Clinical analysis of 45 cases of primary pulmonary lymphoepithelioma-like carcinoma_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

YANG Xi ¹ , WANG Chunyu ¹ , LI Siru ² , ZUO Zhuo ³ , YIN Cunli ² , LU Yingchun ² ,  LIU Bin ⁴

1. School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610032, P. R. China;
2. School of Medicine, University of Electronic Science and Technology of China, Chengdu People's Republic of China, Chengdu, Sichuan 610056, P. R. China;
3. Department of Pathology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, Sichuan 610042, P. R. China;
4. Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, Sichuan 610042, P. R. China;

Corresponding author：

LIU Bin, Email: binliu202003@126.com

Keywords：

Primary pulmonary lymphoepithelioma-like carcinoma; lung cancer; Epstein-Barr virus; prognosis

DOI：

10.7507/1671-6205.202305056

Video：

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Objective To investigate the clinicopathological features, treatment and prognosis of primary pulmonary lymphoepithelioma-like carcinoma (PPLELC). Methods Forty-five patients with PPLELC admitted to Sichuan Cancer Hospital from April 2016 to March 2023 were retrospectively analyzed. Their clinical data and survival were collected and summarized. Results Of the 45 patients, 28.9% (13/45) were asymptomatic, 97.2% (35/36) were positive for Epstein-Barr virus encoded small RNA, 83.3% (10/12) were positive for programmed cell death-ligand 1 (PD-L1), and the tumor proportion score (TPS) fluctuated between 10.0% to 95.0%. Genetic testing revealed 1 case of EGFR gene 19-Del mutation. Among the 45 patients, 28 cases received surgical treatment, of which 16 received adjuvant chemotherapy, 8 received adjuvant radiotherapy, and 2 received neoadjuvant chemotherapy. As of the follow-up cut-off date, 33 patients survived and 12 patients died, with a median survival time not reached and an overall survival rate of 70.2% and 63.2% at 3 and 5 years, respectively. The 3- and 5-year disease-free survival rates were 67.2% and 57.6% for the 28 operated patients, respectively, and the progression-free survival rates were 58.3% and 29.2% for the 13 stage Ⅳ patients, respectively. Conclusions PPLELC is associated with Epstein-Barr virus infection and is a rare subtype of non-small cell lung cancer (NSCLC). Most patients do not have common gene mutations such as EGFR or ALK and have a high rate of positive PD-L1 expression. The disease is usually treated with a multi-method combination of mainly surgery, and is sensitive to radiotherapy and chemotherapy and has a better prognosis than other types of NSCLC.

Citation： YANG Xi, WANG Chunyu, LI Siru, ZUO Zhuo, YIN Cunli, LU Yingchun, LIU Bin. Clinical analysis of 45 cases of primary pulmonary lymphoepithelioma-like carcinoma. Chinese Journal of Respiratory and Critical Care Medicine, 2023, 22(7): 500-505. doi: 10.7507/1671-6205.202305056 Copy

