Advanced gastric small cell carcinoma with immunotherapy-based treatment: A case report

Abstract

BACKGROUND

The clinical and pathological characteristics of primary gastric small cell carcinoma (GSCC) resemble those of small cell lung cancer, which is less sensitive to chemotherapy and has a poor prognosis. Currently, platinum-etoposide chemotherapy is a primary chemotherapy regimen for small cell carcinoma, but it is still imperfect. Programmed cell death ligand 1 (PD-L1) inhibitors are recommended for the treatment of small cell lung cancer. However, to determine whether PD-L1 inhibitors are optimal for metastatic GSCC requires more clinical data.

CASE SUMMARY

A 67-year-old male experienced upper abdominal pain without any obvious cause for 1 week. Gastroscopy examination revealed a mass in the gastric body. Pathological examination of the biopsy specimen combined with immunohistochemistry showed a high-grade neuroendocrine carcinoma (small cell carcinoma). Genetic tests showed TP53, CREBBP, RB1, ABCB1, DNMT3A, and HGF gene mutations. Computed tomography (neck + chest + abdomen) showed multiple enlarged lymph nodes, occupying space in the greater curvature of the stomach and intrahepatic metastases. A regimen consisting of cisplatin and etoposide combined with durvalumab was administered every three weeks as palliative chemotherapy, for seven cycles. Durvalumab was then maintained every three weeks. However, the tumor recurred two months after the completion of chemotherapy. A regimen consisting of carboplatin and irinotecan combined with durvalumab was then given every three weeks. The tumor in the gastric body and liver shrank significantly, and the patient did not report any specific discomfort.

CONCLUSION

GSCC is a highly malignant tumor with a poor prognosis. Whether immune-related drugs are optimal for metastatic GSCC requires further exploration.

Key Words: Gastric; Small cell carcinoma; Programmed cell death ligand 1; Immunotherapy; Prognosis; Case report

Core Tip: The clinical and pathological characteristics of primary gastric small cell carcinoma (GSCC) resemble those of small cell lung cancer, but it is less sensitive to chemotherapy and has a poor prognosis. Here we report a case of a 67-year-old man who was found to have a primary stage IV GSCC with metastasis to the liver. The patient was treated with chemotherapy combined with a programmed cell death ligand 1 (PD-L1) inhibitor. Whether PD-L1 inhibitors are optimal for metastatic GSCC requires further exploration.

INTRODUCTION

The incidence of gastric small cell carcinoma (GSCC) is low, and most reports in the literature are case reports. Due to the small number of cases, the understanding of GSCC is limited. National Comprehensive Cancer Network and European Society for Medical Oncology guidelines recommend combining programmed cell death ligand 1 (PD-L1) inhibitors (durvalumab or atezolizumab) with platinum-etoposide chemotherapy as the first-line standard treatment for extensive-stage small-cell lung cancer (ES-SCLC)[1,2]. However, whether PD-L1 inhibitors are optimal for metastatic GSCC requires more clinical data.

We here report a case of GSCC, and discuss its clinical characteristics and treatment with chemotherapy and durvalumab. In addition, we review the relevant literature to improve the understanding of this tumor.

CASE PRESENTATION

Chief complaints

A 67-year-old man was admitted to our hospital due to upper abdominal pain for one week. Self-administration of omeprazole did not achieve significant relief.

History of present illness

The patient’s symptoms had lasted 2 weeks.

History of past illness

The patient had a history of stroke.

Personal and family history

The patient was a hepatitis B carrier whose older brother died of hepatocellular carcinoma.

Physical examination

Physical examination of the patient showed no abnormalities.

Laboratory examinations

The neuron-specific enolase blood level was 16.80 ng/mL.

Imaging examinations

Computed tomography (neck + chest + abdomen; plain scan + enhancement) showed enlarged lymph nodes in the anterior upper mediastinum, occupying space in the greater curvature of the stomach. In addition, multiple intrahepatic metastases with multiple lymph node metastases were observed in the hepatogastric space and around the abdominal aorta (Figure 1). Gastroscopy examination revealed a mass in the gastric body (Figure 2).

Figure 1 Abdominal and pelvic computed tomography showing gastric mass. A: Gastric mass and lymph node involvement before treatment; B: The gastric mass disappeared after seven cycles of chemotherapy; C: The gastric tumor reappeared two months after the completion of chemotherapy; D: The tumor in the gastric body and liver shrank significantly after three cycles of new chemotherapy.

