Impact of the new TNM Staging System (8th edition) on oral tongue cancers.

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

Evaluation of 18F-FDG PET/CT as an early imaging biomarker for response monitoring after radiochemotherapy using cetuximab in head and heck squamous cell carcinoma.

BACKGROUND: To determine whether 18 F-PET/CT is able to identify treatment response as early as 1 week after the end of chemoradiotherapy, whether 18 F-PET/CT can identify prognostic markers concerning progression free survival and can identify patients who need additional consolidation therapy. METHODS: A total of 54 patients with head and neck cancer were prospectively enrolled in this single-center, randomized study from 03/2012-04/2015. Patients underwent FDG-PET/CT imaging at three predefined time points: pretreatment (PET/CT1), 1 week postprimary radiochemotherapy (PET/CT2) and 3 months postprimary radiochemotherapy (PET/CT3). Tumors were assessed quantitatively based on size and glucose uptake (SUVmax) concerning response at each time point. Response assessment was correlated with progression free survival. All patients had a minimum follow-up period of 18 months. Multivariate regression analysis was performed to find independent predictors for progression free survival (PFS). RESULTS: Thirty-two (32) patients (64%) overall remained disease free, 11 patients (22%) had recurrence and 7 patients (14%) had persistent disease. There was no significantly different metabolic parameter ratio found concerning responders and nonresponders at posttreatment (PET/CT2 and 3) time points (P > .05) during clinical follow-up. Multivariate regression analysis demonstrated both SUVmax and diameter assessed at time point PET/CT3 represent independent predictors of progression free survival (PFS). There was also no statistically significant difference in PFS between responders and nonresponders by means of PET/CT2 in both study arms (P > .05). Imaging responders at time point PET/CT3 showed a significantly longer PFS compared to nonresponders after the end of consolidation therapy (P < .01). CONCLUSIONS: Early response of head/neck cancer after radiochemotherapy can be accurately assessed with PET/CT 1 week after RCT. SUVmax and lesion diameter are independent predictors of PFS at time point PET/CT3. PET/CT2 has no prognostic value concerning PFS and cannot identify high risk patients for consolidation therapy. Imaging responders showed a significantly longer PFS compared to nonresponders and therefore PET/CT might serve as a prognostic biomarker. TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT01435252.

A Review of Controversial Issues in the Management of Head and Neck Cancer: A Swiss Multidisciplinary and Multi-Institutional Patterns of Care Study-Part 1 (Head and Neck Surgery).

Background: The Head and Neck Cancer Working Group of Swiss Group for Clinical Cancer Research (SAKK) has investigated the level of consensus (LOC) and discrepancy in everyday practice of diagnosis and treatment in head and neck cancer. Materials and Methods: An online survey was iteratively generated with 10 Swiss university and teaching hospitals. LOC below 50% was defined as no agreement, while higher LOC were arbitrarily categorized as low (51-74%), moderate (75-84%), and high (≥85%). Results: Any LOC was achieved in 62% of topics (n = 60). High, moderate and low LOC were found in 18, 20, and 23%, respectively. Regarding Head and Neck Surgery, Radiation Oncology, Medical Oncology, and biomarkers, LOC was achieved in 50, 57, 83, and 43%, respectively. Conclusions: Consensus on clinical topics is rather low for surgeons and radiation oncologists. The questions discussed might highlight discrepancies, stimulate standardization of practice, and prioritize topics for future clinical research.

A Review of Controversial Issues in the Management of Head and Neck Cancer: A Swiss Multidisciplinary and Multi-Institutional Patterns of Care Study-Part 2 (Radiation Oncology).

