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In Video S1, a new surgical technique for hybrid primary tracheoesophageal (TE) puncture in stapler-assisted total laryngectomy is shown. The video describes the surgical steps of the procedure and illustrates some tips and tricks. The procedure incorporates an upper mini-pharyngotomy to enable retrograde placement of the voice prosthesis (VP), eliminating the need for rigid esophagoscopy. This has made it possible to exploit, without additional risks, the potential of the stapler combined with primary TE puncture and VP placement. In our experience, this hybrid procedure in stapler-assisted total laryngectomy is not related to adverse events such as pharyngocutaneous fistula (PCF), hypertonicity, and functional complications. Therefore, it can be considered a valid technique that allows for easy insertion of a primary voice prosthesis also in case of mechanical sutures., (© 2023 Wiley Periodicals LLC.)

Objectives: We aim to analyse long-term voice outcomes and quality of life (QoL) in patients undergoing open partial horizontal laryngectomy type II (OPHL type II) and to compare them to those obtained by patients undergoing total laryngectomy (TL) with voice prosthesis (VP)., Design: Cross-sectional cohort study., Setting: Patients undergoing surgery for advanced laryngeal cancer, assessed during the usual follow-up consultations at the Phoniatric Unit (February 2020-December 2020)., Participants: Forty-five patients were enrolled and divided into two groups: OPHL group and TL group., Main Outcomes Measures: Acoustic analysis, maximum phonation time, INFV 0  scale, I-SECEL, UW-QoL-V4 and MDADI questionnaires were used to assess the long-term outcomes., Results: Voices of patients undergoing OPHL Type II were worse than those of laryngectomised patients with VP. Nevertheless, scores in voice and dysphagia-related QoL were comparable and scores in the social domain of QoL were higher in OPHL group., Conclusions: Open partial horizontal laryngectomy Type II allows an acceptable voice recovery and a satisfactory QoL., (© 2022 John Wiley & Sons Ltd.)

There are controversial results about the role of "ex novo" HLA-DR expression by tumor cells and its correlation with the oncological outcomes. Unfortunately, little is known about HLA-DR expression in laryngeal cancer tumor cells. The main purpose of this retrospective study is to strengthen the usefulness of studying "ex novo" HLA-DR expression on tumor cells from primary laryngeal squamous cell carcinoma (LSCC) patients and investigate its correlation with clinical outcome. We analyzed HLA-DR expression by immunohistochemical analysis in 56 patients with LSCC. The "ex novo" HLA-DR expression on laryngeal cancer tumor cells, assessing non-neoplastic LSCC - adjacent tissue, and the association of HLA-DR expression (HLA-DR+) with clinical outcomes were investigated. HLA-DR+ tumor cells were detected in 18/56 LSCC patients (32.1%). All specimens of non-neoplastic laryngeal carcinoma-adjacent tissue resulted HLA-DR negative (HLA-DR-). A statistically significant association was observed between HLA-DR + and well differentiated tumors (G1) (p<0.001). The Kaplan-Meier method showed how HLA-DR+ is significantly associated with both a better disease specific survival (HLA-DR+=100% vs. HLA-DR-=77.4%; p=0.047) and a better relapse free survival (HLA-DR+=100% vs. HLA-DR-=72.3%; p=0.021). Cox regression univariate analysis for death of disease confirmed a higher HR for HLA-DR absence on the surface of epithelial tumor cell [HR:37.489; 95% CI:0.750-18730.776; p=0.253] and for high-grade (G3) tumors [HR:18.601; 95% CI:3.613-95.764; p<0.0001]. Our results confirm that MHC class II HLA-DR expression is activated in a sub-set of LSCC patients. Evaluation of HLA-DR expression in LSCC could be useful for prognosis and future approaches towards personalized therapy., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To describe a remote approach used with patients with voice prosthesis after laryngectomy during the COVID-19 pandemic and the resulting clinical outcomes in terms of voice prosthesis complications management, oncological monitoring, and psychophysical well-being., Study Design: Prospective cohort study., Setting: Otolaryngology Clinic of the University Polyclinic A. Gemelli, IRCCS Foundation., Subjects and Methods: All patients with voice prosthesis who underwent laryngectomy followed by our institute were offered enrollment. Patients who agreed to participate were interviewed to inquire about the nature of the need and to plan a video call with the appropriate clinician. Before and 1 week after the clinician's call, patients were tested with the Hospital Anxiety and Depression Scale. Degrees of satisfaction were investigated with a visual analog scale. A comparison between those who accepted and refused telematic support was carried out to identify factors that influence patient interest in teleservice., Results: Video call service allowed us to reach 37 (50.68%) of 73 patients. In 23 (62.16%) of 37 cases, the video call was sufficient to manage the problem. In the remaining 14 cases (37.83%), an outpatient visit was necessary. Participants who refused telematic support had a significantly shorter time interval from the last ear, nose, and throat visit than patients who accepted (57.95 vs 96.14 days, P = .03). Video-called patients showed significantly decreased levels of anxiety and depression (mean Hospital Anxiety and Depression Scale total score pre- vs post-video call: 13.97 vs. 10.23, P < .0001) and reported high levels of satisfaction about the service., Conclusion: Remote approach may be a viable support in the management of patients with voice prosthesis rehabilitation.

