Correlating intraepithelial papillary capillary loops of vocal cord leukoplakia with histopathology.

BACKGROUND: The pathology of vocal fold leukoplakia (VFL) was hard to predict before surgery. OBJECTIVES: To investigate the correlation of intraepithelial papillary capillary loops (IPCLs) with the malignant transformation in VFL. MATERIALS AND METHODS: The IPCLs in 90 patients were classified according to 2019 Ni classification. Type I-III represented to non- to moderate dysplasia in pathology being viewed as 'benign leukoplasia', type IV-VI represented to severe dysplasia/cancer in situ, cancerization being viewed as 'malignant leukoplasia'. The corresponding relationship of IPCLs with pathology was calculated. RESULTS: Forty-one cases were classified as type I-III, the consistency of type I-III with pathology was 61.0%, with 100.0% of type I, 47.1% of type II and 30.0% of type III. 49 cases were classified as type IV-VI, all were 'malignant leukoplasia', the consistency of type IV-VI and pathology was 100.0%. The accuracy of type I-III, IV-VI to predict pathology were 61.0, 100.0%. The sensitivity, specificity, accuracy, positive predictive value, negative predictive value of Ni classification corresponding to 'benign/malignant leukoplasia' was 75.8, 100.0, 82.2, 100.0, 60.0%, respectively. CONCLUSIONS AND SIGNIFICANCE: IPCLs of type IV-VI in vocal cord leukoplasia had a close correlation with pathology. The degree of dysplasia was underestimated in type II and type III.

Optical Biopsy: Automated Classification of Airway Endoscopic Findings Using a Convolutional Neural Network.

OBJECTIVES/HYPOTHESIS: Create an autonomous computational system to classify endoscopy findings. STUDY DESIGN: Computational analysis of vocal fold images at an academic, tertiary-care laryngology practice. METHODS: A series of normal and abnormal vocal fold images were obtained from the image database of an academic tertiary care laryngology practice. The benign images included normals, nodules, papilloma, polyps, and webs. A separate set of carcinoma and leukoplakia images comprised a single malignant-premalignant class. All images were classified with their existing labels. Images were randomly withheld from each class for testing. The remaining images were used to train and validate a neural network for classifying vocal fold lesions. Two classifiers were developed. A multiclass system classified the five categories of benign lesions. A separate analysis was performed using a binary classifier trained to distinguish malignant-premalignant from benign lesions. RESULTS: Precision ranged from 71.7% (polyps) to 89.7% (papilloma), and recall ranged from 70.0% (papilloma) to 88.0% (nodules) for the benign classifier. Overall accuracy for the benign classifier was 80.8%. The binary classifier correctly identified 92.0% of the malignant-premalignant lesions with an overall accuracy of 93.0%. CONCLUSIONS: Autonomous classification of endoscopic images with artificial intelligence technology is possible. Better network implementations and larger datasets will continue to improve classifier accuracy. A clinically useful optical cancer screening system may require a multimodality approach that incorporates nonvisual spectra. LEVEL OF EVIDENCE: NA Laryngoscope, 132:S1-S8, 2022.

Prognostic Correlation of Glycolysis-Related Gene Signature in Patients with Laryngeal Cancer.

BACKGROUND: Aerobic glycolysis is one of the metabolic characteristics of tumor cells, which is regulated by many genes. The aim of our study was to construct glycolysis-related gene signature to accurately predict the prognosis of laryngeal cancer (LC) patients. METHODS: We analyzed the mRNA expression profiles of LC patients from The Cancer Genome Atlas (TCGA). Eleven glycolysis-related gene sets were analyzed by gene set enrichment analysis (GSEA). In order to acquire the gene signature related to prognosis, we used univariate and multivariate Cox regression analysis. RESULTS: We confirmed that a gene signature composed of two genes (STC2, LHPP) can predict the overall survival (OS) of patients with LC. Based on each patient's risk score, we found that the survival results of patients in the high-risk group were significantly lower than those in the low-risk group (log-rank test P-value=0.002). Multivariate Cox regression analysis confirmed that gene signature could independently predict OS in LC patients (HR = 1.981, 95% CI 1.446-2.714 P<0.001). In addition, a nomogram including the age, sex, grade and risk score was constructed. The nomogram demonstrated good accuracy for OS prediction, with a C-index of 0.752. CONCLUSION: The glycolysis-related two-gene risk score model could be used as a biomarker for LC prognosis.

