Early Diagnosis of Oral Cancer: A Complex Polyhedral Problem with a Difficult Solution.

Oral and oropharyngeal cancers are a growing problem, accounting for 377,713 and 98,412 new cases per year all over the world and 177,757 and 48,143 deaths annually, respectively. Despite the substantial improvement in diagnostic procedures and treatment techniques in recent years, the mortality rate has not decreased substantially in the last 40 years, which is still close to 50% of cases. The major cause responsible for this high mortality is associated with the high percentage of oral cancers diagnosed in advanced stages (stages III and IV) where the treatment harbors poor efficacy, resulting in challenges, mutilations, or disability. The main reason for cancer to be diagnosed at an advanced stage is a diagnostic delay, so it is critical to reduce this delay in order to improve the prognosis of patients suffering from oral cancer. The causes of oral cancer diagnostic delay are complex and concern patients, healthcare professionals, and healthcare services. In this manuscript, oral cancer diagnostic delay is critically reviewed based on current evidence, as well as their major causes, main problems, and potential improvement strategies.

Prognostic and Clinicopathological Significance of CCND1/Cyclin D1 Upregulation in Melanomas: A Systematic Review and Comprehensive Meta-Analysis.

Our objective was to evaluate the prognostic and clinicopathological significance of cyclin D1 (CD1) overexpression/CCND1 amplification in melanomas. We searched studies published before September 2019 (PubMed, Embase, Web of Science, Scopus). We evaluated the quality of the studies included (QUIPS tool). The impact of CD1 overexpression/CCND1 amplification on overall survival and relevant clinicopathological characteristic were meta-analyzed. We performed heterogeneity, sensitivity, small-study effects, and subgroup analyses. Forty-one studies and 3451 patients met inclusion criteria. Qualitative evaluation demonstrated that not all studies were performed with the same rigor, finding the greatest risk of bias in the study confounding domain. Quantitative evaluation showed that immunohistochemical CD1 overexpression had a statistical association with Breslow thickness (p = 0.007; OR = 2.09,95% CI = 1.23-3.57), significantly higher frequency of CCND1/cyclin D1 abnormalities has been observed in the primary tumor compared to distant metastases (p = 0.004), revealed also by immunohistochemical overexpression of the protein (p < 0.001; OR = 0.53,95% CI = 0.40-0.71), while the CCND1 gene amplification does not show association (p = 0.43); while gene amplification, on the contrary, appeared more frequently in distant metastases (p = 0.04; OR = 1.70,95% CI = 1.01-2.85) and not in the primary tumor. In conclusion, CCND1/cyclin D1 upregulation is a common molecular oncogenic alteration in melanomas that probably favors the growth and expansion of the primary tumor. This upregulation is mainly consequence to the overexpression of the cyclin D1 protein, and not to gene amplification.

Worldwide prevalence of oral lichen planus: A systematic review and meta-analysis.

The objective was to assess the global oral lichen planus prevalence. We searched PubMed, EMBASE, Web of Science, and Scopus for studies published before September 2019. We evaluated the quality of studies and carried out several meta-analyses. The global pooled prevalence was 1.01%, with a marked geographical difference (p < .001). The highest prevalence was reported from Europe (1.43%) and the lowest in India (0.49%), where tobacco-associated keratosis appears to mask oral lichen planus resulting in attenuation of its prevalence. From the age of 40 years, the prevalence increases significantly and progressively (OR = 3.43, 95% CI = 2.48-4.73, p < .001). Studies that define diagnostic criteria report a higher prevalence (1.31% vs. 0.70%, p = .03), although the application of the WHO criteria (year 1978-2007) does not increase the ability to diagnose the disease compared with other criteria (p = .11). The studies performed by oral medicine/oral pathology specialists report significantly higher prevalence (1.80%) than dentists (0.61%) and dermatologists (0.33%; p < .001). In conclusion, we propose that reliable diagnostic criteria should be defined, which should include a set of essential criteria including the presence of white reticular lesions in any location of the oral mucosa. The impact of histopathological confirmation with defined diagnostic criteria must be researched in the future, although its main use should be to determine the presence or absence of epithelial dysplasia. The necessity to improve the knowledge of oral lichen planus among dentists and dermatologists through continuing education is apparent in the results of this meta-analysis.

