Need for adjuvant radiotherapy in oral cancer: depth of invasion rather than tumor diameter

PURPOSE The 8th edition of the TNM Cancer Staging Manual incorporates depth of invasion (DOI) into the pathologic tumor classification for oral squamous cell carcinoma (OSSC). While deep invading tumors with small tumor diameters (TD) have been categorized as early stage tumors in the 7th edition, they are now upstaged, potentially influencing the decision to initiate adjuvant radiotherapy (RT). METHODS OSCC patients surgically treated with curative intent between 2010 and 2019 were consecutively included. Tumors were staged based on TD only (according to the 7th edition TNM Cancer Staging Manual), then restaged based solely on DOI. RESULTS Of the 133 included patients, 58 patients (43.6%) had a different pT-stage when using DOI instead of TD for staging (upstaging in 23.3%). Overall survival (OS) was significantly worse in patients who were upstaged with DOI. In addition, stratification by adjuvant RT showed significant worse OS in upstaged patients without receiving adjuvant RT. CONCLUSIONS DOI seems to be an import indicator for adjuvant RT in OSCC-patients

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

Background p16(INK4a) (p16) immunohistochemistry is the most widely used biomarker assay for inferring HPV causation in oropharyngeal cancer in clinical and trial settings. However, discordance exists between p16 and HPV DNA or RNA status in some patients with oropharyngeal cancer. We aimed to clearly quantify the extent of discordance, and its prognostic implications. Methods In this multicentre, multinational individual patient data analysis, we did a literature search in PubMed and Cochrane database for systematic reviews and original studies published in English between Jan 1, 1970, and Sept 30, 2022. We included retrospective series and prospective cohorts of consecutively recruited patients previously analysed in individual studies with minimum cohort size of 100 patients with primary squamous cell carcinoma of the oropharynx. Patient inclusion criteria were diagnosis with a primary squamous cell carcinoma of oropharyngeal cancer; data on p16 immunohistochemistry and on HPV testing; information on age, sex, tobacco, and alcohol use; staging by TNM 7th edition; information on treatments received; and data on clinical outcomes and follow-up (date of last follow-up if alive, date of recurrence or metastasis, and date and cause of death). There were no limits on age or performance status. The primary outcomes were the proportion of patients of the overall cohort who showed the different p16 and HPV result combinations, as well as 5-year overall survival and 5-year disease-free survival. Patients with recurrent or metastatic disease or who were treated palliatively were excluded from overall survival and disease-free survival analyses. Multivariable analysis models were used to calculate adjusted hazard ratios (aHR) for different p16 and HPV testing methods for overall survival, adjusted for prespecified confounding factors. Findings Our search returned 13 eligible studies that provided individual data for 13 cohorts of patients with oropharyngeal cancer from the UK, Canada, Denmark, Sweden, France, Germany, the Netherlands, Switzerland, and Spain. 7895 patients with oropharyngeal cancer were assessed for eligibility. 241 were excluded before analysis, and 7654 were eligible for p16 and HPV analysis. 5714 (74middot7%) of 7654 patients were male and 1940 (25middot3%) were female. Ethnicity data were not reported. 3805 patients were p16-positive, 415 (10middot9%) of whom were HPV-negative. This proportion differed significantly by geographical region and was highest in the areas with lowest HPV-attributable fractions (r=-0middot744, p=0middot0035). The proportion of patients with p16+/HPV- oropharyngeal cancer was highest in subsites outside the tonsil and base of tongue (29middot7% vs 9middot0%, p<0middot0001). 5-year overall survival was 81middot1% (95% CI 79middot5-82middot7) for p16+/HPV+, 40middot4% (38middot6-42middot4) for p16-/HPV-, 53middot2% (46middot6-60middot8) for p16-/HPV+, and 54middot7% (49middot2-60middot9) for p16+/HPV-. 5-year disease-free survival was 84middot3% (95% CI 82middot9-85middot7) for p16+/HPV+, 60middot8% (58middot8-62middot9) for p16-/HPV-; 71middot1% (64middot7-78middot2) for p16-/HPV+, and 67middot9% (62middot5-73middot7) for p16+/HPV-. Results were similar across all European sub-regions, but there were insufficient numbers of discordant patients from North America to draw conclusions in this cohort. Interpretation Patients with discordant oropharyngeal cancer (p16-/HPV+ or p16+/HPV-) had a significantly worse prognosis than patients with p16+/HPV+ oropharyngeal cancer, and a significantly better prognosis than patients with p16-/HPV- oropharyngeal cancer. Along with routine p16 immunohistochemistry, HPV testing should be mandated for clinical trials for all patients (or at least following a positive p16 test), and is recommended where HPV status might influence patient care, especially in areas with low HPV-attributable fractions. Copyright (c) 2023 The Author(s). Published by Elsevier Ltd

