Oncology

With regard to the spread of neoplasms, which of the following statements is false?

A. Metastatic cells enter the lymph nodes via the subcapsular space and later permeate the sinusoids of the node

B. Carcinoma in situ is a lesion with histopathologic characterisitics of malignancy but without detectable invasion beyond the basement membrane

C. Lymphatic involvement is common with epithelial neoplasms, whereas most sarcomas metastasize hematogenously

D. The Metastatic process is highly efficient, as evidenced by the fact that the number of circulating tunor cells correlates with the metastatic burden.

Answer: DAnswer: D

Regarding oncogenes and proto-oncogenes, which of the following statements are true?

A. Proto-oncogenes are proteins capable of inhibiting oncogenes.

B. Oncogenes are nucleic acid sequences unique to the viral genome.

C. Exposure to carcinogens causes insertion of oncogenes into the human genome.

D. Proto-oncogenes may be activated by mutation, amplification, or translocation.

Answer: DAnswer: D

Development of Cancer

• Oncogenes are genes that, when expressed, contribute to the devlopment of malignancy

• Proto-oncogenes are genes found in normal tissues that, when activated by mutation, amplification or translocation become oncogenes and may lead to transformation of the cell to a malignant phenotype. e.g. - RET (?)

• Tumor suppresor genes are different – the loss of their expression leads to devlopment of cancer.

– Most common tumor suppressor gene -

Medullary Thyroid CancerMedullary Thyroid Cancer

p53

Regarding metastatic cancer, which of the following statements is true?

A. Axillary lymph node dissection is essential for staging a sarcoma of the breast

B. Melanoma tends to metastasize first to the lung, brain, and gastrointestinal tract.

C. Bone is frequently the site of metastasis for cancer of the breast and prostate.

D. Primary brain cancers have a predilection for metastasis to the lung.

Answer: CAnswer: C

Which of the following options is/are appropriate for treatment of metastatic cancer?

A. A Whipple procedure to relieve obstructive jaundice in a patient with adenocarcinoma of the head of the pancreas and multiple small metastatic lesions in the liver.

B. Resection of three liver lesions, metastatic from a colorectal primary tumor, in the absence of another site of disease.

C. Resection of two lung metastases from a sarcoma of the lower extremities in the absence of other metastatic disease.

D. Radiation therapy for a painful hip lesion in a patient with diffuse metastases from prostate cancer.

Answer: B,C,DAnswer: B,C,D

Which of the following historical characteristics of a mass suggest(s) malignancy?

A. Sudden devlopment of a painful, tender mass.

B. Slow, progressive, painless growth of mass.

C. Sudden dramatic enlargement of a previously stable-sized mass

D. A mass that waxes and wanes in size with or without associated tenderness.

Answer: BAnswer: B

Performing which of the following operations would be inappropriate without first obtaining a biopsy specimen confirming the presence of cancer?

A. Radical right hemicolectomy for an “apple core” narrowing of the ascending colon.

B. Modified radical mastectomy for a clinically and mammographically obvious breast cancer with overlying “skin puckering”.

C. A pancreaticoduodenectomy for a large, hard mass in the head of the pancreas that produces painless jaundice.

D. Parotidectomy for a 2 cm, slowly growing solid parotid mass without evidence of facial nerve dysfunction.

Answer: BAnswer: B

Which of the following tumors requires resection of the largest margin of normal tissue around the clinically obvious tumor to achieve an acceptable likelihood of control at the local primary site. Assume that no other treatment will be used.

A. Adenocarcinoma of the colon

B. Basal Cell carcinoma of the skin

C. Invasive breast cancer

D. Squamous carcinoma of the distal esophagus

E. Squamous carcinoma of the skin

Answer: DAnswer: DColon – 2cmColon – 2cmEsophageal and gastric malignancy can spread in submucosal Esophageal and gastric malignancy can spread in submucosal plane as far as 10cm from primary siteplane as far as 10cm from primary site

Partial of complete resection of which of the following organs could be justified to prevent a future cancer?

A.Colon

B.Pancreas

C.Breast

D.Testicle

E.Thyroid

Answer: A, C, D, E inAnswer: A, C, D, E inFAP, BRCA1 or 2, Undescended testicle, MEN IIFAP, BRCA1 or 2, Undescended testicle, MEN II

In which of the following circumstances would palliative surgery not be indicated?

