Mechanisms of Cancer Spread, Grading, and Staging PDF

29 MECHANISMS OF CANCER SPREAD, GRADING AND STAGING ILOs By the end of this lecture, students will be able to 1. Delineate pathways of spread in relation to tumor subtypes 2. Correlate the tumor grading and staging to tumor prognosis Pathways of Canc...

29 MECHANISMS OF CANCER SPREAD, GRADING AND STAGING ILOs By the end of this lecture, students will be able to 1. Delineate pathways of spread in relation to tumor subtypes 2. Correlate the tumor grading and staging to tumor prognosis Pathways of Cancer Spread : Cancer dissemination occurs by three routes: Direct spread: To invade the nearby structures due to lack of a capsule. Lymphatic spread Transports tumor cells to regional nodes (through lymphatic vessels at tumor margins) and ultimately throughout the body. Lymph nodes draining tumors are frequently enlarged; this can result from metastatic tumor cell proliferation or from reactive hyperplasia as reaction to tumor antigens. Biopsy of the proximal sentinel lymph node draining a tumor can allow accurate assessment of tumor metastasis (for purpose of tumor staging). Carcinomas usually prefer metastasis by lymphatics prior to hematogenous spread. Hematogenous spread is typical of sarcomas but also is the favored route for certain carcinomas (e.g., renal). Because of their thinner walls, veins are more frequently invaded than arteries, and metastasis follows the pattern of venous flow; understandably, lung and liver are the most common sites of hematogenous metastases. Seeding of body cavities and surfaces (Transcoelomic spread): occurs by dispersion into peritoneal, pleural pericardial, subarachnoid, or joint spaces. Ovarian carcinoma typically spreads transperitoneally to the surface of abdominal viscera, often without deeper invasion. Mucus-secreting appendiceal carcinomas can fill the peritoneum with a gelatinous neoplastic mass called pseudomyxoma peritonei. Perineural spread: Invades the nerves in the tissue. Clinically this presents as pain. Mechanism of spread: 1. Angiogenesis: In the absence of new vessels, tumor cannot access the vasculature so that angiogenesis also clearly influences metastatic potential. Tumors require nutrients and waste removal; thus they cannot enlarge beyond a 1- to 2-mm size without inducing host blood vessel growth (angiogenesis). New tumor vessels differ from normal vasculature by being dilated and leaky with slow and abnormal flow. Endothelial growth proteins include vascular endothelium growth factor (VEGF) and basic fibroblast growth factor (bFGF); proteases can also release preformed angiogenic mediators (e.g., bFGF) from the extracellular matrix (ECM). Page 1 of 4  2. Invasion and Metastasis: It involves the following steps: I. Invasion of Extracellular Matrix: To metastasize, tumor cells must dissociate from adjacent cells, and then degrade, adhere, and migrate through ECM. Detachment: Normal epithelial cells bind each other through adhesion molecules, called cadherins. In several carcinomas, there is downregulation of epithelial (E)-cadherins, thereby reducing cellular cohesion. ECM degradation: Tumors elaborate proteases or can induce stromal cell to produce them. Matrix metalloproteinase 9 (MMP9) degrades epithelial and vascular basement membrane type IV collagen, in addition to releasing ECM-sequestered pools of VEGF. ECM attachment: Invading cells must express adhesion molecules that allow interaction with the ECM. Migration: In addition to diminished adhesivity, tumor cells have increased locomotion. They also migrate in response to stromal cell chemotactic factors, degraded ECM components, and liberated stromal growth factors. II. Vascular Dissemination and Homing of Tumor Cells: Tumor cells embolize in the bloodstream as self-aggregates and by adhering to circulating leukocytes and platelet. Exactly where tumor cell emboli eventually lodge and begin growing is influenced by the following: 1) Vascular and lymphatic drainage from the site of the primary tumor. 