Oral Oncology 2021-04-11

The importance of understanding the terminology on oral lichenoid lesions for future research: in reply

Miguel Ángel González-Moles, Pablo Ramos-García, Saman Warnakulasuriya

Publication date 11-04-2021


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Integrative sequencing discovers an ATF1-motif enriched molecular signature that differentiates hyalinizing clear cell carcinoma from mucoepidemoid carcinoma

M.E. Heft Neal, E. Gensterblum-Miller, A.D. Bhangale, A. Kulkarni, J. Zhai, J. Smith, C. Brummel, S.K. Foltin, D. Thomas, H. Jiang, J.B. McHugh, J.C. Brenner

Publication date 08-04-2021


Salivary gland tumors are comprised of a diverse group of malignancies with widely varying prognoses. These cancers can be difficult to differentiate, especially in cases with limited potential for immunohistochemistry (IHC)-based characterization. Here, we sought to define the molecular profile of a rare salivary gland cancer called hyalinizing clear cell carcinoma (HCCC), and identify a molecular gene signature capable of distinguishing between HCCC and the histopathologically similar disease, mucoepidermoid carcinoma (MEC). We performed the first integrated full characterization of five independent HCCC cases. We discovered insulin-like growth factor alterations and aberrant IGF2 and/or IGF1R expression in HCCC tumors, suggesting a potential dependence on this pathway. Further, we identified a 354 gene signature that differentiated HCCC from MEC, and was significantly enriched for genes with an ATF1 binding motif in their promoters, supporting a transcriptional pathogenic mechanism of the characteristic EWSR1-ATF1 fusion found in these tumors. Of the differentially expressed genes, IGF1R, SGK1 and SGK3 were found to be elevated in the HCCCs relative to MECs. Finally, analysis of immune checkpoints and subsequent IHC demonstrated that CXCR4 protein was elevated in several of the HCCC cases. Collectively, our data identify an ATF1-motif enriched gene signature that may have clinical utility for molecular differentiation of HCCCs from other salivary gland tumors and discover potential actionable alterations that may benefit the clinical care of recurrent HCCC patients.

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Endoscopic-assisted multi-portal compartmental resection of the masticatory space in oral cancer: Anatomical study and preliminary clinical experience

Alberto Schreiber, Davide Mattavelli, Remo Accorona, Vittorio Rampinelli, Marco Ferrari, Alberto Grammatica, Giovanni Leo Tomacelli, Vincenzo Verzeletti, Enrico Fazio, Monir Abousiam, Aurel Nebiaj, Alberto Deganello, Piero Nicolai, Barbara Buffoli, Rita Rezzani, Cesare Piazza, Luca Calabrese

Publication date 08-04-2021


To present an anatomical cadaver dissection study and our preliminary surgical experience with endoscopic-assisted multi-portal compartmental resection of the masticatory space (MS) in locally advanced oral squamous cell carcinoma (OSCC) of the retromolar area. Two fresh-frozen cadaver heads were dissected in the Laboratory of Anatomy to define the surgical steps of an endoscopic-assisted multi-portal compartmental approach to the MS. After this preclinical anatomical study, patients affected by locally advanced OSCC originating from the retromolar area with extension to the MS were prospectively enrolled and operated at two Italian referral centers for head and neck cancer between October 2019 and May 2020. Surgical technique of endoscopic-assisted multi-portal compartmental resection of the MS was preclinically defined step by step in 3 phases: transnasal, transoral/trancervical, and multi-portal. Compartmental resection of the MS was successfully completed in all specimens (4 MSs dissected). The surgical technique was subsequently applied in 3 patients affected by primary OSCC of the retromolar area, providing satisfactory results in terms of negative resection margins and local control. Multi-portal compartmental resection of the MS combining the transnasal and transoral/transcervical corridors is technically feasible. Such an approach to the MS in locally advanced OSCC provides different angles of incidence to the target and full control of tumor margins.

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Exosomes-carrying Epstein-Barr virus-encoded small RNA-1 induces indoleamine 2, 3-dioxygenase expression in tumor-infiltrating macrophages of oral squamous-cell carcinomas and suppresses T-cell activity by activating RIG-I/IL-6/TNF-α pathway

Ati Burassakarn, Sawarot Srisathaporn, Chamsai Pientong, Weerayut Wongjampa, Patravoot Vatanasapt, Natcha Patarapadungkit, Tipaya Ekalaksananan

Publication date 06-04-2021


Although exosomes carrying Epstein-Barr virus-encoded small RNA-1 (EBER-1) are involved in the immunosuppressive tumor microenvironments of EBV-associated head and neck carcinomas, the effects of EBER-1-associated exosomes on tumor-infiltrating macrophages are poorly understood. The association between EBV infection and expression of indoleamine 2,3-dioxygenase (IDO) was assessed in 165 paraffin-embedded oral squamous cell carcinoma (OSCC) tissue samples. Using in vitro techniques, we investigated whether stimulation of the RIG-I/IL-6/TNF-α pathway by exosomes carrying EBER-1 is critical for IDO induction in macrophages. We performed a thymidine incorporation and a cell cytolytic assay to test for up-regulated IDO in macrophages that can block the proliferation and function of effector T cells. Some infiltrated macrophages expressed levels of IDO higher than OSCC cells which was significantly associated with presence of EBV. The production of IDO, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in human monocyte-derived macrophages (MDMs) was induced by EBV-associated exosomes in vitro. Mechanistically, the retinoic acid-inducible gene I (RIG-I) pathway in MDMs was stimulated by EBV-encoded small RNA-1 (EBER-1) whereas the inhibition of these pathways by BX-795 almost abolished the production of these two cytokines and IDO induction. Also, the EBER-1-activated IDO in MDMs suppressed the proliferation of T lymphocytes and diminished the cytolytic activity of CD8 Exosomes carrying EBER-1 could induce IDO expression in MDMs, considerably aided by an IL-6 and TNF-α-dependent mechanism via the RIG-I signaling pathway, which might create an immunosuppressive microenvironment affecting T-cell immune responses.

