Case Report

Clinicopathological Study of Eight Cases of Gastric Neuroendocrine Carcinoma

Keishiro Aoyagi*, Junya Kizaki, Taro Isobe, Taizan Minami and Yoshito Akagi
Department of Surgery, Kurume University School of Medicine, Japan

*Corresponding author: Keishiro Aoyagi, Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan


Published: 02 Dec, 2016
Cite this article as: Aoyagi K, Kizaki J, Isobe T, Minami T, Akagi Y. Clinicopathological Study of Eight Cases of Gastric Neuroendocrine Carcinoma. Ann Clin Case Rep. 2016; 1: 1197.

Abstract

Neuroendocrine carcinoma (NEC) of the stomach accounts for 0.1% to 0.6% of all gastric carcinomas, and its prognosis is poor. This report describes eight patients with NEC of the stomach. Only one patient had been correctly diagnosed before surgery; the others had been misdiagnosed with tubular adenocarcinoma, poorly differentiated adenocarcinoma, and malignant lymphoma. Five patients had type 2 cancer on macroscopic examination. Histological findings of the resected specimens showed that three NECs were associated with tubular adenocarcinoma and that one was associated with signet ring cell carcinoma. Liver metastases were found in four patients, but none had peritoneal metastases. The cancer stroma volume and tumor infiltration indicated the medullary type in seven patients and expanding growth type in six. Neither the scirrhous type nor infiltrative growth type was found. All eight patients had moderate or marked lymphatic invasion, and six had venous invasion. Six patients underwent postoperative chemotherapy. The median survival time was 10 months, and the 5-year survival rate was 37.5%. The causes of death were liver metastases in five patients and metastases to the lung and brain in one. One patient with lung metastasis who underwent multimodal treatment comprising surgery, radiation, and chemotherapy with cisplatin + irinotecan and S-1 + paclitaxel remained alive for 74 months postoperatively. NEC was difficult to diagnose preoperatively. High frequencies of capillary invasion and hematogenous metastasis, such as to the liver, were observed, and the prognosis was poor. However, long-term survival was higher among patients with NEC who underwent multimodal therapy.

Introduction

The World Health Organization classification of 2010 defined neuroendocrine carcinoma (NEC) as a subgroup of neuroendocrine neoplasms. Neuroendocrine neoplasms are classified as neuroendocrine tumors or NECs according to their bioactivity, which is determined by the mitotic rate and Ki67 index (Table 1) [1]. The Japanese classification of gastric carcinoma defines NEC as a special type in the histological classification of gastric tumors and considers NEC to be either small cell type or large cell type [2].
NECs are characterized by many mitoses (≥20) and high proliferative activity (Ki67 index of ≥20%) (Table 1) [1]. Many NECs show medullary, expanded, and trabecular proliferation, and rosette structures are seen pathologically [3,4]. Argyrophilic granules, which are stained by Grimelius stain, or argentaffin granules, which are stained by Fontana–Masson stain, are detected in the cytoplasm of NEC cells. Neuroendocrine granules are seen in the cytoplasm of NEC cells on electron microscopy. NECs are positive for neuroendocrine markers such as chromogranin A, synaptophysin, and neural cell adhesion molecule (NCAM/CD56) on immunohistochemical staining [5]. NEC of the stomach is relatively rare,
accounting for 0.1% to 0.6% of all gastric carcinomas [6,7]. It has a high frequency of capillary invasion, lymph node metastasis, and hematogenous metastasis, such as to the liver and lung. Its prognosis is poor [3,4].
The details of eight cases of NEC of the stomach resected in our institute are herein presented.

Case Presentation

Patients
From 1994 to 2013, 2559 patients with histologically confirmed primary gastric cancer underwent surgery at the Department of Surgery, Kurume University School of Medicine, Kurume, Japan. During this time, eight patients (0.31%) were diagnosed with NEC of the stomach. All eight patients were male, and their mean age was 69.6 years (range, 64-76 years). All eight patients underwent clinicopathological examination. The clinicopathological terms used were those outlined in the 3rd English edition [2] and 14th Japanese edition [5] of the Japanese Classification of Gastric Carcinoma.
This study was conducted in accordance with the Declaration of Helsinki and approved by the Research Ethics Committee of Kurume University School of Medicine. The requirement for informed consent was waived because of the retrospective study design.
Special staining
Grimelius staining was performed for four patients. Immunohistochemical staining was performed using chromogranin A antibody for seven patients, synaptophysin antibody for three patients, CD56 antibody for three patients, and neuron-specific γ-enolase (NSE) antibody for four patients.
Ki67 index
Ki67 staining was performed immunohistochemically for all eight patients. Ki67-positive cancer cells per 1000 cancer cells were counted in 10 high-power fields (HPF), and the Ki67 index (%) was calculated.
Mitotic count
Cancer cells with mitoses were counted in 10 HPF.
Survival
Overall survival for all eight patients was calculated according to the Kaplan–Meier method.

