48 hours, it turns softer
and edematous. From 2 to 10 days, the brain becomes gelatinous and fraible. Later (from 10
days to 3 weeks) the tissue liquefies and eventually is removed, leaving a fluid-filled cavity.
Histologically, infarct is initially associated with a polymorphonuclear leukocyte
infiltration and is followed with progressive and prolonged infiltration by macrophages that
digest the infarcted tissue. This first stage that shows brain softening is followed in the second
stage by resorption of the destroyed myelin substance. Microscopical examination of the
lesion with medium power reveals absence of the normal brain structure; rather, the tissue has
spongy structure with the disappearance of neurons, glial cells and myelinated fibers. The
area of ischemic necrosis reveals numerous round cells, the cytoplasm of which is filled with
fat droplets that in paraffin sections are dissolved and thus, cytoplasm has a vacuolated
appearance (foamy cells). These granular fatty cells have eccentrically located nuclei and are
either phagocytic microglial cells or macrophages that have come in via blood vessels.
Reactive glial reaction (astrocytosis) occurs about the second week of resolution and in the
final state produces a fibrillary gliosis that surrounds the necrotic region.
4. ATROPHY OF THE LIVER (Brown atrophy)
Atrophy refers to the decrease in size of an organ or cell by reduction in cell size
(simple atrophy) and/or reduction in cell numbers (numerical atrophy). Simple atrophy is
shrinkage in the size of cell due to loss of cell substance. Atrophic cells have diminished
function but are not dead. They exhibit autophagy with a reduction in the number of cell
organelles, and often a marked increase in the number of autophagic vacuoles (indigestible
remnants of cell organelles and cytoplasmic materials). Components resisting digestion are
converted to lipofuscin granules, which in sufficient numbers make the organ brown (brown
atrophy). Macroscopically, liver is shrunken, brown and with wrinkled capsule.
Microscopically, liver cells in acinocentral zones with increasing age tend to
accumulate finely granular yellowish-brown pigment named lipofuscin. The pigment is best
seen in histologic sections stained only with hematoxylin without a counterstain with eosin.
Using high power, brown pigment cytoplasmic granules can be seen in liver cells surrounding
the central vein of hepatic lobule. Lipofuscin granules should be differentiated from ironcontaining pigment hemosiderin that may be found chiefly in hepatocytes at the periphery of
the liver lobule. The Prussian blue reaction colors the hemosiderin deep blue.
5. FATTY INFILTRATION OF THE HEART
33
In stromal fatty infiltration or ”fatty heart”, there is an increase in fat cells in the
myocardium, such as is normally present to a small degree in the anterior portion of the right
ventricle and occurs markedly in generalized obesity. Accumulation of fat cells in heart and
pancreas is designated also as lipomatosis. The right ventricle is generally more severely
affected than the left one. An increase of subepicardial fat is observed as finger-like
projections extending between the muscle bundles. Stromal fatty infiltration should be
differentiated from lipid accumulation in cells, especially in the heart muscle and liver cells
that is called steatosis (fatty change).
Microscopically, adult fat cells (round cells with optically clear cytoplasm and nuclei
located peripherally) separate but do not damage the adjacent myocardial cells. The muscle
fibers may be somewhat atrophic and incidentally show deposits of lipofuscin granules
collections of which are present at the poles of the nuclei.
6. EXTRACELLULAR HYALINE CHANGES (Hyaline arteriolosclerosis
of the kidney)
Hyalin refers to any alteration within cells or in the extracellular space, which gives a
homogeneous, glassy, pink appearance in routine histologic sections stained with hematoxylin
and eosin. Hyalin is so a catchall word used to describe a variety of lesions of diverse origin
that have a similar appearance when examined with the light microscope. Its name was
derived from its resemblance to hyaline cartilage. Hyalin has various sites of localization and
electron microscopical and immunohistochemical studies have shown that the structure and
chemical composition of hyalin may be different in different sites and under different
conditions. Principally two sorts of hyalin are recognized: intracellular and extracellular.
Extracellular hyalin occurs most frequently in atherosclerosis, hyaline arteriolosclerosis, in
damaged glomeruli and in old scars. Hyaline arteriolosclerosis of the kidney occurs typically
in elderly patients, particularly those with mild hypertension and mild diabetes mellitus. The
lesion is thought to reflect endothelial injury with subsequent leakage of plasma components
into arteriolar walls, and smooth muscle synthesis of extracellular matrix.
Microscopically, this kind of hyalin named also ”vascular hyalin” lies subintimally and
leads to thickening of arteriolar walls. It is composed of plasma proteins, lipids, and basement
membrane material. Hyalinization affects usually afferent arterioles with narrowing of their
lumina. Decreased vascular perfusion leads to hyalinized thickening of some capillary loops
and terminates in complete obliteration of a glomerulus. Cells of mesangium probably form
the hyalin in glomerulus.
7. HYALINE DROPLETS IN THE RENAL TUBULES
Hyaline droplets represent intracellular type of hyalin. This change does not have a
macroscopically defined picture. Besides the kidney, Russell bodies in plasma cells and
Mallory bodies in liver cells of alcoholics belong to this type of the hyalin. Hyaline droplets
are protein particles that were reabsorbed from the lumen of the proximal renal tubules by
process of heterophagocytosis and transiently are stored in phagolysosomes. Glomerular
lesions, e.g. glomerulonephritis, frequently condition proteinuria as a basic disorder that
gives rise to hyaline droplets of the renal tubules. Hyaline droplets are better visualized by
PAS staining.
Microscopically, protein hyaline droplets appear in the cytoplasm of tubular epithelial
cells mostly in supranuclear regions. Proximal tubule cells reveal swelling due to infiltration
of deep red (in hematoxylin-eosin sections) or purple red (in PAS sections) and somewhat
refractile protein particles. The lumen contains granular precipitates of protein or hyaline
casts. One rarely can see single epithelial cells, filled with protein-containing droplets, also in
the lumen.
8. HYALINE CHANGES IN SPLENIC CAPSULE
This type of hyalin belongs to the group of the extracellular hyalin. Macroscopically,
hyaline depositions in splenic capsule can create two forms of lesions: either diffuse
thickening resembling ”sugar icing” or local change in the form resembling drops of wax.
The latter lesion was formerly designated by Latin term as ”perisplenitis cartilaginea
guttata”.
Histologically, the capsule of the spleen is focally thicker due to deposition of the
extracellular hyalin. It is seen as a homogeneous substance stained pink-red in hematoxylin-
35
eosin sections. It is red in sections stained with van Gieson and blue when stained with
trichrom. Between fibrils there are depositions of acid mucopolysaccharides and
noncollagenous proteins that are visible with trichrom stain. Electron microscopically, hyalin
maintains quarternary structure of collagen but the arrangement of fibrils is tangled.
9. FIBRINOID NECROSIS (DEGENERATION) IN RHEUMATOID
NODULE
Fibrinoid necrosis or degeneration develops after severe acute disturbance of vascular
permeability with subsequent sudden leakage of blood plasma into the vessel and the
surrounding connective tissue. Because of this, damaged tissues are either obscured or
destroyed. Fibrinoid change cannot be seen by naked eye. It is observed mainly in rheumatic
fever, rheumatoid arthritis, polyarteritis nodosa and malignant hypertension. Rheumatoid
nodules are a part of the manifestation of the rheumatoid arthritis and are localized in the
skin in the sites of pressure points and in the vicinity of joints. Nodules are firm, palpable
subcutaneous masses, rarely exceeding 2 cm in diameter.
Histologically, nodules have a central focus of fibrinoid necrosis surrounded by an
intensive inflammatory infiltrate of palisade epithelioid histiocytes, external to which are
numerous lymphocytes, macrophages, and plasma cells. Fibrinoid is mostly homogeneous red
substance in hematoxylin-eosin sections, yellow in sections stained with van Gieson method,
red in trichrom staining and slightly positive in Weigert stain for the fibrin component. The
necrotic material is resistant to phagocytosis and therefore, the nodules are very persistent.
Proliferation of small blood vessels may be remarkable in the early stage of formation of a
rheumatoid nodule.
10. AMYLOIDOSIS OF THE KIDNEY
Amyloid represents a heterogeneous group of pathologic fibrillar proteins that
accumulate in various tissues and organs of the body. All these proteins are deposited in
extracellular space. Depending on tissue of deposition, distribution and degree of
involvement, amyloid may be asymptomatic and found only as an anatomic change, or may be
life threatening. There are two major and several minor chemically distinct classes of amyloid
fibrils. Two most important are AL (amyloid light chain protein) and AA (amyloid-associated
protein). Amyloidosis is subdivided on clinical basis into systemic (generalized) and localized
(tissue-specific) forms, and is further subclassified on the basis of predisposing conditions.
Systemic amyloidosis is composed of AL-type of amyloid and is frequently associated with Bcell (lymphocyte) dyscrasias (primary amyloidosis), e.g. multiple myeloma. Another form of
systemic amyloidosis named also secondary or reactive amyloidosis is associated with
chronic inflammatory or tissue destructive processes, e.g. rheumatoid arthritis, so-called
”collagenoses”, bronchiectases and chronic osteomyelitis. This type of amyloidosis typically
involves kidneys, spleen, liver, lymph nodes and adrenals.
Microscopically, the amyloid is deposited primarily in glomeruli producing diffuse
mesangial widening accompanied by uneven thickening of the basement membrane of the
glomerular capillaries. Increasing depositions cause capillary narrowing and eventually lead
to their obliteration. With progression of the disease, the glomeruli are flooded by confluent
masses or broad ribbons of amyloid making them appear as large, amorphous and
eosinophilic balls. The diagnosis of amyloidosis can be confirmed by examination of Congo
red-stained sections. Under ordinary light, the dye imparts a pink-red color to amyloid
deposits and under polarized light, the amyloid shows apple-green birefringence. The same
process of amyloid accumulation occurs in the media of the arcuate arteries and afferent
arterioles. Secondarily, amyloid is deposited in precapillary interstitial tissues and the tubular
basement membranes. Many of the proximal convoluted tubules are dilated and contain casts,
which have a hyaline appearance.
11. FATTY CHANGE OF THE LIVER (Fatty liver)
The lipids of the liver are normally bound to cell components and are not seen by
histological investigation. When fat appears in the form of droplets in the cytoplasm of the
liver cells, the condition is known as steatosis or fatty change. This represents a normal
constituent accumulating in excess and leading to an absolute increase in intracellular lipids.
Pathogenesis of fatty liver is very complex and includes alcohol abuse, protein malnutrition,
diabetes mellitus, obesity, toxins, and anoxia. The condition may result from defects in any
one of the following mechanisms: excessive entry of free fatty acids into the liver, enhanced
37
fatty acids synthesis, decreased fatty acid oxidation, increased esterification of fatty acids to
triglycerids, decreased apoprotein synthesis, and impaired lipoprotein secretion from the
liver. Fatty change of the liver occurs in three forms: 1. peripheral; 2. central; and 3. diffuse.
Macroscopically, fatty liver is enlarged, yellow and greasy.
Microscopically, the extent of visible fat accumulation varies from minute droplets
(microvesicular steatosis) scattered in the cytoplasm of a few hepatocytes to distension of the
entire cytoplasm of most cells by coalesced droplets (macrovesicular steatosis). In the latter
situation, the liver cell is scarcely recognizable as such and bears a resemblance to an
adipocyte, the nucleus being squeezed into the rim of cytoplasm displaced to the periphery of
the cell about the fat vacuole. Fat is dissolved in paraffin sections, therefore fat droplets are
seen as optically clear spaces in hematoxylin-eosin staning. Examination of preparations
stained with Sudan shows red positivity of the fat deposits.
12. VIRUS-INDUCED CELL INJURY (Molluscum contagiosum)
Viruses as obligate intracellular parasites are the most common causes of human
illnesses, yet most human viral infections are asymptomatic and go unrecognized. An example
of virus-induced change with characteristic lesion is a common, self-limiting viral disease of
the skin caused by a poxvirus named molluscum contagiosum. This disease is transmitted by
direct contact. Macroscopically, lesions of molluscum contagiosum create firm, pruritic, pink
to skin-colored, umbilicated papules, which are localized typically on the trunk or anogenital
regions. Cheesy material containing diagnostic molluscum bodies can be expressed from
central part of the lesions.
Microscopically, it is a flask-shaped lesion produced by verrucous epidermal
hyperplasia with pathognomic structures - molluscum bodies - that occur as large (up to 35
μm), ellipsoid, homogeneous, cytoplasmic inclusions in cells of the stratum granulosum and
the stratum corneum of the epidermis. These inclusions representing aggregates of elementary
bodies of the virus (numerous virions) are eosinophilic in the stratum granulosum and acquire
red to pale blue hue in the stratum corneum.
13. DYSTROPHIC CALCIFICATIONS IN THE HEART
Pathologic calcification implies the abnormal depositions of calcium salts in soft
tissues. When the depositions occur in nonviable or dying tissues, it is known as dystrophic
calcification. This type of calcification may occur in the absence of derangements in calcium
metabolism and despite normal serum level of calcium. When calcium salts are deposited in
living tissues, and calcium metabolism is abnormal and associated with hypercalcemia, the
condition is known as metastatic calcification. Macroscopically the calcium salts appear as
fine, white granules or clumps, and range from gritty, sandlike grains to firm, rock-hard
material.
Microscopically with the routine hematoxylin-eosin stain, the calcium salts have a
basophilic (dark blue), amorphous or granular, sometimes clumped appearance. With time,
heterotopic bone may be formed in the focus of calcification. On occasion, single necrotic
cells may represent seed crystals and with progressive acquisition of outer layers, lamellated
psammoma bodies may form. Extensive calcifications of the myocardium occur in necrosis
together with hypercalcemia, for example in hyperparathyroidism. Calcified muscle fibers of
myocardium are fragmented and stains blue with hematoxylin. The sections without
decalcification are often disrupted when the calcium deposits are huge.
14. CHOLESTEROL CRYSTALS IN THE EPIDERMAL CYST
Epithelial cysts filled with keratin and variable amounts of admixed, lipid-containing
debris derived from sebaceous secretions are common lesions situated in the dermis or
subcutaneous tissue. There are two types of these cysts referred to as keratinous cysts. The
more common type is known as epidermal or epidermoid type. Although some of these cysts
result from traumatic inclusion of epidermis, the majority probably arise from the upper
(infundibular) portion of hair follicles. The second type of keratinous cyst is the pilar or
trichilemmal type. It occurs almost exclusively in the scalp and arises from the deeper part of
the hair follicle.
Microscopically, epidermal cyst is lined by cornified epithelium, has a distinct granular
layer, and contains lamellated keratin without calcification. Trichilemmal cyst is characterized
by a trichilemmal type of keratinization, i.e., sudden keratinization without the formation of a
granular layer. The cells adjacent to the contents of the cyst are large cells with abundant pale
cytoplasm. The keratin inside the cyst is not lamellated (it appears as homogeneous
39
eosinophilic material) and focal calcification is frequent. When a keratinous cyst ruptures and
the contents are released into the dermis, a considerable inflammatory and foreign-body
reaction with numerous multinucleated giant cells results, forming a keratin granuloma.
Depositions of needle-shaped, elongated cholesterol crystals seen in routine hematoxylin–
eosin preparations as unstainable, optically clear structures (clefts) without internal details
form a prominent part of keratin granuloma. Lipid-laden macrophages with foamy cytoplasm
can be found in the contents of a cyst as well.
15. EXOGENOUS PIGMENTATION (Anthracosis of the lung)
Pigments are naturally colored substances, which can be normal constituents of cells or
they accumulate under pathological conditions. They are laid down in either diffuse or
granular fashion. Pigments are traditionally divided into endogenous, and exogenous forms.
Anthracosis refers to the storage of carbon particles in the lungs and regional lymph nodes.
Virtually all urban dwellers inhale particulates of organic carbon generated by the burning of
fossil fuels. These particles accumulate in alveolar macrophages (called anthracophages) and
blacken the pulmonary tissue and lymph nodes. Although the gross appearance of lungs of
persons with anthracosis may be alarming, the condition is entirely innocuous.
Carbon particles reaching the alveoli are phagocytosed by type I pneumocytes or
macrophages. The coal dust is insoluble, and phagocytic cells carry it into the lymphatic
vessels. It is deposited mainly in the interstitial tissues of the lung. It is seen as dark black
anthracotic pigment consisting of high-density small granules that are negative in Prussian
blue stain and also in examination under polarized light. The host reaction consists
occasionally of slight fibrosis or formation of perilymphatic connective tissue without cellular
infiltration.
16. HEMOSIDEROSIS OF THE LIVER
Hemosiderin is a product of the degradation of ferritin and is characterized as a
hemoglobin-derived, iron-containing, golden-yellow or rusty-brown granular or crystalline
pigment. It is formed when there is a local or systemic excess of iron. The most common
causes of hemosiderosis of the liver (also termed secondary hemochromatosis) are the severe
anemias associated with ineffective erythropoiesis and administration of transfusions.
Grossly, liver is brown but in contradistinction to brown atrophy is of normal size.
Microscopically, hemosiderosis of the liver is associated with depositions of hemosiderin
granules in the cytoplasm of the liver cells and occasionally also in Kupffer cells. In contrast
to lipofuscin granules, hemosiderin is found chiefly in hepatocytes at the periphery of liver
lobules, especially near the bile canaliculus. The pigment appears yellowish-brown in
hematoxylin-eosin sections, but the Prussian blue stain (named also Pearls reaction) colors the
pigment deep blue.
17. SILICOSIS OF THE LUNG
The pneumoconiosis is a pulmonary disease induced mainly by inorganic particulates.
Silicosis is a pneumoconiosis caused by the inhalation of silicon dioxide (silica), usually in
crystalline form as quartz. Particles of quartz dust ranging from 1 to 5 m in diameter are the
most dangerous because they reach the peripheral zones, namely the smallest bronchioles
and acini, and upon entering the terminal air spaces they are ingested by alveolar
macrophages. Quartz can cause direct injury to tissue and cell membranes. Moreover, silica
triggers macrophages to release products mediating an inflammatory response and initiating
fibroblast proliferation and collagen deposition. The fibrous nodules start as small lesions in
the upper portions of lungs, but grow larger and more diffuse as the disease progresses.
Coalescence of nodules forms large areas of dense scars and concomitant blackening of coal
dust is often present.
Microscopically, nodules have a characteristic whorled appearance, with concentrically
arranged hyalinized (acellular) collagen that forms the largest part of the nodule. At the
periphery there are aggregates of mononuclear cells, mostly lymphocytes, and fibroblasts.
Histiocytes containing carbon (coal dust) can be seen mainly at the periphery of the silicotic
nodule. In silicotic nodule there are very few blood vessels. The silica particles are colorless
and not visible in routine hematoxylin-eosin staining but can be detected readily under
41
polarized light. The cracks in the tissue are caused by shrinkage during processing.
18. HYPERTROPHY OF THE HEART
Hypertrophy is an increase in the size of a cell accompanied by an augmented
functional capacity and increased number of organelles (e.g. myofilaments). With such
change, there is an increase in the size of the organ. Hypertrophy can be physiologic or
pathologic. The striated muscle cells in both the heart and skeletal muscles are most capable
of hypertrophy, perhaps because they cannot adapt to increased metabolic demands by
mitotic division and formation of more cells to share the work. In cardiac hypertrophy weight
of heart may reach more than 500 - 600 gm instead of normal weight of 300 - 350 gm. The
examples of adaptive hypertrophy involve patients with hypertension (high blood pressure)
and with diseased cardiac valves. The DNA content of heart muscle cells in myocardial
hypertrophy depends on the age. In adults, tetraploidy predominates and with increasing
cardiac load, polyploidy increases.
Microscopically, myocardial hypertrophy can be appreciated by comparing the width of
the muscle fibers, the size and shape of their nuclei, and the number of nuclei per unit area. In
cardiac hypertrophy, muscle fibers are thickened twofold to threefold over normal, the
number of nuclei per unit area is decreased and the nuclei, mirroring an increase in DNA
content, are enlarged, hyperchromatic and misshapen (angulated). In cross-sectioned
sarcoplasm one can see thickened myofilaments that are increased in number.
19. CHRONIC PASSIVE CONGESTION OF THE LIVER (”Nutmeg
liver”)
Congestion, or passive hyperemia, refers to the engorgement of an organ with venous
blood. In chronic heart failure, when the right side of the heart fails to maintain its output, the
inferior vena cava and hepatic veins become congested. Grossly, the liver is enlarged and
dark red. On the cut surface, the contrast between red-blue congested centers rimmed by tanbrown, and sometimes fatty parenchyma of peripheral portions of the lobules produces the
”nutmeg” pattern. When marked congestion of the liver has been present for some time,
congestion also involves intermediate zones of lobules and the peripheral zones are only
affected where lobules adjoin each other. Thus, congested bands of tissue are formed which
connect one liver lobule with another and lead to a reversal of the previous liver pattern so
that the periportal field is in the middle of a red ring of hyperemia.
Microscopically, the central vein and the sinosoids of centrilobular regions become
dilated. The increased venous pressure and hypoxia lead to atrophy of the centrilobular
hepatocytes, whereas the surrounding hepatocytes, suffering from less severe hypoxia,
develop fatty change. With ongoing and more pronounced congestion, the periportal fields are
seen to be at the centers of communicating and coalescing congested areas that contain greatly
dilated sinusoids and disappearing liver cells. In extreme cases with severe cardiac failure,
frank hemorrhagic necroses of the central hepatocytes are conspicuous.
20. CHRONIC PASSIVE CONGESTION OF THE LUNG (Brown
induration of lung)
Chronic passive congestion of the lungs results from an impediment to the exit of blood
from the lungs (e.g. mitral stenosis or chronic failure of the left ventricle). As a consequence,
the pressure in the alveolar capillaries is increased (postcapillary hypertension), and these
vessels become engorged with blood. Grossly, the lungs are heavy, firm and brown. Changes
such as these not only impair normal respiratory function but also predispose to infection.
Thus, bronchopneumonia often terminates long-term congestive heart failure.
