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Refractory Gastroesophageal Variceal Bleeding Secondary to Neuroendocrine Carcinoma in the Pancreatic Tail
Case Report Pancreatology 2011;11:228–232 DOI: 10.1159/000328392
Published online: May 12, 2011
Refractory Gastroesophageal Variceal Bleeding Secondary to Neuroendocrine Carcinoma in the Pancreatic Tail Huaizhi Wang Ping Bie Leida Zhang Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, PR China
Key Words Pancreatic neuroendocrine carcinoma ⴢ Gastroesophageal variceal bleeding ⴢ Regional portal hypertension
Abstract The main cause of gastroesophageal variceal bleeding (GEVB) is portal hypertension (PH) due to liver cirrhosis. Here, we report a case of regional PH and refractory GEVB secondary to neuroendocrine carcinoma (NC) in the pancreatic tail. This condition was treated using a pancreatic tail resection, splenectomy, and portal azygous devascularization. Regional PH caused by a pancreatic NC is rare and is usually presented as isolated gastric varices. This case report of regional PH details simultaneous esophageal and gastric varices that were caused by a pancreatic NC, which is a rare occurrence. Therefore, after excluding liver cirrhosis, unusual causes should be considered in cases of refractory GEVB with PH. Copyright © 2011 S. Karger AG, Basel and IAP
H.W. and P.B. contributed equally to this work.
© 2011 S. Karger AG, Basel and IAP 1424–3903/11/0112–0228$38.00/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com
Accessible online at: www.karger.com/pan
Introduction
The main cause of gastroesophageal variceal bleeding (GEVB) is portal hypertension (PH) due to liver cirrhosis. In addition to liver cirrhosis, a number of factors can result in PH. The blockage of a branch of the portal vein can lead to increased pressure in the drainage area of the portal vein, which is known as regional PH. The major complications of regional PH include ascites, splenomegaly, hypersplenism, and GEVB [1]. Here, we report a rare case of regional PH and refractory GEVB that was secondary to neuroendocrine carcinoma (NC) in the pancreatic tail. Case Presentation A 61-year-old male presented with ‘repeated hematemesis and melena for more than 4 years, recurrence of these symptoms lasted for 1 week’. He was admitted to the Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Chongqing, China, on December 7, 2010. In September 2006, the patient presented with the following symptoms: unexplained hematemesis, melena accompanied by dizziness, amaurosis, heart palpitations, no abdominal pain or diarrhea, no icterus of the skin or sclerae, no chills, and no fever. The patient visited a local clinic and was diagnosed with GEVB
Huaizhi Wang, MD, PhD Institute of Hepatopancreatobiliary Surgery of the PLA Southwest Hospital, Third Military Medical University Chongqing 400038 (PR China) Tel. +86 23 6876 5148, E-Mail whuaizhi @ gmail.com
with no specific cause. Blood transfusions and hemostatics were used to stop the bleeding. In October 2006, these symptoms reappeared, and the patient was treated in the Nanchong Central Hospital. A gastroscopic examination suggested that gastroesophageal varices with bleeding had occurred by an unknown cause. The doctor’s advice at that time was to conduct a portal azygous devascularization (Hassab’s operation). The procedure would have been performed as a splenectomy combined with extensive devascularization of the cardioesophageal junction. The surgery would have likely resulted in control of the hemorrhage and a negligible incidence of encephalopathy. However, the patient did not accept the doctor’s advice. An upper abdominal computed tomography (CT) scan on November 25, 2006, revealed a diffuse shadow near the inside edge of the spleen below the splenic hilum. An enhanced scan revealed a ring-like enhancement which was closely connected to the neighboring pancreatic tail. Additionally, the volume of the pancreatic tail increased with an uneven density. The result of the tumor marker test was negative. Therefore, the patient was thought to have an infectious disease. After the tests were conducted, hematemesis and recurrent melena attacks continued to occur 4–5 times per year, and the bleeding volume (approx. 2,000 ml) increased every time. Blood transfusions and hemostatics were administered in the emergency department after each attack. On December 1, 2010, the patient experienced a recurrence of these symptoms accompanied by dizziness, headache, amaurosis, heart palpitations, no abdominal pain or diarrhea, no icterus of the skin or sclerae, no chills, and no fever. To treat the patient in our hospital, a CT scan was completed, which indicated that a pancreatic carcinoma was invading the splenic hilum. Therefore, the patient was admitted to our department with pancreatic cancer. The patient’s mental status, appetite, and sleep quality were ordinary, his urine volume was normal, his stool was black, and his body weight had not changed significantly. The patient denied any medical history of pancreatitis, hypertension, or