A. Carcinoma of the body of the pancreas that produces severe back pain

B. A large gastric cancer obstructing the gastroesophageal junction, associated with two small liver metastses

C. A bleeding cecal cancer, 5cm in diamter, with multiple liver metastasis

D. Adenocarcinoma of the head of the pancreas with partial portal vein involvement

Answer: AAnswer: A

Which of the following statements concerning sentinel lymph node biopsy is not true?

A. The technique utilizes injection of a vital blue dye and/or radioactive tracer to identify the sentinel node

B. The sentinel node is the first draining node, from a particular location, in each basin.

C. There is only one sentinel node in each basin.

D. The technique is not useful in patients with suspicious palpable adenopathy.

Answer: CAnswer: C

Which of the following chemotherapeutic agents is/are known to cause nephrotoxicity?

A. Cisplatin

B. Carboplatin

C. Ifosfamide

D. Methotrexate

E. Cyclophosphamide

F. 5-FU

Answer: A,DAnswer: A,D

Rapid Fire

• Most sensitive phase of cell cycle to radiation

– MM• Extremity Sarcoma – method of excisional biopsy

– Longitudinal incisionLongitudinal incision• Ret proto-oncogene diagnostic for:

– Medullary Thyroid CancerMedullary Thyroid Cancer -treatment?

– Total ThyroidectomyTotal Thyroidectomy• Adverse effect of Tamoxifen

– DVT and endometrial CA

Alphabet Soup

• CEA

– Colon CaColon Ca• AFP

– Liver CaLiver Ca• CA 19-9

– Pancreatic CaPancreatic Ca• CA 125

– Ovarian CaOvarian Ca• Beta-HCG

– Testicular CA, choriocarcinoma

•PSA-Prostate-Prostate

•NSE-Small cell Lung CA-Small cell Lung CA

Familial Cancer SyndromesFamilial Cancer Syndromes• Breast/ovarian

– BRCA1 – breast, ovary, colon, prostateBRCA1 – breast, ovary, colon, prostate– BRCA2 – “ “, GB/biliary tree, pancreas, stomach, melanomaBRCA2 – “ “, GB/biliary tree, pancreas, stomach, melanoma

• Cowden’s dis– breast, endometrium, thyroidbreast, endometrium, thyroid

• FAP– APC – colorectal, duodenal, gastric, medulloblastomas, osteomasAPC – colorectal, duodenal, gastric, medulloblastomas, osteomas

• Familial melanoma– CDK4 – melanoma, pancreas, dysplastic nevi, atypical molesCDK4 – melanoma, pancreas, dysplastic nevi, atypical moles

• HNPCC– colorectal, endometrial, tcc of ureter, stomach, sb, pancreas, ovarycolorectal, endometrial, tcc of ureter, stomach, sb, pancreas, ovary

• Li-Fraumeni– p53 – breast/phyllodes, soft tissue and osteosarcoma, brain, adrenal, Wilms, pancreas, p53 – breast/phyllodes, soft tissue and osteosarcoma, brain, adrenal, Wilms, pancreas,

leukemia, neuroblastomaleukemia, neuroblastoma• MEN1

– MEN1 – pancreas, parathyroid hyperplasia, pituitaryMEN1 – pancreas, parathyroid hyperplasia, pituitary• MEN2MEN2

– RET – MTC, pheo, parathyroid hyperplasiaRET – MTC, pheo, parathyroid hyperplasia

Familial Cancer SyndromesFamilial Cancer Syndromes• NF1NF1

– NF1 – Neurofibromas/fibrosarcoma, AML, brainNF1 – Neurofibromas/fibrosarcoma, AML, brain• NF2NF2

– NF2 – Acoustic neuromas, meningiomas, gliomas, ependymomasNF2 – Acoustic neuromas, meningiomas, gliomas, ependymomas• Peutz-JeghersPeutz-Jeghers

– GI CAs, breast, testicular, pancreas, benign pigmentation of skin/mucosaGI CAs, breast, testicular, pancreas, benign pigmentation of skin/mucosa• RetinoblastomaRetinoblastoma

– RB – Rb, sarcomas, melanomaRB – Rb, sarcomas, melanoma• Tuberous sclerosisTuberous sclerosis

– TSC1/2 – hamartomas, renal cell, astrocytomaTSC1/2 – hamartomas, renal cell, astrocytoma• VHLVHL

