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An integrated augmented reality (AR) surgical navigation system that potentially improves intra-operative visualization of concealed anatomical structures. Integration of real-time tracking technology with a laser pico-projector allows the surgical surface to be augmented by projecting virtual images of lesions and critical structures created by multimodality imaging. We aim to quantitatively and qualitatively evaluate the performance of a prototype interactive AR surgical navigation system through a series of pre-clinical studies. Four pre-clinical animal studies using xenograft mouse models were conducted to investigate system performance. A combination of CT, PET, SPECT, and MRI images were used to augment the mouse body during image-guided procedures to assess feasibility. A phantom with machined features was employed to quantitatively estimate the system accuracy. All the image-guided procedures were successfully performed. The tracked pico-projector correctly and reliably depicted virtual images on the animal body, highlighting the location of tumour and anatomical structures. The phantom study demonstrates the system was accurate to 0.55 ± 0.33mm. This paper presents a prototype real-time tracking AR surgical navigation system that improves visualization of underlying critical structures by overlaying virtual images onto the surgical site. This proof-of-concept pre-clinical study demonstrated both the clinical applicability and high precision of the system which was noted to be accurate to

Squamous cell carcinoma in the head and neck region is one of the most widespread cancers with high morbidity. Classic treatment comprises the complete removal of the lymphatics together with the cancerous tissue. Recent studies have shown that such interventions are only required in 30% of the patients. Sentinel lymph node biopsy is an alternative method to stage the malignancy in a less invasive manner and to avoid overtreatment. In this paper, we present a novel approach that enables a future augmented reality device which improves the biopsy procedure by visual means. We propose a co-calibration scheme for axis-aligned miniature cameras with pinholes of a gamma ray collimating and sensing device and show results gained by experiments, based on a calibration target visible for both modalities. Visual inspection and quantitative evaluation of the augmentation of optical camera images with gamma information are congruent with known gamma source landmarks. Combining a multi-pinhole collimator with axis-aligned miniature cameras to augment optical images using gamma detector data is promising. As such, our approach might be applicable for breast cancer and melanoma staging as well, which are also based on sentinel lymph node biopsy.

Sentinel lymph node biopsy (SNB) is a surgical method to stage certain cancer types in a minimally invasive manner. However, the current sensing methods for SNB are limited in accuracy, as they are based on acoustic feedback radiation probes to detect tracer enriched sentinel lymph nodes. We present a deep neural network approach to learn the latent spatial activity distributions from a simulated gamma source on 2D activity images. Data processing can then be applied for multi-pinhole collimator optimization, lymph node visualization or surgical navigation to further support SNB. Using simulations of photon multi-pinhole collimator interaction, we generate labeled synthetic 2D activity images to train convolutional neural networks (CNN). These CNNs are then evaluated on synthetic as well as on real experimental data from a radioactive point-like source, collected by our own stationary small form factor multi-pinhole collimator. We achieve good results on synthetic data for the xy-component ensemble learners with a localization class accuracy of 0.97, while depth estimation achieves a localization class accuracy of 0.55. Accuracy on real experimental data is limited due to the small sample set and its variability, compared to the simulation.

(18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET)/CT imaging of squamous cell carcinoma of the head and neck (HNSCC) renders the possibility to study metabolic tumor activity by measuring FDG-uptake expressed as maximum standardized uptake value (SUV(max)). A correlation between SUV(max) and several factors including T-classification, histological tumor differentiation or different anatomic subsites is of potential interest in HNSCC. The aim of this study was to evaluate how metabolic tumor activity derived from FDG-PET correlates with prognostic clinical and pathological parameters including these factors. 262 patients with HNSCC undergoing PET/CT for initial staging were assessed separately for a potential correlation between SUV(max) and T-classification, histological grading, and anatomical subsites of the primary tumor. Nonparametric testing showed a significant correlation between SUV(max) and T-classification (P0.001). On the contrary, no statistically significant correlation was found between SUV(max) and histological tumor grading. Furthermore, no statistical significant correlation between the different anatomical subsites and SUV(max) were found. There was no significant correlation of SUV(max) and tumor grading after adjustment for T-stage and anatomical localization of the tumor, neither.Metabolic tumor activity correlates with T-stage of HNSCC. However, histological tumor grading does not correlate with SUV(max). The role of primary tumor SUV(max) as a predictor of outcome or survival remains unclear. Clinicians should therefore exercise caution in attributing any clinical importance to SUV(max) obtained from a single PET/CT exam.

