Laryngopharyngeal Reflux in Hypertrophic Laryngeal Diseases.

OBJECTIVES: To evaluate the characteristics of laryngopharyngeal reflux (LPR) in patients with different hypertrophic laryngeal diseases and to explore the relationship between LPR and these diseases. METHODS: A retrospective analysis was performed. The clinical data of 154 patients were collected. According to their diagnoses, patients were divided into 3 groups. Group 1 included 49 patients with vocal cord polyps. Group 2 contained 52 patients with vocal cord leukoplakia. Group 3 included 53 patients with laryngeal carcinoma. The reflux symptom indexes (RSIs), reflux finding scores (RFSs), and Ryan scores of all patients were evaluated and compared. RESULTS: Patients with vocal cord polyps were the youngest of the 3 groups, and those with laryngeal carcinoma were the oldest. A male preponderance emerged in each group. In total, 128 patients (83.12%) had positive RSI/RFS values and 60 (60/146, 41.1%) patients had positive Ryan scores. The positive RSI/RFS rates of both groups 1 and 2 (89.80% and 92.16%, respectively) were significantly higher than that of group 3 (69.81%). Moreover, the positive Ryan score rates in both groups 1 and 2 (39.58% and 53.85%, respectively) were significantly higher than that of group 3 (28.26%). CONCLUSIONS: Laryngopharyngeal reflux occurs in many patients with vocal cord polyps, vocal cord leukoplakia, and vocal cord carcinoma, indicating that LPR may be important in the pathogenesis of these diseases. Laryngopharyngeal reflux occurs more common in patients with vocal cord polyps and leukoplakia and less common in those with laryngeal carcinoma, suggesting the role of LPR on these diseases may be different.

Involvement of Laryngopharyngeal Reflux in Select Nonfunctional Laryngeal Diseases: A Systematic Review.

OBJECTIVES: To investigate the existing published evidence supporting the role of laryngopharyngeal reflux (LPR) in the development of the select nonfunctional laryngeal diseases of laryngotracheal stenosis, granuloma, leukoplakia, and laryngeal infections. DATA SOURCES: PubMed, Cochrane Library, and Scopus. REVIEW METHODS: A systematic review was performed by 3 independent investigators for studies providing information about the prevalence and role of LPR in the development of laryngotracheal stenosis, granuloma, leukoplakia, and laryngeal infections. Diagnostic criteria and clinical outcome evaluation of included studies were analyzed with PRISMA criteria. RESULTS: Of the 64 relevant publications, 27 clinical and 4 basic science studies were included. Ten studies used objective reliable examinations for LPR diagnosis (eg, dual- or triple-probe or oropharyngeal pH monitoring, multichannel intraluminal impedance-pH monitoring, or pepsin detection). According to the bias analysis and the results of studies, the association between LPR and laryngotracheal stenosis, leukoplakia, laryngeal papillomatosis, or vocal fold granuloma remains poorly demonstrated. There is a notable heterogeneity among included studies regarding their inclusion criteria, diagnostic methods, and clinical outcome evaluation. Although some experimental findings support the involvement of bile salts and other gastroduodenal proteins active in alkaline pH, no included clinical studies assessed the role of nonacid and mixed reflux through multichannel intraluminal impedance-pH monitoring. CONCLUSION: The involvement of LPR in the development of leukoplakia, laryngotracheal stenosis, vocal fold granuloma, and laryngeal papillomatosis is currently not demonstrated. The potential relationship between LPR and these select nonfunctional laryngeal diseases must be confirmed through future clinical and experimental studies considering acid, nonacid, and mixed LPR.

Recognition of oral potentially malignant disorders and transformation to oral cancer.

Oral potentially malignant disorders refer to oral mucosal disorders with increased risk for malignant transformation, primarily to oral squamous cell carcinoma (SCC). Leukoplakia and erythroplakia are the most common of these disorders, but others have been identified. Transformation rates to oral cancer vary based on multiple factors. Healthcare providers should be aware of risk factors and clinical manifestations of these disorders and should intervene early to monitor and/or treat them to reduce the potential for malignant transformation.