Microscopically, the raised blood pressure in the pulmonary capillaries causes them to
become dilated and tortuous. The alveolar septa are widened both by dilatation of alveolar
capillaries and by edema fluid that collects within the interstitial space of alveolar septa. Red
cells leak into the alveolar lumens, and macrophages also present in the alveoli ingest them.
Some of the macrophages are very large and distended with hemosiderin derived from
broken-down hemoglobin of the phagocytized erythrocytes. These macrophages containing
hemosiderin are called siderophages or ”heart failure cells”. The Prussian blue reaction shows
that the pigment contains iron. The siderophages tend to congregate around the respiratory
bronchioles and may release iron-containing salts which are then deposited in the connective
tissue of the lung. In time, the edematous septa become fibrotic and, together with the
hemosiderin pigmentation, constitute the basis for the designation brown induration. The van
43
Gieson stain demonstrates an intensely red-stained network of fibers. The long-standing
congestion and pulmonary hypertension may cause progressive thickening of the walls of the
pulmonary arteries and arterioles.
21. THROMBOSIS (Mural thrombosis in aorta)
Thrombosis is defined as the intravital formation of a clotted mass of blood constituents
within the noninterrupted cardiovascular system. There are three predisposing factors that
may result in thrombus formation: 1) injury to endothelium, 2) alterations in normal blood
flow, and 3) changes in the blood constituents (hypercoagulability). In the heart chambers
and aorta, because of rapid bypassing flow, thrombi are nonocclusive and are designated as
mural. They are soft, friable, and grayish red or dark red, with fine alternating bands of
yellowish layers, the so-called lines of Zahn. These rib-like projections of platelets seen on the
surface of the thrombus give it a rippled appearance crosswise to the direction of blood flow
like the pattern of a wind-swept sand dune or a sandbank at the bottom of a river.
Microscopically, thrombus adheres to the vessel wall and has a typical appearance.
Conglutinated blood platelets are built up into a coral-like laminated scaffold. Under high
magnification, the platelets appear as finely granular, anuclear usually fused particles 1-4 μm
in diameter. Fibrin seen as light pink network surrounds and also lies between the columns of
platelets, giving an appearance like that of a reinforced steel building. Leukocytes are
enmeshed in the fibrin and accumulate like mantles around the bands of blood platelets.
Trapped collections or masses of erythrocytes lie throughout the thrombus.
22. WHITE INFARCT OF THE KIDNEY
An infarct is a localized area of ischemic necrosis in an organ or tissue, resulting most
often from sudden occlusion of its arterial supply. Infarcts are classified on the basis of their
color as hemorrhagic or red and ischemic known as pale or white. White infarcts occur in
solid organs with end arteries (those having few anastomoses) such as kidneys, heart and
spleen. White infarct of kidney is most frequently caused by embolic obstruction of a branch
of the renal artery resulting in a wedge-shaped area of coagulation necrosis with the base at
the cortical surface and the apex pointing toward the medulla. On gross examination, 1 to 2
days after initial hyperemia, the pale infarct becomes yellow, dry and sharply delineated.
Examination of the section with a scanning lens reveals a pale red, wedge-shaped area,
surrounded by bluish, highly cellular zone outside of which there is a thin red rim.
Histologically, the central portion of the wedge-shaped area reveals typical signs of
coagulative necrosis: there is no nuclear staining and the cytoplasm is deeply eosinophilic. On
the whole, early infarcts will still show the faint outlines of tubules and glomeruli.
Polymorphonuclear leukocytes accumulate in the peripheral zone and they present with signs
of nuclear disruption (pyknosis, karyorrhexis, lysis or finely scattered nuclear debris).
Surrounding this cellular area, there is a zone of reactive hyperemia. It is remarkable that
often a subcapsular strip of preserved parenchyma is without signs of necrosis because it
receives its blood supply from the capsular vessels.
23. RED INFARCT OF THE LUNG
Red or hemorrhagic infarct is encountered with venous occlusion, in loose tissues or in
tissues having a double or anastomotic circulation, and in tissues previously congested.
Hemorrhagic infarct of lung denotes focal necrosis and hemorrhage of lung tissue following
embolic occlusion of a middle-sized branch of the pulmonary artery in the presence of passive
hyperemia in the bronchial circulation which inadequately compensates for the loss of supply
from the plugged branch of pulmonary artery. This circumstance is often found in congestive
heart failure. Stasis and increased pulmonary venous pressure is usually also present.
Grossly, the infarct of lung is a dark red hemorrhagic, wedge-shaped, raised mass, with its
”base” on the pleural surface. Often the apposed pleura is covered with a fibrinous exudate.
Naked eye inspection of a histologic section usually reveals a wedge-shaped, red and
homogeneous lesion. The embolic occlusion of the nutrient branch of the pulmonary artery
cannot be always seen.
Microscopically, the diagnostic feature is the ischemic necrosis of the lung substance
within the area of hemorrhage, affecting the alveolar walls, bronchioles, and vessels. The
lesion discloses monotonous histologic picture: the alveolar spaces are filled with densely
packed erythrocytes that are seen in older infarcts as shadow forms or are disintegrated. The
alveolar septa are necrotic (without any stainable nuclei), and can scarcely be distinguished
45
from the contents of the alveoli. The capillaries are full of blood but endothelial and alveolar
epithelial cells cannot be detected.
24. PULMONARY EDEMA
Edema is an abnormal accumulation of fluid within interstitial spaces or body cavities.
Edema may be localized or systemic (generalized). Major clinical causes of systemic edema
are congestive heart failure, renal diseases and sodium retention, and diffuse hepatic diseases
with decreased synthesis of serum proteins. Pulmonary edema can result from hemodynamic
disturbances or from direct increase in capillary permeability, owing to microvascular injury.
The most common hemodynamic mechanism is associated with left ventricular failure that
causes increase in the blood pressure abruptly in the pulmonary veins and in the capillaries
in the walls of the alveoli in the lungs. Pulmonary edema may be interstitial or alveolar. The
former represents the earliest phase and when the fluid can no longer be contained in the
interstitial space, it spills into the alveoli (condition termed alveolar edema).
Macroscopically, the lungs are heavy and wet, and in far-advanced cases assume a rubbery
gelatinous consistency. Sectioning of the parenchyma permits the free escape of frothy, pink
watery fluid representing a mixture of edema fluid and air bubbles.
Histologically, the alveolar capillaries are engorged and alveoli are filled with
homogeneous eosinophilic material, which has leaked from the congested capillaries. A
transsudate of this type is usually cell-free but there may be present a few solitary, exfoliated
alveolar epithelial cells, i.e. alveolar macrophages. In some places, alveolar fluid has been lost
and thus, the presence of empty spaces has resulted (air bubbles).
25. ACUTE SEROUS INFLAMMATION OF SMALL INTESTINE
Inflammation is the reaction of vascularized living tissue to local injury. Inflammation
consists of a series of complex reactions by vascular and connective tissue elements to
various damaging agents. Major events in the acute phase of inflammation involve changes in
vascular flow and caliber, increased vascular permeability, and leukocyte exudation. In
serous inflammation, protein-rich thin fluid leaks from the blood vessels with a relatively low
cellular content. When mucus hypersecretion accompanies serous inflammation of a mucous
membrane, the appearance is described as catarrhal. Macroscopically, small bowel mucosa
appears congested (bluish red) due to vascular dilatation and edematous.
Microscopically, most bacterial infections exhibit a general nonspecific pattern: damage
of the surface epithelium occasionally with desquamation of the isolated cells, decreased
epithelial cell maturation, and an increased mitotic rate in mucosal crypts (”regenerative
change”). Goblet cells may display hypersecretion. Blood vessels in edematous lamina
propria are hyperemic. Mild cases show increased numbers of plasma cells, and some degree
of neutrophilic infiltration into the lamina propria and epithelial layer. More severe cases are
accompanied by a more pronounced neutrophilic response and villous atrophy but a decreased
number of plasma cells.
26. CHRONIC INFLAMMATION OF THE NASAL CAVITIES
Inflammatory diseases are the most common disorders of the nasal cavity and
paranasal sinuses, and are named rhinitis and sinusitis, respectively. As usual, they are
associated with infection (mainly of viral origin but often complicated by superimposed
bacterial agents) and allergy. Chronic inflammation may follow acute inflammation, may
result from repeated bouts of acute inflammation, or most commonly it begins insidiously as a
primary chronic inflammation. Often a deviated nasal septum is a contributory factor.
Chronic rhinitis or sinusitis is characterized by mucosal thickening and increased consistency
with production of nasal polyps. They are not true neoplasms, but rather focal inflammatory
swellings of mucosa of the nose or paranasal sinuses. They are divided into allergic and
nonallergic types. Macroscopically, polyps appear as sessile or pedunculated, smooth, pale,
movable, rounded tumors protruding into the airways.
Histologically, polyps are lined externally by respiratory epihelium sometimes
undergoing squamous metaplasia and frequently resting on a thick basement membrane. They
often contain hyperplastic or cystic mucous glands within a loose mucoid stroma. Persistent
hyperemia of stromal blood vessels is observed as well. Inflammatory infiltrate consists of a
variety of cells including lymphocytes, plasma cells (sometimes with eosinophilic
cytoplasmic inclusions called Russell bodies), eosinophils (prominent in allergic polyps),
neutrophils and mast cells.
47
27. ACUTE PURULENT (SUPPURATIVE) MENINGITIS
The term meningitis usually refers to inflammation in subarachnoid space involving the
arachnoid and pia mater, i.e. leptomeningitis. However, under certain circumstances it may
involve predominantly the dura mater (pachymengitis) usually being the consequence of
contiguous infection, such as otitis media or mastoiditis. Leptomeningitis is frequently a result
of blood-borne infection, but it can arise from direct spread from the skull bones, or from
penetrating wounds as well. In acute purulent leptomeningitis, pyogenic organisms (Neisseria
meningitidis, Streptococcus pneumoniae, etc.) spread throughout the subarachnoidal space.
This may happen very rapidly and the persons may die within a few hours. Macroscopically,
the meningeal vessels are engorged and stand out prominently. The normally clear
cerebrospinal fluid is cloudy and sometimes is frankly purulent. The inflammatory exudate
collects in the subarachnoid space and the location of the exudation varies dependent on
etiologic agents.
Microscopic examination with low power reveals a dense cellular infiltrate in the
leptomeninges. Higher magnification shows that polymorphonuclear leukocytes fill the entire
subarachnoidal space. They are found predominantly around the leptomeningeal blood vessels
in less severe cases. Cellular infiltrates are focally intermingled with fibrin strands. In
fulminant cases, the inflammation may extend into the substance of brain (focal encephalitis)
by means of inflamed leptomeningeal veins. In untreated meningitis, Gram stain reveals
numbers of causative microorganisms, although they are frequently not present in treated
cases.
28. ACUTE PURULENT APPENDICITIS
Acute appendicitis is an inflammatory disease of the wall of the vermiform appendix
that often results in transmural necrosis and perforation, with subsequent peritonitis. It is
often associated with obstruction, usually in the form of fecalith. However, no obstruction is
demonstrated in significant minority of cases, and the factor precipitating the disease remains
unknown. Macroscopically, resected appendix is congested, tense, and covered by fibrinous
exudate. The lumen often contains purulent material, and a fecalith may be evident.
At the earliest stages, only a scant neutrophils may be found in the lamina propria and
the inflammation proceeds with a focal suppurative lesion at the bottom of a crypt. Following
this, the surface epithelium is breached and the mucosa is destroyed by focal inflammatory
exudation of fibrin and leukocytes. Later on, the necrotic tissue may slough and an ulcer
forms (acute ulcerative appendicitis). The acute inflammatory process tends to spread along
the muscular and serous coats, particularly if the lumen is obstructed. This form of acute
appendicitis is named phlegmonous. The mucosa is largely destroyed in advanced states, only
a few remnants of the glands remaining. The blood vessels are greatly dilated and the whole
of the appendiceal wall is infiltrated with polymorphonuclear leukocytes. As the
inflammatory process is getting worse, there is abscess formation within the wall. There is
also reactive exudation of fibrin and leukocytes over the peritoneal aspect. Eventually, further
appendiceal compromise may lead to necrosis of the wall, followed by perforation and
subsequent purulent peritonitis.
29. CHRONIC GRANULOMATOUS INFLAMMATION (Tuberculosis of
the lung)
Granulomatous inflammation is a distinctive pattern of chronic inflammatory reaction
and is characterized by formation of granulomas. The classic example of granulomatous
disease
is
tuberculosis,
but
sarcoidosis,
syphilis,
cat-scratch
disease,
leprosy,
lymphogranuloma inguinale, brucellosis, deep fungal infections, beryliosis and reactions to a
foreign body, all evoke this pattern. Tuberculosis of the lung may be primary or secondary.
Primary form occurs in individuals lacking previous contact with tubercle bacilli. The route
of infection is generally by inhalation of droplets from other individuals suffering from the
disease. The secondary tuberculosis denotes active infection in a previously sensitised
individual. Most cases represent reactivation of dormant bacilli from primary lesions.
Secondary tuberculosis is generally found in the apices of the lungs. These lesions may
progress to cavitary fibrocaseous tuberculosis, tuberculous bronchopneumonia, or miliary
tuberculosis.
Histologically, coalescent granulomas are present in pulmonary parenchyma.
Granulomas are small (0,5 – 2 mm) collections of modified macrophages called ”epithelioid
49
cells” (with epithelial-like appearance), usually rimmed by lymphocytes. They have abundant,
pink, plump cytoplasm with indistinct cell boundaries, often appearing to merge into one
another. Epithelioid cells may coalesce and fuse to form multinucleate giant cells known as
Langhans’ cells. Their nuclei are arranged around the cell periphery creating a horseshoe
pattern. The granulomas caused by Mycobacterium tuberculosis are named tubercles. The
typical tubercle consists of a necrotic center (caseification), a zone of epithelioid cells,
Langhans’ giant cells, and a more or less well-marked outer margin of lymphocytes and a few
plasma cells. Caseous necrosis seen as eosinophilic, homogeneously and finely granular area
without recognizable remnants or cell outlines of the original tissue may sometimes
completely dominate the picture and specific granulation tissue (epithelioid cells, Langhans’
cells and lymphocytes) is visible only as a narrow border. Tubercle bacilli are very difficult to
stain and they can be detected as red rods only in sections stained by the Ziehl-Neelsen
method for staining acid-fast bacilli.
30. CHRONIC GRANULOMATOUS INFLAMMATION (Sarcoidosis of
lymph node)
Sarcoidosis is a granulomatous noncaseating inflammatory disease of unknown etiology
which affects many tissues, including lymph nodes. These are involved in almost all cases,
particularly hilar and mediastinal nodes, but any other node in the body may be affected.
Macroscopically, lymph nodes are considerably enlarged, discrete, and sometimes lobulated
or calcified.
Microscopically, the normal architecture of the node may be largely destroyed, with
some blue-staining lymphoid tissue surviving mostly beneath the capsule and between the
round sarcoid granulomas. Sarcoid epithelioid cell granulomas are numerous and in part
confluent. In contrast to tuberculosis, there is no caseation and granulomas tend to fibrose
from the periphery toward the center. Higher magnification shows epithelioid cells having
plump eosinophilic cytoplasm with vesicular nuclei. Several multinucleated giant cells of
Langhans’ type are also present. Some sarcoid granulomas contain intensively basophilic
calcified and laminated Schaumann bodies, and occasionally also star-shaped inclusions
called asteroid bodies enclosed within giant cells. None of these structures are specific for
sarcoidosis because they can be found in other granulomatous diseases (e.g. berylliosis). The
capsule of the lymph node becomes frequently somewhat fibrotic.
31. GRANULATION TISSUE (Inflammation in the (sub)chronic stages,
connective tissue repair)
In the (sub)chronic stages of the inflammation and connective tissue repair,
proliferative changes may predominate. They are associated with proliferation of fibroblasts
and formation of new small blood vessels termed neovascularization or angiogenesis. These
two components are the main histologic constituent elements of granulation tissue.
Macroscopically, the term ”granulation tissue” is derived from its pink, soft granular
appearance on the base of a skin ulcer; when the repair process is observed, the capillary
loops are visible and impart a granular texture. Such a name is less appropriate for an
internal repair, but is used despite this. The formation of granulation tissue is a regulated
process involving a number of events, including growth of new capillaries, fibrogenesis, and
involution during maturation of the scar. Granulation tissue must not be confused with a
granuloma (an aggregate of epithelioid histiocytes).
Microscopically, new vessels originate by budding or sprouting of pre-existing vessels.
These new capillaries have leaky interendothelial junctions, allowing the passage of proteins
and erythrocytes into the extravascular space. Therefore, new granulation tissue is often
edematous. In newly developing granulation tissue, fibroblasts proliferate and appear as large
cells having plump, sometimes basophilic cytoplasm and hyperchromatic nuclei. They
produce collagen which is the basic component of a scar. Some of the large fibroblasts
acquire features of smooth muscle cells and thus, they are named myofibroblasts. These cells
are responsible for wound contraction. Besides fibroblasts and capillaries, macrophages,
neutrophils, lymphocytes and plasma cells are almost always present in granulation tissue.
Mast cells and eosinophils may sometimes be seen as well. In the course of the healing
process, many of the blood vessels undergo thrombosis and degeneration, and are digested by
macrophages. The end result of granulation tissue is a scar composed of inactive-looking,
spindle-shaped fibrocytes, dense collagen, fragments of neoformed elastic tissue, extracellular
matrix, and relatively few vessels.
32. ORGANIZED AND RECANALIZED THROMBUS
51
A newly developed thrombus has potency for several modes of outcome. It may 1)
propagate and cause obstruction of some vessels, 2) give rise to an embolus, 3) be removed by
fibrinolytic action, or 4) become organized and possibly recanalized. The process of
organization converts the thrombus into a firm and grayish white connective tissue, acquiring
somewhat spongy appearance if prominently vascularized. Recanalization is the process by
which new lumina lined by endothelial cells form in an organized thrombus.
Microscopically, the appearance of recanalization of an arterial thrombus depends on
the age, mass of the thrombus and the degree of recanalization. In the beginning of thrombus
organization, phagocytic and proteolytic activity of the macrophages and leukocytes
decompose fragments of fibrin, red cells and platelets. Concurrently fibroblasts and
capillaries proliferate and invade the base of thrombus where it is attached to the underlying
vessel wall. Thus, the lumen is occupied by a mass which is penetrated by thin-walled and
widely patent blood vessels. Some of them may differentiate into small veins or arteries. The
vascular channels may anastomose to produce communications that traverse the thrombus
and through which the blood flow may at least in part be re-established. The black-brownish
granules found in the organizing tissue are intracellular broken-down products of
hemoglobin, i.e. hemosiderin. Special stains would show abundant reticulin but few mature
collagen fibers. The wall of thrombotic artery demonstrates atherosclerotic changes.
potiaľ
33. CHRONIC
GRANULOMATOUS
INFLAMMATION
AROUND
FOREIGN BODIES (Foreign body granuloma)
Granulomatous inflammation is typical tissue response elicited by miscellaneous injury.
The hallmark of this distinctive pattern of chronic inflammation is the presence of small
collections of epithelioid cells (i.e. modified macrophages) referred to as granulomas.
Epithelioid cells may transform into multinucleated giant cells, the presence of which is
another feature of the granulomatous inflammation. So-called foreign body-type giant cells
are characteristically seen in relation to particulate foreign-body indigestible material (talc
crystals, suture material from the surgical incision, miscellaneous exogenous material –
wood, metal, oil or paraffin).
Microscopically, the nodules of chronic granulomatous inflammation around foreign
bodies basically consist of granulation tissue with dilated thin-walled blood vessels,
lymphocytes and plasma cells, and elongated fibroblasts. Occasionally, polymorphonuclear
leukocytes predominate. The most notable feature, however, is the presence of multinucleated
giant cells of foreign body-type. They are large cells formed by the cytoplasmic fusion of
macrophages with numerous (up to 50–100) separate nuclei randomly scattered throughout
their cytoplasm. Typically, they contain fragments of foreign material or conglomerate around
a foreign body. Foreign body granuloma may have a zone of scarring process at the periphery.
34. SQUAMOUS METAPLASIA OF CYLINDRICAL EPITHELIUM
Metaplasia refers to a reversible transformation of one mature differentiated cell type
(epithelial or mesenchymal) into another. It often represents a response to persistent stress or
injury. This process can be thought of as an adaptive substitution of cells more sensitive to
stress by cell types better able to withstand the adverse environment. It should be emphasized
that metaplasia is not necessarily a harmless process and, in most circumstances, represents an
undesirable change. The most common adaptive mataplasia is the replacement of a glandular
epithelium by a squamous one. Columnar lining cells commited to differentiated functions,
such as mucus production, assume a simpler form providing more protection against
pernicious chemical action or the effects of chronic inflammation. A very common example
of the above-mentioned process is the substitution of the normal cylindrical epithelium of the
cervical mucosa (or of an endocervical polyp) by metaplastic squamous epithelium.
Endocervical polyp is a focal, hyperplastic or inflammatory protrusion of endocervical fold
and appear as a single, pedunculated or sessile, smooth or lobulated outgrowth originating in
the mucus-secreting columnar epithelium of the endocervix.
Histologically, endocervical polyps are composed of loose fibromyxomatous stroma
containing dilated, mucus-secreting endocervical glands. Blood vessels are usually thickwalled and may be prominent. The lesion is frequently associated with acute or chronic
inflammation and squamous metaplasia of varying degrees. The latter process entails first the
proliferation of endocervical basal ”reserve cells” and then the differentiation of these cells
into squamous cells rather than mucin-producing cells. Initially, the reserve cells do not have
squamous characteristics; rather, they appear as cuboidal cells with round nuclei growing
beneath the mucinous epithelium. After the reserve cells proliferate and stratify, they
differentiate into squamous cells that initially have only slightly increased amounts of
53
cytoplasm (immature squamous metaplasia). Later the cells may fully mature to glycogencontaining squamous cells indistinguishable from the superficial cells of the exocervix,
progressively lift up and finally push off the cylindrical epithelium.
