| OBJECTIVE:Lung cancer is one of the most common malignancies that has been threating human health globally. The morbidity and mortality of lung cancer worldwide has been rising. According to statistical report in 2002, the incidence of lung cancer was approximately 1.35 million, and about 1.18 million died of it, which made lung cancer be the No.l killer around the world. In particular, the incidence of lung cancer in male was the first in the rank among all kinds of malignancies, while the correspondence figure in female was second in the rank. From the perspective of pathology and physiology, lung cancer is a disease that is highly heterogeneous and complicated in nature. General speaking, lung cancer can be the divided into two categories:non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Squamous cell carcinoma (SCC), adenocarcinoma (AD), large cell cancer (LCC), et al. belong to the category of non-small cell lung cancer, accounting for 80%-85% of all the lung cancer cases. Early diagnosis is fairly difficult in non-small cell lung cancer and about 85% of these patients already have advanced diseases at the time of diagnosis. The therapeutic outcome of surgery is not ideal and 5-year survival after surgery is poor. According to a retrospective survey 2004-2005, the lung cancer mortality in China rose to 30.83/100000, of which the mortality in male patients rose to 41.34/100000 and the figure in female patients was 19.84/100000. Therefore, lung cancer has become one of the most significant cancer issues both in China and worldwide.Lymphoepithelioma like carcinoma (LELC) is a rare malignant tumor which could originate from the nasopharynx and some organs developed from foregut, such as salivary gland, stomach, lung and oral cavity. Lymphoepithelioma like carcinoma is a very rare undifferentiated cancer and is histologically different from other subtypes of non-small cell lung cancer. Its characteristics include low incidence, well response to chemotherapy drugs, low metastasis rate, et al. This special type of lung cancer was first reported by Begin in 1987. According to the WHO classification of lung cancer (version 2004), this disease was categorized into the subgroup of large cell lung cancer. But in the updated WHO classification of lung cancer (version 2015), it was further categorized into the group of other unclassified lung cancer which made it become a special subtype of lung cancer. Lymphoepithelioma like carcinoma origin in the nasopharynx is an undifferentiated carcinoma with a characteristic of lymphocyte infiltration in the stroma. Most of the previous studies have confirmed that there is a close relation between nasopharyngeal lymphoepithelioma like carcinoma and Epstein-Barr virus (EBV), and EBV should play a very important role in the development of nasopharyngeal LELC. Since the first report of primary lung LELC in 1987, less than 200 cases have been reported in the literature and most of the cases were from Southeast Asian, including southeast coast of China, Taiwan and Hongkong. On the other hand, it was rarely reported in the Caucasus and other ethnic population. Because the Epstein-Barr virus has obvious geographical epidemiology, which is consistent with prevalent area of lung LELC, many studies have showed EBV may also play a very critical role for the occurrence and development of primary lung LELC. But the true relationship between the virus and the tumor is still unknown which warrants further study.In lung adenocarcinoma, if epidermal growth factor receptor (EGFR) mutations are present, it means that the lung cancer patients would benefit from tyrosine kinase inhibitors (TKI) treatment. However, EGFR mutation status is still unclear for primary pulmonary lymphoepithelioma like carcinoma. Chang et al. reported that 17.4% of pulmonary lymphoepithelioma like carcinoma harbored EGFR mutation, while the study from Tam et al. demonstrated that EGFR mutations in lung LELC is very rare (1/11). Both Liang Y’s and Liu QW’s researchers found that all the EGFR tests in lung LELC specimens were of wild-type. Due to the uncertainty of TKI treatment, multidisciplinary treatment should be more important in the management of lung LELC. For instance, in Liang Y’s study, adjuvant chemotherapy was showed to improve the survival rate of the patients with stage IIIA lung LELC (P<0.05).The previous studies showed that the prognosis and treatment outcome of primary lung lymphoepithelioma like carcinoma are significantly better than those of other non-small cell lung cancer. For example, in the study cohort of Liang Y et al. which analyzed 52 cases of lung LELC, the 2-year and 5-year overall survival rates were 88% and 62% respectively. And Sun YH and his colleagues compared the surgical outcome among 46 cases of classical large cell lung cancer,30 cases of large cell neuroendocrine carcinoma and 18 cases of primary lung LELC. They found there was no significant difference regarding 5 years disease-free survival (DFS) among 3 groups; however, the overall survival in lung LELC group was much better than the other 2 groups. In order to further study the prognosis of primary lung LELC, a recent study compared the