Neoplasia (Benign and Malignant Tumour) PDF

Neoplasia (Benign and malignant tumour)  Neoplasia Is a new growth or an abnormal outgrowing mass of tissue and uncoordinating with the normal tissue, which may persist after the cessation of the stimuli. General Charachteristics of Neoplasms 1. Unrespon...

Neoplasia (Benign and malignant tumour)  Neoplasia Is a new growth or an abnormal outgrowing mass of tissue and uncoordinating with the normal tissue, which may persist after the cessation of the stimuli. General Charachteristics of Neoplasms 1. Unresponsive to the normal growth factors controlling cell division (continue to replicate ). 2. Competing with the normal cells and tissues for their metabolic needs. 3. Have degree of autonomy steadily increasing in size regardless of their local environment and the nutritional status of the host. 4. Require endocrine stimulatory signals for their growth. Epidemiology of Cancer The incidence of cancer varies with age, race, geographic factors, and genetic backgrounds. Cancers are most common at the two extremes of age. The geographic variation results mostly from different environmental exposures. Most cancers are sporadic, but some are familial. Predisposition to hereditary cancers may be autosomal dominant or autosomal recessive. The former usually are linked to inheritance of a germ line mutation of cancer suppressor genes, whereas the latter typically are associated with inherited defects in DNA repair. Familial cancers tend to be bilateral and arise earlier in life than their sporadic counterparts. Some acquired diseases, known as preneoplastic disorders, are known to be associated with an increased risk for development of cancer. Genetic Lesions in Cancer Tumor cells may acquire mutations through several means, including point mutations, and nonrandom chromosomal abnormalities that contribute to malignancy; these include balanced translocations, deletions, and cytogenetic manifestations of gene amplification. Balanced translocations contribute to carcinogenesis by overexpression of oncogenes or generation of novel fusion proteins with altered signaling capacity. Deletions frequently affect tumor suppressor genes, whereas gene amplification increases the expression of oncogenes. Overexpression of miRNAs can contribute to carcinogenesis by reducing the expression of tumor suppressors, while deletion or loss of expression of miRNAs can lead to overexpression of proto-oncogenes. Tumor suppressor genes and DNA repair genes also may be silenced by epigenetic changes, which involve reversible, heritable changes in gene expression that occur not by mutation but by methylation of the promoter. Insensitivity to Growth Inhibitory Signals Tumor suppressor genes encode proteins that inhibit cellular proliferation by regulating the cell cycle. Unlike oncogenes, both copies of the gene must be dysfunctional for tumor development to occur. In cases with familial predisposition for development of tumors, affected persons inherit one defective (nonfunctional) copy of a tumor suppressor gene and lose the second one through somatic mutation. In sporadic cases, both copies are lost through somatic mutations. Neoplasm is “a tumour OR swelling”. Tumours can be subdivided into 1. Benign considered innocent: remaining localized, not spreading to other sites, may produce local effects. 2. Malignant tumours, cancers, which can invade and destroy adjacent structures and spread to distant sites (metastasize). Benign tumours Resemble their normal cells of origin morphologically and functionally Well differentiated cells Mitoses are very scanty in number and are of normal configuration Grow slowly, localized, not infilterate. Acquired preneoplastic disorders 1. Persistent regenerative cell replication, e.g. long standing skin ulcer, and hepatic cirrhosis. 2. Hyperplastic and dysplastic proliferations, e.g. endometrial hyperplasia and dysplastic changes of the bronchus. 3. Chronic atrophic gastritis. 4. Chronic ulcerative colitis. 5. Leukoplakia of the oral cavity. 6. Villous adenomas of the colon.  Nomenclature of Benign tumours - Cell type from tumour arises + suffix “-oma” , e.g. fibroma, chondroma, leiomyoma. - according to cells of origin, e.g.: Adenoma: glandular pattern. Papilloma: epithelial surfaces, producing microscopic or macroscopic finger-like structure. Polyp: Is a mass projects above the mucosal surface to form a macroscopically visible structure. Cystadenomas: Hollow cystic masses (in the ovary). Fibroadenoma of the breast and benign mixed tumour of salivary glands (pleomorphic adenoma): Mixed type Malignant tumours 1. Pleomorphism: variation in size and shape. 2. Hyperchromasia: Increased nuclear pigmentation. 3. High nuclear/ cytoplasmic (N/C) ratio. 4. Giant cells may be formed containing several nuclei. 5. Nuclear pleomorphism, with coarse and clumped chromatin. 6. Numerous mitoses with atypical forms. 7. Loss of polarity: cells fail to form a recognizable pattern of orientation. 8. Dysplasia: loss in the uniformity of individual cells and their architectural orientation (partial or the entire thickness of the epithelium (carcinoma in situ)). - Rapidly growing tumour with progressive infiltration, invasion, destruction and penetration of the surrounding tissue. - Metastasis: secondary implants discontinuous with the primary tumour. Pathways: 1. Seeding within body cavities. 2. Lymphatic spread typical for carcinomas. 