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Keywords:

  • pulmonary lymphoepithelioma-like carcinoma;
  • lung cancer;
  • epidermal growth factor receptor;
  • overall survival

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. FUNDING SOURCES
  9. REFERENCES

BACKGROUND:

Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare kind of cancer.

METHODS:

In this study, the authors evaluated 52 patients with pulmonary LELC who had long-term follow-up. Clinical characteristics, tumor markers, epidermal growth factor receptor (EGFR) mutation status, treatments, and outcomes were analyzed.

RESULTS:

Pulmonary LELC mostly affected young, nonsmoking patients. Most patients were in early or locally advanced stages and received multimodality treatment. Serum levels of neuron-specific enolase and cytokeratin 19 fragment 21-1 were elevated in 11 of 20 patients and 10 of 16 patients, respectively. Mutational analysis of EGFR was done in 11 patients, and all were wild type. The median overall survival (OS) for all the patients was not reached, and the 2-year and 5-year OS rate was 88% and 62%, respectively. The patients with early tumor stage, normal serum lactate dehydrogenase level, normal serum albumin level, without lymph node metastasis, and those who underwent complete resection had significantly better OS (P < .05); and the serum albumin level was an independent prognostic factor in a Cox regression model (P = .005). For all patients who underwent complete resection, whether or not they received adjuvant chemotherapy did not affect OS (P > .05); whereas, for patients with stage IIIA disease who underwent complete resection, adjuvant chemotherapy was correlated with a significantly better prognosis (P < .05).

CONCLUSIONS:

Pulmonary LELC obviously is a distinct entity of lung cancer that has a better prognosis, because patients with LELC can receive multimodality treatment, and LELC has biologic behavior similar to that of nasopharyngeal carcinoma. The current results indicated that future collaborative efforts are needed to determine the optimal treatment methods for this uncommon malignancy. Cancer 2012. © 2012 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. FUNDING SOURCES
  9. REFERENCES

Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare kind of tumor with morphology similar to that of undifferentiated nasopharyngeal carcinoma (NPC).1 Begin et al first reported LELC in 1987 and observed that it is an Epstein-Barr virus (EBV)-associated epithelial neoplasm.2 Pulmonary LELC is classified as a form of large cell carcinoma according to the World Health Organization classification.3 However, compared with other types of nonsmall cell lung cancer (NSCLC), patients with pulmonary LELC have a significantly better prognosis.4 Over the past 24 years, lt;200 cases have been reported in the literature, including no more than 20 cases from Western populations.5-7 The 3 largest reported cohorts were from Taiwan (46 patients),4 Southern China (32 patients),8 and Hong Kong (19 patients).9 Among the reported cases of pulmonary LELC, most patients had early, resectable disease (stage I or II). The standard treatment for early stage disease is complete resection; whereas multimodality treatment (surgery, chemotherapy, radiotherapy) has been applied in locally advanced disease, and palliative chemotherapy has been used for metastatic disease. However, because of the low incidence, the treatment of advanced LELC is controversial.10

In this study, we report on 52 patients with primary pulmonary LELC, and most of these patients had long-term follow-up. The objective of this study was to analyze the clinical characteristics, tumor markers, immunohistochemical profiles, epidermal growth factor receptor(EGFR) mutation status, treatments, and outcomes of primary pulmonary LELC. In addition, we attempted to identify the prognostic factors for primary pulmonary LELC.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. FUNDING SOURCES
  9. REFERENCES

Patients

We retrospectively investigated a cohort of 52 individuals who were diagnosed with pulmonary LELC and treated in Sun Yat-sen University Cancer Center from January 2000 to January 2011. Pulmonary LELC was diagnosed according to criteria described by the World Health Organization.11 We excluded undifferentiated carcinomas without lymphoid infiltrates and Epstein-Barr virus (EBV)-encoded RNA (EBER) staining in our study. All patients underwent endoscopic examination of the nasopharynx to rule out metastatic LELC from the nasopharynx. Approval to review, analyze, and publish the data in this study was given by the Sun Yat-sen University Cancer Center Research Ethics Board. Informed consent for the collection of medical information was obtained from all patients at their first visit.

