Reported large series of RP from both single and multi-institutional data sets report, albeit at a low rate, that GS ≤6 cancer has the ability to metastasize to pelvic lymph nodes. Von Bodman et al. evaluated biochemical recurrence in patients with positive LN at RP and reported 3 patients with GS ≤6 and positive LN out of a total cohort of 4,648.(33
) Similarly, Allaf et al. reported 2 patients with GS ≤6 and a positive LN out of 4000 radical prostatectomies performed between 1992–2003.(2
) A multi-institutional series evaluating pre-operative LN metastases prediction tools, used data from the Surveillance, Epidemiology, and End Results (SEER). Out of 7,765 men identified with GS ≤6 on RP, LN metastases were reported in 17 (0.2%).(1
) Other large outcome series have shown higher LN metastasis rate of up to 3% in men with reported GS ≤6 at RP.(6
In order to determine the true rate of GS ≤6 with positive LN at RP, we retrospectively identified and histologically reviewed these cases using the updated Gleason grading schema. Prior to histological review of the cases in the current study, a hypothesis to explain the higher incidence of GS≤6 with LN metastases pre vs. post 2005 might have been that the earlier era encompassed cases prior to PSA detected prostate cancer; pre PSA larger GS≤6 tumors might have had an increased risk of LN metastasis. This explanation would have been consistent with the higher pre-operative mean PSA in the pre-2005 cases when compared to the cohort post-2005.
However, histological review confirmed that under-grading primarily accounted for the larger number of cases with LN positive GS ≤6 in the pre-ISUP era. Combining all 4 academic centers, 14 pre-ISUP cases were upgraded to Gleason score 7 (3+4 in 11 cases, 4+3 in 2 cases, 4+3 with tertiary 5 in 1 case). Cribriform glands were present in all 14 cases and represented the dominant source of upgrading on review of the slides. A major point of divergence of the updated from the original Gleason system is grading cribriform glands. Within Gleason’s original illustrations of his cribriform pattern 3, he depicted large, cribriform glands.(10
) At the time of the 2005 ISUP grading consensus meeting, expert uropathologists uniformly had been diagnosing these lesions as cribriform pattern 4. The consensus conference proposed extremely stringent criteria for cribriform Gleason pattern 3. (9
) However, when various images were shown to the participants of the consensus meeting, almost none of them met the criteria for cribriform pattern 3 based on subtle features, such as slight irregularities of the outer border of the cribriform glands. It was the consensus that the vast majority of cribriform patterns be diagnosed as Gleason pattern 4 with only rare cribriform lesions satisfying diagnostic criteria for cribriform pattern 3. Subsequent to the 2005 meeting, a study reviewed 3590 consecutive prostate cancers where 30 needle biopsy cases were selected that possibly represented cribriform Gleason pattern 3 cancer. (18
) Even in a highly selected set of images thought to be the best candidates for cribriform pattern 3, most experts interpreted the cribriform patterns as pattern 4. There was poor reproducibility amongst experts as to cribriform pattern 3 vs. pattern 4 due to: 1) Disagreement as to what were the key diagnostic features in a given case (i.e. irregular distribution of lumina & variable slit-like lumina, favor pattern 4 vs. small glands & regular contour, favor pattern 3; and 2) Disagreement as to assessment of given criteria: regular vs. irregular distribution of lumina & regular vs. irregular contour. In a subsequent study specifically addressing the prognosis of cribriform prostate cancer glands, both small and large cribriform glands were equally linked to progression after radical prostatectomy. (16
) These findings fit conceptually, as one would expect the change in grade from pattern 3 to pattern 4 to be reflected in a distinct architectural paradigm shift where cribriform as opposed to individual glands are formed, rather than merely a subjective continuum of differences in size, shape and contour of cribriform glands. The only reason why cribriform pattern 3 even exists is because of the original Gleason schematic diagram. Gleason never specifically published the prognostic difference between what he called cribriform Gleason pattern 3 compared to Gleason pattern 4. Many of Gleason’s cribriform Gleason pattern 3 cancers may not even have been infiltrating carcinomas due to the lack of availability of immunohistochemistry for basal cell markers. Today we might have diagnosed them either as cribriform high grade PIN or intraductal carcinoma of the prostate (concepts not present in Gleason’s era). (3
) Based on all the above data, all cribriform cancer should be interpreted as Gleason pattern 4 and not pattern 3.
In the current series, three of our initially undergraded cancers also contained glomeruloid glands which we now regard as Gleason pattern 4. Glomeruloid structures are characterized by dilated glands containing an intraluminal cribriform structure with a single point of attachment. There was no consensus in the 2005 ISUP conference on grading glomeruloid glands. A study from our institution subsequent to the consensus conference indicated that glomerulations were overwhelmingly associated with concurrent Gleason pattern 4 or higher grade carcinoma. (19
) One can also see a transition between small glomerulations, large glomeruloid structures, and cribriform pattern 4 cancer. These data suggest that glomerulations represent an early stage of cribriform pattern 4 cancer and are best graded as Gleason pattern 4.