[Clinical analyses of 263 patients with laryngeal leukoplakia].

Objective: To investigate the etiology, clinical and pathological characteristics of laryngeal leukoplakia and the predictive risk factors of recurrence and malignant transformation. Methods: Clinical data of 263 patients with laryngeal leukoplakia between January 2000 and December 2015 were analyzed retrospectively. Results: The pathological diagnoses included squamous epithelial hyperplasia (54.4%), mild dysplasia (17.9%), moderate dysplasia (12.2%), severe dysplasia and carcinoma in situ (12.5%), and invasive carcinoma (3.0%). Age and the extent of lesion were statistically different among different pathological groups (P<0.05). Gender, smoking and alcohol consumption did not show statistical differences among different pathological groups (P>0.05). Follow-up of 215 patients, excluding 6 cases of invasive carcinoma. The recurrence rate was 20.6%(43/209), and the malignant transformation rate was 5.3%(11/209). Multivariate analysis showed that pathological classification of moderate to severe dysplasia was the independent risk factor for recurrence and malignant transformation of laryngeal leukoplakia (P<0.05). In patients with severe dysplasia and carcinoma in situ, the recurrence proportion of conservative treatment, vocal cords (partial) resection and radiotherapy were 8/10, 0/10 and 2/11 respectively. Conclusions: Laryngeal leukoplakia occurs frequently in elderly men with long-term smoking history. Pathological diagnoses are different. The grade of dysplasia is the predictive risk factor for the recurrence and malignant transformation of laryngeal leukoplakia. More aggressive treatment and closer follow-up should be warranted for patients with moderate dysplasia, severe dysplasia and carcinoma in situ.

[Analyses of pathogenic factors and clinicopathological characteristics of vocal leukoplakia].

Objective: To investigate the pathogenic factors of vocal leukoplakia and its clinical and pathological features. Methods: Eighty-one patients with vocal cord leukoplakia who underwent surgery between February 2010 and December 2016 and 160 volunteers without pharyngeal symptoms designed as controls were included in this case control study. The clinicopathological characteristics of 81 patients were summarized and analyzed synthetically. Results: There was statistical significance in reflux symptom index(RSI), reflux finding score(RFS), smoking index, and drinking index between case group and control group(Z=-5.35, -4.82, -4.76, -2.44, P<0.05). The voice-using duration per day in case group was significantly longer than that of control group.There was no statistical significance in hospital anxiety and depression scale for anxiety(HADA) scores、hospital anxiety and depression scale for depression(HADD) scores between case group and control group(P>0.05). In 42 patients who received 24-hour dual probe pH monitoring the prevalence of pathologic LPR was 42.8%. In 81 patients, 39(48%)patients were pathologically diagnosed as squamous cell hyperplasia, 18(22%)patients as mild dysplasia, 12(15%)sides as moderate dysplasia , 10(12%)patients as severe dysplasia and 2(2%)patients as carcinoma in-situ. The average age of high-risk pathological vocal leukoplakia was significantly higher than that of low-risk leukoplakia(t=-2.73, P<0.01). The propotion of speckled leukoplakia in high-risk leukoplakia was significantly higher than that of low-risk leukoplakia(χ(2)=23.81, P<0.01). There was no statistical significance between high-risk leukoplakia and low-risk leukoplakia in the prevalence of pathologic LPR(P>0.05). The bilateral lesions, speckled leukoplakia were more likely to relapse(χ(2)=4.27, 12.17, P<0.05). The more serious the pathology, the more likely it was to relapse (Z=-2.168, P=0.03). There was no statistical significance between recurrence group and non-recurrence group in the prevalence of pathologic LPR(P>0.05). Conclusions: LPR, smoke constitute the risk factors of vocal cord leukoplakia. Drinking, voice abuse are related to vocal cord leukoplakia. Senile, speckled leukoplakia are more likely to be malignancy. A speckled leukoplakia, bilateral leukoplakia, severe pathological degree are important factors to predict recurrence.

