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Abstract

Malignant transformation of a heterotopic pancreas in the duodenum is very rare. To our knowledge, only 15 cases have been reported worldwide, including the present case. We herein report a rare case of malignant transformation of a heterotopic pancreas in the duodenum along with a review of the literature.

A 65-year-old man was admitted to our hospital for evaluation of dyspepsia and vomiting. Esophagogastroduodenoscopy showed a stricture of the duodenal bulb. Laparoscopic distal gastrectomy was performed. Although a duodenal tumor had not been suspected, histopathological examination of the surgical specimen showed adenocarcinoma arising from a heterotopic pancreas (Heinrich type III) in the duodenum. Four months postoperatively, the patient received adjuvant chemotherapy. He was still alive without recurrence at 24 months of follow-up.

Adenocarcinoma arising in a heterotopic pancreas is rare; therefore, preoperative diagnosis is difficult to obtain. Effective management of a heterotopic pancreas depends on the presence or absence of symptoms. Awareness of the possibility of malignant change in a heterotopic pancreas of the duodenum prior to surgery is helpful for the diagnosis and appropriate management of such patients.

Keywords

Adenocarcinoma heterotopic pancreas ectopic pancreas duodenum case report malignant transformation

Introduction

Heterotopic pancreas, also known as ectopic or aberrant pancreas, is defined as pancreatic tissue located in abnormal anatomical sites that lacks anatomic continuity with the orthotopic pancreas and has its own vascular and ductal systems.¹ Heterotopic pancreas is usually found in the submucosal layer of the gastrointestinal tract and is difficult to diagnose preoperatively because of its small size.² The incidence of heterotopic pancreas is reportedly 0.2% in upper abdominal surgeries³ and 0.55% to 13.7% at autopsy.⁴ Heterotopic pancreas has been found in the duodenum (30%), stomach (25%), jejunum (15%), Meckel’s diverticulum (6%), and rarely the ileum (3%).⁵ Malignant transformation in heterotopic pancreas is very rare, with only 14 cases reported in the literature to date. We herein report a case of adenocarcinoma arising from a heterotopic pancreas in the first part of the duodenum. We also present a review of other case reports describing malignant transformation of heterotopic pancreas in the duodenum as indexed in the PubMed database up to March 2022.

Case report

A 65-year-old man was referred to our institution with dyspepsia and repeated vomiting. He had a medical history of a gastric ulcer. The patient had initially presented to a local hospital for assessment and underwent esophagogastroduodenoscopy. This revealed a stricture of the duodenal bulb, and the endoscope could not be advanced beyond the first part of the duodenum (Figure 1). Subsequent computed tomography showed mildly enhanced wall thickening and narrowing at the gastric pylorus and proximal duodenum (Figure 2); the other abdominal organs, including the pancreas, were unremarkable. Because no tumor cells were identified in the biopsy specimen obtained from the lesion, the patient was treated with proton pump inhibitors for 2 months. However, his symptoms persisted and progressed to repeated vomiting; therefore, the patient visited our hospital for further evaluation, and balloon dilation was performed to relieve the symptoms of duodenal obstruction. His symptoms did not improve after balloon dilation, and surgical resection was performed for therapeutic purposes. Based on radiological imaging and endoscopic examination findings, a benign stricture of the duodenal bulb was suspected rather than a duodenal tumor. Therefore, laparoscopic distal gastrectomy was performed with the patient’s written consent for treatment. The patient also provided written consent for publication of this case report.

Figure 1.

Esophagogastroduodenoscopy showed deformity and stricture of the duodenal bulb.

Figure 2.

Abdominal computed tomography showed mildly enhanced wall thickening and narrowing (arrow) at the gastric pylorus and proximal duodenum in the (a) transverse and (b) coronal planes