Cirugía transoral en cáncer de laringe estadificado T1-T2 / Transoral surgery in T1-T2 staged laryngeal cancer

Se realizó un estudio prospectivo y descriptivo, incluyendo 103 pacientes que fueron tratados por cáncer de laringe en etapa inicial (T1-T2) con cirugía transoral. De ellos, 55 se diagnosticaron en estadio T1, 16 en estadio T1-b y 32 en estadio T2. El control local inicial (CLI) en pacientes con tumores malignos de laringe estadificados T1 fue 91%, el control local con rescate (CLR) 96%, la preservación de la función de la laringe (PFL) 93% y la sobrevida específica 96%. En T1-b, el CLI fue 81%, el CLR 94%, la PFL 94% y la sobrevida específica 94%. En T2, el CLI fue 63%, el CLR 94%, la PFL 72% y la sobrevida específica 78%. La cirugía transoral en cáncer de laringe con T inicial tiene resultados oncológicos similares a otros tratamientos (cirugía externa o radioterapia), pero consideramos que es la mejor opción por su baja morbilidad, menor duración del tratamiento, y porque deja abiertas todas las posibilidades para tratar posibles recurrencias. (AU)

A prospective and descriptive study was conducted, including 103 patients who were treated for early stage laryngeal cancer (T1-T2) with transoral surgery. Of these, 55 were diagnosed in stage T1, 16 in stage T1-b and 32 in stage T2. The initial local control (CLI) in patients with malignant T1 laryngeal tumors was: 91%, local control with rescue (CLR) 96%, preservation of larynx function (PFL) 93% and specific survival 96%. In T1-b the CLI was 81%, the CLR 94%, the PFL 94% and the specific survival 94%. In T2 the CLI was 63%, the CLR 94%, the PFL 72% and the specific survival 78%. Transoral surgery in laryngeal cancer with initial T has oncological results similar to other treatments (external surgery or radiotherapy), but we consider that it is the best option because of its low morbidity, shorter duration of treatment, and because it leaves open all the possibilities to treat possible recurrences. (AU)

Update on Neuroendocrine Carcinomas of the Larynx.

OBJECTIVES: Laryngeal neuroendocrine carcinomas are heterogeneous neoplasms characterized by neuroendocrine differentiation. Their prognoses are dependent on tumor type, therefore different classifications have been developed. Moreover, other tumors have overlapping pathologic features posing a range of diagnostic possibilities. METHODS: A review of the literature was performed to comprehensively understand the classification and diagnosis of these tumors. RESULTS: We review the past and present classification systems, with emphasis to the latest 2017 World Health Organization Classification of Head and Neck Tumors. We highlight salient clinicopathologic features and discuss the presumptive etiologic role of human papilloma virus. We share a practical algorithmic approach to the diagnosis of suspected neuroendocrine neoplasms of the larynx including a novel marker for neuroendocrine differentiation, insulinoma-associated protein 1. CONCLUSIONS: Accurate diagnosis and grading of laryngeal neuroendocrine carcinomas is critical for prognostication and therapeutic decision making. The use of an algorithm is instrumental in assuring the exclusion of mimickers.

Differing characteristics of cartilaginous lesions of the larynx.

INTRODUCTION: The tissues of the laryngeal region only rarely harbor primary cartilaginous lesions, and squamous cell carcinoma remains the most frequently encountered malignant tumor in this area. MATERIALS AND METHODS: We reviewed the salient histological features of cartilaginous laryngeal lesions to provide differential diagnostics and guidelines for distinguishing the benign from the malignant ones. RESULTS: Cartilaginous neoplasms of the larynx include chondroma and chondrosarcoma. Among the overarching group of all forms of laryngeal sarcoma, chondrosarcoma forms the most common entity in the larynx, followed by rhabdomyosarcoma. Cartilaginous tumors comprise about 0.1%-1% of all laryngeal neoplasms with chondrosarcomas being more frequently encountered than chondromas. Several neoplasms earlier reported as giant-cell tumors of the larynx would most likely, using current terminology, be classified as cases of undifferentiated pleomorphic sarcoma (previously known as malignant fibrous histiocytoma, giant-cell variant) or aneurysmal bone cyst. CONCLUSION: When true laryngeal sarcomas do exist, they may prove to be challenging lesions both for the pathologist and the treating clinician. The diagnostic problems are mainly a result of the infrequent exposure of clinicians and diagnosticians to these lesions.

