Review Article
Duodenal Epithelial Polyps
A Clinicopathologic Review
Katrina Collins, MD; Saverio Ligato, MD
 Context.—Duodenal epithelial polyps are reported in
1.5% to 3% of individuals referred for upper endoscopy.
Most duodenal epithelial polyps are asymptomatic and
nonneoplastic; however, a small subset is neoplastic and
may progress to adenocarcinoma. Recent advances in
immunohistochemical and molecular techniques have
helped further characterize these polyps, shedding light
on their origin, classification, and risk of progression to
adenocarcinoma.
Objective.—To provide a comprehensive clinicopatho-
logic review of nonneoplastic and neoplastic duodenal
epithelial polyps, with particular emphasis on recent
developments in classification schemes and risk stratifica-
D uodenal epithelial polyps have been reported in
approximately 1.5% to 3.0% of individuals referred
for upper endoscopy. Recent advances in endoscopic
techniques have increased the detection rate of these polyps
and have allowed removal of lesions up to 2 cm in diameter.1
Duodenal epithelial polyps can occur as sporadic polyps,
usually identified incidentally during upper endoscopy
performed for other reasons, or in the setting of familial
polyposis, in which they are typically multiple in number and
often carpet the entire duodenal surface. They may present as
sessile or pedunculated polyps, nodules, excrescences, or
subtle abnormalities of the mucosa and can be located either
in the duodenal bulb, ampullary/periampullary region, or
distal duodenum. Most are benign and associated with peptic
injury, duodenitis, or inflammatory lesions; however, a small
subset is neoplastic with the potential for progression to
adenocarcinoma. Histologically, duodenal polyps are largely
divided into nonneoplastic epithelial polyps and neoplastic
epithelial polyps (Table 1). In this article, we review the
salient clinicopathologic features and treatment options of
duodenal epithelial polyps, and provide an update on their
classification and risk stratification based on morphologic,
Accepted for publication May 18, 2018.
Published online October 24, 2018.
From the Department of Pathology & Laboratory Medicine,
Hartford Hospital, Hartford, Connecticut.
The authors have no relevant financial interest in the products or
companies described in this article.
Corresponding author: Katrina Collins, MD, Hartford Hospital,
Department of Pathology and Laboratory Medicine, 80 Seymour
Street, Hartford, CT 06102 (email: katrina.collins@hhchealth.org).
370 Arch Pathol Lab Med—Vol 143, March 2019
tion based upon immunohistochemical and molecular
profiles.
Data Sources.—This review is based on peer-reviewed
literature and the authors’ experiences.
Conclusions.—In this review we provide an update on
the clinicopathologic, immunohistochemical, and molecu-
lar features of duodenal epithelial polyps and discuss the
surveillance recommendations and treatment options
available. Particular attention should be placed on
recognizing duodenal adenomas with intestinal, gastric,
and serrated phenotype, as they have an increased risk of
malignant transformation if not completely excised.
(Arch Pathol Lab Med. 2019;143:370–385; doi: 10.5858/
arpa.2018-0034-RA)
immunophenotypic, and molecular features, and correlation
with clinical outcome.
NONNEOPLASTIC DUODENAL EPITHELIAL POLYPS
Nonneoplastic duodenal epithelial polyps include Brunner
gland hyperplastic nodule/polyps (also known as Brunner
gland hyperplasia), Brunner gland hamartomas, Brunner
gland cysts, ectopic gastric mucosa, pancreatic heterotopia,
hyperplastic polyps, inflammatory polyps, and hamartoma-
tous polyps.
Brunner Gland Hyperplastic Nodules/Polyps and Brunner
Gland Hamartomas
The distinction between Brunner gland hyperplastic nod-
ules/polyps and Brunner gland hamartomas is arbitrary and
has been traditionally based mainly on size. Brunner gland
hyperplastic polyps are usually small (0.5 cm–1.5 cm),
asymptomatic, and discovered incidentally during upper
endoscopy performed for other reasons. Brunner gland
hamartomas are larger (.2 cm), and when symptomatic,
present as gastrointestinal (GI) hemorrhage or intestinal
obstruction, often requiring endoscopic or surgical resection.2–4
In the past, the terms Brunner gland hyperplasia, Brunner
gland hamartoma, and Brunner gland adenoma have been
used interchangeably causing some confusion in the
pathologic classification of these lesions.3,5,6 In fact, prior
reports of several large Brunner gland proliferative lesions
without definitive evidence of cytologic atypia that were
reported as Brunner gland adenomas,5,7 in retrospect,
represent examples of Brunner gland hyperplastic polyps
or Brunner gland hamartomas.2 Brunner gland hyperplastic
nodules/polyps and Brunner gland hamartomas are now
Duodenal Epithelial Polyps: A Review—Collins & Ligato
 Table 1. Histologic Classification of Duodenal adipose tissue and/or smooth muscle intermixed with
Epithelial Polyps multilobulated hyperplastic and sometimes cystically dilated
Brunner glands (Figure 1, C and D).
Category Incidence Immunohistochemically, both lesions are positive for
MUC6 protein (a pyloric gland mucin marker), are negative
Nonneoplastic
for MUC5AC (a foveolar mucin marker), and demonstrate a
Brunner gland hyperplastic nodule/polyp Frequent
very low proliferative activity index by Ki-67/MIB-1.3,4,8
Brunner gland hamartoma Less frequent However, in our experience these 3 markers are not usually
Brunner gland cyst Very rare necessary for the diagnosis of these 2 lesions.
Ectopic gastric mucosa Clinical Significance and Treatment.—As previously
Gastric foveolar metaplasia Frequent mentioned, owing to their larger size, Brunner gland
Gastric heterotopia Less frequent hamartomas may cause GI hemorrhage or intestinal obstruc-
Pancreatic heterotopia Less frequent tion requiring endoscopic and sometimes surgical resection.
Hyperplastic polyp Very rare
Inflammatory polyp Less frequent ‘‘Brunner Gland Adenoma’’
Hamartomatous polyps The concept of Brunner gland adenoma is very contro-
Peutz-Jeghers polyp Rare versial and still a matter of ongoing debate.11 Some authors
Juvenile polyp Rare believe that Brunner gland adenoma is a distinct preneo-
Cowden syndrome polyp Rare plastic lesion with gastric phenotype, nuclear atypia, and
Cronkhite-Canada syndrome Very rare immunohistochemical profile identical to the pyloric gland
adenoma of the stomach.12 Others, however, contend that
Neoplastic there are no well-documented cases of either true glandular
Adenoma, intestinal type dysplasia or carcinoma arising from the proliferation of the
Tubular Less frequent Brunner glands.9 In fact, in reviewing the limited literature
Tubulovillous Less frequent on Brunner gland adenocarcinoma and dysplasia (adeno-
Adenoma, gastric type ma), these authors concluded that the dysplastic or
Pyloric gland adenoma Less frequent neoplastic glandular epithelium in these polyps does not
Foveolar adenoma Very rare originate from Brunner glands, but rather from the ducts or
Serrated adenoma with TSA-like features Rare the surface epithelium overlying the Brunner glands often
Neuroendocrine tumors involved by gastric foveolar metaplasia. Hence, they
Gastrinoma Less frequent
concluded that the term Brunner gland adenoma is mislead-
ing and should be discouraged; instead the term Brunner
Somatostatinoma Rare
gland hyperplasia should be used.9 Although in this review,
Gangliocytic paraganglioma Rare
when we refer to these dysplastic lesions we will use the
Abbreviation: TSA, traditional serrated adenoma. term duodenal pyloric gland adenoma rather than Brunner
gland adenoma, we acknowledge some recent studies, both
believed to represent a morphologic continuum of benign in human and animal models, that have described a new
hyperplastic/proliferative lesions of Brunner glands.8 As class of duodenal adenoma and carcinoma demonstrating
such, the term Brunner gland hyperplasia/hamartoma has dysplastic Brunner glands associated with gastric metapla-
been proposed for describing these nonneoplastic lesions.9 sia.13
Clinical and Endoscopic Findings.—Brunner gland Brunner Gland Cysts
hyperplastic/hamartomatous polyps are benign and are
preferentially located in the duodenal bulb, but may also Brunner gland cysts are very rare polypoid or nodular
extend into the second or third part of the duodenum. lesions of the duodenum characterized by a submucosal
Endoscopically, they may be multiple and present as sessile cystic dilation of the Brunner gland ducts. In the past, they
or pedunculated submucosal nodules and show no sex or have also been referred to as Brunner gland cystadenoma,
mucocele of the Brunner glands, and most recently, Brunner
racial predilection.
gland duct cysts.14 The largest case series reported to date
Etiology and Pathogenesis.—Although the exact etiol-
consists of 25 cases with a mean age of 66.2 years and
ogy is still poorly understood, associations with duodenal
approximately equal sex distribution.15 Endoscopically they
injury secondary to gastric acid hypersecretion, Helicobacter present as single or multiple polypoid/nodular lesions, often
pylori infection, end-stage renal disease, and uremia have detected incidentally in the first or second part of the
been reported.2,10 duodenum. They vary in size between 3 mm and 18 mm,
Histopathology and Immunohistochemistry.—Brunner and owing to their cystic nature, during the biopsy
gland hyperplastic nodules/polyps are characterized by a procedure they may rupture and become flattened.16
lobular proliferation of hyperplastic glands, histologically Histologically, they show unremarkable surface duodenal
indistinguishable from normal Brunner glands. They are mucosa with a unilocular or multinodular cystic dilatation of
predominantly located in the submucosa of the duodenal the Brunner gland ducts immediately underneath the
bulb but can extend through the muscularis mucosa into the muscularis mucosae. The cysts are lined by an undulating
lamina propria (Figure 1, A and B). They can be associated single layer of cytologically bland cuboidal or columnar
with surface villous shortening, gastric foveolar metaplasia, epithelium with clear cytoplasm and basally located nuclei
or peptic injury secondary to peptic duodenitis. The usually without cytologic atypia (Figure 2). However, in
histology of Brunner gland hamartomas is similar to that some cases, a variable papillary architecture involving at
of Brunner gland hyperplastic nodules/polyps, but also least part of the cyst may be identified. Historically, they
shows a minor mesenchymal component composed of were believed to represent benign retention cysts without
Arch Pathol Lab Med—Vol 143, March 2019 Duodenal Epithelial Polyps: A Review—Collins & Ligato 371
Figure 1. A, Brunner gland hyperplastic nodule/polyp. At low power, hyperplastic lobules of proliferating Brunner glands filling the submucosa, and
partially the mucosa, are lined by normal duodenal mucosa. B, At high power, the Brunner glands are composed of benign uniform, mucin-
containing columnar cells. C, Brunner gland hamartoma. At low power, it appears as a multilobular proliferation of Brunner glands (D) separated by
a minor mesenchymal component of smooth muscle fibrous bands and adipose tissue (inset) (hematoxylin-eosin, original magnifications 310 [A],
320 [B, D, and D inset], and 34 [C]).

