INTRODUCTION

It has been reported that the incidence rate of gastric neuroendocrine carcinoma (GNEC) is relatively low and accounts for 0.1% to 0.6% of all gastric cancers[1]. However, the incidence rate has been increasing in the past 20 years[2]. Due to its high degree of malignancy and poor prognosis, GNEC is receiving increasing attention. In 2019, the World Health Organization (WHO) listed poorly differentiated GNEC separately from the type 4 gastric neuroendocrine tumor and further subdivided it into two subtypes: Gastric large cell neuroendocrine carcinoma and gastric small cell neuroendocrine carcinoma[3]. Herein, we first report a 57-year-old male diagnosed with mixed large and small cell neuroendocrine carcinoma (L/SCNEC) of the stomach.

CASE PRESENTATION

Chief complaints

A 57-year-old man was referred to our hospital for the treatment of gastric cancer.

History of present illness

Two months prior, he visited a clinic complaining of upper abdominal discomfort. Pathologic examination of the biopsy under esophagogastroduodenoscopy revealed cardiac adenocarcinoma in another hospital.

History of past illness

The patient remained recurrence- and metastasis-free 8 mo after surgery.

Personal and family history

由表可知，礦石中的鎢主要分布在白鎢礦中，約占78.35%，黑鎢礦中鎢僅占4.12%。通過對主要鎢礦物化學分析，白鎢礦中的鎢為60.81%，黑鎢礦中的鎢為58.22%。鎢礦物粒度整體集中在0.1～0.01 mm，粒度較細，可通過浮選對金尾礦進行綜合回收。

Physical examination

Physical assessment revealed no abnormalities.

（1）母材 雙相不銹鋼是在含C較低的情況下，C r含量在18%～28%，N i含量在3%～10%。有些鋼還含有Mo、Cu、Nb、Ti、N等合金元素，本文介紹的工藝采用UNS S32205鋼管，厚度3.91mm，管徑2in（1in=25.4mm）。

Laboratory examinations

GNEC is a malignant tumor with poor biological behavior. The incidence rate of GNEC has been increasing in recent years[2]. In 2019, the WHO listed poorly differentiated GNEC separately from the type 4 gastric neuroendocrine tumor and further subdivided it into two types: large cell neuroendocrine carcinoma and small cell neuroendocrine carcinoma. Mixed adenoneuroendocrine carcinoma (MANEC) has also been expanded to mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN), and it is stipulated that both neuroendocrine and non-neuroendocrine components should exceed 30%[3]. However, the cutoff point of 30% has been controversial for a long time[4]. Jiang

[5] believed that more than 20% of neuroendocrine components could affect the prognosis in gastric adenocarcinoma, and Park

[6] advocated that the cutoff value should be set at 10%. Even though the neuroendocrine component accounts for a relatively low proportion in the primary focus, it can become the main component in the metastatic lymph nodes, suggesting that the GNEC component has higher malignant behavior, and the vessels and lymphatic vessels could be invaded in the early stage[7]. This case of GNEC did not receive neoadjuvant therapy and was mixed with large cell and small cell neuroendocrine components, both of which were more than 30%. A few reports of L/SCNEC have been seen in the lung, uterus and other organs in the past[8,9]. However, to the best of our knowledge, this is the first time it has been reported in the digestive system.

首先，嚴格落實統(tǒng)一供種、統(tǒng)一水肥管理、統(tǒng)一技術指導、統(tǒng)一病蟲害防治、統(tǒng)一機械化操作的五統(tǒng)一技術路線，確保整個示范區(qū)內(nèi)各項工作的統(tǒng)一性。同時還要在示范區(qū)內(nèi)明確標志示范牌，示范牌要詳細注明創(chuàng)建單位、主導品種、產(chǎn)量目標和關鍵生產(chǎn)技術。同時還要確保有專業(yè)技術人員負責，有專業(yè)配套措施扶持，定期開展觀摩示范活動計劃，有效發(fā)揮示范區(qū)的宣傳示范帶動作用。

Imaging examinations

Esophagogastroduodenoscopy showed that an ulcerative tumor was approximately 1-3 cm away from the esophagogastric junction with a deep ulcer bottom and covered with dirt and white moss on the surface (Figure 1). Contrast-enhanced computed tomography scans revealed uneven thickening of the lesser curvature of the cardia and corpus, in accordance with gastric cancer, and coalesced lymph nodes in the cardiac area, approximately 0.8 cm in diameter (Figure 2).