diabetes mellitus. The data from the admission examination showed that the patient’s temperature was 36.2 ° C, his pulse was 100/min, his breathing rate was 20/min, and his blood pressure was 137/69 mm Hg. The patient appeared to have severe anemia, no jaundice of the skin or mucous membranes, no palmar erythema, and no nevus araneus. His abdomen was soft and symmetrical, and there were no abnormal varicose veins, intestinal shapes, or peristaltic wavers. The lower edge of the liver was located 4 cm below the costal margin and had a normal texture. Splenomegaly was found 8 cm below the costal margin, the spleen was hard, and there was no tenderness. The entire abdomen lacked tenderness, rebound tenderness, or muscle tension, and was negative for Murphy’s sign. No percussion pain was apparent in the liver, kidney, or spleen areas. Drum sounds were obtained using percussion of the entire abdomen, and no shifting dullness was detected. Bowel sounds occurred 4 times/min. The results of the laboratory tests revealed that the patient’s blood had a white blood cell count of 3.22 ! 109/l, a red blood cell count of 1.79 ! 1012/l, a hemoglobin concentration of 37 g/l, and a hematocrit level of 13.8%. Coagulation function was normal, hepatitis B virus markers were negative, liver function was normal, and electrolyte levels were normal. Furthermore, the levels of carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA 125), and carbohydrate antigen 15-3 (CA 15-3) were normal.
The results of the CT scan revealed a splenomegaly and a lowdensity lesion in the pancreatic tail with an unclear boundary to the splenic hilum. An enhanced low-density image revealed uneven edges in the spleen with a size of approximately 4.5 ! 3.5 cm and a focal splenic infarction at the lower pole (fig. 1a, b). The results of the CT angiography (CTA) revealed splenic artery enlargement, portal vein enlargement, splenic vein enlargement and meandering, a thickening of the venous plexus in the splenic hilum, varices in the esophageal venous plexus and the left gastric veins (fig. 1c), varices in the left and right gastroepiploic veins, and absence of the splenic artery in the mid-lower pole. Based on these observations, there was a high probability that a pancreatic carcinoma had invaded the spleen. The preliminary diagnosis included the following: (1) pancreatic tail occupancy was apparent; however, it was unclear whether the pancreatic cancer had a splenic metastasis or an inflammatory mass in the pancreas and spleen; (2) GEVB was present, and (3) regional PH was present. Due to the large number of varicose blood vessels that surrounded the pancreatic tail mass, a needle biopsy could have caused a massive hemorrhage. Therefore, no biopsy was completed before surgery. On December 15, 2010, a pancreatic tail resection, splenectomy, and portal azygous devascularization were performed under general anesthesia. An intraoperative exploration revealed that the liver had a normal size, shape, and texture. No intra-abdominal ascites were observed. The gastroepiploic vessel was significantly varicose with a maximum diameter of approximately 1.0 cm. The spleen was significantly enlarged to dimensions of approximately 20 ! 14 ! 8 cm3 and appeared to be congested. After the gastrocolic ligament transection, significant varicosity was observed in the short gastric veins, and gastric varicose veins could be clearly seen. A hard mass was observed in the pancreatic tail (approximately 3 ! 2 ! 2 cm3) that was attached to the splenic hilum. An intraoperative examination of a sample of the frozen pancreatic mass suggested the possibility of a NC. The pancreatic tail was traversed approximately 4 cm from the mass. A complete resection of the pancreatic tail was performed, which included both the tumor and the spleen (fig. 1d). Finally, a portal azygous devascularization was performed. A pathological examination revealed cancer tissue in both the pancreatic tumor and the splenic hilar mass. The cancer cells were small and round, oval-like, or short and spindle-like with reduced cytoplasm. Their nuclei were round, oval-like, or short and spindle-like with abnormalities and visible mitosis. The cancer cells were arranged in nested groups, were cord-like or trabecular in shape, and displayed necrosis in some locations (fig. 2a). Immunohistochemical staining showed that the pancreatic tumor was chromogranin A (CgA)-positive (fig. 2b), CD56-positive (fig. 2c), cytokeratin (CK)-positive (fig. 2d), ␣-antitrypsin (␣-AT)-positive, probably vimentin (Vim)-positive, -catenin (-cate)-negative, and CD10-negative (data not shown). Furthermore, the tumor had !5% Ki-67-positive cells. Because CgA is a serum marker of neuroendocrine tumors of the pancreas, the tumor was designated as a NC in the pancreatic tail. After recovery, the patient was discharged on December 27, 2010, and he returned to the oncology department at a local hospital for further treatment. The patient has received follow-up examinations for 3 months. At the last examination, he was doing well.
