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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
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
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
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
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
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 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%
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.
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
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
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 (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
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
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
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
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
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)