HPV-assoziierte Oropharynxkarzinome: Update zu Diagnose und Management

In den vergangenen Jahren konnte auch in der Schweiz eine Zunahme von Plattenepithelkarzinomen im Oropharynx festgestellt werden. Schon seit mehr als zwanzig Jahren wird ein Zusammenhang zwischen einer Infektion mit Hochrisikotypen des humanen Papillomvirus (HR-HPV) und der Entstehung von Oropharynxkarzinomen (OPSCC) vermutet. Vor allem bei jüngeren Patienten ohne die Risikofaktoren Rauchen und Alkoholkonsum wird eine erhöhte Prävalenz dieser Tumoren festgestellt. HPV-assoziierte Karzinome entstehen hauptsächlich im lymphatischen Gewebe des Oropharynx und stellen klinisch und molekularbiologisch eine eigenständige Entität dar. Sie zeigen ein signifikant besseres Therapieansprechen und haben eine bessere Prognose im Vergleich zu den noxenassoziierten Tumoren, unabhängig von der durchgeführten Therapie. Vermutet wird eine vergleichbare Tumorentstehung wie beim Zervixkarzinom über Vorstufenläsionen bis zum invasiven Karzinom. Bisher wurden aber im Pharynx keine HPV-assoziierten Vorstufen gefunden. Das in der Zervix etablierte weltweite Screeningprogramm hat zu einer signifikanten Reduktion der Inzidenz von Zervixkarzinomen geführt, sodass der Anteil HPV-assoziierter Tumoren im Oropharynx die Zahl derer in der Zervix überschreiten wird. Seit 2017 ist eine immunhistochemisch nachweisbare Überexpression des Zellzyklusproteins p16 als Surrogatmarker für HPV ein entscheidender Faktor bei der Tumor-Klassifikation des Oropharynxkarzinoms. Eine klare, international gültige Definition eines HPV-assoziierten Tumors fehlt aber bisher. Die alleinige Detektion von HPV-DNA oder der isolierte Einsatz der p16-Immunhistochemie im Tumorgewebe weisen eine ungenügende Sensitivität und Spezifität auf. Die Kombination dieser Parameter erhöht die Zuverlässigkeit im Vergleich zum Goldstandard RNA. Eine für die Diagnostik valide Alternative ist der serologische Nachweis von Antikörpern gegen HPV-Onkoproteine, der sich auch als prädiktiver und prognostischer Marker zu bewähren scheint. = In the past decades, an increasing incidence of oropharyngeal squamous cell cancer could be observed. More than twenty years ago, a correlation between a pharyngeal Human papillomavirus high-risk type infection and the development of oropharyngeal cancer has been suspected. Especially younger patients without the former risk factors smoking and alcohol have a higher prevalence for this cancer type. HPV-associated cancer is developing in the lymphatic tissue of the tonsils and the base of the tongue. HPV-driven tumors can be defined as a clinical and morphologic distinct tumor entity with a significantly better prognosis compared to tumors based on smoking and alcohol consumption. They are demonstrating a clearly better treatment response irrespective of the treatment modality. The tumor development is assumed to be comparable to cervical cancer, probably through a step-wise process from dysplasia to invasive cancer. In the pharynx, no HPV-associated precursor lesions have been detected so far. Therefore, Screening program proven to be very successful in the cervix have not could not have been implemented so far. The reduction of HPV-associated tumor burden in the cervix is likely to be compensated by the rising number of HPV-driven oropharyngeal cancer. P16 as a surrogate marker for HPV has been implemented in the 8th edition of the TNM classification for oropharyngeal cancer. A worldwide accepted definition of an HPV-driven tumor is lacking so far. P16 immunhistochemistry or HPV-DNA detection by PCR as single markers have an insufficient sensitivity and specificity. A combination of both markers demonstrates a higher accuracy compared to the gold standard RNA. Antibodies to HPV oncoproteins are reliable diagnostic and prognostic markers that could in the future possibly serve for early tumor detection. = Durant les dernières décennies, on observe une augmentation des cas de cancer de l’oropharynx. Ceci est probablement dû à une infection à des virus de type papillomavirus humain (HPV) dits à haut-risque. Ce type de cancer touche spécialement des patients jeunes et sans exposition aux facteurs de risque classiques que sont la cigarette et l’abus d’alcool. Ces cancers se développent depuis les tissus lymphatiques des amygdales et de la base de la langue situés dans l’oropharynx. Ces tumeurs dues à l’HPV représentent d’une part une entité à l’étiopathogénie et d’autre part une présentation clinique distincte. Ces tumeurs ont souvent un pronostic sensiblement meilleur que les cancers induits par l’exposition à la cigarette et l’alcool, et ce quel que soit le type de traitement choisi (chirurgie ou radiothérapie). Une infection au virus HPV conduit probablement à des changements dans l’épithélium, en passant progressivement de la dysplasie au carcinome invasif, comme cela se produit dans les cancers du col de l’utérus. Toutefois, la détection de lésions précoces n’est pas encore possible dans l’oropharynx, rendant pour l’instant impossible l’implémentation d’un programme de screening, comme c’est le cas pour le col de l’utérus. Dans le futur, il est probable que la réduction des cas de cancer du col utérin grâce au screening soit malheureusement dépassée par l’augmentation des cas de cancer de l’oropharynx. En clinique, on utilise le marqueur «p16» pour identifier les cas du cancer de l’oropharynx dû au virus HPV. Bien que celui-ci soit maintenant intégré à la récente 8ème édition du système international de classification des tumeurs TNM, il manque encore une définition acceptée de tous pour déterminer la causalité de HPV pour un cas spécifique de cancer de l’oropharynx. La recherche par PCR de l’ADN de HPV ou l’immunohistochimie pour p16 est en effet inexactes. La combinaison de ces deux procédés montre une meilleure performance diagnostique comparée au standard de référence qu’est la recherche d’ARN. Dans le futur, la recherche d’anticorps associés à HPV dans le sang pourrait permettre une détection précoce des cas de récidives et une surveillance plus aisée

