Pathology of Solid Tumors

Megan Troxell, MD/PhDOHSU 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

Undiff. tumor HMB45+ Melanoma

H=hematoxylin, nucleic acids, purple

E=eosin, protein, pink

Diagnostic Methods in Tumor Pathology• Immunohistochemistry– May help subclassify– Rarely, may imply specific

genetic rearrangement

TFE3 +nuclear

Aberrant TFE3 protein expression as a result of t(X;1)(p11.2;q21)

Argani. AJSP 26:1553-66

Pediatric Kidney Cancer

Loss of PMS2 expression, colon cancerMismatch repair protein deficient (Lynch)

Normal

Cancer

Diagnostic Methods in Tumor Pathology

FISH & CytogeneticsCharacteristic

translocations

t(11;22) Ewing’sEWS-FLI1Breakapart FISH probe

(courtesy of Helen Lawce)

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) forC-kit mutations in GISTCorless 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. MalignantUterus

Robbins 7-22

Normal, Benign, Malignant

Normal colon (lower) & tubular adenoma (benign, upper left)

Normal colon and invasive adenocarcinoma (right, Malignant)

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”

Hanahan and Weinberg.“The Hallmarks of Cancer”Cell. 100:57-70. 2000

Mechanisms & chronology of acquired capabilities vary By organ/tumor type By subtype, etc

“The Genomic Landscapes of

Breast and Colorectal Cancer”

Wood et al. Science. 2007318: 1108-113

“Tumors as Complex Tissues”or, “It takes a village”

Hanahan and Weinberg.“The Hallmarks of Cancer”Cell. 100:57-70. 2000

• Malignant cells that have not yet breached the basement membrane (still confined)

Concept: Carcinoma in situ (CIS)

DCIS: breast

DCIS & invasive

p63

Calponin

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

Carcinoma in situ (CIS)

SquamousCell CIS

Carcinoma in situ (CIS)Carcinoma in situ (CIS)

Squamous CIS

Invasive SCC

Invasion & metastasis1’tumor

Lymph

Platelets

ECM

BM

Robbins 7-42

Colon CA in lymphatic channel

Vein

Vein

Artery

Artery

Tumor growth and spread

Normal cell(Lung)

Single tumor cell

30 doublings

1 gm=109 cellsSmallest clinically detectable mass

10 doublings

1 kg=1012 cellsMaximum mass compatible w/ life

Robbins 7-12Liver mets

Tumor angiogenesis

Robbins 7-41

Leaky vessels

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

Robbins. 7th ed. Figure 17-60

APCAPC-cat

P5318q21SMAD2,4

Telomerases, etcKras

Histologic and Molecular Progression:Histologic and Molecular Progression:ColonColon

LG dysplasia HG dysplasia Carcinoma

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-u1.0-B978-1-4160-2805-5..50208-1..gr5.jpg from Cecil Medicine 23 ed (Saunders, Elsevier)

Histologic and molecular progression:Breast

Tissue

Invasion

Robbins Fig 23-15

NormalFlorid

proliferation ADH DCISInfiltratingCarcinoma

True precursor?

Non-obligate precursor?