Postoperative pathological results

A gross examination of the surgically resected specimen showed that a protuberant tumor with a size of 3 cm × 1 cm × 0.6 cm could be seen at the esophagogastric junction. Microscopically, mixed large (70%) and small (30%) carcinoma cells invaded the propria muscularis layer, with a negative margin (Figure 3). Vascular tumor thrombus and nerve invasion could be seen. Some lymph nodes were found to have metastatic carcinoma (5/21). One of them was large cell carcinoma components. One of them was mixed large and small cell carcinoma components. Three lymph nodes were small cell carcinoma components (Figure 4). Immunohistochemistry (Figure 5) showed AE1/AE3 (2+), Syn (3+), CD56 (3+), CgA (2+), Ki-67 (60-70%), p53 (80%), AFP (-), c-Met (-), EGFR (-), GPC3 (-), HER2 (0), MLH1 (+), MSH2 (+), MSH6 (+), PMS2 (+), Sall4 (2+), and S-100 (-). In situ hybridization showed EBER (-). The pTNM classification was T2N2M0 (stage IIB).

FINAL DIAGNOSIS

Informed written consent was obtained from the patient for publication of this report and any accompanying images.

TREATMENT

We performed a laparoscopic-assisted subtotal gastrectomy with D2 lymphadenectomy. The patient refused adjuvant treatment.

北京市豐臺區(qū)南方莊社區(qū),陳益君老人每天都往來于住所和頤養(yǎng)康復養(yǎng)老照料中心之間。陳益君的老伴患多種慢性病,長期臥床,“雇了兩個保姆還不行,有時候還得把上班的兒子叫回來幫忙,真是伺候不過來?！标愐婢硎?“現(xiàn)在住進照料中心,都是像我老伴一樣不能下床的老人,比原來省心方便多了?！?/p>

OUTCOME AND FOLLOW-UP

He had diabetes for 30 years, for which he was taking metformin daily.

1.1 一般資料 在中國知網(wǎng)的“文獻來源”中檢索輸入“大理學院學報”“大理大學學報”，按照被引頻次由高至低排序，將被引頻次≥20次的論文納入研究范圍，共計54篇論文納入統(tǒng)計分析范圍，在統(tǒng)計范圍內(nèi)的論文發(fā)表時間自2002年8月30日至2013年1月15日，而以《大理大學學報》為刊名的第1期發(fā)表于2016年1月，并且在《大理大學學報》上發(fā)表的論文最高被引頻次為5次，無符合統(tǒng)計要求的論文，故將檢索詞“大理大學學報”剔除。統(tǒng)計截至2017年10月22日。

DISCUSSION

Laboratory examinations, including the tumor marker levels, revealed no abnormalities.

The origin of GNEC and MiNEN has not been determined. One view is that during the proliferation of normal enterochromaffin-like cells, superimposed gene mutations result in gastric neuroendocrine tumor formation, which further progresses to GNEC, diffuse gastric adenocarcinoma and finally signet ring cell carcinoma[10-12]. Another view is that gastric neuroendocrine cells predominantly arise from neuroendocrine precursor cell clones occurring in preceding adenocarcinoma components, which transform into neuroendocrine cells during rapid clonal expansion. The adenocarcinoma component may become necrotic or desquamate, while the neuroendocrine component rapidly develops. Thus, MANEC seems to be a transitional stage in the transformation from gastric adenocarcinoma to GNEC. Gene sequencing[13-15] and mucin phenotype expression[16] of GNEC, gastric adenocarcinoma and two components in MANEC have tested and supported the hypothesis. GNEC is usually diagnosed at an advanced stage, which also supports this viewpoint. There is a potential consensus that adenocarcinoma cells and neuroendocrine cancer cells can originate from the same kind of precursor cells. However, Makuuchi

[17] found that there were significant differences in gene expression between GNEC and gastric adenocarcinoma by whole exon sequencing. The vast majority of mutated genes in GNEC (517/557, 92.8%) were not mutated in gastric adenocarcinoma. Lewin[18] histologically divided MANEN into a combination type (two components adjacent but not mixed), collision type (two components cross mixed with each other) and double secretion type (tumor cells secreting mucus and expressing neuroendocrine markers at the same time). The tumorigenesis of different types may be distinct, which may explain the differences in the above research results.

