Gleason grading system

Links

 Susan J. Maygarden and Raj Pruthi. Gleason Grading and Volume Estimation in Prostate Needle Biopsy Specimens Am J Clin Pathol Pathology Patterns Reviews 2005 123:S58-S66; doi : PDF)

 Grading of prostatic adenocarcinoma: current state and prognostic implications
Jennifer Gordetsky and Jonathan Epstein. Diagnostic Pathology 2016; 11:25. doi : 10 1186/s13000-016-0478-2 (Free)

Historical background

In the 1960s and 1970s, Donald F. Gleason and collaborators characterized various architectural patterns of prostatic cancer and grouped them into five grades or patterns, thus establishing the Gleason grading system.

More than four decades since its introduction, the Gleason system still remains the key prognostic factor in patients with prostatic cancer.

The Gleason system was derived largely from observations in larger specimens, such as prostatectomy and transurethral prostatic resection specimens.

Donald F. Gleason in 1966 created a unique grading system for prostatic carcinoma based solely on the architectural pattern of the tumor.

Another innovative aspect of this system was, rather than assigning the worst grade as the grade of the carcinoma, the grade was defined as the sum of the two most common grade patterns and reported as the Gleason score. The original description of this system was based on a study of 270 patients from the Minneapolis Veterans Administration Hospital.

Initially, Gleason intended to classify carcinomas into four Gleason patterns (GPs), but a small group of distinctive tumors (clear cell) was observed and they were placed in a separate 5th category (pattern 4).

Certain aspects of the original Gleason system would be interpreted differently in today’s practice. The cribriform pattern described, as a component of Gleason’s original pattern 2 and 3 would today typically be considered higher grade.

Individual cells listed under Gleason’s original pattern 3 would also be currently assigned a higher grade.

Pattern 4 has become significantly expanded beyond Gleason’s original description of tumors with clear cytoplasm that resembled renal cell carcinoma.

By 1974, Gleason and the Veterans Administration Cooperative Urological Research Group expanded their study to 1,032 men.

Gleason pattern 4 was described in a figure legend, as “raggedly infiltrating, fused-glandular tumor, frequently with pale cells, may resemble hypernephroma of kidney.”

The Gleason system was further refined by Mellinger in 1977 when the papillary and cribriform tumor under Gleason pattern 3 was described as having a “smooth and usually rounded edge”.

In describing the breakdown of Gleason patterns amongst 2,911 cases, Gleason pattern 1 was seen in 3.5%; pattern 2 in 24.4%; pattern 3 in 87.7%; pattern 4 in 12.1%; and pattern 5 in 22.6%.

These percentages added up to approximately 150% since 50% of the tumors showed at least two different patterns.

In 1977, Gleason provided additional comments concerning the application of the Gleason system. “Grading is performed under low magnification (40-100x).” He also stated “an occasional small area of fused glands did not change a pattern 3 tumor to pattern 4. A small focus of disorganized cells did not change a pattern 3 or 4 tumor to pattern 5.”

The only comment relating to tertiary patterns was “occasionally, small areas of a third pattern were observed.”

Synopsis Gleason Grade or Gleason Pattern Identification

The Gleason Grade is also known as the Gleason Pattern and ranges from 1 to 5:

 Gleason Grade 1 – Here, cancerous tissue is well differentiated and looks like normal prostate tissue. Glands are well packed and formed.
 Gleason Grade 2 – Here, well-formed large glands have more tissue between them.
 Gleason Grade 3 – Glands begin to look darker and show signs of randomness. They seem to be breaking away from monotony of their existence and invading surrounding tissue.
 Gleason Grade 4 – Majority of glands appear to be interspersed with surrounding tissue. A few recognizable glands are still present though.
 Gleason Grade 5 – There are no recognizable glands. Cells with distinct nuclei appear in sheets within surrounding tissue.

Description

Numerous grading systems have been designed for histopathological grading of prostate cancer. The main controversies have been whether grading should be based on glandular differentiation alone or a combination of glandular differentiation and nuclear atypia, and also whether prostate cancer should be graded according to its least differentiated or dominant pattern.

The Gleason grading system named after Donald F. Gleason is now the predominant grading system, and in 1993, it was recommended by a WHO consensus conference.

As described by Gleason, the initial grading of prostate carcinoma should be performed at low magnification using a 4x or 10x lens.

After one assesses the case at scanning magnification, one may proceed to use the 20x lens to verify the grade. For example, at low magnification one may have the impression of fused glands or necrosis but may require higher magnification at 20x to confirm its presence.

However, one should not initially use the 20x or 40x objectives to look for rare fused glands or a few individual cells seen only at higher power which would lead to an overdiagnosis of Gleason pattern 4 or 5, respectively.

