Multicenter clinical trial on functional evaluation of transoral laser microsurgery for supraglottic laryngeal carcinomas.

BACKGROUND: Transoral laser microsurgery (TLM) is an accepted and effective treatment strategy for supraglottic carcinomas. Data on oncologic and to a lesser extent functional outcomes have been published by mainly European specialized single institutions. TLM for supraglottic carcinomas has never been tested in a multicenter trial on its applicability as surgical standard at every hospital. OBJECTIVES: To test the efficacy of TLM supraglottic laryngectomy (TLM-SGL) in terms of swallowing function, oncologic outcome parameters, morbidity, complications of treatment, and quality of life in a multicenter setting. METHODS: The study is designed as a multicenter (approximately 25 centers), non-randomized, single-arm study with a targeted number of 200 previously untreated patients with squamous cell carcinomas (SCC) of the supraglottic larynx T2/T3 N0-3 M0; UICC stage II-IVa. The surgical treatment consists of TLM-SGL and elective or therapeutic uni- or bilateral selective neck dissection (SND). After pathologic risk stratification adjuvant radio- (RT) or radiochemotherapy (RCT) is indicated. Patients are followed-up for 2 years post surgically. Swallowing function is assessed by fibreoptic endoscopic evaluation of swallowing (FEES). The primary endpoint is aspiration-free swallowing at 12 months as established using FEES and defined as grade < 6 of penetration-aspiration scale (PAS). Secondary endpoints include local control, larynx preservation, overall and disease-free survival, complications and side effects of treatment, prevalence of tracheostomy and percutaneous endoscopic gastrostomy (PEG)-tube-feeding, and dysphagia-specific quality of life (QoL) assessed by the MD Anderson Dysphagia Inventory (MDADI) as well as voice-related QoL assessed by the Voice Handicap Index (VHI).

[The impact of smoking habit alteration on prognosis of head and neck cancer patients]. / Eine Änderung des Rauchverhaltens beeinflusst das Überleben von HNSCC-Patienten.

INTRODUCTION: The influence of smoking on survival in patients with HNSCC is well documented in the literature. There is little data on changes in smoking habits after diagnosis. Here, the effect on survival of the reduction of smoking compared to full smoking cessation is investigated. PATIENTS AND METHODS: Patient records and tumor documentation of 643 consecutive HNSCC cases of the Head and Neck Tumor Center of the University Hospital Kiel are evaluated retrospectively: smoking habits before and after treatment and survival are evaluated. RESULTS: Change in smoking behavior at the initial diagnosis of HNSCC leads to a significant positive effect on the prognosis compared to continued smoking. There is no difference between smoke reduction and weaning. This effect is based solely on those patients who are treated exclusively by surgery. Lifelong non-smokers have a significant survival advantage over active and ex-smokers, with no difference between the latter two groups. CONCLUSIONS: The positive influence of changed smoking habits on the prognosis runs parallel to the negative direct effect of active smoking on therapy, which is attributed to peritumoral hypoxia with a negative effect on the effectiveness of R(C)T. The positive effect of the change in smoking behaviour during surgery alone is most likely due to reduced peri-operative complications. Patients should be encouraged to at least minimize smoking with the cancer diagnosis. In addition, former smokers should be considered active smokers for survival estimates and therapy planning.

[Smoking and co-morbidity - it's impact on dose achievement in radio(chemo)therapy for HNSCC]. / Rauchen und Komorbidität ohne Einfluss auf geplante Zieldosis der Radio(chemo)therapie.

Smoking worsens the prognosis of patients with HNSCC. Furthermore, smoking is associated with the prevalence of co- and multimorbidity, so that it is assumed that not smoking per se, but co-/multimorbidity worsens the prognosis due to lack of compliance to therapy, e. g. by reducing the dose of the planned radio(chemo)therapy (RCT). However, data on this topic are currently sparse and contradictory, especially for HNSCC.Patient records and tumor documentation of 643 consecutive cases of the Head and Neck Tumor Center of the University Hospital Kiel were retrospectively evaluated. Patient characteristics and smoking habits were recorded and correlated with co-/multimorbidity and treatment course.The 643 patient files examined show that 113 (17.6 %) patients did not smoke, 349 (54.3 %) were active and 180 (28 %) patients had previously smoked. 315 (49 %) are treated exclusively by surgery; 121 (18.8 %) by surgery + adjuvant RCT and 72 (11.2 %) by surgery + adjuvant RT. 111 (17.3 %) receive a primary RCT and 24 (3.7 %) a primary RT. 131 (20.4 %) show co-/multimorbidity and 512 (79.6 %) do not. Smoking (> 10 py) is significantly associated with comorbidity (p = 0.002). However, smoking and comorbidity, neither alone nor in combination, are correlated with the achievement of the target dose of RCT (p > 0.05).As expected, smoking is significantly linked to co-/multimorbidity. Dose reduction of R(C)T is just as frequent in active smokers and patients with co-/multimorbidity as in non-smokers and patients without co-/multimorbidity. Thus, smoking and co-/multimorbidity influence the prognosis in other ways than by interfering with planned therapy regimens.