Refractory GEVB Secondary to NEC in the Pancreatic Tail
Pancreatology 2011;11:228–232
229
Fig. 1. CT and CTA images and a photograph of the resected gross specimen. a CT
scan showing a low-density lesion in the pancreatic tail (arrow) with an invasion of the splenic hilum (arrowhead). b An enhanced CT scan showing a large number of varicose blood vessels surrounding the pancreas (arrow) and a low-density lesion in the splenic hilum (arrowhead). c CTA showing a portal vein enlargement, splenic vein enlargement and meandering, a thickened venous plexus in the splenic hilum, varices in the left and right gastroepiploic veins and the left gastric veins (arrow), and varices in the esophageal venous plexus (arrowhead). d Photograph of the resected gross specimen showing the resection of the pancreatic tail mass (arrowhead) and its invasion of the splenic hilum (arrow).
a
b
c
d
a
b
c
d
Fig. 2. Pathological images. a Cancer tis-
sue was found in both the pancreatic tail mass and the splenic hilar mass. The cancer cells were small and round, oval-like, or short and spindle-like with reduced cytoplasm. The nuclei of the cells were round, oval-like, or short and spindle-like with abnormalities and visible mitosis. The cancer cells were arranged in nested groups, had cord-like or trabecular shapes, and displayed necrosis in some areas. b Immunohistochemistry revealed CgApositive cells. c Immunohistochemistry revealed CD56-positive cells. d Immunohistochemistry revealed CK-positive cells.
230
Pancreatology 2011;11:228–232
Wang/Bie/Zhang
Discussion
Pancreatic NCs are rare and account for less than 5% of all pancreatic tumors [2]. These tumors have traditionally been believed to originate in the islet cells, but now they are thought to originate in the pancreatic ductal cells with an ability to differentiate in a multipotent manner. This tumor type usually grows slowly, and the prognosis is better than that of other malignant pancreatic tumors [3]. These tumors have a young age of onset, and the disease sites are primarily located in the head of the pancreas. Tumors of this type can also be found in the body and tail of the pancreas. Because pancreatic endocrine carcinomas have the ability to secrete hormone-like substances, corresponding syndrome can be clinically manifested. However, some NCs lack this neuroendocrine function. Therefore, it is difficult to discover these carcinomas at an early stage, and the patient usually displays symptoms of constriction of splenic vein that are produced by the tumors or the destruction of pancreatic function. Preoperative imaging does not provide a clear diagnosis of these tumors. With no characteristic features, the CT image often appears as a low-density occupancy in the pancreas. An enhanced CT scan could show uneven enhancements. Thus, it is difficult to distinguish these tumors from pancreatic ductal adenocarcinomas [4]. To date, no markers are available to confidently exclude pancreatic NCs. The levels of CA19-9 are not high in most pancreatic NC patients, but these levels are significantly increased in the majority of patients with pancreatic ductal adenocarcinoma. Therefore, the possibility of pancreatic NC should be considered when a tumor is detected in the pancreas in the absence of high CA19-9 levels. Because CgA is a serum marker of neuroendocrine tumors in the pancreas, the raised serum level of CgA suggests the diagnosis of neuroendocrine tumors [5]. However, in general, pathological and immunohistochemical examinations are necessary to make the final diagnosis [6]. The positive immunohistochemical staining for CgA in this case demonstrated that GEVB was secondary to NC in the pancreatic tail. The patient in the current case had experienced repeated GEVB for the past 4 years. The CT scan in the primary hospital revealed a small mass in the splenic hilum near the pancreatic tail. It was considered to be an infectious lesion due to the negative results of tumor markers. This patient had no carcinoid syndrome, a negative tumor marker test, recurrent GEVB lesions for 4 years, a lesion that was not growing significantly, and Refractory GEVB Secondary to NEC in the Pancreatic Tail
