About Perineural Invasion
Perineural invasion (PI) in skin cancers is a significant finding potentially requiring additional treatment. There are four levels of PI: perineural inflammation, minimal microscopic invasion of small nerves, larger nerve invasion, and invasion with clinical symptoms (pain, numbness, or motor deficits). With greater level of PI, there is a greater risk of recurrence, lymph node metastases, and distant metastases.
Neurotropism of cancer cells was at one time believed to be caused by the spread along perineural lymphatics. The current theory of perineural spread is based on the cleavage plane between the perineurium and the nerve – an area of lower mechanical resistance to tumor spread.
Perineural spread is more common in tumors ≥2.5 cm and in the head and neck area. The majority of perineural spread is < 1 cm while spread >2cm is unusual. The spread is believed to be continuous – tumor “skip areas” along the nerve are thought to be artifactual. However, some aggressive cancers can spread significant distance through perineural invasion as far as the skull base. In such cases the cancers also invade adjacent structures and can metastasize.
The incidence of perineural invasion for basal cell carcinomas is 1-6% and for squamous cell carcinomas 3-14%. Incidence is higher for spindle cell and adenosquamous cell variants. In fact, microcystic adnexal carcinoma (MAC), known for its silent subcutaneous spread, carries an 80% incidence of perineural spread.
The lowest level of perineural invasion is suggested by finding of perineural inflammation. Inflammation can be traced out microscopically to reveal perineural tumor cells in deeper sections. Several studies have shown that perineural inﬂammation may serve as a marker for or even mask perineural invasion. This assertion is supported by the fact that over 60% of basal cell carcinomas exhibit moderate to heavy peritumoral infiltrate of helper T cells. Some authors have even suggested rapid immunohistochemistry staining with antihuman epithelial antigen (Ber-EP4) and cytokeratins to reveal BCC masked by inflammation.
The next level of PI is minimal microscopic invasion of small nerves <0.1mm. This is likely equivalent to the cases of perineural inflammation. Local recurrences rate with small caliber nerve involvement is up to 9%.
Large caliber nerve involvement by PI has been defined at ≥0.1mm. The incidence of recurrence has been estimated as high as 50% and risk of death at 32%. Involvement of named nerves by PI is analogous to large caliber nerve involvement. Usually, large caliber nerve involvement is found in tumors larger than 2 cm, invading 1 cm or more, and poor histologic differentiation. 10-year local control rate of 62% has been reported.
Invasion with Clinical Symptoms
Finally, perineural invasion with clinical symptoms of nerve involvement is another indicator of aggressive behavior and of poor prognosis. These symptoms include pain, numbness, paresthesias, and motor deficit. 10-year local control rate has been reported to be only 50%.
Treatment when perineural invasion is discovered must involve more aggressive surgery and occasionally radiation. When PI is found with Mohs surgery, removal of an additional surgical stage is recommended after tumor-free margins are obtained. Radiation therapy of the local area is indicated with larger caliber nerve (≥0.1mm) or named nerve involvement. Radiation to the skull base or the involved cranial nerve ganglia is appropriate in these cases. Some argue to the futility of radiation because perineural tumor spread is slow and thus less amenable to radiotherapy. This decision can be modulated by the tumor behavior and its growth rate: the more rapid the tumor growth – the more radiosensitive the tumor.
Perineural invasion can be an indicator of significant tumor extension, metastases, possible future recurrence, and decreased survival. In the first few years after treatment, close follow-up of these patients is required – both with physical examination and with imaging.
HISTORY: 82-year-old man with a 1 year history of squamous cell carcinoma on the right lower cheek biopsied on 4/28/2017. Radical resection of the right cheek carcinoma and deep facial lymph node biopsy was performed. Intraoperative Mohs margin evaluation confirmed clear margins. Final permanent histology margins were close but clear. Evidence of perineural invasion…Read More
History 78-year-old man with a recurrence of squamous cell carcinoma of forehead following surgery and radiation. Resection was performed in 4/2016 and radiation followed. Lesion recurred within 1 week of completion of radiation within radiation field. Originally presented with squamous cell carcinoma with perineural invasion and 4.5mm depth of invasion, arising from squamous cell carcinoma…Read More
HISTORY 91 year old man presented with a recurrent right medial canthus BCC that was previously treated with 45 days of radiation (SRT at Hoag Hospital). Biopsy showed infiltrative sclerosing basal cell carcinoma with focal perineural invasion. MRI in December of 2016 showed the mass was fixed on the lamina papyracea adjacent to the medial…Read More
HISTORY 104 year old man presented in 2/2017 with basal cell carcinoma of the left frontal scalp and basosquamous carcinoma of the left eyebrow. On 3/21/2017 the patient underwent a wide local excision and Mohs margin excision of orbit and forehead. At the time he also had Mohs excision of the scalp forehead basal cell…Read More
HISTORY 79 year old man presented in 3/2017 with basal cell carcinoma of the right ear involving the parotid and the tragal cartilage. 3 levels of Mohs were done without clear margins. Mapping biopsies were performed on 3/20/17 showing metatypical basal cell carcinoma with perineural invasion in the parotid but not the facial nerve. On…Read More
HISTORY This 81 year old man presented with invasive squamous cell carcinoma with perineural invasion of the left forehead and scalp. Mohs was performed on 2/21/2017. Additional wide margin resection was performed on 2/27/17. It was negative for residual squamous cell carcinoma. DISCUSSION This 81-year-old man presented with invasive squamous cell carcinoma with perineural invasion…Read More
HISTORY 82 year old man presented in 02/2017 with a 3 year history of a crusty forehead lesion treated with cryoablation and 5-FU. Incisional biopsy in 2016 revealed poorly differentiated sclerosing squamous cell carcinoma, with perineural invasion. Excision a few months later was performed with residual circumferentially involved margins. CT with contrast showed only local…Read More
Perineural invasion is strongly indicative of aggressive behavior and risk of metastases. True perineural invasion requires histologic finding of cancer invasion of the nerve or cancer invasion of the epineurium adjacent to the nerve. This must be distinguished from cancer near a nerve, cancer encompassing a nerve, and perineural inflammation. Cancer cells within the nerve…Read More
A man in his thirties with lifelong h/o severe actinic cheilitis of left lower lip. Recurrent flare-ups of cheilitis have been treated as recurrent herpetic infection. Recently he has experienced worsening of cheilitis and appearance of the lesion. Biopsy found squamous cell carcinoma with perineural invasion. Lip invasion was histologically measured to be > 2mm…Read More
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