NEOPLASIA -4 Dr Samal Nauhria

Viral and Bacterial Oncogenesis HTLV-1 : a retrovirus, endemic in Japan, the Caribbean, and parts of South America and Africa causes adult T-cell leukemia/lymphoma

■ HTLV-1 encodes the viral protein Tax, which turns on progrowth and pro-survival signaling pathways (PI3K/AKT, NF-κB)  leading to a polyclonal expansion of T cells ■ long latent period (decades) a small fraction of infected individuals develop ATLL presumably due to acquisition of additional mutations in the host cell genome

HPV: Benign warts Cervical cancer, and Oopharyngeal cancer

Oncogenic types of HPV encode two viral oncoproteins  E6 and E7  that bind to Rb and p53, respectively with high affinity and neutralize their function ■ HPV cancers can be prevented by vaccination against high-risk HPV types

EBV  Implicated in the pathogenesis of – 1.Burkitt lymphomas, 2.B-cell lymphomas in patients with T-cell immunosuppression (HIV infection, transplant recipients), and 3.several other cancers

■ The EBV genome harbors several genes encoding proteins that trigger B cell signaling pathways These signals are potent inducers of B cell growth and transformation

■ In the absence of T-cell immunity, EBV- infected B cells can rapidly “grow out” as aggressive B-cell tumors ■ In the presence of normal T-cell immunity, a small fraction of infected patients develop EBV-positive B-cell tumors (Burkitt lymphoma, Hodgkin lymphoma) or carcinomas (nasopharyngeal, gastric carcinoma)

Hepatitis B virus and C virus Cause 70% and 85% of HCC worldwide ■ Oncogenic effects are multifactorial; dominant effect seems to be immunologically mediated chronic inflammation, hepatocellular injury, and reparative hepatocyte proliferation ■ HBx protein of HBV and the HCV core protein can activate signal transduction pathways that also may contribute to carcinogenesis

H. pylori Implicated in gastric adenocarcinoma and MALT lymphoma ■ Pathogenesis of H. pylori-induced gastric cancers is multifactorial  1.including chronic inflammation and 2.reparative gastric cell proliferation

■ H. pylori pathogenicity genes, such as CagA, also may contribute by stimulating growth factor pathways ■ Chronic H. pylori infection  polyclonal B- cell proliferations  give rise to a monoclonal B-cell tumor (MALT lymphoma) of the stomach as a result of accumulation of mutations

Clinical Aspects of Tumors Cachexia: progressive loss of body fat and lean body mass, profound weakness, anorexia, and anemia, (that is caused by release of factors by the tumor or host immune cells)

Paraneoplastic syndromes:  symptom complexes in individuals with cancer that cannot be explained by tumor spread or release of hormones that are indigenous to the tumor “cell of origin.”

For example: ■ Endocrinopathies (Cushing syndrome, hypercalcemia) ■ Neuropathic syndromes (polymyopathy, peripheral neuropathies, neural degeneration, myasthenic syndromes) ■ Skin disorders (acanthosis nigricans) ■ Skeletal and joint abnormalities (hypertrophic osteoarthritis) ■ Hypercoagulability (migratory thrombophlebitis, disseminated intravascular coagulation, nonbacterial thrombotic endocarditis)

Grading Determined by cytologic appearance; Behavior and differentiation are related  Poorly differentiated tumors having more aggressive behavior

Staging Determined by surgical exploration or imaging, is based on  – size, – local and regional lymph node spread, and – distant metastases of greater clinical value than grading

Laboratory Diagnosis of Cancer Several sampling approaches exist for the diagnosis of tumors, including  1.Excision biopsy 2.Fine-needle aspiration, and 3.Cytologic smears

Immunohistochemistry and flow cytometry  diagnosis and classification of tumors, because distinct protein expression patterns define different entities

Molecular analyses used to determine  1.Diagnosis 2.Prognosis, the 3.Detection of minimal residual disease, and 4.Diagnosis of hereditary predisposition to cancer

Molecular profiling (the future) done by  1.RNA expression profiling, 2.DNA sequencing, and 3.DNA copy number arrays Useful in molecular stratification of otherwise identical tumors or those of distinct histogenesis that share a mutation for the purpose of targeted treatment and prognostication

Proteins released by tumors into the serum, such as PSA, can be used to screen populations for cancer and to monitor for recurrence after treatment

Selected Tumor Markers 1.Calcitonin  Medullary carcinoma of thyroid 2.Catecholamine and metabolites  Pheochromocytoma 3.α-Fetoprotein  Liver cell cancer, nonseminomatous germ cell tumors of testis 4.Carcinoembryonic antigen  Carcinomas of the colon, pancreas, lung, stomach, and heart 5.Immunoglobulins  Multiple myeloma and other gammopathies 6.CA-125  Ovarian cancer 7.CA-19-9  Colon cancer, pancreatic cancer 8.CA-15-3  Breast cancer

Assays of circulating tumor cells and of DNA shed into blood, stool, sputum, and urine are under development

Thank you