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Future Sci OA
Future Sci OA
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10.1080/20565623.2024.2384878
2384878
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Research Article
Research Article
Clinical treatment strategy and follow-up of lymphoepithelioma-like carcinoma: a retrospective study
Zhang Shilong ‡ a b
Lin Yufu ‡ a c d
Li Zhiyong a c d
Wang Zhiming a b
Luo Rongkui * e
https://orcid.org/0000-0002-8117-2925
Zhang Xiuping ** a c d
a Department of Medical Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
b Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
c Xiamen Clinical Research Center for Cancer Therapy, Xiamen, China
d Clinical Research Center for Precision Medicine of Abdominal Tumor of Fujian Province, Xiamen, China
e Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
* CONTACT: luo.rongkui@zs-hospital.sh.cn
** CONTACT: zhang.xiuping@zsxmhospital.com
‡ Shilong Zhang and Yufu Lin contributed equally to this paper

30 8 2024
2024
30 8 2024
10 1 2384878Aptara25 7 2024
28 8 2024
14 6 2024
22 7 2024
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

Aim: To investigate the clinical features, diagnosis and treatment of lymphoepithelioma-like carcinoma (LELC).

Materials & methods: The clinical data of 114 LELC patients were retrospectively analyzed.

Results: Ninety-eight patients (86.0%) were Epstein-Barr virus-encoded small RNA (EBER) positive detected by situ hybridization. A 67.1% (51/76) patients had PD-L1 expression. The 5-year overall survival rate of EBER negative patients was 51.6% while the rate of positive patients was 84.8% (p = 0.015). The 5-year progression free survival rate of EBER negative patients was 40.2% while the rate of positive patients was 70.2% (p = 0.004).

Conclusion: The progression of LELC is relatively slow and present a better prognosis. The occurrence of tumor is closely related to Epstein–Barr virus infection and PD-L1 is highly expressed in tumor cells.

Plain Language Summary

Lymphoepithelioma-like carcinoma (LELC) is a rare and special malignant tumor. The characteristics of it are not clear. We collected the data of 114 LELC patients. Then we found this tumor grew slowly. Eighty six percent of patients had been infected with EBV. Through microscopic observation, we found that 67.1% of patients had PD-L1 expression in tumor tissue. These characteristics can help people predict how long LELC patients will live and choose useful treatments.

Article highlights

The progression of lymphoepithelioma-like carcinoma is relatively slow and present a better prognosis.

Surgery is the main treatment.

The occurrence of tumor is closely related to Epstein–Barr virus infection, and PD-L1 is highly expressed in tumor cells in most cases.

The genomic variation spectrum is similar to nasopharyngeal carcinoma, which may benefit from immunotherapy.

Keywords: 

Epstein–Barr (EB) virus
lymphoepithelioma-like carcinoma
prognosis
PD-L1
retrospective study
treatment
Fujian Provincial Health Technology Project 10.13039/501100017686 2021QNB020 Natural Science Foundation of Xiamen Municipality 10.13039/100016808 3502Z202372069 This study was supported by Fujian provincial health technology project (2021QNB020) and Natural Science Foundation of Xiamen (3502Z202372069).
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pmc1. Introduction

Lymphoepithelioma-like carcinoma (LELC) is an undifferentiated or minor differentiated malignant tumor. The biological behavior of LELC is similar to the lymphoepithelioma of the nasopharynx, but can occur outside nasopharynx, like liver, lung, stomach and other parts of the body. Despite the fact that LELC is clinically uncommon, tumorigenesis is closely related to Epstein–Barr virus (EBV) infection and different treatments can be tailored to the site of tumorigenesis with an overall good prognosis. This may be due to the significant lymphoid-like cells of the mesenchyme that play an important role in the immune response to the tumor. At present, there are few reports about LELC, which still lack of standard treatment plan. Therefore, our study retrospectively analyzed the clinical treatment and follow-up of 114 patients with LELC treated by our center in recent years, and compared with relevant reports of nasopharyngeal carcinoma in China, especially in aspects of EBV, pathogenesis, lymphocyte infiltration in immune microenvironment and PD-1 and PD-L1. In this study, we analyze the clinical features, pathogenesis, diagnosis and the clinical outcomes of different treatment methods in patients with LELC in our center, in order to improve the understanding of the clinical characteristics and strategies of LELC.