a final diagnosis through a pathological examination. Thus, our report demonstrates again that the growth of pancreatic NC is slow, and an early diagnosis is difficult to achieve. Large, infectious lesions in the pancreatic tail may constrict or spread to the splenic vein, which can cause regional PH and recurrent esophageal and/or gastric variceal bleeding. However, small, infectious lesions do not usually lead to symptoms. Thus, the possibility of a NC in the pancreatic tail invading the splenic vein should also be considered when small lesions eventually lead to a regional PH and recurrent GEVB, even if the test for tumor markers is negative. Regional PH is rare and accounts for only 5% of all cases of PH. The direct cause is splenic vein thrombosis or occlusion [7]. The common causes of splenic vein thrombosis or occlusion are principally chronic pancreatitis and primary pancreatic tumors. Other diseases, such as retroperitoneal inflammatory disease, cancer, and diseases of the spleen itself, may also cause regional PH. Thus, the etiology can be divided into pancreatic, splenic, and retroperitoneal origins. Management of gastroesophageal varices usually includes vasoactive agents, endoscopic sclerotherapy, and surgery. Endoscopic sclerotherapy is an effective treatment for bleeding gastroesophageal varices. Sclerosants can produce significant thrombosis, inflammatory reactions and fibrous degeneration to eliminate the varices. This procedure can be repeatedly performed in response to recurrent bleeding incidents [8]. The patient in the present case was treated in a local clinic and small hospitals, where the facilities and equipment were inadequate, before he came to our hospital. Therefore, the patient’s prior physicians could not perform endoscopic sclerotherapy. After the patient came to our hospital, we suspected that he had a pancreatic carcinoma in the pancreatic tail. Therefore, we performed pancreatic tail resection, splenectomy, and portal azygous devascularization after we received informed consent from the patient. The main pathological feature was splenic vein occlusion, which could have been caused by inflammation or a tumor. Splenic blood flows to the portal vein through the short gastric venous plexus and the left gastric vein. In most cases, a gastroscopy can only access the isolated gastric varices that are limited to the gastric fundus or cardia areas. There are four clinical features of regional PH: a clear primary lesion, such as a pancreatic lesion, retroperitoneal tumor, or splenic lesion; isolated gastric varices; significant hypersplenism, and clinical signs of PH with Pancreatology 2011;11:228–232
231
normal liver function. Isolated gastric varices with no liver cirrhosis are the most typical feature of regional PH [9]. Daveson et al. [10] and others [11–13] have recently reported several cases of regional PH that were caused by pancreatic NC with only isolated gastric varices. Both gastric and esophageal varices were found in the current case, which is rare. The primary reason for this combination of varices might have been due to the slow growth of pancreatic NCs (which occurred over 4 years without effective treatment), which could have eventually resulted in varices in the esophageal veins. Therefore, when a case of simultaneous esophageal and gastric varices with no liver cirrhosis is encountered, regional PH should also be considered.
Acknowledgements The authors wish to thank Dr. Qinliang Wang for supplying the histopathological images. This study was supported by the National Natural Science Foundation of China (No. 81072439).
Disclosure Statement The authors have no conflicts of interest to declare.
References 1 Liu QD, Zhou NX, Zhang WZ, et al: Diagnosis and management of regional portal hypertension. Chin J Dig Dis 2005;6:87–92. 2 Rampurwala MM, Kumar A, Kannan S, et al: Non-functioning pancreatic neuroendocrine tumors – a case report and review of literature. J Gastrointest Cancer 2011 (in press). 3 Satahoo-Dawes S, Palmer J, Manning EW III, et al: Breast and lung metastasis from pancreatic neuroendocrine carcinoma. World J Radiol 2011;3:32–37. 4 Franko J, Feng W, Yip L, et al: Non-functional neuroendocrine carcinoma of the pancreas: incidence, tumor biology, and outcomes in 2,158 patients. J Gastrointest Surg 2010;14: 541–548.
