DIFFERENTIATION. DYSPLASIA. CARCINOGENESIS.
DYSPLASIA
-is an abnormality of both differentiation and maturation
-dysplasia is a condition of disordered cell growth and proliferation which
may arise de novo or from tissues already showing pathological hyperplasia,
metaplasia, or chronic irritation and inflammation
-early stage dysplasia- reversible- if the stimulus is removed
-advanced dysplasia can progress to neoplasia- cancer
most important microscopic features of dysplasia:
-nuclear abnormalities - d. is characterized by increased size of nucleus
(absolute and relative to the amount of cytoplasm)- increased
nuclear/cytoplasmic ratio
increased chromatin content
abnormal chromatin distribution- coarse chromatin, clumping
nuclear membrane abnormalities- thickening
-cytoplasmic abnormalities -result from failure of normal differentiation,
for example lack of mucin secretion (in glandular epithelium), lack of
keratinization (in squamous epithelium)
-increased rate of cell proliferation - is characterized by increased
number of mitotic figures in many layers of epithelium (in contrast to the normal
state in which mitoses are limited to basal and parabasal layers)
mitoses are morphologically normal
-disordered maturation - dysplastic epithelium resemble basal (stem) cells
grades of dysplasia
- mild-moderate-severe
Significance of dysplasia
-epithelial dysplasia is premalignant lesion = lesion associated with higher
risk of development of cancer = general term for invasive aggressive malignant
tumor with potential to metastasize
Clinical examples of the dysplasia to neoplasia sequence:
1.- Benign colorectal polyps (adenomas)- are composed of
dysplastic epithelial glands-if left without surgical treatment- the majority of
these will turn into malignant tumors
2.- dysplasia in the uterine cervical epithelium- changes known as
CIN- cervical intraepithelial neoplasia- if not treated- they will develop into
maligant tumor
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3.- atypical hyperplasia, dysplasia and carcinoma- breast, uterine
endometrium
the risk of developing the cancer depends on
-grade of dysplasia
-duration of d.
-site of dysplasia (d.in urinary bladder has high risk, d. of uterine cervix lower
risk)
Differences between dysplasia and cancer
d. differs in two important respects:
-1. invasiveness
-2. reversibility
ad 1. in dysplasia the abnormal cell proliferation does never invade
the BM. Complete removal of dysplastic tissue is curative
cancer in contrast, invades the BM and spreads through lymphatic and blood
vessels, thus excision may not be curative
ad 2. reversibility- d. may sometimes return to normal- unlike
cancer which is irreversible
NEOPLASIA: CLASSIFICATION, NOMENCLATURE, EPIDEMIOLOGY,
CARCINOGENESIS, CLINICAL FEATURES, STAGING AND GRADING.
CLASSIFICATION OF TUMORS
tumor- neoplasia- is an abnormality of cellular differentiation, maturation and
control of growth
tumor- the term can be applied to any swelling- inflammatory tumor
but most commonly it is used to denote suspected neoplasm
neoplasms are - benign and malignant - depends on several features, chiefly the
ability of malignant tumor to spread from the site of origin
cancer- denotes a malignant tumor
definition of neoplasm: a neoplasm is an abnormal mass of tissue, the
growth of which exceeds and is uncoordinated with that of the surrounding
normal tissues and persists in the same excessive manner after cessation of
the stimuli that evoked the change.