The primary functional issues following conservative therapy for advanced laryngeal cancer concern swallowing. Here, we evaluated the recovery of swallowing after supracricoid partial laryngectomy (SCL) in patients with primary or recurrent laryngeal cancer. We evaluated the swallowing recovery in 27 SCL patients through oropharyngoesophageal scintigraphy, and we evaluated their quality of life using EORTC questionnaires. Four patients underwent total laryngectomy during follow-up. Patients who retained their larynges were able to feed without nutritional support and without tracheostoma. The only significantly different parameter between the primary and salvage cases was the time elapsed to the removal of nasogastric/PEG tubes, which was longer in salvage cases. SCL has been demonstrated as a valuable option for primary and recurrent laryngeal cancer patients. The present data demonstrate good functional results, particularly in terms of swallowing after previous treatments and in primary settings. The combination of oropharyngoesophageal scintigraphy and questionnaires appears to be an adequate, standardizable approach to assessing swallowing function after SCL.

Background: Several studies in the last decade evaluated conservative surgical procedures and, in particular, supracricoid operations as an alternative to total laryngectomy for the salvage of recurrences of laryngeal squamous cell carcinoma (SCC) after a first attempt of organ preservation., Methods: The clinical records of 68 consecutive patients primarily treated by irradiation or endoscopic surgery and surgically salvaged by total laryngectomy or supracricoid partial laryngectomy in 2 large university hospitals in Italy from 2004 to 2010 were reviewed., Results: The survival was not affected by the primary treatment or by salvage modality. The only parameter always keeping a prognostic value is the involvement of resection margins of salvage surgery. Patients with early relapse seem to have a worse prognosis than patients with a delayed relapse (p = .05 at Cox multivariate analysis and p = .048 at Wilcoxon test for overall survival [OS] from the primary treatment)., Conclusion: Supracricoid operations, if the indications are careful, can prove reliable salvage procedures., (© 2014 Wiley Periodicals, Inc.)

Background: Functional outcome and quality of life (QOL) have become relevant endpoints in the field of laryngeal oncology, leading to the emergence of organ-preserving strategies., Methods: The medical records of 166 patients with advanced (stages III and IV) laryngeal squamous cell carcinoma (SCC) who were treated with a total laryngectomy, radiochemotherapy, or cricohyoidopexy (CHP) were reviewed., Results: In the whole series, no statistically significant differences among the 3 treatment arms with respect to the overall survival (OS) and disease-specific survival (DSS) rates were observed. The organ-preservation rate was 45% for radiotherapy and 76.7% for CHP (p = .0002). Among the cT4a cases, a longer survival was observed for the patients treated with total laryngectomy (3 yr-OS = 78% vs 68% for CHP and 54% for radiochemotherapy, p = .031)., Conclusions: In advanced laryngeal SCC, CHP shows survival rates comparable to those of radiochemotherapy and a higher larynx-preservation rate, although it may not replace radiochemotherapy because it can be recommended only in selected cases., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Treatment for laryngeal squamous cell carcinoma (SCC) has been predominantly surgical for decades, but in the last 20 years nonsurgical modalities (radiotherapy), with the aim of organ preservation, also became predominant among advanced stages. Retrospectively evaluating our series of stage III and stage IV laryngeal SCCs, we compared the 2 main therapeutic modalities., Methods: Medical records of 65 consecutive patients with advanced laryngeal SCC, from November 2005 to January 2009, were reviewed., Results: Among irradiated patients 2-year organ preservation was 86% for cT2, 43% for cT3, and 17% for cT4a (p = .037, Wilcoxon test). With respect to survival, the only significant differences between surgery and radiotherapy were detected among cT4a SCCs (p = .03, Wilcoxon test), in favor of surgery., Conclusions: The present results confirm the surgical recommendation for cT4a laryngeal SCCs. On the other hand, for T < 4, our results confirm that radiochemotherapy warrants a survival similar to that of total laryngectomy, thus allowing us to preserve the larynx in a relevant number of cases., (Copyright © 2011 Wiley Periodicals, Inc.)

Background and Purpose: To compare oncological outcome and voice quality among a uniform and well-defined subset of patients with T1 glottic carcinoma., Patients and Methods: Patients, affected by laryngeal glottic carcinoma, treated by laser CO2 surgery or radiotherapy, have been analyzed. Overall survival and disease-free survival were calculated. In order to verify differences in functional outcomes and voice quality, all patients were interviewed during their last follow-up visit during 2009 using the VHI (Voice Handicap Index) questionnaire. The data were analyzed using the MedCalc software., Results: A total of 143 patients were analyzed: 73 underwent surgery and 70 underwent radiotherapy. No statistically significant differences were found between the two groups in terms of overall survival and disease-free survival; dividing patients into stages T1a and T1b also made no difference. In order to evaluate the differences in outcomes for surgery and radiotherapy, patients were interviewed using the VHI questionnaire. Better scores for each category in the VHI were found for patients receiving radiotherapy compared to surgery (physical: p = 0.0023; functional: p < 0.0001; environmental: p < 0.001). The median VHI score for radiotherapy patients was 4, while for surgical patients it was 18 (p < 0.0001)., Conclusion: This study confirms the well-known knowledge that results from radiotherapy and surgery in early glottic cancer treatment are equivalent. Furthermore, the role of patient preference in the treatment modality choice and the value of a multidisciplinary approach for a detailed and multi-oriented discussion with the patient are outlined.