The Gleason grading system is based on glandular architecture; nuclear atypia is not evaluated. Nuclear atypia as adopted in some grading systems, correlates with prognosis of prostate cancer but there is no convincing evidence that it adds independent prognostic information to that obtained by grading glandular differentiation alone.

The Gleason grading system defines five histological patterns or grades with decreasing differentiation.

 Normal prostate epithelial cells are arranged around a lumen.
 In Gleason patterns 1 to 3, there is retained epithelial polarity with luminal differentiation in virtually all glands.
 In pattern 4, there is partial loss of normal polarity.
 In pattern 5, there is an almost total loss of polarity with only
occasional luminal differentiation.

Prostate cancer has a pronounced morphological heterogeneity and usually more than one histological pattern is present.

The primary and secondary pattern, i.e. the most prevalent and the second most prevalent pattern are added to obtain a Gleason score or sum.

It is recommended that the primary and secondary pattern as well as the score be reported, e.g. Gleason score 3+4=7.

If the tumour only has one pattern, Gleason score is obtained by doubling that pattern, e.g. Gleason score 3+3=6.

Gleason scores 2 and 3 are only exceptionally assigned, because Gleason pattern 1 is unusual.

Gleason score 4 is also relatively uncommon because pattern 2 is usually mixed with some pattern 3 resulting in a Gleason score 5.

Gleason score 2-4 tumour may be seen in TURP material sampling the transitional zone.

With the introduction of the needle core biopsy technique, the Gleason system evolved to accommodate needle biopsy practice, in which the grading was done on limited biopsy core tissue.

In needle biopsy material, it has been proposed that a Gleason score of 2-4 should not be assigned. Gleason scores 6 and 7 are the most common scores and include the majority of tumours in most studies.

Gleason pattern 1

Gleason pattern 1 is composed of a very well circumscribed nodule of separate, closely packed glands, which do not infiltrate into adjacent benign prostatic tissue. The glands are of intermediate size and approximately equal in size and shape. This pattern is usually seen in transition zone cancers. Gleason pattern 1 is exceedingly rare. When present, it is usually only a minor component of the tumour and not included in the Gleason score.

Gleason pattern 2

Gleason pattern 2 is composed of round or oval glands with smooth ends. The glands are more loosely arranged and not quite as uniform in size and shape as those of Gleason pattern 1. There may
be minimal invasion by neoplastic glands into the surrounding non-neoplastic prostatic tissue. The glands are of intermediate size and larger than in Gleason pattern 3. The variation in glandular size and separation between glands is less than that seen in pattern 3. Although not evaluated in Gleason grading, the cytoplasm of Gleason pattern 1 and 2 cancers is abundant and pale-staining. Gleason pattern 2 is usually seen in transition zone cancers but may occasionally be found in the peripheral zone.

Gleason pattern 3

Gleason pattern 3 is the most common pattern. The glands are more infiltrative and the distance between them is more variable than in patterns 1 and 2. Malignant glands often infiltrate between adjacent non-neoplastic glands. The glands of pattern 3 vary in size and shape and are often angular. Small glands are typical for pattern 3, but there may also be large, irregular glands. Each gland has an open lumen and is circumscribed by stroma. Cribriform pattern 3 is rare and difficult to distinguish from cribriform high-grade PIN.

Gleason pattern 4

In Gleason pattern 4, the glands appear fused, cribriform or they may be poorly defined. Fused glands are composed of a group of glands that are no longer completely separated by stroma. The edge of a group of fused glands is scalloped and there are occasional thin strands of connective tissue within this group. Cribriform pattern 4 glands are large or they may be irregular with jagged edges. As opposed to fused glands, there are no strands of stroma within a cribriform gland. Most cribriform invasive cancers should be assigned a pattern 4 rather than pattern 3. Poorly defined glands do not have a lumen that is completely encircled by epithelium. The hypernephromatoid pattern described by Gleason is a rare variant of fused glands with clear or very pale staining cytoplasm.

Gleason pattern 5

In Gleason pattern 5, there is an almost complete loss of glandular lumina. Only occasional lumina may be seen. The epithelium forms solid sheets, solid strands or single cells invading the stroma. Care must be applied when assigning a Gleason pattern 4 or 5 to limited cancer on needle biopsy to exclude an artefact of tangential sectioning of lower grade cancer. Comedonecrosis may be present.

Grade progression

The frequency and rate of grade progression is unknown. Tumour grade is on average higher in larger tumours. However, this may be due to more rapid growth of high grade cancers. It has been demonstated that some tumours are high grade when they are small.

