University of California San Francisco Department of Pathology 35 th - - PDF document

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University of California San Francisco Department of Pathology 35th Annual Current Issues in Anatomic Pathology May 23, 2019 12:15-1:15 pm Problematic Cases on the GI service grace.kim@ucsf.edu

Topics Covered Focus on problematic areas in the gastrointestinal tract and pancreatobiliary tree on biopsy or resection that are encountered in daily practice, particularly to recognize relevant differential diagnoses and order appropriate stains. Objective Distinguish polyps and their malignant risks Develop differential diagnosis and strategies to resolve them Apply immunohistochemical stains to facilitate diagnosis Disclosures Shareholder / Adicet Bio and Five Prime Therapeutics Consultant / Celgene Outline

• I. Colonic serrated polyps
• II. Gallbladder polyps

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• I. Colonic serrated polyps

Case A History: The patient is a 51-year-old woman undergoing colorectal carcinoma screening. Colonoscopy showed a 3 mm sessile polyp in the ascending colon. Case B History: The patient is a 58-year-old woman with history of colonic polyp undergoing surveillance colonoscopy. Colonoscopy showed a 12 mm sessile polyp in the transverse colon. Case C History: The patient is a 72-year-old woman with undergoing surveillance colonoscopy. Endoscopy revealed a 12 mm sessile polyp in the rectum. Brief review on colonic serrated polyps Histology/Immunohistochemistry Serrated lesions share a serrated/stellate architecture of the epithelium

• Distinguishing features of sessile serrated adenoma (SSA)1 , 2 - a low power assessment

SSA Hyperplastic polyp (microvesicular) Crypts size and shape Marked variation; asymmetric Uniform evenly spaced, straight or funnel shaped crypts; orderly growth Serration location Excess of deeper crypt serrations; basal 1/3 Increases towards surface epithelium; limited to upper 2/3 Serration Variation in size of serration Architecture of crypt base Inverted growth, boot or anchor shaped; horizontal growth No deep lateral crypt growth, narrow Proliferation zone Away from crypt base; variable from crypt to crypt Basal portion uniformly Quantification 1 to 3 abnormal crypts without prolapse effect Bettington et al in their SSA study used the following features: (1) any horizontal growth along the muscularis mucosa; (2) dilatation of the crypt base (basal third of the crypt) such that it is wider than the luminal opening; (3) serration extending into the crypt base; or (4) asymmetric proliferation.3

• Problematic when not optimally oriented, then perform level sections to visualize base of
• crypt. If still not present, diagnosis as “serrated polyp, unclassified” with an explanation in

the comment. In these cases, the ones in the right colon are likely managed as SSA and those from the left as hyperplastic polyp

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SSA with dysplasia is not subclassified into low and high grade. Morphologic abrupt transition from non-dysplastic SSA to area with increased complex architecture and various forms of cytologic atypia including: 1) Resembles conventional adenoma with columnar cells with elongated pseudostratified nuclei mitotically active 2) Cytologically have high grade nuclear features in low columnar to cuboidal cells with eosinophilic cytoplasm and round stratified nuclei 3) Similar to #1 but cells are cuboidal and have round nuclei (more MSI)

• Pitfall is “enteric metaplasia”4 that is not dysplastic that look like normal small intestinal

absorptive cells and are composed of tall cuboidal cells with eosinophilic cytoplasm, ovoid nuclei, but are not mitotically active.

• It is not recommended to grade dysplasia in serrated polyps2

Loss of MLH1 is found in SSA with dysplasia Polyp Reference 5 Reference 6 SSA with dysplasia 23% 73% Non-dysplastic crypts in polyps with SSA 18% 32% Distinguishing features of traditional serrated adenoma (TSA)1 TSA TVA Gross Sessile Location Left colon Architecture Villous with bulbous tips (tennis racquet like) Tall villous architecture (25%-75%) and rest is tubular structures Cytology Tall columnar cells, eosinophilic cytoplasm, bland

• val elongated nuclei without

mitotic activity Pseudostratified nuclei Cytoplasm Eosinophilic (enteric metaplasia-like*) or have predominant goblet cells Glandular aspect Luminal: Undulating border Basal: Small abortive crypts (ectopic crypts) Smooth luminal border Mitosis Ectopic crypts or deep aspect near muscularis mucosae Mitotic activity may be brisk *Absorptive-like enterocytes line the crypts and are composed of tall columnar eosinophilic cytoplasm and elongated benign-appearing nuclei, luminal surface has prominent brush border

• Problematic when TSA are flat and minimally polypoid, but key is enteric metaplastic

epithelium and locating a few ectopic crypts; not prominently villous

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• TSA can also develop conventional dysplasia like a villous adenoma or exhibit serrated

cytologic dysplasia (similar to SSA 2) above) Reporting

• AJCC 8th edition pT stage for Colon and Rectum key change is that high grade dysplasia is
• nly HGD and not considered pTis

T Category T Criteria Tis Carcinoma in situ, intramucosal carcinoma

• Surgical resection is recommended for carcinoma in a polyp if it contains high grade

carcinoma, lymphatic/venous invasion, or invasive carcinoma at or <1mm from resection. Colonoscopy surveillance recommendation based on first colonoscopy findings7 *Proximal is to sigmoid colon and Distal is defined as rectosigmoid References

• 1. Snover DC. Diagnostic and reporting issues of preneoplastic polyps of the large intestine with

early carcinoma. Ann Diagn Pathol. 2019 Apr;39:1-14.

