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Grading of prostate cancer in the 21st century

Abstract

Urologia 2016; 83(1): 1 - 3

Article Type: EDITORIAL

DOI:10.5301/uro.5000163

Authors

Jonathan I. Epstein, Rodolfo Montironi

Article History

Disclosures

Financial support: The authors have no financial disclosures to make.
Conflict of interest: The authors have no conflict of interest.

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The Gleason grading system was developed in the later 1960s and early 1970s by Dr. Donald Gleason (1-2-3). Due to changes in prostate cancer detection and treatment, newer technologies to better characterize prostatic pathology subsequently described variants of carcinoma, and additional data relating various morphologic patterns to prognosis and the application of the Gleason system, vary considerably in contemporary surgical pathology practice. First in 2005 and more recently in 2014, consensus conferences were held to update prostate cancer grading (4, 5). A summary of the changes in the grading of prostate cancer since the original Gleason systems along with the rationale for changing is presented below.

Gleason scores 2-4 are no longer assigned on needle biopsy and Gleason scores 2-5 are virtually never diagnosed on other types of prostate samples.

Rationale: The diagnosis of Gleason scores 2-4 suffer from (1) poor reproducibility even among experts; (2) poor correlation with prostatectomy grade with almost all cases showing higher grade at resection; and (3) a diagnosis of Gleason score 3-4 may misguide clinicians and patients into believing that the tumor is indolent. Very low-grade tumors exist, but there are small tumors in the transition zone that are not sampled on needle biopsy. Furthermore, in radical prostatectomy specimens, there are typically higher grade dominant nodules that determine the prognosis such that it is not necessary for the pathologist to comment in the pathology report on the smaller incidental lower grade lesions. Furthermore, on transurethral resections, it does not make a difference prognostically whether tumor occupying less than 5% of the specimen is in 3 + 3 = 6 or lower grade.

All cribriform glands, regardless of morphology, are graded as Gleason pattern 4.

Rationale: In the original Gleason diagram, variably sized, more regular cribriform glands were allowed in Gleason pattern 3, with more irregular cribriform glands assigned to pattern 4. This distinction was not based on any data presented in Gleason’s articles. In 2005, it was demonstrated that experts in prostate pathology virtually never diagnosed cribriform Gleason pattern 3, and when they did, there was very poor interobserver reproducibility in its diagnosis. Subsequently, numerous articles have demonstrated that cribriform morphology is associated with a relatively more aggressive prognosis, regardless of the morphology of the cribriform glands.

Poorly formed glands are also a component of Gleason pattern 4.

Rationale: In Gleason’s original diagram, only fused glands and irregular cribriform glands were included in pattern 4. However, experts in prostate pathology in more recent times have graded clusters of poorly formed glands as pattern 4. Their studies show that Gleason scores 3 + 4 = 7 and 4 + 3 = 7, with poorly formed glands as a component of Gleason pattern 4, have a worse prognosis than Gleason score 3 + 3 = 6, defined as tumor composed of only well-formed individual glands.

As a result of points 2 and 3 above, there has been a shift in grading with an increased proportion of Gleason score 7 relative to Gleason score 6 cancer, and a correspondingly better prognosis for contemporary graded Gleason score 6 tumors than historic tumors with the same grade.

Rationale: Removing cases that today would be graded as Gleason pattern 4 from what in the past was diagnosed as Gleason pattern 3 leaves today’s Gleason pattern 3 as a homogeneous grade composed of well-differentiated individual glands with an excellent prognosis. Whereas prior to 2005, a small percentage of tumor graded as Gleason score 3 + 3 = 6 at radical prostatectomy were associated with lymph node metastases and death; currently, tumors composed of pure Gleason pattern 3 (i.e., 3 + 3 = 6) lack the potential for metastatic disease. Consequently, current Gleason score 3 + 3 = 6 cancers are ideal tumors in the appropriate patients for active surveillance.

Variants are typically graded on the basis of their underlying architectural pattern, with the exception of small cell carcinoma.

Rationale: Studies have shown that one can grade most variants using the same criteria as applied for usual prostatic adenocarcinoma. Doing so, pseudohyperplastic cancer is Gleason pattern 3. Foamy gland carcinoma can be variably Gleason patterns 3-5. Mucinous adenocarcinoma of the prostate is typically Gleason pattern 4, yet can be pattern 3. Ductal adenocarcinoma is most commonly composed of cribriform or papillary glands and is Gleason pattern 4, yet can have necrosis (Gleason pattern 5) or manifest as individual well-formed glands (PIN-like ductal adenocarcinoma) which is graded as Gleason pattern 3. Small cell carcinoma, although resembling Gleason pattern 5 with no gland formation, has a unique morphology, treatment, and prognosis, and is not assigned a grade.

In the setting of high-grade cancer, one should ignore lower-grade patterns if they occupy less than 5% of the area of the tumor.

Rationale: When a tumor is almost entirely high grade, it is expected that the tumor will be aggressive, even if there is a very small focus of lower-grade cancer. For example, a needle biopsy composed of 99% Gleason pattern 4 with just a few well-formed glands of Gleason pattern 3 would be graded as Gleason score 4 + 4 = 8.

In the setting of three patterns on needle biopsy (i.e., patterns 3-5), the most common pattern is added to the highest grade pattern.

Rationale: On needle biopsy, it is thought that any pattern 5 on needle biopsy, even if it is the third most common pattern, is significant and should be incorporated into the Gleason score; it would likely not be so limited if it was not for undersampling on needle biopsy.

