REVIEW

Brunner’s Gland Hamartoma of the Duodenum:A Literature Review

Menghua Zhu . Hongyu Li . Yanyan Wu . Yang An . Yuye Wang .

Chun Ye . Dan Zhang . Rui Ma . Xuehan Wang . Xiaodong Shao .

Xiaozhong Guo . Xingshun Qi

Received: March 18, 2021 / Accepted: April 15, 2021 / Published online: April 29, 2021� The Author(s) 2021

ABSTRACT

Brunner’s gland hamartoma is a benign tumorof the duodenum, but has malignant potentialwith a very low risk of progression into adeno-carcinoma. It is uncommon with a frequency ofless than 1.0% among the primary tumors ofthe small intestine. In addition, its clinicalmanifestations are nonspecific, etiologyremains unclear, and treatment strategy needs

to be further refined. This literature reviewmainly discusses the epidemiology, clinicalfeatures, possible etiology and pathogenesis,diagnostic methods, malignant potential,treatment, and prognosis of Brunner’s glandhamartoma.

Keywords: Brunner’s gland; Duodenum;Etiology; Hamartoma; Hyperplasia

Menghua Zhu and Hongyu Li are co-first authors.

M. Zhu � H. Li � Y. Wu � Y. An � Y. Wang � X. Shao(&) � X. Guo (&) � X. Qi (&)Department of Gastroenterology, General Hospitalof Northern Theater Command (Formerly GeneralHospital of Shenyang Military Area), No. 83Wenhua Road, Shenyang 110840, LiaoningProvince, People’s Republic of Chinae-mail: sxdsys608@189.cn

X. Guoe-mail: guo_xiao_zhong@126.com

X. Qie-mail: xingshunqi@126.com

M. Zhu � Y. Wu � Y. WangPostgraduate College, Jinzhou Medical University,Jinzhou, People’s Republic of China

Y. AnPostgraduate College, Shenyang PharmaceuticalUniversity, Shenyang, People’s Republic of China

C. Ye � D. Zhang � R. MaDepartment of General Surgery, General Hospital ofNorthern Theater Command (Formerly GeneralHospital of Shenyang Military Area), No. 83Wenhua Road, Shenyang 110840, LiaoningProvince, People’s Republic of China

X. WangDepartment of Pathology, General Hospital ofNorthern Theater Command (Formerly GeneralHospital of Shenyang Military Area), No. 83Wenhua Road, Shenyang 110840, LiaoningProvince, People’s Republic of China

Adv Ther (2021) 38:2779–2794

https://doi.org/10.1007/s12325-021-01750-6

Key Summary Points

Why carry out this study?

Duodenal Brunner’s gland hamartoma is arare benign tumor, which accounts for lessthan 1% of the primary tumors of thesmall intestine, and usually does notproduce clinical symptoms.

Its clinical manifestations are nonspecific,etiology remains unclear, and treatmentstrategy needs to be further refined.

Endoscopic biopsies are mostly negative,because the mass is often covered byintact duodenal mucosa, and the depth ofbiopsy is usually insufficient to reach thetumor tissue located in the submucosa.

This lesion has been insufficientlyrecognized.

What was learned from the study?

Brunner’s gland hamartoma often refers toa benign proliferative lesion of theduodenum.

Underlying risk factors of Brunner’s glandhamartoma include high gastric acidsecretion, Helicobacter pylori infection,chronic pancreatitis, inflammatorystimulation, mucosal injury, etc.

Endoscopic ultrasonographic features areas follows: mucosal and submucosalinvolvement, variable echogenicity(sometimes mixed with hypoechoic), andmultiple cystic changes inside the tumor.Endoscopic ultrasonography-guided fine-needle aspiration can improve thediagnostic accuracy of Brunner’s glandhamartoma.

With the growth of benign proliferativelesions of Brunner’s glands, mucosalulcers may develop, thereby leading to therepair of gastric foveolar metaplasia withpapillary architecture and then malignanttransformation.

For asymptomatic patients with Brunner’sgland hamartoma, conservative treatmentof small lesions is acceptable, whileexcision of large lesions is recommendedto prevent bleeding and obstruction. Forsymptomatic patients, endoscopic orsurgical resection should be considered.

DIGITAL FEATURES

This article is published with digital features,including a summary slide and slide deck, tofacilitate understanding of the article. To viewdigital features for this article, go to https://doi.org/10.6084/m9.figshare.14406650.

