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DEFINITIONS
Neoplasia = the process of new growth Neoplasia Neoplasm = new growth (Tumor (Tumor) ) Tumor = Oncos (Greek) Oncology = The study of tumors or neoplasms Cancer = common term for the malignant tumors
Definitions
Neoplasm
An abnormal tissue mass whose growth exceeds and is uncoordinated with that of adjacent normal tissue and whose growth persists after cessation of the stimuli that provoked it
Tumors - consist of
Neoplastic cell (parenchyma parenchyma) ) 2) supportive supportive stroma (connective tissue and blood vessel),
stroma parenchyma
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desmoplasia
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NOMENCLATURE
Tumors consist of parenchyma and supportive stroma, nomenclature is based on parenchyma
Fibroadenoma of the breast
NOMENCLATURE
Cancer Prefixes Point to Location
Prefix adenoadeno chondrochondro erythroerythro hepatohepato lipolipo lympholympho melanomelano myelomyelo myomyo osteoosteo Meaning gland cartilage red blood cell liver fat lymphocyte pigment cell bone marrow muscle bone
NOMENCLATURE
Tumors consist of parenchyma and supportive stroma, nomenclature is based on parenchyma
Benign tumors
oma : most benign tumors Adenoma = adeno + oma gland (= benign glandular tumor)
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Nomenclature
Benign tumors
Cystadenomas
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Nomenclature
Benign tumors
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Nomenclature
Malignant tumors
Sarcomas malignant tumors arising from mesenchymal tissue Carcinomas malignant neoplasms of epithelial origin Adenocarcinoma Adeno carcinoma carcinomas with a glandular growth pattern Squamous cell carcinoma carcinomas producing recognizable squamous cells
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Leukemias: Leukemias :
Bloodstream
Lymphomas:
Lymph nodes
Nomenclature
Malignant tumors
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Nomenclature
Malignant tumors
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Nomenclature
Malignant tumors
Melanoma carcinoma of melanocytes Seminomas carcinomas of testicular origin
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Nomenclature
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Nomenclature
Malignant tumors
Seminomas carcinomas of testicular origin
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Nomenclature
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Nomenclature
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Nomenclature
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Nomenclature
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Nomenclature
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Nomenclature
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an increased number of cells Hyperplasia an while generally preserving the normal tissue structure increase in the size of individual Hypertrophy increase cells, cells , which may result in enlargement of the organ, but preserves normal architecture Metaplasia process in which fullyfully-differentiated cells of one type are replaced by fullyfully -differentiated cells of another type
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Anaplasia
lack of differentiation Pleomorphic nuclei Hypertrophied cells Hyperchromatic and convoluted nuclei Increased nuclear nuclear/ /cytoplasmic ratio Mitotic figures Tumor giant cells with multiple nuclei
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Anaplasia
Anaplastic tumor of the skeletal muscle (rhabdomyosarcoma). Note the marked cellular and nuclear pleomorphism, hyperchromatic nuclei, and tumor giant cells.
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Anaplastic
Dysplasia
loss of uniformity of the individual epithelial cells loss in their architectural orientation pleomorphism and hyperchromatic may not progress to cancer if dysplastic changes are marked and involve the entire thickness of the epithelium (preinvasive neoplasm neoplasm) ) = carcinoma in situ
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Dysplasia Alterations in cell size and morphology, with or without disorganized growth pattern
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Carcinoma in situ. A, This lowlow-power view shows that the entire thickness of the epithelium is replaced by atypical dysplastic cells. There is no orderly differentiation of squamous cells. The basement membrane is intact and there is no tumor in the subepithelial stroma. B, A highhigh-power view of another region shows failure of normal differentiation, marked nuclear and cellular pleomorphism, and numerous mitotic figures extending toward the surface
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Rate of growth
Growth rate of tumors correlates with their level of differentiation differentiation, , and thus most malignant tumors grow more rapidly than do benign tumors
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Local invasion
benign tumors grow as cohesive expansile masses that remain localized to their site of origin and do not have the capacity to infiltrate, invade, or metastasize
growth of cancers is accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue
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Metastasis
Malignant Tumor Pathways of spread body cavities and surfaces (tumor seeding) peritoneal, pleural, pericardial lymphatic spread Carcinomas > Sarcomas hematogenous spread Sarcomas > Carcinomas
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kinetics of tumor cell growth tumor angiogenesis tumor progression and heterogeneity mechanisms of invasion and metastasis
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Cell cycle
