Pathology of Solid Tumors Megan Troxell, MD/PhD OHSU Pathology troxellm@ohsu.edu 8-1770

Objectives Diagnostic Techniques Common terminology, definitions in cancer Multi-step carcinogenesis Invasion & Metastasis Tumor grading Tumor staging Newer prognostic/predictive testing

http://www.cancer.org

Diagnostic Methods in Tumor Pathology Histology-morphology ‘Old fashioned’ microscope, H &E slides, formalin fixed paraffin embedded (FFPE) Immunohistochemistry Esp. tumor differentiation, mitotic rate H=hematoxylin, nucleic acids, purple E=eosin, protein, pink Undiff. tumor HMB45+ Melanoma

Diagnostic Methods in Tumor Pathology Pediatric Kidney Cancer Immunohistochemistry May help subclassify Rarely, may imply specific genetic rearrangement Loss of PMS2 expression, colon cancer Mismatch repair protein deficient (Lynch) TFE3 +nuclear Argani. AJSP 26:1553-66 Cancer Aberrant TFE3 protein expression as a result of t(X;1)(p11.2;q21) Normal

Diagnostic Methods in Tumor Pathology (courtesy of Helen Lawce) Diagnostic Methods in Tumor Pathology t(11;22) Ewing’s EWS-FLI1 Breakapart FISH probe FISH & Cytogenetics Characteristic translocations

Diagnostic Methods in Tumor Pathology Molecular/PCR Esp. hematopathology T- B-cell clonality Characteristic mutations (Coming: gene arrays, etc) FISH: Her2 amplification (breast cancer) Courtesy Dana Bangs PCR/HPLC (WAVE) for C-kit mutations in GIST Corless Am J Pathol. 2002 160:1567-72

Nomenclature Hypertrophy: increase in size of cells Hyperplasia: increase in the # of cells in organ/tissue Neoplasia: “new growth” Growth exceeds/uncoordinated with normal tissue Growth persists after stimulus removed CLONAL Benign or malignant Neoplasm=proliferating cells & associated stroma

Neoplasia: Benign Cohesive, expansile masses (tumors) Remain localized No capacity to invade, metastasize Slow growing Often encapsulated Well differentiated (still resemble normal) Often named with suffix “-oma” Chondroma (benign neoplasm of cartilage) Hemangioma (benign neoplasm of blood vessels) Leiomyoma (benign neoplasm of smooth muscle) Adenoma (benign epithelial neoplasm) Cystadenoma, Papilloma etc

Neoplasia: Malignant Invade and destroy surrounding tissue Capacity for metastasis Spread through blood vessels/lymphatics to distant sites Higher rate of growth Pleomorphism (variation in size/shape) Abnormal nuclear morphology & hyperchromasia De-differentiation/Anaplasia Nomenclature: Malignant epithelial neoplasm: carcinoma Malignant mesenchyma: sarcoma Malignant hematolymphoid: leukemia, lymphoma Malignant melanocytic: melanoma Malignant germ cell: seminoma, and others

Neoplasia: Benign vs. Malignant Robbins 7-22 Uterus

Normal, Benign, Malignant Normal colon and invasive adenocarcinoma (right, Malignant) Normal colon (lower) & tubular adenoma (benign, upper left)

Adenoma, colon (TVA)

Normal, Benign, Malignant Normal breast Benign hyperplasia Invasive carcinoma

Histologic Features of Malignant Cells http://www.usc.edu/hsc/dental/PTHL312abc/312a/05/Reader/reader.html

Transformation “Malignant change in the target cell” What features define a transformed cell? Hanahan and Weinberg. “The Hallmarks of Cancer” Cell. 100:57-70. 2000 And Genomic Instability

Transformation: Darwinian? “Malignant change in the target cell” Mechanisms & chronology of acquired capabilities vary By organ/tumor type By subtype, etc Hanahan and Weinberg. “The Hallmarks of Cancer” Cell. 100:57-70. 2000

“The Genomic Landscapes of Breast and Colorectal Cancer” Wood et al. Science. 2007 318: 1108-113

“Tumors as Complex Tissues” or, “It takes a village” Hanahan and Weinberg. “The Hallmarks of Cancer” Cell. 100:57-70. 2000

Concept: Carcinoma in situ (CIS) Malignant cells that have not yet breached the basement membrane (still confined) DCIS & invasive DCIS: breast

Calponin p63 Carcinoma In Situ (right) and Invasive carcinoma (left), breast Calponin p63

Carcinoma in situ (CIS) Squamous Cell CIS Squamous CIS Invasive SCC

Invasion & metastasis Vein Artery Colon CA in lymphatic channel ECM 1’tumor BM Vein Artery Lymph Colon CA in lymphatic channel Platelets ECM Vein Artery Robbins 7-42

Tumor growth and spread Normal cell (Lung) Single tumor cell 30 doublings 1 gm=109 cells Smallest clinically detectable mass 10 doublings 1 kg=1012 cells Maximum mass compatible w/ life Liver mets Robbins 7-12

Tumor angiogenesis Leaky vessels Robbins 7-41

Transformation Some benign neoplasms have propensity to acquire additional genetic changes and progress to malignancy (precursors) Example: colonic adenoma carcinoma Others rarely undergo transformation Example: Uterine leiomyomas, salivary gland pleomorphic adenomas

Histologic and Molecular Progression: Colon LG dysplasia HG dysplasia Carcinoma P53 18q21 SMAD2,4 Telomerases, etc Kras APC b-cat APC Robbins. 7th ed. Figure 17-60

It’s never that simple… http://www.rr-research.no/wcache/650x_58df157ee0b2a665ce8c99e0dd99e435Adenoma_carcinoma.jpg

http://www. mdconsult. com/das/book/body/128522719-2/0/1492/f4-u1 http://www.mdconsult.com/das/book/body/128522719-2/0/1492/f4-u1.0-B978 -1-4160-2805-5..50208-1..gr5.jpg from Cecil Medicine 23 ed (Saunders, Elsevier)

Histologic and molecular progression: Breast True precursor? Non-obligate precursor? Florid proliferation Infiltrating Carcinoma Normal ADH DCIS Tissue Invasion Robbins Fig 23-15