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ORIGINAL ARTICLE
Year : 2017  |  Volume : 13  |  Issue : 5  |  Page : 807-812

Lymphoepithelioma is a nonkeratinizing squamous cell carcinoma with Epstein–Barr virus infection in China


1 Department of Pathology, Xiangya Hospital/School of Basic Medicine, Central South University, Hunan, China
2 Department of Oncology, Xiangya Hospital, Central South University, Hunan, China
3 Center for Medicine Research, Xiangya Hospital, Central South University, Hunan, China
4 Cancer Research Institute, School of basic medicine, Central South University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education; Key Laboratory of Carcinogenesis, National Health and Family Planning Commission, Hunan, China

Date of Web Publication13-Dec-2017

Correspondence Address:
Desheng Xiao
Department of Pathology, Xiangya Hospital, Central South University, Changsha 410078; Department of Pathology, School of Basic Medicine, Central South University, Changsha 410078, Hunan
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_280_17

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 > Abstract 


Objective: The objective of this study is to investigate the histogenesis of lymphoepithelial carcinoma (LEC) and its relationship with Epstein–Barr virus (EBV).
Materials and Methods: The expression of EBV was detected using in situ hybridization, and the CK5/6, p63, and p40 expression levels were detected using immunohistochemistry in 45 paraffin-embedded tissues from LEC.
Results: In 45 paraffin-embedded LEC tissues from 10 different samples, the positive CK5/6 signals were located in the cell membrane. The positive signals for p63 and p40 were located in the cell nucleus. In all LEC cases, the positive rates of CK5/6, p63, and p40 were 93.3% (42/45), 95.6% (43/45), and 93.3% (42/45), respectively. The positive EBV-encoded RNA (EBER) signals were located in the cell nucleus. In the 45 LEC cases, the expression of EBER was strongly positive with a positive rate of 100% (45/45).
Conclusions: LEC is closely related to EBV, and EBV plays an important role in the development of LEC. LEC showed positive squamous cell markers, indicating that the samples contain squamous cell carcinoma (SQCC). LEC is EBV (+) with nonkeratinizing SQCC, and this name better reflects the nature of this disease.

Keywords: Epstein–Barr virus, lymphoepithelial carcinoma, squamous cell carcinoma


How to cite this article:
He Q, Zhou Y, Fu C, Zhu W, Zhou J, Liu S, Tao Y, Xiao D. Lymphoepithelioma is a nonkeratinizing squamous cell carcinoma with Epstein–Barr virus infection in China. J Can Res Ther 2017;13:807-12

How to cite this URL:
He Q, Zhou Y, Fu C, Zhu W, Zhou J, Liu S, Tao Y, Xiao D. Lymphoepithelioma is a nonkeratinizing squamous cell carcinoma with Epstein–Barr virus infection in China. J Can Res Ther [serial online] 2017 [cited 2020 Oct 29];13:807-12. Available from: https://www.cancerjournal.net/text.asp?2017/13/5/807/220467




 > Introduction Top


Lymphoepithelial carcinoma (LEC), also called lymphoepithelioma-like carcinoma, malignant lymphoepithelial lesion, undifferentiated carcinoma with lymphoidstroma, undifferentiated carcinoma, and carcinoma ex lymphoepithelial lesion,[1],[2] is defined as an undifferentiated carcinoma or poorly differentiated squamous cell carcinoma (SQCC), which is accompanied by a prominent, reactive lymphoplasmacytic infiltrate. LEC can occur in many organs, such as the nasopharynx, lung, thymus, salivary gland, esophagus, cervix, bladder, skin, and others,[3],[4],[5],[6],[7],[8],[9],[10],[11],[12] but it is most common in the head and neck regions, including the pharynx. However, there has been some debate over the years about their histologic classification and the meaning of their histopathological changes. They have different names in different parts of the body, which have long plagued the clinical and pathological diagnosis. In this study, we analyzed all diagnosed LEC and some nonkeratinizing undifferentiated carcinoma cases from November 2010 to April 2016 in our hospital to explore their common features and immunophenotypes.


 > Materials and Methods Top


Clinical data

We collected 45 LEC paraffin-embedded tissues from 2010 to 2016 with a complete clinical history and pathological data, including the nasopharynx in 12 cases, lung in 12 cases, mediastinum in 2 cases, lymph nodes in 3 cases, parapharyngeal space in 1 case, submaxillary gland in 2 cases, parotid gland in 8 cases, cheek in 2 cases, cervix in 2 cases, and skull base in 1 case, which were confirmed by pathological diagnosis. All specimens were fixed with 40 g/L formalin and embedded in paraffin; then, serial sections (4 μm) were cut.

