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Fibroblastic reticular cells (FRCs) direct the interaction and activation of immune cells in discrete microenvironments of lymphoid organs. Despite their important role in steering innate and adaptive immunity, the age- and inflammation-associated changes in the molecular identity and functional properties of human FRCs have remained largely unknown. Here, we show that human tonsillar FRCs undergo dynamic reprogramming during life and respond vigorously to inflammatory perturbation in comparison to other stromal cell types. The peptidase inhibitor 16 (PI16)-expressing reticular cell (PI16+ RC) subset of adult tonsils exhibited the strongest inflammation-associated structural remodeling. Interactome analysis combined with ex vivo and in vitro validation revealed that T cell activity within subepithelial niches is controlled by distinct molecular pathways during PI16+ RC–lymphocyte interaction. In sum, the topological and molecular definition of the human tonsillar stromal cell landscape reveals PI16+ RCs as a specialized FRC niche at the core of mucosal immune responses in the oropharynx.

B cell zone reticular cells (BRCs) form stable microenvironments that direct efficient humoral immunity with B cell priming and memory maintenance being orchestrated across lymphoid organs. However, a comprehensive understanding of systemic humoral immunity is hampered by the lack of knowledge of global BRC sustenance, function and major pathways controlling BRC–immune cell interactions. Here we dissected the BRC landscape and immune cell interactome in human and murine lymphoid organs. In addition to the major BRC subsets underpinning the follicle, including follicular dendritic cells, PI16+ RCs were present across organs and species. As well as BRC-produced niche factors, immune cell-driven BRC differentiation and activation programs governed the convergence of shared BRC subsets, overwriting tissue-specific gene signatures. Our data reveal that a canonical set of immune cell-provided cues enforce bidirectional signaling programs that sustain functional BRC niches across lymphoid organs and species, thereby securing efficient humoral immunity.

Sentinel node biopsy (SNB) is considered the standard surgical procedure for detecting occult neck node metastasis in oral squamous cell carcinoma (OSCC) in many centers around the world. Due to the fact that this method removes and evaluates the first lymph node(s) reached by the lymphatic flow from the tumor area, this has raised the question of whether SNB could also be considered a therapeutic procedure by targeted lymphadenectomy instead of elective neck dissection (END). Compared to END, its safety and low morbidity have been established. However, the surgical management of the clinical node-negative (cN0) neck in T1/T2 oral carcinoma has been under ongoing debate due to the lack of randomized studies comparing SNB to END in terms of overall survival (OS), disease-free survival (DFS) and neck recurrence rates (NRRs). In the last years, two prospective randomized studies have proven with high-level evidence the noninferiority of SNB compared to END in terms of oncologic outcome while reducing costs and morbidity. In our opinion, SNB should be offered as the new standard therapeutic procedure in early OSCC.

The aim of this study was to investigate the value of metabolic tumor imaging using hybrid PET for the preoperative detection of extranodal extension (ENE) in lymph node metastases of oropharyngeal squamous cell carcinoma (OPSCC).We performed a retrospective analysis of a consecutive cohort of patients with OPSCC treated with primary surgery with or without adjuvant (chemo-) radiotherapy at the Kantonsspital Sankt-Gallen and the University Hospital Zurich, Switzerland, from 2010 until 2019. Hybrid PET was compared to conventional cross-sectional imaging with MRI and CT. Histopathological presence of ENE of neck dissection specimen served as gold standard.A total number of 234 patients were included in the study, 95 (40.6%) of which had pathological ENE (pENE). CT has a good specificity with 93.7%; meanwhile, MRI was the most sensitive diagnostic method (72.0%). The nodal metabolic tumor parameters (SUVCT achieved the best specificity, while MRI had the best sensitivity to detect ENE. Nodal metabolic tumor parameters differed significantly between ENE-positive/negative and p16-positive/negative patients. Hence, quantitative data obtained by metabolic imaging might predict presence of ENE and, therefore, could be helpful in customizing therapy management.

BACKGROUND Epithelial-mesenchymal transition and cancer stem-like cells (CSC) have been linked to increased metastatic potential. We evaluated the prognostic impact of CD44, a CSC biomarker, on depth of invasion (DOI) and outcome in oral squamous cell carcinoma (OSCC). METHODS Using a multivariable logistic regression model, we evaluated in early OSCCs the relationship between CD44 expression at the invasive tumor front, DOI, sentinel lymph node biopsy, extension of nodal involvement, and survival. We also assessed whether CT and/or MRI could predict DOI preoperatively. RESULTS CD44 expression was associated with increased DOI (P = .018), worse disease-specific survival (P = .041) but not with positive sentinel lymph node biopsy (P > .05). Each millimeter increase in DOI was associated with a 31.1% higher risk for positive sentinel lymph node biopsy (95% CI: 5.8%-62.4%, P = .013) and with higher metastatic ratio (P = .015). Preoperative estimation of DOI by CT and/or MRI and histopathological DOI showed a strong correlation (P

AIM OF THE STUDY For tumours of the oral tongue, the most recent 8th edition of the AJCC/UICC staging system has introduced depth of infiltration (DOI) as a novel parameter. With this study we wanted to investigate its impact regarding this risk stratification compared with the preceding 7th edition. METHODS Between 2008 and 2017, 161 patients of two tertiary referral centres in Switzerland (Kantonsspital St. Gallen and University Hospital Zurich) with T1 N0 or T2 N0 tongue cancers were enrolled in this study. The primary tumours were restaged according to the 8th edition of the TNM classification. Kaplan-Meier curves for overall and disease-specific survival were calculated. RESULTS According to the 7th edition, of the 161 patients, 102 were staged after surgery as pT1 (stage I) and 59 as pT2 (stage II). According to the 8th edition, 36 patients (22.4%) were re-staged to a higher stage. Of these 36 patients, 8 (22.2%) experienced a recurrence, and 9 (25%) died. In the remaining, not re-staged group, 20 patients (16.0%) experienced a recurrence (p = 0.55) and 14 (11.2%) died (p = 0.025*). The 7th edition showed a statistically significant difference between pT1 and pT2 tumours for overall survival (p = 0.025), but not for disease-specific survival (p = 0.091), whereas the 8th edition was able to well discriminate between pT1, pT2 and pT3 for both overall (pT1 vs pT2, p = 0.016*; pT2 vs pT3, p = 0.031*) and disease-specific survival (pT1 vs pT2, p = 0.037*; pT2 vs pT3, p = 0.023*). CONCLUSION The recent TNM 8th edition provides a more accurate prediction of overall and disease-specific survival for this subgroup of patients. Hence, a more aggressive treatment should be considered for patients re-staged to pT3 due to depth of infiltration.

