FDG PET-CT for the Detection of Occult Nodal Metastases in Head and Neck Cancer: A Systematic Review and Meta-Analysis.

Because of an estimated 20-30% prevalence of occult lymph node (LN) metastases in patients with head and neck squamous cell carcinoma (HNSCC), neck dissection is often proposed, despite its potential morbidity. In this systematic review and meta-analysis, the diagnostic performance of FDG PET-CT in detecting occult LN metastases was evaluated in patients with clinically negative necks (cN0) and in whom histopathology of a neck dissection specimen served as gold standard. Overall, 16 studies out of 2062 screened on PubMed and EMBASE fulfilled the inclusion criteria (n = 1148 patients). Seven of these sixteen studies were split into two or three studies because they contained data that could be processed distinctly in our meta-analysis. For this reason, a total of 25 studies were identified and included in the analysis (n total = 1918 patients). The overall prevalence of metastatic nodes per patient was 22.67%. The pooled sensitivity, specificity, diagnostic odds ratios, and negative predictive value (NPV) were 0.71 (95%CI: 0.66-0.75), 0.90 (95%CI: 0.84-0.93), 20.03 (95%CI: 13.51-29.70), and 0.92 (95%CI: 0.89-0.95), respectively. The main causes of inter-study heterogeneity included different reference standards (evaluation per patient, per neck side, or per neck level). The current meta-analysis showed that FDG PET-CT has a high specificity and NPV for ruling out nodal involvement in cN0 necks, but a limited sensitivity.

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.

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.

Mediastinal abscess revealed by computed tomography after pharyngeal fish-bone impaction.

Fishbone impactions in the upper aerodigestive tract are frequent but rarely cause serious complications when recognized and treated early. In this report, we describe the case of a patient that sought medical attention as late as 2 weeks after the fishbone impaction. A 52-year-old male was presented with fever, odynophagia and a toxic appearance. CT scan revealed a large cervicomediastinal abscess. The patient was immediately started on large-spectrum antibiotics, treated by surgical drainage, and recovered uneventfully. This case report highlights the occurrence of severe complications of upper digestive tract fishbone impaction and the usefulness of a preoperative CT scanner in this context.

A new dimension of success in the management of airway disease in children with neurological deficit.

OBJECTIVES: Anomalies of the larynx and trachea can cause respiratory distress in infants and older children. Depending on its nature, degree and extent of the disease invasive open surgery is indicated. Non-airway-related co-morbidities increase the challenges in its treatment. Neurological deficit poses a great challenge as it is associated with hypotonia and causes diminished laryngeal coordination. The definition of success in treatment of laryngotracheal disease has always focused on the post-operative functional outcomes: breathing, voice swallowing. The aim of this study is to describe a new dimension of success in the management of laryngotracheal disease in children with moderate neurological deficit, where the expected functional gain is less than in otherwise healthy children. METHODS: This retrospective observational study includes all patients who have undergone open reconstructive airway surgery between 2012 and 2017. Control patients without neurological deficit and cases with moderate neurological deficit were included. Functional outcome data was obtained from clinical records and two questionnaires were filled in by the parents of the children: one the pediatric voice-handicap index (pVHI) and a quality of life questionnaire. RESULTS: Thirty-two children were included of which ten had moderate neurological deficit. Both groups revealed post-operatively an improvement in the functional outcomes: breathing, voice and swallowing, however, as expected, a trend was observed towards less functional improvement in children with neurological deficit. Both groups reveal a remarkable gain in quality of life (QoL). CONCLUSION: Indicating the QoL to be an unidentified, dimension of success in the management of laryngotracheal disease in children with moderate neurological deficit.

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.

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.

Expression of Prox1 in Medullary Thyroid Carcinoma Is Associated with Chromogranin A and Calcitonin Expression and with Ki67 Proliferative Index, but Not with Prognosis.

Medullary thyroid carcinoma (MTC) has been shown to express Prospero homeobox protein 1 (Prox1), a transcription factor whose expression is altered in a variety of human cancers. We conducted a retrospective study on a series of 32 patients with MTC to test the correlation of Prox1 expression in MTC with clinicopathological features and to evaluate its prognostic significance. Correlation of Prox1 immunohistochemical expression with tumor size, proliferative index (Ki67), and calcitonin and CEA serum levels prior to surgery was tested for significant correlations. The difference in Prox1 and Ki67 immunohistochemical expression according to the immunohistochemical staining intensity of CEA, chromogranin A, and calcitonin was tested using the Kruskal-Wallis H test and linear regression analysis. The prognostic value of Prox1 and Ki67 for our patient cohort was assessed by Kaplan-Meier log rank survival analysis. We demonstrated a positive correlation between Prox1 expression and Ki67 index. Prox1 also showed significant difference in expression according to chromogranin A and calcitonin immunohistochemical expression, with higher Prox1 expression in tumors with stronger chromogranin A or calcitonin staining. Prox1 expression did not correlate with PFS or OS based on Kaplan-Meier log rank survival analysis. In conclusion, Prox1 expression in MTC is positively correlated with Ki67 and with the immunohistochemical expression of chromogranin A and calcitonin. However, the present study does not support a role for Prox1 in MTC prognosis.

