Pancreatic somatostatinoma with obscure inhibitory syndrome and mixed pathological pattern

Pancreatic somatostatinoma with obscure inhibitory syndrome and mixed pathological pattern 1 first-author 1 1 2 1 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:wuyulian@medmail.com.cn †E-mail:wuyulian@medmail.com.cn wuyulian@medmail.com.cn Department of Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China Department of Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China Department of Pathology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China Department of Pathology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China Somatostatinoma is a very rare neuroendocrine tumor that originates from D cells and accounts for less than 1% of all gastrointestinal endocrine tumors. The duodenum is the most frequent site for this tumor, followed by the pancreas. We here describe a 46-year-old Chinese woman who developed pancreatic somatostatinoma presenting with the characteristic “inhibitory” syndrome, but the symptoms were obscure and seemingly uncorrelated. This case is also unique for its large tumor size and mixed pathological pattern. Distal pancreatectomy was performed, and the patient has remained well since operation. As the syndromes of somatostatinoma may be obscure and atypical, clinicians should review all clinical findings to obtain an accurate diagnosis. Aggressive surgery is preferred to improve the survival. Neuroendocrine tumor Somatostatinoma Somatostatinoma syndrome Pancreatic hormone-producing tumor Pancreatectomy Introduction 1 Somatostatin-producing neuroendocrine tumor is a rare neoplasm usually arising in the pancreas and duodenum. Since its first description in 1977 (Larsson et al., 1977 1977 ; Soga and Yakuwa, 1999 1999 ), fewer than 200 cases have been reported in the literature (Marakis et al., 2005 2005 ), with the prevalence estimated to be only one in 40 million. The tumor is characterized by positive immunochemical staining for somatostatin (Sakazaki et al., 1983 1983 ). Early detection of pancreatic somatostatinoma is difficult due to its rarity and the variable nonspecific clinical presentations. Only a few patients present with typical somatostatinoma syndrome, including diabetes mellitus, steatorrhea, and cholelithiasis (Konomi et al., 1990 1990 ; Anene et al., 1995 1995 ). In the present study, we describe a case of pancreatic somatostatinoma presenting with complete somatostatinoma syndrome. The available English literature on this tumor type is reviewed. Case report 1 A 46-year-old Chinese woman was admitted to our hospital with recurrent upper abdominal pain for one year. The patient also had had nausea, anorexia, repeated diarrhea, and weight loss for several months. She had a history of cholecystectomy for cholecystolithiasis one year ago and twice thyroid adenoma resection, but no history of diabetes or gastric ulcer. On admission, no abnormality on physical examination was noted except for multiple thyroid nodules. Computed tomography (CT) indicated an isodense mass of 8.4 cm×3.7 cm in the body and tail of the pancreas with notable enhancement (Figs. 1a–1c 1a–1c ). On magnetic resonance imaging (MRI), the tumor displayed a slightly low signal intensity on T1-weighted images and high signal intensity on T2-weighted images compared with normal pancreatic parenchyma (Figs. 1d and 1e 1d and 1e ). Ultrasonography of the thyroid revealed bilateral multiple nodules. Carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), blood glucose, calcium and amylase levels were within normal ranges. The high plasma glucose level of 2 h post glucose-load (10 mmol/L at 2 h; reference, ≤7.8 mmol/L) indicated an impaired glucose tolerance. A series of endocrine hormones, including thyroid hormones (T3, T4), human thyroid stimulating hormone (h-TSH), follicle-stimulating hormone (FSH), luteotrophic hormone, estrogen, proestrogen, prolactin, adrenocorticotrophic hormone (ACTH), cortisone, insulin, C-peptide, calcitonin, and vanillylmandelic acid (VMA), were further tested to exclude the diagnosis of type I multiple endocrine neoplasia (MEN-1). There was no abnormal finding except for elevated calcitonin (2.0 ng/ml; reference, < 0.5 ng/ml). No morphologic abnormalities of the pituitary, parathyroids, or adrenal gland were found by either cranial MRI or cervical/abdominal ultrasonography. No liver metastasis or peritoneal dissemination was identified by laparotomy, but a huge