– Renal cell, hemangioblastomas of retina and CNS, pheoRenal cell, hemangioblastomas of retina and CNS, pheo• WilmsWilms

– WT – wilm’s, aniridia, genitourinary abnormalities, mental retardationWT – wilm’s, aniridia, genitourinary abnormalities, mental retardation

Familial Adenomatous PolyposisFamilial Adenomatous Polyposis

• APC gene, autosomal dominantAPC gene, autosomal dominant– Scaffolding protein, cell adhesion, migrationScaffolding protein, cell adhesion, migration– Frameshift (68%), nonsense mutation (30%), deletion (2%)Frameshift (68%), nonsense mutation (30%), deletion (2%)

• 1% of all colorectal cancers1% of all colorectal cancers• >90% develop cancers>90% develop cancers• 100s to 1000s of adenomatous polyps100s to 1000s of adenomatous polyps

– Phenotype expressed in 20-30s with CA by 35-40Phenotype expressed in 20-30s with CA by 35-40– Polyps not inherently more cancerousPolyps not inherently more cancerous

• Extracolonic manifestationsExtracolonic manifestations– UGI polyps, desmoid tumors, thyroid CAUGI polyps, desmoid tumors, thyroid CA

• Stomach/duodenum polyps(90%) by 70 yearsStomach/duodenum polyps(90%) by 70 years• Duodenal adenoCA 3Duodenal adenoCA 3rdrd cause of death cause of death

Familial Adenomatous PolyposisFamilial Adenomatous Polyposis

• Attenuated FAPAttenuated FAP– <100 adenomas<100 adenomas– Proximal colonic polyp distributionProximal colonic polyp distribution– Cancer occurs 15 years laterCancer occurs 15 years later

• Gardner’s syndromeGardner’s syndrome– Colorectal CA, Osteomas of mandible/skull, epidermal cysts, skin/soft Colorectal CA, Osteomas of mandible/skull, epidermal cysts, skin/soft

tissue tumors (desmoids and thyroid)tissue tumors (desmoids and thyroid)

• MYHMYH-associated polyposis (MAP)-associated polyposis (MAP)– Autosomal recessive, 50% penetranceAutosomal recessive, 50% penetrance– Cancer occurs at 50 yearsCancer occurs at 50 years– Extracolonic manifestationsExtracolonic manifestations

• Breast (18%)Breast (18%)• UGI polyps (33%)UGI polyps (33%)

Hereditary Nonpolyposis Colorectal CancerHereditary Nonpolyposis Colorectal Cancer

• Lynch’s Syndrome• Autosomal dominant, mismatch repair genes• 5-10% of all colorectal CA’s• Type 1 (Colorectal), Type 2 (Extracolonic)• Right sided colon CAs (70% proximal to splenic flexure) at

earlier age (~44)• Increased synchronous and metachronous lesions• Increased speed of tumor progression

– Adenomas progress to CA in 2-3 years vs 8-10

• Extracolonic– Endometrium/ovary

BRCA1 / BRCA2BRCA1 / BRCA2

• Tumor suppressor geneTumor suppressor gene– Frameshift or nonsense mutations with truncated protein productsFrameshift or nonsense mutations with truncated protein products– DNA repair, gene expression regulation, cell cycle controlDNA repair, gene expression regulation, cell cycle control– 2 hit hypothesis2 hit hypothesis

• 5-10% of all breast CAs are hereditary5-10% of all breast CAs are hereditary• 25% of high-risk families have mutations25% of high-risk families have mutations• 80% risk in 70 yo woman80% risk in 70 yo woman• Ovarian CA in 60%/27% (1 vs 2) ; Prostate CA in menOvarian CA in 60%/27% (1 vs 2) ; Prostate CA in men

MEN 1MEN 1

• MEN 1MEN 1– Autosomal dominant germline mutationsAutosomal dominant germline mutations– Tumor suppressor, Loss of fx mutations (80%)Tumor suppressor, Loss of fx mutations (80%)

• Menin – transcription regulation, DNA repairMenin – transcription regulation, DNA repair

– Parathyroid gland, pancreatic islet cell, pituitary glandParathyroid gland, pancreatic islet cell, pituitary gland• Lipomas, adrenal/thyroid adenomas, cutaneous angiofibromas, Lipomas, adrenal/thyroid adenomas, cutaneous angiofibromas,

carcinoid tumorscarcinoid tumors

MEN 2MEN 2

• ret proto-oncogene (re-arranged during transfection)ret proto-oncogene (re-arranged during transfection)– Tyrosine kinase receptor becomes constitutively activatedTyrosine kinase receptor becomes constitutively activated

