neoplasm 2
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Histopathology of Neoplasia
Definitions
Classification
Nomenclature
Characteristics off benign and malignant
Factors affecting incidence of cance
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Nomenclature
- All tumors have two basic components
Proliferating neoplastic cells that constitutetheir parenchyma
Supportive stroma made up of connectivetissue & blood vessels
- The growth & evolution of neoplasms are
critically dependent on their stroma.- The nomenclature of tumors is based on the
parenchymal component
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Neoplasms are named based upon two factors
On the histologic types : mesenchymal and
epithelial On behavioral patterns : benign and
malignant neoplasms
Nomenclature
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- Benign tumors of mesenchymal cells are
designated by attaching the suffix oma to
the cell of origin
- Malignant tumors arising in mesenchymal
tissue are usually called sarcoma
Nomenclature
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Tumors of mesenchymal originConnective tissue and derivatives
Benign Malignant
Fibrous tissue Fibroma Fibrosarcoma
Fat tissue Lipoma Liposarcoma
Cartilage Chondroma Chondrosarcoma
Bone Osteoma Osteosarcoma
Nomenclature
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Endothelial and related tissues
Benign Malignant
Blood vessels Hemangioma Angiosarcoma
Lymph vessels Lymphangioma Lymphangiosarcoma
Synovium Synovial sarcoma
Nomenclature
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Muscle
Benign Malignant
Smooth Leiomyoma Leiomyosarcoma
Striated Rhabdomyoma Rhabdomyosarcoma
Nomenclature
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- Benign epithelial tumors are variously
classified, some based on
Cell of origin ,
Microscopic architecture &
Macroscopic patterns
Nomenclature
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Adenoma the term applied for benign
epithelial neoplasm that form glandular
pattern
Nomenclature
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Papillomas - benign neoplasmsproducing microscopically or
macroscopically visible finger like
projection or warty projection from
epithelial surface
Nomenclature
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- Benign tumors that form large cystic masses are
referred as cystadenoma. Some tumors produce
papillary patterns that protrude into cystic
spaces are called papillary cystadenoma
- When tumor produces macroscopically visible
projection above a mucosal surface , it is termed
polyp- Malignant neoplasms of epithelial cell origin are
called carcinomas
Nomenclature
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Teratomas are made up of a variety of
parenchymal cell types representative of
more than one germ layer
- They arise from totipotent cells.
- So mostly are found in gonads
Nomenclature
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Characteristics of benign and malignant
neoplasms
A. Differentiation and anaplasia
- Differentiation refers to the extent to which
parenchymal cells resemble comparable normal
cells both morphologically and functionally.
- Thus, well-differentiated tumors cells resemble
mature normal cells of tissue of origin. Poorly
differentiated or undifferentiated tumors haveprimitive appearing, unspecialized cells.
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- In general, benign neoplasms are welldifferentiated.
- Malignant neoplasms in contrast, range fromwell differentiated, moderatelydifferentiated to poorly differentiate types.
- Malignant neoplasm composed of
undifferentiated cells are said to beanaplastic,
- literally anaplasia means to form backward.
Characteristics of benign and malignant
neoplasms
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Morphologic changes which mark anaplasia
Pleomorphism both cells & nuclei show
variation in size & shapeAbnormal nuclear morphology the nuclei
contain abundant chromatin & are extremely
dark staining (hyperchromatic), high nuclear
cytoplasmic ratio 1:1(normally 1:4 to 1:6)
Characteristics of benign and malignant
neoplasms
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The cell usually reveals large nucleoli with
high number and often abnormal mitoses
Tumor giant cellsNecrosis (in many anaplastic tumors, large
central areas undergo ischemic necrosis.)
Characteristics of benign and malignant
neoplasms
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- Anaplastic tumor of the skeletal muscle (rhabdomyosarcoma). Notethe marked cellular and nuclear pleomorphism, hyperchromaticnuclei, and tumor giant cells
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Dysplasia
- Disordered growth
- It is characterized by changes that include a loss
in the uniformity of the individual cells as well asa loss in their architectural orientation
- When dysplastic changes are marked & involve
the entire thickness of the epithelium but the
lesion remains confined to the normal tissue ,it is
considered preinvasive neoplasm & is referred toas Carcinoma in situ
Characteristics of benign and malignant
neoplasms
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The better the differentiation of the
transformed cell, the more completely it
retains the functional capabilities found in its
normal counterparts.
