Pathology of the Gastrointestinal Tract III and IV Part 2 Small and Large Intestines

1. Pathology of the Gastrointestinal Tract III and IV Part 2Small and Large Intestines Grace Guzman, M.D. The Department of Pathology University of Illinois at Chicago

2. Neoplasms of the Intestines • Colorectal cancer ranks #2 as a cancer killer • Lung cancer #1 cancer killer • Adenocarcinoma constitutes 70% of malignant tumors of the GI tract

3. Neoplasms of the small intestines Adenoma -25% of SI benign tumors -mostly in ampulla of vater -familial polyposis coli prone to amp of v adenoma -30-60 yrs -pancreatoduodenectomy • Perplexingly uncommon compared to tumors in other segments of GI tract • 3-6% of GI tumors • Benign -Adenomas -”Leiomyomas” -Lipomas -Angiomas • Malignant -Adenocarcinoma -Primary lymphoma -Carcinoids -GISTS Maligmant -rare -annual death rate: <1000 -1% of all GI malignancies -5 YSR: 70% if rected en bloc -jejunum and ileum -40-60 years -napkin ring like growth -n,v, wt loss, pain anemia -tumor lead pt in intussuception

4. Malignant-Adenocarcinoma-Primary lymphoma-Carcinoids-Gastrointestinal stromal tumors (GISTS) GI lymphomas: sporadic but occur more frequently on certain populations: 1. pxs with H. pylori 2. natives of Mediterranean region 3. pxs with immunodeficiency states 4. HIV infected individuals 5. pxs in immunosuppressive therapy 6. patients with refractory sprue 30-40 yrs • Primary lymphoma • Arises from lymphoid aggregates in the wall with no evidence of other primary sites • Gastric lymphomas are most common and have better prognosis than SI or LI if early • refractory (celiac) sprue associated with TCL; mostly in jejunum Due to random changes brought about by t(11;18) H. pylori reactive T helper cells produces cytokine that allows growth of monoclonal B cell population Therefore Tx: H.pylori Location in: Stomach: 50-60% SI: 25-30% Distal colon: up to 10% Lymphomas -40% extranodal -GI primary extranodal site -1-4% of all GI malignancies MALT lymphoma -arise in B cells of GUT Mucosal Associated Lymphoid Tissue (MALT) -occur focally or early stages -relapses exclusively in GI -unique t(11;18) -no sex predilection Overall, most intestinal lymphomas are B cell type (> 95%) Rare T cell tumors (Refractory sprue) Have better outcome than lymphomas from other sites 10 YSR: 85% if limitted to mucosa and submucosa PX: depend on depth, local invasion, size, grade of tumor, mets

5. Appendiceal and rectal carcinoids almost never metastasize. 90% of ileal, gastric and colon carcinoids have already met to LNs at time of diagnosis Malignant-Adenocarcinoma-Primary lymphoma-Carcinoids-Gastrointestinal stromal tumors (GISTS) Most common sites in the order of frequency: Appendix Ileum (SI) Rectum Stomach Colon Carcinoids • arise from NE cells • may secrete bioactive amines (serotonin: diarrhea, flushing of face, bronchospasm, cyanosis -carcinoid syndrome) • common in SI (50% of SI malignancies; 2% of colorectal malignancies) • 5 YSR: 90% • 5 YSR with liver mets: 50% • if widespread - death Electron microscopy: neurosecretory granules Carcinoid syndrome occurs in about 1% of all patients with carcinoid and 20% of those with widespread metastasis. Excess elaboration of serotonin 5HT and 5 HIAA; present in blood and urine. 5 HIAA is deactivated in the liver. Therefore in GI carcinoids, liver mets have to be present for the development of the syndrome. Not true for ovary and lung carcinoids. Other products: Histamine, bradykinin and prostaglandins