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Diagnostic efficacy of PET-CT, CT, and MRI in preoperative assessment of mandibular invasion caused by head and neck cancer: A systematic review and meta-analysis

Chang Cao, Xinyan Gan, Yan He, Yonglin Su, Zheran Liu, Xiaolin Hu, Xingchen Peng

Publication date 24-03-2021


This study aims to conduct a systematic review and meta-analysis of the performance of PET-CT, CT, and MRI in diagnosing mandible invasion induced by head and neck cancer (HNC). The MEDLINE, Embase, Science Direct, CNKI and CQVIP databases were searched from inception until August 1, 2020. Then, a meta-analysis was conducted to calculate the combined diagnostic values with the corresponding 95% CIs. Two independent researchers completed the full text screening, data abstraction, and risk assessment. This meta-analysis included 53 studies (N = 2 946 participants). For the pooled sensitivity (SEN), MRI (SEN: 0.88, 95% CI: 0.81-0.93) was found to have a significantly higher SEN (P = 0.0045), when compared to CT (SEN: 0.77, 95% CI: 0.71-0.82), while compared with PET-CT (SEN: 0.88, 95% CI: 0.64-0.97), the SEN was approximately equal (P > 0.05). The analysis revealed that the combined specificity (SPE) of MRI (SPE: 0.83, 95% CI: 0.74-0.89) and PET-CT (SPE: 0.81, 95% CI: 0.57-0.93) was lower than that of CT (SPE: 0.87, 95% CI: 0.83-0.90), but there was no statistical significance among these (P > 0.05). The comparison of the area under curve (AUC) reflected that PET-CT, CT and MRI have approximately equal summary diagnostic power in detecting mandibular invasion (P > 0.05). The findings suggest that compared with CT, MRI is significantly superior for higher SEN in diagnosing mandibular invasion. The SEN of MRI and PET-CT were approximately equal. For the summary of diagnostic power, more prospective clinical trials that directly compare these three methods are needed in the future.

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All HPV-negative head and neck cancers are not the same: Analysis of the TCGA dataset reveals that anatomical sites have distinct mutation, transcriptome, hypoxia, and tumor microenvironment profiles

Hugh Andrew Jinwook Kim, Peter Y.F. Zeng, Mushfiq Hassan Shaikh, Neil Mundi, Farhad Ghasemi, Eric Di Gravio, Halema Khan, Danielle MacNeil, Mohammed Imran Khan, Krupal Patel, Adrian Mendez, John Yoo, Kevin Fung, Pencilla Lang, David A. Palma, Joe S. Mymryk, John W. Barrett, Paul C. Boutros, Anthony C. Nichols

Publication date 17-03-2021


Head and neck squamous cell carcinoma (HNSCC) affects various anatomical sites, which often dictates whether the cancer is managed with primary surgery or radiation. This study aimed to assess differences in single nucleotide variation (SNV), copy number, mRNA abundance, methylation, and tumor microenvironment (TME) between HPV-negative oral cavity (OC), oropharyngeal (OPC), hypopharyngeal (HPC), and laryngeal (LC) cancers within The Cancer Genome Atlas (TCGA). We downloaded the clinical information and molecular data for the TCGA HNSCC cohort from the data portal and published literature. The TME was estimated using mRNA abundance data. We conducted our analyses within the Bioconductor statistical framework in the R environment. CNA and mRNA abundance results were correlated and grouped with SNV results for downstream pathway analysis. LC had a higher mutational burden than OC and OPC (p <10 We identified significant genomic, transcriptional, and microenvironmental differences between HPV-negative HNSCC. Further study is warranted to determine if these findings portend differential response to specific treatment modalities.

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MICA A5.1 homozygous genotype is associated with a risk for early-onset oral cancer

Ryouji Tani, Nanako Ito, Kensaku Matsui, Sachiko Yamasaki, Atsuko Hamada, Koichiro Tokumaru, Shigeaki Toratani, Tetsuji Okamoto

Publication date 18-03-2021


Genetic predisposition is reportedly involved in early-onset oral cancer, although the genetic basis of this cancer remains unclear. The major histocompatibility complex class I-related chain A (MICA) plays a crucial role in eliminating malignant tumors by activating NKG2D, the natural killer (NK) receptor. MICA polymorphism might affect its binding to NKG2D. We aimed to find whether MICA gene microsatellite polymorphism is involved in the risk of oral squamous cell carcinoma (OSCC) development in a Japanese population. We recruited 386 patients with OSCC and 103 healthy controls. Genomic DNA was analyzed by PCR for microsatellite repeat polymorphism in the transmembrane region of the MICA gene. The groups were compared for the prevalence of various alleles and their association with disease prognosis and survival. We found that adolescents and young adults (AYA) with OSCC were more likely to have the MICA A5.1 homozygous genotype than healthy controls (P = 0.0001), but their survival rate was higher than with other MICA genotypes (P = 0.0185). These results suggest that cancer's immune escape is facilitated by MICA's failure to activate the NK cells. MICA A5.1 homozygosity plays a role in individual susceptibility to OSCC, increasing the risk of early-onset oral cancer. However, such patients have a better prognosis than those with other MICA genotypes.

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Impact of the weekday of the first intensity-modulated radiotherapy treatment on the survival outcomes of patients with nasopharyngeal carcinoma: A multicenter cohort study

Yunyan Mo, Bin Zhang, Yufei Pan, Qinghua Qin, Yaomin Ye, Xi Li, Liying Huang, Wei Jiang

Publication date 12-03-2021


This study's purpose was to assess whether the weekday on which intensity-modulated radiotherapy (IMRT) is initiated influences survival outcomes in patients with nasopharyngeal carcinoma (NPC). A total of 1440 patients with NPC who received IMRT were enrolled in this study between January 2010 and June 2016. The patients were divided into five groups according to the weekday of their first radiotherapy treatment. Group 1 (n = 322), Group 2 (n = 322), Group 3 (n = 286), Group 4 (n = 292) and Group 5 (n = 218) received first radiotherapy on Monday, Tuesday, Wednesday, Thursday and Friday respectively. Differences in the rates of overall survival (OS), disease-free survival (DFS), loco-regional relapse-free survival (LRRFS) and distant metastasis-free survival (DMFS) were compared among the five groups using the Kaplan-Meier method and Cox regression models. No significant differences were found in OS, DFS, LRRFS or DMFS among the five groups. The Cox regression analysis showed that the weekday on which the radiotherapy was initiated was not an independent predictor of OS (Hazard Ratio [HR], 1.056; 95%CI: 0.959-1.164, P = 0.268), DFS (HR, 1.067; 95% CI: 0.980-1.161, P = 0.137), LRRFS (HR, 1.069; 95% CI: 0.914-1.249, P = 0.404) and DMFS (HR, 1.027; 95% CI: 0.929-1.134, P = 0.607). The subgroup analysis showed no significant differences among the five groups. This study showed that the day of the week that patients with nasopharyngeal carcinoma begin radiotherapy has no effect on their survival outcomes.

