Differential diagnosis, investigation and treatment
As a result of the examination, the patient was diagnosed with primary GB cancer and metastasis of right lower lobe (S6) lung cancer (adenocarcinoma, cT1N2 M0, cStage ⅢA). Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of lymph nodes in the hepatoduodenal ligament revealed small-cell-type neuroendocrine carcinomas (SCNEC) which indicated primary GB cancer with lymph node metastasis, rather than metastases of the lung adenocarcinoma.
Prognosis of GB carcinoma with lymph node metastasis and SCNEC is quite poor [5, 6]. The patient, an octogenarian, had performance status of 0 (CTC Version 2.0) , but he had various critical comorbid diseases such as recurrence of lung cancer. Therefore, we first recommended chemotherapy instead of definitive surgery. However, the standard platinum-based regimen of SCNEC proved intolerable because of his general status. Although there are few studies suggesting that nivolumab is effective against neuroendocrine carcinoma and GB cancers [4, 7], Nivolumab monotherapy (240 mg, every two weeks) was initiated. At that time, neuron-specific enolase (NSE) was significant (35.7 ng/mL).
Outcome and follow-up
After 10 courses of nivolumab, a CT scan showed that the GB tumor had shrunk without remarkable lymphadenopathy in the hepatoduodenal ligament, but with limited lymphadenopathy adjacent to the abdominal aorta (Figure 2). A tumor marker, NSE, turned negative (12.9 ng/mL) (Figure 3). Even though prognosis of GB carcinoma with lymph node metastases is quite poor (median OS: 13.5 months) [8], radical resection of the tumor can prolong survival in cases in which metastases disappear after chemotherapy. Therefore, we decided to operate for the following reasons: 1. We could remove the tumor completely with lymphadenectomy next to the abdominal aorta. 2. If the tumor increased during further nivolumab monotherapy, we would have been unable to achieve complete resection by surgery.
Furthermore, surgery seemed likely to be tolerated by the patient because he was almost healthy and because the surgery did not require major hepatectomy or bile duct resection. We meticulously explained the foregoing to the patient and his family and obtained consent for surgery. Then, an extended cholecystectomy and lymphadenectomy around hepatoduodenal ligament and sampling of lymph nodes proximal to the abdominal aorta were performed. After surgery, no major adverse events were observed, except delayed gastric emptying, Clavien dindo grade Ⅱ, and acute gastric mucosal lesions, Clavien dindo grade IIIa. Histopathologically, the atrophied gallbladder had a tumor in its fundus (15x8x10 mm). (Figure 4). Upon microscopic examination, NEC and adenocarcinoma (in situ) components were mixed (Figure 5). Most components of the tumor were NEC, and adenocarcinoma in situ (AIS) was present at both ends of the NEC. Histologically, there was no metastasis in the hepatoduodenal ligament, but there was metastasis beside the abdominal aorta. PD-L1 28-8 IHC showed that the PD-L1 expression rate was less than 10% (Figure 5). Histological evaluation of the chemotherapeutic effect was Grade 0, no change (6th Ed. of General Rules for Clinical and Pathological Studies of Cancer of the Biliary Tract). One month after the surgery, adjuvant nivolumab monotherapy was initiated. Three months have elapsed since the surgery, and no recurrent lesion has been observed.