Clinical predictors of negative/equivocal SPECT imaging outcomes in primary hyperparathyroidism: Factors calling for 18F-choline-PET.

PURPOSE: For minimally invasive surgery of parathyroid adenomas, exact localization diagnostics are essential. Main imaging modalities used for diagnostics are sonography, SPECT with/without CT (traditional imaging) and 18F-choline-PET. The aim of our study was to identify predictors for inconclusive SPECT imaging and subsequently determine in which cases 18F-choline-PET is needed. METHODS: Retrospective analysis of 138 patients with histologically confirmed primary hyperparathyroidism (pHPT). After sonography, patients underwent SPECT or SPECT/CT imaging, with subsequent 18F-choline-PET in cases of disconcordant results. Logistic regression analysis was used to identify clinical and laboratory factors predictive for negative SPECT results. RESULTS: Sensitivity rates for sonography, SPECT, SPECT/CT, and choline-PET were 47 %, 49 %, 71.7 %, and 97 %, respectively. Logistic regression revealed lower PTH levels (p < 0.001), presence of structural thyroid disease (p = 0.018), and negative sonography (p < 0.001) as predictive of negative/equivocal SPECT outcome. An additional traditional imaging CT scan to a SPECT enhanced detection odds, as did greater adenoma weight. Urolithiasis, osteoporosis, and calcium values as measurement of activity and duration of disease showed no significant association with the detection rate. Furthermore, our study demonstrated that 18F-choline-PET exhibited remarkable sensitivity in detecting adenomas among patients with negative/equivocal SPECT results. CONCLUSION: Our study reveals potential predictive factors for a negative/equivocal SPECT outcome in pHPT. Identifying these factors might allow minimizing futile SPECT examinations and perhaps encourage timely utilization of 18F-choline-PET imaging. Our study reinforces the clinical significance of 18F-choline-PET, especially in complex cases with disconcordant results by conventional parathyroid imaging methods.

Prognostic implications of p16 and HPV discordance in oropharyngeal cancer (HNCIG-EPIC-OPC): a multicentre, multinational, individual patient data analysis.

BACKGROUND: p16INK4a (p16) immunohistochemistry is the most widely used biomarker assay for inferring HPV causation in oropharyngeal cancer in clinical and trial settings. However, discordance exists between p16 and HPV DNA or RNA status in some patients with oropharyngeal cancer. We aimed to clearly quantify the extent of discordance, and its prognostic implications. METHODS: In this multicentre, multinational individual patient data analysis, we did a literature search in PubMed and Cochrane database for systematic reviews and original studies published in English between Jan 1, 1970, and Sept 30, 2022. We included retrospective series and prospective cohorts of consecutively recruited patients previously analysed in individual studies with minimum cohort size of 100 patients with primary squamous cell carcinoma of the oropharynx. Patient inclusion criteria were diagnosis with a primary squamous cell carcinoma of oropharyngeal cancer; data on p16 immunohistochemistry and on HPV testing; information on age, sex, tobacco, and alcohol use; staging by TNM 7th edition; information on treatments received; and data on clinical outcomes and follow-up (date of last follow-up if alive, date of recurrence or metastasis, and date and cause of death). There were no limits on age or performance status. The primary outcomes were the proportion of patients of the overall cohort who showed the different p16 and HPV result combinations, as well as 5-year overall survival and 5-year disease-free survival. Patients with recurrent or metastatic disease or who were treated palliatively were excluded from overall survival and disease-free survival analyses. Multivariable analysis models were used to calculate adjusted hazard ratios (aHR) for different p16 and HPV testing methods for overall survival, adjusted for prespecified confounding factors. FINDINGS: Our search returned 13 eligible studies that provided individual data for 13 cohorts of patients with oropharyngeal cancer from the UK, Canada, Denmark, Sweden, France, Germany, the Netherlands, Switzerland, and Spain. 7895 patients with oropharyngeal cancer were assessed for eligibility. 241 were excluded before analysis, and 7654 were eligible for p16 and HPV analysis. 5714 (74·7%) of 7654 patients were male and 1940 (25·3%) were female. Ethnicity data were not reported. 3805 patients were p16-positive, 415 (10·9%) of whom were HPV-negative. This proportion differed significantly by geographical region and was highest in the areas with lowest HPV-attributable fractions (r=-0·744, p=0·0035). The proportion of patients with p16+/HPV- oropharyngeal cancer was highest in subsites outside the tonsil and base of tongue (29·7% vs 9·0%, p<0·0001). 5-year overall survival was 81·1% (95% CI 79·5-82·7) for p16+/HPV+, 40·4% (38·6-42·4) for p16-/HPV-, 53·2% (46·6-60·8) for p16-/HPV+, and 54·7% (49·2-60·9) for p16+/HPV-. 5-year disease-free survival was 84·3% (95% CI 82·9-85·7) for p16+/HPV+, 60·8% (58·8-62·9) for p16-/HPV-; 71·1% (64·7-78·2) for p16-/HPV+, and 67·9% (62·5-73·7) for p16+/HPV-. Results were similar across all European sub-regions, but there were insufficient numbers of discordant patients from North America to draw conclusions in this cohort. INTERPRETATION: Patients with discordant oropharyngeal cancer (p16-/HPV+ or p16+/HPV-) had a significantly worse prognosis than patients with p16+/HPV+ oropharyngeal cancer, and a significantly better prognosis than patients with p16-/HPV- oropharyngeal cancer. Along with routine p16 immunohistochemistry, HPV testing should be mandated for clinical trials for all patients (or at least following a positive p16 test), and is recommended where HPV status might influence patient care, especially in areas with low HPV-attributable fractions. FUNDING: European Regional Development Fund, Generalitat de Catalunya, National Institute for Health Research (NIHR) UK, Cancer Research UK, Medical Research Council UK, and The Swedish Cancer Foundation and the Stockholm Cancer Society.

