|Ahead of print publication
Contemporary grading of prostate cancer: 2017 update for pathologists and clinicians
Silvia Gasparrini1, Alessia Cimadamore1, Marina Scarpelli1, Francesco Massari2, Andrea Doria1, Roberta Mazzucchelli1, Liang Cheng3, Antonio Lopez-Beltran4, Rodolfo Montironi1
1 Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy
2 Division of Oncology, S. Orsola-Malpighi Hospital, Bologna, Italy
3 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
4 Department of Pathology and Surgery, Faculty of Medicine, Cordoba, Spain
|Date of Submission||17-Feb-2017|
|Date of Acceptance||26-May-2017|
|Date of Web Publication||04-Aug-2017|
Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy
Source of Support: None, Conflict of Interest: None
The Gleason grading system for prostate cancer (PCa) was developed in the 1960s by DF Gleason. Due to changes in PCa detection and treatment, the application of the Gleason grading system has changed considerably in pathology routine practice. Two consensus conferences were held in 2005 and in 2014 to update PCa Gleason grading. This review provides a summary of the changes in the grading of PCa from the original Gleason grading system to the prognostic grade grouping, as well as a discussion of the clinical significance of the percentage of Gleason patterns 4 and 5.
Keywords: Gleason grading; Gleason system; prognostic grade grouping; prostate cancer; tertiary pattern
Article in PDF
|How to cite this URL:|
Gasparrini S, Cimadamore A, Scarpelli M, Massari F, Doria A, Mazzucchelli R, Cheng L, Lopez-Beltran A, Montironi R. Contemporary grading of prostate cancer: 2017 update for pathologists and clinicians. Asian J Androl [Epub ahead of print] [cited 2018 Jul 20]. Available from: http://www.ajandrology.com/preprintarticle.asp?id=212223
Silvia Gasparrini, Alessia Cimadamore
These authors contributed equally to this work.
| Introduction|| |
Treatment of prostate cancer (PCa) is based on the clinical and pathological features that predict the course of the disease. The risk of local or systemic recurrence is usually based on data obtained from prostate needle biopsy or radical prostatectomy (RP) specimens. The Gleason grading system is one of the most important prognostic factors.,,
In 1966, DF Gleason created a grading system for PCa based on tumor architectural patterns. Dr. Gleason recognized the heterogeneity of PCa by assigning two grades to the two most common architectural patterns, reported as the Gleason score (GS). Dr. Gleason reported that the presence of more than two architectural patterns was quite rare to allow for an accurate evaluation of the prognostic role of the third most prevalent pattern (i.e., the tertiary pattern).
The management of PCa has changed since the original system was proposed. In particular, patients in the 1960s and 1970s were not treated with RP because they presented with advanced disease and because of the greater morbidity associated with surgery; therefore, grading of RPs with multiple tumor foci and tertiary patterns was not fully investigated by Dr. Gleason. With the PSA screening and 18-gauge needle biopsies, pathologists faced new issues, such as how to report multiple cores with PCa of different GSs and how to grade small amounts of PCa. Pathologists needed guidance for applying the grade to newly described histological patterns and variants of PCa, and modifications of the original Gleason system were needed to reflect the modern practice. The Gleason grading system has undergone changes as a result of two International Society of Urological Pathology (ISUP) consensus conferences held in 2005 and 2014.,
A summary of the changes to PCa grading from the original Gleason grading system to the latest prognostic grade grouping is presented. This review also includes a discussion of the clinical significance of the percentage of Gleason patterns 4 and 5.
| The 2005 and 2014 Modified Gleason Grading Systems|| |
One of the biggest changes to the Gleason grading system was the classification of Grades 1 and 2. Grade 1 tumors are generally benign, and Grade 2 tumors do not appear to differ from those classified as Grade 3. In 2005, Grade 2 was recommended to be used "rarely, if ever," and in the 2014 modified Gleason grading system, grading started from 3. This modification accounted for some of the observed rises in Gleason scores. A second change causing an increase in Gleason scores was the narrowing of the definition of Gleason 3 and concomitant expansion of Gleason 4.
