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Sporadic pancreatic vasoactive intestinal peptide-producing tumor (VIPoma) in a 47-year-old male
case report Sporadic pancreatic vasoactive intestinal pep2;tide-producing tumor (VIPoma) in a 47-year-old male Ahmed Abu-Zaid Tarek Amin b
a,b,*
, Ayman Azzam
b,c
, Zainab Abudan a, Amani Algouhi a, Hadeel Almana d,
a College of Medicine, Alfaisal University, Riyadh, Saudi Arabia, b Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, c Faculty of Medicine, Alexandria University, Alexandria, Egypt, d Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
* Corresponding author at: College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia. Tel.: +966 567 566 622; fax: +966 11 215 7611 Æ [email protected] Æ Accepted for publication 18 March 2014 Hematol Oncol Stem Cell Ther 2014; xx(xx): xxx–xxx ª 2014 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved. DOI: http://dx.doi.org/10.1016/j.hemonc.2014.03.002
VIPoma is an exceedingly unusual neuroendocrine neoplasm that autonomously secretes vasoactive intestinal polypeptide (VIP). Its reported incidence is approximately 1 per 10 million individuals per year. Herein, we report the case of sporadic pancreatic VIPoma in a 47-year-old male who presented with a six-month history of chronic, plentiful, watery diarrhea. On physical examination, the patient looked sick, lethargic and had signs of dehydration. Laboratory investigations revealed high VIP hormone level (989 pg/mL), hypokalemia, hypercalcemia, hyperglycemia, high blood urea nitrogen, high creatinine, and metabolic acidosis on arterial blood gas. Contrast-enhanced computed tomography (CT) scan showed a 3.1 · 3.3 · 4.7 cm, well-defined, enhancing lesion involving the pancreatic tail with a cystic component. Moreover, a 5.7 · 6.1 · 6.8 cm metastatic hepatic lesion was identified. The patient underwent distal pancreatectomy with splenectomy, hepatic lesion resection, and lymph node dissection. Histopathological and immunohistochemical examination of the pancreatic and hepatic lesions revealed neuroendocrine tumor (VIPoma). Postoperatively, the patient received radiofrequency ablation for the hepatic lesion. A post-operative six-month follow-up showed significant symptomatic relief, reduced VIP hormone level (71 pg/mL) and normalized electrolyte and acid–base profiles. However, a magnetic resonance imaging (MRI) scan showed a small residual metastatic liver lesion which was considered for hepatic artery embolization (HAE). The patient is still alive with a residual hepatic disease at 18 months. We also present a brief literature review on VIPoma.
CASE REPORT
A
47-year-old male presented with a six-month history of chronic, plentiful, watery diarrhea. The patient declared around 12–15 loose bowel movements and estimated average volume loss of nearly 2.5–3.5 L per day. Furthermore, diarrhea was uniformly continuous, unstopped by fasting, non-responding to loperamide (anti-diarrheal agent) and free of mucus, fat or blood. Diarrhea was associated with abdominal bloating (indigestion), nausea, vomiting, facial redness, muscle weakness, palpitation, and unintentional weight loss of approximately 13 kg. The patient denied any history of recent travel to tropical areas, food intoxication, laxative abuse, herbal
Hematol Oncol Stem Cell Ther xx(xx)
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use, visual field defects. Past medical history was remarkable for hypertension controlled on losartan medication. Past surgical history was unremarkable. On physical examination, the patient looked sick, lethargic, and had signs of severe dehydration such as dry skin, decreased skin turgor, delayed capillary refill, and sunken eyes. Vital signs were remarkable for low blood pressure (84/55 mmHg), tachycardia (121 beats/min), and tachypnea (23 breaths/min). Initial laboratory findings revealed high vasoactive intestinal polypeptide (VIP) hormone level (989 pg/ mL), hypokalemia (2.6 mmol/L), hypercalcemia (3.2 mmol/L), hyperglycemia (172 mg/dL), high blood urea nitrogen (45 mg/dL), high blood creatinine (1.4 mg/dL), and metabolic acidosis on arterial
1
case report
Fig. 1. A cross-sectional, contrast-enhanced computed tomography (CT) scan showed a 3.1 · 3.3 · 4.7 cm, well-defined, enhancing lesion involving the pancreatic tail with a cystic component (red arrow). Moreover, a 5.7 · 6.1 · 6.8 cm, focal, well-defined, metastatic lesion with a cystic component involving the left hepatic lobe was identified (yellow arrow). No other sites of distant metastases were recognized.