6. Malignant-Adenocarcinoma-Primary lymphoma-Carcinoids-Gastrointestinal stromal tumors (GISTS) -all are potentially malignant -may be low risk or high risk -high risk if > 5 cm in size and mitosis >10/10 hpf • Gastrointestinal stromal tumor (GIST) • uncommon • arise in wall of bowel (interstitial cells of Cajal) • portrude into lumen; ulcerate; GI bleed • mostly slow growing; cured by surgery • 30% recurrence/liver mets within 10 years • may progress to high grade sarcoma • c-kit proto-oncogene, receptor type tyrosine kinase Interstital cells of Cajal stained for c-kit Correct notes: should read“high grade sarcoma”

7. Types of intestinal polyps -Occassionally seen - long standing IBD: UC > Crohn • Pseudopolyp • Hamartomatous polyp (rare) -Juvenile inflammatory polyp -Peutz Jeghers polyp • Hyperplastic polyps • Lymphoid polyps • Adenomatous polyps -tubular adenoma (very common) -tubulovillous adenoma (seen less than TA) -villous adenoma (occasionally seen) *Polyps with no malignant potential: Non-neoplastic Very common 90% of all epithelial polyps found in >1/2 of all persons over the age of 60 Preneoplastic polyps

8. Neoplasms of the colon and rectum • Benign non-neoplastic polyps -Hyperplastic polyps -very common (we see it every day) -proliferation of mature goblet cells; size <0.5 cm -commonly found in adults > 60 years old Gross-nipple like -hemispheric -smooth moist protrusions of the mucosa -often multiple -> 1/2 in rectosigmoid Micro-well formed glands -crypts lined by non-neoplastic cells -goblet cell/absorptive cell differentiation -serrated lumen

9. Juvenile Polyps or inflammatory polyps • usually solitary • -most frequently in rectum • -JP tend to be large: 1-3 cm. • -isolated IP may be found in adults: • “retention polyp” • which are smaller < 1 cm. with stalks • up to 2 cm • -Lamina propria is the bulk of the • polyp with cystically • dilated glands, surface ulceration • -Rare autosomal dominant JP syndrome • does carry a risk of adenoma and • hence adenocarcinoma • -Rare; focal hamartomatous polyps • -virtually no malignant potential (exception: Juvenile polyposis syndrome) • -commonly found in children younger than age 5

10. Hamartomatous Polyp: Peutz Jeghers polyp • Rare • Large polyp with arborizing (tree-like) projections with smooth muscle present at the mucosal surface • Polyps with no malignant potential, but patients at risk for other malignancies: pancreas, breast, lung, ovary, and uterus

11. Adenomas • All adenomas show dysplastic epithelium • All are precancerous • May proceed to intramucosal or invasive carcinoma • May occur anywhere in the LI, most occur in the left colon, specifically, rectosigmoid • Risk of malignant transformation is dependent on polyp size, architecture, severity of dysplasia Corless -Cancer is rare in TA <1cm in size -The risk of cancer is high (approximately 40%) in sessile villous lesions > 4cm -Severe dysplasia when present is often seen in villous areas

12. Severe dysplasia when present is often seen in villous areas • Old terminology: severe dysplasia/carcinoma in situ Intramucosal Adenocarcinoma • Carcinoma arising in a tubular adenoma that has not invaded into the submucosa • little or no metastatic potential • if 1.) no lymphatic invasion, 2.) not poorly differentiated, and 3.) superficial with margin is free of ca, then polypectomy is an adequate procedure • because this has no propensity to metastasize at this point Submucosal stalk rich in lymphatic channel Tubulovillous adenoma with intramucosal adenocarcinoma

13. Invasive adenocarcinoma • The tumor has invaded through the mucosa, into submucosa (in this case it is seen to the level of the muscularis propria) • The submucosa contains large lymphatics which are conduits for metastases Most worrisome lesions are villous adenoma > 4 cm. When invasive carcinoma occurs, there is no stalk as a buffer zone and invasion is directly into the wall of the colon (submucosa or deeper). Invasive adenocarcinoma arising in villous adenoma

