Neoadjuvant immunochemotherapy—a promising strategy for primary pulmonary lymphoepithelioma-like carcinoma

Abstract

Objective

Neoadjuvant immunochemotherapy has been a promising choice for patients with locally advanced non-small cell cancer (NSCLC). However, whether neoadjuvant immunochemotherapy impacted the subsequent surgical or pathological outcomes of patients with pulmonary lymphoepithelioma-like carcinoma (PLELC) remains relatively unknown. This study aimed to evaluate the safety and efficacy of neoadjuvant immunochemotherapy in PLELC patients.

Methods

A retrospective study was conducted on patients who received neoadjuvant immunochemotherapy in combination with chemotherapy followed by surgery between 2019 and 2022. The clinical records of the patients were analyzed.

Results

Among the 31 patients with PLELC who underwent neoadjuvant immunochemotherapy followed by surgery, 18 patients (58.0%) experienced tumor downstaging. Nineteen patients (61.5%) achieved a partial response, 2 patients (6.4%) achieved a complete response, and 2 (6.4%) exhibited progressive disease. Pathological evaluation of resected specimens revealed that 8 (25.8%) patients achieved major pathological response (MPR), and 2 (6.4%) pathological complete response (PCR). The mean disease-free survival (DFS) was 17.4 months, which was not significantly different from the value in lung squamous cell carcinoma (LSQ) patients (15.1 months, P = 0.54)).

Conclusion

Neoadjuvant immunochemotherapy is a safe and effective approach to reduce the extent of tumor, render unresectable to resectable, and offer an opportunity to receive modified surgery, which may be a promising strategy for patients with PLELC.

Introduction

Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare and distinct subtype of lung cancer, accounting for less than 1% of all lung neoplasms [1]. First reported by Begin and colleagues in 1987, PLELC was found to be an epithelial neoplasm associated with Epstein‒Barr virus (EBV) infection [2]. In 2015, the World Health Organization (WHO) classified PLELC as a non-small-cell lung cancer (NSCLC) [3], and in 2021, it was reclassified as a subtype of lung squamous cell carcinoma (LSQ) according to the latest WHO Classification of lung tumors [4].

Currently, there is no standard treatment for PLELC, surgical resection remains the cornerstone therapy. However, most patients with PLELC present with non-specific symptoms, resulting in diagnostic delays and detection at an unresectable stage.

Immune checkpoint inhibitors has been established as the first-line therapy for locally advanced NSCLC. Numerous clinical trials [5,6,7] have demonstrated the effectiveness of neoadjuvant immunotherapy, including reducing the extent of tumor, eliminating micrometastases and contributing to survival outcomes. Besides, the trial [5] have also shown that neoadjuvant immunochemotherapy leads to superior outcomes in NSCLC, particularly in LSQ, which exhibits a better tumor response than other subtypes. Given the histologic and genetic similarity between pulmonary lymphoepithelioma-like carcinoma (PLELC) and LSQ, it is plausible that programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors could be another promising therapeutic option against this rare tumor. Additionally, evidence suggests (8–9) that PLELC has a higher proportion of PD-L1 positive tumor cells than lung adenocarcinoma or LSQ, which may provides a possible justification for immunotherapy. Recent studies [10,11,12] also highlighted the potential benefits of immunotherapy in advanced PLELC, demonstrating a significant improvement in progression-free survival (PFS) outcomes.

Notwithstanding, clinical trials of anti-PD-1/PD-L1 therapy in NSCLC have rarely enrolled patients with PLELC due to its rarity, which means that the potential for using neoadjuvant immunotherapy to make initially inoperable advanced PLELC operable and improve long-term survival remains relatively unknown.

Herein, we aimed to evaluate the safety and efficacy of neoadjuvant immunochemotherapy in PLELC. In addition, the clinical outcomes of PLELC and LSQ were compared to enhance our understanding of this uncommon malignancy.

Method

During the study period, from July 2019 to January 2022, data from patients with PLELC and LSQ who underwent neoadjuvant immunotherapy followed by surgery were retrieved. Demographics, surgical and perioperative details, and survival outcomes were respectively analyzed. Follow-up information was obtained from medical records and direct patient contact.

Preoperative workup

All patients received standard diagnosis and staging procedures. Computed tomography (CT) scans and/or positron emission tomography (PET) were routinely performed to evaluate primary tumors. For any suspicion of metastatic lymph nodes by chest CT or PET/CT, invasive modalities such as endobronchial ultrasound was subsequently performed for pathological confirmation of N stage in these cases. Metastatic disease was assessed with brain magnetic resonance imaging and positron emission tomography. Specimens for histological characterization were collected via bronchoscopy or subcutaneous needle biopsy before treatment. Genetic testing was conducted for all patients, confirming the absence of driver mutations, such as EGFR and ALK.

