According to the World Health Organization (WHO), mouth and oropharyngeal cancers are the most frequent head and neck malignancies; 390 thousand new cases are reported every year.1 In Brazil, mouth and oropharyngeal cancers are the fifth most frequent malignancies among males (9.2% of cases) and the seventh most frequent in females (3.6% of cases) not including skin cancers.2 In total these malignancies are 6.7% of all cancer cases. These malignancies occur most frequently in south and southeast Brazil.2,3 Estimates for 2007 had suggested that there would be 10.91 new cases or mouth cancer for each 100,000 males and 3.58 new cases for each 100,000 females.4 The incidence rate is increasing and the WHO foresees further increase in the next decades.5 Around 95% of mouth cancers are squamous cell carcinomas (SCC); the remaining 5% are sarcomas, lymphomas and salivary gland tumors.

The prognosis of oral cancer remains unfavorable with high mortality rates, notwithstanding advances in diagnosis and therapy, including radical surgery, novel chemotherapy, and hyperfractionated/conformational radiotherapy. Mortality rates have ranged from 2.16 to 2.96 for each 100,000 males and 0.48 and 0.70 for each 100,000 females6 between 1979 and 1998 in Brazil; the mortality rate has increased at an annual 0.72% rate.7 According to Sessions et al., the 5-year survival rate remains low, at about 48% (overall survival) and 57% (disease-specific survival).8

The biological behavior of oral SCC is uncertain; many of these tumors have an aggressive biological behavior at initial stages with early regional metastases and death. On the other hand, advanced tumors may metastasize slowly, and these patients may remain disease-free for long periods after surgery.

This uncertainty in tumor progression has led researchers to seek factors that might alter the prognosis. Such factors may be related to patients (age, sex, race, social and economic status, and habits such as smoking and alcohol intake), to the tumor (site, stage, tumor thickness, histopathology, and expression of certain molecular markers), and to the treatment (type of treatment, adjuvant therapy). Investigation of these factors aims to learn more about the biological behavior of the tumor, so that specific strategies may be applied individually; thus aggressive therapy may be given to patients with the worst prognosis.

The presence of neck metastases is the most important prognostic factor for oral SCC; if present, there is a 50% reduction in survival rates.9,10 TNM staging, the histological grade and safety margins are other factors with unknown roles. Some studies have suggested that TNM staging (a tool used for establishing a prognosis) cannot predict individual tumor biological behavior. The prognostic value of the histological grade is controversial in this tumor;11 studies have suggested that poorly differentiated carcinomas tend to metastasize and to have involved margins more often. These tumors are associated with decreased survival rates.12 There is still controversy in the literature about margin status.

The purpose of this paper was to evaluate variables related to patient, tumor and treatment variables affecting survival rates in mouth SCC.

Mouth SCCs have a poor prognosis and tend to recur in the primary site and the neck. The 5-year survival rate in our sample was 39%, which is lower than other published results. This is probably due to the higher presence of patients with metastatic lymph nodes (52.2%) and the fact that the sample consisted mostly of tongue and floor of mouth cancers (82%), which are recognizably more difficult to control. These values differ from Sessions et al.”s series in which only 26% of patients had metastatic lymph nodes.8 Furthermore, our sample contained 34.8% of T3/T4 tumors; this percentage in Sessions et al.”s series was 26.5%.8 Additionally the biological behavior of mouth SCCs is heterogeneous, depending of poorly known host and primary tumor factors. Figueiredo et al. have previously published data on the first 15 mouth tumors in our present series, showing that these patients expressed highly the PRAME gene; this finding is related with the presence of lymphatic metastases.14

We detected no patient-related factor among those we studied that had any effect on survival; age, sex, smoking and alcohol use had no statistically significant effect. There is no consensus in the literature about the influence of these factors; according to EIBAND, there is no correlation with age, sex or the prognosis,15 while smoking and alcohol use are seen as risk rather than prognostic factors.

Tumor-related factors (subsite, size, tumor differentiation, peritumor inflammation, and vascular, lymphatic and perineural spread) had no statistical significance. Kademani et al. have shown that the tumor site has not effect on survival; these authors did suggest that the histological grade was a statistically significant prognostic factor.12 The histological grade appears not to have affected survival due to the limited number of cases of undifferentiated carcinomas in our sample (two cases). There is no consensus in the literature about whether vascular, lymphatic and perineural spread decrease survival.16 The sensitivity of the method for detecting spread (immunohistochemistry is much more sensitive than hematoxyllin-eosin) and the expertise of the pathologist may explain these conflicting conclusions.

Neck metastasis was the only tumor-related factor that has been shown to decrease survival in this sample (p=0.017), confirming most of the corresponding published results.9,10 It is relevant to point out that the metastatic rate in our sample of mouth cancers was 57.7%.

Treatment-related factors, such as compromised surgical margins and supplementary radiotherapy, had an impact on survival. Confirmation that margin status has an effect on survival is important, as compromised margins may be avoided by ample surgical resection. According to Mistry et al., however, this is not an easy task; these authors found that measurements of free mucosal margins - attained in surgery - decreased by up to 23% postoperatively, particularly in T1/T2 tumors.19 Spiro et al. found an increased local recurrence in patients with involved margins, which did not alter overall survival.18

The presence of compromised margins, which was statistically significant (p=0.004) in our sample, agrees with Sessions et al.”s results in showing that compromised margins decreased disease-free survival; these authors also found that when patients with compromised margins underwent postoperative radiotherapy, disease-specific survival increased significantly.8 Chao et al. also demonstrated that postoperative radiotherapy provided good results in patients with compromised margins; this group of patients had the same survival and local control that was found in patients with free margins. Postoperative radiotherapy did not improve survival in our sample.17 Other authors also did not find the abovementioned significance (Kademi et al.).12

The log-rank test showed that postoperative radiotherapy (p=0.056) had an opposite effect, namely that patients undergoing radiotherapy had a lower survival rate. Radiotherapy was not statistically significant (p=0,816), however, when considering radiotherapy, neck metastasis and compromised margins jointly in the Cox regression model; other variables were statistically significant. This may be a result of indication of treatment criteria whereby only more aggressive tumors were treated with radiotherapy postoperatively. Radiotherapy should be indicated carefully - as well as taking into account tumor aggressiveness - as according to Brandwein-Gensler et al., radiotherapy is only useful when applied in cases with a high risk of recurrence (truly compromised margins).21

While Ord et al.”s study involved only one surgeon - to decrease added effects20 - many surgeons participated in our study, as our institution has a residency program.

Molecular assessment may provide additional information about tumors; thus the Gencapo study group - in counting tumors in many institutions - may in the near future provide relevant data for improving individual treatment.

We may conclude that neck metastases from mouth SCCs (a tumor-related prognostic factor) and surgical margin status (related to therapy) affected the survival of patients.