Hepatic cholera: a case report with literature review

Abstract

Background

Vasoactive intestinal peptide-secreting tumors (VIPomas), also known as WDHA syndrome (or “pancreatic cholera”), are rare neuroendocrine tumors (NETs) with an incidence of 0.05 to 2%. It secretes excessive amounts of VIP, leading to watery diarrhea, hypokalemia, and hypochlorhydria. In adults, they occur most commonly between the ages of 30 and 50 years and are mostly intrapancreatic, occurring in the tail of the pancreas, and rarely located in other segments of the gastrointestinal tract, such as the adrenal glands (35%), paraspinal retroperitoneal ganglia (30–35%), posterior mediastinum (20%), head and neck (1–5%), pelvis (2–3%), and rarely (1%) thymus, lung, kidney, anterior mediastinum, and liver.

Case presentation

Our patient, a 22-year-old man, was admitted with recurrent episodes of large-volume chronic watery diarrhea, generalized muscle weakness, and significant weight loss. After a complete workup, a solitary primary hepatic VIPoma was diagnosed. The patient underwent surgical resection of the liver lesion. Following surgery, there was immediate regression of diarrhea and electrolyte abnormalities, with no recurrence at the 1-year follow-up.

Conclusion

Neuroendocrine tumors, particularly VIPomas, are rare and mostly intrapancreatic. Solitary primary hepatic VIPoma is extremely rare, and to the best of our knowledge, only four cases without any evidence of a pancreatic lesion have been reported. Diagnosis remains challenging, as it is often not detected on conventional imaging. The prognosis mostly depends on tumor grade, stage, and surgical resectability.

Introduction

VIPomas are rare neuroendocrine tumors that secrete excessive amounts of VIP, with an incidence of 0.05–2%. Also referred to as WDHA syndrome (or “pancreatic cholera”), this condition is characterized by watery diarrhea, hypokalemia, and achlorhydria. In adults, they occur most commonly between the ages of 30 and 50 years and are primarily intrapancreatic (80–90%), with 42–75% occurring in the tail of the pancreas [1]. In young children (< 10 years old) and rarely in adults (5% of adult cases), they may be extrapancreatic [2]. This report presents a rare case of an isolated hepatic VIPoma without evidence of a pancreatic lesion.

Case report

Our patient, a 22-year-old man with no known systemic illness, was admitted with recurrent episodes of large-volume chronic painless watery diarrhea, small bowel type for the past 2 years, and generalized muscle weakness with significant weight loss (12 kg) in the past 1 year. Further evaluation revealed chronic secretory diarrhea (> 7 L/day) and profound hypokalemia (2.1 mmol/L). He required daily fluid/electrolyte replacement and showed minimal improvement with loperamide. The patient was evaluated for secretory diarrhea. On examination, the patient was afebrile and general and systemic examinations were normal. The CBC and LFTs were normal. Stool culture, leukocyte, hemoccult, ova and parasite, qualitative fat, Clostridioides difficile toxin assays, and cathartic screening were all negative. The colonoscopy and biopsy findings were unremarkable. EGD: Antral gastritis; small bowel biopsies negative; CRP, ESR, IgA tissue transglutaminase, gastrin, calcitonin, ACTH, TSH, and urinary 5-HIAA were all normal. Abdominal ultrasound showed an 8 × 6.1 cm mass lesion in segment five of the liver. Computed tomography (CT) revealed a 6.5 × 8.7 cm large well-defined heterogeneous density mass in segment five of the right lobe of the liver with inhomogeneous enhancement on contrast administration. Abdominal MRI (Fig. 1A) revealed a well-defined subcapsular lesion in segment five of the right lobe that appeared hypointense on T1W and hyperintense on T2W images with restriction on DWI and with post-contrast enhancement and central non-enhancing cystic areas. AFP level was normal. The plasma VIP level was 834 pg/mL (normal, ≤ 50 pg/mL). PET-CT Gallium-68 Dotatate (Fig. 1B) showed a well-defined, predominantly exophytic mass adjacent to segments IVb and V of the liver, measuring 9 × 8.5 cm, with a prominent, irregular central hypodense non-enhancing focus. The lesion showed fairly homogenous arterial phase enhancement with gradual iso-attenuation with the liver parenchyma in the portal and venous phases. No calcification was observed. No other lesions expressing somatostatin receptors were observed in the remainder of the liver. Our comprehensive evaluation did not reveal any other extrahepatic primary or metastatic lesion. Octreotide therapy was administered, and the patient was scheduled for surgical resection of the lesion. Surgical resection confirmed a bulging subcapsular lesion from the inferior aspect of the liver (Fig. 2). Following surgery, there was an immediate regression of diarrhea and electrolyte abnormalities.