2. Materials & methods

2.1. Patients

A total of 114 patients pathologically diagnosed of LELC from July 2014 to July 2019 in Zhongshan Hospital, Fudan University (Xiamen Branch) and Zhongshan Hospital, Fudan University. The gender, location, tumor sites, treatment plan, EBV expression and PD-1/PD-L1 expression were collected. Patients were followed up with imaging every 2–4 months. As of 31 July 2022, the median follow-up time was 55.1 months (95% CI: 48.673–61.527). Progression-free survival (PFS) and overall survival (OS) were analyzed. This study was approved by the Ethics Committee of Zhongshan Hospital, Fudan University (Xiamen Branch): Approval No.: B2023–114. All patients signed informed consent prior to our study.

2.2. Statistics

All data analysis were performed by SPSS 22.0. Kaplan–Meier method was used to analyze OS and PFS and Log-rank test was used to evaluate the significance of OS and PFS. Statistical significance was considered when p < 0.05.

3. Results

3.1. Clinical features

All cases were Chinese, and 97.4% of them were from the south of China. There were 66 males and 48 females, aged from 17 to 82 years (median 60 years). The Karnofsky Performance Scale (KPS) score of all patients was about 70–100. A total of 39 cases (34.2%) were lung LELC, 31 cases (27.2%) were liver LELC, 28 cases (24.6%) were stomach LELC, eight cases (7%) were parotid LELC and eight cases (7%) were other organs or sites LELC. Among 114 patients, 34.2% (39/114) had tumor node metastasis (TNM) classification stage I, 26.3% (30/114) had TNM classification stage II, 21.1% (24/114) had TNM stage classification III and 18.4% (21/114) had TNM stage classification IV. In this study, 98 patients (86.0%) were Epstein-Barr virus-encoded small RNA (EBER) positive by situ hybridization. Also, PD-L1 was detected in 76 patients (66.7%), and 67.1% (51/76) of patients had PD-L1 expression on tumor surface (Supplementary Table S1).

3.2. Treatment plan

The median follow-up time of 114 patients was 55.1 months (95%CI 48.673–61.527), 16 patients died and 22 patients were loss of follow-up. A total of 96 patients (84.2%) underwent surgery treatment, seven cases were treated by surgery combined postoperative radiotherapy, nine cases were treated by surgery combined postoperative adjuvant chemotherapy, according to the primary site, five patients received surgery combined with interventional therapy or radiofrequency therapy, eight patients received immunotherapy during the course of disease and 25 patients received comprehensive treatment including surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy and interventional therapy.

3.3. Survival analysis

As shown in Figure 1, the 1-year OS rate was 97.1%, 2-year OS rate was 93.1% and 5-year OS rate was 84.6%. The 1-year PFS rate of 114 patients was 88.5%, the 2-year PFS rate was 80.5% and the 5-year PFS rate was 66.2% (Figure 2). The 5-year OS rate was 79.7% in patients with primary lung LELC, 64.5% in patients with primary liver LELC, 91.6% in patients with primary gastric LELC, 87.5% in patients with primary parotid gland LELC and 83.3% in patients with other types. There was no significant difference in OS and PFS among patients at different sites (p > 0.05) (Figures 3 & 4). The 5-year survival rates of stage I/II, stage III and stage VI were 91.1, 77.7 and 48.0%, respectively. There were significant differences among different stages (p = 0.00). The involved OS rates of patients with different stages are shown in Figure 5. The 5-year 0S rate of EBER negative patients and positive patients was 51.6 and 84.8%, respectively, and the difference was statistically significant (p = 0.015) (Figures 6 & 7). The 5-year PFS rate of EBER negative patients and positive patients was 40.2 and 70.2%, respectively (p = 0.004). However, in this study, there was no statistical difference in the effect of different PD-1 and PD-L1 expression status on OS and PFS (p > 0.05), as shown in Figure 8 & Supplementary Figures S1–S3.

Figure 1. The overall survival curve of 114 lymphoepithelioma-like carcinoma patients.

Figure 2. The progression-free survival curve of 114 lymphoepithelioma-like carcinoma patients.

Figure 3. The overall survival curves of lymphoepithelioma-like carcinoma patients with EBER positive and negative.

EBER: Epstein-Barr virus-encoded small RNA.

Figure 4. The progression-free survival curves of lymphoepithelioma-like carcinoma patients with EBER positive and negative.

EBER: Epstein-Barr virus-encoded small RNA.

Figure 5. The overall survival curves of lymphoepithelioma-like carcinoma patients with different expressions of PD-1.