p16(INK4a) overexpression predicts translational active human papillomavirus infection in tonsillar cancer.

The causal role of human papillomaviruses (HPV) in squamous cell carcinogenesis of tonsillar cancers (TSCC) depends on the activity of the viral oncoproteins E6 and E7, leading to inactivation of the cellular tumor suppressor p53 and the retinoblastoma gene product pRb. Because of the negative feedback mechanisms, the pRb inactivation causes an increase of the inhibitor of the cyclin-dependent kinases p16(INK4a). In 39 TSCC specimens, genotyping based on the amplification of HPV DNA was carried out using PCR by applying HPV type-specific oligonucleotides. Subsequently, amplicons were hybridised with fluorescence-labeled complementary probes using the Southern blot technology. For HPV E6/E7 mRNA expression, Northern hybridization and RT-PCR were performed, and for p16(INK4a) detection, immunohistochemistry was performed. With 21/39 (53%) HPV-positives, the detection rate is within the range that can be expected in TSCC. The E6/E7 oncogene mRNA was detectable in 11 cases, 10 of which showed positive signals after p16(INK4a) staining. Albeit the small study group was investigated, the correlation of the HPV DNA status with the p16(INK4a) expression was of statistical significance (p = 0.02). Kaplan-Meier estimations revealed better survival outcome for patients with HPV-positive tumors with detectable E6/E7 mRNA and p16(INK4a) overexpression (p = 0.02, median observation time 29 months). As mRNA expression tests are not routinely available in many clinical diagnostic laboratories, and based on the high correlation of p16(INK4a) staining with HPV E6/E7 mRNA expression, in conclusion we suggest for a deeper exploration for the use of p16(INK4a) as a surrogate marker with the potential to impact the standard of care of HPV DNA-positive head and neck carcinomas.

Alteration of smoking habit at time of first diagnosis influences survival of patients with HNSCC.

The impact of smoking on survival in patients with squamous cell carcinoma of the head and neck is well established, despite some conflicting data in the literature. However, data on alterations of smoking habit following cancer diagnosis is sparse. In the present study, the effect of reduction of smoking compared with cessation on the course of disease was studied. Data from 643 patients with HNSCC from the tumor documentation registry of the Department of Otorhinolaryngology, Head and Neck Surgery of the Christian-Albrechts-University Kiel were collected and statistically analyzed, looking at pre- and post-treatment smoking habit and survival. Alteration of smoking at the first diagnosis of HNSCC led to a significantly beneficial effect on survival outcomes compared with continued smoking, without significant differences between reduction and cessation of smoking. Detailed analysis revealed that this effect was solely dependent on patients treated by surgery only. Lifelong non-smokers exhibited a significant survival advantage compared with active and former smokers, with no difference in survival between these last two groups. The positive influence of altered smoking habit following first time diagnosis on disease-specific survival paralleled the negative direct effect of active smoking on therapy, which is predominantly attributed to peritumoral tissue hypoxia leading to impaired efficacy of radiochemotherapy (RCT). In the present study cohort, the positive effect of smoking habit alterations were primarily observed in patients treated by surgery only instead of RCT, possibly due to fewer perioperative complications. These findings indicated that patients should be encouraged to at least minimize smoking following cancer diagnosis. Furthermore, for survival estimates and therapy planning, former smokers should be considered as active smokers.

No association between HPV-status in tonsillar tissue and sexual behavior of the patients in a northern German population - Critical view of the link between HPV natural history and HPV-driven carcinogenesis.

