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Keywords:

  • Epstein–Barr virus;
  • lung;
  • lymphoepithelioma-like carcinoma;
  • prognosis;
  • treatment

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EPIDEMIOLOGY
  5. PATHOLOGY
  6. CLINICAL MANIFESTATIONS AND DIAGNOSIS
  7. STAGING
  8. TREATMENT AND PROGNOSIS
  9. CONCLUSION
  10. ACKNOWLEDGEMENT
  11. REFERENCES

Abstract:  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. Histologically, it is indistinguishable from undifferentiated nasopharyngeal carcinoma. The carcinogenic role of latent Epstein–Barr virus infection in causing LELC of the lung has been evident almost exclusively in Asians compared with Caucasians. Among the reported cases, more than half were in early resectable stages (I or II) and there was a tendency for peribronchovascular spread with vascular encasement in advanced diseases. In order to establish the diagnosis of LELC of the lung, both nasopharyngeal carcinoma and lymphoma have to be excluded by endoscopic biopsy (with or without magnetic resonance imaging of the nasopharynx) and immunohistochemical staining of the biopsy samples. The mainstay of treatment for early-stage disease is curative surgical resection, whereas multimodality treatment (surgery, chemotherapy, radiotherapy) has been adopted in advanced or metastatic diseases. The overall survival is more favourable in LELC of the lung compared with non-LELC type of non-small cell lung carcinoma. Future collaborative studies especially on optimizing treatment for this uncommon malignancy are clearly warranted.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EPIDEMIOLOGY
  5. PATHOLOGY
  6. CLINICAL MANIFESTATIONS AND DIAGNOSIS
  7. STAGING
  8. TREATMENT AND PROGNOSIS
  9. CONCLUSION
  10. ACKNOWLEDGEMENT
  11. REFERENCES

Lymphoepithelioma, originally described in the nasopharynx, refers to undifferentiated carcinoma with predominant lymphocytic infiltration. Begin et al. first reported a primary carcinoma of lung mimicking undifferentiated nasopharyngeal carcinoma (NPC) histologically in 1987, which was termed lymphoepithelioma-like carcinoma (LELC).1 In the same report, the relationship between this peculiar form of carcinoma and Epstein–Barr virus (EBV) was also suggested. Since then, studies on the epidemiology, histopathology, pathogenetic role of EBV and treatment have been reported. Over the past two decades, there were approximately 40 manuscripts published in the literature on LELC of the lung, involving just more than 150 cases. The majority of these patients were ethnically Orientals, with nearly two-thirds arising from Southern China,2,3 Taiwan4,5 and Hong Kong.6–16 The characteristic clinical and pathological features of LELC of the lung that are clearly different from the other counterparts of primary lung cancer define a distinct entity of special interest especially in the Asian–Pacific region.

EPIDEMIOLOGY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EPIDEMIOLOGY
  5. PATHOLOGY
  6. CLINICAL MANIFESTATIONS AND DIAGNOSIS
  7. STAGING
  8. TREATMENT AND PROGNOSIS
  9. CONCLUSION
  10. ACKNOWLEDGEMENT
  11. REFERENCES

Currently, there have been 33 case reports and/or series describing the occurrence of LELC of the lung,1–33 which are summarized in Table 1. The patients were predominantly East Asians, and Caucasians accounted for only 18 of 153 cases. Based upon the two largest reported series from Southern China3 and Taiwan,4 LELC of the lung represented 0.9% of primary lung cancers. Similar data in the Western population is lacking but the apparently fewer reported cases in the literature suggests a much lower incidence. There is no gender predilection, which is in contrast to male predominance for other histological types of lung cancer. The mean age of affected patients has been reported to be 10 years younger than that of other histological types of lung cancer in a Taiwanese series.5 The youngest reported patient of LELC of the lung was an 8-year-old child.24 There is also a greater tendency for this tumour type to occur in non-smokers (71 non-smokers of 103 cases with available smoking data, i.e. 69%), which suggests there are alternative aetiological factors apart from cigarette smoking.