blood gas (pH: 7.15, bicarbonate level: 6.4 mmol/L). Complete blood count, hepatic, coagulation, prolactin, thyroid and parathyroid profiles were unremarkable. Stool for ova and parasites, culture and sensitivity were negative. In view of possible VIPoma and resultant severe dehydration, electrolyte and acid–base imbalances, the patient was admitted for further workup. On admission, patient was started on fluid replenishment, electrolyte replacements and octreotide administration for symptomatic control of diarrhea. The patient showed marked improvement. A contrast-enhanced computed tomography (CT) scan showed a 3.1 · 3.3 · 4.7 cm, well-defined, enhancing lesion involving the pancreatic tail with a cystic component. Moreover, a 5.7 · 6.1 · 6.8 cm, focal, well-defined, metastatic lesion with a cystic component involving the left hepatic lobe was identified. No other sites of distant metastases were recognized (Fig. 1). CT-guided needle-core biopsies from the pancreatic and hepatic lesions were obtained, and histopathological and immunohistochemical evaluations were consistent with neuroendocrine tumor (VIPoma). The patient underwent distal pancreatectomy with splenectomy, hepatic lesion resection, and lymph node dissection (pancreatic, celiac and porta hepatic lymph nodes). Macroscopic and microscopic examination of lymph node dissections showed unremarkable pathology and were negative for malignancy.
2
SPORADIC PANCREATIC VIPOMA
Grossly, the distal pancreatectomy measured 12 cm in the maximum diameter. Cut-surface showed a 2.7 · 2.9 · 4.6 cm, irregular, white-tanned and firm mass involving the pancreatic tail. Microscopically, the tumor was made up of solid sheets/cords of relatively uniform, intermediate-sized cuboidal cells with centrally located nuclei, stippled chromatin, and delicately granular eosinophilic cytoplasm (Fig. 2A and B). Mitosis was depicted as 4 mitoses per 10 high power fields (HPF). There was proof of vascular and perineural invasion. Surgical excision borders were tumor-free. Immunohistochemically, tumor cells stained positive for chromogranin A, synaptophysin, VIP, somatostatin and Ki-67 (17%) (Fig. 3A–E). The hepatic lesion was shown to be a metastatic VIPoma lesion. Collectively, according to the clinical, laboratory, radiological, histopathological and immunohistochemical profiles, a final diagnosis of primary functioning neuroendocrine tumor (VIPoma), World Health Organization (WHO) grade 2, the American Joint Committee on Cancer (AJCC) stage VI (hepatic metastasis) was confirmed. The patient had an uneventful recovery following surgery. Postoperatively, patient received radiofrequency ablation for the hepatic lesion. A post-operative six-month follow-up showed significant symptomatic relief, reduced VIP hormone level (71 pg/mL) and normalized electrolyte and acid–base profiles. However, a magnetic resonance imaging (MRI) scan showed a small residual metastatic hepatic lesion, which was considered for hepatic artery embolization (HAE). The patient is still alive with residual hepatic disease at 18 months.
DISCUSSION VIPoma is also known as VIPoma syndrome, pancreatic cholera syndrome, Verner-Morrison syndrome, and the WDHA syndrome (watery diarrhea, hypokalemia, and hypochlorhydria or achlorhydria).1 VIPoma is an exceedingly unusual neuroendocrine neoplasm that autonomously secretes VIP. Its reported incidence is 1 per 10 million individuals per year.2 The majority of VIPomas happen sporadically as isolated pancreatic neoplasms. However, roughly 5% of VIPomas occur in conjunction with multiple endocrine neoplasia type 1 (MEN-1).1 Almost all VIPomas (90%) originate from pancreatic tissues (in adults) whereas the remaining 10% originate from extra-pancreatic tissues (in pediatrics) such as bronchus, colon, liver, and neural
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case report
SPORADIC PANCREATIC VIPOMA
Fig. 2. Microscopic examination of the resected pancreatic mass. (A) Tumor cells are arranged in solid sheets or cord-like patterns separated by fibrovascular stroma (magnification power, 10·). (B) Tumor cells are made of relatively uniform intermediate-sized cuboidal cells with centrally located nuclei, stippled (salt-and-pepper) chromatin outline, and delicately granular eosinophilic cytoplasm (magnification power, 40·).