HPV-infection in patients with HNSCC is reportedly correlated with sexual behavior, age, and tobacco/alcohol-consumption. HPV-infections of the oral cavity are regarded as sexually transmitted. Comparable data of patient populations outside the U.S. are sparse or missing. Questionnaires regarding sexual behavior, education tobacco- and alcohol-consumption, were given to 28 patients with tonsillar hyperplasia (H) and 128 patients with tonsillar carcinomas (CA), all with tissue-typed HPV-DNA-status performing PCR. Answers were correlated among groups and HPV-status. 106 questionnaires were analyzed. Comparisons between H- (n = 25) and CA- (n = 81) patients showed that CA-patients were older (61.1yrs ± 9.3) than H-patients (45.2yrs ± 11.9; p < 0.0001; Student's t-test); had a lower educational level (p = 0.0095); and lower number of sexual partners (p = 0.0222; Fisher's exact test). All groups showed a significant correlation between smoking and lack of HPV-DNA-positivity (p = 0.001). Further Fisher's exact tests and logistic regression analysis revealed in all 106 patients no significant correlations between tissue-HPV-status and the analyzed parameters. Despite the limited sample size, we were able to confirm the established correlation between smoking and tissue-HPV-status. The correlation between sexual behavior and HPV-infection was not confirmed. No consensus exists in the literature about the latter. Our data does not support the strict classification of oral HPV-infections and HPV-driven HNSCCs as STDs.

The Influence of Smoking and Co-morbidity on Dose Achievement in Primary or Adjuvant Radio(Chemo)Therapy in Head and Neck Squamous Cell Carcinoma (HNSCC).

Introduction: Smoking has a negative impact on survival of HNSCC patients. In addition, smoking is associated with the prevalence of co-morbidities and, thus, it may be assumed that not smoking per se but co-morbidities impact the course of therapy in terms of lower compliance and dose-reduction. However, data addressing this issue is sparse and conflicting at present, specifically for HNSCCs. Patients and methods: Patient files and tumor documentation from 643 consecutive cases of the University Head and Neck Cancer Centre Kiel were analyzed retrospectively. Patient characteristics and smoking habits were assessed and correlated with co-morbidities and course of treatment. Results: The examined 643 patient files showed that 113 (17.6%), 349 (54.3%), and 180 (28%) patients were never, active, and former smokers, respectively. Three hundred fifteen (49%) were treated by surgery only; 121 (18.8%) received surgery + adjuvant RCT and 72 (11.2%) surgery + adjuvant RT. 111 (17.3%) received primary RCT and 24 (3.7%) primary RT. 131 (20.4%) and 512 (79.6%) had no or had co-morbidities, respectively. Smoking (>10 py) was significantly associated with co-morbidities (p = 0.002). However, smoking and co-morbidities, neither alone nor in combination, were correlated with failure in reaching target doses of radio(chemo)therapy (p > 0.05). Applying (verified) Carlson-Comorbidity-Index (CCI) did not change the results. Conclusions: As expected, smoking is significantly associated with co-morbidities. Dose-reduction of radio(chemo)therapy is as common among active smokers and patients with co-morbidities as among never smokers and patients without co-morbidities. Thus, smoking and co-morbidity seems to impact survival by other means than impairing planned therapy regimens.

Human papillomavirus and p53 polymorphism in codon 72 in head and neck squamous cell carcinoma.

The impact of a polymorphism of the wild-type human tumour suppressor gene p53(wt) on carcinogenesis is subject of controversy ever since a higher susceptibility of p53 to HPV-E6 mediated degradation when encoding for Arginine at codon 72 (p53Arg) was first reported. The issue remained unclear because various studies investigating this question for different tumour entities and different geographical regions demonstrated diverging results. In the present study, the HPV status and p53 genotype frequency of 42 head and neck cancers was analysed and compared to results reported in the recent literature. Applying PCR and cycle sequencing techniques, HPV DNA was demonstrated in 12/42 (29%) of the cases and the overall distribution of the p53 allele was: 64, 31 and 5% for p53Arg, p53Arg/Pro and p53Pro, respectively. There was no statistically significant association between HPV status and p53 genotype distribution. The results of our study and of the reviewed literature do not support a relevant role of the p53 polymorphism in head and neck carcinogenesis, either taken alone or in association with the HPV status.

Cystic masses of the lateral neck - Proposition of an algorithm for increased treatment efficiency.

