The pancreas parenchyma is composed of three cell types: ductal cells, acinar cells, and endocrine cells, including islets of Langerhans. These three cell types are thought to be derived from the embryonic foregut1; therefore, three types of pancreatic tumors—ductal, acinar, and endocrine tumors—develop from the pancreas parenchyma. Mixed tumors including these elements, although very rare, are known to develop from the pancreas parenchyma. These tumors are mixed ductal-endocrine tumor, mixed acinar-endocrine tumor, mixed ductal-acinar tumor, and mixed ductal-acinar-endocrine tumor.

Mixed ductal-endocrine carcinoma, one of the histologic variants, is defined according to World Health Organization criteria as “a carcinoma in which ductal and endocrine cells are intimately admixed.”1,2 Because pancreatic ductal carcinomas frequently exhibit endocrine components, as is the case with carcinomas in other organs, the endocrine cell component must constitute more than 30% of the tumor area to meet the diagnostic criteria for mixed ductal-endocrine carcinoma.2 We report here a case of mixed ductal-endocrine carcinoma of the pancreas complicated by renal cell carcinoma.

Case Report

In 2006, a 68-year-old man was referred to Gunma University Hospital for treatment of a pancreatic tumor and a right renal tumor detected by physical examination. He had no symptoms but had been treated for hypertension, hyperlipidemia, and hyperuric acidemia. He had undergone surgery for right lung cancer in 2004 and for rectal cancer in 1988. His blood cell counts and biological chemistry data were nearly within normal ranges. Tumor marker levels (carbohydrate antigen 19-9, carcinoembryonic antigen, and DUPAN-2) were not elevated. Based on further imaging of the lesions, we suspected that the pancreatic tumor was an endocrine tumor, even though endocrinologic laboratory findings were almost within the normal range. The gastrin level was slightly elevated (210 pg/mL), and the patient had been treated with a proton pump inhibitor. No lesion was found in the upper gastrointestinal fiber.

Enhanced computed tomography (CT) revealed a hypervascular tumor, 2 cm in diameter, at the pancreas uncus and an isodensity tumor, 1.5 cm in diameter, at the upper portion of the right kidney (Fig. 1A and 1B). Abdominal angiography with CT during arteriography (CTA) revealed that the pancreatic tumor was fed by the inferior pancreatic duodenal artery branching from the superior mesenteric artery and was partially fed by the anterior superior pancreatic duodenal artery branching from the gastroduodenal artery (Fig. 1C). The right renal tumor was fed by an upper branch of the right renal artery. The pancreatic tumor was markedly enhanced in the arterial phase and was rapidly washed out in the venous phase. Abdominal ultrasonography revealed that both the pancreatic tumor and the renal tumor were hypoechoic. Endoscopic retrograde pancreatography revealed no lesion at the main pancreatic duct. ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) revealed abnormal accumulation (maximum standard uptake value [SUV], 9.0) at the pancreas head lesion but no abnormal accumulation at the right renal lesion (Fig. 1D).

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Based on the diagnosis of a pancreatic endocrine tumor with malignant potential and right renal cell carcinoma, we performed pyrolus-preserving pancreaticoduodenectomy with regional lymph node resection and right nephrectomy. A resected specimen of the pancreatic tumor was macroscopically a solid tumor with a hemorrhage lesion (Fig. 2A). The renal tumor was a round tumor with a capsule. Pathologic study revealed that the pancreatic tumor had 2 components: invasive ductal carcinoma and neuroendocrine tumor (Fig. 2B). Immunohistochemically, the lesion with ductal carcinoma had 30% stainings for the Ki-67 labeling index, and the neuroendocrine tumor had stainings of chromogranin A and synaptophysin (Fig. 2D, 2E, and 2F). Other immunohistologic findings, including those for insulin, glucagon, gastorin, and somatostatin, had no staining at the pancreatic lesion. The renal tumor was a typical renal cell carcinoma (Fig. 2C). The resected regional lymph nodes were not metastasized. We diagnosed mixed ductal-endocrine carcinoma of the pancreas complicated by renal cell carcinoma. The patient was discharged 30 days after the operation and had had no recurrence 52 months after the surgery.