We collected the clinical data from patients' medical records. We focused on patients' sex, age, symptoms, smoking status, tumor size, staging, initial treatments, and salvage treatments. Pathologic or clinical staging was performed according to the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (IUCC) staging system (the 1997 TNM Classification of Malignant Tumors),12 which is based on tumor size, location, and the presence of lymph node or distant metastases. Tumor assessment was based on Response Evaluation Criteria in Solid Tumors13 after at least 2 cycles of chemotherapy. Follow-up information was obtained from patients' medical records or by telephone interview. We focused on relapse-free survival (RFS) for patients who underwent complete resection and overall survival (OS) for all patients.

Immunohistochemistry Staining

Immunohistochemical staining with the antibodies listed in Table 1 was carried out and evaluated according to the manufacturer's instructions.

Table 1. Immunohistochemical Findings of Primary Pulmonary Lymphoepithelioma-Like Carcinoma
AntibodySourceCloneNo. of Positive Patients/Total (%)
  1. Abbreviations: TTF-1, thyroid transcription factor 1.

CytokeratinSanta Cruz Biotechnology (Santa Cruz, Calif)AE321/21 (100)
Cytokeratin 5/6DAKO (Carpinteria, Calif)D5/16B411/11 (100)
TTF-1DAKO8G7G3/12/8 (25)
p63Santa Cruz BiotechnologyBC4A415/16 (94)

In Situ Hybridization of Epstein-Bar Virus-Related RNAs

We used a chromogenic in situ hybridization technique (Hybridizer; Dako Denmark A/S, Glostrup, Denmark) according to the manufacturer's instructions. Briefly, after deparaffinization and inhibiting endogenous peroxidase activity, we digested proteinase K for 10 minutes at room temperature. A fluorescein-conjugated EBER probe was hybridized to its target on the section at 37°C for 2 hours. Then, an antidigoxigenin antibody and a secondary antibody with diaminobenzidine and Harris hematoxylin counterstaining were applied.

Mutational Analysis of Epidermal Growth Factor Receptor

EGFR tyrosine kinase exons 18, 19, 20, 21 were amplified by using nested polymerase chain reaction with specific primers.14 The resulting amplicons were sequenced using the BigDye Terminator kit (Applied Biosystems, Foster City, Calif) and an ABI Prism 3700 DNA Analyzer (Applied Biosystems) according to the manufacturer's instructions.

Analysis of Serum Tumor Markers

Serum tumor makers, such as neuron-specific enolase (NSE), cytokeratin 19 fragment 21-1 (cyfra21-1), squamous cell carcinoma antigen (SCC), tumor-specific growth factor (TSGF), and carcinoembryonic antigen (CEA), were measured using a corresponding electrochemiluminescence assay kit (ECLIA; Roche Diagnostics, Indianapolis, Ind) during pretreatment clinical evaluation and after treatment. The reference ranges of serum tumor marker levels were provided by the corresponding kit provider.

Statistical Analyses

All statistical analyses were performed using PASW Statistics 18.0 software (Apache Software Foundation, Forest Hill, Md). OS was measured from the date of diagnosis to the date of death from any cause or was censored at the date of the last follow-up evaluation. RFS was measured from the date of diagnosis to the date of disease relapse. Survival functions were estimated by using life tables and the Kaplan-Meier method and were compared using the log-rank test. Significance levels and estimates of hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated with a Cox regression model. Differences between the results from comparative tests were considered significant if the 2-sided P value was < .05.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. FUNDING SOURCES
  9. REFERENCES

