Comparison of Japanese General Rules of Prostatic Cancer and Gleason grading system

BACKGROUND: We compared the prognostic efficacy between the Japanese General Rules of Prostatic Cancer (JGRPC) and the Gleason grading system (GGS) by applying them to a single set of patients and assessing the survival outcome. METHODS: One hundred and seventy-six patients with previously untreated prostate cancer were studied. One experienced Japanese pathologist graded the slides with JGRPC. Another experienced American pathologist graded the same slides with the Gleason grading system. The JGRPC grades were correlated with the Gleason scores (GS) grouped into three (GS 2-4, 5-7 and 8-10) or four (GS 2-4, 5-6, 7 and 8-10) tiers. RESULTS: The highest cancer death rates were seen in the higher grade groups in both systems. Comparison of JGRPC grade and three-tiered grouping of the GS showed identical grades in 81 of 176 cases (46.0%). The overall kappa value of agreement was only 0.151. The 96 cases of JGRPC moderately differentiated carcinoma group contained two nearly equal-sized groups by the Gleason grading system, those with GS 5-7 (47cases) and GS 8-10 (49 cases). There was a significant difference in survival rate between the GS 5-7 and GS 8-10 groups. No significant differences were noted in the reverse analysis of survival by JGRPC groups within patients with the same GS three-tiered groups. Similar trends were seen when JGRPC was compared with the four-tiered grouping of the GS. CONCLUSION: Both JGRPC and the Gleason grading system are useful in estimating the prognosis of prostate cancer, but only a mild correlation was found between the two systems. The Gleason grading system may provide more prognostic information than JGRPC in the moderately differentiated group.     

Histologic grading of primary prostatic carcinoma--study of Gleason histologic grading

Gleason histologic grading for prostatic carcinoma was evaluated in a retrospective analysis. The present study comprises 98 cases of prostatic adenocarcinoma followed from January, 1973 to December, 1985. Histological materials were obtained by needle biopsy, transurethral resection or by suprapubic prostatectomy. Such slides were examined by a pathologist without previous knowledge of the patients and were assigned according to the General Rules for Clinical and Pathological Studies on Prostatic Cancer (1985) or Gleason system. Most patients fell within a Gleason score of 6, 7 and 8, and had a correspondingly high stage tumors. The survival rate for the patients was analyzed according to Gleason score. Because of the small numbers of patients some scores were combined. There were no cancer deaths for the 15 patient with a Gleason score under 5. Patients with a higher score (9-10) had a poorer prognosis (32% of survival rate at 2,234 days), but there was no significant correlation between a Gleason score of 6, 7 or 8, or that of a higher score (9-10) and survival rate.     

Correlation between histological grading and the prognosis of prostatic carcinoma--a comparative study of the Japanese General Rules of Prostatic Cancer (JGRPC) and Gleason's classification

One hundred and sixty-seven patients with newly diagnosed, previously untreated prostatic adenocarcinoma, during the period between July, 1971 and March, 1934, were studied. The histopathologic specimens of the prostate were classified by the Japanese General Rules of Prostatic Cancer (JGRPC) and by Gleason's classification. The number of patients with well, moderately and poorly differentiated prostatic carcinomas according to the JGRPC classification was 42, 74 and 51 respectively, and the number of the patients with Gleason's pattern 1, 2, 3, 4, and 5 was 24, 20, 32, 43 and 48, respectively. The number of patients with Gleason's score (primary plus secondary pattern) 2 to 4, 5 to 7 and 8 to 10 groups was 40, 76 and 51 respectively. There was no significant difference in survival rate between well and moderately differentiated groups, but the survival rate of the group with poorly differentiated tumor was significantly lower than that of the moderately differentiated (p less than 0.01) and well differentiated (p less than 0.001) groups. There was no significant difference in 10-year survival rate between the score 2-4 and score 5-8 groups, but the score 9-10 group had a significantly lower survival rate than the score 5-8 group (p less than 0.01) and score 2-4 (p less than 0.005) group. JGRPC and Gleason's classification are thought to be equally useful in estimating prognosis of prostatic cancer, but the former is more concise and easily applicable than the latter.     