Thus, benign neoplasms and well-
differentiated carcinomas of endocrine glands
frequently elaborate the hormones
characteristic of their origin
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Highly anaplastic undifferentiated cells, lose their
resemblance to the normal cells from which they
have arisen.
In some instances, new and unanticipated
functions emerge.
Some tumors may elaborate fetal proteins
(antigens) not produced by comparable cells inthe adult.
Carcinomas of non-endocrine origin may
produce a variety of hormones, often calledectopic hormones.
For example, bronchogenic carcinomas may
produce corticotropin, parathyroid-like hormone,
insulin, and glucagons, as well as others
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Characteristics of benign and malignant
neoplasms
B. Rate of growth
The rate of growth of a tumor is determined
by three main factors: the doubling time of tumor cells,
the fraction of tumor cells that are in the
replicative pool, and
the rate at which cells are shed and lost in the
growing lesion.
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- Most benign tumors grow slowly whereas;
most malignant tumors grow rapidly
sometimes, at erratic pace
- In general, the growth rate of neoplasms
correlate with their level of differentiation
and thus, most malignant neoplasms grow
more rapidly than do benign neoplasms.
Characteristics of benign and malignant
neoplasms
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C. Local invasion- Nearly all benign neoplasms grow as cohesive
expansile masses thatremains localizedto
their site of origin and do nothave the
capacity to infiltrate , invade or metastasize as
malignant tumors.
- Because they expand & grow slowly, they
usually develop a rim of compressedconnective tissue, called fibrous capsule
Characteristics of benign and malignant
neoplasms
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C. Local invasion- Such encapsulations tend to contain the benign
neoplasms as a discrete, palpable and easily
movable masses that can be easily surgically
enucleated(removed).
- Hemangiomas and neurofibromas are
exceptions.
Characteristics of benign and malignant
neoplasms
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C. Local invasion
The growth of malignant neoplasms is
accompanied by progressive infiltration,
invasion and destruction of the surrounding
tissue. Generally, they are poorly demarcated
from the surrounding normal tissue (and a
well-defined cleavage plane is lacking)
Characteristics of benign and malignant
neoplasms
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C. Local invasion
Next to the development of metastasis,
invasiveness is the most reliable feature that
differentiates malignant from benign
neoplasms.
Characteristics of benign and malignant
neoplasms
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Most carcinomas begin as localized growth
confined to the epithelium in which they
arise. As long as this early cancers do not
penetrate the basement membrane on which
the epithelium rests such tumors are
called carcinoma in-situ.
Characteristics of benign and malignant
neoplasms
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D. Metastasis
Metastasis are tumor implants discontinuouswith the primary tumor
Metastasis unequivocally marks a tumor asmalignant because benign neoplasms dontmetastasize
The invasiveness of cancers permits them topenetrate into blood vessels, lymphatics &body cavities , providing the opportunity tospread
Characteristics of benign and malignant
neoplasms
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D. Metastasis
With few exception, all cancers can
metastasize.T
he major exception aregliomas & basal cell carcinomas of the skin.
The more aggressive, the more rapidly
growing, & the larger the primary
neoplasms , the greater the likelihood that
it will metastasize
Characteristics of benign and malignant
neoplasms
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Pathway of spread
Seeding of body cavities & surfaces(transcoelomic spread)
- It may occur whenever a malignant neoplasmpenetrates into a natural open field
- Most often involved is the peritoneal cavity
but other cavities - pleural, pericardialsubarachinoid & joint space may be affected
- It is often characteristic of ovarian carcinoma
Characteristics of benign and malignant
neoplasms
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Pathway of spread
Lymphatic spread
- Lymphatic route is the most common pathwayfor the initial dissemination of carcinomas
- The pattern of lymph node involvement
follows the natural routes of drainage.
