Eugen Divjak Mentor: A. Žmegač Horvat Colorectal Carcinoma Eugen Divjak Mentor: A. Žmegač Horvat 00:00

Intestinal tumors Non-neoplastic Polyps Hyperplastic polyps Hamartomatous polyps Juvenile polyps Peutz-Jeghers polyps Inflammatory polyps Lymphoid polyps Neoplastic Epithelial Lesions Benign polyps Adenomas Malignant lesions Adenocarcinoma Squamous cell carcinoma of the anus Other Tumors Gastrointestinal stromal tumors Carcinoid tumor Lymphoma Epithelial tumors of the intestines: major cause of morbidity and mortality worldwide Colon, including rectum: host to more primary neoplasms than any other organ in the body

Adenocarcinoma 98% of all cancers in large intestine almost always arise in adenomatous polyps, generally curable by resection

Epidemiology peak incidence: 60 to 70 years of age < 20% cases before age of 50 adenomas – presumed precursor lesions for most tumors males affected ≈ 20% more often than females

Epidemiology worldwide distribution highest incidence rates in United States, Canada, Australia, New Zealand, Denmark, Sweden, and other developed countries

Etiology genetic influences: preexisting ulcerative colitis or polyposis syndrome hereditary nonpolyposis colorectal cancer syndrome (HNPCC, Lynch syndrome) → germ-line mutations of DNA mismatch repair genes

Etiology environmental influences: dietary practices low content of unabsorbable vegetable fiber corresponding high content of refined carbohydrates high fat content decreased intake of protective micronutrients (vitamins A, C, and E) use of Aspirin® and other NSAIDs: protective effect against colon cancer? cyclooxygenase-2 & prostaglandin E2

Carcinogenesis chromosome instability pathway

Carcinogenesis mismatch repair (microsatellite instability) pathway

Morphology 25% of colorectal carcinomas: in cecum or ascending colon similar proportion: in rectum and distal sigmoid 25%: in descending colon and proximal sigmoid remainder scattered elsewhere multiple carcinomas present → often at widely disparate sites in the colon

Morphology all colorectal carcinomas begin as in situ lesions tumors in the proximal colon: polypoid, exophytic masses that extend along one wall of the cecum and ascending colon

Morphology in the distal colon: annular, encircling lesions that produce “napkin-ring” constrictions of the bowel and narrowing of the lumen both forms of neoplasm eventually penetrate the bowel wall and may appear as firm masses on the serosal surface

Morphology all colon carcinomas - microscopically similar almost all - adenocarcinomas range from well-differentiated to undifferentiated, frankly anaplastic masses many tumors produce mucin secretions dissect through the gut wall, facilitate extension of the cancer and worsen the prognosis cancers of the anal zone are predominantly squamous cell in origin

Clinical Features may remain asymptomatic for years symptoms develop insidiously cecal and right colonic cancers: fatigue weakness iron deficiency anemia left-sided lesions: occult bleeding changes in bowel habit crampy left lower quadrant discomfort anemia in females may arise from gynecologic causes, but it is a clinical maxim that iron deficiency anemia in an older man means gastrointestinal cancer until proved otherwise

TNM Staging of Colon Cancer Clinical Features TNM Staging of Colon Cancer Tumor (T) T0 = none evident Tis = in situ (limited to mucosa) T1 = invasion of lamina propria or submucosa T2 = invasion of muscularis propria T3 = invasion through muscularis propria into subserosa or nonperitonealized perimuscular tissue T4 = invasion of other organs or structures Lymph Nodes (N) 0 = none evident 1 = 1 to 3 positive pericolic nodes 2 = 4 or more positive pericolic nodes 3 = any positive node along a named blood vessel Distant Metastases (M) 1 = any distant metastasis 5-Year Survival Rates T1 = 97% T2 = 90% T3 = 78% T4 = 63% Any T; N1; M0 = 66% Any T; N2; M0 = 37% Any T; N3; M0 = data not available Any M1 = 4% spread by direct extension into adjacent structures and by metastasis through lymphatics and blood vessels favored sites for metastasis: regional lymph nodes liver lungs bones other sites including serosal membrane of the peritoneal cavity carcinomas of the anal region → locally invasive, metastasize to regional lymph nodes and distant sites

Clinical Features detection and diagnosis: digital rectal examination fecal testing for occult blood loss barium enema, sigmoidoscopy and colonoscopy confirmatory biopsy computed tomography and other radiographic studies serum markers (elevated blood levels of carcinoembryonic antigen) molecular detection of APC mutations in epithelial cells, isolated from stools tests under development: detection of abnormal patterns of methylation in DNA isolated from stool cells

Therapy chemotherapy radiotherapy photodynamic therapy radical surgery gene therapy

True or false? 98% of all cancers in the large intestine are adenocarcinomas. Use of Aspirin® and other NSAIDs may cause development of colon cancer. Chromosome instability and the mismatch repair are two carcinogenesis pathways. Tumors in the proximal colon tend to be annular, encircling lesions that produce “napkin-ring” constrictions of the bowel and narrowing of the lumen, while those in the distal colon tend to grow as polypoid, exophytic masses. Colorectal carcinoma may remain asymptomatic for years.

References: http://www.liebertonline.com/doi/abs/10.1089/pho.2008.2238 http://clincancerres.aacrjournals.org/cgi/content/abstract/5/9/2359 Elsevier. Kumar et al: Robbins Basic Pathology 8e