Figure 6. The progression-free survival survival curves of lymphoepithelioma-like carcinoma patients with different expressions of PD-L1.

Figure 7. The overall survival curves of lymphoepithelioma-like carcinoma patients with different expressions of PD-L1.

Figure 8. The progression-free survival curves of lymphoepithelioma-like carcinoma patients with different expressions of PD-L1.

4. Discussion

LELC is an undifferentiated or poorly differentiated malignant tumor [1], which can occur in multiple organs throughout the body, including thyroid, esophagus, stomach, lung, mammary gland, uterus, bladder and thymus [2–5]. Among them, the lung is the most common primary site of LELC, accounting for only 0.92% of lung cancer. It was first described by Begin et al. in 1987 [6], which was commonly seen in relatively young non-smoking Asian population without significant gender difference. Primary LELC in the liver is extremely rare and can be further divided into lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) and lymphoepithelioma-like cholangiocarcinoma (LEL-CC) according to the results of immunohistochemistry [7]. Lymphoepithelioma-like gastric carcinoma (LELGC) is relatively rare. However, Carrasco-Avino et al. [8] found that the incidence in American countries is higher than that in Asian countries and prevalence of men is twice that of women. Moreover, there is no significant correlation between Helicobacter pylori infection, which is closely related to the occurrence of gastric cancer, but it is closely related to the infection of RBV [9]. LELC can also occur in other organs, including parotid gland, thymus, submandibular gland, esophagus, cervix, ureter and other parts and almost reported as individual cases [10].

In this study, there were 39 cases (34.2%) of lung LELC, 31 cases (27.2%) of liver LELC, 28 cases (24.6%) of stomach LELC and eight cases (7%) of parotid gland LELC. The distribution of LELC is dominated by Asians, and mostly found in south areas in China. As shown in our study, a total of 111 patients (97.4%) in our study were from the south of Yangtze River, while three patients were from the north, suggesting the disease may have a wider regional distribution. The clinical manifestations of LELC are nonspecific and can be found by chance due to physical examination. It can also present as the related symptoms caused by the tumor. Among 114 patients in this study, 58 (50.9%) patients were found by physical examination, and 56 (49.1%) patients had corresponding symptoms due to tumor invasion in different parts of the body [11].

The pathogenesis of LELC is not clear, but EBV has been confirmed to be closely related to LELC and most of patients are EBER positive. Chang et al. [12] found that higher copies of EBV in patients serum of primary lung LELC was positively correlated with higher tumor volume and pathological stage. The pathogenesis of LEL-HCC is still unclear, but EBV has been confirmed to be closely related to LELC [13], especially lymphoepithelioma-like intrahepatic cholangiocarcinoma (LEL-ICC) [14]. More than 80% of gastric LELCs are associated with EBV infection [15]. In this study, EBER situ hybridization is strongly positive in 98(86%) cases, indicating that all 98 patients were infected with EBV, which was consistent with literature reports [16]. The possible mechanism of EBV causing LELC is that EBV breaking into cells through Ephrin A2 receptor of epithelial cells and producing six nuclear antigens of EBV (EBNA-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, EBNA-LP) and three latent membrane proteins (LMP-1, LMP-2A, LMP-2B), which can help EBV escape the immune surveillance of the host and induce the carcinogenesis of the host cells. Particularly, LMP-1 protein can downregulate the expression of tumor suppressor genes, which contributes to tumorigenesis. However, LMP-2 protein can promote the division and proliferation of tumor cells through PI3K/AKT signaling pathway, thus promoting the occurrence and development of tumor.