Background: The Head and Neck Cancer Working Group of Swiss Group for Clinical Cancer Research (SAKK) has investigated the level of consensus (LOC) and discrepancy in everyday practice of diagnosis and treatment in head and neck cancer. Materials and Methods: An online survey was iteratively generated with 10 Swiss university and teaching hospitals. LOC below 50% was defined as no agreement, while higher LOC were arbitrarily categorized as low (51-74%), moderate (75-84%), and high (≥85%). Results: Any LOC was achieved in 62% of topics (n = 60). High, moderate, and low LOC were found in 18, 20, and 23%, respectively. Regarding Head and Neck Surgery, Radiation Oncology, Medical Oncology, and biomarkers, LOC was achieved in 50, 57, 83, and 43%, respectively. Conclusions: Consensus on clinical topics is rather low for surgeons and radiation oncologists. The questions discussed might highlight discrepancies, stimulate standardization of practice, and prioritize topics for future clinical research.

A Review of Controversial Issues in the Management of Head and Neck Cancer: A Swiss Multidisciplinary and Multi-Institutional Patterns of Care Study-Part 3 (Medical Oncology).

Background: The Head and Neck Cancer Working Group of Swiss Group for Clinical Cancer Research (SAKK) has investigated the level of consensus (LOC) and discrepancy in everyday practice of diagnosis and treatment in head and neck cancer. Materials and Methods: An online survey was iteratively generated with 10 Swiss university and teaching hospitals. LOC below 50% was defined as no agreement, while higher LOC were arbitrarily categorized as low (51-74%), moderate (75-84%), and high (≥85%). Results: Any LOC was achieved in 62% of topics (n = 60). High, moderate, and low LOC were found in 18, 20, and 23%, respectively. Regarding Head and Neck Surgery, Radiation Oncology, Medical Oncology, and biomarkers, LOC was achieved in 50, 57, 83, and 43%, respectively. Conclusions: Consensus on clinical topics is rather low for surgeons and radiation oncologists. The questions discussed might highlight discrepancies, stimulate standardization of practice, and prioritize topics for future clinical research.

A Review of Controversial Issues in the Management of Head and Neck Cancer: A Swiss Multidisciplinary and Multi-Institutional Patterns of Care Study-Part 4 (Biomarkers).

Background: The Head and Neck Cancer Working Group of Swiss Group for Clinical Cancer Research (SAKK) has investigated the level of consensus (LOC) and discrepancy in everyday practice of diagnosis and treatment in head and neck cancer. Materials and Methods: An online survey was iteratively generated with 10 Swiss university and teaching hospitals. LOC below 50% was defined as no agreement, while higher LOC were arbitrarily categorized as low (51-74%), moderate (75-84%), and high (≥85%). Results: Any LOC was achieved in 62% of topics (n = 60). High, moderate, and low LOC were found in 18, 20, and 23%, respectively. Regarding Head and Neck Surgery, Radiation Oncology, Medical Oncology, and biomarkers, LOC was achieved in 50, 57, 83, and 43%, respectively. Conclusions: Consensus on clinical topics is rather low for surgeons and radiation oncologists. The questions discussed might highlight discrepancies, stimulate standardization of practice, and prioritize topics for future clinical research.

The expression of PD-L1 in salivary gland carcinomas.

Objective was to analyze the role of PD-L1 and its relation to demographic, patho-clinical and outcome parameters in salivary gland carcinoma (SGC) patients. Patients treated for salivary gland carcinomas between 1994 and 2010 were included. A retrospective chart review for baseline characteristics, pathohistological, clinical and outcome data was performed. Immunohistochemistry for PD-L1 was performed using tissue microarrays. PD-L1 expression was assessed in tumor cells and tumor-infiltrating immune cells (TIIC) and statistical analysis with regard to baseline and outcome data was performed. Expression of PD-L1 (by means ≥1% of the cells with PD-L1 positivity) was present in the salivary gland carcinoma cells of 17%, in the TIIC of 20% and in both tumor cells and TIIC of 10% the patients. PD-L1 expression in tumor cells and both tumor cells and TIIC was related to tumor grading (p = 0.035 and p = 0.031, respectively). A trend towards higher grading was also seen for PD-L1 expression in TIICs (p = 0.058). Patients with salivary duct carcinomas and PD-L1 expressing TIICs showed a significantly worse DFS and OS (p = 0.022 and p = 0.003, respectively), those with both tumor cells and TIIC expressing PD-L1 a significantly worse DFS (p = 0.030). PD-L1 expression is present in 17% and 20% of salivary gland carcinoma cells and TIIC. Ten percent of the patient showed a PD-L1 positivity in both tumor cells and TIIC. This is related to high tumor grading and therefore might be a negative prognostic factor.