Many studies addressing the issue of grade progression have a selection bias, because the patients have undergone a repeat transurethral resection or repeat biopsy due to symptoms of tumour progression.

The observed grade progression may be explained by a growth advantage of a tumour clone of higher grade that was present from the beginning but undersampled. In patients followed expectantly there is no evidence of grade progression within 1-2 years.

Grading minimal cancer on biopsy

It is recommended that a Gleason score be reported even when a minimal focus of cancer is present. The correlation between biopsy and prostatectomy Gleason score is equivalent or only marginally worse with minimal cancer on biopsy. It is recommended that even in small cancers with one Gleason pattern that the Gleason score be reported. If only the pattern is reported, the clinician may misconstrue this as the Gleason score.

Tertiary Gleason patterns

The original Gleason grading system does not account for patterns occupying less than 5% of the tumour or for tertiary patterns.

In radical prostatectomy specimens, the presence of a tertiary high
grade component adversely affects prognosis. However, the prognosis is not necessarily equated to the addition of the primary Gleason pattern and the tertiary highest Gleason pattern.

For example, the presence of a tertiary Gleason pattern 5 in a Gleason score 4+3=7 tumour worsens the prognosis compared to the same tumour without a tertiary high grade component.

However, it is not associated with as adverse prognosis as a Gleason score 4+5=9. When this tertiary pattern is pattern 4 or 5, it should be reported in addition to the Gleason score, even when it is less than 5% of the tumour.

Although comparable data do not currently exist for needle biopsy material, in the setting of three grades on biopsy where the highest grade is the least common, the highest grade is incorporated as the secondary pattern.

An alternative option is in the situation with a tertiary high grade pattern (i.e. 3+4+5 or 4+3+5) is to diagnose the case as Gleason score 8 with patterns 3, 4 and 5 also present.

The assumption is that a small focus of high grade cancer on biopsy will correlate with a significant amount of high grade cancer in the prostate such that the case overall should be considered high grade, and that sampling artefact accounts for its limited nature on biopsy.

Reporting Gleason scores in cases with multiple positive biopsies

In cases where different positive cores have divergent Gleason scores, it is controversial whether to assign an averaged (composite) Gleason score or whether the highest Gleason score should be considered as the patient’s grade.

In practice, most clinicians take the highest Gleason score when planning treatment options.

Grading of variants of prostate cancer

Several morphological variants of prostate adenocarcinoma have been described (e.g. mucinous and ductal cancer).

They are almost always combined with conventional prostate cancer and their effect on prognosis is difficult to estimate.

In cases with a minor component of a prostate cancer variant, Gleason grading should be based on the conventional prostate cancer present in the specimen.

In the rare case where the variant form represents the major component, it is controversial whether to assign a Gleason grade.

Grading of specimens with artefacts and treatment effect

Crush artefacts

Crush artefacts are common at the margins of prostatectomy specimens and in core biopsies. Crush artefacts cause disruption of the glandular units and consequently may lead to overgrading
of prostate cancer. These artefacts are recognized by the presence of noncohesive epithelial cells with fragmented cytoplasm and dark, pyknotic nuclei adjacent to preserved cells. Crushed areas should not be Gleason graded.

Hormonal and radiation treatment

Prostate cancer showing either hormonal or radiation effects can appear artefactually to be of higher Gleason score. Consequently, Gleason grading of these cancers should not be performed. If there is cancer that does not show treatment effect, a Gleason score can be assigned to these components.

Correlation of needle biopsy and prostatectomy grade

Prostate cancer displays a remarkable degree of intratumoural grade heterogeneity. Over 50% of total prostatectomy specimens contain cancer of at least three different Gleason grades, and cancer of a single grade is present in only 16% of the specimens.

Of individual tumour foci, 58% have a single grade, but most of these foci are very small.

Several studies have compared biopsy and prostatectomy Gleason score. Exact correlation has been observed in 28.2-67.9% of the cases. The biopsies undergraded in 24.5-60.0% and overgraded in 5.2-32.2%.

Causes for biopsy grading discrepencies are undersampling of higher or lower grades, tumours borderline between two grade patterns, and misinterpretation of patterns.

The concordance between biopsy and prostatectomy Gleason score is within one Gleason score in more than 90% of cases.

Reproducibility

Pathologists tend to undergrade. The vast majority of tumours graded as Gleason score 2 to 4 on core biopsy are graded as Gleason score 5 to 6 or higher when reviewed by experts in urological pathology.

In a recent study of interobserver reproducibility amongst general pathologists, the overall agreement for Gleason score groups 2-4, 5-6, 7, and 8-10 was just into the moderate range.

