The Clinical Impact of Comedonecrosis Within Intraductal Carcinoma of the Prostate Open Access

Upon approval by the institutional review board, including the request to waive patient consent documentation, we assessed consecutive patients who had undergone robot-assisted radical prostatectomy for prostate cancer at our institution during the entire years of 2010 and 2011. Within our surgical pathology database, we identified a total of 569 cases with GG2 or higher cancer (including those with the original diagnosis of Gleason score 3 + 3 = 6, with tertiary pattern 4). Cases that had undergone short-term neoadjuvant therapy prior to radical prostatectomy (n = 6), as well as those for which the histology slides had been unavailable for review (n = 5), were excluded from analysis.

We retrieved clinicopathologic findings, such as age at surgery, preoperative prostate-specific antigen (PSA) value, pT and pN staging category, surgical margin status, and estimated cancer volume, as well as follow-up data. Two genitourinary pathologists independently evaluated the presence or absence of IDC-P based on those defined in the most recent 2016 World Health Organization classification²  (ie, malignant epithelial cells filling large acini and prostatic ducts, with preservation of basal cells, and either a solid/dense cribriform pattern or a loose cribriform/micropapillary pattern with marked nuclear atypia or comedonecrosis, as originally described by Guo and Epstein¹⁰ ), as well as comedonecrosis within IDC-P. In most of the available cases, benign ducts and/or basal cells associated with IDC-P could be morphologically recognized (see Figure 1, A). However, in 7 cases with comedonecrosis that were ambiguous for IDC-P (see Figure 1, B and C) as well as 10 other cases randomly selected, the presence of basal cells was confirmed by immunohistochemistry (ie, PIN4 multiplex staining). Gleason score/GG was also reevaluated based on the recommendations by the ISUP^5,6  as well as the GUPS,⁷  and IDC-P without (ie, Gleason pattern 4) or with (ie, Gleason pattern 5) necrosis was incorporated into the score only for multivariate analysis of prognostic factors. Biochemical recurrence after prostatectomy in patients with no adjuvant therapy was defined as a single PSA level of 0.2 ng/mL or higher, and PSA failure in those undergoing adjuvant treatments, such as hormonal therapy (n = 9), radiotherapy (n = 29), or their combination (n = 7), immediately after prostatectomy (ie, prior to disease progression) was defined as an increase in PSA value of 2 ng/mL or more or 50% or higher than nadir.^11,12  PSA recurrence in those both with and without adjuvant therapy immediately after prostatectomy, as well as the initiation of any other salvage therapy, was considered disease progression.

Data were analyzed using the Student t test for continuous variables and the χ² test or Fisher exact test for noncontinuous variables. The survival rate 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 the statistical significance of prognostic factors in a multivariate setting. All statistical analyses were performed using EZR software,¹³  a graphical user interface for R version 4.0.2 (The R Foundation for Statistical Computing), and GraphPad Prism version 5 (GraphPad Software). P values less than .05 were considered to be statistically significant.

In a retrospective, blinded manner, we examined a total of 558 radical prostatectomy cases showing GG2 or higher cancer. Table 1 summarizes the clinicopathologic characteristics of these patients. IDC-P was found in 213 of these cases (38.2%), including 167 (78.4%) with no necrosis (IDC-P⁺/N⁻) and 46 (21.6%) with necrosis (IDC-P⁺/N⁺) within IDC-P.

First, in the entire cohort, we analyzed the clinicopathologic findings in cases with versus without IDC-P (Supplemental Table 1; see Supplemental Digital Content containing 3 tables and 1 figure at https://meridian.allenpress.com/aplm in the January 2023 table of contents). The presence of IDC-P was significantly associated with older age as well as with adverse features, including higher PSA, tumor grade, and pT/pN stage; positive surgical margin; and larger tumor volume. Patients with IDC-P significantly more often underwent adjuvant therapy immediately after prostatectomy (prior to disease recurrence) compared with those with no IDC-P.