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5 O’Dorisio TM, Krutzik SR, Woltering EA, et al: Development of a highly sensitive and specific carboxy-terminal human pancreastatin assay to monitor neuroendocrine tumor behavior. Pancreas 2010;39:611–616. 6 Alsamarai S, Libutti SK, Saif MW: Updates in pancreatic neuroendocrine carcinoma. Highlights from the 2010 ASCO Annual Meeting, Chicago, June 4–8, 2010. JOP 2010; 11:336–340. 7 Shi B, Wang X, Zhang L, et al: Regional portal hypertension diagnosed by ultrasonography: imaging findings and diagnostic values. Hepatogastroenterology 2005;52:1062–1065. 8 Shi B, Wu W, Zhu H, et al: Successful endoscopic sclerotherapy for bleeding gastric varices with combined cyanoacrylate and aethoxysklerol. World J Gastroenterol 2008; 14: 3598–3601. 9 Köklü S, Yüksel O, Arhan M, et al: Report of 24 left-sided portal hypertension cases: a single-center prospective cohort study. Dig Dis Sci 2005;50:976–982.
Pancreatology 2011;11:228–232
10 Daveson J, Masson J, Cameron D, et al: A case of an isolated gastric variceal bleed secondary to a pancreatic neuroendocrine tumour. Eur J Gastroenterol Hepatol 2007; 19: 1144–1148. 11 Metz DC, Benjamin SB: Islet cell carcinoma of the pancreas presenting as bleeding from isolated gastric varices. Report of a case and review of the literature. Dig Dis Sci 1991; 36: 241–244. 12 Dalvi AN, Rege SA, Bapat MR, et al: Nonfunctioning islet cell tumor presenting with ascites and portal hypertension. Indian J Gastroenterol 2002; 21:227–228. 13 Thompson RJ, Taylor MA, McKie LD, et al: Sinistral portal hypertension. Ulster Med J 2006;75:175–177.
Wang/Bie/Zhang
Published online: May 12, 2011
Refractory Gastroesophageal Variceal Bleeding Secondary to Neuroendocrine Carcinoma in the Pancreatic Tail Huaizhi Wang Ping Bie Leida Zhang Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, PR China
Key Words Pancreatic neuroendocrine carcinoma ⴢ Gastroesophageal variceal bleeding ⴢ Regional portal hypertension
Abstract The main cause of gastroesophageal variceal bleeding (GEVB) is portal hypertension (PH) due to liver cirrhosis. Here, we report a case of regional PH and refractory GEVB secondary to neuroendocrine carcinoma (NC) in the pancreatic tail. This condition was treated using a pancreatic tail resection, splenectomy, and portal azygous devascularization. Regional PH caused by a pancreatic NC is rare and is usually presented as isolated gastric varices. This case report of regional PH details simultaneous esophageal and gastric varices that were caused by a pancreatic NC, which is a rare occurrence. Therefore, after excluding liver cirrhosis, unusual causes should be considered in cases of refractory GEVB with PH. Copyright © 2011 S. Karger AG, Basel and IAP
H.W. and P.B. contributed equally to this work.
© 2011 S. Karger AG, Basel and IAP 1424–3903/11/0112–0228$38.00/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com
Accessible online at: www.karger.com/pan
Introduction
The main cause of gastroesophageal variceal bleeding (GEVB) is portal hypertension (PH) due to liver cirrhosis. In addition to liver cirrhosis, a number of factors can result in PH. The blockage of a branch of the portal vein can lead to increased pressure in the drainage area of the portal vein, which is known as regional PH. The major complications of regional PH include ascites, splenomegaly, hypersplenism, and GEVB [1]. Here, we report a rare case of regional PH and refractory GEVB that was secondary to neuroendocrine carcinoma (NC) in the pancreatic tail. Case Presentation A 61-year-old male presented with ‘repeated hematemesis and melena for more than 4 years, recurrence of these symptoms lasted for 1 week’. He was admitted to the Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Chongqing, China, on December 7, 2010. In September 2006, the patient presented with the following symptoms: unexplained hematemesis, melena accompanied by dizziness, amaurosis, heart palpitations, no abdominal pain or diarrhea, no icterus of the skin or sclerae, no chills, and no fever. The patient visited a local clinic and was diagnosed with GEVB
Huaizhi Wang, MD, PhD Institute of Hepatopancreatobiliary Surgery of the PLA Southwest Hospital, Third Military Medical University Chongqing 400038 (PR China) Tel. +86 23 6876 5148, E-Mail whuaizhi @ gmail.com