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

Background Adult laryngotracheal reconstruction for airway stenosis and after oncologic ablation can be extremely challenging. Methods Patients with the above conditions not amenable to or refractory to conventional treatments were offered specialized reconstruction by wrapping a contoured costal cartilage graft with a vascularized microvascular carrier. All constructs were lined with buccal mucosa grafts. Decannulation rates, quality of life questionnaires, and pulmonary function tests were performed and analyzed. Results Eleven patients underwent this procedure, 6 for stenosis and 5 for laryngotracheal oncologic defects. Ten patients were successfully decannulated after the procedure (91%). Median time to decannulation was 4 months. At mean follow-up of 76 months, all evaluated patients had a serviceable voice, tolerated a normal diet, and had minimal subjective shortness of breath. Conclusion Vascularized composite autograft can be successfully used to treat severe subglottic stenosis or reconstruct large laryngotracheal defects not amenable to or refractory to conventional treatments. © 2014 Wiley Periodicals, Inc. Head Neck 38: 253–259, 2016

Objective Follow-up of patients with oral cavity squamous cell carcinoma (OCSCC) after tumor resection and reconstruction with tissue transfer is challenging. We compared contrast-enhanced computed tomography (ceCT), 18F-fluorodeoxyglucose-positron emission tomography combined with noncontrast enhanced CT (18F-FDG-PET/CT), and 18F-FDG-PET combined with ceCT (18F-FDG-PET/ceCT) to determine the accuracy for detection of residual/recurrent disease after flap reconstruction for OCSCC. Study Design and Methods Two readers (R1, R2) retrospectively reviewed a total of 27 18F-FDG-PET/ceCT scans in patients after resection of stage II to IV OCSCC. They recorded the presence of local persistence/recurrence (LR), lymph node metastasis, or distant metastasis independently for ceCT, 18F-FDG-PET/CT, and 18F-FDG-PET/ceCT. Histological workup, imaging follow-up, or clinical follow-up served as the standard of reference. Maximum standardized uptake value (SUVmax) was evaluated to discriminate between physiological uptake and LR. Results The highest accuracy to detect LR was achieved with 18F-FDG-PET/ceCT, with a sensitivity/specificity of 88%/89% and 88%/79% for R1 and R2, respectively, as compared to ceCT with 75%/79% for R1 and 88%/68% for R2 and 18F-FDG-PET/CT with 88%/58% for both R1 and R2. Receiver-operating-characteristic analysis determined a cutoff value for SUVmax of 7.2, yielding a sensitivity and specificity of 75% and 94%, respectively, to distinguish LR from physiological 18F-FDG uptake. Conclusion 18F-FDG-PET/ceCT seems to be the most reliable tool for locoregional surveillance of OCSCC patients after resection and reconstruction. Level of Evidence 4. Laryngoscope, 125:1861–1868, 2015

Previous preclinical studies of localized intraoperative virtual endoscopy-image-guided surgery (LIVE-IGS) for skull base surgery suggest a potential clinical benefit.The first aim was to evaluate the registration accuracy of virtual endoscopy based on high-resolution magnetic resonance imaging under clinical conditions. The second aim was to implement and assess real-time proximity alerts for critical structures during skull base drilling.Patients consecutively referred for sinus and skull base surgery were enrolled in this prospective case series.Five patients were used to check registration accuracy and feasibility with the subsequent 11 patients being treated under LIVE-IGS conditions with presentation to the operating surgeon (phase 2).Sixteen skull base patients were endoscopically operated on by using image-based navigation while LIVE-IGS was tested in a clinical setting.Workload was quantitatively assessed using the validated National Aeronautics and Space Administration Task Load Index (NASA-TLX) questionnaire.Real-time localization of the surgical drill was accurate to ~1 to 2 mm in all cases. The use of 3-mm proximity alert zones around the carotid arteries and optic nerve found regular clinical use, as the median minimum distance between the tracked drill and these structures was 1 mm (0.2-3.1 mm) and 0.6 mm (0.2-2.5 mm), respectively. No statistical differences were found in the NASA-TLX indicators for this experienced surgical cohort.Real-time proximity alerts with virtual endoscopic guidance was sufficiently accurate under clinical conditions. Further clinical evaluation is required to evaluate the potential surgical benefits, particularly for less experienced surgeons or for teaching purposes.