Table 1

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Table 1
World Health Organization 2010 classification of neuroendocrine neoplasms.

Table 2

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Table 2
Eight patients with neuroendocrine carcinoma of the stomach [1].

Table 3

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Table 3
Preoperative diagnosis.

Table 4

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Table 4
Eight patients with neuroendocrine carcinoma of the stomach [2].

Table 5

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Table 5
Grimelius and immunohistochemical staining, mitoses, and Ki67 index.

Table 6

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Table 6
Tumor markers.

Figure 1

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Figure 1
CDDP (90 mg, day1) + CPT-11 (days 1, 8, 15) (28-day cycle) + radiation 45 Gy : 6 courses , 2: S-1 (80 mg, days 1-14) + PTX (70 mg, days 1, 8) (21-day cycle) : 9 courses, 3: amrubicin (60 mg days 1-3) (21-day cycle) : 6 courses, 4: CBDCA (280 mg, day 1) + etoposide (130 mg, days 1-3) (21-day cycle) : 4 courses, 5: nogitecan (1.1 mg, days 1-5) (28-day cycle) : 6 courses, 6: docetaxel (70 mg, day 1) (21-day cycle) : 8 courses a: Mass of recurrence, 20 mm in size was recognized at S10 of the left lung. b: Chest CT revealed no mass at S10 of the left lung. c: Swelling of a lymph node 20mm in size, is recognized at the hilum of the left lung. d: Chest CT showed that the mass lesion at S10 increased to 46 x 30 mm in size. e: Chest CT revealed that the mass lesion at S10 increased to 65 x 40 mm, and a small amount of effusion had developed. f: Brain MRI revealed multiple mass lesion with ring-like enhancement. g: MRI of vertebrae showed bone metastases in the thoracic vertebrae.

