Gallbladder Neuroendocrine Carcinoma

Gallbladder neuroendocrine carcinoma is a poorly differentiated (small cell or large cell) neuroendocrine malignancy of the gallbladder. It is aggressive, usually diagnosed late and has a poor prognosis.

It accounts for under 0.5% of gallbladder cancers and under 1% of gastroenteropancreatic neuroendocrine neoplasms, with a peak age of 60 to 75 years and a female predominance, similar to gallbladder cancer. Median survival is under 1 year in metastatic disease and about 1 to 3 years after complete resection.

It is defined by a proliferation index (Ki-67) over 20% and more than 20 mitoses in 2 mm2. Mixed neuroendocrine and non-neuroendocrine neoplasms contain adenocarcinoma. Well differentiated neuroendocrine tumours of the gallbladder are far rarer and behave better.

Pathophysiology.

Chronic inflammation and gallstones are associated, and tumours may arise from neuroendocrine metaplasia of the epithelium. TP53 and RB1 loss are common, which is also true of small cell carcinoma at other sites.

Right upper quadrant pain, weight loss, jaundice, nausea, a palpable mass or incidental discovery in a cholecystectomy specimen. Carcinoid syndrome is rare.

Red flags.

• Jaundice with a mass.
• Rapid weight loss.
• Liver metastases at presentation.

CT and magnetic resonance imaging show a gallbladder mass with liver invasion, nodes or metastases. Histology with synaptophysin, chromogranin A, CD56 and Ki-67 confirms the diagnosis, with immunostaining to exclude metastasis from the lung. Stage with chest CT and positron emission tomography; gallium-68 somatostatin receptor imaging is less informative in poorly differentiated disease. Serum chromogranin A and neuron specific enolase are optional.

Differential diagnosis.

• Gallbladder adenocarcinoma.
• Metastatic small cell lung carcinoma.
• Well differentiated gallbladder neuroendocrine tumour.
• Gallbladder lymphoma.
• Mixed neuroendocrine and non-neuroendocrine neoplasm.

Localised disease is treated by radical cholecystectomy (gallbladder with the adjacent liver segments IVb and V and lymphadenectomy), followed by adjuvant platinum based chemotherapy. Metastatic disease is treated with the systemic therapy used for small cell carcinoma.

• Cisplatin with etoposide: cisplatin 75 mg/m2 IV on day 1 and etoposide 100 mg/m2 IV on days 1 to 3 of a 21-day cycle for 4 to 6 cycles; maximum 6 cycles; monitor blood counts, creatinine, magnesium, hearing and neuropathy; use carboplatin (area under the curve 5) when creatinine clearance is under 60 mL/min, and reduce etoposide in hepatic impairment (bilirubin over 51 micromol/L) and renal impairment.
• Second line options (irinotecan based regimens, temozolomide with capecitabine) are specialist decisions.

Biliary drainage relieves obstruction. Early palliative care is advised.

Monitoring. Imaging every 3 months after treatment for 2 years, then every 6 months.

Referral and escalation. Hepatobiliary surgery, oncology and the neuroendocrine tumour team.