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Ampulla of Vater

Carcinoma

Adenocarcinoma


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 11 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
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● By definition, centered in ampulla of Vater, arises from ampullary intestinal mucosa
● If advanced, cannot distinguish tumor origin between ampulla, distal common bile duct or pancreas

Etiology
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● May arise from villous adenoma or villoglandular polyp; usually is a co-existing adenoma
● Carcinomas of pancreas, gallbladder, extrahepatic bile ducts and ampulla have common embryonic cellular ancestry, differentiation pathways, mucosal histologic patterns and population-related tumor development, indicating a field effect in carcinogenesis
● Carcinomas of pancreas are more common than at these other sites because pancreatic ductal system has a greater surface area (Arch Pathol Lab Med 2009;133:67)

Sites
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● May arise within ampulla (intra-ampullary) or in periampullary duodenum without significant ampullary involvement
● Site of origin may be difficult to determine

Clinical features
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● 5% of GI malignancies are ampullary or periampullary adenocarcinoma
● 80% of ampullary neoplasms and 90% of ampullary malignancies are adenocarcinomas
● Peak age in 70ís, men affected more than women
● 1/3 have other malignancies
● May be associated with multiple polyposis syndrome and neurofibromatosis
● Causes jaundice, abdominal pain, occasionally pancreatitis
● Nodal metastases at diagnosis in 35% (usually adjacent periampullary nodes)
● Immunohistochemically detected lymph node micrometastasis indicates intensive lymphatic spread, and adversely affects the survival of patients with ampullary carcinoma (World J Surg 2006;30:985)
● Metastasizes to liver, lung, peritoneum, pleura
● On CT scan, a small intra-ampullary tumor may show dilated ducts without a mass; ultrasound may be better imaging modality

Prognostic factors and survival
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● 5 year survival after resection is 40-50%, 80% if no nodal metastases - better than pancreatic or bile duct carcinoma (10-20%)
Poor prognostic factors: high stage (J Surg Oncol 2012;105:266), tumor size 2.5 cm or more, signet-ring, poorly differentiated or non-papillary histology, perineural invasion, angiolymphatic invasion, ulceration, invasion of muscle of sphincter of Oddi, invasion into pancreatic parenchyma, nodal metastases, positive margins, tumor budding (Am J Surg Pathol 2010;34:1417)
● Also total bilirubin greater than 5 mg/dl (Scand J Surg 2011;100:92), Ki-67 / mitotic activity index (MI) (World J Surg 2010;34:2115)
● Possibly osteopontin-positive infiltrating tumor-associated macrophages (Cancer Biol Ther 2010;10:144)
Good prognostic factors: papillary histology, intestinal type (Hepatogastroenterology 2007;54:1641), carcinomas arising in adenomas (J Surg Oncol 2009;100:598), promyelocytic leukemia gene expression (Ann Oncol 2009;20:78), Bax expression (J Clin Pathol 2005;58:159)

Case reports
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● 41 year old woman with adenocarcinoma arising in ampullary villous adenoma with synchronous malignant duodenal GIST (J Clin Pathol 2004;57:1118)
● 54 year old woman with neurofibromatosis type 1 (Mod Pathol 2001;14:1169)
● 56 year old and 67 year old women with signet-ring cell carcinoma (Ann Clin Lab Sci 2004;34:471, JOP 2004;5;495)
● 72 year old man with double malignancy of colon and ampulla (Saudi J Gastroenterol 2012;18:143)
● Presentation as recurrent pancreatitis (Acta Gastroenterol Belg 2004;67:309)

Treatment
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● Whipple procedure

Gross description
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● Tumor bulges into duodenal lumen, may be intra-, peri-ampullary or mixed
● Often small
● Common bile duct often dilated

Gross images
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Mass with central ulceration


Contributed by Dr. Semir Vranic, University of Sarajevo, Bosnia and Herzegovina

Micro description
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● Usually poorly differentiated, may have papillary component resembling villous adenoma or villoglandular polyp
● Intestinal (arising from covering intestinal mucosa of papilla, large elongated tubules) or pancreaticobiliary (arise from ductal epithelium that penetrates duodenal muscularis propria, smaller glands/tubules with desmoplastic stroma)
● 50% have vascular invasion, occasional perineural invasion
● Non-invasive papillary lesions resemble colorectal villous adenoma; may be associated with familial colonic polyposis with a high risk for malignant transformation
● Differentiation is based on % glands (well: >95%, moderate: 50-95%, poor: 5-49%, undifferentiated: <5%)
● Lamina propria invasion is considered by some as invasion due to rich lymphatics (Am J Surg Pathol 1991;15:1188)
● Also PanIN (1/3, Mod Pathol 2001;14:139), pancreatitis (1/3)
Variants: colloid, hepatoid, medullary, micropapillary, mixed acinar-endocrine, mucinous, neuroendocrine, Paneth cell, signet ring cell

Micro images
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Intestinal, pancreaticobiliary and other subtypes

 
Various images


Early tumor


Advanced tumor


Budding




Line 1: H&E; Line 2: CEA, CK7, CK20, MSH2
Contributed by Dr. Semir Vranic, University of Sarajevo, Bosnia and Herzegovina



Potential diagnostic pitfalls


CDX2 staining: various images


DPC4 staining in invasive carcinoma and adenomas with high grade dysplasia

Positive stains
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Intestinal and pancreaticobiliary types: CD24, P-cadherin, S100 A4 (Mod Pathol 2009;22:306)
Intestinal type: MUC2+, CDX2+ (Mod Pathol 2004;17:1392), MUC1-, MUC5AC-, CD17-; also CK7-, CK20-
Pancreaticobiliary type: MUC1+, MUC5AC+, CK17+ (Am J Surg Pathol 2005;29:359), MUC2-, CDX2-; also CK7+, CK20- (Am J Surg Pathol 2004;28:875)
Mucinous type: frequently CK7+ and MUC6+ (Am J Surg Pathol 2011;35:1830)
● Also COX2 (J Clin Pathol 2006;59:492), mesothelin (Am J Clin Pathol 2005;124:838), p53 (>50%)

Negative stains
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● Loss of DPC4 in 34%
● Reduced expression of Raf-1 kinase inhibitory protein (Virchows Arch 2012;460:61)

Molecular description
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● K-ras activating point mutations in 40% (Am J Clin Pathol 2011;135:202)
● Microsatellite instability develops early in adenomatous stage and is reliably detectable in the precursor lesion
● Mismatch repair deficient molecular pathway of ampullary and colonic carcinomas are similar (Am J Surg Pathol 2009;33:691)


Kras mutations: Am J Clin Pathol 2011;135:202

Differential diagnosis
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● Adenomatous changes in submucosal glands / ductules simulating invasion, cautery artifact, reactive epithelial atypia (Am J Clin Pathol 2009;132:506)
● Common bile duct carcinoma: thickening of common bile duct, granular mucosa, usually well differentiated adenocarcinoma formed by small glands with marked desmoplasia
● Duodenal adenocarcinoma-not ampullary: may also arise in villous adenoma

Additional references
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eMedicine, Diagn Pathol 2011;6:102

End of Ampulla of Vater > Carcinoma > Adenocarcinoma


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