2) Interaction with specific receptors. Certain tumor cells express adhesion molecules that bind high endothelial venules in lymph nodes. Other tumors exhibit specific chemokine receptors that interact with ligands uniquely expressed in certain vascular beds. 3) The microenvironment of the organ or site (e.g., a tissue rich in protease inhibitors might be resistant to penetration by tumor cells). Grading and staging of malignant Tumors This assessment provides a semiquantitative estimate of the clinical gravity of a tumor. Both histologic grading and clinical staging are valuable for prognostication and for planning therapy, although staging has proved to be of greater clinical value. Grading is based on the degree of differentiation of malignant tumor (how much the tumor resembles its normal counterpart). It depends on architectural features and\or number of mitoses. Grading is evaluated by histological examination of malignant tissue. Tumors are classified into; Grade I: well differentiated: contains 75% or more of well differentiated tumor cells. (Lower grade, slower growth rate and radioresistant) Grade II: moderately differentiated: contains 25-75% differentiated tumor cells. Grade III: poorly differentiated: contains less than 25% tumor cells. (Higher grade, Rapidly growing and is radiosensitive). Staging is based on the extent of local and distant spread. The major system currently used is the American Joint Committee on Cancer (AJCC) staging; the classification involves a TNM designation: Page 2 of 4  T for tumor (size and local invasion) N for regional lymph node involvement M for distant metastases. Staging is a clinical procedure depending on clinical, radiological and sometimes histological evaluation. Diagnosis of neoplasia: 1. Clinically 2. Radiological methods: CT- PET -CT, Ultrasound, MRI, Mammogram, and others. 3. Laboratory Clinical Aspects of Neoplasia Although malignant tumors are more threatening than benign, any tumor can cause morbidity and mortality. Local Effects Tumors of the GI tract may cause obstruction of the bowel or may ulcerate and cause bleeding, or pain. Cancer Cachexia: Loss of body fat, lean body mass, and profound weakness. It is multifactorial but is largely driven by TNF and other cytokines elaborated by inflammatory cells in response to tumors which lead to: Loss of appetite Reduced synthesis and storage of fat and increased mobilization of fatty acids from adipocytes Increase catabolism of muscle and adipose tissue. Paraneoplastic syndrome\ Hormone production: Malignant tumors may acquire the ability to elaborate hormone-like substances giving rise to aberrant hormonal effects such as hypoglycaemia (insulin production) or hypercalcemia (parathyroid hormone [PTH]-producing tumors). Laboratory Diagnosis of Cancer 1- Histologic and Cytologic Methods Histologic examination is the most important method of diagnosis. In addition to traditional formalin-fixed and paraffin-embedded sections, quick-frozen sections provide rapid diagnoses during procedures. Cytologic interpretation is based chiefly on changes in the appearance of individual cells. Screening (Pap) smears involve examination of shed cells; exfoliative cytologic examination is used most commonly in the diagnosis of cancer of the uterine cervix. Fine-needle aspiration involves aspiration of cells and fluids from tumors or masses. Page 3 of 4 1- Tumor markers: Tumor markers are tumor-derived or - associated molecules (antigens) that are detected in tumor tissues, blood or other body fluids. Examples and clinical applications: Prostate-specific antigen (PSA) elaborated by prostate epithelium; elevated levels can reflect malignancy. 2- Molecular methods: Prognosis of malignancy: Certain genetic alterations are associated with poor prognosis; identification of these can stratify treatment. HER-2-NEU overexpression in breast cancer is an indication for monoclonal antibody therapy against epithelial growth factor receptor. Detection of residual disease: The ability to detect extremely small numbers of malignant cells can be useful for evaluating therapy efficacy or for assessing tumor recurrence. Diagnosis of hereditary predisposition to cancers: e.g., predisposition to breast cancer can be detected by analysis of BRCA-1, BRCA-2 allowing family screening and risk stratification. References: 1. Kumar, Abbas, Aster. Robbins Basic Pathology, 10th ed. Elsevier. 2. Mitchell, Kumar, Abbas, Aster. Pocket Companion to Robbins and Cotran Pathologic Basis of Disease, 9th ed. Elsevier. 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