Pancreatic intraepithelial neoplasia arising from an ectopic pancreas in the small bowel

Francisco Igor Macedo, Deepa Taggarshe, Tafadzwa Makarawo, Barry Herschman and Michael J Jacobs

Southfield, USA

Pancreatic intraepithelial neoplasia arising from an ectopic pancreas in the small bowel

Francisco Igor Macedo, Deepa Taggarshe, Tafadzwa Makarawo, Barry Herschman and Michael J Jacobs

Southfield, USA

BACKGROUND:Ectopic pancreatic tissue is relatively uncommon,and is characterized as pancreatic tissue with no contact with the normal pancreas, and with its own ductal system and blood supply. It is usually asymptomatic, and can be incidentally diagnosed by conventional imaging studies.

METHOD:A 69-year-old woman with a prior history of bilateral breast carcinoma presented with ectopic pancreatic intraepithelial neoplasia (PanIN) that was identified incidentally in the small bowel during an oncological resection of a synchronous primary pancreatic adenocarcinoma, and renal cell carcinoma.

RESULTS:The patient underwent subtotal pancreatectomy with splenectomy, regional lymphadenectomy, radical left nephrectomy,and small bowel resection with primary anastomosis of ectopic PanIN-2. She had an uneventful hospitalization and was discharged home on postoperative day 7.

CONCLUSIONS:The occurrence of ectopic PanIN is extremely unusual with only few cases previously reported in the literature.The need for negative margins after surgical resection of ectopic PanIN lesions remains controversial.

(Hepatobiliary Pancreat Dis Int 2014;13:658-661)

ectopic pancreas;

pancreatic intraepithelial neoplasia;

PanIN;

pancreatic adenocarcinoma

Introduction

Ectopic pancreatic tissue is relatively rare, estimated around 2%-15% of all autopsies. It results from detachment of pancreatic tissues during the process of rotation of the foregut and fusion of the ventral and dorsal parts of the pancreas.[1]Malignant transformation of this tissue is extremely uncommon with only few cases being previously reported.[1-3]

Pancreatic intraepithelial neoplasia (PanIN) was recently described as a preinvasive precursor lesion of pancreatic ductal adenocarcinoma.[4,5]This lesion was initially described as a result of great efforts for early detection of pancreatic cancer and, therefore, aiming at optimizing outcomes. PanINs are microscopic lesions, and present a spectrum of cytoarchitectural changes (PanIN-1 to 3) with increasing accumulation of molecular genetic abnormalities. Herein, we report a case of PanIN arising from an ectopic pancreatic tissue located in the small bowel in a patient with concurrent multiple synchronous primary malignancies, and discuss histopathological aspects, management and outcomes of PanIN lesions.

Case report

A 69-year-old woman with a recent history of bilateral mastectomy, right axillary node dissection, and immediate breast reconstruction was referred to our office for an abnormal staging computed tomography (CT) scan that revealed a pancreatic lesion and a left renal mass. Institutional Review Board was obtained waiving the need for informed consent. Her past medical history was significant for a left breast ductal carcinomain situin 2001 that was subjected to breast conservation surgical therapy and external beam radiation. She received hormonal therapy with tamoxifen for five years. The patient had remained disease-free until 2012 when she noticed a mass in her right breast. Mammographyand ultrasound showed a 2×3 cm lobulated mass in the central aspect of the right breast (BIRADS-5). The left breast was normal. The biopsy showed metaplastic carcinoma of the right breast. Her family history was negative for cancer and genetic testing for BRCA1 and BRCA2 was negative. The patient was not tested for other genetic mutations that could predispose multiple neoplastic syndromes. She underwent bilateral total mastectomy with right superficial lymph node dissection and immediate reconstruction with tissue expanders. Microscopic examination confirmed ductal invasive carcinoma that was triple receptor negative and node negative (pT2, pN0) (Fig. 1A). During her staging workup before chemotherapy, the patient had a contrastenhanced CT of the abdomen and pelvis that revealedan incidental 1.3 cm distal pancreatic mass and a 4.7 cm solid heterogeneous mass in the superior aspect of the left kidney that was suggestive of renal cell carcinoma (RCC) (Fig. 2). No metastatic disease was otherwise noted. Endoscopic ultrasound showed a 1.5×1.5 cm hypoechoic pancreatic body mass, and fine-needle aspiration cytology confirmed pancreatic adenocarcinoma. The patient underwent subtotal pancreatectomy with splenectomy, regional lymphadenectomy, and radical left nephrectomy. Intraoperatively, a small bowel neoplasm was located at approximately 6 cm distal to the ligament of Treitz that was resected with primary small bowel anastomosis. This lesion was not detected by preoperative radiological studies. Microscopic examination revealed node positive (5/26 nodes) invasive poorly-differentiated adenocarcinoma of distal pancreas with features of PanIN-3 or carcinoma in situ (Fig. 1B). Fuhrman grade-2 clear cell carcinoma of the left kidney was confirmed (Fig. 1C), and the small bowel mass was consistent with ectopic pancreatic tissue containing PanIN-2 (Fig. 3). The patient had an uneventful hospitalization and was discharged home on postoperative day 7.

