Neoplasia 4
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NEOPLASIA 4Fe A. Bartolome, MD, FPASMAP
Department of Pathology
Our Lady of Fatima University
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Chemical Carcinogenesis
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Chemical Carcinogenesis
• Initiation results from exposure of cells to a sufficient dose of a carcinogenic agent (initiator).
• Initiation alone is not sufficient for tumor formation.
• Initiation causes permanent DNA damage (mutations). It is rapid and irreversible and has “memory.”
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Chemical Carcinogenesis
• Unrepaired alterations in the DNA are essential first steps in the process of initiation. For the change to be heritable,
the damaged DNA template must be replicated
For initiation to occur, altered cells must undergo at least one cycle of proliferation so that DNA change becomes fixed
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Chemical Carcinogenesis
• Promoters (e.g. Phorbol esters, hormones, phenols, and drugs) can induce tumors in initiated cells, but they are non-tumorigenic by themselves
• Tumors do not result when the promoting agent is applied before, rather than after, the initiating agent.
• The cellular changes resulting from application of promoters do not affect DNA directly and are reversible.
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Chemical Carcinogenesis
• Application of promoters leads to proliferation and clonal expansion of initiated (mutated) cells Mutated cells with reduced
growth factor requirements
• Process of tumor promotion includes multiple steps: proliferation of pre-neoplastic cells, malignant conversion, and tumor progression
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Chemical Carcinogenesis: Initiators
Direct-Acting Agents
• Require no metabolic conversion to become carcinogenic
• Most are weak carcinogens; some are chemotherapeutic drugs (e.g. Alkylating drugs)
• Risk of induced cancer is low.
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Chemical Carcinogenesis: Initiators
Indirect-Acting Agents
• Requires metabolic conversion to an ultimate carcinogen before they become active
• Polycyclic hydrocarbons present in fossil fuels; animal
fats during process of broiling meats; smoked meat and fish
Principal active product: epoxides form adducts with DNA, RNA, and proteins
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Chemical Carcinogenesis: Initiators
Indirect-Acting Agents
• Most of the known carcinogens are metabolized by the cytochrome P-450-dependent mono-ozygenases
Example: benzo[a]pyrene light smokers with the susceptible genotype CYP1A1 with 7x higher risk of developing lung cancer
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Chemical Carcinogenesis: Initiators
Molecular Targets
• DNA is the primary target
• Any gene may be the target commonly mutated are RAS and p53
Aflatoxin B1 cause G:C T:A transversion in codon 249 of p53
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Radiation Carcinogenesis
Ultraviolet Rays
• UV rays derived from sun increased incidence of SCCA, basal cell carcinoma, and skin melanoma
• Degree of risk depends on:1. Type of UV ray2. Intensity of exposure3. Quantity of light-absorbing
protective coat of melanin
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UVB radiation is the main cause of sunburn and skin cancer although mounting evidence suggests UVA may also play a role. UVB does not penetrate the skin as deeply as UVA but has more energy and therefore does more damage to the skin.
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UVB sunlight is directly absorbed by DNA resulting in single strand breaks and the formation of pyrimidine
dimers.
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Radiation Carcinogenesis
Ionizing Radiation
• Electromagnetic (x-rays, gamma rays) and particulate (α particles, β particles, protons, neutrons) radiation are all carcinogenic
• Lead to formation of reactive oxygen species or free radicals
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Radiation Carcinogenesis
Ionizing Radiation
• High vulnerability: acute and chronic myeloid leukemia; thyroid cancer (only in the young)
• Intermediate: breast, lungs, salivary glands
• Resistant: skin, bone, GIT
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DNA is damaged due to ionization or excitation caused by radiation. Clustered DNA damage would be produced where the density of ionization/excitation is high, whereas the isolated damage would be generated where it is low.
