1. Epidemiology 242: Pathology Basis of Caner Jian-Yu Rao, MD Professor of Pathology and Epidemiology Fall, 2009

2. OBJECTIVES To learn basic histopathological terminology. To learn basic histopathological terminology. To know different types of tumor. To know different types of tumor.

3. Tumor is a disorder of cells A neoplasm (Greek, Neo-New, plasma, thing formed) is the autonomous growth of tissue that have escaped the normal restraints on cell proliferation and exhibit varying degrees of fidelity to their precursors. A neoplasm (Greek, Neo-New, plasma, thing formed) is the autonomous growth of tissue that have escaped the normal restraints on cell proliferation and exhibit varying degrees of fidelity to their precursors. It is usually appears as a tumor ( a swelling) made of mass of cells.“Abnormal growth of cells”, “Unlimited growth of cells”. It is usually appears as a tumor ( a swelling) made of mass of cells.“Abnormal growth of cells”, “Unlimited growth of cells”.

4. What is the difference between “tumor” vs “cancer” Tumor – Either benign or malignant Cancer – Usually malignant

5. Classification of Tumors - Based on histological origin (epithelial, mesenchyme, etc..) - Based on biological behavior (benign vs malignant) (benign vs malignant)

6. PATHOLOGICAL REPORT Tumor histological type. Tumor histological type. Tumor stage. Tumor stage. Tumor grade. Tumor grade. Other features (size, % necrosis, lymphovascular invasion…) Other features (size, % necrosis, lymphovascular invasion…)

7. CANCER HISTOLOGICAL TYPE Three Major Categories: Three Major Categories: –Epithelial – “Carcinoma” –Mesenchyme – “Sarcoma” –Hematopoitic – “Leukemia/Lymphoma” Other Minor Categories: Other Minor Categories: –Nevocytic – “Melanoma” –Germ cell – Teratoma, Seminoma, Yolk sac tumor, Choriocarcinoma, etc… –Endocrine/Neuro – Carcinoid/Insulinoma/small cell carcinoma, etc…

8. CARCINOMA Squamous – Squamous Cell Carcinoma. Squamous – Squamous Cell Carcinoma. Glandular - Adenocarcinoma. Glandular - Adenocarcinoma. Transitional – Transitional Cell Carcinoma. Transitional – Transitional Cell Carcinoma. Small cell – Small cell carcinoma Small cell – Small cell carcinoma

9. SARCOMA Muscle Muscle –Smooth muscle: Leiomyosarcoma –Skeletal muscle: Rhabdomyosarcoma Fat – Liposarcoma Fat – Liposarcoma Skeleton – Osteosarcoma Skeleton – Osteosarcoma Cartilage – Chondrosarcoma Cartilage – Chondrosarcoma

10. Classification of tumor according to their morphologic features (histology) Morphologic classification refers to the histologic classification made by pathologist based on microscopic examination. Morphologic classification refers to the histologic classification made by pathologist based on microscopic examination.

11. Benign vs Malignant Tumor The main distinction between benign and malignant tumor is: The main distinction between benign and malignant tumor is: –Malignant tumor has invasion and metastatic potential whereas benign tumor does not. –Malignant tumor has features of abnormal cellular differentiation whereas benign tumor usually not.

14. Why histologic classification is important in cancer epidemiology? Cancer is not ONE disease Cancer is not ONE disease Different cancer types of same organ may have different exposure etiology, pathogenesis, as well as behavior, i.e., HETEROGENEITY Different cancer types of same organ may have different exposure etiology, pathogenesis, as well as behavior, i.e., HETEROGENEITY

15. Carcinoma Carcinoma (Cancer of the epithelium) 85% Carcinoma (Cancer of the epithelium) 85% Epithelium is the term applied to the cells that cover the external surface of the body or that line the internal cavities, plus those cells derived from the linings that form glands.

16. Why most common cancers are epithelial origin? These cells are the first point of contact of the body with environmental substances, either directly (squamous cells) or indirectly (glandular cells). These cells are the first point of contact of the body with environmental substances, either directly (squamous cells) or indirectly (glandular cells). Epithelial cells usually have fast turn over rate, i.e., fast cell division, and their DNA can be damaged by carcinogens more often than non-dividing cells. Epithelial cells usually have fast turn over rate, i.e., fast cell division, and their DNA can be damaged by carcinogens more often than non-dividing cells.

17. Carcinoma: Squamous cell Originates from stratified squamous epithelium of the skin, mouth, esophagus, and vagina, as well as from areas of squamous metaplasia, as in the bronchi or squamocolumnar junction of the uterine cervix. SCC is marked by the production of keratin. Originates from stratified squamous epithelium of the skin, mouth, esophagus, and vagina, as well as from areas of squamous metaplasia, as in the bronchi or squamocolumnar junction of the uterine cervix. SCC is marked by the production of keratin.

18. Skin Cancer

19. Squamous Cell Carcinoma

20. Carcinoma, Transitional Cell Transitional cell carcinoma - arise from the transitional cell epithelium of the urinary tract, such as bladder. Transitional cell carcinoma - arise from the transitional cell epithelium of the urinary tract, such as bladder.

