Context.—

Grading small foci of prostate cancer on a needle biopsy is often difficult, yet the clinical significance of accurate grading remains uncertain.

Objective.—

To assess if grading of limited adenocarcinoma on prostate biopsy specimen is critical.

Design.—

We studied 295 consecutive patients undergoing extended-sextant biopsy with only 1-core involvement of adenocarcinoma, followed by radical prostatectomy.

Results.—

The linear tumor lengths on these biopsy specimens were: less than 1 mm (n = 114); 1 mm or more or less than 2 mm (n = 82); 2 mm or more or less than 3 mm (n = 35); and 3 mm or more (n = 64). Longer length was strongly associated with higher Grade Group (GG) on biopsy or prostatectomy specimen, higher risk of extraprostatic extension/seminal vesicle invasion and positive surgical margin, and larger estimated tumor volume. When cases were compared based on biopsy specimen GG, higher grade was strongly associated with higher prostatectomy specimen GG, higher incidence of pT3/pT3b disease, and larger tumor volume. Outcome analysis further showed significantly higher risks for biochemical recurrence after radical prostatectomy in patients with 1 mm or more, 2 mm or more, 3 mm or more, GG2-4, GG3-4, GG4, less than 1 mm/GG2-4, less than 1 mm/GG3-4, less than 2 mm/GG3-4, 3 mm or more/GG2-4, or 3 mm or more/GG3-4 tumor on biopsy specimens, compared with respective control subgroups. In particular, 3 mm or more, GG3, and GG4 on biopsy specimens showed significance as independent prognosticators by multivariate analysis. Meanwhile, there were no significant differences in the rate of upgrading or downgrading after radical prostatectomy among those subgrouped by biopsy specimen tumor length (eg, <1 mm [44.7%] versus ≥1/<2 mm [41.5%] versus ≥2/<3 mm [45.7%] versus ≥3 mm [46.9%]).

Conclusions.—

These results indicate that pathologists still need to make maximum efforts to grade relatively small prostate cancer on biopsy specimens.

The numbers of new prostate cancer cases and cancer-related deaths throughout the world have risen from an estimated 1 111 700 and 307 500 in 20121  to 1 276 106 and 358 989 in 2018,2  respectively. Prostate cancer has thus been the most commonly diagnosed malignancy among men in many countries.1,2  While radical prostatectomy offers excellent oncologic control in most patients with localized disease, a considerable number of these patients develop biochemical recurrence after the surgery.3  On the other hand, in men with low-risk or favorable intermediate-risk prostate cancer, active surveillance is often offered as the optimal management option.4,5  Accordingly, adequate risk stratification, even at the time of prostate cancer diagnosis, is critical for accurately predicting patient outcomes.

One of the traditional criteria for predicting clinically insignificant disease includes a less than 3-mm focus of prostate cancer present in only 1 biopsy specimen core.6  Since the introduction of screening with prostate-specific antigen (PSA) testing, small volume/low stage prostate cancer has frequently been detected. Specifically, prostate needle core biopsy specimens often show a minute focus (eg, <1 mm in length) of prostatic adenocarcinoma where grading and/or scoring may be difficult.711  This may result in undergrading or overgrading the biopsy specimen when compared with the final grade in the corresponding radical prostatectomy specimens, which is relatively common even on biopsy specimens with a considerable amount of tumor.10,12,13 

Pathologists have thus attempted grading even small foci of adenocarcinoma on prostate biopsy specimens. However, it may be possible that grading of limited prostate cancer is of little clinical importance. To determine this possibility, we assessed a series of extended-sextant prostate biopsy specimens that had only 1 core involved by adenocarcinoma, and compared the findings in corresponding radical prostatectomy specimens as well as the long-term oncologic outcomes of patients.

Upon approval by the institutional review board, including the request to waive the documentation of patient consent, we assessed consecutive patients who had undergone extended-sextant prostate needle core biopsy (≥12 cores) followed by robot-assisted radical prostatectomy (performed within 6 months of the biopsy) for prostate cancer between 2008 and 2017. Within our surgical pathology database, we identified a total of 295 men who met the inclusion criteria for only 1 core involvement of adenocarcinoma on the biopsy specimen. Cases showing carcinoma on targeted biopsy specimens (even if this was the only lesion and sextant biopsy specimen was negative for tumor) or discontinuous tumor foci separated by intervening benign tissue, as well as those undergoing neoadjuvant therapy before prostatectomy was performed, were excluded from analysis. In 8 men with multiple procedures at our institution that yielded positive biopsy specimens (eg, active surveillance cases), data only from the latest biopsy specimens were used.