Reagents

Ready-to-use Quick Staining Immunohistochemistry (IHC) MaxVision™ detection kit (Code No. K5030); CK5/6, p63, and p40 primary antibodies and DAB Color Developing Reagent Kit were purchased from Dako-An Agilent Technologies Company, Denmark. Microwave pretreatment was adopted. In situ, hybridization reagents, namely, an RNA probe (ISH-6022) and an in situ hybridization detection kit (Code No. K150408), were obtained from ZSGB-BIO Company, China.

Histology and immunohistochemistry

Four-micron-thick sections were cut from paraffin blocks and stained with either hematoxylin and eosin (H and E) staining or IHC. The latter technique was performed using the S-P immunohistochemical method, and the experiment was performed according to the detection kit instructions. Appropriate positive and negative controls were included. The test results were evaluated using light microscopy.

CK5/6, p63, and p40 staining were considered positively by ascertaining membranal or nuclear expression. The determination result was obtained from semi-quantitative classification according to 10 more visual fields (×200). The slides were first scored as 0 (negative), 1 (buff), 2 (pale brown), and 3 (tan). Positive expression was scored as 0 (negative), 1 (<10% of positively-staining tumor cells), 2 (11%–50% of positively-staining tumor cells), 3 (50%–75% of positively-staining tumor cells), and 4 (>75% of positively-staining tumor cells). Both the scores by multiply were regarded as the determination result. More than four was positive.[12],[13],[14]

In situ hybridization

Two serial sections (4 μm) of the specimens (one for in situ hybridization detection and one for negative control) were loaded onto an 3-aminopropyltriethoxysilane-treated glass slide. Then, they were processed with routine deparaffinage, hydration, proteinase k digestion, and dehydration with gradient ethanol. Probe (15–20 μl) was added; then, it was hybridized at 37°C for 2 h, incubated with 1% anti-FITC/AP, colored with 2% BCIP/NBT, counterstained with 1% methyl green, and mounted with neutral balsam.


 > Results Top


Histopathologic examination

In the 45 cases of LEC (30 males and 15 females; average age of 43 years), the tumor cells are present in infiltrating sheets, islets, or cord-like sheets, which are surrounded by lymphoid mesenchyme. The tumor cells have unclear cell boundaries, pale eosinophilic cytoplasms, large vacuole-like nuclei, distinct nucleoli, and rich cytoplasms and they form clusters as symplasm. Cancer cells are distributed in the nest or scattered with rich infiltration of lymphocytes and plasmacytes as well as reactive lymphoid follicle-like structures [Figure 1]. The lymphoid composition is particularly obvious, including the blend of T and B cells, resulting in difficult identification of the epithelial compositions in tumors. The tumor islets from some cases have rich baby's breath-like histiocytes. The other features that are not common include noncaseous granulomas, presence or absence of multinuclear giant cells, amyloid deposits, and cyst formation in tumor islands as well as perineural and lymphovascular infiltration.
Figure 1: H and E staining of lymphoepithelial carcinoma. The tumor cells have unclear cell boundaries, pale eosinophilic cytoplasms, large vacuole-like nuclei, distinct nucleoli, and rich cytoplasms and they form clusters as symplasm. Cancer cells are distributed in the nest or scattered with rich infiltration of lymphocytes and plasmacytes as well as reactive lymphoid follicle-like structures. (a) Lymphoepithelial carcinoma of the nasopharynx (×200); (b) lymphoepithelial carcinoma of the lung (×200); (c) lymphoepithelial carcinoma of the parotid gland (×200); (d) lymphoepithelial carcinoma of the lymph node (×200); (e) lymphoepithelial carcinoma of the thymus (×200); and (f) lymphoepithelial carcinoma of the cervix uteri (×200)

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The CK5/6, p63, and p40 antibody expression levels in lymphoepithelial carcinoma

The positive CK5/6 signals were located in the cell membrane. In all LEC cases, the positive rate of CK5/6 was 93.3% (42/45). The positive signals for p63 were located in the cell nucleus. In all LEC cases, the positive rate of p63 was 95.6% (43/45). The positive p40 signals were located in the cell nucleus. In all LEC cases, the p40 positive rate was 93.3% (42/45) [Figure 2] and [Table 1].
Figure 2: Immunohistochemical staining of lymphoepithelial carcinoma. The protein expression locations of CK5/6, p63, and p40 differed in lymphoepithelial carcinoma. (a) The tumor cells were positive for CK5/6 protein in the membrane (×400). (b) The tumor cells were positive for p63 protein in the nucleus (×400). (c) The tumor cells were positive for p40 protein in the nucleus (×400)

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Table 1: The results of immunohistochemistry and in situ hybridization in lymphoepithelial carcinoma