atypia, developing secondary to local obstruction of the
draining duct of the Brunner gland.16 However, some recent
studies have suggested that at least some of them may
represent an early neoplastic process reminiscent of branch-
duct type intraductal papillary mucinous neoplasms.14,17 In
fact, the epithelial lining may demonstrate either a pure
foveolar (MUC5ACþ) or mixed foveolar/intestinal (MU-
C5AC and CDX2þ) phenotype, and some of the cells
(especially in the papillary component) may demonstrate
cytologic atypia consistent with a low-grade dysplasia as
supported by expression of S100P (an immunomarker
consistently expressed in low-grade pancreatic intraepithe-
lial neoplasia, but not in reactive lesions).17 However,
further studies are needed to confirm this hypothesis.
Ectopic Gastric Mucosa
Clinical and Endoscopic Features.—Ectopic gastric
mucosa is a common finding in duodenal biopsies, generally
372 Arch Pathol Lab Med—Vol 143, March 2019
identified in the duodenal bulb. It consists either of gastric
foveolar metaplastic cells without oxyntic glands, known as
gastric foveolar metaplasia, or may be associated with oxyntic
glands and referred to as gastric heterotopia.2 The endoscopic
appearance is that of 1 or multiple small (,1.5 cm) patches,
nodule(s), or, less commonly, pedunculated lesions (Figure
3, A).
Etiology and Pathogenesis.—Gastric foveolar metapla-
sia of the duodenum is generally considered as a reactive/
reparative process usually secondary to acid-peptic injury,
duodenal ulcer, H pylori infection, or chronic inflammation.3
Gastric heterotopia is indistinguishable from normal oxyntic
gland mucosa of the stomach and traditionally has been
considered congenital and benign in nature.
Histopathology.—In duodenal gastric foveolar metapla-
sia the epithelium consists of gastric foveolar-type columnar
cells containing neutral mucin replacing both absorptive
cells and goblet cells of the villi (Figure 3, B). Duodenal
gastric heterotopia consists of oxyntic gastric mucosa with
Duodenal Epithelial Polyps: A Review—Collins & Ligato

Figure 2. Brunner gland cyst. Cystic dilatations of Brunner glands
immediately underneath the muscularis mucosae. At high power
(inset), the cyst is lined by a single layer of bland columnar epithelium
without cytologic atypia (hematoxylin-eosin, original magnifications
310 and 320 [inset]).
both parietal and chief cells and overlying surface gastric
foveolar metaplastic epithelium (Figure 3, C). The adjacent
duodenal mucosa may be normal or associated with varying
degrees of inflammation.2
Clinical Significance and Treatment.—Although in
most cases gastric foveolar metaplasia and gastric hetero-
topia represent benign lesions, some studies have raised the
possibility that a subset of them may be preneoplastic and
represent a precursor of adenomas and gastric-type
adenocarcinomas.18,19 In fact, in a recent study Matsubara
et al20 identified mutations in GNAS and/or KRAS in 55% of
cases with duodenal gastric foveolar metaplasia and 28% of
cases with gastric heterotopia. These lesions are usually
small and asymptomatic; however, when very large they
may cause obstruction or intussusception requiring endo-
scopic or rarely, surgical excision.
Pancreatic Heterotopia
Clinical and Endoscopic Features.—Pancreatic hetero-
topia is a developmental abnormality in which normal
pancreatic tissue is found in an abnormal location without
accompanying anatomic and/or vascular connection to
orthotopic pancreas.21 Pancreatic heterotopia can be ob-
served in any GI tract organ. It is most common in the
duodenum but can also be found in the jejunum, liver,
biliary tract, and omentum.22 The endoscopic appearance of
pancreatic heterotopia is that of a small nondescriptive
nodule covered by normal duodenal mucosa, often with
central umbilication corresponding to the opening of the
main duct. Such lesions when large may become symp-
tomatic, most commonly presenting with abdominal pain,
obstruction, intussusception, stricture, or bleeding.
Etiology and Pathogenesis.—Although the pathogene-
sis is unknown, the most likely hypothesis is that it
originates from embryonic migration of pancreatic buds
into the duodenal wall.
Arch Pathol Lab Med—Vol 143, March 2019
Histopathology.—Pancreatic heterotopia consists of nor-
mal-appearing pancreatic tissue, and the Von Heinrich
classification recognizes 3 types: type I, the most common,
consists of all 3 pancreatic elements (complete pancreatic
heterotopia) (Figure 3, D); type II contains acini and ducts;
and type III is composed only of ducts and rare acinar cells.23
Gaspar Fuentes et al24 classify ectopic pancreas into 4 types:
type I composed of all pancreatic elements (complete
heterotopia); type II composed of ducts only (canalicular
heterotopia), which when surrounded by smooth muscle is
also referred to as adenomyoma25; type III with only acini
(exocrine heterotopia); and type IV with only clusters of
neuroendocrine cells (endocrine heterotopia).
Clinical Significance and Treatment.—Pancreatic het-
erotopia can undergo pathologic changes similar to those
observed in the pancreas such as pancreatitis, pseudocyst,
abscess formation, and rarely, dysplasia and malignancy.22
Endoscopic or surgical resection is the treatment of choice
when they become large and symptomatic or show evidence
of dysplastic features.
Hyperplastic Polyps
Clinical and Endoscopic Features.—Hyperplastic pol-
yps of duodenum are very rare and a total of 16 cases have
so far been reported.26–30 The largest series consists of 9
cases including 3 male and 6 female patients with a mean
age of 52.2 years (range, 21–72 years).27 Typically, they are
asymptomatic and discovered incidentally and most com-
monly located in the second part of the duodenum. The
endoscopic appearance may reveal a sessile or pedunculated
polyp with or without surface ulceration ranging in size
between 5 mm and 27 mm. Rarely they may cause
symptoms such as anemia or GI bleeding.
Etiology and Pathogenesis.—Their pathogenesis has not
been clarified yet; however, most patients with hyperplastic
polyps are associated with H pylori infection or other form of
gastroduodenal disease. No evidence of association with
serrated polyposis or other chronic inflammatory diseases
has been identified.27
Histopathology, Immunohistochemistry, and Molecu-
lar Characteristics.—Most duodenal hyperplastic polyps
reported so far in the literature (14 of 16 cases; 87.5%) have
the histologic appearance of a microvesicular hyperplastic
polyp of the large bowel, characterized by hyperplastic,
columnar microvesciular mucinous epithelium with luminal
and crypt serration lacking cytologic atypia (Figure 4, A).27
However, in a few case reports,28,30 a gastric phenotype with
polypoid hyperplasia of the surface has been described,
raising the possibility that at least some of these lesions may
represent examples of inflammatory duodenal polyps with
gastric foveolar metaplasia rather than hyperplastic polyps.
Similar to the colorectal hyperplastic polyps, MUC6 is
expressed only at the crypt bases and MUC5AC on the
superficial hyperplastic epithelium. MUC2 is identified only if
goblets cells are present and CDX2 usually shows negativity.
The latter is particularly helpful in differentiating hyperplastic
duodenal polyps, usually CDX2, from duodenal serrated
adenomas with traditional serrated adenoma (TSA)–like
features, which are usually CDX2þ and have a more
aggressive behavior. The proliferative activity index by Ki-
67/MIB-1 is low and no p53 overexpression is identified. In
one study,27 BRAFV600E mutations were described in 2 of 6
cases (33%) and KRAS mutations in another 2 cases (33%).27
These findings support the hypothesis that these duodenal
Duodenal Epithelial Polyps: A Review—Collins & Ligato 373
Figure 3. Ectopic gastric mucosa. A, Gross appearance of multiple duodenal nodules (arrow) located in the duodenal bulb. B, Gastric foveolar
metaplasia. Papillary projections lined by gastric foveolar-type epithelium (inset). C, Gastric heterotopia. Low-power view composed of a polypoid
proliferation covered by gastric foveolar metaplastic epithelium. At high power (inset), normal-appearing parietal and oxyntic cells are seen. D,
Pancreatic heterotopia. Normal duodenal mucosa with submucosal pancreatic tissue composed of acini associated with pancreatic ducts and nests
of islet cells, similar to the parenchyma of the normal pancreas (inset) (hematoxylin-eosin, original magnifications 310 [B through D], 320 [B and D
insets], and 340 [C inset]).