(D)-F-18-fluoromethyltyrosine (D-F-18-FMT), or BAY 86-9596, is a novel F-18-labeled tyrosine derivative rapidly transported by the L-amino acid transporter (LAT-1), with a faster blood pool clearance than the corresponding L-isomer. The aim of this study was to demonstrate the feasibility of tumor detection in patients with non-small cell lung cancer (NSCLC) or head and neck squamous cell cancer (HNSCC) compared with inflammatory and physiologic tissues in direct comparison to F-18-FDG. Methods: 18 patients with biopsy-proven NSCLC (n = 10) or HNSCC (n = 8) were included in this Institutional Review Board-approved, prospective multicenter study. All patients underwent F-18-FDG PET/CT scans within 21 d before D-F-18-FMT PET/CT. For all patients, safety and outcome data were assessed. Results: No adverse reactions were observed related to D-F-18-FMT. Fifty-two lesions were F-18-FDG-positive, and 42 of those were malignant (34 histologically proven and 8 with clinical reference). Thirty-two of the 42 malignant lesions were also D-F-18-FMT-positive, and 10 lesions had no tracer uptake above the level of the blood pool. Overall there were 34 true-positive, 8 true-negative, 10 false-negative, and only 2 false-positive lesions for D-F-18-FMT, whereas F-18-FDG was true-positive in 42 lesions, with 10 false-positive and only 2 false-negative, resulting in a lesion-based detection rate for D-F-18-FMT and F-18-FDG of 77% and 95%, respectively, with an accuracy of 78% for both tracers. A high D-F-18-FMT tumor-to-blood pool ratio had a negative correlation with overall survival (P = 0.050), whereas the F-18-FDG tumor-to-blood pool ratio did not correlate with overall survival. Conclusion: D-F-18-FMT imaging in patients with NSCLC and HNSCC is safe and feasible. The presented preliminary results suggest a lower sensitivity but higher specificity for D-F-18-FMT over F-18-FDG, since there is no D-F-18-FMT uptake in inflammation. This increased specificity may be particularly beneficial in areas with endemic granulomatous disease and may improve clinical management. Further clinical investigations are needed to determine its clinical value and relevance for the prediction of survival prognosis.

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

Objectives/Hypothesis To identify or confirm any new or suggested independent histopathological predictors in Merkel cell carcinoma (MCC) of the head and neck (HN) correlated with outcome. Study Design Retrospective chart and pathology review. Methods Between 1990 and 2010, 58 patients with Merkel cell carcinoma of the head and neck HNMCC were identified for study. Pathologic specimens were reviewed and evaluated for independent prognostic factors and correlated with locoregional recurrence and disease-specific survival. Results The 2- and 5-year disease-specific survival (DSS) rates were 72.7% and 63.6%, respectively. The local and regional recurrence rates were 12.0% and 24.1%, respectively. A total of 25.9% of the patients developed distant metastases during follow-up. Tumor size ( 1 cm) and the presence of a positive deep resection margin were independently found to be significantly associated with regional recurrence (P = 0.01 and P = 0.04, respectively). No other prognostic factors could be identified. Conclusion Adjuvant radiotherapy cannot remediate a positive resection margin. Given these results, consideration for revision surgery should be considered for a positive deep margin. Frozen section analysis may help to define the margins in this invasive and aggressive disease. Level of Evidence 2b. Laryngoscope, 123:3043–3048, 2013

Background The purpose of this study was to evaluate the efficacy of preoperative versus intraoperative mandibular contouring using rapid prototyping technology. Methods Ten patients requiring mandibular reconstruction had a preoperative mandibular plate contoured to a fabricated 3D mandibular model based on preoperative imaging. A traditional intraoperative plate was also contoured. Two surgeons blinded to the study compared the plates with respect to conformance, surface-area contact, and best overall match. A cost–benefit analysis was then performed. Results The average time to contour was 867 ± 243 seconds and 833 ± 289 seconds for the preoperative and intraoperative plates, respectively (p = .83). Interobserver analysis revealed no statistically significant differences in conformance (p = .38) or surface area contact (p = .14). In 7 of 9 cases, the preoperative plate was selected for the final reconstruction. In 1 case, an intraoperative plate was not contoured because of the lateral extent of the tumor. Conclusion In cases of mandibular distortion secondary to disease, pathologic fracture or defects involving multiple mandibular subsites this method is particularly advantageous. © 2013 Wiley Periodicals, Inc. Head Neck 36: 828–833, 2014

Objectives/Hypothesis The aim was to compare the value of 18-Fluoro-Deoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) regarding contralateral lymph node (LN) metastasis in the neck. Study Design Retrospective analysis of 61 patients staged by 18F-FDG-PET/CT. Methods Cytology/histology served as a reference standard. Further, metabolic midline invasion (MI) of the primary tumor and the presence of bilateral LN metastases were assessed. Results A true positive rate in the ipsilateral neck of 80% versus 65% in the contralateral neck was found (P = 0.067). Median-standardized uptake value (SUV)-max for suspicious LN ipsilaterally was 7.6 versus 5.8 contralaterally (P = 0.038). There was no positive correlation between metabolic MI and bilateral metastasis (P = 0.82). Conclusions The rate of true positive detected LN by 18F-FDG-PET/CT is less on the contralateral neck side; therefore, all suspicious LNs should be verified by cytology. A high SUV in the contralateral neck suggests metastatic disease regardless of nodal size. Metabolic MI needs to be addressed carefully as it was not predictive for bilateral LN involvement. Level of Evidence 4.

