sign in sign up
<<
Home , Carcinoid, Pheochromocytoma, Somatostatin, VIPoma

SPECIAL FEATURE

Case Report

Pancreatic Secreting Vasoactive Intestinal and With Pulmonary Emboli: A Case Report

Naris Nilubol, Esther M. Freedman, Martha M. Quezado, Dhaval Patel, and Electron Kebebew Downloaded from https://academic.oup.com/jcem/article/101/10/3564/2764892 by guest on 30 September 2021 Endocrine Branch (N.N., E.M.F., D.P., E.K.) and Laboratory of (M.M.Q.), Center for Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

Context: The vasoactive intestinal peptide-secreting neuroendocrine tumor (VIPoma) is a very rare . We report the first case of a patient with VIPoma that co-secreted dopamine and had pulmonary emboli.

Case Description: A 67-year-old woman presented with 2 months of watery , severe gen- eralized weakness,6.8 kg of weight loss, a facial rash, and . Colonoscopy did not reveal the cause of the chronic diarrhea. Initial biochemical testing showed markedly elevated serum vasoactive intestinal peptide (VIP) and . Computed tomography scan of the and pelvis revealed a 5.4-cm distal pancreatic mass. Octreoscan showed an intense up- take in the area of the pancreatic mass. Incidental pulmonary emboli were found and treated. Additional biochemical testing revealed a markedly elevated urinary dopamine level. The patient received preoperative ␣-blockade and . She underwent a successful laparoscopic distal pancreatectomy. Postoperative urinary dopamine and pancreatic polypeptide were within normal limits. Serum VIP decreased by half but remained elevated. Pathology confirmed a grade 1 pan- creatic neuroendocrine tumor without . The patient’s symptoms resolved and no longer required octreotide. Metastatic workup including computed tomography, F18- fluorodeoxglucose positron emission tomography, and Ga68-DOTATATE scans were negative dur- ing 4 years of follow-up.

Conclusions: VIPoma is a rare subtype of pancreatic neuroendocrine tumor that can secrete do- pamine and can be associated with thromboembolism. (J Clin Endocrinol Metab 101: 3564–3567, 2016)

ancreatic neuroendocrine tumors (PNETs) are rare VIPoma exhibited co-secretion. We report P of the . The annual in a unique case of a PNET that secreted both vasoactive the United States was estimated to be three to five cases per intestinal peptide (VIP) and dopamine and highlight a 100 000 individuals (1). Although Ͼ 85% of PNETs are unique clinical presentation as well as a thromboembolic nonfunctioning, patients with functioning PNETs typi- event. cally present with clinical syndromes associated with ex- cessive hormonal secretion. The vasoactive intestinal pep- tide-secreting neuroendocrine tumor (VIPoma), also Case Presentation known as Verner-Morrison syndrome, is a very rare tumor with an annual incidence of one in 10 million individuals A 67-year-old woman with a history of type 2 (2). However, none of the previously reported cases of mellitus, , hypothyroidism, and gastroesoph-

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: CT, computed tomography; FDG, fluorodeoxglucose; PET, positron emis- Printed in USA sion tomography; PNET, pancreatic neuroendocrine tumor; VIP, vasoactive intestinal pep- Copyright © 2016 by the Endocrine Society tide; VIPoma, VIP-secreting neuroendocrine tumor. Received May 8, 2016. Accepted August 29, 2016. First Published Online September 1, 2016

3564 press.endocrine.org/journal/jcem J Clin Endocrinol Metab, October 2016, 101(10):3564–3567 doi: 10.1210/jc.2016-2051 doi: 10.1210/jc.2016-2051 press.endocrine.org/journal/jcem 3565

treotide treatment (50 ␮g sc daily) dramatically improved her diarrhea. Her social and family histories were unremarkable. The patient pre- sented without distress and had nor- mal vital signs and oxygenation on room air. She had a facial erythem- atous maculopapular rash. She had no palpable abdominal mass or or- ganomegaly. Her significant labora- tory values included low hemoglobin Downloaded from https://academic.oup.com/jcem/article/101/10/3564/2764892 by guest on 30 September 2021 at 10.2 g/dL (11.2–15.7 g/dL), ele- vated VIP at 3750 pg/mL (Ͻ75 pg/ mL), pancreatic polypeptide at 106 000 pg/mL (Ͻ312 pg/mL), and 24-hour urine dopamine at 1592 ␮g/24 hours (65–400 ␮g/24 hours). Urinary , epineph- Figure 1. Radiographic imaging of a patient with VIPoma. A, Contrast-enhanced CT scan of the rine, and total were abdomen showed pancreatic tail mass (blue arrow). B, A pulmonary CT angiography showed within normal limits. In addition to a right segmental pulmonary artery-filling defects. C, Octreoscan. D, F18-FDG PET/CT scan showed solid mass in the tail of the pancreas, an intense uptake in the pancreatic tail mass. we found incidental pulmonary em- ageal reflux disease presented with watery diarrhea several boli in the right lower-lobe arteries times a day for 2 months, severe generalized weakness, and (Figure 1B), which were treated with enoxaparin. A ve- 6.8 kg of weight loss. She was initially admitted and nous duplex study of the lower extremities revealed no treated for and hypokalemia. A colonoscopy thrombus. An octreoscan showed intense uptake in the showed an ulcerative lesion in the ascending colon and area of the pancreatic tail mass (Figure 1C), which had colitis. The patient came to the National Institutes of increased uptake on F18-fluorodeoxglucose (FDG) posi- Health because a computed tomography (CT) scan of her tron emission tomography (PET)/CT with a standardized abdomen demonstrated a 5.4 ϫ 3.8-cm solid mass with a uptake value of 7.9 (Figure 1D). Because of the elevated focal calcification at the tail of the pancreas (Figure 1A), dopamine level, was given preopera- and her serum VIP level was markedly elevated. Oc- tively. The patient provided an informed written consent for and research. She under- went an uncomplicated laparoscopic distal pancreatectomy and splenec- tomy. An intraoperative of the and pancreas revealed no additional lesions. The patient was discharged on postoperative day 5 with a drain for a self-limited, grade 1 . Pathology showed a 5.5-cm grade 1 PNET with a 1% Ki67 index and negative mar- gins (Figure 2A). All 13 of her lymph nodes were negative for metastasis. The tumor cells stained positive for , chromogranin, pan- creatic polypeptide, VIP, and DO- PA-decarboxylase (Figure 2, B–D, and Figure 3, B and D) and stained

