NEOPLASIA REVIEW PLUS

9-16-2014T. Davis

1. A new test for prostate cancer (PC) is developed. 90% of men with PC test positive. 80% of men without PC test

negative. 2. In a population of 1000 men, 30%

(300 men) have the disease (the prevalence is 30%).

Calculate sensitivity, specificity and PPV.

Sensitivity and specificity

• 90% sensitivity• 90% of 1000 or 900

would be the true positives

• 10% of 1000 or 100 would be the false negatives

• 80% specificity• 80% of 1000 or 800

would be the true negatives

• 20% of 1000 or 200 would be the false positives

PPV (predictive value) of a +with a prevalence of 30%

• 410 men have a positive test: 270 TP (90%x300) and 140 FP (20%x700)

• PPV= TP/FP+TP• PPV= 270 / 270 + 140 270/410 or about 66%

A 68 y.o. male farmer has an ulcerated, pearly nodule on his upper lip. Dx?

• A. Malignant melanoma• B. Dermatofibtoma• C. Actinic keratosis• D. Nevocellular nevus• E. Basal cell carcinoma

E, BCC

• Ulcerated• Pearly• Peripheral palisading• Chronic solar damage• Malignant but rare to metastasize

45 y.o. i.v dug user has huge scalp lesion. Diagnosis?

• A. Basal cell carcinoma• B. Melanoma• C. Systemic lupus erythematosis• D. Squamous cell carcinoma• E. Ulcer

D, Squamous cell carcinoma

• Aids patient (drug abuse)• Immune supression• Deep invasion

Cancer Precursor Lesions

• Actinic keratosis• Atyp. Hyp. Breast • Ulcerative Colitis• Endom. Hyperplasia• Esoph. Metaplasia

(Barrett’s)• Gastric metaplasia and

lymphocytosis (Helicobacter)

• Cirrhosis

• Sq. Cell CA• Ductal CA• Adeno CA colon• Adeno CA endom.• Esoph. Adeno CA• Gastric Adeno CA(and low grade or MALT

Lymphoma)• Adeno CA liver

Precursors (2)

• Scar in lung

• Sq. Dysplasia/cervix, lung/larynx

• Adenomatous polyp

• Adeno CA

• Sq. Cell CA

• Adeno CA colon

Malignant Tumors and Endocrinopathies

• Cushings;SIADH• HCG/gynecomastia• PTH/hyperCa++• Calcitonin/hypoCa++• Insulin/hypoglycemia• Erythropoetin/

polycythemia or HiHct

• Small Cell• ChorioCA/testis• SC CA/lung• Med CA/thyroid• Islet cell• Renal Cell CA

Hepatocellular CA

The following image is most c/w which malignancy

• A. Medullary Carcinoma of Thyroid• B. Small cell carcinoma of Lung• C. Sq. Cell Carcinoma of Lung• D. Metastatic melanoma• E. Renal Cell Adenocarcinoma

Ans. C, SCC of Lung

• These tumors frequently make a parathormone-like substance resulting in hypercalcemia and metastatic calcifications in lung and kidney.

Anaplasia = Lack of differentiation

• Anaplasia is considered a hallmark of malignant transformation.

• Anaplastic features include: - Cellular/nuclear pleomorphism - Increased nuclear-cytoplasmic ratio - Nuclear hyperchromasia (increased DNA content) - Large nucleoli

- Also called: Undifferentiated, poorly differentiated, high grade

Anaplastic rhabdomyosarcoma

GRADING TUMORS

• Malignant tumors only• Differentiation and mitotic rate• Grades I-III/IV (higher grades are more

anaplastic)• Important for some tumors: breast,

prostate, endometrium, astocytomas• Dysplasias of the cervix are “graded”• Based on microscopic features

Squamous cell carcinoma with “squamous pearls” (SP)

SP

SP

*

*

Intercellular bridges (*)

STAGING TUMORS

• How far has the tumor spread• Malignant tumors only• Tumor size (T), lymph node (LN)

involvement, distant metastases (M)• Staging often involves: the Pathologist,

radiology or other imaging, lab tests (tumor markers)