with no specific cause. Blood transfusions and hemostatics were used to stop the bleeding. In October 2006, these symptoms reappeared, and the patient was treated in the Nanchong Central Hospital. A gastroscopic examination suggested that gastroesophageal varices with bleeding had occurred by an unknown cause. The doctor’s advice at that time was to conduct a portal azygous devascularization (Hassab’s operation). The procedure would have been performed as a splenectomy combined with extensive devascularization of the cardioesophageal junction. The surgery would have likely resulted in control of the hemorrhage and a negligible incidence of encephalopathy. However, the patient did not accept the doctor’s advice. An upper abdominal computed tomography (CT) scan on November 25, 2006, revealed a diffuse shadow near the inside edge of the spleen below the splenic hilum. An enhanced scan revealed a ring-like enhancement which was closely connected to the neighboring pancreatic tail. Additionally, the volume of the pancreatic tail increased with an uneven density. The result of the tumor marker test was negative. Therefore, the patient was thought to have an infectious disease. After the tests were conducted, hematemesis and recurrent melena attacks continued to occur 4–5 times per year, and the bleeding volume (approx. 2,000 ml) increased every time. Blood transfusions and hemostatics were administered in the emergency department after each attack. On December 1, 2010, the patient experienced a recurrence of these symptoms accompanied by dizziness, headache, amaurosis, heart palpitations, no abdominal pain or diarrhea, no icterus of the skin or sclerae, no chills, and no fever. To treat the patient in our hospital, a CT scan was completed, which indicated that a pancreatic carcinoma was invading the splenic hilum. Therefore, the patient was admitted to our department with pancreatic cancer. The patient’s mental status, appetite, and sleep quality were ordinary, his urine volume was normal, his stool was black, and his body weight had not changed significantly. The patient denied any medical history of pancreatitis, hypertension, or diabetes mellitus. The data from the admission examination showed that the patient’s temperature was 36.2 ° C, his pulse was 100/min, his breathing rate was 20/min, and his blood pressure was 137/69 mm Hg. The patient appeared to have severe anemia, no jaundice of the skin or mucous membranes, no palmar erythema, and no nevus araneus. His abdomen was soft and symmetrical, and there were no abnormal varicose veins, intestinal shapes, or peristaltic wavers. The lower edge of the liver was located 4 cm below the costal margin and had a normal texture. Splenomegaly was found 8 cm below the costal margin, the spleen was hard, and there was no tenderness. The entire abdomen lacked tenderness, rebound tenderness, or muscle tension, and was negative for Murphy’s sign. No percussion pain was apparent in the liver, kidney, or spleen areas. Drum sounds were obtained using percussion of the entire abdomen, and no shifting dullness was detected. Bowel sounds occurred 4 times/min. The results of the laboratory tests revealed that the patient’s blood had a white blood cell count of 3.22 ! 109/l, a red blood cell count of 1.79 ! 1012/l, a hemoglobin concentration of 37 g/l, and a hematocrit level of 13.8%. Coagulation function was normal, hepatitis B virus markers were negative, liver function was normal, and electrolyte levels were normal. Furthermore, the levels of carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA 125), and carbohydrate antigen 15-3 (CA 15-3) were normal.
The results of the CT scan revealed a splenomegaly and a lowdensity lesion in the pancreatic tail with an unclear boundary to the splenic hilum. An enhanced low-density image revealed uneven edges in the spleen with a size of approximately 4.5 ! 