Table 1.  Demography of reported cases of lymphoepithelioma-like carcinoma of the lung
Author (reference no.)/yearNo. casesAge (years)GenderRaceISH EBERNo. smokers
MaleFemaleAsianCaucasian
  • Only 28 of 33 case reports or series are tabulated to avoid duplication of cases in some series, including 153 cases in total.

  • NA, not available; ND, not done; ISH EBER, in situ hybridization for Epstein–Barr virus-encoded small nuclear RNA.

Begin et al.1/1987 140 0 1 10ND0
Butler et al.17/1989 456–72 1 3 13 13
Gal et al.18/1991 168 1 0 10 1NA
Miller et al.19/1991 165 0 1 01 01
Pittaluga et al.16/1993 533–73 5 0 50 5NA
Chow et al.15/1995 256, 66 2 0 20NDNA
Wong et al.13/1995 933–71 8 1 90 94; 1 NA
Wockel et al.20/1995 147 0 1 01 0NA
Chan et al.14/19951138–73 6 5110112; 3 NA
Higashiyama et al.21/1995 255, 65 2 0 20 2NA
Ferrara and Nappi22/1995 264, 78 1 1 02 01
Frank et al.23/1997 167 1 0 01 00
Curcio et al.24/1997 1 8 0 1 10 10
Chen et al.5/1998 543–66 2 3 50 50
Chan et al.12/1998 925–64 5 4 90 7; 2 ND1
Kasai et al.25/1999 139 0 1 10 11
Barroso et al.26/2000 125 1 0 01 01
Han et al.3/20003239–73221032030NA
Castro et al.27/2001 649–75 4 2 06 06
Guerrero et al.28/2001 162 1 0 10NANA
Chang et al.4/20022342–80 716230236
Jha et al.29/2002 157 0 1 01 0NA
Morbini et al.30/2003 125 1 0 01 10
Kobayashi et al.31/2004 167 0 1 10 1NA
Ngan et al.7/20041952.7 (mean) 910190198
Ho et al.6/20041038–71 5 5100 6; 4 ND2
Bildirici et al.32/2005 166 1 0 01 01
Yoshino et al.33/2005 160 0 1 10 01

PATHOLOGY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EPIDEMIOLOGY
  5. PATHOLOGY
  6. CLINICAL MANIFESTATIONS AND DIAGNOSIS
  7. STAGING
  8. TREATMENT AND PROGNOSIS
  9. CONCLUSION
  10. ACKNOWLEDGEMENT
  11. REFERENCES

Histological characteristics

The typical lung LELC consists of undifferentiated carcinoma cells with ill-defined cytoplasmic borders arranged in syncytial sheets and nests. The tumour cell nuclei are round, oval or elongated with mildly irregular nuclear outline, vesicular chromatin and distinct nucleoli.3 The stroma shows thick fibrous bands that contain large numbers of reactive lymphoplasmacytic cells as well as other inflammatory cells.3,14 Many inflammatory cells infiltrate the tumour islands and become admixed with the tumour cells (Fig. 1). Because of the absence of any diagnostic glandular or squamous differentiation, LELC is categorized as a form of large cell carcinoma according to World Health Organization classification.34 Less commonly, squamoid features without cellular keratinization or intercellular bridge formation; spindle cell differentiation with peripheral palisading arrangement;3 and rarely, focal gland-like configurations have been described.13 The stroma may show foreign body or tuberculoid granulomatous reaction,3 and occasionally, intratumoural amyloid globules with positive Congo red staining have been reported.4,14

image

Figure 1. Histology of lymphoepithelioma-like carcinoma: a sheet of tumour cells are surrounded by abundant lymphoplasmacytic cells in the stroma. The tumour cells show indistinct cell borders with prominent nucleoli (arrows) and are closely admixed with infiltrating inflammatory cells (arrowheads). Haematoxylin and eosin stain.

