Diagnosis and treatment of pulmonary lymphoepithelioma-like carcinoma: A case report

Abstract

BACKGROUND

Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare primary epithelial lung cancer associated with the Epstein-Barr virus. Standard treatment guideline for PLELC is yet not to be established, surgery remains the primary treatment for early-stage PLELC, and platinum chemotherapy is the most common first-line treatment for advanced PLELC. While targeted therapy and immunotherapy has emerged as effective way to treat various malignant tumors, including lung cancer, reports on PLELC are relatively scarce.

CASE SUMMARY

A 38-year-old man was diagnosed with right PLELC. Chest computed tomography (CT) revealed a mass in the medial segment of the middle lobe of the right lung, with lymph node metastasis in the mediastinum and right hilum of the lung. CT-guided lung tumor biopsy was performed and the postoperative pathological examination combined with immune phenotype analysis and in situ hybridization confirmed PLELC. Standard molecular testing for patients with non-small cell lung cancer was negative and programmed cell death ligand-1 expression was about 2%. The patient declined radiotherapy and chemotherapy. Consequently, immunotherapy was administered, which included toripalimab 240 mg on day 1 and anlotinib 10 mg on days 1-14 for 10 cycles, followed by a maintenance dose of anlotinib 10 mg daily every 3 weeks. As a result, his progression-free survival reached 48 months.

CONCLUSION

A combination of toripalimab and anlotinib may benefit patients with advanced diseases who have not received systematic antitumor therapy.

Key Words: Pulmonary lymphoepithelioma-like carcinoma; Epstein-Barr virus; Anlotinib; Toripalimab; Case report

Core Tip: We report a case of a 38-year-old man who was diagnosed with right pulmonary lymphoepithelioma-like carcinoma (PLELC). Chest computed tomography (CT) revealed a mass in the medial segment of the middle lobe of the right lung, with lymph node metastasis in the mediastinum and right hilum of the lung. CT-guided lung tumor biopsy was performed and the postoperative pathological examination combined with immune phenotype analysis and in situ hybridization confirmed PLELC. Standard molecular testing for patients with non-small cell lung cancer was negative and programmed cell death ligand-1 expression was about 2%. However, the patient declined radiotherapy and chemotherapy treatment. Consequently, immunotherapy was administered, which included toripalimab 240 mg on day 1 and anlotinib 10 mg on days 1-14 for 10 cycles, followed by a maintenance dose of anlotinib 10 mg daily every 3 weeks. As a result, his progression-free survival reached 48 months. PLELC is a rare primary epithelial lung cancer. Currently, there is no standard treatment for PLELC. A combination of toripalimab and anlotinib may benefit patients with advanced diseases who have not received systematic anti-tumor therapy. However, its long-term efficacy requires further comprehensive research and validation.

INTRODUCTION

Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare primary epithelial lung cancer associated with the Epstein-Barr virus (EBV). Its incidence rate is less than 1% of non-small cell lung cancer (NSCLC)[1]. Bégin et al[2] first reported a case of malignant tumor originating from the lung and resembling lymphoepithelioma-like carcinoma in 1987, which was subsequently named PLELC. The diagnosis of PLELC presents significant challenges owing to its histological similarity to undifferentiated nasopharyngeal carcinoma (NPC) and its pathological resemblance to lung squamous cell carcinoma. However, PLELC has unique epidemiological, molecular and clinical features. No standardized treatment guidelines exist for PLELC and common driver genes in NSCLC rarely occur in PLELC[1]. Moreover, existing treatment methods are ineffective. Identifying new treatments is essential for enhancing the survival and prognosis of these patients. Surgery is the primary treatment for early-stage PLELC, and platinum chemotherapy is the most common first-line treatment for advanced PLELC[3]. Targeted therapy and immunotherapy are a new era of precision medicine in cancer treatment. Herein, we conducted a retrospective analysis of a patient with PLELC to explore its clinical characteristics, diagnosis and treatment methods.

CASE PRESENTATION

Chief complaints

A 38-year-old man presented with a complaint of a chronic recurrent dry cough over a month. He denied fever, sputum or blood production and chest pain. A chest computed tomography (CT) revealed pulmonary masses at an external hospital. The patient was admitted to the oncology department for further evaluation and treatment.

History of present illness

Complaint of a chronic recurrent dry cough over a month.