Most lung LELC is in the early or locally advanced stage (stage I or II), which generally removed completely by surgery. For advanced LELC, surgery combined with radiotherapy and chemotherapy is used, presenting better prognosis [17]. Patients with early and locally advanced nasopharyngeal carcinoma are mainly treated with concurrent chemoradiotherapy, while patients with advanced nasopharyngeal carcinoma are treated with chemotherapy combined with immunotherapy. Liang et al. conducted long-term follow-up of 52 PLELC patients and found that the median survival time of PLELC patients was 31.55 months (3.6–128.1 months), the 2-year OS rate was about 88%, and the 5-year OS rate was about 62% [18]. LEL-ICC is a relatively rare liver tumor, of which the main treatment remaining surgical resection. For unresectable tumors, systematic chemotherapy or radiotherapy or chemotherapy is required. Most study have reported that the prognosis of patients with LEL-HCC is better than that of typical hepatocellular carcinoma, which may relate to a large number of lymphocytes infiltrating the tumor tissue, but the specific mechanism is still unclear [19–21]. LELGC is a unique pathological type of gastric cancer, compared with common type of the stomach, LELGC presenting a better prognosis. The main treatment of LELGC is surgical resection of primary tumor and surrounding lymph nodes, based on tumor location, size, lymph nodes around the situation which can be supplemented by postoperative chemotherapy [22]. A retrospective study involving 1248 cases of various types of gastric cancer showed that EBV-associated LELC had the best prognosis [23]. Meanwhile, another meta-analysis also suggested that compared with nongastric LELC, gastric LELC has a higher proportion of early stage, which is manifested by less lymphnodes and neurovascular invasion, and gastric LELC patients have a better prognosis than nongastric LELC patients [24]. In this study, the 5-year OS rate was 79.7% in patients with primary lung LELC, 64.5% in patients with primary liver LELC, 91.6% in patients with primary gastric LELC, 87.5% in patients with primary parotid LELC and 83.3% in patients with other types. Among 114 patients, the 5-year survival rate of stage I/II was 91.1%, stage III was 77.7% and stage VI was 48.0%.

Recent studies have shown that immune checkpoint inhibitors (ICIs) have a significant effect on EBV infection-related gastric cancer, nasopharyngeal carcinoma, Merkel cell carcinoma and so on. Many studies have shown LELC is associated with EBV infection and PD-L1 is overexpressed in tumor cell of most LELC patients, indicating a possible benefit of immunotherapy [25–27]. In this study, 76 (66.7%) of 114 patients were further tested for PD-L1 by immunohistochemical staining. The results showed that PD-L1 was expressed on the tumor surface of 67.1% (51/76) patients, and 28.9% (22/76) of them were highly expressed (≥50%). 38.2% (16/76) were moderately expressed (5–49%) [28,29]. Another study found that three LELC patients with PD-L1 TPS of 15, 30 and 60%, respectively, achieved good efficacy after immunotherapy, suggesting that lung LELC patients can benefit from ICIs [29]. In recent years, more and more studies have confirmed that gastric LELC has a higher positive expression rate of PD-L1 than nongastric LELC [24]. Therefore, immunotherapy may be more suitable for the treatment of this subtype of gastric cancer [30–32]. PD-L1/PD-1 is a pair of immune costimulators. The activation of PD-L1/PD-1 signaling pathway promotes tumor cells to escape from the surveillance and killing of the body’s immune system, leading to the occurrence and development of tumors. A study on immunotherapy of PD-L1 positive EBVaGC conducted by Kubota et al. in Japan suggested that 33% of patients with advanced EBVaGC subtype had improved PFS after anti-PD1 treatment, but further studies are needed to verify [33]. Due to the small number of patients who used ICIs in our study, more clinical data of prognosis of LELC after ICIs treatment are needed in the future.

5. Conclusion

The mechanism of the occurrence of LELC has not been fully elucidated, but some studies have shown that it is related to EBV infection, and the genomic variation spectrum is similar to nasopharyngeal carcinoma, which may benefit from immunotherapy and have a better prognosis. The genomic variation spectrum of LELC may need to be further discussed in the future in order to provide a new basis and target for precision diagnosis and treatment of LELC.

Supplementary Material

Supplementary Materials

Supplemental material

Supplemental data for this article can be accessed at https://doi.org/10.1080/20565623.2024.2384878

Author contributions

Conceptualization, ZM Wang, RK Luo and XP Zhang; methodology, SL Zhang; software, SL Zhang and ZY Lia; validation, YF Lin; formal analysis, YW; investigation, XP Zhang; data curation, SL Zhang; writing—original draft preparation, SL Zhang and XP Zhang; writing—review and editing, ZM Wang and RK Luo; visualization, XP Zhang; supervision, ZM Wang; project administration, ZM Wang; funding acquisition, XP Zhang. All authors contributed to the article and approved the submitted version.

Financial disclosure

This study was supported by Fujian provincial health technology project (2021QNB020) and Natural Science Foundation of Xiamen (3502Z202372069). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing disclosure

No funded writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

This study was approved by the Ethics Committee of Zhongshan Hospital, Fudan University (Xiamen Branch): Approval No.: B2023-114. All patients signed informed consent prior to our study.