35. PSEUDOTUMOR (Epidermoid cyst)
Pseudotumor is a pathologic lesion that grossly or clinically bears some resemblance to a
genuine tumor but its real nature is nonneoplastic. From the biological point of view, all
pseudotumors are benign. Many miscellaneous pathological changes (some developmental
anomalies, hypertrophy, hyperplasia, cysts, some pathological material and inflammation) are
included in this category of pseudotumors. The cyst is a cavity that arises from dilatation of a
pre-existing structure and is generally lined by epithelium. Epidermoid (epidermal) cysts are a
common type of keratinous cysts (cysts filled with keratin). They are situated in the dermis or
subcutaneous tissue and appear spontaneously as a rule (probably arising from the upper
portion of hair follicles) but may also originate from epidermis transplanted into the deeper
layers of the skin by trauma. They grow slowly to reach several cm in diameter, elevating the
overlying skin. The second type of keratinous cyst is pillar or trichilemmal cyst.
Epidermal cysts have a wall composed of true epidermis, as seen on the skin surface and in
the infundibulum of hair follicles. In young cysts, several layers of squamous and granular
cells can usually be recognized. In older epidermal cysts, the wall often is markedly atrophic
and may consist of only one or two rows of greatly flattened cells. The cyst is filled with horny
keratinous material arranged in laminated layers without calcifications. A considerable
foreign-body reaction results when the wall of a cyst ruptures, thus forming a keratin
granuloma.
36. PRENEOPLASTIC DISORDER (Cervical dysplasia)
Dysplasia means deranged development: however, in common usage it is applied to
either epithelial or mesenchymal cells, principally to former, that have undergone
proliferation and atypical cytologic alterations involving cell size, shape, and organisation. In
the case of cervical dysplasia it is but one example of precancerous lesions in two types of
local lining epithelia. Occasionally, this change may be reversible and, with removal of the
putative inciting causes, the epithelium may revert to normal. However, after some time
intervals (usually expressed in years) these lesions may gradually intensify and convert to
preinvasive and finally to invasive neoplastic disease. The cervical location is one of the most
frequent sites of preneoplastic epithelial changes. After puberty, or later, due to physiological
changes in the position of the cervical squamo-columnar junction the local, metaplastic
squamous epithelium exposed to different types of irritation (e.g. low pH, infectious agents,
etc.) becomes labile and this area is called ”transformation zone”. Gradually, a spectrum of
various microscopical changes develops within the superficial cervical epithelium or in the
same epithelium replacing cylindrical epithelium of underlying cervical mucous glands.
The width of the epithelium (acanthosis) and the basal cell activity is individually
increased. The superficial zone of the squamous epithelium may show parakeratosis and
hyperkeratosis (not present in the normal, noncornifying epithelium). The individual epithelial
cells may become dysplastic (atypical cells) with abnormal nuclei. Individual cells may
cornify and mitotic figures may be found also higher than in the basal cell layer. There is a
disordered maturation of the cells as they proceed to the superficial layers. The increased
proliferative activity produces greater amounts of DNA causing more intense basophilia of
the nuclei. A large part of cellular changes: hyper- and parakeratosis, characteristic
perinuclear vacuolisation (= koilocytosis), dyskeratosis, bi- or multinucleation and
papillomatosis of the epithelium may be attributed according to the results of modern
molecular biology techniques to human papilloma virus (HPV) infection.
Due to progression of the disease and increase in histological severity these epithelial
preneoplastic (precancerous) changes reach individual degree of severity even in different
parts of the same specimen. Therefore, dysplasia is subdivided into mild, moderate, and
severe, depending on the proportion of the thickness of squamous epithelium involved by
atypical cells. Grade 1 represents less than one-third involvement of the thickness of the
epithelium (basal third). Grade 2 represents involvement of one-third to two thirds, and
Grade 3 two thirds to almost full thickness, leaving only a thin, supermost layer of nontransformed cells. For the same lesion in many Western countries instead of the term
”dysplasia” the term ”Cervical intraepithelial neoplasia” (CIN) is widely used. Such
morphological diagnosis can be made not only in the biopsy material, but also cytologically.
As already shown in the Introduction, cytology is a simple, relatively safe, and non-invasive
method of detecting precancerous changes in the cervix uteri introduced by Papanicolaou,
which can be used as a screening programme in large groups of population at risk. The next
55
step in the progression of a severe dysplastic lesion (Grade 3), which has reached already
true neoplastic character, is called ”Carcinoma in situ” (CIS) or non-invasive (preinvasive)
carcinoma (see the next paragraph).
37. CARCINOMA IN SITU (Intraductal carcinoma of the breast)
The term ”Carcinoma in situ” (CIS) refers to an epithelial neoplasm, containing all
cellular features associated with malignancy, which has not yet invaded through the epithelial
basement membrane separating it from potential routes of metastasis – blood and lymphatic
vessels – and thus having no signs of invasive growth. The phase of ”in-situ” growth may last
for several years before invasion commences.
Microscopical appearances of non-invasive carcinoma of the breast are variable. The
intraductal pattern of growth may be papillary, cribriform, or so-called comedocarcinoma. In
cribriform carcinoma the tumor cells with variable-sized nuclei fill the large and mediumsized secretory ducts, producing multiple small lumina, giving the intraductally growing
tumor a characteristic sieve-like appearance. In comedo-carcinoma the dilated ducts are also
distended by the solid growth of pleomorphic carcinoma cells, with frequent mitotic figures,
centrally undergoing necrosis in many places. Micro-calcifications and stromal reaction are
frequent supplementary findings. The intraductal papillary carcinoma occurs mostly in
postmenopausal women: papillary neoplastic structures fill the distended ducts. Another
example of an in-situ pattern of neoplastic growth in the breast is the carcinoma lobulare in
situ (CLIS), developing characteristically from breast lobule epithelia. Each untreated case
of CIS carries the risk of progression to an invasive carcinoma.
38. METASTASIS OF CARCINOMA IN THE LYMPH NODE
Metastases are tumor implants discontinuous with the primary tumors. The invasiveness
of cancers permits them to penetrate into the blood vessels, lymphatics, and body cavities,
providing the opportunity for spread. Discovery of atypical (neoplastic) epithelial tissue in a
lymph node indicates metastatic carcinoma. The appearance of lymph node metastasis can
have diagnostic (the first clinical manifestation of an occult carcinoma), prognostic (i.e. bad
sign), and therapeutic significance.
Transport through the lymphatics is the commonest pathway for the initial
dissemination of carcinomas. The spread of sarcomas may also be similar. The lymph nodes
are invaded by groups (islands) of metastatic carcinoma cells lying in distended sinuses or
infiltrating diffusely a part or the whole lymph node. Floating groups of neoplastic cells may
also be present in lymphatic vessels leaving or entering the nodal hilus.
39. CHARACTERISTICS OF MALIGNANT NEOPLASMS (Parenchyma
and stroma, anaplasia, and atypical mitoses)
Most of malignant neoplasms grow in a solid manner. Only a small number of tumors
has cystic appearance on its surface as well as on cut section. All tumors consist of neoplastic
cells and stroma, embedding and supporting the ”parenchymal” neoplastic cells.
The neoplastic cells reproduce to a variable extent the growth and structural pattern and
synthetic activity of the parent cell of origin. Depending on its functional resemblance to the
parent tissue, it continues to synthetize and secrete cell products, such as bile, keratin, mucin,
melanin pigment, hormones etc. The presence of these products is helpful in recognizing the
origin (histogenesis) of the tumor cells. The cells are growing in various forms, forming solid
sheets, nests, islands, glandular or trabecular patterns or – after total loss of cellular cohesivity
– separately (individually), surrounded by the more or less actively proliferating stroma.
Cytologically, the neoplastic cells differ widely in their morphological properties, such as the
number of cells per unit, the size and shape of their cytoplasm, variability of individual nuclei
and nucleoli. Frequently, the cytoplasmic/nuclear ratio is changed. The nuclei are not only
irregularly larger but also have thickened nuclear membrane with indentations of their outline.
The chromatin is coarse and deeply stained. Some of the neoplastic cells may be bi- or
multinuclear and occasionally can transform to tumor giant cells. The number, shape,
dimensions and prominent staining of nucleoli is another common feature of malignant
neoplastic cells, adding to their anaplasia. Microscopically, many neoplastic cells divide,
reflecting their growth activity. In malignant tumors the mitoses are not only abundant but
may show either normal or frequently pathological forms (tripolar, or other bizarre shapes).
Mitosis counting, DNA measurements, and other techniques can estimate the rate of cellular
proliferation. The growth rate of a tumor is a balance between cellular proliferation and cell
57
loss due to ischemic necrosis and apoptosis. The stroma (from the Greek word meaning a
mattress) mechanically supports and provides nutrition and metabolic pathways to the
neoplastic parenchymal cells. It contains collagen and several other types of fibrils and blood
and lymphatic vessels, which grow under the influence of different growth and angiogenic
factors. The presence of extensive stromal formation in tumors is called ”desmoplastic
reaction”. Stromal myofibroblasts with their contractility are responsible for the puckering
and retraction of adjacent structures. Individually dense infiltrates of the stroma composed of
lymphocytes, plasmocytes, polymorphonuclear leucocytes, eosinophils and monocytes
(macrophages) reflect a host immunopathologic reaction to the antigens presented by tumor
cells.
40. FIBROMA
Fibroma is a benign, occasionally pedunculated and well-circumscribed tumor arising
from ubiquitous fibroblasts occurring in the skin and mucous membranes. Despite the
widespread distribution of connective tissue throughout the body, fibromas are surprisingly
limited in their sites of origin. Some of the so-called ”fibromas” are more precisely classified
as fibromatoses, growing in different anatomical locations, fibroepithelial polyps, irritation
fibromas or fibrous hyperplasia (frequently in oral mucosa), hyperplastic fibrous tissue and
reno-medullary interstitial cell tumor (a small nodule growing within the renal medulla).
This tumor is rich in fully matured and typical fibroblasts and scant or abundant
collagenous fibrous connective tissue. The amount of collagen has important influence upon
the tumor consistency. The cells may be laid down in random array or sometimes are aligned
parallel in broad ribbons. Fibroblastic nuclei tend to be spindle or boat shaped. Delicate
intercellular reticulin network may be demonstrated by silver impregnation.
41. FIBROSARCOMA
Fibrosarcoma is a spindle cell and collagen and reticulin forming malignant tumor with
characteristic histologic appearance. It arises from fibroblasts anywhere in the body, but is
most common in the retroperitoneum, in the thigh, in the bones and in the breast. The tumor
has locally invasive growth and recurrences are found in over half of the cases. The tumor is
capable of early or late metastases, chiefly via the blood stream.
Microscopically, the tumor contains all degrees of cell differentiation and is richly
cellular. The elongated, predominantly spindle-shaped cells with hyperchromatic polymorphic
nuclei lie parallel in interlacing fascicles and contain constantly enlarged nucleoli and
plentiful mitoses. Primitive collagen and reticulin fibres are present between the tumor cells.
Infiltrative neoplastic growth into the surrounding normal tissues may be observed at the
periphery of the tumor.
42. LIPOMA
Lipoma is a benign, lobulated and mostly encapsulated tumor derived from mature fat
cells. Lipomas are most frequently found in subcutaneous or retroperitoneal adipose tissue or
in various organs (e.g. in the bowel wall). Some of the collections of fatty tissue represent the
co-called non-neoplastic lipomatous masses, which are developmental in origin and not true
neoplasms. Special forms of lipoma are: intramuscular lipoma (so-called infiltrating lipoma),
fibrolipoma with admixed fibrous tissue, hibernoma found usually in the shoulder and neck
region, angiomyolipoma mostly of the kidney, myelolipoma of the adrenals, retroperitoneum
or pelvis, lipoblastomatosis (foetal lipoma) and diffuse lipomatosis on extremities or within
the trunk.
The tumor is composed of cells that deviate from mature fat cells only in their variation
in cell size. The cell borders are distinct. Typically, the rounded nuclei are situated at the cell
periphery. The optically empty (clear) cytoplasm appears so because of dissolution of lipids in
organic solvents during processing (ethyl alcohol, xylol, benzol).
43. CHONDROMA
59
Chondroma is a benign tumor composed of mature hyaline cartilage. It arises most
often centrally within the medullary cavity of(hands and feet short bones. Because of this
tendency, it is usually called ”enchondroma”. Osteochondroma is synonymously described as
exostosis and represents a developmental aberration rather than true neoplasm.
Enchondromatosis (Ollier's disease) is the counterpart of multiple exostoses. In this form
there is a considerable risk of transformation in chondrosarcoma. The chondroma found in
the lung is a hamartoma and not a true neoplasm.
The tumor is composed of lobulated masses of differentiated, i.e. mature hyaline
cartilage, separated and encapsulated by a thin layer of connected tissue containing nutritive
blood vessels. Cartilage cells are irregularly dispersed throughout the matrix and are located
singly or in small groups within clearly defined lacunar spaces. Often there are foci of
calcification or/and ossification.
44. OSTEOMA
Osteoma regardless of its microscopical structure is a benign lesion consisting of welldifferentiated mature bone tissue, with a predominantly lamellar structure, and showing very
slow progression. Osteomas are almost entirely restricted to the skull and mandible and
sometimes grow into and diminish paranasal sinuses as dense ivory-like sessile bony masses.
If the tumor is composed predominantly of dense, irregularly laid down lamellar bone, it
is called eburneating osteoma. If cancellous bone predominates, it is a cancellous osteoma.
The Haversian canals in the tumor are narrow and have a smooth lining. The intertrabecular
spaces are filled with fibrous stroma that is sometimes highly vascularized and may contain
foci of haematopoiesis.
45. CHONDROSARCOMA
Chondrosarcoma is a malignant tumor of cartilage. In contrast to osteosarcoma, it
grows slowly and metastasizes late not only to long bones but also to the pelvis, ribs, spine
and other locations, e.g. in the larynx. Chondrosarcomas vary widely in their clinical
behaviour depending on the individual level of anaplasia. Most have a slow clinical evolution
and metastasize late, providing a much better prognosis than the more aggressive
osteosarcomas. It can develop directly in orthotopic cartilage (so-called primary
chondrosarcoma) or in a benign tumor of cartilage (so-called secondary chondrosarcoma).
The abnormal cartilage forming tumor mass is much more cellular than the normal
cartilage. The neoplastic cells vary in size and some have abnormally large hyperchromatic
nuclei with coarse chromatin. Abnormal mitoses are found infrequently. The cartilage cells
are irregularly distributed. Multinucleated and giant cells including bizarre forms are frequent.
The matrix may show areas of calcification or ossification. The different microscopic features
of chondrosarcomas are basis for their histological grading.
46. CAVERNOUS HAEMANGIOMA
Cavernous haemangioma is a benign lesion composed predominantly of cavernous
vascular structures. The tumor develops most frequently in infancy and childhood in the liver,
deep dermis, subcutaneous tissue, lips or in the tongue. The cavernous spaces are filled with
fluid blood or sometimes with blood with disturbed flow characteristics that, in rare cases,
consumption coagulopathy can occur. A frequent finding in older lesions is an focal
organized thrombosis. This tumor in some individuals may be multiple.
The neoplastic cavernous (large) vascular spaces are lined by a single layer of
endothelial cells and tightly packed with blood cells. Cavernous haemangioma is traversed by
connective tissue septa. The tumor mass is sharply defined, but not encapsulated.
47. LEIOMYOMA
Leiomyoma is a benign and occasionally richly vascular tumor of smooth muscle cells
arising also from blood vessel walls, showing little variation in their appearance and
characterized by the presence of non-striated myofibrils within their cytoplasm. Collagen
formation present in all leiomyomas may be excessive and at times may obscure the basic
structure of the tumor. The tumor occurs less frequently in the superficial skin andalso in
deep locations (myometrium /in this location it is frequently multiple – so-called
leiomyomatosis/, retroperitoneum, wall of the gastrointestinal tract, breast, bladder, etc.).
61
Histologically it is composed of interlacing smooth muscle cells with elongated,
cylindrical, blunt-ended nuclei. Interspersed between groups of neoplastic cells is a dense
collagen network. Hyalinization, calcification, and ossification are frequent regressive
changes in advanced large tumors. Focal necroses and successive pseudocystic changes are
another frequent findings. Mitotic figures are scarce, and giant cells and anaplasia are not
present.
48. MALIGNANT FIBROUS HISTIOCYTOMA (MFH)
Malignant fibrous histiocytomas are distinctive neoplasms because they are composed
of a mixture of cells resembling fibroblasts, myofibroblasts, histiocytes, and primitive
mesenchymal cells and cells having intermediate or mixed features (i.e. fibrohistiocytoid
cells). Additional features include rich vascularisation and varying numbers of giant cells and
lipid-laden xanthomatous cells. It occurs preponderantly in soft tissues, but also occasionally
in bone. These neoplasms represent 20 to 30% of soft tissue sarcomas. They may appear at
any age with a peak incidence of the more common variant in the seventh decade, somewhat
more commonly in males. The sites of origin of soft tissue MFH are lower extremities
(approximately 50%), upper extremities (20%), abdominal cavity, retroperitoneum (20%),
and other sites uncommonly. Soft tissue lesions grossly are multilobulated, grey-white, fleshy,
infiltrative, unencapsulated, but deceptively circumscribed masses. Haemorrhages and areas
of necrosis are common.
Five histologic variants of MFH have been described. The most common is called
storiform-pleomorphic and the next most common is myxoid MFH. The three less common
variants are giant cell, inflammatory and angiomatoid variants.
The storiform-pleomorphic variant is composed mainly of (1) polygonal histiocytoid cells
with prominent oval nuclei, (2) spindle-shaped fibroblasts and myofibroblasts and (3) smallersized non-specialized polygonal to oval mesenchymal cells with small nuclei. Characteristic is
the tendency for the spindle cells to be disposed in a cartwheel (storiform) pattern often about
slit-like vessels. Pleomorphism, mitotic activity and hyperchromatic tumor giant cells as well
as numerous slit-like vessels and scattered lymphocytes or plasma cells are present.
Areas of loose myxoid stroma interspersed with areas of cellularity mark the myxoid variant
of MFH. The myxoid areas are rich in acid mucopolysaccharides and contain disperse
spindled or sometimes stellate mesenchymal cells, some having coarse cytoplasmic vacuoles
of mucopolysaccharides.
Metastases are present in almost 50% of storiform-pleomorphic lesion at the time of
diagnosis, but in only 25% of myxoid tumors. Overall, the five-year survival is approximately
50%.
49. SQUAMOUS CELL PAPILLOMA OF THE ORAL CAVITY
This common benign tumor of the oral mucosa occurs on the cheek, gingiva, palate,
lips, and tongue. It is found in all ages, even in the childhood, and is usually a solitary lesion.
Papillomas vary in size and may be either sessile or pedunculated. Inverted forms are
sometimes found. Papillomas present as warty or cauliflower-like growths with white or pink
surface depending on the amount of keratin present. Such tumors are likely to share a
common pathogenesis with other squamous papillomas in that they result from human
papilloma virus (HPV) infection.
Histologically they are made up of numerous slender papillae having fibrovascular
cores covered by keratinized, stratified squamous epithelium. The arrangement of cells is
regular and, as a rule, there is no increase in mitoses nor there are signs of infiltrative growth.
Dysplastic changes are rare and malignant transformation is even rarer.
50. PAPILLARY CARCINOMA OF THE THYROID GLAND
Papillary carcinoma of the thyroid is the most common form of thyroid cancer. It is one
of the malignancies known to be associated with radiation exposure, whether as X-rays to the
neck or due to the nuclear fall-out, containing radioactive radioisotopes of iodine, which are
selectively trapped by the gland’s epithelial cells. Papillary carcinoma of the thyroid is a
slow-growing and well-differentiated form of carcinoma most commonly found in children or
in younger adults (less than 45 years old). It presents as non-encapsulated, infiltrative mass,
which may be firm and white due to fibrosis.
It consists of complicated, ramifying epithelial papillary projections most sharply
outlined by the papilliform axial fibrovascular stroma. A single layer of well-oriented, regular
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cuboidal epithelium covers this framework. In areas the tumor cells may form groups of
colloid-containing follicles. All degrees of atypicality and disorientation of cells and
formations of glands or sheets of cells may be encountered in the more obviously aggressive
lesions. Microscopically, small calcified and layered bluish spherules (the so-called
”psammoma bodies”) are encountered in the axial stroma in almost half of all cases. Some of
the epithelial cell nuclei ma reveal central clear areas, representing invaginations of the
cytoplasm. For this reason, they are termed ”Orphan Annie eye nuclei”, ”ground glass nuclei”
or ”bird’s eye nuclei”. Such nuclei are also used as a criterion for classifying this tumor as
papillary.
51. SQUAMOUS CELL CARCINOMA OF THE LIP
Cancer of the lip is more common than intra-oral cancers. It is usually seen in elderly
people and has a definitive relationship to sunlight exposure. Lip cancers are usually welldifferentiated squamous carcinomas, which spread directly into surrounding tissues, and
through the lymphatic vessels to regional lymph nodes.
These cancers begin as in-situ lesions, sometimes with surrounding intraepithelial areas
of dysplasia. The tumor invades the subepidermal connective tissue as tongues or islands of
cancer cells usually surrounded by a prominent inflammatory infiltrate. In well-differentiated
tumors, the neoplastic epithelium is obviously squamous in type and consists of prickle cells
with a limiting layer of basal cells around the periphery. Intercellular prickles and keratin
pearls are often found. In less well-differentiated tumors the keratin pearls are sparse or
absent and the prickle cells and their nuclei are much more pleomorphic. In the poorly
differentiated forms of these tumors the epithelial cells are even more irregular and primitive
so that they may hardly be recognized as squamous cells.
52. BASAL CELL CARCINOMA OF THE SKIN (Basalioma)
Basal cell carcinoma is a frequent, locally destructive, slowly expanding skin tumor
composed of basal cells. It appears often as ulcerated, irregular lesion with a raised pearly
border (so-called ”ulcus rodens”). Basalioma is most common on the face of elderly people.
