Neoplasia assignment power point presentation.pptx

Neoplasia

1. Vascular and Cardiac Pathology Dr. Bukenya Ali 07 TH /Mar/2025

2. PRESENTATION - OUTLINE VASCULAR PATHOLOGY CARDIAC PATHOLOGY KEY CONCEPTS DISCUSSION

3. VASCULAR PATHOLOGY Key Concepts Vasculitis - Fundamental Principles A. Definition and Structure Vasculitis refers to the inflammation of blood vessel walls. The arterial wall consists of three layers: the endothelial intima, the smooth muscle media, and the connective tissue adventitia. B. Etiology The cause of vasculitis is often unclear, with the majority of cases being noninfectious. C. Clinical Manifestations Common nonspecific inflammatory symptoms such as fever, fatigue, weight loss, and myalgias. Symptoms indicative of organ ischemia resulting from luminal narrowing or thrombosis in the affected vessels.

4. NEOPLASIA Definition: Refers to new tissue growth that is unregulated, irreversible, and monoclonal; these features distinguish it from hyperplasia and repair. Monoclonal means that the neoplastic cells are derived from a single mother cell. Clonality was historically determined by glucose-6-phosphate dehydrogenase (G6PD) enzyme isoforms. Multiple isoforms (e.g., G6PD4, G6PD,, and G6PD ) exist; but only one isoform is inherited from each parent. In females, one isoform is randomly inactivated in each cell by lyonization(G6PD is present on the X chromosome). The normal ratio of active isoforms in cells of any tissue is 1:1 (e.g., 50% of cells have G6PD, and 50% of cells have G6PD).

5. NEOPLASIA 1:1 ratio is maintained in hyperplasia, which is polyclonal (cells are derived from multiple cells). Only one isoform is present in neoplasia, which is monoclonal. Clonality can also be determined by androgen receptor isoforms, which are also present on the X chromosome. Clonality of B lymphocytes is determined by immunoglobulin (Ig) light chain phenotype. Ig is comprised of heavy and light chains. Each B cell expresses a light chain that is either kappa or lambda. Normal kappa to lambda light chain ratio is 3:1. This ratio is maintained in hyperplasia, which is polyclonal.

6. NEOPLASIA Ratio increases to > 6:1 or is inverted (e.g., kappa to lambda ratio = 1:3) in lymphoma, which is monoclonal. Neoplastic tumors are benign or malignant. Benign tumors remain localized and do not metastasize. Malignant tumors (cancer) invade locally and have the potential to metastasize. Tumor nomenclature is based on lineage of differentiation (type of tissue produced) and whether the tumor is benign or malignant.

7. Examples of Tumor Nomenclature

8. EPIDEMIOLOGY Cancer is the 2nd leading cause of death in both adults and children. The leading causes of death in adults are-Cardiovascular disease and in children - Accidents. The most common cancers by incidence in adults are; Breast/prostate, Lung, and Colorectal. The most common causes of cancer mortality in adults are; Lung, Breast/prostate, and Colorectal.

9. Role of Screening Cancer begins as a single mutated cell. Approximately 30 divisions occur before the earliest clinical symptoms arise. Each division (doubling time) results in increased mutations. Cancers that do not produce symptoms until late in disease will have undergone additional divisions and, hence, additional mutations. Cancers that are detected late tend to have a poor prognosis. Screening seeks to catch dysplasia (precancerous change) before it becomes carcinoma or carcinoma before clinical symptoms arise; efficacy of screening, however, requires a decrease in cancer-specific mortality.

10. Role of Screening Common screening methods include Pap smear-detects cervical dysplasia (CIN) before it becomes carcinoma Mammography-detects in situ breast cancer (e.g., DCIS) before it invades or invasive carcinoma before it becomes clinically palpable. Prostate specific antigen (PSA) and digital rectal exam-detects prostate carcinoma before it spreads. Hemoccult test (for occult blood in stool) and colonoscopy-detect colonic adenoma before it becomes colonic carcinoma or carcinoma before it spreads

11. CARCINOGENESIS BASIC PRINCIPLES Cancer formation is initiated by damage to DNA of stem cells. The damage overcomes DNA repair mechanisms, but is not lethal. Carcinogens are agents that damage DNA, increasing the risk for cancer. Important carcinogens include chemicals, oncogenic viruses, and radiation. DNA mutations eventually disrupt key regulatory systems, allowing for tumor promotion (growth) and progression (spread). Disrupted systems include proto-oncogenes, tumor suppressor genes, and regulators of apoptosis.

