Metastatic Pancreatic Carcinoid Complicated by Gastric Outlet Obstruction

Running Title: Complications of pancreatic carcinoid

Assistant Profesor Dr. Mohamed Hadzri Hasmoni ( Hadzri M.H ) Department of Internal Medicine, Kulliyyah of Medicine, International Islamic University Malaysia, Kuantan, Pahang, Malaysia

Dr. Shiaw Hooi Ho ( Ho S.H ) Gastrointestinal Endoscopy Unit, Gastroenterology and Hepatology Division, Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia.

Associate Profesor Dr. Ida Hilmi ( Ida H ) Gastrointestinal Endoscopy Unit, Gastroenterology and Hepatology Division, Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia.

Profesor Dr. Khean Lee Goh ( Goh K.L ) Gastrointestinal Endoscopy Unit, Gastroenterology and Hepatology Division, Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia.

Correspondence: Assistant Professor Dr. Mohamed Hadzri Hasmoni Department of Internal Medicine Kulliyyah of Medicine International Islamic University Malaysia Kuantan 25200, Pahang MALAYSIA Tel: +609-5716400 Fax: +609-5177631 E-mail: hadzri@iium.edu.my / drhadzri@gmail.com

Title: Metastatic Pancreatic Carcinoid Complicated by Gastric Outlet Obstruction

Abstract Pancreatic carcinoid is an uncommon subset of carcinoid, a neuroendocrine tumor. We presented a 78 year-old man with an advanced metastatic pancreatic carcinoid. The tumor was large with multiple large liver metastases causing obstruction to the surrounding organs. He initially complained of obstructive jaundice with constitutional symptoms. It was further complicated with gastric outlet obstruction due to progression of the disease. The tumor was aggressive despite on somatostatin analogue therapy. His symptoms were successfully relieved with insertion of plastic biliary stent and metallic duodenal stent.

Key words: Pancreatic carcinoid, metastasis, gastric outlet obstruction, somatostatin analogue, duodenal stent.

Title: Metastatic Pancreatic Carcinoid Complicated by Gastric Outlet Obstruction

Introduction Carcinoid tumors are the most frequent neuroendocrine tumors of the gastrointestinal tract. Pancreatic carcinoid, on the other hand, is very rare and found to constitute less than 1% of all carcinoids.1 It is an indolent tumor and by the time of diagnosis they are usually very large and have multiple metastases. It has been reviewed that most of these patients have carcinoid symptoms and the common sites are the body and tail.

Case Report A 78 year-old man with a long standing history of hypertension and diabetes mellitus, presented with progressive yellowish discoloration of sclera, abdominal pain with tea colored urine and pale stools for two weeks. The symptoms were associated with loss of appetite and significant loss of weight. There was no episode of flushing noted. Initial ultrasound of the hepatobiliary system showed grossly dilated common bile duct (CBD) and intra-hepatic duct (IHD) with a large pancreatic mass. An urgent ERCP performed revealed grossly dilated CBD and IHD secondary to external compression. A plastic biliary stent (8cm, 7F) was successfully inserted. Subsequent abdominal CT scan showed a large tumor mass measuring 4.8cm in diameter in the region of the head of pancreas. The tumor was encasing the distal common bile duct and invaded areas adjacent to the second part of duodenum (Figure 1). There were also multiple heterogenous

hypodense foci in segment VII and VIII of the liver, compatible with metastasic disease, and multiple large liver cysts (Figure 2). Laboratory evaluation showed elevated serum chromogranin A of 180U/L, but with normal levels of tumor markers and urinary 5-Hydroxyindole acetic acid (5-HIAA). EUS guided FNA biopsy of the pancreatic mass was planned but the patient refused. However he agreed for a CTguided biopsy of the hepatic lesions. The biopsy revealed clusters of tumor cells (Figure 3). No evident of mitosis or any necrosis was seen in the biopsy. Interestingly, the

immunohistochemical study of the tumor for chromogranin A was strongly positive. Therefore a diagnosis of advance pancreatic carcinoid with multiple liver metastases was made. In view of the stage of the disease, a conservative approach was agreed upon by all the consultants involved from various specialties (gastroenterologist, oncologist and surgeon) and the patient. He was started on somatostatin analogue octreotide for one month and was later changed to long-acting lantreotide injection (lanreotide intramuscular 60mg) every 3-weeks. Unfortunately, he presented again two months later with complaints of nausea, vomiting and early satiety. An urgent gastroscopy showed an external mass, most likely progression of the pancreatic tumor, compressing the pylorus. It was later confirmed by a repeat CT scan of the abdomen. A diagnosis of malignant duodenal stenosis secondary to advance pancreatic carcinoid was made and a duodenal metallic stent, 12cm x 10F (WallFlex duodenal, Boston Scientific), was placed (Figure 4a and 4b). He improved symptomatically and was discharged home.

