INTRODUCTION

Neuroendocrine tumors (NET) are rare, indolent tumors originating most commonly in the small intestine, followed by pancreas and lung.1 Diagnosis and staging of these tumors can be notoriously difficult due to unpredictable tumor localization and nonspecific array of potential hormonal side effects. Chylous ascites is a rare form of ascites that is characterized by a milky-white appearance and a triglyceride content greater than 200 mg/dL.

We present the case of an elderly man presenting with chronic diarrhea and dyspnea, originally thought to have metastatic cancer with malignant ascites. Our report illustrates the thoughtful multidisciplinary workup that led to the diagnosis of chylous ascites occurring as a rare complication of pancreatic NET compression of the pancreatic duct, including paracentesis fluid studies and the role of specialized somatostatin scans. This case highlights the importance of perseverant workup and patient advocacy as it can affect the prognostication and management of NET.

CASE REPORT

A 75-year-old man with coronary artery disease presented with 2 weeks of progressive dyspnea and 1-year of intermittent diarrhea. He denied recent travel, sick contacts, or changes to his medications or lifestyle habits. He described his diarrhea as intermittent, frequent small volume loose stools which were normal in color requiring adult diapers due to unpredictability with incontinence at home which did not change with dietary modifications. He also noted 2 weeks of progressive shortness of breath when ambulating around his one-floor home which was relieved with rest. He remained independent of activities of daily living at home which primarily consisted of toileting, eating, and watching television at home, and relied on family to deliver his precooked meals and laundry, and help with finances. The patient’s past medical history included 4-vessel cardiac bypass surgery 15 years prior but otherwise was not regularly engaged with primary care since. Due to concerns leaving his home during a pandemic, he mostly remained indoors for the previous months and was not taking any medications or supplements other than daily aspirin. He denied recent smoking, alcohol use, or illicit drug use. Given his hesitancy with endoscopic procedures, he pursued outpatient gastroenterology evaluation and underwent capsule endoscopy 2 weeks prior to presentation, which showed negative stool studies as well as diffuse bowel edema and nonspecific ulcerations of unclear etiology. Due to his worsening dyspnea, he presented prior to his follow-up gastroenterology appointment.

Vital signs were stable on room air. Physical exam revealed frailty, bibasilar dullness on lung exam, distended abdomen with fluid wave, and 3+ lower extremity edema. Blood cultures and stool pathogen studies were negative. CT and MRI of chest, abdomen, and pelvis revealed multiple pulmonary emboli, large pleural effusions and ascites, enhancement of the pancreatic head, and peripancreatic lymphadenopathy. Diagnostic paracentesis done in the ED triage yielded exudative fluid without evidence of infection or overt malignancy. The initial diagnosis of metastatic pancreatic cancer with pulmonary emboli was made. He was ultimately admitted to inpatient primary medicine team for treatment with anticoagulation and diuretics. Oncology was consulted for further workup. Endoscopic ultrasonography revealed a supra-pancreatic 25-mm mass compressing the common bile duct that on biopsy was positive for synaptophysin NET marker. The large exudative ascites was considered to be from likely peritoneal metastases, which rendered a poor prognosis. Palliative care was consulted at the suggestion of Oncology, and recommendations were made to transition to comfort measures and hospice care over the pursuit of aggressive chemotherapy.

At the patient’s request and with advocacy from the primary medical team, further workup was pursued to thoroughly investigate the tumor stage to explore alternative treatment options. Gallium-68 DOTATATE positron emission tomography/computed tomography (PET/CT) revealed metastases to the uncinate process and para-aortic and para-esophageal lymph nodes, but not in the liver or peritoneum. Twenty-four-hour urinary 5-HIAA (5-hydroxy-indole acetic acid) was 11.5mg (normal < 6) and chromogranin was 483 ng/mL (normal <140) (Fig. 1a–c). Large-volume paracentesis was done to improve the yield of cells and for additional fluid studies not done on initial diagnostic paracentesis (Fig. 1d). Four liters of milky, nonmalignant fluid was obtained which showed triglyceride 318 mg/dL and no 5-HIAA or chromogranin (Table 1). Chylous ascites was suspected to be from tumor compression of the pancreatic duct.

Figure 1
figure 1

Histological, radiological, and clinical evidence of well-differentiated neuroendocrine tumor (NET) with chylous ascites. a Histopathological analysis of the biopsied supra-pancreatic mass was positive for synaptophysin, a NET marker. b Coronal view of Ga-68 DOTATE PET/CT scan demonstrates tracer uptake at the pancreatic head and uncinate mass (arrow). c Axial view of Ga-68 DOTATE PET/CT also revealed metastases to the para-aortic and para-esophageal lymph nodes (arrows). d Large-volume paracentesis yielded 4L of milky chylous ascitic fluid.

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Table 1 Ascitic Fluid Characteristics
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Treatment with octreotide led to the resolution of his symptoms within a week, and he was successfully discharged to rehabilitation.

DISCUSSION

NETs are rare, indolent tumors originating most commonly in the small intestine, followed by the pancreas and lung.1 Clinical manifestations of NET and associated carcinoid syndrome vary widely, making the diagnosis challenging.2 Liver and peritoneum metastases are common, and peritoneal spread has worse disease-specific survival (Hazard Ratio 2.9).3 In this case, the initial presentation was mistaken for a diagnosis of metastatic pancreatic cancer with malignant ascites, which upon biopsy was concluded to be pancreatic NET with metastases to lymph nodes based on imaging and presumptively to peritoneum based on exudative ascites. It was only after further workup that a correct and complete diagnosis could be made.

