Ampulla of Vater
Last revised 2 November 2008
Last major update March 2005
Copyright (c) 2001-2008, PathologyOutlines.com, Inc.
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Benign/non-neoplastic: normal anatomy, normal histology, adenomyoma, fibrosis, gangliocytic paraganglioma, pancreatic heterotopia, papillary hyperplasia
Premalignant/noninvasive: adenoma, IPMN
Carcinoma: adenocarcinoma, colloid, hepatoid, mixed acinar-endocrine, neuroendocrine, paneth cell
Other malignancies: carcinoid, lymphoma, pancreatoblastoma
Miscellaneous: grossing, TNM staging, features to report
AJCC Cancer Staging Manual (6th Ed)
American Journal of Clinical Pathology (AJCP), January 1971 to March 2005
American Journal of Surgical Pathology (AJSP), January 1981 to March 2005
Archives of Pathology and Laboratory Medicine (Archives), January 1980 to March 2005
Human Pathology (Hum Path), January 1970 to January 2005
Modern Pathology (Mod Path), March 1988 to March 2005
Rosai, J: Ackerman’s Surgical Pathology (9th Ed); C. V. Mosby, 2004
Sternberg, S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins, 2004
Please refer to these primary references for more detailed discussions
Ampulla means flask like dilatation (spreading or stretching) of a tubular structure
May refer to
Ampulla of Vater, or portion of fallopian tube, vas deferens, semicircular
canal or colon
Vater (“fah-ter”) is German anatomist Abraham Vater (1684-1751) who first
described this structure
Usually refers to confluence of distal common bile duct and main pancreatic duct in second portion of duodenum near pancreatic head, although in 42% of patients, ampulla is termination of common bile duct only as the pancreatic duct enters the duodenum separately next to ampulla; in these cases, ampulla may be difficult to locate or nonexistent
Ampulla traverses duodenal wall, opens into the duodenal lumen through (major) duodenal papilla, a 0.5 cm in diameter mucosal elevation with mucosal reduplications (valves of Santorini) that probably prevent regurgitation
Minor papilla, also called accessory pancreatic duct of Santorini, is 2 cm proximal and slightly anterior to major papilla
Ampulla is surrounded by muscular fibers of sphincter of Oddi
Drawings: local anatomy (called common duct); papilla
Mucosa forms prominent papillary folds / reduplications resembling fallopian tubal fimbriae with fibrovascular cores
Lined by pancreaticobiliary-type ductal epithelium with occasional goblet cells, no absorptive-type cells
Lamina propria has only occasional lymphocytes, plasma cells and mast cells
May have adjacent pancreatic acini, but usually no islets around major papillae
Common bile duct can be distinguished from main pancreatic (Wirsung) duct by its larger size, more prominent folds, thicker musculature, intraluminal bile
Also called adenomyomatous hyperplasia
Rare, benign
Usually stomach, duodenum, jejunum
Often causes pain in right upper quadrant, radiating to back
May cause biliary obstruction and common bile duct dilation (Archives 1987;111:388)
Case report: 55 year old woman with history of duodenal ulcers (Archives 2001;125:701)
Treatment: excision
Gross: mass at head of pancreas, usually 0.5 cm or more
Micro: well circumscribed, nodular proliferation of smooth muscle cells, ducts and glands, clearly disorganized compared to normal; ducts and glands are lined by columnar/cuboidal cells; no atypia, no mitoses, usually no pancreatic tissue
Micro images: benign ducts with whorled smooth muscle stroma
DD: normal intraampullary common bile duct (normally has dense muscular layer), ectopic pancreatic tissue, fibroadenoma, Brunner gland hyperplasia
Signs/symptoms of right sided upper abdominal pain and pinpoint ampullary opening
Associated with chronic gallbladder or pancreatic disease
Rare tumor of periampullary region and second part of duodenum
Usually benign, rarely has local metastases of endocrine component but even these cases are indolent
May recur if incompletely excised
May derive from endodermal-neuroectodermal complexes in the embryonic ventral pancreas
Presents with GI bleeding or incidental finding