Predictive Value of Pretherapeutic Maximum Standardized Uptake Value (Suvmax) In Laryngeal and Hypopharyngeal Cancer.

The aim of the study was to evaluate whether pretherapeutic metabolic tumor parameters from 18-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging could predict larynx preservation in laryngeal and hypopharyngeal cancer patients prior to primary chemoradiation. Tumor metabolic parameters [maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG)] were retrospectively assessed in a consecutive cohort of laryngeal and hypopharyngeal cancer patients undergoing primary (chemo-)radiation. Main outcome measures were larynx preservation and survival. The study included 97 patients with a median follow-up of 32 months (IQR 20-54.5). For hypopharyngeal cancer, multivariable analysis showed that patients with a primary tumor's SUVmax > 9.5 entailed a higher risk of undergoing salvage pharyngolaryngectomy after chemoradiation (HR = 8.64, 95% CI = 1.1-67.3, P = 0.040). In laryngeal cancer, SUVmax did not predict the need for salvage laryngectomy. The only predictor for larynx preservation in laryngeal cancer patients was T-classification at initial diagnosis (HR = 6.67, 95% CI = 0.82-53.9, P = 0.039). In conclusion, SUVmax of primary tumor could be used as a predictor of larynx preservation prior to primary chemoradiation in hypopharyngeal cancer patients. This information may be important for patient counseling, as high SUVmax was correlated with reduced probability of larynx preservation. However, in laryngeal cancer patients, SUVmax does not seem to be predictive of outcome.

First Clinicopathologic Evidence of a Non-PSMA-Related Uptake Mechanism for 68Ga-PSMA-11 in Salivary Glands.

The intense accumulation of prostate-specific membrane antigen (PSMA) radioligands in salivary glands is still not well understood. It is of concern for therapeutic applications of PSMA radioligands, because therapeutic radiation will damage these glands. A better understanding of the uptake mechanism is, therefore, crucial to find solutions to reduce toxicity. The aim of this study was to investigate whether the accumulation of PSMA-targeting radioligands in submandibular glands (SMGs) can be explained with PSMA expression levels using autoradiography (ARG) and immunohistochemistry (IHC). Methods: All patients gave written informed consent for further utility of the biologic material. The SMG of 9 patients, pancreatic tissue of 4 patients, and prostate cancer (PCA) lesions of 9 patients were analyzed. Tissue specimens were analyzed by means of PSMA-IHC (using an anti-PSMA-antibody and an immunoreactivity score system [IRS]) and ARG using 177Lu-PSMA-617 (with quantification of the relative signal intensity compared with a PSMA-positive standard). The SUVmax in salivary glands, pancreas, and PCA tissues were quantified in 60 clinical 68Ga-PSMA-11 PET scans for recurrent disease as well as the 9 primary tumors selected for ARG and IHC. Results: PCA tissue samples revealed a wide range of PSMA staining intensity on IHC (IRS = 70-300) as well as in ARG (1.3%-22% of standard). This variability on PCA tissue could also be observed in 68Ga-PSMA-11 PET (SUVmax, 4.4-16) with a significant correlation between ARG and SUVmax (P < 0.001, R2 = 0.897). On IHC, ARG, and 68Ga-PSMA-11 PET, the pancreatic tissue was negative (IRS = 0, ARG = 0.1% ± 0.05%, SUVmax of 3.1 ± 1.1). The SMG tissue displayed only focal expression of PSMA limited to the intercalated ducts on IHC (IRS = 10-15) and a minimal signal on ARG (1.3% ± 0.9%). In contrast, all SMG showed a high 68Ga-PSMA-11 accumulation on PET scans (SUVmax 23.5 ± 5.2). Conclusion: Our results indicate that the high accumulation of PSMA radioligands in salivary glands does not correspond to high PSMA expression levels determined using ARG and IHC. These findings provide evidence, that the significant accumulation of PSMA radioligands in SMG is not primarily a result of PSMA-mediated uptake.

