[Malignant external auditory canal tumors : management of a rare tumor]. / Tumeurs malignes du conduit auditif externe : prise en charge d'une tumeur rare.

Malignant tumors of the external auditory canal are rare tumors and very often diagnosed at an advanced stage due to non-specific symptoms. The best treatment is the radical surgery, eventually followed by radiotherapy. A multidisciplinary team is essential to realize an optimal management. Prognosis remains unfavorable for advanced tumors.

Les tumeurs malignes du conduit auditif externe (CAE) sont rares et leur diagnostic est souvent retardé en raison de symptômes peu spécifiques. Le traitement de choix consiste en une chirurgie radicale, éventuellement suivie d'une radiothérapie. Une équipe multidisciplinaire est indispensable pour une prise en charge optimale. Le pronostic reste défavorable dans les tumeurs avancées.

The transcription factor FOXM1 regulates the balance between proliferation and aberrant differentiation in head and neck squamous cell carcinoma.

Sustained expression of FOXM1 is a hallmark of nearly all human cancers including squamous cell carcinomas of the head and neck (HNSCC). HNSCCs partially preserve the epithelial differentiation program, which recapitulates fetal and adult traits of the tissue of tumor origin but is deregulated by genetic alterations and tumor-supporting pathways. Using shRNA-mediated knockdown, we demonstrate a minimal impact of FOXM1 on proliferation and migration of HNSCC cell lines under standard cell culture conditions. However, FOXM1 knockdown in three-dimensional (3D) culture and xenograft tumor models resulted in reduced proliferation, decreased invasion, and a more differentiated-like phenotype, indicating a context-dependent modulation of FOXM1 activity in HNSCC cells. By ectopic overexpression of FOXM1 in HNSCC cell lines, we demonstrate a reduced expression of cutaneous-type keratin K1 and involucrin as a marker of squamous differentiation, supporting the role of FOXM1 in modulation of aberrant differentiation in HNSCC. Thus, our data provide a strong rationale for targeting FOXM1 in HNSCC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Mouse model of postsurgical primary tumor recurrence and regional lymph node metastasis progression in HPV-related head and neck cancer.

HPV-positive head and neck squamous cell carcinoma (HNSCC) is increasingly frequent. Management is particularly debated in the case of postsurgical high-risk features, that is, positive surgical margins and extracapsular spread (ECS). In this increasingly complex emerging framework of HNSCC treatment, representative preclinical models are needed to support future clinical trials and advances in personalized medicine. Here, we present an immunocompetent mouse model based on the implantation of mouse tonsil epithelial HPV16-E6/E7-expressing cancer cells into the submental region of the floor-of-the-mouth. Primary tumors were found to replicate the patterns of human HNSCC local invasion and lymphatic dissemination. To study disease progression after surgery, tumors were removed likely leaving behind residual disease. Surgical resection of tumors was followed by a high rate of local recurrences (>90%) within the first 2-3 weeks. While only 50% of mice had lymph node metastases (LNM) at time of primary tumor excision, all mice with recurrent tumors showed evidence of LNM. To study the consecutive steps of LNM progression and distant metastasis development, LNs from tumor-bearing mice were transplanted into naïve recipient mice. Using this approach, transplanted LNs were found to recapitulate all stages and relevant histological features of regional metastasis progression, including ECS and metastatic spread to the lungs. Altogether, we have developed an immunocompetent HPV-positive HNSCC mouse model of postsurgical local recurrence and regional and distant metastasis progression suitable for preclinical studies.

[Head and neck cancer : promising results of immunotherapy]. / Cancers de la sphère ORL : l'immunothérapie donne de la voix !