We then compared histopathologic features between IDC-P⁺/N⁻ and IDC-P⁺/N⁺ cases (Table 2). The presence of necrosis was associated with higher incidence of GG3, 4, or 5 (P < .001), GG4 or 5 (P < .001), GG5 (P < .001), pT3 (P = .009), pT3b (P < .001), pN1 (P = .02), and larger tumor volume (P < .001). Gleason pattern 5 in conventional cancer was present in 27 of 46 IDC-P⁺/N⁺ cases (58.7%; 16 showing GG5, 10 showing GG3 with minor tertiary pattern 5, and 1 showing GG2 with minor tertiary pattern 5) versus 35 of 167 IDC-P⁺/N⁻ cases (21.0%) (P < .001). There were no significant differences in age (P = .16) or PSA level (P = .64), whereas adjuvant therapy immediately after prostatectomy was more often performed in IDC-P⁺/N⁺ patients (P = .004).

Kaplan-Meier analysis coupled with the log-rank test was performed to assess the impact of IDC-P and necrosis within IDC-P on prognosis following radical prostatectomy. As expected, in the entire cohort, IDC-P was associated with a significantly (P < .001) increased risk of disease progression when compared with non–IDC-P (Supplemental Figure 1). Moreover, patients with IDC-P⁺/N⁺ had a significantly (P < .001) higher risk of progression compared with IDC-P⁺/N⁻ patients (Figure 2). The difference in progression-free survival between those with no IDC-P versus IDC-P⁺/N⁻ remained statistically significant (P < .001). The prognosis was also separately assessed in subgroups of patients. The presence of IDC-P necrosis was associated with significantly worse outcomes in those who had not (P = .01; Figure 3, A) or had (P = .03; Figure 3, B) undergone adjuvant therapy immediately after radical prostatectomy as well as in those who had pN0 disease (P < .001; Figure 3, C), but not in those who had pN1 disease (P = .24; Figure 3, D). To further assess the prognostic impact of IDC-P necrosis as a potential Gleason pattern 5, we compared cases exhibiting both IDC-P and conventional grade 5 component. Surprisingly, the risk of disease progression was significantly higher in those with IDC-P necrosis than in those with no IDC-P necrosis (P = .02; Figure 4).

To determine if IDC-P necrosis was an independent predictor of disease progression following prostatectomy, multivariate analysis was performed using the Cox regression model. When IDC-P was not incorporated into Gleason score/GG, IDC-P necrosis (hazard ratio, 2.000; 95% CI, 1.198–3.341; P = .008), as well as GG, pT, and pN, showed significance for progression (Table 3). When IDC-P without (as pattern 4) or with (as pattern 5) necrosis was incorporated into Gleason score/GG, IDC-P⁺/N⁺ still showed significance for progression (hazard ratio, 1.768; 95% CI, 1.002–3.121; P = .049; Table 4). Similarly, in a multivariate setting, the presence of IDC-P, without (Supplemental Table 2) or with (Supplemental Table 3) its incorporation into Gleason score/GG, was significantly associated with the risk of progression.

In prostatic adenocarcinoma, the Gleason grade remains the most important prognosticator.^2,14  In contrast to geographic necrosis, comedonecrosis, a well-defined central plug of coagulative necrosis, is a feature of Gleason pattern 5.¹⁴  Meanwhile, comedonecrosis has been found predominantly in IDC-P, although it can be associated with invasive cribriform cancer. Specifically, in radical prostatectomy specimens immunostained for basal cell markers, comedonecrosis was more often detected in only IDC-P (60%–63%) than in only invasive cancer (5%–23%).^8,9  Its strong association with IDC-P therefore raised an issue on routine grading of comedonecrosis as pattern 5.

IDC-P likely includes 2 biologically distinct diseases, a pure form and another admixed with invasive carcinoma. Indeed, pure IDC-P has been shown to represent a genomically distinct in situ or precursor-like lesion.^3,15  However, in most cases of pure IDC-P seen on needle biopsy, the invasive component was found to be unsampled.^3,16  Moreover, subclonal evolution analysis suggested a common ancestral origin for IDC-P and invasive adenocarcinoma.¹⁷  Accordingly, the majority of IDC-Ps are thought to represent retrograde colonization of invasive carcinoma into the ducts or acini.