3.5 cm and a focal splenic infarction at the lower pole (fig. 1a, b). The results of the CT angiography (CTA) revealed splenic artery enlargement, portal vein enlargement, splenic vein enlargement and meandering, a thickening of the venous plexus in the splenic hilum, varices in the esophageal venous plexus and the left gastric veins (fig. 1c), varices in the left and right gastroepiploic veins, and absence of the splenic artery in the mid-lower pole. Based on these observations, there was a high probability that a pancreatic carcinoma had invaded the spleen. The preliminary diagnosis included the following: (1) pancreatic tail occupancy was apparent; however, it was unclear whether the pancreatic cancer had a splenic metastasis or an inflammatory mass in the pancreas and spleen; (2) GEVB was present, and (3) regional PH was present. Due to the large number of varicose blood vessels that surrounded the pancreatic tail mass, a needle biopsy could have caused a massive hemorrhage. Therefore, no biopsy was completed before surgery. On December 15, 2010, a pancreatic tail resection, splenectomy, and portal azygous devascularization were performed under general anesthesia. An intraoperative exploration revealed that the liver had a normal size, shape, and texture. No intra-abdominal ascites were observed. The gastroepiploic vessel was significantly varicose with a maximum diameter of approximately 1.0 cm. The spleen was significantly enlarged to dimensions of approximately 20 ! 14 ! 8 cm3 and appeared to be congested. After the gastrocolic ligament transection, significant varicosity was observed in the short gastric veins, and gastric varicose veins could be clearly seen. A hard mass was observed in the pancreatic tail (approximately 3 ! 2 ! 2 cm3) that was attached to the splenic hilum. An intraoperative examination of a sample of the frozen pancreatic mass suggested the possibility of a NC. The pancreatic tail was traversed approximately 4 cm from the mass. A complete resection of the pancreatic tail was performed, which included both the tumor and the spleen (fig. 1d). Finally, a portal azygous devascularization was performed. A pathological examination revealed cancer tissue in both the pancreatic tumor and the splenic hilar mass. The cancer cells were small and round, oval-like, or short and spindle-like with reduced cytoplasm. Their nuclei were round, oval-like, or short and spindle-like with abnormalities and visible mitosis. The cancer cells were arranged in nested groups, were cord-like or trabecular in shape, and displayed necrosis in some locations (fig. 2a). Immunohistochemical staining showed that the pancreatic tumor was chromogranin A (CgA)-positive (fig. 2b), CD56-positive (fig. 2c), cytokeratin (CK)-positive (fig. 2d), ␣-antitrypsin (␣-AT)-positive, probably vimentin (Vim)-positive, -catenin (-cate)-negative, and CD10-negative (data not shown). Furthermore, the tumor had !5% Ki-67-positive cells. Because CgA is a serum marker of neuroendocrine tumors of the pancreas, the tumor was designated as a NC in the pancreatic tail. After recovery, the patient was discharged on December 27, 2010, and he returned to the oncology department at a local hospital for further treatment. The patient has received follow-up examinations for 3 months. At the last examination, he was doing well.
Refractory GEVB Secondary to NEC in the Pancreatic Tail
Pancreatology 2011;11:228–232
229
Fig. 1. CT and CTA images and a photograph of the resected gross specimen. a CT
scan showing a low-density lesion in the pancreatic tail (arrow) with an invasion of the splenic hilum (arrowhead). b An enhanced CT scan showing a large number of varicose blood vessels surrounding the pancreas (arrow) and a low-density lesion in the splenic hilum (arrowhead). c CTA showing a portal vein enlargement, splenic vein enlargement and meandering, a thickened venous plexus in the splenic hilum, varices in the left and right gastroepiploic veins and the left gastric veins (arrow), and varices in the esophageal venous plexus (arrowhead). d Photograph of the resected gross specimen showing the resection of the pancreatic tail mass (arrowhead) and its invasion of the splenic hilum (arrow).
a
b
c
d
a
b
c
d
Fig. 2. Pathological images. a Cancer tis-
sue was found in both the pancreatic tail mass and the splenic hilar mass. The cancer cells were small and round, oval-like, or short and spindle-like with reduced cytoplasm. The nuclei of the cells were round, oval-like, or short and spindle-like with abnormalities and visible mitosis. The cancer cells were arranged in nested groups, had cord-like or trabecular shapes, and displayed necrosis in some areas. b Immunohistochemistry revealed CgApositive cells. c Immunohistochemistry revealed CD56-positive cells. d Immunohistochemistry revealed CK-positive cells.