Clinicopathological and prognostic significance of PD-L1 in oral cancer: A preliminary retrospective immunohistochemistry study.

OBJECTIVE: To evaluate the relation between PD-L1 expression in oral cavity squamous cell carcinomas and clinicopathological features as well as survival outcomes. METHODS: A retrospective immunohistochemical study was carried out on 55 archived tumours from 55 patients. Tumours were stained for PD-L1 and scored by the proportion of tumour cells with positive membranous staining. PD-L1 scores were compared to the patient's clinicopathological characteristics for any significant associations. Kaplan-Meier curves were constructed for PD-L1 positive and negative tumours to investigate any advantage to survival. RESULTS: Positive PD-L1 staining was found in 58% of tumours and was significantly more likely in non-smokers, non-drinkers and in tongue squamous cell carcinomas. Increased PD-L1 was also associated with increased lymphocyte infiltration as well as PD-L1 staining in lymphocytes and the epithelium adjacent to tumour invasion. No survival benefit was seen from PD-L1 expression in tumour cells. CONCLUSIONS: PD-L1 expression is more common in non-smokers and non-drinkers, and its presence in the adjacent non-tumour epithelium suggests it may be involved in early oncogenesis.

Prognostic and Clinicopathological Significance of FADD Upregulation in Head and Neck Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis.

Fas-associated death domain (FADD) upregulation, i.e., gene amplification, protein phosphorylation and/or overexpression, has shown promising prognostic implications in head and neck squamous cell carcinoma (HNSCC). This systematic review and meta-analysis aims to evaluate the clinicopathological and prognostic significance of FADD upregulation in HNSCC. We searched studies published before February 2020 through PubMed, Embase, Web of Science, Scopus and Google Scholar. We evaluated the quality of the studies included using the QUIPS tool. The impact of FADD upregulation on survival and clinicopathological variables was meta-analysed. We explored heterogeneity and their sources, conducted sensitivity analyses and investigated small-study effects. Thirteen studies (1,923 patients) met inclusion criteria. FADD immunohistochemical overexpression was statistically associated with worse overall survival (hazard ratio [HR] = 1.52, 95% confidence intervals [CI] = 1.28-1.81, p < 0.001), disease-specific survival (HR = 2.52, 95% CI = 1.61-3.96, p < 0.001), disease-free survival (HR = 1.67, 95% CI=1.29-2.15, p < 0.001), higher clinical stage (odds ratio [OR] = 1.72, 95% CI = 1.17-2.51, p = 0.005) and a large magnitude of effect with N+ status (OR = 2.36, 95% CI = 1.85-3.00, p < 0.001). FADD phosphorylation in ser-194 demonstrated no prognostic value, while no conclusive results can be drawn for FADD gene amplification. In conclusion, our findings indicate that immunohistochemical assessment of FADD overexpression could be incorporated into the prognostic evaluation of HNSCC.

Clinicopathological and prognostic characteristics of oral squamous cell carcinomas arising in patients with oral lichen planus: A systematic review and a comprehensive meta-analysis.