Other minor patterns responsible for upgrading in our series included 3 cases with poorly formed glands and one with ductal adenocarcinoma features. These patterns were also only added to the Gleason grading schema as Gleason pattern 4 after the ISUP consensus panel in 2005.(9
The presence of tertiary pattern 4 in the RP represented a source of undergrading in several of our cases. In radical prostatectomy specimens, tertiary Gleason patterns are associated with higher pathological stage and biochemical recurrence as compared to the same Gleason score cancers without tertiary patterns. (12
) Gleason score 3+3=6 with tertiary pattern 4 has a prognosis that is in between Gleason score 3+3=6 without tertiary pattern 4 and Gleason score 3+4=7. A problem with tertiary grade patterns in RP is that they are not incorporated in the Gleason score but just noted separately in the pathology report. When institutions report GS in their databases and subsequent articles relating to their databases, tertiary patterns are typically not included, which occurred in two cases within the current series. Another three cases had tertiary grade patterns that were identified on review that were not noted in the original pathology report; tertiary grade patterns in RP were only first emphasized in 2000. (22
One case in our series was upgraded to Gleason 4+5=9. Upon review, there was a large colloid carcinoma dominant nodule that had irregular cribriform structures and sheets of cells floating in mucin. Gleason pattern 3+3=6 was seen in a separate nodule. The original pathology report had only assigned a grade to the non-colloid adenocarcinoma. The ISUP consensus panel was split on whether to grade all colloid carcinomas as 4+4=8 or ignore the extracellular mucin and grade the tumor on the underlying architecture. Either method used would still upgrade the tumor in our case.
In addition to upgrading due to utilization of the updated Gleason grading system, 7 cases initially identified as GS ≤6 with LN metastasis in our databases represented an error in database entry. One study analyzing error in research oncology databases at a single institution detected error rates up to 13.5% per database.(11
) Errors were commonly seen with both incorrect and missing information.
One potential criticism of our study is that we did not review the cohort of GS≤6 RP without LN metastases. Presumably, some of those cases would also be upgraded upon review. Although it may have reduced the denominator of total number of GS≤6, the numerator of cases with GS≤6 and LN metastasis would have been unchanged. Our conclusion would similarly be the same that reports of LN metastases of GS≤6 at RP are most likely due to pathologic undergrading. Another limitation of the current study is that most patients did not undergo extended lymph node dissection, such that metastases may have been missed. However, the more limited node dissection is currently standard of care in the United States for low risk patients.
This study was particularly difficult to perform since many institutions do not submit and embed the prostate in its entirety. Otherwise, one could not be sure that a small focus of Gleason pattern 4 was left unsampled. Even for the institutions in the current series, some potential cases were limited by an only recently adopted policy of total submission of the prostate in RP specimens. Additionally, many surgeons do not perform LN dissections at the time of surgery with a GS≤6 on biopsy unless the patient appears to be clinically high stage and/or a high PSA. This restricted the number of participating institutions to 4 despite an initial attempt to include additional centers with large RP databases. However, out of over 14,000 totally embedded RPs from multiple institutions with concurrent LN dissections, there was not a single case of a GS≤6 tumor with LN metastases. In contrast to prevailing assumptions, Gleason score ≤6 tumors do not appear to metastasize to LNs. Rather, Gleason patterns 4 or 5, as better defined by the current ISUP updated grading system, is required for metastatic disease.
The current study also indirectly supports that the updated Gleason system is more accurate. The majority of studies have found that the updated needle biopsy grade correlates better with radical prostatectomy grade than does the original Gleason grade system.(14
) Several studies have also demonstrated better correlation between the updated radical prostatectomy grade and outcome, compared to the original Gleason system grade. (4
) A consequence of the updated Gleason system is overall higher Gleason scores when compared to the original Gleason system, reflecting that some of the histological features of Gleason pattern 3 in the original Gleason system are now classified as Gleason pattern 4 in the updated Gleason system. (5
) In the updated Gleason system, GS≤6 is histologically more uniform with a more predictable excellent prognosis. In a previous study from one of the authors evaluating biochemical recurrence in men with pathologically organ-confined GS ≤6 at RP, histological review assigned a higher grade to 24 of 38 cases with recurrence. Excluding these regraded cases, biochemical and local recurrence in this population was extremely rare.(21
) Even including patients with non-organ confined disease, patients with Gleason score ≤6 in the post-ISUP era have an excellent prognosis with a 5 year biochemical cure rate of 94.6% following RP (Hopkins unpublished data). In an associated study, post-operative follow-up of over 2500 patients with GS ≤6 at RP (median 5 years) showed no development of systemic disease or death due to prostatic adenocarcinoma.(15
) Based on the current study, it can now be added that GS≤6 using the updated system lacks the potential to metastasize to pelvic lymph nodes.