Patient Characteristics

Clinical features of the study patients are provided in Table 2. In the previous 11 years, 52 patients were diagnosed with primary pulmonary LELC at our hospital. All patients had normal nasopharyngoscopy findings. Among these patients, 29 (55.8%) were male, and 23 (44.2%) were female. The patients ranged in ages from 9 years to 74 years, the median age was 51 years, and 14 patients (26.9%) patients were aged >60 years when they were diagnosed with primary pulmonary LELC. Fifteen patients (28.8%) were asymptomatic, and clinical manifestations in the other 37 patients (71.2%) included dry cough (19 patients), cough with bloody sputum (8 patients), chest pain (6 patients), body weight loss (3 patients), and fever with pain of the limbs (1 patient). Thirteen patients (25%) were former or current smokers, including 9 heavy smokers (smoking index, >400), and 39 patients (75%) were nonsmokers. The majority of our patients had early stage disease (stage IA, 7 patients; stage IB, 9 patients; stage IIA, 5 patients; stage IIB, 4 patients) or locally advanced disease (stage IIIA, 18 patients; stage IIIB, 6 patients), and distant metastatic disease occurred in 3 patients (5.8%). The tumor ranged in size from 1.2 cm to 11 cm, and the median tumor size was 4.0 cm. Serum levels of lactate dehydrogenase (LDH) and albumin (ALB) were available for all patients at the time of LELC diagnosis. LDH levels were elevated (>240 U/L) in 7 patients (13.5%) and were normal in the other 45 patients (86.5%). Albumin levels were decreased (<35.0 g/L) in 5 patients (9.6%) and were normal in the other 47 patients (90.4%).

Table 2. All Patients' Clinical Characteristics and Analysis of Prognostic Factors for Overall Survival
  Overall Survival
   Multivariate Analysis
VariableNo. of Patients (%)Univariate Analysis: PRR [95% CI]P
  • Abbreviations: ±, with or without; CI, confidence interval; CT, chemotherapy; LDH, lactate dehydrogenase; NA, not applicable; RR, relative risk; RT, radiotherapy.

  • a

    These P values reached significance.

  • b

    Univariate and multivariate analyses were used to determine whether or not patients underwent complete resection.

Sex    
 Male29 (55.8).4730.415 [0.050-3.461].416
 Female23 (44.2)   
Age, y    
 Median51   
 Range9-74   
 <6038 (73.1).2900.567 [0.030-10.613].704
 ≥6014 (26.9)   
Stage    
 IA/IB7/9 (13.5/17.3).019a0.749 [0.067-8.344].814
 IIA/IIB5/4 (9.6/7.7)   
 IIIA18 (34.6)   
 IIIB/IV6/3 (11.5/5.8)   
Smoking status    
 Former or current smoker13 (25).6300.439 [0.062-3.103]0.410
 Nonsmoker39 (75)   
Tumor size, cm    
 ≤318 (34.6).2587.446 [0.406-136.469].176
 >334 (65.4)   
LDH level    
 Normal45 (86.5).004a0.085 [0.007-1.098].059
 Elevated7 (13.5)   
Albumin level    
 Normal47 (90.4).044a0.030 [0.003-0.352].005a
 Decreased5 (9.6)   
Initial treatment    
 Complete resection18 (34.6).000ab4.173 [0.559-31.130]b0.164b
 Complete resection+CT±RT22 (42.3)   
 Incomplete resection+CT3 (5.8)   
 Palliative CT8 (15.4)   
 Palliative RT+CT1 (1.9)   
Outcome    
 Died of tumor5 (9.6)NANANA
 Died of other cause6 (11.5)   
 Alive41 (78.9)   

Treatment and Outcomes for All Patients

Most of the patients in our cohort received multimodality treatment, which produced encouraging results. Forty patients underwent complete resection as initial therapy. Among these patients, 16 received adjuvant chemotherapy, including 1 patient with stage IA disease, 3 patients with stage IB disease, 3 patients with stage IIA disease, 2 patients with stage IIB disease, and 7 patients with stage IIIA disease. Six patients received adjuvant chemotherapy and radiotherapy, including 1 patient with stage IIA disease and 5 patients with stage IIIA disease.

For the 40 patients who underwent complete resection, the tumor recurred in 6 patients 10.6 to 41.1 months after surgery; and, among those 6 patients, 4 received further palliative chemotherapy, 1 patient received further palliative chemotherapy with radiotherapy, and 1 patient received no further treatment (this man aged 56 years died 2 weeks after tumor relapse was diagnosed).

