EBV Causes Lymphoepithelioma-like Lung Cancer

Lymphoepthelioma-like carcinomas are associated with Epstein-Barr virus infection, particularly in Asian countries. It is also more common in Asian countries than in western countries; LELC accounts for 5.4% of primary non-small cell lung carcinomas in Hong Kong. This may be related to EBV infection occurring earlier in life in developing countries. LELC also appears to be associated with nonsmoking. Thus, there is the potential for confounding by infection in passive smoking studies, which has not been addressed in any of the reviews of the subject.

"EBV has been detected in the vast majority of gastric lymphoepithelial carcinomas and in a high proportion of lymphoepithelial carcinomas of the lung and salivary gland. A smaller proportion of gastric adenocarcinomas is also EBV-associated. EBV DNA has been detected occasionally in epithelial tumours at a wide variety of other anatomical sites. An etiological role for EBV in lymphoepithelial and adenocarcinomas has not been conclusively established." (Epstein Barr Virus and Kaposi's Sarcoma Herpesvirus/Human Herpesvirus 8. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans). IARC Monograph 70. Lyon: International Agency for Research on Cancer; 1997.)

IARC Monograph 70, Epstein-Barr Virus, summary (1997) / IARC (pdf, 10 pp)

Epstein-Barr virus related lymphoepithelioma-like carcinoma of lung. LR Begin, J Eskandari, J Joncas, L Panasci. J Surg Oncol 1987 Dec;36(4):280-283. A case report of an Asian female nonsmoker. "The histology was of nasopharyngeal-like carcinoma character and ultrastructural examination confirmed a diagnosis of nonkeratinizing, poorly differentiated squamous cell carcinoma. The clinicopathologic findings were more suggestive of a primary pulmonary origin than the manifestations of an occult nasopharyngeal primary. The immunological profile was highly suggestive of an Epstein-Barr virus (EBV) associated epithelial neoplasia. This case might widen the spectrum of EBV-associated neoplasia, by inclusion of lower respiratory tract as a target organ."

Begin - J Surg 1987 abstract / PubMed

Analysis of lymphoepithelioma and lymphoepithelioma-like carcinomas for Epstein-Barr viral genomes by in situ hybridization. LM Weiss, LA Movahed, AE Butler, SA Swanson, HF Frierson, PH Cooper, TV Colby, SE Mills. Am J Surg Pathol 1989 Aug;13(8):625-631. EBV found in only 1/14 LELCs, in an Asian patient.

Weiss - Am J Surg Pathol 1989 abstract / PubMed

Lymphoepithelioma-like carcinoma of the lung. AE Butler, TV Colby, L Weiss, C Lombard. Am J Surg Pathol 1989 Aug;13(8):632-639. Four cases from the Mayo Clinic, one EBV+ by ISH.

Butler - Am J Surg Pathol 1989 abstract / PubMed

Detection of Epstein-Barr virus in lymphoepithelioma-like carcinoma of the lung. AA Gal, ER Unger, MN Koss, TS Yen. Mod Pathol 1991 Mar;4(2):264-268. Case report in a Chinese patient, EBV+ by PCR and ISH.

Gal - Mod Pathol 1991 abstract / PubMed

Clonal Epstein-Barr virus in lymphoepithelioma-like carcinoma of the lung. S Pittaluga, MP Wong, LP Chung, SL Loke. Am J Surg Pathol 1993 Jul;17(7):678-682. "Interestingly, these tumors have shown a geographic distribution similar to nasopharyngeal lymphoepithelioma, with relatively high frequency of EBV positive cases in Asian patients." 5/5 EBV+ by ISH.

Pittaluga - Am J Surg Pathol 1993 abstract / PubMed

Prevalence of serum IgG and IgM antibodies against Epstein-Barr virus capsid antigen in Indian patients with respiratory tract carcinomas. A Roy, S Dey, R Chatterjee. Neoplasma 1994;41(1):29-33. "[T]he antibody positivity rate among the patients declined with the advanced stages of the disease;" otherwise levels were raised.

Roy - Neoplasma 1994 abstract / PubMed

Incidence of latent infection of Epstein-Barr virus in lung cancers -- an analysis of EBER1 expression in lung cancers by in situ hybridization. K Kasai, Y Sato, T Kameya, H Inoue, H Yoshimura, S Kon, K Kikuchi. J Pathol 1994 Dec;174(4):257-265. "This study indicates that the morphological features of EBV-associated lung cancers are not restricted to the typical LELC type."