Preoperative discrimination of solitary cervical branchial cleft cysts from cystic lymph node metastasis often is challenging. Surgical excision of the cystic formation and consecutive histopathological examination of tissue specimens are the only means resulting in the correct diagnosis. However, in case of malignancies surgery on the lateral neck prior to the definitive treatment is considered to negatively influence the patients' outcome. The rate of cystic lymph node metastasis in patients presenting with a lateral branchial cleft cyst, localization of the primary tumour and oncological outcome were investigated. Retrospective chart review of 131 patients presenting clinically with solitary lateral cervical cysts between. A malignant tumour was detected in 12 patients (9.2%). Malignant tumours were significantly more frequent in patients older than 40 years of age (22.0%; p = 0.0001). In patients older than 40 years of age with solitary lateral cervical cysts a malignancy should be presumed.

Transoral Laser Microsurgery for Supraglottic Cancer.

INTRODUCTION: Transoral laser microsurgery (TLM) is an accepted and effective treatment strategy for supraglottic carcinomas. Early supraglottic carcinoma has excellent outcomes independently of the treatment approach. The role of TLM for the treatment of locally advanced tumors is debated. Particularly, the functional outcomes after TLM have to be proven by functional assessment of large cohorts of patients. This study analyzes the oncologic and functional outcomes after TLM for supraglottic carcinomas. PATIENTS AND METHODS: Ninety-one patients with pT1-pT4a supraglottic carcinomas treated between January 2002 and December 2012 were analyzed. Distribution of tumors (UICC 2010) was 11 patients with pT1, 31 patients with pT2, 36 patients with pT3, and 13 patients with pT4a tumors. Node status was positive in 40 (43.6%) patients; 61 (67.1%) patients had stage III or IVa disease. Local control and survival were estimated using the Kaplan-Meier method. For the assessment of functional outcomes, the MD Anderson Dysphagia Inventory (MDADI), the Voice Handicap Index-10 (VHI-10), and the performance status scale for head and neck cancer [Performance Status Scale for Head and Neck (PSS-HN)] were used. RESULTS: The median age was 62 years (range, 33-88 years). Fourteen (15.4%) patients developed a local or locoregional recurrence. The 5-year local control rate and 5-year ultimate local control rate were 72 and 92%, respectively. The 5-year overall survival rate was 63%. Twelve (13.2%) patients needed temporary tracheostomy. Sixty-eight (74.0%) patients had a nasogastric feeding tube post-operatively. At 1-year post-operative follow-up, only three patients were PEG dependent. The median VHI-10 score was 35, the median MDADI composite score was 80, and the median score of the domain "normalcy of diet" in the PSS-HN was 91. CONCLUSION: The oncologic outcomes are comparable to the results of open surgery for early and advanced supraglottic carcinomas. Functional swallowing outcome is superior to open surgery and to concomitant chemoradiation. Patients treated with TLM perceive low levels of voice- and swallowing-related quality of life impairment.

Detection of human papillomavirus DNA in benign and malignant sinonasal neoplasms.

Infections with human papillomaviruses are divided basically into three different infection types: those producing specific clinically visible lesions, those remaining subclinical, and those being latent. The assumed infection type thought to be present in tissue specimens has influence on the conclusions that can be made from an analysis, i.e. whether or not the HPV infection has a causal relationship with other epidemiological or molecular investigation observations. To determine whether HPV DNA detection in different entities of the upper aerodigestive tract represents a coincidental, persistent/latent or specific infection, 20 clinically intact mucosa specimens of the upper aerodigestive tract, 20 sinonasal polyps, 26 inverted papillomas, and 20 squamous cell carcinomas of the paranasal sinuses were investigated. HPV DNA was not detectable in specimens derived from clinically intact mucosa or in nasal polyps. Yet, three out of 26 inverted papillomas were HPV-positive, each showing double infection with HPV6 and 11. Four out of 20 squamous cell carcinomas were HPV16 positive. To our knowledge, we are presenting the first study contemporaneously analyzing benign as well as malignant non-proliferative and proliferative mucosal entities whilst applying identical methodical standards. The data corroborate the hypothesis that HPV DNA demonstration in tissue specimens represents a specific infection of the mucosa of the upper aerodigestive tract. It can thus be assumed that there is a causative involvement of HPV infections in the alteration of cell proliferation and in the case of infection with high risk HPV types even on progression to malignant transformation.

HPV16 DNA in histologically confirmed tumour-free neck lymph nodes of head and neck cancers.