Recurrent unilateral peripheral facial palsy in a patient with an enlarged styloid process.

BACKGROUND: Recurrent peripheral facial paresis is a rare symptom that may be caused by multiple pathologic conditions. METHODS: We report a case of recurrent peripheral facial palsies caused by an ipsilateral enlarged styloid process. A surgical excision of the process was performed. RESULTS: The treatment was well tolerated. Postoperatively, no further recurrent paresis was observed. CONCLUSION: To the best of our knowledge, this is the first case study of an enlarged styloid process with facial paresis. A detailed workup, including imaging, should be performed in cases with recurrent facial paresis and/or cases with a history of trauma and facial paresis and, of course, to exclude a neoplastic etiology.

Use of MRI and FDG-PET/CT to predict fixation of advanced hypopharyngeal squamous cell carcinoma to prevertebral space.

BACKGROUND: We evaluated the ability of different (18F)fluoro-deoxy-d-glucose (FDG)-positron emission tomography (PET)-based and magnetic resonance (MR)-based parameters to identify prevertebral space (PVS) infiltration by hypopharyngeal carcinoma. METHODS: Retrospective study on 59 patients with advanced hypopharyngeal squamous cell carcinoma undergoing cross-sectional imaging and triple endoscopy for staging. RESULTS: Obliteration of retropharyngeal fat plane on T1-weighted MR images was found more often (P < .001) in tumors fixated to the PVS. Complete fat plane obliteration best predicted tumor fixation to PVS (accuracy 99%; CI: 97%-100%; P < .001). With similar accuracy, PET-based models predicted PVS fixation (combination of standardized uptake value [SUVmax ] of the primary tumor and presence of focal FDG-uptake in prevertebral muscles [accuracy 98%; CI 94%-100%; P < .001]; metabolic tumor volume [MTV] [accuracy 98%; CI 95%-100%; P < .001]). CONCLUSION: Both the MR-based parameter of complete fat plane obliteration and PET-based models (increased SUVmax in combination with presence of focal FDG-uptake of prevertebral muscles; increased MTV) predict PVS involvement independently with high accuracy.

Preoperative assessment of CD44-mediated depth of invasion as predictor of occult metastases in early oral squamous cell carcinoma.

BACKGROUND: Epithelial-mesenchymal transition and cancer stem-like cells (CSC) have been linked to increased metastatic potential. We evaluated the prognostic impact of CD44, a CSC biomarker, on depth of invasion (DOI) and outcome in oral squamous cell carcinoma (OSCC). METHODS: Using a multivariable logistic regression model, we evaluated in early OSCCs the relationship between CD44 expression at the invasive tumor front, DOI, sentinel lymph node biopsy, extension of nodal involvement, and survival. We also assessed whether CT and/or MRI could predict DOI preoperatively. RESULTS: CD44 expression was associated with increased DOI (P = .018), worse disease-specific survival (P = .041) but not with positive sentinel lymph node biopsy (P > .05). Each millimeter increase in DOI was associated with a 31.1% higher risk for positive sentinel lymph node biopsy (95% CI: 5.8%-62.4%, P = .013) and with higher metastatic ratio (P = .015). Preoperative estimation of DOI by CT and/or MRI and histopathological DOI showed a strong correlation (P < .0001). CONCLUSIONS: CD44 expression correlates with DOI, which predicts occult lymph node metastasis. Preoperative CT and/or MRI provides an accurate estimation of histopathological DOI. Both pieces of information gained preoperatively can help surgeons tailor their operation in regard to the surgical management of the neck.

Comparison of contemporary staging systems for oropharynx cancer in a surgically treated multi-institutional cohort.

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.

Maximum Standardized Uptake Value (SUVmax) of Primary Tumor Predicts Occult Neck Metastasis in Oral Cancer.