It very rarely metastasizes and is closely associated with chronic sunlight and weather
exposure, affecting more lightly pigmented people. As with squamous cell carcinoma, the
incidence of basal cell carcinoma raises sharply with immunosuppression and in patients with
inherited defects in DNA replication or repair. The indolent clinical behaviour of basal cell
carcinoma may relate in part to local immunity limiting the growth of these commonly
encountered and usually definitively curable tumors of elderly people.
Histologically the tumor is formed by clumps of small dark basophilic cells surrounded
by a rim of cells whose nuclei line up like a picket fence (these cells show a typical ”palisade”
arrangement reminiscent of the basal layer of the epidermis or follicular epithelium). At least
some of the superficially located neoplastic clumps are directly connected with the epidermal
epithelium from which the tumor usually originates. Centrally located superficial ulceration is
a frequent finding. Two patterns are seen, either multifocal growths originating from the
epidermis and extending over several square centimetres or more of skin surface (so-called
multifocal superficial type), or nodular lesions, growing downward deeply into the dermis as
cords or islands of variably basophilic cells with hyperchromatic nuclei, embedded in a
mucinous matrix, and often surrounded by many fibroblasts and lymphocytes.
53. TRANSITIONAL (UROTHELIAL) CELL CARCINOMA OF THE
BLADDER
Transitional cell or urothelial carcinoma arises from the urothelium and is frequently
multiple (multicentric). Carcinoma is often preceded or surrounded by epithelial dysplasia.
Painless haematuria is the commonest presenting feature, with dysuria, frequency and
urgency occurring in some patients. When found near a ureteric orifice, obstruction causes
unilateral pyelonephritis or hydronephrosis. Many of these tumors are papillary, others may
be described as flat lesions. Tumor cells are frequently shed into the urine where they can be
detected cytologically. Histologically similar tumors arise in the renal pelvises, ureters and in
urethra.
As shown earlier, most urothelial bladder tumors are papillary, forming delicate fronds
65
covered by an abnormally thick layer of neoplastic urothelium, with atypical cytological
features. With increasing cytological abnormalities the likelihood of invasion of the lamina
propria increases. Transitional cell carcinomas are graded I – III according to the degree of
cytologic atypia exhibited by the cancer cells. This is one guide to prognosis. Staging is also
used to judge prognosis (the TNM system is used). A proportion of these tumors may show
microscopically foci of squamous, or more rarely, glandular metaplasia. Such tumors are then
termed ”mixed tumors”.
54. ADENOCARCINOMA OF THE COLON
Cancer of the colon and rectum is one of the commonest forms of malignancy. In the
rectum, the majority of cancers are of the ulcerating type, causing bleeding. The annular,
stenosing and encircling type is more common in the descending colon and sigmoid, where it
usually produces symptoms of obstruction. Polypoid and larger fungous cancers are more
common in the right colon where they tend to give rise to recurrent occult bleeding. Ninetyfive percent of all cancers of the colon are adenocarcinomas. In a small proportion of cases
adenosquamous carcinomas (in the rectum), small cell undifferentiated carcinomas (of
presumable neuroendocrine cell origin) and infiltrative, poorly differentiated carcinomas are
occasionally encountered.
Unlike the gross pathology, the microscopic characteristics of most right- and left-sided
colonic carcinomas are adenocarcinomas, showing varying degrees of mucin production and
differentiation of tumor cells. To a limited extent, the degree of differentiation (grade)
determines the outlook for the patient after surgery. The grade of differentiation of neoplastic
glands varies from place to place even in the same specimen. Much more valuable guide to
prognosis is the completeness of excision and the extent of spread. If microscopic
examination of the resection margin established that the operation has been potentially
curative, then the extent of spread through the bowel wall and the presence of lymph node
metastases are the major prognostic determinants. The extent of spread is given by the three
Duke’s stages:
A. The tumor is confined to the submucosa or muscle layer.
B. The tumor has spread through the muscle layer, but does not yet involve the regional
lymph nodes.
C. Any tumor involving the lymph nodes.
55. NEURINOMA
Neurinoma is a round, solitary and discrete tumor, growing intracranially in the
pontine-cerebellar angle or extracranially, anywhere in the course of peripheral sensory
nerves. These tumors arise from Schwann cells (the synonymous term for this tumor is
”Schwannoma” or ”neurilemmoma”).
Histologically, neurinomas exhibit two main patterns: densely packed spindle-shaped
cells with frequent nuclear palisading (Antoni A tissue) and more loosely structured areas
with myxoid stroma, which may contain small pseudocysts (Antoni B areas). The blood
vessels in neurinomas often have hyaline thickening, around which there may be
pseudopalisading of tumor cells. By contrast to neurofibromas no nerve fibres are present in
the body of the tumor, although the residual nerve of origin of the tumor may be occasionally
found compressed to one side. This compression of the nerve of origin of a neurinoma admits
the possibility of its complete removal without requiring transection of the nerve. This can be
clinically extremely important with acoustic neurinomas: skilled removal of the tumor may
help preservation of homolateral auditory function.
56. PIGMENTED NEVUS OF THE SKIN (Nevocellular nevus)
Pigmented intradermal nevus represents an advanced or last stage in the evolution of
pigmented nevi, in which its evolution is completed. Macroscopically, nevocellular nevi are
tan-to-brown, uniformly pigmented, small (usually less than 1 cm), solid regions of elevated
skin (papules) with well-defined, rounded borders.
In this final stage of development all the junctional melanocytes have entered the
dermis. These lesions are often pink because the intradermally located cells produce little or
no melanin pigment and because the overlying epidermis contains only normal numbers of
active melanocytes. The melanocytes grow in nests only in the uppermost dermis near the
dermoepidermal junction (also called ”interface”) and get smaller with depth growing in
fascicles or cords and finally individually, being loosely situated between the collagen and
elastic fibres. Here the melanocytes frequently become spindle-shaped and even cluster to
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resemble special neural tissue. This sequence of maturation of melanocytes is of diagnostic
importance in distinguishing some benign nevi from malignant melanoma.
57. MALIGNANT MELANOMA OF THE SKIN
Malignant melanoma is the malignant variant of pigmented tumors and biologically is
characterized by the frequency, with which it metastasizes. Sunlight appears to play an
important role in the development of this tumor.
Histologically the tumor is composed of melanocytes that resemble in part carcinoma
and in part sarcoma cells. These part sarcoma-like and part carcinoma-like cells are absolutely
characteristic of malignant melanoma. Cytologic evidences of malignancy are present: cell
atypia (cells of different sizes, shapes, nuclear and nucleolar properties), mitoses and invasion
of epidermis and dermis. About 10 percent of malignant melanomas are not pigmented
(amelanotic melanoma). When present, melanin has a dark brown colour. The melanoma cells
grow as poorly formed nests or as individual cells at all levels of epidermis and, in the dermis,
as expansible, balloon-like nodules. The growth pattern of the progressed tumor is both
horizontal and vertical in individual cases. The nature and extent of the vertical growth phase,
however, determines the biologic behaviour of malignant melanoma. Therefore, the depth of
vertical invasion of the tumor in the dermis is
an important prognostic sign (Clark´s
classification). Routinely, for prognostic purposes also the tumor thickness is measured by the
method described by Breslow.
58. BENIGN TERATOMA (ADULT CYSTIC TYPE) OF THE OVARY
Germ cells differentiate along three embryonic lines from which teratomas may arise.
Therefore these tumors contain elements of all three germ cell layers – ectoderm, endoderm
and mesoderm, growing usually in younger patients. The possible sites of teratomas are male
and female gonads (testis and ovary), retroperitoneum, anterior mediastinum, sacrococcygeal
and epipharyngeal regions. The commonest germ cell tumor is ovarian benign cystic
teratoma (also called ”dermoid cyst”). It is a dysontogenic neoplasm arising from different
embryonic cells and containing among others mostly mature epidermis, skin appendages, and
not infrequently, bone or teeth. Macroscopically, the tumor appears as a mass of an irregular
mixture of tissues intimately neighbouring with the compressed ovarian tissue and a smoothwalled, unilocal cyst of variable diameter (defined in centimetres), containing sebaceous
material and hair. Ten to fifteen percent of these tumors may be bilateral.
The cystic space is lined with epidermis-like stratified squamous epithelium, beneath
which are found hair shafts, sweat and sebaceous glands, surrounded by tissue equivalent to
dermis and subcutaneous fat tissue. Many other tissues may be found admixed in individual
biopsy specimens, from other germ layers, such as brain tissue, solid or microcystic structures
resembling parts of respiratory, digestive, or endocrine systems. Diagnostically and
prognostically most important finding is that all tissues within this tumor are of mature,
differentiated character. About 1% of the dermoid cysts may undergo malignant
transformation of any one of the component elements (most commonly the squamous cell
carcinoma).
59. FIBROADENOMA OF THE BREAST
Unlike the situation in other glandular tissues, the commonest type of a benign tumor of
the breast is a combined growth of both connective tissue and epithelial (glandular) cells –
called fibroadenoma. Benign forms of purely epithelial tumors of the breast (adenomas) also
exist but are extraordinary rare. Fibroadenomas occur preferentially in younger women,
usually before the age 30. Multiple small areas closely resembling a fibroadenoma are found
in some cases of the fibrocystic disease of the breast (in this setting it is called
fibroadenomatosis). Fibroadenomas are well-circumscribed, demarcated spherical tumors
with a lobulated appearance. Lack of fixation of the tumor to the surrounding and partly
compressed breast tissue accounts for its mobility on clinical (manual) examination and easy
extirpation at surgery . Their size varies from under 1 cm to more than 10 to 15 cm.
The epithelial component of fibroadenoma forms either numerous small, rounded, ductlike structures or thin, branching and curving ductular structures lined by double-layered or
flattened breast epithelium, around which are masses of more or less overgrown connective
tissue. Small cysts may occasionally be seen. The old morphologic differentiation of
fibroadenoma in ”intracanalicular” and ”pericanalicular” subtype is biologically unimportant
and therefore abandoned in the recent literature.
Such two patterns of epithelial and
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mesenchymal proliferation often coexist within the same tumor.
60. SEMINOMA OF THE TESTIS
Seminoma is the commonest type of testicular malignant tumors, having a germ cell
origin, and arising in the seminiferous epithelium from primary germ cells. A homogenous
grey-white solid mass, replacing all or part of the body of testis may markedly enlarge the
testis harvesting the tumor. Seminomas metastasize preferentially by way of the lymph stream.
The commonest, so-called ”typical” or ”classical” subtype of seminoma (85%) is
composed of sheets of uniform and pale appearing cells with well-defined cell borders,
arranged in islands or lobules. The cytoplasm is vacuolated or watery-appearing and contains
glycogen and, rarely, lipid granules. In most of these tumors, the stroma forming delicate
septa of fibrous tissue contains a variable lymphocytic infiltrate, a favourable prognostic
feature. In some tumors a histiocytic granulomatous response in the stroma along with fibrosis
may be found. Mitoses are usually frequent. In 5 to 10% the tumor is anaplastic. The third
variant, a spermatocytic seminoma, is encountered in 4 to 6%, affecting older men (over the
age of 65) and having excellent prognosis.
61. CHORIOCARCINOMA
Choriocarcinoma is a relatively rare, highly malignant neoplasm arising from both
trophoblastic layers of human placenta or in germ cell tumors. The tumor cells retain the
cytolytic trophoblastic activity giving rise to destructive growth. It grows rapidly and
metastasizes early. Most choriocarcinomas arise on the basis of a preexisting hydatidiform
mole (about 60 percent of cases). Both the primary tumor and its metastases are unusually
haemorrhagic. One of the tumor constituents (syncytiotrophoblast) produces gonadotropin
(HCG), and its presence in the blood serves for the diagnosis and estimation of the
progression or – if absent – a possible cure of neoplastic disease. HCG can also be easily
demonstrated in the choriocarcinoma tissue by means of immunohistochemistry.
The tumor is histologically presented by individually large cellular groups of more
regular, polygonal Langhans cells (cytotrophoblast) with distinct cell borders as well as by
variably formed syncytiotrophoblast in lamellar or vacuolated forms surrounding groups of
cytotrophoblastic cells. Among the vital parts, necrotic and haemorrhagic areas are frequently
observed and invasion of veins may be also found. Placental villi are never seen within the
tumor.
62. INFECTIVE (BACTERIAL) ENDOCARDITIS
Infective endocarditis is an acute or subacute inflammation resulting from bacterial
infection of a focal area of the endocardium. The line of closure of the heart valves is chiefly
involved, but mural endocardium or endocardium of congenital defects (e.g. patent ductus
arteriosus or site of the coarctation of the aorta) may be also affected. This disease is
frequently observed in unusual hosts such as patients with prosthetic heart valves, the elderly,
and drug addicts and gives rise to the state called septicopyemia.
The characteristic macroscopic lesion is the vegetation – from small nodules to large or
numerous friable, bulky, even several cm long masses adhering to the valve leaflets or to
chordae tendineae. At the beginning, deposits of fibrin and platelets adhere to the
endocardium. Circulating microorganisms colonise the platelet thrombus and proliferate to
form micro-colonies. A thin layer of superficial fibrin prevents the phagocytes from reaching
the bacteria. In areas foci of suppuration may be found. Calcification and fibrous thickening
of the leaflets indicates that there had been previous inflammation of a different
etiopathogenesis with subsequent scarring (e.g. rheumatic endocarditis). A possible finding in
examined heart leaflets is destruction, ulceration and perforation of the heart valve and also
possible direct spread into the underlying myocardium causing myocarditis . The vegetations
in acute endocarditis tend to be bulkier than in the subacute disease. With early diagnosis and
appropriate treatment more patients are cured. This is why more and more cases of ”healed
endocarditis” are now identified.
63. ACUTE MYOCARDIAL INFARCTION
Acute myocardial infarction represents morphologically usually an area of
left
ventricular necrosis, caused most frequently by ischemia due to coronary artery atheroma
71
with superimposed occlusive thrombus or plaque haemorrhage. Complications include
arrhythmias, cardiac failure, mitral incompetence, myocardial rupture leading to
haemopericardium, mural thrombosis leading to embolism, and cardiac aneurysm.
The chief microscopical feature of an acute, 8 to 12 hours old myocardial infarction is
ischemic coagulative necrosis, surrounded by heavy inflammatory cell interstitial infiltration
by polymorphonuclear leucocytes at its periphery. The sarcoplasm is homogenized, and the
cross-striation is absent. Myocardial nuclei have disappeared, and the necrotic cytoplasm of
myofibres is deeply eosinophilic. In the margins of an acute infarction fine droplets of lipids
in the viable cells adjacent to those that have died and the so-called ”vacuolar degeneration”
or myocytolysis are observed. Another light-microscopical finding in acute phase is edema
and haemorrhage. After few days following the acute attack, the first signs of resorption
develop and gradual repair by granulation tissue and later fibrosis will be seen during the first
weeks following the acute episode.
64. HEALING MYOCARDIAL INFARCTION
The necrotic heart muscle will largely be resorbed by macrophages and removed by
granulation tissue during the course of 2 – 7 weeks, depending on the size of the infarct.
Macroscopically, in the healing phase of fresh myocardial infarction the lesion appears red
with remnants of central yellow-brown, usually softened necrotic tissue.
Histologically there is an irregularly shaped area with a necrotic zone with
disintegration of dead myofibres and resorption of sarcoplasm by macrophages in the centre, a
richly cellular layer bordering the necrotic zone, represented by granulation tissue (a
fibrovascular response), and bordered in turn by the less deeply eosin-stained normal heart
muscle. Now the nuclei of the interstitial tissue cells in the necrotic zone have completely
disappeared. Gradually, the granulation tissue replacing the necrotic heart muscle turns into a
hypocellular and hypovascular scar.
65. MYOCARDITIS
An acute inflammation of the heart muscle has different forms, depending on the
histological findings. Serous, purulent, nonpurulent interstitial, granulomatous, giant cell and
necrotizing forms create a spectrum of possible morphological findings, depending on the
specific causative agent. Macroscopically, the heart during the active phase of myocarditis
may appear normal or enlarged with dilatation of all or isolated chambers. The acute
inflammatory lesions either resolve, leaving no residue, or undergo progressive fibrosis of
different extent, depending on the character and dimension of the original damage to the
myocardium.
A serous myocarditis is manifested by inflammatory edema of interstitial tissue,
separating the individual myofibres. Purulent myocarditis is characterized by metastatic
microabscesses in the heart muscle containing bacterial colonies or a phlegmonous neutrophil
infiltrate. Nonpurulent interstitial myocarditis has either degenerative character, or
lymphohistiocytic form or in some other cases, a granulomatous reaction (e.g. in the active
rheumatic fever there are many
perivascular Aschoff´s nodules /granulomas/ present).
Necrotizing myocarditis is characterized by focal necroses (myocytolysis) of individual
amount and lympho-histiocytic infiltrates. Fiedler´s and idiopathic giant cell myocarditis are
both characterized by focal necroses associated with a granulomatous reaction containing
multinucleate giant cells, interspersed with lymphocytes, many eosinophils, plasma cells and
macrophages.
66. ATHEROSCLEROSIS OF THE AORTA
Atherosclerosis starts as fatty streaks (lipidosis) early in young individuals. The process
of atherosclerosis is initiated by a reaction of smooth muscle cells in the intima and then
becomes more progressive and complex.
The fundamental lesions of atherosclerosis, the atheromatous plaques, have essentially
three components:
1. Cells, including smooth muscle cells, macrophages, and leucocytes;
2. Connective tissue, including collagen, elastic fibres, and proteoglycans;
3. Intra- and extracellular lipid deposits.
Typically, the plaques are composed of a superficial part (the fibrous cap), made up of smooth
muscle cells with a few leucocytes and relatively dense connective tissue; a cellular area
beneath and to the side of the cap, consisting of a mixture of macrophages, smooth muscle
cells, and T lymphocytes; and a deeper necrotic ”core”, in which there is a disorganized mass
73
of lipid material, cholesterol clefts, cellular debris, lipid-laden ”foam cells”, fibrin, and other
plasma proteins. Particularly at the periphery of the lesions one can see neovascularization of
the plaques in older lesions.. Hyalinization and dystrophic calcification is found in individual
extent.
67. POLYARTERITIS NODOSA
Polyarteritis nodosa is an inflammatory disorder of small and medium-sized muscular
arteries of unknown etiology causing among others muscle and joint pain, fever, ischemic
lesions in many organs, neuropathy and renal damage. It has been demonstrated recently that
many patients have circulating antibody against a cytoplasmic constituent of endothelial
cells, associated with alkaline phosphatase. Biopsy of a skin lesion or from other sites may
show the histological appearances of necrotizing arteritis.
Microscopically, the changes in the vessels may be divided in acute, healing, and healed
stages. The acute lesions are characterized by fibrinoid necrosis, which may extent to involve
the full thickness of the arterial wall, particularly in small arteries. The necrosis may involve
the entire circumference of the wall but it is often localized to a segment. The affected portion
may later bulge in an aneurysmal fashion. Healing lesions are characterized by fibroblastic
proliferation in addition to the continuing necrotizing process. The adventitial inflammatory
infiltrate will now exhibit large numbers of macrophages, eosinophils, and plasma cells. The
thrombosis - if present - undergoes organization The healed lesions consist merely of marked
fibrotic thickening of the affected arterial wall being sometimes complicated by formation of
an aneurysm. The internal elastic lamina and the smooth muscle media are partly or
completely destroyed and gradually replaced by fibrous tissue. All three described stages may
coexist in the same specimen.
68. ACUTE PURULENT BRONCHITIS
Normally, bronchi are sterile, owing to ventilation, phagocytosis, unimpaired
immunologic surveillance and mucociliary function. Obstruction of airways, mucociliary
insufficiency, retention of mucous secretion, and aspiration may facilitate bronchial infection.
Non-specific viral and bacterial inflammation is a frequent form of acute bronchitis. The
purulent form of acute bronchitis is recognized by exudate filling the lumen, rich in
granulocytes. Other signs of an acute bronchial inflammation are hypersecretion of mucus,
hyperaemia, damage and desquamation of ciliary epithelia and leucocytic infiltration of
lamina propria mucosae.
Similar changes are observed in bronchiolitis.
69. BRONCHIAL ASTHMA
Bronchial asthma is defined as increased irritability and responsiveness of the
bronchial tree to various stimuli with paroxysmal narrowing of the bronchial airways caused
by constriction (bronchospasm), which may reverse spontaneously or after treatment.
Microscopically the bronchi are plugged with thick, viscous mucus, containing whorls
of shed epithelium, eosinophils, neutrophils, and rarely tiny Charcot-Leyden´s crystals. The
latter are collections of crystalloids made up of eosinophil membrane protein. Mucous glands
and bronchial wall smooth muscles are hypertrophied. The basal membrane is mostly
thickened. Edema, chronic inflammatory cells and eosinophils (5 to 50% of cellular infiltrate)
are found in the lamina propria mucosae.
70. BRONCHOPNEUMONIA
Pneumonia is usually due to infection affecting distal airways, especially alveoli, with
the formation of an inflammatory exudate. The two anatomical patterns, lobar pneumonia and
bronchopneumonia, can result from infection by one of several types of bacteria, or other
pathogens. Sometimes these two patterns overlap. Bronchopneumonia has a characteristic
patchy distribution, centred on inflamed bronchioles and bronchi with subsequent spread to
surrounding groups of alveoli.
Histology shows focal acute inflammation of the lungs with suppurative exudate filling
the bronchi, bronchioli and adjacent alveoli. Besides polymorphonuclear leucocytes, the
exudate contains small amount of fibrin, causative microorganisms (better demonstrated by
bacterioscopic stains /e.g. Gram stain/), macrophages and desquamated pneumocytes. With
75
antibiotics and physiotherapy, the areas of bronchopneumonia may fully resolve during the
course of the disease, or, under bad circumstances, heal by organisation of exudate by
granulation tissue and scarring (so-called ”carnification”) within the alveoli and bronchioles.