INTRODUCTION

Brunner’s glands are branched acinotubularglands which are mainly located in the deepmucosal or submucosal layers of the proximalduodemum [1] and their size and number areremarkably decreased at the distal duodenum[2, 3]. In some cases, Brunner’s glands extend tothe proximal jejunum [4]. The main function ofBrunner’s glands is to secrete alkaline sub-stances and bicarbonate to neutralize acidicchyme and gastric acid in the stomach, and toproduce and secrete urinary suppressant toinhibit gastric acid secretion [5], which canprotect the integrity of duodenal mucosalepithelium and maintain an alkaline environ-ment in the small intestine for intestinalabsorption [6]. Brunner’s glands appear fromthe 13th to 14th weeks of embryonic develop-ment [2, 3]. Prevalence of Brunner’s glands inthe duodenum is decreasing from 55.0% ininfancy to 35.0% in persons aged 50 years old[3].

Brunner’s gland hyperplasia and hamartomaare benign proliferative lesions of the duode-num. Brunner’s gland hyperplasia is mostly alesion of less than 0.5 cm, which is character-ized as neutral mucin-containing glandsexpanding at least 50.0% of duodenal mucosain a biopsy specimen [1, 7]; by comparison,Brunner’s gland hamartoma, also called as

2780 Adv Ther (2021) 38:2779–2794

Brunner’s gland adenoma, is usually a lesion ofgreater than 0.5 cm regardless of number oflesions [2, 6], which refers to these proliferativeglands involving duodenal submucosa, mixedwith cystically dilated glands and smoothmuscle proliferation [8]. The fundamental dif-ference between them lies in the admixture ofother benign component (smooth musclefibers) with glands to be qualified as ‘‘hamar-toma’’. A majority of Brunner’s gland hamar-tomas are isolated pedunculated polyps, and aminority of them are sessile polyps. Theirdiameter varies from 1.0 to 2.0 cm, rarely largerthan 5.0 cm and even up to 12.0 cm [5, 9]. Mostof the lesions are located at the proximal duo-denum, and their occurrence gradually decrea-ses with an increase in the distance from thepyloric ring: 57.0% in the duodenal bulb, 27.0%in the descending part, and 7.0% in the hori-zontal part [4]. Histologically, Brunner’s glandhyperplasia is a single or multiple nodularlesion of excessive Brunner’s glands separatedby fibrous septa. Brunner’s gland hamartoma isan isolated mass, which contains a mixture ofBrunner’s glands, ducts, smooth muscle, fibroustissue, adipose tissue, lymphocytes, etc.[2, 10, 11]. In 1934, Dr. Feyrter for the first timeclassified these proliferative lesions of Brunner’sglands into three types: type 1, diffuse nodularhyperplasia with sessile projections distributedamong most of the duodenal area; type 2, cir-cumscribed nodular hyperplasia with sessileprojections limited to the duodenal bulb; andtype 3, glandular adenoma with pedunculatedor sessile polypoid mass. However, it remainsunclear whether all three types undergo thesame pathological process [3, 12].

EPIDEMIOLOGY

Brunner’s gland hamartoma is rare with a fre-quency of 5.0–10.0% [3, 11, 13] in benignduodenal tumors and less than 1.0% [14] inprimary tumors of the small intestine. Amongthe patients who undergo routine esopha-gogastroduodenoscopy (EGD) examination,Brunner’s gland hamartoma can be found in0.01–0.07% [14] and Brunner’s gland hyper-plasia in 0.3% [15]. Brunner’s gland hamartoma

has no remarkable preference for race or gender[3], but it is more common in people between50 and 70 years old [3, 5].

ETIOLOGY AND PATHOGENESIS

The etiology and pathogenesis of Brunner’sgland hamartoma remain unclear. The mostplausible hypothesis holds that the essence ofhamartoma is embryonic dysplasia of the duo-denum [9, 16]. Other underlying risk factorsinclude high gastric acid secretion, Helicobacterpylori (Hp) infection, chronic pancreatitis,inflammatory stimulation, mucosal injury, etc.(Fig. 1).

It is often believed that high gastric acidsecretion can stimulate glandular hyperplasia,considering that Brunner’s glands can secretealkaline mucus [3, 5, 17]. Among the patientswith duodenal ulcer, Brunner’s glands usuallybecome proliferatively thickened, especiallynear the ulcers [18], suggesting that excessivesecretion of gastric acid may play a role in thepathogenesis of Brunner’s gland hamartoma.However, the conclusion is a bit controversial. Astudy involving 20 patients with confirmedBrunner’s gland hamartoma or hyperplasiarevealed that only 45.0% of these patients hadhyperchlorhydria [19]. In addition, acid inhibi-tors could not eliminate this lesion [20].Therefore, the causal relationship between highgastric acid secretion and these lesions shouldbe further confirmed.