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

The expression of the cancer testis antigen MAGE A4: A favorable prognostic biomarker in salivary gland carcinomas related to low tumor grading.

BACKGROUND: Aim was to analyze the expression of different cancer testis antigens (CTA) and to assess its prognostic value in salivary gland carcinomas. METHODS: Patients with salivary gland carcinomas diagnosed 1994 to 2010 were included. Baseline characteristics, pathohistological, clinical, and outcome data were assessed. Tissue microarrays were constructed and immunohistochemistry for different CTA (NY-ESO1, NY-BR1, MAGE A1, MAGE A3, MAGE A4, MAGE C1/CT7, and MAGE C2/CT10) was performed. CTA expression was assessed and statistically correlated with pathological and outcome data. RESULTS: Expression rates of CTA in salivary gland tumors ranged from 0% to 40%. MAGE A4 expression was associated with a lower tumor grade tumor grading (P = .017), and a favorable recurrence-free (P = .003), disease-specific (P = .046) and overall survival (P = .028). CONCLUSIONS: MAGE A4 is a highly significant prognostic marker in salivary gland carcinoma; its expression is associated with low-grade histology, a low rate of distant metastasis and a favorable survival. LEVEL OF EVIDENCE: 4.

[18F]Fluorocholine Uptake of Parathyroid Adenoma Is Correlated with Parathyroid Hormone Level.

PURPOSE: The aim of the study was to investigate the relationship between [18F]fluoromethyl-dimethyl-2-hydroxyethylammonium ([18F]FCh) positron emission tomography (PET) parameters, laboratory parameters, and postoperative histopathological results in patients with primary hyperparathyroidism (pHPT) due to parathyroid adenomas. PROCEDURES: This retrospective study was conducted in 52 patients with biochemically proven pHPT. [18F]FCh-PET parameters (maximum standardized uptake value: SUVmax) in early phase (after 2 min) and late phase (after 50 min), metabolic volume, and adenoma-to-background ratio (ABR), preoperative laboratory results (PTH and serum calcium concentration), and postoperative histopathology (location, size, volume, and weight of adenoma) were assessed. Relationship of PET parameters, laboratory parameters, and histopathological parameters was assessed using the Mann-Whitney U test and Spearman correlation coefficient. MRI characteristics of parathyroid adenomas were also analyzed. RESULTS: The majority of patients underwent a PET/MR scan, 42 patients (80.7 %); 10 patients (19.3 %) underwent PET/CT. We found a strong positive correlation between late-phase SUVmax and preoperative PTH level (r = 0.768, p < 0.001) and between late-phase ABR and preoperative PTH level (r = 0.680, p < 0.001). The surgical specimen volume was positively correlated with the PET/MR lesion volume (r = 0.659, p < 0.001). No significant association was observed between other [18F]FCh-PET parameters, laboratory parameters, and histopathological findings. Cystic adenomas were larger than non-cystic adenomas (p = 0.048). CONCLUSIONS: [18F]FCh uptake of parathyroid adenomas is strongly correlated with preoperative PTH serum concentration. Therefore, the preoperative PTH level might potentially be able to predict success of [18F]FCh-PET imaging in hyperparathyroidism, with higher lesion-to-background ratios being expected in patients with high PTH. PET/MR is accurate in estimating the volume of parathyroid adenomas.

Reducing morbidity and complications after major head and neck cancer surgery: the (future) role of enhanced recovery after surgery protocols.

PURPOSE OF REVIEW: To review the development and the benefits of enhanced recovery after surgery (ERAS) protocols in non-head and neck disciplines and to describe early implementation efforts in major head and neck surgeries. RECENT FINDINGS: Several groups have adopted ERAS protocols for major head and neck surgery and demonstrated its feasibility and effectiveness. SUMMARY: There is growing evidence that clinical and financial outcomes for patients undergoing major head and neck surgery rehabilitation can be significantly improved by standardizing preoperative, intraoperative, and postoperative treatment protocols. Current experience is limited to single centers. A future goal is to broaden the adoption of ERAS in head and neck surgical oncology to include national and international collaboration, data sharing, and learning.