[Observational study on patients with laryngeal cancer and/or vocal leukoplakia concurrent with laryngopharyngeal reflux].

Objective: To observe the incidence and to determine the significance of laryngopharyngeal reflux (LPR) in laryngeal cancer and vocal leukoplakia. Methods: The patients who had been diagnosed as laryngeal cancer or vocal leukoplakia between January 2014 and June 2017 were included in this study. All of them received 24-hour multichannel intraluminal impedance-pH monitoring. The prevalence of LPR and numerous parameters from the 24-hour pH monitoring in laryngeal cancer patient and vocal leukoplakia patient groups were analyzed. The chi-square test was used for counting data, t test and Mann-Whitney U were used for measuring data. Results: In the 91 laryngeal cancer patients, the prevalence of pathologic LPR was 28.6%(26/91), the median number[P(25), P(75), P(95)]of acid reflux events was 0[0, 3, 5], time of acid exposure was 0[0, 14, 234]s, number of weakly acidic reflux events was 3[0, 6, 11]. In the 54 vocal leukoplakia patients, the prevalence of pathologic LPR was 29.6%(16/54), the number of acid reflux events was 0[0, 3, 4], time of acid exposure was 0[0, 13, 118]s, number of weakly acidic reflux events was 1.5[0, 5, 9]. The incidence of LPR did not vary in the laryngeal cancer patient and vocal leukoplakia patient groups, but were both higher than healthy Chinese volunteers according to a report in the other literature. Furthermore, all the three patients with no history of tobacco or alcohol existed acid or weakly acidic reflux episodes. Conclusions: Laryngopharyngeal reflux might play a role as an etiologic factor in laryngeal cancer and vocal leukoplakia.

[The role of NF-κB signaling pathway in laryngeal leukoplakia recurrent with laryngeal reflux].

Objective: To study the mechanism of vocal mucosal barrier damage mediated by NF-κB and NF-κB-regulated signaling pathway via probing the expression of inflammatory factors and essential proteins for node of NF-κB signaling pathway. Methods: The patients suffering from vocal leukoplakia accompanied with larygopharyngeal reflux(LPR) were treated with oral administration of proton pump inhibitor(PPI). Mucosal specimens of vocal cord were collected from all patients before PPI treatment. And the mucosal specimens of vocal cord were collected from the patients with suspected recurrence at 8 weeks after PPI treatment. HE staining was used to observe the histopathological changes of the mucosa. ELISA was utilized to detect the levels of inflammatory factors including tumor necrosis factor(TNF)-α, interleukin(IL)-1 and IL-6. Western blot was used to detect the expression of p-p65, p-IKK and p-IκB. Immunofluorescence method was adopted to detect the entrance of p65 to cell nucleus.Data was analyzed by SPSS 23.0 software. Results: In PPI untreated group, the expressions of IL-1ß, TNF-α and IL-6 in the specimens of 8 weeks after operation were not different significantly from those obtained during operation.But in the PPI-treated group, the expressions were down-regulated.The expression of p-p65 in the middle and high grade heterogenous hyperplasia group was higher than that of low level heterogenous hyperplasia group.The difference of p65 and p-p65 expression between 8 weeks after surgery and surgery in PPI-untreated group was statistically insignificant (P>0.05). The difference of p65 expression between PPI-treated group and PPI pre-treatment group was statistically insignificant (P>0.05). The expression of p-p65 in the PPI-treated group was lower than that of the PPI pre-treatment group (P<0.05). The expressions of IL-1ß, TNF-α and IL-6 were positively related with that of NF-κB-p65. Immun of luorescence method revealed the entrance of p65 to cell nucleus in PPI pre-treatment group, which meant that NF-κB was activated. In the PPI-treated group, few activated p65 could be observed in the cell nucleu. Conclusion: The possible mechanism of vocal mucosal barrier damage in vocal leukoplakia accompanied with LPR maybe the vocal mucosal inflammation mediated by NF-κB and NF-κB-regulated signaling pathway activated with refluxed materials.