Kasai - J Pathol 1994 abstract / PubMed

Lymphoepithelioma-like carcinoma of the lung. Two cases diagnosed in Caucasian patients. G Ferrera, O Nappi. Tumori 1995 Mar-Apr;81(2):144-147. 2 cases EBV- by ISH.

Ferrera - Tumori 1995 abstract / PubMed

[The role of Epstein-Barr virus infection and infective copy number in pulmonary carcinogenesis]. L Zhang, H Liu, Z Wang. Zhonghua Bing Li Xue Za Zhi 1995 Jun;24(3):132-135. "Infective copy number of EBV rather than simple EBV infection may play an important role in pulmonary carcinogenesis."

Zhang - Zhonghua Bing Li Xue Za Zhi 1995 abstract / PubMed

Detection of Epstein-Barr virus only in lymphoepithelial carcinomas among primary carcinomas of the lung. JK Chan, PK Hui, WY Tsang, CK Law, CC Ma, TT Yip, YF Poon, VW Ma. Histopathology 1995 Jun;26(6):576-578.

Chan - Histopathology 1995 (no abstract) / PubMed

Primary lymphoepithelioma-like carcinoma of the lung. A clinicopathologic study of 11 cases. JK Chan, PK Hui, WY Tsang, CK Law, CC Ma, TT Yip, YF Poon. Cancer 1995 Aug 1;76(3):413-422. Hong Kong: "Two of the 8 patients were smokers... There is no strong association with cigarette smoking." Equal incidence by sex.

Chan - Cancer 1995 abstract / PubMed

Lymphoepithelioma-like carcinoma of the lung: analysis of two cases for Epstein-Barr virus infection. M Higashiyama, O Doi, K Kodama, H Yokouchi, R Tateishi, K Horiuchi, K Mishima. Hum Pathol 1995 Nov;26(11):1278-1282. Both EBV+ by PCR and ISH.

Higashiyama - Hum Pathol 1995 abstract / PubMed

In situ detection of Epstein-Barr virus in non-small cell lung carcinomas. MP Wong, LP Chung, ST Yuen, SY Leung, SY Chan, E Wang, KH Fu. J Pathol 1995 Nov;177(3):233-240. 9/167 consecutive unselected primary non-small cell lung carcinomas (5.4%) were EBV+ by ISH. All EBV+ tumors were LELC-type, and no other types were EBV+. "Smoking was not a risk factor."

Wong - J Pathol 1995 abstract / PubMed

Lymphoepithelioma-like carcinoma of the lung. W Wockel, G Hofler, HH Popper, A Morresi. Pathol Res Pract 1995 Nov;191(11):1170-1174. Comment in Pathol Res Pract 1995 Nov;191(11):1175-1177. " A reevaluation of the literature showed an interesting and surprising fact: in all lung cases, so far reported, the tumour cells were positive for EBV in Asians and negative in Caucasians. Due to the high prevalence of EBV infections in the Asian population it might be speculated, that EBV positivity could be an epiphenomenon in Asian cases of lymphoepithelioma-like carcinoma of the lung." (However - virtually the entire population of the world is infected by EBV. The main difference is in the age at primary infection. In the Third World and in lower socioeconomic groups, infection occurs early in childhood. In the more privileged, it does not occur until young adulthood, when it causes infectious mononucleosis, which is rare in those infected at younger ages. And, malaria does not cause cancer, but malaria plus EBV infection in children results in Burkitt's lymphoma.)

Wockel - Pathol Res Pract 1995 abstract / PubMed

[Detection of EB virus in pulmonary carcinoma by in situ hybridization]. L Zhang, H Liu, Z Wang. Zhonghua Bing Li Xue Za Zhi 1996 Feb;25(1):1-3. "The positive rate of EBV infection in carcinoma tissue and peripheral lung tissue were 37.9% (33/87) and 11.5% (10/87) respectively." EBV positivity was greater in less differentiated carcinomas.