Results

Clinicopathological study
All eight patients were symptomatic on admission. One patient had early cancer, but the other patients had advanced cancer (Table 2). Before surgery, only one patient was diagnosed with NEC, five patients were diagnosed with poorly differentiated adenocarcinoma, and two patients were diagnosed with tubular adenocarcinoma. Two patients were diagnosed with malignant lymphoma on preoperative diagnostic imaging (Table 3). Five patients had type 2 cancer, and the NECs of four patients occurred in the lower third (L) of the stomach. A 65-year-old man (Case 3) who underwent distal gastrectomy for a duodenal ulcer 35 years earlier had an NEC arising from the gastric suture line of his remnant stomach. A 64-year-old man (Case 4) had two gastric cancer lesions; one was type 2 cancer with an NEC in the L region with duodenal invasion, and the other was a 0-IIc lesion with a histological diagnosis of tub1 in the upper third part (U) of the stomach. At the time of surgery, seven patients had lymph node metastases, five patients had stage T4a or T4b cancer, and four patients had liver metastases. A 74-year-old man (Case 8) had simultaneous liver, lung, and distant lymph node metastases. However, no patients had peritoneal metastases (Table 2). Histological examination revealed that five patients had small cell carcinoma and three patients had large cell carcinoma. All patients had moderate or marked lymphatic invasion (ly2 or ly3), and six patients had venous invasion. Seven patients had medullary type NEC, and no patients had scirrhous type NEC. Six patients had expanding growth (INFa), and no patients had infiltrative growth (INFc). Case 1 showed medullary and irregular infiltration of tumor cells with little cytoplasm and round or spindle-shaped chromatinrich nuclei. Some of the tumor cells formed a glandular or trabecular pattern, and necrotic tissue was seen in some areas. In Case 6, the tumor cells were arranged in a sheet formation, and many mitoses were seen. The mean major axis of the tumors was 60.0 mm (range, 25-90 mm). Well-differentiated tubular adenocarcinoma was seen in the superficial region in three patients. A 67-year-old man (Case 7) showed non medullary infiltration and signet ring cell carcinoma in the superficial region, with distribution of intramural metastases throughout the entire stomach; this patient remained alive without recurrence for 72 months after surgery (Table 4). The mean number of cancer cells with mitoses in 10 HPF was 102.8 (range, 32–183 per 10 HPF). The mean Ki67 index was 37.8% (range, 23.1%–80.5%). Four tumors were positive on Grimelius staining, and four were positive for NSE. Three tumors were positive for synaptophysin. Six tumors were positive and one was negative for chromogranin. Two tumors were positive and one was negative for CD56 (Table 5).
Tumor markers
Carcinoembryonic antigen was upregulated in two patients and not upregulated in six patients. Carbohydrate antigen 19-9 was upregulated in one patient and not upregulated in seven patients. Cancer antigen 72-4 was upregulated in one of six patients tested. NSE was upregulated in three of four patients tested. Both carcinoembryonic antigen and carbohydrate antigen 19-9 were highly upregulated in a 74-year-old man (Case 8) who had liver, lung, and distant lymph node metastases and died 1 month after surgery. Although cytokeratin 19 fragment is a sensitive marker for non-small cell lung cancer, it was a very sensitive marker for progression and metastases in a 69-year-old man (Figure 1) (Table 6).
Surgery
Three patients underwent distal gastrectomy. Four patients underwent total gastrectomy. One patient underwent resection of the remnant stomach. On lymph node dissection (D), one patient was D1, two were D1+, and five were D2. Four patients underwent curative resection, and four underwent non curative resection due to liver or liver + distant metastases (lung and para-aortic lymph node metastases) (Table 4).
Chemotherapy and radiation
Six patients underwent chemotherapy for metastases or postoperative adjuvant chemotherapy. Two patients did not undergo chemotherapy because they either refused or had a poor general condition due to rapid tumor growth. A 71-year-old man (Case 1) who refused postoperative chemotherapy remained alive for 124 months without recurrence. A 76-year-old man (Case 2) with early cancer did not undergo postoperative chemotherapy but underwent chemotherapy after liver recurrence. Four patients underwent intrahepatic arterial infusion (IHA) using 10 or 20 mg of cisplatin (CDDP) for liver metastases. A 67-year-old man (Case 7) underwent postoperative adjuvant therapy only. A 71-year-old man (Case 5) required third-line chemotherapy for liver metastases including IHA using CDDP, irinotecan (CPT-11), and paclitaxel (PTX) (Table 2). A 69-year-old man (Case 6) underwent several chemoradiotherapy regimens, including CDDP + CPT-11 + radiation, S-1 + PTX, amrubicin (AMR), carboplatin (CBDCA) + etoposide (ETP), nogitecan (NGT), and docetaxel (DOC), for metachronous lung metastases and radiation for brain and bone metastases for 43 months. He finally died of brain metastases 74 months after surgery (47 months after recognition of the lung metastases) (Table 2) (Figure 1).
Prognosis
The median overall survival time was 10 months (range, 1–124 months). The 5-year survival rate was 37.5%. Six patients died of recurrence and metastasis of NECs, and two patients were alive without recurrence for more than 5 years after surgery. A 69-year-old man (Case 6) with metachronous lung metastases at 27 months after surgery survived for 74 months with multimodal therapy including surgery, chemotherapy, and radiation. The cause of death was liver metastasis in five patients and brain metastasis in one. A 76-year-old man (Case 2) with early gastric cancer died of metachronous liver metastases.