Another hypothesis is that Hp infection maycontribute to the pathogenesis of Brunner’sgland hamartoma. Three studies found thatpatients with Brunner’s gland hyperplasia orhamartoma have a high positive Hp infectionrate of 56.6–71.0% [21–23], but another studyreported that none had Hp infection [10](Table 1). Thus, it is necessary to further analyzethe relationship of Hp infection with Brunner’sgland hamartoma.

Stolte et al. [24] put forward chronic pan-creatitis as a contributing factor of Brunner’sgland hyperplasia in 1981. Pathological analy-ses found that 75.7% of patients with chronicpancreatitis had diffuse nodular hyperplasia ofBrunner’s gland [24]. This might be attributed

Adv Ther (2021) 38:2779–2794 2781

to adaptive response to pancreatic exocrineinsufficiency [25]. In addition, Brunner’s glandhamartoma has vast lymphocyte infiltration onhistology, which supports the ‘‘inflammatoryhypothesis’’ that the lesion may be secondary toinflammatory stimulation [25]. But the presenceof lymphocytes in the normal gastrointestinalsubmucosa compromises this hypothesis [5].

Brunner’s gland hamartoma is often associ-ated with gastric foveolar metaplasia, which isan indispensable mechanism of mucosal repairin duodenal ulcer lesions. Therefore, it is con-sidered that repeated mucosal injury activatesmucosal repair and promotes the occurrence ofthis disease. Mechanical stimulation, Hp infec-tion, and a highly acidic environment in theduodenum may cause mucosal injury together[26].

Collectively, this disease may be associatedwith multiple risk factors, which still need to besupported by more epidemiological evidenceand strict pathological confirmation.

CLINICAL MANIFESTATIONS

Most patients with Brunner’s gland hamartomaare asymptomatic, and the clinical manifesta-tions of symptomatic patients are nonspecific,including dyspepsia, abdominal distension,abdominal pain, nausea, vomiting, gastroin-testinal bleeding and obstruction, iron defi-ciency anemia, etc. [16, 17, 27] (Table 2).Among them, gastrointestinal bleeding andobstruction are the major causes for seekingmedical treatment [28].

Melena and hematemesis may occur whenthere is ulceration or tumor vascular erosion,and these manifestations are related to the sizeand location of lesions [25]. The average size ofhamartoma is 2.8 cm in patients who developgastrointestinal bleeding [28]. Lesions located atdescending and horizontal parts of the duode-num have a higher bleeding tendency as com-pared to those located at the bulb part, probablyas a result of higher pressure from digestive tractmovement and vascular damage in thedescending and horizontal parts [28, 29].

Gastrointestinal obstruction occurs whenthe nodules of Brunner’s gland hyperplasia arediffuse or the size of a single hamartoma is largeenough (the average diameter should be greaterthan 2.1 cm) [28], which can present withabdominal distension, abdominal pain, nausea,vomiting, and weight loss [1, 30]. Generally, itis more related to large hamartoma than diffusehyperplasia. Krishnamurthy et al. [11] reviewed16 cases with gastrointestinal obstruction

Fig. 1 Underlying risk factors of Brunner’s glandhamartoma

Table 1 Helicobacter pylori (Hp) infection in Brunner’sgland proliferating lesions

Firstauthor(year)

Number ofpatients in total

Hp infection (1)

Number ofpatients

Frequency

Destek

(2019)

18 12 67.0%

Kim

(2012)

25 0 0

Sakurai

(2005)

129 73 56.6%

Kovacevic

(2001)

7 5 71.0%

2782 Adv Ther (2021) 38:2779–2794

Table2

Mainclinicalfeatures

ofpatientswithBrunn

er’sglandhamartoma:an

overview

ofliterature

Firstauthor

(year)

Sex

Age

(years)

Com

plaint

Location

Shape

Size

(cm)

Diagnosis

Treatment

Com

plication

Outcome

Walden(1998)

Male

28Melena,

exertional

dyspnea

Duodenalbulb

Pedunculated

polyp

4.09

2.59

2.0

Brunn

er’s

gland

hamartoma

End

oscopicresection

Uneventful

Asymptom

atic

with

14months

follow-up

Rocco

(2006)