As mentioned above, assigning a Gleason grade to pure IDC-P is not currently recommended. However, the current recommendations by the ISUP⁶  and GUPS⁷  as to whether or not the IDC-P component in concurrent invasive prostate cancer could be incorporated into Gleason score are inconsistent. Meanwhile, in a study involving 52 patients undergoing radical prostatectomy, no significant differences in the rate of biochemical recurrence and the need for radiotherapy were identified between cases with comedonecrosis within invasive cancer only and IDC-P only, although lymph node metastasis was more often (P = .02) seen in the former group.⁹  It thus remains controversial how IDC-P with necrosis should be handled and reported in prostate specimens.

In our current study, we compared radical prostatectomy findings and long-term oncologic outcomes in 558 prostate cancer patients with or without IDC-P, the former of whom included 213 cases showing IDC-P with versus without comedonecrosis. We first confirmed that the presence of IDC-P was associated with worse histopathologic features in radical prostatectomy specimens and poorer postsurgical prognosis as an independent predictor. In addition, univariate analysis showed a significant difference in progression-free survival between IDC-P⁻ and IDC-P⁺/N⁻ cases. These findings support the clinical significance of IDC-P in men undergoing radical prostatectomy.

We then found that IDC-P comedonecrosis was significantly associated with higher rates of GG3 through 5, GG4 and 5, GG5, grade 5 component, and pT3, pT3b, or pN1 disease; larger tumor volume; and the need for adjuvant therapy immediately after prostatectomy compared with IDC-P with no necrosis. However, there were no significant differences in the level of preoperative PSA or the incidence of positive surgical margin between IDC-P⁺/N⁻ and IDC-P⁺/N⁺ cases. More strikingly, we demonstrated that patients with IDC-P comedonecrosis, as an independent predictor, had a significantly higher risk of disease progression following prostatectomy. Importantly, both the presence of necrosis within IDC-P and IDC-P itself remained independent prognosticators when they were incorporated into Gleason score/GG. In addition, the prognostic value of IDC-P⁺/N⁺ was still noted in subgroups of patients, including those with or without adjuvant therapy and those with no lymph node metastasis. These findings indicate an important role of comedonecrosis associated with IDC-P in risk stratification in prostate cancer patients undergoing radical prostatectomy. Interestingly, in cases with both IDC-P and Gleason pattern 5 component, the presence of necrosis within IDC-P was associated with a significantly higher risk of disease progression, suggesting that the prognostic impact of IDC-P necrosis is not comparable to that of grade 5 in invasive cancer. Our data may thus support the GUPS recommendations⁷  for independently reporting IDC-P with no grade assignment, particularly when comedonecrosis is present within IDC-P.

Potential limitations in our present work include its retrospective nature, which may have introduced selection bias, although we have analyzed consecutive patients who met the inclusion criteria (except 5 cases where the histology slides had been unavailable for review). In addition, we compared only radical prostatectomy cases, and the clinical significance of IDC-P comedonecrosis in patients undergoing other treatment options, such as radiation therapy and hormonal therapy, was not evaluated. Finally, in our IDC-P cohort, there were only 27 patients who had pN1 disease. As such, further studies in larger patient cohorts, as well as in biopsy specimens, are warranted to validate our results.

In conclusion, compared with IDC-P without necrosis, the presence of comedonecrosis within IDC-P was found to be associated with worse histopathologic features in radical prostatectomy specimens and poorer oncologic outcomes as an independent predictor. In particular, the prognosis of IDC-P⁺/N⁺ appeared to be considerably worse than that of conventional cancer exhibiting grade 5 pattern. The presence or absence of not only IDC-P but also necrosis within IDC-P may thus need to be specified in the pathology reports for radical prostatectomy.