Update on Neuroendocrine Carcinomas of the Larynx

Carolina Strosberg, MD; Alfio Ferlito, MD, DLO, DPath, FRCSEd ad hominem, FRCS (Eng, Glasg, Ir) ad eundem, FDSRCS ad eundem, FACS, FHKCORL, FRCPath, FASCP, IFCAP; Asterios Triantafyllou, PhD (Lond), FRCPath; Douglas R. Gnepp, MD; Justin A. Bishop, MD; Henrik Hellquist, MD, PhD, SAPath (Stockh), FRCPath; Primoz Strojan, MD, PhD; Stefan M. Willems, MD, PhD; Göran Stenman, DMD, PhD, FRCPath; Alessandra Rinaldo, MD, FRCSEd ad hominem, FRCS (Eng, Ir) ad eundem, FRCSGlasg, FACS; Juan C. Hernandez-Prera, MD


Am J Clin Pathol. 2019;152(6):686-700. 

In This Article

Algorithmic Approach to Suspected Neuroendocrine Neoplasms of the Larynx

Overlapping morphology and immunophenotype, along with variable diagnostic criteria used by different classification schemes, make the diagnosis of neuroendocrine neoplasms of the larynx a potential source of confusion. Formulating a final diagnosis can be eased by the practical use of immunohistochemistry in conjunction with light microscopy findings. The first step is to recognize the possible neuroendocrine nature of the lesion by identifying a constellation of architectural features, including organoid architecture, nesting, rosettes, ribbons, trabeculae, and peripheral palisading Figure 1. Scanning routine H&E stained slides at low-power magnification would assist this.

Figure 1.

Algorithmic approach to suspected neuroendocrine neoplasms of the larynx. aRule out an oropharyngeal primary with extension into the supraglottis. Human papillomavirus (HPV)-specific testing such as HPV RNA in situ hybridization may be appropriate to confirm actively transcribed HPV and/or define site of origin, if the tumor is not clearly arising from the oropharynx. HMW keratin, high-molecular-weight keratin; hpf, high-power field; IHC, immunohistochemistry; INSM1, insulinoma-associated protein 1; TTF-1, thyroid transcription factor 1.

If the architectural pattern is suggestive of a neuroendocrine neoplasm, the next step is to evaluate the cytomorphologic features of the tumor cells. Well-differentiated and moderately differentiated neuroendocrine carcinoma, paraganglioma, and medullary thyroid carcinoma are characterized by predominantly monomorphic cells with subtle differences, especially in biopsies. The diagnosis can be narrowed down by an initial immunohistochemistry panel, including pancytokeratin, chromogranin, synaptophysin, INSM1, calcitonin, S100, and TTF1. In general, the absence of cytokeratin expression and presence of S100 protein-positive sustentacular cells are diagnostic for paraganglioma, which can be further supported by positive GATA3 staining. A strong reactivity for cytokeratin, calcitonin, and TTF1, together with a thyroid-based mass and increased serum calcitonin levels, would favor a medullary thyroid carcinoma.

Well- and moderately differentiated neuroendocrine carcinomas share a similar immunoprofile and are distinguished by the number of mitoses and presence of necrosis. Due to sampling, the distinction between the two may pose a challenge when dealing with a small biopsy. If samples are too small for grading, the pathologist may render a diagnosis of neuroendocrine carcinoma and add a note explaining that the tumor falls within the spectrum of a well- to moderately differentiated neuroendocrine carcinoma and suggest a conservative resection with clean margins to allow a more precise classification.

For tumors with high-grade cell morphology and neuroendocrine architecture, the amount of cytoplasm and nuclear features can lead to two different immunohistochemical diagnostic workups. Tumors characterized by moderate to abundant cytoplasm and open vesicular chromatin should be initially tested for chromogranin, synaptophysin, INSM1, p63, and high-molecular-weight cytokeratins (CK5/6 and 34βE12). Confirmation of neuroendocrine differentiation using at least two markers is imperative for the diagnosis of large cell neuroendocrine carcinoma. Diffuse staining for p63 and high-molecular-weight cytokeratins favor a basaloid squamous cell carcinoma, which can also express SOX10. The immunohistochemical workup for tumors composed of cells with scant cytoplasm and densely hyperchromatic nuclei include similar markers, with the addition of TTF-1, CD117, and p16. Small cell neuroendocrine carcinoma is typically positive for neuroendocrine markers and TTF-1, while HPV-related nonkeratinizing squamous cell carcinoma and adenoid cystic carcinoma is normally negative. The staining patterns of high-molecular-weight cytokeratins and p63 can further help in distinction between HPV-related nonkeratinizing squamous cell carcinoma and adenoid cystic carcinoma. The former shows diffuse reactivity for both markers, while the latter shows variable positivity (myoepithelial cells). In addition, HPV-related nonkeratinizing squamous cell carcinoma is diffusely positive for p16, while adenoid cystic carcinoma is strongly positive for MYB/MYBL1 (immunohistochemical stain), focally positive for p16, and variably positive (ductal cells) for CD117.