Data availability statement

The datasets supporting the conclusions of this article are included within the article and its additional files.
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References

Papers of special note have been highlighted as: • of interest; •• of considerable interest

1. Shinoda M, Kadota Y, Tsujikawa H, et al. Lymphoepithelioma-like hepatocellular carcinoma: a case report and a review of the literature. World J Surg Oncol. 2013;11 :97. doi:10.1186/1477-7819-11-97 23642182
2. Bittar Z, Fend F, Quintanilla-Martinez L. Lymphoepithelioma-like carcinoma of the stomach: a case report and review of the literature. Diagn Pathol. 2013;8 :184. doi:10.1186/1746-1596-8-184 24188515
3. Uesato M, Kono T, Shiratori T, et al. Lymphoepithelioma-like esophageal carcinoma with macroscopic reduction. World J Gastrointest Endosc. 2014;6 :385–389. doi:10.4253/wjge.v6.i8.385 25132923
4. Yoshino T, Ohara S, Moriyama H. Lymphoepithelioma-like carcinoma of the urinary bladder: a case report and review of the literature. BMC Res Notes. 2014;7 :779. doi:10.1186/1756-0500-7-779 25367311
5. Aridi T, Fawwaz M, Kassab A, et al. Lymphoepithelioma-like carcinoma of the breast: a case report unveiling several clinical and histopathological challenges. Case Rep Surg. 2018;2018 :8240534. doi:10.1155/2018/8240534 30123609
6. Bégin LR, Eskandari J, Joncas J, et al. Epstein-Barr virus related lymphoepithelioma-like carcinoma of lung. J Surg Oncol. 1987;36 :280–283. doi:10.1002/jso.2930360413 2826922
• Shows us the history of how lymphoepithelioma-like carcinoma discovered.

7. Watanabe H, Enjoji M, Imai T. Gastric carcinoma with lymphoid stroma. Its morphologic characteristics and prognostic correlations. Cancer. 1976;38 :232–243. doi:10.1002/1097-0142(197607)38:1<232::aid-cncr2820380135>3.0.co;2-4 947518
8. Carrasco-Avino G, Riquelme I, Padilla O, et al. The conundrum of the Epstein–Barr virus-associated gastric carcinoma in the Americas. Oncotarget. 2017;8 :75687–75698. doi:10.18632/oncotarget.18497 29088902
9. Khokhar N, Nasir H, Amir M, et al. Lymphoepithelioma-like carcinoma of the esophagus: a rare tumor. J Coll Physicians Surg Pak. 2017;27 :S114–S116.28969745
10. Ngan RK, Yip TT, Cheng WW, et al. Circulating Epstein–Barr virus DNA in serum of patients with lymphoepithelioma-like carcinoma of the lung: a potential surrogate marker for monitoring disease. Clin Cancer Res. 2002;8 :986–994.
11. Wang L, Long W, Li PF, et al. An elevated peripheral blood monocyte-to-lymphocyte ratio predicts poor prognosis in patients with primary pulmonary lymphoepithelioma-like carcinoma. PLOS ONE. 2015;10 :e0126269. doi:10.1371/journal.pone.0126269 25950432
• Explains possible influences affecting the efficacy of immunotherapy for primary pulmonary LELC.

