What is the recommended treatment for a patient with a Gleason score of 4+3 and evidence of perineural invasion?

Treatment Recommendation for Gleason 4+3 with Perineural Invasion

For a patient with Gleason score 4+3 (Grade Group 3) and perineural invasion, definitive treatment with either radical prostatectomy with pelvic lymph node dissection or external beam radiation therapy (minimum 70 Gy) combined with 4-6 months of androgen deprivation therapy is strongly recommended, as this represents intermediate-to-high risk disease with significantly worse prognosis than Gleason 3+4. 1, 2

Risk Stratification and Prognostic Significance

Gleason 4+3 represents distinctly worse biology than Gleason 3+4:

• Patients with Gleason 4+3 have a 5-year biochemical progression rate of 40% compared to only 15% for Gleason 3+4, and a 10-year progression rate of 84% versus 29% 3
• The risk of developing metastatic disease is nearly three times higher with Gleason 4+3 (10.5%) compared to 3+4 (3.9%) 3
• Extraprostatic extension occurs in 52.7% of Gleason 4+3 cases versus 38.2% in 3+4 cases 3

Perineural invasion adds independent adverse prognostic value:

• Perineural invasion doubles the risk of cancer progression after treatment 4
• Combined with Gleason 7-10, perineural invasion predicts significantly increased biochemical failure rates (74% vs 91% 5-year control in favorable cases) 5
• Perineural invasion is an independent predictor of progression even when controlling for PSA and clinical stage 4

Treatment Algorithm

For Patients with Life Expectancy >10 Years:

Primary Treatment Options:

1. Radical Prostatectomy with Pelvic Lymph Node Dissection (PLND):

   • Perform PLND if predicted probability of lymph node metastasis is ≥2% (which applies to Gleason 4+3) 2
   • Provides complete pathological staging and potential cure 1
   • 10-year cancer-specific survival of 85% even for Gleason 8-10 disease when organ-confined 6
   • Caution: Expect erectile dysfunction in up to 80% and urinary incontinence in up to 49% of patients 1

2. External Beam Radiation Therapy (3D-CRT/IMRT with daily IGRT):

   • Minimum target dose of 70 Gy in 2.0 Gy fractions 2, 1
   • Must combine with androgen deprivation therapy (ADT) for 4-6 months (neoadjuvant/concomitant/adjuvant) 2, 1
   • This combination provides cancer-specific survival benefit in intermediate-risk disease 2
   • Consider pelvic imaging with MRI or CT if Partin tables indicate >15% risk of nodal involvement 2

Staging Workup Required:

Bone scan is indicated if Gleason score is >4+3 (which applies here as 4+3 equals Gleason 7 with predominant pattern 4) or PSA >15 ng/mL 2

Treatment NOT Recommended:

• Active surveillance is contraindicated for Gleason 4+3 with life expectancy >10 years 2, 1
• Brachytherapy as monotherapy is not recommended for any Gleason pattern 4 or 5 component 2
• Primary ADT alone is insufficient and should not be used as definitive treatment 2

Critical Clinical Pitfalls

Do not underestimate the difference between 3+4 and 4+3:

• The predominant pattern (listed first) fundamentally changes prognosis 3
• Mean time to progression is 3.2 years for 4+3 versus 4.4 years for 3+4 3

Perineural invasion must influence treatment intensity:

• This finding should shift decision-making toward more aggressive local therapy 5, 4
• Consider this an additional adverse feature when counseling patients about treatment options 2

If radical prostatectomy is chosen:

• Adjuvant treatment was used in 45% of high-grade cases and appears to improve progression-free survival (52% vs 23% at 10 years) 6
• Monitor with sensitive PSA assay postoperatively, with salvage radiotherapy considered for PSA failure 2

If radiation therapy is chosen:

• Short-term ADT (4-6 months) is essential for intermediate-risk disease with adverse features 2, 1
• Patients should receive antiandrogen coverage to prevent disease flare when starting LHRH agonist 2
• Consider prophylactic breast irradiation (8-10 Gy single fraction) if using bicalutamide to prevent painful gynecomastia 2