Figure 2  Esophagogastroduodenoscopic view of the gastric mass in the posterior wall of the gastric body.

FINAL DIAGNOSIS

Small blue round cells infiltrated all layers of the gastric wall, and nuclear mitosis was visible (Figure 3). Immunohistochemically, the tumor cells diffusely expressed cytokeratin (CK), synaptophysin, cluster of differentiation 56, and INSM1 indicating that the tumor was a gastric neuroendocrine carcinoma (NEC) (small cell carcinoma) (Figure 4). CK20, p40, CK5/6, chromogranin A (CgA), and somatostatin receptor 2 were all negative. The Ki67 index was approximately 95%. p53 was mutant (nonsense mutation). RB1 showed a loss of expression while INI-1 and BRG1 showed preserved expression. The combined positive score of PD-L1 was 1.

Figure 3 Pathological morphology of gastric small cell carcinoma. A: Under low-power magnification, sheets of small blue cells infiltrated into the mucosa; B: Under high-power magnification, tumor cells were poorly differentiated, with scant cytoplasm and high mitosis.

Figure 4 Tumor cell expression. A: Tumor cells diffusely expressed synaptophysin; B: Tumor cells diffusely expressed INSM1.

TREATMENT

A regimen consisting of cisplatin (day 1, 30 mg/m² per day) and etoposide (day 1 to day 3, 100 mg/m² per day) combined with durvalumab (day 1, 1000 mg/day) was given every three weeks as palliative chemotherapy for seven cycles. Durvalumab was then maintained every three weeks. However, the tumor recurred two months after the completion of chemotherapy. A regimen consisting of carboplatin (day 1, 400 mg/m² per day) and irinotecan (day 1, 100 mg/m² per day) combined with durvalumab (day 1, 1000 mg/day) was then given every three weeks. Genetic tests showed TP53, RB1, CREBBP, ABCB1, DNMT3A, and HGF gene mutations. The tumor mutation burden (TMB) was low (5.1 mutations/megabase), and microsatellite instability remained stable.

OUTCOME AND FOLLOW-UP

During the 16-month follow-up, the tumor in the gastric body and liver showed marked shrinkage, and the size of the lymph nodes also decreased (Figure 1). The patient did not report any specific discomfort, and there was a significant improvement in mental and physical condition.

DISCUSSION

GSCC is a specific histological subtype of gastric cancer and a highly malignant NEC[3]. There is a lack of standardized treatment for GSCC and the literature on immunotherapy for GSCC is limited. The treatment of primary small cell carcinoma refers to that of small cell carcinoma of the lung. This article analyzes and summarizes the pathology, clinical manifestations, treatment, and prognosis of GSCC, and adds experience in its clinical diagnosis and treatment.

GSCC has a male predominance, with a median patient age of 62 years[4]. The clinical symptoms and physical changes are similar to those of general gastric cancer, making it difficult to differentiate. Symptoms include pain and discomfort in the upper abdomen, as well as loss of appetite and progressive weight loss. Some patients also experience varying degrees of swallowing difficulty. In our case, there was no obvious cause for the onset of upper abdominal pain and bloating. Self-administration of omeprazole did not result in significant relief.

Histologically, the tumor exhibited a nest-like and solid sheet arrangement, with no evidence of glandular differentiation. The cell morphology of GSCC can be round or oval, with scant cytoplasm. Nucleoli are not prominent, and necrosis is commonly observed. Mitotic figures are frequently seen. As a tumor with small blue round cells, it needs to be differentiated from the following tumors: (1) Ewing’s sarcoma or peripheral primitive neuroectodermal tumor: EWS-FLI-1 gene fusion can be detected by reverse transcription-polymerase chain reaction; (2) Alveolar rhabdomyosarcoma: This tumor shows diffuse positivity for MyoD1, myogenin, and desmin. Characteristic chromosomal translocations t (2; 13) and t (1; 13) are observed in this tumor; (3) Lymphoma: Tumor cells are mainly round and express lymphoma markers such as leukocyte common antigen. Immunohistochemically, synaptophysin, CgA, and insulinoma-associated protein 1 are particularly significant and can help diagnosis; and (4) Metastatic small cell carcinoma from the lung: Tumors from the lung express thyroid transcription factor-1 more frequently, and chest computed tomography can identify the primary lesion.