The aim of this study was to investigate the predictability of occult lymph node metastasis using maximum standardized uptake value (SUVmax) in the primary tumor on pre-treatment 18-fluorodeoxyglucose positron emission tomography FDG-PET in oral squamous cell carcinoma (OSCC) patients who were clinically node negative (cN0) before surgery. A retrospective analysis of all patients treated at the University Hospital Zurich from 2007 to 2016 for OSCC with available pre-therapeutic FDG-PET was performed. We assessed the correlation of SUVmax of the primary tumors with the presence of occult nodal disease in the neck dissection specimen (pN+). The study included a total of 71 patients. In the nodal negative group (cN0/pN0), the median SUVmax of primary tumors was 9.0 (interquartile range (IQR) 7.4–13.9), while it was 11.4 (IQR 9.9–15.7) in the occult metastatic group (cN0/pN+). The difference was statistically significant (independent samples median test, P = 0.037). In a multivariable model, the only independent predictor of occult metastatic disease for cN0 patients was a SUVmax ≥ 9.5 (P = 0.028). Further, primary tumors with SUVmax ≥ 9.5 had a significantly higher risk of local recurrence (Log rank test, P = 0.020). In conclusion, we showed that higher SUVmax (≥9.5) of the primary tumor is associated with higher occurrence of occult metastatic nodal disease and worse local survival. High SUVmax of the primary tumor may encourage clinicians towards more aggressive treatment.

Objectives The aim of the study was to evaluate whether HPV associated OPSCC with tobacco exposure follows a different carcinogenic pathway compared to HPV associated OPSCC without tobacco exposure and to investigate its prognostic significance. The question was addressed with focus on components of the PI3K pathway. Methods 184 patients with newly diagnosed OPSCC treated with curative intent were consecutively enrolled. The expression level of p16, p53, PI3K, mTOR, and PTEN was assessed by immunohistochemistry and analyzed in relation to the risk factors HPV status and tobacco exposure. Results 94 of 184 (51%) patients were p16 positive, p53 overexpression was detected in 48 of 184 (26%) cases. PI3K overexpression with 70 of 184 (38%) cases was significantly higher in p16 positive tumors. mTOR overexpression was present in 90 of 184 (49%) cases and significantly higher in p16 negative tumors. PTEN loss was found in 42 of 184 (23%) cases without association to p16 expression. p16 positive OPSCC showed lower rates of p53 expression and mTOR expression as well as higher rates of PI3K expression irrespective of tobacco exposure. Survival analysis showed a distinct intermediate survival rate of p16 positive smokers. The markers PI3K, mTOR, and PTEN did not have a significant impact on survival. Conclusion HPV associated OPSCC with tobacco exposure follows the same expression level of the PI3K pathway as HPV associated OPSCC without tobacco exposure. The impaired survival rate of the intermediate risk group cannot be explained by different expression patterns of PI3K, mTOR, and PTEN. Level of evidence 2b.

IMPORTANCE: Predicting the duration of poststroke dysphagia is important to guide therapeutic decisions. Guidelines recommend nasogastric tube (NGT) feeding if swallowing impairment persists for 7 days or longer and percutaneous endoscopic gastrostomy (PEG) placement if dysphagia does not recover within 30 days, but, to our knowledge, a systematic prediction method does not exist. OBJECTIVE: To develop and validate a prognostic model predicting swallowing recovery and the need for enteral tube feeding. DESIGN, SETTING, AND PARTICIPANTS: We enrolled participants with consecutive admissions for acute ischemic stroke and initially severe dysphagia in a prospective single-center derivation (2011-2014) and a multicenter validation (July 2015-March 2018) cohort study in 5 tertiary stroke referral centers in Switzerland. EXPOSURES: Severely impaired oral intake at admission (Functional Oral Intake Scale score

Background Applicability of sentinel node biopsy (SNB) for tumors of the floor of mouth (FOM) is controversial. Methods Prospective evaluation of the accuracy of gamma-probe-guided superselective neck dissection of the preglandular triangle of level I for SNB in FOM squamous cell carcinoma (SCC) after preoperative lymphoscintigraphy and single photon emission CT (SPECT)/CT. Results In total, 22 sentinel lymph nodes were harvested in level I. Eight of 22 (36%) were seen on lymphoscintigraphy and 11 (50%) on SPECT/CT. Eleven sentinel lymph nodes (50%) were only detected intraoperatively. In unilateral tumors, 20% were contralateral, and, in midline tumors, 93% showed bilateral level I sentinel lymph nodes. The false-negative rate was 8.3%, the negative predictive value was 96.4%, and the false-omission rate was 3.6%. The ultimate neck control rate, including salvage treatment, was 100%. Conclusion SNB in FOM can be reliably performed using the presented surgical technique. Level I exploration, bilaterally in midline tumors, is mandatory irrespective of the visualization of sentinel lymph nodes in other levels. © 2016 Wiley Periodicals, Inc. Head Neck, 2016