71. LOBAR PNEUMONIA
Lobar pneumonia is an acute bacterial infection of a large portion of a lobe or of an
entire lobe of the lung. It tends to occur at any age but is relatively uncommon in infancy and
in late life. Classic lobar pneumonia is now encountered much less often, owing to the
effectiveness with which antibiotics abort these infections and prevent the development of fullblown lobar consolidation. 90 – 95% of all lobar pneumonias are caused by pneumococci
(Streptococcus
pneumoniae);
occasionally
Klebsiella
pneumoniae,
staphylococci,
streptococci, Haemophilus influenzae, and some of the gram-negative organisms, such as the
Pseudomonas and Proteus bacilli, are also responsible for this lobar distribution of
involvement. The most common portal of entry is the air passages. A lobar distribution
appears merely to be a function of the virulence of the organism and the vulnerability of the
host. Heavy contamination by virulent pathogens may evoke this pattern in healthy adults,
whereas organisms of lower virulence may accomplish the same in the predisposed patient. In
lobar pneumonia there is more extensive exudation that leads to spread through the pores of
Kohn. Moreover, the copious mucoid encapsulation produced by the pneumococci protects
the organisms against immediate phagocytosis, and thus favours their spread.
Four stages of the inflammatory response have classically been described:
The first stage of congestion represents the developing bacterial infection at lasts for about 24
hours (and thus is rarely seen histologically). It is characterized by vascular engorgement,
intra-alveolar fluid with few neutrophils, and often the presence of numerous bacteria.
Grossly, the involved lobe is heavy, boggy, red and subcrepitant.
The stage of red hepatisation that follows on the second and third days is characterized by
increasing numbers of neutrophils and the precipitation of fibrin to fill the alveolar spaces.
The massive confluent exudation obscures the pulmonary architecture. Extravasation of red
cells causes the coloration seen on gross examination. In many areas, the fibrin strands stream
from one alveolus through the pores of Kohn into the adjacent alveolus. The white cells
contain engulfed bacteria. An overlying fibrinous or fibrinosuppurative pleuritis is almost
invariably present. On gross examination, the lobe now appears distinctly red, firm, and
airless with a liver-like consistency, hence the term hepatisation.
The stage of grey hepatisation follows from the fourth to sixth day with a continuing
accumulation of fibrin associated with the progressive disintegration of inflammatory white
cells and red cells. This exudate contracts somewhat to yield a clear zone adjacent to alveolar
walls. In the usual case, the alveolar septa are preserved. The progressive disintegration of red
cells and the persistence of fibrinosuppurative exudate give the gross appearance of a greyishbrown, dry surface. Sometimes, when the bacterial infection extends into the pleural cavity,
the intrapleural fibrinosuppurative reaction produces what is known as empyema.
The final stage of resolution (yellow hepatisation) follows in the great preponderance of
cases with a favourable outcome on the seventh and eighth days. The consolidated exudate
within the alveolar spaces undergoes progressive enzymic digestion to produce granular, semi
fluid debris that is resorbed, ingested by macrophages, or coughed up. In such favourable
cases, the normal lung parenchyma is restored to its normal state. The pleural reaction may
similarly resolve, but more often it undergoes organisation, leaving fibrous thickening or
permanent adhesions.
Many complications may supervene during this classic evolution. The type 3 pneumococcus
and the Klebsiella bacillus characteristically produce an abundant mucinous secretion. These
same organisms and the staphylococci frequently cause abscess formation. Organization of
the exudate may convert the lung into a solid tissue (the process called carnification).
Bacteremic dissemination to the heart valves, pericardium, brain, kidneys, spleen, and joints
may cause metastatic abscesses, endocarditis, meningitis, or suppurative arthritis.
72. PRIMARY ATYPICAL PNEUMONIA
The term primary atypical pneumonia (PAP) was initially applied to an acute febrile
respiratory disease characterized by patchy inflammatory changes in the lung, largely
confined to alveolar septa and pulmonary interstitium. The term ”atypical” denotes the lack
of alveolar exudate, but a much more accurate designation is interstitial pneumonitis. The
pneumonitis is caused by a variety of organisms, the most common being Mycoplasma
pneumoniae. Other etiologic agents are viruses, including influenza virus types A and B, the
respiratory syncytial viruses (RSV), adenovirus, rhinoviruses, and rubella and varicella
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viruses; Chlamydia (psittacosis); and Coxiella burnetii (Q fever). In some cases, the cause is
undetermined. Any one of these agents may cause merely an upper respiratory tract infection,
recognized as the common cold, or a more severe lower respiratory tract infection. The
circumstances that favour such extension of the infection are often mysterious but include
malnutrition, alcoholism, and underlying debilitating illnesses. All causal agents produce
essentially similar morphologic patterns. The pneumonic involvement may be patchy or may
involve whole lobes bilaterally or unilaterally. The affected areas are red-blue, congested,
and subcrepitant.
Predominant in histologic pattern is the interstitial nature of the inflammatory reaction,
virtually localized within the wall of alveoli. The alveolar septa are widened and oedematous
and usually have a mononuclear inflammatory infiltrate of lymphocytes, histiocytes, and
occasionally plasma cells. In very acute cases, neutrophils may also be present. The alveoli
may be free of exudate, but in many patients there are intra-alveolar proteinaceous material, a
cellular exudate, and characteristically pink hyaline membranes lining the alveolar walls,
similar to those seen in hyaline membrane disease of infants. These changes reflect alveolar
damage similar to that seen diffusely in the adult respiratory distress syndrome. Subsidence of
the disease is followed by reconstitution of the native architecture.
73. FIBROPLASTIC PLEURITIS (Pleurisy)
Pleuritis may result from the extension of any pulmonary infection to the visceral
pleura, bacterial infections within the pleural cavity, viral infections, or pulmonary infarction
that involves the surface of the lung. The most striking symptom is sharp, stabbing chest pain
on inspiration.
In acute inflammatory conditions of the lung such as lobar pneumonia, an inflammatory
exudate may form in the pleural cavity, with deposition of fibrin on the visceral pleura. After
the acute phase of the illness, fibrin on the pleural surface undergoes organization. All the
fibrin has not been removed by the macrophages and the fibroblasts in the granulation tissue
have formed considerable amounts of collagen, thereby converting the granulation tissue into
cellular but still fairly vascular fibrous tissue. The end-result will be a layer of fibrous tissue,
which if abundant may greatly restrict the respiratory movements of the lung. If this thickened
pleura is peeled off, pulmonary function improves markedly. It is likely that the process
designated “shrinking pleuritis with atelectasis”, “folded lung syndrome”, or “round
atelectasis” represents a variation on this theme.
74. SQUAMOUS CELL CARCINOMA OF THE LUNG
Squamous cell carcinoma is probably the most common type of bronchogenic
carcinoma. Squamous carcinomas are more common in men than in women, usually develop
in middle or later life, and are strongly associated with cigarette smoking. Roughly two thirds
of squamous carcinomas are central tumours, involving the main or lobar bronchi, whereas
one third arise in the lung periphery, either in small bronchi or in association with scars.
Bronchial involvement may take the form of a warty endobronchial protrusion, or the tumour
may ulcerate the bronchus and grow outward. If the tumour obstructs a large bronchus, the
lung distal to the tumour will often be the site of obstructive pneumonia and bronchiectasis.
The most common symptoms, in decreasing order of frequency, are cough, weight loss, pain,
increased sputum production, haemoptysis, malaise, fever, and those resulting from
paraneoplastic manifestations. Peripherally located lesions are clinically silent until they
reach a sufficient size to ulcerate into a bronchus or to involve the pleural space. Carcinomas
located in the superior pulmonary sulcus result in a clinical picture peculiar to their location,
known as Pancoast's syndrome. This is characterized by pain in the distribution of the ulnar
nerve and is often accompanied by Horner's syndrome secondary to involvement of the
sympathetic chain.
Microscopically, the diagnosis of malignancy is based on cell atypia and invasiveness,
and the diagnosis of squamous cell type on the detection of keratin and/or intercellular
bridges. Keratinised cells can be recognized in sections by their brightly eosinophilic
refractile and pyknotic nuclei. Whorls or eddies of cells may be keratinised (epidermoid
pearls), the whole centre of the lobule may be filled with keratin, or at the other extreme only
a few single cells may be keratinised.
75. SMALL CELL CARCINOMA OF THE LUNG
Small cell carcinoma comprises 10% to 20% of all lung cancers. Most of the patients
are males, their median age is 60 years, and 85% or more are smokers. Small cell carcinoma
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is typically a lesion of the central portions of the lung, but occasionally it is found in a
peripheral location. Grossly, the tumour is white-tan, soft, friable, and extensively necrotic.
When centred in a large bronchus (the usual situation), it may involve it in a circumferential
fashion and/or spread widely beneath the normal mucosa. The bronchus may be totally
occluded in the late stages, but pure or predominant endobronchial involvement is highly
unusual.
Microscopically several patterns are recognized. The oat cell type consists of round or
elongated poorly cohesive cells 10 to 12 m in length or slightly larger than lymphocytes.
The tumour cells have dark clumped cytoplasm. The nuclei are finely granular and very
hyperchromatic, nucleoli are inconspicuous, mitoses are frequent, and the cytoplasm is so
scanty as to be unrecognisable in routine preparations. In some instances the cells have an
elongated (fusiform) shape. Nuclear "molding," a change first described in cytologic smears,
can also be appreciated in microscopic preparations. Necrosis is usually present and
widespread in larger tumours. The pattern of tumour growth is diffuse but with some division
into lobules by vessels and stroma, which helps to distinguish oat cell carcinoma from
lymphoma. Small cell carcinoma is highly malignant and almost invariably has metastasised
by the time of diagnosis.
76. EXTRAMEDULLARY HAEMATOPOIESIS
Extramedullary haematopoiesis is characteristic for a number of blood diseases,
including pernicious anaemia, the haemolytic anaemias and the leukaemias. It also occurs
with extensive metastases to bone. Also it may be presented in immature newborn liver.
Histologically, there are numerous focal infiltrates that under higher magnification are
revealed as groups of cells in dilated sinuses making the pressure atrophy of surrounding
parenchyma. The cells here are primarily of the erythropoietic sequence (particularly
erythroblasts and normoblasts), large cells with pale nuclei and light basophilic cytoplasm or
smaller cells with pyknotic nucleus and a thin rim of pink coloured cytoplasm. But there are
also cells from the leucocytic series, from which eosinophilic myelocytes and mature
leukocytes predominate, and even some megakaryocytes. In Kupffer cells, less in
hepatocytes, iron pigment in different amount is present. In portobiliar spaces also rich
haematopoiesis happens with the infiltration of the connective tissue stroma with
erythropoietic and leukopoietic cells. In long lasting process connective tissue diffusely
enhances, which tends to the liver fibrosis.
77. CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) IN THE LIVER
Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the elderly,
with 90% of cases occurring after 50 years of age. CLL is the most indolent of all leukaemias.
Males are affected twice as commonly as females. Patients with more advanced disease and
correspondingly poorer prognosis exhibit mild but generalized lymphadenopathy, hepatoand splenomegaly, anaemia and thrombocytopenia. CLL shows considerable overlap with
small lymphocytic lymphoma. The vast majority of cases are of B-cell type. T-cell CLL is rare,
less then 5% of all cases. Patients with CLL are often asymptomatic. When the symptoms are
present, they are non-specific and include easy fatigability, loss of weight, and anorexia.
Total leukocyte count may be increased only slightly or may reach 200000 per mm3. In all
cases there is absolute lymphocytosis of small, mature-looking lymphocytes. Only a small
fraction of lymphocytes are large ones with indented nuclei and nucleoli. Smudge cells
(crushed nuclei of lymphocytes) are commonly seen in peripheral smears. Because the
leukaemic B-cells are non-functional, these patients often have hypogamaglobulinaemia and
increased susceptibility to bacterial infections. The course and prognosis of CLL are
extremely variable and depend primarily on the clinical stage. Overall, the median survival is
four to six years. Transformation to acute leukaemia with blast crisis is rare.
Microscopically in chronic lymphatic leukaemias the immature cells (lymphoblasts,
lymphocytes) permeate the periportal fields, while the sinusoids contain only a limited
number of nucleated cells. Under low magnification, the significantly dilated, bluish
periportal fields are prominent. They are usually spherical. Median and high magnifications
reveal infiltration of the periportal connective tissue by lymphatic cells having dense and
vesicular nuclei with little cytoplasm. Macroscopically organ is enlarged.
78. CHRONIC MYELOID LEUKAEMIA (CML) IN THE LIVER
Chronic myelocytic leukaemia (CML), one of the myeloproliferative disorders, is a
neoplasm derived from pluripotential stem cell, in which differentiated cells of the
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granulocytic series predominate in the blood and marrow. CML occurs in all ages and both
sexes but predominantly in middle-aged adults. A slight male preponderance has been noted,
but the clinical course of the disease is similar in both sexes. CML is associated with the
presence of a distinctive chromosomal abnormality, the Ph1 (Philadelphia) chromosome. The
onset of CML is usually slow, and the initial symptoms may be quite non-specific. They are
caused by anaemia or by hypermetabolism due to increased cell turnover and include easy
fatigability, weakness, weight loss, and anorexia. Sometimes the first symptom is a dragging
sensation in the abdomen caused by the extreme splenomegaly characteristic of this
condition. Usually, there is marked elevation of the leukocyte count, commonly exceeding
100000 cell per mm3. The course of CML is one of slow progression, and even without
treatment a median survival of three years can be expected. After a variable period averaging
three years, approximately 50% of patients enter an ”accelerated phase”, during which there
is a gradual failure of response to treatment, increasing anaemia and thrombocytopaenia,
acquisition of additional cytogenic abnormalities, and finally, transformation into a picture
resembling acute leukaemia (”blast crisis”). In the remaining 50%, blast crisis occur
abruptly without an intermediate accelerated phase. Morphologically, the myeloid cells
appear relatively normal. However, leukaemic neutrophils failing to differentiate normally
are indicated by low or absent leukocyte alkaline phosphatase and inadequate phagocytic
activity.
The unrestricted increase in the number of immature, early forms of granulocytes leads
to the accumulation and multiplication of myeloblasts, promyelocytes and myelocytes in the
sinusoids of the liver. Under low magnification the organ structure appears to be intact. Under
median magnification there is a marked increase in the cellular content of the sinusoids. The
sinusoids are dilated and tightly packed with large nucleated cells. The periportal fields are
infiltrated only slightly or not at all. The liver cells may show evidence of pressure atrophy
and degenerative changes.
79. NON-HODGKIN´S LYMPHOMA (NHL) IN LYMPH NODE
Lymphomas other than Hodgkin’s arise from lymphocytes (B cells or T cells) or from
histiocytes (histiocytic lymphomas, malignant histiocytomas). The usual presentation of NHL
is a localised or generalised lymphadenopathy. In about one third of cases it may be primary
in other sites where lymphoid tissue is found, e.g., in the oropharyngeal region, gut, bone
marrow, and skin. Lymphomatous involvement often produces marked nodal enlargement,
which is almost always nontender. Some, after becoming widespread, spill over into the
blood, creating a leukaemia-like picture in the peripheral blood. Although we speak of NHL
as a group, we should recognise that it encompasses a wide spectrum of disorders, differing
in patient age of onset, the cells of origin, and response to therapy. It is therefore necessary to
classify NHL into various subgroups.
Well-differentiated lymphocytic lymphoma consists of mature lymphocytes and may be
regarded as the counterpart in the tissue of chronic lymphocytic leukaemia. The normal
architecture of the node has been replaced by a diffuse infiltrate of small round cells
resembling mature lymphocytes. They are fairly uniform in size and shape, with deeply
staining nuclei and only a sparse rim of cytoplasm. There is no evidence of follicle formation.
Larger pale-staining histiocytes with large vesicular nuclei are scattered amongst them. The
vast majority of the cells are small lymphocyte – type cells with round basophilic nuclei and
thin rim of cytoplasm. Lymphoblastic lymphoma occurs at all ages but most often in children
and adolescent. The normal population of cells of this node has been replaced by a
monomorphic infiltrate of cells with ovoid or round nuclei, in which the chromatin is evenly
dispersed. Multiple small nucleoli are visible in some nuclei. Cytoplasm is fairly scanty and
not well defined.
80. MULTIPLE MYELOMA (Plasmacytoma)
Multiple myeloma is basically a multifocal plasma cell cancer of the osseous system
that in the course of its dissemination may involve many extraosseous sites. Plasma cell
myeloma, or multiple myeloma, is characterized by proliferation and accumulation of
neoplastic cells within the marrow that usually constitute greater than 20% of the marrow
cells that morphologically resemble plasma cells. Usually the myeloma cells secrete
immunoglobulins (Ig), light chains (Bence Jones protein), or both. IgG and IgA are most
frequent, IgD and IgE are rarely secreted, and nonsecretory myeloma occurs in 1% of cases.
Within the marrow, proliferations may be diffuse or form nodular masses. The diagnosis can
usually be made by iliac crest biopsy. Clinical manifestations stem from the effects of
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infiltration of organs, particularly the bones, by tumourous masses of plasma cells; and the
abnormal immunoglobulins secreted by the tumour cells.
Microscopically the marrow in myeloma is infiltrated by plasma cells that may exhibit a
range of cytologic appearances. Most commonly, the tumour cells closely resemble mature
plasma cells, forming extensive perivascular and paratrabecular infiltrates, scattered nodules
or confluent infiltrates. But all ranges of immaturity may be encountered, including
undifferentiated cells resembling lymphoid precursors as well as lymphocyte-plasma cell
intermediates. Important is their abnormal aggregation or evidence of their destructive
potential in the form of infiltration, invasion, and erosion. In a section or smear of bone
marrow, characteristic atypical plasma cells are present that have eccentric nuclei with
chromatin arranged like the spokes of a wheel. There may be multinucleated plasma cells and
giant cells. The protein aggregates may appear as acidophilic inclusions known as Russel
bodies, but are not pathognomic. The bone resorption results from the activation of
osteoclasts by osteoclast-activating factors secreted by the myeloma cells. Grossly, on section
the bony defects are filled with red, soft, gelatinous tissue.
81. PLEOMORPHIC ADENOMA OF THE SALIVARY GLAND
Pleomorphic adenoma is the most common tumour of the parotid, submandibular, and
other minor salivary glands, they constitute 65 – 80% of tumours in the major salivary
glands. The palate is the most common site for pleomorphic adenomas arising from the minor
salivary glands and occurring on the hard and soft palates with about equal frequency.
Because of their remarkable histologic diversity, these neoplasms have in the past been called
mixed tumours. They may appear at any age, most frequently in the fifth and sixth decades,
with a small but distinct female preponderance. The great majority arise in the parotids and
only rarely in the other major and minor salivary glands. Single tumours are the rule, but
rarely two or more lesions appear simultaneously on the same or both sides. Grossly the
tumours are rounded to bossed, somewhat lobulated masses ranging up to 6 cm in greatest
dimension, and surrounded by a fibrous capsule of varying thickness. Expansive growth
produces tongue like protrusions that may be left behind at the surgical excision, accounting
for the recurrence rate of 5 to 50%. The cut surface is grey-white with variegated myxoid
areas and areas of blue translucence representing chondroid.
In essence, they are composed of epithelial elements dispersed throughout a matrix of
mucoid, myxoid, and chondroid tissue. In some lesions, the epithelial elements predominate,
but in others the reverse obtains. The epithelial elements form ducts, acini, irregular tubules,
or strands or sheets of cells, or squamous structures. They have ductal or myoepithelial origin.
The cells lining ductal or glandular formations are cuboidal or columnar, and often there is
PAS-positive secretion within the glandular or ductular spaces. Often small, dark, spindled,
myoepithelial cells underlie the cuboidal epithelium to create distinctive double strands of
epithelial cells. In addition, the myoepithelial elements may be dispersed in islands or strands,
often embedded within a loose connective tissue or myxoid tissue. The myoepithelial cells
may be present as eosinophilic spindle cells resembling smooth muscle. Hyaline, myxoid,
chondroid or rarely bone areas result from the accumulation of mucoid or hyaline material
between myoepithelial cells, which alter their appearance. Accumulation of basophilic
mucoid material separates the myoepithelial cells, and vacuolar degeneration of the
myoepithelial cells results in an appearance very similar to cartilage. The epithelial and
apparent mesenchymal elements are randomly intermixed. The histologic diversity is almost
limitless, but it is precisely this feature that characterises the pleomorphic adenoma.
82. OESOPHAGEAL VARICES
Portal hypertension, when sufficiently prolonged or severe, induces the formation of
collateral bypass channels wherever the portal and caval systems interdigitate. The
collaterals here develop in the region of the lower oesophagus when portal flow is diverted
through the coronary veins of the stomach into the plexus of oesophageal submucosal veins,
thence into the azygous veins, and eventually into the systemic circulation. The increased
pressure in the oesophageal plexus produces tortuous vessels called varices. In addition to
the most often cause of hepatic cirrhosis, oesophageal varices result from superior vena cava
obstruction, portal vein thrombosis, hepatic vein thrombosis (Budd-Chiari syndrome),
pylephlebitis, and tumour compression of the major portal trunk. Varices occur in
approximately two thirds of all cirrhotic patients and are most often associated with alcoholic
cirrhosis. They are less commonly found in association with pigment cirrhosis and
postnecrotic scarring of the liver and are rarely produced by biliary or cardiac cirrhosis.
Very infrequently, varices are encountered in systemic amyloidosis and sarcoidosis.
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Furthermore, rare cases have been described without evident cause for the portal
hypertension. Rupture and bleeding are the most serious problems related to oesophageal
varices.
Varices appear as tortuous dilated veins lying primarily within the submucosa of the
distal esophagus and proximal stomach; venous channels directly beneath the esophageal
epithelium may also become massively dilated. The net effect is irregular protrusion of the
overlying mucosa into the lumen. When the varix is unruptured, the overlying mucosa may be
normal, but often is eroded and inflamed because of its exposed position. If rupture has
occurred in the past, thrombosis or superimposed inflammation may be seen. They are
covered by a thin mucous membrane. The increased venous pressure, with or without
inflammation or ulceration, often results in massive and frequently fatal haemorrhage.