polyps may be similar to the microvesicular hyperplastic
polyps of large bowel, which also harbor BRAFV600E or KRAS
mutations in 70% and in 10% to 15% of cases, respectively.31
Clinical Significance and Treatment.—Although duo-
denal hyperplastic polyps are rare, benign, and usually
asymptomatic, Rosty et al27 have raised the possibility that
some of them, especially those harboring KRAS mutation,
may represent a precursor lesion of the duodenal serrated
adenoma with TSA-like features. In fact, it has been shown
that both hyperplastic polyps and duodenal serrated
adenomas with TSA-like features harbor KRAS mutations
more frequently (33% and 38% of cases, respectively) than
hyperplastic polyps of the colon (15%). However, this
hypothesis needs further validation and until then the risk of
recurrence and progression of hyperplastic polyps of
duodenum should be considered as uncertain and treated
with complete endoscopic resection.27
Inflammatory Polyps
Clinical and Endoscopic Features.—Nonneoplastic
inflammatory polyps are inflammatory proliferations of the
duodenal mucosa (inflammatory pseudopolyps) usually
374 Arch Pathol Lab Med—Vol 143, March 2019
associated with Crohn disease, ulcerative colitis, or other
inflammatory processes such as peptic duodenitis, or rarely
with primary immunodeficiency.32 They are usually small
and asymptomatic; however, when large, they may result in
heme-positive stools, GI bleeding, or recurrent abdominal
pain due to intermittent obstruction. The most common
inflammatory polyps of duodenum are the pseudopolyps
found associated with Crohn disease.
Histopathology.—These lesions are characterized either
by polypoid proliferations of elongated glands, resembling
hyperplastic polyps of stomach, or polypoid growths of
granulation tissue with acute and chronic inflammation of
the lamina propria, and ulceration of the surface epithelium
(Figure 4, B). These lesions may also show granulomas
when associated with Crohn disease.
Treatment.—Snare polypectomy for small lesions, endo-
scopic mucosal resection, or submucosal endoscopic dissec-
tion for larger lesions is the treatment of choice.
Hamartomatous Polyps
Hamartomatous polyps of the duodenum represent a
heterogeneous group of inflammatory polypoid lesions
Duodenal Epithelial Polyps: A Review—Collins & Ligato
Figure 4. A, Hyperplastic polyp. At low power, elongated fronds of surface epithelium with a sawtooth appearance and crypts composed of small
crowded mucinous glands. At high power (inset), the hyperplastic epithelium shows microvesicular mucinous cells and rare goblet cells with apical
mucin vacuoles. No cytologic atypia is seen. B, Inflammatory polyp. At low power, a central polypoid epithelial proliferation surrounded on both
sides by ulcerated duodenal mucosa (pseudopolyp). C, Peutz-Jeghers polyp. Lower power: the polyp is characterized by an arborizing network of
smooth muscle bundles surrounded by benign glandular epithelium and normal lamina propria. D, Juvenile polyp. Polypoid mucosa with areas of
surface epithelial erosion showing cystically dilated glands embedded in an expanded lamina propria with areas of dense stroma and vascular
congestion (hematoxylin-eosin, original magnifications 310 [A through D] and 320 [A inset]).

often occurring in the setting of familial polyposis syn-
dromes33,34 or very rarely as isolated sporadic polyps.2
Clinical and Endoscopic Features.—Syndromic hamar-
tomatous polyps may involve the entire GI tract; however,
the duodenum is usually much less commonly involved.
Endoscopically, they may present as small polyps or nodules
or as large lesions that may produce symptoms of intestinal
obstruction or intussusception.
Histopathology.—Microscopically, they are usually
characterized by a variable mixture of epithelial and
stromal elements featuring epithelial hyperplasia, cystic
dilation of glands, stromal overgrowth, edema, acute and
chronic inflammation, surface erosion, and Brunner gland
hyperplasia. The correct identification and classification of
these lesions is critical to the management of these
patients because of their association with the develop-
ment of GI malignancies as well as other extraintestinal
lesions.
Arch Pathol Lab Med—Vol 143, March 2019
Specific Hamartomatous Duodenal Polyps
Peutz-Jeghers Polyps.—Peutz-Jeghers polyposis is an
autosomal dominant syndrome characterized by multiple
benign GI hamartomatous polyps, mucocutaneous pigmen-
tation, and tumors of ovary or testis resulting from
mutations in the serine-threonine kinase (STK) 11 tumor
suppressor gene located on chromosome band 19p13.3 in
approximately 50% of the families with Peutz-Jeghers
polyposis.2 Additional genes are yet to be identified. They
can be located throughout the GI tract and especially in the
jejunum and duodenum, where they are identified in 78% of
cases.
Endoscopically, they may appear sessile or pedunculated
with a smooth multilobulated appearance varying in size
from a few millimeters up to several centimeters. Histolog-
ically, they are characterized by branching bands of smooth
muscle surrounded by glandular epithelium and normal
lamina propria (Figure 4, C). Sometimes, they may have foci
Duodenal Epithelial Polyps: A Review—Collins & Ligato 375
of adenomatous mucosa and very rarely progress to
adenocarcinoma.34 Polypectomy is recommended in order
to achieve an accurate diagnosis and because these polyps
have a risk of malignant transformation.35
Juvenile Polyps.—These polyps may be sporadic or
associated with juvenile polyposis syndrome (JPS), which is
an autosomal dominant syndrome with high penetrance
linked to abnormalities in the signaling of transforming
growth factor-b (TGF-B) via genetic abnormality of SMAD4
or BMPR1AI genes in about 50% to 60% of patients with
JPS.2 Endoscopically, they typically appear as smooth,
pedunculated, or sessile mucosal lesions that may be
associated with surface ulceration. The histology consists
of cystically dilated glands mixed with a markedly edema-
tous/inflamed stroma, erosions of surface epithelium, and
underlying granulation tissue (Figure 4, D). Juvenile
polyposis syndrome is associated with increased risk of
cancer (~10%), particularly in colon and stomach; however,
the rarity of these lesions in the duodenum precludes an
adequate assessment of their neoplastic risk in this location.
Polyps in Cowden Syndrome.—This syndrome, also
known as PTEN (phosphatase and tensin homolog)
hamartoma tumor syndrome, is a rare autosomal dominant
disorder that has been linked to germline mutations in the
PTEN gene located on chromosome band 10q23.3. It is
characterized by multiple hamartomas and hyperplastic
lesions of the skin, mucous membranes, brain, thyroid, and
entire GI tract.2 In the GI tract, these hamartomatous polyps
may occur in the duodenum more commonly than
previously believed (36.5%).36 Endoscopically, they appear
as small (2–5 mm) lesions with a color similar to the
surrounding duodenal mucosa. Histologically, they may
present as multiple hamartomatous polyps of differing types
featuring juvenile-type polyps, ganglioneuromas, lipomas,
and adenomas.37 If a PTEN mutation is identified, the risk of
adenocarcinoma of breast, thyroid, and endometrium
appears increased; however, an excess risk of GI cancer
has not been well established.
Polyps in Cronkhite-Canada Syndrome.—Cronkhite-
Canada syndrome is a rare acquired nonfamilial form of
diffuse GI polyposis that typically affects adults in their fifth
and sixth decade of life. These polyps are usually identified
in the stomach but may also involve the duodenum.38 In
isolation, they may be indistinguishable from juvenile or
hyperplastic polyps, and are usually diagnosed in the
presence of dramatic GI symptomatology characterized by
weight loss, diarrhea, and nutritional deficiencies.2 Owing to
the accompanying findings of hypoalbuminemia, hypocal-
cemia, anemia, severe electrolyte deficiencies, and severe
malabsorption, these patients have a poor prognosis with a
mortality rate of 60%. Histologically, these polyps appear
similar to juvenile polyps, but in contrast with the classical
juvenile polyps, the intervening mucosa, both in the
stomach and duodenum, is also abnormal featuring severe
edema, congestion, and inflammation.
NEOPLASTIC DUODENAL EPITHELIAL POLYPS
At present, duodenal adenomatous polyps are classified
according to the mucin phenotype into intestinal (89.1%)
and gastric type (10.9%). The intestinal-type polyps are
morphologically subdivided into tubular and tubulovillous
adenomas and the gastric-type into pyloric gland adenomas
and foveolar adenomas.19,39 The most recently described
neoplastic duodenal polyp is the serrated adenoma with
376 Arch Pathol Lab Med—Vol 143, March 2019
TSA-like features resembling the TSA of the large bowel.
This polyp represents a new distinct category of duodenal
dysplastic polyp characterized by a significant risk for
progression to adenocarcinoma.40,41
Duodenal Adenoma With Intestinal Phenotype
Clinical and Endoscopic Features.—Duodenal adeno-
mas with intestinal phenotype account for approximately
25% of benign neoplasms of the small intestine. They are
classified according to their location: ampullary, periampul-
lary, or distal to the ampulla. They are also classified
clinically into sporadic duodenal adenomas and adenomas
associated with genetic syndromes such as familial adeno-
matous polyposis (FAP), attenuated FAP, or MUTYH-
associated adenomatous polyposis (MAP). Sporadic duode-
nal adenomas account for approximately 40% of all
intestinal-type duodenal adenomas and are usually identi-
fied in elderly men (60–80 years of age). Most are
asymptomatic, usually arising in the second part of the
duodenum, and endoscopically appearing as sessile or flat
rather than pedunculated polyps.19,42 In a study evaluating
the risk of adenocarcinoma in nonampullary sporadic
duodenal adenomas, Okada et al43 concluded that lesions
with low-grade dysplasia and smaller than 20 mm have a
low risk of progression to adenocarcinoma (4.7%) and some
risk of progression to high-grade dysplasia (HGD), whereas
adenomas that are larger than 20 mm, or have HGD, have a
higher rate of progression to adenocarcinoma (approxi-
mately 54.5%). However, most duodenal adenomas with
intestinal phenotype are found in individuals with FAP
(60%) and in approximately 17% to 25% of individuals with
MAP. Endoscopically, they present as multiple sessile
polyps with a predilection for the distal duodenum and
periampullary region, and owing to their small size may be
missed during upper endoscopy. However, with the aid of
chromoscopic techniques, the number of detected polyps
may increase considerably.
Etiology and Pathogenesis.—Familial adenomatous
polyposis is an inherited autosomal dominant syndrome
due to a germline mutation in 1 copy of the adenomatous
polyposis coli (APC) gene, a tumor suppressor gene located
on the long arm of chromosome 5 (5q21-22). This condition
is characterized by the formation of hundreds of intestinal-
type adenomas in the colon and small bowel with
approximately 65% of people with this condition developing
duodenal adenomas.44 The pathogenesis of both sporadic
duodenal adenomas and FAP-associated duodenal adeno-
mas is not well elucidated; however, it is believed that it may
be analogous to that proposed for colorectal carcinoma in
which there is progressive accumulation of abnormalities in
the APC pathway. Instead, MAP is an autosomal recessive
condition caused by biallelic germline mutations of the
MUTYH gene. Carriers of 1 MUTYH gene mutation have a
milder clinical presentation and not much is known about
the impact on the development of duodenal polyps.
Histopathology, Immunohistochemistry, and Molecu-
lar Characteristics.—Sporadic duodenal adenomas, FAP-
related adenomas, and MAP-related adenomas are mor-
phologically indistinguishable and are characterized by
adenomatous transformation of the small intestinal epithe-
lium, similar to that observed in the colonic adenomas. They
are classified as tubular adenoma, composed of small
tubular glands lined by eosinophilic absorptive epithelium
with pseudostratified hyperchromatic nuclei (Figure 5, A),
Duodenal Epithelial Polyps: A Review—Collins & Ligato
Figure 5. Duodenal adenoma with intestinal phenotype. Tubular adenoma (A) and tubulovillous adenoma (B) composed of neoplastic epithelium
with crowded columnar cells demonstrating hyperchromatic and pseudostratified nuclei without loss of nuclear polarity. The intestinal phenotype is
confirmed by positivity for CD10 (C) and CDX2 (D) (hematoxylin-eosin, original magnification 320 [A and B]; original magnification 320 [C and D]).