Zhang - Zhonghua Bing Li Xue Za Zhi 1996 abstract / PubMed

Absence of evidence for an etiologic role for Epstein-Barr virus in neoplasms of the lung and pleura. EJ Conway, SD Hudnall, A Lazarides, A Bahler, AE Fraire, PT Cagle. Mod Pathol 1996 May;9(5):491-495. 80 pulmonary adenocarcinomas and 50 mesotheliomas were negative by ISH.

Conway - Mod Pathol 1996 abstract / PubMed

Primary lymphoepithelioma-like carcinoma of the lung in a child. Report of an Epstein-Barr virus-related neoplasm. LD Curcio, JS Cohen, FW Grannis, IB Paz, R Chilcote, LM Weiss. Chest 1997 Jan;111(1):250-251.

Curcio - Chest 1997 abstract / PubMed
Curcio - Chest 1997 Full Article

[Lymphoepithelioma-like lung carcinomas]. W Wockel, G Hofler, HH Popper, A Morresi-Hauf. Pathologe 1997 Mar;18(2):147-152. Review.

Wockel - Pathologe 1997 abstract / PubMed

Lymphoepithelioma-like carcinoma of the lung. MW Frank, TW Shields, AW Joob, MS Kies, CD Sturgis, A Yeldandi, AJ Cribbins, DA Fullerton. Ann Thoracic Surg 1997 Oct;64(4):1162-1164. A case in a 67-year-old white man, who had "severe arthritic complaints that resolved after resection of the tumor."

Frank - Ann Thorac Surg 1997 abstract / PubMed

Epstein-Barr virus-associated nonsmall cell lung carcinoma: undifferentiated "lymphoepithelioma-like" carcinoma as a distinct entity with better prognosis. FF Chan, JJ Yan, WW Lai, YT Lin, IJ Su. Cancer 1998 Jun 15;82(12):2334-2342. 5/5 LELC (100%); 6/43 squamous cell carcinomas (14%); 0/67 adenocarcinomas (0%); 12/12 large cell carcinoma (100%) were EBV+. "All 5 LE patients were smokers, whereas 3 of the 6 patients with EBER1-positive SCC (50%) were smokers."

Chen - Cancer 1998 abstract / PubMed

[Transformation of human bronchial epithelium by EB virus gene LMP1 and EBNA2.] L Zhang, H Liu, T Liu, S Cheng. Zhonghua Bing Li Xue Za Zhi 1999 Aug;28(4):277-280. "Expression of both LMP1 and EBNA2 led to decreased anchorage dependence and increased proliferation rate" of the cell line.

Zhang - Zhonghua Bing Li Xue Za Zhi 1999 abstract / PubMed

Association of Epstein-Barr virus with lymphoepithelioma-like carcinoma of the lung in southern China. AJ Han, M Xiong, YS Zong. Am J Clin Pathol 2000 Aug;114(2):220-226. 32/3663 (0.9%) of consecutive primary lung carcinomas were classified LELC. 30/32 (94%) were EBV EBER+. 0/19 non-LELC were positive for EBER, LMP1, or VCA.

Han - Am J Clin Pathol 2000 abstract / PubMed

Relationship between epstein-barr virus and lymphoepithelioma-like carcinoma of the lung: A clinicopathologic study of 6 cases and review of the literature. CY Castro, ML Ostrowski, R Barrios, LK Green, HH Popper, S Powell, PT Cagle, JY Ro. Hum Pathol 2001 Aug;32(8):863-872. 0/6; abstract does not state what evidence of EBV they looked for.

Castro - Hum Pathol 2001 abstract / PubMed
Castro - Hum Pathol 2001 Full Article

Circulating Epstein-Barr virus DNA in serum of patients with lymphoepithelioma-like carcinoma of the lung: a potential surrogate marker for monitoring disease. RKC Ngan, TTC Yip, W-W Cheng, JKC Chan, WCS Cho, VWS Ma, K-K Wan, S-K Au, C-K Law, W-H Lau. Clin Cancer Res 2002 Apr;8(4):986-994. "Prospectively collected serum samples from five patients and retrospectively collected serum samples from two patients who had clinical disease at initial serum measurement showed detectable levels of EBER-1. Retrospectively collected serum samples from four patients with no clinical disease had negative sera. There is consistent correlation between the clinical response to treatment and subsequent clinical course of LELC and serum EBER-1 levels in the three prospective patients with longitudinal serum monitoring."