• 2. Pai RK, et al. An update on the morphology and molecular pathology of serrated colorectal

polyps and associated carcinomas. Mod Pathol. 2019 Apr 25. doi: 10.1038/s41379-019-0280-2. [Epub ahead of print]

• 3. Yokoo H, et al. Colorectal polyps with extensive absorptive enterocyte differentiation:

histologically distinct variant of hyperplastic polyps. Arch Pathol Lab Med. 1999 May;123(5):404-10.

• 4. Bettington M, et al. Critical appraisal of the diagnosis of the sessile serrated adenoma. Am J

Surg Pathol. 2014;38(2):158–166.

• 5. Yozu M, et al. Loss of expression of MLH1 in non-dysplastic crypts is a harbinger of neoplastic

progression in sessile serrated adenomas/polyps. Histopathology. 2019 Apr 11. doi: 10.1111/his.13874. [Epub ahead of print]

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• 6. Liu C, et al. Sessile serrated adenomas with dysplasia: morphological patterns and

correlations with MLH1 immunohistochemistry. Mod Pathol. 2017 Dec;30(12):1728-1738.

• 7. Lindholm CR, et al. The dark side of the colon: current issues surrounding the significance,

prevalence, detection, diagnosis and management of serrated polyps. Curr Opin Gastroenterol. 2019 Jan;35(1):34-41.

• II. Gallbladder polyp

Case E History: 52 y/o woman with history of gallstone pancreatitis. Gross description: A 1 cm transmural nodule in the fundus. Case F History: 42 y/o woman with acute abdominal pain. CT scan revealed probable small gallstones and questionable gallbladder wall thickening. Gross description: Free-floating within the specimen container are two golden yellow, polypoid and friable soft tissue fragments (up to 0.5 cm in greatest dimension). No choleliths are identified within the lumen or the specimen container. Case G History: 62 y/o woman with right upper quadrant pain. A 1.1 cm gallbladder polyp was seen on ultrasound. Gross description: A green polypoid soft tissue (0.8 x 0.6 x 0.2 cm) is received separately within the container. Per surgeon, this is the gallbladder polyp that came loose from the gallbladder wall in the operating room. Case H History: 59 y/o woman with a 1.9 cm fundal gallbladder mass on abdominal ultrasound/1.3 cm on CT scan. Gross description: Free-floating in the container is a fragment of yellow-brown tissue (1.4 x 0.9 x 0.6 cm), consistent with a polyp. Case I History: 47 y/o woman with epigastric pain and ultrasound showing gallstones. Gross description: Three firm stones and a 0.4 cm polyp. Case J History: 35 y/o man with 2 cm gallbladder mass. Gross description: One, soft, irregular, red-tan mass of tissue (1.8 x 1 x 0.6 cm) is free floating within the gallbladder. No cholelith. Case K History: 45 y/o woman with 2.5 cm mass.

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Case L History: 45 y/o man with gallbladder mass. Gross description: 1.7 cm tan nodular mass. Case M History: 44 y/o man with history of ulcerative colitis, primary sclerosing cholangitis and cholelithiasis with a mass Gross description: Gallbladder wall thickened up to 0.9 cm with firm ill-defined area (2.8 x 2.7 x 0.6 cm). A 2 x 1 cm area of mucosa has clusters of red nodules. Teaching point

• Levels can be useful to find helpful features to make this distinction1, 2

Involvement by Aschoff- Rokitansky sinuses (ARS) Invasive carcinoma Continuity with surface Present Absent Lobular islands of normal glands Yes No Orientation of glands Perpendicular to surface Parallel to surface Size/shape of glands Long tubular, branching, flask- like Small-medium round or cord-like Epithelial lining of glands Columnar Cuboidal but can also be columnar Dilated/content of glands Yes / inspissated mucin or bile No Distribution of glands Widely Glands surrounded by stromal reaction Can mimic desmoplastic-like stroma Can lack desmoplastic stroma Relationship to muscular layer ARS were in gaps of smooth muscle Invade or lying in smooth muscle References:

• 1. Albores-Saavedra J, et al. In situ and invasive adenocarcinomas of the gallbladder extending

into or arising from Rokitansky-Aschoff sinuses: a clinicopathologic study of 49 cases. Am J Surg

• Pathol. 2004 May;28(5):621-8.
• 2. Ozde RD, Goldblum JR. (2015) Surgical Pathology of the GI Tract, Liver, Biliary Tract, and
• Pancreas. (3rd ed) Philadelphia, PA: Elsevier Saunders.