1.	Anand A, Zayac A, Curtiss C, et al. Pulmonary lymphoepithelioma-like carcinoma disguised as squamous cell carcinoma. J Thorac Oncol, 2018, 13(5): e75-e76.
2.	宋琳, 韩锋锋, 崔志磊, 等. 原发性肺淋巴上皮瘤样癌一例并文献复习. 中国呼吸与危重监护杂志, 2017, 16(6): 575-580.
3.	Bégin LR, Eskandari J, Joncas J, et al. Epstein-Barr virus related lymphoepithelioma-like carcinoma of lung. J Surg Oncol, 1987, 36(4): 280-283.
4.	Wu YX, Zhang WL, Wang TM, et al. Genomic landscapes of Epstein-Barr virus in pulmonary lymphoepithelioma-like carcinoma. J Virol, 2022, 96(4): e0169321.
5.	He J, Shen J, Pan H, et al. Pulmonary lymphoepithelioma-like carcinoma: a Surveillance, Epidemiology, and End Results database analysis. J Thorac Dis, 2015, 7(12): 2330-2338.
6.	WHO. WHO Classification of Tumours·5th Edition. Switzerland: World Health Organization, 2021, 94-96.
7.	Groome PA, Bolejack V, Crowley JJ, et al. The IASLC Lung Cancer Staging Project: validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol, 2007, 2(8): 694-705.
8.	Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol, 2016, 11(1): 39-51.
9.	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(6): 715-723.
10.	Beasley MB, Brambilla E, Travis WD. The 2004 World Health Organization classification of lung tumors. Semin Roentgenol, 2005, 40(2): 90-97.
11.	Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol, 2015, 10(9): 1243-1260.
12.	Nicholson AG, Tsao MS, Beasley MB, et al. The 2021 WHO Classification of Lung Tumors: Impact of Advances Since 2015. J Thorac Oncol, 2022, 17(3): 362-387.
13.	Chau SL, Tong JH, Chow C, et al. Distinct molecular landscape of Epstein-Barr virus associated pulmonary lymphoepithelioma-like carcinoma revealed by genomic sequencing. Cancers (Basel), 2020, 12(8): 2065.
14.	Yener NA, Balikçi A, Çubuk R, et al. Primary lymphoepithelioma-like carcinoma of the lung: report of a rare case and review of the literature. Turk Patoloji Derg, 2012, 28(3): 286-289.
15.	Han AJ, Xiong M, Zong YS. Association of Epstein-Barr virus with lymphoepithelioma-like carcinoma of the lung in southern China. Am J Clin Pathol, 2000, 114(2): 220-226.
16.	Liang YS, Shen C, Che GW, et al. Primary pulmonary lymphoepithelioma-like carcinoma initially diagnosed as squamous metaplasia: a case report and literature review. Oncol Lett, 2015, 9(4): 1767-1771.
17.	Lin L, Lin TY, Zeng BW. Primary lymphoepithelioma-like carcinoma of the lung: An unusual cancer and clinical outcomes of 14 patients. Oncol Lett, 2017, 14(3): 3110-3116.
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(19): 4748-4758.
19.	Lin Z, Situ D, Chang X, et al. Surgical treatment for primary pulmonary lymphoepithelioma-like carcinoma. Interact Cardiovasc Thorac Surg, 2016, 23(1): 41-46.
20.	Jiang WY, Wang R, Pan XF, et al. Clinicopathological features and prognosis of primary pulmonary lymphoepithelioma-like carcinoma. J Thorac Dis, 2016, 8(9): 2610-2616.
21.	Han AJ, Xiong M, Gu YY, et al. Lymphoepithelioma-like carcinoma of the lung with a better prognosis. A clinicopathologic study of 32 cases. Am J Clin Pathol, 2001, 115(6): 841-850.
22.	Mo Y, Shen J, Zhang Y, et al. Primary lymphoepithelioma-like carcinoma of the lung: distinct computed tomography features and associated clinical outcomes. J Thorac Imaging, 2014, 29(4): 246-251.
23.	Huang CJ, Chan KY, Lee MY, et al. Computed tomography characteristics of primary pulmonary lymphoepithelioma-like carcinoma. Br J Radiol, 2007, 80(958): 803-806.
24.	Ma H, Wu Y, Lin Y, et al. Computed tomography characteristics of primary pulmonary lymphoepithelioma-like carcinoma in 41 patients. Eur J Radiol, 2013, 82(8): 1343-1346.