History of past illness

The patient had no history of hypertension, coronary heart disease, diabetes, cerebral venous thrombosis or hemorrhage, tuberculosis, chronic hepatitis B virus infection and other diseases.

Personal and family history

The patient had no family history of hereditary diseases.

Physical examination

Physical examinations revealed a temperature of 37.2 °C, a pulse rate of 118 beats/minute, a respiratory rate of 20 breaths/minute and a blood pressure reading of 106/69 mmHg. The patient was conscious, with clear respiration and pulmonary sounds; no dry or wet rales were detected. The abdomen appeared flat and soft, with no palpable mass detected. Renal and liver percussive pain were negative. No edema was observed in the lower extremities.

Laboratory examinations

Laboratory examinations were as follows: White blood cells: 7.97 × 10⁹/L (reference value: 4.0-10.0 × 10⁹/L), hemoglobin: 142 g/L (reference value: 115-150 g/L), platelets: 287 × 10⁹/L (reference value: 100-300 × 10⁹/L) and neutrophil percentage 46.7% (reference value: 40%-75%). Urinalysis, routine stool and coagulation function showed no significant abnormalities. Total prostate-specific antigen: 5.77 ng/mL (reference value: < 4 ng/mL), cytokeratin 19 fragment: 13.39 ng/mL (reference value: 0-3.3 ng/mL) and neuron-specific enolase: 17.5 μg/L (reference value: 0-16.3 μg/L). Thyroid function showed no significant abnormalities. Electrolytes, liver and kidney function, myocardial enzymes and inorganic ions were normal. Treponema pallidum-specific antibody, hepatitis B surface antigen, hepatitis C antibody, human immunodeficiency virus antibody and tuberculosis immunoglobulin (Ig) M and IgG antibodies were all negative. EBV antibody was weakly positive.

Immunological examination: Bronchoscopy examination showed chronic mucosa inflammation and focal alveolar epithelial hyperplasia, and a tendency towards atypical adenomatous hyperplasia. No cancer cells were found in the bronchoalveolar lavage fluid. CT-guided lung tumor biopsy was performed on March 23, 2020. The postoperative pathological examination combined with immune phenotype and in situ hybridization (ISH) confirmed PLELC. Immunohistochemistry results were as follows: Cytokeratin 5/6 (CK5/6) (+), Ki67 (+), P40 (+). ISH results were as follows: Epstein-Barr encoding region (EBER) (+) (Figure 1A). Standard molecular testing for patients with NSCLC was negative and programmed cell death ligand-1 (PD-L1) was about 2%.

Figure 1 Right pulmonary lymphoepithelioma-like carcinoma. A: Histopathology of the middle lobe of the right lung (hematoxylin and eosin staining; magnification × 200): Pulmonary lymphoepithelioma-like carcinoma, tumor cells are arranged in a nest-like pattern, accompanied by massive lymphocyte infiltration. Immunohistochemistry: Cytokeratin 5/6 (+), Ki67 (+), P40 (+); in situ hybridization: Epstein-Barr encoding region (+); B: A mass in the middle lobe of the right lung (approximately 1.6 cm × 1.7 cm); C and D: Lymph node metastasis in the mediastinum and right hilum of the lung (the largest lymph node, approximately 5.4 cm × 4.2 cm, was located in the right hilum). CK5/6: Cytokeratin 5/6; HE: Hematoxylin and eosin; EBER: Epstein-Barr encoding region.

Imaging examinations

Chest CT revealed a mass in the medial segment of the middle lobe of the right lung (approximately 1.6 cm × 1.7 cm), with lymph node metastasis in the mediastinum and right hilum of the lung (the largest lymph node, approximately 5.4 cm × 4.2 cm, was located in the right hilum) (Figure 1B-D). Notably, this condition affected the superior vena cava, right pulmonary artery and superior right pulmonary vein. The head magnetic resonance imaging (MRI) revealed a coronal ischemic lesion. Abdominal CT, nasopharyngeal MRI and bone emission CT (ECT) showed no abnormalities.

FINAL DIAGNOSIS

The patient was diagnosed with right PLELC (T1bN2M0 stage IIIA).