Undergrading is decreased with teaching efforts and a substantial interobserver reproducibility can be obtained.

Prognosis

Multiple studies have confirmed that Gleason score is a very powerful prognostic factor on all prostatic samples. This includes the prediction of the natural history of prostate cancer and the assessment of the risk of recurrence after total prostatectomy or radiotherapy.

Several schedules for grouping of Gleason scores in prognostic categories have been proposed.

Gleason scores 2 to 4 behave similarly and may be grouped.

Likewise, Gleason scores 8 to 10 are usually grouped together, although they could be stratified with regard to disease progression in a large prostatectomy study.

There is evidence that Gleason score 7 is a distinct entity with prognosis intermediate between that of Gleason scores 5-6 and 8 to 10, respectively.

Although the presence and amount of high grade cancer (patterns 4 to 5) correlates with tumour prognosis, reporting the percentage pattern 4/5 is not routine clinical practice.

Gleason score 7 cancers with a primary pattern 4 have worse prognosis than those with a primary pattern 3.

ISUP 2005 modifications

A group of urological pathologists convened at the 2005 United States and Canadian Academy meeting in San Antonio in an attempt to achieve consensus in controversial areas relating to the Gleason grading system.

The goal of the meeting was to achieve consensus amongst leading urological pathologists in specific areas of Gleason grading, including areas where there was either a lack of data or scant information as to the optimal method of grading.

In the latter instances, the consensus was based on personal and institutional experience with a large number of cases. Over 70 urological pathologists from around the world were invited to attend, with most attending.

For the purposes of this meeting, we defined “consensus” when two-thirds of the participants were in agreement, although for almost all of the issues discussed a much higher degree of agreement was reached.

See also : ISUP 2005 modifified Gleason score

At the turn of the century, attempts and recommendations were made in order to clarify how the Gleason system should be applied in practice, since it was evident that differences in Gleason system interpretation and application existed.

However, several issues remained unresolved, as this system was ultimately dependent on a subjective interpretation of various morphological patterns of cancer.

For example, it was unclear what extent of variations in size and shape of neoplastic glands should be scored as Gleason pattern (GP) 3 and what represented the scope of gland fusion patterns, interpreted as GP4.

Additional problematic issues included the grading of ill-defined glands with poorly formed lumina, defining the morphological spectrum of cribriform glands, and the grading of a tertiary grade, when it was higher than the primary and secondary grades.

In order to resolve these and other issues pertaining to Gleason grading in practice, the International Society of Urological Pathology (ISUP) convened a consensus conference on Gleason grading at the 2005 United States and Canadian Academy of Pathology Annual Meeting in San Antonio, TX, USA.

Uropathologists from 20 countries attempted to clarify and standardize the contemporary use of the Gleason system by providing consensus recommendations, based on accumulated evidence and practice standards, as to how the Gleason system should be applied and reported in contemporary practice.

Thus, a 2005 ISUP modified Gleason system was proposed, outlining the morphological patterns 1–5, which were accompanied by a modified diagram, similar to the original Gleason system.

It was reiterated that GP1 and GP2 are quite rare on biopsy and prostatectomy.

The most significant modifications pertained to patterns 3 and 4.

GP3 was restricted to discrete glandular units (as in the original system) and to smoothly circumscribed but only small cribriform tumour nodules, which, in essence, reduced the spectrum of cribriform glands interpreted as pattern 3.

Pattern 4 included fused glands and large cribriform glands or cribriform glands with border irregularities, as well as hypernephromatoid glands.

Additionally, a category of ill-defined glands or glands containing poorly formed glandular lumina was introduced (not present previously) and was included under GP4.

GP5 was reserved for cancers containing essentially no glandular differentiation, composed of solid sheets, cords, and single cells, as in the original system.

Comedocarcinoma with central necrosis was also retained in pattern 5, regardless of whether it was surrounded by papillary, cribriform or solid sheets.

The consensus also provided clarifications on the grading of variants and variations of acinar adenocarcinoma of prostate, which were illustrated by examples.

These included the issues of interpretation and grading of: vacuoles, foamy gland cancer, ductal adenocarcinoma, colloid (mucinous) carcinoma, small cell carcinoma, adenocarcinoma with focal mucinous extravasation, mucinous fibroplasia (collagenous micronodules), glomeruloid structures, and pseudohyperplastic carcinoma.

The consensus also recommended that secondary patterns of higher grade when present to a limited extent (≤5% of the tumour area) should always be reported on needle biopsy, while there was no consensus on reporting on prostatectomy.

Secondary patterns of lower grade when present to a limited extent (≤5% of the tumour area) in needle biopsies, prostatectomies and transurethral resections of prostate should be ignored.