Detecting Laryngopharyngeal Reflux by Immunohistochemistry of Pepsin in the Biopsies of Vocal Fold Leukoplakia.

Laryngopharyngeal reflux (LPR) may contribute to the development of laryngeal diseases including vocal fold leukoplakia. Clinical methods of determining LPR are limited. Pepsin, as an exogenous protein, is considered as a biomarker of LPR. The aim of the current study was, therefore, to detect pepsin by immunohistochemistry in the biopsies from patients with vocal fold leukoplakia, and by which, to determine the potential association of LPR and vocal leukoplakia. A total of 26 biopsies from patients with vocal fold leukoplakia were examined in comparison with 20 vocal fold biopsies from control subjects. We found that 2 out of 26 patients (7.7%) were strongly positive, 4 of the 26 (15.4%) patients were positive, 11 of the 26 (42.3%) patients were weakly positive, and 9 of the 26 (34.6%) were negative staining for pepsin. In contrast, only 4 of the 20 (20.0%) control subjects were weakly positive and the rest (16; 80.0%) were negative staining for pepsin. There was significant difference between the two groups in terms of positivity of pepsin staining (χ2 = 24.181, P <0.001). These findings suggest that pepsin immunohistochemical staining could be a biomarker of LPR and that LPR may be a risk factor for the development of vocal fold leukoplakia.

[THE ROLE OF PAPILLOMAVIRUS INFECTION IN THE DEVELOPMENT OF BACKGROUND DISEASE OF THE CERVIX].

Papillomavirus infection is one of the most common sexually transmitted infections. The aim of the study was to study the etiologic significance of the papillomavirus infection in the development of background diseases of the cervix and neoplasia. Under observation were 62 patients aged 18 to 55 years infected with human papillomavirus. All patients underwent complex clinical and anamnestic, laboratory and instrumental examination. Also, a review and advanced colposcopy was performed. As a result of the study, 53 (85.4%) women under observation were found to have various pathologies of the cervix. Dysplasia of mild degree (CIN 1 degree) was found in 12 (57.1%), moderate dysplasia (CIN 2 degree) - in 9 (42.9%) women. With further examination, it was found that patients along with dysplasia of varying severity had concomitant pathology of the cervix uteri. Cervical dysplasia was most often diagnosed in combination with another pathology of the cervix, which accounted for 85.7% of cases. It has been established that squamous epithelial lesion of the cervix is most often a consequence of late diagnosis and an untreated background process. At the same time, modern diagnostics requires a whole range of diagnostic measures to establish a diagnosis in the early stages of development and conduct differential diagnosis of a benign or malignant process.

Prevalence and distribution of oral mucosal lesions: a cross-sectional study in Shanghai, China.

BACKGROUND: An epidemiological study on the oral mucosal lesions (OMLs) in general population from China was scarce. The objective of this study was to investigate the prevalence and distribution of OMLs in Shanghai, China and to evaluate their association with demographic factors and smoking/drinking habits based on a large scaled population on a wide spectrum. METHODS: In this population-based cross-sectional study, 11054 community-dwelling individuals (M/F: 5140/5914; age range, 1-96 years) were randomly selected and examined according to WHO criteria. RESULTS: The prevalence of OMLs was 10.8% in this study. A total of 1192 (M/F: 543/649; mean age, 56.9 years) individuals were presented with different types of OMLs. The most common type of OMLs was fissured tongue (prevalence of 3.15%), followed by recurrent aphthae (1.48%), traumatic ulcer (1.13%), and angular cheilitis (0.86%). The two most common potentially malignant disorders were oral lichen planus (0.81%) and leukoplakia (0.22%). Regression analysis revealed that the elderly age, smoking, and alcohol intake were statistically significant risk factors of OMLs with emphasis on leukokeratosis, leukoplakia, and lichen planus. CONCLUSION: The prevalence and distribution of OMLs were elucidated in an eastern area of China, and the importance of tobacco and alcohol in the pathogenesis of OMLs was evidenced. Our data have provided baseline information about epidemiologic aspects of OMLs that can be valuable in organized program targeting on oral health and hygiene.

