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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 (SUV max , 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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Between the publication of the Union of International Cancer Control staging system (UICC) 7th and 8th editions, other staging algorithms for oropharyngeal squamous cell carcinoma (OPSCC) were proposed from Radiation Therapy Oncology Group (RTOG), MD Anderson Cancer Center (MDACC), and Yale University., Methods: With C-statistics, the above-mentioned five staging algorithms were compared for overall and relapse-free survival endpoints in a multi-institutional cohort of OPSCC cases (n = 338) treated with primary surgery., Results: Pathological UICC 8th ed yielded the highest C-indexes in the entire cohort and in the HPV- subset, whereas MDACC was superior for HPV+ OPSCC. RTOG was the simplest and holistic algorithm with a noninferior discriminatory power., Conclusion: UICC 8th ed, MDACC, and RTOG offer moderate and comparable efficacy for staging in this OPSCC patient cohort undergoing surgical treatment. Notable discrepancy between clinical and pathological UICC 8th ed algorithms poses potential concerns in diagnosis, treatment, research, and data management., (© 2018 Wiley Periodicals, Inc.)

Background: Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) has an improved outcome and may allow for treatment de-escalation. High-risk HPV (HR-HPV) infection is associated with deregulated expression of the cell cycle-associated proteins p16 INK4 , pRB, cyclin D1 and p53. The objective of this study was to assess cell cycle proteins as potential surrogate markers for HR-HPV DNA testing to identify OPSCC with favorable prognosis after resection., Methods: Tissue microarray cores of 313 surgically treated OPSCC were stained for p16 INK4a , pRB, cyclin D1 and p53 using immunohistochemistry. Protein expression was scored as high or low based on the proportion of positive carcinoma cells. Tumor samples were analysed for HR-HPV DNA with polymerase chain reaction-based testing. Associations between cell cycle protein expression and HR-HPV DNA status were evaluated by calculating sensitivity, specificity, predictive values, and diagnostic odds ratios (DOR). Kaplan-Meier and Cox regression analysis were applied to evaluate associations between cell cycle protein expression and patient outcome., Results: High expression of p16 INK4a , cyclin D1, pRB and p53 in tumor cells were observed in 51.8%, 51.4%, 41.9% and 33.5% of OPSCC, respectively. HR-HPV DNA positive were 158/313 (50.5%) tumor samples (HPV16: 147, HPV18: 1, HPV33: 5, HPV35: 2, HPV56: 2, and HPV59: 1). P16 INK4a showed a higher DOR to predict HR-HPV DNA positivity than pRB, cyclin D1 and p53. Both the p16 INK4a /pRB and the p16 INK4a /pRB/cyclin D1/p53 signatures had lower DOR than p16 INK4a alone. Improved 5-year overall and disease-specific survival were associated with HR-HPV DNA positivity, high p16 INK4a , low pRB, low cyclin D1, and low p53 expression. Associations with improved outcome were also observed for the marker combinations high p16 INK4a /positive HR-HPV DNA, high p16 INK4a /low pRB and high p16 INK4a /low pRB/low cyclin D1/low p53. In a multivariate analysis adjusted for age, smoking history, pT and pN category, high p16 INK4a expression showed the lowest hazard ratio for death., Conclusions: High p16 INK4a expression is a reliable marker for survival prognostication in surgically treated OPSCC patients. Protein signatures including the pRB, cyclin D1 and p53 proteins do not further increase the prognostic performance of p16 INK4a as a single marker.

Background: Knowledge about prognostic factors in surgically treated patients with oropharyngeal squamous cell carcinoma (SCC) is limited. The purpose of this study was to identify influential factors on survival in a large cohort of patients with surgically treated oropharyngeal SCC., Methods: Retrospective analysis of survival estimates in patients with surgically treated oropharyngeal SCC using tumoral positivity for human papillomavirus (HPV) and risk-of-death categories according to a study from 2010 as stratification factors., Results: The 5-year overall survival (OS) and disease-specific survival (DSS) rates after surgery alone were higher in HPV-associated oropharyngeal SCC (OS 80% vs 62%; P = .01; DSS 92% vs 76%; P = .03). Patients in the low-risk category had higher survival rates (OS 91%; DSS 99%) than patients in the intermediate-risk group (OS 63%; DSS 83%), and high-risk group (OS 61%; DSS 75%)., Conclusion: Nonsmokers with HPV-positive oropharyngeal SCC have a better prognosis than smokers with HPV-positive oropharyngeal SCC and also than patients with HPV-negative tumors when treated by surgery alone., (© 2017 Wiley Periodicals, Inc.)