Diagnosis and staging of NET require extensive evaluation for metastases as it can impact management and prognosis. The patient was prematurely limited to comfort care options, which was later expanded to targeted symptom-relieving therapy due to patient and primary team advocacy.

The differential for chylous ascites can be categorized as acquired, through obstruction of the thoracic duct or an increase in lymph production, or congenital, where the lymphatic vessels are disrupted or dilated.4 Etiologically, chylous ascites can be due to portal causes: portal hypertension due to pre-hepatic portal or splenic vein thromboses, intra-hepatic sinusoidal congestion from fibrosis or other infiltrative diseases, or post-hepatic consequences such as fluid overload from cardiomyopathy or Budd-Chiari syndrome resulting in increased lymph production.5 Nonportal causes of chylous ascites are broad: congenital (primary lymphatic hyperplasia, intestinal lymphangiectasia, etc.), inflammatory (radiation, pancreatitis, etc.), infectious (tuberculosis, filariasis, etc.), neoplastic (lymphoma, carcinoid tumors, etc.), postoperative or trauma-related abdominal changes which can trigger leakage of chyle from the lymphatics into the peritoneal cavity.5

Chylous ascites makes up only 1% of ascites cases and has only been described eighteen times in the literature in the setting of NETs.1,2,6,7,8,9,10,11,12,13,14,15,16,17,18,19 Pancreatic NET is exceptionally complicated by chylous ascites, which is caused by mechanical obstruction from compression by tumor and by local fibrosis from serotonin overproduction.5,14 Somatostatin analogs, like octreotide, have been shown to impact both these pathways: octreotide has an antiproliferative effect by modulation of intracellular transduction pathways to inhibit cell proliferation in NET tissue, and also has been shown to reduce lymph excretion by acting directly on somatostatin receptors within intestinal wall lymphatic vessels.1,4,20,21,22,23

This case highlights the need for a thorough investigation, including a complete analysis of ascitic fluid and specialized imaging modalities to ascertain the presence and location of metastases (Table 1). Because NETs overexpress cell membrane somatostatin receptor, somatostatin analogue Ga-68 DOTATATE-labeled PET/CT can be used as a highly sensitive imaging modality for NET diagnosis and localization, especially when the location of metastases is unknown; however, it is not widely available.24 Additionally, elevated levels of serotonin-breakdown product 5-HIAA in the urine can diagnose concomitant carcinoid syndrome.25 NET management is unique given that it has two treatment targets—the tumor itself and the consequences from the excess hormone. Early in the disease course, chylous ascites can be remarkably responsive to dietary modification, diuretics, and medications such as somatostatin or octreotide therapy.2,3,20,21

Given its extremely rare occurrence, NET and chylous ascites caused by local tumor compression of the pancreatic ductal system can be mistaken for metastatic pancreatic cancer with malignant ascites. Prognosis and management of NET depend on the extent of metastases and presence of concordant carcinoid syndrome.1 Chylous ascites is a rare complication from mechanical compression of the lymphatics and has a much better prognosis than liver or peritoneal metastases.1 A study investigating disease-specific survival between NET patients with peritoneal metastasis and liver metastasis determined that the presence of peritoneal metastases nearly halved survival compared to those without metastases.3

Considering the extent to which the prognosis differs, this case is illustrative of how biases can potentially result in suboptimal care of a patient, no matter the rarity of occurrence. Without further advocacy by the primary medical team with consideration of rare alternative explanations and insights after close discussion with consulting specialists, motivated by the patient’s insistence, a treatable condition may have gone unnoticed.

The biases that may have impacted the initial evaluation of the patient include anchoring, availability, and confirmation biases (Table 2). Anchoring bias, the tendency for decisions to be made off the first piece of evidence that is presented, occurred when the ascites was assumed to be of malignant origin, prompting the suggestion for palliative care and hospice.26 If the initial paracentesis fluid had been analyzed for triglycerides and a more thorough imaging had been performed, the appropriate diagnosis may have been determined earlier. Availability bias, having the disposition to overestimate how often an event occurs because information about it is more easily recalled, was also present.26 Metastatic pancreatic cancer with malignant ascites is much more prevalent than pancreatic NET with chylous ascites, and thus, a diagnosis of the former was determined early on. Finally, confirmation bias, the proclivity to look for information supportive of previously held beliefs, most likely played a role in the cursory paracentesis—the workup done was mainly to rule out infection or overt malignancy with chylous ascites not being a consideration at that point.27

Table 2 Summary of Biases and Their Effects on Decision-Making in this Case
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Heuristics are used often to expedite information gathering and decision-making; however, in some circumstances, the assumptions made may cause critical information to be missed either because it did not occur to the provider to pursue it or because it was thought to be insignificant in the overall clinical context. Our case highlights the importance to rigorously consider other possibilities before suggesting end-stage care to the patient if in alignment with their goals of care. A thorough physical examination, urine and repeat ascitic fluid studies, biopsy of tumor, and newer NET-targeted functional imaging collectively can provide a more complete diagnosis and treatment plan—and can even change prognosis entirely, from comfort measures to cure.