Female

58Epigastric

discom

fort

Duodenalbulb

Pedunculated

polyp

3.09

4.0

Brunn

er’s

gland

hamartoma

End

oscopicresection

Uneventful

Asymptom

atic

with

6months

follow-up

Gao

(2004)

Male

32Epigastric

discom

fort,

melena

Duodenalbulb

Pedunculated

polyp

3.59

3.09

2.0

Brunn

er’s

gland

hamartoma

Surgicalresection

Uneventful

Asymptom

atic

at postoperative

period

Rana(2019)

Male

76Vom

iting,

melena

Duodenal

descending

Pedunculated

polypwith

multiple

ulcerson

surface

10.0–1

2.09

3.59

1.5

Brunn

er’s

gland

hamartoma

End

oscopicresection

NA

NA

Peloso

(2017)

Male

72Epigastricpain,

vomiting

Duodenal

descending-

horizontal

junction

Broad-based

lesion

4.0

Brunn

er’s

gland

hamartoma

Polypexcision

via

duodenotom

yUneventful

Asymptom

atic

at postoperative

period

Akaki

(2014)

Male

26Melena,anem

iaGastroduodenal

junction

Pedunculated

polyp

6.49

3.0

Brunn

er’s

gland

hamartoma

Distalgastrectom

yUneventful

Asymptom

atic

with1year

follow-up

Tan

(2002)

Male

70Melena,anem

iaDuodenal

descending

Pedunculated

polyp

10.0

92.09

1.5

Brunn

er’s

gland

hamartoma

Laparotom

yviaa

transduodenal

approach

Uneventful

Asymptom

atic

with2years

follow-up

Martinez

(2014)

Male

60Epigastric

discom

fort,

vomiting

Duodenalbulb

Subepithelial

mass

3.09

4.0

Brunn

er’s

gland

hamartoma

Surgicalresection

NA

NA

Adv Ther (2021) 38:2779–2794 2783

Table2

continued

Firstauthor

(year)

Sex

Age

(years)

Com

plaint

Location

Shape

Size

(cm)

Diagnosis

Treatment

Com

plication

Outcome

Hizaw

a(2002)

Female

62NA

Duodenalbulb

Broad-based

lesion

0.7

Brunn

er’s

gland

hamartoma

End

oscopicresection

Uneventful

NA

Female

71Broad-based

lesion

1.8

Male

63Sessile

polyp

1.5

Male

65Sessile

polyp

withsurface

dimples

1.5

Male

34Sessile

polyp

withsurface

dimples

2.0

Female

36Pedunculated

polyp

2.0

Kostalas(2016)

Female

52Mildly

deranged

liver-

function

tests,weight

loss

Duodenalbulb

and

descending

Asolid

mass

NA

Brunn

er’s

gland

hamartoma

Pancreatoduodenectom

yNA

NA

Petersen

(2008)

Female

56Epigastricpain,

nausea,

vomiting,

weightloss,

anorexia

Pylorus-

duodenal

descending

Subm

ucosal

long

tubular

mass

8.59

7.0

Brunn

er’s

gland

hamartoma

Billroth

Iprocedure

Uneventful

Asymptom

atic

at postoperative

period

Gourtsoyiannis

(1990)

Male

74Melena,

weakness,

dizziness

Duodenal

descending

Pedunculated

polyp

5.09

3.09

4.0

Brunn

er’s

gland

hamartoma

Surgicalresection

NA

NA

Takeuchi

(2015)

Female

52A

sticking

sensation

wheneating

Duodenalbulb

Pedunculated

polyp

5.09

3.0

Brunn

er’s

gland

hamartoma

Laparoscopicpartial

duodenectomy

NA

NA

Male

67Epigastric

discom

fort

6.09

3.5

Laparoscopicand

endoscopictumor

resection

Female

52Asymptom

atic

3.59

2.7

Laparoscopicpartial

duodenectomy

2784 Adv Ther (2021) 38:2779–2794

caused by these lesions, and found that 81.3%(13/16) of them were from Brunner’s glandhamartoma and the remaining cases were fromBrunner’s gland hyperplasia. There are also afew cases of diffuse nodular hyperplasia withinvolvement of pylorus causing pyloricobstruction [11, 13] and giant hamartomacausing gastroduodenal intussusception [31].

