Case Report

Pancreas-preserving segmental duodenectomy for gastrointestinal stromal tumor of the duodenum and splenectomy for splenic angiosarcoma Mirko Muroni, Matteo Ravaioli, Massimo Del Gaudio, Giuseppe Nigri, Francesco D'Angelo, Stefania Uccini and Giovanni Ramacciato Rome, Italy

BACKGROUND: Gastrointestinal stromal tumors are the most common mesenchymal tumors of the gastrointestinal tract and occur rarely in the duodenum. Splenic angiosarcoma is an aggressive neoplasm with an extremely poor prognosis. METHODS: We report a case of a 70-year-old man hospitalized for abdominal pain in the upper quadrants, dyspepsia and nausea, previously treated for Hodgkin lymphoma 30 years ago. Abdominal CT showed a solid nodular lesion in the third portion of the duodenum, the presence of retropancreatic, aortic and caval lymph nodes, and four nodular splenic masses. 111 In-octreotide scintigraphy revealed pathological tissue accumulation in the duodenal region, and in the retropancreatic, retroduodenal, aortic and caval lymph nodes, suggesting a nonfunctioning neuroendocrine peripancreatic tumor. RESULTS: At exploratory laparotomy, an exophytic soft tumor was found originating from the third portion of the duodenum. Pancreas-preserving duodenectomy with duodenojejunostomy, splenectomy and lymphnodectomy of retropancreatic aortic and caval lymph nodes were performed. Pathological evaluation and immunohistochemical studies showed the presence of a duodenal gastrointestinal stromal tumor with low mitotic activity and a well-differentiated angiosarcoma localized to the spleen and invading lymph nodes.

Author Affiliations:  Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery (Muroni M, Ravaioli M, Gaudio MD, Nigri G, D'Angelo F and Ramacciato G) and Department of Clinical and Molecular Medicine (Uccini S), La Sapienza University of Rome, Second School of Medicine, St. Andrea Hospital, via di Grottarossa 1035, 00189 Rome, Italy Corresponding Author: Mirko Muroni, MD, Division of Hepato-BiliaryPancreatic Surgery, Department of General Surgery, La Sapienza University of Rome, Second School of Medicine, St. Andrea Hospital, viale Gino Cervi 53 L, 00139 Rome, Italy (Tel: 39-328-4521618; Fax: 39-06-33775322; Email: [email protected]) © 2012, Hepatobiliary Pancreat Dis Int. All rights reserved. doi: 10.1016/S1499-3872(12)60169-6

CONCLUSIONS: We speculated that the angiosarcoma and duodenal gastrointestinal stromal tumors of this patient were due to the treatment of Hodgkin lymphoma with radiotherapy 30 years ago. Pancreas-preserving segmental duodenectomy can be used to treat non-malignant neoplasms of the duodenum and avoid extensive surgery. Splenectomy is the treatment of choice for localized angiosarcomas but a strict follow-up is mandatory because of the possibility of recurrence. (Hepatobiliary Pancreat Dis Int 2012;11:325-329) KEY WORDS: duodenal neoplasms; gastrointestinal stromal tumors; hemangiosarcoma; splenectomy; splenic neoplasms; pancreaticoduodenectomy

Introduction

G

astrointestinal stromal tumors (GISTs) are mesenchymal tumors of the digestive tract usually localized in the stomach, small intestine, colon and rectum. Only 5% occur in the duodenum.[1] Surgical resection remains the main curative treatment modality. Different surgical procedures for duodenal GIST have been described, such as wedge and local resection, pancreas-preserving segmental duodenectomy, pancreas-preserving total duodenectomy and pancreaticoduodenectomy.[2, 3] Angiosarcoma of the spleen is a rare neoplasm and the pathogenesis is unknown. It is an aggressive tumor and frequently presents with hematological or metastatic diseases. Splenectomy is the treatment of choice. This is the first case of a GIST associated with splenic angiosarcoma.

Case report A 70-year-old man was admitted for abdominal pain

Hepatobiliary Pancreat Dis Int，Vol 11，No 3 • June 15，2012 • www.hbpdint.com • 325