Purpose: In primary squamous cell carcinoma of the larynx (LSCC), Ca(2+) binding S100A2 protein underexpression was already found to be associated with poor tumour differentiation and shorter overall survival. In the present work, the role of S100A2 protein expression in the prediction of regional metastasis-free survival (MFS) was investigated to guide neck management in LSCC., Experimental Design: Specimens of LSCC from 62 consecutive untreated patients were examined for S100A2 content by immunocytochemistry; the patients were followed up for a median of 44 months (range 2-90 months) after initial surgical resection. MFS was calculated from the date of first surgery to that of regional neck node recurrence., Results: S100A2 was detected in 18 of 19 (95%) low-grade tumours and in 22 of 43 (51%) high-grade tumours. The 5-year regional MFS was 81% for patients with S100A2-positive tumours and 55% for patients with S100A2-negative tumours. By multivariate analysis, the S100A2 status appeared to be a significant independent predictive factor for MFS (p = .02)., Conclusions: Our results suggest that the assessment of S100A2 status at diagnosis may identify a subset of LSCC patients highly susceptible to neck node metastases and may thus help define therapy accordingly.

A correlation between laryngo-pharyngeal reflux and laryngeal carcinoma is currently debated. Chronic inflammation is a mutagen factor confirmed in the cancerogenesis of various tumours. Aim of the present study was to evaluate, in an objective and consecutive way, with 24h multi-electrode pH-metry the presence of proximal and distal oesophageal reflux in patients presenting pre-cancerosis or squamous cell laryngeal and/or pharyngeal carcinomas. From our data, a strict correlation emerged between laryngo-pharyngeal reflux and neoplasias of the upper airways, documented through multi-electrode pH-metry. Data emerging from this study would seem to support the theory that the protracted exposure (> 20 years) to biliary reflux would represent a statistically significant added risk factor in the precancerous lesions and squamous pharyngo-laryngeal carcinoma as it occurs at oesophageal level. Moreover, a significant statistical association (p < 0.0001) emerged between laryngeal carcinoma and previous gastro-resection (odds ratio 3.8).

Background: It has been previously observed that patients with head and neck squamous cell carcinoma or with laryngeal leucoplakia present a significant reduction in plasma folate levels. The current Phase IIA pilot study assessed the effectiveness of folic acid as a chemopreventive agent in patients affected by glottic laryngeal leucoplakia., Methods: Forty-three untreated patients affected by glottic laryngeal leucoplakia were enrolled in the Ear, Nose, and Throat Department (Universita Cattolica del Saco Cuore, Rome, Italy). Glottic leucoplakia was initially diagnosed by indirect laryngoscopy and successively confirmed by diagnostic direct microlaryngoscopy with a biopsy for histologic assessment. Folic acid (Folina, Schwarz Pharma, Germany) was administered orally (5 mg every 8 hours) for 6 months. Patients were monitored every 30 days by videolaryngoscopy., Results: Twelve (28%) patients had no response, 19 (44%) had a partial response, and 12 (28%) had a complete response. The mean increase in serum folate levels (10.06 +/- 0.53) and the mean decrease in homocysteine serum (3.65349 +/- 0.85526) at the end of the study were highly significant (P = .0001)., Conclusions: The larynx is 1 of the sites of major interest and a good model for the development of chemopreventive agents, but so far the proposed agents have shown no clear efficacy on precancerous lesions or on the development of second malignancies.

Background and Study Aims: Gastroesophageal reflux disease may be associated with laryngeal damage caused by reflux material. The aim of this study was to investigate the accuracy of laryngeal examinations during routine upper gastrointestinal endoscopy as a method of screening for major laryngeal injury in a series of patients with reflux symptoms., Patients and Methods: A total of 100 consecutive patients with reflux symptoms and 100 control individuals underwent upper gastrointestinal endoscopy with standard or high-resolution magnifying video endoscopes. Any laryngeal abnormalities were initially identified by the gastroenterologist before the scope was inserted into the esophagus. All of the examinations were recorded on video and subsequently reevaluated by an otorhinolaryngologist. All of the patients underwent standard laryngoscopy as a reference procedure., Results: All of the patients completed the study. The sensitivity, specificity, negative predictive value, and positive predictive value of the preliminary laryngeal exploration for detecting laryngeal abnormalities (such as laryngitis and vocal leukoplakia) were 90%, 90%, 92%, and 89%, respectively. High-resolution magnifying endoscopy had a higher sensitivity and specificity than standard endoscopy for detecting laryngeal pathology. Two patients were found to have laryngeal leukoplakia., Conclusions: This study shows that preliminary diagnosis of laryngeal disorders can be accurately carried out by the gastroenterologist when patients are undergoing upper endoscopy for reflux symptoms. This approach could also be helpful for the timely diagnosis of major reflux-related laryngeal disease.

Objective: To analyze oncologic results in patients with glottic cancers treated respectively, by laser CO 2 or open surgery, taking into account specific-disease survival, rate of locoregional recurrences, and their salvageability., Study Design: Retrospective study of 198 patients treated from January 1993 to June 2002 in the department of otorhinolaryngology at a Catholic university in Rome., Methods: Glottic carcinoma were treated by laser CO 2 cordectomy in 132 patients (group 1) and by open surgery in 66 patients (group 2). The statistical analysis was performed by Kaplan Meyer method, log rank test, and chi 2 test., Results: The log-rank test points out significant differences between the 2 groups regarding specific-disease survival; no differences were found for disease-free survival. Within group 1, 16 patients developed local failure, which was retreated in 6 cases with laser surgery; in 9 (6.8%) with total laryngectomy, only 1 case was inoperable. In this group, 10 patients (62.5%) were salvaged. Within group 2, 18 patients developed local recurrences, which was retreated in 14 (21.21%) cases with total laryngectomy; the other 4 cases were not suitable for surgery. Of these 18, 8 patients (44.5%) were salvaged., Conclusions and Significance: Our results show significant differences between the 2 groups concerning the specific-disease survival and the salvageability of local recurrences. In fact, in group 1 we found a higher salvage rate and a lower incidence of total laryngectomy. As already suggested, laser therapy leaves the laryngeal cartilaginous framework intact, avoiding the spread of the tumor out of laryngeal organ and resulting in a more favorable oncologic outcome.