Discussion

Iwafuchi et al. [8] described four pathogenetic pathways of stomach NEC: from common-type adenocarcinoma, from a carcinoid tumor, from multipotential stem cells, and from immature neuroendocrine cells. Many NECs of the stomach have recently been considered to originate from common-type adenocarcinoma. The cell clone of the endocrine cell carcinoma is believed to originate from intramucosal adenocarcinoma [8]. Differentiated tubular adenocarcinoma is thought to be particularly significant for the occurrence of endocrine cell carcinoma because well-to-moderately differentiated tubular adenocarcinoma is frequently seen in the superficial regions of the stomach in many patients with NEC [9]. In the present study, well-differentiated tubular adenocarcinoma was seen in the superficial region of the stomach in three patients, and Case 7 showed non medullary infiltration and signet ring cell carcinoma in the superficial region of the stomach. Iino et al. [10] reported that the biological characterization of NEC depended on the histological type of adenocarcinoma from which it was generated or the component of adenocarcinoma that was dedifferentiated with growth of the NEC. In Case 7, signet ring cells were seen and the NEC cells showed infiltrative growth [11].
More than 50% of NECs are localized in the lower third of the stomach; approximately 80% are macroscopic type 2, and many NECs show medullary infiltration and expanded proliferation [3,4]. These features were found in the present study.
NEC has a poor prognosis and is characterized by a high frequency of capillary invasion, lymph node metastasis, and hematogenous metastasis, such as to the liver and lung, either intraoperatively or in the early postoperative phase [8,9]. Nishikura et al. [9] reported that 75% of gastric NECs were advanced cancers and that 83% of gastric NECs had capillary invasion. Iwafuchi et al. [8] reported that capillary invasion was detected in 82.4% of 17 early gastric NECs. In the present study, all patients had moderate or marked lymphatic invasion (ly2 or ly3), six patients had venous invasion, and seven patients had advanced cancer. Hematogenous metastases such as to the liver and/or lung occurred in six patients, including one with early gastric NEC.
Establishment of a definitive diagnosis of gastric NEC before surgery was difficult in the present study because many gastric NECs mainly develop in the submucosal layer. Only one patient in the current study was diagnosed with NEC before surgery. The differential diagnoses included carcinoid, malignant lymphoma, undifferentiated carcinoma, metastatic carcinoma from small cell lung cancer; solidtype poorly differentiated adenocarcinoma, and poorly differentiated squamous cell carcinoma [8].
NSE is reportedly a sensitive tumor marker for neuroendocrine tumors [12]. In the present study, NSE was upregulated in three of four patients. All four patients who underwent immunohistochemical staining for NSE showed positive results.
With respect to the treatment of gastric NEC, the National Comprehensive Cancer Network guideline recommends multimodal therapy including surgical resection of the stomach and postoperative administration of a regimen for small cell lung cancer, such as CDDP + ETP, CDDP + CPT-11, or CBDCA + ETP [13]. S-1 alone or S-1 + CDDP has been administered as the standard treatment for advanced gastric cancer [14]. Additionally, several case reports documented good clinical effects of S-1 or S-1 + CDDP for NEC of the stomach in Japan [15-17]. Hainsworth et al. [18] performed a phase II trial of three anticancer drugs including taxane (PTX, CBDCA, and ETP) in patients with poorly differentiated NEC of the gastrointestinal tract and reported a response rate of 53% and median progression-free survival time of 14.5 months. Five patients underwent IHA using CDDP for liver metastases. However, in these patients who underwent IHA, IHA was not thought to be effective for liver metastasis of gastric NECs. Case 6 underwent several chemoradiotherapy regimens including CDDP + CPT-11 + radiation, S-1 + PTX, AMR, CBDCA + ETP, NGT, and DOC for metachronous lung metastasis and radiation for brain and bone metastases for 43 months. He finally died of brain metastases 74 months after surgery (47 months after recognition of the lung metastases). While this patient’s first regimen included CDDP + CPT-11 + radiation and the clinical effect was a complete response, a single metastatic nodule was localized to S10 of the left lung; thus, radiation was thought to be effective as local therapy for this metastatic nodule. Moreover, radiation was performed for brain and bone metastases and was thought to be useful for prolonging survival and improving the patient’s quality of life. This case suggests that the addition of S-1 and taxane to a small cell lung cancer regimen with radiation prolongs the survival of patients with recurrent NEC of the stomach [19]. In the present study of patients with gastric NEC, we recommended resection of the stomach including the metastatic site. Chemotherapy for small cell lung cancer was also needed as postoperative adjuvant treatment. Multimodal therapy including surgery, chemotherapy, and radiation was needed for management of inoperable and recurrent NEC.
The prognosis of gastric NEC was poor in the present study. In previous studies, the 5-year survival rate and median survival time of patients with gastric NEC were reportedly 24.2% and 7 to 9 months, respectively [20,21]. In our study, the median overall survival time was 10 months (range, 1-124 months), and the 5-year survival rate was 37.5%. The cause of death was liver metastasis in five patients, including one with early gastric cancer, and brain metastasis in one patient. The 5-year survival rate of our patients was better than that in previous reports. However, the median survival time of our patients was almost the same as that in previous reports.

Conclusion

In this study, NEC was difficult to diagnose preoperatively. High frequencies of capillary invasion and hematogenous metastasis, such as to the liver, were seen in our patients with NEC, and the prognosis was poor. Even early NEC was thought to require postoperative adjuvant chemotherapy. However, patients with NEC who underwent multimodal therapy had longer-term survival.

Acknowledgments

The authors express their sincere appreciation to Professor Masayoshi Kage of the Department of Diagnostic Pathology, Kurume University Hospital for providing assistance with interpretation of the pathological findings and performing the immunohistochemical workup.

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