3. Hæmatogenous spread for sarcomas, but carcinomas also metastasize by this route. The liver and lungs →most secondary sites. Mechanisms of Local And Distant Spread 1. Invasion of ECM: reach to the basement membrane, then invade the interstitial connective tissue and then penetrate the blood vessels’ basement membrane; As four stages: A. Detachment of tumour cells from each other by loss of surface E-cadherins. B. Attachment of tumour cells to matrix components. C. Degradation of ECM by production and induction of fibroblasts to produce proteases, especially metalloproteinases including gelatinases, collagenases and stromelysins. D. Migration of tumour cells by cell-derived cytokines, cleavage products of matrix components and some growth factors. 2. Vascular dissemination: - Intravasation: by degradation of blood vessels’ basement membrane, forming tumour emboli by aggregation with leukocytes and platelets, hiding tumour cells from the immune system. - Extravasation of free tumour cells involves adhesion to the endothelium followed by transgression through the basement membrane by a similar mechanism to intravasation. Development of Sustained Angiogenesis Vascularization of tumors is essential for their growth and is controlled by the balance between angiogenic and antiangiogenic factors that are produced by tumor and stromal cells. Hypoxia triggers angiogenesis through the actions of HIF-1α on the transcription of the pro-angiogenic factor VEGF. Many factors regulate angiogenesis; for example, p53 induces synthesis of the angiogenesis inhibitor Ability to invade tissues, a hallmark of malignancy, occurs in four steps: loosening of cell–cell contacts, degradation of ECM, attachment to novel ECM components, and migration of tumor cells. Cell–cell contacts are lost by the inactivation of E-adherin through a variety of pathways. Basement membrane and interstitial matrix degradation is mediated by proteolytic enzymes secreted by tumor cells and stromal cells, such as MMPs Proteolytic enzymes also release growth factors sequestered in the ECM and generate chemotactic and angiogenic fragments from cleavage of ECM glycoproteins. The metastatic site of many tumors can be predicted by the location of the primary tumor. Many tumors arrest in the first capillary bed they encounter (lung and liver, most commonly). Some tumors show organ tropism, probably due to activation of adhesion or chemokine receptors whose ligands are expressed by endothelial cells at the metastatic site. Nomenclature of Malignant tumours - Mesenchymal origin→ sarcomas e.g. fibrosarcoma, chondrosarcoma, leiomyosarcoma. - Epithelial origin (endo, meso and ectoderm) →carcinomas, e.g. squamous cell carcinoma, adenocarcinoma. - Two components (mesenchymal and epithelial) e.g. Teratomas → divergent differentiation into all embryonic layers, commonly seen in the ovaries and testicles, being benign or malignant. Characteristics of Benign and Malignant Tumors Benign and malignant tumors can be distinguished from one another based on the degree of differentiation, rate of growth, local invasiveness, and distant spread. Benign tumors resemble the tissue of origin and are well differentiated; malignant tumors are poorly or completely undifferentiated (anaplastic). Benign tumors are slow-growing, whereas malignant tumors generally grow faster. Benign tumors are well circumscribed and have a capsule; malignant tumors are poorly circumscribed and invade the surrounding normal tissues. Benign tumors remain localized to the site of origin, whereas malignant tumors are locally invasive and metastasize to distant sites. Laboratory Diagnosis of Cancer Several sampling approaches exist for the diagnosis of tumors, including excision, biopsy, fine-needle aspiration, and cytologic smears. Immunohistochemistry and flow cytometry studies help in the diagnosis and classification of tumors, because distinct protein expression patterns define different entities. Proteins released by tumors into the serum (tumor markers), such as PSA, can be used to screen populations for cancer and to monitor for recurrence after treatment. Molecular analyses are used to determine diagnosis, prognosis, the detection of minimal residual disease, and the diagnosis of hereditary predisposition to cancer. Molecular profiling of tumors by cDNA arrays and sequencing can determine expression of large segments of the genome and catalog all of the mutations in the tumor genome and thus may be useful in molecular stratification of otherwise identical tumors or those of distinct histogenesis that share a mutation for the purpose of treatment and prognostication. Tumour antigens (tumour markers): 1. Tumour-specific antigens: unique antigens for tumours. - melanoma associated antigen-1 (MAGE-1) - some pancreatic and breast carcinoma (CA-125, CA-119). 2. Tumour-Associated Antigens: shared by normal untransformed cells, -prostate-specific antigens (PSA -alfa-fœtoprotein (AFP) in hepatocellular carcinoma - carcinoembryonic (CEA) antigen in colorectal carcinomas. Grading And Staging Grading: based on cytological differentiation of tumour cells and the number of mitoses within the tumour. Graded I, II, III or IV in order of increasing anaplasia. Staging: is based on: 1. The size of the primary lesion. 2. Extent of spread to regional lymph nodes. 3. Presence or absence of metastases. TNM staging system: T: tumour size, N: Lymph node metastases, M: Distant metastases.