Immunotherapy, especially checkpoint inhibitors such as anti-PD1 and anti-PDL1 antibodies, has changed the standard of care and the prognosis of melanoma, but also more recently of lung cancer, renal cancer and Hodgkin lymphoma. Results of preliminary studies in head and neck squamous cell carcinoma (HNSCC) as well as in less frequent tumors of the region, such as nasopharyngeal carcinoma and high grade salivary gland carcinoma, are also promising. Indeed, in a recent phase 3 study, the PD1 inhibitor nivolumab has recently demonstrated a significant improvement in overall survival for platin-resistant recurrent and/or metastatic HNSCC.

L'immunothérapie, en particulier les inhibiteurs de points de contrôles immunitaires (checkpoints) tels que les anticorps anti-PD1 et anti-PDL1, a déjà modifié la prise en charge standard et le pronostic du mélanome, mais également du cancer pulmonaire, rénal et du lymphome de Hodgkin. Les résultats des études préliminaires sont aussi prometteurs dans le traitement des carcinomes épidermoïdes ORL, ainsi que pour des cancers plus rares de la sphère tête et cou, comme les carcinomes nasopharyngés et les carcinomes de haut grade des glandes salivaires. Le traitement anti-PD1 par nivolumab a récemment démontré un bénéfice de survie globale chez les patients présentant un carcinome épidermoïde ORL récidivant et/ou métastatique résistant aux platines dans une étude de phase 3.

Surgery Versus Radiotherapy for Early Oropharyngeal Tumors: a Never-Ending Debate.

Therapeutic options for early stage oropharyngeal squamous cell carcinoma (OPSCC) include both surgery and radiotherapy as single treatment modality. Retrospective data reporting on locoregional control and survival rates in early stage OPSCC have shown equivalent efficacy, although no prospective randomized trials are available to confirm these results. Given the assumed comparable oncologic results in both groups, complication rates and functional outcomes associated with each modality play a major role when making treatment decisions. Radiotherapy is used preferentially in many centers because few trials have reported higher complication rates in surgical patients. However, these adverse effects were mainly due to traditional invasive open surgical approaches used for access to the oropharynx. In order to decrease the morbidity of these techniques, transoral surgical (TOS) approaches have been developed progressively. They include transoral laser microsurgery (TLM), transoral robotic surgery (TORS), and conventional transoral techniques. Meta-analysis comparing these new approaches with radiotherapy showed equivalent efficacy in terms of oncologic results. Furthermore, studies reporting on functional outcomes in patients undergoing TOS for OPSCC did not show major long-term functional impairment following treatment. Given the abovementioned statements, it is our practice to treat early stage OPSCC as follows: whenever a single modality treatment seems feasible (T1-2 and N0-1), we advocate TOS resection of the primary tumor associated with selective neck dissection, as indicated. In our opinion, the advantage of this approach relies on the possibility to stratify the risk of disease progression based on the pathological features of the tumor. Depending on the results, adjuvant radiation treatment or chemoradiotherapy can be chosen for high-risk patients. For tumors without adverse features, no adjuvant treatment is given. This approach also allows prevention of potential radiation-induced late complications while keeping radiotherapy as an option for any second primary lesions whenever needed. Definitive radiotherapy is generally reserved for selected patients with specific anatomical location associated with poor functional outcome following surgery, such as tumor of the soft palate, or for patients with severe comorbidities that do not allow surgical treatment.

Rosai-Dorfman disease presenting as stridor and hoarseness in a young female patient.

Rosai-Dorfman disease is a non-Langherans cell histiocytosis typically revealed by lymphadenopathy. Extranodal involvement occurs in 43% and most commonly involves the head and neck, skin, and bones. Few reports have described laryngeal lesions. We report the case of a Rosai-Dorfman disease in a 27-year-old female, presenting as an obstructing transglottic mass. We provide the results of the MRI and PET-scanner examination. As the treatment relies on surgical excision and the diagnosis depends on pathological examination, we also detail the analysis results that followed the surgical resection. This report highlights the necessity to consider Rosai-Dorfman disease as a potential diagnosis in case of a laryngeal submucosal mass.

CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers.