12. Chang YL, Wu CT, Shih JY, et al. New aspects in clinicopathologic and oncogene studies of 23 pulmonary lymphoepithelioma-like carcinomas. Am J Surg Pathol. 2002;26 :715–723. doi:10.1097/00000478-200206000-00004 12023575
13. Iezzoni JC, Gaffey MJ, Weiss LM. The role of Epstein–Barr virus in lymphoepithelioma-like carcinomas. Am J Clin Pathol. 1995;103 :308–315. doi:10.1093/ajcp/103.3.308 7872253
14. Patel KR, Liu TC, Vaccharajani N, et al. Characterization of inflammatory (lymphoepithelioma-like) hepatocellular carcinoma: a study of 8 cases. Arch Pathol Lab Med. 2014;138 :1193–1202. doi:10.5858/arpa.2013-0371-OA 25171701
15. Xu Q, DU J, Liu B. Lymphoepithelioma-like gastric carcinoma located in the lesser curvature of the gastric body: a case report and review of the literature. Mol Clin Oncol. 2016;4 :405–408. doi:10.3892/mco.2015.717 26998292
16. Zhang H, Li Y, Wang HB, et al. Author correction: ephrin receptor A2 is an epithelial cell receptor for Epstein–Barr virus entry. Nat Microbiol. 2018;3 :1075. doi:10.1038/s41564-018-0155-1 29679064
17. Huang CJ, Feng AC, Fang YF, et al. Multimodality treatment and long-term follow-up of the primary pulmonary lymphoepithelioma-like carcinoma. Clin Lung Cancer. 2012;13 :359–362. doi:10.1016/j.cllc.2012.01.002 22410385
18. Liang Y, Wang L, Zhu Y, et al. Primary pulmonary lymphoepithelioma-like carcinoma: fifty-two patients with long-term follow-up. Cancer. 2012;118 :4748–4758. doi:10.1002/cncr.27452 22359203
19. Nagtegaal ID, Odze RD, Klimstra D, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020;76 :182–188. doi:10.1111/his.13975 31433515
20. Emile JF, Adam R, Sebagh M, et al. Hepatocellular carcinoma with lymphoid stroma: a tumour with good prognosis after liver transplantation. Histopathology. 2000;37 :523–529. doi:10.1046/j.1365-2559.2000.00952.x 11122434
21. Solinas A, Calvisi DF. Lessons from rare tumors: hepatic lymphoepithelioma-like carcinomas. World J Gastroenterol. 2015;21 :3472–3479. doi:10.3748/wjg.v21.i12.3472 25834311
22. Wang ZH, Zhao JJ, Yuan Z. Lymphoepithelioma-like gastric carcinoma: a case report and review of the literature. World J Gastroenterol. 2016;22 :3056–3061. doi:10.3748/wjg.v22.i10.3056 26973402
23. Huang SC, Ng KF, Yeh TS, et al. Subtraction of Epstein–Barr virus and microsatellite instability genotypes from the Lauren histotypes: combined molecular and histologic subtyping with clinicopathological and prognostic significance validated in a cohort of 1,248 cases. Int J Cancer. 2019;145 :3218–3230. doi:10.1002/ijc.32215 30771224
24. Pyo JS, Kim NY, Son BK, et al. Clinicopathological features and prognostic implication of gastric carcinoma with lymphoid stroma. Gastroenterol Res Pract. 2020;2020 :6628412. doi:10.1155/2020/6628412 33343655
• Explains one of the importance reasons why lymphoepithelioma-like gastric carcinoma is benefit from immunotherapy.

25. Kim ST, Cristescu R, Bass AJ, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med. 2018;24 :1449–1458. doi:10.1038/s41591-018-0101-z 30013197
26. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359 :1350–1355. doi:10.1126/science.aar4060 29567705
27. Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 blockade with pembrolizumab in advanced merkel-cell carcinoma. N Engl J Med. 2016;374 :2542–2552. doi:10.1056/NEJMoa1603702 27093365
28. Xie Z, Liu L, Lin X, et al. A multicenter analysis of genomic profiles and PD-L1 expression of primary lymphoepithelioma-like carcinoma of the lung. Mod Pathol. 2020;33 :626–638. doi:10.1038/s41379-019-0391-9 31659278
29. Chang YL, Yang CY, Lin MW, et al. PD-L1 is highly expressed in lung lymphoepithelioma-like carcinoma: a potential rationale for immunotherapy. Lung Cancer. 2015;88 :254–259. doi:10.1016/j.lungcan.2015.03.017 25862146
30. Pereira MA, Batista D, Ramos M, et al. Epstein–Barr virus positive gastric cancer: a distinct subtype candidate for immunotherapy. J Surg Res. 2021;261 :130–138. doi:10.1016/j.jss.2020.12.029 33429221
31. Sasaki S, Nishikawa J, Sakai K, et al. EBV-associated gastric cancer evades T-cell immunity by PD-1/PD-L1 interactions. Gastric Cancer. 2019;22 :486–496. doi:10.1007/s10120-018-0880-4 30264329
•• Article explains possible mechanisms of immune-resistance in EBV-associated gastric cancer.

32. Re V, Brisotto G, Repetto O, et al. Overview of Epstein–Barr–virus-associated gastric cancer correlated with prognostic classification and development of therapeutic options. Int J Mol Sci. 2020;21 :9400. doi:10.3390/ijms21249400 33321820
33. Kubota Y, Kawazoe A, Sasaki A, et al. The impact of molecular subtype on efficacy of chemotherapy and checkpoint inhibition in advanced gastric cancer. Clin Cancer Res. 2020;26 :3784–3790. doi:10.1158/1078-0432.CCR-20-0075 32156744
