Combined Neuroendocrine and Squamous Cell Carcinoma of the Sinonasal Tract: A Morphologic and Immunohistochemical Analysis and Review of Literature

Abstract

Sinonasal malignancies constitute 3% of head and neck cancers, with squamous cell carcinoma (SCC) the most common histology. Neuroendocrine carcinomas (NEC) are rare, with a subset showing neuroendocrine carcinoma and a non-neuroendocrine component. The pathogenesis of these combined tumors is largely unknown, and TP53 driver mutations may play a role. A database search for combined NEC was performed across two institutions (UNM and UCSF) spanning 15 years. Excluding NUT midline carcinoma, 3 cases met inclusion criteria. All were morphologically NEC + SCC and underwent a comprehensive immunohistochemical evaluation. Tumors demonstrated two components histologically: moderately to poorly differentiated SCC and high-grade NEC. Divergent differentiation was confirmed with lineage-specific markers. Only one patient received neoadjuvant chemotherapy prior to surgery, with a remarkable response (a marked decrease in the size of the primary lesion and resolution of liver metastases). Immunohistochemical staining for p53 was increased in 2 of 3 cases (both components), suggesting a role in the carcinogenesis of these tumors. Aberrant expression of beta-catenin was not identified. One case tested positive for p16, which can be seen in high grade NECs due to inactivation of Rb gene. Additionally, both cases with a small cell NEC component expressed PD-L1, suggesting that immunotherapy may be an effective treatment. Findings in this study support the role of p53 mutation in a subset of combined NEC + SCC of the sinonasal tract. Recognition of this rare entity is essential for optimal management of these aggressive neoplasms.

Keywords: Carcinoma; Combined; Neuroendocrine; Squamous cell; TP53; p53.

Fig. 1

Case 1 (Clinical and morphology) A CT with contrast shows a 4.1 cm mass in the right maxillary sinus; B, C Fine needle aspirate smear showed small blue cell morphology, Diff-Quick (C Inset shows the small blue cell clusters in the cell block, H&E); D Presurgical biopsy shows a moderately differentiated squamous cell carcinoma, H&E; E Histologic section from the resection specimen (post neo-adjuvant therapy) showing both squamous cell and neuroendocrine components, H&E; F High power view of the more basaloid appearing squamous cell component in the resection specimen, H&E; G High power view of the small cell NEC component in the resection specimen, H&E. Magnification in B is ×10; C is ×40; D, F, G is ×20; and E is ×4

Fig. 2

Case 1 (IHC) A CK5/6-p40 (cocktail stain) and p63 (B, inset) stain the squamous cell carcinoma component; C and D Chromogranin and CD56 (respectively) stain the small cell NEC component; E Tumor showed high expression of p53. Magnification in A, B and E is ×4 while C and D is ×10

Fig. 3

Case 2 A Maxillofacial CT showed opacification of the left maxillary sinus; B High power view of the moderately differentiated SCC component, H&E; C High power view of the large cell NEC component; D p53 expression. Magnification in B and C is ×20 and D is ×10

Fig. 4

Case 2 A Combined SCC and NEC juxtaposed, H&E (Black arrows: SCC, Red arrow: NEC); B and C p63 and CK5/6 expression in SCC component (respectively); D Synaptophysin (weak) expression in NEC. Magnification in A–D is ×10

Fig. 5

Case 3 A A post biopsy CT showed residual tumor involving the left inferior turbinate and medial wall of the left maxillary sinus; B High power view of the SCC component, H&E; C High power view of the small cell NEC component, H&E; D p16 expression; E HPV hr ISH; F p53 expression. Magnification in B, C, and F is ×20 while D and E is ×10

Fig. 6

Case 3 A Combined SCC and NEC juxtaposed, H&E (Black arrows: SCC, Red arrow: NEC); B and C p63 and CK5/6 expression in SCC component (respectively); D Synaptophysin (weak) expression in NEC. Magnification in A–D is ×10

Fig. 7

A Representative image of PD-L1 expression (Case 1); B Representative image of Beta-catenin (Case 1). Magnification in both A and B is ×10