Objectives: High risk human papillomavirus (HR-HPV) infection leads to a subgroup of oropharyngeal cancer (OPSCC) characterized by improved treatment response. However an universally accepted definition of an HR-HPV-attributable cancer is lacking., Methods: Detailed, type-specific HPV antibody responses were analyzed by multiplex serology in HR-HPV-attributable OPSCC patients, defined by p16 INK4A overexpression and HR-HPV DNA detection by PCR amplification and sequencing., Results: Fifty patients were prospectively enrolled. 26/50 (52%) tumor samples were positive for both p16 INK4A expression and HR-HPV DNA (22 HPV16, 4 HPV33). Seropositivity was present in 26/26 HPV-attributable OPSCC and one p16 INK4A -positive/HPV DNA-negative case. The sensitivity and specificity to diagnose an HR-HPV-attributable tumor was 100% and 96%, respectively for anti-E6 reactivity, 82% and 100%, respectively for anti-E2 reactivity, and clearly lower for anti-E7, anti-E1, anti-E4 and anti-L1-reactivity. 3yr-overall (OS) and disease specific survival (DSS) was higher in patients with HR-HPV-attributable tumors (OS 88% vs 64%, p=0.02; DSS 90% vs 80%, p=0.07) and seropositive patients (OS 88% vs 62%, p=0.01; DSS 92% vs 78%, p=0.05) than HR-HPV-negative or seronegative patients., Conclusions: Detection of HR-HPV type-specific antibodies highly correlated with HPV-attributable OPSCC and was associated with better survival. HR-HPV antibodies are promising diagnostic, prognostic and potentially screening markers in HR-HPV-attributable OPSCC., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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

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.)

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.

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

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., (Copyright © 2012 Wiley Periodicals, Inc.)

Objectives/hypothesis: To assess the quality of life in long-term survivors with oropharyngeal cancer (OPSCC), compare the results with our historic cohort in relation to the radiation technique, and explore the influence of treatment strategy and p16 expression on quality of life (QoL)., Study Design: Retrospective chart analysis and patient response to EORTC QLQ-C30 and EORTC QLQ-H&N35 survey questionnaires., Methods: 98/120 (82%) survivors treated by primary intensity modulated chemoradiation (n = 55), or surgery with (n = 30) or without (n = 13) adjuvant radiotherapy (RT), completed and returned the questionnaires., Results: Surgically treated patients complained about significantly less troubles with dry mouth and teeth compared to the nonsurgically treated group. Comparing patients treated with surgery alone and those receiving any kind of RT (primary or adjuvant) the latter group complained about significantly more problems. Patients with p16-positive tumors demonstrated significantly higher tumor stages, but significantly better scores in physical and role functions., Conclusions: Early disease can be treated with high long-term QoL by surgery alone. Primary surgery with postoperative RT in selected patients with limited primary tumors and advanced neck disease renders excellent QoL. Our results suggest that IMRT is superior to former radiation techniques with regard to QoL, and should be considered as standard of care in patients undergoing RT for OPSCC. Patients with p16 positive tumors appear to show not only a better outcome but also report on a better QoL., (Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.)

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., (Copyright © 2012 Wiley Periodicals, Inc.)

In patients with early stage oral or oropharyngeal squamous cell carcinoma (OSCC) sentinel node biopsy (SNB) is a reliable method to detect occult disease in the neck. However, patients with a history of surgery or radiotherapy in the neck may have aberrant lymphatic drainage caused by disruption of lymphatic channels. Therefore, treatment of the same levels at risk as in the primary setting may not be appropriate. The aim of our prospective observational study was to evaluate the clinical application of SNB in previously treated OSCC. Between 2003 and 2010 twenty-two patients were included. Lymph node mapping consisted of preoperative lymphoscintigraphy, SPECT/CT, intraoperative use of gamma-probe and patent blue. Endpoints were the sentinel node (SN) detection rate, unexpected lymphatic drainage patterns, negative predictive value and regional tumor control. 4/22 (18%) Patients were previously treated only on the contralateral site. The SN detection rate was 100% and unexpected drainage was found in 1/4 patients. The other 18 patients had ipsi- or bilateral previous neck treatment and a SN detection rate of 83%. The upstaging rate was 7% and 67% had unexpected lymphatic drainage patterns. The median follow-up was 22 months. Regional tumor control and negative predictive value were 100%. SNB in previously treated OSCC patients is feasible. SN detection is reliable and regional tumor control after staging by SNB is excellent. Moreover, SNB renders an assessment of the individual lymphatic drainage pattern, compensating for a potential variability after previous treatment of the neck., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

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.