Sinonasal carcinomas are uncommon neoplasms accounting for approximately 3% to 5% of all upper respiratory tract malignancies. Sinonasal malignancies in most cases do not cause early symptoms and present in an advanced stage of disease. Exact staging necessitates a clinical and endoscopic examination with biopsy and imaging. Tumor resection using an open or endoscopic approach is usually considered the first treatment option. In general, sinonasal carcinomas are radiosensitive, so adjuvant or neoadjuvant radiation treatment may be indicated in advanced disease. Multidisciplinary surgical and medical oncologic approaches, including ablation and reconstruction, have enhanced the survival outcome over the past few decades.

Morbidity of cancer is still high and this is especially true for squamous cell carcinoma in the oral cavity and oropharynx which is one of the most widespread cancers worldwide. To avoid spreading of the tumor, often the lymphatic tissue of the neck is removed together with the tumor. Such neck dissections are inherently dangerous for the patient and only required in roughly 30 % of the patients as has been shown by studies. To prevent overtreatments, sentinel lymph node biopsy is used where the first lymph node after the tumor is probed for cancerous cells. The lymphatic tissue is then only completely removed when tumor cells are found. This sentinel node is localized by means of detecting a radioactive tracer that is injected near the tumor. Its uptake is then measured and observed. State-of-the-art support for the specialist is a 1-dimensional audio-based gamma detection unit which makes it challenging to detect and excise the true sentinel lymph node for an effective histologic examination and therefore correct staging.

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.

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.

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

BACKGROUND: The objective of this study was to link expression patterns of B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and p16 to patient outcome (recurrence and survival) in a cohort of 252 patients with oral and oropharyngeal squamous cell cancer (OSCC). METHODS: Expression levels of Bmi-1 and p16 in samples from 252 patients with OSCC were evaluated immunohistochemically using the tissue microarray method. Staining intensity was determined by calculating an intensity reactivity score (IRS). Staining intensity and the localization of expression within tumor cells (nuclear or cytoplasmic) were correlated with overall, disease-specific, and recurrence-free survival. RESULTS: The majority of cancers were localized in the oropharynx (61.1%). In univariate analysis, patients who had OSCC and strong Bmi-1 expression (IRS >10) had worse outcomes compared with patients who had low and moderate Bmi-1 expression (P = .008; hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.167-2.838); this correlation was also observed for atypical cytoplasmic Bmi-1 expression (P = .001; HR, 2.164; 95% CI, 1.389-3.371) and for negative p16 expression (P < .001; HR, 0.292; 95% CI, 0.178-0.477). The combination of both markers, as anticipated, had an even stronger correlation with overall survival (P < .001; HR, 8.485; 95% CI, 4.237-16.994). Multivariate analysis demonstrated significant results for patients with oropharyngeal cancers, but not for patients with oral cavity tumors: Tumor classification (P = .011; HR, 1.838; 95%CI, 1.146-2.947) and the combined marker expression patterns (P < .001; HR, 6.254; 95% CI, 2.869-13.635) were correlated with overall survival, disease-specific survival (tumor classification: P = .002; HR, 2.807; 95% CI, 1.477-5.334; combined markers: P = .002; HR, 5.386; 95% CI, 1.850-15.679), and the combined markers also were correlated with recurrence-free survival (P = .001; HR, 8.943; 95% CI, 2.562-31.220). CONCLUSIONS: Cytoplasmic Bmi-1 expression, an absence of p16 expression, and especially the combination of those 2 predictive markers were correlated negatively with disease-specific and recurrence-free survival in patients with oropharyngeal cancer. Therefore, the current results indicate that these may be applicable as predictive markers in combination with other factors to select patients for more aggressive treatment and follow-up. Cancer 2011;. © 2011 American Cancer Society.

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.

Purpose: To assess the diagnostic value of O-2-fluoro-18(F)-ethyl-l-tyrosine (18F-FET) positron emission tomography/computed tomography (PET/CT) for patients with advanced head and neck squamous cell carcinoma compared with 18F-fluoro-2-deoxy-d-glucose (18F-FDG) PET/CT at initial staging and following radiochemotherapy. Procedures: Thirteen patients were prospectively enrolled; each of them underwent an 18F-FDG PET/CT and 18F-FET PET/CT before treatment. Ten of those were scanned 10weeks after treatment. Results: Sensitivity, specificity, and accuracy for 18F-FDG PET/CT (primary and lymph node metastases) at initial staging were 89%, 50%, and 81%. For 18F-FET PET/CT the numbers were 70%, 90%, and 74%. Sensitivity, specificity, and accuracy for 18F-FDG PET/CT at follow-up were 71%, 65%, and 67%. For 18F-FET PET/CT the numbers were 29%, 100%, and 83%. Additionally, 18F-FDG PET/CT detected a higher number of second malignancies or distant metastases. Conclusions: 18F-FET is no substitute for 18F-FDG. Although it is more specific, too many malignant lesions are missed due to its lower sensitivity