Clinical utility and effectiveness of a training programme in the application of a new classification of narrow-band imaging for vocal cord leukoplakia: A multicentre study.

OBJECTIVE: To analyse the application of a new narrow-band imaging (NBI) classification in the diagnosis of vocal cord leukoplakia by laryngologists with different levels of laryngoscopic experience and to explore the impact of NBI training programmes on laryngologists' identification of benign and malignant leukoplakia. DESIGN: Prospective multicentre study. SETTING: Tertiary hospitals. PARTICIPANTS: Sixteen laryngologists were divided into less-experienced and experienced groups and received NBI training course. Thirty cases of vocal cord leukoplakia were investigated. MAIN OUTCOME MEASURES: Diagnostic accuracy and interobserver agreement under white light imaging (WLI), before and after NBI training, were analysed among doctors with varying levels of experience. RESULTS: The accuracy in the less-experienced group was significantly lower than that of experience group (0.59 vs 0.69) under WLI. There was no significant difference in the diagnostic accuracy between the less-experienced group and the experienced group before NBI training (0.75 vs 0.74) and after NBI training (0.79 vs 0.83). NBI training could improve the interobserver agreement from fair or moderate to good agreement. CONCLUSION: The new NBI diagnostic classification is helpful for identifying benign and malignant vocal cord leukoplakia. In addition, the NBI training programme can improve the diagnostic accuracy and interobserver agreement of less-experienced doctors to the level of experienced laryngologists.

Some Considerations on the WHO Histological Classification of Laryngeal Neoplasms.

A new edition of the World Health Organization (WHO) Histological classification of tumours of the hypopharynx, larynx, trachea and parapharyngeal space was published in 2017. We have considered this classification regarding laryngeal neoplasms and discuss the grounds for said revision. Many of the laryngeal neoplasms described in the literature and in the previous WHO edition from 2005 have been omitted from this current revision. Many are described elsewhere in the book but it may give the new generation of pathologists/surgeons/oncologists the false impression that these tumour entities do not exist in the larynx.

Systemic therapy in non-conventional cancers of the larynx.

Laryngeal cancer (LC) remains a challenging disease to treat. The majority of LCs diagnosed worldwide are squamous cell carcinomas (SCC), and current treatment guidelines are designed to address conventional laryngeal SCC. However, several histologically rare tumor types can originate in the larynx. There is a lack of guidelines regarding the best therapeutic approaches to these tumors and their treatment is often modeled after their recommended management at non-laryngeal sites. Understanding the role for systemic therapy in these rare tumors is important, especially for patients with advanced disease or those who are not surgical candidates. We provide in this manuscript a detailed and comprehensive overview of systemic therapy considerations for the following histologic tumor types of the larynx: verrucous carcinoma (VC), HPV-related SCC, basaloid SCC (BSCC), lymphoepithelial carcinoma (LEC), adenosquamous carcinoma (ASC), typical and atypical carcinoid, small cell neuroendocrine carcinoma (SCNC), large cell neuroendocrine carcinoma (LCNC), NUT midline carcinomas (NUTMC), melanoma, adenoid cystic carcinoma, rhabdomyosarcoma (RMS), malignant fibrous histiocytoma (MFH), lymphoma, mucoepidermoid carcinoma (MEC), acinic cell carcinoma, and spindle cell carcinoma (SpCC).

Recent Changes of Classification for Squamous Intraepithelial Lesions of the Head and Neck.