Comprehensive SNP scan of DNA repair and DNA damage response genes reveal multiple susceptibility loci conferring risk to tobacco associated leukoplakia and oral cancer.

Polymorphic variants of DNA repair and damage response genes play major role in carcinogenesis. These variants are suspected as predisposition factors to Oral Squamous Cell Carcinoma (OSCC). For identification of susceptible variants affecting OSCC development in Indian population, the "maximally informative" method of SNP selection from HapMap data to non-HapMap populations was applied. Three hundred twenty-five SNPs from 11 key genes involved in double strand break repair, mismatch repair and DNA damage response pathways were genotyped on a total of 373 OSCC, 253 leukoplakia and 535 unrelated control individuals. The significantly associated SNPs were validated in an additional cohort of 144 OSCC patients and 160 controls. The rs12515548 of MSH3 showed significant association with OSCC both in the discovery and validation phases (discovery P-value: 1.43E-05, replication P-value: 4.84E-03). Two SNPs (rs12360870 of MRE11A, P-value: 2.37E-07 and rs7003908 of PRKDC, P-value: 7.99E-05) were found to be significantly associated only with leukoplakia. Stratification of subjects based on amount of tobacco consumption identified SNPs that were associated with either high or low tobacco exposed group. The study reveals a synergism between associated SNPs and lifestyle factors in predisposition to OSCC and leukoplakia.

[Oral cavity changes in patients after kidney transplantation and preventive-treatment algorithms]. / Zmiany chorobowe w jamie ustnej u pacjentów po transplantacji nerki i algorytmy postepowania profilaktyczno-leczniczego.

Kidney transplantation is the best option of treatment for patients with end-stage renal failure. However, following kidney transplantation many stomatological abnormalities are frequently reported. It is mainly due to immunosuppressive therapy and subsequent impaired immune response. There is an increased risk of infections and malignancies. The most frequent findings in the oral cavity include: aphthae, erosions of bacterial, viral and fungal origin, lichen-like or leukoplakia-like changes. The another type of change is gingival hyperplasia and its periodontologial consequences. In this review etiology, clinical symptoms of periodontological changes are described together with algorithm of pre- and posttransplant management of oral healthy is provided.

Prevalence of CYP1A1 and GST polymorphisms in the population of northeastern India and susceptibility of oral cancer.

Individual cancer susceptibility is the result of several host factors, including differences in lifestyle habits and genetic susceptibility. There is a correlation between CYP1A1 polymorphism (MspI) and oral cancer susceptibility. Individuals carrying the deletions of GSTM1 and GSTT1 are at high risk of developing oral cancers. In the present study on healthy tribal and nontribal individuals of Assam, we found that the genetic variation of GSST polymorphisms is evident (p = 0.20) with differential dose of toxic exposure. Prevalence of different polymorphic alleles of CYP1A1 also proves the same result. A mini-case-control study with very small sample size showed no marked increase in the risk of developing oral cancer as the frequencies of the studied GST genotypes did not show any statistical significance. But GSTT1-null genotypes were found to have higher risk of developing leukoplakia (OR 1.94, 95% CI 2.61-18.54). CYP1A1 genotype m2 allele was also not found to be associated with the risk of developing leukoplakias in the population.