25.	Xie M, Wu X, Wang F, et al. Clinical significance of plasma Epstein-Barr virus DNA in pulmonary lymphoepithelioma-like carcinoma (LELC) patients. J Thorac Oncol, 2018, 13(2): 218-227.
26.	宋洪俊, 熊晓凤, 吴妹清, 等. 肠道EB病毒相关淋巴组织增殖性疾病误诊为肠结核一例. 中国呼吸与危重监护杂志, 2020, 19(4): 410-413.
27.	Samanta M, Takada K. Modulation of innate immunity system by Epstein-Barr virus-encoded non-coding RNA and oncogenesis. Cancer Sci, 2010, 101(1): 29-35.
28.	Lee KL, Wu MH, Jhang YY, et al. Computed tomography-based differentiation of primary pulmonary lymphoepithelioma-like carcinoma and small-cell lung cancer. J Chin Med Assoc, 2020, 83(10): 936-942.
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(3): 254-259.
30.	Jiang L, Wang L, Li PF, et al. Positive expression of programmed death ligand-1 correlates with superior outcomes and might be a therapeutic target in primary pulmonary lymphoepithelioma-like carcinoma. Onco Targets Ther, 2015, 8: 1451-1457.
31.	Wu Z, Xian X, Wang K, et al. Immune checkpoint blockade therapy may be a feasible option for primary pulmonary lymphoepithelioma-like carcinoma. Front Oncol, 2021, 11: 626566.
32.	Fang W, Hong S, Chen N, et al. PD-L1 is remarkably over-expressed in EBV-associated pulmonary lymphoepithelioma-like carcinoma and related to poor disease-free survival. Oncotarget, 2015, 6(32): 33019-33032.
33.	Wang L, Lin Y, Cai Q, et al. Detection of rearrangement of anaplastic lymphoma kinase (ALK) and mutation of epidermal growth factor receptor (EGFR) in primary pulmonary lymphoepithelioma-like carcinoma. J Thorac Dis, 2015, 7(9): 1556-1562.
34.	Chang YL, Wu CT, Shih JY, et al. Unique p53 and epidermal growth factor receptor gene mutation status in 46 pulmonary lymphoepithelioma-like carcinomas. Cancer Sci, 2011, 102(1): 282-287.
35.	Liu Q, Ma G, Yang H, et al. Lack of epidermal growth factor receptor gene mutations in exons 19 and 21 in primary lymphoepithelioma-like carcinoma of the lung. Thorac Cancer, 2014, 5(1): 63-67.
36.	Yin K, Feng HB, Li LL, et al. Low frequency of mutation of epidermal growth factor receptor (EGFR) and arrangement of anaplastic lymphoma kinase (ALK) in primary pulmonary lymphoepithelioma-like carcinoma. Thorac Cancer, 2020, 11(2): 346-352.
37.	Lin CY, Chen YJ, Hsieh MH, et al. Advanced primary pulmonary lymphoepithelioma-like carcinoma: clinical manifestations, treatment, and outcome. J Thorac Dis, 2017, 9(1): 123-128.
38.	Yang H, Lin Y, Liang Y. Treatment of Lung carcinosarcoma and other rare histologic subtypes of non-small cell lung cancer. Curr Treat Options Oncol, 2017, 18(9): 54.
39.	Qiu ZX, Zhou P, Wang K. Primary pulmonary lymphoepithelioma-like carcinoma response favorably to nivolumab: a case report. Onco Targets Ther, 2019, 12: 8595-8600.
40.	Zhang L, Hao T, Wei Y, et al. Primary pulmonary lymphoepithelioma-like carcinoma: a case report of pathological complete response (pCR) by neoadjuvant treatment. Medicine (Baltimore), 2021, 100(11): e24987.
41.	Kim C, Rajan A, DeBrito PA, et al. Metastatic lymphoepithelioma-like carcinoma of the lung treated with nivolumab: a case report and focused review of literature. Transl Lung Cancer Res, 2016, 5(6): 720-726.
42.	Narayanan A, Knollmann FD, Walby JAS, et al. EBV-positive primary pulmonary lymphoepithelioma-like carcinoma response to PD-L1 blockade. Clin Lung Cancer, 2019, 20(3): e238-e241.
43.	Kwong YL, Chan TSY, Tan D, et al. PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood, 2017, 129(17): 2437-2442.
44.	Nishikawa J, Iizasa H, Yoshiyama H, et al. Clinical importance of Epstein-Barr virus-associated gastric cancer. Cancers (Basel), 2018, 10(6): 167.
45.	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(5): 359-362.