Background Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) has an improved outcome and may allow for treatment de-escalation. High-risk HPV (HR-HPV) infection is associated with deregulated expression of the cell cycle-associated proteins p16INK4, pRB, cyclin D1 and p53. The objective of this study was to assess cell cycle proteins as potential surrogate markers for HR-HPV DNA testing to identify OPSCC with favorable prognosis after resection. Methods Tissue microarray cores of 313 surgically treated OPSCC were stained for p16INK4a, pRB, cyclin D1 and p53 using immunohistochemistry. Protein expression was scored as high or low based on the proportion of positive carcinoma cells. Tumor samples were analysed for HR-HPV DNA with polymerase chain reaction-based testing. Associations between cell cycle protein expression and HR-HPV DNA status were evaluated by calculating sensitivity, specificity, predictive values, and diagnostic odds ratios (DOR). Kaplan-Meier and Cox regression analysis were applied to evaluate associations between cell cycle protein expression and patient outcome. Results High expression of p16INK4a, cyclin D1, pRB and p53 in tumor cells were observed in 51.8%, 51.4%, 41.9% and 33.5% of OPSCC, respectively. HR-HPV DNA positive were 158/313 (50.5%) tumor samples (HPV16: 147, HPV18: 1, HPV33: 5, HPV35: 2, HPV56: 2, and HPV59: 1). P16INK4a showed a higher DOR to predict HR-HPV DNA positivity than pRB, cyclin D1 and p53. Both the p16INK4a/pRB and the p16INK4a/pRB/cyclin D1/p53 signatures had lower DOR than p16INK4a alone. Improved 5-year overall and disease-specific survival were associated with HR-HPV DNA positivity, high p16INK4a, low pRB, low cyclin D1, and low p53 expression. Associations with improved outcome were also observed for the marker combinations high p16INK4a/positive HR-HPV DNA, high p16INK4a/low pRB and high p16INK4a/low pRB/low cyclin D1/low p53. In a multivariate analysis adjusted for age, smoking history, pT and pN category, high p16INK4a expression showed the lowest hazard ratio for death. Conclusions High p16INK4a expression is a reliable marker for survival prognostication in surgically treated OPSCC patients. Protein signatures including the pRB, cyclin D1 and p53 proteins do not further increase the prognostic performance of p16INK4a as a single marker.

Purpose: The aim of the study was to evaluate 18F-FDG-PET/CT for the detection of synchronous primaries at initial staging of patients with head and neck squamous cell carcinoma (HNSCC). Methods: FDG-PET/CT images acquired between March 2001 and October 2007 in 589 consecutive patients (147 women, 442 men; mean age 61.5years, age range 32-97years) with proven HNSCC were reviewed for the presence of synchronous primaries. Cytology, histology and/or clinical and imaging follow-up served as reference standard. Results: FDG-PET/CT showed 69 suspected synchronous primaries in 62 patients of which 56 were finally confirmed in 44 patients. Of the 56 second cancers, 46 (82%) were found in the aerodigestive tract in the following locations: lung (26, 46%), head and neck (15, 17%), oesophagus (5, 9%). Ten second cancers (18%) were located outside the aerodigestive tract (colon, five; stomach, lymphoma, breast, thymus and kidney, one each). Six patients had three synchronous primaries and three patients had four synchronous cancers. Nine synchronous cancers were not detected by PET/CT (four head and neck, two lung, two oesophageal, one gastric). False-positive PET/CT findings were mainly related to benign FDG uptake in the intestine due to benign or precancerous polyps or physiological FDG uptake in other head and neck regions. Overall the prevalence of synchronous second primaries according to the reference standard was 9.5%, of which 84% were detected with FDG-PET/CT. In 80% of the patients, therapy was changed because of the detection of a synchronous primary. Conclusion: FDG-PET/CT detects a considerable number of synchronous primaries (8.0% prevalence) at initial staging of patients with HNSCC. Synchronous cancers were predominantly located in the aerodigestive tract, primarily in the lung, head and neck and oesophagus. Detection of second primaries has an important impact on therapy. PET/CT should be performed before panendoscopy

The aim of this study was to investigate the predictability of occult lymph node metastasis using maximum standardized uptake value (SUVmax) in the primary tumor on pre-treatment 18-fluorodeoxyglucose positron emission tomography FDG-PET in oral squamous cell carcinoma (OSCC) patients who were clinically node negative (cN0) before surgery. A retrospective analysis of all patients treated at the University Hospital Zurich from 2007 to 2016 for OSCC with available pre-therapeutic FDG-PET was performed. We assessed the correlation of SUVmax of the primary tumors with the presence of occult nodal disease in the neck dissection specimen (pN+). The study included a total of 71 patients. In the nodal negative group (cN0/pN0), the median SUVmax of primary tumors was 9.0 (interquartile range (IQR) 7.4–13.9), while it was 11.4 (IQR 9.9–15.7) in the occult metastatic group (cN0/pN+). The difference was statistically significant (independent samples median test, P = 0.037). In a multivariable model, the only independent predictor of occult metastatic disease for cN0 patients was a SUVmax ≥ 9.5 (P = 0.028). Further, primary tumors with SUVmax ≥ 9.5 had a significantly higher risk of local recurrence (Log rank test, P = 0.020). In conclusion, we showed that higher SUVmax (≥9.5) of the primary tumor is associated with higher occurrence of occult metastatic nodal disease and worse local survival. High SUVmax of the primary tumor may encourage clinicians towards more aggressive treatment.

BACKGROUND High-risk human papillomavirus (HR-HPV) infection is associated with improved prognosis and a better response to treatment in patients with oropharyngeal squamous cell carcinoma (OPSCC). Brush cytology is a noninvasive method with which to collect cells from the surface of mucosal lesions. The objective of the current study was to assess the performance of OPSCC brush cytology for the detection of HR-HPV. METHODS Liquid-based brush cytology specimens were prospectively collected during panendoscopy from 51 patients with OPSCC. Cell suspensions were analyzed with Papanicolaou staining, polymerase chain reaction-based HPV DNA testing, and p16 immunostaining. HPV testing and p16 staining were also performed on paired OPSCC biopsy or surgical resection specimens. The detection of HR-HPV DNA alone and the combined positivity for HR-HPV DNA and p16 protein in dysplastic squamous cells were used to calculate accuracy, sensitivity, specificity, and positive and negative predictive values for HR-HPV detection using brush cytology samples. RESULTS Approximately 96% of OPSCC brush cytology samples (49 of 51 samples) were classified as satisfactory for evaluation. Dysplastic squamous cells were found in 88% of samples (43 of 49 samples). HPV DNA testing was conclusive in 95% of samples (41 of 43 samples) and revealed HR-HPV DNA in approximately 54% of patients (22 of 41 patients) (HPV type 16 in 19 patients and HPV type 33 in 3 patients). Approximately 49% of brush cytology samples (20 of 41 samples) were positive for HR-HPV DNA and p16 expression. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of brush cytology to identify HR-HPV DNA-positive and p16-positive OPSCC samples were 88%, 83%, 94%, 95%, and 81%, respectively. CONCLUSIONS Brush cytology appears to be a valid approach with which to determine the HR-HPV status of patients with OPSCC. Cancer (Cancer Cytopathol) 2015;123:732–738. © 2015 American Cancer Society.