Figure 2. Histology of PNET secreting VIP and dopamine. A, Hematoxylin and eosin staining; B, negative for , , synaptophysin; C, chromogranin; and D, pancreatic polypeptide immunohistochemistry. and . Her pancreatic polypep- 3566 Nilubol et al VIPoma Secreting Dopamine and Pulmonary Emboli J Clin Endocrinol Metab, October 2016, 101(10):3564–3567

cal symptoms of profuse watery di- arrhea, hypokalemia, and dehydra- tion universally found in patients with (2), our patient had incidentally found pulmonary em- boli. Thromboembolisms in patients with VIPomas have rarely been re- ported. Interestingly, the first case of VIPoma was described in 1957 in a patient who presented with severe diarrhea, hypokalemia, and a pan- Downloaded from https://academic.oup.com/jcem/article/101/10/3564/2764892 by guest on 30 September 2021 creatic tail mass with liver metasta- sis. Her clinical course was compli- cated by popliteal artery thrombosis that required leg amputation (7). The mean age of patients at presen- tation of VIPomas is between 50 and 60 years (2, 8). The tumor location in our patient was consistent with pre- Figure 3. VIP expression in the adjacent normal pancreas (A) and in the PNET (B). DOPA- decarboxylase expression in the adjacent normal pancreas (C) and in the PNET (D). vious reports demonstrating that 72% of VIPomas were in the body or tail of the pancreas. However, unlike tide and urine dopamine levels were normalized postop- two-thirds of patients with VIPomas who present with eratively. The patient’s VIP level decreased but remained metastatic disease (2), there was no radiographic evidence elevated at 1510 pg/mL (Ͻ75 pg/mL) and did not increase of metastasis at the time of diagnosis and during follow- significantly over 4 years of follow-up. Annual radio- up. It is possible that our patient has microscopic metas- graphic surveillance with octreoscans, F18-FDG PET/CT tasis because her VIP levels remain elevated. However, scans, Ga-68 DOTATATE PET/CT scans, and contrast- occult VIPoma has been reported in a patient with a clin- enhanced CT scans showed that the patient had no evi- ical syndrome consistent with VIPoma, and primary and dence of disease during 4 years of follow-up after surgery. metastatic lesions were discovered 3 years later (9). This The patient remained asymptomatic without any treat- suggests that the clinical course of VIPoma can be indo- ment. for MEN1, VHL, and NF1 germline lent, similar to other PNETs. Because PNETs can secrete was negative. multiple and , VIPomas have been re- ported to secrete several other hormones such as pancre- atic polypeptide, , , , gastric Discussion inhibitory peptide, , glucagon, insulin, and so- Neuroendocrine tumors are a heterogeneous group of tu- matostatin (10). To our knowledge, our patient is the first mors originating from various types of specialized cells whose VIPoma secreted dopamine. There have been re- that express markers for and frequently secrete ports of that secreted dopamine and peptides or amines, resulting in diverse clinical presenta- VIP (11, 12). This suggests that neuroendocrine cells can tions and biological behaviors. To the best of our knowl- secrete both and pancreatic peptides. Be- edge, this is the first case of a VIPoma co-secreting dopa- cause most patients with VIPomas have tumors larger than mine. We found strong nuclear expression of VIP and 3 cm, a contrast-enhanced CT scan or magnetic resonance DOPA-decarboxylase in the patient’s tumor sample. Few imaging has Ͼ 80% sensitivity in detecting the primary reports of patients with VIPoma demonstrated that VIP and metastatic sites (2, 13). Functional imaging studies, can express in nuclei and cytoplasm (3, 4). Elevated cat- such as octreoscan and Ga-68 DOTATATE PET/CT, can echolamines and metabolites have been reported in 8% be useful in detecting primary tumors and metastasis be- (n ϭ 9 of 115) of patients with neuroendocrine tumors (5). cause most VIPomas express somatostatin receptors. F18- Immunohistochemistry suggested that neuroendocrine FDG PET/CT can be more sensitive than somatostatin cells can express and DOPA-decar- receptor imaging in patients with poorly differentiated boxylase, which convert tyrosine to L-DOPA and L-dopa neuroendocrine tumors. However, it is common for well- to dopamine, respectively (6). In addition to the typi- differentiated neuroendocrine tumors to be F18-FDG doi: 10.1210/jc.2016-2051 press.endocrine.org/journal/jcem 3567