From the 2005 to the 2014 consensus conferences, the histologic criteria for Gleason patterns 3 and 4 changed, resulting in the reduction of pattern 3 and expansion of pattern 4. In the original system, pattern 3 included some cribriform as well as poorly formed glands. Only well-formed discrete glands are included in pattern 3 in the 2014 modified Gleason grading system. In particular, cribriform glands lacking basal cells, independently of their morphology and size, are considered as pattern 4 in the 2014 modified Gleason system.,,,,,,,,,,, Fused, poorly formed, and glomeruloid glands are part of the morphologic spectrum of the current Gleason pattern 4.
As some patterns that were previously included in Gleason pattern 3 are now considered pattern 4, PCas with a GS of 3 + 3 = 6 based on the ISUP 2014 modified system have a far better prognosis than PCas with a GS 6 based on the original Gleason system. The concordance between biopsy and RP grades has also improved.,,
A further modification to the grading system in 2005 with regard to needle biopsy was that for high-grade tumors, the lower grade or pattern should not be included in the GS if it is <5% of the tumor. In needle biopsy findings with three distinct patterns, the most prevalent pattern is combined with the highest grade to form the GS, thus discarding to the second most common pattern. Grading is based on the "first plus the worst," that is, the most prevalent pattern plus the highest grade, such that if patterns 3, 4, and 5 are present in that order of prevalence, the grade is 3 + 5 = 8.
A recommendation from the 2014 consensus conference was that the percentage of pattern 4 is recorded in all GS 7 (3 + 4, 4 + 3) tumors., This further stratifies GS 7 and allows for identification of tumors with a limited (i.e., ≤10%) or extensive (i.e., >75%) amount of pattern 4. The practical value is that selected patients with GS 7 (3 + 4) and a small amount of pattern 4 (such as ≤10%) may be still enrolled in active surveillance programs.,,
Main limitations of the 2005 and 2014 modified Gleason scoring systems
From a clinical perspective, the 2005 and 2014 modified Gleason systems are suboptimal due to several reasons as follows:,,,,,
- Patients with GS 3 + 3 = 6 are considered to have intermediate-risk cancer, even though GS 6 is the lowest score used on prostate biopsies
- The category of GS 7 includes tumors with 3 + 4 = 7 and 4 + 3 = 7, with studies showing better outcome for GS 7 with primary pattern 3 versus 4
- GS 9-10 tumors have a poorer prognosis than that seen with GS 4 + 4 = 8 tumors,
- Different grouping systems have been used to combine tumors with different GSs for treatment as well as for estimated prognosis.
| Grade Groups|| |
A novel grading system for PCa was adopted in 2014 to address some of the above limitations, which included five distinct Grade Groups (GGs), from 1 to 5 ([Table 1]). The clinical importance of the GGs has been shown in clinical studies ([Table 2]).,,,,,,,,,,,, However, it has been suggested that the GG system should be used in parallel with the 2014 Gleason grading system.,
|Table 2: Studies showing the clinical significance of the grade groups system |
Click here to view
Genomics and grade group
A genomic study using whole exome and genome sequencing data from 426 localized PCas treated by RP supports the clinical significance of the prognostic GGs. This study showed an increase in the frequency of both genomic deletions and amplifications associated with an increasing risk strata and of nonsynonymous point mutations. Low-risk GG 1 tumors were haploid, whereas GG 2-5 tumors showed an increasing frequency of polyploidy. Distinct genomic profiles among the five GGs were seen with Principal Component Analysis, giving support to GG 1 through GG 3 being distinct categories; however, there is genomic similarity between GG 4 and GG 5.
Excellent prognosis for GG 1
PCa with GS 6 is not considered to be a lethal cancer, even though tumor progression and/or lymph node deposits have been documented in a small number of patients., In a study of 395 RPs, where 151 patients were GG 1 (i.e., GS 3 + 3 = 6), four of the patients with GG 1 (2.6%) showed disease recurrence and progression, three were alive after a mean follow-up of 82 months, and one died after 108 months. A histologic review of the slides of these four patients resulted in an upgrade of three cases to GG 2 (i.e., GS 3 + 4 = 7), while the fourth case was still considered as a GG 1 (i.e., GS 3 + 3 = 6) albeit with positive surgical margins. Aside from the three patients with a minor component of pattern 4 (two cribriform and one glomeruloid) and one patient with positive surgical margins, the other 147 patients were GG 1 (i.e., GS 3 + 3 = 6) and remained alive without tumor relapse or recurrence after a follow-up period of 8-10 years.
