Laryngopharyngeal reflux disease:Updated examination of mechanisms,pathophysiology,treatment,and association with gastroesophageal reflux disease

Laryngopharyngeal reflux disease(LPRD)is an inflammatory condition in the laryngopharynx and upper aerodigestive tract mucosa caused by reflux of stomach contents beyond the esophagus.LPRD commonly presents with symptoms such as hoarseness,cough,sore throat,a feeling of throat obstruction,excessive throat mucus.This complex condition is thought to involve both reflux and reflex mechanisms,but a clear understanding of its molecular mechanisms is still lacking.Currently,there is no standardized diagnosis or treatment protocol.Therapeutic strategies for LPRD mainly include lifestyle modifications,proton pump inhibitors and endoscopic surgery.This paper seeks to provide a comprehensive overview of the existing literature regarding the mechanisms,pathophysiology and treatment of LPRD.We also provide an in-depth exploration of the association between LPRD and gastroesophageal reflux disease.

A combined treatment for patients with dry eye and associated laryngopharyngeal reflux:a real-life approach

AIM:To evaluate the efficacy and tolerability of administering a combined therapy in patients with dry eye syndrome(DES)and associated laryngopharyngeal reflux(LPR).METHODS:The study was retrospective,open,observational,and conducted in a real-life setting.Patients had pathological symptom assessment in dry eye(SANDE)and reflux symptom index(RSI)at baseline.Patients were re-assessed after 1mo and at the end of treatment.The treatment consisted of a three-month course based on the combined therapy:Gastroftal eye drops,one drop three times a day,and Gastroftal tablets,two tablets after lunch and two tablets after dinner.Tear break-up-time(TBUT)test,Schirmer test,RSI,and SANDE questionnaire were evaluated.RESULTS:The study included 253 patients.The mean age was 58±11.19y.TBUT test score and Schirmer’s test significantly increased(both P<0.001)after 1mo and at the end of treatment.The RSI score and SANDE scores significantly decreased(both P<0.001)after 1mo and at the end of treatment.CONCLUSION:The current,retrospective,and open study shows that combined therapy using Gastroftal eye drops and tablets could represent a valuable option in managing patients with DES associated with LPR.

Nissen fundoplication vs proton pump inhibitors for laryngopharyngeal reflux based on p H-monitoring and symptom-scale

AIM To compare the outcomes between laparoscopic Nissen fundoplication(LNF)and proton pump inhibitors(PPIs)therapy in patients with laryngopharyngeal reflux(LPR)and typeⅠhiatal hernia diagnosed by oropharyngeal p H-monitoring and symptom-scale assessment.METHODS From February 2014 to January 2015,70 patients who were diagnosed with LPR and type I hiatal hernia and referred for symptomatic assessment,oropharyngeal p H-monitoring,manometry,and gastrointestinal endoscopy were enrolled in this study.All of the patients met the inclusion criteria.All of the patients underwent LNF or PPIs administration,and completed a2-year follow-up.Patients’baseline characteristics and primary outcome measures,including comprehensive and single symptoms of LPR,PPIs independence,and satisfaction,and postoperative complications were assessed.The outcomes of LNF and PPIs therapy were analyzed and compared. RESULTS There were 31 patients in the LNF group and 39patients in the PPI group.Fifty-three patients(25 in the LNF group and 28 in the PPI group)completed reviews and follow-up.Oropharyngeal p H-monitoring parameters were all abnormal with high acid exposure,a large amount of reflux,and a high Ryan score,associated reflux symptom index(RSI)score.There was a significant improvement in the RSI and LPR symptom scores after the 2-year follow-up in both groups(P<0.05),as well as typical symptoms of gastroesophageal reflux disease.Improvement in the RSI(P<0.005)and symptom scores of cough(P=0.032),mucus(P=0.011),and throat clearing(P=0.022)was significantly superior in the LNF group to that in the PPI group.After LNF and PPIs therapy,13 and 53 patients achieved independence from PPIs therapy(LNF:44.0%vs PPI:7.14%,P<0.001)during follow-up,respectively.Patients in the LNF group were more satisfied with their quality of life than those in the PPI group(LNF:62.49±28.68 vs PPI:44.36±32.77,P=0.004).Body mass index was significantly lower in the LNF group than in the PPI group(LNF:22.2±3.1kg/m^2 vs PPI:25.1±2.9 kg/m^2,P=0.001).CONCLUSION Diagnosis of LPR should be assessed with oropharyngeal p H-monitoring,manometry,and the symptom-scale.LNF achieves better improvement than PPIs for LPR with type I hiatal hernia.