and tubulovillous adenoma demonstrating a villous archi- Clinical Significance and Treatment.—Individuals with
tecture covered by dysplastic epithelium with cytologic FAP-related duodenal adenomas have a 100- to 300-fold
features similar to those described in tubular adenomas increased lifetime risk for developing duodenal or periam-
(Figure 5, B). When they progress to HGD both architectural pullary carcinoma.9 Spigelman et al46 developed a 4-stage
complexity, characterized by distorted and/or cribriform classification (0–IV) system for evaluating the severity of
glands, and cytologic atypia with large hyperchromatic duodenal adenomatosis in individuals with FAP (Table 2),
nuclei with prominent nucleoli and loss of nuclear polarity, and based on the degree of risk of developing carcinoma,
are observed. Immunophenotypically, they are defined by recommendations on the frequency of surveillance and
the expression of CD10 (Figure 5, C), CDX2 (Figure 5, D), treatment options were issued (Table 3).
and/or MUC2 proteins but not MUC5AC and MUC6.
This staging system has been validated by other stud-
However, in a recent study, 76.9% of duodenal adenomas
ies47,48 and stratifies the risk of developing duodenal
with intestinal phenotype demonstrated focal gastric phe-
carcinoma from the number, size, histology, and degree of
notype, which is supported by MUC5AC and MUC6
positivity.19 Emerging evidence shows that both sporadic dysplasia of the polyps. Based on this system, approximately
duodenal adenomas and FAP-related adenomas show
molecular alterations similar to those observed in colorectal
adenoma characterized by frequent genetic alterations, Table 2. Modified Spigelman Score
involving the APC and KRAS genes. DNA mismatch repair Factor 1 Point 2 Points 3 Points
abnormalities and TP53 mutations are identified only rarely
and no BRAF mutations are present.45 Instead, duodenal Polyp number ,4 5–20 .20
cancer developing in MAP-related adenomatous polyps Polyp size, mm 1–4 5–10 .10
demonstrates a specific somatic KRAS mutation variant (c.34 Histology Tubular Tubulovillous Villous
G.T in codon 12), which is found in approximately 64% of Dysplasia Low-grade — High-grade
cases. Abbreviation: —, not applicable.
Arch Pathol Lab Med—Vol 143, March 2019 Duodenal Epithelial Polyps: A Review—Collins & Ligato 377
 Table 3. Spigelman Stage: Recommended Duodenal
Surveillance Frequency
Spigelman Total
Stage Points Frequency of Surveillance
0 0 Every 4 y
I 4 Every 2–3 y
II 5–6 Every 1–3 y
III 7–8 Every 6–12 y
IV 9–12 Expert surveillance every 3–6 mo
Surgical evaluation
Complete mucosectomy or
duodenectomy or Whipple
procedure if duodenal papilla is
involved
70% to 80% of patients with FAP have stage II or III
duodenal disease and 20% to 30% have stage I or IV disease.
Although surgery is considered the standard treatment for
FAP patients with severe polyposis (stage IV), in less
advanced cases, depending on the size and number of the
polyps, snare polypectomy or advanced endoscopic tech-
niques like endoscopic mucosal resection or endoscopic
submucosal dissection may be used.35
Because for approximately 4% of individuals with MAP
their condition may progress to invasive duodenal carcino-
ma, surveillance and management recommendations anal-
ogous to those used for individuals with FAP, using the
Spigelman criteria, have been proposed.
As previously mentioned, sporadic duodenal adenomas
with low-grade dysplasia have a low risk of progression to
adenocarcinoma and consequently can be closely followed
up with biopsies. However, HGD lesions and nonampullary
sporadic duodenal adenomas larger than 40 mm in diameter
show high risk of progression to adenocarcinoma and
therefore should be treated by snare polypectomy, advanced
endoscopic techniques, or surgery.43
Duodenal Adenomas With Gastric Phenotype
Duodenal adenomas with gastric phenotype are subclas-
sified into pyloric gland adenoma and foveolar adenoma.19,49
In contrast to the duodenal adenomas with intestinal
phenotype, they are preferentially located in the proximal
duodenum19 and very often have a pedunculated appear-
ance.39
Clinical and Endoscopic Features.—Duodenal pyloric
gland adenoma is a rare neoplasm demonstrating morpho-
logic, immunohistochemical, and molecular similarities to
the pyloric gland adenoma of the stomach. Lesions with
similar morphology and immunohistochemical phenotype
have also been described in the pancreas, biliary tree,
esophagus, and rarely in the rectum; however, their most
frequent localization is in the duodenum and in the
stomach.50–53 They usually occur in older individuals with
a mean age of 74 years (range, 52–87 years). Additionally,
they may be associated with syndromic polyposis such as
FAP54 and according to some reports, with Lynch syn-
drome.55 Endoscopically, they may present as submucosal
nodules, flat lesions, or more often as protruding polypoid
lesions varying in size between 5 mm and 28 mm with a
median diameter of 15.3 mm.
Etiology and Pathogenesis.—The histogenesis of duo-
denal pyloric gland adenomas remains unclear. Kushima et
al53 was the first to suggest that pyloric gland adenoma may
378 Arch Pathol Lab Med—Vol 143, March 2019
originate from Brunner glands. According to these authors,
when the duodenal mucosa is damaged, a process of
mucosal regeneration ensues in the Brunner glands, giving
origin to generative cell zones (‘‘neo-G zones’’) with
proliferation of pluripotent stem cells within Brunner glands
and ducts.
These cells may differentiate toward the surface, forming
areas of gastric foveolar metaplasia or downwards giving
rise to Brunner gland hyperplasia or Brunner gland
hamartoma. According to this hypothesis, metaplastic
foveolar epithelium originating from the ‘‘neo-G zone’’ is
prone to mutation errors leading to the generation of
dysplastic polyps, such as pyloric gland adenoma, and
ultimately carcinoma.53,56 In support of this hypothesis is the
observation that in all the sites of origin pyloric gland
adenoma is often, but not always, associated with gastric
foveolar metaplasia and/or gastric heterotopia.11,54,57,58 Ad-
ditionally, in a recent molecular study a significant number
of cases of gastric foveolar metaplasia (55%) and gastric
heterotopia (28%) of the duodenum were found to be
associated with GNAS and/or KRAS mutations which,
interestingly, represent the same type of mutations usually
identified in the duodenal pyloric gland adenoma and
adenocarcinoma with gastric phenotype.20
Histopathology, Immunohistochemistry, and Molecu-
lar Characteristics.—Most duodenal pyloric gland adeno-
mas present as polypoid lesions (Figure 6, A) composed of
tightly packed pyloric tubules (Figure 6, B) or cystically
dilated glands lined by a monolayer of cuboidal to low
columnar cells with basally located nuclei, demonstrating a
very subtle atypia and slightly enlarged nucleoli. The
cytoplasm is abundant, glassy, and slightly eosinophilic
and some of the glands may contain mucinous cells and
clear cells. Occasionally, rare goblets cells or Paneth cells
may be identified; however, they represent most likely
residual native intestinal epithelial cells rather than a
component of pyloric gland adenoma.50,57,58 Other times,
they may present as submucosal nodules (Figure 6, C) or as
flat lesions (Figure 6, D).
When these adenomas progress to low-grade dysplasia,
the glands become irregularly shaped, with enlarged and
hyperchromatic nuclei, inconspicuous nuclei, and rare
mitotic figures (Figure 6, C [inset]). Instead, in HGD, the
glands are more complex with some cribriform architecture,
enlarged nuclei with loss of polarity, mild membrane
irregularity, nuclear pleomorphism, scattered enlarged
nucleoli, and increased mitotic activity50,53 (Figure 6, D
[inset]). The immunoprofile of duodenal pyloric gland
adenomas is defined by diffuse expression of pyloric gland
mucin MUC6 (Figure 6, E) and selective expression of
MUC5AC (Figure 6, F) along the superficial gastric foveolar
epithelium and only focally in the underlying glands. This
last finding is useful in differentiating a pyloric gland
adenoma from Brunner gland lesions, especially in small
biopsy specimens. In fact, MUC5AC shows positivity in the
superficial and focally in the glandular component of pyloric
gland adenomas but negativity in Brunner glands. In
addition, CDX2, CD10, and MUC2 (intestinal markers)
usually show negativity and this is helpful in differentiating
duodenal adenomas with pyloric phenotype from those with
intestinal phenotype. An increased proliferative activity
index by Ki-67/MIB-1 and overexpression for p53 may also
be found especially in those polyps with HGD.50 Adeno-
carcinoma arising in these polyps is either of gastric or
mixed (gastric and intestinal) phenotype as supported by
Duodenal Epithelial Polyps: A Review—Collins & Ligato
Figure 6. Duodenal pyloric gland adenoma. A, Exophytic pattern of duodenal pyloric gland adenoma. B, In this example, the polyp is composed of
villous fronds of surface epithelium and tightly packed, variably dilated glands lined by cuboidal cells (inset). C, Duodenal pyloric gland adenoma
with a submucosal/nodular morphology featuring glands with round contours and enlarged/hyperchromatic nuclei consistent with low-grade
dysplasia (inset). D, Flat pyloric gland adenoma with most glands demonstrating round contours focally becoming complex and cribriform with large
nuclei, some prominent nucleoli, and loss of nuclear polarity consistent with high-grade dysplasia (inset). E, Most of the glands are positive for MUC6,
whereas (F) the surface foveolar epithelium and some of the glands are positive for MUC5AC (hematoxylin-eosin, original magnifications 310 [A and
C], 320 [B and D], and 340 [B, C, and D insets]; original magnification 310 [E and F]).