Prostate cancer grading: the effect of stratification of needle biopsy Gleason Score 4 + 3 as high or intermediate grade

Study Type – Prognosis (case series)
Level of Evidence 4

OBJECTIVES

To assess the discrepancy between needle biopsy (NB) and radical prostatectomy (RP) Gleason score (GS) in Irish men, specifically the influence of the stratification of GS 4 + 3 on overall levels of agreement, levels of discrepancy and κ coefficients, as the GS assigned to prostate cancer NBs affects clinical decision‐making and influences future therapeutic strategies.

PATIENTS AND METHODS

We reviewed retrospectively a database of the discrepancies between NB and RP Gleason grades (GG) from 2003 to 2008. All patients had clinically localized prostate cancer, and none had had neoadjuvant therapy. Grading of 206 NB specimens was compared with their corresponding RP specimens. The discrepancy rate between NB and RP GS was assessed for each combination of GG. Intermediate‐ (GS 7, defined as GS 3 + 4 alone vs GS 7) and high‐grade (GS 4 + 3 and GS 8–10 vs GS 8–10) classifications were compared. The level of agreement and the κ coefficient for each system was assessed.

RESULTS

In NB, GS 6 was most frequently diagnosed (53%); after RP, GS 3 + 4 was most frequent (36%). In 42% of cases the exact GG remained unchanged after RP, increasing to 48% for GS 6 and GS 3 + 4. Overall 42% of cases showed an increase in their GG. In GS 6 NBs, the rate of increase in the primary GG or increase in the GS was 52%. Biopsy GS 6 and 3 + 4 showed the highest levels of agreement between NB and RP. Low‐grade prostate cancer on NB was upgraded in 52% of cases; high‐grade prostatic adenocarcinoma was downgraded in 27–77% of cases depending on the grading system used.

CONCLUSIONS

Classification of high‐grade prostate cancer as GS 4 + 3 and GS 8–10 results in higher levels of agreement between NB and RP GS. Reliable identification of well differentiated prostatic adenocarcinoma in NB specimens represents an ongoing diagnostic challenge, necessitating careful preoperative consideration of the definitive grade of a patient’s disease.     

Gleason grading of prostate cancer: a predictor of survival

The Gleason grading system was employed in the pathologic assessment of 82 patients with carcinoma of the prostate diagnosed between 1962-1965 and subsequently followed to death. The data suggest that the Gleason grade gives long-term prognostic information independent of stage with a direct correlation between increasing Gleason grade and cancer death rate index. Furthermore, the sum of clinical stage plus Gleason grade is a more significant prognostic factor than either stage or grade alone.     

Combined histoarchitectural and cytological biopsy grading improves grading accuracy in low-grade prostate cancer

Objectives: Accurate tumor grading on prostate biopsy represents the mainstay for therapy planning. Biopsy undergrading is a persistent diagnostic dilemma with therapeutic relevance. We questioned whether Gleason grading combined with an established alternative grading system incorporating cytological parameters improves grading accuracy. Methods: Needle biopsies of 968 patients and the corresponding radical prostatectomy specimens were graded according to the Gleason grading system. In addition, all biopsies were graded according to the histo‐ and cytological grading system of Helpap. Biopsy Gleason grade, as well as the combined Gleason/Helpap grade, was compared with the final Gleason score and the pathological tumor‐stage of the corresponding radical prostatectomy. Results: In biopsy Gleason score 6 cancers, an upgrading was seen in 76.0% of the patients (98/129), and 30.2% of them (39/129) showed non‐organ confined disease. In combined biopsy Gleason 6/Helpap 2a patients, a final Gleason score of 6 was found in 22 out of 24 patients (91.7%, P < 0.0001), and all 24 patients showed organ‐confined disease (pT2a). In biopsy Gleason 6/Helpap 2b cancers, a final Gleason score of 6 was found in just 9 out of 105 patients (8.6%), and the rate of organ‐confined disease decreased to 62.8% (66/105, P = 0.0001). In higher Gleason grades, combined biopsy grading failed to show a diagnostic benefit over sole Gleason grading. Conclusion: Combined biopsy Gleason/Helpap grading improves the identification of low‐grade/low‐stage cancers and might contribute to more precise therapy planning in prostate cancer management.     