Case reports: 43 year old man (Archives 2002;126:1239)
Gross: usually 1-3 cm, sessile or polypoid, no capsule
Micro: unencapsulated submucosal lesions; triphasic, with epithelioid, spindle cell (Schwann cell like), and ganglion type cells of varying proportions resembling carcinoid tumor (endocrine type cells in compact nests and trabeculae), paraganglioma and ganglioneuroma; usually infiltrative pattern; variable stromal amyloid
Gross/micro images: ganglion-like (fig 3), spindle (fig 4A) & epithelial cells (fig 4B)
Positive stains: endocrine cells - pancreatic polypeptide, somatostatin; ganglion cells - chromogranin, synaptophysin, neuron specific enolase, somatostatin; spindle cells - S100
EM: dense core granulesl
DD: ganglioneuroma, paraganglioma, carcinoid, carcinoma
Reference: Archives 2001;125:1098 (nasopharyngeal tumor)
Very common
May cause obstructive jaundice
Poorly defined concept
No clinical significance
Micro: more prominent papillary folds than usual, no dysplasia
DD: adenoma (dysplastic epithelium)
Premalignant/noninvasive
Increased in familial adenomatous polyposis syndrome
Endoscopic brush cytology is sensitive and specific for adenomas/carcinomas, although diagnosis of adenoma does not exclude coexisting carcinoma (AJCP 1998;109:540)
Associated with high grade PanIN in 40% of cases, similar rate as adenocarcinomas
Excellent prognosis if completely excised
Treatment: polypectomy or pancreatoduodenectomy since premalignant
Micro: tubular, villous or mixed, similar to adenomas in colon, although (a) dysplastic epithelium may have only subtle changes of mild cellular stratification and fine chromatin pattern; (b) often contain prominent Paneth cells (with coarse, large, red-pink, refractile granules in supranuclear cytoplasm), endocrine cells (dark, red-purple, fine small granules in basal cytoplasm) and goblet cells
Micro images: tubular adenoma with mild dysplasia; villous adenoma
DD: intraductal papillary mucinous neoplasms of pancreas or common bile duct adenoma extending into ampulla
Intraductal papillary mucinous neoplasm (IPMN)
Analogous to tumor of pancreas
Often associated with invasive carcinoma (so examine thoroughly)
May recur and progress
Carcinoma
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
80% of ampullary neoplasms and 90% of ampullary malignancies are adenocarcinoma
5% of GI malignancies are ampullary or periampullary adenocarcinoma
May arise from villous adenoma or villoglandular polyp; usually is a co-existing adenoma
May be associated with multiple polyposis syndrome and neurofibromatosis; 1/3 have other malignancies
Peak age in 70’s, men affected more than women
Causes jaundice, abdominal pain, occasionally pancreatitis
On CT scan, a small intra-ampullary tumor may show dilated ducts without a mass; ultrasound may be better
Nodal metastases present at diagnosis in 35% (usually adjacent periampullary nodes); should examine at least 10 lymph nodes in a pancreaticoduodenectomy specimen
Also metastasizes to liver, lung, peritoneum, pleura
Lamina propria invasion is considered by some as invasive carcinoma due to rich lymphatics (AJSP 1991;15:1188)
1/3 associated with high grade PanIN (Mod Path 2001;14:139); 1/3 associated with pancreatitis
Although pancreaticobiliary subtypes morphologically resemble primary pancreatic tumors, failure of DPC4 expression or K-ras status to correlate with ampullary histologic type suggests these tumors may not be related genetically (Mod Path 2003;16:272)
Site: may arise within ampulla (intra-ampullary), in periampullary duodenum without significant ampullary involvement (peri-ampullary), or mixed; may be difficult to determine
Treatment: Whipple procedure
Prognosis: 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, tumor size 2.5 cm or more, perineural invasion, angiolymphatic invasion, invasion of muscle of sphincter of Oddi, nodal metastases, signet-ring histology, poorly differentiated, positive margins
Good prognostic factors: papillary histology
Case reports: associated with neurofibromatosis-1, (Mod Path 2001;14:1169), signet ring subtype (Ann Clin Lab Sci 2004;34:471, JOP 2004;5:495), presentation as recurrent pancreatitis (Acta Gastroenterol Belg 2004;67:309)
