First Foundations in Pathology, Part 5: Neoplasia

1. First Foundations in Pathology, Part 5: Neoplasia Paul G. Koles, MD Asst. Professor Pathology and Surgery Director of Pathology Education Boonshoft School of Medicine at Wright State University

2. Impact of Neoplasia • 1.4 million new cases of non-skin cancer in the United States annually • ACS estimates 565,000 deaths in U.S. from malignant neoplasms in 2006. • 25% all deaths • Outstanding improvements in diagnosis and therapy of many malignant neoplasms, such that overall survival rates are improving. • More effective therapies depend on elucidation of pathobiology of neoplasia.

3. Neoplasia Defined • Neoplasm = “new growth”, but how to distinguish from reactive hyperplasia? • Dr. Willis: “ … an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the sameexcessive manner after cessation of the stimuli which evoked the change.” • Why do neoplasias persistently grow for no good reason, to the detriment of the host?

4. Genetic Basis of Neoplasia Nobel Prize in Medicine to Eric Fearon and Bert Vogelstein for identifying specific genetic changes which correlate with morphologic features of colorectal neoplasia (Cell 61:759, 1990) Persistence of neoplasm for no good reason is based on: that are replicated in the progeny of a single abnormal: genetictransformation of a single cell initiates neoplasia Genetic mutations

5. Common features of all neoplasms • Proliferating neoplastic cells comprise the • of a neoplasm • Connective tissue and blood vessels which support the growth of neoplastic cells comprise the • Nomenclature of tumors is based on the cell of origin (differentiation) and architectural features (arrangement) of the proliferating neoplastic cells and whether the neoplasm is benign or malignant. parenchyma stroma

6. Nomenclature of Neoplasia Most common benign neoplasm of colon, grossly a pedunculated or sessile polyp, and microscopically composed of epithelial cells forming glandular structures with a central lumen Epithelial cells forming glands = Benign neoplasm “aden” “oma”

7. Neoplasms of Epithelium Hepatocellular adenoma Hepatocellular carcinoma nevus malignant melanoma

8. Mesenchymal Neoplasms hemangioma angiosarcoma

9. Other Neoplasms leukemias Immature teratoma or teratocarcinoma Mature teratoma

10. Gross Clues in Neoplasia

11. Smooth Muscle Neoplasia Leiomyoma Leiomyosarcoma

13. 4 phases of malignant neoplasia: transformation proliferation (growth) local invasion metastasis Which of first 3 phases of tumor development increases the likelihood that a neoplasm will become metastatic? Local invasion

14. Phases of Malignant Neoplasia Deep edge of ulcerated sessile mass in colonic mucosa demonstrating: Local invasion How deep ? Into muscularis propria Liver of woman with invasive ductal carcinoma of breast demonstrating: Distant metastasis

15. Anatomic Pathways to Metastasis Pathway Most common initial pathway used by: Lymphatic spread carcinomas Hematogenous spread sarcomas Direct extension

16. Growth Kinetics Early: most transformed cells are in proliferative pool Clinical phase: 1-20% transformed cells in proliferative pool 3 factors which limit growth fraction of neoplasm (# cells in cell cycle): Reversion to G0, terminal differentiation, apoptotic cell death

18. Incidence of Malignant Neoplasia in U.S.

19. Mortality from Malignant Neoplasia in U.S.

20. Non-Genetic Influences The differences in liver cancer mortality most likely due to geographic variations in the incidence and prevalence of: Chronic Hepatitis B infection The differences in stomach cancer mortality are most likely due to: Environmental influence (? food)

21. Occupation-related cancers Site of human cancer associated with chronic exposure Mesothelioma (pleural/peritoneal) leukemia; Hodgkin lymphoma Lung carcinoma Prostate carcinoma Lung carcinoma Lung carcinoma Lung carcinoma Angiosarcoma of liver

22. 4 types of genetic mutations that contribute to cancer 1 2 4 3

23. Regulation of G1/S cell cycle transition Cell cycle arrest at G1/S (in response to DNA damage or other stressors) is medicated through which gene? p53 (levels of p53 under negative regulation by MDM2 and p14 ARF)

24. 1: Failure of DNA Repair (acquired) Normal function of p53 is to upregulate activity of which 2 genes to allow repair of DNA? p21 GADD45

25. Hereditary Non-Polyposis Colon Cancer Syndrome: the most commoninheritedcancer predisposition syndrome (failure of DNA repair, inherited) • Mechanism HNPCC: inactivation of a gene which functions in • Mutations in 2 genes account for 90% of cases: • Clinical manifestations: earlier onset and more frequent carcinomas involving 2 GI sites and 2 female genital organs: DNA mismatch repair MSH2 and MLH1 Colon, stomach and ovary, uterus

26. 2) Activation Growth-Promoting Oncogenes Which signal transduction pathway is continuously activated by mutant RAS? MAP kinase pathway Point mutations of ras are seen in what % of all human malignancies? 15-20%

27. 3) Inactivation Tumor-Suppressor Genes p53 on 17p13 is the “guardian of the genome” Most common target for genetic mutations in human neoplasia: % of human neoplasms have mutant p53 Most cases: somatic cells acquire inactivation of both alleles of p53 In which syndrome does person inherit mutant allele of p53, causing 25x increased incidence of cancer by age 50 ? >50% Li-Fraumeni syndrome (multiple primary cancers in young)

28. 3) Inactivation Tumor-Suppressor Genes Normal: APC complexed with B-catenin keeps intracellular B-catenin low levels  secreted WNT signals at receptor lead to inactivation of this complex, and increased intracellular B-catenin Mutation in APC makes cell unable to destroy B-catenin, constant stimulation of nucleus to transcribe cell cycle genes

29. 4) Alterations in genes regulating apoptosis Mutation inducing overexpression of Bcl-2 prevents activation of caspase by which 2 cytosolic proteins? Cytochrome c Apaf-1

30. Translocations creating oncogenes Myc normally functions as “early response’ gene promoting cell division Which therapeutic agent specifically inhibits the tyrosine kinase produced by the bcr-abl hybrid gene? Imatinib mesylate

31. Tumor Biology: Metastasis After subclone with ability to invade develops, that subclone of carcinoma must invade through 3 basement membranes to accomplish metastasis to another solid organ: 1- organ of origin 2- lymphatic or capillary in organ of origin 3) Capillary in another organ

32. Sequential events in local invasion through basement membrane by carcinomas Loosening of intercellular junctions through down-regulating expression of: cadherin Attachment: receptor-mediated attachment of tumor cells to basement membrane protein: laminin

33. Sequential events in local invasion through basement membrane by carcinomas Degradation: Malignant cells secrete proteolytic enzyme to loosen basement membrane: Type IV collagenase Migration into and through ECM facilitated by tumor cell receptors for: fibronectin

34. Progress, not success Our world awaits further elucidation of the pathogenesis & treatment of cancer by the class of 2011 ! (after the quiz in June)