Malignant Transformation of Heterotopic Pancreatic Tissue in a Patient with BRCA2 Mutation

: Background: Malignant transformation of heterotopic pancreatic tissue is a rare entity with only several case reports published in the scientiﬁc literature. Adjuvant chemotherapy following oncological resection for lesions with nodal metastasis has not been well described and there are no guidelines available to guide the management of these patients. Case Presentation: We present a case of gastric heterotopic pancreatic carcinoma with nodal metastasis in a young patient with breast cancer gene (BRCA) 2 mutation. He had undergone a laparoscopic wedge resection for a gastric lesion initially thought to be a gastrointestinal stroma tumor. Given the involvement of the wedge resection margins, the patient underwent a distal gastrectomy with oncological lymph nodal clearance. One out of the 33 harvested lymph nodes harboured micrometastasis while the main gastrectomy specimen did not have any residual malignancy. Following the histological diagnosis, he received an adjuvant chemotherapy regime akin to that prescribed for locally advanced pancreatic adenocarcinoma with good response. This is, to our knowledge, also the ﬁrst such case report in a patient with BRCA2 mutation. Conclusions: Pre-operative diagnostic conﬁrmation is challenging and endoscopic procedures pose signiﬁcant false negatives. Reports of nodal metastasis following oncological resection are limited and there are no guidelines regarding adjuvant therapies. We would recommend a chemotherapy regimen similar to that for primary locally advanced pancreatic carcinoma in patients found to have nodal metastasis.


Introduction
Heterotopic pancreatic tissue can be found in various locations of the gastrointestinal tract and malignant transformation of this tissue is exceedingly rare with only a few documented cases in scientific literature. Following oncological resection of these lesions, adjuvant therapy for those with a positive nodal status has not been well described and guidelines with regards to management of these patients are lacking. The authors present a young male patient with gastric heterotopic pancreatic carcinoma with nodal metastasis who was subsequently detected to have the breast cancer gene (BRCA) 2 mutation. He had good response to adjuvant chemotherapy following oncological resection. This is to our knowledge, the first such case report in a patient with BRCA2 mutation.

Case Report
We present a case of a 33-year-old Chinese male initially presenting with dyspepsia for which an oesophagoduodenoscopy was performed. This revealed a submucosal bulge with central umbilication at the antrum (Figure 1), and a subsequent computed tomographic (CT) scan of the abdomen and pelvis showed a 2.3-cm enhancing nodule over the anterior aspect of the pylorus suggestive of a gastrointestinal tract stromal tumour (GIST) (Figures 2 and 3).
The patient underwent laparoscopic wedge resection of the tumour. Histopathological assessment ( Figure 4) demonstrated the presence of heterotopic pancreatic tissue displaying cellular proliferation resembling acinar cells and ducts of the pancreas. An adjacent invasive adenocarcinoma comprising malignant glands was present and demonstrated areas of central necrosis and perineural invasion. The tumour extended to the radial and deep margins. On immunohistochemistry, the tumour showed positive staining for CK7 and focal staining for CDX2 was noted. The stains for synaptophysin, chromogranin, TTF-1, CK20 and Gata3 were negative. ki-67 proliferative index was in the region of 75%. The findings were consistent with a pancreatic ductal adenocarcinoma arising from heterotopic pancreas within the stomach.    A CT scan of the thorax after the first surgery confirmed no distant metastasis. Given the involvement of the wedge resection margins, the patient underwent a distal gastrectomy with oncological lymph nodal clearance. One out of the 33 harvested lymph nodes harboured micrometastasis while the main gastrectomy specimen did not have any residual malignancy. Postoperatively, the patient underwent adjuvant chemotherapy with oxaliplatin, irinotecan, folinic acid and fluorouracil (FOLFOXIRI). The chemotherapy regime was guided by the standard of care for pancreatic cancer after discussion at our multidisciplinary tumour board meeting. A CT scan of the thorax, abdomen and pelvis one year after the surgery did not demonstrate any evidence of local recurrence or metastasis. Tumour markers were not assessed prior to surgery, however cancer antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA) levels have remained within the normal range after the surgery.
Following surgery, a discussion regarding hereditary cancer syndromes was held with the patient and he was offered genetic testing consisting of the following genes: APC, ATM, BMPR1A, BRCA1, BRCA2, CDKN2A (p14ARF), CDKN2A (p16INK4a), EPCAM, MEN1, MLH1, MSH2, MSH3, MSH6, NF1, PALB2, PMS2, SMAD4, STK11, TP53, TSC1, TSC2, VHL. This returned as positive for a pathogenic variant in the BRCA2 gene, whereby c.7007 + 1G > C (splice donor) was reported. Of note, he does not have a significant family history of malignancy and genetic screening was also offered to his first-degree family members. The patient will continue to be closely followed up for other BRCA2-related malignancies like breast and prostatic cancer.