Arch Pathol Lab Med—Vol 143, March 2019 Duodenal Epithelial Polyps: A Review—Collins & Ligato 379

Figure 7. Duodenal adenoma with gastric foveolar phenotype.
Protruding polyp composed of cells resembling gastric foveolar-type
epithelium with nuclear pseudostratification. All tumor cells are positive
for MUC5AC (inset) (hematoxylin-eosin, original magnification 320;
original magnification 310 [inset]). Courtesy of Takehiro Mitsuishi, MD.
maintained coexpression of MUC6, MUC5AC, and CDX2
immunostains.19,59–61 The most frequent molecular abnor-
malities detected in duodenal pyloric gland adenomas
include mutations in oncogenes KRAS (70%) and GNAS
(50%), and less frequently, CTTNB1 and tumor suppressor
genes SMAD4 and TP53. APC mutations are usually
absent.58,59
Clinical Significance and Treatment.—Duodenal pylo-
ric gland adenomas are neoplastic lesions with a reported
malignant transformation rate between 12% and 30% of
cases. In a series of 19 pyloric gland adenomas of
duodenum, Chen et al50 found low-grade dysplasia in
10.5% of these cases, HGD in 42.1%, and invasive
carcinoma in 10.5%. Furthermore, Vieth et al51 showed
focal transition to adenocarcinoma in 30% of cases. It
appears that there is a correlation between size increase of
the lesion (20 mm) and occurrence of HGD and
adenocarcinoma.39 However, regardless of the degree of
atypia and mucin phenotype, if these polyps are completely
resected, no cases of recurrence or progression have been
reported. Instead, in cases where the polyps were not
completely excised, progression to adenocarcinoma with
gastric phenotype has been documented.60
Duodenal foveolar-type adenomas are very rare le-
sions,19,39,62 representing approximately 2.7% of duodenal
adenomas with gastric phenotype and have a median tumor
diameter of 9.7 mm (range, 8–20 mm). All of these lesions
are polypoid and histologically have a tubulovillous
architecture with tall columnar epithelium resembling
foveolar gastric epithelium with various degrees of dyspla-
sia19 (Figure 7). Immunohistochemically, they are composed
of MUC5AC-positive (Figure 7 [inset]) cells, rare MUC6-
positive cells, and complete absence of intestinal-type mucin
phenotype.19 Owing to their rare occurrence, little is known
about their molecular abnormalities.
Duodenal Serrated Adenoma With TSA-like Features
‘‘Traditional Serrated Adenoma of Duodenum’’
Duodenal serrated adenoma is a very rare type of
adenoma morphologically resembling serrated adenomas
of colorectum, but reportedly demonstrating different
380 Arch Pathol Lab Med—Vol 143, March 2019
molecular alterations and a more aggressive clinical
behavior.40,41
Clinical and Endoscopic Features.—Review of the
literature has identified approximately 73 serrated adenomas
with TSA-like features involving the upper GI tract
(esophagus [1], stomach [35], duodenum [35], pancreas
[1], and gallbladder [1]) with almost 53.4% demonstrating
HGD or association with adenocarcinoma.41,63 Currently,
approximately 36 serrated adenomas with TSA-like features
have been reported in the duodenum,40,63–66 with the largest
series consisting of 13 patients (12 serrated adenomas and 1
serrated adenocarcinoma) with a median age of 71 years and
a similar male to female ratio.40 Although slow growing,
these polyps have been associated with an aggressive
behavior, with almost 28.6% progressing to adenocarcino-
ma.40 Endoscopically, they appear as papillary lesions
varying in size from a few millimeters to a few centimeters.
Etiology and Pathogenesis.—The etiology and the
causes for their aggressive behavior are unknown; however,
some studies have raised the possibility that hyperplastic
polyps of the duodenum, especially those with KRAS
mutation, may represent a precursor lesion of serrated
adenomas with TSA-like features.27 More recently, Rubio41
has also proposed an alternative pathway of carcinogenesis
in which CpG island methylation phenotype (CIMP-high)
would play a pivotal role in the development of these polyps
independently of BRAF mutation.
Histopathology, Immunohistochemistry, and Molecu-
lar Characteristics.—Histologically, they are similar to
TSAs of the colorectum, featuring a prominent serration in
more than 50% of the polyp, ectopic crypt foci, and
predominance of cells with tall eosinophilic cytoplasm and
pencillate/pseudostratified nuclei41 (Figure 8, A and B). They
can demonstrate low- or high-grade dysplasia and may
progress to adenocarcinoma with serrated morphology63
(Figure 8, C and D). Furthermore, several examples with a
mixed TSA-like and adenomatous morphology have also
been described.65 Immunohistochemically, they demon-
strate an intestinal phenotype with expression of CDX2,
abnormal nuclear staining for b-catenin in 23% of cases, and
abnormal p53 expression in 31% of cases. MUC2 expression
is observed only in serrated adenomas containing goblets
cells (58%), and high Ki-67/MIB-1 expression is seen in 62%
of cases with HGD. As previously mentioned, expression of
CDX2 may be clinically useful in distinguishing benign
hyperplastic polyps (CDX2) from potentially aggressive
traditional serrated adenomas (CDX2þ).40 The molecular
profile is characterized by KRAS mutation in 38% of cases,
CpG island methylation phenotype (CIMP-high) in 50% of
cases, and MGMT (O(6)-methylguanine-DNA methyltrans-
ferase) in 8% of cases. Interestingly, no BRAFV600E mutation
or loss of expression of MLH1 was identified in any case.40
This molecular profile differs from that reported in TSAs of
the colon, in which BRAF mutation is identified in 67% of
cases and KRAS mutation in 22% of cases.67 These
preliminary results suggest that TSAs of duodenum do not
develop through the same serrated neoplasia pathway as in
the large bowel, in which CIMP-high and BRAF mutation
evolve concomitantly,68 but rather from an alternative TSA
pathway of carcinogenesis in which CIMP-high represents
an early and common molecular event independently of
BRAF mutation.40 Summarized in Tables 4 and 5 are the
main immunohistochemical and molecular features of the
above-discussed clinically significant duodenal epithelial
polyps.
Duodenal Epithelial Polyps: A Review—Collins & Ligato
Figure 8. Duodenal serrated adenoma with traditional serrated adenoma (TSA)–like features. A, Polyp with elongated fronds demonstrating a
serrated architecture with sawtooth pattern. B, On intermediate power, ectopic crypt formation (arrow) and low-grade pseudostratified nuclei with
eosinophilic cytoplasm resembling a TSA of colon are seen. C, Low-power view of duodenal serrated adenoma with high-grade dysplasia. D, High-
power view highlights the prominent pseudostratification and hyperchromasia of nuclei with loss of nuclear polarity (hematoxylin-eosin, original
magnifications 310 [A and C] and 320 [B and D]).
Figure 9. Duodenal neuroendocrine tumor. A, Submucosal tumor nests composed of tightly packed round cells with a rosette-like architecture
(inset). B, High-power view of another duodenal neuroendocrine tumor composed of small to medium-sized glands with eosinophilic and finely
granular cytoplasm, nuclei with stippled chromatin, and intraluminal microcalcifications. An immunostain for somatostatin (inset) shows positivity,
suggesting the diagnosis of somatostatinoma (hematoxylin-eosin, original magnifications 310 [A], 340 [A inset], and 320 [B]; original magnification
340 [B inset]).