Prediction of extranodal extension in oropharyngeal cancer patients and carcinoma of unknown primary: value of metabolic tumor imaging with hybrid PET compared with MRI and CT.

OBJECTIVES: 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). METHODS: 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. RESULTS: 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 (SUVmax, TLG, MTV) were significantly higher in patients with positive ENE (p < 0.001 for all three parameters) than in patients with negative ENE (p < 0.001, for all three parameters). CONCLUSIONS: CT 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.

Expanding the clinicopathological spectrum of TGFBR3-PLAG1 rearranged salivary gland neoplasms with myoepithelial differentiation including evidence of high-grade transformation.

PLAG1 rearrangements have been described as a molecular hallmark of salivary gland pleomorphic adenoma (PA), carcinoma ex pleomorphic adenoma (CEPA), and myoepithelial carcinoma (MECA). Several fusion partners have been described, however, commonly no further assignment to the aforementioned entities or a morphological prediction can be made based on the knowledge of the fusion partner alone. In contrast, TGFBR3-PLAG1 fusion has been specifically described and characterized as an oncogenic driver in MECA, and less common in MECA ex PA. Here, we describe the clinicopathological features of three TGFBR3-PLAG1 fusion-positive salivary gland neoplasms, all of which arose in the deep lobe of the parotid gland. Histopathology showed high morphological similarities, encompassing encapsulation, a polylobular growth pattern, bland basaloid and oncocytoid cells with myoepithelial differentiation, and a distinct sclerotic background. All cases showed at least limited, unusual foci of minimal invasion into adjacent salivary gland tissue, including one case with ERBB2 (Her2/neu) amplified, TP53 mutated high-grade transformation, and lymph node metastases. Of note, all cases illustrated focal ductal differentiation. Classification remains difficult, as morphological overlaps between myoepithelial-rich cellular PA, myoepithelioma, and MECA were observed. However, evidence of minimal invasion advocates classification as low-grade MECA. This case series further characterizes the spectrum of uncommon cellular myoepithelial neoplasms harboring TGFBR3-PLAG1 fusion, which show recurrent minimal invasion of the adjacent salivary gland tissue, a predilection to the deep lobe of the parotid gland, and potential high-grade transformation.

SUVmax for predicting regional control in oropharyngeal cancer.

