A 76-year-old woman presented to our hospital with complaints of epigastralgia since a day prior to admission.
Laboratory data on admission revealed an elevation of aminotransferase, alanine aminotransferase, ɤ-guanosine triphosphate, and alkaline phosphatase.
Serum total bilirubin and tumor markers, carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), SPan-1, and neuron-specific enolase (NSE), were all within normal ranges.
Abdominal computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) showed a mass in an enlarged gallbladder and bulky hepatic lymph nodes surrounding the hepatic hilum (Fig.1a, ​b).
There were also no apparent lesions in upper and lower gastrointestinal endoscopy.
Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) was performed to obtain tissue from the hilar lymph node.
Immunohistochemical staining of the specimen identified diffuse positivity for keratin, CD56, and synaptophysin in the tumor cells, which is consistent with NEC.
An endoscopic naso-gallbladder drainage (ENGBD) catheter was placed, and the bile cytology revealed class V malignant cells.
Therefore, positron emission tomography/computed tomography (PET/CT) examination was performed to evaluate other primary or metastatic lesions.
It revealed that no other accumulated lesions were identified, and the accumulation of 18F fluorodeoxyglucose (FDG) was in the gallbladder (SUVmax 7.8) and lymph nodes (SUVmax 13.4) (Fig.1c, d).
On the basis of these findings, the most likely diagnosis was a gallbladder NEC that was confined to the regional hepatic hilar lymph nodes metastasis.
Finally, we decided to perform surgical resection prior to chemotherapy because of concerns about complications developing from mechanical obstruction of the hepatic hilum by the enlarged lymph node.
She underwent cholecystectomy, hepatic hilar lymphadenectomy, extrahepatic biliary duct resection, and hepaticojejunostomy.
The bulky lymph nodes were totally resected as “en bloc”.
There were no apparent residual lesions surgically.
The postoperative course was uneventful and she was discharged on the tenth day after surgery.
Macroscopically, the tumor was 58 × 42 mm in size and was located in the fundus, which contained a yellowish gallstone (Fig.2a).
A portion of the hepatic hilar lymph nodes (71 × 37 mm) was also excised separately (Fig.2b).
Microscopic examination of the gallbladder revealed a moderate to well differentiated tubular adenocarcinoma infiltrating from the mucosa to the muscular layer, but not the serosal surface, without any NEC components (Fig.2c, ​d).
The tumor cells in the gallbladder are slightly positive for synaptophysin and CD56, but negative for chromogranin A (Fig.2e–g).
The resection margin from the liver bed was negative for tumor cells.
The epithelium around the carcinoma showed intestinal metaplasia with the goblet cells (Fig.4a), which area was stained by alcian blue (Fig.4b).
On the other hand, the hepatic hilar lymph nodes were composed of small round tumor cells with hyperchromatic nuclei and scant cytoplasm (Fig.3a).
Some of the tumor cells were large and had vesicular nuclei.
The tumor cells were arranged in sheets, cords, or in a trabecular or rosette fashion and were interspersed with focal necrosis.
They were immunohistochemically positive for CD56, synaptophysin, and chromogranin A (Fig.3b–3d).
The mitotic count was 24 per 10 high-power microscopic fields, and the Ki-67 proliferation index was 70–80%, consistent with NEC.
The surgical dissection margin of the hepatic lymph nodes was microscopically cauterized within the tumor cells.
There was no invasion to the extrahepatic biliary duct.
As the result of thorough pathological re-evaluation by total segmentation, a negligible area of adenocarcinoma was detected in the lymph nodes (Fig.3e, ​f).
The adenocarcinoma component and the intestinal metaplastic epithelium in the gallbladder were both positive for CDX2 (Fig.4a), but the neuroendocrine component in hilar lymph nodes was negative for CDX2 (Fig.4b).
Postoperatively, the patient received three cycles of carboplatin (area under the curve of 5 on day 1 repeated every 21 days) and etoposide (80 mg/m2 on days 1 through 3 repeated every 21 days).
During the first course, grade 4 neutropenia occurred and it was managed with prophylactic fluoroquinolones.
After 4 months, multiple recurrences in the para-aortic lymph nodes were detected, which was pathologically demonstrated via EUS-FNA to be NEC.
The patient underwent second-line chemotherapy with amrubicin (24 mg/m2 on days 1 through 3 repeated every 21 days).
Grade 4 neutropenia and anemia developed during the courses, and she needed to receive pegylated granulocyte colony-stimulating factor and red blood cell transfusion.
However, she died of progressive disease 8 months after surgery.