Polymorphisms at p53, p73, and MDM2 loci modulate the risk of tobacco associated leukoplakia and oral cancer.

Polymorphisms at loci controlling cellular processes such as cell cycle, DNA repair, and apoptosis may modulate the risk of cancer. We examined the association of two linked polymorphisms (G4C14-A4T14) at p73 and one polymorphism (309G > T) at MDM2 promoter with the risk of leukoplakia and oral cancer. The p73 and MDM2 genotypes were determined in 197 leukoplakia patients, 310 oral cancer patients and in 348 healthy control subjects. The p73 GC/AT genotype increased the risk of leukoplakia (OR = 1.6, 95% CI = 1.1-2.3) and oral cancer (OR = 2.4, 95% CI = 1.7-3.3) but the 309G > T MDM2 polymorphism independently could not modify the risk of any of the diseases. Stratification of the study population into subgroups with different tobacco habits showed that the risk of the oral cancer is not modified further for the individuals carrying p73 risk genotype. However, leukoplakia patients with smokeless tobacco habit showed increased risk with combined GC/AT and AT/AT (OR = 3.0, 95% CI = 1.3-7.0) genotypes. A combined analysis was done with our previous published data on p53 codon 72 pro/arg polymorphism. Analysis of pair wise genotype combinations revealed increase in risk for specific p73-MDM2 and p73-p53 genotype combinations. Finally, the combined three loci analyses revealed that the presence of at least one risk allele at all three loci increases the risk of both leukoplakia and oral cancer.

[Chronic laryngitis--associated factors and voice assessment]. / Chronische Laryngitis--assoziierte Faktoren und subjektive Stimmeinschätzung.

BACKGROUND: Chronic laryngitis may be a predisposing factor for laryngeal carcinoma. METHOD: 100 consecutive chronic laryngitis patients were assessed for associated factors for this disease. Voice assessment was undertaken, including objective measurement, subjective assessment of sound and a self-assessment by questionnaire--the so-called Voice Handicap Index (VHI). When laryngostroboscopy of the vocal cords was suspicious, then microlaryngoscopy with biopsy and histological examination was undertaken. RESULTS: The main associated factors were found to be nicotine abuse (50 patients), gastro-esophageal/laryngo-esophageal reflux (35 patients) and inhaled corticosteroid therapy (25 patients). Subjectively, all patients considered their voices to be relatively healthy (VHI less than 15). Objective voice parameters and subjectively listening were of no prognostic significance. Indirect microscopic examination could diagnose chronic laryngitis in 31 of cases, rising to 69 when leucoplakia was present. In 6 patients the mucosal wave was found stroboscopically to be abnormal. Additionally these patients underwent direct laryngoscopy and biopsy. On histological examination one of them had a high grade dysplasia and two of them had a carcinoma in situ. CONCLUSION: Patients with chronic laryngitis or development of vocal cord leucoplakia often abuse nicotine, use inhaled corticosteroids for bronchial asthma or suffer from acid reflux. As many patients with chronic laryngitis/leucoplakia subjectively often do not experience any voice limitations, stroboscopic investigation is useful for the early recognition of malignant change.

Morsicatio mucosae oris--a chronic oral frictional keratosis, not a leukoplakia.

PURPOSE: Morsicatio mucosae oris (MMO) presents as white papules and plaques that may resemble leukoplakia, and are often biopsied. The objective of this study is to document the clinical features and histopathology of MMO and to reevaluate the prevalence of dysplasia and/or cancer when this frictional keratosis is removed from the category of leukoplakia. MATERIALS AND METHODS: Cases that were submitted to a single laboratory with a provisional diagnosis of "leukoplakia," "hyperkeratosis," or "white lesion" were evaluated. RESULTS: Fifty-six lesions of MMO from 56 patients were identified out of 584 white lesions. Most cases occurred in the third to sixth decades of life. Thirty (53.6%) and 18 (32.1%) out of 56 lesions were located on the lateral tongue and buccal mucosa, respectively. The lesions showed hyperparakeratosis with a characteristic frayed, shaggy, peeling surface, and acanthosis with insignificant inflammation. When MMO is removed from the category of leukoplakia, the percentage of true leukoplakia that are dysplastic or malignant increased by 12.9%. CONCLUSIONS: MMO is a form of chronic oral frictional keratosis that has no malignant potential, and should be signed out as such and not merely "hyperparakeratosis and acanthosis" so that it can be removed from the category of leukoplakia where it does not belong.