crest-derived tissues (sympathetic nerve chains, pituitary, thyroid and adrenal glands).3 Diagnosis of VIPoma is characteristically delayed.4 Around 60–80% of VIPomas have already metastasized by the time of clinical diagnosis.5 Although the liver is the most common site of metastasis, lymph nodes, lungs, and kidneys have also been reported.6 Clinically, VIPoma patients typically present with watery diarrhea, hypokalemia, and hypochlorhydria or achlorhydria (WDHA) syndrome.7 These
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manifestations are induced by VIP secretion that stimulates intestinal cyclic adenosine monophosphate (cAMP) production, which in turn promotes water and electrolyte secretion into lumen, resulting in copious watery diarrhea, drastic electrolyte disturbances, and radical acid–base imbalances.7 The diarrhea is characterized by being chronic, profuse, secretary, unaffected by fasting, exceeding 3 L/day, odorless, tea-colored, blood-free, mucus-free, high-sodium concentrated, and with low osmolal gap.3
3
case report
SPORADIC PANCREATIC VIPOMA
Fig. 3. Immunohistochemical examination of the resected pancreatic mass (magnification power, 40·). (A) Tumor cells stained positive for chromogranin A. (B) Tumor cells stained positive for synaptophysin. (C) Tumor cells stained positive for vasoactive intestinal peptide (VIP). (D) Tumor cells stained positive for somatostatin. (E) Tumor cells stained positive for ki-67 (17%).
Hypokalemia can be attributed to: (1) VIPomainduced chronic plentiful diarrhea, (2) aldosterone production, or (3) direct potassium secretion by intestinal absorptive cells (enterocytes).4 Symptoms related to hypokalemia may include muscle weakness, flaccid paralysis, abdominal muscle cramps, respiratory depression, and ECG-changes (flattened T-waves). In addition to potassium loss in stool, there is also bicarbonate wasting, resulting in hypokalemic nonanion gap metabolic acidosis.8 Hypochlorhydria or achlorhydria is thought to occur due to the
4
VIP-induced inhibitory effect on gastric mucosa parietal cells, resulting in decreased gastric acid production.9 Hypo- or achlorhydria can lead to various dietary deficiencies secondary to malabsorption of basic electrolytes (e.g., magnesium, zinc) and vitamins (e.g., Vitamin C, K and B family). Other reported symptoms associated with VIPoma include: facial flushing, skin rash, bloating, indigestion, nausea, vomiting, backache, lethargy, and documented unintentional weight loss.10 Dehydration with unreplenished volume loss can lead to
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case report
SPORADIC PANCREATIC VIPOMA
Fig 3. (continued)
potential renal failure and possibly death – if VIPoma is left unmanaged.3 Blood laboratory findings most often reveal elevated plasma VIP levels (60–2100 pg/mL; greater than 200 pg/mL is diagnostic),10 hypokalemia, hypochlorhydria or achlorhydria, non-anion gap metabolic acidosis, hyperglycemia and hypercalcemia.8 Pathophysiological mechanisms of hyperglycemia and hypercalcemia are inadequately understood. However, the hypercalcemia in MEN-1-associated VIPomas can be broadly attributed to the hyperparathyroidism component of MEN-1 syndrome.