TREATMENT

The patient underwent wedge resection of the right middle lobe of the lung on March 31, 2020. The postoperative pathological examination demonstrated the diagnosis of PLELC. However, the patient and his family declined radiotherapy and chemotherapy treatment. Therefore, the immunotherapy regimen was initiated with full informed consent. The patient received a combination of toripalimab at a dosage of 240 mg on day 1 and anlotinib at a dosage of 10 mg on days 1-14 for two cycles, administered on April 30, 2020, and May 21, 2020, respectively, with no adverse reactions reported. Immunotherapy was discontinued after 10 cycles of toripalimab, while anlotinib at a dosage of 10 mg per day, administered every 3 weeks, has been used to sustain the treatment to the present day. The patient mainly experienced mild rash.

OUTCOME AND FOLLOW-UP

The patient has undergone 10 cycles of toripalimab at a dosage of 240 mg and anlotinib at a dosage of 10 mg daily, administered every 3 weeks as maintenance treatment, initiated after surgery and continuing to date. (Figure 2A-C). On April 9, 2022, a re-examination of the chest CT revealed no significant changes compared with postoperative imaging results. Soft tissue nodules were observed in the surgical area and enlarged lymph nodes in the mediastinum and right hilum of the lung. However, no nodules were found in the anterior segment of the right upper lobe. The therapeutic effect was evaluated as stable disease (SD) (Figure 2D). The follow-up examination between August 7, 2023 and October 8, 2024, showed no significant changes in the soft tissue shadows, pulmonary hilum and mediastinal lymph nodes in the surgical area compared with postoperative imaging results (Figure 2E and F). The therapeutic effect was also evaluated as SD. The patient has been disease-free for approximately 48 months.

Figure 2 Postoperative follow-up status of lymph node metastasis in the mediastinum and right hilum of the lung. A: Before surgical treatment; B: After 4 cycles of toripalimab treatment; C: After 10 cycles of toripalimab treatment; D-F: Follow-up imaging after surgery. The therapeutic effect was evaluated as stable disease.

DISCUSSION

PLELC is a subtype of NSCLC that frequently manifests in young, non-smoking individuals of Asian descent. PLELC is characterized by atypical clinical manifestations, including respiratory symptoms, such as cough with or without hemoptysis, chest pain and shortness of breath, weight loss, night sweats, fever, etc.[4]. The patient in this case only presented with recurrent cough symptoms, without obvious chest pain, shortness of breath, fever, night sweats or other associated symptoms. Chest serves as a foundational tool for the diagnosis of PLELC. Pulmonary CT typically reveals PLELC as nodular formations or masses, often appearing as isolated pulmonary nodules or masses near the pleura, measuring < 3.5 cm in diameter and usually not involving lymph nodes. Advanced-stage PLELC is frequently marked by the presence of peribronchial lymph node metastasis, as well as vascular wrapping and dilation[5]. The chest CT of this patient showed a solitary nodule in the middle lobe of the right lung with clear edges, with lymph node metastasis in the mediastinum and right hilum of the lung (the largest lymph node, measuring about 5.4 cm × 4.2 cm, was located in the right hilum). Notably, this condition affected the superior vena cava, right pulmonary artery and superior right pulmonary vein. Additionally, because it is challenging to differentiate PLELC from undifferentiated NPC in histopathology, diagnosing PLELC necessitates ruling out NPC lung metastasis. In this case, NPC was excluded through nasopharyngeal MRI and bone ECT. Importantly, pathological examination is the gold standard for diagnosing PLELC in clinical practice. The defining pathological characteristic of PLELC involves the infiltration of numerous lymphocytes and plasma cells within the stroma and among cancer cells, indicative of a reactive alteration in proliferative activity[6]. In PLELC immunohistochemistry, CK5/6, epithelial membrane antigen, tumor protein p63 and p40 are often positive, whereas CK7, thyroid transcription factor-1 and glycoprotein hormones, alpha polypeptide are lowly expressed. This is because PLELC originates from epithelial tissue rather than neuroendocrine or glandular epithelium, and the detection of EBV in tumor cell nuclei by EBER is crucial for diagnosis[7]. Our patient tested positive for CK5/6, p40 and Ki-67. Meanwhile, the ISH results also revealed EBV infection, thus confirming PLELC. The pathological diagnosis of squamous cell carcinoma in the present case was obtained through bronchoscopy, and the postoperative pathology was PLELC, which may be due to limited tissue sampling under bronchoscopy and difficulty in PLELC diagnosis.