Ngan / Clin Cancer Res 2002 Full Article

New aspects in clinicopathologic and oncogene studies of 23 pulmonary lymphoepithelioma-like carcinomas. YL Chang, CT Wu, JY Shih, YC Lee. Am J Surg Pathol 2002 Jun;26(6):715-723. 6 patients were smokers versus 17 nonsmokers, and 7 were male versus 16 female; all 15 patients tested were EBV-positive.

Chang - Am J Surg Pathol 2002 abstract / PubMed

Demonstration of Epstein-Barr virus in carcinomas of various sites. S Grinstein, MV Preciado, P Gattuso, PA Chabay, WH Warren, E De Matteo, VE Gould. Cancer Res 2002 Sep 1;62(17):4876-4878. "In 4 of 54 (7.4%) carcinomas, EBV nuclear immunostaining was noted involving a range of 5–10% of neoplastic cells. All major histological types of lung carcinoma, i.e., squamous, adenocarcinoma, and neuroendocrine carcinoma, were represented among the positive cases (Fig. 1, e and f) . Two cases, although classified as squamous and neuroendocrine carcinomas, respectively, because of the heavy predominance of these phenotypes, showed focal adenocarcinoma. Notably, reactions were recognized in both patterns of differentiation. No EBV reactions were noted in 6 hyperplastic bronchial and alveolar epithelium or normal lung, nor was any staining recognized in any of 12 bronchial carcinoids studied."

Grinstein / Cancer Res 2002 full article

Clinical role of circulating Epstein-Barr virus DNA as a tumor marker in lymphoepithelioma-like carcinoma of the lung. RK Ngan, TT Yip, WW Cheng, JK Chan, WC Cho, VW Ma, KK Wan, JS Au, CK Law. Ann N Y Acad Sci 2004 Jun;1022:263-270. "Measurable levels of EBV DNA were detected in 11 of 12 patients with a pre-therapy serum sample and a clinically evident tumor. A low level of EBV DNA was also detectable in one of the two other patients whose first serum samples were obtained after some chemotherapy. There was no detectable EBV DNA in the five patients without evidence of tumor. The longitudinal serum EBV DNA profile of seven patients showed consistent correlation with response to therapy and clinical outcome. Patients with a pre-therapy serum EBV DNA >10,000 copies/mL had significantly inferior overall survival. This study suggests that circulating serum EBV DNA can be used as a tumor marker in the clinical management of patients with LELC of the lung."

Ngan - Ann N Y Acad Sci 2004 abstract / PubMed

Detection of oncogenic virus genomes and gene products in lung carcinoma. L Brouchet, S Valmary, M Dahan, A Didier, F Galateau-Salle, P Brousset, B Degano. Br J Cancer 2005 Feb 28;92(4):743-746. 122 cases of small cell lung carcinomas and non-small cell lung carcinomas for the presence of viral genomes (DNA) and/or RNA transcripts and/or proteins of human papillomaviruses (HPV) 16, 18, 31, 33, 51, Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), human cytomegalovirus (HCMV) and simian virus 40 (SV40): "None of the cases displayed a single positive tumour cell for all the viruses tested whatever the technique applied." [That's what they used to claim about EBV and western nasopharyngeal cancer -cast]

Brouchet - Br J Cancer 2005 abstract / PubMed

Lymphoepithelioma-like carcinoma of the lung. JC Ho, MP Wong, WK Lam. Respirology 2006 Sep;11(5):539-545. Review. "Lymphoepithelioma-like carcinoma (LELC) of the lung was first reported in 1987. In the past two decades, there have been just more than 150 cases reported in the literature. This uncommon but distinct form of non-small cell lung carcinoma has a predilection for young non-smoking Asians, without gender distinction."

Ho - Respirology 2006 abstract / PubMed

[Detection of Epstein-Barr virus in lung carcinoma tissue by in situ hybridization]. CM Li, GL Han, SJ Zhang. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi 2007 Sep;21(3):288-290. 108 surgically resected lung carcinoma specimens. "EBER1 was detected in 36 of the 108 primary lung carcinoma cases, and in 1 of the 22 normal lung tissues. The positive rates of EBV infection in squamous cell carcinoma, adenocarcinoma, small cell carcinoma and large cell carcinoma were 35.9%, 31.6% 31.0%, 1/2, respectively." EBER1 expression was significantly higher in poorly and moderately differentiated carcinomas.