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Elevated serum blood urea nitrogen (BUN) and creatinine levels can happen due to the marked VIPomainduced dehydration (diarrhea) and resultant renal insufficiency/failure. As the vast majority of pancreatic VIPomas are located in the pancreatic tail (75%) and are greater than 3 cm in diameter at the time of clinical presentation, the neoplastic masses can be straightforwardly identified by CT scan.11 MRI has a reported sensitivity of 75–100% in diagnosing pancreatic neoplasms,12 and can localize neoplasms as small as 1 cm in diameter.12 As nearly 80–
5
case report
SPORADIC PANCREATIC VIPOMA
Fig 3. (continued)
90% of all VIPomas are somatostatin receptor-positive, octreoscan scintigraphy is an extremely helpful radiological intervention, although it is rarely used.13 Intraoperative ultrasonography (IOUS) is useful in the detection of obscure neoplasms that are not visible with the preoperative conventional imaging modalities.14 Histopathologically,15 VIPomas are classical neuroendocrine tumors. Immunohistochemically,15 VIPomas stain positively for VIP, chromogranin A, synaptophysin, somatostatin, neuron specific enolase, and cytokeratin. Surgical resection, whenever possible, is the gold standard of management in patients with primary and secondary (metastatic) VIPoma disease4,14 and has been shown to effectively ameliorate symptoms and prolong disease-free survival.9 Medical (non-surgical) treatment is indicated for symptomatic relief of diarrhea (palliation) in individuals unwilling to undergo surgery or presenting with inoperable metastatic diseases. Octreotide (somatostatin analogue) has been shown to greatly control diarrhea, reduce VIP hormonal levels and stabilize VIPoma tumor growth (anti-proliferative properties).16 Chemotherapy has been utilized in limited series of unresectable metastatic diseases with varying success rates. Doxorubicin/streptozocin is the recom-
6
mended combination regimen.17 A 5-fluorouracil/ streptozocin combination regimen can be considered whenever doxorubicin is contraindicated.17 Prognosis of VIPoma is largely dependent on VIPoma tumor grading, staging and surgical resectability.18 Poor prognostic factors include: age less than 40 years and more than 60 years, tumor size more than 4 cm in diameter, poor management of water, electrolyte and acid–base profiles, presence of metastases, poor tumor differentiation, positive telomerase activity, and tumor surgical unresectability.19 Patients with surgically benign resected tumors and without distant metastases have extremely favorable prognosis, with a reported five-year survival rate of nearly 95%.20 Conversely, patients with distant metastases have an estimated five-year survival rate of approximately 60%.20 Morbidity/mortality of VIPoma results from untreated WDHA syndrome leading to long-standing dehydration with severe electrolyte and acid–base imbalances, and possibly resulting in renal failure. Renal failure, in turn, if left untreated, may cause cardiac arrest and eventually death.
CONFLICTS OF INTEREST None declared.
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REFERENCES 1. Goldfinger SE. The VIPoma syndrome. In: Tanabe KK, Whitcomb DC, Grover S, editors. UpToDate Patient Preview. Waltham, Massachusetts, USA: UpToDate; 2013. 2. Friesen SR. Update on the diagnosis and treatment of rare neuroendocrine tumors. Surg Clin North Am 1987;67(2):379–93. 3. Krejs GJ. VIPoma syndrome. Am J Med 1987;82(5B):37–48. 4. Bieligk SC, Jaffe BM. VIPoma. In: Percopo V, Kaplan EL, editors. GEP and Multiple Neuroendocrine Tumors. Padua (Padova), Italy: Piccin Nuova Libraria S.p.A; 1996. p. 357–69. 5. Smith SL, Branton SA, Avino AJ, Martin JK, Klingler PJ, Thompson GB, et al. Vasoactive intestinal polypeptide secreting islet cell tumors: a 15year experience and review of the literature. Surgery 1998;124(6):1050–5. 6. Ayub A, Zafar M, Abdulkareem A, Ali MA, Lingawi T, Harbi A. Primary hepatic vipoma. Am J Gastroenterol 1993;88(6):958–61. 7. Verner JV, Morrison AB. Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Am J Med 1958;25(3):374–80.