12. Important Carcinogens and Associated Cancers

13. ONCOGENES Proto-oncogenes are essential for cell growth and differentiation; mutations of proto-oncogenes form oncogenes that lead to unregulated cellular growth. Categories of oncogenes include growth factors, growth factor receptors, signal transducers, nuclear regulators, and cell cycle regulators. Growth factors induce cellular growth (e.g., PDGFB in astrocytoma). Growth factor receptors mediate signals from growth factors (e.g., ERBB2 [HER2/neu] in breast cancer). Signal transducers relay receptor activation to the nucleus (e.g., ras ).

14. Ras is associated with growth factor receptors in an inactive GDP-bound state. Receptor binding causes GDP to be replaced with GTP, activating ras . Activated ras sends growth signals to the nucleus. Ras inactivates itself by cleaving GTP to GDP; this is augmented by GTPase activating protein. Mutated ras inhibits the activity of GTPase activating protein. This prolongs the activated state of ras , resulting in increased growth signals. Cell cycle regulators mediate progression through the cell cycle (e.g., cyclin and cyclin-dependent kinase). ONCOGENES Cont. . .

15. ONCOGENES Cont. . . Cyclins and cyclin-dependent kinases (CDKs) form a complex which phosphorylates proteins that drive the cell through the cell cycle. e.g : the cyclin D/CDK4 complex phosphorylates the retinoblastoma protein, which promotes progression through the G/ S checkpoint.

16. Important Carcinogens and Associated Cancers

17. Regulate cell growth and, hence, decrease ("suppress") the risk of tumor formation; p53 and Rb (retinoblastoma) are classic examples. p53 regulates progression of the cell cycle from G1 to S phase. In response to DNA damage, p53 slows the cell cycle and upregulates DNA repair enzymes. If DNA repair is not possible, p53 induces apoptosis. p53 upregulates BAX, which disrupts Bcl2. Cytochrome c leaks from the mitochondria activating apoptosis. TUMOR SUPPRESSOR GENES

18. Both copies of the p53 gene must be knocked out for tumor formation (Knudson two-hit hypothesis). Loss is seen in > 50% of cancers. Germline mutation results in Li-Fraumeni syndrome (2nd hit is somatic), characterized by the propensity to develop multiple types of carcinomas and sarcomas. Rb also regulates progression from G1 to S phase. Rb "holds" the E2F transcription factor, which is necessary for transition to the S phase. E2F is released when RB is phosphorylated by the cyclin D/cyclin-dependent kinase 4 (CDK4) complex. TUMOR SUPPRESSOR GENES

19. Rb mutation results in constitutively free E2F, allowing progression through the cell cycle and uncontrolled growth of cells. Both copies of Rb gene must be knocked out for tumor formation (Knudson two hit hypothesis). Sporadic mutation (both hits are somatic) is characterized by unilateral retinoblastoma. Germline mutation results in familial retinoblastoma (2nd hit is somatic), characterized by bilateral retinoblastoma and osteosarcoma. TUMOR SUPPRESSOR GENES

20. Prevent apoptosis in normal cells, but promote apoptosis in mutated cells whose DNA cannot be repaired (e.g., Bcl2) Bcl2 normally stabilizes the mitochondrial membrane, blocking release of cytochrome c. Disruption of Bcl2 allows cytochrome c to leave the mitochondria and activate apoptosis. Bcl2 is overexpressed in follicular lymphoma. t(l4;18) moves Bcl2 (chromosome 18) to the lg heavy chain locus (chromosome 14), resulting in increased Bcl2. Mitochondrial membrane is further stabilized, prohibiting apoptosis. REGULATORS OF APOPTOSIS

21. B cells that would normally undergo apoptosis during somatic hypermutation in the lymph node germinal center accumulate, leading to lymphoma. REGULATORS OF APOPTOSIS