Characteristics of benign and malignant
neoplasms
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For example carcinomas of the breast usually
arise in the upper outer quadrants, they
generally disseminate first to the axillary
lymph nodes.
Cancers of the inner quadrant may drain
through lymphatics to the nodes within the
chest along the internal mammary arteries.
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Pathway of spread
Hematogenous spread
- It is typical for sarcoma but is also seen withcarcinoma
- Liver & lung are most frequently involved in
hematogenous spread
Characteristics of benign and malignant
neoplasms
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Arteries, with their thicker walls, are less readilypenetrated than are veins.
With venous invasion, the blood-borne cells
follow the venous flow draining the site of theneoplasm.
Understandably the liver and lungs are mostfrequently involved secondarily in such
hematogenous dissemination. All portal area drainage flows to the liver, and all
caval blood flows to the lungs.
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Characterstics Benign Malignant
Differentiation/anaplasia Well differentiated;
structure may be typical of
tissue of origin
Some lack of differentiation with
anaplasia; structure is often
atypical
Rate of growth Usually progressive and
slow; may come to a
standstill or regress;
mitotic figures are rare and
normal
Erratic and may be slow to rapid;
mitotic figures may be numerous
and
abnormal
Local invasion Usually cohesive and
expansile well-demarcated
masses that do not
invade or infiltrate
surrounding normal tissues
Locally invasive, infiltrating the
surrounding normal tissues;
sometimes may be
seemingly cohesive and expansile
Metastasis Absent Frequently present; the larger
and more undifferentiated the
primary, the more
likely are metastases
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Geographic factors Specific differences in incidence rates of
cancers are seen worldwide.
For exampleStomach carcinoma - Japan
Lung cancer - USA
Skin cancer - New zeland & Australia
Liver cancer - Ethiopia
Epidemiology
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Epidemiology
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Environmental factors
Asbestos ------- lung cancer, mesothelioma,
Esophagus and, stomach Ca
Vinyl chloride -------- Angiosarcoma of liver
Benzene ------------------ Leukemias
Cigarette smoking----- Brochogenic Ca.
Venereal infection -----Cervical carcinoma
Epidemiology
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Age
- Most cancers in adults occur in those over 55
years of age.
- Children under 15 years of age however, aresusceptible to acute leukemia, central
nervous system tumors, neuroblastoma,
wilm's tumour, retinoblastoma,
rhabdomyosarcoma and etc..
Epidemiology
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Genetic predisposition to cancer
- It can be divided into
Autosomal dominant inherited cancer
syndromes- It includes several well-defined cancers in
which inheritance of a single mutant gene
greatly increases the risk of developing atumor.
- Eg familial retinoblastoma
Epidemiology
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Defective DNA repair syndromes
- A group of cancer predisposing conditions is
collectively characterized by defects in DNA
repair & resultantDNA instability
- These conditions include Xeroderma
pigmentosum, ataxia- telangectasia & Bloom
syndrome
Epidemiology
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Familial cancers
- Cancers may occur at higher frequency in certainfamilies without a clearly defined pattern oftransmission.
- These include carcinoma of colon, breast, ovary& brain , melanoma
- Features that characterize familial cancers
include early age at onset, tumors arising in twoor more close relatives of the index case &sometimes , multiple or bilateral tumors.
Epidemiology
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onhereditary predisposing conditions
Precancerous conditions
These are non neoplastic conditions with welldefined association with cancer
Epidemiology
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Regenerative, hyperplasic and dysplasticproliferations are fertile soil for the origin ofmalignant neoplasm.
- Endometrial hyperplasia -- endometrialcarcinoma
- Cervical dysplasia - - cervical cancer
- Bronchial dysplasia - - bronchogeniccarcinoma
- Regenerative nodules -- liver cancer
Epidemiology
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Certain non-neoplastic disorders may
predispose to cancers.