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8. Mekhjian HS, O'Dorisio TM. VIPoma syndrome. Semin Oncol 1987;14(3):282–91. 9. Remme CA, de Groot GH, Schrijver G. Diagnosis and treatment of VIPoma in a female patient. Eur J Gastroenterol Hepatol 2006;18(1):93–9. 10. Peng SY, Li JT, Liu YB, Fang HQ, Wu YL, Peng CH, et al. Diagnosis and treatment of VIPoma in China: (case report and 31 cases review) diagnosis and treatment of VIPoma. Pancreas 2004;28(1):93–7. 11. Kirkwood KS, Debas HT. Neuroendocrine tumors: common presentations of uncommon diseases. Compr Ther 1995;21(12):719–25. 12. Semelka RC, Custodio CM, Cem Balci N, Woosley JT. Neuroendocrine tumors of the pancreas: spectrum of appearances on MRI. J Magn Reson Imaging 2000;11(2):141–8. 13. Ghaferi AA, Chojnacki KA, Long WD, Cameron JL, Yeo CJ. Pancreatic VIPomas: subject review and one institutional experience. J Gastrointest Surg 2008;12(2):382–93. 14. Aspestrand F, Kolmannskog F, Jacobsen M. CT, MR imaging and angiography in pancreatic apudomas. Acta Radiol 1993;34(5):468–73. 15. Ram R, Natanzi N, Saadat P, Eliav D, Vadmal MS. Skin metastasis of pancreatic vasoactive
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intestinal polypeptide tumor: case report and review of the literature. Arch Dermatol 2006;142(7):946–7. 16. Brentjens R, Saltz L. Islet cell tumors of the pancreas: the medical oncologist's perspective. Surg Clin North Am 2001;81(3):527–42. 17. Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocinfluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 1992;326(8):519–23. 18. Loh HH, Tan F. Pancreatic vasoactive intestinal peptide producing tumor (VIPoma): a case report and literature review. Endokrinolojide Diyalog 2013;10(1):32–7. 19. Karim N, Zarzour A, Daw HA, Palaparty P, Taftaf R, Shehata M, et al. Prolonged survival in a patient with metastatic vasoactive intestinal peptide producing pancreatic neuroendocrine tumors. J Clin Case Rep 2012;2:210. 20. Soga J, Yakuwa Y. Vipoma/diarrheogenic syndrome: a statistical evaluation of 241 reported cases. J Exp Clin Cancer Res 1998;17(4):389–400.
7
a,b,*
, Ayman Azzam
b,c
, Zainab Abudan a, Amani Algouhi a, Hadeel Almana d,
a College of Medicine, Alfaisal University, Riyadh, Saudi Arabia, b Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, c Faculty of Medicine, Alexandria University, Alexandria, Egypt, d Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
* Corresponding author at: College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia. Tel.: +966 567 566 622; fax: +966 11 215 7611 Æ [email protected] Æ Accepted for publication 18 March 2014 Hematol Oncol Stem Cell Ther 2014; xx(xx): xxx–xxx ª 2014 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved. DOI: http://dx.doi.org/10.1016/j.hemonc.2014.03.002
VIPoma is an exceedingly unusual neuroendocrine neoplasm that autonomously secretes vasoactive intestinal polypeptide (VIP). Its reported incidence is approximately 1 per 10 million individuals per year. Herein, we report the case of sporadic pancreatic VIPoma in a 47-year-old male who presented with a six-month history of chronic, plentiful, watery diarrhea. On physical examination, the patient looked sick, lethargic and had signs of dehydration. Laboratory investigations revealed high VIP hormone level (989 pg/mL), hypokalemia, hypercalcemia, hyperglycemia, high blood urea nitrogen, high creatinine, and metabolic acidosis on arterial blood gas. Contrast-enhanced computed tomography (CT) scan showed a 3.1 · 3.3 · 4.7 cm, well-defined, enhancing lesion involving the pancreatic tail with a cystic component. Moreover, a 5.7 · 6.1 · 6.8 cm metastatic hepatic lesion was identified. The patient underwent distal pancreatectomy with splenectomy, hepatic lesion resection, and lymph node dissection. Histopathological and immunohistochemical examination of the pancreatic and hepatic lesions revealed neuroendocrine tumor (VIPoma). Postoperatively, the patient received radiofrequency ablation for the hepatic lesion. A post-operative six-month follow-up showed significant symptomatic relief, reduced VIP hormone level (71 pg/mL) and normalized electrolyte and acid–base profiles. However, a magnetic resonance imaging (MRI) scan showed a small residual metastatic liver lesion which was considered for hepatic artery embolization (HAE). The patient is still alive with a residual hepatic disease at 18 months. We also present a brief literature review on VIPoma.