Of the most frequent malignancies in the United States, cancers of the larynx and of the uterine corpus are the only ones not to show an increase in 5-year survival rates over the last 30 years. The increasing use of chemo- and radiotherapy and conservative surgery to preserve organs and their functions has probably led to a better quality of life in patients with laryngeal cancer, but has definitely failed to improve survival, which remains the primary aim. In our opinion, to reduce laryngeal cancer-related mortality, a change in clinical approach is required. We have reviewed the literature on the potential role of molecular markers in the clinical management of laryngeal cancer. We believe that some of the most significant biological markers might be integrated with the evaluation of behavioural risk factors, clinical TNM staging and histopathological grading for a novel clinicomolecular approach to laryngeal cancer. We foresee the use of the most promising biological markers in the phases of prevention, diagnosis, prognostic assessment and drug design.

Background: The authors evaluated serum levels of folate, homocysteine, and vitamin B(12) in patients with head and neck squamous cell carcinoma (HNSCC) and in patients with laryngeal leukoplakia, a well known preneoplastic lesion., Methods: One hundred forty-four consecutive, untreated patients with HNSCC and 40 consecutive, untreated patients with laryngeal leukoplakia were enrolled in the Department of Otolaryngology at the authors' institution. Data from those patients were compared with data from one control group, which included 90 smokers, and from another control group, which included 120 nonsmokers. Serum levels of homocysteine, folate, and vitamin B(12) were measured by an automated immunoassay method based on fluorescence polarization immunoassay technology., Results: Comparing groups by Student-Newman-Keuls test, serum folate levels were significantly lower in patients with HNSCC and in patients with laryngeal leukoplakia compared with serum folate levels in both the smoker control group and the nonsmoker control group. Serum homocysteine levels in patients with HNSCC were significantly higher compared with homocysteine levels both in the smoker and nonsmoker control groups and in patients with laryngeal leukoplakia. There were no statistically significant differences between groups in serum vitamin B(12) levels., Conclusions: A role for folate deficiency as a risk factor in head and neck carcinogenesis is plausible. A chemoprevention protocol with folate is both feasible and ethically correct and is in progress at the authors' institution. Homocysteine levels in patients with HNSCC probably are affected largely by the HNSCC phenotype. An accumulation of homocysteine may reveal a genetic defect, which, theoretically, may be a target for pharmacologic therapy, for example, with antifolic drugs., ((c) 2004 American Cancer Society.)

In this paper, we try to briefly review the most recent knowledge on head and neck cancer, and especially multistep laryngeal carcinogenesis, and to simply explain how this has modified our understanding of field cancerisation phenomenon. Experimental studies, made possible by the recent evolution of microdissection systems, have demonstrated that the "spatial progression"of the histopathological phenotype in the surroundings of malignant or premalignant head and neck lesions correlates with molecular progression. Such a "spatial progression" can be hypothesised to reflect temporal progression. The field cancerisation process has been divided into three phases, each with its own histological and molecular characteristics. Each of these phases may have clinical implications: detection and monitoring of fields may help cancer prevention (molecular epidemiology), early detection of recurrence (or, more exactly, of second field tumours (SFTs)) (molecular diagnostics) and prognostic prediction after treatment. This model appears plausible, especially in explaining the development of multiple primary tumours (MPTs) in adjacent head and neck mucosal regions, with peculiar clinical and prognostic implications: These tumours can be defined as multiple field tumours (SFTs). However, the model, in our opinion, does not convincingly explain the development of second primary tumours (SPTs) at more distant sites, such as the lung, colon and prostate.

Objective: To investigate the association between gastric surgery and cancer of the larynx., Summary Background Data: Biliary reflux is frequent after gastric surgery and may reach the proximal segment of the esophagus and the larynx. It is possible that duodenal content (consisting in bile acids, trypsin), together with pepsin and acid residues when gastric resection is partial, may cause harmful action on the multistratified epithelium of the larynx., Methods: A retrospective case-control study on subjects admitted between January 1987 and May 2002 in the same hospital in Rome was carried out. The study included 828 consecutive patients with laryngeal cancer (cases) and 825 controls with acute myocardial infarction. Controls were randomly sampled out of a total of 10,000 and matched with cases for age, sex, and year of admission. Logistic regression models were used to assess the role of gastric resection in determining laryngeal cancer risk while controlling for potential confounding factors., Results: Previous gastrectomy was reported by 8.1% of cases and 1.8% of the controls (P < 0.0001). A 4-fold association emerged between gastric surgery and laryngeal cancer risk (adjusted OR = 4.3, 95% CI: 2.4-7.9). The risk appeared strongly increased 20 years after surgery (OR = 14.8, 95% CI: 3.4-64.6). Heavy alcohol drinking (OR = 2.5, 95% CI: 1.8-3.5), smoking (OR = 4.7, 95% CI: 3.3-6.7), and blue-collar occupation (OR = 4.6, 95% CI: 3.2-6.7) were all independently associated with the risk of laryngeal cancer., Conclusions: Previous gastric surgery is associated with an increased risk of laryngeal cancer. A periodic laryngeal examination should be considered in long-term follow-up of patients with gastric resection.