Gross examination of the surgically resected specimen revealed severe thickening and stenosis from the pylorus to the duodenal bulb, whereas the mucosa appeared normal (Figure 3). An ill-defined, grayish-white, and focal yellowish solid lesion with a diameter of 20 mm was identified on the cut surface of the specimen. Histopathological examination confirmed the presence of atypical glands that had developed in the submucosal layer and infiltrated the muscularis propria and subserosa of the duodenal bulb (Figure 4(a)). The lesion had also invaded bundles of nerves (Figure 4(b)). The glands were composed of cells with irregular nuclear membranes and prominent nucleoli with a tubular growth pattern, consistent with moderately differentiated adenocarcinoma. Coexisting pancreatic tissue consisting of ducts and a few acini (Heinrich type III) was identified adjacent to the tumor, supporting the diagnosis of adenocarcinoma arising from heterotopic pancreas in the first portion of the duodenum (Figure 4(c)). These cells stained positive for cytokeratin 7 but negative for synaptophysin and chromogranin (Figure 4(d)). Because malignancy was not suspected, an intraoperative frozen section for evaluation of the resection margin was not obtained. However, tumor cells were found in the duodenal resection margin; therefore, additional chemotherapy was planned. Four months after surgery, the patient received adjuvant chemotherapy using the combination FOLFIRINOX regimen (fluorouracil + leucovorin + irinotecan + oxaliplatin), which is used to treat pancreatic cancer. The patient was alive without recurrence at 24 months of follow-up.

Figure 3.

Gross examination of the surgically resected specimen revealed severe thickening and stenosis from the pylorus to the duodenal bulb, with a normal-appearing mucosa

Figure 4.

Histopathological examination findings. (a) Diffuse proliferation of moderately differentiated adenocarcinoma from the submucosal layer to the subserosa (×40). (b) Invasion of nerve bundles by tumor cells (arrow) (×100). (c) Ectopic pancreatic tissue composed of pancreatic ducts and a few acini in the duodenal muscle layer was identified in direct transition to duct-like structures of the adenocarcinoma (×100). (d) The tumor cells stained positive for cytokeratin 7.

The reporting of this study conforms to the CARE guidelines.⁶

Discussion

Heterotopic pancreas is a benign disease characterized by the presence of submucosal tumors in the gastrointestinal tract. It is often found incidentally during surgery or endoscopic examination and rarely causes clinical symptoms. In 1909, Von Heinrich classified heterotopic pancreatic tissue into four histopathologic types according to the presence or absence of pancreatic ducts, acini, and islet cells.^7,8 Malignant transformation of heterotopic pancreas is very rare; thus, it is usually neither suspected nor included as a differential diagnosis. Most cases are diagnosed after surgery by pathological examination of a resected specimen. The reported incidence of malignancy arising from heterotopic pancreas ranges from 0.7% to 1.8%.^9,10 Guillou et al.⁹ proposed the following histopathologic criteria for the diagnosis of malignant transformation of heterotopic pancreas: (1) the tumor must be within or near the heterotopic pancreatic tissue, (2) a direct transition between the pancreatic structures and carcinoma must be present, and (3) the non-neoplastic heterotopic pancreatic tissue must contain fully developed acini and/or ductal structures. The lesion in our case fulfilled all three criteria.

We performed a search of PubMed and found 14 other well-documented cases of malignancy arising in a heterotopic pancreas of the duodenum from 2000 to 2021 (Table 1).^7,11–23 Including our case, the patients’ mean age was 69.1 years (range, 56–86 years), and nine and six patients were male and female, respectively. Most patients had common clinical symptoms, including vomiting or abdominal pain due to obstruction by the tumor. Excluding five cases that were not described in detail, 50% of the remaining cases had increased carbohydrate antigen 19-9 or carcinoembryonic antigen levels. Most of the tumors (86.7%) were located in the first or second part of the duodenum, leading to symptoms of intestinal obstruction. Three patients underwent gastrectomy, eight underwent pancreaticoduodenectomy (including subtotal stomach-preserving pancreaticoduodenectomy), and four underwent duodenectomy. Histologically, 12 of the 15 patients were diagnosed with adenocarcinoma (tubular adenocarcinoma, poorly differentiated adenocarcinoma, papillary adenocarcinoma, and mucinous adenocarcinoma).

Table 1.

Clinical features of previously reported cases of adenocarcinoma arising from heterotopic pancreas in the duodenum.

