We evaluated the clinical significance of index tumor location after radical prostatectomy with a negative surgical margin using whole-mount section analysis. Index tumors located in the central zone, although infrequent, were the strongest prognostic factors for early BCR, even if the surgical margin was negative.

A negative surgical margin is imperative for urological surgeons because it enables a cancer-free status. However, some patients experience BCR even with negative surgical margins, at a rate is about 87-96% [5, 16, 17]. The preoperative serum PSA level, Gleason score, pathological T stage, and margin status are widely accepted as significant prognostic factors in those patients [3,4,5]. A report from the USA showed significant risk factors for BCR in patients with organ-confined prostate cancer and negative surgical margins, including African American race, suspicious digital rectal examination, serum PSA level, and ISUP grades 4 and 5 on prostatectomy pathology [16]. In a retrospective multicenter cohort study conducted in Belgium, the 5- and 10-year BCR-free survival rates were 90% and 87%, respectively [5]. On the multivariate analyses, serum PSA level and pathological Gleason score of 7 or above were significantly associated with BCR in men with organ-confined prostate cancer with negative surgical margins. Oikawa et al. reported that the 5- and 10-year BCR-free survival rates were 89.0% and 87.8% after radical prostatectomy in patients with those statuses [3]. Multivariate analysis revealed that the proportion of biopsy-positive cores was significantly associated with BCR. In contrast, biopsy Gleason score and D’Amico risk classification were not significant predictive factors. Our study showed that the 1-, 5-, and 10-year BCR-free survival rates were 96.4%, 88.3%, and 84.3%, respectively. We evaluated the predictive factors of early BCR (within 1-year), adding the index tumor location to the general clinicopathological factors. Consequently, an index tumor in the central zone was the strongest prognostic factor for early BCR after radical prostatectomy in patients with negative surgical margins, which did not lead to overall BCR.

Index tumors were first introduced by McNeal et al., and refer to tumor nodules that are most likely to exhibit more aggressive biological behavior among the multifocal tumor nodules within the prostate [9]. A previous study revealed a correlation between the index tumor location and pathological features within the prostate. Billis et al. showed that index tumors with a predominantly posterior location were significantly associated with a higher total tumor extent, biopsy and prostatectomy Gleason score, lymph node metastasis, and preoperative PSA level [18]. Van de Voorde et al. found that extraprostatic extension, seminal vesicle involvement, surgical margin status, and lymph node metastasis were observed in 33 %, 17 %, 29 %, and 4% of index tumors in the transitional zone, respectively, compared with 58%, 20%, 48%, and 6% of index tumors in the peripheral zone [19]. In addition, O’Neil et al. compared transitional zone tumors with peripheral zone tumors and found that the former was larger, more frequently lower grade, organ-confined, and preferentially involved the bladder neck (49% vs. 6%, p < 0.001) [20]. Cohen et al. performed a characterization and comparative analysis of central zone carcinomas [12]. They detected 1,767 index tumors of zonal origin: 1,360 (77%) in the peripheral zone, 348 (19.7%) in the transitional zone, and 59 (3.3%) in the central zone. Cancer in the central zone is significantly more aggressive than that in other zonal locations, with a high risk of worse pathological factors and margin status. Our study showed that index tumors located in the central zone, although infrequent (5.0%), had significantly worse clinical and pathological features among the three locations within the prostate gland in patients with negative surgical margins. In recent years, there has been significant progress in developing nomograms for evaluating the presence of index tumors [21], as well as in studies aimed at extracting the location information of these tumors [22]. Future comprehensive studies on index tumors in prostate cancer will strengthen our results.

The central zone is located around the ejaculatory duct, contacts the bladder on the ventral side, and penetrates the nerve on the posterolateral side [23]. Therefore, prostate cancer that is localized in the central zone easily progresses outside the prostate gland and exhibits lymphovascular invasion. Prostate cancer localized in the central zone is relatively rare; however, it tends to be more aggressive than that in other zones [12]. Our study demonstrates the significance of the index tumor location and suggests the following therapeutic strategies. Adjuvant therapy may be required if pathology after prostatectomy reveals an index tumor in the central zone, even with complete surgical resection. Furthermore, if an index tumor in the central zone is suggested during preoperative evaluation, a multimodal treatment combining neoadjuvant hormonal therapy and/or chemotherapy with radical prostatectomy may be required. Recently, index tumors have been evaluated preoperatively using radiological and biopsy approach [24, 25]. Our results may allow urologists and patients to reconsider the therapeutic strategies for prostate cancer.

This study had several limitations. First, our study was a retrospective investigation conducted at a single medical facility. Considering the complexity introduced by this study design, generalizing our results to a broader population may be challenging. Furthermore, potential biases in patient selection could impact our outcomes, potentially affecting the overall reliability of our results. Second, in our cohort, the attending physician determined the necessity and extent of lymph node dissection during radical prostatectomy based on the patient’s cancer status and treatment era, revealing that only 0.3% of patients had lymph node metastasis. Indications for lymph node dissection vary by institution, and our data reflect real-world settings in a single Japanese medical center. Third, in our analysis, all patients were of Asian descent. It is recognized that biological characteristics and responsiveness to treatment in prostate cancer may vary among different racial groups [26]. Therefore, it is imperative to acknowledge the potential influence of racial differences when interpreting our results. While several limitations exist, our results are highly uniform and reliable for surveys, because we collected our data from a single team conducting radical prostatectomies, and a single pathologist diagnosed all the whole-mount sections. In the future, large-scale multicenter analyses and prospective studies are required to resolve these limitations and establish a more robust analysis.