Challenging Tumor Heterogeneity with HER2, p16 and Somatostatin Receptor 2 Expression in a Case of EBV-Associated Lymphoepithelial Carcinoma of the Salivary Gland

Abstract

Background: Lymphoepithelial carcinoma of the salivary glands (LECSG) is a rare disease in the Western hemisphere that is typically associated with an EBV infection. The molecular mechanisms of LECSG tumorigenesis are poorly understood.

Results: Here we report a case of EBV-associated LECSG with an unusual immunophenotype. The tumor exhibited bi-morphic histological features with a mutually exclusive expression of HER2 and p16. The p16-positive domain of the tumor immunohistochemically co-expressed late membrane protein 1 (LMP-1), while the HER2 positive domain did not. Both tumor regions expressed SSTR2.

Methods: In situ hybridization confirmed the EBV origin of the tumor while extensive immunohistochemical characterization and the recently established RNA-based next generation sequencing panel ("SalvGlandDx" panel) did not reveal evidence for another salivary gland neoplasm. No HPV co-infection was detected by in situ hybridization or PCR-based screenings and no ERBB2 gene amplification was detected by fluorescence in situ hybridization.

Conclusion: These findings suggest tumor heterogeneity and lack of genomic aberrations in EBV-associated LECSGs. The heterogenous and unusual immunohistochemical features explain the diagnostic difficulties and simultaneously extend the immunophenotype spectrum of this tumor entity.

Keywords: EBV; HER2; Lymphoepithelial carcinoma; SSTR2; Salivary gland; p16.

Fig. 1

A solitary tumor mass in the parotid gland. A ¹⁸F-FDG-PET computer tomography scan showed no evidence of other tumor manifestations in the head and neck area. B A fine needle aspirate showed basaloid cells with high-grade atypia in the Papanicolaou stain, scale bar 20 μm. C A representative hematoxylin eosin stain of the lymphoepithelial carcinoma with bi-morphic histological features of the tumor, scale bar 500 μm. A higher magnification of the tumor area with broad sheets of syncytial tumor cells with only few intermingled lymphocytes in D and anastomosing tumor islands creating a jigsaw puzzle-like appearance with lymphoid infiltrates in E, scale bar 20 μm. Varying expression patterns of CK 5/6 expression within the two tumor regions (F) and (G), scale bar 20 μm. The broad sheets of syncytial tumor cells reveal strong nuclear expressions of p40 and p63 and scattered sparse p63 positive nuclei in the jigsaw puzzle-like area in H and J, scale bar 200 μm, inset 20 μm

Fig. 2

A bi-morphic tumor with SSTR2 and mutually exclusive p16 and HER2 expression. A In situ hybridization for EBER confirmed a ubiquitous presence of EBV in the tumor. B LMP-1 was immunohistochemically expressed only the in the p63 and p40- positive domain of the tumor. C This area revealed a strong and diffuse positivity for p16. D No presence of high-risk HPV viruses in this tumor area in the RNA in situ hybridization. E and F Wildtype expression pattern of p53 and Rb1. G The jigsaw puzzle-like domain of the tumor exhibited a moderate complete membranous HER2 expression. H No amplification of ERBB2 was detected in the fluorescence in situ hybridization, Scale bar 20 μm. I Intense membranous positivity SSTR2 in both tumor regions. Scale bar for ISH and IHC 200 μm, insets 20 μm