At present, there are some hypotheses regarding the mechanism of GSCC, but its genetic characteristics are still unclear. The pathogenesis and molecular genetic alterations of GSCC are considered to have a high mutation rate and a mutation profile different from that of conventional gastric adenocarcinoma. Both TP53 and RB1 mutation can help distinguish GSCC from neuroendocrine tumor G3. However, with the construction of the human gastric NEC genome atlas, MYC has been identified as a key driver of the disease[5], which could provide new ideas regarding its biological characteristics and treatment. In our case, genetic tests showed TP53 and RB1 mutation, as well as new mutations including ABCB1, DNMT3A, and HGF gene mutations. Deciphering the molecular pathways of GSCC carcinogenesis will not only aid in guiding targeted therapies but also provide references crucial for prognosis.

The treatment for GSCC depends on the clinical stage. If the tumor is localized and there is no distant metastasis, radical resection is recommended, supplemented by postoperative radiotherapy or chemotherapy[6]. For advanced GSCC, neoadjuvant chemotherapy before surgery is recommended, followed by evaluation once every two months. This can improve the resection rate and prognosis of patients[7]. Surgery combined with chemotherapy remains the first-line treatment for GSCC patients. Chemotherapy is usually a platinum-based regimen with etoposide[8]. For stage IV GSCC, the National Comprehensive Cancer Network in the United States recommends chemotherapy as first-line treatment, without mentioning surgical treatment. However, there is still controversy over whether palliative resection of the primary tumor can bring survival benefits to patients with stage IV GSCC[9,10]. Most studies have shown that chemotherapy can improve the prognosis regardless of the stage[11,12]. Studies also showed that patients who experience recurrent metastasis and receive adjuvant radiochemotherapy have a significantly longer overall survival compared to the best supportive care[12]. However, other studies found that chemotherapy did not improve the prognosis of GSCC patients[13].

Immune checkpoint inhibitors (ICIs) have significantly transformed cancer treatment strategies over the past decade[14]. The most extensively studied immune checkpoints are programmed death 1 and its ligand PD-L1. High TMB and high microsatellite instability can enhance the efficacy of immunotherapy and have been approved by the Food and Drug Administration as companion diagnostics for ICIs. A meta-analysis showed that chemo-immunotherapy provided better progression-free survival and overall survival compared with chemotherapy alone as first-line treatment in ES-SCLC, including durvalumab, atezolizumab and nivolumab[15]. However, data on chemo-immunotherapy in GSCC are very rare, and its clinical value is unknown. In our case, surgery was not feasible due to liver metastases and multiple lymph node metastases. Thus, chemotherapy was administered. Whether chemotherapy should be combined with durvalumab is debatable as different doctors have different opinions, and clinical data are limited. Our patient received seven cycles of chemotherapy combined with durvalumab. After chemotherapy, the size of the tumor in the gastric body and lymph node significantly decreased, but the patient refused subsequent surgery due to fear. Durvalumab was then maintained every three weeks. The patient is in good overall condition, which indicates that even in low TMB and microsatellite stable cases, durvalumab is a viable option for patients with GSCC. This is consistent with key insight from pivotal SCLC trials: The clinical benefit of adding ICIs to chemotherapy was independent of these biomarkers. Although high TMB and microsatellite instability-high have been confirmed as predictive biomarkers for ICI efficacy in many solid tumors, this does not apply to chemotherapy immunotherapy combination treatment for SCLC. This case may demonstrate the applicability of principles derived from SCLC to GSCC. The efficacy of this combination in the low-TMB setting may stem from the immunomodulatory effects of chemotherapy. Platinum drugs and etoposide can induce immunogenic cell death, release tumor antigens, and create a proinflammatory microenvironment. This chemotherapy-induced priming may render tumors more sensitive to checkpoint inhibition by a mechanism that is less dependent on the baseline neoantigen load of the tumor. This may challenge the widespread use of TMB as a predictive biomarker and emphasizes that, for certain histologies, synergy between chemotherapy and immunotherapy may be the primary mechanism of action. However, the tumor recurred two months after the completion of chemotherapy. A regimen consisting of carboplatin and irinotecan combined with durvalumab was then given every three weeks. The tumor shrank, and the patient’s condition is stable.

CONCLUSION

Durvalumab combined with chemotherapy provides significant survival benefits in ES-SCLC. Given the highly aggressive nature and poor prognosis of GSCC, along with the lack of standard treatment options, it is reasonable to adopt one of the most effective therapeutic strategies for SCLC.