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In situ hybridization

In the 45 LEC cases, the expression of Epstein–Barr virus (EBV)-encoded RNA (EBER) was strongly positive, with a positive rate of 100% (45/45). The positive EBER signals were located in the cell nucleus. The signal had the following three different forms according to the different distribution of the positive signals: the inner nuclear membrane type, perinucleolar type, and intranuclear dispersive type [Figure 3].
Figure 3: In situ hybridization of EBV-encoded RNA, and the signal has the following three different forms according to the different distribution of the positive signals: the inner nuclear membrane type, perinucleolar type, and intranuclear dispersive type. (a) The tumor cells were positive for EBV-encoded RNA in the inner nuclear membrane (×400). (b) The tumor cells were positive for EBV-encoded RNA in the perinucleolar area (×400). (c) The tumor cells were positive for EBV-encoded RNA in the intranuclear dispersive area (×400)

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 > Discussion Top


Hilderman first reported on LEC in 1962, and there have been multiple aliases for LEC. In 1991, the WHO Salivary Neoplasms/Pathology named this disease “undifferentiated carcinoma with lymphoidstroma”.[13],[14] In 2005, the WHO Head and Neck Neoplasms/Pathology named it “lymphoepithelial carcinoma.”[2] In 2015, the WHO Lung Neoplasms/Pathology named it “unclassified carcinoma.”[15] Many cases are reported as undifferentiated carcinoma in addition to LEC. Recent research shows that this malignant tumor type is not associated with autoimmune disease (Sjogren syndrome). The observation of its ultrastructure also indicated that it is a poorly differentiated SQCC in the epithelium. Its occurrence has obvious regional characteristics, which mostly occurs in Eskimo-inhabited areas, Greenland and South China. In addition, studies have showed that the tumor occurrence is closely related to EBV.[16],[17],[18],[19],[20],[21]

LEC is a rarely seen malignant tumor type, and its pathogenesis is unclear at present. In addition, there remain controversies over its clinical diagnosis and treatment. Furthermore, it has confusing nomenclature, some patients have a poor prognosis, and this topic requires further research. Along with the development of precision medicine, pathologic diagnosis that only relies on morphology has already been challenged and has aimed to divide the tumor into various subtypes with different prognoses according to their clinical manifestations, imaging features, pathologic characteristics, gene expression, and molecular biomarkers, which, consequently, direct the clinical diagnosis and therapy. Based on the above situations, IHC plays an increasingly important role in the pathologic diagnosis. IHC has been widely recognized for its conciseness and economical and practical characteristics. Although there is no gold standard for diagnosis, studies have already shown that IHC has improved the accuracy and repeatability of diagnosis.[22] Diagnostic markers that are in common use for SQCC include p63, p40, and CK5/6 (cytokeratin 5/6).

The p63 gene is located on the chromosome region 3q27-29, and it has structural homology with p53. p63 has two promotors, which could produce two relative albuminoids through alternative splicing, full-length TAp63 protein (contains the transactivation domain), and truncated ΔNp63 protein (lacks the transactivation domain), which is known as p40. p63- and p40-positive staining are found in the cell nucleus. The sensitivity of p63 for diagnosing lung SQCC was close to 100%.[23] In additionally, p63 is stably expressed in SQCC and is irrelevant to its differentiation degree, which is a highly stable marker.[24] The main limitation of clinical p63 use is its low specificity, which is approximately 60%–86%.[25] The positive p63 rate in ADC is approximately 16%–65%,[26] which is 50% in lymphoma.[27] Overall, p63 is a marker with high specificity and sensitivity, reflecting squamous differentiation.

In 2000, Hibi et al. first studied the p40 antibody using the IHC method and found that p40 is completely sensitive and specific to SQCC according to the analysis of 23 lung cancer cases.[28] Pelosi et al. studied 20 cases of whole tissue lung SQCC sections in addition to 46 cases of small specimens, cytological specimens, and biopsy specimens of NSCLC. The authors found that the p40 antibody is 100% specific for SQCC.[29],[30] In another study, they adopted immunostaining of p63 (4A4) and ΔNp63 (p40) in 150 cases of lung ADC and 50 cases of SQCC. As a result, p63 and p40 both presented with diffuse positive staining in all SQCC. p63 was positive in 27 cases (18%) of ADC while p40 was negative. The p40 sensitivity in diagnosing SQCC is equivalent to p63, but its specificity is higher than p63.[31]