If Brunner’s gland hamartoma involved theduodenal ampulla, biliary obstruction woulddevelop, which can present with jaundice, acutepancreatitis, and dilatation of the common bileduct and pancreatic duct [2, 3]. These lesions aresimilar to peri-ampullary or pancreatic malig-nancy [32].

DIAGNOSTIC APPROACHES

EGD can provide direct visualization and accu-rate location of Brunner’s gland hamartoma[25]. But there is still a missed diagnosis of thislesion on EGD, especially when it is located atthe posterior wall of the duodenal bulb, transi-tional part, and the beginning of the descend-ing part.

Endoscopic ultrasonography (EUS) has beenincreasingly used to evaluate the origin, extent,and vascular distribution of suspected lesions.On EUS, Brunner’s gland hamartoma is shownas inhomogeneous solid or cystic mass in thesubmucosa [25, 33]. There are some endoscopicultrasonographic features, as follows: mucosaland submucosal involvement; variableechogenicity (sometimes mixed with hypoe-choic); and multiple cystic changes inside thetumor [30, 34, 35]. EUS-guided fine-needleaspiration can improve the diagnostic accuracy,but needs high technical requirements for theoperators [36–38].

Barium X-rays and computed tomography(CT) scans can be complementary approaches todecrease the rate of missed diagnoses. BariumX-ray examination is noninvasive and safe, butsometimes it may not be easy for small lesions.For larger lesions, the findings of Brunner’sgland hamartoma are nonspecific with smoothand sessile or pedunculated polypoid-fillingdefects in the duodenum [3, 5, 6] without evi-dence of duodenal wall stiffening [34]. Bleeding

Table2

continued

Firstauthor

(year)

Sex

Age

(years)

Com

plaint

Location

Shape

Size

(cm)

Diagnosis

Treatment

Com

plication

Outcome

Kitagaw

a(2018)

Female

64Anemia

Duodenalbulb

Pedunculated

polyp

7.0

Brunn

er’s

gland

hamartoma

End

oscopicmucosal

resection

NA

NA

Jung

(2013)

Male

45Melena

Pyloricring

Pedunculated

polyp

4.89

3.2

Brunn

er’s

gland

hamartoma

Piecem

ealendoscopic

mucosalresection

NA

Norelapsewith

5months

follow-up

NAnotavailable

Adv Ther (2021) 38:2779–2794 2785

spots, erosion, or superficial ulcers on the sur-face of the lesion are rarely seen [39]. Hypotonicduodenography is considered to be appropriateto examine the changes of lesion surface [9, 39].As for diffuse nodular Brunner’s gland hyper-plasia, there are multiple small filling defects inthe duodenum shown on barium X-ray exami-nation [29].

Large Brunner’s gland hamartoma can bedetected by CT [17]. CT is considered as the firstchoice in many cases. It is helpful to confirmthe absence of extraluminal extension and todefine its relationship with adjacent structures,such as pancreas, common bile duct, and bloodvessels [25, 31]. The internal cysts and pediclesshown on CT may be conducive to a diagnosisof Brunner’s gland hamartoma, which areespecially useful in patients who are intolerantto EGD [40]. A differential diagnosis of Brun-ner’s gland hamartoma should be made withisolated duodenal masses, such as leiomyoma,gastrointestinal stromal tumor, lymphoma,neuroendocrine tumor, pyloric mucosal pro-lapse, or Peutz-Jeghers polyps [21, 31, 34].Brunner’s gland hamartoma should be consid-ered if contrast-enhanced CT reveals somespecific imaging features, including a mass withcentral low attenuation in the bulb anddescending parts of the duodenum, circumja-cent enhancement, and/or internal small cysticchange [35], which indicate solid proliferationof Brunner’s gland, superficial duodenalmucosa, and internal cysts on histology,respectively [41].

An exact diagnosis of Brunner’s glandhamartoma requires pathological evidence. Ongross pathology (Fig. 2), Brunner’s glandhamartoma is generally characterized by a solidmass with well-defined boundary, smooth sur-face covered by normal duodenal mucosa, pinkor tawny cut surface, lobules separated byfibrous septa, and internal cystic changes[6, 42]. Microscopically (Fig. 3), there is a mix-ture of smooth muscle, adipose tissues, largeducts, and infiltrating lymphocytes in the pro-liferative Brunner’s glands [1]. The cytoplasm ofhyperplastic Brunner’s gland cells is rich inneutral mucin, with small round nucleus loca-ted at their base in the absence of mitoticactivity and atypia. Sclerotic glandular foci,