- Chronic atrophic gastritis - gastric cancer
- Solar keratosis of skin - skin cancer
- Chronic ulcerative colitis --- colonic cancer
- Leukoplakia of the oral cavity, vulva andpenis - squamous cell carcinoma
Epidemiology
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Large cumulative experiences indicate that
most benign neoplasms do not become
malignant however, it can constitute
pre neoplastic conditions including
- Villous colonic adenoma - colonic cancer
- Carcinoma arising in pleomorphic adenoma
Epidemiology
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Molecular basis of cancer
- The fundamental principles in cancer genetics
include
Non-lethal genetic damage lies at the heartof carcinogenesis. Such genetic damage
(mutation) may be acquired by the action of
environmental agents such as chemicals,
radiation or viruses or it may be inherited in
the germ line
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Molecular basis of cancer
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A tumor is formed by the clonal
expansion of a single precursor cell that
has incurred the genetic damage(tumors are monoclonal)
Molecular basis of cancer
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The three classes of normal regulator genes
are the principal targets of genetic damage
The growth promoting proto-oncogenes
- Proto-oncogenes activation gives rise to
oncogenes (cancer causing genes).
Molecular basis of cancer
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Growth inhibiting tumor suppressor genes
- Its physiologic role is to regulate cell growth
however, the inactivation of tumor suppressor
genes is the key event in cancer genesis
Molecular basis of cancer
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Molecular basis of cancer
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Genes that regulate programmed celldeath (apoptosis)
Genes that regulate DNA repair
- These genes affect cell proliferation orsurvival indirectly by influencing theability of the organism to repair nonlethal damage in other genes. It
predisposes to mutation & to neoplastictransformation
Molecular basis of cancer
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CARCINOGENESIS
Carcinogenesis is a multistep process
both at the phenotypic and genotypic levels
-A large number of agents cause genetic damagesand induce neoplastic transformation of cells.They fall into three categories
Chemical carcinogens
Radiant energy
Oncogenic viruses & some other microbs
Molecular basis of cancer
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A) Chemical carcinogenesis
- Chemical carcinogenic agents fall into twocategories
Direct acting compounds these dont requirechemical transformation for theircarcinogenicity
Indirect acting compounds or procarcinogens ,
which require metabolic conversion to produceultimate carcinogens capable of transformingcells
Molecular basis of cancer
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These include
Direct-acting alkylating agents
-T
herapeutic agents such as cyclophosphamideused as anticancer agents have been
documented to induce lymphoid neoplasms &
leukemia
Molecular basis of cancer
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Polycyclic aromatic hydrocarbons
- These agents represent some of the most
potent carcinogens
Eg they are produced in the combustion of
tobacco & contribute to the causation of lung
& bladder cancer
Molecular basis of cancer
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Aromatic amines & Azo dyes
Nitrosamines & amides
Naturally occurring carcinogens
Eg Aflatoxin B1 is a potent hepatic carcinogen ,
produced by some strains of the fungus
Aspergillus flavus that thrives on improperly
stored food
Molecular basis of cancer
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b) Radiation carcinogenesis
Radiant energy whether in form of ultraviolet
(UV) sun light or ionizing electromagnetic (X
rays and gamma ( ) rays) and particulates
(, , protons and neutrons) radiation can
transform and induce neoplasm in both
humans and experimental animals.
Molecular basis of cancer
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UV rays induce an increased incidence of
squamous cell carcinoma, basal cell
carcinoma and possibly malignant melanoma
of skin
Molecular basis of cancer
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c) Viral and microbial carcinogenesis
Large groups ofDNA and RNA viruses have
proved to be oncogenic and there is an
association between infections by the
bacterium HelicobacterPylori and gastric
lymphoma
Molecular basis of cancer
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i) DNA oncogenic viruses
This group includes
Human Papilloma Virus (HPV)
Epstein Barr Virus (EBV)
Hepatitis B Virus (HBV)
Molecular basis of cancer
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Human papilloma Virus (HPV)
HPV definitely causes benign squamous
papilloma (warts) (type 1,2,3,4, 7).