Histopathological Features of Parathyroid Adenoma and 18F-Choline Uptake in PET/MR of Primary Hyperparathyroidism

BACKGROUND The aim of this study was to assess the relationship between the histopathological properties of hyperfunctioning parathyroids and parathyroid 18F-choline uptake. PATIENTS AND METHODS A total of 31 parathyroid adenomas were retrospectively analyzed in patients with primary hyperparathyroidism and preoperative 18F-choline PET/MR. PET/MR parameters of parathyroid glands (SUVmax and target-to-background ratio in early-phase [EP] and late-phase [LP]), MRI volume, preoperative parathyroid hormone (PTH) serum concentration, and postoperative histopathology (predominant cell type and growth pattern of adenoma cells, location and size of adenoma) were assessed. The relationship of PET/MR parameters, PTH, and histological parameters was determined using linear regression, Spearman correlation and Kruskal-Wallis test. RESULTS The median volume of parathyroid adenoma was 421.78 ± 142.46 mm3 (46.39-4412.69). Adenomas were predominantly composed of chief, water-clear, and oncocytic/oxyphilic cells in 27/31, 2/31, and 2/31 cases, respectively. The growth pattern was predominantly solid, follicular, and trabecular in 18/31, 8/31, and 5/31, respectively. The SUVmax was 6.71 ± 3.39 in EP and 6.91 ± 3.97 in LP. Follicular growth pattern had slightly higher EP SUVmax (trabecular: 4.12 ± 0.56; solid: 6.62 ± 3.19; follicular: 8.56 ± 3.96; P = 0.046). Spearman correlation showed strong positive correlation between volume and both EP and LP SUVmax (0.626; P = 0.0001 and 0.576; P = 0.0001, respectively). Linear regression analysis revealed significant correlation between PTH level and EP and LP SUVmax (both P = 0.001); in contrast, no correlation was found between PTH level and both cell type and growth pattern. CONCLUSIONS Our findings suggest that 18F-choline uptake of parathyroid adenomas might be associated both with the histological growth pattern and adenoma volume, but not with a specific cell type

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

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

Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures

Aggressive pheochromocytomas and paragangliomas (PPGLs) are difficult to treat, and molecular targeting is being increasingly considered, but with variable results. This study investigates established and novel molecular-targeted drugs and chemotherapeutic agents for the treatment of PPGLs in human primary cultures and murine cell line spheroids. In PPGLs from 33 patients, including 7 metastatic PPGLs, we identified germline or somatic driver-mutations in 79% of cases, allowing us to assess potential differences in drug responsivity between pseudohypoxia-associated cluster 1- (n=10) and kinase signaling-associated cluster 2-related (n=14) PPGL primary cultures. Single anti-cancer drugs were either more effective in cluster 1 (cabozantinib, selpercatinib, 5-FU) or similarly effective in both clusters (everolimus, sunitinib, alpelisib, trametinib, niraparib, entinostat, gemcitabine, AR-A014418, high-dose zoledronic acid). High-dose estrogen and low-dose zoledronic acid were the only single substances more effective in cluster 2. Neither cluster 1- nor cluster 2-related patient primary cultures responded to HIF-2α inhibitors, temozolomide, dabrafenib, or octreotide. We showed particular efficacy of targeted combination treatments (cabozantinib/everolimus, alpelisib/everolimus, alpelisib/trametinib) in both clusters, with higher efficacy of some targeted combinations in cluster 2 and overall synergistic effects (cabozantinib/everolimus, alpelisib/trametinib) or synergistic effects in cluster 2 (alpelisib/everolimus). Cabozantinib/everolimus combination therapy, gemcitabine, and high-dose zoledronic acid appear to be promising treatment options with particularly high efficacy in SDHB-mutant and metastatic tumors. In conclusion, only minor differences regarding drug responsivity were found between cluster 1 and cluster 2: some single anti-cancer drugs were more effective in cluster 1 and some targeted combination treatments were more effective in cluster 2

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

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