Arch Pathol Lab Med—Vol 143, March 2019 Duodenal Epithelial Polyps: A Review—Collins & Ligato 381
 Table 4. Immunohistochemical Profile
MUC6 MUC5AC CD10 CDX2 MUC2
Brunner gland hyperplasia/hamartoma þþ (diffuse)    
Adenoma with pyloric gland phenotype þþ (diffuse) þ (patchy)a   þ (goblet cells)
Adenoma with foveolar gastric phenotype þ/ þþ (diffuse)   
Adenoma with intestinal phenotype   þ þ þ (goblet cells)
Hyperplastic polyps þþ (crypts) þ (surface)   þ (goblet cells)
Serrated adenoma with TSA-like features þþ (crypts) þ/ (surface) þ/ þþ þ (goblet cells)
Abbreviations: TSA, traditional serrated adenoma; þ, positive; , negative.
a
Surface epithelium and focally underlying glands.

Prognosis and Treatment.—Because of their rarity, the
natural history, prognosis, and appropriate clinical man-
agement is unclear. However, the high frequency of HGD
suggests that these serrated adenomas may represent
aggressive lesions with high malignant potential. Conse-
quently, the recommendation is for a complete removal by
either endoscopic or surgical procedures to rule out the
possibility of a synchronously growing invasive carcinoma
or to prevent cancer progression.
NEUROENDOCRINE TUMORS
Clinical and Endoscopic Features.—Intestinal neuro-
endocrine tumors (carcinoids) are most commonly encoun-
tered in the ileum,69 with only less than 5% localized in the
duodenum and ampulla.70
They present usually as subepithelial polypoid lesions
ranging from 1 to 2 cm in diameter. Endoscopically, they
appear as a white or yellow polyp-like lesion with central
dimpling or ulceration.71 They are often clinically ‘‘silent’’
tumors but hormonal expression can be identified by
immunohistochemistry. Occasionally, they can be func-
tional and associated with clinical syndromes due to
hormone hypersecretion, such as the gastrinoma.71 Based
on the World Health Organization 2010 classification
scheme, neuroendocrine tumors of duodenum are classi-
fied as malignant tumors and graded as low grade (grade
1), intermediate grade (grade 2), neuroendocrine carcino-
mas (grade 3), and mixed adenoneuroendocrine carcino-
mas. The grading system of these neoplasms is based on
the mitotic rate and Ki-67 labeling index, as described in
Table 6.72
Gastrin-producing neuroendocrine tumors (gastrinomas)
are the most common neuroendocrine tumors of the
duodenum (62%). They may occur sporadically or in
association with multiple neuroendocrine neoplasia type 1
(MEN-1) syndrome and are often associated with Zollinger-
Ellison syndrome. They may be multicentric, deeply
infiltrating and even when small (,1 cm) can demonstrate
an aggressive behavior with lymph node metastasis (5%–
10% of cases), especially if functional.72
Histopathology.—Duodenal gastrinoma exhibits rib-
bons, insular, or trabecular patterns of growth, and
occasional rosetting. The nuclei are usually centrally located
and demonstrate a fine stippled ‘‘salt and pepper’’
chromatin (Figure 9, A, and inset). Nucleoli are infrequent
and usually only rare mitoses are observed. The cells are
immunoreactive for chromogranin A and synaptophysin is
positive only in about 50% of cases.
Duodenal somatostatinoma is the second most common
(18%) neuroendocrine tumor of the duodenum and is
associated with neurofibromatosis type 1 in one-third of
cases. In contrast to pancreatic somatostatinoma, the
duodenal somatostatinoma is usually nonfunctioning,
presents with abdominal pain, nausea, or obstructive
jaundice. However, rarely it may be functional and
associated with the clinical triad of diabetes mellitus,
cholelithiasis, and steatorrhea.73 Histologically, it demon-
strates a glandular or tubular architecture with intraluminal
psammomatous calcifications and can be mistaken for a
metastatic carcinoma. The cells are immunoreactive for
chromogranin A, synaptophysin, and somatostatin74 (Fig-
ure 9, B, and inset).
Duodenal/ampullary gangliocytic paragangliomas are rare
(9%) neoplasms also included as neuroendocrine tumors of
the duodenum. In a review of the literature, Okubo et al75
identified 192 cases with an age range from 15 years to 84
years (mean, 52.3 years) and a size range from 5.5 to 100
mm (mean, 25 mm). They may be asymptomatic or present
with GI bleeding (45.1%), abdominal pain (42.8%), and
anemia (14.5%).75 Endoscopically, they may present as
sessile submucosal nodules or as subepithelial pedunculated
polyps (Figure 10, A). Histologically, they are triphasic
tumors containing a mixture of spindle cells (often positive
for S100, chromogranin, and synaptophysin), epithelial cells
organized in nests (staining for chromogranin and synapto-
physin), and ganglion-type cells, which stain for neuro-

Table 5. Molecular Profile

BRAF KRAS GNAS MGMT CIMP-H APC
Ectopic gastric mucosa  þ/ þ   
Adenoma with pyloric gastric phenotype  þþ þþ Unknown Unknown 
Adenoma with foveolar gastric phenotype Unknown Unknown Unknown Unknown Unknown Unknown
Adenoma with intestinal phenotype  þþ  þ/ þ/ þþ
Hyperplastic polyps þ þ Unknown Unknown Unknown Unknown
Serrated adenoma with TSA-like features  þ Unknown þ þþ Unknown
Abbreviations: APC, adenomatous polyposis coli; CIMP-H, CpG island methylator phenotype-high; MGMT, O(6)-methylguanine-DNA
methyltransferase; TSA, traditional serrated adenoma; þ, positive; , negative.
382 Arch Pathol Lab Med—Vol 143, March 2019 Duodenal Epithelial Polyps: A Review—Collins & Ligato
 Table 6. World Health Organization 2010 regional lymph nodes in 25% to 50% of cases, mainly
Classification of Neuroendocrine Tumors (NETs) in attributable to the endocrine component of the lesion.76
the Gastrointestinal and Pancreatobiliary Tract Ampullary neuroendocrine tumors appear to have a more
aggressive behavior than nonampullary neuroendocrine
Mitotic Count/ Ki-67 Labeling
Grade 10 HPFs Index, % tumors; in fact they generally are higher-grade tumors with
a clinical presentation often characterized by obstructive
NET, grade 1 ,2 ,3 jaundice due to compression or obstruction of the ampulla.76
NET, grade 2 2–20 3–20 Treatment.—Neuroendocrine tumors up to 2 cm in size
NEC, grade 3 .20 .20 that are limited to the submucosa and without lymph node
Abbreviations: HPF, high-power field; NEC, neuroendocrine carcino- metastasis can be removed endoscopically. In situations of
ma.
multifocality or larger duodenal neuroendocrine tumors,
surgery will be required.
markers such as neurofilament and Hu protein, but also for In conclusion, it is our hope that this review will be a
many neuroendocrine markers75 (Figure 10, B through E). useful resource for the clinician and surgical pathologist in
Although most duodenal gangliocytic paragangliomas the diagnosis, risk stratification, and treatment of common
have a good prognosis, if they involve the muscular wall and relatively uncommon duodenal epithelial polyps en-
and have a size greater than 2 cm, they can metastasize to countered in daily practice.

