Pulmonary Pathology Society

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May, 2025
Case of the Month

Clinical History:

A middle-aged man of Asian descent had an incidental pulmonary nodule progress to a 3 cm solid well-circumscribed mass on follow-up. Investigations for infectious etiologies were negative. There was no history of smoking, no other lesions identified in imaging, and no other significant history.

The patient underwent lobectomy, and gross examination showed a solid round well-circumscribed mass. The figures show low and high power H&E morphology of the tumor (Figure 1 and 2 respectively), and p40 (Figure 3), TTF1 SPT24 (Figure 4) and TTF1 8G7G3/1 (Figure 5) immunohistochemistry. In situ hybridization for EBER is shown in Figure 6.

Q1. Which of the following correctly describes EBV association of pulmonary lymphoepithelial carcinoma:

Common in Asian patients, but rare in patients of European descent
Common in patients of Asian and European descent
Rare in patients of Asian and European descent
Rare in Asian patients, but common in patients of European descent

Q2. Which of the following driver mutations is common in lymphoepithelial carcinoma

EGFR
KRAS
TP53
None of the above

Q3. Which of the following clinical features is more characteristic of patients with lymphoepithelial carcinoma than those with other pulmonary squamous cell carcinomas:

Age >70 years
Never smoking
Caucasian ethnicity
Prior radiation treatment

Answers to Quiz

Q1. A
Q2. D
Q3. B

Diagnosis

Pulmonary lymphoepithelial carcinoma

Discussion

Lymphoepithelial carcinoma is characterized by syncytial growth of carcinoma cells with lymphoplasmacytic infiltrates, although in rare cases the lymphoplasmacytic infiltration is minimal. Focal keratinization has also been reported, and rarely amyloid deposition within the tumor has been seen. The epithelial cells have abundant eosinophilic cytoplasmic and often prominent nucleoli. The tumor borders are often pushing, in keeping with the typical gross morphology of an ovoid or round well-circumscribed nodule. Lymphoepithelial carcinoma can also present as a cavitary nodule.

On immunohistochemistry the carcinoma cells are typically diffusely positive for pancytokeratins and markers of squamous carcinoma including p40. The infiltrating lymphocytes are a mixture of T-cells and B-cells. TTF1 immunohistochemistry is typically negative in lymphoepithelial carcinoma, though focal staining with some antibody clones may be seen. The SPT24 TTF1 antibody clone is generally regarded as less specific for pulmonary adenocarcinoma than the 8G7G3/1 clone, and showed focal areas of moderate staining in the presented case.

Over 90% of lymphoepithelial carcinomas in Asian patients are EBV associated, whereas the proportion associated with EBV is much lower among patients of European descent. Driver mutations in EGFR, KRAS and TP53 typically do not occur in lymphoepithelial carcinoma.

Correlation with clinical and imaging work-up to exclude the possibility of a metastasis, such as from a nasopharyngeal carcinoma, is recommended. NUT carcinoma may be considered in the differential diagnosis but typically has more prominent infiltrating neutrophils. The strong cytokeratin immunoreactivity excludes the possibility of non-Hodgkin lymphoma.

Unlike other pulmonary squamous cell carcinomas, lymphoepithelial carcinoma predominantly affects patients who have never smoked, with a median age of approximately 51 years.

Prognosis for lymphoepithelial carcinoma tends to be more favorable than for conventional non-small cell lung carcinoma.

Take home message for trainees:

Consider performing EBER in situ hybridization in the diagnostic work-up of a p40-positive carcinoma in an Asian patient who has never smoked.

References

Chou T-Y, Wong MP, Chang Y-L. Lymphoepithelial carcinoma of the lung. In: WHO Classification of Tumours Editorial Board. Thoracic tumours. Lyon (France): International Agency for Research on Cancer; 2021. (WHO classification of tumours series, 5th ed.; vol. 5). https://publications.iarc.fr/595.

Hsieh M-S, Wu CT, Chang Y-L. Unusual presentation of lymphoepithelioma-like carcinoma of lung as a thin-walled cavity. Ann Thorac Surg 2013;96:1857–1859.

Sathirareuangchai S, Hirata K. Pulmonary lymphoepithelioma-like carcinoma. Arch Pathol Lab Med. 2019;143:1027–1030.

Vidarsdottir H, Tran L, Nodin B, et al. Comparison of three different TTF-1 clones in resected primary lung cancer and epithelial pulmonary metastases. Am J Clin Pathol. 2018;150:533–544.

Yoon J-Y, Pal P, Ko HM. Primary pulmonary lymphoepithelioma-like carcinoma: A potential source of misdiagnosis on radial probe endobronchial ultrasound-guided transbronchial aspiration cytology. Cytopathol Off J Br Soc Clin Cytol. 2019;30:653–656.

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