• germline mutationsgermline mutations• MEN 2AMEN 2A

– MTC (100%), Pheocromocytoma (50%), Hyperparathyroidism (25%)MTC (100%), Pheocromocytoma (50%), Hyperparathyroidism (25%)

• MEN 2BMEN 2B– MTC, Pheo, mucosal neuromas (tongue, lips)MTC, Pheo, mucosal neuromas (tongue, lips)

• Intestinal ganglioneuromatosis, marfanoid habitusIntestinal ganglioneuromatosis, marfanoid habitus

– Sporadic Sporadic retret mutations more common mutations more common

• UV – skinUV – skin– UVB most important (UVC filtered by ozone layer)UVB most important (UVC filtered by ozone layer)

• Formation of pyrimidine dimers repaired by nucleotide excision repair pathwayFormation of pyrimidine dimers repaired by nucleotide excision repair pathway

– SCCA, basal cell, malignant melanomaSCCA, basal cell, malignant melanoma– Xeroderma PigmentosaXeroderma Pigmentosa

• Autosomal recessive, NER gene mutationsAutosomal recessive, NER gene mutations• Extreme photosensitivity, 2000x increased risk of skin CAExtreme photosensitivity, 2000x increased risk of skin CA

• Ionizing – multiple cancersIonizing – multiple cancers– Electromagnetic, particulateElectromagnetic, particulate– Carcinogen at low doses, therapeutic agent at high dosesCarcinogen at low doses, therapeutic agent at high doses– Causes inflammatory reaction with production of reactive oxygen Causes inflammatory reaction with production of reactive oxygen

and nitrogen speciesand nitrogen species– Leukemias and solid organ (breast, colon, thyroid, lung) tumorsLeukemias and solid organ (breast, colon, thyroid, lung) tumors

• Head/neck irradiation in kids – thyroid CA as adultsHead/neck irradiation in kids – thyroid CA as adults

Radiation CarcinogenesisRadiation Carcinogenesis

Viral CarcinogenesisViral Carcinogenesis

• ~15% of all human tumors caused by viruses~15% of all human tumors caused by viruses– Mostly cervical CA by HPV and HCC by HBV/HCVMostly cervical CA by HPV and HCC by HBV/HCV

• Establish long-term persistent infections in target cellsEstablish long-term persistent infections in target cells

EBV Burkitt’s, Hodgkin’s, Immunosuppresion-related lymphoma, Nasopharyngeal CA

Hep B/C HCC

HIV type I Kaposi’s

HPV 16 & 18 Cervical, Anal

HTLV-1 Adult T-cell leukemia

H. pylori Gastric adenoCA

Opisthorchis viverrini CholangioCA, HCC

Schistosoma haematobium Urinary bladder

Protein Tumor MarkersProtein Tumor Markers

• α-Fetoprotein – HCC– Oncofetal antigen – synthesized by hepatocytes, endodermal GI tissues– Normal <25 ng/ml (nonpregnant), half-life 5 days– 10-20% of HCCs nondetectable levels– Also found in:

• nonseminomatous testicular CA• > 5ng/ml in 20% of gastric, pancreatic 5% colorectal, lung• Hepatitis, inflammatory bowel dis, cirrhosis

– Sensitivity/Specificity 25-75% / 76-94% ; PPV 9-50%– AFP and ultrasound = 100% in one study– Reflects tumor size ; correlates with stage and prognosis

• >400 ng/ml associated with larger tumors

– Drops after resection/ablation ; usually drops with chemo• <10 ng/ml if complete rsxn

AFP level (ng/ml) Sensitivity/Specificity

20 30/80

100 72/56

400 70/94

Protein Tumor MarkersProtein Tumor Markers

• Carbohydrate Antigen 19-9 – pancreatic CACarbohydrate Antigen 19-9 – pancreatic CA– Upper limit normal 37 U/mlUpper limit normal 37 U/ml– Sensitivity/Specificity 67-92% / 68-92%Sensitivity/Specificity 67-92% / 68-92%– Not a good diagnostic marker, better for monitoring therapy Not a good diagnostic marker, better for monitoring therapy

responseresponse• Acute/chronic biliary dis elevates serum levelsAcute/chronic biliary dis elevates serum levels• Low sensitivity in early-stage diseaseLow sensitivity in early-stage disease• Benign biliary dis can have levels up to 400 U/ml, 87% with concentrations >70 Benign biliary dis can have levels up to 400 U/ml, 87% with concentrations >70