Epstein-Barr virus (EBV) uses nasal mucosa-associated lymphoid tissue (NALT) as a portal of entry to establish life-long persistence in memory B cells. We previously showed that naïve and memory B cells from NALT are equally susceptible to EBV infection. Here we show that memory B cells from NALT are significantly more susceptible to EBV infection than those from remote lymphatic organs. We identify β 1 integrin, which is expressed the most by naïve B cells of distinct lymphoid origin and by memory B cells from NALT, as a mediator of increased susceptibility to infection by EBV. Furthermore, we show that BMRF-2-β 1 integrin interaction and the downstream signal transduction pathway are critical for postbinding events. An increase of β 1 integrin expression in peripheral blood memory B cells provoked by CD40 stimulation plus B-cell receptor cross-linking increased the susceptibility of non-NALT memory B cells to EBV infection. Thus, EBV seems to utilize the increased activation status of memory B cells residing in the NALT to establish and ensure persistence.

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.

The aims were to assess the technical feasibility of using a single electrode in the posterior arytenoid muscles (PAM) for intraoperative monitoring of the recurrent laryngeal nerve (RLN) in thyroid surgery, to validate the new method against the insertion of electrodes placed in the vocal cord muscle, and to report the results of the clinical application of the new concept. A total of 52 patients were enrolled. The handling and safety of RLN monitoring was tested by simultaneous registration of the EMG response from vocal fold electrodes and PAM electrodes. Acoustically and electromyographically we found nearly the same values for the arytenoid muscles as for the vocal folds, although the signals taken from the vocal folds were slightly stronger. PAM recording using a single bipolar electrode is technically feasible and as reliable compared to the standard vocal cord monitoring.

Follow-up of patients with oral cavity squamous cell carcinoma (OCSCC) after tumor resection and reconstruction with tissue transfer is challenging. We compared contrast-enhanced computed tomography (ceCT), (18) F-fluorodeoxyglucose-positron emission tomography combined with noncontrast enhanced CT ((18) F-FDG-PET/CT), and (18) F-FDG-PET combined with ceCT ((18) F-FDG-PET/ceCT) to determine the accuracy for detection of residual/recurrent disease after flap reconstruction for OCSCC.Two readers (R1, R2) retrospectively reviewed a total of 27 (18) F-FDG-PET/ceCT scans in patients after resection of stage II to IV OCSCC. They recorded the presence of local persistence/recurrence (LR), lymph node metastasis, or distant metastasis independently for ceCT, (18) F-FDG-PET/CT, and (18) F-FDG-PET/ceCT. Histological workup, imaging follow-up, or clinical follow-up served as the standard of reference. Maximum standardized uptake value (SUVmax) was evaluated to discriminate between physiological uptake and LR.The highest accuracy to detect LR was achieved with (18) F-FDG-PET/ceCT, with a sensitivity/specificity of 88%/89% and 88%/79% for R1 and R2, respectively, as compared to ceCT with 75%/79% for R1 and 88%/68% for R2 and (18) F-FDG-PET/CT with 88%/58% for both R1 and R2. Receiver-operating-characteristic analysis determined a cutoff value for SUVmax of 7.2, yielding a sensitivity and specificity of 75% and 94%, respectively, to distinguish LR from physiological (18) F-FDG uptake.(18) F-FDG-PET/ceCT seems to be the most reliable tool for locoregional surveillance of OCSCC patients after resection and reconstruction.4.

Purpose Optimum management of the N0 neck is unresolved in oral cancer. Sentinel node biopsy (SNB) can reliably detect microscopic lymph node metastasis. The object of this study was to establish whether the technique was both reliable in staging the N0 neck and a safe oncological procedure in patients with early-stage oral squamous cell carcinoma. Methods An European Organisation for Research and Treatment of Cancer-approved prospective, observational study commenced in 2005. Fourteen European centres recruited 415 patients with radiologically staged T1–T2N0 squamous cell carcinoma. SNB was undertaken with an average of 3.2 nodes removed per patient. Patients were excluded if the sentinel node (SN) could not be identified. A positive SN led to a neck dissection within 3 weeks. Analysis was performed at 3-year follow-up. Results An SN was found in 99.5% of cases. Positive SNs were found in 23% (94 in 415). A false-negative result occurred in 14% (15 in 109) of patients, of whom eight were subsequently rescued by salvage therapy. Recurrence after a positive SNB and subsequent neck dissection occurred in 22 patients, of which 16 (73%) were in the neck and just six patients were rescued. Only minor complications (3%) were reported following SNB. Disease-specific survival was 94%. The sensitivity of SNB was 86% and the negative predictive value 95%. Conclusion These data show that SNB is a reliable and safe oncological technique for staging the clinically N0 neck in patients with T1 and T2 oral cancer. EORTC Protocol 24021: Sentinel Node Biopsy in the Management of Oral and Oropharyngeal Squamous Cell Carcinoma.

