Nivolumab exerts therapeutic effects against metastatic lesions from early gastric adenocarcinoma with a small proportion of neuroendocrine carcinoma after gastrectomy: a case report

Hiroshi Sawayama1,3 · Yoshihiro Komohara2 · Hiroki Hirao1 · Kazuya Sakata1 · Noboru Takata1 · Ichirou Yoshinaka1 · Kazunori Harada1 · Hideo Baba3

Abstract

Gastric neuroendocrine carcinoma (NEC) is an aggressive disease with high metastatic ability. Gastric cancer has intratumoral and intra-patient heterogeneity and may contain NEC. We discuss the case of a 75-year-old man who underwent distal gastrectomy for early gastric cancer. Tumor pathology revealed that nearly all of the tumor (> 95%) was well-differentiated adenocarcinoma, with NEC detected in a small area (< 5%) at the invasion front. No metastasis was identified in the dissected lymph nodes (LN). Multiple liver metastases were detected 3 months after surgery. The metastatic lesion was resistant to both chemotherapy regimens; namely, SOX (S-1 combined with oxaliplatin) and ramucirumab combined with paclitaxel. However, tumor regression was detected after nivolumab treatment. The tumor regression continued for 26 cycles (13 months). Irinotecan treatment was then administered. After 18 irinotecan treatment cycles for 11 months, the para-aortic LN rapidly enlarged. Following biopsy, the swollen para-aortic LN was diagnosed as the recurrence of NEC components of the gastric cancer. Treatment with carboplatin combined with etoposide has been effective and continued. We report a case of NEC para-aorta LN metastases from early gastric cancer with a low proportion of NEC (< 5%). A partial response of the distant metastatic lesions was observed with nivolumab therapy.

Keywords Gastric neuroendocrine cancer · Heterogeneity · Para aorta lymph node metastasis · Nivolumab · PD-1

Introduction

In 2010, the World Health Organization classified gastrointestinal (GI) neuroendocrine tumors as well-differentiated neuroendocrine tumor (G1), well-differentiated neuroendocrine carcinoma (G2), and poorly differentiated neuroendocrine carcinoma (NEC) (G3) [1].
Extra-pulmonary NECs are most often found in the GI tract. GI-NECs account for 35–55% of all extra-pulmonary NECs and are mainly located in the esophagus [2]. Gastric NECs are rare, accounting for only 7% of GI NECs. Gastric NECs are aggressive and have a poor prognosis [3, 4].
Gastric cancer is a complex disease with heterogeneity, intra-tumoral heterogeneity within the primary tumor, and intra-patient heterogeneity between the primary tumor and its metastases. Phenotypic heterogeneity in tumor cell populations is associated with therapeutic resistance [5]. NECs are classified into adenocarcinoma with neuroendocrine carcinoma (> 70% adenocarcinoma and < 30% NEC), mixed adenoneuroendocrine carcinoma (MANEC, 30% adenocarcinoma and > 30% NEC), and neuroendocrine carcinoma with adenocarcinoma (< 30% adenocarcinoma and > 70% NEC).
This report describes the diagnosis and treatment of a patient with gastric adenocarcinoma with NEC. In this case, the NEC comprised less than 5% of the primary tumor. Furthermore, we also discuss the characteristics of Gastric NEC and the current treatments.