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Tumour-infiltrating lymphocytes have been shown to be predominantly CD8-positive and T cell intracytoplasmic antigen (TIA-1)-positive cytotoxic T cells.31 The negative expression of granzyme-B in these tumour-infiltrating T lymphocytes may indicate that the cytotoxic T lymphocytes are in a resting state, possibly because of inhibition by local immunosuppressive factors in the tumour environment.25 Furthermore, in situ hybridization (ISH) has demonstrated extensive expression of monocyte chemo-attractant protein-1 transcripts by the tumour cells, implicating its role in the close topographical relationship between tumour-associated macrophages and tumour cells.11

Pathogenetic role of EBV

Since the first report of LELC of the lung in 1987,1 an aetiological association with EBV has been suggested. The presence of EBV in LELC has been demonstrated by PCR for EBV DNA, ISH for EBV DNA and RNA, and immunohistochemistry for EBV-associated proteins.13,21,35 In particular, the demonstration of abundant EBV-encoded small nuclear RNA (EBER) by ISH in the majority of tumour cells (Fig. 2) has become the standard test to show the tumour-specific association of EBV, distinguishing it from persistent EBV infection in circulating lymphocytes carried to the tumour site. Furthermore, the finding of a single episomal form of EBV in the tumours indicates that clonal tumour cell expansion was preceded by EBV infection, further supporting the oncogenic role of EBV.13,16 Interestingly, although tumours resembling LELC have been reported in other organs such as the urinary bladder, cervix, liver, etc., and in both Western and Oriental populations, only tumours from the upper aero-digestive tract (lung, salivary gland, stomach) and thymus have shown an association with EBV. Moreover, for LELC of the salivary gland and lung, the association is exclusively found in Asians, whereas for gastric and thymic LELC, there is no apparent ethnic predisposition.36 It is notable that primary NPC, a common cancer in southern Chinese with a similar histology to LELC, is also associated with EBV.37 A detail expression profile of EBV viral proteins in lung LELC has not been reported. However, similar to NPC, expression of the viral oncoprotein latent membrane protein 1 has been reported in only 10–50% of lung LELC.3,13 Together with differences in viral protein expression profiles in various EBV-related lymphomas, a differential role of the viral oncoproteins in tumour development, dependent on the genetic background of the epithelial or lymphoid tissues concerned, has been suggested.3,5,13,38

image

Figure 2. In situ hybridization for Epstein–Barr virus-encoded small nuclear RNA, showing intense signals in the nuclei of the majority of tumour cells.

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CLINICAL MANIFESTATIONS AND DIAGNOSIS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EPIDEMIOLOGY
  5. PATHOLOGY
  6. CLINICAL MANIFESTATIONS AND DIAGNOSIS
  7. STAGING
  8. TREATMENT AND PROGNOSIS
  9. CONCLUSION
  10. ACKNOWLEDGEMENT
  11. REFERENCES

Clinical features

The clinical features of the reported cases of LELC of the lung are summarized in Table 2. Of the 107 cases with reported symptoms and signs at presentation, the predominant clinical presentations were cough either alone or with other symptoms (47% in total; 30% had cough with haemoptysis) and incidental finding in asymptomatic subjects (22%). The rest of the symptoms on presentation included chest pain (13%), dyspnoea (5%), weight loss (5%), night sweat (3%), joint pain (3%) and fever (2%). The majority of the reported cases were in early resectable stages (I, 39%; II, 14%) and locally advanced stages (IIIA, 23%; IIIB, 10%), and distant metastatic disease occurred in 15%.

Table 2.  Clinical characteristics of reported cases of lymphoepithelioma-like carcinoma of the lung
Author (reference no.)/yearNo. casesSymptoms and signs (no.)Tumour stage (no.)Treatment (no.)
  • Only 28 of 33 case reports or series are tabulated to avoid duplication of cases in some series, including 153 cases in total.

  • NA, not available; NR, not reported; RT, radiotherapy.