Tumor microenvironments (TMEs) influence cancer progression but are complex and often differ between patients. Considering that microenvironment variations may reveal rules governing intratumoral cellular programs and disease outcome, we focused on tumor-to-tumor variation to examine 52 head and neck squamous cell carcinomas. We found that macrophage polarity-defined by CXCL9 and SPP1 (CS) expression but not by conventional M1 and M2 markers-had a noticeably strong prognostic association. CS macrophage polarity also identified a highly coordinated network of either pro- or antitumor variables, which involved each tumor-associated cell type and was spatially organized. We extended these findings to other cancer indications. Overall, these results suggest that, despite their complexity, TMEs coordinate coherent responses that control human cancers and for which CS macrophage polarity is a relevant yet simple variable.

Development and validation of a multivariable prediction model for the identification of occult lymph node metastasis in oral squamous cell carcinoma.

BACKGROUND: There have been few recent advances in the identification of occult lymph node metastases (OLNM) in oral squamous cell carcinoma (OSCC). This study aimed to develop, compare, and validate several machine learning models to predict OLNM in clinically N0 (cN0) OSCC. METHODS: The biomarkers CD31 and PROX1 were combined with relevant histological parameters and evaluated on a training cohort (n = 56) using four different state-of-the-art machine learning models. Next, the optimized models were tested on an external validation cohort (n = 112) of early-stage (T1-2 N0) OSCC. RESULTS: The random forest (RF) model gave the best overall performance (area under the curve = 0.89 [95% CI = 0.8, 0.98]) and accuracy (0.88 [95% CI = 0.8, 0.93]) while maintaining a negative predictive value >95%. CONCLUSIONS: We provide a new clinical decision algorithm incorporating risk stratification by an RF model that could significantly improve the management of patients with early-stage OSCC.

Prediction of Occult Lymph Node Metastasis in Head and Neck Cancer with CD31 Vessel Quantification.

OBJECTIVE: The management of occult lymph node metastasis (LNM) in head and neck squamous cell carcinoma has been a matter of controversy for decades. The vascular density within the tumor microenvironment, as an indicator of ongoing angiogenesis, could constitute an attractive predictor of LNM. The use of the panvascular endothelial antibody CD31 as a marker of occult LNM has never been reported. The aim of this study was to assess the predictive value of CD31 microvascular density for the detection of occult LNM in squamous cell carcinoma of the oral cavity and oropharynx. STUDY DESIGN: Case series with chart review. SETTING: Tertiary university hospital. SUBJECTS AND METHODS: Intra- and peritumoral microvascular density values were determined in 56 cases of squamous cell carcinoma of the oral cavity (n = 50) and oropharynx (n = 6) with clinically negative necks using the CD31 marker. Statistical associations of CD31 microvascular densities with clinicopathologic data were then established. RESULTS: Peritumoral CD31 microvascular density was significantly associated with occult LNM in multivariate analysis ( P < .01). Recursive partitioning analysis for this parameter found a cutoff of 19.33, which identified occult LNM with a sensitivity of 91%, a specificity of 65%, a positive predictive value of 40%, a negative predictive value of 97%, and an overall diagnostic accuracy of 71%. CONCLUSION: Peritumoral CD31 microvascular density in primary squamous cell carcinoma of the oral cavity and oropharynx allows accurate prediction of occult LNM.

[Diagnosis and management of sinusitis of odontogenic origin]. / Les sinusites d'origine dentaire: diagnostic et prise en charge.

Maxillary sinusitis are common infections. A dental origin is found in about 10% of the cases. The roots of the posterior maxillary teeth are adjacent to the sinus floor. Extensions of dental infections are therefore possible to the sinus. An odontogenic source should be considered in patients with a history of dental pain or recent oral surgery and those with extended unilateral sinusitis or unilateral sinusitis resistant to conventional treatment. Maxillary sinusitis of dental origin are polymicrobial infections. Conventional radiographs and CT-scans are required for the diagnosis and proper management. Dental treatments to remove the underlying cause combined with oral antibiotics to treat the infection are required. Endoscopic or open surgery may be necessary to complete the treatment and restore adequate sinusal function.