PURPOSE: To investigate the predictive value of pretherapeutic metabolic tumor imaging using 18-fluorodeoxyglucose positron emission tomography (FDG-PET) for regional response in oropharyngeal cancer patients undergoing primary (chemo)radiation. METHODS: Retrospective analysis of oropharyngeal cancer patients treated with primary (chemo)radiation at the University Hospital Zurich from 2010 to 2019 with available FDG-PET. The SUVmax of the largest lymph node metastases was recorded. Regional response was assessed using posttherapeutic FDG-PET at 12 weeks and regional recurrence-free survival. RESULTS: 95 patients with a mean age of 68.5 years (SD 10.3) were included. The median pretherapeutic nodal SUVmax was 8.3 (interquartile range 4.4-13.3). A pretherapeutic nodal SUVmax above 6 significantly predicted poorer regional recurrence-free survival (log-rank test, P = 0.009) in univariate analysis. However, in multivariate analysis SUVmax above 6 was not significant in predicting regional recurrence-free survival (Cox regression P = 0.189). Clinical N category showed a trend in which a more severe stage had a poorer regional survival (Cox regression P = 0.073). CONCLUSION: The SUVmax of the largest lymph node metastasis seems to play a role in predicting regional response in oropharyngeal cancer patients, after stratifying for N category. More research is needed to investigate whether highly metabolically active disease is less likely to respond to chemoradiation.

Cost-utility of two minimally-invasive surgical techniques for operable oropharyngeal cancer: transoral robotic surgery versus transoral laser microsurgery.

BACKGROUND: In the past few decades, a re-evaluation of treatment paradigms of head and neck cancers with a desire to spare patients the treatment-related toxicities of open surgery, has led to the development of new minimally invasive surgical techniques to improve outcomes. Besides Transoral Laser Microsurgery (TLM), a new robotic surgical technique namely Transoral Robotic Surgery (TORS) emerged for the first time as one of the two most prominent and widely used minimally invasive surgical approaches particularly for the treatment of oropharyngeal cancer, a sub-entity of head and neck cancers. Recent population-level data suggest equivalent tumor control, but different total costs, and need for adjuvant chemoradiation. A comparative analysis of these two techniques is therefore warranted from the cost-utility (C/U) point of view. METHODS: A cost-utility analysis for comparing TORS and TLM was performed using a decision-analytical model. The analyses adopted the perspective of a Swiss hospital. Two tertiary referral centers in Lausanne and Zurich provided data for model quantificantion. RESULTS: In the base case analysis TLM dominates TORS. This advantage remains robust, even if the costs for TORS reduce by up to 25%. TORS begins to dominate TLM, if less than 59,7% patients require adjuvant treatment, whereby in an interval between 55 and 62% cost effectiveness of TORS is sensitive to the prescription of adjuvant chemoradiation therapy (CRT). Exceeding 29% of TLM patients requiring a revision of surgical margins renders TORS more cost-effective. CONCLUSION: Non-robotic endoscopic surgery (TLM) is more cost-effective than robotic endoscopic surgery (TORS) for the treatment of oropharyngeal cancers. However, this advantage is sensitive to various parameters, i.e.to the number of re-operations and adjuvant treatment.

Lymphovenous Anastomosis for the Treatment of Thoracic Duct Lesion: A Case Report and Systematic Review of Literature.

BACKGROUND: Chylous leak is an uncommon complication after head and neck surgery and typically results from a lesion of the thoracic duct (TD). Beside conservative treatment, different minimally invasive and surgical procedures exist, of which almost all lead to a total closure of the TD. METHODS: We report on a rare case of microsurgical lymphovenous anastomosis to treat a TD lesion. An additional systematic review on surgical procedures to treat TD lesions with special attention to lymphovenous anastomoses was performed according to the PRISMA guidelines. RESULTS: A 52-year-old patient with a chylous fistula after modified radical neck dissection was successfully treated by a lymphovenous anastomosis of the TD and external jugular vein with additional coverage by sternocleidomastoid muscle flap. The patient showed a complete resolution of chylous leak with an uneventful postoperative course.The systematic search of literature yielded 684 articles with 4 case reports on lymphovenous anastomosis in chylous leak with a high success rate. Other surgical techniques include transcervical, thoracoscopic, or video-assisted thoracoscopic TD ligation, either alone or combined with a local muscle flap. CONCLUSIONS: Lymphovenous anastomosis of the TD is a feasible and safe technique allowing for treatment of cervical TD lesions, especially if minimally invasive procedures fail. Compared with other techniques, lymphatic circulation can successfully be maintained.

Patterns of antibody responses to nonviral cancer antigens in head and neck squamous cell carcinoma patients differ by human papillomavirus status.