Begin et al.1/1987 1AsymptomaticISurgery
Butler et al.17/1989 4Asymptomatic (3); cough, haemoptysis, night sweats (1)I (3), IIIA (1)Surgery (3), surgery + RT (1)
Gal et al.18/1991 1CoughIIIBSurgery + RT
Miller et al.19/1991 1Cough, haemoptysis (1)IISurgery
Pittaluga et al.16/1993 5NRI (4), II (1)Surgery
Chow et al.15/1995 2Haemoptysis (1), haemoptysis + fever (1)I (2)Surgery
Wong et al.13/1995 9NRI (4), II (2), IIIA (3)Surgery
Wockel et al.20/1995 1Unexplained sweatingIIIASurgery
Chan et al.14/199511Chest pain (3); dyspnoea (1); asymptomatic (2); cough and/or haemoptysis (5)I (7), II (1), IIIA (1), IIIB (1), IV (1)Surgery (9), biopsy only (2)
Higashiyama et al.21/1995 2Blood-stained sputum (2)I (2)Surgery
Ferrara and Nappi22/1995 2Chest wall mass (1); pneumonia (1)NRSurgery
Frank et al.23/1997 1Joint painI (1)Surgery + chemotherapy
Curcio et al.24/1997 1Clubbing of fingers and toesIIIAChemotherapy + surgery
Chen et al.5/1998 5NRI (3), IIIA (2)Surgery
Chan et al.12/1998 9Cough (2); cough + weight loss (1); haemoptysis (1); haemoptysis + weight loss (1); neck mass (3); back pain (1)I (1), II (1), IIB (2), IV (5)Surgery + chemotherapy (2), surgery + RT (1), chemotherapy (1), chemotherapy + RT (5)
Kasai et al.25/1999 1CoughIIIBChemotherapy + surgery
Barroso et al.26/2000 1Haemoptysis, chest pain, sweating, breathlessnessIIIBChemotherapy
Han et al.3/200032Cough (1); cough + haemoptysis (12); cough + haemoptysis + chest pain (5); cough + haemoptysis + weight loss (1); chest pain (1); cough + joint pain (2); asymptomatic (10)I (12), II (8), IIIA (11), IV (1)Surgery (14), surgery + RT (14), surgery + chemotherapy (1), surgery + RT +  chemotherapy (3)
Castro et al.27/2001 6NRI (4), II (1), IIIA (1)Surgery (5), surgery + RT (1)
Guerrero et al.28/2001 1NRIIBSurgery + chemotherapy
Chang et al.4/200223Cough + haemoptysis (2); cough + haemoptysis + weight loss (2); cough (6); cough + chest pain (1); chest pain (1); haemoptysis (1); dyspnoea (1); cough + weight loss (1); cough + dyspnoea + chest pain + fever (1); pleural effusion (1); fever (1); asymptomatic (5)I (8), II (3), IIIA (7), IIIB (1), IV (4)Surgery (17), biopsy only (6)
Jha et al.29/2002 1CoughISurgery
Morbini et al.30/2003 1Haemoptysis and dyspnoeaIVChemotherapy + radiotherapy
Kobayashi et al.31/2004 1NANANA
Ngan et al.7/200419NRI (4), II (2), IIIA (5), IIIB (3), IV (5)Surgery (4), chemotherapy (6), chemotherapy + RT (3), RT (2)
Ho et al.6/200410Cough (4); cough + haemoptysis (4); cough + chest pain (1); asymptomatic (1)IIIA (1), IIIB (4), IV (5)Chemotherapy (2), chemotherapy + RT (8)
Bildirici et al.32/2005 1CoughNRNR
Yoshino et al.33/2005 1AsymptomaticIASurgery

In a recent study investigating the radiological features of LELC of the lung, thoracic CT scans of 12 patients with biopsy-proven LELC of the lung and 25 patients with non-LELC non-small cell lung cancer were compared.39 The LELC tumours were significantly larger than controls (45.67 vs. 17.71 cm2, P = 0.02) and were closely associated with the mediastinum, that is, mainly centrally situated. More LELC tumours were associated with well-defined borders (80% vs. 12%, P = 0.02) but fewer with spiculated borders (20% vs. 64%, P < 0.001) than non-LELC tumours. There were increased peribronchovascular nodal metastases (80% vs. 16%, P = 0.01) and vascular encasement (70% vs. 24%, P = 0.02) in LELC compared with non-LELC tumours. Although the number of subjects in the study was relatively small because of the rarity of the condition, advanced LELC of the lung apparently had distinct radiological features characterized by central and peribronchovascular spread with vascular encasement.