Li - Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi 2007 abstract / PubMed

Lack of epidermal growth factor receptor gene mutations in exons 19 and 21 in primary lymphoepithelioma-like carcinoma of the lung. Q Liu, G Ma, H Yang, J Wen, M Li, H Yang, K Luo, Y Hu, J Fu. Thorac Cancer 2014 Jan;5(1):63-67. "Eleven (34.4%) of the patients were male and 21 (65.6%) patients female. The mean age at diagnosis was 50.9 years (range, 25-71 years). Seven (21.9%) of the patients were smokers. In situ hybridization for Epstein-Barr virus-encoded small RNAs (EBERs) showed positive signals in all 32 patients."

Liu - Thorac Cancer 2014 abstract / PubMed

Primary Lymphoepithelioma-like Carcinoma of the Lung: Distinct Computed Tomography Features and Associated Clinical Outcomes. Y Mo, J Shen, Y Zhang, L Zheng, F Gao, L Liu, C Xie. J Thorac Imaging 2014 Jul;29(4):246-251. 35 patients. "The distinct clinical features of primary lung LELC include no significant predilection for sex, minimal association with a history of smoking, strong association with EBV in Asians, and a predilection for early or locally advanced stage of the disease."

Mo - J Thorac Imaging 2014 abstract / PubMed

Detection of rearrangement of anaplastic lymphoma kinase (ALK) and mutation of epidermal growth factor receptor (EGFR) in primary pulmonary lymphoepithelioma-like carcinoma. L Wang, Y Lin, Q Cai, H Long, Y Zhang, T Rong, G Ma, Y Liang. J Thorac Dis 2015 Sep;7(9):1556-1562. 42 LELCs were positive for EBER by IHC.

Wang - J Thorac Dis 2015 full article / PubMed Central
Wang / J Thorac Dis 2015 full article

Mechanisms

Herpesvirus-specific CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection. N Khan, A Hislop, N Gudgeon, M Cobbold, R Khanna, L Nayak, AB Rickinson, PA Moss. J Immunol 2004;173(12):7481-7489. "Interestingly, the effect of age upon EBV-specific responses depends upon donor CMV sero-status. In CMV seropositive donors, the magnitude of the EBV-specific immune response is stable with age, but in CMV seronegative donors, the response to EBV increases significantly with age. By contrast, the influenza-specific CD8 T cell immune response decreases with age, independent of CMV status. The functional activity of the herpesvirus-specific immune response decreases in elderly donors, although the characteristic phenotypes of CMV- and EBV-specific memory populations are retained. This demonstrates that aging is associated with a marked accumulation of CMV-specific CD8 T cells together with a decrease in immediate effector function. Moreover, infection with CMV can reduce prevailing levels of immunity to EBV, another persistent virus. These results suggest that carriage of CMV may be detrimental to the immunocompetent host by suppressing heterologous virus-specific immunity during aging."

Khan / J Immunol 2004 full article

See also:

HPV Causes Lung Cancer HPV DNA has been detected in 24.5% of 4508 lung cancers [2009] and the same high risk types implicated in other squamous cell cancers have been identified.
Adenoviruses Are Implicated in Lung Cancer Via "hit-and-run" transformation, even tumors that lack any detectable virus-specific molecules may be of viral origin.
Confounding By Infection False smoking risks are generated by ignoring the role of infection.
The Lie That p53 Mutations Are the Mechanism Behind Lung Cancer Viruses can disable its function without mutations.
The EPA's ETS Lies - If HPV is the true cause of only 20% of lung cancers, this would equal over 30,000 US cases, or ten times the number of pretended secondhand smoke deaths.
What the ACS Knew In 1955 - The American Cancer Society has ignored the role of infection in lung cancer for seven decades.

EBV Causes Nasopharyngeal Cancer
Epstein-Barr Virus Causes Lymphomas
Epstein-Barr Virus Causes Gastric Carcinoma
EBV & Socioeconomic Status
EBV Causes Interstitial Lung Disease
EBV and Other Diseases
EBV Causes Multiple Sclerosis
Epstein-Barr Virus Causes Sjogren’s Syndrome
EBV Causes Lupus

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cast 01-16-16