Laryngopharyngeal reflux in patients with reflux esophagitis

AIM: To assess the prevalence of laryngopharyngeal reflux (LPR) in patients with reflux esophagitis and dis-close factors contributing to the development of LPR. METHODS: A total of 167 patients who proved to have reflux esophagitis by endoscopy were enrolled. They received laryngoscopy to grade the reflux find-ings for the diagnosis of LPR. We used validated ques-tionnaires to identify the presence of laryngopharyn-geal symptoms, and stringent criteria of inclusion to increase the specificity of laryngoscopic findings. The data of patients were analyzed statistically to find out factors related to LPR. RESULTS: The prevalence rate of LPR in studied sub-jects with reflux esophagitis was 23.9%. Age, hoarse- ness and hiatus hernia were factors significantly as-sociated with LPR. In 23 patients with a hiatus hernia, the group with LPR was found to have a lower trend of esophagitis grading. CONCLUSION: Laryngopharyngeal reflux is present in patients with reflux esophagitis, and three predicting factors were identified. However, the development of LPR might be different from that of reflux esophagi-tis. The importance of hiatus hernia deserves further study.

How many cases of laryngopharyngeal reflux suspected by laryngoscopy are gastroesophageal reflux disease-related?

AIM:To investigate the prevalence of gastroesophageal reflux disease(GERD) in patients with a laryngoscopic diagnosis of laryngopharyngeal reflux(LPR).METHODS:Between May 2011 and October 2011,41 consecutive patients with laryngopharyngeal symptoms(LPS) and laryngoscopic diagnosis of LPR were empirically treated with proton pump inhibitors(PPIs) for at least 8 wk,and the therapeutic outcome was assessed through validated questionnaires(GERD impact scale,GIS;visual analogue scale,VAS).LPR diagnosis was performed by ear,nose and throat specialists using the reflux finding score(RFS) and reflux symptom index(RSI).After a 16-d wash-out from PPIs,all patients underwent an upper endoscopy,stationary esophageal manometry,24-h multichannel intraluminal impedance and pH(MII-pH) esophageal monitoring.A positive correlation between LPR diagnosis and GERD was supposed based on the presence of esophagitis(ERD),pathological acid exposure time(AET) in the absence of esophageal erosions(NERD),and a positive correlation between symptoms and refluxes(hypersensitive esophagus,HE).RESULTS:The male/female ratio was 0.52(14/27),the mean age ± SD was 51.5 ± 12.7 years,and the mean body mass index was 25.7 ± 3.4 kg/m 2.All subjects reported one or more LPS.Twenty-five out of 41 patients also had typical GERD symptoms(heartburn and/or regurgitation).The most frequent laryngoscopic findings were posterior laryngeal hyperemia(38/41),linear indentation in the medial edge of the vocal fold(31/41),vocal fold nodules(6/41) and diffuse infraglottic oedema(25/41).The GIS analysis showed that 10/41 patients reported symptom relief with PPI therapy(P < 0.05);conversely,23/41 did not report any clinical improvement.At the same time,the VAS analysis showed a significant reduction in typical GERD symptoms after PPI therapy(P < 0.001).A significant reduction in LPS symptoms.On the other hand,such result was not recorded for LPS.Esophagitis was detected in 2/41 patients,and ineffective esophageal motility was found in 3/41 patients.The MII-pH analysis showed an abnormal AET in 5/41 patients(2 ERD and 3 NERD);11/41 patients had a normal AET and a positive association between symptoms and refluxes(HE),and 25/41 patients had a normal AET and a negative association between symptoms and refluxes(no GERD patients).It is noteworthy that HE patients had a positive association with typical GERD-related symptoms.Gas refluxes were found more frequently in patients with globus(29.7 ± 3.6) and hoarseness(21.5 ± 7.4) than in patients with heartburn or regurgitation(7.8 ± 6.2).Gas refluxes were positively associated with extraesophageal symptoms(P < 0.05).Overall,no differences were found among the three groups of patients in terms of the frequency of laryngeal signs.The proximal reflux was abnormal in patients with ERD/NERD only.The differences observed by means of MII-pH analysis among the three subgroups of patients(ERD/NERD,HE,no GERD) were not demonstrated with the RSI and RFS.Moreover,only the number of gas refluxes was found to have a significant association with the RFS(P = 0.028 andP = 0.026,nominal and numerical correlation,respectively).CONCLUSION:MII-pH analysis confirmed GERD diagnosis in less than 40% of patients with previous diagnosis of LPR,most likely because of the low specificity of the laryngoscopic findings.