BACKGROUND Knowledge about prognostic factors in surgically treated patients with oropharyngeal squamous cell carcinoma (SCC) is limited. The purpose of this study was to identify influential factors on survival in a large cohort of patients with surgically treated oropharyngeal SCC. METHODS Retrospective analysis of survival estimates in patients with surgically treated oropharyngeal SCC using tumoral positivity for human papillomavirus (HPV) and risk-of-death categories according to a study from 2010 as stratification factors. RESULTS The 5-year overall survival (OS) and disease-specific survival (DSS) rates after surgery alone were higher in HPV-associated oropharyngeal SCC (OS 80% vs 62%; P = .01; DSS 92% vs 76%; P = .03). Patients in the low-risk category had higher survival rates (OS 91%; DSS 99%) than patients in the intermediate-risk group (OS 63%; DSS 83%), and high-risk group (OS 61%; DSS 75%). CONCLUSION Nonsmokers with HPV-positive oropharyngeal SCC have a better prognosis than smokers with HPV-positive oropharyngeal SCC and also than patients with HPV-negative tumors when treated by surgery alone.

Objectives High risk human papillomavirus (HR-HPV) infection leads to a subgroup of oropharyngeal cancer (OPSCC) characterized by improved treatment response. However an universally accepted definition of an HR-HPV-attributable cancer is lacking. Methods Detailed, type-specific HPV antibody responses were analyzed by multiplex serology in HR-HPV-attributable OPSCC patients, defined by p16INK4A overexpression and HR-HPV DNA detection by PCR amplification and sequencing. Results Fifty patients were prospectively enrolled. 26/50 (52%) tumor samples were positive for both p16INK4A expression and HR-HPV DNA (22 HPV16, 4 HPV33). Seropositivity was present in 26/26 HPV-attributable OPSCC and one p16INK4A-positive/HPV DNA-negative case. The sensitivity and specificity to diagnose an HR-HPV-attributable tumor was 100% and 96%, respectively for anti-E6 reactivity, 82% and 100%, respectively for anti-E2 reactivity, and clearly lower for anti-E7, anti-E1, anti-E4 and anti-L1-reactivity. 3 yr-overall (OS) and disease specific survival (DSS) was higher in patients with HR-HPV-attributable tumors (OS 88% vs 64%, p = 0.02; DSS 90% vs 80%, p = 0.07) and seropositive patients (OS 88% vs 62%, p = 0.01; DSS 92% vs 78%, p = 0.05) than HR-HPV-negative or seronegative patients. Conclusions Detection of HR-HPV type-specific antibodies highly correlated with HPV-attributable OPSCC and was associated with better survival. HR-HPV antibodies are promising diagnostic, prognostic and potentially screening markers in HR-HPV-attributable OPSCC.

Regional metastasis is a prominent feature of head and neck squamous cell carcinoma (HNSCC) and is an important prognostic factor. The currently available imaging techniques for assessment of the neck have limitations in accuracy; thus, elective neck dissection has remained the usual choice of management of the clinically N0 neck (cN0) for tumors with significant (≥20%) incidence of occult regional metastasis. As a consequence, the majority of patients without regional metastasis will undergo unnecessary treatment. The purpose of this review was to discuss new developments in techniques that potentially improve the accuracy of the assessment of the neck in patients with HNSCC. Although imaging has improved in the last decades, a limitation common to all imaging techniques is a lack of sensitivity for small tumor deposits. Therefore, complementary to improvements in imaging techniques, developments in more invasive diagnostic procedures, such as sentinel node biopsy (SNB) will add to the accuracy of diagnostic algorithms for the staging of the neck.

Background Sentinel lymph node biopsy is a reliable technique for accurate determination of the cervical lymph node status in patients with early oral and oropharyngeal cancer but analyses on the distribution pattern of metastatic spread within sentinel lymph nodes are lacking. Methods The localizations of carcinoma deposits were analyzed with a virtual microscope by creating digital images from the microscopic glass slides. Results Metastatic deposits were not randomly distributed within sentinel lymph nodes but were predominant in the central planes closer to the lymphatic inlet. Initial evaluation of the 4 most central slices achieved a high rate of 90% for the detection of micrometastases and of 80% for the detection of isolated tumor cells (ITCs). Conclusion Based on the distribution we recommend an initial cut through the hilus and to proceed with the 4 most central 150-µm slices. Complete step sectioning is only required in case of a so far negative result. © 2014 Wiley Periodicals, Inc. Head Neck 37: 1477–1482, 2015

Neck dissection is an important treatment for metastases from upper aerodigestive carcinoma; an event that markedly reduces survival. Since its inception, the philosophy of the procedure has undergone significant change from one of radicalism to the current conservative approach. Furthermore, nonsurgical modalities have been introduced, and, in many situations, have supplanted neck surgery. The refinements of imaging the neck based on the concept of neck level involvement has encouraged new philosophies to evolve that seem to benefit patient outcomes particularly as this relates to diminished morbidity. The purpose of this review was to highlight the new paradigms for surgical removal of neck metastases using an evidence-based approach.

The International Conference on Innovative Approaches in Head and Neck Oncology is a biennial joint meeting under the auspices of the European Society for Radiotherapy and Oncology, the European Head and Neck Society and the European Society of Medical Oncology. The conference focuses on recent developments in head and neck oncology. The main topics of this year were new insights in the epidemiology of head and neck cancer, the emerging role of human papillomavirus in head and neck cancer, update on randomized trials and new management approaches. The format of the meeting included invited key note lectures, interactive symposia, updates on large randomized trials, proffered paper sessions, poster presentations and tumor boards. The meeting was very well balanced, with abundant information and opportunities for interdisciplinary interaction.

BACKGROUND: Analysis of the impact of risk factors on survival in patients with oropharyngeal squamous cell carcinoma (OPSCC) treated by primary intensity-modulated radiotherapy (IMRT). METHODS: One hundred forty patients were included with tissue microarray (TMA) construction and immunohistochemical analysis in 124 patients (87%). RESULTS: Survival analysis of patients classified into 3 risk categories according to an algorithm based on p16, smoking, T classification, and N classification revealed significant differences with a low, intermediate, and high-risk group. There was a significant impact of p53 expression as surrogate marker for smoking on outcome. In multivariate analysis, p16-positivity was a positive predictor and alcohol as well as N classification was a negative predictor for survival. The algorithm was modified based on alcohol instead of smoking with even more significant differences between the groups. CONCLUSIONS: A risk model based on multiple factors instead of p16 as single marker can define different risk groups to select patients for treatment deintensification in future prospective clinical trials. © 2013 Wiley Periodicals, Inc. Head Neck, 2013.