Comparative evaluation of national prostatic cancer treatment group and gleason systems for pathologic grading of primary prostatic cancer

Multivariable analysis was used to investigate the relationship between risk of disease progression or death in patients who were treated with adjuvant therapy after definitive treatment for prostatic adenocarcinoma and the components of the National Prostatic Cancer Treatment Group (NPCTG) and Gleason systems for pathologic grading of prostatic cancer. Data were available for 203 patients who were treated on NPCTG Protocols 900 and 1,000, which involve surgical and radiation therapy as definitive treatment. Since less than 10 per cent of these patients have died, analysis of survival was not attempted. The study focus was progression free survival, which is the minimum of time to progression or death. The analysis demonstrates that a new measure, the NPCTG score (the sum of the glandular and nuclear grades) is superior to the previously reported NPCTG grade (the maximum of the two grades). In addition, the Gleason score is somewhat superior to the new NPCTG score. All of this, however, applies only to the primary tumor and not the nature of any present or future metastatic lesions.     

Histological grading of prostatic carcinoma in prostatectomy specimens. Comparison of prognostic accuracy of five grading systems

The prognostic accuracy of 5 histological grading systems (Broders, Anderson, Mostofi, Gleason and Mostofi-Schroeder) was compared. Grading was performed on 50 prostatectomy specimens by 5 pathologists. The results were averaged so as to reduce the impact of inter-observer variation. The Cox proportional hazards model was used to estimate the relationship between average grading scores and both time-to-recurrence and time-to-death by prostatic carcinoma. Age at surgery was considered to be a possible confounding factor and adjusted accordingly. The prognostic impact of the 5 grading systems (related to both recurrence and death caused by prostatic carcinoma) was judged by the likelihood ratio (LR) test score (chi 2 distributed with 1 df); for time-to-recurrence for the Mostofi-Schroeder score the LR was 6.54 and for the Gleason system it was 1.79. A stepwise procedure demonstrated that the best prognostic performance was reached with the Mostofi-Schroeder and Broders systems used together (with Mostofi-Schroeder weighted 1.5 times larger than Broders). For time-to-recurrence the median grading result was also used, giving results similar to the mean grading result. For time-to-death from prostatic carcinoma the LR test scores for all grading systems were relatively low. In this analysis the outcome of the Gleason system showed a minimum of prognostic ability, whereas the Broders and Mostofi-Schroeder systems had a reasonable predictive ability. Since the inter-observer variation of the Mostofi-Schroeder system was large, the Broders system is preferable. The restrictions and implications of this study are discussed and a brief review of the prognostic importance of grading of prostatic carcinoma is presented.     

Reproducibility and prognostic value of Gleason's and Gaeta's histological grades in prostatic carcinoma

Two histopathologic grading systems for prostatic adenocarcinomas are reevaluated: the Gleason system and the Gaeta system. Two pathologists reviewed 234 specimens to assess reproducibility. Exact agreement is achieved in 88% with the Gaeta system, in 65% with the Gleason system. Nevertheless, agreement to within one score unit is achieved in 94% with the Gleason grading. One pathologist's autoreproducibility exceed 80% with either system. Actuarial survival curves and mortality index (deaths per patient-year of follow-up) provided evidence of their predictive value. Regardless of the clinical stage these two grading systems select groups of patients sharing a good, intermediate or bad prognosis but none can predict a given patient's accurate survival. The Gleason system would allow a better discrimination between poorly and highly aggressive tumors of intermediate grade.     

Relationship between histologic grading and serum prostate specific antigen in prostatic carcinoma

Prostate specific antigen (PSA) is the most important tumour marker which, used routinely, proved to have a positive correlation with tumour volume and pathological stage. To evaluate the relationship between serum PSA and histologic grading of prostatic carcinoma, preoperative PSA determinations were made in 25 patients with prostatic cancer. Biopsy materials were evaluated and the Gleason scores were adjusted for histologic grading. The higher values of PSA were proportional to the Gleason scores of the primary prostatic biopsy.     