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., (Copyright © 2011 UICC.)

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.

Background: This study evaluates the oncological outcome of patients with recurrent oropharyngeal squamous cell carcinoma (OPSCC) after primary radiation therapy +/- chemotherapy, primary surgical therapy, and surgical therapy followed by radiation therapy +/- chemotherapy., Methods: A total of 156 patients (36%) of a cohort of 427 treated for OPSCC between 1990 and 2006 developed recurrent disease. Fifty-one patients (12%) qualified for salvage treatment. Study endpoints were 5-year overall survival (OS) and disease-specific survival (DSS)., Results: The 5-year OS and DSS rates after salvage treatment were 29% and 40%; after initial primary radiation therapy, 25% and 40%; after initial surgery followed by radiation therapy, 40% and 40%; and after initial surgery alone, 20% and 40%., Conclusions: Patients with an advanced OPSCC have a considerable risk for recurrence. Despite poor ultimate outcome, salvage treatment should be attempted in patients with resectable disease, good performance status, and absence of distant metastases., (2009 Wiley Periodicals, Inc. Head Neck, 2010.)

Proteins of the lysyl oxidase (LOX) family are important modulators of the extracellular matrix. However, they have an important role in the tumour development as well as in tumour progression. To evaluate the diagnostic and prognostic value of the LOX protein in oral and oropharyngeal squamous cell carcinoma (OSCC) we performed QRT-PCR and immunohistochemical analysis on two tissue microarrays (622 tissue samples in total). Significantly higher LOX expression was detected in high grade dysplastic oral mucosa as well as in OSCC when compared to normal oral mucosa (P < 0.001). High LOX expression was correlated with clinical TNM stage (P = 0.020), lymph node metastases for the entire cohort (P < 0.001), as well as in the subgroup of small primary tumours (T1/T2, P < 0.001). Moreover, high LOX expression was correlated with poor overall survival (P = 0.004) and disease specific survival (P = 0.037). In a multivariate analysis, high LOX expression was an independent prognostic factor, predicting unfavourable overall survival. In summary, LOX expression is an independent prognostic biomarker and a predictor of lymph node metastasis in OSCC. Moreover, LOX overexpression may be an early phenomenon in the pathogenesis of OSCC and thus an attractive novel target for chemopreventive and therapeutic strategies.

Background: 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., Methods: A consecutive cohort of 58 patients was evaluated using SNB with additional SPECT/CT to preoperative LS., Results: 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%., Conclusions: 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.

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

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

Objectives: This study evaluates the oncologic outcome with regard to survival and locoregional tumor control in a cohort of patients with oropharyngeal squamous cell carcinoma (OPSCC) treated according to a uniform algorithm., Study Design: Retrospective chart review., Methods: A total of 427 consecutive patients with OPSCC were treated from 1990 to 2006. Treatment modalities were surgery alone (n = 102), surgery with adjuvant radio(chemo)therapy (n = 159), and primary radio(chemo)therapy (n = 166). Study endpoints were the five-year overall survival (OS) and disease-specific survival (DSS) stratified for primary tumor subsite, stage, T and N category, and age., Results: The five-year OS and DSS for the entire cohort were 57.9% and 68.6%, respectively. OS and DSS for surgery alone were 70.3% and 76.5%, for surgery with radiation 66.6% and 78.9%, and for primary radiation 40.8% and 52.6%, respectively. Survival was significantly better for low stages (stage I/II vs. III/IV), small tumors (T1/2 vs. T3/4), limited nodal involvement (N0/1 vs. N2/3), and younger age at diagnosis., Conclusions: Together with our previous study on quality of life, we were able to show that our selection process gives excellent oncologic outcome in combination with high levels of function and quality of life. Surgery alone for early OPSCC and surgery followed by radiation for advanced OPSCC remain valuable treatment options. Primary radiochemotherapy is a strong alternative for patients who are not candidates for function-preserving surgery.