Cellular Barcoding Identifies Clonal Substitution as a Hallmark of Local Recurrence in a Surgical Model of Head and Neck Squamous Cell Carcinoma.

Local recurrence after surgery for head and neck squamous cell carcinoma (HNSCC) remains a common event associated with a dismal prognosis. Improving this outcome requires a better understanding of cancer cell populations that expand from postsurgical minimal residual disease (MRD). Therefore, we assessed clonal dynamics in a surgical model of barcoded HNSCC growing in the submental region of immunodeficient mice. Clonal substitution and massive reduction of clonal heterogeneity emerged as hallmarks of local recurrence, as the clones dominating in less heterogeneous recurrences were scarce in their matched primary tumors. These lineages were selected by their ability to persist after surgery and competitively expand from MRD. Clones enriched in recurrences exhibited both private and shared genetic features and likely originated from ancestors shared with clones dominating in primary tumors. They demonstrated high invasiveness and epithelial-to-mesenchymal transition, eventually providing an attractive target for obtaining better local control for these tumors.

Correlation between podoplanin expression and extracapsular spread in squamous cell carcinoma of the oral cavity using subjective immunoreactivity scores and semiquantitative image analysis.

BACKGROUND: The correlation between podoplanin expression and extracapsular spread in head and neck squamous cell carcinoma (HNSCC) has never been reported. The purpose of this study was to assess the predictive value of podoplanin expression for this parameter. METHODS: Subjective immunoreactivity scores and semiquantitative image analysis of podoplanin expression were performed in 67 patients with primary oral squamous cell carcinoma and in their corresponding lymph nodes. Neck classification showed 34 cases (51%) of pN0 and 33 cases (49%) of pN+. Correlation between the levels of podoplanin expression and the histopathological data was established. RESULTS: In lymph nodes, a high level of podoplanin expression correlated with the presence of extracapsular spread by multivariate analysis (p = .03). A strong correlation between subjective and semiquantitative image analysis was observed (r = 0.77; p < .001). CONCLUSION: A high level of podoplanin expression in lymph node metastases of oral squamous cell carcinoma is independently associated with extracapsular spread. © 2016 Wiley Periodicals, Head Neck 39: 98-108, 2017.

Minimizing adjuvant treatment after transoral robotic surgery through surgical margin revision and exclusion of radiographic extracapsular extension: A Prospective observational cohort study.

BACKGROUND: We investigated in a prospective cohort of patients treated with trans-oral robotic surgery (TORS) for oropharyngeal cancer (OPC), who were selected for the absence of radiographic extra-capsular extension (ECS) and surgically revised for inadequate margins, the possibility of reducing adjuvant radiation (RT)/chemo-radiation therapy (CRT) without jeopardizing tumor control and functional outcome. METHODS: We conducted a prospective observational cohort of patients treated with TORS for oropharyngeal cancer. RESULTS: Twenty-nine patients with T1/2N0 to N2B stage cancers were treated with TORS. Forty-five percent of them were treated for secondary primaries. Nine of 29 patients (31%) were revised for close/positive margins. Adjuvant RT was prescribed for 2 of 19 patients with early squamous cell carcinoma (SCCs) and CRT for 1 of 10 patients with advanced oropharyngeal SCCs. Overall survival (OS), disease-specific survival (DSS), and locoregional control at 2 years were 85%, 96%, and 93%, respectively. Posttreatment Functional Outcome Swallowing Scale (FOSS) scores worsened with prior or adjuvant RT, local recurrence, site, and revision for margins. CONCLUSION: Patients with early and moderately advanced oropharyngeal SCC selected for radiographic ECS and revised for inadequate margins have excellent tumor control and favorable functional recovery. © 2017 Wiley Periodicals, Inc. Head Neck 39: 965-973, 2017.

Complete and long-lasting regression of disseminated multiple skin melanoma metastases under treatment with cyclooxygenase-2 inhibitor.