therapeutic outcomes between 32 cases of lung LELC and 84 cases of other non-small cell lung cancer. All the patients successfully underwent surgical resection. There were 12 cases of stage I disease,8 cases of stage II disease, 11 cases of stage IIIA disease and 1 cases of stage IV disease in lung LELC group, while there were 27 cases of stage I disease,29 cases of stage II diseases,26 cases of stage III disease and 2 cases of stage IV disease in NSCLC group. Adjuvant radiotherapy and/or chemotherapy was given to the patients with relatively advanced diseases. The results showed that patients in lung LELC group experienced a better 5-year overall survival than those in NSCLC group, especially for stage II diseases (62.5% vs.30.3%, P<0.02) and stage III/IV diseases (60.6% vs.21.4%, P<0.05). Cancer recurrence and tumor necrosis were considered as unfavorable prognostic indicators. In the further analysis, it is found that the low expression of p53 and cerebB-2 in the cancer cells, and CD8 positive cytotoxic T lymphocytes infiltration may have contributed to the better prognosis of lung LELC. Because of the low incidence of lung LELC, the survival analysis with an adequately large sample size is still lacking. Therefore, this study aimed to analyze the clinical characteristics, imaging features, biological behavior and prognosis of the patients with this special subtype of NSCLC in a relatively large group.METHODS:1, This was a retrospective clinical study and it analyzed 39 cases of primary lung lymphoepithelioma like carcinoma. All 39 patients underwent surgical treatment with curative intent in the Department of Thoracic Surgery, First Affiliated Hospital of Guangzhou Medical University from January 2009 to December 2013. The inclusion criteria of this study included:(1) according to the WHO classification of lung cancer (2015 version), the pathological diagnosis was confirmed to be lung lymphoepithelioma like carcinoma; (2) routine chest CT scan, brain CT or MR, abdominal CT or ultrasound, and bone scan to exclude brain, liver, adrenal or bony metastasis; (3) adjuvant or neoadjuvant radiotherapy and/or chemotherapy were consistent with NCCN guidelines; (4) surgical treatment was curative in nature; (5) primary lung lymphoepithelioma like carcinoma was confirmed by excluding nasopharyngeal lymphoepithelioma like carcinoma; (6) patients were followed up until their death or at least 2 years after surgery. Candidates must meet all the above criteria before recruitment. The exclusion criteria included (1) patients were diagnosed of other malignancies within 5 years prior to the diagnosis of lung LELC; (2) the clinical data and/or follow-up data were incomplete; (3) postoperative pathological specimens were missing; (4) patients received palliative surgery; (5) lung LELC was mixed with other subtypes of non-small cell lung cancer. (6) cancer metastasis was identified at the time of diagnosis. Candidates would be excluded from study if they meet one or more of the above exclusion criteria.2, The aim of this study was to collect all the clinical data and follow-up information, and then analyze and summarize the clinical characteristics (age, gender, relation with smoking, signs and symptoms et al.), medical imaging features (CT scans and PET/CT scans), histological features (histology, immunohistochemistry, Epstein-Bar virus encoding of small RNA and EGFR mutation status), and prognosis (2 years and 3 years disease-free survival). Prognostic value would also be explored in some clinicopathological factors like pathological stage, tumor size, lymph node status, age (under 50 years old or 50 years old above), gender (male or female), smoking history, adjuvant treatment et al via univariate and multivariate survival analyses. A comprehensive understanding of the clinicopathological characteristics of primary pulmonary lymphoepithelioma like carcinoma was expected to achieve by analyzing this relatively large cohort. The results of this study would also support further basic and clinical researches for this special subtype of lung cancer in the future.RESULTS:1, All the basic information of 39 primary lung LELC patients were collected and summarized. The demographical data showed median age of lung LELC was 47 years (ranging from 36 to 81 years old), female patients were slightly more than male patients (24 vs.15 cases), and non-smokers were more common, accounting for 82.1% of the patients in our cohort. Regarding clinical symptoms, the most common one at the time of presentation was cough (35.9%), and the second most common one was hemoptysis (15.4%). However, most patients in our group were asymptomatic at the time of diagnosis, and the lung lesions were only identified in routine physical examination (41.0%).2. Imaging features included (1) CT scan features:peripheral lesions were more than central lesions (22 vs.17 cases). The mean diameter of the tumors was 4.27 cm. Lobulated lesions were identified in 28 cases (71.8%), speculation sign was found in 15 cases (38.4%), and lesions with both lobulation and spiculation signs were demonstrated in 4 cases (10.3%). The boundaries in most lesions were clear (64.1%), without the formation