Laryngopharyngeal reflux is now of major interest as an aetiologic factor in chronic inflammatory and neoplastic lesions of upper digestive tract. However, reports in the literature refer only to the irritating action of the acid component of reflux, while possible damaging action of other reflux components remains unknown. Aim of this study was to verify the hypothesis that alkaline-bile reflux could also be involved in onset of inflammatory, precancerous and neoplastic laryngeal lesions. A total of 40 consecutive gastrectomized patients coming to our Clinic from Gastroenterology Outpatient Unit for an anamnestic and clinical evaluation with videolaryngoscopy of upper digestive airways, entered the study. All presented bile or alkaline reflux as a direct consequence of gastroduodenal anastomosis (Billroth I) and gastrojejunal anastomosis (Billroth II) performed over a time span > 20 years. Oesophagogastroduodenoscopy revealed the presence of bile in the residual gastric cavity in all operated patients objectively confirming duodenogastric reflux. Examination of data showed that 3 patients (7.5%) had undergone CO2 laser cordectomy in the 3 years prior to the study for squamous cell laryngeal carcinoma, 3 patients (7.5%) had leukoplakia, 8 (20%) vocal cord chronic oedema with signs of chronic diffuse laryngitis, 6 (15%) posterior laryngitis, 8 (20%) interarytenoid oedema while only 12 (30%) showed no ENT lesions. Statistical analysis revealed a significant correlation between incidence of inflammatory and neoplastic laryngeal lesions and type of surgery (Billroth II and total gastrectomy) with respect to other types of gastric resection. There was also a significant increase in presence and severity of laryngopharyngeal lesions in relation to time elapsed after surgery. These results, although preliminary, seem to confirm that some components of reflux (duodenal content), other than the acid component, play a damaging role involved in the onset of multiple clinical signs and symptoms of laryngopharyngeal reflux disease. It is concluded that systematic use of bile measurement, together with 24-hour pH monitoring, is advisable in subjects with clinical signs and symptoms of laryngopharyngeal reflux, but unresponsive to classic medical treatment, and in gastrectomized patients in order to confirm, on larger series, this fascinating aetiopathogenetic hypothesis.

Background: Duodenogastroesophageal reflux is common after total or partial gastrectomy. No data are available on the effect of duodenal reflux on the larynx., Hypothesis: Premalignant or malignant changes occur more frequently among subjects with gastric surgery., Design: Historical cohort study., Setting: Outpatient setting for upper endoscopy., Patients: Ninety-three subjects who had undergone gastric resection at least 5 years previously, and 93 matched dyspeptic individuals who did not undergo gastric surgery., Intervention: Clinical histories of all patients were obtained and recorded. All subjects underwent an otolaryngologic evaluation., Results: Of 93 patients with gastric resection, 7 patients had current or previous laryngeal malignancies or current precancerous mucosal changes. In the control group, 1 subject had a leukoplakia on the vocal cord. The adjusted odds ratio (having included sex, age, and alcohol [yes or no] and smoking [yes or no] history in the regression model) was 9.88 (95% confidence interval, 1.01-97.31; likelihood ratio chi2 = 28.77; P<.001). Furthermore, there was a significant increased prevalence of benign laryngeal lesions in patients with gastric resection vs the control group., Conclusions: The risk of developing laryngeal malignancies is higher for patients with gastric resection. A periodic otolaryngologic evaluation in subjects with gastric surgery may contribute to early diagnosis of laryngeal disorders.

Hypothesis: At present, main factors considered responsible for the onset of squamous cell carcinoma are tobacco smoking, alcohol abuse, and exposure to viral and toxic agents. In last years, great interest has been focused on gastroesophageal reflux as independent carcinogenic factor and co-carcinogen in association with smoking and alcohol assumption., Study Design: Initially, the aim of this study was to objectively evaluate the presence of distal and proximal esophageal reflux with multielectrode pH measurement in patients with cancer of the larynx and/or hypopharynx (group A). However, in the course of the study, pharyngolaryngeal cancer was also observed in 4 patients with achlorhydria; therefore, the hypothesis that alkaline reflux might be involved in the onset of laryngeal cancer was tested (group B)., Methods: Twenty-one consecutive patients with laryngeal or hypopharyngolaryngeal squamous cell carcinoma (group A) entered the study. Twenty-one patients without laryngo-pharyngeal diseases were used as control subjects. A validated questionnaire of the clinical history was completed by all patients who underwent 24-hour pH monitoring. Group B included 40 consecutive gastrectomized patients (28 males and 12 females) in whom biliary or alkaline reflux was directly consequent to Billroth I or Billroth II operation. The control group was composed of 40 non-gastrectomized dyspeptic patients. The clinical history was controlled and obtained; EDGS and ENT examination with videolaryngoscopy was performed in all patients., Results: In group A, pH measurement showed pathological reflux in 80.9% (17 of 21) of patients with no typical symptoms in 63.7% of them. The difference was significant with respect to the control group. In group B, 6 of 40 (15%) had preneoplastic lesions or a history of laryngeal tumor. The difference was significant with respect to the control group. A total of 7.5% of group B patients had previously undergone CO2 laser cordectomy for laryngeal squamous cell carcinoma and 7.5% had leukoplakia. We found a significantly higher incidence (<.05) of neoplastic and preneoplastic disease of the larynx in patients undergoing Billroth II and total gastrectomy than in those undergoing Billroth I and Roux-en-Y resection. We also found a significant increase (<.01) in ENT lesions in the group of patients who had undergone gastrectomy more than 20 years previously., Conclusions: In agreement with literature reports, results obtained in group A confirmed that gastroesophageal reflux is often present in patients with neoplastic lesions of the pharynx and larynx. Furthermore, gastric resection is indicated for the first time as an additional risk factor or cofactor of precancerosis and squamous cell carcinoma of the pharynx or larynx. Further studies are necessary to establish the cause and effect relationship between biliary reflux and pharyngo-laryngeal tumors.

