In our external validation, the AUC of the Briganti 2019 nomogram was the lowest compared with that of the other nomograms calculated under the same conditions. There are currently three reports of external validations of the Briganti 2019 nomogram [21,22,23], all of which are from Europe and include a common author. Table 3 shows the AUCs of the nomograms calculated with their cohorts. Notably, Oderda et al. highlighted a similar trend in their study, where the lowest AUC was obtained from the Briganti 2019 nomogram when compared to the other validated nomograms . In addition, the AUCs of all nomograms calculated in our cohort were relatively low compared to the original and the other external validation cohorts. The calibration plot of the Briganti 2019 is below the ideal line, which indicates that the predicted probability of LNI as determined by the nomogram is overestimated compared to the actual probability. Meanwhile, sensitivity and specificity were not significantly improved if the cutoff point was changed. Therefore, changing the cutoff could not compensate for the overestimation. However, for nomograms aimed at reducing unnecessary lymph node dissection while minimizing missed lymph node metastases, the Briganti 2019 nomogram performed relatively better than other nomograms capable of assessing cases of cT3 when the cutoff was set at 7%.
The differences in the patient characteristics between the original cohort, other external validation cohort, and our cohort need to be considered. In comparison with the original cohort and our cohort, our cohort had a higher PSA and smaller prostate volume, while the maximum diameter of the index lesion on MRI was similar. Also, regarding the diagnostic accuracy of MRI to determine cT3 or higher, clinical stage tended to be underestimated compared to pathological stage in all of the studies, but the degree was the smallest in our cohort. As for the pathology results, our cohort was in a higher Gleason grade group for biopsies compared to the original cohort and other external validations. Meanwhile, when comparing the biopsy results with the final results of the surgical specimen, the other reports all tended to be upgraded while our cohort was likely to downgraded, and these tendencies in diagnostic technique may have been assumed to influence the results. In fact, between our cohort and the original cohort, the percentages of patients below the cutoff set at 7% were 30.2% and 57%, respectively, which reflect a relatively higher score in our validation cohort. Meanwhile, the results above also suggested that preoperative evaluation in our cohort tended to be overestimated, which seemed to result in low AUCs of the nomograms and a gentle gradient in the calibration plot of the Briganti 2019 nomogram. It should be noted that, in terms of the detection ability of LNI, although there were differences in surgical techniques of prostatectomy between the cohorts, the median number of lymph nodes removed was comparable, suggesting that the quality of lymph node dissection in our study was well established.
When multiple parameters were used to measure AUC, the highest AUCs for biopsy pathology were obtained using the total biopsy results rather than the targeted ones. The Gleason grade of the target lesion did not necessarily reflect cancer progression. Rather, a higher Gleason grade obtained from a systematic biopsy may reflect the extension of high-grade cancer beyond the target lesion, which could be considered as a more significant risk factor of lymph node metastasis. This may explain the lower AUC of the Briganti 2019 nomogram compared to the other nomograms, and is supported by the fact that 28 (10.1%) of the 278 cases in our cohort exhibited negative systematic biopsies, none of which were positive for LNI. Although MRI-targeted biopsy is quite useful as a diagnostic tool to increase the accuracy of cancer detection, combined MRI-targeted and systematic biopsy was considered more appropriate to determine the required therapeutic strategy.
Meanwhile, a positive systematic biopsy around the target lesion, the larger diameter of the index lesion, and higher clinical stage on MRI should have similar implications in terms of the presence of extensive malignant findings, depending on the accuracy of the imaging diagnosis of the target lesion. The diameter of the index lesion and clinical stage on MRI, both used as parameters in Briganti 2019 for positive and negative LNI, were not statistically significant. This could be due to the fact that systematic biopsies may reflect malignancies further from the target lesion, whereas our study measured the maximum diameter of the index lesion only at coronal sections, which may not accurately reflect the total tumor volume (the Briganti 2019 nomogram did not specify how the measurement was performed in the original cohort). In addition, the rate of positive LNI in cases in which pT3b was diagnosed in surgical specimens was 29.2% (7/24 cases), which was significantly higher than the 9.8% (25/254 cases) of cases with pT3a or lower. There was only one case in which the imaging and pathological diagnoses of seminal vesicle invasion were in agreement. Notably, the modified AUC of the Briganti 2019 nomogram, calculated by replacing clinical stage with pathological stage in our cohort, was increased to 0.76. An accurate assessment of the clinical stage on MRI may be key to predicting LNI.
Our study only included cases diagnosed by MRI-targeted biopsy. Cases in which the target lesion could not be identified by MRI or those in which the cancer could not be identified from the target lesion were excluded. Future studies including such cases are required.
Other parameters also remain to be studied in the future. Sato et al. reported that prostate cancer located in the anterior are less aggressive than those located in the posterior . A study at our institution also suggested that cases with negative digital rectal examinations (DRE), i.e., ventral lesions, were relatively slow to progress compared to cases with positive DRE, i.e., dorsal lesions (Yoshitomi 2020, unpublished data), and further investigation regarding the relationship between the location of the tumor and its aggressiveness would be required.
Limitations of our study should be noted. First, this was a single-institute study with relatively small sample size and number of events, limiting its generalizability. Gandaglia et al. highlighted the need to generalize their nomogram to other races, stating that their cohort including mainly Caucasian males was one of the limitations of their study . The majority of our cohort was Japanese, which may similarly be considered as a limitation. However, since this is the first study to include an Asian cohort when compared to all of the external validations to date, it helps to address the limitation of the original study. Also, we did not evaluate the quality of the surgical technique and the outcomes of the disease, which was not the main purpose of this study; we only evaluated the number of lymph node removed. Finally, the retrospective nature of our study is another limitation.
In conclusion, we externally validated the 2019 Briganti nomogram for the selection of patients with high-risk prostate cancer in a different cohort. Further research is warranted to identify more accurate decision-making tools, aimed at reducing unnecessary invasion while accurately identifying relevant patients and minimizing the number of LNI missed.