Gross: tumor bulges into duodenal lumen, may be intra-, peri-ampullary or mixed; often small; common bile duct often dilated
Gross images: mass with central ulceration #1; #2; #3
contributed by Dr. Semir Vranic, University of Sarajevo, Bosnia and Herzegovina - #1; #2
Micro: usually poorly differentiated, may have papillary component resembling villous adenoma or villoglandular polyp; morphology is either intestinal (arising from covering intestinal mucosa of papilla, may have more favorable clinical outcome; large elongated tubules) or pancreaticobiliary (derived from ductal epithelium that penetrates duodenal muscularis propria, smaller glands/tubules with desmoplastic stroma); less common subtypes are signet ring, mucinous, medullary or mixed; 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%)
Micro images: adenocarcinoma #1; #2 (poorly differentiated); early tumor #1; #2; advanced tumor; well differentiated; tumor infiltrating towards duodenal surface
Micro images: (1) DPC4 staining in invasive carcinoma and high grade dysplasia; (2) CDX2 staining in A: metastatic colonic carcinoma to lung; B: pancreatic ductal adenocarcinoma in duodenum; C: ampullary adenocarcinoma
contributed by Dr. Semir Vranic, University of Sarajevo, Bosnia and Herzegovina - #1; #2; #3; nodal metastasis; CEA; CK7; CK20; MSH2
variants (see also below): colloid, hepatoid, mixed acinar-endocrine, neuroendocrine, paneth cell, signet ring cell
Report the presence of PanIN at the resection margin
Frozen section: major criteria for malignancy are nuclear size variation of at least 4:1 between ductal epithelial cells, incomplete ductal lumens, disorganized duct distribution; minor criteria are huge, irregular epithelial nucleoli, necrotic glandular debris, glandular mitoses, glands unaccompanied by connective tissue stroma within smooth muscle bundles, perineural invasion (AJSP 1981;5:179)
Positive stains: p53 (>50%), CK17 (but see below); also mesothelin, loss of DPC4 in 34%
Ampullary carcinoma of pancreaticobiliary origin: MUC1+, MUC5AC+, CK17+, MUC2-, CDX2-; also CK7+, CK20-
Ampullary carcinoma of intestinal type (duodenal papillary origin): MUC2+, CDX2+, MUC1-, MUC5AC-, CD17-; also CK7-, CK20-
Molecular: K-ras activating point mutations in 40%
DD: common bile duct carcinoma (thickening of common bile duct, granular mucosa, usually well differentiated adenocarcinoma formed by small glands with marked desmoplasia), other nonampullary duodenal adenocarcinomas (resemble ampullary tumors, may also arise in villous adenoma)
References: AJCP 2001;115:695 (cytokeratin staining), AJSP 2003;27:1418 (mesothelin staining), AJSP 2004;28:875 (comparison of histologic subtypes), AJSP 2005;29:359 (CDX2, CK17, MUC1 & 2), Mod Path 2004;17:1392 (CDX2)
Usually associated with intraductal papillary mucinous neoplasm or tubular/tubulovillous adenoma (AJSP 2002;26:56)
Similar prognosis to other periampullary adenocarcinomas (in above study)
Micro: predominantly mucin lakes with floating malignant epithelial cells and minimal conventional adenocarcinoma; may contain signet ring cells
Micro images: colloid carcinoma
Rare; similar tumors found in lung, ovary, stomach
Produce alpha-fetoprotein in blood
Micro: tubular, papillary, trabecular; hepatoid-like with PAS positive hyaline globules
Positive stains: AFP, CEA
Mixed acinar-endocrine carcinoma
May arise in heterotopic pancreatic cells
Acinar cell carcinoma component is composed of pancreatic acinar cells with zymogen granules on EM
Case reports: 78 year old man with coexisting primary renal and prostate carcinomas (Hum Path 2002;33:449)
Micro: nests of tumor cells with acinar structures and endocrine immunoreactivity and endocrine granules on EM
Positive stains: amylase, trypsin, synaptophysin
EM: endocrine and zymogen granules
Rare; case report of large cell tumor in 74 year old woman (Archives 2003;127:221)
Large cell tumors are highly aggressive
Micro: large cell tumor - islands and trabeculae of large cells with brisk mitotic activity and extensive necrosis; cells have more cytoplasm than small cell carcinoma, irregular chromatin, frequent nucleoli