Adult laryngotracheal reconstruction for airway stenosis and after oncologic ablation can be extremely challenging.Patients with the above conditions not amenable to or refractory to conventional treatments were offered specialized reconstruction by wrapping a contoured costal cartilage graft with a vascularized microvascular carrier. All constructs were lined with buccal mucosa grafts. Decannulation rates, quality of life questionnaires, and pulmonary function tests were performed and analyzed.Eleven patients underwent this procedure, 6 for stenosis and 5 for laryngotracheal oncologic defects. Ten patients were successfully decannulated after the procedure (91%). Median time to decannulation was 4 months. At mean follow-up of 76 months, all evaluated patients had a serviceable voice, tolerated a normal diet, and had minimal subjective shortness of breath.Vascularized composite autograft can be successfully used to treat severe subglottic stenosis or reconstruct large laryngotracheal defects not amenable to or refractory to conventional treatments.

Summary Imaging head and neck cancer is crucial for treatment decisions and follow-up of patients. The choice of the appropriate imaging modality for staging and re-staging head and neck cancer can be troublesome. This review highlights the important questions of imaging from a clinician's perspective. The recommendations focus on mucosal squamous cell carcinoma of the head and neck since this is the most common one.

BACKGROUND: Hurthle cell carcinoma (HCC), a variant of a follicular carcinoma of the thyroid, is an aggressive type of differentiated thyroid cancer now considered a distinct pathologic entity. It may present as a low-grade tumor or as a more aggressive type. Prognosis depends on the age of the patient, tumor size, extent of invasion, and initial nodal or distant metastasis. Although thoracic involvement is not unusual with this tumor, this is the first report, to our knowledge, of latent pleural and lung metastases that were detected by a thoracentesis. PATIENT AND METHODS: A 63-year-old woman underwent total thyroidectomy for a thyroid mass in 1990 that was diagnosed as HCC. In December 2006, she presented with symptoms of dyspnea and an abnormal chest x-ray. A subsequent ultrasound-guided thoracentesis revealed a malignant, exudative effusion. Cytopathologic analysis revealed the malignancy to be consistent with HCC. She was reevaluated by her original oncologist and is undergoing treatment for metastatic HCC. CONCLUSIONS: Although rare, HCC may present years after definitive therapy as metastatic pleural and lung disease. Further studies are needed to determine the cause of latency in such cases.

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.The localizations of carcinoma deposits were analyzed with a virtual microscope by creating digital images from the microscopic glass slides.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).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.

OBJECTIVE: Assess the influence of 2 different patient positions during [18F]fluorodeoxyglucose (FDG) uptake phase on physiologic FDG accumulation of the floor of mouth (FOM) muscles. Study design: A prospective study design was used. METHODS: Two hundred prospectively enrolled patients were included in the study: (a) head and neck cancer (HNC) patients in supine or (b) sitting position, (c) patients with other malignant tumours in supine or (d) sitting position. An intra-individual analysis was done on patients (b) and (d) when such scans were available. Maximum standardized uptake values without correction and corrected for blood pool activity were assessed. RESULTS: The inter-individual analysis (sitting vs supine) revealed no significant differences (P = 0.17 and P = 0.56). The subgroup analysis on the patients with HNC (P = 0.56 and P = 0.15) and in patients with other malignancies (P = 0.14 and P = 0.08) revealed no significant difference; neither did the intra-individual analysis. CONCLUSIONS: The supine or sitting position during the uptake phase for FDG-positron emission tomography/computed tomography has no effect on the amount and distribution of physiologic FDG activity in the muscles of the FOM.

Sinonasal carcinomas are uncommon neoplasms accounting for approximately 3% to 5% of all upper respiratory tract malignancies. Sinonasal malignancies in most cases do not cause early symptoms and present in an advanced stage of disease. Exact staging necessitates a clinical and endoscopic examination with biopsy and imaging. Tumor resection using an open or endoscopic approach is usually considered the first treatment option. In general, sinonasal carcinomas are radiosensitive, so adjuvant or neoadjuvant radiation treatment may be indicated in advanced disease. Multidisciplinary surgical and medical oncologic approaches, including ablation and reconstruction, have enhanced the survival outcome over the past few decades.

