Perineural invasion detected on biopsy in patients on active surveillance for low-risk prostate cancer is strongly associated with upgrading, investigators reported at the American Urological Association’s 2022 annual meeting in New Orleans, Louisiana.

Among 1969 patients in the 1995-2021 Johns Hopkins active surveillance (AS) registry, 1282 men were diagnosed with very low-risk and 687 men with low-risk disease. The median PSA level was 4.9 ng/mL. Over a median follow-up of 36 months on AS, 198 men (10.0%) displayed perineural invasion on at least 1 biopsy, including at diagnosis.

“Perineural invasion — the presence of cancerous cells tracking along or around a nerve within the perineural space — is a well-established mechanism by which prostate cancer cells spread outside of the capsule,” Claire M. de la Calle, MD, of Johns Hopkins University, Baltimore, Maryland explained in an interview. “It can be found in low-grade tumors and tumors that are otherwise thought to be indolent and not requiring treatment. Little is known about how to best manage these patients who are otherwise great active surveillance candidates.”

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During AS, a significantly greater proportion of men with vs without perineural invasion experienced upgrading to Gleason grade group 2 (43.9% vs 26.3%), Dr de la Calle reported on behalf of her team. Patients with perineural invasion had a significantly higher number of positive cores and maximum core involvement (median 10% vs 5%).

In a multivariable analysis, the presence of perineural invasion was significantly associated with a 3.3-fold greater risk of upgrading. “In men with low-risk disease, perineural invasion was a stronger predictor of reclassification than MRI,” Dr de la Calle noted.

Each 0.1 unit increase in PSA density was significantly associated with a 1.3-fold increased risk of upgrading. For every 1-year increase in age (median age of cohort 66 years), the risk of upgrading significantly increased by 5%. Results also showed that an increasing number of positive cores was significantly associated with higher risk of upgrading.

The 2- and 5-year rates of grade reclassification-free survival were significantly lower in the PNI than no-PNI group (79.3% and 59.7% vs 87.6% and 71.3%, respectively), Dr de la Calle reported. The 2- and 5-year rates of biochemical recurrence-free survival did not differ significantly between the PNI and no-PNI groups (94.0% and 76.4% vs 96.3% and 87.1%, respectively).

Active treatment was chosen by a significantly greater proportion of men on AS with than without perineural invasion: 60.6% vs 37.7%, Dr de la Calle revealed. Radical prostatectomy was selected by a greater proportion of the perineural invasion group: 31.8% vs 22.0%. At surgery, a significantly greater proportion of the perineural invasion group had extraprostatic extension (33.3% vs 19.5%), but not adverse pathology (defined at Gleason grade 3 or higher, pT3 or higher, and/or lymph node involvement).

“Perineural invasion is not always a reliable pathological characteristic as it is often missed on biopsy, but it should not preclude low-risk patients from AS,” Dr de la Calle said. “Our findings will allow us to better counsel men with [perineural invasion] choosing AS versus treatment and help us determine how aggressively to monitor them while on AS.

“In our active surveillance program, we recommend MRI right after diagnosis and prior to confirmatory biopsy. Any patient with multiple clinical indicators of potentially unsampled higher grade disease such as high PSA density, large tumor volume, and perineural invasion will be recommended close monitoring with early confirmatory biopsy.”

GG1 patients with perineural invasion require closer monitoring than those without perineural invasion, she said. In her program, these patients receive biannual PSA checks, biopsies every 2-5 years, and MRI every 2-3 years, she said.”

“Currently, we recommend treatment to patients with perineural invasion that reclassify to GG2 or higher as early evidence suggests that these patients have worse outcomes,” Dr de la Calle said.


de la Calle C, Mamawala M, Landis P, et al. Clinical significance of detection of perineural invasion in low-risk men on active surveillance. Presented at: AUA 2022; May 13-16, 2022. Abstract MP43-01.