Lymphovascular invasion is an independent prognostic factor in prostatic adenocarcinoma

PURPOSE: Gleason grade and tumor stage are well established prognostic factors in prostate cancer. Histological demonstration of tumor in lymphovascular spaces has been associated with poor prognosis in many tumor types but it is not included in current prostate cancer grading and staging schemes. Whether lymphovascular invasion is an independent prognostic factor for disease progression in prostate cancer is uncertain. We retrospectively investigated lymphovascular invasion as a predictive factor for biochemical failure and cancer specific survival following radical prostatectomy. MATERIALS AND METHODS: The records of 504 patients with prostatic adenocarcinoma undergoing radical prostatectomy were reviewed for lymphovascular invasion. Clinical followup data were available on 459 cases. Mean followup was 44 months (range 1.5 to 144). Multivariate analysis was performed using the Cox model. RESULTS: Lymphovascular invasion was identified in 106 cases (21%). Univariate analysis showed a significant association between lymphovascular invasion and higher preoperative serum prostate specific antigen (PSA), advanced pathological stage, higher Gleason score, positive surgical margins, extraprostatic extension, seminal vesicle invasion, lymph node metastasis and perineural invasion (each p <0.001). No association was observed between lymphovascular invasion and patient age at surgery, prostate weight or high grade prostatic intraepithelial neoplasia. Lymphovascular invasion was an independent predictor of PSA recurrence (HR 1.6, 95% CI 1.12 to 2.38, p = 0.01) and cancer specific survival (HR 2.75, 95% CI 1.04 to 2.28, p = 0.041) after controlling for tumor stage, surgical margins and Gleason grade on multivariate analysis. Five-year cancer specific survival was 90% in men with lymphovascular invasion compared to 98% in those without lymphovascular invasion (p <0.001). CONCLUSIONS: Lymphovascular invasion can be identified in approximately 20% of prostate cancer cases. Lymphovascular invasion is an independent risk factor for PSA recurrence and cancer death in patients with prostate cancer.     

Mast cell variations in tumour tissue and with histopathological grading in specimens of prostatic adenocarcinoma.

OBJECTIVE: To determine whether the number of mast cells (MCs) varies in and around prostatic carcinoma tissue, and with histopathological grading. MATERIALS AND METHODS: Specimens of 27 prostatic carcinomas were stained with the toluidine blue and staged histopathologically using the Gleason grading system. The MCs were counted in five high-power microscopy fields within and around the tissue samples, and the results analysed using the Wilcoxon signed-rank test and Spearman's correlation. RESULTS: The mean number of MCs was 1.7 per field within and 3.31 per field around the cancer tissue, the difference between these being significant (P<0. 05). There was a close correlation between the numbers of MCs within the tumour and Gleason grade (r=0.56, P=0.002) but not between grade and counts around the tumour (r=-0.18, P=0.35). CONCLUSION: These results suggest that some MCs aggregate at the periphery of the prostatic adenocarcinoma and that the number of MCs within the tumour tissue is related to tumour differentiation.     

Evaluation of prostatic cancer histology and grade distribution: experience with the Colorado Central Cancer Registry

Although well-defined grading schemes for prostatic adenocarcinoma have been developed, they are not yet universally accepted by practicing surgical pathologists. The complexity of these schemes often leads surgical pathologists to develop their own modified Broders scheme. This study compared the grade distribution as obtained by a community of surgical pathologists with that obtained using the National Prostatic Cancer Project (NPCP) and Gleason grading schemes. In 1978, 308 cases of prostate cancer were reported to the Colorado Central Cancer Registry (CCCR) from the Denver Standard Metropolitan Statistical Area. Two hundred eighteen of these cases were regraded. The grade distribution as reported by the CCCR revealed a predominance of low-grade tumors (grade I-41%, grade II-28%, grade III-17%, grade IV-3%). Regrading of these same cases revealed a shift to higher grades (NPCP: grade I-14%, grade II-11%, grade III-37%, grade IV-29%; Gleason: pattern scores less than 6-30%, score 6-24%, score 7-12%, score 8-11%, score 9-10%, score 10-4%). Twenty-one cases of histologic variants which were not originally diagnosed were also noted (six mucinous, 12 ductal, two endometroioid, one squamous). There were 18 cases in which no evidence of carcinoma was confirmed. These results suggest that there is a tendency to underestimate grade and potentially malignant behavior when well-defined prostatic cancer grading schemes are not applied.     

Experience with Gleason histopathologic grading of prostatic cancer in Japan

Histologic characteristics of prostate cancer in Japan were evaluated in a retrospective analysis of 267 cases. These specimens were graded by the Gleason histopathologic grading system, and the proportional distribution of histologic features and the death rate were compared with those of Gleason's results in the literature. The system demonstrates significant correlation with mortality rates for each grade group in our cases, and it was also found that the death rates as obtained by our figures were comparable to those of Gleason in each category. The results help to provide the basis for future comparative multinational trials of prostate cancer.     