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Feasibility study of ultrasound-guided resection of tongue cancer with immediate specimen examination to improve margin control – Comparison with conventional treatment

Klijs J. de Koning, Sjors A. Koppes, Remco de Bree, Jan Willem Dankbaar, Stefan M. Willems, Robert J.J. van Es, Rob Noorlag

Publication date 29-03-2021


Squamous cell carcinoma of the tongue (SCCT) is preferably treated by surgery. Free resection margins (≥5 mm) provide local control and disease-free survival. However, close (1-5 mm) and positive margins (<1 mm) are frequently encountered. We present our first experience of in-vivo ultrasound (US) guided SCCT resections followed by ex-vivo US control on the resection specimen to obtain free margins. We compare the results with those from a hisorical cohort of 91 conventionally treated SCCT patients. Ten patients with SCCT were included in a consecutive US-cohort. We aimed for a 5-10 mm margin during surgery, while we visualized the resection plane on US. Ex-vivo US measurements on the resection specimen determined whether there was any need for an immediate re-resection. US measurements were then compared with histopathology. Histopathological margins were compared with a consecutive cohort of 91 patients who had undergone conventional surgery for a SCCT. In the US cohort, 70% of the margins were free. In the conventional cohort, this figure was 17% (P = 0.005). US predicted minimal histopathological margin distance with a mean ± SD error of 1.9 ± 1.8 mm. The mean ± SD of the histopathological overall submucosal/deep margin distance was 7.9 ± 2.1 mm in the US cohort and 7.0 ± 2.2 mm in the conventional cohort (P = 0.188). Ex-vivo examination through use of US indicated an immediate re-resection, which prevented local adjuvant treatment. Use of US-guided SCCT resection is feasible and improves margin control.

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Differentially methylated genes in proliferative verrucous leukoplakia reveal potential malignant biomarkers for oral squamous cell carcinoma

Alejandro Herreros-Pomares, Carlos Llorens, Beatriz Soriano, Leticia Bagan, Andrea Moreno, Silvia Calabuig-Fariñas, Eloísa Jantus-Lewintre, José Bagan

Publication date 04-03-2021


To explore the pathophysiology of proliferative verrucous leucoplakia (PVL) through a methylated DNA immunoprecipitation and high-throughput sequencing (MeDIP-seq) case-control study. Oral biopsies from ten PVL patients and five healthy individuals were obtained and used to compare their epigenetic patterns. Network biology methods and integrative analyses of MeDIP-seq and RNAseq data were applied to investigate functional relations among differentially methylated genes (DMGs). The value of selected genes as malignant biomarkers was evaluated in a large cohort of oral squamous cell carcinoma (OSCC) patients from TCGA. A total of 4647 differentially methylated regions were found, with a prominent state of hypermethylation in PVL patients. At the gene level, differentially methylated regions (DMRs) covered 826 genes with distinct roles, including transcription factors and binding proteins with functions in cell adhesion, migration, proliferation, regulation of transcription, bone morphogenesis, and cell signalling. Network analysis revealed three major hubs, two of them collecting proteins related to the response of the patients to PVL and treatment and one hub collecting proteins related to PVL and cancer. The integrative analysis revealed 8 genes (ARTN, CD8A, GATA3, HOXD10, MYO7A, OSR2, PLCB1, and SPOCK2) significantly upregulated in PVL compared to control and 5 genes (ANKRD6, DLG2, GPX3, PITX2, and ZNF736) significantly downregulated. The status of de-regulation found for PVL patients was concordant with what was found for OSCC samples compared to normal adjacent tissue. Our findings show the potential of methylation markers in PVL and suggest novel OSCC diagnostic biomarkers which may boost the development of novel epigenetic-based therapies.

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Radiotherapy versus partial laryngectomy in the management of early glottic cancer with anterior commissure involvement: A propensity score matched study with 256 patients

Ruichen Li, Qi Wang, Li Yan, Yi Zhu, Shengzi Wang, Shu Tian

Publication date 02-03-2021


The study was intended to compare the outcomes for T1-T2N0M0 glottic squamous cell carcinoma with anterior commissure involvement who had undergone partial laryngectomy (PL) or radiotherapy (RT). We retrospectively analyzed 256 patients who were treated by RT (n = 70) or PL (n = 186). Patients received prophylactic irradiation of the neck in RT group whereas PL was not associated with lymphadenectomy. Propensity score matching (PSM) was used to eliminate the baseline variations. The average age of the RT group (67 years) was significantly higher than that of the PL (59 years). Local recurrence was noted in 14 patients of the RT group and 22 of the PL. While regional recurrence was noted in only 1 patient of the RT group and 23 of the PL. After PSM, the 5-year overall survival (82.8% vs. 83.9%, p = 0.302), 5-year cancer-specific survival (88.3% vs. 89.7%, p = 0.793), 5-year local relapse-free survival (79.3% vs. 84.5%, p = 0.127) were not significantly different between two groups. However, 5-year regional relapse-free survival in the RT group was significantly better than that in the PL (100% vs. 87.1%, p = 0.014). In the PL group, infection, granuloma, laryngeal stenosis, chylous leakage, and pharyngeal fistula were reported in six, 11, 12, one, and two patients, respectively. RT resulted in comparable rates of survival, local control, and larynx preservation compared to PL. However, RT was associated with higher regional control rate. The complication rates were extremely low in RT group.