Fig. 1

A MRI abdomen showing a well-defined subcapsular lesion in segment five of the right lobe appearing hypointense on T1W and hyperintense on T2W images with restriction on DWI and with post-contrast enhancement. B Ga-68 Dotatate PET CT showing a well-defined 9 × 8.5 cm exophytic mass seen adjacent to segments IVb and V of the liver

Fig. 2

A Surgical resection confirmed subcapsular lesion bulging from the inferior aspect of the liver. B Resected surgical specimen

Discussion

VIPoma syndrome was first described by Werner and Morrison in 1958 [3]. Most tumors (80–90%) in adults are pancreatic NETs, with 42–75% occurring in the tail of the pancreas [1]. They are mostly large, solitary tumors that are often metastatic at the time of diagnosis [4]. In young children (< 10 years old) and, rarely, in adults (5% of adult cases), they may be extrapancreatic [2]. Extrapancreatic VIPomas can be classified into neurogenic and non-neurogenic types, of which ganglioneuromas, ganglioneuroblastomas, and pheochromocytomas are common [5]. Other extrapancreatic tumors associated with VIPoma syndrome are mostly in the adrenal glands (35%), followed by the paraspinal retroperitoneal ganglia (30–35%), posterior mediastinum (20%), head and neck (1–5% and pelvis (2–3%); rare locations include the thymus, lung, kidney, anterior mediastinum, and liver [2, 6, 7]. The diagnosis requires large-volume secretory diarrhea that persists with fasting and demonstrates elevated plasma VIP levels, with levels greater than 200 pg/mL being almost always diagnostic [8]. Electrolyte abnormalities include hypokalemia, hypochlorhydria, non-anion gap metabolic acidosis, hyperglycemia, and hypercalcemia may also be seen [8]. The diagnosis of VIPoma is mostly delayed and 60–80% are already metastasized by the time of diagnosis [9]. The common sites of metastasis are the liver, lymph nodes, lungs, and kidneys [10]. In most cases, the tumor may be radiologically detected by computed tomography or magnetic resonance imaging, as tumors are mostly > 3 cm in size. MRI has a reported sensitivity of 75–100% and can localize tumors as small as 1 cm in diameter. As 80–90% of patients are somatostatin receptor-positive, Novel imaging with PET-CT Ga-68 Dotatate is 97% sensitive for the detection of VIPomas, while the responsiveness of contrast-enhanced CT and MRI is 80 and 85%, respectively. Octreoscan scintigraphy may be helpful in the identification of hidden metastatic tumor lesions [11, 12]. Intraoperative ultrasonography is useful for detecting obscure neoplasms that are not visible with conventional imaging modalities. Additionally, endoscopic ultrasound may be useful for defining the precise extent and performing a biopsy of the lesion [13]. Immunohistochemically, VIPomas stain positively for VIP, somatostatin, neuron-specific enolase, chromogranin A, synaptophysin, and cytokeratin [7]. The World Health Organization classified these tumors according to their mitotic rate and Ki67 index. It includes three grades, G1 means Ki67 less than 3% (low grade), G2 means 3–20% (intermediate); and G3, > 20% (high grade). The poor prognosis of VIPoma is associated with the histological grade, staging, and presence of metastasis [14]. In our patient, Ki67 was 8% positive for synaptophysin positive, CK19 weakly positive, and CK7 negative (Fig. 3). Surgical resection is the gold standard for the management of patients with primary and metastatic VIPoma. Medical treatment is indicated in individuals who are unwilling to undergo surgery or have inoperable metastatic diseases. Octreotide has been shown to control diarrhea, reduce VIP hormone levels, and stabilize VIPoma tumor growth. Inoperable tumors are managed by palliative therapy, including cytoreductive surgery, biologics, and chemotherapy [15]. Novel chemotherapy options such as sunitinib, everolimus, cetuximab, and rituximab have recently been used to treat progressive unresectable tumors [16]. To the best of our knowledge, only four cases without any evidence of a pancreatic lesion have been reported (Table 1).

Fig. 3

Immunohistochemistry (IHC) staining: A chromogranin A positive, B cytokeratin 7 negative, C cytokeratin 19 positive, D Ki67 8%, E synaptophysin positive, F salt-and-pepper nuclei and stippled chromatin on hematoxylin and eosin (H&E) stain

Table 1 Summary of cases of primary hepatic VIPomas in literature

Conclusion

Overall, VIPomas are rare neuroendocrine tumors that are most commonly found in the pancreas and are usually diagnosed after metastasis. Rarely, tumors may be extrapancreatic in 5% of adults. The diagnosis is generally confirmed by elevated serum VIP levels and functional PET-CT. Treatment is aimed at symptom management and surgery for isolated tumors whenever possible.