which are characterized by a decreased numberof Brunner’s glands with irregular structure andangulation, sparse cytoplasm, and centerednucleus, can be also seen [10]. Metachronouslesions of Brunner’s gland hamartoma have notbeen reported in the literature yet, but they canbe observed in other gastrointestinal tract dis-eases, such as gastric epithelia dysplasia [43] andcolorectal adenomas [44]. Immunohistochemi-cally, Brunner’s glands always express MUC6 atdifferent levels, and some dilated or angulatedBrunner’s glands also express MUC5AC simul-taneously. MUC5AC expression at the surfaceepithelium suggests a possibility of gastricmetaplasia [10]. Notably, endoscopic biopsiesare mostly negative, because the mass is oftencovered by intact duodenal mucosa, and thedepth of biopsy is usually insufficient to reachthe tumor tissue located in the submucosa [11].

If duodenal polyps were found on EGD, thephysicians would differentiate the Brunner’sgland hamartoma from other types of multipleand sporadic polyps located at the duodenumaccording to the age of onset, distribution at theduodenum, endoscopic appearance, histologi-cal characteristics, and immunohistochemicalmarkers (Table 3) [45–63]. Nearly all cases withfamilial adenomatous polyposis can be accom-panied by duodenal adenomas, and some ofthem have extraintestinal manifestations, suchas jaw and tooth abnormalities, nasopharyngealangiofibromas, and cutaneous lesions (i.e.,lipomas, fibromas, and sebaceous and epider-moid cysts) [58]. Similarly, duodenal adenomasare a relatively common manifestation ofMUTYH-associated polyposis, in which cuta-neous lesions, such as sebaceous gland adeno-mas, epitheliomas, and epithelial carcinomas,can be observed [64].

MALIGNANT POTENTIAL

Brunner’s gland hamartoma or hyperplasia isusually benign [3]. However, with the growth ofbenign proliferative lesions of Brunner’s glands,mucosal ulcers may develop, thereby leading tothe repair of gastric foveolar metaplasia withpapillary architecture and then malignanttransformation [22]. It has been reported that

2786 Adv Ther (2021) 38:2779–2794

Fig. 2 Macroscopic specimen (a) and cut surface (b) of Brunner’s gland hamartoma

Fig. 3 Macroscopic and microscopic findings of Brunner’sgland hamartoma. Case 1. A 55-year-old male patientpresented with abdominal discomfort and underwentendoscopic examination showing a polyp in the duodenalbulb. a Endoscopically resected specimen of about1.5 9 0.8 9 0.7 cm in size. b Histological examinationrevealing massive hyperplasia of Brunner’s glands withfocal dysplasia (hematoxylin and eosin, 9 100). Case 2. A

60-year-old male patient presented with melena andunderwent endoscopic examination showing a polyp inthe duodenal bulb with bleeding. c Endoscopically resectedspecimen of about 3.5 9 2.0 9 1.0 cm in size. d Histo-logical examination revealing massive hyperplasia of Brun-ner’s glands mixed with smooth muscle and infiltratinginflammatory cells (hematoxylin and eosin, 9 100)

Adv Ther (2021) 38:2779–2794 2787

Table 3 Different subtypes of duodenal polyposis and sporadic duodenal polyp

Subtypes[references]

Age of onset(years)

Commonduodenaldistribution

Endoscopicappearance

Histologicalcharacteristics

Immunohistochemicalmarkers

Brunner’s glandhamartoma

[2, 3, 7, 26]

50–70 Duodenalbulb anddescending

Pedunculated/sessilepolyp

Mixture of Brunner’sglands, ducts,smooth muscle,fibrous tissue,adipose tissue,lymphocytes, etc.

MUC6 (?)

Gastricheterotopia

[40, 41]

NA Duodenalbulb anddescending

Isolated or multiplesubmucosal masses

Lesions consisting ofgastric glandscovered by normalduodenal mucosa

b-catenin (?)

Inflammatoryfibroid polyp

[42]

50–80 NA Isolated polyp withsmooth mucosa

Spindle-shaped cellsproliferation withinfiltration ofsmall blood vesselsand eosinophilicinflammation

Vimentin (?), CD34(?)