Case report

A 75-year-old man was referred to our hospital with abnormal shadows on fluoroscopy of the stomach. The patient voiced no complaints and no abnormalities were found upon physical examination. He had a history of hypertension, premature ventricular contraction, and diabetes mellitus. Laboratory findings showed slightly elevated carbohydrate antigen 19–9 (CA19-9; 40.3 mg/mL; reference value, < 37 mg/mL) level, with all other values in the normal ranges. Gastroscopy confirmed a 30-mm protruding lesion with an irregular edge in the gastric antrum. Biopsy revealed well-differentiated adenocarcinoma. Enhanced computed tomography (CT) found no swollen lymph nodes or metastatic lesions. We performed a radical resection with lymph node dissection. The resected specimen measured approximately 35 × 23 × 5 mm (Fig. 1a). Tumor pathology revealed that more than 95% of the tumor was well-differentiated adenocarcinoma with a submucosal depth of invasion (Fig. 1b). However, poorly differentiated carcinoma was detected in less than 5% of the tumor at the invasion front to the submucosa. Microscopy showed > 5 mitoses per high-power field and vessel invasion (Fig. 1c). Immunohistochemistry was positive for CD56, chromogranin A, and synaptophysin (Fig. 1d–g). Based on these clinicopathological findings, the tumor was classified as an adenocarcinoma with NEC.
Multiple liver metastases were detected by enhanced CT (Fig. 2a) and gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging at 3 months after surgery. The maximum standardized uptake value (SUVmax) for 18F fluoro-2-deoxyglucose (18F-FDG) of the metastatic liver tumors were 5.2–11.6 as determined  by positron emission tomography (PET) (Fig. 2g). A slight elevation of CA19-9 (40.3 mg/mL) was detected. Chemotherapy with S-1 120 mg/day combined with oxaliplatin 130 mg/m2 (SOX regimen) was started. After six cycles of treatment for 3 months with the SOX regimen, tumor progression was observed on enhanced CT (Fig. 2b); thus, we changed the regimen to ramucirumab combined with paclitaxel (ramucirumab 8 mg/kg, paclitaxel 80 mg/m2). After four cycles of treatment for 4 months with ramucirumab plus paclitaxel regimen, tumor progression was again observed on enhanced CT (Fig. 2c); thus, we changed the regimen to nivolumab (3 mg/kg). After six nivolumab treatment cycles over 3 months, tumor regression was confirmed by enhanced CT and the SUVmax for 18F-FDG was reduced to the normal range by PET (Fig. 2h). The tumor regression continued for 26 cycles for 13 months (Fig. 2d–f). Due to para-aortic lymph node enlargement, we changed the regimen to irinotecan (150 mg/m2). The size of the para-aortic lymph nodes did not change after irinotecan treatment; however, the contrast effects in the tumor were reduced on enhanced CT.
After 18 irinotecan treatment cycles administered over 11 months, the para-aortic lymph nodes rapidly enlarged. We performed biopsy of the swollen nodes (Fig. 3a) and immunohistochemistry showed positivity for CD56 (Fig. 3b) and synaptophysin (Fig. 3c) and increased Ki-67 expression (Fig. 3d). Based on these clinicopathological findings, the tumor was diagnosed as a recurrence of NEC components from gastric cancer. We changed the regimen from irinotecan to carboplatin combined with etoposide and continued treatment.