1. Anand A, Zayac A, Curtiss C, et al. Pulmonary lymphoepithelioma-like carcinoma disguised as squamous cell carcinoma. J Thorac Oncol, 2018, 13(5): e75-e76.
2. 宋琳, 韩锋锋, 崔志磊, 等. 原发性肺淋巴上皮瘤样癌一例并文献复习. 中国呼吸与危重监护杂志, 2017, 16(6): 575-580.
3. Bégin LR, Eskandari J, Joncas J, et al. Epstein-Barr virus related lymphoepithelioma-like carcinoma of lung. J Surg Oncol, 1987, 36(4): 280-283.
4. Wu YX, Zhang WL, Wang TM, et al. Genomic landscapes of Epstein-Barr virus in pulmonary lymphoepithelioma-like carcinoma. J Virol, 2022, 96(4): e0169321.
5. He J, Shen J, Pan H, et al. Pulmonary lymphoepithelioma-like carcinoma: a Surveillance, Epidemiology, and End Results database analysis. J Thorac Dis, 2015, 7(12): 2330-2338.
6. WHO. WHO Classification of Tumours·5th Edition. Switzerland: World Health Organization, 2021, 94-96.
7. Groome PA, Bolejack V, Crowley JJ, et al. The IASLC Lung Cancer Staging Project: validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol, 2007, 2(8): 694-705.
8. Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol, 2016, 11(1): 39-51.
9. 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(6): 715-723.
10. Beasley MB, Brambilla E, Travis WD. The 2004 World Health Organization classification of lung tumors. Semin Roentgenol, 2005, 40(2): 90-97.
11. Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol, 2015, 10(9): 1243-1260.
12. Nicholson AG, Tsao MS, Beasley MB, et al. The 2021 WHO Classification of Lung Tumors: Impact of Advances Since 2015. J Thorac Oncol, 2022, 17(3): 362-387.
13. Chau SL, Tong JH, Chow C, et al. Distinct molecular landscape of Epstein-Barr virus associated pulmonary lymphoepithelioma-like carcinoma revealed by genomic sequencing. Cancers (Basel), 2020, 12(8): 2065.
14. Yener NA, Balikçi A, Çubuk R, et al. Primary lymphoepithelioma-like carcinoma of the lung: report of a rare case and review of the literature. Turk Patoloji Derg, 2012, 28(3): 286-289.
15. Han AJ, Xiong M, Zong YS. Association of Epstein-Barr virus with lymphoepithelioma-like carcinoma of the lung in southern China. Am J Clin Pathol, 2000, 114(2): 220-226.
16. Liang YS, Shen C, Che GW, et al. Primary pulmonary lymphoepithelioma-like carcinoma initially diagnosed as squamous metaplasia: a case report and literature review. Oncol Lett, 2015, 9(4): 1767-1771.
17. Lin L, Lin TY, Zeng BW. Primary lymphoepithelioma-like carcinoma of the lung: An unusual cancer and clinical outcomes of 14 patients. Oncol Lett, 2017, 14(3): 3110-3116.
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(19): 4748-4758.
19. Lin Z, Situ D, Chang X, et al. Surgical treatment for primary pulmonary lymphoepithelioma-like carcinoma. Interact Cardiovasc Thorac Surg, 2016, 23(1): 41-46.
20. Jiang WY, Wang R, Pan XF, et al. Clinicopathological features and prognosis of primary pulmonary lymphoepithelioma-like carcinoma. J Thorac Dis, 2016, 8(9): 2610-2616.
21. Han AJ, Xiong M, Gu YY, et al. Lymphoepithelioma-like carcinoma of the lung with a better prognosis. A clinicopathologic study of 32 cases. Am J Clin Pathol, 2001, 115(6): 841-850.
22. Mo Y, Shen J, Zhang Y, et al. Primary lymphoepithelioma-like carcinoma of the lung: distinct computed tomography features and associated clinical outcomes. J Thorac Imaging, 2014, 29(4): 246-251.
23. Huang CJ, Chan KY, Lee MY, et al. Computed tomography characteristics of primary pulmonary lymphoepithelioma-like carcinoma. Br J Radiol, 2007, 80(958): 803-806.
24. Ma H, Wu Y, Lin Y, et al. Computed tomography characteristics of primary pulmonary lymphoepithelioma-like carcinoma in 41 patients. Eur J Radiol, 2013, 82(8): 1343-1346.
25. Xie M, Wu X, Wang F, et al. Clinical significance of plasma Epstein-Barr virus DNA in pulmonary lymphoepithelioma-like carcinoma (LELC) patients. J Thorac Oncol, 2018, 13(2): 218-227.