Skull base surgery (SBS) involves operative tasks in close proximity to critical structures in a complex three-dimensional (3D) anatomy. The aim was to investigate the value of virtual planning (VP) based on preoperative magnetic resonance imaging (MRI) for surgical planning in SBS and to compare the effects of virtual planning with 3D contours between the expert and the surgeon in training.Retrospective analysis.Twelve patients with manually segmented anatomical structures based on preoperative MRI were evaluated by eight surgeons in a randomized order using a validated National Aeronautics and Space Administration Task Load Index (NASA-TLX) questionnaire.Multivariate analysis revealed significant reduction of workload when using VP (P.0001) compared to standard planning. Further, it showed that the experience level of the surgeon had a significant effect on the NASA-TLX differences (P.05). Additional subanalysis did not reveal any significant findings regarding which type of surgeon benefits the most (P.05).Preoperative anatomical segmentation with virtual surgical planning using contours in endoscopic SBS significantly reduces the workload for the expert and the surgeon in training.

BACKGROUND: The transcription factor sex determining region Y (SRY)-box 2 (SOX2) (3q26.3-q27) has been recently identified as a recurrently activated major oncogene in squamous cell carcinoma of various sites. Its prognostic value in head and neck squamous cell carcinoma (HNSCC) is currently unclear. AIM: To correlate SOX2 protein expression with the occurrence of occult lymph node metastasis and relapse free survival in early oral SCC. METHODS: SOX2 expression in 120 T1/T2 oral SCC patients was evaluated using a tissue microarray technique. Intensity of SOX2 expression was quantified by assessing the Intensity/Reactivity Scores (IRSs). These scores were correlated with the lymph node status of biopsied sentinel lymph nodes and recurrence. Log rank univariate and Cox regression multivariate analysis was used to determine statistical significance. RESULTS: Twenty-six of 120 primary tumours (21.7%) showed high SOX2 expression. High expression levels of SOX2 significantly correlated with negative lymph node status in univariate (p=0.001) and multivariate analysis (p=0.003). Sensitivity was found to be 95.6% with a negative predictive value of 92.3%. Specificity was 32% with a positive predictive value of 45.7%. CONCLUSION: SOX2 up-regulation is frequent in early SCC of the oral cavity and associated with decreased risk of lymphatic metastasis. SOX2 immunohistochemistry may be used as a predictor for lymph node metastasis in squamous cell carcinoma of the oral cavity.

The purpose of this study was to evaluate the efficacy of preoperative versus intraoperative mandibular contouring using rapid prototyping technology.Ten patients requiring mandibular reconstruction had a preoperative mandibular plate contoured to a fabricated 3D mandibular model based on preoperative imaging. A traditional intraoperative plate was also contoured. Two surgeons blinded to the study compared the plates with respect to conformance, surface-area contact, and best overall match. A cost-benefit analysis was then performed.The average time to contour was 867 ± 243 seconds and 833 ± 289 seconds for the preoperative and intraoperative plates, respectively (p = .83). Interobserver analysis revealed no statistically significant differences in conformance (p = .38) or surface area contact (p = .14). In 7 of 9 cases, the preoperative plate was selected for the final reconstruction. In 1 case, an intraoperative plate was not contoured because of the lateral extent of the tumor.In cases of mandibular distortion secondary to disease, pathologic fracture or defects involving multiple mandibular subsites this method is particularly advantageous.

Background Analysis of the lymphatic drainage pattern, the reliability of a negative sentinel lymph node biopsy (SLNB), as well as the impact of sentinel lymph node (SLN) metastases on regional control and survival in patients with early stage oral and oropharyngeal squamous cell carcinoma (SCC). Methods A prospective consecutive cohort analysis was conducted which included 111 patients diagnosed between 2003 and 2010. Endpoints of the study were neck control rate, overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS), depending on the size of occult metastases. Results Forty-nine of 111 patients (38%) had positive SLNs, 10 had isolated tumor cells (ITCs), 19 had micrometastases, and 13 had macrometastases. OS, DSS, and DFS at 3 years for SLN-negative and SLN-positive patients was 98% and 71%, 95% and 76%, and 98% and 73%, respectively. Furthermore, there was a statistically significant difference between the SLN-negative group and ITCs in DSS as well as between the SLN-negative group and patients with micrometastases in OS and DSS and between the SLN-negative group and patients with macrometastases in all 3 survival estimates. Conclusion Our study is the first to demonstrate that even small tumor deposits only detectable by the extensive histopathologic workup of the SLNB protocol have a significant impact on tumor control and survival in early Oropharyngeal SCC. Whether these findings will translate into different treatment strategies based on the upstaged neck has to be further investigated. © 2012 Wiley Periodicals, Inc. Head Neck, 2013

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.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.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%.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.