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Microbial Carcinogenesis
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Microbial Carcinogenesis
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Microbial Carcinogenesis
Oncogenic RNA Viruses: HTLV type 1
• Only human retrovirus firmly implicated in causation of cancer in humans (T-cell leukemia/lymphoma)
• Does not contain an oncogene
• Viral integration shows clonal pattern site of integration identical within all cells of a given cancer
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Microbial Carcinogenesis
Oncogenic RNA Viruses: HTLV type 1
• With tax regulatory gene1. stimulates viral mRNA transcription 2. activate transcription of several
host cell genes involved in proliferation and differentiation of T cells FOS gene – immediate early gene Genes encoding IL-2 & its
receptor Gene for myeloid growth factor
granulocyte-macrophage colony-stimulating factor
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Microbial Carcinogenesis
Oncogenic RNA Viruses: HTLV type 1
• With tax regulatory gene3. Inactivates the cell cycle inhibitor
p16/INK4a and enhance cyclin D activation
4. Activate NFκβ activation of anti-apoptotic genes
5. Interfere with DNA repair functions6. Inhibits ATM-mediated cell cycle
checkpoints activated by DNA damage
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Microbial Carcinogenesis
Oncogenic DNAViruses: HPV
• High-risk HPVs: types 16 and 18 squamous cell CA of cervix and anogenital region; penile cancer; oropharyngeal CA
• HPV genome integrated into host genome site of integration random but pattern of integration is clonal
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Naturally occurring cancers associated with papillomaviruses [10, 13].
Species Cancer Predominant viral types
Humans Skin carcinomas HPV-5, -8
Lower genital tract cancers HPV-16, -18, -31, -33
Malignant progression of respiratory papillomas
HPV-6, -11
Cattle Alimentary-tract carcinoma HPV-4
Eye and skin carcinoma Not characterized
Sheep Skin carcinoma Not characterized
Cottontail rabbit Skin carcinomaCotton rabbit papillomavirus (CRPV)
Shehata Cancer Cell International 2005 5:10 doi:10.1186/1475-2867-5-10
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Microbial Carcinogenesis
Oncogenic DNAViruses: HPV
• Viral genome integration interruption of viral DNA within E1/E2 open reading frame loss of E2 viral repressor and overexpression of oncoproteins E6 and E7
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Microbial Carcinogenesis
Oncogenic DNAViruses: EBV
• Associated with African form of Burkitt’s lymphoma, a subset of Hodgkin lymphoma, nasopharyngeal Ca and some gastric carcinoma
• Infects B cells and possibly epithelial cells of the oropharynx via complement receptor CD21
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Microbial Carcinogenesis
Oncogenic DNAViruses: EBV
• Infection of B cells is latent no viral replication and destruction of cells
• Involves the “hijacking” of several normal signalling pathways
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Microbial Carcinogenesis
Oncogenic DNAViruses: EBV
• EBV gene LMP-1 (latent membrane protein-1):1. acts as oncogene behaves like a
constitutively active CD40 receptor stimulate B cell growth
2. Activate NFκβ and JAK/STAT signalling pathways
3. Promote B cell survival and proliferation
4. Activate BCL2 – prevent apoptosis5. Induce expression of pro-
angiogenic factors (VEGF, FGF-2, MMP9, COX2)
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Microbial Carcinogenesis
Oncogenic DNAViruses: EBV
• EBV gene EBNA-2 1. Encodes a nuclear protein that
mimics a constitutively active Notch receptor
2. Transactivates several host genes cyclin D and src family of proto-oncogenes
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Microbial Carcinogenesis
Oncogenic DNAViruses: EBV
• EBV genome contains a viral cytokine vIL-10 hijacked from the host genome prevent macrophages and monocytes from activating T cells
• Impair immune competence allow sustained B-cell proliferation
• Cause translocations that activate c-MYC oncogene
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Microbial Carcinogenesis
Oncogenic DNAViruses: HBV and HCV
• Genomes do not encode any viral oncoproteins
• No consistent pattern of integration in liver cells