CASE REPORT
A
47-year-old male presented with a six-month history of chronic, plentiful, watery diarrhea. The patient declared around 12–15 loose bowel movements and estimated average volume loss of nearly 2.5–3.5 L per day. Furthermore, diarrhea was uniformly continuous, unstopped by fasting, non-responding to loperamide (anti-diarrheal agent) and free of mucus, fat or blood. Diarrhea was associated with abdominal bloating (indigestion), nausea, vomiting, facial redness, muscle weakness, palpitation, and unintentional weight loss of approximately 13 kg. The patient denied any history of recent travel to tropical areas, food intoxication, laxative abuse, herbal
Hematol Oncol Stem Cell Ther xx(xx)
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use, visual field defects. Past medical history was remarkable for hypertension controlled on losartan medication. Past surgical history was unremarkable. On physical examination, the patient looked sick, lethargic, and had signs of severe dehydration such as dry skin, decreased skin turgor, delayed capillary refill, and sunken eyes. Vital signs were remarkable for low blood pressure (84/55 mmHg), tachycardia (121 beats/min), and tachypnea (23 breaths/min). Initial laboratory findings revealed high vasoactive intestinal polypeptide (VIP) hormone level (989 pg/ mL), hypokalemia (2.6 mmol/L), hypercalcemia (3.2 mmol/L), hyperglycemia (172 mg/dL), high blood urea nitrogen (45 mg/dL), high blood creatinine (1.4 mg/dL), and metabolic acidosis on arterial
1
case report
Fig. 1. A cross-sectional, contrast-enhanced computed tomography (CT) scan showed a 3.1 · 3.3 · 4.7 cm, well-defined, enhancing lesion involving the pancreatic tail with a cystic component (red arrow). Moreover, a 5.7 · 6.1 · 6.8 cm, focal, well-defined, metastatic lesion with a cystic component involving the left hepatic lobe was identified (yellow arrow). No other sites of distant metastases were recognized.
blood gas (pH: 7.15, bicarbonate level: 6.4 mmol/L). Complete blood count, hepatic, coagulation, prolactin, thyroid and parathyroid profiles were unremarkable. Stool for ova and parasites, culture and sensitivity were negative. In view of possible VIPoma and resultant severe dehydration, electrolyte and acid–base imbalances, the patient was admitted for further workup. On admission, patient was started on fluid replenishment, electrolyte replacements and octreotide administration for symptomatic control of diarrhea. The patient showed marked improvement. A contrast-enhanced computed tomography (CT) scan showed a 3.1 · 3.3 · 4.7 cm, well-defined, enhancing lesion involving the pancreatic tail with a cystic component. Moreover, a 5.7 · 6.1 · 6.8 cm, focal, well-defined, metastatic lesion with a cystic component involving the left hepatic lobe was identified. No other sites of distant metastases were recognized (Fig. 1). CT-guided needle-core biopsies from the pancreatic and hepatic lesions were obtained, and histopathological and immunohistochemical evaluations were consistent with neuroendocrine tumor (VIPoma). The patient underwent distal pancreatectomy with splenectomy, hepatic lesion resection, and lymph node dissection (pancreatic, celiac and porta hepatic lymph nodes). Macroscopic and microscopic examination of lymph node dissections showed unremarkable pathology and were negative for malignancy.
2
SPORADIC PANCREATIC VIPOMA
Grossly, the distal pancreatectomy measured 12 cm in the maximum diameter. Cut-surface showed a 2.7 · 2.9 · 4.6 cm, irregular, white-tanned and firm mass involving the pancreatic tail. Microscopically, the tumor was made up of solid sheets/cords of relatively uniform, intermediate-sized cuboidal cells with centrally located nuclei, stippled chromatin, and delicately granular eosinophilic cytoplasm (Fig. 2A and B). Mitosis was depicted as 4 mitoses per 10 high power fields (HPF). There was proof of vascular and perineural invasion. Surgical excision borders were tumor-free. Immunohistochemically, tumor cells stained positive for chromogranin A, synaptophysin, VIP, somatostatin and Ki-67 (17%) (Fig. 3A–E). The hepatic lesion was shown to be a metastatic VIPoma lesion. Collectively, according to the clinical, laboratory, radiological, histopathological and immunohistochemical profiles, a final diagnosis of primary functioning neuroendocrine tumor (VIPoma), World Health Organization (WHO) grade 2, the American Joint Committee on Cancer (AJCC) stage VI (hepatic metastasis) was confirmed. The patient had an uneventful recovery following surgery. Postoperatively, patient received radiofrequency ablation for the hepatic lesion. A post-operative six-month follow-up showed significant symptomatic relief, reduced VIP hormone level (71 pg/mL) and normalized electrolyte and acid–base profiles. However, a magnetic resonance imaging (MRI) scan showed a small residual metastatic hepatic lesion, which was considered for hepatic artery embolization (HAE). The patient is still alive with residual hepatic disease at 18 months.