of false capsule. In contrast studies, homogeneous enhancement within the tumor was found in 26 cases (66.7%), while heterogeneous enhancement were seen in 13 cases (33.3%). Furthermore, heterogeneous enhancement with small cavity formation happened in 1 case.24 cases of pulmonary lesions showed signs of visceral pleura retraction and/or thickening, which suggested there might be pleural invasion (61.5%). In addition, vascular or bronchial encasement were found in 11 cases which indicated that there may be blood vessels and/or bronchial invasion (28.2%), but only 1 case had significant obstructive pneumonia (2.6%). (2) PET/CT features:there were no special or significant difference regarding PET/CT characteristics between primary lung LELC and other subtypes of NSCLC.11 cases of pulmonary LELC showed moderate to high 18F FDG uptake with a mean SUVmax value of 3.13±0.36, of which SUVmax value>3.0 was found in 9 cases while SUVmax<3.0 in 2 cases.3, Histological features included:for 39 cases of primary pulmonary lymphoepithelioma like carcinoma specimens, macrospcopically, most of the tumors were single round nodules with unclear borders, without capsule and yellow or gray in color. The texture of tumor was slightly soft and often with necrosis or bleeding. Microscopically, most tumors were of typical lymphoepithelioma like carcinoma which was similar with undifferentiated carcinoma of nasopharynx. Lung LELC cells were quite large in size with irregular shapes. Cancer cells were often aggregated in nests, and their cytoplasm were slightly pale staining. Nuclear volume ratio was high with clear nucleolus, and nuclear fission signs were very common. A large number of lymphocytes’ infiltration was found in tumor stroma. Focal squamous epithelial differentiation may occur which often arranged around the borders of cancer nests. However, the intercellular bridge and cytokeratin were generally absent. Occasionally, the cancer cells were distributed in a diffuse nature, but obvious cancer nests could be found in local area, which could be used as a sign to differentiate it from lymphoma. Lymphocytes and plasma cells infiltrated the tumor stoma, and the lymph follicles were occasionally seen. The interstitial fibrous tissue can be significantly proliferated and even result in collagenic change. The presence of giant cell reaction in the tumor stroma of some cases was in line with that of a tuberculous granuloma.4. Immunohistochemistry (IHC) features:the IHC factors with 100% positive expression in our study included p63 (34/34,100%, figure 5) and CK5/6 (23/23, 100%, Figure 6). And the IHC factors that showed more negative expression in our cohort include:CK7 (28/30 and 93.33%), CgA (28/31,90.32%), syn (29/30,96.67%) and TTF1 (30/36,83.33%). Positive expression of Ki-67 was identified in 9 cases, however, the degree of immunostaining were not the same, which means 3 specimens were stained in more than 75% of tumor cells,2 specimens were stained in only 20% of tumor cells, percentages of IHC staining in the remaining four specimens were 50%,40%,15% and 10% respectively.5, Epstein-Barr virus encoded small RNA (EBERs) were tested in 36 lung LELC specimens of our study by using in situ hybridization method. All specimens showed positive expression of EBERs. According to the different distributions of positive signals, there were 4 different types:inner nuclear membrane type, nucleolus-surrounding type, nuclear membrane and nucleolus-surrounding mixed type, and intranuclear diffusion type. In addition, all the other lymphoid interstitial tissue displayed negative expression of EBERs. Furthermore, a total of 19 primary lung LELC samples were tested for EGFR mutation by ARMS method, and the results showed that all the specimens were of EGFR wild-type. No EGFR mutations were found in our cohort.6, The 6-month,12-month,24-month and 36-month disease free survival (DFS) rates for 39 primary lung LELC patients who received surgical treatment were 92%, 82%,73% and 73% respectively. Kaplan-Meier univariate survival analysis showed that pathological stage (P=0.02) and lymph node metastasis (P=0.017) were prognostic factors. But further multivariate analysis confirmed only lymph node metastasis was an independent prognostic factor (P=0.049).CONCLUSION:Primary lung lymphoepithelioma like carcinoma is a rare and special subtype of non-small cell lung cancer. Lung LELC tends to involve younger patients and non-smokers, but its incidence seems to be not different between male and female patients. Molecular biology studies have found that there was a fairly close relationship between lung LELC and Epstein-Barr virus infection, however this special lung cancer does not involve in the epidermal growth factor receptor (EGFR) pathway. Surgery with curative intent could achieve a satisfactory outcome for early-stage lung LELC patients, and regional lymph node metastasis was the only independent prognostic factor in this setting. Because lung LELC is extremely rare in clinical practice, its detailed biological characteristics and more reasonable treatment strategy need to be further explored in the future. |
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