26. 宋洪俊, 熊晓凤, 吴妹清, 等. 肠道EB病毒相关淋巴组织增殖性疾病误诊为肠结核一例. 中国呼吸与危重监护杂志, 2020, 19(4): 410-413.
27. Samanta M, Takada K. Modulation of innate immunity system by Epstein-Barr virus-encoded non-coding RNA and oncogenesis. Cancer Sci, 2010, 101(1): 29-35.
28. Lee KL, Wu MH, Jhang YY, et al. Computed tomography-based differentiation of primary pulmonary lymphoepithelioma-like carcinoma and small-cell lung cancer. J Chin Med Assoc, 2020, 83(10): 936-942.
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(3): 254-259.
30. Jiang L, Wang L, Li PF, et al. Positive expression of programmed death ligand-1 correlates with superior outcomes and might be a therapeutic target in primary pulmonary lymphoepithelioma-like carcinoma. Onco Targets Ther, 2015, 8: 1451-1457.
31. Wu Z, Xian X, Wang K, et al. Immune checkpoint blockade therapy may be a feasible option for primary pulmonary lymphoepithelioma-like carcinoma. Front Oncol, 2021, 11: 626566.
32. Fang W, Hong S, Chen N, et al. PD-L1 is remarkably over-expressed in EBV-associated pulmonary lymphoepithelioma-like carcinoma and related to poor disease-free survival. Oncotarget, 2015, 6(32): 33019-33032.
33. Wang L, Lin Y, Cai Q, et al. Detection of rearrangement of anaplastic lymphoma kinase (ALK) and mutation of epidermal growth factor receptor (EGFR) in primary pulmonary lymphoepithelioma-like carcinoma. J Thorac Dis, 2015, 7(9): 1556-1562.
34. Chang YL, Wu CT, Shih JY, et al. Unique p53 and epidermal growth factor receptor gene mutation status in 46 pulmonary lymphoepithelioma-like carcinomas. Cancer Sci, 2011, 102(1): 282-287.
35. Liu Q, Ma G, Yang H, et al. Lack of epidermal growth factor receptor gene mutations in exons 19 and 21 in primary lymphoepithelioma-like carcinoma of the lung. Thorac Cancer, 2014, 5(1): 63-67.
36. Yin K, Feng HB, Li LL, et al. Low frequency of mutation of epidermal growth factor receptor (EGFR) and arrangement of anaplastic lymphoma kinase (ALK) in primary pulmonary lymphoepithelioma-like carcinoma. Thorac Cancer, 2020, 11(2): 346-352.
37. Lin CY, Chen YJ, Hsieh MH, et al. Advanced primary pulmonary lymphoepithelioma-like carcinoma: clinical manifestations, treatment, and outcome. J Thorac Dis, 2017, 9(1): 123-128.
38. Yang H, Lin Y, Liang Y. Treatment of Lung carcinosarcoma and other rare histologic subtypes of non-small cell lung cancer. Curr Treat Options Oncol, 2017, 18(9): 54.
39. Qiu ZX, Zhou P, Wang K. Primary pulmonary lymphoepithelioma-like carcinoma response favorably to nivolumab: a case report. Onco Targets Ther, 2019, 12: 8595-8600.
40. Zhang L, Hao T, Wei Y, et al. Primary pulmonary lymphoepithelioma-like carcinoma: a case report of pathological complete response (pCR) by neoadjuvant treatment. Medicine (Baltimore), 2021, 100(11): e24987.
41. Kim C, Rajan A, DeBrito PA, et al. Metastatic lymphoepithelioma-like carcinoma of the lung treated with nivolumab: a case report and focused review of literature. Transl Lung Cancer Res, 2016, 5(6): 720-726.
42. Narayanan A, Knollmann FD, Walby JAS, et al. EBV-positive primary pulmonary lymphoepithelioma-like carcinoma response to PD-L1 blockade. Clin Lung Cancer, 2019, 20(3): e238-e241.
43. Kwong YL, Chan TSY, Tan D, et al. PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood, 2017, 129(17): 2437-2442.
44. Nishikawa J, Iizasa H, Yoshiyama H, et al. Clinical importance of Epstein-Barr virus-associated gastric cancer. Cancers (Basel), 2018, 10(6): 167.
45. 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(5): 359-362.

Chinese Journal of Respiratory and Critical Care Medicine

Clinical analysis of 45 cases of primary pulmonary lymphoepithelioma-like carcinoma

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