Regarding the issue of tertiary GP, it was recommended that the Gleason score (GS) on needle biopsy should be derived by adding the primary and the highest pattern, whereas tertiary pattern on prostatectomy, when it is higher than the primary and the secondary patterns, should be reported separately.

Another recommendation was that separate dominant tumour nodules of different Gleason patterns should be scored separately on prostatectomy.

Finally, it was recommended that individual Gleason scores should be reported on needle biopsy specimens with different cores showing different grades, as long as the cores are submitted in separate containers. In addition, it was left as an option to provide an overall GS at the end of the case.

The impact of these recommendations on prostatic cancer grading in contemporary practice remains unknown, because they were introduced relatively recently and because it is uncertain how much they have penetrated and potentially altered routine prostatic pathology practice.

Hence, the objective of this study was to determine whether and how the proposed ISUP consensus recommendations have influenced the application of the modified Gleason system in grading biopsy and prostatectomy specimens in a contemporary setting of a large uropathology practice.

Reporting secondary patterns of lower grade when present to a limited extent

It was the consensus of the ISUP group that 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.

For example, a needle biopsy core that is 100% involved by cancer, with 98% Gleason pattern 4 and 2% Gleason pattern 3 would be diagnosed as Gleason score 4+4=8.

These cases with extensive pattern 4 cancer, where a significant amount of tumor is available for examination, should be considered as high grade (Gleason score>8).

At the other extreme, one can occasionally see small foci of Gleason pattern 4 on needle biopsy with a few glands of pattern 3. In the setting of very limited cancer on needle biopsy, the few glands of pattern 3 would typically occupy over 5% of the area of the tumor focus, and one would grade these tumors as Gleason score 4+3=7. Given the significant potential in this scenario of a sampling error resulting from only limited cancer on biopsy, the presence of a relatively small amount of pattern 3 would most likely correspond to a Gleason score 7 tumor in the corresponding prostate. The same 5% cut off rule for excluding lower grade cancer also applies for TURPs and radical prostatectomy specimens, which in most cases would relate to extensive cancer with more than 95% Gleason pattern 4 tumor.

Reporting secondary patterns of higher grade when present to a limited extent

It was the consensus of the group that high-grade tumor of any quantity on needle biopsy, as long as it was identified at low to medium magnification (see General applications of the Gleason grading system) should be included within the Gleason score. Any amount of high grade tumor sampled on needle biopsy most likely indicates a more significant amount of high grade tumor within the prostate due to the correlation of grade and volume and the problems inherent with needle biopsy sampling. Consequently, a needle biopsy which is entirely involved by cancer with 98% Gleason pattern 3 and 2% Gleason pattern 4 would be diagnosed as Gleason score 3+4=7.

In radical prostatectomy specimens with the analogous situation of a tumor nodule having 98% Gleason pattern 3 and 2% pattern 4, there was no consensus within the group. Approximately half of the group would diagnose these foci in an analogous fashion to that done on needle biopsy and interpret the case as Gleason score 3+4=7 regardless of the percentage of pattern 4. The other half would note these tumors as Gleason score 3+3=6 with a minor component of Gleason pattern 4. The rationale for the latter method is based on radical prostatectomy data; cancers with more than 95% Gleason pattern 3 and less than 5% pattern 4 have pathological stages that are worse than a pure Gleason score 3+3=6 tumor yet not as adverse as a Gleason score 3+4=7 where pattern 4 occupies more than 5% of the tumor.

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Historical background

Donald F. Gleason in 1966 created a unique grading system for prostatic carcinoma based solely on the architectural pattern of the tumor [1, 2, 3]. Another innovative aspect of this system was, rather than assigning the worst grade as the grade of the carcinoma, the grade was defined as the sum of the two most common grade patterns and reported as the Gleason score. The original description of this system was based on a study of 270 patients from the Minneapolis Veterans Administration Hospital.

Initially, Gleason intended to classify carcinomas into four patterns, but a small group of distinctive tumors (clear cell) was observed and they were placed in a separate 5th category (pattern 4) [2]. Certain aspects of the original Gleason system would be interpreted differently in today’s practice. The cribriform pattern described, as a component of Gleason’s original pattern 2 and 3 would today typically be considered higher grade. Individual cells listed under Gleason’s original pattern 3 would also be currently assigned a higher grade. Pattern 4 has become significantly expanded beyond Gleason’s original description of tumors with clear cytoplasm that resembled renal cell carcinoma.