OBJECTIVES: To evaluate current evidence in relation to the prognostic and clinicopathological significance of oral squamous cell carcinomas arising in patients with oral lichen planus (OLP-OSCC). MATERIAL AND METHODS: We searched PubMed, Embase, Web of Science and Scopus for studies published before May-2019. We evaluated the quality of studies (QUIPS tool). We carried out meta-analyses to fulfill our objective. We examined the between-study heterogeneity and small-study effects, and conducted sensitivity and subgroup analyses. RESULTS: Inclusion criteria were met by 27 studies (10,505 patients with OLP, of whom 205 developed a total of 247 OSCCs). The combined 5-year mortality rate was 15.48% for OLP-OSCC (95%CI  =  7.34-25.19), clearly lower than the 34.70-50.00% mortality rate for conventional oral cancer communicated in previous official reports. Also, 14.67% (95%CI  =  6.34-24.81) of OLP-OSCC developed N+ status, compared to 47.00% of conventional oral carcinomas. Likewise, most of the OSCCs in the study were T1/T2 (93.57%, 95%CI  =  82.20-99.88) and presented at stage I/II (81.51%, 95%CI = 68.32-92.38) at the time of diagnosis, which contrasts with 50.00% of conventional carcinomas diagnosed in stages I/II. Furthermore, most of the cases were grade I (well differentiated OSCC) (67.79%; 95%CI = 43.50-88.65), in comparison to conventional OSCCs, which present typically in grade II in 90.00% of cases. Our results also show an 11.21% of the OLP-OSCC patients in this study developed multiple tumors. CONCLUSIONS: Oral squamous cell carcinomas that developed in oral lichen planus show favorable prognostic parameters, especially with regard to the mortality rate. Around 11% of OLP-OSCC patients develop multiple tumors, which confirms that OLP can lead to field cancerization.

Prognostic and clinicopathological significance of PD-L1 overexpression in oral squamous cell carcinoma: A systematic review and comprehensive meta-analysis.

BACKGROUND: The presence of Programmed Death-Ligand 1 protein (PD-L1) in oral squamous cell carcinoma (OSCC) may indicate an ability to evade immune response and has been suggested as a prognostic marker, but there is controversy in the literature. OBJECTIVE: To review the scientific evidence of a prognostic role for PD-L1 levels in OSCC. METHODS: PubMed, Embase, Web of Science, and Scopus were searched for studies published on or before March 02, 2019. Studies measuring PD-L1 levels by immunohistochemistry (IHC) in OSCC were included. Study quality was assessed using the QUIPS tool. Meta-analysis was performed for survival outcomes and clinic-pathological parameters. RESULTS: 26 articles were included comprising 2532 patients. Analysis of studies measuring PD-L1 expression in the cell membrane showed a worse prognosis for disease-specific survival (HR = 1.74, 95% CI = 1.14-2.66, p = 0.01) and disease-free survival (HR = 1.56, 95% CI = 1.16-2.09, p = 0.003). PD-L1 overexpression was more likely in females (OR = 0.69, 95% CI = 0.53-0.91, p = 0.008), non-smokers (OR = 0.45, 95% CI = 0.27-0.75, p = 0.002), non-drinkers (OR = 0.40, 95% CI = 0.16-0.97, p = 0.04), advance stage tumours (OR = 1.63, 95% CI = 1.00-2.64, p = 0.05) and in tumours with high levels of PD-1 (OR = 33.36, 95% CI = 1.88-591.69, p = 0.02), CD4+ (OR = 3.25, 95% CI = 1.36-7.76, p = 0.008) and CD8+ (OR = 3.63 , 95% CI = 1.20-10.99, p = 0.02). CONCLUSION: This meta-analysis found a worse prognosis in OSCCs overexpressing PD-L1 in the cell membrane as measured by disease specific survival and disease-free survival. We also found positive correlations between PD-L1 overexpression and advanced tumours, females, non-smokers, non-drinkers and high levels of tumour PD-1, CD4, and CD8.

Immunophenotypic Conversion between Primary and Relapse Breast Cancer and its Effects on Survival.

