In 2005, International Society of Urological Pathology

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1 ORIGINAL ARTICLE Gleason Score 3+4=7 Prostate Cancer With Minimal Quantity of Gleason Pattern 4 on Needle Biopsy Is Associated With Low-risk Tumor in Radical Prostatectomy Specimen Cheng Cheng Huang, MD,* Max Xiangtian Kong, MD,* Ming Zhou, MD, PhD,*w Andrew B. Rosenkrantz, MD,z Samir S. Taneja, MD,wz Jonathan Melamed, MD,* and Fang-Ming Deng, MD, PhD* Abstract: A modified Gleason grading system as proposed in the 2005 International Society of Urological Pathology (ISUP) consensus meeting is the current grading system for prostate cancer. With this modified ISUP Gleason grading system, many Gleason score (GS) 6 cancers by the old grading system are upgraded to GS7 cancers on biopsy diagnosis even with minimal quantity (r5%) of Gleason pattern 4 (GP4) component (GS7miniGP4). However, grade concordance between the core needle biopsy of GS7miniGP4 and the corresponding radical prostatectomy (RP) specimens has not been studied. In this study, we analyzed the pathologic features of 256 consecutive needle biopsies and their corresponding RP specimens. The quantity of GP4 was calculated as the percentage of total cancer for GS7 cancer in the biopsy. Of 256 biopsies, 88 (34.4%), 107 (41.8%), and 61 (23.8%) had a GS of 6, 3+4 = 7, and 4+3 = 7, respectively. Of 107 biopsies with GS 3+4 = 7, 22 (20.6%) are GS7miniGP4. Ten of 22 cases of G7miniGP4 in the biopsies (45%) had pathologically insignificant tumor in the RP. The quantity of GP4 in the GS7 biopsy significantly correlated with GS, pathologic stage, and total tumor volume in the corresponding RP. The GS, pathologic stages, total tumor volume, and insignificant tumor rate in RP were not significantly different between the biopsy groups of GS 3+3 = 6 and GS7miniGP4, whereas those parameters were significantly different between biopsy groups of GS 3+3 = 6 and GS 3+4 = 7 with GP4 6% to 50% and between biopsy groups of GS7miniGP4 and GS7 with GP4 6% to 50%. Our data demonstrate that pathologic parameters in the RP are similar between the biopsy groups of GS7miniGP4 and GS6, and the grading of cases with biopsy GS7miniGP4 is often downgraded in RP specimens. The clinical significance of minimal quantity (r5%) of GP4 in biopsies with GS7 prostate cancer needs to be further evaluated, From the Departments of *Pathology; wurology; and zradiology, New York University Langone Medical Center, New York, NY. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Fang-Ming Deng, MD, PhD, Department of Pathology, NYU School of Medicine TH-432, 560 First Avenue New York, NY ( fang-ming.deng@nyumc.org). Copyright r 2014 by Lippincott Williams & Wilkins particularly because of its potential impact on clinical decisions between active surveillance versus surgery. Key Words: prostate cancer, modified Gleason grading, Gleason pattern 4, biopsy, radical prostatectomy (Am J Surg Pathol 2014;38: ) In 2005, International Society of Urological Pathology (ISUP) proposed a modified Gleason score (GS) system in response to evolving clinical practice and our understanding of prostate cancer (PCa) pathology. 1 In this modified ISUP GS system, certain patterns, such as poorly formed glands, for example, some of the cribriform glands, originally considered as Gleason pattern 3 are now graded as pattern 4 (GP4). In addition, the ISUP consensus also recommended that the cancer in the needle biopsy be graded with the most common Gleason pattern as the primary pattern and the highest Gleason pattern as the secondary pattern. This is a significant deviation from the original grading method in which a GS was assigned by adding together the most common and the second most common Gleason patterns. 