Three patients underwent incomplete resection and received chemotherapy, including 1 patient with stage IIIA disease, 1 patient with stage IIIB disease, and 1 patient with stage IV disease. Nine patients had inoperable disease when they were diagnosed. Among those 9 patients, 8 received palliative chemotherapy alone, including 1 patient with stage IIIA disease, 5 patients with stage IIIB disease, and 2 patients with stage IV disease; and 1 patient with stage IIIB disease received sequential chemoradiotherapy.

These 17 patients (including the 5 patients who suffered from relapsed disease after undergoing complete resection, the 3 patients who underwent incomplete resection, and the 9 inoperable patients) who received palliative chemotherapy with or without radiotherapy are described in detail in Table 3. During the course of palliative chemotherapy, 9 patients received taxane-containing regimens, 4 patients received pemetrexed-containing regimens, 4 patients received gemcitabine-containing regimens, 3 patients received vinorelbine-containing regimens, and 3 patients received 5-fluorouracil (5-FU)/capecitabine/tegafur-containing regimens; and the disease control rates (combined complete responses, partial responses, and stable disease) were 77.8%, 100%, 100%, 100%, and 100%, respectively. The most commonly used regimens were paclitaxel/docetaxel (TAX/DOC) + cisplatin/carboplatin (DDP/CBP); pemetrexed (PEM) + DDP; gemcitabine (GEM) + DDP; DOC/TAX + DDP + 5-FU; and GEM + vinorelbine (NVB), in that order of frequency. Two patients received an EGFR tyrosine kinase inhibitor: One of those patients maintained stable disease for 4 months with gefitinib, and the other patient developed progressive disease after receiving treatment with erlotinib for 1 month.

Table 3. Clinical Features of Patients Who Received Palliative Chemotherapy
SexAge, ySmoking StatusTumor Size, cmStage/TNMInitial TreatmentRFS, moPalliative CT Regimen (Outcome)OS, moVital Status
  1. Abbreviations: 5-FU, 5-fluorouracil; ADM, Adriamycin (doxorubicin); CBP, carboplatin; CT, chemotherapy; CTX, cyclophosphamide; DDP, cis-diamminedichloroplatinum (cisplatin); DOC, docetaxel; GEM, gemcitabine; IFO, ifosfamide; NA, not available; NVB, vinorelbine; OS, overall survival; PD, progressive disease; PEM, pemetrexed; PR, partial remission; RFS, relapse-free survival; RT, radiotherapy; S, complete resection; SD, stable disease; TAX, paclitaxel; TNM, tumor, lymph node, metastasis classification; VP-16, etoposide; XELOX, capecitabine and oxaliplatin.

Male39Yes3.0IA/T1N0M0S+CT+RT32.2TAX+DDP (SD); NVB+DDP (SD)100.2Alive
Male44No2.5IIA/T2N1M0S+CT41.1Erlotinib (PD); PEM+DDP (PR)44.1Alive
Male40No4.5IIIA/T3N1M0S+CT16.3TAX+CBP (PR); DOC+DDP (SD)60.2Alive
Female9No6.7IIIA/T3N2M0S+CT10.6GEM+NVB (PR); IFO+CBP (PR)37.8Alive
Female50No5.0IIIB/T4N2M0S+CT23.5PEM+DDP (SD)30.2Alive
Male57Yes4.5IIIA/T3N2M0CTTAX+DDP (PD); GEM+NVB (SD)38Dead
Male35No5.5IIIA/T2N2M0CT+RTCTX+ADM+DDP (PR); IFO+ VP-16+DDP (SD)47.2Dead
Female48No4.0IIIA/ T2N2M0CTDOC+DDP (SD); TAX+DDP (SD)49.3Alive
Female51No6.2IIIB/T4N1M0CTFT20737.7Alive
Male56No5.0IIIA/T2N2M0CTDOC+CBP (SD)24.1Alive
Male48No6.0IIIB/T4N2M0CTTAX+DDP (SD); DOC+DDP (PD)21.1Dead
Male60Yes4.0IIIB/T2N3M0CTNA14.2Alive
Female25No3.5IIIB/T4N3M0CT+RTDOC+DDP+5-FU (SD); GEM+DDP (SD); gefitinib (SD); GEM+DDP+ endostatin(SD); PEM (SD)32.1Dead
Male45No5.0IIIB/T2N3M0CTNA16.4Alive
Male44Yes6.0IV/T4N2M1CTTAX+CBP (PD)20.2Dead
Male60No5.2IV/T4N2M1CTTAX+DDP+5-FU (PR); GEM+DDP (SD); XELOX (SD)19.1Alive
Female64No5.0IV/T4N2M1CTPEM+DDP (PR)20.8Alive