Brief review on gallbladder polyps Gross examination Carefully examine the mucosa and specimen content.

• If a polyp is grossly identified, measure the size (important in final diagnosis to distinguish

size of preinvasive versus invasive component) and submit the entire lesion1.

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• If intracholecystic papillary-tubular neoplasms, additionally take 5 sections form

uninvolved gallbladder to exclude high grade dysplasia or invasive carcinoma

• If on microscopy a nodular pyloric gland lesion greater than 3 mm is present, then

reexamine the specimen container since a detach polyp from the mucosa could have inadvertently been overlooked as “debris” by the prosector1.

• Always ink and take section of the cystic duct margin

Types of polyps

• Non-neoplastic
• Cholesterol-type polyp2 – Pedunculated arborizing papillary lesion lined by

normal gallbladder epithelium with edematous core mostly devoid of glands and

• ften (85%) but not always showing cholesterol-laden macrophages. with

abundant foamy cytoplasm filling the lamina propria accompanied by variable mucosal hyperplasia (villous to complex arborizing papillary proliferation). Some refer to these as cholesterol or cholesterolosis polyp.

• Fibromyoglandular polyp2 – broad based polypoid lesion <1 cm with small

pyloric-like glands separated by fibroblastic stroma with variable amounts of smooth muscle

• Inflammatory and stromal polyps2 – inflammatory have edematous stroma or

vascular connective tissue containing an inflammatory infiltrate.

• Pseudopolyps such as segmental adenomyomatosis/adenomyomatous

hyperplasia/adenomyoma

• Intracholecystic papillary-tubular neoplasms (ICPN)3
• Definition: Exophytic (papillary or polypoid) intramucosal GB masses that

measure ≥1.0 cm and are composed of preinvasive neoplastic (dysplastic) cells forming a compact lesion distinct from the neighboring mucosa

• Epithelial cell type is most commonly biliary, then gastric and uncommonly

intestinal or oncocytic Biliary Gastric foveolar Gastric pyloric Intestinal Oncocytic MUC1 74% 69% 35% 25% 100% MUC2 15% 8% 6% 50% MUC5AC 47% 100% 44% 50% MUC6 32% 54% 94% 25% 17% CDX2 14% 8% 6% 75%

• Immunohistochemistry stains to determine cell lineage is not necessary

as it does not impact clinical management

• Assess for dysplasia and grade as low or high grade
• Determine if presence of invasive carcinoma and depth of invasion
• Pitfall extension of dysplasia into Aschoff-Rokitansky sinuses
• AJCC 8th edition pT stage for Gallbladder

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T Category T Criteria Tis Carcinoma in situ T1a Tumor invades the lamina propria T1b Tumor invades the muscular layer T2a Tumor invades the perimuscular connective tissue on the peritoneal side, without involvement of the serosa (visceral peritoneum) T2b Tumor invades the perimuscular connective tissue on the hepatic side, with no extension into the liver

• Treatment according to pT stage4,5

T Category Surgical treatment is simple cholecystectomy (SC) T1a If negative margins, then observe T1b Controversial; usual recommendation is re-resection, but recent international multi-center study revealed similar outcomes for SC and EC3 T2 Extended cholecystectomy (EC) including wedge resection or segmentectomy and regional lymph node dissection4 Prognosis

• Overall survival of ICPN with invasive carcinoma is significantly better than ordinary

pancreatobiliary type invasive adenocarcinoma of the gallbladder (median survival 35 months versus 9 months).

• ICPN with high grade dysplasia has a good prognosis; however long-term follow-up is

warranted References:

• 1. Adsay V, et al. Criteria for pathologic sampling of gallbladder specimens. Am J Clin Pathol.

2013 Aug;140(2):278-80.

• 2. Vance CE, et al. Non-neoplastic polyps of the gallbladder: incidence, histologic types, and

clinicopathologic associations in an analysis of 162 cases. Mod Pathol. 2011 Feb(24, Suppl 1):375A-376A.

• 3. Adsay V, et al. Intracholecystic papillary-tubular neoplasms (ICPN) of the gallbladder

(neoplastic polyps, adenomas, and papillary neoplasms that are ≥1.0 cm): clinicopathologic and immunohistochemical analysis of 123 cases. Am J Surg Pathol. 2012 Sep;36(9):1279-301.

• 4. Zaidi MY, Maithel SK. Updates on Gallbladder Cancer Management. Curr Oncol
• Rep. 2018 Mar 2;20(2):21.
• 5. Kim HS, et al. Optimal surgical treatment in patients with T1b gallbladder cancer: An

international multicenter study. J Hepatobiliary Pancreat Sci. 2018 Dec;25(12):533-543.