Aims

1. Aims • Chemical carcinogens • Viral carcinogenesis • Host defense against tumors • Grading and Staging • Laboratory Diagnosis • Readings: Robbins; Chapter 6

2. Chemical Carcinogenesis • Two step process (initiation and promotion) • Initiation • Results from exposure to carcinogenic agent. • Causes permanent (irreversible) DNA damage. • Not sufficient for tumor formation. • Promotion • Can induce tumors from initiated cells. • Not tumorigenic by itself. • Does not affect DNA directly. • Is ____________________________________.

3. Initiation and Promotion Initiation -Causes permanent DNA damage Memory -Damage is permanent & irreversible Robbins & Cotran’s Pathologic Basis for Disease 7-48

4. Initiation and Promotion • Applications of Promotersdo not effect DNA directly and are Reversible • - They require previous initiation to cause tumors Robbins & Cotran’s Pathologic Basis for Disease 7-48

5. Carcinogenic Chemicals • Diverse in structure. • Both natural and synthetic. • Direct or Indirect (procarcinogens). • All are highly reactive electrophiles that react with electron rich sites in cells (DNA, RNA, and proteins). Robbins & Cotran’s Pathologic Basis for Disease table 7-11 & Robbins Basic Pathology Table 6-4

6. Chemical Carcinogenesis • Most chemical carcinogens are procarcinogens and require metabolic activation to form the ultimate carcinogen. • Balance between metabolic activation and inactivation. Robbins & Cotran’s Pathologic Basis for Disease 7-49

7. Radiation Carcinogenesis • UV rays from sunlight and ionizing radiation (includes X-rays, g-rays, protons, neutrons, other particles). • Can transform all cell types.

8. UV Radiation • Can _______________________________ cell division. • Can inactivate enzymes. • Can induce gene mutations. • Pyrimidine dimers. • Can kill cells.

9. Ionizing Radiation • Both electromagnetic (x-rays &  rays) and particulate ( particles,  particles, protons, & neutrons) are carcinogenic. • The most frequent radiation induced cancers are leukemias (except chronic lymphocytic leukemia) with thyroid cancers in the young being the 2nd most common. • Skin, bone, and GI cancers are relatively resistant to ionizing radiation induced cancers.

10. Viral Carcinogenesis • DNA viruses • Form stable associations with host cells genome. • Papillomaviruses • Involved in the pathogenesis of warts to carcinoma. • Epstein-Barr virus • Involved in the pathogenesis of Burkitt lymphoma and Hodgkin disease. • Hepatitis B virus • Involved in the pathogenesis of liver cancer. • RNA viruses • Human T-cell Leukemia virus type 1 • T cell leukemia/ lymphoma

11. Epstein-Barr Virus • EBV serves as one factor in the development of Burkitt lymphoma. • Other factors include: • Translocation between chromosome 8 and 14. • Mutation of oncogene _________________. Robbins & Cotran’s Pathologic Basis for Disease 7-51

12. Human T-cell Leukemia Virus Type 1 • Transmitted by sexual intercourse or blood transfusions. • Endemic to Japan and the Caribbean. • First infected T cells proliferate due to autocrine and paracrine cytokine stimulation. • Due to viral protein, TAX, which increased IL-2 and IL-2r expression, while inhibiting tumor suppressor genes. • Ultimately one T cell clone mutates during the great amount of replication. Robbins’ Basic Pathology 6-32

13. Hallmarks of Cancer • Most cancers will acquire these properties during their development. • Evade apoptosis • Self sufficient growth signals • Insensitive to anti growth signals • Metastasis • Limitless replication • Sustained angiogenesis Robbins’ Basic Pathology 6-17

14. Host Defense Against Tumors • Tumor specific-shared antigens • Mutated Self Protein. • Antigens resulting from mutations (oncogenes). • Overexpressed or Underexpressed antigens. • Viral antigens.