230
Pancreatology 2011;11:228–232
Wang/Bie/Zhang
Discussion
Pancreatic NCs are rare and account for less than 5% of all pancreatic tumors [2]. These tumors have traditionally been believed to originate in the islet cells, but now they are thought to originate in the pancreatic ductal cells with an ability to differentiate in a multipotent manner. This tumor type usually grows slowly, and the prognosis is better than that of other malignant pancreatic tumors [3]. These tumors have a young age of onset, and the disease sites are primarily located in the head of the pancreas. Tumors of this type can also be found in the body and tail of the pancreas. Because pancreatic endocrine carcinomas have the ability to secrete hormone-like substances, corresponding syndrome can be clinically manifested. However, some NCs lack this neuroendocrine function. Therefore, it is difficult to discover these carcinomas at an early stage, and the patient usually displays symptoms of constriction of splenic vein that are produced by the tumors or the destruction of pancreatic function. Preoperative imaging does not provide a clear diagnosis of these tumors. With no characteristic features, the CT image often appears as a low-density occupancy in the pancreas. An enhanced CT scan could show uneven enhancements. Thus, it is difficult to distinguish these tumors from pancreatic ductal adenocarcinomas [4]. To date, no markers are available to confidently exclude pancreatic NCs. The levels of CA19-9 are not high in most pancreatic NC patients, but these levels are significantly increased in the majority of patients with pancreatic ductal adenocarcinoma. Therefore, the possibility of pancreatic NC should be considered when a tumor is detected in the pancreas in the absence of high CA19-9 levels. Because CgA is a serum marker of neuroendocrine tumors in the pancreas, the raised serum level of CgA suggests the diagnosis of neuroendocrine tumors [5]. However, in general, pathological and immunohistochemical examinations are necessary to make the final diagnosis [6]. The positive immunohistochemical staining for CgA in this case demonstrated that GEVB was secondary to NC in the pancreatic tail. The patient in the current case had experienced repeated GEVB for the past 4 years. The CT scan in the primary hospital revealed a small mass in the splenic hilum near the pancreatic tail. It was considered to be an infectious lesion due to the negative results of tumor markers. This patient had no carcinoid syndrome, a negative tumor marker test, recurrent GEVB lesions for 4 years, a lesion that was not growing significantly, and Refractory GEVB Secondary to NEC in the Pancreatic Tail
a final diagnosis through a pathological examination. Thus, our report demonstrates again that the growth of pancreatic NC is slow, and an early diagnosis is difficult to achieve. Large, infectious lesions in the pancreatic tail may constrict or spread to the splenic vein, which can cause regional PH and recurrent esophageal and/or gastric variceal bleeding. However, small, infectious lesions do not usually lead to symptoms. Thus, the possibility of a NC in the pancreatic tail invading the splenic vein should also be considered when small lesions eventually lead to a regional PH and recurrent GEVB, even if the test for tumor markers is negative. Regional PH is rare and accounts for only 5% of all cases of PH. The direct cause is splenic vein thrombosis or occlusion [7]. The common causes of splenic vein thrombosis or occlusion are principally chronic pancreatitis and primary pancreatic tumors. Other diseases, such as retroperitoneal inflammatory disease, cancer, and diseases of the spleen itself, may also cause regional PH. Thus, the etiology can be divided into pancreatic, splenic, and retroperitoneal origins. Management of gastroesophageal varices usually includes vasoactive agents, endoscopic sclerotherapy, and surgery. Endoscopic sclerotherapy is an effective treatment for bleeding gastroesophageal varices. Sclerosants can produce significant thrombosis, inflammatory reactions and fibrous degeneration to eliminate the varices. This procedure can be repeatedly performed in response to recurrent bleeding incidents [8]. The patient in the present case was treated in a local clinic and small hospitals, where the facilities and equipment were inadequate, before he came to our hospital. Therefore, the patient’s prior physicians could not perform endoscopic sclerotherapy. After the patient came to our hospital, we suspected that he had a pancreatic carcinoma in the pancreatic tail. Therefore, we performed pancreatic tail resection, splenectomy, and portal azygous devascularization after we received informed consent from the patient. The main pathological feature was splenic vein occlusion, which could have been caused by inflammation or a tumor. Splenic blood flows to the portal vein through the short gastric venous plexus and the left gastric vein. In most cases, a gastroscopy can only access the isolated gastric varices that are limited to the gastric fundus or cardia areas. There are four clinical features of regional PH: a clear primary lesion, such as a pancreatic lesion, retroperitoneal tumor, or splenic lesion; isolated gastric varices; significant hypersplenism, and clinical signs of PH with Pancreatology 2011;11:228–232
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normal liver function. Isolated gastric varices with no liver cirrhosis are the most typical feature of regional PH [9]. Daveson et al. [10] and others [11–13] have recently reported several cases of regional PH that were caused by pancreatic NC with only isolated gastric varices. Both gastric and esophageal varices were found in the current case, which is rare. The primary reason for this combination of varices might have been due to the slow growth of pancreatic NCs (which occurred over 4 years without effective treatment), which could have eventually resulted in varices in the esophageal veins. Therefore, when a case of simultaneous esophageal and gastric varices with no liver cirrhosis is encountered, regional PH should also be considered.
Acknowledgements The authors wish to thank Dr. Qinliang Wang for supplying the histopathological images. This study was supported by the National Natural Science Foundation of China (No. 81072439).
Disclosure Statement The authors have no conflicts of interest to declare.
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