Such observations are in agreement with another study, in which no disease-specific death or metastasis was observed in patients with GS ≤6 PCa at RP. Similarly, an earlier study concluded that lymph node metastases do not occur with GS ≤6 tumors, and Gleason patterns 4 or 5 are needed for metastatic PCa. It should be noted that GS 6 tumors have cancerous morphology and exist on a molecular continuum with higher GSs.
Additional studies are needed to investigate the clinical utility of the new GG system in prospective clinical trials. Studies correlating current PCa diagnosis methods with multiparametric magnetic resonance imaging (mpMRI) and PCa GG are yet to be conducted. It is hoped that information will be derived on whether mpMRI can also be used to determine the proportion of high-grade cancer and GGs., This will have a great importance in the multidisciplinary management of patients with PCa, including treatment by urologists, oncologists, uropathologists, and radiation oncologists.
| Clinical Significance of The Percentage of Gleason Patterns 4 and 5|| |
In tumors with GS >7, the percentage of Gleason patterns 4 and 5 has clinical significance from a prognostic perspective. In particular, the presence of even a smaller amount of Gleason pattern 5 (tertiary) is associated with a greater risk of biochemical recurrence. Therefore, the presence of Gleason patterns with unfavorable prognosis in localized PCa, such as Gleason pattern 5, is known to be associated with an increased risk of tumor recurrence and metastasis after primary treatment with RP, external beam radiation therapy, or brachytherapy. According to one study, one of the most accurate predictors of patient outcome is the combined percentage of Gleason patterns 4 and 5, with this method having apparent superiority over GS for identification of patients with an increased risk of disease progression. Evaluation of the combined percentage of Gleason patterns 4 and 5 in RP specimens is recommended, and the percentage of high-grade cancer in a RP specimen should be considered during assessment of patient prognosis and the selection of potential treatment options.
There is evidence to support the clinical utility of including the percentage of high-grade tumor component in the pathology report., However, there is no agreement on how the percentage of Gleason patterns 4 and 5 is to be recorded. For instance, it could be in intervals of 10% or of <5%, 5%-10%, 10%-25%, 25%-50%, 50%-75%, and >75%.
Tertiary pattern 5, grade groups, and integrated quantitative Gleason score
Several studies have evaluated the prognostic significance of tertiary Gleason pattern 5 both in biopsy and in RP.,,,,,,,,,,,,,,,,,,,,,,, The method for reporting the presence of tertiary Gleason pattern 5 on RP specimens has been controversial. The 2005 ISUP consensus conference recommended the inclusion of Gleason pattern 5 in the final GS if it is >5% of the tumor, or to consider it as a tertiary pattern if it is <5% of the tumor. According to the 2014 ISUP consensus conference, tertiary patterns should only be recorded in RP specimens with either 3 + 4 = 7 or 4 + 3 = 7.
It is unclear how to integrate small Gleason pattern 5 components into GG classification. Concerning the tertiary pattern 5 on RP specimens with GS 3 + 4 = 7 and 4 + 3 = 7 tumors, these would be considered to be GG 2 and GG 3, respectively, with a minor higher grade component, or as GGs >2 or >3.,, Following the 2014 ISUP consensus conference, publication of a separate report was planned, with recommendations relating to special scenarios, such as patients with a small percentage of high-grade tumor, tertiary grade patterns, utilization of pattern 4 percentage, and case- versus core-level reporting. Gleason 3 + 5 = 8 cancer is a type of special case, and this biopsy finding predicts an outcome similar to 4 + 4 = 8 tumors, suggesting that 3 + 5 = 8 belongs to GG 4.
Detection of cribriform glands confers a 6-fold odds ratio of PSA failure and an increased risk of metastasis or death. An ongoing shortcoming of the GG grading system is that large gland spaces with cribriform-to-papillary-to-almost-solid cell arrangements (without basal cells, or intraductal carcinoma if basal cells are present) are graded as Gleason pattern 4, which is identical to the fused small gland pattern, yet the outcome for cribriform/intraductal glands is demonstrably more adverse.,,
Since 2011, more than a dozen studies have confirmed the uniquely adverse implications of the cribriform pattern. As a result, urologic pathology reports are required to specify whenever a cribriform growth pattern is present. One of the main practical implications of cribriform/intraductal growth is preclusion of the patient's treatment choice of active surveillance. Ultimately, the presence of these growth patterns will need to be incorporated in the GG system.
