Clear Cell Squamous Cell Carcinoma of the Maxillary Gingiva Associated with PIK3CA and HRAS Mutations: Report of a Case and Literature Review

Abstract

Background: Squamous cell carcinoma (SCC) is the most common oral malignancy, and somatic mutations in some driver genes have been implicated in SCC development. Clear cell SCC (CCSCC) is a rare histological variant of SCC, and various clear cell neoplasms must be considered in the differential diagnosis of CCSCC in the oral cavity. Based on a limited number of CCSCC cases reported in the oral cavity, CCSCC is considered an aggressive variant of SCC with a poor prognosis; however, its genetic characteristics remain unknown.

Methods: A maxillary gingival tumor in an 89-year-old female was described and investigated using immunohistochemical staining, special staining, fluorescence in situ hybridization, and next-generation sequencing (NGS) with a custom panel of driver genes, including those associated with SCC and clear cell neoplasm development.

Results: Histopathological examination revealed a proliferation of atypical epithelial cells with abundant clear cytoplasm and enlarged and centrally placed round nuclei. The tumor was exophytic with deep, penetrating proliferation. The atypical clear cells were continuous with the conventional SCC cells. Immunohistochemical analysis showed that the clear cells were positive for CK AE1/AE3 and CK5/6 and nuclear-positive for p63. In contrast, the clear cells were negative for αSMA, S100, HMB45, Melan-A, CD10, and p16. p53 immunoreactivity exhibited a wild-type expression pattern. Additionally, the clear cells were positive for periodic acid-Schiff (PAS) and negative for diastase-PAS, mucicarmine, and Alcian blue. Based on these results, the diagnosis of CCSCC was confirmed. Molecular analysis of the clear cells identified PIK3CA p.E542K (c.1624G>A) and HRAS p.G12A (c.35 G>C) somatic mutations classified as oncogenic. No pathogenic variants were identified in TP53, EWSR1, AKT1, PTEN, BRAF, KRAS, NRAS, RASA1, or MAML2.

Conclusions: We report a case of CCSCC of the oral cavity with PIK3CA and HRAS mutations. The identification of PIK3CA and/or HRAS mutations is rare in SCC; however, both mutations are important potential targets for antitumor therapy. A detailed analysis of gene mutations in CCSCC may lead to a better understanding of its biological behavior and an improved prognosis, as well as a differential diagnosis from other clear cell neoplasms.

Keywords: Clear cell squamous cell carcinoma; HRAS; Oral tumor; PIK3CA; Squamous cell carcinoma.

Fig. 1

Clinical presentation. a Intraoral finding. Representative coronal computed tomography (CT) images with bone window (b) and with contrast-enhanced (c). The blue arrows indicate a large tumor extension (b). The red arrow indicates a bone penetration at the alveolar process of the right maxilla (c)

Fig. 2

Histological findings of the biopsy. The exophytic tumor mass showed a penetrating growth pattern, resulting in several deep crypts filled with keratin debris (b was the black dotted-box area in a). c The tumor cells featured abundant clear cytoplasm, especially from the parabasal cells to the surface epithelium. d Clear cells exhibited enlarged and centrally placed round nuclei and nuclear and cellular atypia. Arrowheads indicate mitotic figures

Fig. 3

Histological findings of the surgical specimen. a Gross view of the surgical specimen. b Region of clear cell squamous cell carcinoma (CCSCC). CCSCC infiltrated deep connective tissue (inset: cytology of CCSCC). c, d Transitional area between CCSCC (left side) and conventional squamous cell carcinoma (SCC) (right side). c shows the orange lined-box area in a. d shows the black dotted-box area in c. e, f Region of CCSCC or SCC in the transitional area (both from the black dotted-box area in d)

Fig. 4

Immunohistochemical and special stains. a CK AE1/AE3, b p63, c Ki-67, and d p53 immunostains. e Periodic acid-Schiff (PAS), f PAS with diastase, g mucicarmine, and h Alcian blue stains

Fig. 5

Molecular analysis. Direct gene sequencing shows chromatograms for PIK3CA p.E542K (c.1624G>A) (a) and HRAS p.G12A (c.35G>C) (b)