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Pre-treatment PET/MRI based FDG and DWI imaging parameters for predicting HPV status and tumor response to chemoradiotherapy in primary oropharyngeal squamous cell carcinoma (OPSCC)

Omar Freihat, Zoltán Tóth, Tamás Pintér, András Kedves, Dávid Sipos, Zsolt Cselik, Norbert Lippai, Imre Repa, Árpád Kovács

Publication date 01-03-2021


To determine the feasibility of pre-treatment primary tumor FDG-PET and DWI-MR imaging parameters in predicting HPV status and the second aim was to assess the feasibility of those imaging parameters to predict response to therapy. We retrospectively analyzed primary tumors in 33 patients with proven OPSCC. PET/MRI was performed before and 6 months after chemo-radiotherapy for assessing treatment response. PET Standardized uptake value (SUVmax), total lesion glycolysis (TLG), metabolic tumor volume (MTV), and apparent diffusion coefficient (ADC) from pre-treatment measurements were assessed and compared to the clinicopathological characteristics (T stages, N stages, tumor grades, HPV and post-treatment follow up). HPV was correlated to the clinicopathological characteristics. ADCmean was significantly lower in patients with HPV

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Risk groups of laryngeal cancer treated with chemoradiation according to nomogram scores – A pooled analysis of RTOG 0129 and 0522

Musaddiq J. Awan, Haley Gittleman, Jill Barnholtz-Sloan, Mitchell Machtay, Phuc Felix Nguyen-Tan, David I. Rosenthal, Christopher Schultz, Bradley J. Huth, Wade L Thorstad, Steven J. Frank, Harold Kim, Robert L. Foote, Miriam N. Lango, George Shenouda, Mohan Suntharalingam, Jonathan Harris, Qiang Zhang, Quynh-Thu Le, Min Yao, on behalf of the NRG Oncology Group

Publication date 01-03-2021


To develop nomograms predicting overall survival (OS), freedom from locoregional recurrence (FFLR), and freedom from distant metastasis (FFDM) for patients receiving chemoradiation for laryngeal squamous cell carcinoma (LSCC). Clinical and treatment data for patients with LSCC enrolled on NRG Oncology/RTOG 0129 and 0522 were extracted from the RTOG database. The dataset was partitioned into 70% training and 30% independent validation datasets. Significant predictors of OS, FFLR, and FFDM were obtained using univariate analysis on the training dataset. Nomograms were built using multivariate analysis with four a priori variables (age, gender, T-stage, and N-stage) and significant predictors from the univariate analyses. These nomograms were internally and externally validated using c-statistics (c) on the training and validation datasets, respectively. The OS nomogram included age, gender, T stage, N stage, and number of cisplatin cycles. The FFLR nomogram included age, gender, T-stage, N-stage, and time-equivalent biologically effective dose. The FFDM nomogram included age, gender, N-stage, and number of cisplatin cycles. Internal validation of the OS nomogram, FFLR nomogram, and FFDM nomogram yielded c = 0.66, c = 0.66 and c = 0.73, respectively. External validation of these nomograms yielded c = 0.59, c = 0.70, and c = 0.73, respectively. Using nomogram score cutoffs, three risk groups were separated for each outcome. We have developed and validated easy-to-use nomograms for LSCC outcomes using prospective cooperative group trial data.

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Fever range whole body hyperthermia for re-irradiation of head and neck squamous cell carcinomas: Final results of a prospective study

Sebastian Zschaeck, Julian Weingärtner, Pirus Ghadjar, Peter Wust, Felix Mehrhof, Goda Kalinauskaite, Vincent H. Ehrhardt, Vivian Hartmann, Ingeborg Tinhofer, Max Heiland, Annekatrin Coordes, Grzegorz Kofla, Volker Budach, Carmen Stromberger, Marcus Beck

Publication date 25-02-2021


Fever-range whole body hyperthermia (FRWBH) has been shown to improve tumor oxygenation in vivo. A prospective pilot study addressed the question if addition of FRWBH to re-irradiation is feasible in recurrent head and neck squamous cell carcinomas (HNSCC) with unfavorable prognostic features. The study completed accrual with the recruitment of ten patients between April 2018 and March 2020. Re-irradiation was administered using volumetric arc hyperfractionated radiotherapy with bi-daily 1.2 Gray (Gy) single fractions and a total dose of 66 Gy to all macroscopic tumor lesions. Concomitant chemotherapy consisted mostly of cisplatin (7 patients). FRWBH was scheduled weekly during re-irradiation. The study was registered in the clinicaltrials.gov database (NCT03547388). Only five patients received all cycles of FRWBH. Poor patient compliance, active infections during treatment and study restrictions due to the Covid-19 pandemic were the main reasons for omitting FRWBH. No increase of acute toxicity was observed by FRWBH. Exploratory evaluation of outcome data suggests that FRWBH treatment according to protocol does not seem to have a detrimental effect on tumor control or survival and might even increase treatment efficacy. FRWBH is difficult to apply concomitant to re-irradiation in HNSCC. No excess toxicity was observed in patients receiving FRWBH and exploratory analyses suggest potential anti-tumor activity and decreased patient-reported depression scores after FRWBH.

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Effect of age and gender in non-smokers with oral squamous cell carcinoma: Multi-institutional study

Lawrence J. Oh, Rebecca Asher, Michael Veness, Robert Smee, David Goldstein, N. Gopalakrishna Iyer, Deepak Balasubramanian, Tsu-Hui (Hubert) Low, Carsten E. Palme, Ruta Gupta, Jonathan Clark

Publication date 23-02-2021


In developing countries, oral squamous cell carcinoma (OSCC) is predominantly a cancer affecting older males who smoke tobacco. In countries with effective public health strategies, smoking rates are declining rapidly. It is not clear if patients who develop OSCC without these traditional risk factors represent a clinically distinct cohort with different prognosis. A recent analysis found that elderly non-smoking females with OSCC had significantly worse prognosis, concluding that this was a distinct patient population with poorer survival. The primary aim of this study was to determine the effect of gender and age on prognosis in OSCC, and the interaction between these two variables. Multinational multi-institutional data were collected from six sites. The primary outcome of interest was disease specific survival (DSS). Time to local, regional, and distant recurrence were investigated as secondary outcomes. 3379 patients with OSCC were included. Males had significantly worse DSS compared to females (HR 1.24, 95% CI 1.08-1.43, p = 0.003). Females <70 years of age had significantly better DSS compared to females ≥70 years of age (HR 0.69, 95% CI 0.51-0.94, p < 0.001) but elderly females had similar DSS to males, regardless of age. When age was divided into three groups, the middle-aged group (45-69 years) had a significantly better DSS compared to elderly patients (HR 0.87, 95%CI 0.78-0.96, p < 0.001), however younger patients had similar DSS to elderly patients. When the effect of age (young v middle v elderly) was compared in each gender, young and middle-aged females had the most favourable DSS (log-rank p < 0.001). Middle-aged females who smoked had a 10% survival advantage compared to middle-aged males that smoked at five years. Age, gender, tumour subsite, and smoking status are important drivers of survival in OSCC. However, gender appears to be the most important predictor with young and middle-aged females having the most favourable prognosis.

