A High Frequency of Allelic Loss in Oral Verrucous Lesions May Explain Malignant Risk

Abstract

SUMMARY:Verrucous carcinoma (VC), a variant of squamous cell carcinoma (SCC), is distinct from SCC in morphology and behavior. The underlying genetic changes involved in the development of VC and its precursor verrucous hyperplasia (VH) are unknown. This study determined whether chromosomal regions frequently lost during the development of SCC are also lost in the VH/VC variant. Twenty-five VH and 17 VC were analyzed for loss of heterozygosity (LOH) at 19 loci on 7 chromosome arms using microsatellite analysis. These data were compared with those from 47 reactive hyperplasias, 92 dysplasias (54 low-and 38 high-grade), and 41 SCCs. The results showed that VC/VH shared many of the losses present in dysplasia/SCC but differed in two aspects. First, VC/VH showed early acquisition of loss, compared with a gradual accumulation of losses from dysplasias to SCC. The LOH pattern of VH was similar to that of high-grade dysplasia and sharply different from reactive hyperplasia. The loss in VH often involved multiple arms (in 60% of VH vs 0% of reactive lesions). Only a marginal elevation of loss was observed at 9p (p ϭ 0.06) and 4q (p ϭ 0.05) from VH to VC because of the high degree of loss already present in VH. Second, a strikingly lower frequency of loss at 17p was noted in VH/VC compared with dysplasia/SCC and may indicate human papillomavirus (HPV) involvement. The finding of high-risk LOH profiles in VH may partly account for the high-progression risk seen for VH and also has potentially important clinical implications. The difficult pathological diagnosis of VH/VC from reactive hyperplasia frequently requires repeated biopsies and results in delay in diagnosis and significantly increased mortality/morbidity. Microsatellite analysis might facilitate this differential diagnosis. (Lab Invest 2001, 81:629 -634).O ral squamous cell carcinoma (SCC) is similar to SCC in many other organs (eg, uterine, cervix, skin, larynx, and pharynx) in that it is felt to develop in a multistep fashion through a series of histological stages with increasing risk of developing into invasive cancer, namely: epithelial hyperplasia; mild, moderate, and severe dysplasias; and carcinoma in situ (CIS). The presence of dysplasia and the breakage of the basement membrane (ie, invasion) are the hallmarks for judging malignancy in SCC (Fig. 1a). However, verrucous carcinoma (VC) (Fig. 1b), a variant of the conventional SCC in these organs, has unique clinicopathological features and biological behavior. VC and its precursor lesion, verrucous hyperplasia (VH) (Fig. 1c), are characterized by a prominent verrucous configuration, yet show minimal or no dysplasia and no breakage of the basement membrane. In the oral cavity, VC and SCC differ in the site of occurrence, with VC most commonly in the cheek and alveolus/ gingiva and SCC on the ventrolateral tongue and floor of mouth (Jacobson and Shear, 1972). VC does not metastasize, and it grows indolently (a 75% 5-year survival rate for VC versus less than 50% for SCC), although the growth is so relentles...

Frequent Alterations of p16INK4a and p14ARF in Oral Proliferative Verrucous Leukoplakia

“…Approximately 47% of cases presented with LOH in a single marker, 10.5% in two markers, and 5.3% in all three markers located. Similarly, Poh et al evaluated verrucous carcinomas and verrucous hyperplasias for LOH at 9p21 and reported LOH events in 77% and 46%, respectively (19). As summarized in Table 2, the highest LOH rates in PVL patients occurred for the marker D9S171 (45.5%) followed by INFa (35.3%) and D9S1748 (26.3%).…”

“…Chromosomal loss in the region 9p21 was assessed using three markers reported to be highly polymorphic in head and neck tumors, oral dysplasias, and oral verrucous lesions (16,17,19,(30)(31)(32)(33). Consideration to the markers relative location on chromosome 9p was also given.…”

Distinctive chromosomal instability patterns in oral verrucous and squamous cell carcinomas detected by high‐resolution DNA flow cytometry

“…Even in the presence of overall similar LOH patterns, OVC showed higher frequencies of loss at 4q and lower frequencies of loss at 17p. 24 The possible link among these structural and functional features with biological behavior and clinical outcome in OVCs is far from being understood and requires further investigations. In the present study, we have demonstrated that a routine amenable technique like hr DNA-FCM may be used for a more specific assessment of the OVC heterogeneity based on the analysis of the DI values of the DNA aneuploid sublines and their intralesional distribution.…”

Verrucous Hyperplasia: Case report and differential diagnosis

“…10,11 Additionally, the higher expression of interleukin-1β and glutathione S-transferase pi isoenzymes and the allelic loss at 19 loci on seven different chromosome arms may also play an important role in the malignant transformation of VH. [12][13][14] Tumour protein p53, epidermal growth factor receptor and human epidermal growth factor receptor 3 expression can also be used to differentiate VH from VC and SCC. 15,16 Although Greer Jr et al found an association between the human papilloma virus and VH, the role of the virus in the malignant transformation of VH has yet to be confirmed.…”