Background: Human papillomavirus (HPV) infection is suspected to be a risk factor for head and neck, and in particular for laryngeal, carcinogenesis. Cyclin D1 gene (CCND1) overexpression and amplification have been shown to play a role as prognostic factors in many human cancers, among which are head and neck cancers., Methods: A literature review of the role in head and neck cancers of HPV infection and CCND1 overexpression and amplification was undertaken. We have evaluated the extent of the current knowledge in this field under the light of recent acquisitions, in particular, about a correlation between HPV infection, a suspected risk factor, and CCND1 amplification, a frequent mutation (about 20% of laryngeal cancers) and a prognostic factor in laryngeal SCC., Results and Discussion: The significant correlation between HPV infection and CCND1 amplification supports the hypothesis of the involvement of HPV infection in laryngeal carcinogenesis and suggests that HPV positive laryngeal cancers may constitute a different subset of tumors with a peculiar molecular pattern and thus with a different clinical behavior. HPV infection may be considered a synergistic risk factor with smoking and/or alcohol consumption to be investigated in heavy smokers and drinkers, thus contributing to the identification of patient at high-risk for the development of laryngeal cancer who should undergo strict follow-up and primary and secondary prevention., (Copyright 2002 Wiley Periodicals, Inc.)

Purpose: This study was designed to add new data about laryngeal carcinogenesis, a multistep process in which chemical and/or viral agents induce and promote successive alterations in growth factor-linked signal transmission pathways, genetic instability, and mutations in key genes involved in cell growth control. Epidemiological evidence suggests that human papillomavirus (HPV) infection may be associated with the development of laryngeal cancer., Experimental Design: In this report, we have analyzed the prevalence of HPV infection and epidermal growth factor receptor (EGFR) expression in a series of 42 laryngeal squamous cell carcinomas by PCR with HPV consensus primers and by a radioligand receptor assay, respectively., Results: HPV DNA was detected in 15 of 42 (35.7%) tumors, and it belonged almost exclusively to the highly oncogenic HPV-16, HPV-18, and HPV-33 genotypes. At analysis by Mann-Whitney nonparametric statistical test, EGFR level was found to be significantly higher in HPV-infected than in HPV-negative cases (T = 440; P = 0.002). EGFR overexpression (EGFR-positive status >6 fmol/mg protein, the arbitrary cutoff value chosen) was found in 20 of 42 (47.6%) tumors, and it was associated with HPV infection in a statistically significant extent (chi(2) = 4.686; P = 0.03)., Conclusions: Viral oncoproteins have been shown to induce a perturbation of the cell response to signals for growth and differentiation; these findings confirm that enhanced EGFR expression and activation in laryngeal squamous cell carcinoma may occur also as a consequence of HPV infection and support the hypothesis of an involvement of HPV infection in laryngeal carcinogenesis.

The major risk factors for the onset of precancerous lesions and squamous cell carcinoma of the larynx are, above all, tobacco smoke, alcohol abuse and exposure to viral and toxic agents. In recent years, however, gastro-esophageal reflux (GER) has also aroused significant interest not only as carcinogen but also as co-carcinogen in association with smoking and alcohol consumption. The purpose of the present work is to provide an objective evaluation of the presence of distal and proximal esophageal reflux using multi-electrode pH monitoring in patients with precancerous lesions of the larynx and laryngeal and pharyngolaryngeal neoplasms. A total of 24 patients consecutively hospitalized during 2000 were evaluated: 20 with squamous cell carcinoma of the larynx and/or pharynx-larynx and 4 with precancerous vocal cord lesions. All the patients provided a case history using a validated questionnaire and underwent electronic videolaryngoscopy and 24-hour pH monitoring. Data analysis showed that in 83.3% of the cases (20/24) pH monitoring was indicative of pathological GER and 63.7% of these patients had no complaints related to reflux. Moreover, 7/24 patients have had a previous gastrectomy (Billroth II) strictly related to the presence of bile reflux. The Authors conclude that, according with recent literature, pH monitoring data further indicate that patients with precancerous or neoplastic pharyngeal-laryngeal lesions present often a positive history of GER, even though no direct cause-effect relationship can yet be established because of the co-existence of other important risk factors such as smoking and alcohol consumption. Additionally, the achlorhydria found in 7/24 patients with an history of gastrectomy could suggest a possible, as yet unproven, role of other reflux components--in particular, of bile (alkaline) and chlorhydro-peptic (acid) components--as a risk factor or co-factor for tonset of precancerous and/or neoplastic lesions of the larynx.

