Vojko Djukic

Endoscopic supraglottic laryngectomy: a proposal for a classification by the working committee on nomenclature, European Laryngological Society.

In July 1999, the European Laryngological Society (ELS) has accepted a proposal for the classification of different laryngeal endoscopic cordectomies. This is actually a common classification system used as a tool for surgical training, documentation and comparison of results. The same harmonization work is deemed necessary for the treatment of supraglottic lesions. The ELS is proposing a classification of the different laryngeal endoscopic supraglottic partial laryngectomies. This classification comprises four types of supraglottic laryngectomies: Type I, limited excision of small size superficial lesions of the free edge of the epiglottis, the ary-epiglottic fold, the arytenoid, or the ventricular fold or any other part of the supraglottis; Type II, medial supraglottic laryngectomy without resection of the pre-epiglottic space, suitable for T1 lesions of either the suprahyoid or the infrahyoid laryngeal surface of the epiglottis (Type IIa, superior hemi-epiglottectomy or Type IIb, total epiglottectomy, respectively); Type III, medial supraglottic laryngectomy with resection of the pre-epiglottic space, suitable for T1–T2 tumors of the infrahyoid endolaryngeal epiglottis without (Type IIIa) or with (Type IIIb) extension to the ventricular fold, necessitating its excision; finally, Type IV, lateral supraglottic laryngectomy, suitable for tumors of the threefolds’ region, which may include the ventricular fold (Type IVa) or the arytenoid (Type IVb), when involved. As in the cases of endoscopic cordectomies, these operations are similarly classified according to the surgical approach used and the degree of resection completed in order to facilitate their use in daily clinical practice.

Treatment of recurrent respiratory papillomatosis and adverse reactions following off-label use of cidofovir (Vistide®)

Recurrent respiratory papillomatosis (RRP) is caused by a human papilloma virus (HPV). It is a rare, sometimes debilitating disease compromising voice and airway. RRP is characterized by a variable course of disease, potentially leading to frequent annual surgical procedures, the number of which may exceed a hundred during the life time. The therapy focuses on surgical removal of the mucosal lesions in order to keep the airway open and the voice satisfactory. Till now, there is no curative therapy for the virus infection in itself. As recurrent surgery alone has proven to be insufficient in many cases, adjuvant therapy is increasingly being used. One of the mainstays of adjuvant therapy is the administration of intralesional cidofovir (Vistide®). Cidofovir is an antiviral agent, registered for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. Since 1998 the drug has been used to treat patients with RRP [1]. Cidofovir can be regarded as a prodrug. It exerts the antiviral effect by decreasing the efficiency of DNA transcription following incorporation into the growing DNA chain [2]. Its use has been advocated in cases of papilloma refractive to repeated surgery, either due to its spread, or to its recurrence rate. Some case reports and series showed the effect of cidofovir treatment with few or no side effects [3–8]. The only prospective double-blind randomized controlled trail showed a significant improvement in the Derkay severity score between the cidofovir and placebo group but failed to show significant benefit in number of procedures performed [9]. On January 31 2011, an alarming news was communicated by Gilead (the producer of cidofovir) concerning very serious side effects of its off-label use [10]. The warning included reports on nephrotoxicity, neutropenia, oncogenicity and even some fatalities. The manufacturer emphasized that cidofovir is formulated for intravenous infusion only and the indication is CMV infection of AIDS patients. The manufacturer did not specify the severity of the reported complications, neither the off-label indication of the drug nor its way of administration. Unfortunately, up to the end of May 2011 the above mentioned communication was not received by the laryngologists in most countries. The warning caused a lot of discussion within the European Laryngological Society (ELS). The ELS (having >350 active members) is the main laryngological organization in Europe, representing laryngologists from more than 55 countries on all continents (http://www.elsoc.org). The ELS has taken its responsibility and initiated a research project on the side effects of off-label use of cidofovir in RRP patients. The purpose of such a study is to determine whether there are known nephrotoxic, neutropenic, or oncogenic side effects after having used intralesional cidofovir in patients with RRP. Facts are needed to decide whether or not intralesional use of cidofovir in the larynx is safe or not. Side effects might be dose dependent, and occur as a consequence of the number of administrations, the interval between applications or the cumulative dose. To determine the aforementioned, a multicenter retrospective analysis has been initiated among members of the ELS for which, among others, all members of its Scientific Council have been approached. Parallel to the retrospective study we are conducting an update on reported side effects in the literature. Reports of the studies will be submitted for publication in the official journal of the ELS, the European Archives of Otorhinolaryngology, Head and Neck Surgery.