Experimental and clinical evidence indicates that non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors may have anti-cancer activities. Here we report on a patient with a metastatic melanoma of the leg who experienced a complete and sustained regression of skin metastases upon continuous single treatment with the cyclooxygenase-2 inhibitor rofecoxib. Our observations indicate that the inhibition of cyclooxygenase-2 can lead to the regression of disseminated skin melanoma metastases, even after failure of chemotherapy.

Extracapsular spread in head and neck squamous cell carcinoma: A systematic review and meta-analysis.

Extracapsular spread (ECS) is one of the most important prognostic factors in head and neck squamous cell carcinoma (HNSCC). However, despite its major clinical relevance, there are still a number of important remaining issues regarding this condition. Indeed, standardized diagnostic and grading criteria of ECS are still lacking. The imaging modality of choice for its diagnosis is a matter of debate. Current research looking at the identification of specific biomarkers is ongoing. Recent findings demonstrate a direct correlation between the level of extension of ECS and a poor prognosis. Accumulating data show that ECS does not carry the same adverse features in human papilloma virus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC). New treatment strategies based on these factors are currently considered to investigate the possibility of diminishing the toxicity of chemo-radiotherapy while maintaining similar outcomes. The goal of this article was to provide a systematic review of the literature covering all the issues related to ECS. As an additional component of the review, meta-analyses were performed on relevant aspects of ECS for which previous quantitative data were outdated or not available. The results of these meta-analyses confirm the negative impact of ECS on loco-regional recurrence and distant metastasis. They also demonstrate the absence of a negative impact of ECS in HPV-positive OPSCC.

Modified technique of functional vertical hemilaryngectomy for cancer invading 1 hemicricoid.

BACKGROUND: Partial laryngectomy techniques are challenging, especially in young patients where function has to be preserved without compromising the oncologic outcome. We present a modified laryngectomy technique indicated for tumors invading one hemicricoid. METHODS: Vertical hemilaryngectomy with reconstruction of neo-glottis by hemi trachea and placement of an endolaryngeal silicon prosthesis for a 21-y old female patient presenting with a synovial sarcoma located on the left arytenoid area. RESULTS: The prosthesis was removed at 6 w with tracheotomy closure at 8w post-op. Patient underwent adjuvant radiotherapy. Functional outcome showed good swallowing without aspiration. Voice was hoarse. At 5 years post-op the patient is free of recurrence presenting only mild dyspnea upon effort. CONCLUSION: Vertical hemilaryngectomy including a hemicricoid is feasible with single stage reconstruction by a hemi-trachea of 4 to 5 rings intussuscepted into the thyroid cartilage. The functional outcome is good considering oncologic safety and avoidance of a permanent tracheostomy. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1708-1716, 2016.

Transthyrohyoid access to the larynx for endoscopic resection of early-stage glottic cancer.

BACKGROUND: The effectiveness of transoral microsurgery for early-stage glottic cancer relies on the possibility to obtain adequate exposure of the lesion. The purpose of this study was to design a new surgical technique allowing efficient endoscopic removal of these tumors in patients with unsatisfactory transoral exposure. METHODS: A minimal invasive access to the glottis, made through the thyrohyoid membrane and the preepiglottic space, was used for endoscopic resection of an early-stage glottic tumor in a patient with a medical history of previous radiotherapy and unsatisfactory endoscopic exposure of the lesion. RESULTS: This approach provided excellent exposure of the glottis and allowed endoscopic resection with adequate surgical margins. The surgical procedure and the postoperative period were uneventful. Functional outcomes were back to baseline after 1 month. CONCLUSION: This technique represents an attractive solution for patients presenting with early-stage glottic tumors that cannot be exposed transorally and have contraindications to alternative therapeutic procedures. © 2016 Wiley Periodicals, Inc. Head Neck 38:1286-1289, 2016.