Gleason score/Grade Group (GG) was re-evaluated by a senior author (HM) based on the 2014 International Society of Urological Pathology criteria14  as well as the 2019 Genitourinary Pathology Society recommendations.11  In radical prostatectomy specimens with GG2 or GG3 cancer, less than 5% of a minor tertiary pattern 5 was ignored for analysis. We also retrieved clinicopathologic findings, such as age when biopsy was performed, preoperative PSA value, pT and pN staging category, surgical margin status, and estimated cancer volume as well as follow-up data, including biochemical recurrence after prostatectomy was performed defined as a single PSA level of 0.1 or more ng/mL.

Data were analyzed, using the Student's t-test for continuous variables and the X2 test or Fisher's exact test for noncontinuous variables. The rate of recurrence-free survival was calculated by the Kaplan-Meier method, and comparison was made by the log-rank test. In addition, the Cox proportional hazards model was used to determine statistical significance of prognostic factors in a multivariate setting. P values < .05 were considered to be statistically significant.

In a retrospective, blinded manner, we examined a total of 295 sets of prostate biopsy specimens with only 1 core involvement of adenocarcinoma and corresponding radical prostatectomy specimens. Table 1 summarizes clinicopathologic features of these patients. There were no cases showing GG5 on biopsy. The linear lengths of tumor involvement in these biopsies were as follows: less than 1 mm (n = 114); 1 mm or more or less than 2 mm (n = 82); 2 mm or more or less than 3 mm (n = 35); and 3 mm or more (n = 64).

We first compared cases based on tumor length on the biopsy specimen (ie, <1 mm versus ≥1 mm, <2 mm versus ≥2 mm, <3 mm versus ≥3 mm) (Table 2). In biopsy specimens with longer tumor lengths, biopsy specimen GG2-4, biopsy specimen GG3-4, prostatectomy specimen GG2-5 (except <1 versus ≥1 mm), prostatectomy specimen GG3-5, pT3 disease, pT3b disease (except <1 mm versus ≥1 mm), and positive surgical margin were significantly more common, while estimated tumor volume was significantly larger. However, there were no significant differences in age, preoperative PSA level, or pN status between 1-mm or more versus less than 1-mm, 2-mm or more versus less than 2-mm, or 3-mm or more versus less than 3-mm tumors on biopsy specimens. In these comparisons, we assessed the impact of biopsy specimen tumor length on the prognosis. Kaplan-Meier analysis coupled with log-rank test (Figure 1, A) revealed that patients with 1-mm or more (Figure 1, B), 2-mm or more (Figure 1, C), or 3-mm or more (Figure 1, D) tumors had a significantly higher risk for biochemical recurrence after radical prostatectomy was performed, compared with respective control subgroups. Differences in recurrence-free survival between less than 1-mm versus 1-mm or more or less than 2-mm tumors (P = .49), less than 1-mm versus 2-mm or more or less than 3-mm tumors (P = .41), or less than 1-mm versus 1-mm or more or less than 3-mm tumors (P = .40) were not statistically significant.

We next compared cases based on biopsy specimen GG (ie, GG1 versus GG2-4, GG1-2 versus GG3-4, GG1-3 versus GG4) (Table 3). Higher GG was significantly associated with older age (except GG1-3 versus GG4), higher GG on prostatectomy specimen, nonorgan-confined disease, including seminal vesicle invasion (except GG1-3 versus GG4), and larger tumor volume. Preoperative PSA was also significantly higher in patients with a biopsy specimen GG2-4 tumor than in those with a biopsy specimen GG1 tumor. There were no significant differences in lymph node involvement or surgical margin status between GG1 versus GG2-4, GG1-2 versus GG3-4, or GG1-3 versus GG4 cases. Outcome analysis (Figure 2, A) further showed significantly higher risks for biochemical recurrence in patients with GG2-4 (Figure 2, B), GG3-4 (Figure 2, C), or GG4 (Figure 2, D) tumor on biopsy specimens, compared with respective control subgroups. Similarly, the risk of recurrence was higher in biopsy specimen GG2 (P = .06), GG3 (P < .001), or GG2-3 (P = .004) tumors than in GG1 tumors.

We further compared the cases subgrouped by tumor length on biopsy specimens (ie, <1 mm [Table S1], <2 mm [Table S2], ≥1/<2 mm [Table S3], ≥2/<3 mm [Table S4], <3 mm [Table S5], ≥3 mm [Table S6]) and then divided by biopsy specimen GG (ie, GG1 versus GG2-4, GG1-2 versus GG3-4); see supplemental digital content containing 6 tables at https://meridian.allenpress.com/aplm in the April 2022 table of contents. In any of the subgroups, higher biopsy specimen GG was significantly associated with higher GG on prostatectomy specimens. Higher biopsy specimen GG was also often (7 of 12 comparisons) associated with significantly larger tumor volume. In addition, there were significant differences in pT3 disease (<3 mm, GG1 versus GG2-4), pT3b disease (≥3 mm, GG1-2 versus GG3-4), and PSA level (1-2 mm, GG1 versus GG2-4 and 2–3 mm, GG1 versus GG2-4), as well as age (5 of comparisons). There were no significant associations of biopsy specimen GG in these subgroups with the status of lymph node metastasis or surgical margin. Outcome analysis in the subgroups showed significantly higher risks for recurrence in those with less than 1-mm GG2-4 (Figure 3, A) or GG3-4 (Figure 4, A) tumor, less than 2-mm GG3-4 tumor (Figure 4, B), or 3-mm or more GG2-4 (Figure 3, F) or GG3-4 (Figure 4, F) tumor, compared with respective controls, but not in other subgroups (Figures 3 and 4).