To investigate the combined antegrade-retrograde endoscopic rendezvous technique for complete oesophageal obstruction and the swallowing outcome.This single-centre case series includes consecutive patients who were unable to swallow due to complete oesophageal obstruction and underwent combined antegrade-retrograde endoscopic dilation (CARD) within the last 10 years. The patients' demographic characteristics, clinical parameters, endoscopic therapy, adverse events, and outcomes were obtained retrospectively. Technical success was defined as effective restoration of oesophageal patency. Swallowing success was defined as either percutaneous endoscopic gastrostomy (PEG)-tube independency and/or relevant improvement of oral food intake, as assessed by the functional oral intake scale (FOIS) (≥ level 3).The cohort consisted of six patients [five males; mean age 71 years (range, 54-74)]. All but one patient had undergone radiotherapy for head and neck or oesophageal cancer. Technical success was achieved in five out of six patients. After discharge, repeated dilations were performed in all five patients. During follow-up (median 27 mo, range, 2-115), three patients remained PEG-tube dependent. Three of four patients achieved relevant improvement of swallowing (two patients: FOIS 6, one patient: FOIS 7). One patient developed mediastinal emphysema following CARD, without a need for surgery.The CARD technique is safe and a viable alternative to high-risk blind antegrade dilation in patients with complete proximal oesophageal obstruction. Although only half of the patients remained PEG-tube independent, the majority improved their ability to swallow.

PURPOSE: Nuclear imaging plays a crucial role in lymphatic mapping of oral cancer. This evaluation represents a subanalysis of the original multicenter SENT trial data set, involving 434 patients with T1-T2, N0, and M0 oral squamous cell carcinoma. The impact of acquisition techniques, tracer injection timing relative to surgery, and causes of false-negative rate were assessed.METHODS: Three to 24 hours before surgery, all patients received a dose of Tc-nanocolloid (10-175 MBq), followed by lymphoscintigraphy. According to institutional protocols, all patients underwent preoperative dynamic/static scan and/or SPECT/CT.RESULTS: Lymphoscintigraphy identified 723 lymphatic basins. 1398 sentinel lymph nodes (SNs) were biopsied (3.2 SN per patient; range, 1-10). Dynamic scan allowed the differentiation of sentinel nodes from second tier lymph nodes. SPECT/CT allowed more accurate anatomical localization and estimated SN depth more efficiently. After pathological examination, 9.9% of the SN excised (138 of 1398 SNs) showed metastases. The first neck level (NL) containing SN+ was NL I in 28.6%, NL IIa in 44.8%, NL IIb in 2.8%, NL III in 17.1%, and NL IV in 6.7% of positive patients. Approximately 96% of positive SNs were localized in the first and second lymphatic basin visualized using lymphoscintigraphy. After neck dissection, the SN+ was the only lymph node containing metastasis in approximately 80% of patients.CONCLUSIONS: Best results were observed using a dynamic scan in combination with SPECT/CT. A shorter interval between tracer injection, imaging, and surgery resulted in a lower false-negative rate. At least 2 NLs have to be harvested, as this may increase the detection of lymphatic metastases.

Objectives/Hypothesis: To assess the quality of life in long-term survivors with oropharyngeal cancer (OPSCC), compare the results with our historic cohort in relation to the radiation technique, and explore the influence of treatment strategy and p16 expression on quality of life (QoL). Study Design: Retrospective chart analysis and patient response to EORTC QLQ-C30 and EORTC QLQ-H&N35 survey questionnaires. Methods: 98/120 (82%) survivors treated by primary intensity modulated chemoradiation (n = 55), or surgery with (n = 30) or without (n = 13) adjuvant radiotherapy (RT), completed and returned the questionnaires. Results: Surgically treated patients complained about significantly less troubles with dry mouth and teeth compared to the nonsurgically treated group. Comparing patients treated with surgery alone and those receiving any kind of RT (primary or adjuvant) the latter group complained about significantly more problems. Patients with p16-positive tumors demonstrated significantly higher tumor stages, but significantly better scores in physical and role functions. Conclusions: Early disease can be treated with high long-term QoL by surgery alone. Primary surgery with postoperative RT in selected patients with limited primary tumors and advanced neck disease renders excellent QoL. Our results suggest that IMRT is superior to former radiation techniques with regard to QoL, and should be considered as standard of care in patients undergoing RT for OPSCC. Patients with p16 positive tumors appear to show not only a better outcome but also report on a better QoL. Laryngoscope, 2013

Background and Objectives The potential of avoiding a secondary surgery for therapeutic neck dissection (TND) by sentinel node (SN) positivity makes the intraoperative evaluation of SNs an attractive option. The aim of this study was to analyze accuracy of intraoperative frozen section (FS) for detection of occult metastases in a large single institutional patient cohort undergoing SN-biopsy. Methods Between 2000 and 2010, 92 consecutive patients with early stage oropharyngeal squamous cell carcinoma (OSCC) (cT1/cT2/cN0) were prospectively enrolled. Detection rate of occult metastases by monoslice FS was compared with the definitive histopathologic work up by step serial sectioning (SSS) and immunohistochemistry (IHC). In case of SN-positivity on FS TND was performed in the same narcosis. Results 15/92 patients revealed positive SNs by FS compared to 34/92 after SSS and IHC. Sensitivity, NPV and FNR for the detection of all sizes of metastases by FS was 47, 77, and 52%, for isolated tumor cells (ITC) 8, 86, 92%, for micrometastases 43, 90, 57%, and for macrometastases 93, 98, 7%. Conclusion Sensitivity of FS by the monoslice depends on the metastases size and allows a single-stage procedure in half of the SN-positive patients. To improve sensitivity for small tumor deposits either a multislice-technique or molecular methods are needed. J. Surg. Oncol. 2012; 106:816–819. © 2012 Wiley Periodicals, Inc.

