title: 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 >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.
authors.affiliation: Department of Otolaryngology/Head and Neck Surgery, Henry Ford Hospital, Detroit, MI 48202, USA.
authors.forename: Josena K
authors.initials: JK
authors.lastname: Stephen
authors.forename: Mausumi
authors.initials: M
authors.lastname: Symal
authors.forename: Kang Mei
authors.initials: KM
authors.lastname: Chen
authors.forename: Tamer
authors.initials: T
authors.lastname: Ghanem
authors.forename: Robert
authors.initials: R
authors.lastname: Deeb
authors.forename: Veena
authors.initials: V
authors.lastname: Shah
authors.forename: Shaleta
authors.initials: S
authors.lastname: Havard
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Worsham
mesh_terms: D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000601:surgery*; D019175:DNA Methylation; D057890:Epigenomics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052140:Human papillomavirus 11 / Q000235:genetics / Q000502:physiology; D052162:Human papillomavirus 16 / Q000235:genetics / Q000502:physiology; D006801:Humans; D007822:Laryngeal Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000601:surgery*; D007825:Laryngectomy / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000150:complications / Q000235:genetics* / Q000473:pathology; D016609:Neoplasms, Second Primary / Q000150:complications / Q000235:genetics / Q000473:pathology; D030361:Papillomavirus Infections / Q000150:complications / Q000235:genetics / Q000473:pathology; D054047:Surgical Stomas / Q000473:pathology*