22. Telomerase is necessary for cell immortality. Normally, telomeres shorten with serial cell divisions, eventually resulting in cellular senescence. Cancers often have upregulated telomerase, which preserves telomeres. Angiogenesis (production of new blood vessels) is necessary for tumor survival and growth. - FGF and VEGF (angiogenic factors) are commonly produced by tumor cells. OTHER IMPORTANT FEATURES OF TUMOR DEVELOPMENT

23. Avoiding immune surveillance is necessary for tumor survival. Mutations often result in production of abnormal proteins, which are expressed on MHC class I. CDS+T cells detect and destroy such mutated cells. Tumor cells can evade immune surveillance by downregulating expression of MHC class I. Immunodeficiency (both primary and secondary) increases risk for cancer. OTHER IMPORTANT FEATURES OF TUMOR DEVELOPMENT

24. TUMOR INVASION AND SPREAD Accumulation of mutations eventually results in tumor invasion and spread. Epithelial tumor cells are normally attached to one another by cellular adhesion molecules (e.g., E-cadherin). Downregulation of E-cadherin leads to dissociation of attached cells. Cells attach to laminin and destroy basement membrane (collagen type IV) via collagenase. Cells attach to fibronectin in the extracellular matrix and spread locally. Entrance into vascular or lymphatic spaces allows for metastasis (distant spread). TUMOR PROGRESSION

25. ROUTES OF METASTASIS Lymphatic spread is characteristic of carcinomas. Initial spread is to regional draining lymph nodes (Fig. 3.2). Hematogenous spread is characteristic of sarcomas and some carcinomas. Renal cell carcinoma (often invades renal vein). Hepatocellular carcinoma (often invades hepatic vein). Follicular carcinoma of the thyroid. Choriocarcinoma Seeding of body cavities is characteristic of ovarian carcinoma, which often involves the peritoneum ('omental caking'). TUMOR PROGRESSION

26. CLINICAL FEATURES Benign tumors tend to be slow growing, well circumscribed, distinct, and mobile. Malignant tumors are usually rapid growing, poorly circumscribed, infiltrative, and fixed to surrounding tissues and local structures. Biopsy or excision is generally required before a tumor can be classified as benign or malignant with certainty. Some benign tumors can grow in a malignant-like fashion, and some malignant tumors can grow in a benign-like fashion. CLINICAL CHARACTERISTICS

27. HISTOLOGIC FEATURES Benign tumors are usually well differentiated (Fig. 3.4A). Characteristics include; Organized growth Uniform nuclei Low nuclear to cytoplasmic ratio Minimal mitotic activity Lack of invasion (of basement membrane or local tissue) No metastatic potential CLINICAL CHARACTERISTICS

28. Malignant tumors are classically poorly differentiated (anaplastic). Characteristics include Disorganized growth (loss of polarity). Nuclear pleomorphism and hyperchromasia High nuclear to cytoplasmic ratio High mitotic activity with atypical mitosis Invasion (through basement membrane or into local tissue) Metastatic potential is the hallmark of malignancy-benign tumors never metastasize. Immunohistochemistry is used to characterize tumors that are difficult to classify on histology. CLINICAL CHARACTERISTICS

29. Proteins released by tumor into serum (e.g., PSA) Useful for screening, monitoring response to treatment, and monitoring recurrence Elevated levels require tissue biopsy for diagnosis of carcinoma (e.g., biopsy of prostate with elevated PSA). GRADING OF CANCER Microscopic assessment of differentiation (i.e., how much a cancer resembles the tissue in which it grows); takes into account architectural and nuclear features Well differentiated (low grade)- resembles normal parent tissue Poorly differentiated (high grade)-does not resemble parent tissue SERUM TUMOR MARKERS

30. Important for determining prognosis; well-differentiated cancers have better prognosis than poorly-differentiated cancers. STAGING OF CANCER Assessment of size and spread of a cancer Key prognostic factor; more important than grade Determined after final surgical resection of the tumor Utilizes TNM staging system T- tumor (size and/or depth of invasion) N- spread to regional lymph nodes; second most important prognostic factor M- metastasis; single most important prognostic factor SERUM TUMOR MARKERS