By 1974, Gleason and the Veterans Administration Cooperative Urological Research Group expanded their study to 1,032 men [4]. Gleason pattern 4 was described in a figure legend, as “raggedly infiltrating, fused-glandular tumor, frequently with pale cells, may resemble hypernephroma of kidney.” The Gleason system was further refined by Mellinger in 1977 when the papillary and cribriform tumor under Gleason pattern 3 was described as having a “smooth and usually rounded edge” [5]. In describing the breakdown of Gleason patterns amongst 2,911 cases, Gleason pattern 1 was seen in 3.5%; pattern 2 in 24.4%; pattern 3 in 87.7%; pattern 4 in 12.1%; and pattern 5 in 22.6% [5]. These percentages added up to approximately 150% since 50% of the tumors showed at least two different patterns.

In 1977, Gleason provided additional comments concerning the application of the Gleason system [6]. “Grading is performed under low magnification (40-100x).” He also stated “an occasional small area of fused glands did not change a pattern 3 tumor to pattern 4. A small focus of disorganized cells did not change a pattern 3 or 4 tumor to pattern 5.” The only comment relating to tertiary patterns was “occasionally, small areas of a third pattern were observed.”
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Why the need for a consensus on Gleason grading?

It is a testament to the enduring power of the original Gleason grading system that it is the accepted grading system throughout the world, despite its inception almost 40 years ago. How many other things in medicine have stood the test of time so well? Nonetheless, medicine in general and prostate carcinoma in specific has changed dramatically since the late 1960s, when the Gleason grading system was derived. In the 1960s, there was no screening for prostate cancer other than by digital rectal exam, as serum PSA had not yet been discovered. In Gleason’s 1974 study, the vast majority (86%) of men had advanced disease with either local extension out of the prostate on clinical exam or distant metastases. Only 6% of patients had nonpalpable tumor diagnosed by transurethral resection and 8% of patients were diagnosed with a localized nodule on rectal exam [4]. The method of obtaining prostate tissue was also very different from today’s practice. Typically, only a couple of thick gauge needle biopsies were directed into an area of palpable abnormality. The use of 18-gauge thin biopsy needles and the concept of sextant needle biopsies to more extensively sample the prostate were not developed until the 1980s [7]. Consequently, the grading of prostate cancer in thin cores and in multiple cores from different sites of the prostate were not issues in Gleason’s era.

In the 1960s, radical prostatectomy was relatively uncommon, prostates were not as often removed intact, and glands were not processed in their entirety or as extensively and systematically to the degree currently seen. Further issues relating to radical prostatectomy specimens such as the grading of multiple nodules within the same prostate or dealing with tertiary patterns were not addressed within the original Gleason system.

The Gleason system also predated the use of immunohistochemistry. It is likely that with immunostaining for basal cells many of Gleason’s original 1+1=2 adenocarcinomas of the prostate would today be regarded as adenosis (atypical adenomatous hyperplasia). Similarly, many of the cases in 1967 diagnosed as cribriform Gleason pattern 3 carcinoma would probably be currently referred to as cribriform high grade prostatic intraepithelial neoplasia (PIN) or intraductal carcinoma of the prostate, if labeled with basal cell markers [8, 9].

Another issue not dealt with in the original Gleason grading system is how to grade newly described variants of adenocarcinoma of the prostate. Some of the more common variants where grading controversy exists include: mucinous carcinoma, ductal adenocarcinoma, foamy gland carcinoma, and pseudohyperplastic adenocarcinoma of the prostate. In addition, there are certain patterns of adenocarcinoma of the prostate such as those with glomeruloid features and mucinous fibroplasia (collagenous micronodules) where the use of Gleason grading was not defined.

The application of the Gleason system for all of the reasons noted above varies considerably in contemporary surgical pathology practice and has led to several recent attempts to achieve consensus on Gleason grading.
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2005 ISUP consensus conference

A group of urological pathologists convened at the 2005 United States and Canadian Academy meeting in San Antonio in an attempt to achieve consensus in controversial areas relating to the Gleason grading system [10]. The goal of the meeting was to achieve consensus amongst leading urological pathologists in specific areas of Gleason grading, including areas where there was either a lack of data or scant information as to the optimal method of grading. In the latter instances, the consensus was based on personal and institutional experience with a large number of cases. Over 70 urological pathologists from around the world were invited to attend, with most attending. For the purposes of this meeting, we defined “consensus” when two-thirds of the participants were in agreement, although for almost all of the issues discussed a much higher degree of agreement was reached.
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General applications of the Gleason grading system

As described by Gleason, the initial grading of prostate carcinoma should be performed at low magnification using a 4x or 10x lens. After one assesses the case at scanning magnification, one may proceed to use the 20x lens to verify the grade. For example, at low magnification one may have the impression of fused glands or necrosis but may require higher magnification at 20x to confirm its presence. However, one should not initially use the 20x or 40x objectives to look for rare fused glands or a few individual cells seen only at higher power which would lead to an overdiagnosis of Gleason pattern 4 or 5, respectively.

