Neoplasia

1. Neoplasia Dr. Bruce F. Burns Anatomical Pathology Ottawa Hospital

2. Overview • Characteristics of neoplasms compared to normal tissues • Types of neoplasms • Benign vs malignant • Cellular differentiation • Classification schemes • Genetic basis for neoplasia

4. What is a “neoplasm”? • Lay term of “tumor” conveys usual connotations – ie a new growth or mass • Definition revolves around these features: • Monoclonal proliferation of cells with specific mutations • Excessive and unregulated growth of these cells, often at the expense of surrounding normal tissue

5. Biology of tumor growth

6. Terms to know about when discussing neoplasia • Metastasis - spread of a malignant tumor from one site to another via blood or lymph • Benign – typically refers to those tumors incapable of metastasis and having a good clinical outcome (prognosis) • Malignant – those tumors capable of invasive growth and/or metastasis, often fatal if not treated effectively

7. More terms…. • Parenchyma – these are the tumor cells themselves, usually referring to epithelial cells in organs. • Stroma – connective tissue cells that support the parenchymal cells – not actually tumor cells, but are stimulated to grow by the tumor via growth factors, eg angiogenesis

8. Cellular differentiation • Tumors are often “graded” as to how closely they resemble the normal parent tissue that they are derived from. • Well-differentiated means the cells are very similar in appearance and architectural arrangement to normal tissue of that organ

9. Normal cervical “Pap smear”

10. Malignant cervical “Pap smear”

11. Colonic “adenoma” illustrating a “well-differentiated” neoplasm similar to normal colon mucosa

12. Differentiation • “Poorly-differentiated” refers to tumors that show only minimal resemblance to the normal parent tissue they are derived from. • “Anaplastic” means the tumor shows no obvious similarity to it’s parent tissue, usually associated with aggressive behavior

13. So what?????? • Differentiation often provides clues as to the clinical aggressiveness of the tumor • Tumors often lose differentiation features over time as they become more “malignant” and as they acquire more cumulative genetic mutations • Differentiation often predicts responsiveness to certain therapies, eg estrogen receptors and Tamoxifen in breast cancers

14. Gross (macroscopic) features of two breast neoplasms Benign – circumscribed, often encapsulated, pushes normal tissue aside Malignant – infiltrative growth, no capsule, destructive of normal tissues

15. Classification of neoplasms • Epithelial tumors • Benign forms – adenoma , papilloma • Malignant forms – carcinoma, eg adenocarcinoma, squamous cell carcinoma • Mesenchymal tumors • Benign forms – fibroma, leiomyoma, • Malignant forms – sarcoma, eg fibrosarcoma, leiomyosarcoma

16. Classification continued • Tumors of lymphocytes are always malignant – called lymphoma • Tumors of melanocytes • Benign – nevus • Malignant - melanoma

17. Microscopic features of tumors • Loss of normal architectural arrangement –

18. Microscopic features of tumors • Pleomorphism – variation in size and shape of cells within the neoplasm

19. Microscopic features of tumors • Mitotic activity - Increased in more malignant tumors and often abnormal in shape

20. Precursors of neoplasia • Hyperplasia • Metaplasia • Chronic inflammation • dysplasia

21. Metaplasia, dysplasia, neoplasia • Metaplasia – an adaptive change in differentiation, reversible, no mutations necessary. • Eg- change of esophageal mucosa from squamous to gastric type in the setting of acid reflux (“heartburn”). Better able to withstand the corrosive effects of the acid. • Metaplasia is fertile ground for development of “dysplasia” (disordered growth)

22. Metaplasia, dysplasia, neoplasia • Dysplasia refers to recognizable morphologic changes in cells that indicate the presence of genetic mutations beginning the development of a neoplasm • Often graded, eg PAP smears for uterine cervical cancer are low and high grade

23. Causes of Cancer • Most cancer arises as the result of somatic mutations in the genome resulting from: • Chance (ie, we don’t know) • Environmental factors – chemical, radiation, viruses • Ageing • Inherited cancer syndromes- defect in germline DNA

24. Environmental carcinogens • Chemicals capable of DNA damage • Initiators vs Promoters • Common denominator is “electrophilic intermediates” forming adducts with DNA • Some are direct acting, others are activated in the body, usually in the liver by cytochrome P-450 enzymes

26. Radiation • Ionizing radiation – x-rays, gamma rays, radioactive materials such as Radon gas – all cause a variety of defects to DNA • UV light (non-ionizing) – primarily sun-exposure and T-T dimerization – skin cancers

27. Common features of viral carcinogenesis • Oncogenic viruses typically integrate their genomes into host cells and enter a period of “latency” • May be of DNA or RNA type • DNA viruses include EBV, HPV and Hepatitis B virus • RNA viruses include retroviruses like HTLV-1 and indirectly HIV

28. Viral carcinogenesis • Human papilloma virus (HPV) prototype • Cause warts • Some types have stronger cancer causing associations, esp 16 and 18 with uterine cervix cancer - Pap smears of cervix can detect precursor lesions of infection – Rx • Viral genes interact with human genes concerned with cell division

29. How does HPV cause cancer? • Gene products of certain sub-type (eg 16 and 18) interfere with normal cellular proteins • Early viral proteins E6 and E7 bind p53 and RB proteins respectively

30. Other oncogenic viruses • Epstein-Barr virus (EBV) associated with some lymphomas and nasopharyngeal carcinoma • Hepatitis B virus associated with malignant liver tumors