CONTEXT: - Interpretation of atypical squamous lesions of the head and neck has always been a nettlesome task for pathologists. Moreover, many different grading systems for squamous intraepithelial lesions have been proposed in past decades. The recent World Health Organization 2017 classification presents 2 types of 2-tier systems for laryngeal and oral precursor lesions. OBJECTIVE: - To review the recent changes in classification and the clinical significance for squamous intraepithelial lesions of the head and neck. DATA SOURCES: - Personal experience and data from the literature. CONCLUSIONS: - The 2-tier grading system for laryngeal dysplasia, presented by World Health Organization in 2017, is expected to improve diagnostic reproducibility and clinical implication. However, the diagnostic criteria for low-grade dysplasia do not distinguish it clearly from basal cell hyperplasia. The World Health Organization 2017 classification of oral epithelial dysplasia remains unclear, and complicated and variable grading systems still make head and neck intraepithelial lesions difficult to interpret.

What does the 4th edition of the World Health Organization Classification of Head and Neck Tumors (2017) bring new about mucosal melanomas?

The recently published 4th Edition of the World Health Organization Classification of Head and Neck Tumors addresses the most relevant and updated aspects of tumor biology, including clinical presentation, histopathology, immunohistochemistry, and prognosis of head and neck tumors. The objective of the present study is to compare these updates to the 3rd edition of that book with regard to mucosal melanomas and to highlight the potential factors that differ those tumors from cutaneous melanomas. We observed progress in the understanding of oral and sinonasal mucosal melanomas, which also present themselves, in the molecular scope, differently form cutaneous melanomas.

Role of ancillary techniques in profiling unclassified laryngeal malignancies.

Laryngeal biopsies, contrary to biopsies from many other sites of the body, very often contain minute amounts of tumour tissue that may consist of morphologically undifferentiated tumour only. In haematoxylin- and eosin-stained sections, there may be no indicative features of what specific tumour entity that is present. In the larynx, particularly small round cell neoplasms, primary or metastatic, often cause a diagnostic dilemma and where an incorrect diagnosis can induce substantial clinical consequences for the patient (e.g., primary neuroendocrine carcinomas vs metastatic variants, certain sarcomas). If sufficient/representative material has been obtained, the application of immunohistochemistry and/or molecular techniques should in virtually every case reveal the true nature of the malignancy. In cases with sparse amount of material, and therefore a limited number of sections to be cut, a careful and thoughtful stepwise approach is necessary to ascertain a reliable diagnosis, or at least guide the clinician to the most likely diagnoses. With today's advanced and widely available technology with an abundance of markers to discriminate different tumours, the use of the term "undifferentiated" should be largely unnecessary. In the exceptional, and indeed exceedingly rare cases, when a classification is not possible, even after repeat biopsy, we suggest that the laryngeal neoplasm is better termed "unclassified malignant neoplasm" rather than "undifferentiated malignant neoplasm".

Neuroendocrine Carcinomas of the Larynx and Head and Neck: Challenges in Classification and Grading.

Primary neuroendocrine carcinomas (NECs) of the larynx and head and neck are an uncommon and heterogeneous group of neoplasms categorized by the 2017 WHO Classification of Head and Neck Tumors as: (a) well-differentiated (WD-NEC), (b) moderately-differentiated (MD-NEC), and (c) poorly-differentiated (PD-NEC) with small cell and large cell types. The classification incorporates elements of differentiation and grading and closely correlates to the 5-year disease specific survival of 100, 52.8, 19.3 and 15.3% for each diagnostic category. These survival rates are based on historical data limited by the previous lack of standard pathologic diagnostic criteria. The classification has de-emphasized the use of the terms "carcinoid" and "atypical carcinoid" as diagnostic categories. The adoption of uniform pathologic criteria for the classification of NECs of the head and neck should enable the design of high quality studies in order to understand the molecular alterations of these neoplasms.

What does the 4th edition of the World Health Organization Classification of Head and Neck Tumors (2017) bring new about mucosal melanomas?

Abstract: The recently published 4th Edition of the World Health Organization Classification of Head and Neck Tumors addresses the most relevant and updated aspects of tumor biology, including clinical presentation, histopathology, immunohistochemistry, and prognosis of head and neck tumors. The objective of the present study is to compare these updates to the 3rd edition of that book with regard to mucosal melanomas and to highlight the potential factors that differ those tumors from cutaneous melanomas. We observed progress in the understanding of oral and sinonasal mucosal melanomas, which also present themselves, in the molecular scope, differently form cutaneous melanomas.