83. CHRONIC PEPTIC ULCER OF THE STOMACH
Ulcers are defined as a breach in the mucosa of the alimentary tract, which extends
through the muscularis mucosa into the submucosa or deeper. Peptic ulcers are chronic, most
often solitary, lesions that occur in any portion of the gastrointestinal tract exposed to the
aggressive action of acid-peptic juices. Both the acid and the pepsin are critical. They tend to
be less than 4 cm in diameter, may penetrate muscularis mucosa or perforate gastric wall.
They are frequently recurrent, with intermittent healing and are located in the following sites
with decreasing frequency: duodenum, first portion; stomach, usually antrum; within
Barrett´s mucosa; in the margins of a gastroenterostomy (stomal ulcer); in the duodenum,
stomach, or jejunum of patients with Zollinger-Ellison syndrome; within or adjacent to a
Meckel´s diverticulum that contains ectopic gastric mucosa. Chronic ulcers occur with a
frequency of 2,5% and 1,4% respectively, among men and women. Gastric ulcers are more
frequent at an older age, with preponderance among blood groups A. The typical peptic ulcer
is small (about 1 to 2,5 cm in the stomach).
Microscopically four zones are demonstrable: (1) The base and margins have a
superficial thin layer of necrotic fibrinoid debris and beneath this layer the zone of
nonspecific inflammatory infiltrate, with polymorphonuclear leucocytes predominating; (2) it
is lying on an intensely eosinophilic layer of fibrinoid necrosis; (3) that is bordered by
granulation tissue infiltrated with mononuclear leucocytes in the deeper layers, especially in
the base of the ulcer; and (4)the granulation tissue rests on a more solid fibrous or collagenous
scar. Vessel walls within the scarred area are typically thickened by the surrounding
inflammation and are occasionally thrombosed.
84. CHRONIC GASTRITIS
Chronic gastritis is defined as the presence of chronic mucosal inflammatory changes
leading eventually to mucosal atrophy and epithelial metaplasia, usually in the absence of
erosions. The epithelial changes may become dysplastic, and constitute a backround for the
development of carcinoma. Chronic gastritis is notable for distict causal subgroups, location
of disease in the stomach (e.g. antral, corporal), histology, and clinical features. Patterns of
gastritis also vary in different parts of the world. The major etiologic associations of chronic
gastritis are as follows:
Immunologic, associated with pernicious anemia;
Chronic infection, especially Helicobacter pylori;
Toxic, as with alcohol consumption and cigarette smoking;
Postsurgical, especially following antrectomy and gastroenterostomy with reflux of bilious
duodenal secretions;
Motor and mechanical, including obstruction, bezoars (luminal concretions), and gastric
atony;
Radiation;
Granulomatous conditions (e.g. Crohn´s disease);
Miscellaneous – graft versus host disease, amyloidosis, uremia.
So-called atrophic gastritis is not properly classified as an inflammatory condition. Some
uses the term as a synonym for gastric atrophy. It may affect different regions of the stomach
and exhibit varying degrees of mucosal damage. Regardless of cause or location, the
morfologic features are similar. By visual inspection, the mucosa is usually reddened and has
a coarser texture than normal. There may be some flattening of the mucosa. With more severe
chronic gastritis, the mucosa becomes more obviously thinned and flattened.
By microscopy, an inflammatory infiltrate of lymphocytes and plasma cells is present
within the lamina propria. In the early stages, this infiltrate is usually limited to the upper
third of the gastric mucosa (chronic superficial gastritis). In more severe forms, the
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inflammatory infiltrate involves the full thickness of the mucosa. Lymphoid aggregates, some
with germinal centers, are frequently observed in the mucosa. The response of the epithelium
to injury is increased mitotic activity in the neck region of the gastric glands. The less mature
cells that populate the mucosa exhibit enlarged, hyperchromatic nuclei, and diminished to
absent mucin vacuoles. Metaplastic columnar absorptive cells and mucous goblet cells of
intestinal phenotype (primarily small intestine) may partially replace portions of the gastric
mucosa. The body-fundic mucosa also may exhibit the simpler glands characteristic of the
antral-pyloric region. Atrophic change is evident by marked loss in glandular structures
corresponding to the mucosal flattening observed grossly.
85. TRANSMURAL INFARCTION OF SMALL BOWEL (Infarsatio
haemorrhagica intestini tenuis)
Infarction of the small bowel can result from either venous or arterial obstruction. The
infarction, however, is always haemorrhagic, and extensive haemorrhage has occurred into
the mucosa and the deeper tissue. The muscularis mucosae appears viable, with well-stained
nuclei. The villi, however, have lost their epithelial covering and have collapsed. The small
blood vessels are greatly dilated. The crypts of the glands retain their epithelial cells,
although they appear somewhat degenerated. Thrombosis of the mesenteric veins, this cause
of intestinal ischemic occurs under a variety of conditions. Almost all thromboses affect the
superior mesenteric veins, whereas only 5% of the cases involve the inferior mesenteric veins.
The collateral flow in the distribution of the superior mesenteric vein is usually sufficient to
preclude infarction of the intestine.
However, the thrombosis of smaller veins can also lead to transmural infarction. The
infarcted bowel is edematous and diffusely purple. The demarcation between infarcted bowel
and normal tissue is usually sharp, although venous occlusion may lend to a more diffuse
appearance. Extensive haemorrhage is seen in the mucosa and submucosa, the former
becoming necrotic. Although the deep muscle layers are initially preserved, they eventually
also become necrotic. The mucosal surface shows irregular white sloughs, the wall becomes
thin and distended, and bubbles of gas may be present in the mesenteric veins.
86. CARCINOMA OF THE STOMACH
The incidence of carcinoma of the stomach varies greatly in various parts of the world
and among various people. It is known to be particularly frequent in Japan. Most carcinomas
of the stomach arise from the mucus secreting cells. Differentiation is variable as to the extent
and regularity of gland formation, mucus secretion, cytologic features, etc., but in general
they tend to be less well-differentiated and less characteristic than the carcinomas of the
colon and rectum.
Early cancer of stomach is an epithelial infiltrating tumor that is limited to the mucous
membrane. It frequently shows a structure similar to that of the signet-ring carcinoma. The
mucous membrane is still maintaned so that infiltration is freqeuntly missed. The stroma
includes small groups of pale cells that can be identified as signet-ring cells under higher
magnification and particularly with PAS stain. Mucinous carcinoma. This condition is
characterized morphologically by extreme mucin production. The large, lightly basophilic,
finely stranded mucous masses can easily be taken for edema of the stroma. They enclose
small groups of cancer cells that demonstrate only occasional intracytoplasmic mucous
degeneration, much like the signet-ring carcinoma. Scirrhous carcinoma. The scirrhous
carcinoma has particularly fiber-rich stroma that includes only scattered, individual cancer
cells. Low magnification shows the marked thickening of the gastric wall. Under higher
magnification, the small groups of carcinoma cells can be seen. They have large nuclei and
particularly prominent nucleoli. The Van Gieson-red collagen fibres and fibroblasts enclose
them. Very fiber-rich scirrhous carcinomas may present a difficult problem.
87. SUBACUTE HEPATIC NECROSIS
Frequently a more serious variant of acute viral hepatitis is that described by some
investigators as progressive viral hepatitis, which eventually may be fatal.
Frequently, the histologic changes in the liver resemble those of the usual form of acute
viral hepatitis. However, in addition, multiple, larger zones of liver cell necrosis may be seen,
which are confluent, resulting in bridging bands of collapsed stroma infiltrated by
lymphocytes that connect adjacent portal areas or central regions.
Such bridging lesions have been called subacute hepatic necrosis, and their presence
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indicates a severe form of the disease that progress to hepatic failure and death or to
cirrhosis. Subacute hepatic necrosis sometimes may be difficult to distinguish from the lesion
of chronic active hepatitis.
88. MICRONODULAR HEPATIC CIRRHOSIS
The currently accepted definition of cirrhosis requires the term be applied to a liver
with diffuse fibrosis and containing regenerative nodules, which are masses of hepatocytes
lacking the normal blood flow because of the lack of terminal hepatic venules.
Micronodular cirrhosis applies to the liver, in which nearly all the nodules are less than
3 mm in diameter though some have used 1,5 mm as the maximum diameter because that is
the diameter of a normal lobule. Examples of common micronodular cirrhosis include
alcoholic cirrhosis, biliary tract obstruction, and hepatic venous obstruction. Micronodular
cirrhosis develops from a chronic inflammation in the periportal area with secondary
periportal necrosis. This frequently results in the appearance of large and regular parenchymal
islands of similar size surrounded by a ring of connective tissue. The central vein may be in
the centre or in the periphery of the parenchymal islands.
89. HEPATOCELLULAR CARCINOMA IN CIRRHOSIS
This is a malignant tumor that originates from the hepatocytes. Malignant hepatomas
develop most frequently in liver that has undergone cirrhotic changes. The well-known
hepatic carcinogens include arsenic, thorotrast, PVC, and others.
Histologically, the carcinoma consists of solid, trabecular or alveolar cell clusters. The
tumor cells still resemble hepatocytes, but more frequently they have a dark nucleus and show
mitoses and cellular atypia. The infiltrating growth and the invasion of blood vessels is
characteristic of this tumor, which can also produce an amorphous, yellowish-brown bile
pigment.
90. CHRONIC CHOLECYSTITIS
As a rule, cholecystitis is a chronic, recurent, nonbacterial inflammation of the gall
bladder. In chronic inflammation the wall is thickened (chronic hyperplastic cholecystitis).
Chronic cholecystitis is more common in elderly adipose women and is accompanied by
cholelithiasis in more than 90% of all cases. In the acute stage cholecystitis is usually
nonbacterial and is caused by a perfusion disturbance.
The mucosal folds are widened by lymphocytic infiltration and fibrotic connective
tissue proliferation. The surface epithelium undergoes glandular transformation and resembles
Brunner´s glands (intestinal metaplasia). The increased pressure in the lumen leads to
diverticulum like outpouchings of the mucous membranes (Rokitansky-Aschoff´s sinus).
These are empty spaces, lined with cylindrical epithelium that extends beyond the muscularis.
In an advanced stage of chronic cholecystitis, scarring and flattening of the mucosal folds
predominate (chronic atrophic cholecystitis). In the terminal stages of this inflammatory
process the wall of the gall bladder consists of scar tissue only. This is known as porcelain
gall bladder.
91. ACUTE HAEMORRHAGIC PANCREATITIS
Parenchymal and fat tissue necrosis of the pancreas is considered to be autodigestive in
nature (trypsin, lipase) and follows a local circulatory disturbance. The pathogenesis of this
highly complex process is still a matter of debate. Macroscopically in the initial stages there
is edema and focal parenchymal necrosis (large, dirty gray pancreas). In haemorrhagic
necrosis the pancreas is dark red and haemorrhagic. Secondary liquefaction and cavitation
are late developments. Adipose tissue necrosis appears as white, scattered foci. The condition
is most frequent in obese women and in patients with alcoholic fatty degeneration of the liver.
Very early in the disease the pancreas microscopically shows only interstitial edema.
Later the pancreas contains patches of coagulative necrosis rimmed by infiltrates of
polymorphonuclear leukocytes. Still later, necrosis of arteries and arterioles is responsible for
gross haemorrhages. Veins often are thrombosed. Eventually, as bacteria lodges in the
necrotic pancreas, through either the ducts or bloodstream, frank suppuration may occur. A
late complication of acute pancreatitis is the occasional development of a pseudocyst – an
accumulation of enzyme-rich fluid, necrotic debris, and altered blood confined not by an
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epithelial capsule, but by retroperitoneal connective tissue, adherent upper abdominal viscera,
and the peritoneal components of the lesser omental sac.
92. POLYCYSTIC KIDNEY DISEASE
Polycystic kidney disease or autosomal dominant polycystic renal disease is more
common than autosomal recessive (infantile) polycystic renal disease. The disease is inherited
as an autosomal dominant disorder with high penetrance associated with locus on autosome
16. Grossly the kidneys are often huge, weighing more than 150 g apiece.
The innumerable cysts, varying from barely visible to 5 cm in size, produce a
cobblestone-like external surface. On cross section the cysts contain straw yellow,
haemorrhagic, or even gelatinous fluids. The intervening islands of renal parenchyma may be
normal in appearance or may show secondary compression, atrophy, and fibrous
arterionephrosclerosis, or pyelonephritis, resulting in eventual renal failure. Dissections of the
nephrons and collecting ducts in such cases have shown that the cyst dilatations and
proliferations occur in any part of the nephron but have a special predilection for the angle of
Henle´s loop and Bowman´s capsule.
93. BENIGN NEPHROSCLEROSIS (Arterionephrosclerosis)
Benign nephrosclerosis is the most common form of renal disease and is seen in most
persons over 60 years of age. Long staining moderate arterial hypertension induces
arteriosclerotic proliferative and hyaline changes of small muscular branches of the renal
arteries and renal arterioles. These changes result in focal atrophy of tubules and sclerosis of
glomeruli. The intervening kidney is relatively uninvolved, thus renal function is usually fairly
well maintained.
Microscopically the small muscular arteries show intimal thickening because of
proliferation of intimal smooth muscle cells, which deposit new elastic fibres, the lamina of
basement membrane, and collagen fibrils. Under the light microscopy this material has a pink
hyaline appearance. Although some intimal thickening occurs with age, it is most striking
when associated with hypertension. Under low magnification the most prominent feature is
the thickened walls of larger arteries, particularly in the medulla of the kidney. Median
magnification shows elastic-hyperplastic proliferation of the intima. The glomeruli are
partially hyalinized and sclerosed, and their tubules are atrophic, with interstitial fibrosis and
loose infiltration with lymphocytes. If several groups of glomeruli are hyalinized or sclerosed,
atrophy of the tubular system and contraction of the fibrotic connective tissues lead to a
depression on the surface of the kidney (arteriosclerotic scar). The beginner can easily
mistake the arteriosclerotic scars and their lymphocytic infiltrates for chronic pyelonephritis.
94. MEMBRANOPROLIFERATIVE (MESANGIOCAPILLARY)
GLOMERULONEPHRITIS
Glomerulonephritis (GN) is an inflammation of the glomeruli. All glomeruli in both
kidneys may be affected uniformly (diffuseGN) or only single may be involved (focal GN). The
glomerular inflammation follows the general rules of an inflammatory process; exsudation
denotes the leakage of blood plasma and agregation of granulocytes (exsudativeGN).
Cellular proliferation may affect only the mesangium and the endothelium (mesangial and
endocapillary, proliferative GN). In so-called membranous GN, the basement membrane is
principally affected (thickened). Cellular proliferation is not significant. A combination of
basement membrane thickening and cellular proliferation is found in membranoproliferative
GN.
In almost all forms of GN, immune complex can be demonstrated in the mesangium or
on the basement membrane. On the basis, it is assumed that the basic pathogenic mechanism
of GN is an antigen-antibody reaction. This mechanism then explains all the morphologic
features.
The
group
of
glomerular
diseases
called
”membranoproliferative
glomerulonephritis” is characterized by infiltration of inflammatory cells, by proliferation of
intrinsic glomerular cells, and by altered structure and function of the glomerular basement
membrane. Membranoproliferative glomerulonephritis, also known as ”mesangiocapillary
glomerulonephritis”, occurs in 10 to 15% of patients with nephrotic syndrome and is most
common in the second decade. The glomeruli by light microscopy are large and hypercellular
and show distinctive club-shaped glomerular lobules. There is a striking increase in mesangial
cells and mesangial basement membrane substance. The glomerular capillary walls are often
double contoured from splitting of the basement membrane. Neutrophils are seen in these
93
tufts during peaks of clinical activity. Subendothelial and intramembranous complexes
accompany proliferation of the mesangial cells. They overlie and intrude through the
fragmented basement membrane into the periphery of the loops.
95. ACUTE PYELONEPHRITIS
The etiology and pathogenesis of lower as well as upper urinary tract infection are
interrelated. Most cases of acute pyelonephritis occur after infection of the lower tract.
Escherichia coli is the cause of 85% of urinary tract infections. Other common pathogens are
Proteus, Enterococcus and Pseudomonas. With reccurent acute attacs the latter organisms
are more common and may be resistent to antibiotics. Clinically, lower tract infection is
characterized by dysuria, higher frequency of wetting and bacteriuria. A swollen wedgeshaped area involving the papilla and adjacent cortex, infiltrated by gray-white foci of
inflammatory reaction, characterizes grossly acute pyelonephritis in the absence of
obstruction.
Microscopically there are neutrophils in the tubules and in the edematous stroma.
Microabscesses may be present. The glomeruli are relatively spared. The adjacent, uninvolved
kidney is without lesions. With acute obstruction the process may spread to involve the
kidney extensively and even produce necrosis of the renal papillae.
96. NEPHROBLASTOMA (Wilm´s tumor)
Nephroblastoma, a malignant tumor that arises from metanephrogenic tissue, is the
commonest solid abdominal tumor in children. Grossly nephroblastomas are bulky, spherical,
deceptively circumscribed white or gray-white masses occasionally without focal
haemorrhage, necrosis, or cyst formation.
Histologically it is a mixed tumor with a sarcomatous stroma and pseudoglomerular and
pseudotubular differentiated structures. The commonest pattern is a dimorphic distribution of
sheets of undifferentiated immature cells resembling metanephric blastema and variously
differentiated elements, tubules, abortive glomeruli, or even dysontogenetic tissue. Rapid
local invasion and distant metastases, importantly to the lungs, are seen.
97. RENAL CELL CARCINOMA (Adenocarcinoma of kidney)
This tumor comprises 70 – 80% of renal cancers. The designation ”hypernephroma”
reflects an outmoded concept that they arise from ectopic adrenocortical cells. Renal
adenocarcinoma usually occurs between 50 and 70 years of age and twice as common in men
as in women. Metastases may occur early in a variety of sites. Prognosis depends on the
extent of spread and the presence or absence of vascular invasion. The tumors are roughly
spherical and are often large. They are often conspicuously yellow in colour and show central
areas of haemorrhage, coagulative necrosis, and cystic excavation.
This malignant tumor of the kidney consists of typical clear or plant cell-like cells. The
tumor cells are arranged in an alveolar or trabecular or cystopapillar fashion and have a clear,
optically empty cytoplasm (glycogen) and a rounded nucleus. The criteria for malignancy in
hypernephroma are diameter greater than 3 cm, invasion of vessels or the renal pelvis,
mitoses, atypia, and polymorphism (sarcomatous growth).
98. HYDRONEPHROSIS
Mechanical obstruction to urinary outflow causes a rise of luminal pressure and
proximal dilatation of the ureter (hydroureter) and renal pelvis (hydronephrosis). The cause
of obstruction may be congenital anomalies, neuromuscular defects such as cord bladder,
benign and malignant tumors, renal and bladder calculi, infection and subsequent fibrosis,
and pregnancy. The prognosis of the process is determined by the degree and location of
obstruction.
With advanced hydronephrosis the renal parenchyma is stretched over the dilated
caliceal system and undergoes intense fibrous atrophy of all components. When
hydronephrosis is bilateral and early (acute), the kidney may show only moderate tubular
dilatation and flattening and mild chronic interstitial inflammatory infiltrates.
99. BENIGN PROSTATIC HYPERPLASIA (”Hypertrophy”)
95
This is a hormonal hyperplasia of the periurethral prostate gland (so-called inner
prostatic gland) accompanied by diffuse or nodular proliferation of smooth muscle fibres
fibrocytes. The external prostatic gland (the source of carcinoma of the prostate) is displaced
toward the periphery and forms so-called surgical capsule. Adenomatous hyperplasia is a
disease of old men. Macroscopically, there is an enlargement of both lateral lobes and
frequently a pseudomiddle lobe is formed.
Under low magnification it is apparent that there is an increased number of glands and
that they vary in diameter. Under higher magnification there are irregularly shaped lumina,
the result of pseudopapillary evolution of the epithelial lining. These cells are cylindrical,
with a basal nucleus and pale cytoplasm. The cell layer still consists of a single layer (the
section must be examined carefully). The stroma contains elongated, eosinophilic muscle
fibres and fibrocytes. Occasionally a prostatic nodule may have a purely leiomyomatous
structure (its hard consistency may mimic a carcinoma clinically). The lumina of the glands
contain an amorphous, eosinophilic material, inflammatory cells, and concentrically layered,
occasionally calcified protein masses (corpora amylacea).
100. MUCINOUS CYSTADENOMA OF THE OVARY
Mucinous cystadenoma is an benign epithelial tumor arising from the surface
epithelium that is characterized by numerous cysts, filled with thick, viscous fluid. It is less
often bilateral. Typical tumors of this type tend to grow to tremendous size, have a
multilocular structure, and the cyst walls are as thin and translucent as tissue paper. The
cysts are filled with soft gelatinous material. These tumors are benign and more often
pedunculated than the papillary serous cystadenomas and often are removed more succesfully
at operation. However, they may be bilateral or become implanted in the peritoneal surfaces
and slow reccurence may take place, but malignant change is rare.
Microscopically, a single layer of tall columnar epithelium lines the cysts. This typical
”picket – fence” epithelium, with clear, tall cytoplasm and basally placed nuclei, and the
multilocular character of the cyst, and the mucoid fluid contents are diagnostic features of
mucinous cystadenomas of the ovary. The gross specimen shows the multilocular character of
the tumor on its uncut surface. The tense bulging lobules of the tumor, which are filled with
mucinous fluid, are emphasized. The cut surface of the tumor shows the multilocular
character of the cystic growth, the cystic cavities being lined by mucoid secreting tissue. The
epithelium does not invade the wall and the serosa is intact.
101. SEROUS CYSTADENOCARCINOMA OF THE OVARY
Serous cystadenocarcinoma is the most common malignant ovarian tumor arising from
the surface epithelium, accounting for a third of all cancers of the ovary. In half of the
pacients, the tumors are bilateral. Since tumors of advanced stage are bilateral more than
twice as often as tumors of low stage, it is thought that in many cases the cancer spreads to
the other ovary by implantation. On gross examination, serous cystadenocarcinomas usually
present as multiloculated tumors, with soft, delicate papillae lining the entire surface. Solid
areas, often with areas of necrosis and haemorrhage, are commonly present.