15. Tumor-Specific Shared Antigens • MAGE family of genes are antigens usually silent in normal cells and expressed in tumor cells. • Also expressed by immunologically privileged tissue in testis. Robbins’ Basic Pathology 6-33

16. Mutated Self Protein • Various normal self proteins can be mutated by carcinogens (chemicals, radiation, etc.). Robbins’ Basic Pathology 6-33

17. Antigens resulting from Mutant Oncogenes • Mutants present only in tumor cells. • No evidence that this occurs naturally. Robbins’ Basic Pathology 6-33

18. Overexpressed Antigens • Present in both normal cells and tumor cells. • Low levels in normal cells result in non-detection by T cells. Robbins’ Basic Pathology 6-33

19. Viral Antigens • Viral genes (oncogenes) expressed in tumor cells. Robbins’ Basic Pathology 6-33

20. Anti-Tumor Mechanisms Robbins’ Basic Pathology 6-35 7th Ed.

21. Anti-Tumor Mechanisms • Both cell-mediated and humoral immunity can have anti-tumor activity. • Cytotoxic T cells. • Attack cells expressing peptide- ________________________________________. Robbins’ Basic Pathology 6-35 7th Ed.

22. Anti-Tumor Mechanisms • Natural Killer cells. • May provide first line of defense as no prior sensitization is necessary. • Attack tumor cells with lowered levels of MHC class I. • Can also participate in ADCC. Robbins’ Basic Pathology 6-35 7th Ed.

23. Anti-Tumor Mechanisms • Macrophages. • Activated macrophages can be cytotoxic to tumor cells. • Phagocytosis. • cytokine secretion. • Antibody. • Targeting for compliment. • ADCC. Robbins’ Basic Pathology 6-35 7th Ed.

24. Grading & Staging of Tumors • Grading of a cancer is based on the degree of differentiation of the tumor cells and the number of mitoses within the tumor. • Correlates with the neoplasm’s aggressiveness • Tumors are classified as grades I-IV with increasing __________________________________________.

25. Grading & Staging of Tumors • Staging is based on the size of the primary lesion, its extent of spread to regional lymph nodes, and the presence or absence of blood-borne metastases. • Staging has proved to be of greater clinical value than grading • There are 2 systems used • TNM classification system • AJC system (American Joint Committee on Cancer Staging)

26. Grading & Staging of Tumors • TNM System • T for tumor (T1-T4 for increasing size), N for lymph node involvement (N0-N3, for increasing range and # of nodes involved), M for metastases (M0-M2) • Varies for each form of cancer • AJC System • Cancers divided into stages 0-IV which incorporates the size of the lesion as well as nodal involvement and metastases.

27. Laboratory Diagnostics • Histology and Exfoliative Cytology (smears) are the most commonly used techniques in the diagnosis of cancer • Excision or Biopsy • Appropriate preservation of the sample is critical (preservative or freezing) • Fine needle aspiration • Sample is aspirated by a needle and stained before examination • Cytologic (Papanicolaou) smears • Cancer cells have a decreased adhesiveness and are morphologically different.

28. Laboratory Diagnostics • Pap Smear • Normal cells are large and flat • Cancer cells have large hyperchromatic nuclei, polymorphic nuclei, and mitotic cells. Robbins’ Basic Pathology 6-34

29. Laboratory Diagnostics • Newer techniques are continually being added to improve diagnosis of various cancers. • Immunohistochemistry • Allows for categorization of undifferentiated malignant tumors, determination of site of origin of metastatic tumors, and detection of molecules with therapeutic significance. • Molecular diagnosis • Useful in diagnosis as well as predictive and therapetic aspects of cancers.

30. Laboratory Diagnostics • Newer techniques are continually being added to improve diagnosis of various cancers. • Flow cytometry • Can rapidly measure cell characteristics like membrane antigens and DNA content of tumor cells • Tumor markers • These are biochemical markers of various cancer types.

31. Laboratory Diagnostics Immunocytochemistry of a malignant tumor to identify its tissue of origin. (Anticytokeratin antibody to identify epithelial origin) Robbins & Cotran’s Pathologic Basis for Disease 7-56

32. Next Time • Skin Pathologies • Reading: Robbins, Chapter 22

33. Objectives • Describe the process and pathway of chemical carcinogenesis. • Initiation & Promotion • Describe the types of carcinogenic radiation. • Describe the various types & causes of viral carcinogenesis. • DNA Viruses (papilloma virus, EBV, Hepatitis B) • RNA Viruses (HTLV-1) • Describe host defenses against tumors. • Various forms of antigen presentation • Anti-Tumor Mechanisms (Cytotoxic T cells, Natural Killer cells, Macrophages, Antibodies) • Describe the basics of tumor grading & staging. • Describe the laboratory techniques used in diagnosing cancer.