Lipoma

[43, 44]

50–80 Duodenaldescending

Isolated/rarelymultiple,pedunculated/sessile, round/oval,and soft mass withnormal surfacemucosa, whichmay have areas oferosion orulceration

Mature adiposetissue arranged inlobules

CD34 (?)a, desmin(-), S100 protein(-), STAT6 (-),SMA (-)

Leiomyoma

[45, 46]

60–80 NA Lobular mass with aboundary that iswell-defined/irregular/interdigitatingwith normalsmooth muscle

Mature smoothmuscle cells withhyalinedegeneration,coagulativenecrotic stroma,and low mitoticactivity

SMA (?), desmin (?),S100 (-), Ki-67 (-),CD34 (-), HMB4(-)

Carcinoid

[47, 48]

No agepredilection

Proximalduodenum

Intraluminalpolypoid/muralmass

Endocrine secretiongranules observedby a characteristicsilver affinity

Serotonin (?), gastrin(?), somatostatin (?)

Gastrointestinalstromal tumor

[42, 49, 50]

50–65 Duodenaldescending

Smooth submucosalmass withulceration andbleeding areas onthe surface

Most are spindle celltumors withpalisade nuclei,half are mixed withskeinoid fibers, andmore than 20.0%are accompaniedby hemangioma-like vascularproliferation

CD117 (?): 95.0%

CD34 (?): 70.0%

2788 Adv Ther (2021) 38:2779–2794

Table 3 continued

Subtypes[references]Age of onset(years)

Commonduodenaldistribution

Endoscopicappearance

Histologicalcharacteristics

Immunohistochemicalmarkers

Lymphoma

[42, 51]

50–60 Proximalduodenum

Multiple small,rough polyps ornodules

Different histologicalpatterns: diffuselarge B cell,mucosa-associatedlymphoid tissue,mantle cell, andHodgkin’s andfollicularlymphoma

CD20 (?)b, CD10 (?),Bcl-2 (?), BCL6 (?),low Ki-67 index

Non-ampullarysporadicadenoma

[42, 52]

60–90 Distalduodenum

Isolated sessile polyp Mostly tubular cryptswithhyperchromatic,enlarged, andpseudostratifiednuclei

Cytokeratin 7 (?),cytokeratin 20 (?)

Familialadenomatouspolyposis

[52–54]

20–40 Duodenaldescendingandhorizontal,peri-ampullary

Multiple flat polyps Tubular ortubulovillouscrypts mixed withcolumnarepithelial cells,goblet cells, panethcells, andendocrine cells,accompanied byenlarged andelongatedhyperchromaticnuclei

Cytokeratin 7 (?),cytokeratin 20 (?)

Peutz-Jegherssyndrome

[55–57]

10–30 NA Isolated/multiplepolypoid lesions

Branched villousstructurescontaining smoothmuscle core andmultiple types ofcells

Serotonin (?)

Solitary Peutz-Jeghers polyp

[56–58]

NA NA Isolated,pedunculated/rarely sessile,polypoid lesion

Branched villousstructurescontaining smoothmuscle core andmultiple types ofcells

Serotonin (?)

NA not availablea The immunohistochemical marker we describe here is the histologic pattern of spindle cell/pleomorphic lipomab The immunohistochemical marker we describe here is the histologic pattern of follicular lymphoma

Adv Ther (2021) 38:2779–2794 2789

2.1% of the 722 Brunner’s gland hyperplasialesions evaluated had dysplasia and 0.3% inva-sive carcinoma [22].

Histological characteristics of dysplasia ofteninclude (1) crowded glands with slight distor-tion of architecture; (2) atypia cells, expandedand overlapping nuclei, and high mitoticactivity on cytology; and (3) sporadically posi-tive p53, high expression level of Ki-67/MIB-1[10, 65].

There are several signs warning a potentialmalignant transformation of Brunner’s glandhamartoma. First, the size of polypoid lesionsincreases with a change in their morphology.Itsuno et al. reported that the lesion of Brun-ner’s gland hamartoma progressed from sessilepolypoid to fungating ulcerated tumor during a3-year endoscopic follow-up, its size increasedfrom 1.4 9 1.0 cm to 4.3 9 3.1 cm, and it wasfinally diagnosed as adenocarcinoma [66]. Sec-ond, the submucosal tumor-like lesion isaccompanied by a shallow central depression. Aretrospective analysis including 25 cases withduodenal carcinoma arising from Brunner’sglands found that 13 of them had submucosaltumor-like lesions accompanied by a shallowcentral depression [67].