Discussion In contrast to the previous reviews of pancreatic carcinoids, our patient was asymptomatic of carcinoid symptoms and the tumor was at the head of pancreas. The presence of the pancreatic carcinoid at the head of pancreas has been reported before.2 However, the patient in the case report had no compression symptoms. She only had non-specific abdominal pain with rare episodes of flushing. Our patient presented initially with obstructive jaundice due to the compression of the common bile duct by the large tumor at the head of pancreas. In addition, the patient in our case report also showed an aggressive progression of the tumor resulting in gastric outlet obstruction (GOO). GOO has been reported as one of the features of gastric carcinoid,3 but GOO due to pancreatic carcinoid has not been reported. The presence of multiple liver metastases on diagnosis in pancreatic carcinoid was not surprising, since up to 75% of patients with carcinoid tumors developed hepatic metastases regardless of the location of the primary tumor.4 Although long-acting somatostatin analogues have been shown to be highly effective in reducing and controlling the symptoms of carcinoid syndrome,5 tumor regression was unsatisfactory. However, in a study by Aparacio et al,6 somatostatin analogue therapy stabilized tumor growth in nearly 60% of patients over a period of 11 months. Furthermore, in a prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa and their combination, the study showed a partial remission and stable disease of 5% and 23.8% respectively in the lanreotide group.7 Carcinoid patients were 36.2% of the cohort. In a recent clinical trial, another prospective, multicenter trial,8 the authors showed a reduction in tumor size in up to 68% of the patients treated with long acting lanreotide. The purpose of using long acting lanreotide therapy in our patient was for tumor and liver metastases regression. There was a

reported case of successful control of tumor growth and liver metastases in an unresectable malignant carcinoid tumor using slow release lanreotide therapy.9 Unfortunately it did not work for our patient and the tumor progressed causing localized compression of adjacent organs. The use of metallic duodenal stent has been documented to be useful and effective in relieving symptoms of more than six months for patients with metastatic malignancy. It is indicated as a palliative management for patients with metastatic diseases whom are symptomatic, although the patient selection for this intervention continues to be an issue requiring thorough consideration, and studies comparing the method with surgery are warranted.10 In conclusion, patient with metastatic pancreatic carcinoid could present without the typical carcinoid syndrome but it is an aggressive disease with poor prognosis and resistance to somatostatin analogue therapy.

References
1. Mao C, el Attar A, Domenico DR, Kim K, Howard JM. Carcinoid tumors of the

pancreas. Int. J. Pancreatol. 1998; 23(2): 153164.

2. Migliori M, Tomassetti P, Lalli S, et al. Carcinoid of the Pancreas. Pancreatology 2002;

2(2): 163166.
3. Kshirsagar AY, Wader J, Shekhar N, Vinchurkar KM, Zaware SU, Bhosale HB. Gastric

carcinoid presented as gastric outlet obstruction. Int. Surg. 2008; 93(6): 354-7.
4. Landry CS, Scoggins CR, McMasters KM, Martin RC 2nd. Management of hepatic

metastasis of gastrointestinal carcinoid tumors. J. Surg. Oncol. 2008; 97(3): 253258.

5. Ducreux M, Ruszniewski P, Chayvialle JA, et al. The antitumoral effect of the long-

acting somatostatin analog lanreotide in neuroendocrine tumor. Am. J. Gastroenterol. 2000; 95(11): 3276 3281 .
6. Arnold R, Trautmann ME, Creutzfeldt W, et al. Antitumor activity of somatostatin

analogues in progressive metastatic neuroendocrine gastroenteropancreatic tumors. Gut 1996; 38(3): 430438.
7. Faiss S, Pape UF, Bhmig M, et al. Prospective, randomized, multicenter trial on the

antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumorsthe International Lanreotide and Interferon Alfa Study Group. J. Clin. Oncol. 2003; 21(14): 2689 2696.

8. Bajetta E, Procopio G, Catena L, et al. Lanreotide autogel every 6 weeks compared with

lanreotide microparticles every 3 weeks in patients with well differentiated neuroendocrine tumors. A phase III study. Cancer 2006; 107(10): 247481.
9. Bondanelli M, Ambrosio MR, Zatelli MC, Cavazzini L, Al Jandali Rifa'y L, degli Uberti

EC. Regression of liver metastases of occult carcinoid tumor with slow release Lanreotide therapy. World. J. Gastroenterol. 2005; 11(13): 2041-2044.
10. Dormann A, Meisner S, Verin N, Lang AW. Selfexpanding metal stents for

gastroduodenal malignancies: systematic review of their clinical effectiveness. Endoscopy 2004; 36(6): 543-550.

Legends: Figure 1 CT scan of abdomen showing a tumor mass in the region of the head of pancreas encasing the distal common bile duct and invading part of the adjacent second part of duodenum.

Figure 2 CT scan of abdomen showing the large heterogenous mass and multiple large liver cysts.

Figure 3 Histopathological of CT-guided biopsy of liver lesion (H&E magnification x100) revealing a fairly uniform, bland features with dark eccentric nuclei and moderate amounts of eosinophilic cytoplasm, almost rhabdoid in areas.

Figure 4 (a) The proximal end of the metallic duodenal stent seen from the endoscopic view; (b) the position of the stent on fluoroscopy.