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.)

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."

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.

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.

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.

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.

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.

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."

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.

[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."

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.

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.

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.

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."

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.)

[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.

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.

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.

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

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."

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."

[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.

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.

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.

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."

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.

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."

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."

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]

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."

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cast 11-09-06