CK5/6 is a basic cytokeratin with a medium size. In normal tissues, it is mainly expressed in keratinizing (epithelium) and nonkeratinizing (mucous membrane) squamous epithelium as well as the basal muscle epithelium of the prostate, breast, and salivary glands. CK5/6 has also been seen in benign and malignant tumors of the epithelium, mucosal squamous epithelium, and myoepithelium derivations, such as the basal layer and breast cancer mesothelioma. CK5/6 is a sensitive marker that reflects squamous differentiation, and it has been reported that its sensitivity for diagnosing lung SQCC is 75%–100%.[32] Its specificity was 96% in Whithaus et al.'s study.[25] The positive CK5/6 rate in primary lung ADC is very small (2%–8%).[32],[33] Here, we showed that the 45 cases of LEC had characteristic squamous differentiation, and they are all nonkeratinizing SQCC. We clarified that the histogenesis of LEC is squamous epithelium differentiation. Then, there is rich infiltration of lymphocytes and plasma cells in the mesenchyme. According to the literature, these features might be a concern for EBV infections.

EBV is closely correlated with LEC. In 1970, zur Hausen et al. first observed the presence of EBV genomic fragments in NPC patient specimens. Additional researchers have further studied the correlation between EBV and NPC. Iwakiri suggested that LMP2A and EBER are involved in an important mechanism of epithelial carcinogenesis.[34] Abdulamir found that the influence of EBV on NPC is substantially greater than that of other head and neck cancers by detecting the IgG and IgA antibody levels of EBV in serum. Wan-Lun Hsu et al. tracked 9622 men over 20 years and detected their EBV antigen-antibody, anti-EBVCA-IgA, and DNA polymerase levels, which further demonstrated that the EBV infections can lead to NPC.

The positive EBV rate in primary LEC patients is approximately 75%. In addition, this correlation would be affected by geographic and racial differences. Almost all Asian patients have EBV-positive tumors while Caucasian patients have EBV negativity. Since the first reported lung LEC in 1987,[35] there have been 29 studies of lung LEC reported. EBV genes were detected in 28 cases using the ISH method, and 24 cases (85.7%) were positive.[36] The close correlation between salivary LEC and EBV is considered one of its characteristics. Several papers have reported on EB virus infections in salivary LEC, and the virus played an important role in this disease.[37],[38],[39],[40],[41],[42],[43] We can detect the specific expression of the EBV DNA in LEC using the ISH method while it is not expressed in lymphocytes or benign epithelial cells. In addition, there is no expression of the EBV DNA in poorly differentiated salivary cancer of non-LEC. In addition, the existence of EB virosomes as endosomes in diseased anaplastic cells has further verified the close correlation between EBV and salivary LEC.[39] The possible tumorigenic mechanisms include EBV integration into host cell genomes and silencing of the tumor-suppressor gene expression in the host. At the same time, the LMP1 virogene products affect many signaling pathways and promote cell proliferation, suppress cell apoptosis, promote abnormal cell division, inhibit cell differentiation, and promote tumor progression toward undifferentiated carcinoma as tumor necrosis factor receptor.[43],[44],[45]

Compared with other nonsmall cell lung cancers, the prognosis of primary lung LEC is significantly better. According to reports, the overall 2- and 5-year survival rates are 80% and 54%, respectively. Limited data have showed that this difference is more remarkable in high-grade patients. In addition, recurrence is rarely seen after successful radical tumor resection in patients in the early disease stages. Here, we detected the EBER expression in 45 LEC cases using in situ hybridization; the results exhibited a positive EBER rate of 100% (45/45) showing that the LEC occurrence is closely related to EBV infection and indicates that LEC presents with distinct histological characteristics of infectious diseases.


 > Conclusions Top


The LEC nomenclature merely depends on the histologic characteristics, which do not satisfy the requirements of clinical and pathology diagnoses. It has different names in different body parts, leading to confusion in clinical and pathological diagnoses and thus urgently requiring updated scientific nomenclature. With the combination of the comprehensive analysis, IHC and in situ hybridization, we have good reason to believe that LEC is EBV (+) nonkeratinizing squamous carcinoma, and the nature of this disease has been clarified by IHC and in situ hybridization technologies. Based on the analysis of the gene expression and molecular biomarkers, the traditional methods of naming according to histological characteristics are being abandoned and will be replaced by molecular and gene types.

Acknowledgments

We would like to thank all laboratory members for their critical discussion of this manuscript.

Financial support and sponsorship

This work was supported by the National Basic Research Program of China (2015CB553903 [Y.T.]); Hunan Natural Science Foundation of China (12JJ1013 [Y.T.]); and Hunan Science and Technology Project of China (2010SK3130).

Conflicts of interest

There are no conflicts of interest.



 
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Shi Y, Peng SL, Yang LF, Chen X, Tao YG, Cao Y. Co-infection of Epstein-Barr virus and human papillomavirus in human tumorigenesis. Chin J Cancer 2016;35:16.  Back to cited text no. 45
    


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