In patients with early stage oral or oropharyngeal squamous cell carcinoma (OSCC) sentinel node biopsy (SNB) is a reliable method to detect occult disease in the neck. However, patients with a history of surgery or radiotherapy in the neck may have aberrant lymphatic drainage caused by disruption of lymphatic channels. Therefore, treatment of the same levels at risk as in the primary setting may not be appropriate. The aim of our prospective observational study was to evaluate the clinical application of SNB in previously treated OSCC. Between 2003 and 2010 twenty-two patients were included. Lymph node mapping consisted of preoperative lymphoscintigraphy, SPECT/CT, intraoperative use of gamma-probe and patent blue. Endpoints were the sentinel node (SN) detection rate, unexpected lymphatic drainage patterns, negative predictive value and regional tumor control. 4/22 (18%) Patients were previously treated only on the contralateral site. The SN detection rate was 100% and unexpected drainage was found in 1/4 patients. The other 18 patients had ipsi- or bilateral previous neck treatment and a SN detection rate of 83%. The upstaging rate was 7% and 67% had unexpected lymphatic drainage patterns. The median follow-up was 22 months. Regional tumor control and negative predictive value were 100%. SNB in previously treated OSCC patients is feasible. SN detection is reliable and regional tumor control after staging by SNB is excellent. Moreover, SNB renders an assessment of the individual lymphatic drainage pattern, compensating for a potential variability after previous treatment of the neck.

The aims of this study were to assess a cohort of patients with head and neck squamous cell carcinoma (HNSCC) for: (1) the prevalence of synchronous distant metastases (DM) as detected by the initial staging by using (18)F-FDG PET/CT, (2) the prevalence of metachronous DM, and (3) the validity of published risk factors with special emphasis on the maximum standardized uptake value (SUV max) for the prediction of DM. Two hundred and ninety nine patients with advanced HNSCC were included. Following risk factors at the time of diagnosis and during follow-up were analyzed: advanced T/N stage, poor histological differentiation, level IV/Vb lymph nodes, primary site in the larynx/hypopharynx, and SUV max. The prevalence of DM at initial staging and during follow-up was 10% and 11%, respectively. At initial staging, primary site in the larynx/hypopharynx and neck nodes in level IV/Vb, and during follow-up only level IV/Vb nodes achieved statistical significance. The sensitivity for (18)F-FDG PET/CT with regard to the detection of DM was 96.8%, the specificity 95.4%, the positive predictive value (PV) 69.8%, and the negative PV 99.6%. Patients without DM showed a significantly better overall survival (OS) than patients developing DM (p

Background The aim of this study was to compare imaging modalities for staging the neck in a prospective cohort of patients evaluated by CT, ultrasound with fine-needle aspiration cytology (FNAC), and [18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/CT with the histologic evaluation of the neck dissection as the standard of reference. Methods In all, 76 consecutive patients were prospectively enrolled. Results Ultrasound-guided FNAC showed the highest level of agreement with histology for exact N classification. Ultrasound-guided FNAC showed the smallest percentage of overstaged patients, 7%, versus 16% with PET/CT, 13% with CT, and 13% with ultrasound. The rate of understaged patients was comparable between the imaging modalities. With regard to the endpoint N0 versus N+ there were no statistically significant differences to be found. Conclusions Ultrasound-guided FNAC seems to correlate best with histologic staging compared with PET/CT and CT. None of the modality is reliable enough to replace elective neck treatment in cN0 necks. © 2011 Wiley Periodicals, Inc. Head Neck, 2012

Long-term results of sentinel node biopsy (SNB) in early (T1/T2) oral and oropharyngeal squamous cell carcinoma (OSCC) in a single-institution experience.Prospective consecutive cohort analysis of 79 patients (67% male, median age 60 years, age range 34-87 years) included between 2000 and 2006. Lymphatic mapping consisted of preoperative lymphoscintigraphy, single photon emission computed tomography (SPECT/CT), and intraoperative use of a handheld gamma probe. Endpoints of the study were neck control rate, overall (OS), disease-specific (DSS), and disease-free survival (DFS).Twenty-nine of 79 patients (37%) had positive sentinel nodes (SN). Six of 29 (21%) patients showed isolated tumor cells, 14/29 (48%) micrometastases, and 9/29 (31%) macrometastases. OS, DFS, and DSS at 5 years for the entire cohort were 80, 85, and 87%, for SN-negative patients were 88, 96, and 96%, and for SN-positive patients were 74, 73, and 77%, respectively. Only the difference in DSS achieved statistical significance. The neck control rate after 5 years was 96% in SN-negative and 74% in SN-positive patients. This difference was statistically significant.SNB is a safe and accurate staging modality to select patients with clinically stage I/II OSCC with occult lymph node disease for elective neck dissection (END). The promising reported short-term results have been sustained by long-term follow-up. Patients with negative SN and no END achieve an excellent neck control rate which compares favorably with reports on primary END. The neck control rate in SN-negative patients is superior to that in SN-positive patients, which is reflected in superior DSS.

Item does not contain fulltext The trend toward minimally invasive surgery, appropriately applied, has evolved over the past three decades to encompass all fields of surgery, including curative intent cancer surgery of the head and neck. Proper patient and tumor selection are fundamental to optimizing oncological and functional outcomes in such a personalized approach to cancer treatment. Training, experience, and appropriate technological equipment are prerequisites for any type of minimally invasive surgery. The aim of this review was to provide an overview of currently available techniques and the evidence justifying their use. Much evidence is in favor of routine use of transoral laser resection, transoral robot-assisted surgery, transnasal endoscopic resection, sentinel node biopsy, and endoscopic neck surgery for selected malignant tumors, by experienced surgical teams. Technological advances will enhance the scope of this type of surgery in the future and physicians need to be aware of the current applications and trends.