Immunohistochemical Results and Epidermal Growth Factor Receptor Mutation Status

Histopathologic examination demonstrated nests of epithelial tumor cells separated by lymphocytes; and tumor cell nuclei were round, oval, or elongated with a slightly irregular nuclear outline. Immunohistochemically (Table 1), cytokeratin (CK), transcription termination factor 1 (TTF-1), CK5/6, and tumor protein 63 (p63) were expressed in 21 of 21 patients, 2 of 8 patients, 11 of 11 patients, and 15 of 16 patients, respectively (Fig. 1). In situ hybridization for EBERs revealed positive signals in all 52 tumors that were investigated. EBER staining was positive in the nuclei of large neoplastic cells but not in the surrounding lymphocytes (Fig. 2). Eleven patients underwent mutational analysis of EGFR, and all had wild-type EGFR.

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Figure 1. Histopathologic examination revealed nests of epithelial tumor cells separated by abundant lymphocytes in (A,B) hematoxylin and eosin-stained tissue samples; in tissues that had positive immunoreactivity for (C) cytokeratin, (D) cytokeratin 5/6, and (E) p63; and (F) in tissues that had negative immunoreactivity for thyroid transcription factor-1 (original magnification, ×100 in A, C, E, F; ×200 in B and D).

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Figure 2. In situ hybridization for Epstein-Barr virus-encoded RNAs (EBERs) is illustrated. (A,B) In hematoxylin-counterstained sections, EBERs were positive in the nuclei of large neoplastic cells but not in the surrounding lymphocytes (original magnification, ×100 in A, ×200 in B).

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Serum Tumor Markers

Neuron-specific enolase was elevated in 11 of 20 patients (the analysis was not performed in the remaining 32 patients), cyfra21-1 was elevated in 10 of 16 patients, TSGF was elevated in 3 of 16 patients, and CEA was elevated in 1 of 42 patients. The serum titers of EBV-EBV capsid antigen (EBV-VCA) immunoglobulin A (IgA) and EBV-VCA IgG were available for 16 patients at the time pulmonary LELC was diagnosed, and 12 of 16 patients had elevated titer levels.

Survival Curves and Correlation of Clinical Features With Survival

By the end of August 22, 2011, complete survival data were available for all 52 patients. There were 11 deaths, and the other 41 patients were still alive. The median follow-up was 31.55 months (range, 3.6-121.8 months). The 5 deaths from tumor progression occurred within 16.0 months, 20.2 months, 21.1 months, 32.1 months, and 47.2 months after the diagnosis of pulmonary LELC. The median OS for all patients with pulmonary LELC was not reached, and the 2-year and 5-year OS rates were 88% and 62%, respectively (Fig. 3A). There were 12 patients with advanced tumor stages who received palliative chemotherapy with or without radiotherapy; their 1-year, 2-year, and 3-year survival rates were 100%, 76%, and 61%, respectively; and their median survival was 39.1 months (Fig. 3B). For the whole group, OS was not associated with sex, smoking status, age, or tumor size (P > .05). The patients with early stage tumors, with normal serum LDH levels, with normal serum albumin levels, without lymph node metastasis, and those who underwent complete resection had significantly better OS (P < .05) (Fig. 4A-E). For all patients who underwent complete resection, whether or not they received adjuvant chemotherapy did not affect OS (P > .05); whereas, for the patients with stage IIIA disease who underwent complete resection, adjuvant chemotherapy was correlated with a significantly better prognosis (P < .05) (Fig. 4F). For the 40 patients who underwent complete resection, the tumor recurred in 6 patients. However, whether or not those patients developed recurrent disease did not affect their OS (P > .05).