Objectives: The aims were to assess the technical feasibility of sentinel node biopsy (SNB), to validate SNB against elective neck dissection, and to report the results of the clinical application of the SNB concept for early oral and oropharyngeal squamous cell carcinoma., Study Design: Prospective consecutive cohort analysis., Methods: Between 2000 and 2006, a total of 79 patients were included. Lymphatic mapping consisted of preoperative lymphoscintigraphy and intraoperative use of a hand-held gammaprobe. Twenty-eight patients were assessed for feasibility and validation; the SNB was done in context with an elective neck dissection. Fifty-one patients were evaluated in an observational trial; elective neck dissection was performed only in case of positive SNB., Results: Validation revealed a sentinel node detection rate by lymphoscintigraphy of 93%, with the gammaprobe of 100%. The negative predictive value of a negative SNB was 100%. During the observational trial 40% of the patients were upstaged as a result of a positive SNB. Intraoperative frozen section analysis showed a negative predictive value of 83%. Two patients (6%) with negative SNB experienced a neck recurrence, the negative predictive value of SNB was therefore 94%. Patients with positive SNB were treated successfully with elective neck dissection., Conclusions: SNB is technically feasible and reproducible with a high sentinel node detection rate. Validation against elective neck dissection revealed a negative predictive value of 100%. Application of the SNB concept in clinical practice was very successful. The recurrence rate within the neck was very low and the morbidity and cost of an elective neck dissection could be spared to 60% of the patients.

Background: The aim of our study was to assess the value of positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) for the staging of clinically nodal negative necks in oral and oropharyngeal squamous cell carcinoma (SCC) using sentinel lymph node (SLN) biopsy and elective neck dissection (END) as "gold standard" for comparison., Methods: Twelve patients (10 men, 2 women) with oral or oropharyngeal squamous cell carcinoma and no evidence of lymph node metastasis in the physical and radiologic examinations were eligible. At least 24 hours before surgery PET with FDG were performed. The SLN was localized by preoperative lymphoscintigraphy with 99m-Tc-Nanocoll and intraoperative use of a hand-held gamma-probe and selectively excised. All patients then underwent END., Results: SLN and END revealed occult metastasis in 5 of 12 cases. SLN biopsy was accurately feasible in all 12 patients and diagnosed all 5 cases of occult metastasis (sensitivity and specificity of 100%). PET suggested two patients having occult metastasis, of which one turned out to be false positive (sensitivity 25%, specificity 88%). The mean size of the micrometastasis was 1.4 mm (range, 1.2-1.5 mm)., Conclusions: PET with FDG turned out to have a poor sensitivity and specificity in revealing occult metastasis and has no role for the evaluation of otherwise clinically N0 necks. The failure to detect micrometastasis by PET is due to the technical limitations of resolution (4-5 mm). SLN biopsy, with END in cases of positive SLN, provides a highly accurate staging of N0 necks in oral and oropharyngeal carcinoma. Patients with negative SLN could be spared the risks and the morbidity of END., (Copyright 2002 Wiley Periodicals, Inc.)

Objectives: Sentinel lymph node biopsy has been introduced for head and neck cancer with promising results. Research in breast cancer has revealed different histopathological features of occult lymph node metastasis with possibly different clinical and prognostic implications. The aim of the study was to evaluate the histopathological features of occult metastasis detected by sentinel lymph node in oral and oropharyngeal squamous cell carcinoma., Study Design: Prospective., Methods: According to Hermanek (5), occult metastasis was differentiated into isolated tumor cells and infiltration of lymph node parenchyma smaller than 2 mm in diameter (micrometastasis) and larger than 2 mm in diameter (metastasis)., Results: Occult metastases were found in 6 of 19 (32%) sentinel lymph nodes. Three patients showed micrometastasis with a mean size of 1.4 mm (range, 1.2-1.5 mm), the first with three separate micrometastases within the same sentinel lymph node, the second with an additional cluster of isolated tumor cells within the same sentinel lymph node, and the third with an additional micrometastasis in one lymph node of the elective neck dissection. Two patients had macrometastasis (3.4 and 8 mm), both with multiple metastases in the elective neck dissection. One patient had two clusters of isolated tumor cells in the sentinel lymph node and an additional cluster of isolated tumor cells in one lymph node of the elective neck dissection., Conclusions: Occult metastasis can be subdivided histopathologically in isolated tumor cells, micrometastasis, and macrometastasis. We present the first study describing a great variety of these subtypes in sentinel lymph nodes from head and neck squamous cell carcinoma. Because the independent prognostic factor and clinical relevance of these subtypes is still unclear, we emphasize the importance of reporting these findings uniformly and according to well-established criteria.