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

Abstract

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.

Keywords: Conventional squamous cell carcinoma; HPV infection; Larynx; Neuroendocrine carcinomas; Precursor lesions, classification; Variants of conventional squamous cell carcinoma.

Fig. 1

Invasive non-keratinizing squamous cell carcinoma of the laryngeal ventricular fold. a Large islands of tumor cells with well-defined borders on the right and central side, on the left bottom side, more infiltrative growth pattern is present. b The same part of the tumor showing strong and diffuse p16 immunostaining, both nuclear and cytoplasmic. c The same part of the tumor; cancer cells show positive in situ hybridization for E6/E7 mRNA for high-risk HPV with numerous dot-like signals highlighting the viral infection

Fig. 2

a Verrucous carcinoma. Prominent surface keratinization, projection and invagination of well-differentiated squamous epithelium invading the stroma with pushing margins. b Spindle cell carcinoma of the larynx. Proliferation of malignant spindle cells with marked mitotic activity. b Inset Positive immunohistochemical reaction for Snail in some tumor cells

Fig. 3

Spectre of dysplasia and carcinoma in situ. a Low-grade dysplasia. Hyperplastic squamous epithelium showing increased number of basal-parabasal cells, occupying the lower epithelial third; epithelial cells show minimal atypias with only slightly enlarged nuclei compared to basal cells; the upper two thirds without epithelial changes. b High-grade dysplasia. Hyperplastic squamous epithelium, two thirds, up to the entire epithelial thickness occupy atypical cells with still preserved polarity; cellular and nuclear atypias are present, increased mitotic activity is evident in the lower epithelial half; surface is covered by the thin parakeratotic layer. c High-grade dysplasia. The entire epithelial thickness is occupied by the atypical epithelial cells with still preserved polarity. d Carcinoma in situ. Pronounced architectural and cellular abnormalities of the whole epithelium with prominent nuclear and cellular atypias. The epithelial surface is covered by the parakeratotic layer. e The same epithelial changes are seen on the right side, occupying up to the two thirds of the epithelial thickness

Fig. 4

Laryngeal neuroendocrine carcinoma. a Moderately-differentiated neuroendocrine carcinoma. Submucosal tumor composed of neural-type rosettes, glandular and trabecular growth with mild to moderate nuclear polymorphism, and rare mitoses. b Poorly-differentiated neuroendocrine carcinoma, small cell. Irregular ribbons and nests of hyperchromatic cells with oval to spindle-shaped nuclei, increased nuclear-cytoplasmic ratio, and indistinct cellular borders. Small foci of crush artefacts are present. c Poorly-differentiated neuroendocrine carcinoma, large cell. Cords and trabecules of tumor cells with abundant cytoplasm, round pleomorphic nuclei and prominent nucleoli; mitoses and apoptotic cells are evident. d Poorly-differentiated neuroendocrine carcinoma, large cell. Immunohistochemistry shows diffuse positive staining for synaptophysin