Familial Adenomatous Polyposis (FAP) Most common, 1:10,000 individuals Most common, 1:10,000 individuals Risk of CA of affected patients: 100% Risk of CA of affected patients: 100% 100’s to 1,000’s, appear at average 16 y/o, most CA at 39 y/o-if untx 93% have CA before ’s to 1,000’s, appear at average 16 y/o, most CA at 39 y/o-if untx 93% have CA before 50 More than 90% also have duodenal polyps, with lifetime risk of duodenal/periampullary CA of up to 10% More than 90% also have duodenal polyps, with lifetime risk of duodenal/periampullary CA of up to 10% Homozygous inactivation of APC gene on chromosome 5q-autosomal dominant Homozygous inactivation of APC gene on chromosome 5q-autosomal dominant

FAP Patient with few rectal polyps can have rectal preservation, but MUST be continuously monitored-more than 50% will develop CA in this area despite surveillance Patient with few rectal polyps can have rectal preservation, but MUST be continuously monitored-more than 50% will develop CA in this area despite surveillance Must evaluate upper GI tract at time of diagnosis and every 1-3 years Must evaluate upper GI tract at time of diagnosis and every 1-3 years Duodenal adenomas Duodenal adenomas Gastric adenomas, but most common fundic gland polyps Gastric adenomas, but most common fundic gland polyps

Gastric Fundic Gland Polyps Benign cystic and polypoid proliferation of oxyntic glands Benign cystic and polypoid proliferation of oxyntic glands Have alterations of APC Beta catenin pathway in syndromic and sporadic Have alterations of APC Beta catenin pathway in syndromic and sporadic Common, more than 50% of gastric polyps Common, more than 50% of gastric polyps More common in females, single or multiple. More common in females, single or multiple.

-In FAP:-fundic gland polyps can have dysplasia—excellent marker of FAP -Can have over 100 polyps -Can also Be seen in Sporadic Polyps. -Risk of CA Is low

Attenuated FAP Average of 30 polyps, typically right-sided, adenomas and CA arise 10 yrs later than FAP Average of 30 polyps, typically right-sided, adenomas and CA arise 10 yrs later than FAP Can spare rectum Can spare rectum Can have numerous flat polyps Can have numerous flat polyps Mutations in the 5’ region of APC gene Mutations in the 5’ region of APC gene

Other adenomatous polyposis FAP can have extraintestinal manifestations: desmoid tumors, fibromas, but if these are numerous: FAP can have extraintestinal manifestations: desmoid tumors, fibromas, but if these are numerous: Gardner's syndrome: polyposis, skin lesions (epidermal cysts), bony lesions (osteomas), dental abnormalities- -soft tissue lesions can precede polyps by years Gardner's syndrome: polyposis, skin lesions (epidermal cysts), bony lesions (osteomas), dental abnormalities- -soft tissue lesions can precede polyps by years Turcot’s syndrome: have brain tumors, particularly medulloblastomas- - high mortality, can be seen before polyps Turcot’s syndrome: have brain tumors, particularly medulloblastomas- - high mortality, can be seen before polyps

Second most common, incidence 1/10th of FAP Second most common, incidence 1/10th of FAP Autosomal dominant but with variable and incomplete penetrance Autosomal dominant but with variable and incomplete penetrance Two major components: Two major components: Hamartomatous polyps (jejunum, ileum, colon, stomach, duodenum and appendix) Hamartomatous polyps (jejunum, ileum, colon, stomach, duodenum and appendix) Pigmented macules in mucous membranes and skin Pigmented macules in mucous membranes and skin Peutz-Jeghers Syndrome

Peutz-Jegher polyp

PJ syndrome Dx made in infancy because of pigmentation within 2 yrs. (can be present at birth, around mucosas of face) Dx made in infancy because of pigmentation within 2 yrs. (can be present at birth, around mucosas of face) Small bowel polyps can be symptomatic- - intussusception and obstruction, in rectum can prolapse and bleed. Small bowel polyps can be symptomatic- - intussusception and obstruction, in rectum can prolapse and bleed.

