Malignancies.pptx

Malignancies

1. Malignancies M. Bilal

2. Operating definitions Benign Tumor: Tumors can be benign ( non cancerous) or malignant ( cancerous). Benign tumors are slow growing and donot spread. Malignant tumor: A term for diseases in which abnormal cells divide without control and can invade nearby tissues Malignant cells can also spread to other parts of the body through the blood and lymph systems .

3. Types of malignancy Carcinoma is a malignancy that begins in the skin and organ linings. Sarcoma is a malignancy that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue Leukemia is a malignancy that begins in blood-forming tissue, such as the bone marrow Lymphoma and multiple myeloma are malignancies that begin in the cells of the immune system

4. Hallmarks of cancer The formation and growth of cancer constitute a multistep process, during which gene mutations result in the formation of a cancerous cell. For cells to initiate carcinogenesis successfully, they require key characteristics referred to as the hallmarks of cancer.

5. 1. Genome instability and mutation Under normal circumstances, cellular DNA repair mechanisms are so effective that almost all spontaneous mutations are corrected without producing phenotypic changes. In cancer cells, the surveillance system is compromised and the cells become more sensitive to mutagenic actions or develop DNA repair mechanism failure.

6. 2. Resisting cell death 1. Apoptosis: This is programmed cell death The most important regulator of apoptosis is the TP53 tumor suppressor gene and it induces apoptosis in response to genomic damage. 2. Autophagy: This is a catabolic process during which cellular constituents are degraded by lysosomal machinery within the cell.

7. 3. Necrosis: This is the premature death of cells and is characterized by the release of cellular contents into the local tissue microenvironment, Necrosis results in the recruitment of inflammatory immune cells, angiogenesis, cellular proliferation and tissue invasion, thereby enhancing rather than inhibiting carcinogenesis.

8. 3. Sustaining proliferative signalling Stimulation of the cell cycle Cancer cells abnormal proliferation due to growth factors tyrosine kinase-mediated signalling cascade gene expression and promoting cellular proliferation and growth Examples include transforming growth factor-alpha (TGF-α) and platelet-derived growth factor (PDGF), epidermal growth factor etc This results in abnormal cell growth in response to physiological growth factor stimulation or even in the absence of growth factor stimulation.

9. 4. Evading growth suppressors The genes that inhibit progression play an important part in tumour prevention and are referred to as tumour suppressor genes (e.g. TP53 The products of these genes deactivate the cyclin–CDK complexes and are thus able to halt the cell cycle. Mutations within inhibitory proteins are common in cancer.

10. 5. Inducing angiogenesis Tumours require sustenance in the form of nutrients and oxygen, as well as an ability to evacuate metabolic waste products and carbon dioxide This entails the development of new blood vessels, which is termed angiogenesis Angiogenesis is dependent on the production of angiogenic growth factors such as vascular endothelial growth factor (VEGF)

11. 6. Activating invasion and metastasis Invasion and metastasis begin with local tissue invasion, followed by infiltration of nearby blood and lymphatic vessels by cancer cells. Malignant cells are eventually transported through haematogenous and lymphatic spread to distant sites within the body Cadherin-1 (CDH1) is a glycoprotein that facilitates assembly of organised cell sheets in tissues, In situ tumours usually retain CDH1 production, whereas loss of CDH1 production has been observed in human cancers thus causing invasion and metastasis.

12. 7. Evading immune destruction Deficiencies in the development or function of CD8+ cytotoxic T lymphocytes, CD4+ Th1 helper T cells or natural killer cells can each lead to increase in cancer incidence

13. Environmental and genetic determinants of cancer 1. Environmental Factors:

14. Cause Process Disease Occupational exposure Dye and rubber manufacturing (aromatic amines) Asbestos mining, construction work, shipbuilding (asbestos) Bladder cancer, lung cancer, mesothelioma, liver angiosarcoma, acute leukemia Chemicals Chemotherapy AML Cigarette smoking Hydrocarbons Lung and Bladder cancer Viral infection EBV, HPV, Hep B and C Burkitt lymphoma and nasopharyngeal CA Cervical CA Hepatocellular CA Dietary factors Low roughage Nitrosamines Aflatoxins Colonic CA Gastric CA Hepatocellular CA Radiation UV CT Therapeutic chemo Basal cell CA Cholangiocarcinoma Medullary thyroid tumor

15. 2. genetic factors: They result from inherited mutations in genes that regulate cell growth, cell death and apoptosis Examples include the BRCA1, BRCA2 and AT (ataxia telangiectasia) genes that cause breast and ovarian cancer the FAP gene that causes bowel cancer and the RB gene that causes retinoblastoma

16. Investigations the type of tumour the extent of disease, as assessed by staging investigations the patient’s general condition and any comorbidity.