Epidermal growth factor receptor (EGFR) overexpression is an unfavorable prognostic marker in laryngeal squamous cell carcinoma (SCC). EGFR stimulates cyclooxygenase-2 (COX-2) expression in normal human keratinocytes and squamous carcinoma cells. Based on these observations a prognostic role of COX-2 expression in laryngeal SCC can be hypothesized. Consequently, COX-2 expression was studied in laryngeal SCC (median follow-up = 47 months; range: 2-87 months) by quantitative immunohistochemistry (n = 61) and EGFR by binding assay (n = 51). Well-differentiated regions of laryngeal SCC revealed strong COX-2 immunostaining, whereas histologically normal areas neighboring tumor as well as poorly-differentiated tumors were negative. Immunohistochemical results were confirmed by Western blot analyses. Cox's regression analysis showed that the combination of low levels of COX-2 integrated density and high levels of EGFR covariates provided strong prediction, at 5-year follow-up, of both poor overall survival (chi(2) = 12.905; p = 0.0016) and relapse-free survival (chi(2) = 9.209; p = 0.01). In vitro studies on CO-K3 cell line, obtained from an EGFR positive, COX-2 negative poorly-differentiated laryngeal SCC, revealed that EGF stimulation failed to induce COX-2 expression and PGE2 production suggesting a change in EGFR signaling pathway. These findings indicate that COX-2 is overexpressed in less aggressive, low grade laryngeal SCC, whereas its expression is lost when tumors progress to a more malignant phenotype., (Copyright 2001 Wiley-Liss, Inc.)

We investigated by immunocytochemistry the expression of the Ca(2+) binding protein S100A2 in 62 cases of laryngeal squamous-cell carcinoma (SCC). S100A2 was detected in 18/19 (95%) low-grade tumors and in 22/43 (51%) high-grade tumors, which were partially keratinizing. The remaining 21/43 (49%) high-grade tumors were non-keratinizing, anaplastic tumors and clearly S100A2-negative. In normal laryngeal squamous epithelium and in laryngeal SCC, S100A2 expression was strictly associated with that of cytokeratins 14 (P = 0.0002) and 17 (P = 0.0021), suggesting an association of S100A2 expression and cell commitment to squamous differentiation. A correlation was found between S100A2 tumor positivity and longer relapse-free (P = 0.0005) and overall (P = 0.0095) survival., (Copyright 2000 Wiley-Liss, Inc.)

We report the case of a patient with a laryngeal carcinoma in whom asymptomatic hyperparathyroidism was also detected during the preoperative work-up. A planar (201)Thallium/(99m)Tc-pertecnetate subtraction scintigraphy was performed in order to locate the suspected parathyroid adenoma. The study showed a single area of increased (201)Thallium uptake just above the thyroid isthmus, likely due to the laryngeal tumor. The scintigraphic study was repeated using (99m)Tc-Sestamibi and (99m)Tc-pertechnetate and employing the SPECT technique. Both SPECT studies made it possible to identify correctly the parathyroid adenoma, located inferiorly and in a posterior position to the lower third of the right thyroid lobe. The laryngeal tumor and parathyroid adenoma could be excised in a single surgery session. This case is of interest due to the rarity of the coexistence of two neck tumors and the clear advantage shown by the SPECT technique with (99m)Tc-Sestamibi over the planar technique with 201Thallium.

Specimens of laryngeal squamous cell carcinoma (LSCC) were examined for epidermal growth factor receptor (EGFR) content using a radioreceptor method; 140 untreated consecutive patients with primary LSCC undergoing initial surgical resection were followed up for a median of 49 months (range 2-84 months) after surgery. Cox univariate regression analysis using EGFR as a continuous variable showed that EGFR levels were directly associated with the risk of lymph node metastasis. A significant relationship between EGFR status and cervical node metastasis was observed. The cutoff value of 20 fmol/mg protein was the best prognostic discriminator. The 5-year metastasis-free survival (MFS) was 66% for patients with EGFR- tumors compared with 15% for patients with EGFR+ tumors. By multivariate analysis, the EGFR status appeared to be a significant independent prognostic factor for MFS. Our results suggest that the assessment of EGFR status at the time of diagnosis may identify a subset of LSCC patients highly susceptible to neck node metastases thus defining therapy accordingly.

The aim of this study was to verify the oncological and functional outcome of conservative surgical treatment of primary supraglottic squamous cell carcinoma (SGSCC) and related neck disease in order to verify the effectiveness of supraglottic laryngectomy (SL) and the validity of an "observation" policy in the control of clinically negative (N0) necks. Of a total of 252 consecutive patients affected by primary SGSCC seen between 1975 and 1990 at the Department of Otolaryngology of the University of Perugia (1975-1987) and the Catholic University of the Sacred Heart of Rome (1988-1990), a subset of 132 patients treated with classical SL was evaluated after presenting sufficient clinicopathological data and a follow-up period of at least 5 years. Tumors were staged according to the 1992 UICC TNM classification and grouped into stages I-II (n = 94) and III-IV (n = 38). Comprehensive neck dissections were performed only in the clinically positive (N+) necks (25/132 cases), while in the clinically N0 ones (107/132 cases) an "observation" policy under strict follow-up conditions was adopted. After primary surgery, the 5-year relapse-free survival (RFS) was 74%. The RFS was 80% for T1-2 disease and 65% for T3. The RFS was 80% for stages I-II tumors and 71% for stages III-IV. The actual 5-year overall survival (OS) was 89% for T1-T2 tumors and 67% for T3 disease or 93% for stage I-II and 69% for stages III-IV. The OS was 89% for N0 neck and 73% for N+. The 5-year-metastasis-free survival (MFS) was 83% for N0 patients, 74% for N+, 84% for T1-T2 N0, 71% for T1-T2 N+, 81% for T3 N0 and 68% for T3 N+. In all, SL was found to be highly effective in the management of primary SGSCC. In the presence of clinically N0 neck "observation" under strict follow-up with therapeutic comprehensive neck dissection for delayed nodal recurrence, SL was suitable for controlling the neck cancer, as well as for salvaging recurrent disease. Bilateral elective, selective or functional neck dissection in every instance of supraglottic cancer was best performed only in those SGSCC patients who were more likely to have occult nodal disease on the basis of biological factors and imaging data.