Flow cytometric DNA analysis of stage D2 prostatic carcinoma.

Flow cytometric DNA analysis was performed on 34 samples of prostatic carcinoma patients with stage D2 disease to study the relationship between DNA ploidy pattern, Gleason sum score, and prognosis. Nuclei were extracted from paraffin-embedded needle biopsy specimens. The DNA ploidy pattern was diploid in 53% of the tumors, tetraploid in 38%, and aneuploid in 9%. A significant correlation between DNA ploidy pattern, Gleason sum score, and prognosis was not proved. It was considered that DNA ploidy pattern and Gleason sum score of limited primary lesion did not allow a prognosis of the patients with stage D2 prostatic carcinoma to be made.     

Intraobserver and interobserver reproducibility of WHO and Gleason histologic grading systems in prostatic adenocarcinomas

In this study a total of 96 patients with prostatic carcinoma were evaluated retrospectively. Sections prepared from paraffin blocks were examined and all cases were scored according to the World Health Organization (WHO) and Gleason grading systems. We investigated intraobserver and interobserver reproducibility of two grading systems in prostatic adenocarcinomas. In our study the intraobserver reproducibilities of the WHO and Gleason systems were 75.0% and 78.1%, respectively. The interobserver reproducibilities of the WHO and Gleason grading systems were 60.4% and 70.8%, respectively. While there was no difference between intraobserver and interobserver variations in the Gleason system (p>0.05), there was significant difference between intraobserver and interobserver variations in the WHO system (p<0.05).     

Grading of Prostate Cancer: Past,Present, and Future

The grading of prostate cancer has undergone significant changes since the adoption of the Gleason grading system in the 1970s. Gleason patterns 1 and 2 are no longer in use and the current Gleason score 6 of 10 is the lowest grade possible. Several specific morphologies that were historically considered Gleason grade 3 are currently assigned a Gleason pattern 4. Consequently, current Gleason score 6 cancers have a better prognosis than historic ones. There is now ample literature that supports that Gleason score 7 includes patients with very different prognosis; those with Gleason score 3?+?4 have a much better prognosis than patients with Gleason score 4?+?3. Within patients with high-grade cancer, it is now also clear that patients with Gleason score 8 have a significantly better prognosis than men with Gleason scores 9–10. Additionally, more recent studies have demonstrated that there is no significant difference in the prognosis of patients with Gleason score 9 or 10, making the distinction between the two pointless. A new contemporary grading system has been proposed that addresses these changes/problems and provides a simpler system with only five grades that reflect more accurately the prognosis of each group. We review the different changes applied to the Gleason scoring system since its conception as well as the studies leading to a new contemporary grading system.     

Tertiary Gleason pattern 5 is a powerful predictor of biochemical relapse in patients with Gleason score 7 prostatic adenocarcinoma