TREATMENT AND PROGNOSIS

For asymptomatic patients with Brunner’s glandhamartoma, conservative treatment of smalllesions is acceptable, while excision of largelesions is recommended to prevent bleedingand obstruction [68]. For symptomatic patients,endoscopic or surgical resection should beconsidered [13].

Endoscopic resection of Brunner’s glandhamartoma has been increasingly employed [5].Its technical success is related to the size, loca-tion, and pedicle of the lesions [1]. Its advan-tages include low invasiveness, high safety, lowcost, and short duration of hospitalization[5, 29]. Endoscopic mucosal resection (EMR)and endoscopic submucosal dissection (ESD) aremajor endoscopic resection options for superfi-cial non-ampullary duodenal epithelial tumors.ESD can completely remove the lesions, but hasa higher risk of intraoperative and delayed

perforation than EMR [69]. Such a higher inci-dence of delayed perforation after ESD may bedue to the large ulceration produced by ESD aswell as chemical stimulation of pancreatic juiceand bile [34, 69]. Over-the-scope clips [70] andpolyglycolic acid sheets combined with fibringlue [71] can prevent delayed perforation bycompletely closing the mucosal defect.

Endoscopic resection of a giant peduncu-lated Brunner’s gland hamartoma is oftenchallenging. Notably, the duodenal cavity isnarrow with poor visibility. Additionally, theintestinal peristalsis can carry the mass to thedistal end [4]. Therefore, it has often been con-sidered that the head of the tumor can be pulledinto the gastric antrum with a snare for furtherresection [4]. If the tumor is too large to passthrough the pyloric ring, piecemeal EMR can beselected [68]. If the specimen is inadvertentlylost to the distal duodenum, magnesium citratecan contribute to its fast passage in the stoolbefore degradation [4].

Surgical resection, such as polypectomy,wedge duodenal resection, and partial duo-denectomy plus gastrectomy, is required forcomplex lesions and large/sessile tumors [12].Pancreaticoduodenectomy is usually consideredfor giant hamartoma and diffuse nodularhyperplasia lesions, which imitate the nature ofmalignancy in the pancreatic-duodenal region[27]. This consideration is potentially reason-able, because the consequence of missing anundiagnosed pancreatic cancer is much moreserious than the risk of radical surgery [1, 12].

The most common treatment option forBrunner’s gland adenocarcinoma of the duode-num is pancreaticoduodenectomy, followed bypartial duodenectomy plus gastrectomy, partialduodenectomy, and endoscopic resection [72].Recurrence is rare after endoscopic or surgicaltreatment [3, 30].

CONCLUSIONS

Brunner’s gland hamartoma is an uncommonbenign tumor of the duodenum with non-specific clinical manifestations. Its mechanismsremain unclear, but may be related to highgastric acid secretion, Hp infection, chronic

2790 Adv Ther (2021) 38:2779–2794

pancreatitis, inflammatory stimulation, andmucosal injury. Malignant transformationshould be cautiously evaluated by histologycombined with immunohistochemistry, espe-cially if the size of lesion is increased and itsmorphology is changed. A wait-and-see strategyis employed in a majority of cases with Brun-ner’s gland hamartoma. If necessary, endo-scopic and/or surgical resection is required. Infuture, it is worthwhile to carry out experi-mental studies to further explore the molecularcharacteristics of Brunner’s gland hamartomaand adenocarcinoma and to determine thepotential targets for chemoprevention andregression of these lesions.

ACKNOWLEDGEMENTS

Funding. No funding or sponsorship wasreceived for this study or publication of thisarticle.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Authorship Contributions. The first draft ofthe manuscript was written by Menghua Zhuand Xingshun Qi; Study conception and design,material preparation, data collection, and writ-ing–review and editing were performed by allauthors, including Menghua Zhu, Hongyu Li,Yanyan Wu, Yang An, Yuye Wang, Chun Ye,Dan Zhang, Rui Ma, Xuehan Wang, XiaodongShao, Xiaozhong Guo, and Xingshun Qi; Allauthors contributed to the manuscript. Allauthors read and approved the finalmanuscript.

Disclosures. Menghua Zhu, Hongyu Li,Yanyan Wu, Yang An, Yuye Wang, Chun Ye,Dan Zhang, Rui Ma, Xuehan Wang, XiaodongShao, Xiaozhong Guo, and Xingshun Qi havenothing to disclose.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any new studies withhuman participants or animals performed byany of the authors.

Data Availability. The datasets generatedduring and/or analyzed during the currentstudy are available from the correspondingauthor on reasonable request.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

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