Background: Lymphoepithelioma-like carcinoma, an uncommon epithelial tumor, is mostly originated form the nasopharynx and also occurs in foregut-derived organs, such as lung, stomach, salivary gland, and thymus. Primary pulmonary lymphoepithelioma-like carcinoma (PPLELC) is a rare subtype accounting for around 0.9% of non-small cell lung cancer (NSCLC). We aimed to evaluate clinicopathological features, treatment modalities, and prognosis of PPLELC.
Methods: In the current study, a retrospective analysis on 8 patients diagnosed with PPLELC at Hunan Cancer Hospital between October 2013 and June 2016 was conducted with respect to their clinical characteristics and outcomes, in order to deeply investigate this rare subtype of lung cancer.
Results: In all 8 patients, 62.5% (5/8) were female, and the median age was 51.5 years (range 41 years-64 years). The majority (87.5%) were never smokers and 50.0% were asymptomatic at diagnosis. About 37.5% presented with stage I disease, 50.0% had stage III disease and 12.5% had stage IV disease. Histologically, the tumor morphology was indistinguishable from undifferentiated carcinoma of the nasopharynx and were characterized by poorly differentiated tumor cells with large vesicular nuclei and prominent nucleoli showing syncytial growth patterns and accompanied by heavy lymphocytic infiltration. The tumor cells were presented as positive for P63 (100.0%, 6/6), CK5/6 (100.0%, 5/5), CK (100.0%, 5/5). The expression of programmed cell death ligand 1 (PD-L1) in 8 patients was detected. When membranous staining was present in ≥5% of the cells, it was defined as PD-L1 positive. The PD-L1 expression frequency was 50.0% (4/8), and the tumor proportion score (TPS) fluctuated between 20.0% and 70.0%. Epidermal growth factor receptor(EGFR) mutations were detected in 3 cases and all tested samples were wild type; moreover, ALK rearrangement was negative in 2 patients with available data. KRAS, B-raf, C-kit, HER2, VEGFR1 and VEGFR2 were detected in 1 case. The results showed that KRAS was wild type, B-raf and C-kit mutation was negative, and HER2, VEGFR1 and VEGFR2 were moderately expressed. All patients underwent surgery with or without adjuvant therapy. Among these patients, 5 patients received adjuvant chemotherapy, including 2 patients with stage Ib disease, 2 patients with stage IIIa disease and 1 patient with stage IV disease. 1 patient with stage IIIa disease received adjuvant chemotherapy and radiotherapy and 1 patient with stage IIIa disease received neoadjuvant chemotherapy. All patients survived until the deadline for follow-up. The median survival time of all LELC patients is 57 months. The 3- and 5-year overall survival (OS) rates of LELC patients were 87.5% and 50.0%, disease-free survival (DFS) rates were 87.5% and 50.0%, respectively.
Conclusions: PPLELC is uncommon but distinct subtype of NSCLC with unique clinicopathologic characteristics that tends to affect young nonsmoking patients, without significant predilection for sex and with strong association with Epstein-Barr virus (EBV) infection. Histology and immunohistochemistry are the main diagnostic methods. Rare or no driver gene mutations were found in the common oncogenes such as EGFR mutations and ALK gene rearrangement, implying that the mutagenesis of these genes was not involved in the tumorigenesis of PPLELC. PD-1 and PD-L1 may be potential therapeutic targets for PPLELC. The patients are diagnosed at an earlier stage and have a better prognosis than those with other non-small cell lung cancer. No standardized treatment regimens currently exist for this rare tumor. 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. Due to its low incidence, further research is needed to determine its biological characteristics and optimal treatment options.
【中文题目：原发性肺淋巴上皮瘤样癌8例临床分析】 【中文摘要：背景与目的 淋巴上皮瘤样癌为罕见的上皮肿瘤，多来源于鼻咽部，也发生在前肠起源器官，如肺、胃、唾液腺和胸腺。原发性肺淋巴上皮瘤样癌（primary pulmonary lymphoepithelioma-like carcinoma, PPLELC）是一种罕见的非小细胞肺癌（non-small cell lung cancer, NSCLC），约占肺癌的0.9%。本文目的在于探讨PPLELC的临床病理特点、治疗方法以及预后情况。方法 回顾性分析湖南省肿瘤医院2013年10月-2016年6月收治的PPLELC患者8例，对其临床资料及预后进行临床分析，以深入研究这种罕见的肺癌亚型。结果 8例患者中，62.5%（5/8）为女性，中位年龄为51.5岁（41岁-64岁），大多数（87.5%）患者不吸烟，50.0%患者无症状，约37.5%为I期，50.0%为III期，12.5%为IV期。PPLELC的典型病理特征与未分化的鼻咽癌相同，其特点是分化较差的肿瘤细胞，具有大的泡状核和核仁突出，呈合胞体生长，伴有淋巴细胞浸润。免疫表型：癌细胞P63（100.0%, 6/6）、CK5/6（100.0%, 5/5）、CK（100.0%, 5/5）阳性。对8例患者的程序性死亡配体-1（programmed cell death-ligand 1, PD-L1）表达进行了检测，当≥5%的细胞膜染色时定义为PD-L1阳性，PD-L1表达频率为50.0%（4/8），肿瘤细胞阳性比例分数（tumor proportion score, TPS）波动在20.0%-70.0%。3例行表皮生长因子受体（epidermal growth factor receptor, EGFR）基因突变检测，结果呈阴性；2例行EML4-ALK融合基因检测，结果呈阴性；1例行KRAS、B-raf、C-kit、HER2、VEGFR1、VEGFR2检测，结果示KRAS野生型，B-raf、C-kit无突变，HER2、VEGFR1、VEGFR2中等表达。所有患者均接受了手术治疗，其中接受了辅助化疗者5例，其中Ib期2例，IIIa期2例，IV期1例；辅助放化疗者1例，分期为IIIa期，接受了新辅助化疗者1例，分期为IIIa期。截止至随访截止期，所有患者均存活，中位存活时间为57个月，3年和5年总生存率（overall survival, OS）分别为87.5%和50.0%；无病生存率（disease-free survival, DFS）分别为87.5%和50.0%。结论 PPLELC是一种罕见但独特的NSCLC亚型，具有明显的临床病理学特征，通常发生于年轻的非吸烟患者，无性别倾向，并与EB病毒（Epstein-Barr virus, EBV）感染有关，组织形态及免疫组化是诊断的主要手段。大多数患者缺乏EGFR和ALK等常见基因突变，提示这些基因的突变与PPLELC的发生无关。PD-1和PD-L1可能是潜在的治疗靶点。与其他类型的NSCLC相比，大多数患者处于早期或局部晚期，预后较好。目前还没有针对这种罕见肿瘤的标准化治疗方案。早期以手术切除为主，中晚期或转移阶段则采用手术、化疗、放疗等多种治疗方式。由于其发病率低，为了确定其生物学特性和最佳治疗方案，还需要进一步的研究。】 【中文关键词：淋巴上皮瘤样癌；肺肿瘤；临床病理；预后】.
Keywords: Clinicopathological features; Lung neoplasms; Lymphoepithelioma-like carcinoma; Prognosis.