Perineural invasion and perineural spread in periocular squamous cell carcinoma

Abstract

Perineural invasion (PNI) in cutaneous squamous cell carcinoma (SCC) of the periocular region is a prognostic marker of adverse tumour outcomes. PNI carries a well-established risk of tumour recurrence, regional metastasis and higher likelihood of mortality. This review will explore and stratify the risks conferred by histological PNI parameters. The radiological features of perineural spread (PNS) and the imaging sequences that delineate these findings will also be highlighted. Surgical excision with en face margin control is the preferred technique for achieving histological clearance. Adjuvant radiotherapy improves treatment outcomes in the setting of concomitant high-risk features. For locally advanced or metastatic cutaneous SCC, immunotherapy represents a novel treatment alternative. This review will provide an algorithm for the diagnosis and management of periocular SCC with PNI and PNS.

Fig. 1. Histological findings in perineural invasion (PNI).

A, B Haematoxylin & eosin stain demonstrating invasion of tumour cells into the perineural space involving at least one-third of the nerve circumference. C Perineural lymphocytic inflammation is characteristic of adjacent PNI. D, E Immunohistochemical staining for pancytokeratin (carcinoma) and S100 (nerve) improves the detection of PNI. F Intratumoral PNI is defined as an involved nerve within the bulk of the tumour mass. G Extratumoral PNI describes nerve involvement that is distant from the main tumour mass. H, I Large-calibre and small-calibre nerves are distinguished by a threshold of 0.1 mm in nerve diameter.

Fig. 2. MRI findings in periocular squamous cell carcinoma with perineural spread.

A Axial T1-weighted sequence demonstrates thickening of the right nasociliary nerve and anterior ethmoidal nerve (arrow). B Perineural spread in the orbit can manifest as a cystic mass with a hyperintense T2 signal (arrow), which may be representative of hypercellularity secondary to neoplastic infiltration. C T2 coronal sequence demonstrating right frontal nerve enhancement and enlargement. D–F Coronal T1 fat-suppressed contrast-enhanced sequences demonstrating different examples of V1 and V2 perineural spread with enlargement and enhancement of the nasociliary nerve (D), frontal nerve (E, F) and infraorbital nerve (F).

Fig. 3. Management algorithm.

The definition of high-risk factors encompasses both high-risk PNI parameters and high-risk clinical and histological tumour factors. High-risk PNI parameters include extratumoral involvement, large-calibre (≥0.1 mm diameter), named nerve, multiple nerves or deep invasion beyond subcutaneous fat. Other high-risk histological factors include poor differentiation, aggressive histological subtype and lymphovascular invasion. Additional high-risk clinical factors include chronic immunosuppression, tumour size larger than 2 cm and tumour thickness greater than 6 mm. CCPDMA complete circumferential peripheral and deep margin assessment via intraoperative frozen section or permanent sections with delayed reconstruction, MRI magnetic resonance imaging, PD-1 programmed cell death protein 1, PNI perineural invasion, PNS perineural spread, SCC squamous cell carcinoma.