Figure 10. Duodenal gangliocytic paraganglioma. A, Endoscopic view showing a pedunculated polyp (arrow). B, Low-power microscopic view of
submucosa multinodular lesion. C, Higher-power view: the lesion consists of a spindle cell component (left side) with isolated ganglion cells (arrow)
and clusters of epithelioid cells (right side). D, Immunostaining for S100 shows positivity in the spindle cells. E, Chromogranin highlights the
epithelioid and ganglion cells (arrow) (hematoxylin-eosin, original magnifications 34 [B] and 310 [C]; original magnification 34 [D and E]).
Arch Pathol Lab Med—Vol 143, March 2019 Duodenal Epithelial Polyps: A Review—Collins & Ligato 383
 References
1. Maruoka D, Matsumura T, Kasamatsu S, et al. Cold polypectomy for
duodenal adenomas: a prospective clinical trial. Endoscopy. 2017;49(8):776–
783.
2. Riddell R, Jain D. Lewin, Weinstein, and Riddell’s Gastrointestinal Pathology
and Its Clinical Implications. Vol 2. 2nd ed. Philadelphia, PA: Wolters Kluwer/
Lippincott Williams & Wilkins Health; 2014:1331–1335.
3. Terada T. Pathologic observations of the duodenum in 615 consecutive
duodenal specimens: I, benign lesions. Int J Clin Exp Pathol. 2012;5(1):46–51.
4. Jung SH, Chung WC, Kim EJ, et al. Evaluation of non-ampullary duodenal
polyps: comparison of non-neoplastic and neoplastic lesions. World J Gastro-
enterol. 2010;16(43):5474–5480.
5. Gupta V, Gupta P, Jain A. Giant Brunner’s gland adenoma of the duodenal
bulb presenting with ampullary and duodenal obstruction mimicking pancreatic
malignancy. JOP. 2011;12(4):413–419.
6. Gao Y-P, Shu J-S, Zheng W-J. Brunner’s gland adenoma of duodenum: a
case report and literature review. World J Gastroenterol. 2004;10(17):2616–2617.
7. So CS, Jang HJ, Choi YS, et al. Giant brunner’s gland adenoma of the
proximal jejunum presenting as iron deficiency anemia and mimicking
intussusceptions. Clin Endosc. 2013;46(1):102–105.
8. Kim K, Jan SJ, Song HJ, Yu E. Clinicopathologic characteristics and mucin
expression in Brunner’s gland proliferating lesions. Dig Dis Sci. 2013;58(1):194–
201.
9. Odze RD, Goldblum JR. Surgical Pathology of the GI Tract, Liver, Biliary
Tract, and Pancreas. 3rd ed. Philadelphia, PA: Saunders; 2014:582.
10. Paimela H, Tallgren LG, Stenman S, von Numers H, Scheinin TM. Multiple
duodenal polyps in uraemia: a little known clinical entity. Gut. 1984;25(3):259–
263.
11. Vieth M, Montgomery EA. Some observations on pyloric gland adenoma:
an uncommon and long ignored entity. J Clin Pathol. 2014;67(10):883–890.
12. Suda K, Hamada S, Takahashi, et al. A true Brunner’s gland adenoma.
Endoscopy. 2007;39(suppl 1):E37–E38.
13. Wang Y, Shi C, Lu Y, Poulin EJ, Franklin JL, Coffey RJ. Loss of Lrig1 leads to
expansion of Brunner glands followed by duodenal adenomas with gastric
metaplasia. Am J Pathol. 2015;185(4):1123–1134.
14. Pehlivanoglu B, Xue Y, Reid M, et al. ‘‘Brunner gland/duct cysts’’ with
dysplasia: further characterization of a distinctive lesion in the duodenum of
probable precursor nature (abstract No. 828). Mod Pathol. 2018(S2);31:295–296.
15. Brown IS, Miller GC. Brunner’s gland cyst: a clinicopathological study of 25
cases highlighting an underappreciated lesion. Pathology. 2017;49(5):476–478.
16. Powers M, Sayuk GS, Wang HL. Brunner gland cyst: report of three cases.
Int J Clin Exp Pathol. 2008;1(6):536–538.
17. Alpert L, Whitcomb E, Westerhoff M, Hart J, Xiao S-Y. Brunner gland duct
adenoma mimichking pancreatic intraductal papillary mucinous neoplasm
(abstract No. 572). Mod Pathol. 2015;28(S2):145A–146A.
18. Rubio CA. Gastric duodenal metaplasia in duodenal adenomas. J Clin
Pathol. 2007;60(6):661–663.
19. Mitsuishi T, Hamatani S, Hirooka S, et al. Clinicopathological character-
istics of duodenal epithelial neoplasms: focus on tumors with a gastric mucin
phenotype (pyloric gland-type tumors). PLoS One. 2017;12(4):e0174985.
20. Matsubara A, Ogawa R, Suzuki H, et al. Activating GNAS and KRAS
mutations in gastric foveolar metaplasia, gastric heterotopia, and adenocarcino-
ma of the duodenum. Br J Cancer. 2014;112(8):1398–1404.
21. Armstrong CP, King PM, Dixon JM, Macleod IB. The clinical significance of
heterotopic pancreas in the gastrointestinal tract. Br J Surg. 1981;68(6):384–387.
22. Jun S-Y, Son D, Kim M-J, et al. Heterotopic pancreas of the gastrointestinal
tract and associated precursor and cancerous lesions: systemic pathologic studies
of 165 cases. Am J Surg Pathol. 2017;41(6):833–848.
23. Von Heinrich H. Ein peitrang zur histrologie des sogen akzessorischen
pancreas. Virchows Arch. 1909;198:392–401.
24. Gaspar Fuentes A, Campos Tarrech JM, Fernandez Burgui J, et al. Ectopias
pancreáticas. Rev Esp Enferm Apar Dig. 1973;39(1):255–268.
25. Bromberg SH, Camilo Neto C, Borges AFA, et al. Pancreatic heterotopias:
clinical pathological analysis of 18 patients. Rev Col Bras Cir. 2010;37(6):413–
419.
26. Roche HJ, Carr NJ, Laing H, Bateman AC. Hyperplastic polyps of the
duodenum: an unusual histological finding. J Clin Pathol. 2006;59(12):1305–
1306.
27. Rosty C, Buchanan DD, Walters RJ, et al. Hyperplastic polyp of the
duodenum: a report of 9 cases with immunohistochemical and molecular
findings. Hum Pathol. 2011;42(12):1953–1959.
28. Franzin G, Novelli P, Fratton A. Hyperplastic and metaplastic polyps of the
duodenum. Gastrointest Endosc. 1983;29(2):140–141.
29. Sarbia M, Jüttner S, Bettstetter M, Berndt R. Serrated polyps of the
duodenum: three cases with immunohistological and molecular pathological
findings. Pathologe. 2013;34(4):347–351.
30. Katawaratumi H, Tsujimoto T, Nishimura N, et al. A case of lobulated and
pedunculated duodenal hyperplasia polyp treated with snare polypectomy. Case
Rep Gastroenterol. 2011;5(2):404–410.
31. O’Brien MJ, Yang S, Mack C, et al. Comparison of microsatellite instability,
CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and
traditional adenomas indicates separate pathways to distinct colorectal carcino-
ma end points. Am J Surg Pathol. 2006;30(12):1491–1501.
32. Remmele W, Hartmann W, von der Laden U, et al. Three other types of
duodenal polyps: mucosal cysts, focal foveolar hyperplasia, and hyperplastic
384 Arch Pathol Lab Med—Vol 143, March 2019
polyp originating from islands of gastric mucosa. Dig Dis Sci. 1989;34(9):1468–
1472.
33. Liu X, Chen D, Dugum M, Horvath B, Yuan L, Xiao S-Y. Syndromic and
sporadic inflammatory/hyperplastic small-bowel polyps: a comparative study.
Gastroenterol Rep. 2015;3(3):222–227.
34. Sekino Y, Inamori M, Hirai M, et al. Solitary Peutz-Jeghers type
hamartomatous polyps in the duodenum are not always associated with a low
risk of cancer: two case reports. J Med Case Rep. 2011;5:240.
35. Gaspar JP, Stelow EB, Wang AY. Approach to the endoscopic resection of
duodenal lesions. World J Gastroenterol. 2016;22(2):600–617.
36. Saito K, Nomura E, Sasaki Y, et al. Characteristics of small bowel polyps
detected in Cowden syndrome by capsule endoscopy. Case Rep Gastrointest
Med. 2015;125:Article 475705.
37. Huber AR, Findeis-Hosey JJ, Whitney-Miller CL. Hereditary gastrointestinal
polyposis syndromes: a review including newly identified syndromes. J Gastroint
Dig Syst. 2013;3:155.
38. Slavik T, Montgomery EA. Cronkhite–Canada syndrome six decades on: the
many faces of an enigmatic disease. J Clin Pathol. 2014;67(10):891–897.
39. Hijikata K, Nemoto T, Igarashi Y, Shibuya K. Extra-ampullary duodenal
adenoma: a clinicopathological study. Histopathology. 2017;71(2):200–207.