An analysis of the role of the percentage of Gleason patterns 4 and 5 in a large cohort of more than 10 000 patients has demonstrated the importance of the percentage of these Gleason patterns in predicting PCa aggressiveness. A Gleason 5 component correlated with cancer progression and predicted, independently of its amount, further deterioration in the clinical course. A system for integration of both patterns into a continuous numerical scale or score, i.e., integrated quantitative (IQ) - Gleason score, was developed that provides a method for combining quantitative Gleason grading and tertiary Gleason patterns into a single prognostic value. This approach may enable clinicians to utilize the minor component of high-grade tumors and tertiary grade patterns in association with the PCa Gleason grading system, including the GGs.
| Conclusions|| |
The proposed GG system reduces PCa grades to the lowest number of grades, each being associated with a unique prognosis. This simplified grading system of five groups allows for more accurate stratification of patients than Gleason systems, with the potential for reducing overtreatment of PCa. The shift from a lowest value of 6 to 1 has a positive impact from a psychological perspective on patients' disease awareness, thus facilitating patients' choice of treatment, including prostatectomy, targeted cryoablation, radiotherapy, hormonal therapy, and active surveillance. In particular, GS 6 cancer is characterized by indolent growth with an excellent prognosis. However, it should still be considered potentially metastatic since it is rarely localized so as not to mislead patients seeking a cure. The GG system has been considered by the international community to be a new grading system, although most urologic pathologists consider it to be a novel grouping of the 2014 ISUP modified Gleason system.
| Author Contributions|| |
R Montironi and MS were involved in conception and design of the manuscript, R Mazzucchelli was involved in acquisition of data, FM was involved in analysis and interpretation of data, SG and AC were involved in preparation of drafting manuscript, ALB and LC were involved in critical revision of the manuscript for intellectual content, AD provided technical and material support, and RM (Rodolfo Montironi) supervised the preparation of the manuscript.
| Competing Interests|| |
All authors declared no competing interests.
| Acknowledgments|| |
This medical writing assistance was funded by the Polytechnic University of the Marche Region.
| References|| |
Montironi R, Santoni M, Mazzucchelli R, Burattini L, Berardi R, et al
. Prostate cancer: from Gleason scoring to prognostic grade grouping. Expert Rev Anticancer Ther
2016; 16: 433-40.
Magi-Galluzzi C, Montironi R, Epstein JI. Contemporary Gleason grading and novel Grade Groups in clinical practice. Curr Opin Urol
2016; 26: 488-92.
Yeong J, Sultana R, Teo J, Huang HH, Yuen J, et al
. Gleason grade grouping of prostate cancer is of prognostic value in Asian men. J Clin Pathol
2017; pii: jclinpath-2016-204276. [Doi: 10.1136/jclinpath-2016-204276].
Epstein JI, Allsbrook WC Jr, Amin MB, Egevad LL, Committee IG. The 2005 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma. Am J Surg Pathol
2005; 29: 1228-42.
Egevad L, Mazzucchelli R, Montironi R. Implications of the International Society of Urological Pathology modified Gleason grading system. Arch Pathol Lab Med
2012; 136: 426-34.
Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR, et al
. The 2014 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. Am J Surg Pathol
2016; 40: 244-52.
Dong F, Yang P, Wang C, Wu S, Xiao Y, et al
. Architectural heterogeneity and cribriform pattern predict adverse clinical outcome for Gleason grade 4 prostatic adenocarcinoma. Am J Surg Pathol
2013; 37: 1855-61.
Kweldam CF, Wildhagen MF, Steyerberg EW, Bangma CH, van der Kwast TH, et al
. Cribriform growth is highly predictive for postoperative metastasis and disease-specific death in Gleason score 7 prostate cancer. Mod Pathol
2015; 28: 457-64.
Kweldam CF, Nieboer D, Algaba F, Amin MB, Berney DM, et al
. Gleason grade 4 prostate adenocarcinoma patterns: an interobserver agreement study among genitourinary pathologists. Histopathology
2016; 69: 441-9.
Kweldam CF, Kümmerlin IP, Nieboer D, Verhoef EI, Steyerberg EW, et al
. Disease-specific survival of patients with invasive cribriform and intraductal prostate cancer at diagnostic biopsy. Mod Pathol
2016; 29: 630-6.