Hepatobiliary & Pancreatic Diseases International

localized in the upper quadrants and jaundice for over a month. The patient had inconstant symptoms of dyspepsia and nausea. Past medical history revealed Hodgkin lymphoma treated with radiotherapy and chemotherapy 30 years ago, atrial fibrillation treated with antiarrhythmic drugs (propafenone), and recent acute biliary pancreatitis treated with medical therapy and operative ERCP. The patient was hospitalized in another institution for biliary pancreatitis with jaundice 30 days before our observation. Abdominal ultrasound revealed gallbladder stones. Abdominal CT showed a 20-mm solid nodular lesion in the third portion of the duodenum (Fig. 1), and a 24×21 mm mass with a fluid component in the pancreatic body associated with three 15-mm retropancreatic lymph nodes and 20-mm and 12-mm aortic and caval lymph nodes. Also, nodular splenic masses between 7 and 18 mm showed on the CT scan (Fig. 2), suggesting a nonfunctioning neuroendocrine peripancreatic tumor. Integration of somatostatin receptor imaging with 111 In-octreotide was performed. The scintigraphic exam showed pathological tissue accumulation of 111 In-octreotide in the duodenal region, and in the retropancreatic, retroduodenal, aortic and caval lymph

nodes. The radiotracer distribution in the spleen was not diagnostic, because there was a normal tissue accumulation of 111In-octreotide due to vascularization of the spleen. The patient was transferred to the Department of Surgery of our hospital for surgical treatment. Laboratory tests on admission showed the total white cell count was 4400 cells/mm3, normal hemoglobin level (13.8 g/dL) and the C-reactive protein level (PCR) 1.4 mg/dL. The tumor markers were within the normal levels: CEA 1.71 ng/mL (normal range 0.00-3.00), CA125 5.40 IU/mL (normal range 0.00-35.00), CA19.9 28.00 IU/mL (normal range 0.00-37.00), tissue polypeptide antigen (TPA) 50.90 IU/L (normal range 2.00-75.00). On the basis of these features we diagnosed gallbladder stones, previous biliary pancreatitis, and suspected a nonfunctioning neuroendocrine peripancreatic tumor. At exploratory laparotomy, a 2.5-cm exophytic elastic soft tumor was found originating from the third portion of the duodenum (Fig. 3). No evidence of local invasion of the pancreas was found. The intra-operative histological examination revealed a soft tissue tumor with no malignant component. The intra-operative peripancreatic lymph node biopsy showed the absence of neoplastic cells. The pancreatic mass was a pancreatic pseudocyst as suggested by CT scan. No resection of any part of the pancreas was necessary. Thus, distal segmental duodenectomy preserving the pancreas, retropancreatic, aortic and caval lymph node dissection, cholecystectomy and splenectomy were performed. The gastrointestinal tract was reconstructed with side-by-side head-preserving duodenojejunostomy. Histological examination of the specimen demonstrated a GIST of the duodenum and a splenic and lymph node angiosarcoma. The duodenal neoplasm had a low mitotic activity Fig. 1. CT of the upper abdomen showing a 20-mm solid nodular (5 mitoses/50 HPF) and immunohistochemical studies lesion into the third duodenal portion (arrow). revealed positivity for c-Kit (CD117) (Fig. 4). The splenic

Fig. 2. CT of the upper abdomen showing splenic nodular lesions (arrows).

Fig. 3. The GIST localized into the third duodenal portion (arrow).

326 • Hepatobiliary Pancreat Dis Int，Vol 11，No 3 • June 15，2011 • www.hbpdint.com

Pancreas-preserving segmental duodenectomy

Fig 4. Histological features of duodenal GIST. A: Neoplastic cells of duodenal GIST. There is residual normal intestinal mucosa and submucosa in the upper right corner (HE staining, original magnification ×25). B: The tumor is composed of rounded, epithelioid and spindled cells (HE staining, original magnification ×400). C: Diffuse positive staining of CD117 (original magnification ×400).

Fig 5. Histological features of splenic angiosarcoma (original magnification ×400). A: The angiosarcoma is composed of well differentiated cells within solid areas. There is an appreciable mitotic activity (arrow) and numerous vascular structures containing red cells (HE staining). B: Diffuse positive staining of CD31. C: Tumor cells immunostained for CD34.

neoplasm was a well-differentiated angiosarcoma. The neoplastic cells were positive for CD31 and CD34 (Fig. 5) and negative for CD68. The mitotic activity was 10 mitoses/10 HPF (score 2). Four out of six aortic and caval lymph nodes were positive for recurrences of angiosarcoma (pT1b, pN1). During the post-operative course, the patient was maintained on parenteral nutrition for 8 days and subsequently a clear liquid diet was given. An ordinary diet was started on postoperative day 12 and he was discharged on the postoperative day 14. The patient refused any systemic adjuvant treatment and a six-month follow-up revealed no tumor recurrences and absence of symptoms and signs related to the previous diseases.