There have been hints that nonviral cancer antigens are differentially expressed in human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC). Antibody responses (AR) to cancer antigens may be used to indirectly determine cancer antigen expression in the tumor using a noninvasive and tissue-saving liquid biopsy. Here, we set out to characterize AR to a panel of nonviral cancer antigens in HPV-positive and HPV-negative HNSCC patients. A fluorescent microbead multiplex serology to 29 cancer antigens (16 cancer-testis antigens, 5 cancer-retina antigens and 8 oncogenes) and 29 HPV-antigens was performed in 382 HNSCC patients from five independent cohorts (153 HPV-positive and 209 HPV-negative). AR to any of the cancer antigens were found in 272/382 patients (72%). The ten most frequent AR were CT47, cTAGE5a, c-myc, LAGE-1, MAGE-A1, -A3, -A4, NY-ESO-1, SpanX-a1 and p53. AR to MAGE-A3, MAGE-A9 and p53 were found at significantly different prevalences by HPV status. An analysis of AR mean fluorescent intensity values uncovered remarkably different AR clusters by HPV status. To identify optimal antigen selections covering a maximum of patients with ≤10 AR, multiobjective optimization revealed distinct antigen selections by HPV status. We identified that AR to nonviral antigens differ by HPV status indicating differential antigen expression. Multiplex serology may be used to characterize antigen expression using serum or plasma as a tissue-sparing liquid biopsy. Cancer antigen panels should address the distinct antigen repertoire of HPV-positive and HPV-negative HNSCC.

No benefit for regional control and survival by planned neck dissection in primary irradiated oropharyngeal cancer irrespective of p16 expression.

The aim of the study was to assess regional control and survival in primary irradiated oropharyngeal cancer patients with advanced neck disease (≥cN2a) receiving planned neck dissection (PND) irrespective of the nodal response compared to salvage neck dissection (SND) in case of regional persistence or reccurence in relation to tumoral p16 overexpression. 96 consecutive patients treated at the University Hospital of Zurich, Switzerland were included. Tissue microarray-based scoring of p16 expression was obtained. 5 years overall (OS) and disease-specific survival (DSS) in the PND and SND cohort were 70 vs. 57 % (p = 0.20) and 80 vs. 65 % (p = 0.14), respectively. Regional control in PND and SND achieved 95 vs. 87 % (p = 0.29), respectively. There was no statistically significant impact of neck treatment (PND vs. SND) on regional control or survival among patients with p16-negative tumors (5 years OS 59 vs. 50 %, p = 0.66; 5 years DSS 59 vs. 57 %, p = 0.89) nor among patients with p16-positive tumors (5 years OS 84 vs. 67 %, p = 0.21; 5 years DSS 95 vs. 81 %, p = 0.24). The type of neck dissection after primary intensity-modulated radiotherapy (IMRT) had no impact on regional control and survival even in human papillomavirus (HPV)-associated disease. Therefore we are convinced that based on the accuracy of newer diagnostic modalities the surveillance of a radiologically negative neck after primary chemoradiation (CRT) is oncologically safe irrespective of p16 expression of the tumor.

Zenker's diverticulum: outcome of endoscopic surgery is dependent on the intraoperative exposure.

The purpose of the present study is to evaluate long-term outcome and patients' satisfaction after endoscopic therapy of Zenker's diverticulum (ZD) and to analyze the results of the stapler technique in comparison with the application of the carbon dioxide (CO2) laser. A retrospective cohort study with outcome analysis of patients undergoing endoscopic cricopharyngeal myotomy with either stapler or CO2 laser between October 2000 and December 2010 by a single surgeon was performed. Patient's medical charts were reviewed with respect to symptoms before intervention, intra and post operative complications, reasons for the choice of endoscopic technique, and postoperative relief of symptoms. Long-term follow-up was acquired by a standardized self-assessment questionnaire. Seventy-four patients (51 men, 23 women) with a median age at operation of 74 years (range 45-93 years) were enrolled in this study. Forty-five patients underwent endoscopic repair of a ZD with stapler, 29 patients with CO2 laser. The mean follow-up was 4.7 years. We did not observe significant differences for intra and post operative complications, hospital stay, time until normal oral food intake, need for revision, and long-term subjective symptom relief between the two groups. Overall complication (12 %) and recurrence rate (11 %) for the endoscopic techniques were low. Endoscopic surgery had also a high success rate in recurrence cases (87.5 %). According to our study, the most important factor for the success rate of endoscopic treatment was the intraoperative exposure of the ZD. The endoscopic minimally invasive approach is a safe and effective treatment modality and can be considered as the treatment of choice for primary and recurrent ZD. The intraoperative exposure is decisive for the technique applied and the long-term success.