Immunolocalization of CD163+ Tumor-Associated Macrophages and Symmetric Proliferation of Ki-67 as Biomarkers to Differentiate New Different Grades of Laryngeal Dysplasia.

OBJECTIVES: To evaluate CD163+ tumor-associated macrophages (TAMs), Ki-67, and cyclin D1 to differentiate laryngeal dysplasia in the 2017 World Health Organization classification. METHODS: Immunohistochemistry for CD163, Ki-67, and cyclin D1 was performed using paraffin-embedded specimens. CD163+ TAMs infiltrating the epithelium were estimated. Ki-67 and cyclin D1 were evaluated in four parts of the epithelium-basal, parabasal, middle third, and upper third layers. RESULTS: In total, 133 specimens were analyzed, including low-grade dysplasia (n = 31), high-grade dysplasia (n = 49), carcinoma in situ (n = 23), and normal mucosa (n = 30). CD163+ TAMs infiltrating the epithelium were significantly higher in high-grade dysplasia than in low-grade dysplasia. In the basal layer, Ki-67+ and cyclin D1+ cells were overexpressed in high-grade dysplasia (P < .0001). The area under the curve was 0.958 for Ki-67 and 0.909 for CD163+ TAMs (P < .0001). CONCLUSIONS: CD163+ TAMs infiltrating the epithelium and Ki-67 overexpression in the basal layer may serve as biomarkers to differentiate low-grade dysplasia from high-grade dysplasia of the larynx. A symmetric proliferative pattern was observed during laryngeal carcinogenesis following Ki-67 overexpression.

A novel classification scheme for advanced laryngeal cancer midline involvement: implications for the contralateral neck.

PURPOSE: There are insufficient data concerning risk factors for contralateral regional metastases in laryngeal cancer. The aim of this study was to investigate the frequency and risk factors for contralateral lymph node metastases and their dependence on midline involvement of the primary tumor in patients with advanced laryngeal squamous cell carcinoma. METHODS: 58 consecutive patients (8 females, 50 males; mean age 64.2 ± 9.8 years; AJCC stage III disease in 43.1%, IVA disease in 54.4%) undergoing primary total laryngectomy with bilateral neck dissection between 2002 and 2016 have been retrospectively investigated at one of the largest university medical centers in Europe. Preoperative staging computed tomography (CT) scans were analyzed for midline involvement of the primary laryngeal cancer. As a result, a classification scheme has been established (type A: clear, type B: involved, type C: exceeded, and type D: bilateral/origin side indeterminable). RESULTS: Contralateral lymph node metastases (pN2c necks) were found in six cases (10.3%), from which four were diagnosed with type D (23.5% of type D cases), and one each with type B and type C midline involvement. In cases with no midline involvement (type A), a risk ratio reduction of 100% was seen. CT-based midline typing resulted in fourfold increased sensitivity for predicting contralateral metastases compared to conventional staging. Positive nodal status (pN+) significantly reduced overall and disease-free survival (HR 2.706, p < 0.05). CONCLUSIONS: As a consequence, for type A category, a contralateral neck dissection might be avoidable accompanied by a reduction in surgical complications and operating time.

Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: What is New in the 2017 WHO Blue Book for Tumours of the Hypopharynx, Larynx, Trachea and Parapharyngeal Space.