• Immunologically-mediated chronic inflammation with hepatocyte death regeneration and genomic damage
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Microbial Carcinogenesis
Helicobacter pylori
• First bacterium classified as a carcinogen
• Implicated in gastric adenocarcinoma and gastric lymphomas
• Involves increased epithelial cell proliferation in a background of chronic inflammation contain genotoxic agents such as ROS
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Microbial Carcinogenesis
Helicobacter pylori
• Contains a “pathogenicity island” that contains cytotoxin-associated A (CagA) gene Penetrates into gastric epithelial
cells initiate signalling cascade that mimics unregulated growth factor stimulation
• Additional mutations may be acquired (e.g. (11:18) translocation) cause constitutive activation of NF-κβ
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Tumor Immunity
Immune surveillance
• A normal function of the immune system is to survey the body for emerging malignant cells and destroy them (+) lymphocytic infiltrates around
tumors and in LN draining sites of cancer
Increased incidence of cancer in immunocompromised individuals
Demonstration of tumor-specific T cells and antibodies
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Tumor Immunity
Tumor antigens
• Poorly immunogenic• Initially classified as:
1. Tumor-specific antigens Present only on tumor cells and
not on any normal cells
2. Tumor-associated antigens Present on tumor cells and also
on some normal cells
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Tumor Immunity
Tumor antigens
• Modern classification based on molecular structure and source
1. Products of mutated genes Synthesized in cytoplasm of
tumor cells enter class I or class II MHC pathways
Not present in normal cells do not induce self-tolerance
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Tumor Immunity
Tumor antigens
2. Overexpressed or aberrantly expressed cellular proteins May be normal cellular proteins
abnormally expressed in tumor cells elicit immune response
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Tumor Immunity
Tumor antigens
3. Antigens produced by oncogenic viruses Most potent: proteins produced
by latent DNA viruses (e.g. HPV and EBV)
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Tumor Immunity
Tumor antigens
4. Oncofetal antigens (CEA, AFP) Proteins that are expressed at
high levels on cancer cells and in normal developing (fetal) but not adult tissues
Genes silenced during development and activated during malignant transformation
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Tumor Immunity
Tumor antigens
5. Altered cell surface glycolipids and glycoproteins Include gangliosodes, blood group
antigens, and mucins present at higher levels in cancer cells than on normal cells
Melanomas: high levels of gangliosides GM2, GD2, and GD3
Target for cancer therapy with specific antibodies
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Loss of normal topology and polarization of epithelial cells in cancer results in secretion of mucins into the bloodstream. The tumor cells invading the tissues and bloodstream also present such mucins on their cell surfaces
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Cancer cells entering the bloodstream form complex thromboemboli with platelets and leukocytes, which are thought to facilitate arrest at ectopic sites, assist interactions with the endothelium, and help in evasion of the immune system. Current data suggest that this phenomenon can be explained by interactions between platelet and/or endothelial P-selectin and carcinoma mucins.
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Tumor Immunity
Tumor antigens
6. Cell type-specific differentiation antigens Specific for particular lineages or
differentiation stages of various cell types
Typically normal self-antigens do not induce immune response
Potential targets for immunotherapy and for identifying the tissue of origin of tumors
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Tumor Immunity
Anti-tumor Effector Mechanisms
1. Cytotoxic T lymphocytes
Play a protective role against virus-associated neoplasms
Demonstrated in blood and tumor infiltrates of cancer patients
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In this diagram the various mechanisms elicited by stress for stimulating innate and adaptive immunity against cancer are illustrated.