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Relationship of depth of invasion to survival outcomes and patterns of recurrence for T3 oral tongue squamous cell carcinoma

M. Newman, P.T. Dziegielewski, N.T.A. Nguyen, H.S. Seikaly, M. Xie, D.A. OConnell, J.R. Harris, V.L. Biron, M.K. Gupta, S.D. Archibald, B.S. Jackson, J.E.M. Young, K.J. Keyes, D.S. Nichols, H. Zhang

Publication date 23-02-2021


Current research is elucidating how the addition of depth of invasion (DOI) to the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging for oral cavity squamous cell carcinoma influences its prognostic accuracy. However, there is limited research on survival in pT3N0M0 oral tongue SCC (OTSCC) patients when stratifying by DOI. Determine 5-year overall survival (OS), and cancer-specific survival (CSS) for patients with pT3N0M0 oral OTSCC based on shallow DOI (<10 mm) and deep DOI (10-20 mm). Retrospective review involving three tertiary care cancer centers in North America. cT3N0M0 OTSCC patients receiving primary surgical treatment from 2004 to 2018 were identified.
Inclusion: age > 18 years old and confirmation of pT3N0M0 OTSCC on surgical pathology.
Exclusion: patients undergoing palliative treatment or previous head and neck surgery/radiotherapy.
Analysis comprised two groups: shallow pT3 (tumor diameter > 4 cm, DOI < 10 mm) and deep pT3 (DOI 10 mm-20 mm). One hundred and four patients with pT3N0M0 OTSCC were included. Mean age was 59.1 years (range: 18-80.74). Age, gender, and Charlson Comorbidity Index were similar between the two groups (p > 0.05). Recurrence, LVI, PNI, and positive margins were more common in deep T3 tumors (P < 0.05). 5-year OS (50% vs 26%, p = 0.006) and CSS (72% vs 24%, p = 0.005) were worse in deep pT3 tumors. Deep pT3 disease was an independent predictor of OS (p = 0.004) and CSS (p = 0.01) on Cox-Regression analysis. DOI is an independent predictor of poor survival in pT3N0M0 OTSCC patients. Consideration should be given to escalating adjuvant therapy for deep pT3N0M0 OTSCC patients.

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Detection of deletions in 1q25, 1p36 and 1pTEL and chromosome 17 aneuploidy in oral epithelial dysplasia and oral squamous cell carcinoma by fluorescence in situ hybridization (FISH)

Silvia Helena Barem Rabenhorst, Rafael Lima Verde Osterne, Cassiano Francisco Weege Nonaka, Andre Montezuma Sales Rodrigues, Renato Luiz Maia Nogueira, Rommel Mário Rodriguez Burbano, Roberta Barroso Cavalcante

Publication date 21-02-2021


To identify chromosome deletions in 1q25, 1p36 and 1pTEL, and chromosome 17 ploidy status in oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC). Samples from 57 OED and 63 OSCC were selected. FISH was performed using centromeric probes 17 and n LSIR 1p36/LSI 1q25 Dual Color Probe. In OED, deletions were found only in 1pTEL region (29.8%). In OSCC, there was a higher frequency of deletion in 1pTEL (79.4%), followed by 1p36 (73.0%), and 1q25 (20.6%). Advanced TNM clinical stages (III/IV) showed all the deletions studied; at early clinical stages (I/II) of OSCC, deletions were observed only in 1pTEL. The frequency of deletion in 1p36 was 17.0 times higher in OSCC at advanced clinical stages (PR: 17.00). The median number of cell nuclei with chromosome 17 aneuploidy was higher in OSCC than in OED (P < 0.001). Early clinical stages of OSCC showed lower median number nuclei with aneuploidy when compared to advanced tumors (P < 0.05). Tumors harboring deletions in 1p36, 1q25 and 1pTEL revealed higher median numbers of trisomic/polysomic nuclei when compared to lesions exhibiting no abnormalities in chromosome 1 (P < 0.05). A higher prevalence of chromosomal abnormalities was found in OSCC than in OED, while in OSCC, higher abnormalities were present in lesions with higher TNM staging. 1pTEL deletion and monosomy of chromosome 17 are possible markers for progression of OED to OSCC. 1p36 deletion and trisomy/polysomy of chromosome 17 could be markers of worse prognosis of OSCC.

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Stereotactic body radiotherapy (SBRT) for primary non-metastatic head and neck cancer: When less is enough

Monali Swain, Sarbani Ghosh-Laskar

Publication date 27-03-2021


The advantage of highly conformal dose distribution and steep dose gradient has resulted in rapidly increasing use of stereotactic body radiotherapy (SBRT) in multiple cancer sites. Also there has been a surge in the use of SBRT in head neck cancer over the last decade. It is predominantly exploited in retreatment setting for recurrent and second primary head neck cancer as well as in metastatic setting. The literature on SBRT in primary non-metastatic head neck cancer is sparse and evolving. In the current review, available literature was critically analyzed focusing on the potential applications of SBRT in primary untreated non-metastatic head neck cancer. SBRT boost following external beam radiotherapy is temping as a method of dose escalation. Special attention was paid to the application of SBRT as a sole modality of treatment. The shorter treatment schedule makes it an attractive option for treatment in primary head neck cancer especially in elderly, co-morbid and medically unfits patients. Future investigation is needed to establish SBRT as an additional armamentarium in the radiotherapeutic management of head and neck cancers.