Types of biological behavior of tumors:
represents a spectrum of various clinical outcomes
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benign- grows slowly and is encapsulated, no tissue destruction- no
infiltration, no spread to distant sites- no metastasis
malignant- grow rapidly, the tumor infiltrates and destroys surrounding
tissues, it causes metastases throughout the body, possibly with lethal results
intermediate (borderline)- neoplasm are locally aggressive but have low
metastatic potential- low-grade malignancies
Summary of features differentiating benign and malignant neoplasms:
grossly - benign- smooth surface with a fibrotic capsule, compression of
surrounding tissues,
-malignant- irregular surface without encapsulation, destruction of
surrounding tissues
microscopic features-benign- growth by compression of surrounding
tissues, highly differentiated- resembling normal tissue of origin, cells similar to
normal presenting a uniform appearance, few mitoses, those present are normal,
well-formed blood vessels, necrosis is unusual, distant spread-metastasis does
not occur
-malignant- growth is aggressive by invasion of
surrounding tissues, tumour is poorly or well differentiated, most malignant
tumours do not resemble the normal tissue of origin, anaplasia-the neoplastic
cells have no morphologic resemblance to normal tissues, cytologicallyirregularities, including enlarged, hyperchromatic irregular nuclei with large
nucleoli, marked variation of nuclear shape- polymorphism, increased mitotic
activity- abnormal mitoses, bizarre mitotic figures present, increased nuclearcytoplasmic ratio, blood vessel numerous and poorly formed, necrosis and
haemorrhages are common, typically- metastasis to distant sites
clinical features- benign- it grows slowly, it is rarely fatal even if
untreated- except in central nervous system, where even benign tumour may
cause fatal complications
-malignant- rapid growth, usually fatal if untreated
CARCINOGENESIS- is the process which results in the development of a
malignant neoplasm
- cells may undergo malignant transformation as a result of several
genetic mutations- risk of mutation increases with the number of mitotic
divisions- labile cells are more prone to neoplastic change than stable and
permanent cells
carcinogen- is a substance which can cause neoplasia- there may be long
latent period between exposure to the carcinogen and development of cancer
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-carcinogenesis- multistep process
EPIDEMIOLOGICAL FACTORS IN CARCINOGENESIS
-cancer is a disorder in cell differentiation and growth, its ultimate cause thus
must be defined at the molecular and cellular level, but cancer epidemiology can
contribute to understanding of the origin of the cancer
a variety of factors predispose an individual or a population to the development
of cancer
 Cancer incidence-most common malignant tumours in men include prostatic gland cancer (41%)
and lung cancer, in women breast cancer (31%) and lung (13%), estimated
cancer deaths include in men lung (32%) and in women lung ( 25%)
 geographic and environmental factors-environmental factors significantly influence the occurrence of different
forms of cancer in different countries, for example
-breast cancer is more common in the United States and Western Europe
than in Japan
-gastric cancer is more common in Japan than in the U.S. or Europe in
both sexes (about seven times higher in Japan than in the States) –diet with
smoked foods are likely to be linked to gastric cancer
-conversely, colorectal cancer is more common in States than in Japan
-cigarette smoking- close link to lung cancer both in men and women
 increased risk of certain cancers with occupational exposure-asbestos- cancer of lung, malignant mesothelioma
 age-in general, frequency of cancer increases with age, most of cancer
related deaths occur over 55 years of age- possible factors: accumulation of
somatic mutations, decline of immune competence in age
-certain cancers are particularly common in children-.lymphoblastic
leukemia, lymphomas, neuroblastoma, Wilms tumor of the kidney,
retinoblastoma, etc.