PURPOSE: In radical prostatectomy specimens Gleason score 7 is among the most commonly assigned scores for prostate carcinoma accounting for 30% to 50% of cases. Gleason score 7 is different from other more differentiated prostate carcinomas (tumors of Gleason scores 5 and 6) with a significantly worse outcome and higher rate of recurrence. Nonetheless, Gleason score 7 tumors are heterogeneous. In this study we examined the differences in clinical outcome between primary Gleason grade 3 and 4 tumors in patients who underwent radical prostatectomy, and determined the influence of tertiary Gleason pattern 5 on patient outcome. MATERIALS AND METHODS: A total of 504 patients underwent radical prostatectomy for prostate cancer and 228 of the patients (45%) had a Gleason score of 7. Cases were analyzed for a variety of clinical and pathological parameters. The influence of primary Gleason pattern and tertiary Gleason pattern 5 on patient outcome was assessed in the Cox regression model. RESULTS: Among 228 patients with Gleason score 7 prostatic adenocarcinoma, 91 (40%) had a primary Gleason pattern 4 and 137 (60%) had primary Gleason pattern 3. Patients of the former group were more likely to have a higher pathological stage (p = 0.003), more likely to have PSA recurrence (p = 0.02) and more likely to have a tertiary Gleason pattern 5 (p <0.0001). A total of 37 (41%) patients with primary Gleason 4 had a tertiary Gleason pattern 5, whereas only 13 (9%) patients with primary Gleason 3 had a tertiary Gleason pattern 5. In the Cox regression model controlling for tumor stage and surgical margin status, the primary Gleason pattern was not an independent predictor of PSA recurrence (p = 0.80), whereas the presence of tertiary Gleason pattern 5 was a significant predictor of PSA recurrence (hazard ratio 2.10, 95% CI 1.24-3.55, p = 0.006). Five-year PSA recurrence-free survival was 70% for patients without a tertiary Gleason pattern 5 compared to 19% for those patients with a tertiary Gleason pattern 5. CONCLUSIONS: Among patients with Gleason score 7, primary Gleason grade 4 indicates a likelihood of higher tumor stage and higher probability of PSA recurrence than does primary pattern 3. However, it does not independently predict a worse outcome after controlling for other known prognostic parameters associated with disease progression. Regardless of whether the primary Gleason pattern is 3 or 4, a tertiary Gleason pattern 5 is the strongest predictor of a worse outcome in patients with Gleason grade 7 prostatic adenocarcinoma. Therefore, tertiary pattern 5 should be reported in radical prostatectomy specimens.     

Clinical validity of proliferating cell nuclear antigen as an objective marker for evaluating biologic features in patients with untreated prostate cancer

BACKGROUND: Although Gleason grading may be the most useful system for evaluating biological activity of untreated prostate cancer, lack of interobserver validity with Gleason scores (GS) is an unsolved issue. In this study, the proliferating cell nuclear antigen labeling index (PCNA LI) in untreated prostate cancer was investigated in order to clarify the usefulness of supplemental and objective markers for evaluating the biologic features of prostate cancer. METHODS: Sixty cases of prostate cancer were randomly selected from the cancer registry in Gunma University Hospital for this study. PCNA LI were evaluated using paraffin-embedded biopsy cores taken at diagnosis. Correlation of PCNA LI with the Gleason grading system, clinical stage, serum prostate-specific antigen (PSA) levels and age were evaluated. Cumulative rates of freedom from cause-specific death were also evaluated stratified by various clinicopathologic features, including PCNA LI using Kaplan-Meier analysis. RESULTS: Proliferating cell nuclear antigen labeling index was significantly higher in patients with PSA levels over 100 ng/mL, advanced clinical stage (>T4, N1 or M1 disease), higher Gleason grade or with a higher GS than in those with other clinicopathologic features. The 5-year cumulative rate of death from prostate cancer was significantly higher at 62% in patients with a PCNA LI of 20 or more than those with PCNA LI of less than 20, who accounted for 4%. CONCLUSIONS: Proliferating cell nuclear antigen labeling index in combination with Gleason grading system may be of clinical value in evaluating biologic features and also in predicting cause specific survival of prostate cancer in an objective, reliable and reproducible manner.     

The prognostic significance of tertiary Gleason pattern 5 in radical prostatectomy specimens

In the Gleason grading system for prostatic cancer only the two most prevalent patterns are reported, although a third (tertiary) pattern grade may be present. We compared the pathologic stage of 227 radical prostatectomies with tertiary pattern 5 to the pathologic stage of 604 radical prostatectomies lacking a tertiary component. Gleason score 3 + 4 tumors with a tertiary pattern of 5 were more likely to present with higher stage disease than those Gleason score 3 + 4 tumors without a tertiary component (P = 0.012) and at a stage similar to Gleason score 3 + 5 tumors. Gleason score 4 + 3 tumors with a tertiary pattern of 5 were less likely to be organ-confined than Gleason score 4 + 3 tumors (P = 0.02) and less likely to have lymph node metastases than Gleason score 4 + 4 tumors (P = 0.027). However, Gleason score 4 + 4 with a tertiary pattern of 5 were indistinguishable from Gleason score 4 + 4 tumors. The relative effects of a tertiary pattern of 5 were greatest when the primary and secondary stages were low but become obscured by the already aggressive nature of advanced primary and secondary patterns. Therefore, except for very high-grade tumors, tertiary scoring of prostatic adenocarcinoma at radical prostatectomy should be reported as it has prognostic significance.