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Figure 3. (A) For patients with pulmonary lymphoepithelioma-like carcinoma, the 2-year and 5-year overall survival rate was 88% and 62%, respectively, and the median survival was not reached at the last follow-up. (B) For all patients who had unresectable disease, the 1-year, 2-year, and 3-year survival rates were 100%, 76%, and 61%, respectively, and the median survival was 39.1 months.

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thumbnail image

Figure 4. For all patients with pulmonary lymphoepithelioma-like carcinoma, overall survival was associated significantly with (A) serum lactate dehydrogenase (LDH) level (P = .004), (B) serum albumin level (P = .044), (C) tumor stage (P = .019), (D) lymph node metastasis (P = .014), and (E) complete resection (P = .000). (F) For all patients with stage IIIA disease who underwent complete resection, adjuvant chemotherapy was correlated with a significantly better prognosis (P = .034).

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. FUNDING SOURCES
  9. REFERENCES

Primary pulmonary LELC is a very rare and clinicopathologically distinctive cancer that was first reported in 1987 by Begin et al,2 and it represents approximately 0.92% of lung cancers, as reported by Chang et al.4 Over the past 2 decades, <200 cases have been reported in the literature, and, to our knowledge, the cohort reported here is the largest to date. In our cohort, there were 29 male patients and 23 female patients, and the male/female ratio (1.26:1) was consistent with the results reported by Chan et al (6:5).15 The patients ranged in age from 9 years to 74 years, and their median age was 51 years, which was similar to the reports of Han et al8 and Frank et al.16 The youngest patient with pulmonary LELC reported to date was a child aged 8 years,17 and the youngest patient in our cohort was a girl aged 9 years. Only 25% of patients were former or current smokers, similar to the results reported by Ho et al.10 The lower rate of cigarette smoking in patients who had pulmonary LELC compared with patients who had other lung cancers (>60% were former or current smokers) indicates that there may be an alternative pathogenesis apart from cigarette smoking.4 Nearly 33% of our patients were asymptomatic when they were diagnosed with pulmonary LELC, whereas others present with symptoms similar to those observed in other lung cancers, such as cough, chest pain, bloody sputum, etc. Most of our patients had early stage or locally advanced disease, and only 3 patients had distant metastatic disease, which may explain in part the better prognosis for patients with pulmonary LELC than for patients with other, non-LELC lung cancers.

The diagnosis of LELC depends mainly on morphologic characteristics, which exhibit solid nests of tumor cells with prominent nucleoli in a syncytial arrangement surrounded by lymphocyte infiltrates. All immunohistochemical staining in our study was performed not to determine the diagnosis of LELC but, rather, to help us define LELC. In nearly all patients, we detected high levels of CK, CK5/6, and p63 expression, which indicates that LELC originates from epithelial tissue and belongs to the category of squamous carcinoma. Since Begin et al first reported LELC in 1987, an etiologic association with EBV has been observed. The presence of EBV in LELC can be demonstrated with immunohistochemistry for EBV DNA and RNA or with immunohistochemistry for EBV-associated proteins,18, 19 whereas the analysis of EBER with immunohistochemistry is the most specific and highly sensitive method for latent EBV detection in paraffin sections. The most abundant transcription of EBER can be detected during latent EBV infection; the secondary structure of EBERs is very stable, and most EBERs are located within the nucleus, where they are conjugated with the cellular protein La.20 In our cohort, all 52 patients had positive results from in situ hybridization for EBERs, thus confirming the association of EBV infection with pulmonary LELC. However, the largest cases report from non-Asian countries demonstrated that all 6 Western patients had EBV-negative disease, suggesting that there may be no association between EBV and pulmonary LELC in the Western population and indicating that EBV is not a necessary factor in the pathogenesis of LELC.6 Many studies have indicated that the EGFR pathway and the echinoderm microtubule-associated protein-like 4–anaplastic lymphoma kinase (EML4-ALK) fusion gene plays an important roles in the pathogenesis of lung cancers.21 Patients with NSCLC who have EGFR mutations respond better to EGFR tyrosine kinase inhibitors than those without such mutations, and patients with the EML4-ALK fusion gene are very sensitive to ALK tyrosine kinase inhibitors, such as crizotinib.22 The positive rate of EGFR mutation and EML4-ALK was >30% and nearly 10% in East Asian patients, respectively.23 Chang et al reported that only 17.4% of patients with lung LELCs harbored EGFR mutations,4 and Tam et al observed that EGFR mutations were uncommon in LELC (1 of 11 patients were positive).24 In our study, EGFR mutation analysis data were available for 11 patients; however, all of those patients had wild-type EGFR. Because of the small number of case reports from Western countries, data are lacking on the EGFR status of patients with pulmonary LELC in those populations. Wong et al25 analyzed EML4-ALK expression profiles in 11 patients with pulmonary LELCs and observed that no patients had that fusion gene. Thus, the relatively low rate of EGFR mutation and EML4-ALK in pulmonary LELCs indicates that it is a distinct type of lung cancer, especially in East Asians.