U/mlU/ml• Pts with negative LewisPts with negative Lewisaa blood group (10% pop) cannot synthesize CA 19-9 blood group (10% pop) cannot synthesize CA 19-9

• Present in CAs of biliary tree (95%), stomach (5%), colon (15%), HCC (7%), Lung Present in CAs of biliary tree (95%), stomach (5%), colon (15%), HCC (7%), Lung (13%)(13%)

– Levels correlate with tumor burden and tx responseLevels correlate with tumor burden and tx response• 95% of unresectable cancers have levels >1000 U/ml95% of unresectable cancers have levels >1000 U/ml

Protein Tumor MarkersProtein Tumor Markers

• Prostate specific antigenProstate specific antigen– Tissue specific, not cancer specific, not present post prostatectomy Tissue specific, not cancer specific, not present post prostatectomy

or in womenor in women– Elevated in BPH, prostatitis, massage, bx, and DREElevated in BPH, prostatitis, massage, bx, and DRE– Widely used screening tool for prostate CAWidely used screening tool for prostate CA

• 1:8 cancers kills host if left untreated1:8 cancers kills host if left untreated

– Upper limit normal 4ng/ml, >10ng/ml suspicious for malignancyUpper limit normal 4ng/ml, >10ng/ml suspicious for malignancy• Half-life 18 daysHalf-life 18 days

• Upper limit increases with ageUpper limit increases with age

– Measuring PSA as ratio to total volume or ratio of free to total PSA Measuring PSA as ratio to total volume or ratio of free to total PSA improves specificity when values in intermediate rangeimproves specificity when values in intermediate range

– Levels should normalize within 2-3 weeksLevels should normalize within 2-3 weeks• If levels elevated for 6 months – relapse almost certainIf levels elevated for 6 months – relapse almost certain

Protein Tumor MarkersProtein Tumor Markers

• Carbohydrate antigen 125Carbohydrate antigen 125– Present in the fetus and adult fallopian tubes, endometrium, endocervix, Present in the fetus and adult fallopian tubes, endometrium, endocervix,

peritoneum, pleura, pericardium, amnionperitoneum, pleura, pericardium, amnion– NOT present in adult nor fetal ovarian epitheliumNOT present in adult nor fetal ovarian epithelium– Upper limit normal 35 U/mlUpper limit normal 35 U/ml– Increased levels found in 80% ovarian cancersIncreased levels found in 80% ovarian cancers– Useful for monitoring disease course and recurrenceUseful for monitoring disease course and recurrence– Sensitivity/Specificity 75% / 90% in pts with ovarian massesSensitivity/Specificity 75% / 90% in pts with ovarian masses– Also present in cancer of: fallopian tube, endometrium, cervix, pancreas, Also present in cancer of: fallopian tube, endometrium, cervix, pancreas,

colon, lung, livercolon, lung, liver– Elevated in endometriosis, adenomyosis, fibroids, PID, cirrhosis, ascitesElevated in endometriosis, adenomyosis, fibroids, PID, cirrhosis, ascites

Protein Tumor MarkersProtein Tumor Markers

• αα-Fetoprotein and Human Chorionic Gonadotropin-Fetoprotein and Human Chorionic Gonadotropin– Nonseminomatous testicular cancers: embryonal CA, choriocarcinoma, yolk Nonseminomatous testicular cancers: embryonal CA, choriocarcinoma, yolk

sac tumors, teratomassac tumors, teratomas– HCG – 90% choriocarcinomasHCG – 90% choriocarcinomas– AFP – 90-95% yolk sac tumors, 20% teratomas, 10% embryonal CasAFP – 90-95% yolk sac tumors, 20% teratomas, 10% embryonal Cas– Pts with nonseminomatous testicular germ cell tumors: 50% HCG and 60% Pts with nonseminomatous testicular germ cell tumors: 50% HCG and 60%

AFP, 90% either/orAFP, 90% either/or– AFP >500ng/ml or HCG >1000 ng/ml gives poor prognosisAFP >500ng/ml or HCG >1000 ng/ml gives poor prognosis– Levels correlate with chemo responseLevels correlate with chemo response

THE END!