Fig. 1.A: Invasive ductal breast carcinoma. Round to irregular invasive glands causing dense desmoplastic reaction in the stroma;B: Pancreatic ductal adenocarcinoma. Nuclear atypia, desmoplasia, necrotic glandular debris, and glandular mitotic figures are clear-cut features of the invasive nature of the lesion;C: Renal cell carcinoma. The neoplastic cells have clear cytoplasm and are arranged in nests with intervening blood vessels. With this microscopic appearance, tumor is also known as "clear cell carcinoma" (all original magnification ×400).

Fig. 2.A: A focal dilated pancreatic duct associated with pancreatic parenchymal atrophy and abnormal parenchymal attenuation with a suspicious 1.3 cm mass at the level of the pancreatic body (arrow);B: A 4.7 cm solid left renal mass highly suspicious for primary renal cell carcinoma (asterisk). There are no findings to suggest the involvement of retroperitoneal lymph nodes, vascular structures, or the left adrenal gland.

Fig. 3.Ectopic pancreatic PanIN-2. This picture displays an isolated focus of ectopic pancreatic tissue within duodenal muscularis propria (D-MP) containing a duct diameter less than 0.5 cm that is mostly lined by PanIN-1 (A, original magnification ×40), and further characterized by flat simple columnar epithelium (B, original magnification ×100). The presence of focal nuclear atypia and papillary growth upgrades the lesion to PanIN-2 (C, original magnification ×400).

Discussion

Ectopic pancreas may develop during the embryologic stage of gut rotation in a location distant from the normal pancreas, whereby it has its own ductal system and blood supply. The most frequent sites are the gastric antrum (30%), duodenum (30%), jejunum (20%), and Meckel's diverticulum (5%).[1]Most patients are asymptomatic and when present, symptoms are usually nonspecific and depend on the site of the lesion.[6]The ectopic tissue is susceptible to the same pathological changes that occur in the normal pancreas, such as pancreatitis and pseudocyst formation. The malignant transformation of ectopic pancreas has been reported in different sites of the gastrointestinal tract.[7,8]The diagnosis may be difficult, and is incidentally found by conventional imaging studies or intraoperatively. The actual prognosis of ectopic pancreatic adenocarcinoma has yet to be determined because of its rare occurrence, with survivals ranging between six months to ten years.[7,9,10]In this case, the ectopic pancreatic tissue containing PanIN-2 is a precursor lesion of pancreatic ductal adenocarcinoma. This lesion is microscopically papillary or flat, noninvasive, epithelial neoplasm that is usually less than 5 mm and confined to the pancreatic ducts. They are composed of columnar to cuboidal cells with variable amounts of mucin that can be divided into three grades according to the degree of cytological and architectural atypia.[11]Although there is growing evidence supporting genetic association between PanIN and pancreatic adenocarcinoma, the pathogenesis of these lesions has not been well-established. It seems that there is a gradual accumulation of genetic abnormalities, involving K-ras, p16, p53, cyclin D1, BRCA2 and DPC4.[12,13]