DISCUSSION VIPoma is also known as VIPoma syndrome, pancreatic cholera syndrome, Verner-Morrison syndrome, and the WDHA syndrome (watery diarrhea, hypokalemia, and hypochlorhydria or achlorhydria).1 VIPoma is an exceedingly unusual neuroendocrine neoplasm that autonomously secretes VIP. Its reported incidence is 1 per 10 million individuals per year.2 The majority of VIPomas happen sporadically as isolated pancreatic neoplasms. However, roughly 5% of VIPomas occur in conjunction with multiple endocrine neoplasia type 1 (MEN-1).1 Almost all VIPomas (90%) originate from pancreatic tissues (in adults) whereas the remaining 10% originate from extra-pancreatic tissues (in pediatrics) such as bronchus, colon, liver, and neural
Hematol Oncol Stem Cell Ther xx(xx)
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case report
SPORADIC PANCREATIC VIPOMA
Fig. 2. Microscopic examination of the resected pancreatic mass. (A) Tumor cells are arranged in solid sheets or cord-like patterns separated by fibrovascular stroma (magnification power, 10·). (B) Tumor cells are made of relatively uniform intermediate-sized cuboidal cells with centrally located nuclei, stippled (salt-and-pepper) chromatin outline, and delicately granular eosinophilic cytoplasm (magnification power, 40·).
crest-derived tissues (sympathetic nerve chains, pituitary, thyroid and adrenal glands).3 Diagnosis of VIPoma is characteristically delayed.4 Around 60–80% of VIPomas have already metastasized by the time of clinical diagnosis.5 Although the liver is the most common site of metastasis, lymph nodes, lungs, and kidneys have also been reported.6 Clinically, VIPoma patients typically present with watery diarrhea, hypokalemia, and hypochlorhydria or achlorhydria (WDHA) syndrome.7 These
Hematol Oncol Stem Cell Ther xx(xx)
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manifestations are induced by VIP secretion that stimulates intestinal cyclic adenosine monophosphate (cAMP) production, which in turn promotes water and electrolyte secretion into lumen, resulting in copious watery diarrhea, drastic electrolyte disturbances, and radical acid–base imbalances.7 The diarrhea is characterized by being chronic, profuse, secretary, unaffected by fasting, exceeding 3 L/day, odorless, tea-colored, blood-free, mucus-free, high-sodium concentrated, and with low osmolal gap.3
3
case report
SPORADIC PANCREATIC VIPOMA
Fig. 3. Immunohistochemical examination of the resected pancreatic mass (magnification power, 40·). (A) Tumor cells stained positive for chromogranin A. (B) Tumor cells stained positive for synaptophysin. (C) Tumor cells stained positive for vasoactive intestinal peptide (VIP). (D) Tumor cells stained positive for somatostatin. (E) Tumor cells stained positive for ki-67 (17%).