Human papilloma virus and survival of oropharyngeal cancer patients treated with surgery and adjuvant radiotherapy.

Impact of p16 protein, a surrogate marker for human papilloma virus induced cancer, p53 and EGFR as well as clinical factors on survival in a patient cohort with oropharyngeal squamous cell carcinoma (OPSCC) treated by surgical resection and adjuvant radiotherapy (RT) ± concomitant chemotherapy (CT). This is a retrospective analysis of patient's charts and tumor tissue. 57 patients were consecutively included and their tumor tissue assembled on a tissue microarray following immunohistochemical analysis. Survival times were estimated by means of Kaplan-Meier analysis. The importance of clinical and immunohistochemical factors for outcome was estimated by cox proportional hazard models. With 88% 5-year overall survival, 91% 5-year disease-specific survival and 91% 5-year disease-free survival, respectively, we found excellent survival rates in this surgically treated patient cohort of mainly advanced OPSCC (93% AJCC stage III or IV). The only factors positively influencing survival were p16 overexpression as well as p53 negativity and even more pronounced the combination of those biomarkers. Survival analysis of patients classified into three risk categories according to an algorithm based on p16, smoking, T- and N-category revealed a low, intermediate and high-risk group with significant survival differences between the low and the high-risk group. Patients with OPSCC can be successfully treated by surgery and adjuvant RT ± CT with a clear survival benefit of p16 positive, p53 negative patients. We recommend considering a combination of immunohistochemical (p16, p53) and clinical factors (smoking, T- and N-category) for risk stratification.

MRI-based radiomics for predicting histology in malignant salivary gland tumors: methodology and "proof of principle".

Defining the exact histological features of salivary gland malignancies before treatment remains an unsolved problem that compromises the ability to tailor further therapeutic steps individually. Radiomics, a new methodology to extract quantitative information from medical images, could contribute to characterizing the individual cancer phenotype already before treatment in a fast and non-invasive way. Consequently, the standardization and implementation of radiomic analysis in the clinical routine work to predict histology of salivary gland cancer (SGC) could also provide improvements in clinical decision-making. In this study, we aimed to investigate the potential of radiomic features as imaging biomarker to distinguish between high grade and low-grade salivary gland malignancies. We have also investigated the effect of image and feature level harmonization on the performance of radiomic models. For this study, our dual center cohort consisted of 126 patients, with histologically proven SGC, who underwent curative-intent treatment in two tertiary oncology centers. We extracted and analyzed the radiomics features of 120 pre-therapeutic MRI images with gadolinium (T1 sequences), and correlated those with the definitive post-operative histology. In our study the best radiomic model achieved average AUC of 0.66 and balanced accuracy of 0.63. According to the results, there is significant difference between the performance of models based on MRI intensity normalized images + harmonized features and other models (p value < 0.05) which indicates that in case of dealing with heterogeneous dataset, applying the harmonization methods is beneficial. Among radiomic features minimum intensity from first order, and gray level-variance from texture category were frequently selected during multivariate analysis which indicate the potential of these features as being used as imaging biomarker. The present bicentric study presents for the first time the feasibility of implementing MR-based, handcrafted radiomics, based on T1 contrast-enhanced sequences and the ComBat harmonization method in an effort to predict the formal grading of salivary gland carcinoma with satisfactory performance.

Histopathological Analysis of Nodal Disease After Chemoradiation Reveals Viable Tumor Cells as the most Important Prognostic Factor in Head and Neck Squamous Cell Carcinoma.