Microscopically, serous cystadenocarcinomas vary from well differentiated to poorly
differentiated tumors. In the latter, the papillary pattern may be inconspicious, with most areas
being composed of solid sheets of malignant cells. Stromal and capsular invasion by the
tumor cells is evident. Laminated calcified concretions, referred to as psammoma bodies, are
present in one third of the cases.
102. ECTROPION OF THE CERVIX
This is an eversion of the cervical mucosa at the cervical orifice. The cervical mucosa is
very sensitive to mechanical and chemical stimuli, and its cylindrical epithelium is replaced
gradually by squamous epithelium. This replacement may start from the periphery (ascending
overgrowth) or may develop locally in the form of squamous metaplasia.
A fully developed squamous overgrowth of pseudoerosion shows a multilayered,
noncornified, squamous epithelium on the surface, covering the cervical glands. This
interferes with the flow of secretions from the glands and retention cysts develop (Nabothian
cysts).
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103. CYSTIC
GLANDULAR
HYPERPLASIA
OF
THE
ENDOMETRIUM
Cystic hyperplasia is the result of hormonal imbalance, namely the increase and
prolongation of estrogen production. The most common cause of such hyperestrogenism is the
persistence of Graafian follicle of the ovary. This is seen frequently in premenopausal women
over 40 years of age. In younger women similar changes can be seen in the first few periods
after a precending pregnancy (so-called adaptation hyperplasia). In older menopausal
women a hormone-producing ovarian tumor may be present. This is an estrogen-induced
hyperplasia of the stroma and glands. The diagnosis is usually made from curetted material
that consists of large fragments of tissue embedded in blood. Even the naked eye will reveal
that there is abundant material and that some of the pieces are quite large.
Under higherf magnification, it is apparent that the endometrium is in the proliferative
stage and that the stroma is tightly packed with cells. The dominant feature of the field is
cystic dilatation of the endometrial glands. These consist of a single layer of cylindrical
epithelium. In addition to the intact epithelium, there are also smaller pieces of aglandular
stroma and separated glands and epithelial cells. These findings correspond to menstrual
material. It is of diagnostic significance if small, eosinophilic, homogenous, or very finely
granular fibrin thrombi are found, since these represent morphologic evidence for a perfusion.
104. CARCINOMA OF THE UTERINE CERVIX
After several decades as the most common gynecologic cancer, cervical carcinoma is
now in most Western countries encountered less often than endometrial carcinoma. Invasive
cervical carcinoma manifests in three somewhat distinctive patterns: fungating (or
exophytic), ulcerating, and infiltrative cancer. The most common variant is the fungating
tumor, which produces an obviously neoplastic mass that projects above the surrounding
mucosa. Advanced cervical carcinoma extends by direct continuity to involve every
contiguous structure, including the peritoneum, urinary bladder, ureters, rectum, and vagina.
Distant metastasis occurs to the liver, lungs, bone marrow, and other structures.
Histologically, 65% of tumors are large cell, nonkeratinizing, and moderately to well
differentiated, 25% are large cell, keratinizing, producing keratohyalin, epithelial pearls, and
pickle cells, and the rest are composed of small undifferentiated squamous cells.
105. CARCINOMA OF THE ENDOMETRIUM
Endometrial carcinoma is common invasive cancer of the female genital tract and
accounts for 7% of all invasive cancer in women (excluding skin cancer). At one time, it was
far less common than cancer of the cervix, but earlier detection and eradication of in situ
cervical cancer and an increase in endometrial carcinomas in younger age groups have
reserved this ratio. Carcinoma of the endometrium is uncommon in women under age 40. The
peak incidence is in the 55 to 65 year old women.
Histologically, most endometrial carcinomas are adenocarcinomas characterized by
more or less well-defined patterns lined by malignant stratified columnar epithelial cells.
They may be well differentiated (grade 1), having a prominent, easily recognizable glandular
pattern, moderately differentiated (grade 2), showing well-formed glands mixed with solid
sheets of malignant cells, or poorly differentiated (grade 3), characterized by solid sheets of
cells with barely recognizable glands and a great degree of nuclear atypia and mitotic activity.
Most endometrial adenocarcinomas are well differentiated and composed of festoons and
ribbons of collumnar epithelium, forming multiglandular masses. Strands of epithelium that
lacks stroma support typically bridge the gland spaces. Nuclei are large and have irregular
outlines, clumped chromatine, and prominent nucleoli.
106. SPONTANEOUS ABORTION
The spontaneous abortion applies to a pregnancy that terminates before the fetus is
capable of extrauterine life, which is about the 22nd week of gestation. The principal factors
responsible for abortion are maternal, and fetal, and include the following: infection early in
pregnancy, mechanical factors (e.g. submucous uterine leiomyoma or cervical incompetence),
endocrine factors (e.g. inadequate progesterone production), immunologic factors, and fetal
congenital and chromosomal abnormalities.
Histologically, the aborted material shows secretory endometrium with decidual
reaction of the stroma and placental villi. Frequently, there is also marked infiltration of
99
polymorphonuclear leukocytes which are a response to disintegration and separation of the
endometrium. In the endometrium, there are corkscrew shaped glands having irregular lumen.
The gland epithelium has a pale cytoplasm and the nuclei are at the base. Decidual cells are
large stromal cells having distinct borders, abundant clear (glycogen-containing) cytoplasm,
and a round centrally placed nucleus. The presence of placental villi is histologic evidence of
abortion. The villi are composed of a delicate, cell-poor stroma containing capillaries. The
surface of the placental villi consists of an inner layer of cuboidal cells (cytotrophoblast –
Langhans’ cells) and an outer layer of large multinucleated giant cells without definable
borders (syncytiotrophoblast).
107. HYDATIDIFORM MOLE
Hydatidiform mole is characterized by grossly swollen chorionic villi, resembling
bunches of grapes, accompanied by variable trophoblastic proliferation. It is the most
common precursor of choriocarcinoma. Two types of noninvasive moles can be differentiated:
complete and partial. In contrast to complete moles, partial moles are rarely followed by
choriocarcinoma. The uterus is usually larger than anticipated for the duration of pregnancy.
The uterine cavity is filled with a friable mass of thin-walled, translucent, cystic, grape-like
structures.
Microscopically, the complete mole shows hydropic swelling of chorionic villi which
appear avascular with routine staining. The villi are enlarged and round, and many of them
have cisternae, which are central, acellular fluid-filled spaces devoid of mesenchymal cells.
The trophoblast composed of syncytiotrophoblast, cytotrophoblast and intermediate
trophoblast is diffusely hyperplastic and displays considerable cellular atypia. In partial
moles, dual population of villi is observed, i.e. some of them are enlarged by hydropic
swelling, may show central cavitation and have irregularly scalloped contours, whereas others
show only minor changes. The trophoblastic proliferation is usually more focal and mild than
in complete moles. Typically, blood vessels are found within the chorionic villi and contain
fetal (nucleated) erythrocytes.
108. SUPPURATIVE SALPINGITIS
Salpingitis typically results from ascending infections of the lower genital tract. The
most common causative organisms are N. gonorrhoeae, E. coli as well as streptococci,
staphylococci, Chlamydia and Mycoplasma. Typically, the infection is polymicrobial.
Uncommonly, salpingitis is a primary infection within the fallopian tube or represents a
secondary spread of infection from a nearby perforated viscus, such as the appendix. In acute
salpingitis, the lumen fills with purulent exudate. In the course of days or weeks, the tubal
fimbriae may seal or become plastered against the ovary to create a salpingo-oophoritis and
tubo-ovarian abscess. Pus may collect in these sealed tubes to cause distention (pyosalpinx).
The infection tends to smoulder and becomes chronic for months and even years. The pus may
be transformed to a thin, serous fluid (hydrosalpinx). Other complications of salpingitis are:
peritonitis, fibrous adhesions between the serosa of the tube and surrounding peritoneal
surfaces, infertility and ectopic pregnancy.
Microscopically, the tubal serosa becomes hyperemic and layered with fibrin. The tubal
fimbriae are similarly involved, the lumen fills with purulent exudate and mucosal folds
(plicae) show marked edema, congestion and presence of inflammatory infiltrate of
polymorphonuclear leukocytes. The inflammatory infiltrate in chronic salpingitis is composed
mostly of lymphocytes and plasma cells, and edema and congestion tend to be minimal.
109. TUBAL PREGNANCY WITH ABORTION
Ectopic pregnancy refers to any implantation of the fertilized ovum that develops
outside the endometrium. The most common location is within the fallopian tubes. Tubes
which are fibrosed as a result of chronic inflammation or which are congenitally abnormal
may prevent the passage of the ovum. The retained ovum may undergo fertilization and
implant itself in the wall of the tube to constitute an ectopic (tubal) pregnancy, which may
cause life threatening tubal rupture and intraperitoneal hemorrhage.
The tube is expanded by blood clot (hematosalpinx). The muscle of the tubal wall is
hyperemic and edematous. Mucosal folds may be observed or they may be replaced by welldeveloped decidua. Blood clot in ihe lumen contains chorionic villi composed of a myxoid
core and trophoblast being on the surface. Sheets of trophoblast as well as decidual tissue may
be found lying free in the lumen. Fetal elements may or may not be found among the contents
101
of the tube.
110. FIBROCYSTIC DISEASE (FIBROCYSTIC CHANGES) OF THE
BREAST
Fibrocystic disease of the breast refers to a constellation of morphologic features
characterized by (1) cystic dilatation of terminal ducts, (2) relative increase in fibrous
stroma, and (3) variable proliferation of terminal duct epithelial elements. The cause of
fibrocystic change is unknown. The forms of fibrocystic disease (FD) that do not carry an
increased risk for the development of cancer (termed non-proliferative FD) are far more
prevalent. Some of the florid manifestations appear to be indicators for women at increased
risk for breast cancer. Such lesions are designated proliferative FD. A less common variant is
known as sclerosing adenosis.
Nonproliferative (simple) FD is usually multifocal and often bilateral. The morphologic
hallmarks are an increase in dense fibrous stroma and some degree of cystic dilatation of the
terminal ducts. Cysts are of various sizes. In smaller ones, the epithelium is more cuboidal to
columnar and sometimes multilayered. In larger cysts, it may be flattened or totally atrophic.
Frequently, cysts may be lined by large polygonal cells having an abundant granular,
eosinophilic cytoplasm with small, round, deeply chromatic nuclei (so-called apocrine
metaplasia - cells resemble apocrine sweat gland epithelium). These cells are usually arranged
in single layer but on occasion they form papillary structures. Proliferative FD or epithelial
hyperplasia is the proliferation of epithelial cells which causes an increase in the layers of the
duct-lining epithelium beyond the usual double layer sometimes resulting in a mass
obliterating the lumens. Proliferations may sometimes show architectural and cellular
abnormalities and then they are called the atypical hyperplasia. Sclerosing adenosis is
characterized by proliferation of small ducts and myoepithelial cells (adenosis) and the lesion
is commonly associated with fibrosis (hence the term sclerosing).
111. INVASIVE LOBULAR CARCINOMA OF THE BREAST
Invasive lobular carcinoma probably arises from the terminal ductules of the breast
lobules. It tends to be bilateral and multicentric within the same breast. Grossly, the
presentation of the tumor varies from a discrete firm mass to a more subtle, diffuse, indurated
area according to the amount of fibrosis produced.
Histologically, it consists of strands of infiltrating tumor cells, often in linear
arrangement, only one cell in width (in the form of an "Indian file"), loosely dispersed
throughout the abundant fibrous matrix, or appear individually embedded in this fibrous
tissue. The cells are small and uniform-staining with relatively little pleomorphism.
Irregularly shaped, solid nests and sheets may also occur. The tumor cells are frequently
arranged in concentric rings (target-like pattern) about normal ducts. Identification of
remnants of lobular carcinoma in situ aids in the diagnosis. In invasive carcinomas of breast,
thick bands of eosinophilic material surrounds non-malignant ducts which is composed of
elastin (elastosis).
112. HASHIMOTO´S THYROIDITIS
Hashimoto´s thyroiditis (HT) also termed lymphocytic (lymphadenoid) goiter or struma
lymphomatosa is an autoimmune disease characterized by the presence of circulating
antibodies to thyroid antigens. The basic defect is thought to be a genetically (certain HLA
antigens are commonly found in affected individuals) conditional deficiency in the function of
thyroid-specific supressor T cells. As a consequence there is uncontrolled attack on the
follicular cells by cytotoxic T cells, and simultaneously, the cooperation of helper T cells with
B cells in the thyroid to produce a constellation of autoantibodies. Grossly, the thyroid in
classic goitrous form is characterized by diffuse, moderate enlargement and appears firm,
fleshy and pale. Little or no glandular enlargement is seen in less common atrophic variant
and in some instances, the fibrosis produces a reduction in thyroid size.
Histologically in the goitrous form, the gland is densely infiltrated by lymphocytes and
plasma cells, with lymphoid follicle formation with germinal centers. Many thyroid follicles
disappear. Those remaining are irregular in size and shape, some consisting only of clusters of
epithelial cells. Others are lined by cells which show a characteristic change: they enlarge and
develop eosinophilic granular cytoplasm due to proliferation of mitochondria (Hürthle cells,
oncocytes or Askanazy cells). Very little colloid is present. Atrophic variant reveals much
more abundant fibrosis with a commensurate decrease in the lymphoid infiltrate.
103
113. COLLOID GOITER OF THE THYROID
The term goiter denotes an enlargement of the thyroid in excess of the normal weight
for adults of 25 - 50 g. Hyperplastic changes, which are associated neither with functional
alterations nor with producing nodularity, are known as the diffuse nontoxic (simple) goiter
and include parenchymatous and colloid goiter. Simple goiter occurs in both endemic and
sporadic distribution. Nearly all long-standing simple goiters become transformed into
multinodular goiters. They may be nontoxic or may induce thyrotoxicosis. Grossly, the gland
tends to be soft, glistening, and yellow. Necrotic, fibrotic, hemorrhagic and cystic areas are
common. Calcific foci, which impart a gritty surface, are frequent.
Microscopically, there are follicles seen in the thyroid, which are of various sizes and
accumulate large amount of colloid observed as eosinophilic substance within the follicles.
They may coalesce to form colloid-filled cysts. The epithelial cells lining the follicles are flat
and so-called resorption vacuoles can be seen near the surface of the epithelial cells. There
may be also seen the areas of hemorrhage, fibrosis and dystrophic calcification.
114. PITUITARY ADENOMA
Pituitary adenomas are benign neoplasms of the anterior lobe of the pituitary gland.
They may be derived from any of the hormone-secreting cells and thus may be clinically
manifested by virtue of single hormone overproduction, destruction of surrounding normal
pituitary and consequent hypofunction, and mechanical effect due to intracranial pressure
rise and specific location (pressure effect on the overlying optic chiasma). Pituitary
adenomas were subdivided according to the tinctorial properties of their cells. Thus, they
were classified as acidophil, basophil or chromophobe adenomas. Pituitary adenomas are
today classified according to the hormone(s) elaborated by the neoplastic cells, and this can
be demonstrated by immunohistochemical methods, or by EM.
Microscopically, all adenomas have a fairly uniform appearance. The more or less
uniform polygonal cells are arranged in sheets, cords, or nests, having only a delicate,
vascularized stroma. Sometimes, pseudoglandular or papillary formations are present. Small
or large foci of ischemic necrosis may be present, and psammoma bodies may be found,
accompanied by hemorrhage. Some adenomas, usually those that grow more rapidly, have
some variation in cell and nuclear size and shape. The cytoplasm may be eosinophilic or
basophilic due to presence of granules of various natures. Cells of chromophobe adenoma
mostly do not contain visible granules. Basophil adenoma stains darkly and reacts strongly
with the PAS stain. A distinctive alteration, referred to as Crooke´s hyaline change, may be
seen in the cells.
115. PARATHYROID ADENOMA
Parathyroid adenoma accounts for more than a half of all cases of primary
hyperparathyroidism. The tumor is a circumscribed, reddish-brown, solitary mass, measuring
1 to 3 cm in diameter. Appearance of cut surface is uniform, and cystic changes are
occasionally noted.
On microscopic examination, parathyroid adenoma is composed of sheets of neoplastic
cells embedded in a rich capillary network. For the most part, the cells resemble normal chief
cells, but some water-clear and occasional oxyphilic foci may be present. In some instances,
bizarre, multinucleated cells and other atypical nuclear and cytoplasmic features are noted. On
occasion, the neoplastic cells are arranged in pseudorosettes around blood vessels or as
follicles containing eosinophilic, colloid-like material. A rim of normal parathyroid tissue
should be evident outside the capsule and serves to distinguish an adenoma from parathyroid
hyperplasia.
116. FIBROUS CORTICAL DEFECT (Nonossifying fibroma of the bone)
Fibrous cortical defects are extremely common non-neoplastic developmental defects
being found in 30 to 50 % of all children older than two years. They occur in the metaphyses
of long bones, most frequently the tibia or femur. They create irregular, sharply demarcated,
lobular, radiolucent defects in the metaphyseal cortex with an intact shell of overlying bone.
The margins of these lesions are sometimes slightly sclerotic. They are generally
105
asymptomatic, but larger ones may cause pain and predispose to fracture. They often
disappear spontaneously within a few years. On gross examination, the lesion is granular and
dark red to brown.
Microscopically, almost uniform spindle cells (fibroblasts, which sometimes form
palisades) are arranged in an interlacing, whorled pattern, in which multinuclear giant cells
and foamy macrophages may be seen. There is no evidence of bone formation. The color of
the lesion is caused by hemosiderin, which is present in macrophages.
117. PYOGENIC OSTEOMYELITIS
Pyogenic osteomyelitis almost always is caused by bacteria, rarely by fungi. The
organisms may reach the bone (1) through the bloodstream (in most cases), or (2) locally by
direct extension of a contiguous infection and by direct traumatic (including surgical)
introduction. Almost any pathogen may be responsible, but most often implicated is
Staphylococcus aureus and less frequently E. coli, Pseudomonas, Klebsiella or other pyogens.
In hematogenous osteomyelitis, the reactions usually begin in the metaphyseal marrow. Pus
may spread in the medullary cavity and beneath the periosteum. Considerable necrosis of
bone is liable to occur in osteomyelitis, often through damage to the blood supply.
Histologically, the medullary cavity is full of pus and the collections of
polymorphonuclear leukocytes replace the original marrow. The trabeculae of spongiosa are
necrotic and the bony lamellae are in the process of disappearing. The lacunae are empty,
without osteocytes. Necrotic bone tissue may form a sequestrum. Sometimes the bacterial
colonies as finely granular basophil material may be seen in the exudate. Over time, the host
response evolves including osteclastic bone resorption, ingrowth of fibrous tissue and
deposition of reactive bone in the periphery.
118. OSTEOSARCOMA
Osteosarcoma is a highly malignant mesenchymal tumor characterized by the formation
of neoplastic bone tissue, i.e. osteoid or bone. Osteosarcoma is most frequent in adolescents
between the ages of 10 and 20 years and often arises in the vicinity of the knee, although any
area of a long bone may be affected. The gross appearance of the tumor is highly variable,
depending on the relative amounts of bone, cartilage, stroma and blood vessels. The tumor
invades the medullary cavity and expands the periosteum, sometimes breaking through it. The
cut surface may show any combination of hemorrhagic, cystic, soft, and bony hard areas. It
metastasizes readily by the bloodstream to the lungs and the prognosis is poor.
Histologic examination reveals malignant pleomorphic osteoblasts varying considearbly
in size and shape and frequently having large hyperchromatic nuclei. Bizarre tumor giant cells
are common, as are mitoses, which are often atypical. The most characteristic feature of
osteosarcoma is formation of osteoid and bone. It has a coarse lace-like architecture but is
also deposited in broad sheets or as primitive trabeculae. Neoplastic tissue contains many
vessels and vascular invasion is usually conspicuous. Malignant cartilage and fibrous tissue
may be present in varying amounts. Neoplastic osteoid and bone predominate in welldifferentiated osteosarcoma which is relatively hypocellular. In the teleangiectatic variant, the
majority of the tumor is composed of blood-filled cysts, and the tumor cells reside in the cyst
walls.
119. DENERVATION ATROPHY OF SKELETAL MUSCLE
The pathology of denervation reflects lesions of the lower motor neuron. Denervation
atrophy results from damage to the muscle innervation. This can occur as a consequence of
lesions affecting motor neurons, nerve roots or peripheral nerves. When a skeletal muscle
fiber becomes separated from contact with its lower motor neuron, it invariably atrophies.
The pattern of denervation does not identify the cause of the lesion.
On cross section, the atrophic fibers have a characteristic angular configuration being
compressed by surrounding normal muscle fibers. Intact fibers and denervated ones may lie
side by side. Some loose connective tissue may be between them and there may be an
infiltrate of fat associated with the denervated fibers, which are atrophic and narrow. As the
disease progresses, these fibers are seen in groups, at first in small clusters of several fibers,
and later in larger groups or the whole fasciculi. Sarcolemmal nuclei appear to have increased
number because of the shrinkage of the fibers. If the fiber is not reinnervated, the atrophy
proceeds to complete loss of myofibriles and myofilaments, and the nuclei condense into
aggregates.
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120. NONSUPPURATIVE MYOSITIS
There is a variety of inflammatory diseases involving muscle, including infectious
myositis, noninfectious inflammatory muscle disease (inflammatory myopathies), and
inflammatory processes associated with diffuse systemic inflammatory diseases. Three major
inflammatory myopathies (they are thought to have an autoimmune origin) are recognized,
namely polymyositis, dermatomyositis and inclusion body myositis. At the onset, the muscles
are normal in gross appearance, possibly slightly enlarged owing to diffuse edema. With
advance of the disease, they become atrophic and yellowish-grey as the muscle fibers are
replaced by fibrous tissue and fat.
Histologically, the most prominent characteristics are the presence of inflammatory
mononuclear cells around small blood vessels, in the perimysial conective tissue or in the
endomysium; degeneration manifested by granular change, vacuolar degeneration, increased
eosinophilia, fragmentation and simple necrosis of the muscle fibers sometimes accompanied
by phagocytosis and ”ghost fiber” (unstained muscle fiber) formation; a mixture of atrophic
and regenerating fibers producing large vesicular sarcolemmal nuclei increased in number and
accompanied by sarcoplasmic basophilia; and fibrosis.
