Case report: pulmonary lymphoepithelial carcinoma mimicking tuberculosis

Abstract

Pulmonary lymphoepithelial carcinoma (PLELC) is distinct subtype of primary lung cancer, closely associated with Epstein-Barr virus (EBV) infection. Histopathological features sometimes mimic granulomatous inflammation. We present the case of a woman who was doubted with pulmonary and lymph node tuberculosis based on a pathological demonstration of granulomatous inflammation. A final diagnosis of PLELC was made after lung biopsy and EBV tests. Given the complex and rarely seen of the disease, further studies are needed to investigate the clinical and pathological manifestations in patients with PLELC.

Clinical trial number: Not applicable.

Introduction

Pulmonary lymphoepithelial carcinoma (PLELC) is a rare and distinct subtype of primary lung cancer, accounting for less than 1% of all lung malignancies [1, 2] PLELC is histologically characterized by undifferentiated carcinoma with prominent lymphocytic infiltration, resembling nasopharyngeal carcinoma (NPC) in its morphological and molecular features. Unlike other non-small cell lung cancers, PLELC exhibits a strong etiological association with Epstein-Barr virus (EBV) infection, particularly in Asian populations, suggesting a unique oncogenic pathway driven by viral oncoproteins such as latent membrane protein 1 (LMP1) and EBV-encoded small RNAs (EBERs) [3].

Despite advances in molecular profiling of lung cancers, the clinicopathological understanding of PLELC remains limited due to its rarity and overlapping features with other lymphoepithelial lesions and granuloma. Current diagnostic criteria rely heavily on immunohistochemical staining for cytokeratins and in situ hybridization for EBERs to confirm EBV association [4]. However, challenges persist in differentiating PLELC from other infectious and malignant diseases, underscoring the need for standardized diagnostic procedure.

Here, we report a case of PLELC in a woman who was firstly doubted with tuberculosis. She presented with painless cervical lymphadenopathy and biopsy demonstrated granuloma. PLELC was confirmed after percutaneous lung biopsy and EBV test. Her lung lesions and cervical lymphadenopathy improved after receiving chemotherapy and checkpoint inhibitor. We hope to provide a reference for diagnosis and treatment for this rarely seen disease, particularly for patients with pathological manifestations of granulomas.

Case description

A 37-year-old woman was transferred to our hospital for doubting tuberculosis. She reported intermittent cough and slight chest discomfort for 3 months and painless cervical mass for 1month. She underwent a left cervical lymph node puncture at another hospital one week ago. The pathological tissue showed granulomatous inflammation, with caseous necrosis and Langhans’ giant cells observed. She had no fever, chills, or night sweats. Medical history was untreated congenital heart disease (patent ductus arteriosus) for 20 years and hypertension for half a year, with irregular use of valsartan for blood pressure control. She had no smoking, drinking alcohol and had no history of lung disease. She had no travel history or drug abuse before her illness.

On admission, body examination found a mass measuring approximately 4*3 cm on the left clavicle, which was well-defined, poorly mobile, non-tender, and without surface ulceration or redness. Physical examination of the lungs was unremarkable. A continuous murmur was auscultated at the left sternal border.

Laboratory tests of blood carcinoembryonic antigen (CEA), squamous cell carcinoma antigen, cytokeratin 19 fragment and neuron-specific enolase (NSE) were all normal. Blood routine test, liver and kidney function, electrolytes, procalcitonin (PCT), C-reactive protein (CRP) and T-lymphocyte subsets were all normal. Sputum for acid-fast bacilli (AFB) and GeneXpert MTB/RIF were negative, Blood test of EB virus showed increased antibody title of capsid antigen IgG antibody 750U/mL (Reference:0–20 U/mL), EB virus early antigen IgM antibody 2.57 COI (Cut off index reference:0-1.1) and EB virus core antigen IgG antibody 600U/mL(Reference:0–20 U/mL).

Repeated ultrasound-guided left supraclavicular lymph node puncture was performed. Histopathology showed focal distribution of epithelioid cells and a few multinucleated giant cells, which suggested granulomatous inflammation (Fig. 1). Staining of Acid-fast and methenamine silver were all negative. Lymph node tissue for GeneXpert MTB/RIF and TB culture were all negative.