1 3 For example, a cancer with 99% Gleason pattern 3 and 1% GP4 component was graded as 3+3 = 6 using the original grading system but is graded as GS 3+4 = 7 using the ISUP modified grading system. The distribution of GSs in prostate biopsy specimens after the utilization of the ISUP modified Gleason grading system in core needle biopsy specimens has changed significantly. Many GS 3+3 = 6 PCas were upgraded to GS 3+4 = 7. GS6 cancers decreased from 48% to 22%, whereas GS7 cancers increased from 26% to 68%. 4 Gleason grade in radical prostatectomy (RP) is one of the most powerful prognostic factors and is used as a surrogate marker for clinical outcomes. 5 8 The ISUP modified Gleason grading system also aimed to improve the biopsy-rp GS agreement. Improved biopsy-rp agreement means that biopsy GS would have a better and more precise role in the management and prognostication of patients with PCa. With the modified Gleason grading Am J Surg Pathol Volume 38, Number 8, August 2014

2 Am J Surg Pathol Volume 38, Number 8, August 2014 Gleason Score = 7 Prostate Cancer system, the biopsy-rp agreement was significantly higher than with the original Gleason grading system. 4 However, up to 38% of original GS6 cancers on needle biopsies were upgraded to GS7 or higher in RP However, the correlation between core needle biopsies of GS7 with minimal quantity (r5%) of GP4 (GS7miniGP4) and their corresponding RP specimens has not been described in the literature. In this study, we examined pathologic features including the modified Gleason grade of 256 consecutive needle biopsies with GS6 or 7 and their corresponding RP specimens. We compared the pathologic parameters in RP specimens among the biopsy groups of different GSs with focus on the pathologic findings in RP from those cases with GS7miniGP4 cancer on needle biopsy. MATERIALS AND METHODS Cases and Histology Preparations A total of 256 consecutive needle biopsies with GS6 or 7 and their corresponding RP specimens collected between 2011 and 2012 in our institute were used in this study. The biopsy specimens were from both in-house and consultation services. Of 256 biopsy cases, 88 cases had GS 3+3 = 6, 107 had GS 3+4 = 7, and 61 had GS 4+3 = 7. RPs were performed at the authors institution. Cases from patients who underwent preoperative radiation or androgen deprivation therapy were excluded from this study. For RP specimen, after fixation in 10% neutral formalin overnight, the apex and base of the prostate were amputated and perpendicularly sectioned and entirely submitted. The prostate was then serially sliced perpendicular to the long axis of the prostate at approximately 3 mm intervals from the apex to the base. The sections from the junctions of seminal vesicles and prostate were also submitted for evaluation. RP specimens were totally embedded and processed. All submitted specimens were stained with hematoxylin and eosin for histologic evaluation. Histopathologic Examinations and Tumor Volume Measurement GSs were rendered using the 2005 ISUP modified Gleason grading system. 1,13 15 The quantity of GP4 on needle biopsy was estimated as the percentage of the entire cancer focus independently by at least 2 genitourinary pathologists with consensus. The tumor volume (TV) in the RP specimen was determined using a grid method. 16 Briefly, each cancer lesion was traced on the hematoxylin and eosin slides and measured by an overlaying transparent film with a 2 2 mm grid. The TV was estimated using following formula: area of each gird (0.04 cm 2 )thickness of tissue section (0.3 cm) correction factor for fixation-related tissue shrinkage (1.12) total number of grids. In this study, the pathologically insignificant tumor is defined as an organ-confined tumor (pt2) with total TVr0.5 cm 3 and GSr6 cancers in RP specimen. 