BACKGROUND: The differential expression of oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor 2 (HER2) or Ki-67 between primary tumour and the recurrence has been described. We aimed to determine these changes and their prognostic implications. PATIENTS AND METHODS: We retrospectively reviewed 45 breast cancer patients with relapsed biopsy that were classified into local relapse (LR) or metastatic disease (MD) groups. We analyzed the conversion rate and the value of the immunophenotype of the primary tumour and the relapse as a prognostic factor for relapse-free survival (RFS), progression-free survival (PFS) and overall survival (OS). RESULTS: The conversion rate was 34.8% for Ki-67, 20% for ER, 20% for PR, and 15.6% for HER2. For the LR group, the RFS was 71.9 months and the OS was 141.6 months, without statistical differences according to the immunophenotype of the primary or the relapsed biopsy. For the MD group, the PFS was 20.8 months. According to immunophenotype of the relapse, the PFS were ER+ 24.7 months vs. ER- 9.3 months; PR+ 25.1 months vs. PR- 12.7 months without statistical differences according to HER2 or Ki67. The OS for MD group was 54.4 months without statistical differences according to immunophenotype. CONCLUSION: The characteristics of breast cancer can change over the time. Variations of the ER or PR status in MD group have prognostic value for PFS. To perform a biopsy of relapses is warranted in order to establish the prognostic of the current disease, and probably a more accurate treatment.

An update on the implications of cyclin D1 in melanomas.

Cyclin D1 is a protein encoded by the CCND1 gene, located on 11q13 chromosome, which is a key component of the physiological regulation of the cell cycle. CCND1/cyclin D1 is upregulated in several types of human tumors including melanoma and is currently classified as an oncogene that promotes uncontrolled cell proliferation. Despite the demonstrated importance of CCND1/cyclin D1 as a central oncogene in several types of human tumors, its knowledge in melanoma is still limited. This review examines data published on upregulation of the CCND1 gene and cyclin D1 protein in the melanoma setting, focusing on the pathways and molecular mechanisms involved in the activation of the gene and on the clinical and therapeutic implications.

An update of knowledge on PD-L1 in head and neck cancers: Physiologic, prognostic and therapeutic perspectives.

Programmed cell death-ligand 1 (PD-L1) is a transmembrane protein that acts as a co-inhibitory factor in the immune response. Its receptor, programmed cell death protein 1 (PD-1), is found on immune cells, where binding to PD-L1 can reduce the proliferation of PD-1-positive cells, inhibit their cytokine secretion and induce apoptosis. PD-L1 in immune-privileged tissue plays a crucial role in peripheral tolerance. PD-L1 can be overexpressed in various malignancies, including oral squamous cell carcinoma, where it can attenuate the host immune response to tumour cells and has been associated with a worse prognosis. Monoclonal antibody therapies targeting the PD-1:PD-L1 axis have shown initial promise, but further research is needed to identify which patients will benefit. We provide an update of knowledge on PD-L1, including its structure, function and regulation. We also review studies on the overexpression of PD-L1 in cancer, specifically oral squamous cell carcinoma, and explore its potential value as a therapeutic target.

Malignant transformation risk of oral lichen planus: A systematic review and comprehensive meta-analysis.

OBJECTIVES: To evaluate current evidence on the malignant transformation of oral lichen planus (OLP), oral lichenoid lesions (OLLs), and oral lichenoid reactions (LRs) and to determine the variables with greatest influence on cancer development. MATERIAL AND METHODS: We searched PubMed, Embase, Web of Science, and Scopus for studies published before November 2018. We evaluated the quality of studies (QUIPS tool). We carried out meta-analyses to fulfill our objectives. We examined the between-study heterogeneity and small-study effects, and conducted sensitivity studies and subgroup analyses. RESULTS: Inclusion criteria were met by 82 studies (26,742 patients. The combined malignant transformation rate was 1.14% for OLP (95% CI = 0.84-1.49), 1.88% for OLLs (95% CI = 0.15-4.95) and 1.71% for LRs (95% CI = 0.00-5.46). Subgroup analysis revealed a higher malignant transformation rate in studies when the presence of epithelial dysplasia was not an exclusion criterion (p = 0.001), when both clinical and histopathological criteria were used for diagnosis (p < 0.001), when the follow-up was at least 12 months (p = 0.048), and when there was lower risk of potential bias (p = 0.002). Malignant transformation risk factors were: tongue localization (RR = 1.82, 95% CI = 1.21-2.74, p = 0.004), presence of atrophic-erosive lesions (RR = 4.09, 95% CI = 2.40-6.98, p < 0.001), tobacco use (RR = 1.98, 95% CI = 1.28-3.05, p = 0.002), alcohol consumption (RR = 2.28, 95% CI = 1.14-4.56, p = 0.02), and hepatitis C virus infection (RR = 4.46, 95% CI = 0.98-20.22, p = 0.053). CONCLUSIONS: The malignant transformation rates of OLP, OLLs and LRs are underestimated due essentially to restrictive diagnostic criteria, inadequate follow-up periods, and/or low quality of studies.