Apart from conventional evaluations with various imaging techniques, repeated measurement of tumor markers may play an important role in disease monitoring during treatment and early detection of subsequent relapses. NSE is an isoenzyme of the glycolytic enzyme enolase,26 which is expressed mostly in neuroendocrine tumors.27 Measurement of NSE levels in patients with small cell lung cancer can provide information about the tumor burden and the patient's prognosis.28 CYFRA 21-1 also can be used as a tumor biomarker for squamous cell lung cancers. However, to date, the role of NSE and CYFRA21-1 in pulmonary LELC has not been well studied. In the current study, we observed that >50% of our patients (data available) had elevated levels of serum NSE and CYFRA21-1, and these marker levels decreased to normal after patients underwent complete resection (data not shown), suggesting that serum NSE and CYFRA21-1 may be associated with disease activity. Thus, we recommended regular monitoring of serum NSE and CYFRA21-1 levels during the treatment of patients with pulmonary LELC, and these biomarkers can be used to detect early tumor recurrence.

Most of the reported patients with pulmonary LELC had early stage and resectable disease. Complete resection is the primary approach to obtain a cure. Selected patients, especially those with locally advanced disease, also can receive neoadjuvant or adjuvant chemotherapy. In our cohort, among 40 patients who underwent complete resection, 2 patients with stage IIIA disease received neoadjuvant chemotherapy (TAX + DDP + 5-FU and DOC + CBP, respectively) and had partial remission, resulting in tumor shrinking and subsequent complete resection. In total, 22 patients received adjuvant chemotherapy with or without radiotherapy. However, whether or not patients received adjuvant chemotherapy did not affect the OS of all patients who underwent complete resection (P > .05); whereas, for the patients with stage IIIA disease who underwent complete resection, adjuvant chemotherapy was correlated with a significantly better prognosis (P < .05) (Fig. 4F), consistent with results from the International Adjuvant Lung Trial29 and the Lung Adjuvant Cisplatin Evaluation study,30 in which patients who had stage IIIA NSCLC benefited most from adjuvant chemotherapy. Thus, we suggest that postoperative adjuvant chemotherapy should be received by patients who have locally advanced tumor stages. However, because of the limited number of the patients, prospective randomized studies with a larger number of patients treated with/without adjuvant chemotherapy are needed to confirm these findings. For patients with advanced or metastatic lung LELC, the benefit of chemotherapy largely has been anecdotal because of its rarity. In our cohort, the most commonly used regimens were TAX/DOC + DDP/CBP, PEM + DDP, GEM + DDP, DOC/TAX + DDP + 5-FU, and GEM + NVB, and all these regimens can produce a high disease control rate (>75%). There has been favorable response to combined 5-FU and cisplatin chemotherapy in patients with advanced pulmonary LELC, similar to the responses reported in patients with NPC.31 Ho et al32 reported that 3 of 5 patients with advanced or metastatic pulmonary LELC who received single-agent capecitabine as salvage chemotherapy achieved disease control. Consistent with those results, we observed that a patient who received capecitabine as salvage monotherapy after disease progression also achieved durable disease control. Our results also demonstrate that pulmonary LELC is sensitive to paclitaxel-based or docetaxel-based regimens. Pemetrexed is chemically similar to folic acid and belongs to the folate antimetabolites. It has been widely used as first-line and second-line treatment or as maintenance therapy for patients with nonsquamous cell lung cancers.33 In our study, 4 patients received pemetrexed (as first-line treatment in 2 patients, as second-line treatment in 1 patient, and as fifth-line treatment in 1 patient): two of those patients had a partial remission (50%), the other 2 patients had stable disease (50%), and the disease control rate was 100%, indicating that pemetrexed may have efficacy in the treatment of pulmonary LELC. Gefitinib and erlotinib were used as monotherapy in 1 patient each, but both resulted in disease progression after disease control for 4 months and 1 month, respectively, consistent with the finding that none of the patients carried EGFR mutations in our cohort and, thus, may have had a poor response to EGFR inhibitors.