BACKGROUND: In head and neck squamous cell carcinoma (HNSCC), salvage neck dissection (ND) is required after primary chemoradiation in case of residual nodal disease. Upon histopathological examination, viability of tumor cells is assessed but little is known about other prognostic histopathological features. In particular, the presence of swirled keratin debris and its prognostic value is controversial. The aim of this study is to examine histopathological parameters in ND specimens and correlate them with patient outcome to determine the relevant parameters for histopathological reporting. MATERIALS AND METHODS: Salvage ND specimen from a cohort of n = 75 HNSCC (oropharynx, larynx, hypopharynx) patients with prior (chemo) radiation were evaluated on H&E stains for the following parameters: viable tumor cells, necrosis, swirled keratin debris, foamy histiocytes, bleeding residues, fibrosis, elastosis, pyknotic cells, calcification, cholesterol crystals, multinucleated giant cells, perineural, and vascular invasion. Histological features were correlated with survival outcomes. RESULTS: Only the presence / amount (area) of viable tumor cells correlated with a worse clinical outcome (local and regional recurrence-free survival, (LRRFS), distant metastasis-free survival, disease-specific survival, and overall survival, p < 0.05) in both the univariable and multivariable analyses. CONCLUSION: We could confirm the presence of viable tumor cells as a relevant negative prognostic factor after (chemo) radiation. The amount (area) of viable tumor cells further substratified patients with worse LRRFS. None of the other parameters correlated with a distinctive worse outcome. Importantly, the presence of (swirled) keratin debris alone should not be considered viable tumor cells (ypN0).

The Milan system for reporting salivary gland cytopathology-A single-center study of 2156 cases.

BACKGROUND: Fine-needle aspiration cytology (FNAC) represents an important diagnostic tool for the workup of salivary gland (SG) lesions. The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is a six-tiered system for standardizing diagnoses and improvement of communication between pathologists and clinicians, providing risk of malignancy (ROM) rates for every category. The aims of the present study were (i) to validate the use of MSRSGC in a large series of SG FNAC in a tertiary center in Switzerland, (ii) to determine ROM for each category and compare them with data from MSRSGC and similar studies, and (iii) to investigate whether there were relevant differences of non-diagnostic results between fine-needle aspirations (FNA) performed by cytopathologists compared to non-cytopathologists. METHODS: The files of the department of Pathology in the University Hospital Zurich (UHZ) were searched for SG FNAC between 2010 and 2019. The MSRSGC guidelines were applied retrospectively. Furthermore, ROM, risk of neoplasia (RON), sensitivity, and specificity were calculated based on the cases with histopathological follow-up. RESULTS: A total of 2156 SG FNAC including 753 cases with histopathological follow-up were evaluated. Generally, ROM was within the range of values provided by MSRSGC, with some minor deviations. Sensitivity was 94.6%, and specificity was 99.3%. CONCLUSIONS: Our study confirms the usefulness of MSRSGC. In addition, it provides a detailed insight into the wide spectrum of SG FNAC. Finally, we showed that the rate of non-diagnostic FNA was significantly lower in FNAs performed by cytopathologists compared to non-cytopathologists.

Validity of frozen section in sentinel lymph node biopsy for the staging in oral and oropharyngeal squamous cell carcinoma.

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.

Thyroid incidentalomas in FDG-PET/CT: prevalence and clinical impact.

To evaluate the prevalence of thyroid FDG-PET/CT incidentalomas and the risk of malignancy in focal findings. A retrospective study of 3,062 PET scans was performed between 05/2006 and 09/2009. Prevalence of thyroid incidentalomas, risk of malignancy and correlation between standard uptake value (SUV) and cancer risk were analysed. The overall prevalence of thyroid incidentalomas was 2.4%. 71% showed a focal and 29% a diffuse uptake. In the focal uptake group, the diagnosis was clarified in 79% with cytology/histology. In 23.8% of the patients with a focal uptake, a malignant lesion was found. Diffuse uptake was predominantly associated with autoimmune thyroiditis. There was no statistically significant difference in the SUVmax between benign and malignant focal lesions (p = 0.0982). Patients with incidental focal uptake in the thyroid during FDG-PET/CT bear a considerable risk of malignancy and should undergo cytologic clarification of the diagnosis.

The Role of Regional Disease and Patterns of Treatment Failure in Primary Sinonasal Malignancies.

BACKGROUND: The question how to treat the clinically negative neck in sinonasal malignancies is controversial. OBJECTIVES: To investigate patterns of treatment failure and to assess outcome measures in patients with primary sinonasal malignancies. METHODS: Retrospective cohort study of patients treated for primary malignant sinonasal malignancies. RESULTS: Lymph node (LN) metastases at initial presentation were present in 8 of 152 patients (5.3%). Ipsi- and contralateral LN levels 1 and 2 were identified as nodal basins at risk. We found a 5-year overall survival (OS) of 75.2% and disease free survival of 61.1%. Among patients with cN0 neck, nodal recurrence free survival was not different between patients with and without elective neck treatment (P = .23). On logistic regression analysis, we found initial T classification as an independent factor for achievement of complete remission (CR) and OS. CONCLUSIONS: LN metastases at initial presentation are rare and initial T classification was identified as the most important prognostic factor for OS and CR, emphasizing the need for a thorough initial staging of the primary tumor.