 heredity- hereditary factors play role in the development of cancer even in the presence
of clearly defined environmental factors
-hereditary forms of cancer can be divided into two categories:
1. -inherited cancer syndromes- are characterized by inheritance of single
mutant genes that increase the risk of developing the tumor-, such as in
congenital retinoblastoma
-childhood retinoblastoma is the most striking example of the role of
heredity- approximately 40% of the retinoblastomas are familial
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predisposition to the tumor is autosomal dominant- the carriers of the gene
have a 10 thousand-fold greater risk of developing retinoblastoma
and familial adenomatous polyposis is another hereditary disorder- autosomal
dominant gene mutation-innumerable polyps of GIT- in virtually 100% of cases
colorectal cancer develops
2. -familial cancers- are characterized by clustering in families of certain forms
of cancer, such as breast, colon, brain and ovary cancers
-family history- breast and colon cancer more common in first degree
relatives
CARCINOGENESIS: THE MOLECULAR BASIS OF CANCER:
 nonlethal genetic damage (mutation) is important in carcinogenesis-this mutation can occur because of environmental factors, such as viruses,
chemicals, radiation or can be inherited
 three classes of normal regulatory genes are the principal target
of genetic damage
 growth-promoting proto-oncogenes
 growth-inhibiting cancer supressor genes (antioncogenes)
 genes regulating programmed cell death-apoptosis
 oncogenes- are sequences of DNA in the human genome which when
extracted and injected into a cultured cell can cause neoplastic
transformation
proto-oncogenes- normally do not cause neoplastic transformation- but if
activated- may lead to mutation- this means that the proto-oncogenes may be
amplified- causing excessive production of gene product
-incorporation of tumorigenic viruses into human DNA- may activate protooncogenes in similar way
 onco-supressor genes- these are genes which appear to prevent neoplastic
transformation
-if these genes are inactivated- then the individual is predisposed to cancer
-the best described examples of onco-supressor genes- are the RB-1
gene for familial retinoblastoma and APC gene in familial adenomatous polyposis
(FAP)
 genes that regulate apoptosislarge family of genes that regulate apoptosis has been identified, examples
include bcl-2
it is located on chromosome 18, it is activated by translocation to
the immunoglobulin Ig heavy chain locus on chromosome 14 (mutation is common
in most follicular lymphomas)- activation of bcl-2 results in overexpression of
bcl-2 that protects lymphocytes from apoptosis- accumulation of lymphoid cellsgrowth of the tumor
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-another gene involved in regulation of apoptosis codes for a protein called
p53 which has a role in regulating cell proliferation and very likely participates in
carcinogenesis of many human cancers
-function of normal p53 is to trigger apoptosis if the cells that have been
exposed to mutation-causing agents are unable to repair damaged DNA
-if normal p53 is lost, the cells with such damaged DNA can proliferate
 DNA repair genes- these regulate repair of damaged DNA
-the role of DNA repair genes is best seen in hereditary disorders in which
genes that encode proteins involved in DNA repair are defective
-those born with such inherited mutation of DNA repair genes are at greater
risk of developing cancer
mechanisms underlying activation of oncogenes:
protooncogenes are transformed to oncogenes- this results in two
possible categories of changes
1. changes in structure of gene, resulting in synthesis of abnormal
gene product
2. changes in regulation of gene expression, resulting in enhanced
production of normal oncoprotein, such as amplification of gene
HER-2/neu leads to overexpression of HER-2 oncoproteinassociated with poor prognosis in breast and salivary cancers
 VIRAL CARCINOGENESIS
-a variety of DNA and RNA viruses are known to cause cancers in animals, but
only few of them have been linked with human tumours
 Human papilloma virus (HPV)
-some types of HPV cause benign squamous papillomas (warts)- types 1, 2, 4, 7
-HPV 16 and 18 are present in over than 90% of cases of squamous cell ca of the
uterine cervix
-genital warts are associated with HPV-6 and HPV-11
 Epstein-Barr virus (EBV)
-is associated with at least two human tumors
-Burkitt lymphoma- is a high grade tumor of B-lymphocytesendemic in central Africa- all patients carry EBV genome in tumor cells
-undifferentiated nasopharyngeal cancer- is endemic in southern
China and in Eskimos- EBV genome is found in all such tumors
 hepatitis B virus (HBV)
-there is close association of HBV infection and liver cancer, though mechanism
by which HBV causes cancer is uncertain and probably multifactorial
 Human T-cell leukemia virus type 1 (HTLV-1)
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-this virus has strong afinity to CD4+ T-lymphocytes
-HTLV-1-associated leukemia/lymphoma is endemic in Japan and Caribean
-HTLV-1 proviral DNA is detected in DNA of leukemic cells
NOMENCLATURE: HISTOGENESIS-cell or tissue of origin
-neoplasms are classified and named on the basis of their presumed cell of
origin
classification of tumors- combine several approaches, including cell of origin,
distinction between benign and malignant, site, and other descriptive features
EPITHELIAL TUMORS.