Prediction of occult lymph node metastasis in squamous cell carcinoma of the oral cavity and the oropharynx using peritumoral Prospero homeobox protein 1 lymphatic nuclear quantification.

BACKGROUND: The use of lymphatic vessel density as a predictor of occult lymph node metastasis (OLNM) in head and neck squamous cell carcinoma (HNSCC) has never been reported. METHODS: Staining of the specific lymphatic endothelial cells nuclear marker, PROX1, as an indicator of lymphatic vessel density was determined by counting the number of positive cells in squamous cell carcinomas (SCCs) of the oral cavity and the oropharynx with clinically negative necks. Correlation with histopathological data was established. RESULTS: Peritumoral PROX1 lymphatic nuclear count significantly correlated with the detection of OLNM in multivariate analysis (p < .005). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of this parameter was 60%, 95%, 85%, and 90%, respectively. CONCLUSION: Peritumoral PROX1 lymphatic nuclear count in primary SCCs of the oral cavity and the oropharynx allows accurate prediction of occult lymph node metastasis. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1407-1415, 2016.

Factors Influencing the Incidence of Severe Complications in Head and Neck Free Flap Reconstructions.

BACKGROUND: Complications after head and neck free-flap reconstructions are detrimental and prolong hospital stay. In an effort to identify related variables in a tertiary regional head and neck unit, the microvascular reconstruction activity over the last 5 years was captured in a database along with patient-, provider-, and volume-outcome-related parameters. METHODS: Retrospective cohort study (level of evidence 3), a modified Clavien-Dindo classification, was used to assess severe complications. RESULTS: A database of 217 patients was created with consecutively reconstructed patients from 2009 to 2014. In the univariate analysis of severe complications, we found significant associations (P < 0.05) between type of flap used, American Society of Anesthesiologists classification, T-stage, microscope use, surgeon, flap frequency, and surgeon volume. Within a binomial logistic regression model, less frequently versus frequently performed flap (odds ratio [OR] = 3.2; confidence interval [CI] = 2.9-3.5; P = 0.000), high-volume versus low-volume surgeon (OR = 0.52; CI = -0.22 to 0.82; P = 0.007), and ASA classification (OR = 2.9; CI = 2.4-3.4; P = 0.033) were retained as independent predictors of severe complications. In a Cox-regression model, surgeon (P = 0.011), site of reconstruction (P = 0.000), T-stage (P = 0.001), and presence of severe complications (P = 0.015) correlated with a prolonged hospitalization. CONCLUSIONS: In this study, we identified a correlation of patient-related factors with severe complications (ASA score) and prolonged hospital stay (T-stage, site). More importantly, we identified several provider- (surgeon) and volume-related (frequency with which a flap was performed and high-volume surgeon) factors as predictors of severe complications. Our data indicate that provider- and volume-related parameters play an important role in the outcome of microvascular free-flap procedures in the head and neck region.

Inhibition of angiogenesis by non-steroidal anti-inflammatory drugs: from the bench to the bedside and back.

The formation of new blood vessels, a process globally referred to as angiogenesis, occurs in a number of pathological conditions, such as cancer and chronic inflammation. Recent findings indicate that cyclooxygenase-2 (COX-2), the inducible form of the cyclooxygenase (COX) isoenzymes, acts as a potent inducer of angiogenesis. Non-steroidal anti-inflammatory drugs (NSAIDs) are classical inhibitors of COX enzymes, which are widely prescribed for the treatment of inflammation, pain and fever. Selective COX-2 inhibitors (COXIBs) have been subsequently developed with the purpose to improve the safety profile of this class of therapeutics. More recently, substantial preclinical evidence demonstrated that NSAIDS and COXIBs have anti-angiogenic properties. This newly recognized activity opens the possibility of using these drugs for the treatment of angiogenesis-dependent diseases. In this article we review the most recent advances in understanding the mechanisms by which NSAIDs and COXIBs suppress angiogenesis, and we discuss their potential clinical use as anti-angiogenic drugs.