Laryngopharyngeal reflux disease management for recurrent laryngeal contact granuloma:A case report

BACKGROUND Laryngeal contact granuloma(LCG)is difficult to treat and frequently associated with high persistence and recurrence,despite the availability of both surgical and pharmacological treatment options.An appropriate strategy is therefore needed to help patients with multiple recurrences of LCG to potentially avoid unnecessary surgery.CASE SUMMARY We describe the case of a 34-year-old male patient with recurrent LCG in which a good response was achieved through successful management of laryngopharyngeal reflux disease using a combination pharmacotherapeutic regimen consisting of anti-reflux therapy,pepsin secretion inhibition,bile acid neutralization,and lifestyle modifications.This patient underwent surgery to excise the granuloma,then relapsed,underwent a second surgery,which was followed by a second recurrence.The granuloma then disappeared after 9 mo of combined treatment with ilaprazole enteric-coated capsules(10 mg qd),mosapride tablets(5 mg tid)and compound digestive enzyme capsules(2 tablets).The drug regimen was discontinued after one year,and no recurrence of the lesion has been reported during the one-year follow-up period.CONCLUSION We report a combination of pharmacotherapeutics and lifestyle modifications for the management of laryngopharyngeal reflux disease to address recurring LCG.

Esophageal Functional Changes in Obstructive Sleep Apnea/Hypopnea Syndrome and Their Impact on Laryngopharyngeal Reflux Disease

Background：Obstructive sleep apnea/hypopnea syndrome （OSAHS） and laryngopharyngeal reflux （LPR） disease have a high comorbidity rate,but the potential causal relation between the two diseases remains unclear.Our objectives were to investigate the esophageal functional changes in OSAHS patients and determine whether OSAHS affects LPR by affecting esophageal functions.Methods：Thirty-six OSAHS patients and 10 healthy controls underwent 24-h double-probed combined esophageal multichannel intraluminal impedance and pH monitoring simultaneously with polysomnography.High-resolution impedance manometry was applied to obtain a detailed evaluation of pharyngeal and esophageal motility.Results：There were 13 OSAHS patients （36.1%） without LPR （OSAHS group） and 23 （63.9%） with both OSAHS and LPR （OSAHS and LPR group）.Significant differences were found in the onset velocity of liquid swallows （OVL,P =0.029） and the percent relaxation of the lower esophageal sphincter （LES） during viscous swallows （P =0.049） between the OSAHS and control groups.The percent relaxation of LES during viscous swallows was found to be negatively correlated with upright distal acid percent time （P =0.016,R =-0.507）,and OVL was found to be negatively correlated with recumbent distal acid percent time （P =0.006,R =-0.557） in the OSAHS and LPR group.Conclusions：OSAHS patients experience esophageal functional changes,and linear correlations were found between the changed esophageal functional parameters and reflux indicators,which might be the reason that LPR showed a high comorbidity with OSAHS and why the severity of the two diseases is correlated.

Therapeutic efficacy observation of acupuncture plus medicine for laryngopharyngeal reflux due to liver-qi stagnation and spleen deficiency