Diagnostic algorithm

The clinical protocol to establish the diagnosis of LELC of the lung has been previously described.6 It has been reported that fine-needle aspiration cytology with immunohistochemical analysis may assist in the diagnosis of LELC of the lung.15 However, the relatively scanty material from fine-needle aspirate and sampling errors may limit the utility and accuracy of such techniques. In most instances, histological diagnosis rather than cytology is preferred. In the presence of histological features of LELC, special immunostaining can be performed to exclude lymphoma. ISH for EBER on the biopsy samples helps to demonstrate the presence of EBV infection, which has almost been exclusively found in LELC of the lung from Asian subjects. Very briefly, digoxigenin-labelled antisense riboprobes are generated by in vitro transcription from a Bluescript vector containing the EBER 1 and 2 genes of the virus.13 Hybridization signal is detected by standard immunohistochemical methods, using anti-digoxigenin mAb, biotinylated secondary antibody and streptavidin-alkaline phosphatase complex. As LELC of the lung is histologically indistinguishable from undifferentiated NPC, which is common especially in Southern China, endoscopic examination with or without radiological imaging (e.g. magnetic resonance imaging) of nasopharynx has to be performed to rule out metastatic LELC from the nasopharynx. Serum IgG titres against the viral capsid antigen of EBV may also provide evidence of EBV exposure.

TREATMENT AND PROGNOSIS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EPIDEMIOLOGY
  5. PATHOLOGY
  6. CLINICAL MANIFESTATIONS AND DIAGNOSIS
  7. STAGING
  8. TREATMENT AND PROGNOSIS
  9. CONCLUSION
  10. ACKNOWLEDGEMENT
  11. REFERENCES

Early stage

The majority of reported cases of lung LELC present early and are resectable. Surgical resection is the primary approach to obtaining a cure. In an early series of five cases of resectable LELC, all patients had survived significant periods of time, three for longer than 60 months, one 45 months and one 38 months postoperatively.5 In selected cases, especially for locally advanced disease, adjuvant postoperative radiotherapy or chemotherapy was also given (Table 2). Neoadjuvant chemotherapy consisting of 5-fluorouracil, leucovorin and cisplatin has been used in a child with LELC of the lung, leading to successful tumour downstaging and subsequent surgical resection.24

Advanced stage

For advanced or metastatic stages of lung LELC, the benefit of chemotherapy has been largely anecdotal because of its rare occurrence. A randomized controlled study on different chemotherapeutic agents is not practical. In a clinical series of multimodality treatment for LELC of the lung, combination chemotherapy consisting of cisplatin (100 mg/m2, day 1) and 5-fluorouracil (1000 mg/m2, day 2–4) was given to seven patients with advanced disease and achieved a 71.4% partial response rate.12 A similar combination regimen was studied recently.6 Ten patients (five men, age 47 ± 9.8 years, one in stage IIIA, four in stage IIIB, five in stage IV) with confirmed LELC of the lung received chemo-radiotherapy as first-line treatment. The chemotherapy regimen (FLP) consisted of 5-fluorouracil (1000 mg/m2, day 1–4), leucovorin (200 mg/m2, day 1–4) and cisplatin (100 mg/m2, day 1) at 4-weekly interval for four cycles. The tumour response rates were 60% partial response, 10% stable disease and 30% progressive disease. The median time to progression was 7 ± 0.9 months. At the time of progression, five patients were given salvage chemotherapy including ifosphamide/leucovorin/5-fluorouracil (n = 2), paclitaxel/carboplatin (n = 2) and gemcitabine (n = 1) with one partial response and one stable disease. The median survival time was 23.4 ± 4.7 months, apparently longer than those patients with advanced non-LELC non-small cell lung cancer who received platinum-based doublet chemotherapy. As NPC has similar clinical and biological characteristics as LELC of the lung, the response of the latter to FLP, an effective combination chemotherapy for NPC, is not so surprising.3