For GNEC patients without distant metastasis, surgical resection of the lesion is still the first choice. At present, platinum-based chemotherapy is often used as the first-line treatment for patients with advanced GNEC who have lost the opportunity for radical operation. FOLFIRI (fluorouracil, leucovorin, and irinotecan) or FOLFOX (leucovorin, fluorouracil, and oxaliplatin) can be used as the second-line treatment. The effectiveness of molecular targeted therapy[19], immunotherapy[20] and peptide receptor radionuclide therapy in patients with GNEC needs to be further tested[21]. Okita

[22] found that after receiving EP (cisplatin plus irinotecan) chemotherapy, the response rate of 12 GNEC patients with distant metastasis or postoperative recurrence was 75%. The median progression-free survival time was 212 d, and the median survival time was 679 d. Thus, the EP regimen showed good therapeutic effects. Ma

[23] found that neoadjuvant therapy can improve the prognosis of patients with GNEC (the 5-year survival rates of the neoadjuvant therapy group and direct surgery group were 57.4%

28.5%, respectively). However, there was no effect between the two subgroups of neoadjuvant chemotherapy using regimens based on platinum agents or not. In addition, there has been much discussion about whether adjuvant chemotherapy after radical resection can improve the prognosis of patients with GNEC. In 2020, a multicenter study in China found that after propensity score matching, neither chemotherapy based on platinum agents nor chemotherapy based on 5-fluorouracil agents can improve the prognosis of these patients[24]. The heterogeneity of GNEC may be the reason for the difference in treatment response.

The prognosis of GNEC is worse than that of gastric adenocarcinoma[4], and the prognosis of MANEC is worse than that of gastric adenocarcinoma but better than that of GNEC[25]. A multicenter retrospective study included 503 patients with GNEC, 401 patients with MANEC and 2875 patients with gastric adenocarcinoma. After propensity score matching, the 5-year disease-free survival rates of GNEC and gastric adenocarcinoma were 47.6%

57.6%, respectively (

< 0.001); the 5-year disease-free survival rates of MANEC and gastric adenocarcinoma were 51.1% and 57.8%, respectively (

= 0.02)[26]. The high proportion of neuroendocrine components in MANEC often indicates poor prognosis[27,28]. This may be related to the fact that the components of GNEC are more prone to distant metastasis and lack of responsive chemotherapy.

In our case, although small cell neuroendocrine carcinoma components accounted for a lower ratio in the primary focus, there were more lymph node metastases. Compared with large cell neuroendocrine carcinoma, small cell neuroendocrine carcinoma may have worse biological behavior, at least in this case. However, there are few studies comparing the incidence rate, biological behavior, treatment modalities and prognosis of large cell GNEC and small cell GNEC. Xie

[29] found that in 132 cases of GNEC, small cell carcinoma accounted for 23.7%, and the 3-year survival rate was 63.3%, while large cells accounted for 77.3%, and the 3-year survival rate was 41.6%. A retrospective clinical study also suggested that the prognosis of large cell GNEC was worse in Korea[30]. Whether the prognosis of L/SCNEC is different needs to be further explored in the future. In lung cancer with a higher incidence rate, next-generation sequencing studies have shown that large cell neuroendocrine carcinoma can be further subdivided into two mutually exclusive groups based on their mutational patterns: the small cell carcinoma-like type, characterized by TP53+RB1 co-mutation/loss and other small cell carcinoma-type alterations, including MYCL amplification; and the non-small cell carcinoma-like type, characterized by the lack of co-altered TP53+RB1 and nearly universal occurrence of non-small cell carcinoma-type mutations (STK11, KRAS, and KEAP1)[31]. The prognosis of lung large cell neuroendocrine carcinoma may be further improved by selecting the corresponding chemotherapy regimen according to different molecular subtypes[32].