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Tumor Immunity
Anti-tumor Effector Mechanisms
2. Natural killer cells
Capable of destroying tumor cells without prior sensitization may form first line of defense vs. Tumor
Activated by IL-2 and IL-5; may be activated by tumors that fail to express MHC class I antigens
NKG2D proteins activating receptors; recognize stress-induced antigens expressed on tumor cells
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Tumor Immunity
Anti-tumor Effector Mechanisms
3. Macrophages
Activated by interferon-gamma secreted by T cells and NK cells
Kill tumors by mechanisms similar to those used to kill microbes or by secretion of TNF
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Tumor Immunity
Anti-tumor Effector Mechanisms
4. Antibodies
No evidence of protective effects of antitumor antibodies against spontaneous tumors
Monoclonal antibody vs. CD20 (B-cell surface antigen) treatment of lymphomas
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Tumor Immunity
Tumor Evasion of Immune System
1. Selective outgrowth of antigen-negative variants
Elimination of strongly immunogenic subclones during tumor progression
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Tumor Immunity
Tumor Evasion of Immune System
2. Loss or reduced expression of MHC molecules
Failure to express normal levels of class I MHC molecules escape CTLs but may trigger NK cells
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Tumor Immunity
Tumor Evasion of Immune System
3. Lack of co-stimulation
Express peptide antigens with class I molecules but without co-stimulatory molecules prevent sensitization and render T cells anergic or undergo apoptosis
Express arginase arginine essential component of TCR loss of T cell recognition
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Tumor Immunity
Tumor Evasion of Immune System
4. Immunosuppression
TGF-β secreted in large quantities by many tumors potent immuno-suppressant
Immune response induced by the tumor may inhibit tumor immunity by activation of T-cell inhibitory receptor CTLA4
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Tumor Immunity
Tumor Evasion of Immune System
4. Immunosuppression
Production of COX2 decreased IL-10 and increased IL-12 immunosuppression and promotion of metastasis
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Tumor Immunity
Tumor Evasion of Immune System
5. Antigen masking
Cell surface antigens of tumors may be hidden, or masked, by glycocalyx molecules expressed in greater amounts in tumor cells
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Tumor Immunity
Tumor Evasion of Immune System
6. Apoptosis of CTLs
Some melanomas and hepatomas express FasL kill Fas-expressing T lymphocytes that come in contact with them
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Tumor Immunity
Tumor Evasion of Immune System
7. Dendritic cell defects
a) Tumor secretion of growth factors inhibit formation of DCs in bone marrow
b) Increased IL-10 levels decreased expression of CD80 and CD86 decreased T cell activation
c) Tumor secretion of nitric oxide and hydrogen peroxide DCs undergo cell death
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Clinical Aspects of Neoplasia
• Both malignant and benign tumors cause problems because of:1. Location and impingement on
adjacent structures2. Functional activity (e.g. Hormone
synthesis or development of para-neoplastic syndrome)
3. Bleeding and infections due to ulceration of tumor through adjacent surfaces
4. Symptoms due to rupture or infarction
5. Cachexia or wasting
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Clinical Aspects of Neoplasia
Local and Hormonal Effects
• Cancers arising within or metastatic to an endocrine gland endocrine insufficiency
• Hormone production seen in neoplasms arising in endocrine glands more typical of benign tumor
• Neoplasms in the gut obstruction or intussusception
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Clinical Aspects of Neoplasia
Local and Hormonal Effects
• Non-endocrine tumors may elaborate hormones or hormone-like products paraneoplastic syndromes
• Melena and hematuria characteristic of neoplasms of the gut and urinary tract
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Clinical Aspects of Neoplasia
Paraneoplastic Syndromes
• Symptom complexes in cancer-bearing individuals that cannot readily be explained, either by the local or distant spread of the tumor or by the elaboration of hormones indigenous to the tissue from which the tumor arose
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Clinical Aspects of Neoplasia
Paraneoplastic Syndromes
• Significance:1. May present the earliest
manifestation of an occult neoplasm2. May represent significant clinical
problems in the affected patients3. May mimic metastatic disease
which may complicate treatment
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Clinical Aspects of Neoplasia
Paraneoplastic Syndromes
1. Endocrinopathies
Ectopic hormone production Cushing syndrome – most
common endocrinopathy 50% with small cell CA of lungs; due to excessive corticotropin production
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Clinical Aspects of Neoplasia
Paraneoplastic Syndromes
2. Hypercalcemia
Most common paraneoplastic synd.