Predictive value of CCND1/cyclin D1 alterations in the malignant transformation of potentially malignant head and neck disorders: Systematic review and meta-analysis.

BACKGROUND: To evaluate published evidence on the predictive value of CCND1 amplification/cyclin D1 overexpression as malignant transformation risk markers in potentially malignant disorders (PMDs) of the head and neck. MATERIAL AND METHODS: We searched PubMed, Embase, Web of Science, and Scopus for studies published before June 2018. We conducted a meta-analysis to quantify the impact of CCND1/cyclin D1 amplification/overexpression on malignant transformation of head and neck PMDs. RESULTS: Nine studies met inclusion criteria. Quantitative evaluation indicated strong statistically significant association between CCND1/cyclin D1 amplification/overexpression and the progression of head and neck PMD to head and neck squamous cell carcinoma (risk ratio [RR] = 2.04, 95% confidence interval [CI] = 1.37-3.03, P < .001, and RR = 2.27, 95% CI = 1.32-3.91, P = .003, respectively). We observed moderate heterogeneity among studies (I2 = 40.7%), and we cannot rule out small-study effects such as publication bias. The oral cavity subgroup showed the strongest association between CCND1/cyclin D1 amplification/overexpression and progression to cancer. CONCLUSION: CCND1/cyclin D1 amplification/overexpression is important to predict the malignant transformation risk of head and neck PMDs, especially oral PMDs.

Clinicopathological significance of tumor cyclin D1 expression in oral cancer.

OBJECTIVE: To evaluate the association of cyclin D1 overexpression with clinicopathological parameters classically considered of prognostic value in OSCC (T, N, M, clinical stage, degree of differentiation, invasive morphology and, cellular proliferation index). DESIGN: A retrospective immunohistochemical study was conducted of cyclin D1 and ki-67 expression in 68 OSCCs from 54 patients. Cases were scanned using a digital pathology system. The tumor expression of markers was assessed in four randomly selected fields (40x), and a semi-automatized count was conducted of cyclin D1-positive and -negative cells. RESULTS: Cyclin D1 overexpression was found in 28.7% of the cases of OSCC. It was significantly and positively associated with the following clinicopathological parameters: low tumor differentiation degree (p = 0.030), invasive morphology (p = 0.045), and proliferative phenotype according to tumor cell ki-67 expression (p = 0.018). CONCLUSIONS: Cyclin D1 overexpression is an event of oral carcinogenesis associated with clinicopathological parameters classically associated with a poor prognosis in patients with OSCC.

Prognostic and clinicopathological significance of CTTN/cortactin alterations in head and neck squamous cell carcinoma: Systematic review and meta-analysis.