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Discussion

A pancreatic tumor most often is derived from the exocrine cells (ductal cells), as well as from the endocrine cells (islet cells) and the acinar cells in the pancreatic parenchyma.3 A mixed tumor of the pancreas, which is very rare, includes these cell components. In a series of 645 pancreatic tumors reported by Cubilla et al, ductal cell carcinomas represented 88.8% of pancreatic tumors, while endocrine cell tumors and acinar cell carcinomas represented only 7.4% and 1.2% of tumors, respectively.4 Mixed cell carcinomas were very rare, representing only 0.2% of all cases.4 The Japan Pancreatic Cancer Registry Report 2007 reported 10,851 cases of ductal cell carcinoma (72.8%) and only 9 cases of mixed tumor (0.06%), out of a total of 14,904 cases of pancreatic cancer histologically diagnosed in Japan from 2001 to 2004.5 A mixed tumor of the pancreas includes 4 types of tumors: ductal-endocrine tumor, acinar-endocrine tumor, ductal-acinar tumor, and ductal-acinar-endocrine tumor. We herein report the successful treatment of mixed ductal-endocrine carcinoma of the pancreas occurring as a double cancer—a complication of right renal carcinoma.

The pancreatic tumor of the present case appeared hypervascular, indicating an endocrine tumor. A resected specimen was used for the diagnosis of mixed ductal-endocrine carcinoma of the pancreas. Seventeen case reports of pancreatic mixed ductal-endocrine tumor have been published in English language journals,6–21 as shown in Table 1. A literature review with a case report by Iwamuro M et al showed 34 mixed-tumor cases in Japanese reports.22 As shown in a review of 17 reports (Table 1), mixed ductal-endocrine carcinoma of the pancreas seems to have high malignant potential. Six patients (33%) died 6 to 24 months after diagnosis, and 8 patients (44%) were alive without evidence of disease 3 to 72 months after diagnosis, except for Terada's case, which is delay-complicated by ductal-endocrine carcinoma.14 Follow-up information on 3 cases was not available. The median survival time is 13 ± 11 months (n  =  14). Hepatic metastases were present at initial presentation or during follow-up in 39% (7 cases) of cases. The outcomes of these reports and of the present case suggest that mixed ductal-endocrine carcinoma does not present the same prognosis as invasive ductal carcinoma but has high malignant potential.

Table 1 Mixed ductal-endocrine carcinoma of the pancreas, review of literature

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The present case was diagnosed as a double cancer. The patient had undergone 2 surgeries for lung cancer and rectal cancer. Other reported cases were complicated by malignancy in other organs. Terada et al reported an autopsy case of mixed ductal-endocrine carcinoma presenting as gastrinoma with Zollinger-Ellison syndrome. During the follow-up period, the case was complicated by gallbladder mucosal adenocarcinoma.14 Chatelain et al reported mixed ductal-endocrine carcinoma complicated by squamous cell carcinoma of the gingiva.16 Carter et al reported mixed ductal-endocrine carcinoma complicated by papillary carcinoma in situ of the common bile duct.20 Thus, this tumor tends to complicate synchronous or asynchronous double cancer in other organs, and patients with this type of tumor should undergo long-term monitoring for cancer of other organs.

In the present case, we initially diagnosed this tumor as a pancreatic endocrine tumor because of rapid enhancement in the arterial phase and washing out in the venous phase, as shown by CTA and angiography. Despite the histologic diagnosis in this case, CTA images revealed heterogeneous enhancement, but the lesions were very small. Iwamuro et al reported that, in a case diagnosed before surgery as a nontumor lesion similar to fibrosis, CT images revealed a low-density area surrounding the hypervascular tumor. Other reports have indicated difficulty with the presurgical and histologic diagnosis of this type of tumor. Thus, in cases of a hypervascular lesion with heterogeneous enhancement shown by enhanced CT or CTA, a low-density area surrounding the tumor in CT, or abnormal accumulation in FDG-PET, we propose that, if there is any doubt, surgical resection with a sufficient resection margin and regional lymph node resection should be performed.

In conclusion, we report a case of mixed ductal-endocrine carcinoma of the pancreas complicated by right renal cell carcinoma. The patient should receive careful, long-term monitoring because of the potential for recurrence of this carcinoma and carcinogenesis in other organs. This tumor is very difficult to diagnose before surgical resection and histologic examination. Therefore, when there is doubt, surgical resection with a sufficient resection margin and regional lymph node resection should be performed to improve the patient's prognosis.