PanIN-1 lesions are common incidental findings and can be detected in up to 40% of adult pancreas without invasive carcinoma, whereas high-grade PanIN share the same genetic aberrations as orthotopic pancreatic carcinoma.[14]Overall, PanIN has a better prognosis than adenocarcinoma since these lesions are considered in situ; however they may progress from intraductal hyperplasia to infiltrating carcinoma of the pancreas.[15]The clinical experience of ectopic PanIN is scarce with only a handful cases previously published.[14,16]These lesions were described after being detected in the stomach and duodenum during pathological evaluation of en bloc specimens after resection of pancreatic adenocarcinoma.[14]In such cases, it can be difficult to decide whether high-grade PanIN lesions near infiltrating tumor are precursors or a manifestation of intraductal spread. In the present case, we found a PanIN-2 in the jejunum not adjacent to the orthotopic pancreatic carcinoma. This lesion was completely removed with oncological negative margins. Although PanIN is considered a precursor of pancreatic adenocarcinoma and, in particular, PanIN-3 is considered carcinoma in situ,[17]the impact of positive margins after surgical resection on outcomes remains controversial. Matthaei et al[18]recently published a retrospective series of patients with PanIN lesions at surgical margins after resection of "in situ" pancreatic adenocarcinoma. They found no adverse outcomes in a 18-month follow-up of such patients. Further clinical experience and a longer follow-up are needed to define whether PanIN lesions, especially PanIN-3 at surgical margins are associated with worse outcomes.

In addition to the presence of ectopic pancreatic tissue with dysplastic changes, this case is unique due to the presence of concurrent multiple primary malignancies, including pancreatic adenocarcinoma, RCC, and breast cancer. The occurrence of multiple primary malignant tumors in a single patient is rare. The estimated incidence of a second primary cancer from autopsy series ranges from 3% to 7%.[19,20]The increased diagnosis of a second primary malignancy is attributed to the rise in survival rates in patients with a previous malignancy treated with resection and more effective modalities of chemoradiation. The presence of concurrent breast cancer and pancreatic adenocarcinoma can occur in patients with BRCA1 and BRCA2 mutations.[21,22]The presence of a third malignancy, renal clear cell carcinoma with breast and pancreaticadenocarcinoma, has never been reported. Metastatic carcinoma to the pancreas is uncommon, and accounts for approximately 2% of pancreatic malignancies.[11]These metastases may present synchronously, but tend to occur months to years following resection of the primary tumor, i.e. usually 10 years after nephrectomy for RCC.[23]This patient presented with primary pancreatic adenocarcinoma with no features of RCC.

In conclusion, we have described an ectopic PanIN-2 associated with multiple synchronous primary malignancies. The patient was a non-smoker, BRCA-negative, and had no significant family history of diseases. No other predisposing factors were found to related to these malignancies, suggesting a yet unidentified genetic predisposition for multiple neoplasias in this subset of patients. Ectopic PanIN is extremely rare but may occur in patients undergoing hepatobiliary resections. Further clinical experience is still needed to define whether negative margins are required after resection of these lesions.

Contributors:JMJ proposed the study. Mfiand TD wrote the first draft. Mfiand MT collected the data. HB performed pathological analysis of slides. MFI, MT and JMJ revised and corrected manuscript. All authors contributed to the design and interpretation of the study. Mfiis the guarantor.

Funding:None.

Ethical approval:The study was approved by Institutional Review Board of our hospital.

Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received December 11, 2013

Accepted after revision April 9, 2014

Author Affiliations: Department of General Surgery (Macedo FI, Taggarshe D, Makarawo T and Jacobs MJ) and Department of Pathology (Herschman B), Providence Hospital and Medical Centers, Southfield, MI 48075, USA

Francisco Igor Macedo, MD, Department of General Surgery, Providence Hospital and Medical Centers, 16001 W Nine Mile Rd, Southfield, MI 48075, USA (Tel: +1-786-9994754; Fax: +1-248-8497638; Email: igormacedo1@hotmail.com)

? 2014, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(14)60273-3

Published online June 23, 2014.