17 Statistics The patient s age, prostate-specific antigen (PSA) level, prostate weight, and TV were reported as mean values and ranges. The Student t test was used to compare the mean values of TV, size of largest tumor nodule, extraprostatic extension length, and depth between groups. The w 2 or Fisher exact test was used for categorical variable data analysis. The P values of 0.05 or less were considered statistically significant. All the statistical analyses were performed using GraphPad Prism 5 (GraphPad Software, La Jolla, CA). RESULTS Pathologic Features of Prostate Biopsies Of 256 biopsies, 88 (34.4%), 107 (41.8%), and 61 (23.8%) had GSs of 6, 3+4 = 7, and 4+3 = 7, respectively. Of 107 biopsies with GS 3+4 = 7, 22 (20.6%) had a GP4 in r5% of the cancer focus (GS7miniGP4). The histologic patterns of GP4 in GS7miniGP4 needle biopsy cases were fused glands (5 cases), poorly formed glands (4 cases), cribriform glands (3 cases), glands with glomerulation (2 cases), mixed fused and poorly formed glands (4 cases), and mixed poorly formed gland and glomerulation (4 cases). The histologic patterns of GP4 were similar between cases with GS7miniGP4 and GS7 GP4 6% to 50%. The histologic patterns of GP4 in these 22 GS7miniGP4 cases had no correlation with the likelihood for downgrading of GS in the corresponding RP specimens (data not shown). The pathologic parameters of needle biopsies with GS7miniGP4 and with GP4 6% to 50% is shown in Table 1. The percentage of total positive core, percentage of cores involved by GS 3+4 = 7 cancer, total GS 3+4 = 7 cancer length, and average GS 3+4 = 7 cancer percentage in all cores were significantly lower in cases with GS7miniGP4 than in cases with GP4 6% to 50%, respectively. The percentage of positive GS 3+3 = 6 core, total GS 3+3 = 6 cancer length, and average GS 3+3 = 6 cancer length were not significantly different between these 2 groups. Cases with GS7miniGP4 usually presented with a single positive GS 3+4 = 7 core with a small length of cancer (usually r3.6 mm), along with 1 or 2 positive GS6 cancer cores in the rest of the biopsy cores. Clinicopathologic Features of RP Specimens All 256 patients underwent RP. The mean age at the time of surgery was 64 (range, 42 to 79) years. The mean preoperative serum PSA level was 8.9 (range, 0.7 to 19) ng/ml. The pathologic parameters in RP from the biopsy groups with GS 3+3 = 6, GS 3+4 = 7, and GS 4+3 = 7 are shown in Table 2. The GS, pathologic stage, and total TV were significantly different among the 3 biopsy groups. The cases with higher GS in needle biopsy showed significantly higher GS (Z7) pathologic stages (pt3) and total TV in their corresponding RP specimens. There were no significant differences in prostate weights and positive surgical margin rates among the 3 biopsy groups. r 2014 Lippincott Williams & Wilkins

3 Huang et al Am J Surg Pathol Volume 38, Number 8, August 2014 TABLE 1. Pathological Parameters of Biopsy With GS = 7 Cancers % of GP4 in Prostate Biopsy r5% (n = 22) 6%-50% (n = 85) P Mean percentage of positive core Mean percentage of positive core with 3+4 = 7 PCa (%) < Mean percentage of positive core with 3+3 = 6 PCa (%) Mean total 3+4 = 7 cancer length (mm) < Mean total 3+3 = 6 cancer length (mm) Mean highest 3+4 = 7 cancer percentage in any core (%) Mean highest 3+3 = 6 cancer percentage in any core (%) Mean percentage of 3+4 = 7 PCa in all cores (%) Mean percentage of 3+3 = 6 PCa in all cores (mean) Pathologic Parameters in RP Stratified by the Quantity of GP4 in Prostate Biopsy The GS and pathologic stage in RP among the biopsy groups GS6 (3+3) and GS7 (3+4 or 4+3) with variable GP4 quantities are shown in Table 3. Cases with GS6 and GS7 cancers in prostate biopsy were divided into 5 groups 0%, 