benign- adenoma- benign epithelial tumor producing glandular growth pattern
and/or derived from glandular epithelium- thyroid adenoma, colonic adenoma,
adenoma of adrenal cortex (not necessarily producing glandular/tubular
pattern), kidney
colonic adenoma- tubular or villous- descriptive term incorporated in the name
of the tumor
-papilloma- benign epithelial tumor growing on the surface, the tumor has
a papillary structure (composed of finger-like projections- may arise from
squamous (oral cavity- palate), glandular (intraductal pailloma of mammary gland)
or transitional epithelium (urinary bladder)
cystadenoma- hollow cystic masses, benign epithelial tumors, typically
occur in the ovary, salivary glands
polyp- is a mass that projects above a mucosal surface, the term is usually
used for benign tumors, but malignant ones can be also polypoid
malignant- carcinoma-all malignant epithelial tumors
adenocarcinoma- if derived from glandular epithelium
squamous carcinoma, transitional carcinoma- on the basis of origin
names may include the organ of origin or description of microscopy- clear cell
adenocarcinoma of the kidney, papillary carcinoma of thyroid, etc.
MESENCHYMAL TUMORS.
benign mesenchymal tumors are named after the cell of origin- followed by
suffix -oma
leiomyoma, rhabdomyoma, lipoma, fibroma, chondroma, osteoma,
hemangioma, meningioma, neurofibroma, schwannoma,
malignant mesenchymal tumors are named after the cell of origin to which is
added the suffix --sarcoma
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leiomyosarcoma,
rhabdomyosarcoma,
liposarcoma,
fibrosarcoma,
chondrosarcoma, osteosarcoma, hemangiosarcoma, meningiosarcoma,
Nomenclature exceptional to these rules-is used for hematological malignancies:
leukemias- neoplasms of blood-forming organs- leukemias are subclassified on
the basis of their clinical course- acute and chronic and the cell of originmyeloid and lymphocytic, lymphoblastic
NEUROENDOCRINE TUMORS.
- the term “neuroendocrine” is used for cells which produce hormonal
products, such as serotonin, synaptophysin, ect, the cells contain eletrondense secretory granules
- the term “carcinoid” is used in WHO classification for most of
neuroendocrine tumors, excluding islet cell tumors of pancreas and
medullary carcinoma of thyroid gland
- most carcinoids- GIT (particularly appendix, terminal ileaum, stomach and
rectum), lungs,
mixed tumors- neoplasms composed of more than one neoplastic cell type
adenosquamous carcinoma- two malignant epithelial componentssquamous and adenocarcinomatous
adenoacanthoma- adenocarcinoma with benign squamous metaplasia
carcinosarcoma- malignant epithelial and mesenchymal component
(uterus, lung, urinary bladder)
-single multipotent cell type differentiates along both pathways-epithelial and
mesenchymal
fibroadenoma- benign mixed tumor (breast)
hamartoma and choristoma
-are tumor-like proliferations thought to result of developmental anomalies,
they are not true neoplasms
 hamartoma- composed of tissues that are normally present in the organ in
which the tumor arises- hamartoma of the lung-consists of a disorganized
mass of the bronchial epithelium, cartilage and fibrous tissue
 choristoma-resembles a hamartoma, but contains tissues that are not
normally present in its site of origin
CLINICAL FEATURES OF NEOPLASIA
-all tumours may cause morbidity and mortality, even benign ones
-with few exceptions all tumour masses require histologic evaluation- benign or
malignant
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 EFFECTS OF TUMOR ON HOST
-both benign and malignant- may cause problems because of growing mass,
because of hormone synthesis, bleeding, secondary infections, ulceration-cancers are more threatening to the host than benign tumours
LOCATION-is of importance in both benign and malignant- benign meningioma
may compress the brain- oedema- death
 PRODUCTION OF HORMONES-both benign and malignant tumours of
endocrine organs- may induce life-threatening endocrinopathy- hormone
activity is more likely in well-differentiated adenoma than in carcinoma