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The contribution of artificial intelligence to reducing the diagnostic delay in oral cancer

Betul Ilhan, Pelin Guneri, Petra Wilder-Smith

Publication date 13-03-2021


Oral cancer (OC) is the sixth most commonly reported malignant disease globally, with high rates of disease-related morbidity and mortality due to advanced loco-regional stage at diagnosis. Early detection and prompt treatment offer the best outcomes to patients, yet the majority of OC lesions are detected at late stages with 45% survival rate for 2 years. The primary cause of poor OC outcomes is unavailable or ineffective screening and surveillance at the local point-of-care level, leading to delays in specialist referral and subsequent treatment. Lack of adequate awareness of OC among the public and professionals, and barriers to accessing health care services in a timely manner also contribute to delayed diagnosis. As image analysis and diagnostic technologies are evolving, various artificial intelligence (AI) approaches, specific algorithms and predictive models are beginning to have a considerable impact in improving diagnostic accuracy for OC. AI based technologies combined with intraoral photographic images or optical imaging methods are under investigation for automated detection and classification of OC. These new methods and technologies have great potential to improve outcomes, especially in low-resource settings. Such approaches can be used to predict oral cancer risk as an adjunct to population screening by providing real-time risk assessment. The objective of this study is to (1) provide an overview of components of delayed OC diagnosis and (2) evaluate novel AI based approaches with respect to their utility and implications for improving oral cancer detection.

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Oral potential malignant disorders – A long list not to be forgotten

Pirabu Sakthivel, Sarath Raveendran, Smriti Panda, Chirom Amit Singh

Publication date 05-03-2021


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The tipping point in oral cavity reconstruction: A multi-institutional survey of choice between flap and non-flap reconstruction

Kenneth E. Akakpo, Mark A. Varvares, Jeremy D. Richmon, Caitlin McMullen, Andrew J. Holcomb, Rod Rezaee, Akina Tamaki, Joseph Curry, Matthew O. Old, Stephen Y. Kang, Evan M. Graboyes, Jennifer Gross, Patrik Pipkorn, Sidharth V. Puram, Joseph Zenga

Publication date 04-04-2021


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Primary intraosseous malignant peripheral nerve sheath tumor of the mandible: An unusual presentation mimicking a benign lesion

John Lennon Silva Cunha, Saygo Tomo, Ederson Kerlakian de Paiva Gomes Fernandes, Margarite Maria Delmondes Freitas, Oslei Paes de Almeida, Bruno Augusto Benevenuto de Andrade, Ciro Dantas Soares, Ricardo Luiz Cavalcanti de Albuquerque-Júnior

Publication date 04-04-2021


The malignant peripheral nerve sheath tumor (MPNST) is a rare, aggressive malignant tumor that usually develops in the context of neurofibromatosis type 1. In the oral cavity, these tumors are excelling rare, especially in intraosseous sites. Herein, we report an unusual presentation of intraosseous MPNST affecting the mandible posterior region in a 28-year-old male without neurofibromatosis type 1 discovered as an incidental find on imaging exam. CT scan evaluation showed a solitary, well-defined, round hypodense lesion in the posterior mandibular region extending from tooth 45 to 46. Microscopic evaluation showed a tumor composed of atypical spindle-shaped cells arranged in fascicles and a storiform pattern. Tumor cells were positive for S-100 protein. Epithelial membrane antigen (EMA), pan-cytokeratin AE1/AE3, desmin, alpha-smooth muscle actin (α-SMA), HMB-45, MART-1, MUC4, and CD56 were negative. The diagnosis was low-grade MPNST. The patient underwent wide surgical resection of the tumor. After three years of follow-up, the patient remained with no evidence of recurrence or metastatic disease. When an intraosseous neurogenic tumor is suspected based on radiological characteristics, despite the apparent benign nature, an incisional biopsy is mandatory to rule out malignancy before treatment planning to avoid inadequate conservative treatment.

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Secretory carcinoma ex pleomorphic adenoma of the submandibular gland: An immunohistochemical study

Reydson Alcides de Lima-Souza, João Figueira Scarini, Erika Said Abu Egal, Lívia Crescencio Ramalho, Jezreel Corrêa da Costa, Mário Fernandez Sobral Silva, Alfio José Tincani, Rogério Oliveira Gondak, Albina Altemani, Fernanda Viviane Mariano

Publication date 29-03-2021


Male patient 60-year-old was referred from another service for expert review of a lesion in the submental region. Pathological review revealed morphological features compatible with salivary gland Secretory carcinoma (SC) in cervical lymph node. The patient underwent removal of the left submandibular gland, left neck dissection and biopsy of left labial commissure region. Anatomopathological examination was observed tumor cells arranged in a solid and ductal/cystic pattern, with abundant droplets of secreted eosinophilic material within these structures and extensive hyalinized area, which presented few cells arranged in a ductal pattern. It was possible to observe the presence of extracapsular extension of neoplastic cells > 6 mm, base on this aspects, Carcinoma ex pleomorphic adenoma was suspected. Immunohistochemical panel showed positivity for mammaglobin, s100, CK7, and adipophilin and negativity for myoepithelial markers and PAS in SC cells. The myoepithelial markers showed positivity for residual cellsin hyalinized area, corresponding to residual Pleomorphic adenoma (PA). In view of these findings, the diagnosis of Secretory carcinoma ex pleomorphic adenoma (SCXPA) was established.

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Hypofractionated chemoradiation (2.75\xa0Gy per fraction) in Head and Neck Cancer: Extreme caution required

Muhammad Shahid Iqbal, David Morgan, Nick West, Claire Paterson

Publication date 26-03-2021


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Misinterpretation of head and neck masses can delay the correct diagnosis. A two-step demolitive-reconstruction surgery for saving patient’s life

Massimo Maranzano, Luca DAscanio, Giampietro Ricci, Hadeel Omer, Arianna Di Stadio

Publication date 22-03-2021


To present a rare case of sebaceous cyst masking skin squamous carcinoma. The delayed diagnosis made necessary a two-step (demolition and reconstruction) surgery to save patient's life. A 77-year-old male, suffering from persistent right hemicrania and eye pain referred to different specialists, who misinterpreted his symptoms. The man presented on the right zygomatic area a big sebaceous cyst which masked a squamous cells carcinoma (SCC) infiltrating the surrounding structures including the orbito zygomatic complex and the orbital content that was the cause of the symptoms. Patient underwent biopsy, CT thorax and MRI of the head and neck as pre-operative examinations. A two-step surgery was performed to remove the tumor. The skin biopsy showed the presence of sun damaged skin contains moderately differentiated invasive SCC within the context of sebaceous cyst. While the CT chest was negative, the head and neck MRI showed a huge tumor invading the orbit and periorbital tissue, the zygomatic bone and the soft tissues up to the posterior orbital area, without presence of neck lymph nodes. Le lesion has been classified as cT4 N0 M0 (TNM 8) and a two-step surgery approach (demolition and reconstruction) was performed with successful results at 1 year-follow up. The delayed diagnosis of SCC was due to the misdiagnosis of the signs of the tumor invasion. Demolitive and reconstructive surgeries allowed to preserve patient's life. The careful attention to patient's skin characteristic, the analysis of general and local clinical signs (irradiated pain, cyst and skin type) and the evaluation of the complex differential diagnosis could be the key to avoid delayed treatment in head and neck cancer.