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.

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.

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.

Posturographic pattern of patients with chronic subjective dizziness before and after vestibular rehabilitation.

INTRODUCTION: Chronic subjective dizziness (CSD) is frequently encountered in neurotology clinics. This diagnosis is mainly clinical, but computerized dynamic posturography (CDP) could be a helpful instrumental tool in the identification of these patients and validation of the treatment. This study was aimed to look for a specific posturographic pattern among patients diagnosed with CSD, and to eventually visualize improvement after vestibular rehabilitation. METHODS: Single center, retrospective review from 2009 to 2014. We included patients diagnosed with CSD who underwent CDP in their neurotologic assessment. For those patients who benefited from vestibular rehabilitation, we compared their pre- and post-rehabilitation posturographies. RESULTS: We included 114 patients, of whom 74% had known anxiety disorders and 33% a history of past vestibular disorder. 62% of the assessment posturographies were abnormal. The most affected sub-items were limit of stability, composite score of sensory organization tests and condition 5 in respectively 34%, 23% and 20% of the cases. In univariate analysis, only pathologic videonystagmography and history of unilateral vestibular dysfunction were significantly related to abnormal posturography. In the 42 patients who had vestibular rehabilitation and a post rehabilitation posturography, the proportion of abnormal posturography significantly dropped from 79% to 33% (p < 0.001). When it was assessed, 79% of the patients reported a subjective improvement. CONCLUSION: Patients with CSD have a high rate of abnormal posturography, but without a specific pattern. Vestibular rehabilitation is an effective tool in the therapeutic armamentarium.

Columnar cell variant of papillary thyroid carcinoma: Cytomorphological characteristics of 11 cases with histological correlation and literature review.

BACKGROUND: The columnar cell variant of papillary thyroid carcinoma (PTC-CCV) is a rare entity that demonstrates a more aggressive clinical course compared with the more common subtypes of PTC. On histology, it is defined by papillae or gland-like structures lined by columnar cells displaying prominent nuclear stratification. Because to the authors' knowledge no characteristic cytomorphological features have been identified to date and typical features of PTC often are absent on cytology, the diagnosis of PTC-CCV by fine-needle aspiration (FNA) is challenging. This prompted the authors to evaluate a series of PTC-CCV cases to identify features that could facilitate its diagnosis by FNA. METHODS: A total of 11 surgical specimens of PTC-CCV with corresponding preoperative cytology were identified over a 21-year period. The cytological features of the aspirated specimens, consisting mostly of Papanicolaou and Diff-Quick smears, were evaluated retrospectively. RESULTS: All cases demonstrated the presence of papillary structures. The most important features observed in PTC-CCV FNA specimens were hypercellularity with nuclear superposition and a paucity of nuclear pseudoinclusions and grooves. CONCLUSIONS: Although PTC-CCV may demonstrate features that overlap with those of the classic variant of PTC, hypercellular smears with papillary structures covered by cells with pseudostratified nuclei that show a paucity of nuclear pseudoinclusions and grooves should alert the cytopathologist to the possibility of this diagnosis. Cancer Cytopathol 2017;125:389-97. © 2017 American Cancer Society.

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.

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.

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.

Facial Pain Associated with CPAP Use: Intra-Sinusal Third Molar.

Objective. This paper describes a patient with left hemifacial pain elicited by the use of a CPAP mask. Case Report. A 74-year-old man was referred with a history of pain in the left maxillary sinus related to the use of his CPAP interface, thereby prohibiting the use of the latter. Computed tomography revealed an intra-sinusal ectopic third molar in the left maxillary sinus floor corresponding to the painful area. After removal of the ectopic tooth under local anesthesia by a Caldwell-Luc approach, the patient was relieved of his symptoms. Conclusion. Although an ectopic tooth in the maxillary sinus is rare, this case points out the importance of actively looking for a regional problem if patients cannot tolerate the CPAP interface since this can lead to issues of incompliance and medical complications due to the untreated obstructive sleep apnoea syndrome.