It also implicated in the genesis of squamous
cell carcinomas of cervix and anogenital
region (types 16,18 and also 31,33,35,and 51
found in 85% SCC). It is also linked to the
causation of oral and laryngeal cancers
Molecular basis of cancer
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Epstein Barr virus (EBV)
Member of the herpes family has been implicated
in the pathogenesis of four tumors.
The African form ofBurkitt'slymphoma,
B- cell lymphomas in immuno suppressed
individuals
some cases of Hodgkins disease
Nasopharyngeal carcinoma.
Molecular basis of cancer
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ii) RNA oncogenic viruses
only one retrovirus is firmly implicated in
the causation of cancer and it is Human T
cells leukemia/ lymphoma virus type 1
(HTLV-1) .
It is associated with a form ofT-cell
leukemia /lymphoma
Molecular basis of cancer
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Hepatitis B- virus (HBV) Strong epidemiologic association prevails
between HBV and hepatocellular carcinoma
Helicobacter pylori
-There is an association between gastric infectionswith Helicobacter pylori as a cause of gastriclymphoma. The stronger link is with B celllymphoma of stomach.
-T
reatment of H. pylori with antibiotics results inregression of the lymphoma in most cases.
Molecular basis of cancer
Cli i l f t f t
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Clinical features of tumors
Both benign and malignant neoplasms may cause
problems because of
1. Location and impingement on adjacent
structures
2. Functional activities such as hormone synthesis
3. Bleeding and secondary infection when they
ulcerate through adjacent natural surfaces4. Initiation of acute symptoms caused by either
rupture or infarction
Effects of tumor on host
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Local and hormonal effects
For example pituitary adenoma being located
in critical location can cause serious
endocrinopathies
Analogously cancers arising with or
metastatic to an endocrine organ may cause
an endocrine insufficiency by destroying thegland.
Clinical features of tumors
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Benign neoplasms of endocrine origin mayproduce manifestations by elaboration ofhormones.
For example a benign B- cell adenoma ofpancreatic islets less than 1 cm in diameter mayproduce sufficient insulin to cause fatalhypoglycemia
Neoplasms in the gut (both benign andmalignant) may cause obstruction as theyenlarge
Clinical features of tumors
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The erosive destructive growth of cancers or
expansile pressure on benign tumor of any
natural surface may cause ulceration,
secondary infection and bleeding.
Clinical features of tumors
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Cancer Cachexia
- Cachexia is a progressive loss of body fat and
lean body mass accompanied by profound
weakness, anorexia and anemia .The origin
of cancer cachexia are obscure
Reduced food intake has been related to
abnormalities in taste and central control of
appetite.
Clinical features of tumors
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Cancer Cachexia
- In patients with cancer, calorie expenditureoften remains high and basal metabolic rate
is increased despite reduced food intake. TNF produced by macrophages and possibly
by some tumor cells is the mediator of thewasting syndrome that accompanies cancer.Other cytokines such as IL-1 andIFN synergize with TNF
Clinical features of tumors
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Paraneoplastic syndromes
- It is an aggregate of symptom complexes in
cancer - bearing patients that can not readily be
explained either by the local or distant spread ofthe tumor or by the elaboration of hormones
indigenous to the tissue from which the tumor
arose.- Paraneoplastic syndrome occurs in about 10% of
patients with malignant disease
Clinical features of tumors
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- The endocrinopathies are frequentlyencountered paraneoplastic syndromes. Becausethe cancer cells are not of endocrine origin, the
functional activity is referred as ectopichormone production .
