Letter to the editor regarding “The role of apparent diffusion coefficient values in diagnosing prostate cancer for patients with equivocal PI-RADS 3 lesions a multicenter retrospective study”

Dear Editor,

We read with great interest the recent multicenter study exploring the role of apparent diffusion coefficient (ADC) values in patients with PI-RADS 3 lesions. The authors concluded that ADCmin and prostate volume could be used to guide biopsy decisions and reduce unnecessary procedures[1]. This is a valuable contribution, but we believe several key issues deserve deeper discussion. Addressing these points could help refine the model and ensure that biopsy strategies remain both safe and precise. Besides, this correspondence is totally compliant with the TITAN Guidelines 2025[2].

Firstly, ADCmin is promising, but its meaning is not entirely clear. The authors highlight ADCmin as a superior predictor compared with ADCmean or ADCratio. While the statistical performance is noteworthy, the biological interpretation is less straightforward. ADCmin reflects the lowest single voxel within a lesion. This value may indeed capture the most diffusion-restricted area, but it is also highly vulnerable to noise, magnetic field variation, and partial volume effects[3]. Prior studies have shown that extreme voxel values may not reliably represent the true tumor core but can be influenced by necrosis or stromal density[4]. In contrast, ADCmean and ADCratio provide average measurements across the lesion, which reduce the variability and improve the reproducibility. Without histological validation demonstrating that ADCmin consistently corresponds to regions with the highest Gleason pattern 4 or 5, its clinical superiority remains uncertain. Therefore, we highly suggest that future studies should integrate voxel-wise ADC mapping with targeted histology to establish whether ADCmin truly reflects the most aggressive tumor focus or merely a statistical outlier.

Secondly, prostate volume is useful but may oversimplify the problem. The inclusion of prostate volume as an independent predictor is logical, since larger prostates often reduce cancer detection rates. However, volume-based stratification may oversimplify biology of the disease. Aggressive tumors in the anterior or transition zones of large prostates can be underdiagnosed, as these lesions are often more difficult to detect[5]. Conversely, small prostates may still harbor aggressive cancers with disproportionate clinical consequences. The danger of oversimplification is that biopsy deferral based on prostate size could miss these atypical but clinically significant cases. To address this point, volumetric assessment should be combined with zonal anatomy, lesion-specific features, and PSA density. Recent work supports the integration of zonal-specific risk models, which outperform gland size alone in predicting clinically significant Prostate Cancer (PCa)[6].

Thirdly, Patient-level analysis may miss lesion-level details. The current analysis was performed at the patient level, which may mask important lesion-level differences. Prostate cancer is inherently multifocal and heterogeneous, with different lesions showing distinct ADC characteristics and biological behaviors[7]. By averaging across lesions, clinically significant tumors could be diluted by less aggressive foci, leading to misleading conclusions. A lesion-level approach is critical, especially as focal therapies and targeted treatments become more common. Advanced imaging methods such as radiomics, which extract texture and entropy features beyond mean ADC, have shown promise in capturing lesion heterogeneity[8]. Incorporating these methods would provide a more accurate and nuanced risk assessment than patient-level aggregation alone.

Finally, biopsy deferral is attractive but carries potential risks. These authors indicate that biopsy may be safely deferred in low-risk patients based on prostate volume and ADCmin. While this strategy could reduce unnecessary procedures by half, it carries the inherent risk of delaying the diagnosis of aggressive cancer. Several studies have already shown that even in patients categorized as low-risk, significant cancers can be present and progress rapidly if undetected[9]. Biopsy deferral strategies should therefore be tested in prospective trials with long-term follow-up, not only assessing diagnostic accuracy but also monitoring cancer-specific survival, biochemical recurrence, and treatment outcomes. Until such data are available, biopsy avoidance based solely on ADCmin and prostate volume should be considered experimental.

In conclusion, this study provides valuable evidence that ADCmin and prostate volume may help guide biopsy decisions in PI-RADS 3 lesions. However, their interpretation is not as straightforward as presented. ADCmin needs biological validation, prostate volume risks oversimplification, patient-level analysis may obscure lesion-level truth, and biopsy deferral carries real risks. Moreover, ADC should be understood as more than just a diagnostic cutoff value, similar to how albumin is more than a simple expander. Future research should combine imaging, molecules, and clinical data to create robust, patient-centered strategies.

Ethical approval

Not applicable.

Consent

Not applicable.

Sources of funding

Not applicable.

Author contributions

H.J. and Y. Z.: study concept or design, writing the paper. X.Z.: study concept or design, data collection, data analysis or interpretation, writing the paper.

Conflicts of interest disclosure

The authors declare that they have no conflicts of interest.

Guarantor

Dr. Xudong Zhu.

Research registration unique identifying number (UIN)

Not applicable.

Provenance and peer review

Not commissioned.

Data availability statement

This is a correspondence; a data statement is not required.