PET/CT avid (14). Initial treatment of patients with VI- References Pomas includes hydration and correction of electrolyte 1. Halfdanarson TR, Rubin J, Farnell MB, Grant CS, Petersen GM. abnormalities. A somatostatin analog, such as octreotide, Pancreatic endocrine neoplasms: epidemiology and of can be used to control symptoms. Surgical resection with pancreatic endocrine tumors. Endocr Relat Cancer. 2008;15:409– 427. lymphadenectomy is the treatment of choice in patients 2. Ghaferi AA, Chojnacki KA, Long WD, Cameron JL, Yeo CJ. Pan- with localized or regionalized disease. U.S. Food and Drug creatic VIPomas: subject review and one institutional experience. J Administration-approved treatments for progressive or Gastrointest Surg. 2008;12:382–393. 3. Bani Sacchi T, Bani D, Biliotti G. Are pancreatic VIPomas paran- advanced PNETs include sunitinib and everolimus. Var- euron neoplasms? A clue to the neuroectodermal origin of these ious modalities, such as chemoembolization and radiofre- tumors. Pancreas. 1992;7:87–97. 4. Chen YF, Liu TH, Chen SP, et al. Watery diarrhea syndrome caused quency ablation, have been used to control the progression by multihormonal malignant pancreatic islet cell tumor secreting Downloaded from https://academic.oup.com/jcem/article/101/10/3564/2764892 by guest on 30 September 2021 of liver metastasis. Peptide receptor somatostatin, vasoactive intestinal peptide, serotonin, and prosta- has emerged as a promising modality in patients with avid glandin E–a clinicopathological, biochemical, immunohistochemi- cal, and ultrastructural study. Pancreas. 1986;1:80–89. tumors, as determined by Ga-68 DOTA peptide PET/CT 5. Ciofu A, Baudin E, Chanson P, et al. Catecholamine production in imaging. The 5-year survival for patients with localized patients with gastroenteropancreatic neuroendocrine tumors. Eur J Endocrinol. 1999;140:434–437. and metastatic pancreatic VIPomas is 94% and 60%, re- 6. Goedert M, Otten U, Suda K, et al. Dopamine, norepinephrine and spectively (8). serotonin production by an intestinal tumor. Cancer. 1980;45:104–107. 7. Priest WM, Alexander MK. Isletcell tumour of the pancreas with peptic ulceration, diarrhoea, and hypokalaemia. Lancet. 1957;273: Conclusions 1145–1147. 8. Soga J, Yakuwa Y. Vipoma/diarrheogenic syndrome: a statistical VIPoma is a rare subtype of PNETs that can secrete do- evaluation of 241 reported cases. J Exp Clin Cancer Res. 1998;17: 389–400. pamine and can be associated with thromboembolism. 9. Brunani A, Crespi C, De Martin M, Dubini A, Piolini M, Cavagnini F. Four year treatment with a long acting somatostatin analogue in a patient with Verner-Morrison syndrome. J Endocrinol Invest. 1991;14:685–689. Acknowledgments 10. Perry RR, Vinik AI. Clinical review 72: diagnosis and management of functioning islet cell tumors. J Clin Endocrinol Metab. 1995;80: Address all correspondence and requests for reprints to: Naris 2273–2278. Nilubol, MD, Branch, National Cancer In- 11. Smith SL, Slappy AL, Fox TP, Scolapio JS. Pheochromocytoma pro- ducing vasoactive intestinal peptide. Mayo Clin Proc. 2002;77:97– stitute, National Institutes of Health, Clinical Research Center, 100. Building 10-CRC, Room 4-5932, Bethesda, MD 20892. E-mail: 12. Ikuta S, Yasui C, Kawanaka M, et al. Watery diarrhea, hypokalemia [email protected]. and syndrome due to an adrenal pheochromocytoma. This research was supported by the Intramural Research Pro- World J Gastroenterol. 2007;13:4649–4652. gram of the Center for Cancer Research, National Cancer Insti- 13. King CM, Reznek RH, Dacie JE, Wass JA. Imaging islet cell tu- mours. Clin Radiol. 1994;49:295–303. tute, National Institutes of Health. 14. Squires MH 3rd, Volkan Adsay N, Schuster DM, et al Octreoscan Disclosure Summary: The authors declare no conflict of versus FDG-PET for neuroendocrine tumor staging: a biological interest. approach. Ann Surg Oncol. 2015;22:2295–2301.