PLELC is a rare condition that currently lacks established treatment guidelines. Surgical resection remains the primary treatment for patients with early-stage PLELC; however, there are currently no established recommendations for those with locally advanced and metastatic PLELC. In the next 5 years or even longer in the future, exploring the treatment of PLELC will be the focus and difficulty in this field. A comprehensive treatment regimen, encompassing both chemotherapy and radiotherapy, may be utilized as a multidisciplinary diagnostic and therapeutic approach. Immunotherapy has also been attempted in recent years. The typical driver genes associated with lung cancer are rare in PLELC, and most targeted therapy medications show minimal effectiveness in this condition. Although there are low levels of tumor mutations, the majority of PLELC cases exhibit expression of PD-L1[8]. While some have shown that PLELC patients exhibiting positive PD-L1 expression have longer progression-free survival and overall survival than those with negative expression[9], others have demonstrated that patients with high PD-L1 expression have shorter disease-free survival than those exhibiting low PD-L1 expression[10]. The relationship between PD-L expression and the prognosis of patients PLELC remains elusive. Monoclonal antibody therapy targeting programmed cell death 1 (PD-1) and PD-L1 represents a significant area of interest in PLELC. The patient was diagnosed with PLELC at pathologic stage IIIA, signifying a locally advanced stage. The patient underwent wedge resection of the right middle lobe of the lung but refused radiotherapy and chemotherapy. Therefore, we explored better proactive treatment options.

While immunotherapy has emerged as an effective way to treat various malignant tumors, including lung cancer, reports on PLELC are relatively scarce. Toripalimab is a unique PD-1 inhibitor with high affinity and selectivity. It effectively stimulates the patient’s immune system, strengthens anti-tumor responses, increases tumor cell destruction, and improves the tumor microenvironment[11]. However, PD-1 inhibitors alone have limited effectiveness and a low rate of objective remission; therefore, they are frequently combined with other medications. Anlotinib is a targeted therapy drug that can inhibit tumor angiogenesis, cut off the nutritional supply of tumors and inhibit tumor growth[12]. Standard molecular testing for patients with NSCLC was negative and PD-L1 was about 2%. Therefore, our patient received a combination of immunotherapy and targeted therapy, which included 240 mg of toripalimab on day 1 and 10 mg of anlotinib from days 1 to 14 for 10 cycles, followed by a maintenance treatment of 10 mg of anlotinib daily every 3 weeks. Currently, studies have shown that anlotinib reshapes the immune microenvironment by downregulating PD-L1 expression and increasing the cluster of differentiation 8/forkhead box P3 ratio. Anlotinib combined with PD-1 inhibitors can promote the infiltration of autoimmune cells, including natural killer cells, M1-like tumor-associated macrophages and dendritic cells, to combat tumors[9].

So far, the patient exhibits no recurrence or metastasis. The therapeutic effect was evaluated as SD. The patient has been disease-free for about 48 months. The observed results may arise from various factors: First, anlotinib can inhibit immune suppressive signals by lowering the expression of immune checkpoints. This action modifies the tumor microenvironment's immunosuppressive state, enhancing the effectiveness of toripalimab. Furthermore, toripalimab treatment can activate T cells, improving their ability to destroy tumor cells while also promoting vascular normalization. This process enhances drug delivery and minimizes the chances of adverse events. A combination of anlotinib and toripalimab can produce a synergistic effect, enhancing treatment outcomes.

In short, PLELC challenges doctors in terms of epidemiological characteristics, clinical diagnosis, pathological characteristics and treatment plans. Due to the similarity between PLELC and NPC, perhaps the treatment of NPC can provide new ideas for the future diagnosis and treatment direction of PLELC. For example, early screening of EBV-DNA can also be applied to PLELC. Immunotherapy shows obvious feasibility in advanced NSCLC and NPC, and most PLELCs have PD-L1 positive expression. Immunotherapy combined with or without chemotherapy may become the preferred first-line treatment for advanced PLELC. In addition, due to the low incidence of the disease and the limited number of available samples, there are some limitations in comparing the correlation between PD-L1 expression and treatment response and survival rate, and exploring the difference in efficacy between gene signaling pathways and tumor microenvironments. PLELC's global case reports are mostly presented in the form of case studies and small cohort studies. Large-scale clinical research and forward-looking real-world research are needed to provide the best treatment for PLELC.

CONCLUSION

A combination of toripalimab and anlotinib may benefit PLELC patients with advanced diseases who have not received systematic antitumor therapy. However, its long-term efficacy requires further comprehensive research and validation.