 ULCERATION, BLEEDING AND SECONDARY INFECTIONS- in GI tract
intestinal obstruction, infarction- may cause problems, but also commonly
result in early diagnosis of cancer
 CANCER CACHEXIA-many patients suffer progressive loss of body fat
accompanied by anorexia, weakness and anemia
origin of cancer cachexia is multifactorial-reduced food intake-related to the
central control of appetite, increased metabolic rate, possibly circulating
factors released from activated macrophages- TNF (tumor necrosis factor)
 PARANEOPLASTIC SYNDROMES- complex of symptoms that appear in
cancer patients and are not readily explained by local activity of primary or
metastatic tumour
-in 10-15% of patients, they may represent an early manifestation of the
tumour, may cause significant clinical problems, may mimic metastatic disease
common paraneoplastic syndromes
-hypercalcemia- is the most common paraneoplastic endocrine
manifestation of malignancy, three different pathological associationas are
recognized as underlying mechanism for developing of hypercalcemia
-hypercalcemia associated with skeletal metastases- from solid
tumors, such as breast and lung cancer-because of direct resorption of bone by
enzymes released by tumour cells and osteolytic factors from tumour cells
-hypercalcemia associated with hematological malignancies, such as
multiple myeloma, acute lymphoblastic leukemia, lymphomas
-hypercalcemia not-associated with skeletal metastases-this is
typically present in patients with squamous cell carcinoma, for example of the
lung, and of head and neck region, and with renal cell carcinoma, and carcinoma
of the ovary- neoplasms release humoral factors that result in increased
osteoclastic bone resorption
-ectopic ACTH production with Cushing syndrome- is restricted to a
limited range of tumours, and is not related to the degree of malignancy

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-it is most commonly associated with the following tumours, small cell and
carcinoid tumours of the lung, thymus, thyroid, pancreas, genitourinary system
(prostate and ovary), and rarely tumours such as pheochromocytoma,
neuroblastoma, ganglioneuroma
-clinically the syndrome manifests as muscle weakness, hypertension, edema,
carbohydrate intolerance- metabolic effects of high corticosteroid levels- full
features of Cushing syndrome are seldom present, plasma levels of ACTH are
uniformly elevated
-hypercoaguability of the blood -non-bacterial thrombotic endocarditis
-erythrocytosis- because of increased synthesis of erythropoietin by
renal cell carcinoma, cerebellar hemangioblastoma, uterine myoma
-paraneoplastic neurological syndromes- several different forms of
neurological dysfunctions unrelated to local tumour growth or metastasis may
develop in patients with neoplasms, neurological conditions tend to run a
progressive course and may be fatal
-associated with small cell lung cancer, less commonly with other
carcinomas, myeloma, and lymphomas
-neurological problems derive from peripheral neuropathy- motor neuron
weakness, or mixed sensory and motor nerve involvement
or from cerebellar degeneration-loss of Purkyně cellsor from subacute encephalitis- affects grey matter of brain
GRADING AND STAGING OF CANCER
-methods to quantify the probable clinical aggressiveness- to predict
prognosis
GRADING- attemps to establish some estimate of aggressiveness of the given
cancer or level of malignancy based on cytologic differentiation of tumor cells
and the number of mitoses within the tumor
-criteria for grading are different for different cancers
STAGING-is based on the size of the primary lesion, its extent of spread to
regional lymph nodes, and the presence or absence of distant metastases
-if this assessment is based on clinical and X-ray examination- clinical staging
or on histological examination- pathological staging
TNM system- T- stands for primary tumour, N - for regional lymph node
metastasis, M - for distant metastasis
staging- is the most important predictive indicator in most cancers - of greater
clinical value than grading
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