Hereditary colon cancer in young patients

HEREDITARY COLON CANCER & COLORECTAL CANCER IN YOUNG PATIENTS Introduction: Colorectal Cancer in the Young • peak frequency 6th and 7th decade • often associated with a poor prognosis • delay in diagnosis, advanced lesions, poorly differentiated tumors, mucin-producing tumors • <30 years old (1-17%) • case reports of children as young as 11 (signet-ring cell carcinoma) • 29 Japanese patients under 15; curative resection only possible in 14; only 3 patients survived 10 years • 10% of CRC in patients under 40 secondary to HNPCC Mount Sinai Literature between 1968-1985 • 53 patients; retrospective analysis; <40 • IBD, FAP patients excluded • mean age 34 • 0% Dukes A; 32% B; 34% C; 34% distant metastases • studies investigating ras and c-myc oncogene • ras intensity increased for higher staging • 61% vs 33% 5 year survival difference if had low ras intensity versus high (p<.05) • c-myc staining had no correlation with staging or outcome • compared to 49 patients with UC and 16 with FAP • poorly differentiated tumors significantly higher in UC patients • young patients and patients with UC had significantly higher incidence of colloid features • 3 young patients and 14 UC patients had signet ring cells • no difference in 5 year survival of 3 groups • strongest prognostic variable was stage followed by tumor differentiation, presence of signet cells and ras stain • diploid tumors had better prognosis than nondiploid • 39 of 53 patients had rectal adenocarcinoma within 20 cm of anal verge • 50% presented with metastases • 5 yr survival after curative resection was 53% • 6 patients had a family history of colorectal cancer • one patient develop breast cancer 12 years later, another endometrial cancer 5 years later and a third had melanoma several years prior to the colorectal cancer Introduction: Hereditary Colon Cancer • up to 20% potentially definable inheritable component; 5-6% of all CRC • heritable diseases include familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC), Peutz-Jeghers syndrome, and juvenile polyposis 135 Familial Adenomatous Polyposis (FAP) • genetic origin lagged behind first descriptions-1863 versus 1986 • APC gene (Adenomatous Polyposis Coli)- long arm of chromosome 5 • tumor suppressor gene; location of mutation alters aspects of disease • AD; 1:8300-1:14,025 live births; 1:1 M:F; similar worldwide distribution • Diagnosis • family history; confirmed by >100 colorectal adenomas ; attenuated FAP (<100) • Screening • benign extracolonic manifestations include SI and stomach adenomas, desmoid • tumors, lipomas, fibromas, epidermal cysts, odontomas, osteomas, pigmented ocular fundic lesions • associated CA include duodenal (5-11%), periampullary, jejunal, thyroid, pancreatic (2%), biliary tree (2%), brain (medulloblastoma) (<1%), hepatoblastoma (.7% of children <5 yrs), adrenal • polyps evenly distributed throughout colon; slight predominance to distal colon • attenuated FAP- oligopolyposis (<100 adenomas at presentation; CRC 12 years later than FAP); 70% will develop CRC if polypectomy not performed • Surgical options-subtotal colectomy with ileorectal anastomosis versus proctocolectomy • Medical treatment- nonselective/selective cyclooxygenase-2 inhibitor(sulindac/celecoxib) Hereditary Nonpolyposis Colorectal Caner • Lynch/Whartin; up to 3-7% of CRC; 15% of patients with family history of CRC • 10% of cases under 40 • AD; caused by mutation in one of five MMR genes (mismatch repair) • 70-80% lifetime risk of CRC if have MMR gene mutation; 70% right sided • Lynch I- colorectal cancer • Lynch II- CRC and extracolonic cancer • endometrial (39%), ovarian (9%), transitional cell carcinoma of ureter and renal pelvis (4-10%),stomach(12-19%), pancreas, small bowel (1-4%), larynx, breast, brain (glioblastoma, 4%), biliary tract (2-18%), hematologic • Amsterdam criteria- developed in 1991 for diagnosis of HNPCC; 1999 revised • Genetic defect • hMSH2 on 2p16, hMLH1 on 3q21, hPMS1 on 2q31, hPMS2 on 7q11, hMSH6 on 2p16 • microsatellite instability(MSI) found in 90% of HNPCC versus 15-20% in sporadic CRC • Screening • MSI testing/MMR testing • MSI testing should be first step in genetic testing of tumor for families • Bethesda criteria for MSI testing • Surgery-? prophylactic colectomy; ? prophylactic hysterectomy and oopherectomy Juvenile Polyposis Syndrome-AD; 1:100,000 live births • anemia, diarrhea, and protein-losing enteropathy are often presenting features; digital clubbing 136 • • • risk of CRC 12X general population 3 different gene mutations can cause disease; 5-10 polyps to be suspicious for JPS genetic etiology of almost 50% of juvenile polyps unknown Peutz-Jeghers Syndrome-AD; 1:200,000 live births • mucocutaneous hyperpigmentation, intestinal polyposis, and increase risk of CRC, breast ca, endometrial, pancreatic, lung, and cervix, ovarian sex-cord tumors, testicular sertoli cell tumors • clinically must have intestinal polyps, mucocutaneous melanotic pigmentation, and family history • 84X greater risk for CRC than general population (relative risk); 17X lung cancer, 57X esophageal, 213X gastric, 520X small intestine, 132X pancreatic, 16X endometrial, 27X ovarian • one tumor suppressor gene identified to date associated with Peutz-Jeghers ; LKB1 MYH Mutation • recessive cause of multiple adenomas; first reported by Al-Tassan in 2002 • up to 30% of multiple colorectal adenomas (15-100) might be tied to bi-allelic mutation of MYH (similar endoscopic exam to attenuated FAP) • large % of suspected FAP are APC gene mutation negative • initial data from APC mutant pt’s who had gcà ta mutation which is secondary to oxidative damage; MYH appeared mutated in these patients; inheritance pattern recessive References 1. 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