Stroboscopy in Detection of Laryngeal Dysplasia Effectiveness and Limitations

Vocal fold pathology changes the appearance and vibratory patterns observed during stroboscopic examination, but a strict correlation between the vibratory pattern and the dysplasia type does not exist. The aims of this study were to determine the role of stroboscopy in vocal fold dysplasia assessment and to determine whether stroboscopy is the deciding factor when performing laryngomicroscopy with biopsy in suspicious lesions. This prospective controlled study involved 112 patients with laryngeal dysplasia treated over a 2-year period at a tertiary medical center. Patient data and clinical, stroboscopy, laryngomicroscopy, and histopathologic reports were reviewed. During the stroboscopy, glottic occlusion, phase symmetry, periodicity, amplitude, mucosal wave, and nonvibratory segments were followed. Laryngomicroscopy with different types of endoscopic cordectomies (types I-III) was performed as a therapeutic measure, with a 12-month follow-up period. Nonvibrating segments were present in 15.1% of the patients with mild dysplasia and in 38.5% of the patients with moderate dysplasia. In 45.5% of the patients with severe dysplasia (carcinoma in situ), nonvibrating segments were absent. The amplitude of vocal fold vibrations in patients with mild dysplasia (P=0.03) was a significant factor indicative of recurrent disease, but none of the stroboscopic signs was significant for the disease progression. Severe dysplasia can be related to both nonvibrating and vibrating vocal fold segments. Stroboscopy cannot be used reliably for classifying laryngeal dysplasia and may indicate the need to perform laryngomicroscopy with biopsy in suspicious vocal fold lesions. The warning factors for recurrence and progression of dysplasia are treatment modality, abnormal amplitude of vibration, and nonvibrating segment.

Voice Quality After Treatment of Early Glottic Carcinoma

OBJECTIVES Increasing incidence of laryngeal carcinoma and advancement in diagnostics and therapy methods, have led to constant exploration in that field. Early glottic carcinoma can be treated successfully with several procedures: cordectomy through laryngofissure, laser cordectomy, and radiotherapy. Our objective was to assess the voice quality after these different modalities of treatment. STUDY DESIGN Prospective controlled study with 69 patients, treated in a 1-year period for glottic Tis and T1a carcinoma at the tertiary medical centre. METHODS Nineteen of our patients were treated endoscopically with CO(2) laser (types III-IV cordectomy according to recommended European Laryngological Society classification of endoscopic cordectomies). Thirty-five patients underwent cordectomy through laryngofissure, 15 patients had radiotherapy. Multidimensional computer analysis of voice and speech was conducted 1, 6, and 12 months after the treatment. Three programs included 14 parameters, which were observed. RESULTS While comparing the parameters between the groups, there were significant differences in the values of fundamental frequency (Hz), jitter (%), normalized noise energy (dB), standard deviation of fundamental frequency (Hz), percent silent time (%), and sound-pressure level in the different follow-up periods (P<0.05). CONCLUSION In the long run, patients treated with radiotherapy show better voice quality in comparison with other two groups.

Conductive Hearing Loss in Patients with Active Acromegaly

Objective: There have been rare conflicting results reported concerning possible higher frequency of hearing loss in acromegalic patients. Our goal was to determine whether there is higher frequency of conductive hearing loss in acromegalics and what may cause it if there is any. Study Design: Prospective study. Setting: Tertiary referral center. Patients: Thirty previously untreated patients with acromegaly were compared with 20 age- and sex-matched healthy control subjects. Interventions: In all subjects: Otomicroscopy, tuning fork tests, audiometry tympanometry, cochleostapedial reflex, otoacoustic emissions. In acromegalics: endocrinologic assessment, MRI and if necessary, epipharyngoscopy. Main Outcome Measures: We searched for: 1) Signs of ossicle fixation: absence of stapedial reflex in the presence of normal tympanogram, conductive hearing loss, and absence of or grossly disturbed OAE; 2) Disturbances of middle ear ventilation: excessive negative pressure (tympanogram type C), or middle ear effusion (tympanogram type B). Results: The only statistically significant difference between untreated acromegalics and healthy subjects was the presence of middle ear ventilation problem: 7/30 acromegalics (23%) in comparison to none out of 20 healthy controls (0%), p = 0.033. The acromegalics with middle ear ventilation problem were significantly older, had longer duration of the disease, and lower mean growth hormone (GH) levels in comparison with acromegalics without this problem (51.6 ± 1.7 vs. 44.4 ± 2.5 years, 11.6 ± 2.4 vs. 7.7 ± 0.4 years, 21.68 ± 4.89 vs. 49.98 ± 12.54 &mgr;g/L respectively). Conclusion: Patients with active acromegaly have more frequent middle ear ventilation problem than normal population, especially those with longer duration of the disease. Possible causes are discussed.