14. Quiz time • Question: What if the cancer is in the stalk of a pedunculated polyp - is this an invasive carcinoma? • Answer: Yes, carcinomatous invasion into the submucosal stalk of a pedunculated polyp constitutes an invasive adenocarcinoma. • Question: What is the treatment, polypectomy or colectomy? • Answer: Colectomy, invasive carcinoma can not be adequately treated by polypectomy. Submucosal stalk

15. Tubular adenoma Adenomatous polyps -tubular adenoma -tubulovillous adenoma -villous adenoma • Pedunculated, composed of branching round/ tubular glands on a stalk • Can grow up to 4 cm in diameter • The larger the polyp the greater the chance of harboring carcinoma Common; we see it every day -90% in the colon; rarely in the stomach and SI -solitary in 50% -2 or more in the remaing 50%

16. VILLOUS ADENOMA • VILLOUS ADENOMA -Sessile, broad base rather than a stalk -Composed of numerous , finger-like projections of epithelium -Greater than 50% villous -More than 40% harbor carcinoma • TUBULOVILLOUS ADENOMA -features of both adenomas -25-50% (30%) villous (occassionally seen) Adenomatous polyps -tubular adenoma -tubulovillous adenoma -villous adenoma (not as common as TA)

17. Familial adenomatous polyposis (FAP) Rare, autosomal dominant; genetic defect is in the APC gene on Ch 5q21 Patients with 500-2500 polyps (min 100 polyps) Gardner syndrome a variant of FAP also autosomal dominant polyps similar to FAP but with multiple bone lesions and skin lesions particularly mandible, skull, long bones, epidermal cysts and fibromatosis Turcot syndrome: rare variant, GI polyps and CNS tumors, mostly gliomas Familial syndromes -Familial adenomatous polyposis -Gardner syndrome -Hereditary nonpolyposis colorectal cancer FAP - Cancer preventive measures: prophylactic colectomy as soon as possible early detection of disease in siblings and first degree relatives at risk Familial syndromes Average onset of polyps in each of these adenomatous polyp syndromes is the teens and twenties, followed by cancer in 10-15 years unless surgical resections interrupt the natural progression.

18. Hereditary nonpolyposis colorectal cancer (HNPCC) • Autosomal dominant • lower number of polyps • occur earlier than the general adult population (peak 40-55 years) • cancer often right sided (70%) • more often poorly differentiated • prognosis is better • women at increase risk of endometrial adenocarcinoma • caused by mutation in DNA mismatch repair genes Familial syndromes -Familial adenomatous polyposis -Gardner syndrome -Hereditary nonpolyposis colorectal cancer •Multiple synchronous or metachronous colorectal cancers not always associated with pre-existing adenomas •Association with sebaceous tumors of skin ; Muir-Torre syndrome

19. Inherited mutations in any of four genes that are involved in DNA repair are putatively responsible for familial syndrome of HNPCC.

20. These human mismatch repair genes are involved in genetic proofreading during DNA replication and are referred to as “caretaker” genes. There are 50,000 to 100,000 dinucleotide repeat sequences in the human genome. And mutations in mismatch repair genes can be detected by the presence of widespread alterations in these repeats; this is referred to as microsatellite instability. Patients who inherit a mutant DNA repair gene have normal repair activity because of the normal remaining allele. Mutation rates up to 1000X normal ensue, such that most of the HNPCC tumors show microsatellite instability. About 10-15% sporadic colon cancers have mutations in similar caretaker DNA repair genes.

21. Adenocarcinoma • Accounts for 10% of all cancer related deaths • peak incidence: 60-79 years (<20%: before 50) • worldwide: environment, diet, obesity, physical activity; no causal relationship FAP patients either inherit one defective copy of APC (one hit) or else acquire it during embryogenesis. Deletion of the remaining good APC gene in the colonic stem cell is all that is necessary to start down the road to an adenoma. Two genetic “hits” are necessary to compromise both copies of APC gene with in colonic stem cells in normal individuals. The first hit is usually a point mutation to one gene copy. The second gene copy is then later deleted.