solid, noncapsulated mass, measuring about 10 cm×4 cm, was found in the body and tail of the pancreas associated with surrounding dilated vessels. Distal pancreatectomy was performed to find that the cut surface of the resected specimen was grayish-white. The diagnosis of pancreatic somatostatinoma was made by pathological examination. Microscopically, the tumor cells arranged with a mixed solid nest and trabecular pattern (Figs. 2a and 2b 2a and 2b ), and the invasion of surrounding vessels was observed but without lymph nodes involvement. The neoplastic cells were immunoreactive for somatostatin and synaptophysin (Figs. 2c and 2d 2c and 2d ), as well as CA19-9, chromogranin A (CgA), and Ki-67 (index > 2%), but negative for insulin, gastrin, prolactin and P53. (a) & (b) Hematoxylin and eosin; (c) & (d) Immunohistochemical stain. Original magnification: (a), (b) & (d) ×100; (c) ×200 The postoperative course was uneventful. The patient received no further treatment and remained healthy to date without tumor recurrence. Discussion 1 Pancreatic somatostatin-producing endocrine tumor is one of the rarest neoplasms, which originates from D cells and is characterized by the somatostatinoma syndrome, caused by the predominantly inhibitory actions of somatostatin on other hormones (Mozell et al., 1990 1990 ; Moayedoddin et al., 2006 2006 ). Additional symptoms, such as dyspepsia, weight loss, anemia, and hypochlorhydria, may also exist. Our patient presented with upper abdominal pain, weight loss, iterative diarrhea, and impaired glucose tolerance and had a history of cholecystolithiasis, which could be regarded as typical somatostatinoma syndrome. However, these seemingly unassociated and obscure symptoms did not attract our much attention to take these observations together in the diagnostic process, and the diagnosis of pancreatic somatostatinoma was not taken into consideration. The review articles published recently are listed in Table 1 1 and the largest review work was carried out by Soga and Yakuwa ( 1999 1999 ), including 81 patients with pancreatic somatostatinoma reported before 1999. We further performed a comprehensive review of 15 available reports between 2000 and 2009, and identified another 23 patients with this rare tumor. The clinical findings about these patients were summarized in Table 2 2 . There were 56 women and 48 men (1.17:1), and the mean age was 53.0 years, ranging from 22 to 84 years. Most patients were symptomatic (94.2%), but a few patients presented with complete somatostatinoma syndrome. Most patients displayed hyperglycemia due to the inhibitory effect of somatostatin on insulin, whereas in a small portion of patients, hypoglycemia might be the complaint (Cao et al., 2009 2009 ). With respect to the tumor location, most of these tumors arose in the head of the pancreas, followed by the body and tail. A diffuse distribution throughout the pancreas or arising from the ectopic pancreas was rarely observed (Barahona-Garrido et al., 2009 2009 ). In some reports, pancreatic somatostatinoma was detected in association with neurofibromatosis type 1, MEN-1, and von Hippel-Lindau syndromes (Maki et al., 1995 1995 ; Levy-Bohbot et al., 2004 2004 ; Barahona-Garrido et al., 2009 2009 ). Recently, some clinicians presumed that there might exist an association between gastrointestinal stromal tumors (GIST) and somatostatinoma (Barahona-Garrido et al., 2009 2009 ). Female/Male Age at admission Values are expressed as median (range); S1: diabetes mellitus; S2: cholelithiasis; S3: diarrhea/steatorrhea; L1: head; L2: body; L3: tail; L4: diffuse/ectopic; HS: high somatostatin; LM: liver metastasis; LNM: LN metastasis; NA: not available Ref.: Vinik et al., 1987 1987 Ref.: Konomi et al., 1990 1990 Ref.: Soga and Yakuwa, 1999 1999 Ref.: Present review Alive percentage determined from the records of respective references Twenty-one cases with tumor location information available 2 Case, n 2 Sex a a 2 Age b b (year) 3 Symptom (%) 4 Tumor location (%) 2 HS (%) 2 Malignancy (%) 2 LM (%) 2 LNM (%) 2 Surgery (%) 2 Prognosis (%) # # 2 Ref. S1 S2 S3 L1 L2 L3 L4 27 18/9 52.6 (30–84) 77.8 63.0 40.7 51.8 7.4 18.5 7.4 66.7 85.2 70.4 29.6 NA NA [1] [1] 23 13/10 53.9 (30–84) 65.2 43.5 52.2 56.5 8.7 30.4 4.3 93.7 (15/16) 73.9 69.6 34.8 82.6 56.5 (13/23) [2] [2] 81 45/36 55.3 (30–84) NA NA 60.0 55.6 27.2 7.4 9.8 NA 70.4 39.5 24.7 69.1 NA [3] [3] 23 11/12 44.8 (22–72) 26.1 26.1 39.1 57.1 * * 23.8 14.3 4.8 83.3 (5/6) 73.9 43.5 60.9 