BackgroundThe role of sentinel node biopsy in head and neck cancer is currently being explored. Patients with positive sentinel nodes were investigated to establish if additional metastases were present in the neck, their distribution, and their impact on outcome.MethodsIn all, 109 patients (n = 109) from 15 European centers, with cT1/2,N0 tumors, and a positive sentinel lymph node were identified. Kaplan-Meier and univariate and multivariate logistic regression analysis were used to identify variables that predicted for additional positive nodes and their position within the neck.ResultsA total of 122 neck dissections were performed in 109 patients. Additional positive nodes were found in 34.4% of cases (42/122: 18 same, 21 adjacent, and 3 nonadjacent neck level). Additional nodes, especially if outside the sentinel node basin, had an impact on outcome.ConclusionsThe results are preliminary but suggest that both the number and the position of positive sentinel nodes may identify different prognostic groups that may allow further tailoring of management plans.

Objectives: Computed tomography perfusion (CTP) can provide information about angiogenesis and blood-flow characteristics in tumours. [18F]Fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography (FDG-PET/CT) is one of the major oncological imaging techniques which provides information about viability of the tumour cell and partly also about its aggressiveness. The aim of the study was to investigate the relationship between FDG and CTP data in patients with head and neck cancers. Materials and methods: Forty-one patients with a clinically suspected head and neck cancer were prospectively included. All patients underwent a combined PET/CT with an integrated CTP examination in the area of the head and neck tumour. CTP data (BF, BV and MTT) and PET data (SUVmax, SUVmean, TLG, PETvol) were compared between tumours and (1) healthy contralateral tissue, (2) inflammatory lesions, (3) metastatic lymph nodes, and CTP data and PET data were correlated in tumours. Results: Thirty-five patients had a head and neck cancer. All CTP data were statistically different between tumours, inflammatory lesions, healthy tissue and metastatic lymph nodes; PET/CT data were in part significantly different. CTP and PET parameters were not significantly correlated. Conclusion: CTP and PET parameters were not significantly correlated; thus, the additional CTP values provide additional insights into tumour behaviour and their glycolytic status. Key Points : • Computed tomography perfusion (CTP) can be performed in combined positron emission tomography (PET)/CT. • CTP in addition to PET provides additional insights into tumour behaviour. • CTP can possibly differentiate between head and neck tumours and inflammatory lesions. • PET/CT with integrated CTP is possible without additional contrast media

Background Prognostic factors in predicting occult lymph node metastasis in patients with head and neck squamous-cell carcinoma (HNSCC) are necessary to improve the results of the sentinel lymph node procedure in this tumour type. The E-Cadherin glycoprotein is an intercellular adhesion molecule in epithelial cells, which plays an important role in establishing and maintaining intercellular connections. Objectives To determine the value of the molecular marker E-Cadherin in predicting regional metastatic disease. Methods E-Cadherin expression in tumour tissue of 120 patients with HNSCC of the oral cavity and oropharynx were evaluated using the tissue microarray technique. 110 tumours were located in the oral cavity (91.7%; mostly tongue), 10 tumours in the oropharynx (8.3%). Intensity of E-Cadherin expression was quantified by the Intensity Reactivity Score (IRS). These results were correlated with the lymph node status of biopsied sentinel lymph nodes. Univariate and multivariate analysis was used to determine statistical significance. Results pT-stage, gender, tumour side and location did not correlate with lymph node metastasis. Differentiation grade (p = 0.018) and down regulation of E-Cadherin expression significantly correlate with positive lymph node status (p = 0.005) in univariate and multivariate analysis. Conclusion These data suggest that loss of E-cadherin expression is associated with increased lymhogeneous metastasis of HNSCC. E-cadherin immunohistochemistry may be used as a predictor for lymph node metastasis in squamous cell carcinoma of the oral cavity and oropharynx. Level of evidence: 2b

The aim this study was to evaluate imaging findings using position emission tomography (PET) in combination with computed tomography (CT) and 18F-fluorodeoxyglucose ((18)F-FDG) in sinonasal malignant melanoma (SNMM) of the head and neck in a retrospective analysis of a consecutive cohort of patients. (18)F-FDG-PET/CT examinations were performed for initial staging and compared with CT or magnetic resonance tomography (MRI), and (18)F-FDG-PET alone. Medical records were reviewed retrospectively with regard to the location and the size of the tumor. Furthermore, locoregional and distant metastases with a consecutive change in therapy detected by (18)F-FDG-PET/CT were assessed. Ten patients suffering from sinonasal malignant melanoma were staged and followed by (18)F-FDG-PET/CT imaging. A total of 34 examinations were obtained. (18)F-FDG-PET/CT depicted all primary tumors adequately. Aside from one cerebral metastasis all regional and distant metastases were truly identified by using this method. In summary, if available, (18)F-FDG-PET/CT is a valuable imaging modality for staging and re-staging sinonasal malignant melanoma to evaluate expansion of the primary tumor, locoregional disease, and distant metastases.