Molecular characterization of late stomal recurrence following total laryngectomy

Abstract

The goal was to determine recurrent or second primary status for late stomal malignancies, 16 and 17 years post-total laryngectomy in two laryngeal squamous cell carcinoma (LSCC) patients, based on DNA methylation signatures and HPV typing. Adopting a literature review based definition of late stomal recurrences as new primaries at the site of the stoma or neopharynx occurring more than 5 years after total laryngectomy, we employed a multi-gene candidate approach to examine promoter methylation in 24 tumor suppressor genes and PCR-based assays for HPV status offered additional insights into whether the late stomal tumors post total laryngectomy were related or not. The primary tumor for Patient 1 was negative for HPV but had aberrant hypermethylation of APC, MLH1, and BRCA1. The stomal biopsy 17-years later showed presence of HPV-16 without any methylated genes. In Patient 2, HPV-11 and promoter methylation of APC identified in the primary tumor was also observed in the stomal malignancy 16 years post total laryngectomy. Additional information provided by molecular typing for HPV and methylation markers underscored Patient 1’s and 2’s late stomal presentation as most likely a second primary and recurrence, respectively. DNA methylation markers are particularly advantageous because DNA methylation is an early event in tumorigenesis, and the epigenetic modification, 5-methylcytosine, is a stable marker. Molecular marks to discern genetic heterogeneity or relatedness of stomal malignancies several years post-total laryngectomy can provide clues to their status as either second primaries or likely recurrences. Our results support the hypothesis that a subset of stomal recurrences after total laryngectomy represents second primary tumors.

Identifying the risk factors for late-stage head and neck cancer

“…In a retrospective multi-ethnic primary laryngeal squamous carcinoma (LSCC) cohort, aberrant methylation of ESR1 was an independent predictor of late stage LSCC [15]. DNA methylation patterns also have utility in determining whether a second tumor represents a recurrence of the original malignancy or a second primary cancer [32]. …”

Early detection and personalized treatment in oral cancer: the impact of omics approaches

“…Moreover, Pierini et al described that traditional risk factors (tobacco and alcohol consumption) affect epigenetic modification of specific genes in laryngeal carcinomas, underlining the implication of CDKN2A and MLH1 promoter methylation in invasion of lymph nodes with cancer cells [44]. DNA methylation patterns seem also to be useful to determine whether a second tumor represents a recurrence of the original malignancy or a second primary cancer [45]. Considering the stable, potential reversible nature and variable levels of epigenomic modifications in OSCC, tumor methylation profiling during treatment could provide important insights regarding the treatment efficacy, emphasizing the importance of repeatedly monitoring these patients.…”