Discussion Duodenal GIST usually appears with gastrointestinal hemorrhage, upper abdominal pain or an abdominal mass. Some patients are asymptomatic. Clinical presentation is often vague. Other mesenchymal

tumors involving the duodenum are leiomyomas, leiomyosarcomas, neurofibromas, duodenal adenomas, and stromal tumors.[4-6] Pathological diagnosis must be confirmed according to the histological and immunohistochemical work-up. Duodenal tumors are classified as GIST if tumor cells are positive for CD117 (protein tyrosine kinase Kit). Positivity for CD117 is the gold standard to establish a diagnosis of GIST. However, some tumors have clinicopathologic features of GIST but do not express Kit. GISTs with no detectable Kit expression have been reported to be up to 10%.[7] The treatment of duodenal GISTs consists of complete surgical removal of the tumor with clear surgical margins, including involved adjacent organs if required. Duodenectomy that preserves the pancreas has been reported in recent years.[8-10] It offers many advantages, such as reconstruction of a large duodenal defect caused by surgical resection, and avoids the risk of developing endocrine and exocrine pancreatic insufficiency and many of the risks associated with a biliary or pancreatic jejunostomy anastomosis. We did not choose a limited

Hepatobiliary Pancreat Dis Int，Vol 11，No 3 • June 15，2012 • www.hbpdint.com • 327

Hepatobiliary & Pancreatic Diseases International

procedure, such as wedge duodenal resection, because of the risk of subsequent stenosis as well as tumor recurrence in patients treated using this operation. In the present case, we performed a splenectomy to treat the 4 nodular splenic lesions that preoperatively were supposed to be metastases from the nonfunctioning neuroendocrine peripancreatic tumor. Also, lymph node dissection was carried out since pre-operative scintigraphy showed pathological tissue accumulation of 111In-octreotide in the aortic and caval lymph nodes. However, histological evaluation revealed a splenic and lymph node angiosarcoma. Angiosarcoma is a rare tumor entity originating from endothelial cells and accounts for only 2% of soft tissue sarcomas. Splenic angiosarcomas are aggressive neoplasms with a severe prognosis[11] and they can develop years after radiation therapy for other malignancies.[12] Oncological evaluation suggested chemotherapy that finally was denied by the patient. Various types of chemotherapy for angiosarcomas are discussed in the literature but no protocol for this disease has been established yet. Doxorubicin-based chemotherapy remains the standard treatment of metastatic or unresectable angiosarcomas; clinical benefit and tumour control with taxanes have been reported.[13] Imatinib mesylate is the treatment for locally advanced or metastatic GIST. Imatinib is a signal transduction inhibitor and, in particular, inhibits the binding of adenosine triphosphate to tyrosine kinase that includes PDGFRA and the c-Kit receptor expressed in GISTs.[14] Recently sunitinib malate, an oral receptor tyrosine kinase inhibitor, was approved for the treatment of GISTs after progression or intolerance to imatinib mesylate. Sunitinib inhibits platelet-derived growth factor receptors and vascular endothelial growth factor receptors, which play key roles in tumor angiogenesis and tumor cell proliferation.[15] In the present case, the early diagnosis was a suspected nonfunctioning metastatic neuroendocrine peripancreatic tumor, based on interpretation of 111Inoctreotide scintigraphy. In-octreotide, a synthetic analog of somatostatin, is used to treat patients with endocrine tumors that express cell-surface somatostatin receptors. Recently, somatostatin receptors have also been identified in GISTs and angiosarcomas, and on neoplastic cells; they have high affinity and specificity for somatostatin analogues such as octreotide.[16, 17] This molecular basis could explain the pathological tissue accumulation of 111In-octreotide in the duodenal region, and in the retropancreatic, retroduodenal, aortic and caval lymph nodes. This is the first case described in the literature of

a GIST associated with splenic angiosarcoma. Was this only coincidence or do they have any relations or etiological associations? Most GISTs occur as solitary lesions involving the tubular gastrointestinal tract but have rarely been associated with other benign or malignant neoplasms.[18] The development of GISTs and other associated neoplasms may involve the same carcinogenic agents and may be the result of mutations, genetic predisposition, and exposure to therapeutic agents such as radiation or chemotherapy.[19-21] It is possible that a previous irradiation played an etiological role in the pathogenesis of this GIST. We hypothesized that the angiosarcoma and duodenal GIST in this case were caused by the previous radiotherapy for Hodgkin lymphoma that included the entire abdomen and neck with 30 cycles about 30 years ago. In conclusion, we report a case of duodenal gastrointestinal stromal tumor treated with limited surgical resection and synchronous splenic angiosarcoma treated with splenectomy and local lymph node dissection. Pancreas-preserving segmental duodenectomy is a surgical procedure that can be used to treat non-malignant neoplasms of the duodenum and avoid extensive surgery with significant morbidity and possible mortality such as pancreatoduodenectomy. Contributors: MM conceived the idea, wrote the manuscript, and performed the literature search. RM and GMD assisted in the literature search. US performed the pathological and immunohistochemical studies. NG, DAF and RG reviewed the manuscript. All authors contributed to the intellectual context and approved the final version. MM is the guarantor. Funding: None. Ethical approval: Not needed. 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.