Objective To observe the clinical efficacy of acupuncture plus medicine in treating laryngopharyngeal reflux due to liverqi stagnation and spleen deficiency.Methods A total of 70 patients were divided into a control group and an observation group by the random number table method,with 35 cases in each group.Both groups were treated with conventional medications,and the observation group was treated with additional acupuncture therapy.The reflux symptom index(RSI)and reflux finding score(RFS)were evaluated.Esophageal motility indicators such as lower esophageal sphincter pressure(LESP)and upper esophageal sphincter pressure(UESP),and salivary pepsin level were measured.The clinical efficacy was also compared.Results The total effective rate of the observation group was higher than that of the control group(P<0.05).After treatment,the RSI and RFS scores in both groups decreased significantly(all P<0.05),and the RSI and RFS scores in the observation group were significantly lower than those in the control group(both P<0.05).There were no significant changes in the LESP and UESP in the control group(both P>0.05),while LESP and UESP in the observation group increased significantly(both P<0.05),and higher than those in the control group(both P<0.05).The salivary pepsin levels in both groups decreased(both P<0.05),and the salivary pepsin level in the observation group was significantly lower than that in the control group(P<0.05).Conclusion Acupuncture plus medicine can improve symptoms and signs in patients with laryngopharyngeal reflux due to liver-qi stagnation and spleen deficiency,and regulate esophageal motility and salivary pepsin level.Its efficacy is more significant compared with medicine alone.

Laryngopharyngeal reflux disease, prevalence and clinical characteristics in ENT department of a tertiary hospital Tanzania

Background:Laryngopharyngeal reflux disease(LPRD)is a condition with nonspecific symptoms and most of times patients present late with advanced disease which may pre-dispose to malignancy.The magnitude and clinical characteristics of this condition are not well known among patients attending Otorhinolaryngology services in Tanzania.Materials and methods:This was a hospital based descriptive cross sectional study,conducted in the wards and clinics of Otorhinolaryngology department of Muhimbili National Hospital.Patients with symptoms of Laryngopharyngeal reflux disease were included in the study.Data was collected using questionnaires and clinical examination forms,were processed and analysed by using SPSS.Results presented in frequency tables,cross tabulations and figures.Results:This study recruited 256 participants among them males were 131(51.2%).The mean age was(41.38±13.94)years.Prevalence of Laryngopharyngeal reflux disease was 18.4%without gender predilection.The commonest symptoms were globus sensation,hoarseness of voice and excessive urge to clear the throat with 95.7%,88.1%and 83.0%respectively while the most observed signs were thick endolaryngeal mucus,Vocal cord oedema and partial ventricular obliteration with 90.9%,88.6%and 72.7%respectively.Lying down less than two hours after meal and spices foods consumption were the leading risk factors.Hypertension and Diabetes Mellitus type 2 were the most prevalent co morbid conditions associated with Laryngopharyngeal reflux disease.Conclusion:The prevalence of Laryngopharyngeal reflux disease is high among patients attending Otorhinolaryngology services at Muhimbili national hospital.All patients with Laryngopharyngeal reflux disease related symptoms should get thorough evaluation for early diagnosis and treatment.

Characteristic pathological findings and effects of ecabet sodium in rat reflux esophagitis

AIM： To explore the pathological findings in the entire esophagus in rats with reflux esophagitis, and the effects of ecabet sodium （ES）. METHODS： A rat model of chronic acid reflux esophagitis was used. In the treatment group, ES was administered after surgery （n = 16）. No drug was administered postoperatively to the esophagitis group （n = 9）. Shamoperated rats were used as a control group （n = 5）. Rats were sacrificed on day 7 after the operation. The epithelial thickness and leukocyte infiltration were examined in the upper, middle and lower areas of the esophagus. The survival rate, incidence of esophageal ulcer, and mean surface area and number of esophageal ulcers were determined in the esophagitis and ES groups. Esophageal histology was assessed in all three groups. RESULTS： Leukocyte infiltration in the esophagitis group was 26.3 ± 22.0 in the middle esophagus and 8.2 ± 4.9 in the upper esophagus, which was significantly greater than that in the controls （1.3 ± 1.1 and 1.4 ±1.0, respectively） （P 〈 0.05）. The thickness of the epithelium in the esophagitis group was 210.8 ± 47.7 μm in the lower esophagus and 204.2 ± 60.1 μm in the middle esophagus, which was significantly greater than that in the controls （26.0 ± 5.5 and 21.0 ± 6.5 μm, respectively） （P 〈 0.05）. The mean number of ulcers per animal in the ES group in the entire esophagus was 5.4 =1= 2.5, which was significantly less than that in the esophagitis group （9.0 ± 3.5） （P 〈 0.05）. The epithelial thickness in the ES group was 97.5 ± 32.2 μm in the lower esophagus, which was decreased compared with that in the esophagitis group （210.8 ± 47.7 μm） （P 〈 0.05）. CONCLUSION： Mucosal inflammation extended to the upper esophagus close to the hypopharynx. Our study suggested that ES may have a useful defensive role in reflux esophagitis.