23. transitional cell carcinoma of the urothelium is shown here at low power to reveal the frond-like papillary projections of the tumor above the surface to the left. It is differentiated enough to resemble urothelium, but is a mass. No invasion to the right is seen at this point.

24. TCC at high power

25. Carcinoma: Adenocarcinoma Adenocarcinoma - is carcinoma of glandular epithelium and includes malignant tumors of the gastrointestinal mucosa, endometrium, and pancreas; and is often associated with desmoplasia, tumor-induced proliferation of non- neoplastic fibrous connective tissue, particularly in adenocarcinoma of the breast, pancreas, and prostate. Adenocarcinoma - is carcinoma of glandular epithelium and includes malignant tumors of the gastrointestinal mucosa, endometrium, and pancreas; and is often associated with desmoplasia, tumor-induced proliferation of non- neoplastic fibrous connective tissue, particularly in adenocarcinoma of the breast, pancreas, and prostate.

26. Prostate Ca Ovarian Ca

27. Sarcoma Sarcoma is a malignant tumor of mesenchymal origin Sarcoma is a malignant tumor of mesenchymal origin Sarcoma is often used with a prefix that denotes the tissue of origin of the tumor, as in osteosarcoma (bone), leiomyosarcoma (smooth muscle), rhabdomyosarcoma (skeletal muscle), and liposarcoma (fatty tissue). Sarcoma is often used with a prefix that denotes the tissue of origin of the tumor, as in osteosarcoma (bone), leiomyosarcoma (smooth muscle), rhabdomyosarcoma (skeletal muscle), and liposarcoma (fatty tissue).

28. Classification of tumor according to stage

29. Stage -is clinical assessment of the degree of localization or spread of the tumor. -is clinical assessment of the degree of localization or spread of the tumor. -generally correlated better with prognosis than dose histopathologic grading. -generally correlated better with prognosis than dose histopathologic grading. -is examplified by the generalized TNM system, which evaluates size and extent of tumor (T), lymph node involvement (N), and metastasis (M). -is examplified by the generalized TNM system, which evaluates size and extent of tumor (T), lymph node involvement (N), and metastasis (M). -different staging systems (WHO, TNM, etc), sometimes oriented toward specific tumors, e.g., Dukes system for colorectal carcinomas. -different staging systems (WHO, TNM, etc), sometimes oriented toward specific tumors, e.g., Dukes system for colorectal carcinomas.

32. Classification of Tumor according to its differentiation (grade)

33. Grade of Disease Grading is histo-pathologic evaluation of the lesion based on the degree of cellular differentiation and nuclear features: Grading is histo-pathologic evaluation of the lesion based on the degree of cellular differentiation and nuclear features: Well Differentiated (Grade I) Well Differentiated (Grade I) – more resemble to normal tissue/cell Moderately differentiated (Grade II) - less resemblance of normal tissue/cell Undifferentiated (Grade III) - lost resemblance to normal tissue/cell

34. Gleason's breakthrough was to develop a reproducible description of the glandular architecture, to which one assigns a score from 1 to 5. The pathologist looks for a major pattern and a minor pattern to give a Gleason sum between 2 and 10. On the left is a picture adapted from Gleason's 1977 article demonstrating the changes in gland pattern as one goes from grade 1 to grade 5 cancer. The glands in grade 1 cancer are small and round. Grade 5 cancer is hardly forming glands at all.

35. Benign Prostate: Hyperplasia

36. Gleason Grade 1 Prostate Cancer

37. Gleason Grade 1 Prostate Cancer

38. At right is Gleason 3 CaP. The glands are irregularly shaped. They are mixed in with some normal glands. This tumor is infiltrating the prostate. At higher magnification, there are nests of glands with no intervening stroma. This is characteristic of higher grade CaP

39. The cells are not organized into glands, but are infiltrating the prostate as cords. Here is Gleason 5, or poorly differentiated cancer. You can see that it is invading the seminal vesicle (stage T4)

40. Precursors from intraepithelial neoplasia (INs) to carcinoma in situ (CIS)

41. NORMAL CIN 1 CIN 2 CIN 3 NORMAL LGSIL HG SIL HGSIL

42. Important for Epidemiologist Study nature history of disease progression Study genetic/environmental factors associate with disease progression Develop tools for risk assessment/early detection Targets for chemoprevention

43. Cancer Precancerous Intraepithelial Lesions, (PIN, CIN, PaIN..)e Birth Genetic Suscep. Marker Markers for Exposure Markers of Effect Tumor Markers Exposure to Carcinogen Additional Molecular Event Surrogate End Point Markers CHEMOPREVENTION

44. SUMMARY The key is to understand tumor hetergeneity: The key is to understand tumor hetergeneity: –Human cancer is not one disease, but many different types of diseases (Disease heterogeneity). –The same type/stage/grade of tumor may behave differently in different person (Behavior heterogeneity). –Even within the same tumor, there are may be different histological appearances and molecular expressions/changes (Expression heterogeneity). As an epidemiologist, we should know the basic features of the disease, and design studies accordingly As an epidemiologist, we should know the basic features of the disease, and design studies accordingly

45. Thank You!