40. Rosty C, Campbell C, Clendenning M, Bettington M, Buchanan D, Brown I.
Do serrated neoplasms of the small intestine represent a distinct entity:
pathological findings and molecular alterations in a series of 13 cases.
Histopathology. 2015;66(3):333–342.
41. Rubio C. Traditional serrated adenomas of the upper digestive tract. J Clin
Pathol. 2016;69(1):1–5.
42. Lim C-H, Cho Y-S. Nonampullary duodenal adenoma: current understand-
ing of its diagnosis, pathogenesis, and clinical management. World J Gastro-
enterol. 2016;22(2):853–861.
43. Okada K, Fujisaki J, Kasuga A, et al. Sporadic nonampullary duodenal
adenoma in the natural history of duodenal cancer: a study of follow-up
surveillance. Am J Gastroenterol. 2011;106(2):357–364.
44. Bulow S, Björk J, Christensen IJ, et al. Duodenal adenomatosis in familial
adenomatous polyposis. Gut. 2004;53(3):381–3816.
45. Wagner PL, Chen Y-T, Yantiss R. Immunohistochemical and molecular
features of sporadic and FAP-associated duodenal adenomas of the ampullary
and nonampullary mucosa. Am J Surg Pathol. 2008;32(9):1388–1395.
46. Spigelman AD, Williams CB, Talbot IC, Domizio P, Phillips RK. Upper
gastrointestinal cancer in patients with familial adenomatous polyposis. Lancet.
1989;2(8666):783–785.
47. Saurin JC, Gutknecht C, Napoleon B, et al. Surveillance of duodenal
adenomas in familial adenomatous polyposis reveals high cumulative risk of
advanced disease. J Clin Oncol. 2004:22(3):493–498.
48. Groves CJ, Saunders BP, Spigelman AD, Phillips RKS. Duodenal cancer in
patients with familial adenomatous polyposis (FAP): results of a 10 year
prospective study. Gut. 2002;50:636–641.
49. Xue Y, Vanoli A, Balci S, et al. Non-ampullary-duodenal carcinomas:
clinicopathologic analysis of 47 cases and comparison with ampullary and
pancreatic adenocarcinomas. Mod Pathol. 2017;30(2):255–266.
50. Chen ZM, Scudiere JR, Abraham SC, Montgomery E. Pyloric gland
adenoma: an entity distinct from gastric foveolar type adenoma. Am J Surg Pathol.
2009;33(2):186–193.
51. Vieth M, Kushima R, Borchard, Stotle M. Pyloric gland adenoma: a clinic-
pathological analysis of 90 cases. Virchows Arch. 2003;442(4):317–321.
52. Vieth M, Kushima R, de Jonge JPA, Borchard F, Oellig F, Stolte M. Adenoma
with gastric differentiation (so-called pyloric gland adenoma) in a heterotopic
gastric corpus mucosa in the rectum. Virchows Arch. 2005;446(5):542–545.
53. Kushima R, Rüthlein HJ, Stolte M, Bamba M, Hattori T, Borcahrd F. ‘Pyloric
gland-type adenoma’ arising in heterotopic gastric mucosa of the duodenum,
with dysplastic progression of the gastric type. Virchows Arch. 1999;435(4):452–
457.
54. Wood LD, Salaria SN, Cruise MW, Giardiello FM, Montgomery EA. Upper
GI tract lesions in familial adenomatous polyposis (FAP) enrichment of pyloric
gland adenomas and other gastric and duodenal neoplasms. Am J Surg Pathol.
2014;38(3):389–393.
55. Lee SE, Kang SY, Cho J, et al. Pyloric gland adenoma in Lynch syndrome.
Am J Surg Pathol. 2014;38(6):784–792.
56. Sakurai T, Sakashita H, Honjo G, Kasyu I, Manabe T. Gastric foveolar
metaplasia with dysplastic changes in Brunner gland hyperplasia: possible
precursor lesions for Brunner gland adenocarcinoma. Am J Surg Pathol. 2005;
29(11):1442–1448.
57. Vieth M, Vogel C, Kushima R, Borchard F, Stolte M. Pyloric gland
adenoma—how to diagnose? Cesk Patol. 2006;42(1):4–7.
58. Chlumská A, Waloschek T, Mukenšnabl P, Martı́nek P, Kašpı́rková J,
Zámečnı́k M. Pyloric gland adenoma: a histologic, immunohistochemical and
molecular genetic study of 23 cases. Cesk Patol. 2015;51(3):137–143.
59. Hida R, Yamamoto H, Hirahashi M, et al. Duodenal neoplasms of gastric
phenotype: an immunohistochemical and genetic study with a practical
approach to the classification. Am J Surg Pathol. 2017;41(3):343–353.
60. Ushiku T, Arnason T, Fukayama M, Lauwers GY. Extra-ampullary duodenal
adenocarcinoma. Am J Surg Pathol. 2014;38(11):1484–1493.
61. Reid MD, Balci S, Ohike N, Xue Y, et al. Ampullary carcinoma is often of
mixed or hybrid histologic type: an analysis of reproducibility and clinical
relevance of classification as pancreatobiliary versus intestinal in 232 cases. Mod
Pathol. 2016;29(12):1575–1585.
Duodenal Epithelial Polyps: A Review—Collins & Ligato
 62. Fujisawa T, Horimatsu T, Sakaguchi K, et al. Duodenal adenoma of gastric
foveolar phenotype in the second portion of the duodenum. Dig Endosc. 2006:
18(1):62–66.
63. Park YK, Jeong WJ, Cheon GJ. Slow-growing early adenocarcinoma arising
from traditional serrated adenoma in the duodenum. Case Rep Gastroenterol.
2016;10(2):257–263.
64. Srivastava A, Rege TA, Kim KM, et al. Duodenal serrated adenomas:
evidence for serrated carcinogenesis in the proximal small intestine (abstract No.
705). Mod Pathol. 2000;13:103–106.
65. Taggart M, Rashid A, Estrella J, et al. Serrated polyps of the extracolonic
gastrointestinal tract. Histologic findings and genetic alterations (abstract No.
753). Mod Pathol. 2000;13:212–214.
66. Rubio CA. Serrated adenoma of the duodenum. J Clin Pathol. 2004;57(11):
1219–1221.
67. Bettington ML, Walker NI, Rosty C, et al. A clinicopathological and
molecular analysis of 200 traditional serrated adenomas. Mod Pathol. 2015;
28(3):414–427.
68. Weisenberger DJ, Siegmund KD, Campan M, et al. CpG island methylator
phenotype underlies sporadic microsatellite instability and is tightly associated
with BRAF mutation in colorectal cancer. Nat Genet. 2006;38(7):787–793.
69. Maggard MA, O’Connell JB, Ko CY. Updated population-based review of
carcinoid tumors. Ann Surg. 2004;240(1):117–122.
70. Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid tumors.
Cancer. 1997;79(4):813–829.
71. Grin A, Streutker CJ. Neuroendocrine tumors of the luminal gastrointestinal
tract. Arch Pathol Lab Med. 2015;139(6):750–756.
72. Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. WHO Classification of
Tumours of the Digestive System. 4th ed. Lyon, France: IARC Press; 2010:102.
World Health Organization Classification of Tumours; vol 3.
73. Krejs GJ, Orci LO, Conlin JM, et al. Somatostatinoma syndrome—
biochemical, morphologic and clinical features. N Engl J Med. 1979;301(6):285–
292.
74. Randle RW, Ahmed S, Newman NA, Clark CJ. Clinical outcomes for
neuroendocrine tumors of the duodenum and ampulla of Vater: a population-
based study. J Gastrointest Surg. 2014;18(2):354–362.
75. Okubo Y, Wakayama M, Nemoto T, et al. Literature survey on epidemiology
and pathology of gangliocytic paraganglioma. BMC Cancer. 2011;11:187.
76. Park HK, Han HS. Duodenal gangliocytic paraganglioma with lymph node
metastasis. Arch Pathol Lab Med. 2016;140(1):94–98.

CAP19 Abstract Program

Submission Deadline Approaching
Abstract and case study submissions to the College of American Pathologists (CAP) 2019 Abstract
Program are now being accepted. Pathologists, laboratory professionals, and researchers in related fields
are encouraged to submit original studies for possible poster presentation at the CAP19 meeting.

Submissions will be accepted until 5 p.m. Central Friday, March 8, 2019. Accepted abstracts and case
studies will appear on the Archives of Pathology & Laboratory Medicine Web site as a Web-only
supplement to the September 2019 issue.

Visit the CAP19 Web site (www.thepathologistsmeeting.org) or the Archives Web site (www.
archivesofpathology.org) for additional abstract program information including a link to the submission
site.

Arch Pathol Lab Med—Vol 143, March 2019 Duodenal Epithelial Polyps: A Review—Collins & Ligato 385