Kweldam CF, Kümmerlin IP, Nieboer D, Verhoef EI, Steyerberg EW, et al
. Prostate cancer outcomes of men with biopsy Gleason score 6 and 7 without cribriform or intraductal carcinoma. Eur J Cancer
2016; 66: 26-33.
Choy B, Pearce SM, Anderson BB, Shalhav AL, Zagaja G, et al
. Prognostic significance of percentage and architectural types of contemporary Gleason pattern 4 prostate cancer in radical prostatectomy. Am J Surg Pathol
2016; 40: 1400-6.
Keefe DT, Schieda N, El Hallani S, Breau RH, Morash C, et al
. Cribriform morphology predicts upstaging after radical prostatectomy in patients with Gleason score 3 + 4 = 7 prostate cancer at transrectal ultrasound (TRUS)-guided needle biopsy. Virchows Arch
2015; 467: 437-42.
McKenney JK, Wei W, Hawley S, Auman H, Newcomb LF, et al
. Histologic grading of prostatic adenocarcinoma can be further optimized: analysis of the relative prognostic strength of individual architectural patterns in 1275 patients from the Canary Retrospective Cohort. J Surg Pathol
2016; 40: 1439-56.
Iczkowski KA, Torkko KC, Kotnis GR, Wilson RS, Huang W, et al
. Digital quantification of five high-grade prostate cancer patterns, including the cribriform pattern, and their association with adverse outcome. Am J Clin Pathol
2011; 136: 98.
Berg KD, Thomsen FB, Nerstrom C, Roder MA, Iversen P, et al
. The impact of the 2005 International Society of Urological Pathology consensus guidelines on Gleason grading - A matched pair analysis. BJU Int
2016; 117: 883-9.
Billis A, Guimaraes MS, Freitas LL, Meirelles L, Magna LA, et al
. The impact of the 2005 International Society of Urological Pathology consensus conference on standard Gleason grading of prostatic carcinoma in needle biopsies. J Urol
2008; 180: 548-52.
Epstein JI. An update of the Gleason grading system. J Urol
2010; 183: 433-40.
Ozkan TA, Eruyar AT, Cebeci OO, Memik O, Ozcan L, et al
. Interobserver variability in Gleason histological grading of prostate cancer. Scand J Urol
2016; 50: 420-4.
Moch H, Humphrey PA, Ulbright TM, Reuter V. WHO Classification of Tumours of the Urinary System and Male Genital Organs. Lyon: International Agency for Research on Cancer; 2016.
Sauter G, Steurer S, Clauditz TS, Krech T, Wittmer C, et al
. Clinical utility of quantitative Gleason grading in prostate biopsies and prostatectomy specimens. Eur Urol
2016; 69: 592-8.
Morash C, Tey R, Agbassi C, Klotz L, McGowan T, et al
. Active surveillance for the management of localized prostate cancer: guideline recommendations. Can Urol J Assoc
2015; 9: 171-8.
Chen RC, Rumble RB, Loblaw DA, Finelli A, Ehdaie B, et al
. Active surveillance for the management of localized prostate cancer (Cancer Care Ontario Guideline): American Society of Clinical Oncology practice guideline endorsement. J Clin Oncol
2016; 34: 2182-90.
Srigley JR, Zhou M, Allan R, Amin MB, Chang SS, et al
. Protocol for the examination of specimens from patients with carcinoma of the prostate gland. Version: Prostate 184.108.40.206 Protocol. Posting date: June 2017. Website: www.cap.org/cancerprotocols
Chan TY, Partin AW, Walsh PC, Epstein JI. Prognostic significance of Gleason score 3 + 4 versus Gleason score 4 + 3 tumor at radical prostatectomy. Urology
2000; 56: 823-7.
Makarov DV, Sanderson H, Partin AW, Epstein JI. Gleason score 7 prostate cancer on needle biopsy: is the prognostic difference in Gleason scores 4 + 3 and 3 + 4 independent of the number of involved cores? J Urol
2002; 167: 2440-2.
Amin A, Partin A, Epstein JI. Gleason score 7 prostate cancer on needle biopsy: relation of primary pattern 3 or 4 to pathological stage and progression after radical prostatectomy. J Urol
2011; 186: 1286-90.
Pierorazio PM, Walsh PC, Partin AW, Epstein JI. Prognostic Gleason grade grouping: data based on the modified Gleason scoring system. BJU Int
2013; 111: 753-60.