• CIS is referred to as Stage Zero

METASTASIS• LIVER: (portal circulation) GI tract and

pancreas; lung, breast, melanomas• LUNG: breast, stomach, sarcomas• BONE: 3rd most frequent site for

metastases; lung, breast, prostate, kidney, thyroid; PROSTATE to bone gives osteoblastic lesions on Xray and high serum alkaline phosphatatse

• ADRENAL: most common endocrine site

COLON CANCER

• Grading is not very helpful• STAGING: predicts clinical outcome• TNM• Robbins Table 17-11

Tumor Size (T)

• Tis- insitu; not through the muscularis mucosa

• T1- invades submucosa• T2- into but not through the muscularis

propria• T3- through muscularis propria• T4- invades adjacent organs

TNM Staging System

Lymph Nodes (N)

• N0- no nodes involved• N1- 1-3 regional LNs• N2- 4+ regional LNs

Distant Metastases (M)

• M0- no distant metastasis• M1- distant mets present

• *note• Tx, Nx, Mx- cannot be assessed

Which of the following best describes colon cancer?

• A. Grading is very important• B. Staging is not important• C. Inactivation of a supressor gene• D. X-linked recessive inheritance pattern• E. Autosomal recessive inheritance pattern

Answer: C, inactivation of APC

• This disorder is autosomal dominant with the APC supressor gene on chromosome 5.

COLON CANCER

• OTHER• 50% of colorectal carcinomas show “ras” mutations;

50% of adenomas > 1cm also show ras mutations• CEA (carcinoembryonic Ag) can be used to follow

patients after surgery- tumor monitoring using a tumor marker (CEA also done with PSA, HCG etc.

• Deeply infiltrating tumors cause desmoplasia and cause “apple core/ napkin-ring” appearance

Name the most common human tumor supressor genes and

protooncogene (RESPECTIVELY)

• A. P53 and RB• B. P53 and RAS• C. RB and RAS• D. APC and P53• E. APC and RB

Answer: B, P53 and RAS

• P53 is the tumor supressor gene mutated in over 50% of human tumors. The mutation prevents DNA repair and inhibits apoptosis. The point mutation in the proto-oncogene RAS allows cell proliferation (GTP signal transduction) and is seen 30+% of human tumors

What tumor markers are useful in management of colon cancer?

• A. CEA is used to monitor tumor recurrence• B. CEA is used as a screening test for colon

cancer• C. CEA is used as a confirmation test if the

test for occult blood is positive• D. High PSA in serum is diagnostic• E. High AFP in serum is diagnostic

Answer: A, used to monitor tumor recurrence

• CEA is not specific for colon cancer and not a sensitive test. CEA levels are determined pre- and post-surgery. The CEA level should fall to near zero. If the level falls and then increases, the patient may receive chemotherapy for the recurrence.

Markers

• CEA- colon, pancreas, stomach, lung, breast, (19% smokers, 3% gen. pop.)

• AFP- hepatocellular, germ cell (>500ng/ml)• CA 125- 80% non-mucinous ovarian CA• CA 19-9- pancreatic CA (80%)

Markers (2)

• PSA- (0-4 ng/ml normal) (>10 ng/ml highly suspicious); also AlkPhos elevation in prostate CA assoc. with bone metastasis (osteoblastic)

• HCG- gestational trophoblastic tumors, testicular tumors

Fibroadenoma

Fibroadenoma of breast

C

C

CN

Intraductal carcinoma with cribbiforming (C) and comedonecrosis (CN)

Invasive CA

Mammogram shows a mass and Ca**

Stellatetumor

BREAST CARCINOMA GRADING

• Bloom and Richardson• Tubules present (1-3)• Nuclear atypia (1-3)• Mitoses (1-3)• Total score 3-5: Grade I• Total score 6,7: Grade II• Total score 8,9: Grade III

Breast carcinoma- Grade I

BREAST CARCINOMA STAGING

• Stage 0 (in situ or CIS): 5-year 92%• Stage I. (<2 cm & LN-): 5-year 87%• Stage II. (2-5 cm & 1-3 LN+): 5-year 75%• *Stage III. (5 cm & >4 LN+): 5-year 46%• Stage IV. Distant mets: 5-year 13%

Invasive (infiltrating) ductal carcinoma with lymphatic invasion

BREAST CARCINOMA

• OTHER• Estrogen receptor (+): tumor is stimulated by

estrogen and can be treated with the “anti-estrogen” tamoxifen. This is palliation.