Head and neck squamous cell carcinomas (SCCs) seem to follow a multistep process of carcinogenesis in which chemical and/or viral agents are associated with specific genetic alterations. The prevalence of human papillomavirus (HPV) infection and the amplification of the cyclin D1 (CCND1) gene were evaluated in a series of 75 laryngeal SCCs by PCR with HPV consensus primers and Southern blot analysis with a CCND1-specific probe, respectively. HPV DNA was detected in 22 of 75 (29.3%) tumors, and it belonged almost exclusively to the highly oncogenic HPV-16, HPV-18, and HPV-33. CCND1 gene amplification was found in 15 of 75 (20%) tumors, and it was associated with HPV infection in a statistically significant manner (chi2 = 20.3; P < 0.001). Because the viral oncoproteins E6 and E7 from high-risk HPV types are known to promote genomic rearrangements, these findings suggest that amplification of the CCND1 gene in laryngeal SCCs may occur as a consequence of the genomic instability associated with HPV infection. In turn, amplified CCND1, either alone or in conjunction with a direct action of the viral oncoproteins E6 and E7, could lead to a perturbation of the cell cycle. This model could explain the involvement of high-risk HPV types in laryngeal carcinogenesis.

The activation of telomerase has been shown to be an important step during tumorigenesis in a variety of malignancies and is associated with characteristics of cellular immortality, such as indefinite proliferative potential. We studied telomerase activity in a series of human laryngeal carcinomas. Thirty-six tumors from 35 patients were studied using a sensitive PCR-based technique, the telomeric repeat amplification protocol assay. Telomerase activity was present in 32 tumors (89%), and the level of activity correlated with the stage of disease. In two of four telomerase-negative tumors, we found evidence of an inhibitor of telomerase activity. In many cases, samples of mucosa surrounding the tumor were also studied, and telomerase could be detected in 16 of 21 patients. For this reason, we proceeded to perform a topographical analysis that demonstrated a pattern of telomerase activity suggestive of a spread of telomerase-positive cells. In conclusion, these data indicate that telomerase activation is important for laryngeal carcinogenesis and that telomerase assay might be a valuable addition to determine the spread of the disease.

The aim of the present work was to evaluate whether oro-pharyngeal-esophageal scintigraphy could be used in the dynamic study of the various phases of deglutition and to determine whether it could be applied in otorhinolaryngological practice along with videofluoroscopy and videoendoscopy. The patients were divided into four different groups according to clinical features and the scintigraphic data were analyzed on this basis. Emphasis is placed on the ease of this technique, its tolerability and the low level of radiation. It is pointed out that scintigraphy is quite useful in determinating the exact percentage of the bolus inhaled into the trachealbronchial branch and in measuring the transit time of the various phases of deglutition in detail. In patients affected by upper airway-digestive tract neoplasms it is, therefore, possible to make a semiquantitative evaluation of the results of surgery. Moreover, with this method the results of any rehabilitation can be measured as well as the onset of compensation mechanisms.

The cyclin D1 (CCND1) gene is amplified, rearranged, and overexpressed frequently in human cancer, including squamous cell carcinoma. The gene dosage of CCND1 was examined in 51 primary laryngeal squamous cell carcinomas, and amplification of the gene was found in 9 (17.6%) cases. CCND1 amplification did not correlate with age, tumor localization and extension, cervical lymph node involvement, histopathological grading, and epidermal growth factor receptor levels. In a univariate analysis, CCND1 amplification, tumor extension, lymph node involvement, poor histological differentiation, and high epidermal growth factor receptor levels were correlated significantly with shorter overall survival. In a median follow-up period of 29 months, the overall survival rate was 71.4% for patients affected with tumors displaying a normal CCND1 dosage and only 25.0% for patients affected with tumors carrying amplified CCND1 (P = 0.0288). In a multivariate analysis, only CCND1 and tumor extension retained statistically significant prognostic values (P = 0.037 and 0.041, respectively). This is the first report in which CCND1 amplification is identified as a significant independent prognostic factor in laryngeal carcinoma. Evaluation of CCND1 amplification could be applicable to the clinical management of laryngeal cancer, allowing identification of patients with poor prognoses.

Auditory cortex stimulation was studied by 99Tcm-hexamethylpropyleneamine oxime (HMPAO) single photon emission tomography (SPET) in 11 patients with normal vestibular and auditory tests, as well as computed tomography. Markedly increased temporal and parietal blood flows were found in left brain cortex, contralateral to the stimulus. The right auditory areas showed moderate hyperactivity. The method might be useful for tonotopic mapping of auditory cortex, using various pure tonal stimuli.