Loss Of Fragile Histidine Triad Expression In Laryngeal Carcinoma And Its Potential Clinical Implication

Squamous cell carcinoma (SCC)is the most common histology oflaryngeal tumour.In spite of the advances in new strategies ontherapy and diagnosis,overall long-term survival remains low dueto uncontrollable persistent or recurrent disease.It is required tosearch for new approaches for diagnosis andtreatment . Improvement of molecular biology reveals thatcarcinogenesis is related with a series of genetic events based onthe dysfunction of tumor suppressor genes,oncogenes or growthfactors.Molecular identification of tissue biomarkers in diagnosticbiopsy specimens may potentially offer new modalities for earlydiagnosis,monitoring and treatment alternatives for patients withmalignancy diseases.The fragile histidine triad (FHIT) gene is a candidate tumorsuppressor gene located at chromosome 3p14.2,spanning theFRA3B common fragile site . Frequent allelic losses andhomozygous deletions,as well as the loss of heterozygosity(LOH) in microsatellites located at FHIT gene have been describedat the FHIT locus in several human solid tumors arising fromepithelial cells,including laryngeal carcinoma.However,themechanisms through which FHIT mediates its suppressor functionare not well established. FHIT protein is presumed to have tumorsuppressor function,being as some role as a cell cycle inhibitorfactor and a stimulator of apoptosis.FRA3B is an important targetof environmental carcinogens (tobacco smoking) damage at amolecular level.Fragile sites are susceptible to carcinogen-inducedalterations,and the disruption of FRA3B fragile sites will causeFHIT deletions.The purpose of this work is to investigate the role of FHIT in thepathogenesis and progression of laryngeal squamous cellcarcinoma (LSCC) using immunohistochemistry for Fhitexpression.The FHIT expression status was correlated with toclinicopathologic characteristics,including p53 expression andPCNA (proliferating cell nuclear antigen) expression.We analyzed60 patients with LSCC.In addition,25 adjacent tissues,25laryngeal keratosis tissues and 20 polyp of vocal cord tissues wereserved as internal controls.Normal noncancerous epithelium canpresent as polyp of vocal cord tissues,and precancerous conditioncan present as laryngeal keratosis tissues.Immunohistochemicalanalysis showed a simple and reliable method to detect FHITalterations in tumor cells.Immunohistochemical evaluation wasperformed by a pathologist in a blind test without knowledge of theclinical parameters and outcome.We found 6.7% of abnomal FHIT expression (markedly reduced orlost)in LSCC tissues and none of abnomal FHIT expression wasfound in polyp of vocal cord tissues.Alterations of the FHITexpression have also been found in laryngeal keratosis tissues(32.0%) and adjacent tissues (36.0%) . The results showedstatistically significant but between laryngeal keratosis tissues andadjacent tissues . No correlation was found between FHITexpression and clinical characteristics,including age,gender,tumor primary sites,lymph node status,stage grouping andhistologic grade.LSCC are thought to arise from a multistepprocess with histologically distinct precursor phenotypes thatharbour specific genetic alterations.Our data supports that FHITalteration maybe play an important role in carcinogenesis ofLSCC . It appears particularly important in canceration andindependent of progression.Loss of FHIT protein expressionmaybe a early-stage incident in the malignanttransformation.Patients whose premalignant lesions or adjacenttissues specimens showed low or no expression of FHIT hadsignificantly more risk to occur malignant transformation ofnormal squamous epithelia.Immunohistochemical detection ofFHIT expressionis feasible to detect occult carcinoma in patients atrisks for LSCC,may be an additional tool for selecting patientsthat may benefit from more aggressive treatmentmodalities.During surgical excision,the detection of FHITexpression is also applied to certain surgical region.To thosetissues,whose margins are histological negative,accompaniedwith loss of FHIT expression are,but even so be removed.We did not find the significant association between FHIT and p53alterations . FHIT disruption is independent of p53abnormality.Effects on cell growth inhibition and apoptosisinduced by FHIT seem different from those of p53.In our study,PCNA-LI (PCNA labelling index)of tumoral cellswere compared to FHIT expression.We have found a significantcorrelation between negative FHIT expression and the highPCNA-LI.It suggests that tumor cells with low FHIT expressionproliferate aggressively.and they might contribute to tumorgrowth.In conclusion,we found 61.7% of low FHIT expression in LSCC,and the significant correlation between FHIT expression andPCNA expression.FHIT alteration may play an important role inthe cancer development of LSCC . Alterations of the FHITexpression have also been found in laryngeal keratosis tissues(32.0%) and adjacent tissues (36.0%),at significant frequency.Ourstudy demonstrated Loss of FHIT protein expression maybe play aimportant role in the early-stage of the malignant transformation ofLSCC.FHIT alteration is associated with a high proliferation thatresults in an aggressive behavior.Further investigation in a largerpatient population with the follow-up period more than five yearsis required to verify weather loss of FHIT correlates with prognosisand survival.