Two processes involved:1. Osteolysis induced by cancer2. Production of calcemic
humoral substances in extra-osseous neoplasms
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Clinical Aspects of Neoplasia
Paraneoplastic Syndromes
3. Acanthosis nigricans
Gray-black patches of verrucous hyperkeratosis on the skin
Genetically determined; juveniles or adults
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Clinical Aspects of Neoplasia
Cancer Cachexia
• Progressive loss of body fat and lean body mass accompanied by profound weakness, anorexia, and anemia
• Weight loss results equally from loss of fat and lean muscle
• Due to increased basal metabolic rate despite reduced food intake
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LMF – lipid-mobilizing factor induce breakdown of adipose into fatty acids; PIF – proteolysis-inducing factor induce protein degradation in skeletal muscles. Tumours convert glucose to lactate, which is transferred to the liver, where it is converted back into glucose. This cycle uses a large amount of energy, and might contribute to cachexia.
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Grading and Staging
Cancer Grading
• Based on degree of differentiation of the tumor cells and, in some cancers, the number of mitoses or architectural features
• Provides information about potential behavior of tumor
• Of less clinical value than staging
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Grading and Staging
Cancer Staging
• Based on:1. Size of primary lesion2. Extent of spread to regional LN3. Presence or absence of blood-
borne metastases
• Gives an idea of how extensive or widespread the cancer is
• Determines treatment and outlook for recovery
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Laboratory Diagnosis
Histologic and Cytologic Methods
• Sampling approaches:
1. Excision or biopsy Quick-frozen section desirable
determine the nature of a mass lesion or in evaluating the margins of an excised cancer
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Laboratory Diagnosis
Histologic and Cytologic Methods
• Sampling approaches:
2. Fine-needle aspiration Aspirating cells and attendant
fluid with a small-bore needle Used for more readily
palpable lesions in breast, thyroid, and LN
Less invasive and more rapidly performed
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Laboratory Diagnosis
Histologic and Cytologic Methods
• Sampling approaches:
3. Cytologic (Papanicolau) smears Screen for cervical carcinoma
and also endometrial CA, bron-chogenic CA, bladder and prostatic tumors, and gastric CA
For ID of tumor cells in abdominal, pleural, joint, and cerebrospinal fluids
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Laboratory Diagnosis
Immunohistochemistry
• Uses:
1. Categorization of undifferentiated malignant tumors
(+) cytokeratins carcinoma (+) desmin muscle cell
origin
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Laboratory Diagnosis
Immunohistochemistry
• Uses:
2. Determination of site of origin of metastatic tumors
Detect tissue-specific or organ-specific antigens in a biopsy specimen of the metastatic deposit (e.g. PSA)
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Laboratory Diagnosis
Immunohistochemistry
• Uses:
3. Detection of molecules that have prognostic or therapeutic significance
e.g. Detection of hormone receptors in breast cancer cells of prognostic and therapeutic value
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Laboratory Diagnosis
Flow Cytometry
• Rapidly and quantitatively measure individual cell characteristics (e.g. Membrane antigens, DNA content of tumor cells)
• Useful in ID and classification of tumor arising from T and B cells, and from mononuclear-phagocytic cells
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Laboratory Diagnosis
Molecular Techniques
1. Diagnosis of malignant neoplasms
2. Prognosis of malignant neoplasms
3. Detection of minimal residual disease
4. Diagnosis of hereditary predisposition to cancer
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Tumor Markers
• Biochemical assays for tumor-associated enzymes, hormones, and other tumor markers in the blood
• Contribute to detection of cancer
• Useful in determining the effectiveness of therapy or appearance of recurrence
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