Consistent with other reports,8 patients who had pulmonary LELC in our cohort had a better prognosis compared with patients who had other types of NSCLC. In our study, the median OS for all patients with pulmonary LELC was not reached after a median follow-up of 31.55 months (range, 3.6-121.8 months), and the 2-year and 5-year OS rates were 88% and 62%, respectively. The pathogenesis of pulmonary LELC in Western patients may be different from that in Asian patients; however, similar to the Asian patients with pulmonary LELC, a previous study suggested that the prognosis for these patients appeared to be good, because the patients were alive without evidence of disease at a follow-up of 18 to 30 months.6 Among all patients with pulmonary LELC, early tumor stages, an absence of lymph node metastasis, undergoing complete resection, and normal serum LDH and albumin levels appear to be related to a better prognosis in univariate Kaplan-Meier survival analysis; whereas the serum albumin level was an independent prognostic factor in the Cox regression model (Table 2). In contrast to the results reported by Han et al8 that tumor recurrence and necrosis were poor prognostic factors for survival; in our study, for the 40 patients who underwent complete resection, whether or not those patients developed recurrent disease did not affect OS (P > .05), indicating that salvage therapies were effective in controlling the disease. Novel drugs and regimens, such as pemetrexed and docetaxel, as well as advanced radiotherapy technology may contribute to this difference. For instance, Table 2 includes a man aged 39 years who had a local recurrence 32.2 months after undergoing complete resection. TAX + DDP and NVB + DDP chemotherapy was administered sequentially, resulting in stable disease. Subsequently, the patient received 70 grays of radiation, which also may have contributed to the partial remission. This patient was alive for more than 5 years after disease recurrence. Because patients with NPC have similar clinical and biologic profiles to those of patients with LELC,2 the response of the latter to radiotherapy is not surprising. Thus, we recommend that combination of chemotherapy and radiotherapy should be the standard treatment for locally recurrent disease or locally advanced, unresectable disease.

In conclusion, pulmonary LELC is obviously a distinct group of NSCLC that appears to affect younger, nonsmoking patients. Our current results confirm the association between pulmonary LELC and EBV infection and suggest that the serum albumin level is an independent prognostic factor. The better prognosis for patients with pulmonary LELC may be because of the multimodality treatment and biologic behavior similar to that of NPC. However, because of the low incidence of pulmonary LELC, future collaborative efforts are needed to determine the optimal treatment protocol for this rare malignancy.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. FUNDING SOURCES
  9. REFERENCES

We thank all of the physicians of the Cancer Center, Sun Yat-sen University for allowing us to include their patients. In addition, we appreciate the cooperation of all the pathologists of the Cancer Center, Sun Yat-sen University for their support.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. FUNDING SOURCES
  9. REFERENCES

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. FUNDING SOURCES
  9. REFERENCES