Mixed neuroendocrine-non-neuroendocrine carcinoma of gallbladder: case report

Abstract

Background: Mixed neuroendocrine-non-neuroendocrine tumors (MINEN) of the gallbladder are extremely rare; indeed, the English expert literature reports a mere handful of case reports and case series on this topic. According to the WHO classification of 2010, MINEN are considered to be tumors consisting of two major components, neuroendocrine and non-neuroendocrine, each of which hosts at least 30% of the total cellular population. To date, the etiology and pathogenesis of MINEN have not been precisely determined and the non-specific symptoms generally result in late diagnosis (mainly in the terminal stages of the condition) and contribute to the generally poor prognosis. As far as the management of the disease is concerned, radical surgery plays a crucial role; however, the significance of surgical debulking and biological therapy applying somatostatin analogues has not yet been determined.

Case presentation: A 56-year-old female was referred to our department for a rapidly progressing tumor in the subhepatic area along with the infiltration of S5 and S6 liver segments. With regard to preoperative findings, the tumor appeared as operable, although, during the surgery, an extensive involvement of the hepatoduodenal ligament by the tumor through the lymph nodes was revealed. Due to acute perioperative bleeding from the necrotic tumor, we decided to perform modified resection. Histologically, the tumor was confirmed as MINEN of gallbladder, where the neuroendocrine component was dominant over the non-neuroendocrine component. Six weeks after the discharge, the patient underwent a follow-up CT revealing large recurrence of the disease. Thereafter, the patient was started on systemic therapy with etoposide and carboplatin in combination with somatostatin analogues. Thirteen months after the surgery, the patient is in good clinical condition, and while a recently performed PET/MRI scan revealed a hepatic lesion and hilar lymphadenopathy in full regression, there was a spread of small peritoneal and pleural metastases. The patient remains in the follow-up care.

Conclusions: The occurrence of mixed neuroendocrine-non-neuroendocrine neoplasms is extremely rare. Radical surgery remains the only potentially effective approach to the cure of this disease. The role of biological therapy and debulking in the management of the disease has not yet been precisely defined. In our experience, both of these methods have the potential to positively influence overall survival rates and the postoperational quality of life of patients.

Keywords: Gallbladder cancer; MINEN; Mixed neuroendocrine-non-neuroendocrine tumors; Somatostatin analogues.

Fig. 1

Intimate relation of the adenocarcinomatous component (blue arrows) and the neuroendocrine small cell component (green arrows) in the mixed neuroendocrine carcinoma (hematoxylin eosin, × 200)

Fig. 2

The neuroendocrine component is positively dyed by an anti-synaptophysin antibody whereas the adenocarcinoma’s glands are negative (synaptophysin, × 400)

Fig. 3

More pronounced positivity of cytokeratins in tumor glands in comparison with the expression in neuroendocrine cells (CAM5.2, × 400)

Fig. 4

High proliferation index of the small cell neuroendocrine component (MIB-1, × 400)

Fig. 5

Preoperative CT scan

Fig. 6

Preoperative MRI scan

Fig. 7

Resected specimen of the liver with evident dual tumorous component