To determine if tumor length and grade on biopsy specimens were independent predictors of biochemical recurrence following radical prostatectomy, multivariate analysis was performed using the Cox model (Table 4). Compared with less than 1-mm cases, 3 mm or more showed significance for recurrence (hazard ratio = 16.62, 95% CI = 2.05–134.6, P = .008). Similarly, compared with GG1 cases, GG3 (hazard ratio = 5.76, 95% CI = 1.20–27.62, P = .03), or GG4 (hazard ratio = 20.36, 95% CI = 4.42–93.72, P < .001) was associated with the recurrence risk.

We further assessed the correlation of Gleason score/GG on needle biopsy and corresponding radical prostatectomy (Table 5). Overall, 110 (37.3%) and 21 (7.1%) of 295 cases were upgraded and downgraded, respectively, from a biopsy specimen GG to the prostatectomy specimen GG. Of 202 biopsy specimen GG1 cases, 101 (50.0%) were upgraded on prostatectomy, while 9 (9.7%) and 21 (22.6%) of 93 GG2-4 cases were upgraded and downgraded, respectively. The rates of upgrading or downgrading in biopsy specimen GG1, GG2, GG3, and GG4 cases were 50.0%, 17.2%, 45.5%, and 76.9%, respectively. Of note, 10 (76.9%) of 13 biopsy specimen GG4 cases were downgraded to GG3 (n = 7) and GG2 (n = 3). Thus, biopsy specimen GG1 was significantly more often upgraded or downgraded in prostatectomy specimens, compared with biopsy specimen GG2-4 cases (P = .004), while biopsy specimen GG2 was significantly less often revised, compared with biopsy specimen GG1 (P < .001), GG3 (P = .009), or GG4 (P < .001). In subgroup analysis based on biopsy specimen tumor length, no significant differences in upgrading or downgrading (ie, 44.7% of <1-mm tumors, 41.5% of ≥1/<2-mm tumors, 45.7% of ≥2/<3-mm tumors, 46.9% of ≥3-mm tumors) were observed. In addition, the rates of upgrading or downgrading in less than 3-mm (101 [43.7%] of 231) versus 3-mm or more (30 [46.9%] of 64) tumors were not statistically different (P = .66). When further separated by combinations of biopsy specimen GG and tumor length, there were no significant differences in the rates of upgrading or downgrading from GG2-4. Nonetheless, when compared between less than 3 mm (81 [46.6%] of 174) and 3-mm or more (20 [71.4%] of 28) GG1 tumors, the latter cases were significantly (P = .02) more often upgraded.

Various studies have investigated how pathologists should handle a small focus of atypical glands on prostate biopsy specimens and grade/score such a lesion if it is diagnostic of adenocarcinoma.711  However, it is often particularly difficult to grade and/or score limited cancer. For instance, if primary and secondary Gleason patterns cannot be designated, it is recommended to assign only a pattern or double the pattern as a score.15  Meanwhile, discordance in Gleason score/GG between prostate biopsy and radical prostatectomy specimens, especially upgrading in the latter, is commonly seen (eg, 38% of biopsy specimen GG1 in a meta-analysis12 ). We considered that accurate grading of limited adenocarcinoma on a biopsy might not be critical and therefore assessed extended-sextant prostate biopsy specimens, where adenocarcinoma was detected on only 1 of the cores, and corresponding radical prostatectomy specimens, as well as long-term outcomes of these patients. We excluded cases with discontinuous tumor involvement on the biopsy, where an optimal method for quantifying tumor length (ie, inclusion versus exclusion of intervening benign tissue) remains controversial,16  or any carcinoma on a targeted biopsy specimen, where actual tumor volume is unlikely to be small.

We first compared cases based on biopsy specimen tumor length. We found that longer tumor length was significantly associated with higher GG on biopsy or prostatectomy specimens, higher risks for pT3 or pT3b disease or positive surgical margin, and larger tumor volume in all or most of comparisons between less than 1-mm versus 1-mm or more, less than 2-mm versus 2-mm or more, or less than 3-mm versus 3-mm or more cases, but not with age, preoperative PSA level, or pN status. In addition, in outcome analysis, longer tumor length was associated with a significantly higher risk for biochemical recurrence after performing a radical prostatectomy. These findings suggest that, as reported in cases with multiple core involvement,1719  the length of cancer detected in only 1 core precisely predicts adverse pathologic features.