Software improvement for evaluation of laryngopharyngeal pH testing(Restech)——a comparison between Data View 3 and 4

BACKGROUND When gastroesophageal reflux contents reach above the upper esophageal sphincter,patients may,in addition to typical reflux symptoms,present with atypical,extraesophageal symptoms related to laryngopharyngeal reflux(LPR).Surgical treatment of LPR has shown to lead to 70%symptom improvement,however no gold standard for the diagnosis of LPR exists.In 2007,the Restech Dx-pH was released as a valid method to measure acid exposure above the upper esophageal sphincter.Recently,a new software update was introduced for analysis of measured pH data and calculation of composite scores.The effect of the changes applied to the new software version have not yet been analyzed.AIM To compare results generated by Data View 3 to the most recently released Data View 4.METHODS All patients with gastroesophageal reflux disease symptoms were seen in a specialized surgical outpatient clinic for gastrointestinal function testing.Retrospective chart review was performed of all patients presenting with suspected gastroesophageal reflux disease and extraesophageal reflux symptoms,who underwent laryngopharyngeal pH monitoring using the Restech Dx-pH system(Respiratory Technology Corp.,Houston,TX,United States)and simultaneous esophageal pH monitoring.Data View 3 and Data View 4 were used to evaluate Restech studies obtained.Diary entries such as mealtimes,supine and upright periods,and symptoms were entered manually to ensure accuracy and precise conversion of data between both software versions.Paired t test was performed for statistical analysis of results.RESULTS A total of 174 patients(63.8%female)met inclusion criteria,all suffering from extraesophageal reflux symptoms as well as typical gastroesophageal reflux disease symptoms.Mean RYAN score upright was 48.77 in Data View 3 compared to 22.17 in Data View 4,showing a significant difference(~aP=0.0001).Similar results were shown for supine period(mean RYAN Score Data View 35.29 vs 1.42 in Data View 4,~cP=0.0001).For upright periods 80 patients showed a decrease of value of the RYAN score with a mean of-58.9(mean 51.1%decrease).For supine position 25 patients showed a decrease of value of the RYAN score with a mean of-15.13[range(-153.44)–(-0.01)],which equals a mean decrease of value of 44.5%.Ten patients showed no oropharyngeal acid exposure in Data View 3,but mild/moderate(n=7)or severe(n=3)acid exposure in Data View 4.Correlation with positive esophageal pH measurement was improved in all 10 patients.CONCLUSION Results of both software versions cannot be compared to each other.However,our data suggests that Data View 4 may be an improvement of the Restech pH measurement in the evaluation of LPR.

Gastrointestinal function testing model using a new laryngopharyngeal pH probe(Restech)in patients after Ivor-Lewis esophagectomy

BACKGROUND There is no established correlation between 24-h esophageal pH-metry(Eso-pH)and the new laryngopharyngeal pH-monitoring system(Restech)as only small case series exist.Eso-pH was not designed to detect laryngopharyngeal reflux(LPR)and Restech may detect LPR better.We have previously published a dataset using the two techniques in a large patient collective with gastroesophageal reflux disease.Anatomically,patients after esophagectomy were reported to represent an ideal human reflux model as no reflux barrier exists.AIM To use a human reflux model to examine our previously published correlation in these patients.METHODS Patients after Ivor Lewis esophagectomy underwent our routine follow-up program with surveillance endoscopies,computed tomography scans and further exams following surgery.Only patients with a complete check-up program and reflux symptoms were offered inclusion into this prospective study and evaluated using Restech and simultaneous Eso-pH.Subsequently,the relationship between the two techniques was evaluated RESULTS A total of 43 patients from May 2016-November 2018 were included.All patients presented with mainly typical reflux symptoms such as heartburn(74%),regurgitation(84%),chest pain(58%),and dysphagia(47%).Extraesophageal symptoms such as cough,hoarseness,asthma symptoms,and globus sensation were also present.Esophageal 24-hour pH-metry was abnormal in 88%of patients with a mean DeMeester Score of 229.45[range 26.4-319.5].Restech evaluation was abnormal in 61%of cases in this highly selective patient cohort.All patients with abnormal supine LPR were also abnormal for supine esophageal reflux measured by conventional Eso-pH.CONCLUSION Patients following esophagectomy and reconstruction with gastric interposition can ideally serve as a human reflux model.Interestingly,laryngopharyngeal reflux phases occur mainly in the upright position.In this human volume-reflux model,results of simultaneous esophageal and laryngopharyngeal(Restech)pHmetry showed 100%correlation as being explicable by one of our reflux scenarios.