Cushing syndrome is the most commonendocrinopathy . 50% of the patients have
carcinoma of lung ,chiefly the small cell type. itis caused by excessive production ofcorticotropin
Clinical features of tumors
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Paraneoplastic syndromes
Syndrome Mechanism Example
Cushing's Syndrome ACTH-like substance Lung (oat cell) carcinoma
Hypercalcemia Parathormone-like
substance
Lung (squamous cell)
carcinoma
Hyponatremia Inappropriate ADHsecretion
Lung (oat cell) carcinoma
Polycythemia Erythropoietin-like
substance
Renal cell carcinoma
T
rousseau's Syndrome Hypercoagulable state Various carcinomasHypoglycemia Insulin-like substance Various carcinomas and
sarcomas
Carcinoid Syndrome -hydroxy-indoleacetic acid
(5-HIAA
Metastatic malignant
carcinoid tumors
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Grading and staging of cancers
Grading denotes the level of differentiation
whereas, staging expresses the extent of
tumor spread and forecast the clinical
gravity of cancers
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Grading and staging of cancers
Grading of a cancer is based on the degree of
differentiation of tumor cells and the number
of mitoses within the tumor and presumably
correlates to aggressive character of theneoplasm
Cancers are classified into grades Ito IV with
increasing anaplasia. Criteria for individualgrades vary with each form of neoplasm
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Grading and staging of cancers
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The staging of cancers is based on the size of
primary lesions, its extent of spread to
regional lymph nodes and the presence or
absence of blood-borne metastases
Grading and staging of cancers
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Two major staging systems are currently in use
1. Union internationale contre cancer (UICC)
which utilizes the so- calledTNM system Tfor
primary tumor N for regional lymph node
involvement and M for metastasis
Grading and staging of cancers
G di d t i f
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The TNM staging varies for each specific form
of cancer but there are general principles.
With increasing size, the primary lesion is
characterized as T1 to T4. T0 is added to
indicate an in - situ lesion.
Grading and staging of cancers
G di d t i f
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N0for no nodal involvement whereas, N1 -N3
wound denote involvement of an increasing
number and range of nodes.
M0signifies no distant metastasis whereas
M1 or sometimes M2 indicates the presence of
blood born metastasis
Grading and staging of cancers
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2. The American joint committee (AJC) employs a
some what different nomenclature and divides
all cancers into stages Ito IV incorporating
within each of these stages the size of theprimary lesion as well as the presence of nodal
spread and the distant metastasis
Grading and staging of cancers
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The staging of neoplastic disease has assumed
great importance in the selection of the best
form of therapy for the patient. Indeed staging
has proved to be of greater clinical value thangrading.
Grading and staging of cancers
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Laboratory diagnosis of cancer
Histologic and cytologic methods
Several sampling approaches are available
1. Excision or biopsy
2. Fine needle aspiration
3. Cytologic smears
PAPsmearFluid cytology
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Laboratory diagnosis of cancer
Advanced techniques:-
Immunohistochemistry
Molecular diagnosis
Flow cytometry
Tumor markers
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Immunohistochemistry
- The availability of specific monoclonal
antibodies has greatly facilitates the
identification of cell products and surface
markers
Laboratory diagnosis of cancer
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Flow cytometery
Identification of cell surface antigens by flowcytometery is widely used in the classification
of leukemias and lymphomas Flow cytometery is used for detection of
aneuploidy which is also associated withpoorer prognosis in early stage breast cancer
carcinomas of the urinary bladder lungcancer colorectal cancer, and prostate cancer
Laboratory diagnosis of cancer
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Tumour markers
- Tumour markers are biochemical indicators ofthe presence of a tumor . They include cell
surface antigens, cytoplasmic proteins,enzymes and hormones.
- Tumor markers can not be considered asprimary modalites for the diagnosis of cancerand thus, act as supportive laboratory tests.
Laboratory diagnosis of cancer
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Selected tumor markers
Markers Associated CancersHormones
Human chorionic gonadotropin Trophoblastic tumors, nonseminomatous
testicular tumors
Calcitonin Medullary carcinoma of thyroid
Catecholamine and metabolites Pheochromocytoma and related tumors
Ectopic hormones Paraneoplastic Syndromes
Oncofetal Antigens
a-Fetoprotein Liver cell cancer, nonseminomatous germ
cell tumors of testis
Carcinoembryonic antigen Carcinomas of the colon, pancreas, lung,
stomach, and heart
Isoenzymes
Prostatic acid phosphatase Prostate cancer
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SpecificProteins
Immunoglobulins Multiple myeloma and other
gammopathies
Mucins and Other Glycoproteins
CA-125 O
varian cancer
Selected tumor markers