Micro images: H&E, chromogranin
Positive stains: large cell tumor - cytokeratin, chromogranin, synaptophysin, neuron-specific enolase
DD: carcinoid, small cell carcinoma, lymphoma, poorly differentiated carcinoma, metastases
Rare
Excluding neoplasms, paneth cells usually are limited to lining epithelium of small intestine, appendix and proximal colon
Case report in 64 year old man, with virtually all neoplastic cells resembling Paneth cells (Archives 2004;128:908)
Positive stains (granules): lysozyme, PAS (weak)
Other malignancies
3% of ampullary tumors, more aggressive than duodenal carcinoid tumors
Patients typically present with jaundice
Metastases more common, survival shorter (many die within 1 year) than duodenal carcinoids (usually benign)
Somatostatin producing tumors are common, have a glandular pattern, are associated with psammoma bodies and neurofibromatosis, have 50-70% nodal metastases (AJCP 1991;95:51, AJCP 1983;80:755, AJCP 1992; 97:411, AJSP 1989;13:828)
Micro: somatostatin producing tumors are often mucin+
Micro images: low power shows neoplastic cells in lamina propria and submucosa widening the papilla of Vater
Positive stains: chromogranin (60%), synaptophysin (60%), gastrin (20% vs. 75% of duodenal carcinoids); also somatostatin and pancreatic polypeptide
References: Hum Path 2001;32:1252
DD: adenocarcinoma
Adenocarcinoid
Prognosis intermediate between carcinoids and adenocarcinoma (Hum Path 1989;20:198)
High incidence of follicular lymphoma in duodenum, usually periampullary
May mimic pancreatic adenocarcinoma
Associated with multiple small polyps
Indolent behavior (AJSP 2000;24: 688)
Case reports: follicular lymphoma presenting as obstructive mass (AJSP 1997;21:484)
Case report in 78 year old woman (Archives 2003;127:1501)
Gross images: pancreaticoduodenectomy specimen
Micro images: A-C: H&E; D: CAM5.2; trypsin and related stains
Miscellaneous
Ink pancreatic duct and common bile duct margins, also retroperitoneal margin
Probe common bile duct and pancreatic duct, and section along plane of both probes
Does not apply to carcinoid or other neuroendocrine tumors
pTX: primary tumor cannot be assessed
pT0: no evidence of primary tumor
pTis: carcinoma in situ
pT1: tumor limited to ampulla of Vater or sphincter of Oddi
pT2: tumor invades duodenal wall
pT3: tumor invades pancreas
pT4: tumor invades peripancreatic soft tissues or other adjacent organs or structures
pNX: regional lymph node status cannot be assessed
pN0: no regional lymph node metastasis
pN1: regional lymph node metastasis (number examined, number involved by tumor)
pMX: Distant metastasis cannot be assessed
pM0: No distant metastasis
pM1: Distant metastasis (specify site)
Extent of resection:
R0 - complete resection with gross/microscopically negative margins
R1 - grossly negative, microscopically positive
R2 - grossly and microscopically positive
Not part of TNM but prognostically of great significance
Stage Groupings:
Stage 0: Tis N0 M0
Stage 1A: T1 N0 M0
Stage 1B: T2 N0 M0
Stage 2A: T3 N0 M0
Stage 2B: T1-T3 N1 M0
Stage 3: T4, any N, M0
Stage 4: Any T, any N, M1
* Specimen type
* Tumor site
Presumed tumor origin (intraampullary, periampullary duodenum, mixed, common bile duct, pancreatic)
* Histologic type
* Histologic grade (well, moderate, poor or undifferentiated)
* Tumor size (invasive carcinoma component)
* Depth of invasion, local extension
* Margins - invasive carcinoma; distance to closest margin and identify margin
(recommended to ink posterior retroperitoneal surface of pancreas and submit sections of tumor closest to this margin)
* Margins - carcinoma in situ; involvement of pancreatic duct or common bile duct margin
* Pathologic staging
* Perineural invasion (for resections)
* Angiolymphatic invasion (for resections)
* Lymph nodes
* Additional findings: PanIN / dysplasia, adenoma, inflammation, adenomyosis, pancreatitis, gastritis, other
* mandatory to report for accreditation purposes by American College of Surgeons Committee on Cancer
End of Ampulla chapter