PJ syndrome In adults, can have carcinoma involving GI tract and multiple organ sites ( breast, lung, pancreas, uterus, ovaries (SCTAT), cervix and testes) In adults, can have carcinoma involving GI tract and multiple organ sites ( breast, lung, pancreas, uterus, ovaries (SCTAT), cervix and testes) 93% lifetime risk of cancer, mean age 43 yrs., mostly in colon, stomach and pancreas 93% lifetime risk of cancer, mean age 43 yrs., mostly in colon, stomach and pancreas Most of the reported carcinomas of the gastrointestinal tract in PJS patients have not had evidence of origin from a hamartoma but rather derive from co-existing adenomas Most of the reported carcinomas of the gastrointestinal tract in PJS patients have not had evidence of origin from a hamartoma but rather derive from co-existing adenomas Periodic surveillance of high risk organs Periodic surveillance of high risk organs

Juvenile Polyposis Multiple juvenile or inflammatory polyps in GI tract and/or colon Multiple juvenile or inflammatory polyps in GI tract and/or colon Third most common, sporadic or autosomal dominant, on average 9.5 yrs old, slight male predominance Third most common, sporadic or autosomal dominant, on average 9.5 yrs old, slight male predominance Most common polyp diagnosed in pediatric population, so for dx: more than 5 polyps at a time, extracolonic polyps, juvenile polyps in patient with a family history of JP Most common polyp diagnosed in pediatric population, so for dx: more than 5 polyps at a time, extracolonic polyps, juvenile polyps in patient with a family history of JP Usually present with painless rectal bleeding Usually present with painless rectal bleeding

JPS Significant risk for colon CA, as well as gastric, duodenal and pancreatic cancer. Screening upper endo and colonoscopy in adolescence Significant risk for colon CA, as well as gastric, duodenal and pancreatic cancer. Screening upper endo and colonoscopy in adolescence Two forms: Two forms: Autosomal dominant familial type w/o anomalies Autosomal dominant familial type w/o anomalies Nonfamilial with congenital anomalies Nonfamilial with congenital anomalies 20% have congenital heart disease, hydrocephalus, intestinal malrotation 20% have congenital heart disease, hydrocephalus, intestinal malrotation Digital clubbing, failure to thrive Digital clubbing, failure to thrive

Cowden’s Syndrome Multiple hamartoma syndrome, autosomal dominant Multiple hamartoma syndrome, autosomal dominant Face and oral cavity lesions: strict criteria Face and oral cavity lesions: strict criteria Macrocephaly, breast (most common CA in females), thyroid CA(most common), endometrial CA, Lhermite-Duclos disease (cerebellar gangliocytoma): major criteria Macrocephaly, breast (most common CA in females), thyroid CA(most common), endometrial CA, Lhermite-Duclos disease (cerebellar gangliocytoma): major criteria GI lesions: minor criteria- -NO increased risk GI cancer GI lesions: minor criteria- -NO increased risk GI cancer 80% of families have PTEN mutation 80% of families have PTEN mutation

All types of polyps…JP, PJ, lipomas, ganglioneuromas, leiomyomas

Hyperplastic Polyposis Syndrome Multiple hyperplastic polyps in GI tract, increased risk of colorectal CA Multiple hyperplastic polyps in GI tract, increased risk of colorectal CA More than 5 proximal to sigmoid, two of which are larger than 1cm More than 5 proximal to sigmoid, two of which are larger than 1cm Any number of HP proximal to sigmoid in patient with 1 st degree relative with hx of HPS (at least one large polyp) Any number of HP proximal to sigmoid in patient with 1 st degree relative with hx of HPS (at least one large polyp) 30 or more of any size but evenly distributed throughout colorectum 30 or more of any size but evenly distributed throughout colorectum

HPS Spectrum includes HP (most common), serrated adenomas, mixed ta-hp and tubular adenomas Spectrum includes HP (most common), serrated adenomas, mixed ta-hp and tubular adenomas May be greater than 100, but often in tens, sessile, large polyps have been reported May be greater than 100, but often in tens, sessile, large polyps have been reported Have some degree of cellular and architectural atypia Have some degree of cellular and architectural atypia Low levels of microsatellite instability Low levels of microsatellite instability Up to 35% have synchronous colon CA Up to 35% have synchronous colon CA Pancolonoscopy every 1 to 3 years Pancolonoscopy every 1 to 3 years