BACKGROUND: Human papillomavirus (HPV) has been demonstrated in lymph node neck metastases (NM) of HPV-positive squamous cell carcinomas of the head and neck (HNSCC), underscoring the possible role of HPV for HNSCC progression. Reports on HPV infections in histopathologically tumour-free lymph-nodes of the SCC of the uterine cervix developing higher rates of lymph-node metastases and recurrences later in the survey of the patients was the starting point of the present study. MATERIALS AND METHODS: The presence of HPV-DNA in primary tumours (PT, n=45), NM (n=45) and histologically confirmed tumour-free neck lymph-nodes (LN, n=102) of HNSCC from 60 patients was analysed by PCR and Southern blot hybridisation. RESULTS: A highly positive correlation of simultaneous HPV-DNA detection in PT and NM was demonstrated. In the case of HPV-positivity of PT and/or NM [24/60 cases (40%)], 11/24 (45.8%) LN contained HPV-DNA, as well. Accepting HPV demonstration as a marker for the presence of micro-metastasis, HPV analysis would result in an upstaging of the N category in 4 out of these 11 patients. CONCLUSION: Considering the high agreement of HPV-DNA detection in PT and simultaneous HPV-DNA demonstration in the draining NM corroborating the monoclonal character of the tumour cells, the HPV-DNA presence in LN seems to be indicative of micro-metastasis in these lymph nodes. Thus, HPV analysis might be another powerful tool for the definition of the N-status of HPV-positive HNSCC.

Cyfra 21-1 in diagnosis of distant metastases of head and neck carcinoma.

Follow-up examinations of patients might detect local tumor recurrences at a curable stage, which is more difficult for distant metastases (DM). Recently, elevated Cyfra 21-1 serum levels (CySL) could be shown not only to correlate with HNSCC-tumor size but also with development of DM. We focussed on the CySL of 476 HNSCC patients as a first step. At first time diagnosis, besides regular staging procedures, these patients were screened for CySL higher than 3.3 ng/ml. Seventeen out of 476 (3.9%) patients showed DM. Seventeen out of 19 patients (89.5%) presented elevated CySL: A further 830 patients with HNSCC were tested for changes in CySL in the course of disease (cut-off value 3.3 ng/ml). Seventy-one out of 830 patients (8.6%) showed elevated CySL. Tumor growth was found in 50 out of 71 patients (70.4%). In 54% of these patients (27 out of 50) DM were detected. Routine screening for CySL can lead to timely detection of DM in HNSCC, despite its fairly low sensitivity.

p53 autoantibodies as tumor marker in head and neck squamous cell cancer.

p53 autoantibodies (AAB) are a new serological parameter with unknown potential in patients with malignancies. The reason why and the mechanism by which they develop is still unclear. So far, only in a limited number of studies has the usefulness of p53 AAB in the follow-up of cancer patients been shown. In this study 32 patients with head and neck cancer, seropositive for p53 AAB in their serum detected with an ELISA, were followed-up for at least 42 months. In 9 out of 32 p53 seropositive AAB head and neck cancer patients a correlation with the clinical course of the disease was seen. The remaining 23 of the p53 AAB-positive patients did not demonstrate any significant AAB titer changes during the follow-up and no significant correlation with the clinical course was observed. In conclusion, the clinical value of p53 AAB as a tumor marker for patients with head and neck cancer seems to be limited.

Functional organ preservation in laryngeal and hypopharyngeal cancer.

The principles of open versus laser microsurgical approaches for partial resections of the larynx are described, oncologic as well as functional results discussed and corresponding outcomes following primary radiotherapy are opposed. Over the last decade, the endoscopic partial resection of the larynx has developed to an accepted approach in the treatment of early glottic and supraglottic carcinomas thus leading to a remarkable decline in the use of open surgery. Comparing the various surgical approaches of laryngeal partial resections, the oncological outcome of the patients, as far as survival and organ preservation are concerned, are comparable, whereas functional results of the endoscopic procedures are superior with less morbidity. The surgical procedures put together, are all superior to radiotherapy concerning organ preservation. Transoral laser microsurgery has been used successfully for vocal cord carcinomas with impaired mobility or fixation of the vocal cord, supraglottic carcinomas with infiltration of the pre- and/or paraglottic space as well as for selected hypopharyngeal carcinomas. It has been well documented that laser microsurgery achieves good oncological as well as functional results with reasonable morbidity. However, patients with those tumours have been successfully treated by open partial resections of the larynx at medical centres with appropriate expertise. The initially enthusiastic assessment of study results concerning the efficacy of various protocols of chemoradiation with the intent of organ preservation for laryngeal and hypopharyngeal carcinomas are judged more cautious, today, due to recent reports of rather high rates of late toxicity complications.