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Covid-19 pandemic and head and neck cancers, what should we expect?

Resi Pucci, Andrea Cassoni, Andrea Battisti, Valentino Valentini

Publication date 30-03-2021


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A recurrent leiomyosarcoma of the buccal mucosa: An immunohistochemistry study and literature review

Ivan José Correia Neto, John Lennon Silva Cunha, Carlos Eduardo de Oliveira, Oslei Paes de Almeida, Gilberth Tadeu dos Santos Aciole, Margarite Maria Delmondes Freitas, Ricardo Luiz Cavalcanti de Albuquerque-Júnior

Publication date 17-03-2021


Leiomyosarcoma is a rare type of cancer that affects smooth muscle tissue. Leiomyosarcomas are exceedingly rare in the oral cavity, particularly in the buccal mucosa. The diagnosis is challenging due to non-specific clinical features and significant overlap of morphological findings with several spindle cell tumors. We reported the clinicopathological and immunohistochemical features of a rare recurrent case of leiomyosarcoma in a 73-year-old female presenting clinically as a painful nodule on the posterior right buccal mucosa. Microscopically, the lesion showed atypical spindle cells arranged in a fascicular pattern and frequent mitotic figures. Immunohistochemistry showed strong positivity for vimentin, α-SMA, HHF35, h-caldesmon, and focal positivity for desmin. CD34 highlighted numerous blood vessels distributed throughout all tumor stroma. S-100 protein, myogenin, and pan-cytokeratin (AE1/AE3) were negative. Surgical excision followed by chemotherapy was carried out, and no recurrence was observed after 1 year of follow-up. Careful histopathological and immunohistochemistry analysis of these lesions is essential to ensure a correct diagnosis. Early surgical excision with tumor-free margins and prolonged follow-up is strongly recommended.

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A call for the universal acceptance of the modified Milan system for reporting salivary gland cytopathology

Pirabu Sakthivel, Priyadarsani Subramanian, Shijitha Pulimala, Smriti Panda

Publication date 13-03-2021


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Temporal association between the introduction of public health programs and interest in oral cancers on the internet in the European Union

Romain Lan, Jean-Hugues Catherine, Cyrille Chossegros, Fabrice Campana, Jean-Noel Vergnes, Mehdi Had-Saïd

Publication date 10-03-2021


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Oral tumour causing airway obstruction with stridor: Situation guided team management

Neha Singh, Soumitra Das, Sejal Mehta

Publication date 09-03-2021


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Human papillomavirus-related head and neck adenosquamous carcinoma: A systematic review and individual patient data meta-analysis

Giacomo Fiacchini, Giacomo Benettini, Domenico Tricò, Liborio Torregrossa, Matteo Vianini, Miriana Picariello, Iacopo Dallan, Stefano Berrettini, Luca Bruschini

Publication date 10-03-2021


This work examined published papers of patients affected by human papillomavirus-related head and neck adenosquamous carcinoma. Demographic data, tumor site and sub-site, TNM stage, HPV status (positive VS negative) and the technique used for its identification, the treatments performed, follow-up time and patient's status at follow-up were assessed. Three papers including 26 patients resulted eligible for the study. The incidence of HPV-positive Adenosquamous Carcinomas located in the oropharynx was significantly higher than HPV-negative tumors (p = 0.01), especially if the origin of primary unknown tumors was considered within this anatomical site (p < 0.0001). HPV-positive Adenosquamous Carcinomas had a higher incidence of small primary tumor (Tx + T1) (p = 0.03) and bulky cervical lymph node metastasis (N2) at presentation (p = 0.02). HPV-positive and HPV-negative tumors had similar OS and DFS. Head & Neck HPV-positive Adenosquamous Carcinoma seems to act like HPV-positive conventional Squamous Cell Carcinoma, thus we suggest to determine the HPV status of Adenosquamous Carcinoma during the diagnostic phase.

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Regarding “Comparing unilateral vs. bilateral neck management in lateralized oropharyngeal cancer between surgical and radiation oncologists: An international practice pattern survey” – Intra- and inter-specialty variability and the underutilisation of unilateral radiotherapy as treatment de-intensification

Lachlan McDowell, June Corry

Publication date 06-03-2021


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Challenges in the early diagnosis of oral cancer in rural populations in Peru during the COVID-19 pandemic

Victor Chumpitaz-Cerrate, Lesly Chávez-Rimache, Arturo Rodriguez-Flores

Publication date 15-03-2021


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Should radiological staging of advanced buccal mucosa cancer preclude curative intent treatment? A prospective evaluation

Ashwini Munnangi, Abhimanyu Kadapathri, Vijay Pillai, Vivek Shetty, Vidyabhushan Rangappa, Narayana Subramaniam

Publication date 06-03-2021


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Erratum to “The surgical sequence of neck dissection and primary tumor excision could impact the locoregional recurrence rates in oral squamous cell carcinoma” Oral Oncol. 110 (2020) 104809

K Devaraja

Publication date 01-03-2021


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Frequent omission of radiation after flap reconstruction of head and neck cancer: Are we dooming patients to failure?

Lauren M. North, Erin Harvey, Brigitte Vanle, Aditya Shreenivas, Monica Shukla, Stuart Wong, Musaddiq Awan, Joseph Zenga

Publication date 23-02-2021


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An urgent need for early oral feeding following head and neck reconstruction with oral defects

Chirom Amit Singh, Pirabu Sakthivel, Vimmi Gautam, Suresh Mani, Rajeev Kumar

Publication date 23-02-2021


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Regarding to “Minimaly invasive benign parotid surgery in selected patients: An adaptation example to compensate for COVID19 backlog or new era?”