Discussion
This rare entity of heterotopic pancreatic tissue was first described in 1727 where it was identified by Schultz as an ileal diverticulum and thereafter proven histologically by Klob in 1859 [1]. It has since been found in various locations of the gastrointestinal tract where the most common locations include the stomach, followed by the duodenum, jejunum (accounting for more than 70% of cases) [2,3] and more uncommonly the esophagus, ileum, Meckel diverticulum and biliary tree [4,5]. In the stomach, it has a predilection for the antrum and prepyloric region [6]. Albeit likely under-reported due to its presentation as an incidental finding in most cases, the reported incidence in autopsy studies and upper abdominal surgeries ranges from 0.5% to 13.7% [7]. A further rarity would be the presence of malignant transformation within the heterotopic pancreatic tissue. The incidence of malignant transformation of heterotopic pancreatic tissue is less than 2% [8].
The diagnostic criteria proposed by Guillou et al. to confirm that the malignancy indeed arises from heterotopic pancreatic tissue can be summarized into three main points. Firstly, the tumour must be found within, or close to the aberrant pancreatic tissue. Secondly, identification of a transitional area between pancreatic structures and carcinoma. Lastly, there has to be evidence of pancreatic acini and/or ductal structures seen within the non-neoplastic heterotopic pancreatic tissue [9].
Although the diagnosis of ectopic pancreatic tissue is often incidental, the majority of patients with malignancy are symptomatic at presentation with abdominal pain being the predominant complaint in more than half [10]. These ectopic pancreatic tumours are most commonly found in the stomach and a subepithelial tumour-like appearance is most frequently observed. With histological analysis, adenocarcinoma is the commonest subtype. It is interesting to note that in patients with ectopic pancreatic adenocarcinoma, the rate of having an elevated serum tumour marker is lower than that compared to primary pancreatic cancer [10,11].
It remains a challenge to obtain pre-operative confirmation of the diagnosis with conventional imaging like endoscopic ultrasound or computed tomographic scans as they often reveal a nonspecific mass. Common differentials include gastrointestinal tract stromal tumours (GIST), carcinoid tumours and gastric cancers. More than half of ectopic pancreatic tissue is located within the submucosal layer, while less than a fifth are located within the submucosa and muscularis propria [12]. Given that the commonest location for these tumours is the gastric antrum, endoscopic ultrasound should be a consideration. Ectopic pancreatic tissue is identified based not only on its location within the gastrointestinal wall, but also described to be a poorly defined, low echoic mass with an area of internal spotty high echo inside with a spindle-shaped, thickened muscularis propria neighbouring the lesion [12,13].
However, in majority of the cases described in literature, surgical resection was performed following the initial diagnosis of other tumours like GIST or gastric cancers and the final histology of ectopic pancreatic cancer was confirmed based on the resected surgical specimen [10]. Endo et al. described the diagnosis of malignancy based on preoperative biopsy and have advocated for the use of endoscopic biopsy such as endoscopic ultrasonography-guided, fine-needle aspiration (EUS-FNA) and endoscopic mucosal resection with a transparent plastic cap-fitted panendoscope (EMR-C) followed by a biopsy [10].
Nonetheless, there appears to be a significant false negative rate in the biopsy of submucosal lesions-up to 60% in a series by Matsuki et al. [14].
Besides breast and ovarian cancer, germline mutations in BRCA2 significantly increases the risk of pancreatic cancer with a relative risk of 3.51 [15]. While familial pancreatic cancers account for 5-10% of pancreatic cancers [16], Goggins et al. [17] found that the incidence of germline BRCA2 mutations in apparently sporadic pancreatic cancer may be at least as high (7.3%) as in breast or ovarian cancer, even in patients without family history, suggestive of an inherited predisposition to cancer. There are reports of earlier onset of pancreatic cancer is cases with BRCA2 mutations, with a mean age of 53-62 years [18,19], however 5 year survivals are no different from that of pancreatic cancer patients without genetic mutations. Pancreatic cancer may result from the germline mutations in various cancer susceptibility genes such as BRCA1, BRCA2, TP53, PALB2, p16/CDKN2A, SMAD4, STK11, ataxia-telangiectasia-mutated (AM) gene and mismatch repair (MMR) genes [16].
To date, there are no clear guidelines for the management of malignant ectopic pancreas. Authors have recommended local excision for lesions proven to be benign and extensive resection with oncological lymph nodal clearance for malignant lesions [20]. As such, pre-operative confirmation of the neoplastic process would be beneficial. There are limited reports of adjuvant therapy following oncological resection of these tumours. Hickman et al. describe that the course of ectopic pancreatic carcinomas within the stomach appear to behave like primary gastric cancers and suggest that they be managed in a similar fashion [21], while other patients underwent adjuvant chemotherapy similar to that for pancreatic cancer [22]. There is no available literature on the efficacy of chemotherapy for adenocarcinoma arising from a heterotopic pancreas [23]. In our patient, the adjuvant chemotherapy regime was akin to that prescribed for locally advanced pancreatic adenocarcinoma, for which in the recent PRODIGE 4/ACCORD 11 randomized trials, a four-drug regimen called FOLFIRINOX demonstrated to prolong overall survival compared to conventional gemcitabine monotherapy [24]. Given his BRCA2 status, the patient will continue to be closely followed-up for other associated malignancies like prostatic cancer and his family members have also been offered genetic screening. In terms of follow-up for the malignant ectopic pancreas, the surveillance with regular cross-sectional imaging would not differ from that of locally advanced pancreatic adenocarcinoma.

Conclusions
Adenocarcinoma arising from heterotopic pancreatic tissue as a result of a BRCA2 mutation is exceedingly rare. Pre-operative diagnostic confirmation is challenging and endoscopic procedures pose significant false negatives. Reports of nodal metastasis following oncological resection are limited and there are no guidelines regarding adjuvant therapies. We would recommend a chemotherapy regimen similar to that for primary locally advanced pancreatic carcinoma in patients found to have nodal metastasis. When atypical cancers are found in young patients, genetic counselling should be strongly considered after discussion with the patient.