Prevalence of Transcriptionally Active HPV Infection in Tumor-Free Oropharyngeal Tissue of OPSCC-Patients.

Objectives: The natural history of HPV-related oropharyngeal squamous cell carcinoma (OPSCC) is still largely unknown. Since reports of second primary tumors (SPTs) in patients with HPV-related OPSCCs are increasing, a multifocal HPV infection, hinting a «virus-induced field effect¼, has been hypothesized. This study aimed to investigate the HPV-prevalence in normal appearing oropharyngeal tissue in patients with OPSCCs. Materials and Methods: 49 OPSCC patients undergoing panendoscopy were prospectively enrolled. Tumor specimens and biopsies of normal appearing oropharyngeal tissue adjacent to and distant from the index OPSCC underwent histopathological examination, p16INK4A immunohistochemical staining, HPV DNA and mRNA-detection. Patient characteristics and follow-up data on SPTs were obtained. Results: 26 of 49 (53%) OPSCC were positive for HPV DNA and p16INK4A. HPV mRNA was detected in 23 of 26 (88%) of these tumor samples. HPV DNA was detected in 36% adjacent mucosa and in 17% distant mucosa samples and only in patients with an HPV-related index OPSCC. HPV mRNA could not be detected in tumor-free distant and adjacent mucosa samples. No evidence of association between HPV detection in normal appearing mucosa and development of second primary tumors was found. Conclusions: HPV was detectable but not transcriptionally active in adjacent/distant tumor-free oropharyngeal tissue. This suggests that a multifocal HPV infection, hinting a «virus-induced fielcd cancerization¼, may not be pertaining to HPV-related OPSCC.

VoiceS: voice quality after transoral CO2 laser surgery versus single vocal cord irradiation for unilateral stage 0 and I glottic larynx cancer-a randomized phase III trial.

BACKGROUND: Surgery and radiotherapy are well-established standards of care for unilateral stage 0 and I early-stage glottic cancer (ESGC). Based on comparative studies and meta-analyses, functional and oncological outcomes after both treatment modalities are similar. Historically, radiotherapy (RT) has been performed by irradiation of the whole larynx. However, only the involved vocal cord is being treated with recently introduced hypofractionated concepts that result in 8 to 10-fold smaller target volumes. Retrospective data argues for an improvement in voice quality with non-inferior local control. Based on these findings, single vocal cord irradiation (SVCI) has been implemented as a routine approach in some institutions for ESGC in recent years. However, prospective data directly comparing SVCI with surgery is lacking. The aim of VoiceS is to fill this gap. METHODS: In this prospective randomized multi-center open-label phase III study with a superiority design, 34 patients with histopathologically confirmed, untreated, unilateral stage 0-I ESGC (unilateral cTis or cT1a) will be randomized to SVCI or transoral CO2-laser microsurgical cordectomy (TLM). Average difference in voice quality, measured by using the voice handicap index (VHI) will be modeled over four time points (6, 12, 18, and 24 months). Primary endpoint of this study will be the patient-reported subjective voice quality between 6 to 24 months after randomization. Secondary endpoints will include perceptual impression of the voice via roughness - breathiness - hoarseness (RBH) assessment at the above-mentioned time points. Additionally, quantitative characteristics of voice, loco-regional tumor control at 2 and 5 years, and treatment toxicity at 2 and 5 years based on CTCAE v.5.0 will be reported. DISCUSSION: To our knowledge, VoiceS is the first randomized phase III trial comparing SVCI with TLM. Results of this study may lead to improved decision-making in the treatment of ESGC. TRIAL REGISTRATION: ClinicalTrials.gov NCT04057209. Registered on 15 August 2019. Cantonal Ethics Committee KEK-BE 2019-01506.

Long-term experience in sentinel node biopsy for early oral and oropharyngeal squamous cell carcinoma.

OBJECTIVE: Long-term results of sentinel node biopsy (SNB) in early (T1/T2) oral and oropharyngeal squamous cell carcinoma (OSCC) in a single-institution experience. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.