Neoplasia Lecture 5 PDF

3  Neoplasia Lecture 5 2. Oncogenic DNA Viruses 1. Human papilloma virus (HPV) 4. Polyoma virus called Merkel cell virus 2. Epstein-Barr virus (EBV) 5. Hepatitis B virus (HBV) Kaposi sarcoma...

3  Neoplasia Lecture 5 2. Oncogenic DNA Viruses 1. Human papilloma virus (HPV) 4. Polyoma virus called Merkel cell virus 2. Epstein-Barr virus (EBV) 5. Hepatitis B virus (HBV) Kaposi sarcoma herpesvirus (KSHV, 3. also called human herpesvirus-8 [HHV-8]) Epstein-Barr virus (EBV) General Information: EBV is a member of the herpesvirus family. It was the first virus linked to a human tumor: Burkitt lymphoma. Diseases Associated with EBV: Burkitt A highly aggressive tumor lymphoma 1 Lymphomas in that: Is endemic in parts of Africa. Some forms of 2 immunosuppressed individuals with HIV infection or organ transplantation Occurs sporadically in other Hodgkin 3 regions. lymphoma Nasopharyngeal In endemic areas, almost all T cell lymphomas, 4 carcinoma tumor cells carry the EBV NK cell 5 genome. lymphomas Gastric 6 carcinomas Sarcomas mainly in the immunosuppressed 7 Mechanism of Infection: EBV infects B cells by attaching to the complement receptor CD21. Leads to: Polyclonal B cell proliferation. Immortalization of B lymphoblastoid cell lines. Oncogenesis: Key EBV Genes: LMP-1 (Latent Membrane Protein-1): Functions as an oncogene. Stimulates normal B-cell proliferation pathways. Activates NF-κB and JAK/STAT pathways, promoting proliferation and survival. Prevents apoptosis by inducing BCL-2 expression EBNA-2 (Epstein-Barr Nuclear Antigen-2): Activates cyclin D, promoting cell cycle progression. vIL-10: Inhibits macrophages and monocytes from activating T-cells, allowing infected cells to evade immune detection. Endemic Burkitt Lymphoma: EBV is primarily involved in endemic cases of Burkitt lymphoma, where nearly all tumors are associated with the virus. In nonendemic cases, most (about 80%) are unrelated to EBV. But whether EBV is involved or not, they still develop through similar oncogenic pathways ( t(8;14) translocation or other translocations that dysregulate MYC.) concomitant infections (e.g., malaria) impair immune response, allowing sustained B-cell proliferation Which causes the Development of lymphoma with accurance of additional mutations, such as t(8;14) translocation, which activates the MYC gene. Eventually, cytotoxic T cells eliminate most of the EBV-infected B cells but a small number survive. Nasopharyngeal Carcinoma: Endemic in southern China and parts of Africa. EBV infection is detected in 100% of cases worldwide. Tumor cells exhibit clonal integration of the viral genome. EBV gene LMP-1: Activates NF-κB, upregulating oncogenic factors like VEGF and matrix metalloproteases. Hepatitis B (HBV) and Hepatitis C (HCV) Viruses Contribution to Cancer: Key Mechanisms: 70%-85% of hepatocellular HBV and HCV activate signal NF-κB pathway activation in carcinomas worldwide are caused by transduction pathways: hepatocytes: (which is HBV or HCV. HBx protein (HBV): responsible for the Oncogenic effects are mediated by: Activates transcription proliferetion of hepatocytes in 1. Chronic inflammation. response to chronic viral factors and interferes with 2. Hepatocellular injury and injurey) regeneration. p53 function. Blocks apoptosis. 3. Production of reactive oxygen species HCV core protein: Allows accumulation of (ROS), leading to DNA damage. Promotes oncogenesis. mutations. Helicobacter pylori (H. pylori) Associated Mechanism of CagA Pathogenicity Cancers: Oncogenesis: Island: 1. Gastric Chronic inflammation Injected into gastric adenocarcinoma. stimulates epithelial cell epithelial cells. proliferation and ROS production, damaging 2. MALT lymphoma Mimics unregulated DNA. (gastric B-cell growth factor activation of H.pylori lymphoma). reactive cells stimulation. Sequence of changes: (accures only in 3% of infected patients) 1. Chronic gastritis → Gastric atrophy. 2. Intestinal metaplasia → Dysplasia → Cancer. Laboratory Diagnosis of Cancer Morphologic Methods Immunocytochemistry H&E stain Cytokeratin A-Excision or biopsy. Prostate-specific antigen (PSA) B-Fine-needle aspiration. =prostate carcinoma. C-Cytologic smears Estrogen receptors =breast (Papanicolaou). cancers. D-Frozen sections. Molecular Diagnosis Flow cytometry Diagnosis of cancer ( CML, PCV) It is used routinely in the classification of Prognosis and behavior (HER2 and NMYC ) leukemias and lymphomas. Detection of minimal residual disease ( Fluorescent antibodies against cell CML) surface molecules and differentiation Diagnosis of hereditary predisposition to antigens are used to obtain the cancer (BRCA1 gene) phenotype of malignant cells. Therapeutic decision-making Tumor Markers Tumor Markers A-PSA A-PSA (CEA) α-fetoprotein Carcinoembryonic antigen (CEA) α-fetoprotein CEA and α-fetoprotein assays lack Prostatic carcinoma can be suspected when elevated produced by : carcinomas of the both specificity and sensitivity 1- hepatocellular levels of PSA are found in the blood. colon, pancreas, carcinomas 2-yolk sac remnants in the Although PSA levels are often stomach, and gonads elevated in cancer, PSA levels also may be elevated in benign breast. 3-teratocarcinomas prostatic hyperplasia 4-embryonal cell PSA test suffers from both carcinomas. low sensitivity and low 5-neural tube defect of the specificity. fetus Grading and Staging of Cancer Methods to quantify the probable clinical aggressiveness of a given neoplasm and its apparent extent and spread in the individual patient are determinents of prognosis and treatment protocols.  Grading Grading of cancer is based on: Common practice includes describing Grading schemes vary for each type The degree of differentiation of tumor a neoplasm using descriptive terms, of malignancy and generally range cells. such as: from: The number of mitoses in some cancers. Well-differentiated, mucin-secreting Two categories (low grade–high The presence of certain architectural adenocarcinoma of the stomach. grade). features. Poorly differentiated pancreatic Four categories (I, II, III, IV). adenocarcinoma. Staging Staging of solid cancers is based on: The American Joint Committee on 1. The size of the primary lesion. Cancer Staging system is widely used. 2. The extent of spread to regional This system uses the TNM system lymph nodes. classification: 3. The presence or absence of T: Primary tumor. bloodborne metastases. N: Regional lymph node involvement. M: Metastases. M (Metastases): T (Tumor): N (Nodes): M0: No distant metastases. T1–T4: Increasing size of the N0: No nodal involvement. M1 (or M2): Presence and primary lesion. N1–N3: Increasing number estimated number of T0: Indicates an in situ lesion and range of involved nodes. metastases.