Disease monitoring

Apart from the conventional anatomical tumour measurements with various imaging techniques, repeated measures of tumour markers may help in disease monitoring during treatment and early detection of subsequent relapse. In a recent study of 19 patients with LELC of the lung, serum EBV DNA was measured using a quantitative PCR technique.7 Measurable serum levels of EBV DNA were detected in 11 of 12 patients prior to treatment. Low levels of EBV DNA were also detectable in one of two other patients post chemotherapy. In five patients without clinically evident tumour, EBV DNA was not detectable. The longitudinal profile of serum EBV DNA of seven patients concurred with their response to treatment and clinical outcomes, suggesting it may be potentially useful as a disease marker for monitoring treatment response.

Prognosis

In order to better understand the clinical outcome and prognosis, a recent study compared 32 LELC of the lung patients and 84 non-LELC non-small cell lung cancer patients.2 All LELC patients underwent surgical resection with 12 in stage I, 8 in stage II, 11 in stage IIIA and 1 in stage IV. Similarly all non-LELC patients also underwent surgical resection with 27 in stage I, 29 in stage II, 26 in stage III and 2 in stage IV. Adjuvant radiotherapy and/or chemotherapy were given in the more advanced stages. Patients with LELC had a significantly better 5-year survival than those with non-LELC with stage II disease (62.5% vs. 30.3%, P < 0.025) and stage III/IV disease (60.6% vs. 21.4%, P < 0.05). However, there were similar survival rates in stage I between LELC and non-LELC. In the same study, it was found that tumour recurrence and necrosis were poor prognostic factors for survival. The presence of abundant CD8-positive cytotoxic T lymphocytes adjacent to LELC cells and the underexpression of p53 and c-erb B-2 oncoproteins in tumour cells have been postulated to account for the better prognosis in LELC of the lung.4

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EPIDEMIOLOGY
  5. PATHOLOGY
  6. CLINICAL MANIFESTATIONS AND DIAGNOSIS
  7. STAGING
  8. TREATMENT AND PROGNOSIS
  9. CONCLUSION
  10. ACKNOWLEDGEMENT
  11. REFERENCES

Lymphoepithelioma-like carcinoma of the lung is clearly a distinct entity of non-small cell lung carcinoma that tends to affect younger non-smoking subjects of Asian descent. The pathological resemblance of LELC of the lung to undifferentiated NPC and its association with latent EBV infection have major implications for diagnosis and treatment. Despite the preliminary experience on multimodality treatment, future collaborative efforts, especially in the Asian–Pacific region, are warranted to determine the optimal treatment protocol for this uncommon malignancy.

ACKNOWLEDGEMENT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EPIDEMIOLOGY
  5. PATHOLOGY
  6. CLINICAL MANIFESTATIONS AND DIAGNOSIS
  7. STAGING
  8. TREATMENT AND PROGNOSIS
  9. CONCLUSION
  10. ACKNOWLEDGEMENT
  11. REFERENCES

The authors would like to thank Mr Stanley Sze (University Department of Medicine, The University of Hong Kong) for his clerical assistance.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EPIDEMIOLOGY
  5. PATHOLOGY
  6. CLINICAL MANIFESTATIONS AND DIAGNOSIS
  7. STAGING
  8. TREATMENT AND PROGNOSIS
  9. CONCLUSION
  10. ACKNOWLEDGEMENT
  11. REFERENCES
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    Higashiyama M, Doi O, Kodama K et al. Lymphoepithelioma-like carcinoma of the lung: analysis of two cases for Epstein–Barr virus infection. Hum. Pathol. 1995; 26: 127882.
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    Ferrara G, Nappi O. Lymphoepithelioma-like carcinoma of the lung. Two cases diagnosed in Caucasian patients. Tumori 1995; 81: 1447.
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