Chapter 3 "Tumours of the hypopharynx, larynx, trachea, and parapharyngeal space" of the World Health Organization (WHO) Blue Book 2017 "Classification of Head and Neck Tumours" shows a shortened list of entities, especially due to reducing the number of benign and malignant soft tissue tumours, malignant melanoma and some others, which are transferred to more frequently affected regions of the head and neck. The basic concept of the new edition is to assimilate all advances concerning the discussed tumours in a shorter framework, appropriate for daily work. The main emphasis is on the most frequent lesions and tumors originating from the covering squamous epithelium. Laryngeal and hypopharyngeal conventional squamous cell carcinoma (CSCC), its variants and precursor lesions, occupy a major part of the chapter. New data on etiopathogenesis, with the focus on human papillomavirus (HPV) infection, are discussed in relation to the entities of the squamous epithelium. Although only a small fraction of these lesions are HPV-related, further studies are required for evaluation of the potential prognostic and therapeutic benefit of mRNA HPV determination. In contrast to earlier data, laryngeal and hypopharyngeal verrucous SCC, spindle cell SCC and basaloid SCC are not anymore considered as HPV-related tumours. New data on the pathogenesis of spindle cell SCC exhibiting divergent differentiation by epithelial-mesenchymal transition, are also briefly discussed. The most important innovation is brought by the section on precursor lesions, in which a unified two-tier classification, consisting of low- and high-grade dysplasia, is introduced. The proposed two-tier system can also be transformed into a three-tier classification for treatment purposes, with a distinction between carcinoma in situ and high-grade dysplasia. The reviewed morphological criteria of the proposed system are based on the amended Ljubljana classification. The section on laryngeal neuroendocrine carcinomas (NEC) represents a considerable improvement in terminology and classification. NEC are divided into well-, moderate- and poorly-differentiated neuroendocrine carcinoma. The latter is additionally divided into small cell NEC and large cell NEC (LCNEC). It is of extreme importance that LCNEC, which was associated in the WHO 2005 edition with atypical carcinoid/moderately differentiated neuroendocrine carcinoma, grade II, has now been transferred into the group of poorly differentiated NEC, grade III, displaying a specific morphology and poorer prognosis.

Discordance between clinical and pathological TNM classification: influence on results of treatment and prognosis in patients with laryngeal cancer.

The goals of this retrospective cohort study were to compare the results of clinical and pathological TNM staging in patients with laryngeal squamous cell carcinoma and to determine the impact of the discordance on prognosis and treatment results. A total of 124 patients with laryngeal cancer, primarily indicated for surgical treatment, were enrolled. The concordance or discordance between the clinical and pathological staging was compared with the frequency of cancer relapse and disease-specific survival. Other potential prognostic factors, like age, the stage and location of the primary tumor, the status of neck lymph nodes, histological margins, and an indication for postoperative radiotherapy, were also evaluated. A disparity in at least one component of TNM staging was found in 40 patients (32%). The discordance had significant negative influence on both disease-free survival (DSF) and disease-specific survival (DSS). Other significant negative prognostic factors were the stage of the primary tumor, nodal status and postoperative radiotherapy. Our results indicate that the discordance between clinical and pathological staging affects the results of cancer treatment significantly. Some improvement can be probably achieved with higher preoperative diagnostic method accuracy.

Laryngeal Squamous Intraepithelial Lesions: An Updated Review on Etiology, Classification, Molecular Changes, and Treatment.

Laryngeal carcinogenesis is a multistep process, characterized by an accumulation of genetic changes associated with architectural and cytologic alterations, ranging from squamous hyperplasia to carcinoma in situ and encompassed by the terminology of squamous intraepithelial lesions (SILs). The etiology, classification, genetic changes, and malignant progression of these lesions are reviewed. Tobacco remains the principal etiological factor with gastroesophageal reflux disease recently considered as a possible factor. In contrast, there is little evidence that microbiological agents, especially human papillomavirus infection, are frequently involved in laryngeal carcinogenesis and probably <10% of SILs are driven by biologically active human papillomavirus infection. Light microscopy, despite a degree of subjectivity, remains the mainstay of accurate diagnosis, prognosis, and guidance for a patient's treatment. The currently used classifications, the dysplasia system, squamous intraepithelial neoplasia, and the Ljubljana classification, reflect different standpoints on this important topic. The modified Ljubljana classification, with good interobserver agreement, could be considered as a proposal for a unified classification of laryngeal SILs. This review also briefly discusses recently discovered genetic changes, such as CDKN2A and CTNNB1 genes, and chromosome instability of chromosomes 1 and 7; however, none of these can at present improve histologic diagnosis. Malignant progression of precursor lesions varies from 2% to 74%, according to different studies. Cold-steel microinstruments, CO2 laser, and radiotherapy are used to treat the different grades of precursor lesions. There is as yet no worldwide agreement on the treatment of high-grade lesions and carcinoma in situ.