• HER-2 Neu amplification: by immunostaining or FISH. If HER-2 Neu is amplified (20%), the patient can be treated with Herceptin. This is very expensive and tends to be used in high grade/high stage lesions that are HER-2 Neu positive.

ER (+)

HER-2 Neu (+)

Squamous Carcinoma of Cervix

• Squamous metaplasia• Dysplasia• CIS• Microinvasive cancer (<5mm below BM)• Invasive cancer (>5mm below BM• Stage I: 5-year is 90%• Stage II: 5-year is 70%• Stage IV: 5-year is 10%

HPV and Cervical Cancer

• HPV DNA types 6 and 11: condyloma• HPV 16, 18, 13 others: carcinoma• Viral protein E7 acts via retinoblastoma gene

protein• Viral protein E6 acts via to P53 (TP53).• Proliferation is stimulated and apoptosis is

inhibited

Carcinoma Insitu

Normal Low Grade

Moderate Severe/CIS

Microinvasive Squamous Cell CA

What is the most sensitive test for high grade dysplasia of the cervix?

• A. Pap smear• B. HPV DNA or RNA test for high risk types • C. HPV culture for DNA type 16• D. HPV culture for DNA type 18• E. HPV serum antibodies to DNA type 16

HPV DNA or RNA test are more sensitive tests for High Grade

dysplasia

• Pap smear 55%• HPV DNA 95%

• **RNA test more specific- requires integration into host DNA for expression

LUNG CANCER

• Large cell carcinomas, adenocarcinomas and squamous cell carcinomas: can be cured by surgery if caught early (<1/3); radiation may offer palliation; chemotherapy and targeted therapy improving for adenocarcinomas

• SMALL CELL carcinoma: “always” metastatic at diagnosis, therefore, surgery usually not an option; remains poorly controlled by chemotherapy

Normal

CIS

Squamous CA

Squamous CA Adeno CA

Small cell undifferentiated carcinoma Large cell CA

keratin

Nuclear molding

Squamous Cell Carcinoma Small Cell Carcinoma

Paraneoplastic Syndromes

• Acanthosis nigricans• Eaton-Lambert• Osteoarthropathy• Seborrheic keratosis• Migratory

thrombophlebitis (Trousseau’s)

• Adeno CA (gastric)• Small Cell CA• Bronchogenic CA• Gastric CA

• Pancreatic CA

PARANEOPLASTIC SYNDROMES

• Small Cell CA

• Squamous cell CA hypercalcemia

• Carcinoid tumor (invasive in lung or liver usually)

• ACTH (Cushings); ADH (SIADH)

• PTH-like (Hypercalcemia)

• Serotonin, bradykinin (Carcinoid syndrome- diarrhea, flushing, high output murmur)

Viruses and Cancer (RNA)

• HCV

• HTLV-1

• Hepatocellular

• T-cell leukemia/ lymphoma

Viruses and Cancer (DNA)

• EBV t(8;14)

• HBV (<p53)• HPV 16 (E6/p53)• HPV 18 (E7/RB)• HHSV-8

(HIV/cytokines)

• Burkitt L., NP CA, MC Hodgkin

• Hepatocellular CA• SC CA cervix, anus• Same as HPV 16• Kaposi’s sarcoma in

AIDS

Neoplasms

• Benign

• Non-invasive• Non-metastatic

• Malignant

• Invasive• Metastatic or non-

metastatic

Malignant Tumor Properties

• Penetration of the basement membrane• Invasion and destruction of surrounding tissue• Penetrate organ walls or fungate through the

surface• Local invasion, like metastasis is a marker for

malignancy• See Robbins Table 7-2 for benign vs malignant

features

Exceptions to the Rule

• Benign tumors that may kill the patient

• Meningioma• Leiomyoma

• Malignant tumors without metastasis

• Glioblastoma multiforme

• Basal cell carcinoma

Metastasis

• #1 marker of malignancy• Exceptions: gliomas (astrocytomas) of the brain and

basal cell carcinomas of the skin RARELY metastasize; also, meningiomas LOCALLY invade skull bone, but do not metastasize and are considered benign.