Esophageal Polyps Squamous papilloma -Reflux -Some related to HPV

Leiomyoma: most common benign lesion in esophagus

Granular Cell Tumor Most common site in GI tract for these tumors Most common site in GI tract for these tumors #2 most common stromal tumor of esophagus after leiomyoma #2 most common stromal tumor of esophagus after leiomyoma Usually incidental, in lower esophagus, 90% solitary Usually incidental, in lower esophagus, 90% solitary May cause obstruction if large May cause obstruction if large May be of Schwannian origin—S-100 positive May be of Schwannian origin—S-100 positive Commonly women in 40’s, blacks Commonly women in 40’s, blacks May be underdiagnosed on superficial biopsies that lack lamina propria May be underdiagnosed on superficial biopsies that lack lamina propria

Gastric Polyps: Adenoma Represents 10% of polypoid lesions in stomach. Represents 10% of polypoid lesions in stomach. Is a precursor lesion of gastric adenocarcinoma, but NOT the major one: Is a precursor lesion of gastric adenocarcinoma, but NOT the major one: Can contain focus of carcinoma at time of diagnosis Can contain focus of carcinoma at time of diagnosis 30% risk of carcinoma in adjacent mucosa—marker for CA 30% risk of carcinoma in adjacent mucosa—marker for CA

Intestinal Type: -More common -Usually in background of atrophy or intestinal metaplasia MORE likely to have: -HGD -Adenocarcinoma Foveolar type: -gastric foveolar-type lining

Reactive changes

Xanthoma Lipid-laden histiocytes, CD68 +: bile reflux, H. pylori, hypercholesterolemia Signet ring CA

Inflammatory/Regenerative Polyp 2 nd most common gastric polyp 2 nd most common gastric polyp Due to H.pylori gastritis, mucosal damage (reflux, s/p surgery) Due to H.pylori gastritis, mucosal damage (reflux, s/p surgery) Most common polyp seen in autoimmune gastritis Most common polyp seen in autoimmune gastritis 1.5-3% can undergo malignant transformation 1.5-3% can undergo malignant transformation Adenomatous changes Adenomatous changes More likely in polyps greater than 2cm More likely in polyps greater than 2cm

Carcinoid Tumor Most common primary tumor of the small bowel and appendix. Most common primary tumor of the small bowel and appendix. Accounts for more than 95% of all carcinoids. Accounts for more than 95% of all carcinoids. Arise from enterochromaffin cells, which are considered neural crest cells situated in GI glands. Arise from enterochromaffin cells, which are considered neural crest cells situated in GI glands. Gastrointestinal carcinoids account for 1.5% of all gastrointestinal tumors Gastrointestinal carcinoids account for 1.5% of all gastrointestinal tumors

-Chromogranin -Synaptophysin --positive In stomach: Type I: autoimmune gastritis Type II: ZES Type III: sporadic In Small Bowel: -2/3 are gastrinomas -1/3 are functional--ZES -1/3 are somatostatinomas -1/3 von Recklinghausen dx

Chronic Duodenitis

Heterotopic Gastric Mucosa

Duodenal Polyps Adenomas Heterotopic pancreas

Vanek Polyp (inflammatory fibroid polyp) Stomach, small bowel, colon Stomach, small bowel, colon Can cause gastric outlet obstruction and intussusception Can cause gastric outlet obstruction and intussusception Rare benign lesion, 1-4 cm in size Rare benign lesion, 1-4 cm in size CD34 positive CD34 positive

Histology: -submucosa with reactive changes -spindle cells -onion skin around vessels -eosinophils

Suggested Reference Material pathologyoutlines.com pathologyoutlines.com Serrated polyp quiz Serrated polyp quiz Books: Books: Odze, R—Surgical Pathology of the GI Tract Odze, R—Surgical Pathology of the GI Tract Montgomery, E-GI and Liver Pathology Montgomery, E-GI and Liver Pathology Greenson, J—Diagnostic Pathology Gastrointestinal Greenson, J—Diagnostic Pathology Gastrointestinal Amyrsys Amyrsys