重度气管软化致婴儿咽喉反流1例

1 临床资料患者,男,3月龄,因"反复面色青紫1月余"于2018-11-30入院。患儿于入院前1个月持续剧烈哭闹后出现憋气,表现为面色青紫、双眼紧闭、呼吸暂停、四肢苍白,不伴四肢强直抖动,无吐沫,持续约2 min左右,拍背等刺激后可缓解;反复发作十余次,无发热,无咳嗽,无鼻塞、流涕,无呕吐、腹泻,无烦躁、嗜睡。期间曾两次因"面色青紫"于我院住院:2018-11-15第1次入院,疑诊神经及心血管系统疾病。

Clinical relevance of salivary pepsin detection in diagnosing gastroesophageal reflux disease subtypes

Background:Gastroesophageal reflux disease(GERD)is heterogeneous with a varied symptom spectrum and reflux profiles.Its definite diagnosis often requires invasive tools including endoscopy or reflux monitoring.The aim of this study was to investigate the clinical relevance of salivary pepsin detection as a non-invasive screening tool to diagnose GERD of different subtypes.Methods:A total of 77 patients with suspected GERD symptoms and 12 asymptomatic controls were analysed.All participants performed symptom evaluation,upper endoscopy,esophageal manometry,and 24-hour multichannel intraluminal impedance-dual pH probe monitoring.Saliva was self-collected across three different time points:at early fasting,postprandially,and at symptom occurrence.Salivary pepsin levels were measured via Peptest.The optimal threshold of salivary pepsin for diagnosing distal or proximal reflux was determined according to a receiver-operating characteristic curve.Results:The average salivary pepsin concentration of suspected GERD patients was significantly higher than that of controls(100.63[68.46,141.38]vs 67.90[31.60,115.06]ng/mL,P=0.044),although no difference was found among patients with different symptom spectrums.The distal reflux group had a higher average pepsin concentration than non-reflux patients(170.54[106.31,262.76]vs 91.13[63.35,127.63]ng/mL,P=0.043),while no difference was observed between the distal reflux group and the proximal reflux group.The optimal cut-off value of salivary pepsin concentration for diagnosing pathological distal reflux was 157.10 ng/mL,which was higher than that for diagnosing pathological proximal reflux(122.65 ng/mL).The salivary pepsin concentration was significantly correlated with distal and proximal reflux parameters.Conclusions:Salivary pepsin measurement can help in identifying true GERD with pathological distal reflux or proximal reflux,regardless of different symptom spectrums.A higher threshold should be applied for diagnosing distal reflux than for proximal reflux.

Association of gastroesophageal reflux disease and laryngeal cancer

Objective:Studies examining the association of reflux disease with the risk of developing laryngeal cancer have both proven and disproven the null hypothesis.Methods:This retrospective caseecontrol study examines the association of reflux in two populations exposed to similar risk factors,including tobacco,to the extent that end-organ malignant transformation has occurred.After IRB approval was obtained,a search of our hospital’s cancer center’s database was performed from 2000 to 2013.A retrospective chart review was then performed and the prevalence of gastroesophageal reflux disease among patients with laryngeal cancer(n Z 290)was determined.It was then compared to the prevalence of gastroesophageal reflux disease among patients presenting with lung cancer(n Z 2440)during the same time period.A multivariate logistic regression was performed to determine the association of reflux with laryngeal cancer.Results:Taking into consideration tobacco use,there was a strong association between male gender and occurrence of laryngeal cancer as opposed to lung cancer(OR Z 3.30;95%CI 2.53e4.36,P<0.001).There was a modest association between reflux and laryngeal cancer(OR Z 1.65;95%CI 1.19e2.25,P Z 0.003).However,there was no association between reflux and the propensity for carcinoma in specific laryngeal subsites(P Z 0.47).Conclusions:In this study examining a heterogeneous population with end-organ malignancy there was a modest association between reflux and laryngeal cancer.Further research is necessary to determine the biologic relevance of this finding.