Case	Year	Reference	Age (years)	Sex	Location	Size (mm)	Appearance	Clinical symptoms	Preoperative tumor-specific antigen	Diagnostic approach	Operative method	Heinrich type	Chemotherapy	Histology	Outcome
1	2007	Tison et al.²³	72	M	Second portion	NR	Tumor of the ampulla	Pain and jaundice	NR	Operation	PD	NR	NR	Adenocarcinoma	Death (16 months)
2	2007	Kawakami et al.¹²	65	F	Second portion	12	Tumor of the ampulla	Fatigue and jaundice	WNL	Operation	SSPPD	NR	NR	Acinar cell carcinoma	Alive (19 months)
3	2008	Rosok et al.¹³	59	F	Proximal	50	Cystic lesion	Upper abdominal discomfort	NR	Operation	LR	NR	Not performed	Intraductal papillary mucinous carcinoma	Alive (36 months)
4	2010	Inoue et al.¹⁴	75	M	Second portion	30	Stenosis with elevated lesion	Nausea and vomiting	WNL	Operation	PPPD	III	Not performed	Adenocarcinoma	Alive (72 months)
5	2010	Bini et al.¹¹	56	M	First portion	NR	Duodenal wall thickening	Vomiting	WNL	EUS-FNA	PD	I	Performed (NR)	Adenocarcinoma	NR
6	2011	Stock et al.⁷	79	F	Fourth portion	30	Mass	Abdominal fullness, early satiety, and intermittent left upper quadrant pain	Chromogranin-A, 53 ng/mL	Operation	D	I	Performed (NR)	Adenocarcinoma	NR
7	2012	Kinoshita et al.¹⁵	62	F	First portion	34	Gastric outlet obstruction	Vomiting and epigastralgia	CEA, 8.1 ng/mL CA19-9, 66.9 U/mL	Operation	PD	I	Not performed	Adenocarcinoma	Alive (12 months)
8	2013	Ginori et al.¹⁶	86	F	First portion	30	Stenosis	Abdominal pain and dyspepsia	NR	Operation	STG + DR	I	Not performed	Adenocarcinoma	NR
9	2013	Hamidian Jahromi et al.¹⁷	58	M	First portion	27	Submucosal tumor	Postprandial right upper abdominal pain	NR	Operation	D	NR	Performed (XELOX)	Acinar cell carcinoma	Alive (18 months)
10	2014	Endo et al.¹⁸	75	M	Second portion	22	Submucosal tumor with stenosis	Epigastric pain	CEA, 55.4 ng/mLCA19-9, 54.8 U/mL	EUS-FNA	SSPPD	I	Not performed	Adenocarcinoma	Alive (60 months)
11	2015	Fukino et al.¹⁹	62	M	Fourth portion	15	Submucosal tumor	Weight loss	CA19-9, 500 U/mLDUPAN-2, 226 U/mLSPan-1, 41 U/mLCEA, WNL	Operation	SD	IV	Performed (SP)	Adenocarcinoma	Death (33 months)
12	2019	Kaneko et al.²⁰	81	M	First portion	30	Submucosal tumor	Vomiting	WNL	Operation	DG	I	Not performed	Adenocarcinoma	Alive (18 months)
13	2020	Minami et al.²¹	77	M	First portion	55	Ulcer scar with stenosis	Epigastric pain	CA19-9, 1130 U/mLDUPAN-2, 5287 U/mL	Operation	SSPPD	I	Performed (TS1)	Adenocarcinoma	Alive (18 months)
14	2021	Hirokawa et al.²²	65	F	First portion	NR	Mass with ulcer	Abdominal discomfort	CEA, 445.4 ng/mLCA125, 317.3 U/mLSquamous cell carcinoma antigen, 4.1 ng/mLCA19-9, <2 U/mL	Gastroduodenoscopy	PD	NR	Performed (preoperatively and postoperatively including capecitabine, cisplatin, oxaliplatin, paclitaxel, S-1, and trastuzumab)	Adenocarcinoma	Alive (24 months)
15	2022	Our case	65	M	First portion	20	NR	Vomiting	NA	Operation	STG + DR	III	Performed (FOLFIRINOX)	Adenocarcinoma	Alive (24 months)

M, male; F, female; NR, not reported; NA, not available; WNL, within normal limits; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9; PD, pancreaticoduodenectomy; DG, distal gastrectomy; PPPD, pylorus-preserving pancreaticoduodenectomy; SSPPD, subtotal stomach-preserving pancreaticoduodenectomy; LR, laparoscopic resection of tumor and duodenal wall; SD, segmental duodenectomy; STG + DR, subtotal gastrectomy with duodenal bulb resection; D, (partial) duodenectomy; EUS-FNA, endoscopic ultrasonography-guided fine-needle aspiration; TS1, tegafur/gimeracil/dihydropyrimidine dehydrogenase; SP, TS1 + cisplatin; XELOX, capecitabine + oxaliplatin; FOLFIRINOX, fluorouracil + leucovorin + irinotecan + oxaliplatin.