17. TNM STAGING T= Tumor size N= Lymphatic spread M= Metastasis

18. Tumor markers Immunohistochemical (IHC) staining for tumour markers can provide useful diagnostic information and can help with treatment decisions. Examples: Alpha-fetoprotein (AFP) and human chorionic gonadotrophin ( hCG ) with or without placental alkaline phosphatase (PLAP). These favour germ-cell tumours . Prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP). These favour prostate cancer

19. Common signs of cancer Palpable mass: eg Hepatomegaly may be the first sign of primary liver cancer or tumour metastasis Weight loss and fever

20. Local features of malignant disease Symptom Site of tumor Hemorrhage Stomach, colon, bronchus, endometrium, bladder, kidney Lump Breast, lymph node (any site), testicle Bone pain or fracture bone (primary sarcoma, secondary metastasis from breast, prostate, bronchus, thyroid, kidney ulcer melanoma, basal cell carcinoma (rodent ulcer) Dysphagia esophagus, stomach, anus, skin Ascites ovary, stomach, pancreas

21. Complications of cancer 1. Thromboembolism: Thrombosis and disseminated intravascular coagulation (DIC) are common complications in patients with cancer The interaction between tumour cells, monocytes/macrophages, platelets and endothelial cells can promote thrombus formation, as part of a host response to the cancer

22. 2. Ectopic hormone production: Insulin ACTH vasopressin (antidiuretic hormone, ADH), fibroblast growth factor (FGF)-23, erythropoietin and parathyroid hormone related protein.

23. 3. hypercalcemia It is most commonly due to over-production of PTHrP The incidence is highest in myeloma and breast cancer (approximately 40%), intermediate in non-small cell lung cancer

24. 4. neutropenia It is usually secondary to chemotherapy but may occur with radiotherapy if large amounts of bone marrow are irradiated Neutropenic fever is an emergency in cancer patients as, if left untreated, it can result in sepsis with a high mortality rate

25. 5. Tumor lysis syndrome The acute destruction of a large number of cells can be associated with metabolic sequelae and is called tumour lysis syndrome Related to chemosensitive disease, including lymphoma, leukaemia and germ cell tumours Cellular destruction results in the release of potassium, phosphate, nucleic acids and purines that can cause transient hypocalcaemia , hyperphosphataemia , hyperuricaemia and hyperkalaemia . This can lead to acute impairment of renal function and the precipitation of uric acid crystals in the renal tubular system.

26. metastasis

27. Brain metastasis Lung Breast Melanoma colon

28. Lung metastasis these are common in breast cancer, colon cancer tumours of the head and neck

29. Liver metastasis colorectal cancer, ocular melanoma, neuro-endocrine tumours (NETs)

30. Bone metastasis Bone metastases are a major clinical problem in patients with myeloma and breast or prostate cancers The main presentations are with pain, pathological fractures and spinal cord compression

31. Management of cancer

32. Systemic chemotherapy They have the greatest activity in proliferating cells Chemotherapeutic agents are not specific for cancer cells, however, and the side-effects of treatment are a result of their antiproliferative actions in normal tissues such as the bone marrow, skin and gut. Side effects: Alopecia, mucositis, fibrosis, myelosuppression, renal impairment, neuropathy.

33. Surgical rx Biopsy cytological diagnosis of cancer is necessary, and tissue will also provide important information such as tumour type and differentiation, to assist subsequent management Excision In early, localised cases of colorectal, breast and lung cancer, cure rates are high with surgery

34. radiotherapy Radiation therapy (radiotherapy) involves treating the cancer with ionising radiation; for certain localised cancers it may be curative. Biological differences between normal and tumour tissues are used to obtain therapeutic gain. Normal cells recover from radiation damage faster than malignant cells. Side effects: Acute inflammatory reaction, skin reactions, erythema

35. Hormone therapy Hormone therapy is most commonly used in the treatment of breast cancer and prostate cancer. Breast tumours that are positive for expression of the oestrogen receptor (ER) respond well to anti- oestrogen therapy Progestogens are active in the treatment of endometrial and breast cancer

36. immunotherapy A profound stimulus to the patient’s immune system can sometimes alter the natural history of a malignancy Although solid tumours show little benefit, interferons are active in melanoma and lymphoma, rituximab, an antibody against the common B-cell antigen CD20. It increases complete response rates and improves survival in diffuse large cell non-Hodgkin lymphoma

37. Thanks ;)