Oncological and Functional Outcome after Surgical Treatment of Early Glottic Carcinoma without Anterior Commissure Involvement

Introduction. Glottic carcinoma can be successfully diagnosed in its early stages and treated with high percentage of success. Organ preservation and optimal functional outcomes could be achieved with wide array of surgical techniques for early glottic cancer, including endoscopic approaches or open laryngeal preserving procedures, making surgery the preferred method of treatment of early glottic carcinoma in the last few years. Material and Methods. Prospective study was done on 59 patients treated for Tis and T1a glottic carcinoma over a one-year time period in a tertiary medical center. Patients were treated with endoscopic laser cordectomy (types II–IV cordectomies according to European Laryngological Society classification of endoscopic cordectomies) and open cordectomy through laryngofissure. Follow-up period was 60 months. Clinical and oncological results were followed postoperatively. Voice quality after the treatment was assessed using multidimensional voice analysis 12 months after the treatment. Results. There were no significant differences between oncological and functional results among two groups of patients, though complications were more frequent in patients treated with open cordectomy. Conclusion. Endoscopic laser surgery should be the first treatment of choice in treatment of early glottic carcinomas, though open approach through laryngofissure should be available for selected cases where anatomical factors present limiting adequate tumor removal.

MRI in evaluation of neoplastic invasion into preepiglottic and paraglottic space

OBJECTIVE The purpose of this study was to evaluate whether magnetic resonance (MR) imaging can accurately predict invasion of the preepiglottic and paraglottic space in patients with laryngeal carcinoma. Identification of these fat filling spaces is important for surgical treatment and prognosis. MATERIALS AND METHODS The study was based on the prospective analysis of MRI images in a series of 40 patients (90% males), overall average age 60.1 ± 7.3 years, (49-70 years), with histopathologically diagnosed laryngeal squamous cell carcinoma. Unenhanced T2w, T2w FS, T1w, and contrast-enhanced T1w FS scans were analyzed for the presence of preepiglottic and paraglottic neoplastic invasion and were compared to postoperative histopathologic analysis. RESULTS In 28 patients (70%) the tumor was glottic and in 12 patients (30%) supraglottic. No statistical difference was found in the number of patients with positive MRI findings in comparison to postsurgical patohistology for infiltration of the preepiglottic space (23% vs 20%, respectively). Sensitivity for infiltration of preepiglottic space was 89% and specificity was 97%. However, infiltration of the paraglottic spaces was observed more frequently on MRI than on postsurgical patohistology analysis (60% vs 40%, respectively; p<0.05), with a sensitivity of 67% and a specificity 50%. According to MRI findings, 26 (65%) patients were classified as T3, 14 (35%) patients as T2 while according to histopathologic analysis of specimens after surgery, 19 patients were classified as T3 (48%) and 21 as T2 (52%). CONCLUSION MRI has been shown to be a reliable method for assessment of preepiglottic space while the diagnostic accuracy in patients with infiltration of the paraglottic space is limited.