Gleason patterns
Gleason score 1+1=2

It was the consensus that a Gleason score of 1+1=2 is a grade that should not be diagnosed regardless of the type of specimen, with extremely rare exception. Most cases which were diagnosed as Gleason score 1+1=2 in the era of Gleason would today be referred to as adenosis (atypical adenomatous hyperplasia).
Gleason scores 3-4

These low-grade tumor scores were assigned by members of the consensus panel occasionally on transurethral resection specimens (TURPs) and in multifocal low-grade tumors within radical prostatectomy specimens. In contrast to Gleason’s diagram and text, the consensus was that cribriform patterns are not allowed within Gleason pattern 2. It is now accepted that Gleason score 2-4 should not be assigned to cancer on needle biopsy for several reasons:
•

poor reproducibility even amongst experts;
•

poor correlation with prostatectomy grade with almost all cases showing higher grade at resection;
•

a diagnosis of Gleason score 3-4 may misguide clinicians and patients into believing that the patient has an indolent tumor [11, 12].

The major limitation of rendering a diagnosis of Gleason score 4 on needle biopsy is that one cannot see the entire edge of the lesion to determine if it is completely circumscribed. Consequently, most of the lesions that appear to be very low grade on needle biopsies are diagnosed by urological pathologists as Gleason score 2+3=5 or 3+2=5.
Gleason pattern 3

A departure from the original Gleason classification system is that “individual cells” would not be allowed within Gleason pattern 3. Rather, Gleason pattern 3 cancer consists of variably sized individual glands. A further area of divergence from the original Gleason system is the controversial area of cribriform Gleason pattern 3. Within Gleason’s original illustrations of his cribriform pattern 3, he depicts large cribriform glands, which the consensus panel would uniformly diagnose as cribriform pattern 4. The consensus panel required extremely stringent criteria for the diagnosis of cribriform pattern 3, with remaining cribriform patterns typically falling into Gleason pattern 4. The criteria used to diagnose cribriform pattern 3 were rounded, well circumscribed glands of the same size of normal glands. When various images were shown to the consensus panel of potential candidates for cribriform Gleason pattern 3, almost none of them met the criteria based on subtle features, such as slight irregularities of the outer border of the cribriform glands. Subsequent to the 2005 meeting, this author reviewed 3590 consecutive prostate cancers sent to me over seven months; 30 needle biopsy cases were selected that possibly represented cribriform Gleason pattern 3 cancer [13], 36 digital images were taken and sent to ten experts in prostate pathology with a consensus defined when at least 7/10 experts agreed on the grade. Even in this highly selected set of images thought to be the best candidates for cribriform pattern 3 from a busy consult service, most experts interpreted the cribriform patterns as pattern 4. There was only one consensus pattern 3 case. Furthermore, most of the cribriform foci investigated (73%) were associated with more definitive pattern 4 elsewhere on the needle biopsy specimen. There was poor reproducibility amongst experts as to cribriform pattern 3 vs. pattern 4 due to:
•

disagreement as to what are the key diagnostic features in a given case (i.e. irregular distribution of lumina and variable slit-like lumina, favor pattern 4 vs. small glands and regular contour, favor pattern 3;
•

disagreement as to assessment of given criteria: regular vs. irregular distribution of lumina and regular vs. irregular contour.

Conceptually, one would expect the change in grade from pattern 3 to pattern 4 to be reflected in a distinct architectural paradigm shift where cribriform as opposed to individual glands are formed, rather than merely a subjective continuum of differences in size, shape and contour of cribriform glands.

The only reason why cribriform pattern 3 even exists is because of the original Gleason schematic diagram. Gleason never specifically published the prognostic difference between what he called cribriform Gleason pattern 3 compared to Gleason pattern 4. Many of Gleason’s cribriform Gleason pattern 3 cancers may not even have been infiltrating carcinomas due to the lack of availability of immunohistochemistry for basal cell markers. Today we might have diagnosed them either as cribriform high-grade PIN or intraductal carcinoma of the prostate (concepts not present in Gleason’s era). Based on all the above data, all cribriform cancer should be interpreted as Gleason pattern 4 and not pattern 3.
Gleason pattern 4