Neoadjuvant treatment and response evaluation

Treatment plans were established collaboratively through multidisciplinary team discussions (MDTs), with informed consent obtained from all patients. Preoperative and postoperative staging were evaluated according to the 8th American Joint Committee on Cancer (AJCC) lung cancer manuals on the tumor–node–metastasis (TNM) staging system [13]. Responses were evaluated by specialists according to the Response Evaluation Criteria In Solid Tumors (RECIST) [14].

Follow-up policy

Postoperative assessment was performed using routine CT on day 7 or just before discharge. According to follow-up protocols, outpatient CT scans were scheduled at 1, 3, 6, and 12 months after surgery, with biannual scans thereafter for up to 5 years. Any signs or symptoms suggestive of recurrence prompted further examinations.

Statistical analysis

Categorical variables were summarized as frequencies and percentages, while continuous variables were presented as medians with interquartile ranges. The date of surgical resection was set as the starting point, with death, recurrence, progression, or last follow-up as the endpoint for calculating disease-free survival (DFS). DFS was analyzed using the Kaplan–Meier method and compared with the log-rank test [15]. Multivariable regression analysis was conducted between the two groups. Statistical analysis was performed using R version 4.3.1 (https://www.r-project.org/) and SPSS version 27.0 (IBM Corp., New York, NY, USA). P value of < 0.05 was considered statistically significant.

Results

Patient characteristics

We analyzed patient data that met the eligibility criteria for receiving neoadjuvant immunotherapy followed by surgery. The study included 31 patients, predominantly female (n = 19, 61.3%), with a mean age of 56.8 years. All patients were at stage II-III, with 19 cases (64.5%) classified as N2 disease. The majority of patients (n = 28, 90.3%) underwent 2–4 cycles of preoperative immunochemotherapy. In all cases, surgery was performed, resulting in R0 resection. The mean tumor diameter prior to immunochemotherapy was 5.9 cm (range, 2.7 to 11.9 cm). Table 1 summarizes the detailed baseline characteristics of the patients.

Table 1 Clinical demographics of patients who received neoadjuvant therapy followed by surgery

Preoperative outcomes

Among the 31 patients who underwent neoadjuvant immunochemotherapy followed by surgery, 26 (83.8%) underwent lobectomy, 4 (12.9%) underwent sleeve lobectomy, and 1 (3.2%) received lung autotransplantation. In total, 30 (96.8%) received video-assisted thoracic surgery (VATS). Due to dense adhesions and pulmonary artery hemorrhage, 2 patients converted to thoracotomy. The mean operating time was 199.7 min (range, 105 min to 595 min). The mean intraoperative bleeding volume was 44.8 mL (range, 10 ml to 200 mL). Patients had an average postoperative hospital stay of 5.5 days (range, 2 days to 10 days). Seven patients (22.6%) experienced pneumonia. No serious postoperative complication was observed. No 30-day or 90-day death was occurred. (Table 2).

Table 2 Surgical, radiological, and pathological outcomes of patients who received neoadjuvant immunochemotherapy followed by surgery. Radiological outcomes: ORR = Overall Response Rate, CR = Complete Response, PR = Partial Response, SD = Stable Disease, PD = Progressive Disease. Pathological outcomes: MPR = Major Pathological Response, PCR = Pathological Complete Response

Treatment response

Radiographic response evaluation based on the RECIST [14] criteria was available for all patients. After neoadjuvant treatment, 2 (6.4%) achieved a complete response (CR), 19 (61.5%) patients achieved a partial response (PR), and 2 (6.4%) exhibited progressive disease (PD), corresponding to an overall response rate (ORR) of 72.4% (n = 21). One case was not feasible to evaluate the response of the target lesions radiologically due to pneumonia and dense lung consolidation. Seven patients achieved stable disease (SD), which resulted in a disease control rate (DCR) of 90.3% (n = 28). (Fig. 1)

Fig. 1

Clinical stage of patients before and after neoadjuvant immunochemotherapy

Postoperative pathological evaluation revealed 8 (25.8%) patients achieved major pathological response (MPR), and 2 (6.4%) achieved pathological complete response (PCR). Lymph node metastases was confirmed in 11 (35.5%) patients. (Table 2) Of the 31 patients, 12 (38.7%) underwent next-generation sequencing after surgery, with only 1 patient identified as having an NSD1 mutation.

The media follow-up time was 16 months (range, 3 months to 40 months). All patients received adjuvant treatment. Thirty patients remaining alive during the follow-up period. No tumor-related deaths were observed, only 1 patient died from COVID-19. The mean disease-free survival (DFS) was 17.4 months. And the 1-year disease-free survival (DFS) rate was 96.8%. Recurrence was documented in 4 patients. (Figure. 2).