Prognostic relevance of CD105-assessed microvessel density in laryngeal carcinoma

OBJECTIVE: To examine immunohistochemical expression of CD105 among patients with laryngeal cancer and investigate the prognostic significance of CD105-assessed microvessel density (MVD). STUDY DESIGN: Cross-sectional study. SETTING: University hospital. SUBJECTS AND METHODS: The study comprised 80 patients with laryngeal squamous cell carcinoma who underwent complete excision. Clinicopathological data were collected retrospectively. Immunohistochemical analysis was performed with CD105 (endoglin) antibody. Positive-stained microvessels for CD105 were counted on hot spots of tumors at ×200 magnification. RESULTS: Average CD105-assessed MVD in considered laryngeal squamous cell carcinomas (SCCs) was 12.9 (SD 3.84). High expression of CD105 correlated significantly with advanced T (tumor) classification (P = 0.008), advanced TNM (tumor, node, metastasis) stage (P = 0.001), tumor recurrence (P = 0.001), and age ≥65 years (P = 0.026). The multivariate logistic regression showed that a high CD105+ MVD (odds ratio [OR] 4.27; P = 0.019) and advanced TNM stage (OR 3.72; P = 0.047) were independent markers of tumor recurrence. High MVD, advanced clinical stage, the presence of lymph node metastasis at the time of diagnosis, and age <66 years were associated with worse disease-free survival. Cox regression analysis revealed that expression of CD105 (P = 0.016) and advanced clinical stage (P = 0.05) were the independent factors for disease-free survival. CONCLUSION: The present results suggest that MVD evaluation with CD105 is a promising prognostic factor for the outcome of patients with laryngeal SCC. CD105-assessed MVD could help to identify patients with more aggressive disease and increased risk of developing malignancy recurrence after treatment.

Characterization of the Variability of Epstein-Barr Virus Genes in Nasopharyngeal Biopsies: Potential Predictors for Carcinoma Progression.

Epstein-Barr virus (EBV) infection is a significant factor in the pathogenesis of nasopharyngeal carcinoma, especially in the undifferentiated carcinoma of nasopharyngeal type (UCNT, World Health Organization type III), which is the dominant histopathological type in high-risk areas. The major EBV oncogene is latent membrane protein 1 (LMP1). LMP1 gene shows variability with different tumorigenic and immunogenic potentials. EBV nuclear antigen 1 (EBNA1) regulates progression of EBV-related tumors; however, the influence of EBNA1 sequence variability on tumor pathogenesis is controversial. The aims of this study were to characterize polymorphisms of EBV genes in non-endemic nasopharyngeal carcinoma biopsies and to investigate potential sequence patterns that correlate with the clinical presentation of nasopharyngeal carcinoma. In total, 116 tumor biopsies of undifferentiated carcinoma of nasopharyngeal type (UCNT), collected from 2008 to 2014, were evaluated in this study. The genes EBNA2, LMP1, and EBNA1 were amplified using nested-PCR. EBNA2 genotyping was performed by visualization of PCR products using gel electrophoresis. Investigation of LMP1 and EBNA1 included sequence, phylogenetic, and statistical analyses. The presence of EBV DNA was significantly distributed between TNM stages. LMP1 variability showed six variants, with the detection of the first China1 and North Carolina variants in European nasopharyngeal carcinoma biopsies. Newly discovered variants Srb1 and Srb2 were UCNT-specific LMP1 polymorphisms. The B95-8 and North Carolina variants are possible predictors for favorable TNM stages. In contrast, deletions in LMP1 are possible risk factors for the most disfavorable TNM stage, independent of EBNA2 or EBNA1 variability. A newly discovered EBNA1 subvariant, P-thr-sv-5, could be a potential diagnostic marker, as it represented a UCNT-specific EBNA1 subvariant. A particular combination of EBNA2, LMP1, and EBNA1 polymorphisms, type 1/Med/P-thr was identified as a possible risk factor for TNM stage IVB or progression to the N3 stage.

Evaluation of local and regional spread of malignant tumors of the tongue and floor of the mouth

Malignant tumors of the oral cavity grow rapidly, frequently and early metastazing to the surrounding regional lymph nodes. The aim of this study was to evaluate the correlation between clinically confirmed local and regional spread and intraoperatively and histopathologically verified local spread. A series of 74 patients with carcinoma of the tongue and floor of the mouth were analyzed. All the patients were surgically treated during the period 1991-1995. Clinical evidence of local spread (cT) was in high accord with intraoperatively and histopathologically evidenced spread (pT) amounting to 83.8%. The degree of correlation decreased with the increase of T stage. Clinically observed regional spread (cN) and intraoperatively and histopathologically confirmed regional spread (pN) was lower, amounting to 56.8% in comparison to the corresponding T categories.