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Perineural Invasion

Home > Diagnosis > Uncommon Skin Cancers > Squamous Cell Carcinoma > High Risk SCC > Perineural Invasion


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.

Perineural Inflammation

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.

Minimal Microscopic

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.

Perineural Invasion Minimal Microscopic Level
Perineural Invasion Minimal Microscopic Level

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.

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