Discussion

Extra-pulmonary NECs are rare tumors most often found in the GI tract. Gastric NEC is a rare tumor in GI tract NEC with highly aggressive biological behavior, exhibiting rapid growth leading to vascular invasion and distant metastases. Gastric cancer has intra-tumor heterogeneity and the proportion and location of NEC components in the primary tumor differ between tumors. In this case, NEC could not be diagnosed in preoperative biopsy samples and was identified in examination of the resected specimen after surgery. Uchiyama et al. reported on the primary lesions of four patients diagnosed with adenocarcinoma by preoperative biopsy. After surgery, NEC components were found in the resected gastric adenocarcinomas and the dissected lymph nodes had metastases from NEC components [6]. Chiba et al. reported a case, where the lymph nodes around the superior mesenteric vein were not swollen and were not considered to be sites of metastatic disease during surgery; however, these lymph nodes were diagnosed to have metastatic NEC. In total, 119 gastric NEC cases reviewed. Gastric NEC more frequently exhibited liver metastasis than gastric cancer (26.7% vs. 3.9%). Gastric NEC with a depth of invasion of pT1 had more lymph node metastasis (58.3%) than pT1 gastric cancer (11.8%) [7]. The ratio of NEC components of the gastric cancer varied; however, gastric cancer with NEC components had an unfavorable prognosis when compared with that of gastric cancer without NEC components. The initial site of recurrence for gastric NEC included the liver, which was followed by recurrence in the lymph node and lung. Gastric NEC had less peritoneal recurrence than gastric cancer without NEC components [8, 9]. The recurrence of gastric cancer with NEC components after surgery suggests the possibility of metastatic lesions consisting of NEC despite the low proportion of NEC components in the primary lesion. In the case of early recurrence of liver metastasis or lymph node metastasis from gastric cancer with NEC components, the pathologic diagnosis of a metastatic lesion is best when performing a biopsy of the metastatic lesion.
If unresectable distant metastasis recurrences are detected chemotherapy should be performed based on the pathological findings of the primary lesion. In this case, we did not perform biopsy of the liver metastases after recurrence and instead selected chemotherapeutic regimens in accordance with gastric cancer as the primary lesion was almost completely well-differentiated adenocarcinoma. A biopsy of the rapidly swelling para-aorta lymph node identified during chemotherapy revealed lymph node metastasis from the NEC components of the primary lesion. Lymph node metastases should be treated using chemotherapy regimens for GI NEC.
Gastric NEC is rare and the standard treatment has not yet been established. Platinum-based regimens combined with etoposide or irinotecan are reportedly effective in GI-NEC [3, 10]. The treatment regimens for GI-NEC are generally those used for small lung cell carcinoma. In this case, we selected carboplatin combined with etoposide due to the lymph node swelling under irinotecan treatment and this regimen has been effective.
Notably, this case was resistant to chemotherapeutic agents including S-1, L-OHP, ramucirumab, and paclitaxel; however, a partial response was observed for nivolumab, an immune checkpoint inhibitor. The tumor regression continued for 13 months and the liver metastatic lesion showed a nearly complete response. Lim et al. performed F18-FDGPET in patients with gastric NEC (n = 10) and MANEC (N = 17). All primary lesions in the 27 patients were visualized by PET (average SUVmax = 12.0, range 3.0–41.8) [11]. Liver metastases were detected by PET; however, the accumulation of 18F-FDG in the metastatic lesions disappeared after nivolumab treatment.
PubMed was searched for articles published in English using the terms “neuroendocrine carcinoma” and “nivolumab”. Twenty-five articles were returned; however, none included gastric NEC. Merkel cell carcinoma (MMC) is a neuroendocrine tumor of the skin. Several clinical trials of treatment with immune checkpoint inhibitors were reported, one of which demonstrated partial and complete responses in 12 and 3 of 22 MMC patients administered nivolumab alone (overall response rate: 68%) [12]. The treatment of other primary lesions with nivolumab has been reported (Table 1). Further clinical trials are expected to determine the effects of immune checkpoint inhibitors in GI-NECs.
In this case, pathological analysis was additionally performed to determine the mechanism of resistance to immunotherapy. Hematoxylin–eosin stained sections showed a slight enlargement of proliferating NEC cells in the recurrent lesion (Fig. 4a, b). Immunohistochemistry showed HLA-class I positivity in the primary lesion that was significantly reduced in the recurrent lesion (Fig. 4c, d). The recurrent lesion had also changed to chromogranin-negative (data not shown). Both primary and recurrent lesions were PD-L1-negative (Fig. 4e, f) and were negative for microsatellite instability. The change of characterization and HLA-class I down-regulation might influence immunotherapy resistance.
This case report had a limitation. A biopsy of the liver metastasis was not performed and the pathological diagnosis of the liver metastasis was not determined. Nivolumab exerted a therapeutic effect against the liver and lymph node metastases; however, the diagnosis of NEC was made with the irinotecan treatment following nivolumab treatment.
In conclusion, this report describes a case in which NEC was detected in a metastatic para-aortic lymph node after resection of an early gastric adenocarcinoma in which NEC comprised less than 5% of the primary lesion. In this case, the metastatic lesion was resistant to the anti-cancer agents S-1, L-OHP, ramucirumab, and paclitaxel; however, nivolumab resulted in a partial response for 13 months.

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