References 1    Yang WL, Yu JR, Wu YJ, Zhu KK, Ding W, Gao Y, et al. Duodenal gastrointestinal stromal tumor: clinical, pathologic, immunohistochemical characteristics, and surgical prognosis. J Surg Oncol 2009;100:606-610. 2    Imamura M, Komoto I, Doi R, Onodera H, Kobayashi H, Kawai Y. New pancreas-preserving total duodenectomy technique. World J Surg 2005;29:203-207. 3    de Castro SM, van Eijck CH, Rutten JP, Dejong CH, van Goor H, Busch OR, et al. Pancreas-preserving total duodenectomy versus standard pancreatoduodenectomy for patients with familial adenomatous polyposis and polyps in the duodenum. Br J Surg 2008;95:1380-1386. 4    Suzuki H, Yasui A. Pancreas-sparing duodenectomy for a huge leiomyosarcoma in the third portion of the duodenum. J Hepatobiliary Pancreat Surg 1999;6:414-417.

328 • Hepatobiliary Pancreat Dis Int，Vol 11，No 3 • June 15，2011 • www.hbpdint.com

Pancreas-preserving segmental duodenectomy

5    Miettinen M, Kopczynski J, Makhlouf HR, Sarlomo-Rikala M, Gyorffy H, Burke A, et al. Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the duodenum: a clinicopathologic, immunohistochemical, and molecular genetic study of 167 cases. Am J Surg Pathol 2003; 27:625-641. 6    Cueto J, Benotto JA, Catalina R, Vazquez-Frias JA. Large duodenal villous adenoma requiring head of the pancreas and pylorus-preserving total duodenectomy. Surg Laparosc Endosc Percutan Tech 2005;15:230-233. 7    Medeiros F, Corless CL, Duensing A, Hornick JL, Oliveira AM, Heinrich MC, et al. KIT-negative gastrointestinal stromal tumors: proof of concept and therapeutic implications. Am J Surg Pathol 2004;28:889-894. 8    Buchs NC, Bucher P, Gervaz P, Ostermann S, Pugin F, Morel P. Segmental duodenectomy for gastrointestinal stromal tumor of the duodenum. World J Gastroenterol 2010;16:2788-2792. 9    Spalding DR, Isla AM, Thompson JN, Williamson RC. Pancreas-sparing distal duodenectomy for infrapapillary neoplasms. Ann R Coll Surg Engl 2007;89:130-135. 10 Kalady MF, Clary BM, Tyler DS, Pappas TN. Pancreaspreserving duodenectomy in the management of duodenal familial adenomatous polyposis. J Gastrointest Surg 2002;6: 82-87. 11 Fury MG, Antonescu CR, Van Zee KJ, Brennan MF, Maki RG. A 14-year retrospective review of angiosarcoma: clinical characteristics, prognostic factors, and treatment outcomes with surgery and chemotherapy. Cancer J 2005;11:241-247. 12 Nanus DM, Kelsen D, Clark DG. Radiation-induced angiosarcoma. Cancer 1987;60:777-779. 13 Schlemmer M, Reichardt P, Verweij J, Hartmann JT, Judson I, Thyss A, et al. Paclitaxel in patients with advanced angiosarcomas of soft tissue: a retrospective study of the EORTC soft tissue and bone sarcoma group. Eur J Cancer

2008;44:2433-2436. 14 Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472-480. 15 Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006;368:1329-1338. 16 Reubi JC, Körner M, Waser B, Mazzucchelli L, Guillou L. High expression of peptide receptors as a novel target in gastrointestinal stromal tumours. Eur J Nucl Med Mol Imaging 2004;31:803-810. 17 Reubi JC, Waser B, Laissue JA, Gebbers JO. Somatostatin and vasoactive intestinal peptide receptors in human mesenchymal tumors: in vitro identification. Cancer Res 1996;56:1922-1931. 18 Agaimy A, Wünsch PH, Sobin LH, Lasota J, Miettinen M. Occurrence of other malignancies in patients with gastrointestinal stromal tumors. Semin Diagn Pathol 2006; 23:120-129. 19 Agaimy A, Wuensch PH. Gastrointestinal stromal tumours in patients with other-type cancer: a mere coincidence or an etiological association? A study of 97 GIST cases. Z Gastroenterol 2005;43:1025-1030. 20 Miller PR, Jackson SL, Pineau BC, Levine EA. Radiationinduced gastrointestinal stromal sarcoma of the esophagus. Ann Thorac Surg 2000;70:660-662. 21 Liu YJ, Yang Z, Hao LS, Xia L, Jia QB, Wu XT. Synchronous incidental gastrointestinal stromal and epithelial malignant tumors. World J Gastroenterol 2009;15:2027-2031. Received October 26, 2010 Accepted after revision March 26, 2011

Hepatobiliary Pancreat Dis Int，Vol 11，No 3 • June 15，2012 • www.hbpdint.com • 329