Abstract
BackgroundPatients with tongue cancer frequently show loss of heterozygosity (LOH) of the von Hippel–Lindau (VHL) tumor suppressor gene. However, expression of VHL protein (pVHL) in tongue cancer has rarely been investigated and remains largely unknown. We performed immunohistochemical staining of pVHL in tongue tissues and dysplasia, and examined the association with LOH and its clinical significance.MethodsImmunohistochemical staining of pVHL in formalin-fixed, paraffin-embedded sections of cancerous and other tissues from 19 tongue cancer patients showed positivity for LOH of VHL in four samples, negativity in four samples, and was non-informative in 11 samples. The staining pattern of pVHL was also compared with those of cytokeratin (CK) 13 and CK17.ResultsIn normal tongue tissues, pVHL staining was localized to the cytoplasm of cells in the basal layer and the area of the spinous layer adjacent to the basal layer of stratified squamous epithelium. Positive staining for pVHL was observed in the cytoplasm of cancer cells from all 19 tongue cancer patients. No differences as a result of the presence or absence of LOH were found. Notably, cytoplasm of poorly differentiated invasive cancer cells was less intensely stained than that of well and moderately differentiated invasive cancer cells. pVHL staining was also evident in epithelial dysplasia lesions with pVHL-positive cells expanding from the basal layer to the middle of the spinous layer. However, no CK13 staining was noted in regions of the epithelium, which were positive for pVHL. In contrast, regions with positive staining for CK17 closely coincided with those positive for pVHL.ConclusionsPositive staining for pVHL was observed in cancerous areas but not in normal tissues. pVHL expression was also detected in lesions of epithelial dysplasia. These findings suggest that pVHL may be a useful marker for proliferative lesions.
Highlights
Patients with tongue cancer frequently show loss of heterozygosity (LOH) of the von Hippel–Lindau (VHL) tumor suppressor gene
(1) In normal stratified squamous epithelium, von Hippel–Lindau protein (pVHL) staining was localized to the cytoplasm of cells in the basal layer and parts of the cytoplasm in the spinous layer adjacent to the basal layer
It is likely a result of the different antibodies used and staining conditions. This is the first report of pVHL staining in the basal layer and the spinous layer adjacent to the basal layer of normal squamous epithelium. These results suggest that both stem cells and undifferentiated cells may be positive for pVHL because these cells exist in the same region. pVHL staining has been observed in the cytoplasm of normal epithelial cells in other tissues [26]
Summary
Patients with tongue cancer frequently show loss of heterozygosity (LOH) of the von Hippel–Lindau (VHL) tumor suppressor gene. A previous study of genetic abnormalities in HNSCC revealed more frequent loss of heterozygosity (LOH) at loci on chromosomes 3p, 9p, and 17p [4]. Tumor suppressor genes p16 and p53 are located at loci on chromosomes 9p and 17p, respectively, and both are reported to show genetic alterations, such as mutations and methylation, in approximately 50% of tumor specimens from HNSCC patients [5, 6]. Asakawa et al previously demonstrated that LOH of VHL (3p25.3), a tumor suppressor gene, occurs at a high frequency in tongue cancer, similar to that of 3p14.2 [10]. The biological effect of VHL loss on tongue cancer remains unclear
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