• ** On board exams they sometimes substitute invasiveness for metastasis

Glioblastoma Multiforme (Astrocytoma III/IV

Metastatic melanoma

Cancer Statistics

• 90 % of cancer deaths are due to metastases• 1/3 of breast and colon cancer patients have

lymph node metastases at diagnosis• Frequency overall: liver, lung, bone• #1 endocrine site: adrenal glands

Stage of tumors at diagnosis listed by organ/site

Pathways of Spread• Direct seeding of body cavities: peritoneal #1;

also pleural, pericardial, subarachnoid, joint• Lymphatic spread: carcinoma> sarcoma;

follows natural drainage- breast cancer (Upper-Outer Quadrant) goes 1st to axillary nodes

• Hematogenous spread: esp. sarcoma; also carcinoma; usually veins

• Other: eg. Perineural spread

Breast carcinoma with perineural invasion

Venous Drainage

• Portal: liver• Caval: lungs• Paravertebral plexus: thyroid and prostate

carcinomas metastasize to the vertebrae• Renal Cell CA: invades renal vein and grows

into the vena cava

Liver with metastases

Sentinel LN Biopsy• “The first node in a regional lymphatic

basin that receives lymph flow from the primary tumor”

• Dyes and radiolabeled tracers mark the node• Breast, colon and melanomas• In breast carcinomas it replaces a total

dissection of the axillary lymph nodes and reduces morbidity

ANGIOGENESIS

• Tumors stimulate the growth of host blood

vessels• Any tumor >2 mm in diameter must have a

vascular supply• New vessels supply oxygen and nutrients and

endothelial cells secrete growth factors

Tumor-associated Angiogenic Factors

• VEGF (vascular endothelial growth factor) and bFGF (basic fibroblast growth factor) are made mostly by tumor cells but also by macrophages and stromal cells

ANGIOGENIC SWITCH

• Angiogenesis is delayed; a minority of the cells become angiogenic

• p53 inhibits angiogenesis by inducing production of thrombospondin-1 and down-regulating VEGF

• Angiogenesis inhibitors made by tumor cells: thrombospondin-1; and angiostatin (from plasminogen), endostatin/tumstatin (collagen)

• All are possible therapeutic targets!

Invasion and Metastasis

• Robbins Figure 7-42• Cells break loose, enter and exit vessels and

establish a secondary growth site• Rare malignant cells are successful at

metastasis; Robbins Figure 7-43

Steps in Metastasis

•Detachment of cells from the primary tumor•Invasion of the surrounding tissue•Penetration to blood and lymphatic vessels•Arrest at target sites•Egression (extravasation)•Proliferation•Establishment of a new blood supply

MetastaticCascade

Invasion of the Extracellular Matrix (ECM)

• Basement membrane• Interstitial connective tissue• Vessel basement membrane• Vessel basement membrane• Interstitial connective tissue

Tumor Cells in Circulation

• They clump with each other, RBCs and platelets

• Adhesion to endothelium (integrins-laminin-proteinases)

Metastasis Oncogenes

• SNAIL and TWIST (breast cancer)• E-cadherin is down-regulated and vimentin is

up-regulated

Tumor Tropism

• Different endothelial receptors in different organs

• Different chemokine receptors on the tumor cells- eg. breast cancers express CXCR4 and CCR7 receptors and “matching” chemokines are at high levels in lung and lymph nodes

• “unfertile soil” like skeletal muscle without receptors

Metastases and Tropism

Primary Site and Histology Organ

Clear cell carcinoma (kidney) Thyroid

Cutaneous melanoma Small bowel/brain

Ocular melanoma Liver

Adenocarcinomas Ovary (Kruckenberg of the GI tract tumor)

Follicular carcinoma, thyroid Bone

Targeted Therapy• Signal-transduction Inhibitors• Block enzymes and Growth Factor Receptors• GLEEVEC (imatinib)- GIST and CML (abnormal

tumor enzymes); • IRESSA (gefetinib)- non-small-cell lung cancer

(EGFR)• Zelboraf (vemurafenib)- blocks B-raf/MEK if

V600E BRAF mutation present with apoptosis

Target (2)

• Monoclonal Antibodies

• Herceptin- invasive breast carcinomas (that show overexpression of HER-2-neu)

Target (3)

• Anti-angiogenesis

• Angiostatin (from plasminogen)• Endostatin (from collagen)