Dmitry Tretiakow, Tomasz Przewozny, Andrzej Skorek, Boguslaw Mikaszewski

Publication date 26-02-2021


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Quantitative in situ imaging and grading of oral precancer with attenuation corrected-optical coherence tomography

Biswajoy Ghosh, Avishek Bhandari, Mousumi Mandal, Ranjan Rashmi Paul, Mousumi Pal, Pabitra Mitra, Jyotirmoy Chatterjee

Publication date 21-02-2021


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Fat-free pleomorphic lipoma of the buccal mucosa: An immunohistochemical study and literature review

John Lennon Silva Cunha, Saygo Tomo, Carolina Peres Mota, Ivan José Correia Neto, Sílvia Ferreira de Sousa, Jorge Esquiche León, Ricardo Luiz Cavalcanti de Albuquerque-Júnior

Publication date 20-02-2021


Pleomorphic lipomas are extremely rare in the oral cavity. Due to the significant overlap of morphological findings with several benign and malignant soft tissue tumors, especially in the absence of adipocytes, the diagnosis is challenging. We reported the clinicopathological and immunohistochemical features of an uncommon case of a fat-free variant of pleomorphic lipoma in a 48-year-old female presenting clinically as a painless nodule on the buccal mucosa. Microscopically, the lesion showed atypical spindle cells, numerous floret-like giant multinucleated cells, and abundant ropey collagen fibers bundles. Immunohistochemistry showed strong positivity for vimentin and CD34. Mast cell tryptase highlighted numerous mast cells distributed throughout all tumor stroma. S-100 protein, pan-cytokeratin, desmin, α-SMA, EMA, CD68, STAT6, Bcl-2, MDM2, and CDK4 were negative. Conservative surgical excision was carried out, and no recurrence was observed after 13 months of follow-up. Careful histopathological and immunohistochemistry analysis of these lesions is recommended to ensure the correct diagnosis and provide adequate management through a conservative surgical approach. To the best of our knowledge, this is the second case of fat-free pleomorphic lipoma in the oral cavity.

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Novel use of fluorescent microscopy in determining basement membrane integrity in ambiguous cases

Sachin C. Sarode, Gargi S. Sarode, Nilesh Kumar Sharma, Shankargouda Patil

Publication date 20-02-2021


Indistinct basement membrane due to inflammation always poses a problem to the pathologists for commenting on micro-invasive squamous cell carcinoma. In such a situation, even a special stain would not be able to correctly demonstrate the basement membrane, which is necessary for estimating the depth of invasion. In this paper, we have proposed a novel fluorescent microscopy assisted visualization of basement membrane in such difficult situations. To further validate this approach, we then retrospectively investigated twenty such cases under a fluorescent microscope and could able to repeat the same result. As routine hematoxylin and eosin stained sections are required for evaluation, it is technically less demanding and less time-consuming.

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Prospective assessment of multiple HPV-positive oropharyngeal squamous cell carcinomas

Daniel L. Faden, Connor J. OBoyle, Derrick T. Lin, Daniel G. Deschler, Kevin S. Emerick, Mark A. Varvares, William C. Faquin, Peter M. Sadow, Jeremy D. Richmon

Publication date 20-02-2021


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Looking beyond the lens of dysplasia at surgical margins

Yash P. Merchant, Akshay Kudpaje, Vishal U.S. Rao

Publication date 18-02-2021


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All that glitters is not gold: Clinical implications from the genetic analysis of head and neck cancer recurrences

Oreste Gallo, Luca Giovanni Locatello

Publication date 15-02-2021


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Parosteal osteosarcoma of the mandible in a pediatric patient

Guna Shekhar Madiraju

Publication date 14-02-2021


Gnathic osteosarcoma is a rare malignant mesenchymal neoplasm showing evidence of osteoid matrix formation. Clinical behaviour and radiological appearances overlap with benign osseous lesions and are prone to misdiagnosis. Early diagnosis of osteosarcoma plays a crucial role in the treatment plan and prognosis. Herein a rare case of parosteal osteosarcoma of fibroblastic histologic subtype affecting the angle of the mandible in a 12-year-old female is presented.

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Is there a role for HRCT in head and neck surgical oncology work up during the COVID pandemic?

Bipin T. Varghese, G.M. Divya, Deepak Janardhan, Shaji Thomas

Publication date 13-02-2021


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Secretory carcinoma of salivary glands at the National Cancer Institute: A 20-year retrospective clinical, pathological, immunohistochemical and molecular study

Lísia Daltro Borges Alves, Andreia Cristina de Melo, Luiz Henrique de Lima Araujo, Leandro Souza Thiago, Isabella dos Santos Guimarães, Priscila Valverde Fernandes, Elizangela Marques Rodrigues, Fernando Luiz Dias, Héliton Spindola Antunes, Ana Lucia Amaral Eisenberg, Daniel Cohen Goldemberg

Publication date 13-02-2021


This study aim was to review cases of acinic cell carcinoma (the main differential diagnosis of secretory carcinoma) that were diagnosed and treated at the National Cancer Institute of Brazil (INCA) between 1996 and 2016. The primary objective was to identify underdiagnosed cases of secretory carcinoma via a clinical, immunopathological and molecular reassessment. This is a cross sectional study, with retrospective data collection from medical records and histological specimen review, with staining for periodic acid-Schiff (PAS) and PAS with diastase, immunohistochemistry for S-100, mammaglobin, and DOG-1, and droplet digital RT-PCR for ETV6-NTRK3. The Research Ethics Committee approved this study, and the patients allowed their participation through informed consent. Eighty-three cases of acinic cell carcinoma were diagnosed and treated in the specified period at INCA, of which, seven had their diagnosis changed to secretory carcinoma. The present study adds seven cases of secretory carcinoma to the literature, contributing to a better understanding of the epidemiological, histological, immunohistochemical and molecular characteristics of this recently described tumor. Also, the use of a comprehensive diagnostic approach, including immunohistochemical and molecular methods, along with classical morphological studies, allowed the reclassification of acinic cell carcinoma to secretory carcinoma.

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