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Rates of tumor cell growth (malignant) From 1 transformed cell to smallest clinically detectable mass (1 gm) of 109 cells = 30 doublings To reach 1012cells (1 kg) requires only 10 additional doublings
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kinetics of tumor cell growth tumor angiogenesis tumor progression and heterogeneity mechanisms of invasion and metastasis
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tumor angiogenesis
neo neovascularization vascularization angiogenesis is a necessary biologic correlate of malignancy critical for growth and spread of tumors TumorTumor -associated angiogenic factor Vascular endothelial growth factor
(VEGF)
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kinetics of tumor cell growth tumor angiogenesis tumor progression and heterogeneity mechanisms of invasion and metastasis
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kinetics of tumor cell growth tumor angiogenesis tumor progression and heterogeneity mechanisms of invasion and metastasis
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Four classes classes of normal regulatory genes are the pricipal targets of genetic damage
the growthgrowth-promoting proto proto-oncogenes the growthgrowth-inhibiting tumor suppressor genes genes that regulate programmed cell death (apoptosis apoptosis) ) genes involved in DNA repair
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GF
GFR
Oncogene activation involves a gain of function Activation by point mutation of the oncogene eg. eg. RAS family genes (HRAS, KRAS, and NRAS
Growth factor eg. eg. TGF RTK
Cytoplasm
Grb2 Grb2 SOS
Nucleus
Changes in Gene FOS expression
Ras
Raf MEK
MAPK
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Figure 7-32 Model for action of RAS genes. genes. When a normal cell is stimulated through a growth factor receptor, inactive (GDP(GDP-bound) RAS is activated to a GTP GTP-bound state. Activated RAS recruits RAF and stimulates the MAPMAP-kinase pathway to transmit growth growth-promoting signals to the nucleus. The mutant RAS protein is permanently activated because of inability to hydrolyze GTP, leading to continuous stimulation of cells without any external trigger. The anchoring of RAS to the cell membrane by the 59 Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 18 November 2005 01: 01:31 PM) farnesyl moiety is essential for its action.
2005 Elsevier
Oncogene activation involves a gain of function Activation by chromosomal rearrangement eg. eg. BCR BCR-ABL fusion gene in Philadelphia (Ph1) chromosome in chronic myeloid leukemia leukemia
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BCR-ABL BCRfusion gene 8.5 kb BCRBCR-ABL mRNA p210 BCR BCR-ABL hybrid protein
malignant transformatio n
clonal myeloproliferation
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MOLECULAR BASIS OF CANCER CANCER: : Insensitivity to growth inhibitory signals _ Tumor suppressor genes
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MOLECULAR BASIS OF CANCER CANCER: : Insensitivity to growth inhibitory signals _ Tumor suppressor genes
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Retinoblastoma
Two hit Hypothesis Retinoblastoma Tumor suppressor (Rb)
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Figure 7-31 Subcellular localization and functions of major classes of cancer cancer-associated genes. The protooncogenes are colored red, cancer suppressor genes blue, DNA repair genes green, and genes that regulate apoptosis purple.
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 18 November 2005 01: 01:31 PM) 2005 Elsevier
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Carcinogenesis is a multistep process at both the phenotypic and the genetic levels
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Molecular model for the evolution of colorectal cancers through adenoma adenoma-carcinoma sequence
Wild-type Wildp53 NORMAL COLON MUCOSA AT RISK ADENOMAS
Oncogene-induced Oncogenesenescence
CARCINOMA Germ-line or Somatic Germmutations of tumor suppressor genes (first hit) Inactivation of normal allels (second hit)
Proto-oncogene Protomutations
APC at 5q21
APC -catenin
initiation causes mutations promoters induce tumors in initiated initiated cells effects of promoters are reversible
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Progression
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Chemical Carcinogens
direct acting alkylating agents, polycyclic aromatic hydrocarbons, aromatic amines and azo dyes, naturally occurring carcinogens, nitrosamines and amides, promoters of chemical carcinogenesis
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Radiation carcinogenesis
Ultraviolet rays skin cancer: melanoma, melanoma, squamous cell carcinoma Ionizing radiation (x (x-rays, rays, gamma-rays, rays, alphaparticles, particles , beta- particles, particles, protons, protons, neutrons) neutrons) atomic bomb high incidence of leukemia (after an average of 7-10 y) x-ray (during infancy and childhood) childhood) thyroid cancers (9%) Electrolectro-magnetic wave, microwave
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Immunocytochemistry
-categorization of undifferentiated malignant tumors -categorization of leukemias and lymphomas -determination of site of origin of metastatic tumors -detection of molecules that have prognostic or therapeutic significance
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molecular diagnosis 1. diagnosis of malignant neoplasms 2. prognosis of malignant neoplasms 3. detection of minimal residual disease 4. diagnosis of hereditary predisposition to cancer Other techniques flow cytometry tumor markers
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