1% to 20%, 21% to 40%, 41% to 60%, 61% to 80%, and 81% to 100%, on the basis of the highest percentage of GP4 in the biopsy. The GS and the pathologic stages in RP were grouped into 2 categories because of limited case number for each GP4 percentage group. The GS and the pathologic stage were significantly different among the groups with different quantities of GP4 (Table 3). Higher Gleason grade (Z7) and higher pathologic stage (pt3) in RP specimen were significantly associated with higher quantity of GP4 in needle biopsy (Fig. 1). The higher total TV in RP specimen was also significantly correlated with higher quantity of GP4 (Spearman r = , 95% confidence interval , P < ). Comparison of Pathologic Parameters in RP From Different Biopsy Groups The pathologic parameters were compared among the biopsy groups of GS 3+3 = 6, GS7miniGP4, and GS 3+4 = 7 with GP4 6% to 50% (Table 4). The GS, pathologic stages, total TV, and insignificant tumor rate in RP were not significantly different between the biopsy groups of GS 3+3 = 6 and GS7miniGP4, whereas all these parameters were significantly different between biopsy groups of GS 3+3 = 6 and GS 3+4 = 7 with GP4 6% to 50% and between biopsy groups of GS7miniGP4 and GS7 with GP4 6% to 50%. In 22 RPs from the cases with GS7miniGP4 in the biopsy, GS was 3+3 = 6 in 10, GS 3+3 = 6 with tertiary pattern 4 in 4, GS3+4 = 7 in 7, and GS 4+3 = 7 in 1 case. A total of 63.6% of GS7miniGP4 cases were downgraded to 3+3 = 6 in RP. This rate of downgrading was significantly higher than that in GS 3+4 = 7 with GP4 6% to 50% cases (10.6%) but was similar, 65.9%, in GS 3+3 = 6 cancer whose corresponding RP also had GS 3+3 = 6 (65.9%). The positive surgical margin rates were not significantly different among these biopsy groups. DISCUSSION The GS7 PCa is the most commonly diagnosed cancer in both needle biopsy and RP specimen when using the modified Gleason grading system. The modified Gleason grading system improves not only the interobserver interpretive reproducibility and concordance between the biopsy TABLE 2. Pathologic Characteristics of 256 Patients With PCas Biopsy GS 3+3 = 6 (n = 88) 3+4 = 7 (n = 107) 4+3 = 7 (n = 61) P1* P2* P3* Prostate weight (mean [range]) (g) 45.3 ( ) 48.6 ( ) 46.1 ( ) RP GS (n [%]) 3+3 = 6 58 (55.7) 23 (14.1) 0 (0.0) < < < = 6+T4w 9 (10.2) 8 (7.4) 0 (0) 3+4 = 7 23 (26.2) 67 (62.7) 32 (42.9) 3+4 = 7+T5w 0 (0) 1 (0.9) 5 (7.0) 4+3 = 7 6 (6.8) 15 (14.0) 20 (33.0) 4+3 = 7+T5w 0 (0) 0 (0) 4 (5.6) Z8 1 (1.1) 1 (0.9) 7 (11.5) PR pathological stage (n [%]) T2 69 (78.4) 76 (71.0) 20 (32.8) < < T3a 17 (19.3) 31 (29.0) 33 (54.1) T3b 2 (2.3) 0 (0.0) 8 (13.1) Positive surgical margin (n [%]) 10 (11.4) 9 (8.4) 6 (9.8) Total TV (mean [range]) (cm 3 ) 0.68 ( ) 1.22 ( ) 2.95 ( ) *The pt3a and pt3b cases were combined to calculate the P values. P values: P1, 3+3 = 6 biopsy group versus 3+4 = 7 biopsy group; P2, 3+3 = 6 biopsy group versus 4+3 = 7 biopsy group; P3, 3+4 = 7 biopsy group versus 4+3 = 7 biopsy group. wt4 and T5 refer to tertiary pattern 4 and 5, respectively r 2014 Lippincott Williams & Wilkins

4 Am J Surg Pathol Volume 38, Number 8, August 2014 Gleason Score = 7 Prostate Cancer TABLE 3. Pathological Findings in RP Stratified by the Quantity of GP 4 in Prostate Biopsy GP4 in Biopsy (Case #) 0% (n = 88) 1%-20% (n = 65) 21%-40% (n = 38) 41%-60% (n = 33) 61%-80% (n = 20) 81%-100% (n = 12) Pathologic findings in RP GS* 3+3 = 6 58 (65.9) 29 (44.6) 10 (26.3) 2 (6.1) 0 (0.0) 0 (0.0) Z7 30 (34.1) 36 (55.4) 28 (73.7) 31 (93.9) 20 (100.0) 12 (100.0) pt stage* pt2 69 (78.4) 46 (70.8) 25 (65.8) 21 (63.6) 6 (30.0) 3 (25.0) pt3 19 (21.6) 17 (29.2) 13 (34.2) 12 (36.4) 14 (70.0) 9 (75.0) *w 2, P < in both comparisons of Gleason grades and pathologic stages. and RP GS but also the correlation of the biopsy GS with pathologic stage, metastatic disease, biological recurrence, and cancer-specific survival. 