BACKGROUND: To evaluate the prognostic significance of CTTN/cortactin alterations in head and neck squamous cell carcinoma (HNSCC). MATERIAL AND METHODS: We searched PubMed, Embase, Web of Science, and Scopus for studies published before May 2018. We conducted a meta-analysis to quantify the impact of CTTN/cortactin alterations on clinicopathological and survival variables. RESULTS: Eighteen studies (1633 patients) met inclusion criteria. Quantitative evaluation revealed a strong association of CTTN/cortactin alterations with N+ status (P < .001), higher T status (P < .001), advanced clinical stage (P < .001), high histological grade (P = .001), and lower overall survival (OS) (P < .001). We found heterogeneity in T status, histological grade, and OS and observed small-study effects on N status and OS. In subgroup analyses, a significant association of CTTN amplification and cortactin overexpression with the above variables was preserved. The strongest association between CTTN/cortactin alterations and a worse outcome was observed in the subgroups of Asian patients and pharyngolaryngeal squamous cell carcinomas. CONCLUSIONS: CTTN/cortactin alterations should be evaluated to predict the HNSCC prognosis.

An update of knowledge on cortactin as a metastatic driver and potential therapeutic target in oral squamous cell carcinoma.

Cortactin is a protein encoded by the CTTN gene, localized on chromosome band 11q13. As a result of the amplification of this band, an important event in oral carcinogenesis, CTTN is also usually amplified, promoting the frequent overexpression of cortactin. Cortactin enhances cell migration in oral cancer, playing a key role in the regulation of filamentous actin and of protrusive structures (invadopodia and lamellipodia) on the cell membrane that are necessary for the acquisition of a migratory phenotype. We also analyze a series of emerging functions that cortactin may exert in oral cancer (cell proliferation, angiogenesis, regulation of exosomes, and interactions with the tumor microenvironment). We review its molecular structure, its most important interactions (with Src, Arp2/3 complex, and SH3-binding partners), the regulation of its functions, and its specific oncogenic role in oral cancer. We explore the mechanisms of its overexpression in cancer, mainly related to genetic amplification. We analyze the prognostic implications of the oncogenic activation of cortactin in potentially malignant disorders and in head and neck cancer, where it appears to be relevant in the development of lymph node metastasis. Finally, we discuss its usefulness as a therapeutic target and suggest future research lines.

Asymmetrical proliferative pattern loss linked to cyclin D1 overexpression in adjacent non-tumour epithelium in oral squamous cell carcinoma.

OBJECTIVE: To evaluate cyclin D1 overexpression in oral squamous cell carcinomas and adjacent non-tumour epithelium as a biomarker of premalignant fields and a risk factor for multiple tumour development. DESIGN: We studied cyclin D1 expression in 54 patients with 68 oral squamous cell carcinomas plus adjacent non-tumour epithelia characterized as close (n = 58) or distant (n = 41) from the invasion point. Randomized 40x fields were evaluated (4 in tumour tissue and 1 each in close and distant non-tumour epithelium). Expression in non-tumour epithelium was evaluated in basal, parabasal, middle-third and upper-third compartments. RESULTS: Cyclin D1 overexpression was found in both carcinomas and non-tumour epithelia. Nuclear expression in basal and parabasal layers of distant epithelium was significantly increased in patients with multiple tumours (p < 0.001). A significant association between cyclin D1 overexpression in different epithelial layers was found in both close and distant epithelia. A significant association was found between nuclear expressions of cyclin D1 and Ki-67 in the basal layer of distant epithelium (p = 0.02). CONCLUSIONS: Cyclin D1 overexpression is an early event in oral carcinogenesis linked to loss of the physiological asymmetrical proliferation pattern. Cyclin D1 overexpression in basal and parabasal layers of epithelia distant from the invasion point may act as a potential marker of premalignant fields and multiple tumour development.

Prognostic and clinicopathological significance of cyclin D1 expression in oral squamous cell carcinoma: A systematic review and meta-analysis.

