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.

Squamous cell carcinoma initially occurring on the tongue dorsum: a case series report with molecular analysis

“…Genetic mutations were evaluated in all cases using NGS with a custom panel, as previously described [ 32 ]. NGS identified a TP53 p.C176F (c.527G > T) somatic mutation classified as pathogenic in case 3 and a TP53 p.R282W (c.844 C > T) somatic mutation classified as pathogenic in case 4 (Table 1 ).…”

“…To examine mutational status, we performed next-generation sequencing (NGS) with a custom panel, as previously described [ 32 ]. The gene panel was designed using SureDesign ( https://earray.chem.agilent.com/suredesign ) to cover the exons of TP53 or genes associated with the PI3K/AKT and RAS/RAF signaling pathways ( PIK3CA , AKT1 , PTEN , BRAF , MAP3K3 , KRAS , NRAS , HRAS , and RASA1 ) [ 32 , 33 ]. Two pathologists (SO and KH) identified FFPE blocks with more than 15% abnormal tissue content.…”

L-theanine mechanism and application in the treatment of breast cancer

“…Many gene mutations have been found in breast cancer, from inherited mutations in genes such as BRCA1 and BRCA2 to somatic mutations in body cells [6]. Mutations in key genes such as TP53, PIK3CA, and PTEN [7]have been found in various subtypes of breast cancer and may lead to dysregulation of key cellular processes such as cell cycle control and DNA repair.…”