The overall incidence of primary pulmonary LELC is low. The highest incidence is found in the Chinese population. In Singapore, 76% of the population is Chinese, but, as little is known about the incidence of LELC in Singapore, we sought to study the characteristics, behaviour, and outcomes of LELC in our local population.
Since first described by Begin et al in 1987, only approximately 200 cases have been reported so far globally over last 3 decades, highlighting its rarity [8, 16]. With an incidence of 1500 new cases of lung cancer every year in Singapore, the estimated incidence in our population is 0.1%.
Although the gender predilection of LELC varies, our cohort showed a female predominance with predilection for non-smokers in keeping with the published literature. Chang et al from Taiwan [17], Liang et al from China [8], and Tay et al from Singapore [26] described female predominance in their cohorts similar to ours, whereas Han et al from China described male preponderance [19].
Median age in our cohort was 62 (42-88) years. Previous studies reported the median age of LELC patients to range from 47–58 years [15, 17, 18, 20, 26]. The median age in our cohort was older than those in previous studies but still younger than the reported median age of 70 years for NSCLC, asserting the onset of LELC at a younger age. The older age of the patients in our cohort could be the reflection of the catchment area of our hospital as it lies in the district with the highest number of residents above the age of 65 years [28].
All patients in our cohort were positive for EBV-encoded small non-polyadenylated RNA (EBER), affirming the association between EBV and pulmonary LELC in keeping with the existing literature. Most LELC cases reported in the literature are positive for EBER on in situ hybridization [14, 26]. In addition, Chang et al reported that a higher EBV serology titre represented higher tumour stage and larger tumour size [17]. Due to this, primary pulmonary LELC can be histologically indistinguishable from EBV associated LELC occurring in the nasopharynx (NPC) in Asian population [14, 21]. It is therefore necessary to differentiate NPC with metastasis to lung, from an early stage primary pulmonary LELC where surgical resection is recommended. Hence, all our patients were screened and cleared by ear, nose, and throat (ENT) surgeons for any concurrent nasopharyngeal involvement.
The majority of patients (60%) in our cohort had advanced (stage IV) pulmonary LELC. This is in contrast to the reports from China, Taiwan, and Hong Kong, where the majority of patients presented with early stage and only a minority presented with stage IV disease [8, 17, 27]. However, our results are in keeping with the study from Tay et al [26]. Additionally, at our centre, all lung cancer patients are initially staged using PET/CT of the body and MRI of the brain. Although unconfirmed, one of the reasons for the more advanced stage in our cohort could have been the up-staging of these cancers. This makes a direct comparison with previous reports difficult, where less sensitive and specific imaging techniques could have been used.
LELC is reported to be chemosensitive and radiosensitive cancer [22]. Seven patients were treated with chemotherapy in our cohort out of which 5 (71.4%) received gemcitabine/carboplatin as first line chemotherapy consistent with the published literature. Although the choice of first line chemotherapy was largely an extrapolation from chemotherapy used for NPC, it had shown to offer high disease control rate. Previous studies described good outcomes in patients with multimodality treatment [23]. Ho et al noted that 5-fluorouracil (5-FU)/cisplatin (FLP) demonstrated a high tumour response rate (60% partial response), with a median survival of 23.4 +/- 4.7 months [24]. Liang et al also reported that various regimes of chemotherapy such as paclitaxel/docetaxel + cisplatin/carboplatin, pemetrexed + cisplatin, gemcitabine + cisplatin, docetaxel/paclitaxel + cisplatin + 5-fluorouracil, gemcitabine + vinorelbine in advanced pulmonary LELC had a high disease control rate (>75%) [8].
The median (range) overall survival in our cohort was 24.2 (4.7-59.4) months with 1-year, 2-year, 3-year, and 5-year survival rates of 90%, 50%, 30%, and 10% respectively. Previous reports from China, Hong Kong, Taiwan, and Singapore have described median overall survival rates of 31, 39.1, 23.4, 27.6, and 43 months [5, 8, 23, 24, 26]. In a study of 52 patients (the largest study) with advanced LELC from China receiving chemotherapy (with or without radiotherapy), 1-year, 2-year, and 3-year survival rates of 100%, 76%, and 61% were reported [8]. The 2-year and 5-year survival rates described in another study from China were 90% and 74%, whereas a Singaporean study described 2-year and 5-year survival rates of 78.6% and 54.9% [25, 26]. Worse overall survival rates were seen in patients with higher grading and more advanced tumours [25]. Although the median overall survival and 1-year survival rate in our study were similar, the 2-year and 5-year survival rate in our cohort was lower. This is likely due to the greater proportion of patients with stage IV as well as the refusal of or being unfit to receive chemotherapy in patients with early stages.
When analysed by stage, the median survival in stage II, IIIA, and IV was 27.6, 20.7 (19.8-48.9), and 26.6 (4.7-59.4) months respectively. This is higher compared to NSCLC, where the median survival for stage III and IV is 13.7, and 4 months respectively [29, 30]. The stage by stage comparison with survival data for LELC from other studies showed that our median survival was lower but still significantly higher than the corresponding stages for NSCLC as a whole.
Thus, our cohort demonstrated similarities and differences from other existing literature which may be due to our study limitations. It is a retrospective, single centre study with a small sample size. However, in view of the rarity of this subtype of lung cancer, our study highlights the biological characteristics of LELCs and demonstrated the better survival of these patients, adding to the growing body of evidence and understanding of this rare condition. The biology of LELCs appears to be similar to NPC patients and it is therefore reasonable to consider therapeutic options available for NPC. One such consideration would be the use of adoptive immunotherapy once the results of the on-going phase III trial re-infusing EBV-specific autologous cytotoxic T-lymphocytes are known [31]. The publication of this trial is eagerly awaited. Another consideration would be to use EBV vaccination against virulent EBV antigens such as LMP2 potentially together with other treatment modalities [32].
In conclusion, comparing our study to the reports from China, Hong Kong, and Taiwan, our cohort was similar in terms of low incidence of LELC, Chinese preponderance, association with EBV, lack of smoking, younger age of onset and improved survival compared to other subtypes of lung cancer. Our study differed in terms of older patients, patients with more advanced stage disease, and henceforth an inherent poorer survival. For improving outcomes, future efforts should focus on increased awareness, early diagnosis, development of an ASEAN registry and international collaboration. Options such as EBV-directed adopted immunotherapy or the role of EBV vaccine also merit evaluation.