OBJECTIVES: To evaluate the prognostic significance of cyclin D1 (CD1) overexpression in OSCC. MATERIAL AND METHODS: We searched studies published before August 2017 (Pubmed, Embase, Web of Science, Scopus). We evaluated the quality of the studies included (Quality in Prognosis Studies [QUIPS] tool). The impact of CD1 overexpression on overall survival and disease-free survival, T status, N status, stage, and histological degree was meta-analyzed. We analyzed heterogeneity among studies, conducted sensitivity analyses, analyzed small-study effects, and conducted subgroup analyses. RESULTS: 31 studies (2942 patients) met inclusion criteria. Qualitative evaluation demonstrated that not all studies were performed with the same rigor, finding the greatest risk of bias in the study confounding domain. Quantitative evaluation showed that CD1 overexpression had a strong statistical association with worse overall survival (HR = 2.00, 95% CI = 1.59-2.51, p < 0.001), worse disease-free survival (HR = 1.46, 95% CI = 1.13-1.87, p = 0.003), higher T status (OR = 1.51, 95% CI = 1.07-2.13, p = 0.02), N+ status (OR = 2.16, 95% CI = 1.60-2.92, p < 0.001), advanced stage (OR = 1.44, 95% CI = 1.15-1.81, p = 0.002), and high histological grade (OR = 1.60, 95% CI = 1.12-2.29, p = 0.010). We observed heterogeneity in all parameters except for disease-free survival and clinical stage. We found effect of small studies on T and N status. The tonguel SCC subgroup showed the strongest association between CD1 overexpression and worse development. In addition, application of a cutoff point ≥10% tumor cells with nuclear CD1 expression maintained most of the significant associations reported. CONCLUSIONS: These findings indicate that immunohistochemical assessment of CD1 overexpression may be useful as a prognostic biomarker for OSCC.

Relevance of chromosomal band 11q13 in oral carcinogenesis: An update of current knowledge.

An important event in oral carcinogenesis is the amplification of chromosomal band 11q13, in which numerous oncogenes and some tumor-suppressor genes are localized and frequently co-amplified during the malignant transformation of oral epithelium. The objectives of this study were to review published data on the involvement of 11q13 amplification in oral cancer, to provide an update on novel concepts and terminology related to gene amplification, and to explore the composition of the 11q13 amplicon in OSCC, including its most relevant amplicon cores and potential drivers. We report on the critical oncogenes and tumor-suppressor genes in 11q13 that may play a major role in oral cancer, focusing on their functions, on the characteristics acquired by their amplification, and on their clinicopathological implications. Finally, we discuss the possible usefulness of the 11q13 region as a therapeutic target in oral cancer.

A role for the substance P/NK-1 receptor complex in cell proliferation in oral squamous cell carcinoma.

OBJECTIVE: To investigate the presence and distribution of substance P (SP) and neurokinin 1 receptor (NK-1R) in oral squamous cell carcinoma (OSCC) and their relationship with proliferation. PATIENTS AND METHODS: Ninety OSCCs from 73 patients were immunohistochemically analyzed using monoclonal antibodies against SP, NK-1R and Ki-67 in a case and control study. RESULTS: Seventy-one percent (n=49) of cases expressed SP on tumour cell membrane, 81.3% (n=69) in cytoplasm, 39.4% (n=28) in nucleus, 81.6% (n=71) in infiltrating lymphocytes, and 58.1% (n=43) in peritumoural or intratumoural blood vessels; 14% (n=12) of cases expressed NK-1R on tumour cell membrane, 50% (n=43) in cytoplasm, 48.3% (n=42) in infiltrating lymphocytes and 22.5% (n=18) in tumour blood vessels. All cases expressed Ki-67, which was expressed in >25% of tumour cells in 79.8% of cases (n=63). Direct significant associations were observed in SP expression between different tissue levels (p<0.01), between SP and NK-1R tumour cell membrane expression (p<0.01), and between joint SP and NK-1R expression in tumour cell cytoplasm and a higher expression of Ki-67 (p<0.05). CONCLUSION: The ubiquitous presence of SP strongly suggests a role for SP/NK-1R complex in tumour development and progression and possibly for NK-1R antagonists, such as L-773060, in the management of patients with oral cancer.