D′Amico AV, Whittington R, Malkowicz SB, Fondurulia J, Chen MH, et al
. The combination of preoperative prostate specific antigen and postoperative pathological findings to predict prostate specific antigen outcome in clinically localized prostate cancer. J Urol
1998; 160: 2096-101.
O′Kelly F, Elamin S, Cahill A, Aherne P, White J, et al
. Characteristics of modern Gleason 9/10 prostate adenocarcinoma: a single tertiary centre experience within the Republic of Ireland. World J Urol
2014; 32: 1067.
Tsao CK, Gray KP, Nakabayashi M, Evan C, Kantoff PW, et al
. Patients with biopsy Gleason 9 and 10 prostate cancer have significantly worse outcomes compared to patients with Gleason 8 disease. J Urol
2015; 194: 91.
Epstein JI, Zelefsky MJ, Sjoberg DD, Nelson JB, Egevad L, et al
. A contemporary prostate cancer grading system: a validated alternative to the Gleason score. Eur Urol
2016; 69: 428-35.
Spratt DE, Cole AI, Palapattu GS, Weizer AZ, Jackson WC, et al
. Independent surgical validation of the new prostate cancer grade-grouping system. BJU Int
2016; 118: 763-9.
Spratt DE, Jackson WC, Abugharib A, Tomlins SA, Dess RT, et al
. Independent validation of the prognostic capacity of the ISUP prostate cancer grade grouping system for radiation treated patients with long-term follow-up. Prostate Cancer Prostatic Dis
2016; 19: 292-7.
Berney DM, Beltran L, Fisher G, North BV, Greenberg D, et al
. Validation of a contemporary prostate cancer grading system using prostate cancer death as outcome. Br J Cancer
2016; 114: 1078-83.
Samaratunga H, Delahunt B, Gianduzzo T, Coughlin G, Duffy D, et al
. The prognostic significance of the 2014 International Society of Urological Pathology (ISUP) grading system for prostate cancer. Pathology
2015; 47: 515-9.
Delahunt B, Egevad L, Srigley JR, Steigler A, Murray JD, et al
. Validation of International Society of Urological Pathology (ISUP) grading for prostatic adenocarcinoma in thin core biopsies using TROG 03.04 ′RADAR′ trial clinical data. Pathology
2015; 47: 520-5.
Loeb S, Folkvaljon Y, Robinson D, Lissbrant IF, Egevad L, et al
. Evaluation of the 2015 Gleason Grade Groups in a nationwide population-based cohort. Eur Urol
2016; 69: 1135-41.
Minardi D, Mazzucchelli R, Scarpelli M, Massari F, Ciccarese C, et al
. Prostate cancer glands with cribriform architecture and with glomeruloid features should be considered as Gleason pattern 4 and not pattern 3. Future Oncol
2016; 12: 1431-3.
Leapman MS, Cowan JE, Simko J, Roberge G, Stohr BA, et al
. Application of a prognostic Gleason Grade Grouping system to assess distant prostate cancer outcomes. Eur Urol
2017; 71: 750-9.
He J, Albertsen PC, Moore D, Rotter D, Demissie K, et al
. Validation of a contemporary five-tiered Gleason Grade Grouping using population-based data. Eur Urol
2017; 71: 760-3.
Dell′Oglio P, Karnes RJ, Gandaglia G, Fossati N, Stabile A, et al
. The new prostate cancer grading system does not improve prediction of clinical recurrence after radical prostatectomy: results of a large, two-center validation study. Prostate
2017; 77: 263-73.
Ham WS, Chalfin HJ, Feng Z, Trock BJ, Epstein JI, et al
. New prostate cancer grading system predicts long-term survival following surgery for Gleason score 8-10 prostate cancer. Eur Urol
2017; 71: 907-12.
Epstein JI. New prostate cancer grade group system correlates with prostate cancer death in addition to biochemical recurrence. Br J Cancer
2016; 114: 1069-70.
Epstein JI. Prostate cancer Grade Groups correlate with prostate-specific cancer mortality: SEER data for contemporary graded specimens. Eur Urol
2017; 71: 764-5.
Rubin MA, Girelli G, Demichelis F. Genomic correlates to the newly proposed Grading Prognostic Groups for prostate cancer. Eur Urol
2016; 69: 557-60.