Fig. 2

Kaplan–Meier curve for DFS of patients with PLELC. (DFS = Disease-free survival)

The multivariable regression analysis, which adjusted for confounders such as tumor size and stage, showed that tumor type significantly impacted pathological outcomes after neoadjuvant immunochemotherapy. The pathological regression was better in LSQ than PLELC, with a slightly higher proportion of LSQ patients achieving PCR and MPR (p < 0.01). There was no significant difference in DFS between LSQ and PLELC (p = 0.54). (Table 3)

Table 3 Multivariable regression analysis was performed to adjust for confounders, including tumor size and stage, between PLELC and LSQ

Discussion

The preoperative diagnosis of PLELC presents a significant clinical challenge due to its morphological overlap with other NSCLC subtypes. The rarity of PLELC further complicates this issue, as pathologists may encounter fewer cases in their practice, leading to a lack of familiarity with its subtle cytological features. Additionally, the inflammatory background often present in PLELC can mimic other more common conditions, potentially leading to misdiagnosis. Histopathological examination remains the gold standard, with specimens in our study obtained via bronchoscopy or needle biopsy to ensure diagnostic accuracy.

PLELC is a rare malignancy with limited treatment options demonstrated to improve patient outcomes. Surgical resection is generally recommended for PLELC. However, due to the growth of the tumor, systemic chemotherapy and radiotherapy remain the main treatment focus for patients with locally advanced PLELC [16]. The effectiveness of neoadjuvant immunochemotherapy in treating PLELC remains uncertain. This retrospective study aimed to evaluate the efficacy and safety of neoadjuvant immunochemotherapy in patients with PLELC .

Checkmate-816 trial [5] confirmed that neoadjuvant immunochemotherapy contributed to NSCLC both pathological and survival outcomes with considerable toxic side effects. Besides, the trial showed that patients with locally advanced stages might also experience benefit from neoadjuvant immunochemotherapy. Deng and coworker [17] indicated that the addition of radical surgery after immunochemotherapy in initially unresectable stage IIIB NSCLC was favorably associated with longer DFS/PFS (27.5 months vs. 16.7 months) compared to those without. In our study, total 19 patients achieved PR based on RECIST criteria, including 8 patients with stage IIIB disease that was converted from unresectable to resectable. No severe adverse events occurred during treatment.

The safety and feasibility of neoadjuvant immunochemotherapy followed by surgery had been well confirmed [18,19,20]. Besides, neoadjuvant immunochemotherapy offers an opportunity for patients with compromised lung function to receive modified surgical interventions. In our study, VATS was attempted in 30 patients, only 2 patients converted to thoracotomy. Five patients safely underwent modified surgical procedure to avoid pneumonectomy, including lung autotransplantation (n = 1) and sleeve lobectomy (n = 4), with organ preservation. Seven patients (22.6%) experienced immune-related pneumonitis. No 30-day or 90-day death was occurred.

Previous studies [5, 9] showed that several factors may associated with better outcomes to neoadjuvant immunochemotherapy, including type of NSCLC and PD-L1 expression. Patients with LSQ and/or high PD-L1 expression may achieved better response to immunochemotherapy. Jiang and colleges [8] showed that PLELC has a higher expression of PD-L1 than other NSCLC subtypes. Furthermore, the association of PLELC with EBV infection may contribute to its sensitivity to immunotherapy [2], which may render PLELC responsive to neoadjuvant immunochemotherapy. In our study, 25,8% (n = 8) of patients achieved MPR and 6.4% (n = 2) with PCR. During the follow-up period, the mean DFS was 17.4 months. And the 1-year DFS rate was 96.8%. Only 4 patients experienced recurrence, including 2 distant and 2 local recurrence. Although, LSQ showed higher response rate than PLELC (p < 0.01), no statistically significant difference was detected between these cancer types in terms of DFS (p = 0.54). These findings provide support for the idea that neoadjuvant immunochemotherapy may be a promising option for PLELC.

Despite being one of the large series on neoadjuvant immunochemotherapy followed by surgery, this retrospective study is not without limitations. First, it is subject to potential selection bias, and its sample size is small, which may compromise the statistical power of the analysis. Furthermore, this study lacked long-term outcomes and the exploration of potential biomarkers, which may have provided a more comprehensive understanding of the treatment’s efficacy. Further research is needed in prospective observational studies to confirm these findings and strengthen our understanding of the unique immunobiology driving PLELC.

Conclusion

Neoadjuvant immunochemotherapy is safe and effective approach for patients with locally advanced PLELC, shrinking the primary lesion, rendering unresectable to resectable, and contributing to survival outcomes. Neoadjuvant immunochemotherapy may be a promising strategy for patients with PLELC.