22. Adenoma-carcinoma sequence a. germline or somatic mutations of cancer suppressor genes (first hit) b. methylation abnormalities and inactivation of normal alleles (second hit) c. proto-oncogene mutation d. homozygous loss of additional cancer gene e. additional mutations with gross chromozomal alterations APC at Ch 5q21 APC- B catenin K-ras at Ch 12p12 p53 at Ch 17p13 or loss of heterozygosity Genetic Alterations: the path from normal to cancer

23. K-ras-most frequently observed oncogene in adenomas and colon carcinomas Ch12p12; intracellular transduction mutated in fewer than 10% of adenomas less than 1 cm and 50% of carcinomas DCC-common allelic loss in colon ca is on 18q21 deleted in colon cancer a cell adhesion molecule normally expressed in normal colon mucosa reduced or absent in 70-75% of colon ca LOH in 18q recently it’s role has been questioned, is it DCC or neighboring gene? • Loss of methyl groups in DNA • (hypomethylation) • early change in colonic neoplasm • P53 losses at 17p found in 70-80% of colon cancers • infrequent in adenomas • mutations in p53 occur late in colon carcinogenesis • APC gene “gate keeper gene” • APCmutations is usually the earliest and • possibly the initiating event in about 80% • of sporadic colon ca • less role of fromDNA mismatch repair • genes • alterations in genome lead to progressive • increases in size, level of dysplasia, and • invasive potential of neoplastic lesions

24. Adenocarcinoma -tumor will infiltrate wall of colon and metastasize to lymph nodes and liver-prognosis is related to size and spread of the lesion Astler Coller System - pathologic staging of colorectal cancer: A - mucosa B - submucosa or muscularis propria B1; serosa B2 C - B1 + lymph node met C1; B2 + lymph node met C2 D - Distant mets to lung and liver A: 5YSR - 100% B1: 67% B2: 54% C1: 43%; C2: 23%

25. Right colon adenocarcinoma -usually -asymptomatic for a long period of time -signs and symptoms of iron deficiency anemia due to surface ulceration and resulting blood loss Left colon adenocarcinoma -generally annular -narrow the lumen -change in bowel habits or obstruction -blood in stool (maybe obvious/bright red or occult) -originating from ruptured vessels at the edge of the ulceration Adenocarcinoma Polypoid, fungating non-obstructing rt colon ca Cancer narrows lumen

26. Colorectal Adenocarcinoma Summary • Approximately 5% of all colon cancers are related to a hereditary predisposition • Majority are related to APC mutations (FAP) • Some are due to mismatch repair defects (Lynch Syndrome) • Among sporadic colon cancers • 75% are related to acquired APC mutations • 15% are related to acquired mismatched repair defects • Dietary factors play an important role in both the origin and progression of colon cancers • Screening for adenomatous polyps can prevent colon cancer

27. Neoplasms of appendix (normal appendix mucosa) • Mucocele _ benign dilatation of the lumen by mucinous secretions Mucinous cystadenoma-proliferation of benign neoplastic cells-dilatation by mucinous material -may rupture • Mucinous cystadenocarcinoma -invasion of neoplastic cells (The mucosa is altered by mucinous cells) -Pseudomyxoma peritonei - term describing distention of the peritoneal cavity by the presence of semisolid, mucin containing adenocarcinoma cells

28. Inflammation 1. Sterile peritonitis due to bile or pancreatic juices 2. Surgical procedures 3. Endometriosis 4. Rupture of GI tract (Ruptured appendicitis, acute salphingitis, or diverticulitis) Neoplasms 1. Primary mesothelioma -rare 2. Secondary malignancies -extension, seeding, or implantation (more common) Peritoneum