3,10,11,18,19 However, the biopsy-rp disagreement is still a significant issue. In a recent study that included 7643 cases of matched needle biopsy and RP using the modified Gleason grading system, the cancers were upgraded in RP in 36.3%, 25%, and 30.6% cases from a needle biopsy GS5 or 6, GS 3+4 = 7, and GS 4+3 = 7, respectively. The cancers were downgraded in RP in 24.4% and 41.2% cases from a needle biopsy with GS 3+4 = 7 and GS 4+3 = 7, respectively. 10 In our current study, the upgrading in RP was seen in 34.1%, 14.9%, and 11.5% of the cases from a needle biopsy GS6, GS 3+4 = 7 and GS 4+3 = 7, respectively. The downgrading in RP was seen in 21.5% and 49.9% cases from GS 3+4 = 7 and GS 4+3 = 7 needle biopsy, respectively. Overall, the pathologic findings in RP in our study are consistent with those reported in the literatures. 10,11 FIGURE 1. Tumor grade and stage distribution of biopsy with different quantities of GP4. The distribution of tumor grade (A) and stage (B) in RP correlated with the different quantity of GP4 (%) in biopsy. Note higher Gleason grade (Z7) and higher pathologic stage (pt3) in RP specimen are significantly predicted by higher quantity of GP4 cancers in the needle biopsy. The GS7 cancers are traditionally categorized as GS 3+4 = 7 or GS 4+3 = 7 cancers on the basis of the predominant Gleason pattern. The published data have demonstrated that the cancer with greater component of higher-grade GP4 has a worse prognosis These data suggested that the current 2-tier grading system for GS7 cancer may not be powerful enough for stratification in cancer risk assessment. In this study, we demonstrate the significant correlation between quantity of GP4 in the biopsy and pathologic parameters in the RP. The cancers with greater GP4 component in the biopsy had the higher GS, pathologic stage, and total TV in the RP. Our data support the notion that GS7 cancers are heterogenous in terms of their clinical outcomes, and further classification of this cancer based on the quantity of GP4 component may provide additional information related to clinical outcome. Clinically, the modified Gleason grading system may significantly impact the management of PCa patients, as it leads to an upshift of biopsy Gleason grades. Studies have found that significant a number of cancers graded as GS6 by original Gleason grading system were upgraded as GS7 cancer by the modified Gleason grading system. Such a change in Gleason grading may prevent some patients from being managed with active surveillance, as the generally accepted criteria for active surveillance include absence of Gleason patterns 4 or 5 in the biopsy. The findings that the small quantity of GP4 in the needle biopsy was associated with lower GS and pathologic stage in RP in this study along with the increased incidence of upgrading cancer with the modified Gleason grading system prompt us to investigate the pathologic features of RP in patients with minimal quantity of GP4 cancer in the needle biopsy and raise the question of how the patient should be managed. Our data showed that the pathologic parameters including GS, pathologic stage, total TV, and the rate of insignificant tumor in the RP specimen were significantly different between biopsy groups of GS 3+3 = 6, GS7miniGP4, and GS 3+4 = 7 with GP4 6% to 50%. Importantly, these pathologic parameters in the RP from the biopsy group of GS7miniGP4 were not different from the biopsy group with GS 3+3 = 6. In 22 biopsy cases with GS7miniGP4, 10 (45.5%) cases were downgraded to GS 3+3 = 6 in RP (pathologically insignificant disease). Additional 4 cases showed GS 3+3 = 6 with tertiary 4 in r 2014 Lippincott Williams & Wilkins