In patients with early head and neck squamous cell carcinoma (HNSCC), occult lymph node metastasis is difficult to predict by clinical or pathological parameters. However, such parameters are necessary to select patients either for elective neck dissection or the sentinel lymph node (SLN) procedure. The membrane glycoprotein podoplanin is normally expressed in lymphatic endothelial cells. Recently, expression of podoplanin by cancer cells was demonstrated to promote tumor cell motility and tumor lymphangiogenesis in vitro. The value of cancer cell-expressed podoplanin was to be determined as a predictive marker for SLN metastasis in early HNSCC of the oral cavity and oropharynx. One hundred twenty patients with HNSCC of the oral cavity and oropharynx undergoing a SLN biopsy were enrolled in this prospective clinical trial of SLN biopsy. Cancer cell-expressed podoplanin was determined by immunohistochemistry using tissue microarrays. Podoplanin expression was quantified by the intensity reactivity score and categorized into expression and nonexpression. SLN examination revealed occult metastasis in 45 patients (37.5%). Twenty-nine of 120 (24.2%) primary HNSCC showed podoplanin expression. Podoplanin expression correlated significantly with SLN metastasis (p = 0.029) and remained a significant predictor for lymph node status even after controlling for tumor stage (p = 0.028). As a predictive marker for SLN metastasis, however, podoplanin expression reached a sensitivity of a mere 36% and a specificity of 83%. Podoplanin expression is associated with metastasis to lymph nodes in vivo. Podoplanin immunohistochemistry in early HNSCC of the oral cavity and oropharynx may help to select patients for the SLN procedure and to identify patients with increased risk for presence of occult lymph node metastasis in the neck.

Objectives: To assess the long-term posttreatment quality of life of patients with carcinoma of the oropharynx treated with different treatment modalities. Study Design: Retrospective chart review and patient response to EORTC quality of life core questionnaire QLQ-C30 and EORTC quality of life core head and neck cancer module QLQ-H&N35 questionnaires. Methods: Two hundred and seventeen patients with carcinoma of the oropharynx were treated with curative intent between 1990 and 1998. In January 2001, a total of 111 disease-free survivors were identified and included in this study. The questionnaires were completed by 99 patients (89% completion rate). Results: Of 99 patients, 31 patients were treated with surgery alone, 19 with radiation therapy alone and 49 with surgery followed by postoperative irradiation. Median follow-up for the entire study group was 71 months. Physical, role, emotional, cognitive and social functioning reflected in the functional scale scores of the global EORTC QLQ-C30 were generally good and showed no significant differences for the different treatment modalities. Comparison of the head and neck specific EORTC QLQ-H&N35 scores revealed significantly less troubles with swallowing (P = 0.006), social eating (P = 0.007) and social contact (P = 0.008), dry mouth (P

Item does not contain fulltext Oral cancer represents a common entity comprising a third of all head and neck malignant tumors. The options for curative treatment of oral cavity cancer have not changed significantly in the last three decades; however, the work up, the approach to surveillance, and the options for reconstruction have evolved significantly. Because of the profound functional and cosmetic importance of the oral cavity, management of oral cavity cancers requires a thorough understanding of disease progression, approaches to management and options for reconstruction. The purpose of this review is to discuss the most current management options for oral cavity cancers. 01 juli 2010

This paper was written by members and invitees of the International Head and Neck Scientific Group ( http://www.IHNSG.com ).

Sentinel node biopsy (SNB) for cN0 early squamous cell carcinoma (SCC) of the oral cavity has been validated by numerous studies. Around 30% of SNB will detect occult disease. Several clinical and morphological features of the primary tumor have been claimed to be predictive for occult metastasis in elective neck dissections. The aim of this study was to assess these factors in the context of SNB. Seventy-eight patients undergoing SNB for T1/2 oral SCC from the years 2000 to 2007 were prospectively included. Primary tumors were reviewed for the following morphological and clinical parameters: grade of differentiation, tumor depth, tumor thickness, perineural invasion, lymphatic invasion, vascular invasion, muscle invasion, lymphoplasmacytic infiltration, and mode of invasion, age, gender, primary tumor site, tumor side, and cT category. Statistical analysis revealed significance to predict occult metastasis in the SNB for grade of differentiation (P = 0.002), lymphatic invasion (P

Lymphatic mapping for sentinel node biopsy (SNB) has been shown to be crucial for detection of sentinel lymph nodes (SLN). Previous reports suggested a benefit of single photon emission computed tomography with CT (SPECT/CT) over dynamic planar lymphoscintigraphy (LS) alone. The aim was to assess whether there is an additional value of SPECT/CT over LS alone for lymphatic mapping of SLNs in oral/oropharyngeal SCC.A consecutive cohort of 58 patients was evaluated using SNB with additional SPECT/CT to preoperative LS.In the entire cohort of 58 patients undergoing LS and SPECT/CT, hot spots could be revealed in all but 4 cases. The guidance of the handheld gamma probe was able to reveal 9 additional SLNs within 3 patients not detected by either modality. Lymphoscintigraphy showed full concordance with SPECT/CT in 81% of the cases. SPECT/CT was able to detect additional HS in 11 patients, in 1 case even with additional metastatic disease. The false negative rate for SNB was 6%, and the negative predictive value 98%.SPECT/CT has the potential to detect more SLNs, which might harbor occult disease, than LS alone. With regard to the excellent results achieved with LS and the intraoperative use of the gamma probe, SPECT/CT is not indispensable for successful SNB. Both imaging modalities have difficulties in detecting level I sentinel nodes close to the injection site.

Background. Malignant triton tumors are rare neoplasias consisting of a malignant peripheral nerve sheath tumor with additional rhabdomyoblastic differentiation. These tumors are highly aggressive and prognosis is poor. Our aim is to describe the outcome and to identify potential prognostic factors. Methods. From 1993 to 2005, 7 patients with a malignant triton tumor of the head and neck were treated at our institution. A literature search revealed another 46 published cases. All these cases were analyzed for outcome and prognostic factors. Results. Patients with primary tumors involving the nose and paranasal sinuses have better, patients involving the neck a poor prognosis. All other locations show an intermediate course. Complete surgical removal is of crucial importance. Additional radiation or chemotherapy show little effect. Conclusion. Location of the primary tumor is a key factor for prognosis. Complete surgical removal is the only treatment associated with survival.© 2009 Wiley Periodicals, Inc. Head Neck, 2009

The appearance of lymph node metastases represents the most important adverse prognostic factor in head and neck squamous cell carcinoma. Therefore, accurate staging of the cervical nodes is crucial in these patients. The management of the clinically and radiologically negative neck in patients with early oral and oropharyngeal squamous cell carcinoma is still controversial, though most centers favor elective neck dissection for staging of the neck and removal of occult disease. As only approximately 30% of patients harbor occult disease in the neck, most of the patients have to undergo elective neck dissection with no benefit. The sentinel node biopsy concept has been adopted from the treatment of melanoma and breast cancer to early oral and oropharyngeal squamous cell carcinoma during the last decade with great success. Multiple validation studies in the context of elective neck dissections revealed sentinel node detection rates above 95% and negative predictive values for negative sentinel nodes of 95%. Sentinel node biopsy has proven its ability to select patients with occult lymphatic disease for elective neck dissection, and to spare the costs and morbidity to patients with negative necks. Many centers meanwhile have abandoned routine elective neck dissection and entered in observational trials. These trials so far were able to confirm the high accuracy of the validation trials with less than 5% of the patients with negative sentinel nodes developing lymph node metastases during observation. In conclusion, sentinel node biopsy for early oral and oropharyngeal squamous cell carcinoma can be considered as safe and accurate, with success rates in controlling the neck comparable to elective neck dissection. This concept has the potential to become the new standard of care in the near future.