Kryvenko ON, Epstein JI. Definition of insignificant tumor volume of Gleason Score 3 + 3 = 6 (Grade Group 1) prostate cancer at radical prostatectomy - Is it time to increase the threshold? J Urol
2016; 196: 1664-9.
Anderson BB, Oberlin DT, Razmaria AA, Choy B, Zagaja GP, et al
. Extraprostatic extension is extremely rare for contemporary Gleason score 6 prostate cancer. Eur Urol
2016; pii: S0302-2838(16)30880-6. [Doi: 10.1016/j.eururo. 2016.11.028].
Kweldam CF, Wildhagen MF, Bangma CH, van Leenders GJ. Disease-specific death and metastasis do not occur in patients with Gleason score ≤6 at radical prostatectomy. BJU Int
2015; 116: 230-5.
Ross HM, Kryvenko ON, Cowan JE, Simko JP, Wheeler TM, et al
. Do adenocarcinomas of the prostate with Gleason score (GS) <6 have the potential to metastasize to lymph nodes? Am J Surg Pathol
2012; 36: 1346-52.
Lotan TL, Carvalho FL, Peskoe SB, Hicks JL, Good J, et al
. PTEN loss is associated with upgrading of prostate cancer from biopsy to radical prostatectomy. Mod Pathol
2015; 28: 128-37.
Thurtle D, Hsu RC, Chetan M, Lophatananon A, Hubbard R, et al.
Incorporating multiparametric MRI staging and the new histological Grade Group system improves risk-stratified detection of bone metastasis in prostate cancer. Br J Cancer
2016; 115: 1285-8.
Gordetsky JB, Thomas JV, Nix JW, Rais-Bahrami S. Higher prostate cancer Grade Groups are detected in patients undergoing multiparametric MRI-targeted biopsy compared with standard biopsy. Am J Surg Pathol
2017; 41: 101-5.
Jackson W, Hamstra DA, Johnson S, Zhou J, Foster B, et al
. Gleason pattern 5 is the strongest pathologic predictor of recurrence, metastasis, and prostate cancer-specific death in patients receiving salvage radiation therapy following radical prostatectomy. Cancer
2013; 119: 3287-94.
Cheng L, Koch MO, Juliar BE, Daggy JK, Foster RS, et al
. The combined percentage of Gleason patterns 4 and 5 is the best predictor of cancer progression after radical prostatectomy. J Clin Oncol
2005; 23: 2911-7.
Egevad L, Delahunt B, Samaratunga H, Srigley JR. Utility of reporting the percentage of high-grade prostate cancer. Eur Urol
2016; 69: 599-600.
Diolombi ML, Epstein JI. Metastatic potential to regional lymph nodes with Gleason score ≤7, including tertiary pattern 5, at radical prostatectomy. BJU Int
2017; 119: 872-8.
Jang WS, Yoon CY, Kim MS, Kang DH, Kang YJ, et al
. The prognostic role of tertiary Gleason pattern 5 in a contemporary grading system for prostate cancer. Prostate Cancer Prostatic Dis
2017; 20: 93-8.
Adam M, Hannah A, Budäus L, Steuber T, Salomon G, et al
. A tertiary Gleason pattern in the prostatectomy specimen and its association with adverse outcome after radical prostatectomy. J Urol
2014; 192: 97-101.
Shah RB, Tadros Y. Adenocarcinoma of the prostate with Gleason pattern 5 on core biopsy: frequency of diagnosis, morphologic subpatterns, and relation to pattern distribution based on the modified Gleason grading system. Hum Pathol
2014; 45: 2263-9.
Lucca I, Shariat SF, Briganti A, Lotan Y, Roehrborn CG, et al
. Validation of tertiary Gleason pattern 5 in Gleason score 7 prostate cancer as an independent predictor of biochemical recurrence and development of a prognostic model. Urol Oncol
2015; 33: 71.e21-6.
Taguchi S, Shiraishi K, Fukuhara H, Nakagawa K, Morikawa T, et al
. Impact of Gleason pattern 5 including tertiary pattern 5 on outcomes of salvage treatment for biochemical recurrence in pT2-3N0M0 prostate cancer. Int J Clin Oncol
2016; 21: 975-80.
Kryvenko ON, Epstein JI. Re: clinical significance of prospectively assigned Gleason tertiary pattern 4 in contemporary Gleason score 3 + 3 = 6 prostate cancer. Prostate
2016; 76: 1130-1.