121. SUBACUTE SCLEROSING PANENCEPHALITIS
Subacute sclerosing panencephalitis (SSPE) is a viral infection of the brain caused by
measles virus and generally occurs in children but can be seen in adolescents and young
adults. It has always been preceded by an attack of measles in the distant past, often usually
early in life, or, occasionally, by previous immunization against measles. SSPE usually starts
with personality and behavior changes, followed by the development of involuntary
movements and sensory deficits, and ultimately causes stupor and death, all over a period of
several years.
In tissue sections, the inflammation is highlighted by the presence of prominent
intranuclear eosinophilic or amphophilic inclusions within neurons, oligodendroglia and
astrocytes; ubiqitous perivascular cuffs of lymphocytes, plasma cells and few macrophages;
patchy loss of myelin; extensive neuronal loss and neuronophagia and there is marked
fibrillary astrogliosis in damaged areas in both the grey and white matter (accounting for the
term sclerosing).
122. HEALED INTRACEREBRAL HEMORRHAGE
The most important predisposing factor for intracerebral hemorrhage is arterial
hypertension.
Other
associated
conditions
include
intracerebral
arteriovenous
malformations, tumor, hemorrhagic diathesis, and amyloid angiopathy. The hematoma acts
as a space-occupying lesion causing a rapid increase in intracranial pressure and herniation.
In survivors, resorption of the hematoma eventually occurs, and over period of months a
fluid-filled cavity with a gliotic wall is formed. The wall remains brown-pigmented for years
and thus, suggests the origin of the cavity.
Microscopically, resolution of a hemorrhage begins with appearance of macrophages
that digest the blood clot. The erythrocytes and hemoglobin are taken up by phagocytes and
broken down to hemosiderin and hematoidin. The phagocytes can be seen as granular fatty
cells like those in the brain white infarction but most of macrophages are called pigmented
granular cells, since cytoplasm contains brown hemosiderin granules. Eventually, a slit-like
pseudocyst (a cavity without the epithelium lining the wall) surrounded by a zone of fibrillary
astrocytosis containing scattered hemosiderin-laden macrophages and extracellular deposits of
yellow-brownish pigment (hematoidin).
123. OLIGODENDROGLIOMA
The oligodendroglioma is derived from oligodendrocytes. It is most common in middle
life and arises mostly in the cerebral hemispheres, with a predilection for white matter.
Grossly, oligodendrogliomas are well-circumscribed grey masses, often with cysts, focal
hemorrhage and calcification.
Microscopically, the structure is characteristic. The tumor is highly cellular and is
composed of sheets of regular cells. They have small round nuclei surrounded by a clear halo
of cytoplasm bounded by a well-defined cell membrane. Typically, a delicate network of
capillaries separates the tumor cells into clusters. The calcification, which is present in up to
90% of these tumors, ranges from microscopic foci to massive depositions. The slow growth
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is reflected in an absence of mitotic figures and necrosis.
124. MENINGIOMA
Meningiomas arise from meningothelial cell of the arachnoid. They may be found along
any of the external surfaces of the brain as well as within the ventricular system, where they
arise from the stromal arachnoid cells of the choroid plexus. The most frequent sites are the
parasagittal region, convexities of the cerebral hemispheres, the olfactory groove, and the
lateral wing of the sphenoid. Grossly, meningiomas are usually irregular, well-circumscribed
bosselated masses firmly adherent to the dura that indent the surface of the brain but rarely
invade it. The cut surface presents a gray, whorled pattern.
Histologically, several patterns have been recognized. The histologic hallmark of
syncytial type is the whorled clusters of cells which sit in tight groups without visible cell
membranes. Fibroblastic meningiomas have spindle-shaped bipolar cells that resemble
fibroblasts arranged in bands and swaths. Transitional types share features of the syncytial
and fibroblastic types. Psammomatous type has a dominant pattern of psammoma bodies,
which result from hyalinization and calcification of the syncytial whorl centers. PAS-positive
intracytoplasmic droplets and intracellular lumina by electron microscopy are seen in
secretory type. Microcystic type has a loose, spongy appearance. Some meningiomas are
dominated by blood vessels (angioblastic meningiomas), others have a papillary appearance
(papillary meningiomas). The latter variant is composed of pleomorphic cells arranged around
fibrovascular cores and is associated with a worse prognosis. In addition, various forms of
degeneration can be seen in meningiomas, including xanthomatous and myxomatous
degeneration and bone and, rarely, cartilage formation.
125. PILOCYTIC ASTROCYTOMA
Astrocytoma is tumor of glial origin composed of astrocytes. Pilocytic astrocytomas are
distinguished from other astrocytomas by their distinctive pathologic appearance and almost
invariably benign behavior. They typically occur in children and young adults and usually are
located in the cerebellum, but may also appear in the floor and walls of the third ventricle,
the optic nerves and, occasionally, the cerebral hemispheres. Grossly, pilocytic astrocytoma
is often cystic, with the tumor confined to a mural nodule in the wall of the cyst, but if solid, it
may be well circumscribed or, less frequently, infiltrative.
Microscopically, the tumor is only moderately hypercellular and is composed of
pilocytic astrocytes, which are bipolar cells with long, thin ”hair-like” processes. Rosenthal
fibers (eosinophilic, opaque, elongated, tapering or globular bodies that form in astrocyte
processes) and microcysts are often present. Vascular endothelial proliferation is also
common, but in this tumor, unlike in the other astrocytomas, it does not imply an unfavorable
prognosis. Necrosis and mitoses are almost never present.
126. GLIOBLASTOMA MULTIFORME
Glioblastoma multiforme is a highly malignant tumor of glial origin, which shows the
extreme expression of anaplasia among the glial neoplasms. This tumor is the most common
glial neoplasm. It is distinguished from the other types of glial tumors by its variegated
appearance, hence the term multiforme. Glioblastoma multiforme occurs mostly in white
matter of cerebral hemispheres and typically infiltrates extensively, frequently crossing the
corpus callosum and producing a bilateral lesion likened to a butterfly in its gross
configuration. Some regions may be white and firm, others yellow and soft and foci of
necrosis, cysts and recent or remote hemorrhage are common.
The cardinal histologic features of glioblastoma multiforme are as follows: marked
cellularity, with variable degrees of cellular pleomorphism and multinucleated cells;
serpentine areas of necrosis, which may or may not have pseudopalisading (zones of crowded
tumor cells) around it; and proliferation of endothelial cells, which may form tufts bulging
into the vascular lumen, referred to as ”glomeruloid” formations.
127. BENIGN FIBROUS HISTIOCYTOMA OF THE SKIN
Benign fibrous histiocytoma (also known as subepidermal nodular fibrosis,
dermatofibroma, histiocytoma, and sclerosing hemangioma) refers to a spectrum of firm,
nodular, nonencapsulated, often pigmented lesions that occur chiefly on the extremities.
Clinically, they may be single or multiple and have a flat polypoid or depressed shape. Most
of them are less than 1 cm in diameter, but some can reach huge proportions. When heavily
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pigmented, they may be confused clinically with nevi, malignant melanoma, Kaposi’s
sarcoma, and other vascular tumors. On transection, they are usually solid and rather well
circumscribed but not encapsulated, the color ranging from white to yellow to dark brown,
depending on the relative amounts of fibrous tissue, fat, and hemosiderin. The behavior of this
lesion is benign; local recurrence is rare even if the excision contains little normal tissue
around the lesion.
Microscopically, the papillary and reticular dermis are replaced by fibrous tissue with a
distinctive pattern. There is a cellular fibroblastic proliferation with varying amounts of
collagen deposition, admixed with a variable number of macrophages, most of which contain
fat (thereby acquiring a foamy appearance) or hemosiderin. Some of these histiocytes are
multinucleated and may acquire the features of Touton’s giant cells. The fibrohistiocytic
proliferation is set in a fine vascular network, which can be very prominent (this vascular
component is responsible for this lesion having been regarded in the past as a sclerosing
hemangioma). Focal storiform features may be seen: the fibroblasts tend to form ill-defined
small cartwheel patterns with a small vascular space at the center and thus the curved bundles
of cells and tissue produce a basket-weave pattern. The lesion is characteristically centered in
the upper dermis, but it can involve the deep dermis and occasionally extend into the subcutis.
The tumors are not sharply circumscribed or encapsulated and blend imperceptibly into the
adjacent dermis. The overlying epidermis can be normal, atrophic, or hyperplastic with
elongation of hyperpigmented rete ridges.
128. ECZEMATOUS DERMATITIS (Eczema)
Eczema is a clinical term that embraces a number of pathologically different conditions.
All are characterized by red, papulovesicular, oozing and crusted lesions early on that with
persistence eventuate into raised, scaling plaques. If untreated, the lesions will tend to
become chronic. There are many causes of eczema and histological features tend to be the
same irrespective of the cause.
Histologically, the main features are edema within the epidermis (spongiosis), with
separation and disintegration of clumps of epithelial cells to form vesicles. The dermal
papillae are swollen and edematous and their blood vessels are dilated. There is an infiltrate of
small lymphocytes in both the dermis end epidermis. Mast cells may be found in the
inflammatory infiltrate, which, depending on the cause, may be rich in eosinophils. With time
(days to weeks), the acute vesicular phase of spongiotic dermatitis may subside, giving rise to
progressive epidermal hyperplasia (stratum spinosum thickens – a condition known as
acanthosis) with hyper- and parakeratosis.
129. CONDYLOMA ACUMINATUM
Condylomata acuminata are circumscribed, exophytic, cauliflower-like, fibroepithelial
benign lesions that chiefly occur in the perianal and periurethral regions, or on the penis or
external female genitalia. They are associated with sexually transmitted infection by HPV
type 6 and less commonly type 11. They consist of single or multiple sessile or pedunculated,
red papillary excrescenses that vary from 1 to several milimeters in diameter.
Histologically, a branching, villous, papillary connective tissue stroma is covered by
squamous epithelium of variable thickness and exhibits conspicuous acanthosis,
hyperkeratosis and parakeratosis. Characteristic finding of koilocyte (an epithelial prickle cell
with a perinuclear clear halo of cytoplasm and a wrinkled nucleus) is interpreted as evidence
of HPV infection. The basal stroma is inflamed and vascular. Importantly, no significant cell
atypism is present and the lesion is not a precursor of squamous cell carcinoma.
130. LUPUS ERYTHEMATOSUS OF THE SKIN
Lupus erythematosus (LE) is an autoimmune disease affecting connective tissue. In
many cases of LE the skin is the only organ involved and the disease is then called discoid
LE. The systemic variant may or may not involve the skin but in any case is called systemic
LE. The skin lesions are erythematous, scaly and indurated in the acute forms and slowly
progress to atrophic scarred patches, often with hyperpigmented edges in the older lesions.
They are often symmetrical on the face in a butterfly distribution over the nose and cheeks,
and on the scalp may be associated with scarring alopecia. The scales can often be picked off
and are shaped like tin-tacs.
Histologically, the epidermis is thin, with a very atrophic stratum spinosum. There is
hyperkeratosis, which extends down into the hair follicles, with the formation of follicular
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plugs (tin-tacks). The basal layer of epidermis shows liquefaction degeneration. The dermis is
edematous and hyaline, and there are deposits of eosinophilic fibrin in it. Beneath the
damaged dermis there is a very intense infiltrate of chronic inflammatory cells, predominantly
lymphocytes. The infiltrate is concentrated around dilated blood vessels and hair follicles. The
infiltrate also involves the dermo-epidermal interface and damages the melanocytes. The
melanocytes lose their melanin to dermal macrophages in which the melanin accumulates,
accounting for the hyperpigmentation in older lesions.
131. SCLERODERMA (Progressive systemic sclerosis)
Scleroderma, or the more contemporary term progressive systemic sclerosis (PSS), is
an autoimmune disease of connective tissue characterized by excessive collagen deposition in
the skin and internal organs. Scleroderma which is manifested by thickening of the dermis,
begins on the fingers, later it involves the face and eventually, the skin over large parts of the
body is thickened and stiff. The taut skin restricts movements.
Histologically, there is distinct thinning of the epidermis along with the loss of rete
pegs. The underlying dermis is poorly cellular and contains bundles of numerous thick and
hyalinized collagen fibers. A patchy lymphocytic infiltrate with a few plasma cells is
common. Sweat glands may be entrapped in the thickened fibrous tissue, and hair follicles are
completely lost.
132. SQUAMOUS CELL CARCINOMA OF THE SKIN
Squamous cell carcinoma (SCC) arises from the stratified squamous epithelium of skin,
mucous membrane and also from areas of squamous metaplasia in other types of epithelium.
SCC of the skin is very common and is etiologically related to chronic sunlight exposure or to
chemical carcinogens. SCC may form roughened keratotic areas, ulcers or horns. Although
they show obvious invasion, their behavior is usually fairly indolent and metastasis, when it
occurs, is a late and relatively uncommon complication.
Histologically, squamous cell carcinomas are composed of disorganized keratinocytes
which appear to echo the behavior of the normal upper layers of the epidermis but in a
disordered and malignant fashion. Neoplasms exhibit variable differentiation, ranging from
tumors formed by polygonal squamous cells with pink, plate-like cytoplasm and intercellular
bridges comprising desmosomes, and large zones of keratinization seen as ”epithelial pearls”
to neoplasms formed by highly anaplastic, rounded cells with foci of necrosis and only
abortive, single-cell (monocellular) keratinization (dyskeratosis). The stroma is infiltrated
with lymphocytes and plasma cells.
133. HIDRADENOMA
Hidradenoma is a benign neoplasm of the sweat glands. Papillary hidradenoma arises
from the apocrine sweat glands and it appears chiefly in the labia majora of the vulva as a
sharply circumscribed nodule, rarely larger than l cm.
The tumor is demarcated from the adjoining tissues by a capsule of compressed dermal
connective tissue. Within the tumor, one observes tubular and cystic structures. Papillary
folds having a well-formed fibrous stroma project into the cystic spaces. The lumina are lined
occasionaly with only a single row of columnar cells, which show an oval, pale-staining
nucleus located near the base, a faintly eosinophilic cytoplasm, and active decapitation
secretion as seen in the secretory cells of apocrine glands. Usually, however, the lumina are
surrounded by a double layer of cells consisting of a luminal layer of secretory cells and of an
outer layer of small cuboidal cells with deeply basophilic nuclei. These are myoepithelial
cells.
134. NEUROFIBROMA OF THE SKIN
Neurofibromas are benign tumors of peripheral nerves derived from Schwann cells.
They may be solitary or multiple and may arise on any nerve. The presence of multiple
neurofibromas is diagnostic of neurofibromatosis (type 1 of it is known as von
Recklinghausen´s disease). Cutaneous neurofibromas present as soft, nodular or
pedunculated skin tumors. The cut surface is soft and light gray.
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Histologically, the lesion is generally well-circumscribed and usually unencapsulated. It
consists of spindle cells with elongated slender nuclei, eosinophilic cytoplasm, and indistinct
cell borders. The spindle cells often aggregate to form tiny strands coursing haphazardly
through the tumor. Interspersed among the spindle cells are wavy bands of collagen, an
extracellular loose myxoid matrix, and residual nerve fibers (but they require special stains for
their demonstration).
135. CHORIOAMNIONITIS
Chorioamnionitis refers to inflammation of the placental amnion and chorion and the
extraplacental membranes. It is usually the result of an ascending infection from the maternal
birth canal, most commonly owing to premature rupture of the membranes. The amniotic fluid
is usually cloudy and contains purulent exudate. The membrane walls are slightly opaque,
edematous, and friable. With more extensive spread the umbilical cord may become infected
(funisitis) and exhibit acute vasculitis of one or more umbilical vessels or inflammation of the
cord mesenchyma (Wharton’s jelly).
Polymorphonuclear leukocyte infiltration is seen initially in the extraplacental
membranes related to the cervical os. Neutrophils permeate the trophoblastic layers (stage 1).
The next more advanced stage is where neutrophils have infiltrated into spongy layer of the
amnion (stage 2). In stage 3, all layers of the amnion are involved, but the epithelium is
preserved, and in in stage 4, necrotizing inflammation has destroyed the amnion. The
chorioamnion of the placenta shows edema and congestion of the vessels. The inflammatory
infiltrate involves the adjacent intervillous spaces as well where the polymorphonuclear
leukocytes become enmeshed in fibrin. Spread of inflammation into the vessels and
Wharton’s jelly of the umbilical cord (funisitis) is seen in the established cases.
136. AMNIOTIC FLUID ASPIRATION IN THE LUNG
Fetal lung secretes a liquid that occupies the terminal air spaces and airways and
whose composition and viscosity are different from those of the plasma and amniotic fluid.
Normal breathing movements in utero are insufficient to clear the tracheal dead space, and
therefore the tidal volume is very small. It is under various adverse conditions, that relatively
large volumes of amniotic fluid may be inspired by the fetus. Aspiration of amniotic fluid
occurs during premature respiration when intrauterine stress cause the infant to make a deep
respiratory movement, and concomitantly, to pass meconium into the amniotic fluid.
Aspiration may result in death or the meconium aspiration syndrome of the newborn.
Microscopically, the air passages contain desquamated squamous epithelial cells
(usually without nuclei) and lanugo hair from the fetal skin and eosinophilic protein-rich
amniotic fluid. Squamous cells can be observed as large, flat squames or, they appear
elongated, spindle-shaped strips, when cross-sectioned. Lanugo hair is seen as pale, cylinderlike structures. Typical finding is the presence of small round golden-brown (due to presence
of bilirubin) bodies known as meconium bodies (probably desquamated colonic cells of the
fetus).
137. HYALINE MEMBRANE DISEASE IN NEWBORN (Respiratory
distress syndrome)
Idiopathic respiratory distress syndrome (IRDS) also known as hyaline membrane
disease is particularly liable to affect premature infants. 24 - 72 hours after birth, the child
develops dyspnea and cyanosis. The cause is a deficiency of surfactant secretion by the type II
pneumocytes. The child´s respiratory movements then fail to keep the alveoli fully expanded,
with subsequent exudation of plasma protein (due to capillary damage) into the air spaces.
The lungs are heavy, purple and solid, and sink in water.
Histology shows alternating atelectasis and dilatation of the alveoli. Within expanded
air spaces, proteinaceous edema fluid, and erythrocytes are evident. The alveoli, alveolar
ducts or bronchioli are lined by conspicuous band of amorphous eosinophilic hyaline material
consisting of polysaccharides, proteins and lipids. These substances come from necrotic
alveolar cells and plasma proteins particularly fibrin. The walls of the collapsed alveoli are
thick, the capillaries are congested, and lymphatics are filled with proteinaceous material.
138. PERINATAL PNEUMONIA
Perinatal pneumonia also called intrauterine or congenital pneumonia is ussually
referred to as pneumonia occuring within 48 hours of birth. Most intrauterine pneumonia is
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the result of infection ascending from the birth canal into the amniotic sac. It is associated
with premature rupture of the membranes and aspiration of infected amniotic fluid in utero.
Perinatal pneumonia may be caused by infection acquired during passage through the birth
canal (intrapartal infection) as well. Intrauterine pneumonia has been also observed in
prolonged labor with intact membranes and in the remaining cases, infection is
transplacental.
Histologically, the pneumonia is usually diffuse and distal airways are filled with a
polymorphonuclear inflammatory exudate, which may or may not contain squames as a result
of amniotic fluid aspiration. The most striking feature is the absence of fibrin. The alveolar
septa, bronchioles, and bronchi may be involved as well. Bacteria are not usually observed in
sections, and if present, are few.
139. PNEUMOCYSTIS PNEUMONIA
Pneumocystis pneumonia is a pulmonary infection with a protozoan organism called
Pneumocystis jiroveci (carinii). It is an example of opportunistic infection (caused by an
organism which is not pathogenic in the normal individual, but cause the infection in a
pacient with immunodeficiency). It occurs in prematurely born and malnourished infants in
the 2nd to 6th months of life, in adults with malignant disease, particularly after treatment
with cytotoxic agents, after transplantation and immunosuppresion and it is one of the most
frequent causes of death in patients with AIDS. Inflammation causes a diffuse or patchy
pneumonia and grossly, organ appears airless, red-violet, and beefy.
Microscopically, the lesion comprises the thickened interstitium of interalveolar septa
containing inflammatory infiltrate of lymphocytes, macrophages, and mainly plasma cells,
diffuse alveolar damage and hyperplasia of type II pneumocytes. The alveolar spaces are
filled with a characteristic eosinophilic or amphophilic, foamy, amorphous material,
composed of proliferating parasites and cell debris. The organisms appear as small ”bubbles”
in a background of proteinaceous exudate.
140. CYSTIC FIBROSIS OF THE PANCREAS (Mucoviscidosis)
Cystic fibrosis is an autosomal recessive disorder occuring in children, which is
characterized by defect in the secretory process of all exocrine glands affecting both mucussecreting and eccrine sweat glands throughout the body. The disease results from abnormal
epithelial chloride transport. Clinical manifestations include chronic pulmonary disease,
deficient exocrine pancreatic function, and other complications of inspissated thick mucus in
a number of organs, including the small intestine, the liver and the reproductive tract. The
pancreas becomes small, firm, grayish white, and on the cross section, it loses its
characteristic triangular shape. In the late stages, there are numerous small cysts and the
surface is granular. The large majority of patients have a form of chronic pancreatitis, which
leads to loss of acinar cells and extensive fibrosis.
Microscopically, both the ducts and acini are widely dilated and cystic and lined by
atrophic flat cells.The lumina are distended with dense laminated or homogenous secretion.
Squamous metaplasia of the ductal lining epithelium may be found in some cases as a result
of impaired fat absorption including vitamin A. Dense fibrous tissue has formed around the
lobule and between the persistent individual glands. On the contrary, the islets of Langerhans
in this cystic fibrous tissue do not show marks of injury. In addition, there is scanty
infiltration of lymphocytes and plasma cells.
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