Heterotopic pancreas has been classified into three histopathologic types according to the presence or absence of pancreatic ducts, acini, and islet cells.⁸ Type I consists of typical pancreatic tissues with acini, ducts, and islet cells similar to those seen in the normal pancreas. Type II is composed of pancreatic tissues with only exocrine components (acini and ducts, but no islet cells). Type III is composed of pancreatic tissues with numerous ducts, few to no acini, and no islet cells. Gaspar et al.²⁴ modified the classification by adding a fourth type (type IV), which is composed of pure endocrine heterotopia containing only islet cells. Among the reported cases of adenocarcinoma arising from heterotopic pancreas, the most commonly associated histologic type is Heinrich type I. Only one case of type III and one case of type IV have been reported. Our case arose in a type III heterotopia, which is a rare background for the malignant transformation of heterotopic pancreas.

Malignant transformation of heterotopic pancreas usually occurs intramurally, and involvement of the overlying mucosa often occurs late in the course of the disease; therefore, endoscopic biopsy is not usually helpful for diagnosis of the mass.²⁵ In our case, computed tomography and endoscopic imaging initially showed wall thickening in the first portion of the duodenum. However, multiple biopsies did not reveal the presence of malignancy. Similar to other reports, we were unable to achieve a preoperative diagnosis by endoscopic biopsy because the tumor was located in the submucosal layer; this is a difficult site from which to obtain a tissue sample. Endoscopic ultrasonography (EUS) can aid the preoperative diagnosis of malignant transformation of heterotopic pancreas. In two cases, EUS-guided fine-needle aspiration or biopsy revealed the presence of adenocarcinoma in the duodenal area prior to surgery.^11,18 In our case, surgery was necessary to relieve the symptoms resulting from the duodenal obstruction; therefore, EUS was not performed.

In our review of well-documented cases, the size of the malignant heterotopic pancreas in the duodenum ranged from 12 to 55 mm, with a mean of 29.6 mm. Therefore, we propose early treatment of heterotopic pancreas to prevent malignant transformation, especially when the lesion is larger than 1 cm or associated with clinical symptoms of obstruction or weight loss.

Because of the small number of reports of adenocarcinoma arising from heterotopic pancreas, there is no clear evidence of the efficacy of chemotherapy or the optimal type of adjuvant therapy. In our literature review, a chemotherapy regimen was reported for only three cases. We selected the FOLFIRINOX regimen because it is used to treat primary pancreatic cancer. At the time of this writing, the patient was doing well with no evidence of recurrence at 24 months after surgery.

The prognosis of malignancies arising from heterotopic pancreas in the duodenum is unknown because of the small number of reports. In our review, 66.7% of patients with a described clinical course were alive without evidence of recurrence at least 1 year following surgery. Two patients died of cancer-related complications, with one developing disseminated metastasis and another developing local recurrence. These observations suggest that the prognosis of malignancies arising from heterotopic pancreas in the duodenum may be better than that of ordinary pancreatic cancer, which has a 5-year survival rate of 10%.¹¹ In cases of malignant transformation of heterotopic pancreas in the gastrointestinal tract, the symptoms of intestinal obstruction assist with earlier detection of malignancy than in cases of ordinary pancreatic cancer; this may result in a better prognosis.

In summary, we have reported a rare case of adenocarcinoma arising from heterotopic pancreas in the duodenum. Preoperative diagnosis is very challenging because of the difficulties obtaining samples by endoscopy and the nonspecific imaging features and clinical symptoms. Therefore, we propose early treatment of heterotopic pancreas. Considering the rarity of this condition, accumulation of data from all cases of malignant transformation of heterotopic pancreas in the duodenum will aid the diagnosis and management of such patients.

Footnotes

Author contributions

Seung-Myoung Son and Chang Gok Woo substantially contributed to the writing of the manuscript. Chang Gok Woo and Jisun Lee performed the pathological examination and imaging examination. All authors have read and approved the final manuscript.

Declaration of conflicting interest

The authors declare that they have no competing interests.

Ethics statement

This study adhered to the guidelines established by the Declaration of Helsinki and was approved by the Institutional Review Board of Chungbuk National University Hospital (Cheongju, Korea, IRB No: 2023-01-003).

Funding

This research was supported by the Regional Innovation Strategy (RIS) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (MOE) (2021RIS-001).

ORCID iDs

Chang Gok Woo

Jisun Lee

Seung-Myoung Son

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Adenocarcinoma arising from heterotopic pancreas at the first portion of the duodenum: a case report