Aims: Previous studies have demonstrated that tumor-stroma ratio (TSR) and tumor budding are of prognostic value for oral squamous cell carcinomas (OSCC). Herein we evaluated the prognostic significance of those histological parameters, individually and in combination, for OSCC.Methods: TSR and tumor budding (the presence of ≥ 5 buds at the invasive front) were estimated in 254 patients with OSCC. The clinicopathological association was investigated using a chi-square test, and the prognostic significance (cancer-specific survival and disease-free survival) was verified by Kaplan-Meier analysis and the Cox proportional hazard model.Results: TSR (≥ 50%, stroma-rich) was significantly and independently associated with both shortened cancer-specific survival and poor disease-free survival, whereas tumor budding significantly reduced cancer-specific survival. The TSR/tumor budding model was independently associated with a high-risk of cancer-mortality and recurrence (disease-free survival). In patients with early-stage tumors (clinical stage I and II, n=103), TSR, tumor budding and the TSR/tumor budding model were significantly associated with both cancer-related death and recurrence, while in advanced-stage tumors (clinical stage III and IV, n=144), only TSR and the TSR/tumor budding model were significantly associated with cancer-specific survival.Conclusions: TSR, tumor budding and their combination provide significant information on OSCC outcome, suggesting that their incorporation into the routine evaluation of histopathological specimens might be useful in the prognostication of OSCC patients.

Smnumry We investigated the association between human papillomavirus (HPV) infection and p53 gene mutation in 47 primary uterine cervical cancers. HPV DNA sequences were present in 43 cancers (91.5%), and one of these cancers contained a p53 gene mutation. In addition, one of the remaining four HPV-negative cancers also contained a p53 gene mutation. As a result, p53 inactivation corresponded to the development of 44 of the primary uterine cervical cancers studied (93.6%). We obtained both primary and recurrent tumours from four cases. In two of these cases, the HPV genomes that were present in an episomal state in the primary tumours were observed to have disappeared in the recurrent tumours. One of these recurrent tumours also contained a p53 gene mutation, which suggested the possibility that p53 inactivation was September 1994 mutations could exist in other genes that interact with p53 or downstream of p53 and thus result in an identical physiological defect within the cell. Third, mutations in other genes, which are totally unrelated to p53, could occur in some cancers, resulting in a transformation process that is qualititatively different from HPV-mediated carcinogenesis. Thus, the present study was undertaken to define the molecular mechanism associated with HPV-negative cancer development.The polymerase chain reaction (PCR) and subsequent restriction enzyme typing are sufficiently sensitive to detect a subgroup of HPVs associated with cervical cancer. Both a sense primer, pU-lM, that is homologous to a region in the E6 open reading frame (ORF) and an antisense primer, pU-2R, that is homologous to a region in the E7 ORF were used for amplification. This method is also useful in identifying potentially new HPV types (Fujinaga et al., 1991). Southern blot hybridisation in conjunction with polymerase chain reaction (PCR) was able to detect lo-5 to 106 copies of the HPV genome per cell, which was sufficient to determine the presence of HPVs (Roman and Fife, 1989). We thus studied the frequency of HPV infection in 51 cervical cancers that involved both primary and recurrent tumours, and found four primary and two recurrent tumours that were HPV negative. The p53 gene mutation was recognised in 1 of the 45 HPV-positive tumours and in two of six HPV-negative tumours. The HPV genomes that were present as episomes in two primary cancers were observed to have disappeared in the recurrent tumours, and thus suggested the possible route of HPV-negative cancer development.The disappearance of the HPV genome was followed by the appearance of a new p53 mutation in one of these two recurrent tumours. These findings might thus imply both p53 inactivation in the initiation of cervical cell carcinogenesis and the maintenance of transformed properties even if the frequency of p53 mutation was low in HPV-negative cancers.The closest analogue to the interaction between E6 and p53 in cervical cancers is provided by the murine double minute 2 (MDM2) genes and p53 in sarcomas. An MDM2 gene product which binds to p53 has been sh...

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