Hypokalemia can be attributed to: (1) VIPomainduced chronic plentiful diarrhea, (2) aldosterone production, or (3) direct potassium secretion by intestinal absorptive cells (enterocytes).4 Symptoms related to hypokalemia may include muscle weakness, flaccid paralysis, abdominal muscle cramps, respiratory depression, and ECG-changes (flattened T-waves). In addition to potassium loss in stool, there is also bicarbonate wasting, resulting in hypokalemic nonanion gap metabolic acidosis.8 Hypochlorhydria or achlorhydria is thought to occur due to the
4
VIP-induced inhibitory effect on gastric mucosa parietal cells, resulting in decreased gastric acid production.9 Hypo- or achlorhydria can lead to various dietary deficiencies secondary to malabsorption of basic electrolytes (e.g., magnesium, zinc) and vitamins (e.g., Vitamin C, K and B family). Other reported symptoms associated with VIPoma include: facial flushing, skin rash, bloating, indigestion, nausea, vomiting, backache, lethargy, and documented unintentional weight loss.10 Dehydration with unreplenished volume loss can lead to
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case report
SPORADIC PANCREATIC VIPOMA
Fig 3. (continued)
potential renal failure and possibly death – if VIPoma is left unmanaged.3 Blood laboratory findings most often reveal elevated plasma VIP levels (60–2100 pg/mL; greater than 200 pg/mL is diagnostic),10 hypokalemia, hypochlorhydria or achlorhydria, non-anion gap metabolic acidosis, hyperglycemia and hypercalcemia.8 Pathophysiological mechanisms of hyperglycemia and hypercalcemia are inadequately understood. However, the hypercalcemia in MEN-1-associated VIPomas can be broadly attributed to the hyperparathyroidism component of MEN-1 syndrome.
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Elevated serum blood urea nitrogen (BUN) and creatinine levels can happen due to the marked VIPomainduced dehydration (diarrhea) and resultant renal insufficiency/failure. As the vast majority of pancreatic VIPomas are located in the pancreatic tail (75%) and are greater than 3 cm in diameter at the time of clinical presentation, the neoplastic masses can be straightforwardly identified by CT scan.11 MRI has a reported sensitivity of 75–100% in diagnosing pancreatic neoplasms,12 and can localize neoplasms as small as 1 cm in diameter.12 As nearly 80–
5
case report
SPORADIC PANCREATIC VIPOMA
Fig 3. (continued)
90% of all VIPomas are somatostatin receptor-positive, octreoscan scintigraphy is an extremely helpful radiological intervention, although it is rarely used.13 Intraoperative ultrasonography (IOUS) is useful in the detection of obscure neoplasms that are not visible with the preoperative conventional imaging modalities.14 Histopathologically,15 VIPomas are classical neuroendocrine tumors. Immunohistochemically,15 VIPomas stain positively for VIP, chromogranin A, synaptophysin, somatostatin, neuron specific enolase, and cytokeratin. Surgical resection, whenever possible, is the gold standard of management in patients with primary and secondary (metastatic) VIPoma disease4,14 and has been shown to effectively ameliorate symptoms and prolong disease-free survival.9 Medical (non-surgical) treatment is indicated for symptomatic relief of diarrhea (palliation) in individuals unwilling to undergo surgery or presenting with inoperable metastatic diseases. Octreotide (somatostatin analogue) has been shown to greatly control diarrhea, reduce VIP hormonal levels and stabilize VIPoma tumor growth (anti-proliferative properties).16 Chemotherapy has been utilized in limited series of unresectable metastatic diseases with varying success rates. Doxorubicin/streptozocin is the recom-
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mended combination regimen.17 A 5-fluorouracil/ streptozocin combination regimen can be considered whenever doxorubicin is contraindicated.17 Prognosis of VIPoma is largely dependent on VIPoma tumor grading, staging and surgical resectability.18 Poor prognostic factors include: age less than 40 years and more than 60 years, tumor size more than 4 cm in diameter, poor management of water, electrolyte and acid–base profiles, presence of metastases, poor tumor differentiation, positive telomerase activity, and tumor surgical unresectability.19 Patients with surgically benign resected tumors and without distant metastases have extremely favorable prognosis, with a reported five-year survival rate of nearly 95%.20 Conversely, patients with distant metastases have an estimated five-year survival rate of approximately 60%.20 Morbidity/mortality of VIPoma results from untreated WDHA syndrome leading to long-standing dehydration with severe electrolyte and acid–base imbalances, and possibly resulting in renal failure. Renal failure, in turn, if left untreated, may cause cardiac arrest and eventually death.
CONFLICTS OF INTEREST None declared.
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SPORADIC PANCREATIC VIPOMA
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