Involvement of the cervical lymph nodes is the most important prognostic factor for patients with oral/oropharyngeal squamous cell carcinoma (OSCC), and the decision of whether to electively treat patients with clinically negative necks remains a controversial topic. Sentinel node biopsy (SNB) provides a minimally invasive method for determining the disease status of the cervical node basin, without the need for a formal neck dissection. This technique potentially improves the accuracy of histologic nodal staging and avoids overtreating three-quarters of this patient population, minimizing associated morbidity. The technique has been validated for patients with OSCC, and larger-scale studies are in progress to determine its exact role in the management of this patient population. This document is designed to outline the current best practice guidelines for the provision of SNB in patients with early-stage OSCC, and to provide a framework for the currently evolving recommendations for its use. Preparation of this guideline was carried out by a multidisciplinary surgical/nuclear medicine/pathology expert panel under the joint auspices of the European Association of Nuclear Medicine (EANM) Oncology Committee and the Sentinel European Node Trial (SENT) Committee.

This retrospective study aimed to describe the differences between image readings done with combined positron emission tomography/computed tomography (PET/CT) and PET read together with contrast-enhanced CT (ceCT) in patients with squamous cell carcinoma of the head and neck. In 46 patients, no differences were found between the two readings for assessing infiltration of adjacent structures (P=.63), transgression of the midline (P=.67), lymph node involvement (P=.32), and T- and N stage. PET/CT and PET read together with ceCT have comparable diagnostic yield.

Objectives: Unilateral vocal fold paralysis can cause a persistent incomplete glottal closure during phonation, resulting in impaired voice function. The aim of this study was to evaluate functional results of medialization thyroplasty using a hydroxyapatite implant (VoCoM). Study Design: Prospective observational cohort study. Methods: Between 1999 and 2003, a total of 26 patients (19 men, 7 women) undergoing medialization thyroplasty using a hydroxyapatite implant because of unilateral vocal fold paralysis were enrolled in the study. To evaluate voice function, the following parameters were measured preoperatively and postoperatively: mean fundamental frequency, mean sound pressure level, frequency and amplitude range (voice range profile), and maximum phonation time. A perceptual assessment of hoarseness was conducted using the Roughness, Breathiness, Hoarseness scale. Furthermore, the magnitude of voice related impairment of the patient's communication skills was rated on a 7-point scale. A combined parameter called the Voice Dysfunction Index (VDI) was used to rate vocal performance. Results: All patients showed a statistically significant improvement in the VDI, in perceptual voice analysis, in maximum phonation time, and in the dynamic range of voice. One patient experienced a postoperative wound hemorrhage as a minor complication. No further complications or implant extrusions were observed. Conclusions: Medialization thyroplasty using a hydroxyapatite implant is a secure and efficient phonosurgical procedure. Voice quality and patient satisfaction improve significantly after treatment.

Background. Treatment of head and neck squamous cell carcinoma (HNSCC) addresses the primary tumor and the lymphatic drainage. Modalities for the neck are neck dissection and/or radiation therapy. In most cases, the neck is treated by the modality that seems more appropriate for the primary. The aim of this study was to analyze the results of the neck treatments either by neck dissection alone, by radiation therapy alone or by neck dissection followed by radiation therapy. Methods. This was a retrospective chart analysis of 699 patients treated for a previously untreated HNSCC. The primary endpoint was recurrence at the treated neck. Results. Two hundred eighty-one (40%) patients underwent primary neck irradiation, 219 (31%) neck dissection alone, and 199 (29%) neck dissection followed by adjuvant irradiation. The 5-year regional control rates after neck dissection alone were 83% for pN0, 75% for pN1, 60% for pN2a, 59% for pN2b, and 50% for pN2c; after radiation alone, 89% for cN0, 87% for cN1, 40% for cN2a, 60% for cN2b, and 48% for cN2c; and after neck dissection with adjuvant radiation, 86% for pN0, 96% for pN1, 100% for pN2a, 88% for pN2b, and 88% for pN2c. Conclusions. Radiation or neck dissection alone are efficient to control early neck disease. For advanced N2/3 neck disease, neck dissection followed by adjuvant radiation is highly efficient, whereas primary radiation results in a high number of regional failures. The literature suggests planned neck dissection to improve regional control for these patients. © 2007 Wiley Periodicals, Inc. Head Neck, 2008

Applicability of sentinel node biopsy (SNB) for tumors of the floor of mouth (FOM) is controversial.Prospective evaluation of the accuracy of gamma-probe-guided superselective neck dissection of the preglandular triangle of level I for SNB in FOM squamous cell carcinoma (SCC) after preoperative lymphoscintigraphy and single photon emission CT (SPECT)/CT.In total, 22 sentinel lymph nodes were harvested in level I. Eight of 22 (36%) were seen on lymphoscintigraphy and 11 (50%) on SPECT/CT. Eleven sentinel lymph nodes (50%) were only detected intraoperatively. In unilateral tumors, 20% were contralateral, and, in midline tumors, 93% showed bilateral level I sentinel lymph nodes. The false-negative rate was 8.3%, the negative predictive value was 96.4%, and the false-omission rate was 3.6%. The ultimate neck control rate, including salvage treatment, was 100%.SNB in FOM can be reliably performed using the presented surgical technique. Level I exploration, bilaterally in midline tumors, is mandatory irrespective of the visualization of sentinel lymph nodes in other levels. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1367-1372, 2016.