5 Huang et al Am J Surg Pathol Volume 38, Number 8, August 2014 TABLE 4. Pathologic Findings in RP From Biopsy of GS7 With Minimal GP4 GS in Biopsy GP4r5% (n = 22) 3+3 = 6 (n = 88) GP4 6%-50% (n = 85) P1* P2* P3* Pathologic findings in RP GS 6 14 (63.6)w 58 (65.9) 9 (10.6) < < = 7 7 (31.9) 23 (26.2) 71 (83.6) 4+3 = 7 1 (4.5) 6 (6.8) 4 (4.7) Z8 0 (0.0) 1 (1.1) 1 (1.1) pt stage pt2 20 (90.9) 75 (85.3) 57 (67.1) pt3a 2 (9.1) 12 (13.6) 25 (29.4) pt3b 0 (0.0) 1 (1.1) 3 (3.5) Positive margin 2 (9.1) 10 (11.4) 7 (8.2) TV (mean; cm 3 ) Insignificant tumor 10 (45.5) 30 (34.1) 2 (2.4) < < *P values: P1, 3+3 = 6 group versus GP4r5% group; P2, 3+3 = 6 group versus GP4 6% to 50% group; P3, 3+3 = 6 group versus GP4 51% to 99% group; P4, GP4r5% versus GP4 6% to 50% group. wthe tertiary pattern 4 is seen in 4 cases. RP. The clinical significance of such a tertiary grade 4 region in an otherwise GS6 (3+3) PCa is unclear and probably minimal. There are several reasons for the GS downgrading in RP. Gleason grading is challenging when the GP4 component is minimal in the biopsy. 24 For example, the tangentially sectioned small glands of Gleason pattern 3 are easily misgraded as GP4 poorly formed glands. 25 However, this is not likely the cause in our study as the Gleason grades were reviewed by at least 2 genitourinary pathologists with consensus. Another more plausible reason is the sampling error. The minuscule GP4 component was not represented in the tissues sampled in the processing of RP specimens. Regardless of the cause, our results raise a very important issue when grading PCa with GS 3+4 = 7 with minimal (r5%) GP4 component. Our study found that the pathologic findings of their corresponding RP specimens are same as those of the RP specimens from biopsy GS 3+3 = 6 cases, suggesting that cases of biopsy with GS7miniGP4 cancers may be managed as GS6. Larger studies are obviously in need to validate our findings. Ultimately our findings need to be corroborated with the clinical outcome data (PSA recurrence and survival data). Before a consensus is issued by ISUP regarding the grading of PCa with GS 3+4 = 7 with minimal (< 5%) GP4 component, we recommend documenting the GP4 percentage in all cases with GS 3+4 = 7, especially when the GP4 is <5% of the cancer focus. In addition, significance of such a minor GP4 component, as outlined above, should be communicated with clinicians. In summary, our data showed that there is a progressively positive correlation between the quantity of GP4 in GS7 cancer in the needle biopsy and GS, pathology stage, and total TV in RP. The GS7 cancer with greater quantity of GP4 in the biopsy was more likely to have higher GS, pathologic stage, and total TV in RP. The pathologic findings in RP from GS7miniGP4 in the biopsy were similar to those from GS 3+3 = 6 in the biopsy. A single GS 3+4 = 7 cancer needle core with minimal GP4 in the biopsy was associated with significant incidence of pathologically insignificant tumor. Our data suggest that the quantity of GP4 in GS7 cancer is an important pathologic parameter in the biopsy and should be reported in the pathology report. The clinical significance of minimal quantity (r5%) of GP4 on biopsies with GS7 Pca needs to be further evaluated, and we should reconsider the practice of grading PCa with minimal GP4 (r5%) as GS7 in biopsy. REFERENCES 1. Epstein JI, Allsbrook WC Jr, Amin MB, et al. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. 2005;29: Epstein JI, Allsbrook WC Jr, Amin MB, et al. Update on the Gleason grading system for prostate cancer: results of an international consensus conference of urologic pathologists. Adv Anat Pathol. 2006;13: Fine SW, Amin MB, Berney DM, et al. 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