87.0 61.1 (11/18) [4] [4] Clinical data Results  Gender   Female 53.8% (56/104)   Male 46.2% (48/104)  Age (year)   Mean (range) 53.0 (22–84)  Tumor location   Head 55.9% (57/102)   Body and/or tail 35.3% (36/102)   Diffuse/ectopic 8.8% (9/102)  Symptomatic 94.2% (98/104)  Malignancy 71.2% (74/104)  Liver metastasis 40.4% (42/104)  Surgery 73.1% (76/104) As shown in Table 1 1 , the majority of patients displayed a high level of somatostatin, which is helpful for an accurate diagnosis. However, a laboratory test for serum somatostatin level is often ignored when patients displayed nonspecific symptoms. Usually, somatostatinoma would appear as an iso- or low-density mass on CT images, and contrast enhancement is obvious due to hypervascularity. On MRI, the tumor displays low signal intensity on T1-weighted images and high signal intensity on T2-weighted images (Tjon et al., 1994 1994 ). Somatostatin receptor scintigraphy and positron emission tomography (PET) (Suzuki et al., 2008 2008 ) are recently utilized for detecting and staging somatostatinoma. Cytological and immunochemical detection sampled by the endoscopic ultrasound (EUS)-guided fine needle aspiration can be used for preoperative diagnosis (Stelow et al., 2005 2005 ). Pathologically, the tumor cells arrange in a trabecular pattern including ribbon-like, gyriform and glandular structures, or a solid medullary pattern. Our patient displayed a mixed pathological pattern, consisting of both solid medullary and gyriform structures, which is relatively a rare situation. Psammoma bodies are commonly observed in duodenum somatostatinoma, but rarely in the pancreas (House et al., 2002 2002 ). The accurate diagnosis of somatostatinoma depends on the intense positive immunochemical staining for somatostatin. As demonstrated in Tables 1 1 and 2 2 , most somatostatinomas are malignant (71.2%), with the liver, peripancreatic lymph nodes, and bone being the common metastatic sites (Tomono et al., 2003 2003 ; Marakis et al., 2005 2005 ). There is a unique staging system for pancreatic endocrine tumors including two major categories: well-differentiated endocrine tumors, with benign or low-malignant behavior, and poorly differentiated carcinomas that behave in a highly malignant fashion. The case presented here may be classified as “borderline tumor with uncertain behavior” according to the following clinicopathologic features: well differentiated, confined to the pancreas, > 3 cm in size, angioinvasion, > 2% Ki-67-positive cells/10 high power field (hpf) (Klöppel et al., 2004 2004 ). It should be noted that, for this tumor type, malignancy is not determined by histology but the discovery of metastasis (Marakis et al., 2005 2005 ). Aggressive surgical is preferred for this tumor type. However, the therapeutic procedure for hepatic metastases is controversial. It is generally considered that metastatic lesions should be resected simultaneously, such as hepatic wedge resection, provided it can be done. Palliative therapies, such as lipiodol-transcatheter arterial embolization of the liver, might be effective for those with unresectable liver metastases (Sato et al., 2000 2000 ). Liver transplantation is an alternative option but should be under careful estimation (Zhang et al., 2008 2008 ). Little experience with chemotherapy and radiotherapy has been accumulated. Therapy with octreotide and interferon-α (IFN-α) has been shown to be beneficial in the treatment of the clinical symptoms of functional somatostatinoma (Janson, 2005 2005 ; Nesi et al., 2008 2008 ). The prognosis of somatostatinoma is promising if the tumor is completely resected (Marakis et al., 2005 2005 ). However, patients with unresectable metastases have a poor outcome. Close follow-up is important since the tumor is prone to local recurrence. Surveillance of serum somatostatin level is very useful and elevated levels of this hormone may indicate tumor recurrence. Conclusion 1 In summary, pancreatic somatostatinoma is a rare entity with the diagnosis depending on pathological examination. 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Diagnosis and treatment of pancreatic somatostatinoma: a case report 10.1631/jzus.B0900166 Project (Nos. 30672072 and 30872531) supported by the National Natural Science Foundation of China 2009-06-12 2009-12-02 2009-10-13 2022-01-05 Copyright © Zhejiang University and Springer-Verlag Berlin Heidelberg 2010 2010 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 01 11