In the settings of three patterns in a radical prostatectomy nodule (i.e., patterns 3-5), if pattern 5 is the least common pattern yet occupies more than 5% of the tumor, then pattern 5 is included in the Gleason score. If pattern 5 is the least common pattern and occupies less than 5% of the tumor, then it is recorded as a tertiary pattern. The only time tertiary patterns should be reported in prostate specimens is in the setting of 3 + 4 = 7 with tertiary pattern 5 or 4 + 3 = 7 with tertiary pattern 5.

Rationale: When the entire cancer is evaluable on radical prostatectomy without the sampling artifact on needle biopsy, a small amount of pattern 5 in a Gleason score 7 cancer worsens the prognosis yet not as bad as the next highest grade. A Gleason score 3 + 4 = 7 with tertiary (<5%) pattern 5 has a prognosis in between 3 + 4 and 4 + 3. A Gleason score 4 + 3 = 7 with tertiary (<5%) pattern 5 has a prognosis in between 4 + 3 and 4 + 4.

Intraductal carcinoma of the prostate (IDC-P) should not be assigned a Gleason grade, yet it is typically associated with aggressive disease.

Rationale: IDC-P usually represents extension of high-grade invasive carcinoma into ducts and is typically seen with Gleason scores 7 or higher cancer. However, uncommonly, IDC-P can represent a precursor lesion without adjacent invasive cancer. in the latter situation, it would be inaccurate to assign a Gleason score to a precursor lesion in which the cure rate is 100% if completely removed. Consequently, IDC-P is not given a grade. However, in the uncommon setting in which there is only IDC-P on biopsy in the absence of infiltrating carcinoma, a note is added to the pathology report stating that IDC-P is typically associated with high-grade invasive carcinoma and it is justified to treat these patients definitively with surgery or radiation therapy.

Different tumor nodules in a radical prostatectomy specimen are assigned different Gleason scores.

Rationale: For example, if there is a Gleason score 4 + 4 = 8 in the left posterior lobe and a larger separate Gleason score 3 + 3 = 6 in the right posterior lobe, there is no rationale that the 3 + 3 = 6 tumor would make the 4 + 4 = 8 less aggressive. Consequently, in this example, each tumor nodule would be graded separately and the highest grade (4 + 4 = 8) would be the grade assigned to the patient, rather than adding all tumors together that would have resulted in an inappropriately low grade of 3 + 4 = 7. Experts in prostate pathology have used this grading rule in the past with outcome studies demonstrating that grading each major nodule separately correlates well with prognosis.

A new prostate cancer grading system initially to be used in parallel to the Gleason system has been developed that is simpler and more accurately reflects prognosis.

Rationale: Despite the above changes to the Gleason system, there are still significant deficiencies in its reporting that are described below that have led to a new grading system for prostate cancer.

The Gleason grading system ranges from 2 to 10, yet 6 is the lowest score currently assigned. When patients are told that they have a Gleason score 6 out of 10, they incorrectly yet logically think that they have an intermediate prognosis. A consequence of a grading scale that begins with 6 rather than 1 is that it contributes to patient’s fear of having a more aggressive cancer and potentially less willing to undergo active surveillance.

In the literature and for therapeutic purposes, various scores have been incorrectly grouped together with the assumption that they have a similar prognosis. For example, many classification systems consider Gleason score 7 as a single score without distinguishing 3 + 4 versus 4 + 3. For example, the D’Amico classification system divides prostate cancer into “low grade,” “intermediate grade,” and “high grade.” One of the components of “intermediate grade” cancer is Gleason score 7. Gleason score 7 is misleading, as 4 + 3 = 7 tumors have a much worse prognosis than 3 + 4 = 7 tumors and should be considered differently for treatment and prognostic purposes. Similarly, in the D’Amico classification system, a component of “high-grade” cancer is Gleason scores 8-10. Gleason scores 9-10 tumors have twice a worse prognosis than Gleason score 8 and should be considered separately when determining treatment and prognosis.

In 2013, one of the authors (JIE) proposed a new grading system on the basis of data from Johns Hopkins Hospital resulting in five prognostically distinct grade groups (6).

Grade Group 1 (Gleason score ≤6) – Only individual discrete well-formed glands

Grade Group 2 (Gleason score 3 + 4 = 7) – Predominantly well-formed glands with lesser component of poorly formed/fused/cribriform glands

Grade Group 3 (Gleason score 4 + 3 = 7) – Predominantly poorly formed/fused/cribriform glands with lesser component of well-formed glands

Grade Group 4 (Gleason score 4 + 4 = 8; 3 + 5 = 8; 5 + 3 = 8)

Only poorly formed/fused/cribriform glands or

Predominantly well-formed glands and lesser component lacking glands or

Predominantly lacking glands and lesser component of well-formed glands

Grade Group 5 (Gleason scores 9-10) – Lack gland formation (or with necrosis) with or without poorly formed/fused/cribriform glands

This new system was validated in a multi-institutional study of over 20,000 radical prostatectomy specimens, over 16,000 needle biopsy specimens, and over 5000 biopsies followed by radiation therapy (7). There was broad (90%) consensus for the adoption of this new prostate cancer grading system in a 2014 consensus conference (See Reference 5 for full details of this conference, including Organizing Committee, Grading Committee, sponsoring scientific society, and venue location). The current modified Gleason grading, which forms the basis for the new grade groups, bears little resemblance to the original Gleason system. The new grades would, for the foreseeable future, be used in parallel with the Gleason system [i.e., Gleason score 3 + 3 = 6 (Grade Group 1)]. The new grading system and the terminology Grade Groups 1-5 have also been accepted by the 2016 World Health Organization (WHO).

Disclosures

Financial support: The authors have no financial disclosures to make.
Conflict of interest: The authors have no conflict of interest.
References
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Authors

Affiliations

  • Departments of Pathology, Urology, and Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD - USA
  • Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona - Italy

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