We next compared cases based on biopsy specimen GG. There are few studies examining the predictive values of the Gleason score on biopsy specimens with limited adenocarcinoma. In 2000, Rubin et al15  evaluated 105 cases of prostate biopsy specimens with minimal carcinoma defined as less than 1 mm or less than 5% involvement of 1 core and found that Gleason score did not predict higher tumor stage (odds ratio 1.156; P = .6680). In our study, we found that higher grade was significantly associated with older age, higher preoperative PSA, higher prostatectomy specimen GG, higher risks for pT3 or pT3b disease, and larger tumor volume in all or some of comparisons between GG1 versus GG2-4, GG1-2 versus GG3-4, or GG1-3 versus GG4 cases, but not with lymph node involvement or surgical margin status. The disagreement from the previous observations15  could be owing to the current grading system that has been refined during the last 20 years11,14  and may be a better prognostic parameter than it was before. In addition, the current study is larger, although it includes cases with 1 mm or more or 5% or more involvement. Meanwhile, higher biopsy specimen GG in our cohort was associated with significantly higher risks for biochemical recurrence. These findings suggest that biopsy specimen GG, even in limited adenocarcinoma, still precisely predicts adverse pathologic features.

We then performed subgroup analysis based on both tumor length and GG on biopsy specimens. In all comparisons, GGs on biopsy versus prostatectomy specimens were significantly correlated. In addition, in 7 of 12 comparisons, higher biopsy specimen GG was associated with significantly larger tumor volume. Patients with less than 1-mm GG2-4 or GG3-4 tumor, less than 2-mm GG3-4 tumor, or 3-mm or more GG2-4 or GG3-4 tumor were also found to have a significantly higher risk for biochemical recurrence, compared with respective control subgroups. Of note, multivariate analysis revealed that some biopsy specimen findings, including 3 mm or more (versus <1 mm) and GG3 or GG4 (versus GG1), were independent prognosticators.

As aforementioned, upgrading or downgrading from prostate biopsy to radical prostatectomy specimens is relatively common.10,12,13  The disagreement could be owing to, not only sampling error and borderline grades or interobserver diagnostic variability, but also the minor tertiary grade currently assigned only on prostatectomy. We further compared the rates of discordance of Gleason score/GG on needle biopsy and corresponding radical prostatectomy. Revisions of GG in prostatectomy specimens were significantly more often seen in biopsy specimen GG1 cases (50.0%) than in biopsy specimen GG2-4 cases (32.3%), which were comparable to the findings in previous studies involving 764310  or 297113  cases, whereas they were significantly less often in biopsy specimen GG2 cases (17.2%) than in biopsy specimen GG1 (50.0%), GG3 (45.6%), or GG4 (76.9%) cases. However, there were no significant differences in the rate of upgrading or downgrading in any subgroups divided by biopsy specimen tumor length, suggesting that smaller cancer (eg, <1 mm) was not necessarily upgraded or downgraded more frequently. Surprisingly, when further subgrouped by both GG and tumor length on biopsy specimens, 3-mm or more GG1 tumors (71.4%) were significantly more likely to be upgraded than less than 3-mm GG1 tumors (46.6%) on prostatectomy specimens.

There are a few limitations in our investigation. First, the present study is subject to potential selection bias due to the retrospective design, although we have analyzed consecutive patients who met the inclusion criteria. Second, we compared only radical prostatectomy cases, and the clinical significance of biopsy specimen grading in limited cancer in patients undergoing active surveillance, radiotherapy, hormonal therapy, or other therapies were not evaluated. Third, there were a considerable number of patients with biopsy specimen GG1 cancer some of whom might currently be good candidates for active surveillance, while in most of less than 3-mm GG1 cases prostatectomy had been performed during the first 5 years of the study period (ie, 2008–2012). This could limit the generalizability of the cohort in this study. Moreover, the present cohort did not include any cases with GG5 cancer on biopsy specimen. Further studies in larger patient cohorts are thus warranted to validate our results.

In conclusion, not only the length, but also the GG, of cancer on the prostate biopsy specimen in which only 1 of the cores is involved appears to have an impact on pT stage category, tumor volume, and recurrence risk after radical prostatectomy. Meanwhile, there were no significant differences in the rate of undegrading or overgrading among the groups classified based on the biopsy specimen tumor length. These findings indicate that pathologists still need to make maximum efforts to grade relatively small prostate cancer on needle core biopsy specimens.

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Author notes

Supplemental digital content is available for this article at https://meridian.allenpress.com/aplm in the April 2022 table of contents.

The authors have no relevant financial interest in the products or companies described in this article.

Supplementary data