Ranaweera M, Samaratunga H, Duffy D, Klopfer K, Brunelli M, et al
. Tertiary Gleason pattern 5 on needle biopsy predicts greater tumour volume on radical prostatectomy. Pathology
2011; 43: 693-6.
Fajardo DA, Miyamoto H, Miller JS, Lee TK, Epstein JI. Identification of Gleason pattern 5 on prostatic needle core biopsy: frequency of underdiagnosis and relation to morphology. Am J Surg Pathol
2011; 35: 1706-11.
Trock BJ, Guo CC, Gonzalgo ML, Magheli A, Loeb S, et al
. Tertiary Gleason patterns and biochemical recurrence after prostatectomy: proposal for a modified Gleason scoring system. J Urol
2009; 182: 1364-70.
Servoll E, Saeter T, Vlatkovic L, Lund T, Nesland J, et al
. Impact of a tertiary Gleason pattern 4 or 5 on clinical failure and mortality after radical prostatectomy for clinically localised prostate cancer. BJU Int
2012; 109: 1489-94.
Trpkov K, Zhang J, Chan M, Eigl BJ, Yilmaz A. Prostate cancer with tertiary Gleason pattern 5 in prostate needle biopsy: clinicopathologic findings and disease progression. Am J Surg Pathol
2009; 33: 233-40.
Isbarn H, Ahyai SA, Chun FK, Budäus L, Schlomm T, et al
. Prevalence of a tertiary Gleason grade and its impact on adverse histopathologic parameters in a contemporary radical prostatectomy series. Eur Urol
2009; 55: 394-401.
Sim HG, Telesca D, Culp SH, Ellis WJ, Lange PH, et al
. Tertiary Gleason pattern 5 in Gleason 7 prostate cancer predicts pathological stage and biochemical recurrence. J Urol
2008; 179: 1775-9.
Whittemore DE, Hick EJ, Carter MR, Moul JW, Miranda-Sousa AJ, et al
. Significance of tertiary Gleason pattern 5 in Gleason score 7 radical prostatectomy specimens. J Urol
2008; 179: 516-22. [Discussion 522].
Pan CC, Potter SR, Partin AW, Epstein JI. The prognostic significance of tertiary Gleason patterns of higher grade in radical prostatectomy specimens: a proposal to modify the Gleason grading system. Am J Surg Pathol
2000; 24: 563-9.
Mosse CA, Magi-Galluzzi C, Tsuzuki T, Epstein JI. The prognostic significance of tertiary Gleason pattern 5 in radical prostatectomy specimens. Am J Surg Pathol
2004; 28: 394-8.
Matoso A, Epstein JI. Grading of prostate cancer: past, present, and future. Curr Urol Rep
2016; 17: 25.
Baras AS, Nelson JB, Han M, Parwani AV, Epstein JI. The effect of limited (tertiary) Gleason pattern 5 on the new prostate cancer Grade Groups. Hum Pathol
2017; 63: 27-32.
Hattab EM, Koch MO, Eble JN, Lin H, Cheng L. Tertiary Gleason pattern 5 is a powerful predictor of biochemical relapse in patients with Gleason score 7 prostatic adenocarcinoma. J Urol
2006; 175: 1695-9. [Discussion 1699].
van Oort IM, Schout BM, Kiemeney LA, Hulsbergen CA, Witjes JA. Does the tertiary Gleason pattern influence the PSA progression-free interval after retropubic radical prostatectomy for organ-confined prostate cancer? Eur Urol
2005; 48: 572-6.
Harding-Jackson N, Kryvenko ON, Whittington EE, Eastwood DC, Tjionas GA, et al
. Outcome of Gleason 3 + 5 = 8 prostate cancer diagnosed on needle biopsy: prognostic comparison with Gleason 4 + 4 = 8. J Urol
2016; 196: 1076-81.
Sauter G, Clauditz T, Steurer S, Wittmer C, Büscheck F, et al
. Integrating tertiary Gleason 5 patterns into quantitative Gleason Grading in prostate biopsies and prostatectomy specimens. Eur Urol
2017; pii: S0302-2838(17)30030-1. [Doi: 10.1016/j.eururo.2017.01.015].
Loeb S, Montorsi F, Catto JW. Future-proofing Gleason grading: what to call Gleason 6 prostate cancer? Eur Urol
2015; 68: 1-2.
[Table 1], [Table 2]