[Endoscopic chromoscopy in diagnosing and treatment of complicated gastroesophageal reflux disease].

The authors describe the results of examination and endoscopic treatment of 278 patients with clinical symptoms of gastroesophageal reflux disease. The method of fibroesophagoduodenoscopy with 3% Lugol aqueous solution chromoscopy was introduced in medical-diagnostic algorithm of the patients. Inclusion of chromoendoscopy in the program of examination and treatment of patients with gastroesophageal reflux disease allowed higher detection of severe epithelial dysplasia (to 10.3%), leukoplakia (to 62.1%) and esophagus cancer (to 3.5%) and improvement of the results of endoscopic treatment.

Natural history of potentially malignant oral lesions and conditions: an overview of the literature.

At a workshop coordinated by the WHO Collaborating Centre for Oral Cancer and Pre-cancer in the UK issues related to potentially malignant disorders of the oral cavity were discussed by an expert group. The consensus views of the Working Group are presented in a series of papers. In this report we review the literature on the epidemiology and natural history of potentially malignant disorders (PMD), detailing those characteristics of the patients and lesions thought to be associated with future development of oral squamous cell carcinoma (OSCC). Older patients, particularly females are more at risk than younger patients; the duration of PMD may be important. Those who have never used tobacco seem at greater risk than smokers. OSCC is more likely with PMD on the lateral and ventral tongue, floor of mouth and retromolar/soft palate complex than with those elsewhere. The vast majority of PMD in which OSCC develop are non-homogenous although 5% of homogenous PMD will develop carcinoma. Large lesions covering several intraoral subsites also appear more at risk.

Tobacco smoke induces urokinase-type plasminogen activator and cell invasiveness: evidence for an epidermal growth factor receptor dependent mechanism.

Multiple tobacco smoke-related premalignant and malignant lesions develop synchronously or metachronously in various organ sites, including the oral cavity. Both field cancerization and clonal migration seem to contribute to the occurrence of multiple tumors. Although the importance of endogenous factors (e.g., oncogenes) in regulating clonal migration is well established, little is known about the role of exogenous factors. Hence, the main objective of this study was to elucidate the mechanism by which tobacco smoke stimulated the migration of cells through extracellular matrix (ECM). Treatment of MSK-Leuk1 cells with a saline extract of tobacco smoke induced the migration of cells through ECM. Tobacco smoke induced the expression of urokinase-type plasminogen activator (uPA), resulting in plasmin-dependent degradation of ECM and increased cell migration. AG1478, a small-molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, a neutralizing antibody to EGFR, or an antibody to amphiregulin, an EGFR ligand, also blocked tobacco smoke-mediated induction of uPA and cell migration through ECM. PD98059, an inhibitor of mitogen-activated protein kinase (MAPK) kinase activity, caused similar inhibitory effects. Taken together, these results suggest that tobacco smoke activated the EGFR-->extracellular signal-regulated kinase 1/2 MAPK pathway, causing induction of uPA. This led, in turn, to increased plasmin-dependent degradation of matrix proteins and enhanced cell migration through ECM. These data strongly suggest that chemicals in tobacco smoke can mimic the effects of oncogenes in regulating uPA-dependent cell invasion through ECM. These findings also strengthen the rationale for determining whether inhibitors of EGFR tyrosine kinase reduce the risk of tobacco smoke-related second primary tumors.