Endoscopy:the chronic gastritis is divided into two types under endoscopy,superficial gastritis,and atrophic gastritis with erosion,bile reflux,and bleeding if signs,such as the diagnosis of superficial gastritis or atrophic gastritis with erosion,bile reflux,etc.

At present, many scientists believe that some precursor cells in well-differentiated adenocarcinoma can differentiate into neuroendocrine cancer cells[33]. The tumor as a whole gradually becomes MANEC. Then, as adenocarcinoma cells undergo necrosis, they gradually progress to pure GNEC. In view of the two molecular subtypes of lung large cell neuroendocrine carcinoma, we believe that gastric large cell neuroendocrine carcinoma may also have two subtypes: "small cell carcinoma-like" and "adenocarcinoma-like". However, there are few gene sequencing studies in GNEC. The above hypothesis needs to be further verified by histology and genomics.

CONCLUSION

This report is the first case report on L/SCNEC of the stomach. There is no corresponding classification in the WHO 2019 classification of digestive system neuroendocrine neoplasms. Clinically, most of patients with GNEC did not receive different chemotherapy schemes according to large cells or small cells, which may cause confusion in clinical treatment. We report the first case of L/SCNEC of the stomach and advocate using different chemotherapy regimens according to large or small cell neuroendocrine carcinoma of the stomach for clinical research to clarify the heterogeneity of GNEC and improve the prognosis of patients with GNEC.

認知行為護理作為一種新型的護理模式，以患者為中心，對患者的日常行為進行評估，針對患者的飲食和生活行為進行糾正和干預。進而提高患者的治療依從性，保障治療效果，降低疾病進展風險。同時通過改變患者錯誤理念，糾正負面情緒，醫(yī)患間建立相互信任、相互支持的良好關系，提高協(xié)作有效性，讓患者在心理上對健康的生活方式加以肯定。

1.第一種不健康的消費心理是盲目、跟風的心態(tài)，年輕人受到個人閱歷的影響，很難擁有獨立自主的消費認識。在選擇消費行為時，往往會受身邊人的影響，比如看到周邊有人帶高端的智能手機，也會要求長輩為其購置手機，這一盲目的消費心理，不僅加大了經(jīng)濟支出，也影響了自身的健康成長。

FOOTNOTES

Li ZF and Lu HZ contributed equally to this work; Zhao DB contributed to the conception and design of the study; Li ZF collected the data and wrote the initial draft of the manuscript; Lu HZ reviewed the pathological sections and analyzed and interpreted the data; Chen YT and Bai XF contributed to drafting and revising the manuscript; Wang TB and Fei H participated in the clinical management and follow-up of the patient; all authors made substantial contributions to the intellectual content of this paper and approved the submitted version.

The patient was diagnosed with gastric cancer (L/SCNEC) pT2N2M0 (stage IIB), accompanied by diabetes.

There was no relevant personal or family history.

The authors declare that they have no conflicts of interest related to this manuscript.

The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

China

盡管心中極不情愿，紅琴最終還是跟著風影一起來了。在她的下意識中，感到自己很對不起男人，有一種負罪的感覺，為了贖罪，對風影的話，她還是言聽計從的。站在東泉嶺上，一陣山風徐徐吹來，發(fā)出松濤的嘯聲，她產(chǎn)生了一種異樣的感覺，過去的一切皆隱退成了一場模糊的夢，眼前的一切也變得有些虛幻起來，自己好像來到了另一個世界，從紅塵到仙界?；蛟S老公的選擇也有他的理由，反正到了這里，聞到了來自大自然的濃烈的氣息，浮躁的心就會清靜下來。

Ze-Feng Li 0000-0002-5345-3527; Hai-Zhen Lu 0000-0001-7564-794X; Ying-Tai Chen 0000-0003-4980-6315; Xiao-Feng Bai 0000-0002-8208-3668; Tong-Bo Wang 0000-0003-2113-3681; He Fei 0000-0003-4831-4028; Dong-Bing Zhao 0000-0002-6770-2694.

Gao CC

A

Zhang YL

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