Fig. 1

Biopsy of left neck lymph node showed granulomatous inflammation. (200×)

Enhanced CT scan showed mass in the middle lobe of the right lung and multiple enlarged lymph nodes in left neck, mediastinum and right hilum (Fig. 2). Given the insufficient support of tuberculosis, percutaneous lung biopsy was performed. EBV-positive poorly differentiated carcinoma which consistent with lymphoepithelioma was demonstrated by lung biopsy (Fig. 3). Further nasopharyngoscopy excluded nasopharyngeal carcinoma. The diagnosis of PLELC was confirmed. She was transferred to the oncology department, where she received chemotherapy and immunotherapy with carboplatin and paclitaxel in combination with tislelizumab. Repeated CT 1.5 months later showed significant reduction of lung lesions and cervical enlarged lymph nodes (Fig. 4).

Fig. 2

Chest CT scan showed mass(34 × 43 mm) in the middle lobe of the right lung (A, D; blue arrows) and multiple enlarged lymph nodes in mediastinum (B, C; red arrows)

Fig. 3

(A) Lung biopsy shows lymphoepithelial carcinoma. The tumor cells are densely nestled, the tumor cells have a blurred boundary, large alveoli, eosinophilic nuclei, and the mesenchymal is accompanied by lymphocyte infiltration. (HE staining, 400×)). (B) Immunohistochemical staining shows CK positive in tumor cells (200×). (C) Immunohistochemical staining showed P40 positive in tumor cells (200×). (D) In situ hybridization showed EBER positive in tumor cells (200×)

Fig. 4

Chest CT scan showed a significant improvement of the lung mass(26 × 17 mm)and reduced lymph nodes after chemotherapy and immunotherapy

Discussion

The present case highlights the diagnostic complexity of PLELC, particularly when clinical and histopathological features mimic infectious etiologies such as tuberculosis (TB). Granulomatous inflammation, as observed in the cervical lymph node biopsy of our patient, is an atypical but previously reported feature in PLELC [5]. This overlap may lead to delayed diagnosis of PLELC, as TB remains a primary consideration in regions with high endemicity. Notably, the absence of caseating granulomas and evidence of TB in our case prompted further investigation, underscoring the importance of integrating molecular testing (e.g., EBV-encoded RNA in situ hybridization, EBER-ISH) with histopathological evaluation to resolve diagnostic ambiguity [6, 7]. Similar challenges have been documented in other studies, where PLELC was initially misdiagnosed as sarcoidosis or fungal infections due to granulomatous reactions [8].

The definitive diagnosis of PLELC in this case relied on percutaneous lung biopsy and confirmation of EBV association, aligning with the World Health Organization (WHO) classification criteria for lymphoepithelial carcinoma [1]. EBV’s oncogenic role in PLELC is well-established, with viral proteins such as LMP1 activating NF-κB and JAK/STAT pathways to promote tumor immune evasion and proliferation [9,10,11]. Our patient’s EBV seropositivity and viral load in tumor tissue correlate with studies emphasizing EBV-driven immune dysregulation as a hallmark of PLELC pathogenesis [12]. However, the coexistence of granulomatous inflammation and EBV-positive carcinoma remains poorly understood. Recent evidence suggests that EBV may modulate host immune responses to induce granuloma formation [8], potentially explaining the histopathological mimicry of TB.

The favorable response to platinum-based chemotherapy in this patient aligns with previous reports describing PLELC’s chemosensitivity, despite the lack of standardized treatment guidelines [12]. The regression of both pulmonary lesions and cervical lymphadenopathy suggests systemic efficacy, possibly mediated by chemotherapy-induced apoptosis of EBV-infected tumor cells and suppression of pro-inflammatory cytokines [13]. The role of checkpoint inhibitors as immunotherapy for PLELC have been explored as 63.3–75.8% of the PLELC showed PD-L1 positivity in tumor cells [14, 15]. While our case supports chemotherapy and immunotherapy as a first-line option, long-term follow-up is critical to assess recurrence risk, particularly in EBV-positive malignancies known for latent viral reactivation [16].

Conclusions

In conclusion, we underscore the diagnostic challenge of pulmonary lymphoepithelial carcinoma (PLELC), particularly when presenting with granulomatous inflammation mimicking tuberculosis. As a rare subtype of lung cancer which highly associated with EBV infection, integrating EBV testing into the pathological evaluation of atypical lesions is necessary to avoid delays in diagnosis and oncological management.