A controversial area where consensus was reached was that ill-defined glands with poorly formed glandular lumina also warrant the diagnosis of Gleason pattern 4. Only a cluster of such glands, where a tangential section of Gleason pattern 3 glands cannot account for the histology, would be acceptable as Gleason pattern 4. It was also noted that in most cases ill-defined glands with poorly formed glandular lumina are accompanied by fused glands. Very small, well-formed glands still are within the spectrum of Gleason pattern 3. This definition differs from Gleason’s original description of pattern 4 which only included the hypernephromatoid pattern [2]. Only in subsequent years were fused glandular masses added to the definition [5]. The original schematic diagram of Gleason pattern 4 consisted almost entirely of cribriform patterns without depicting fused glands or ill-defined glands with poorly formed glandular lumina. Gleason pattern 4 closely resembling renal cell carcinoma (hypernephromatoid pattern) makes up only a very small percentage of Gleason pattern 4 cases.
Gleason pattern 5

Gleason pattern 5 consists of individual cells, cords of cells, and sheets of tumor. Although typically one sees comedonecrosis with solid nests, occasionally one can see necrosis with cribriform masses that by themselves might be cribriform pattern 4. If there is true comedonecrosis, the consensus was that these patterns should be regarded as Gleason pattern 5. One must be stringent as to the definition of comedonecrosis, requiring intraluminal necrotic cells and/or karyorrhexis, especially in the setting of cribriform glands. We have noted in two studies using different patient populations the tendency for pathologists to undergrade Gleason pattern 5 in almost 50% of cases sent for a second opinion at the request of the patient of urologist where this author has diagnosed Gleason pattern 5. Pattern 5 was missed more frequently when it was not the primary pattern.

Grading variants and variations of acinar adenocarcinoma of the prostate
Vacuoles

Adenocarcinomas of the prostate may contain clear vacuoles and these should be distinguished from true signet-ring carcinomas which contain mucin. Whereas vacuoles in adenocarcinoma of the prostate are not uncommon, true mucin-positive signet-ring cell carcinomas of prostate are exceedingly rare with only a handful of bona fide cases reported in the literature. Vacuoles may distort the architecture and it is controversial as to what grade should be assigned. Gleason’s only mention of vacuoles described them as signet cells under pattern 5 tumor [6]. The panel concluded that although typically vacuoles are seen within Gleason pattern 4 cancer, it may be seen within Gleason pattern 5 and even Gleason pattern 3 tumors. The consensus was that tumors should be graded, as if the vacuoles were not present, by only evaluating the underlying architectural pattern.
Foamy gland carcinoma

In an analogous fashion to handling cancers with vacuoles, it was the consensus of the panel that in grading foamy gland carcinomas one should ignore the foamy cytoplasm and grade the tumor solely based on the underlying architecture. Whereas most cases of foamy gland carcinoma would be graded as Gleason score 3+3=6, higher grade foamy gland carcinomas exist and should be graded accordingly based on the pattern [14, 15].
Ductal adenocarcinoma

Ductal adenocarcinomas of the prostate most commonly are composed of either papillary fronds or cribriform structures [16]. Ductal adenocarcinomas are recognized as being aggressive tumors with most studies showing comparable behavior to acinar cancer with a Gleason score 4+4=8. The consensus of the panel was that ductal adenocarcinomas should be graded as Gleason score 4+4=8, while retaining the diagnostic term of ductal adenocarcinoma to denote their unique clinical and pathological findings. This can be achieved by diagnosing such a tumor as “prostatic ductal adenocarcinoma (Gleason score 4+4=8).” In cases with mixed ductal and acinar patterns, the ductal patterns should be assigned Gleason pattern 4. The only exceptions to grading ductal adenocarcinoma as Gleason pattern 4 are:
•

PIN-like ductal adenocarcinoma;
•

ductal adenocarcinoma with comedonecrosis.

PIN-like ductal adenocarcinoma consists of individual glands lined by tall pseudostratified columnar cells resembling high grade PIN [17]. Its prognosis appears comparable to Gleason pattern 3. Although it has not been specifically studied, ductal adenocarcinoma with comedonecrosis is graded as Gleason pattern 5.
Colloid (mucinous) carcinoma

The majority of cases with colloid carcinoma consist of irregular cribriform glands floating within a mucinous matrix [18, 19]. It was the uniform consensus that these cases would be scored Gleason score 4+4=8. However, uncommonly one may see individual round discrete glands floating within mucinous pools. There was no consensus in these cases whether such cases should be diagnosed as Gleason score 4+4=8 or Gleason score 3+3=6. Approximately half of the group said that by definition all colloid carcinomas should be assigned a Gleason score of 8, while the other half felt that one should ignore the extracellular mucin and grade the tumor based on the underlying architectural pattern. The excellent prognosis of mucinous carcinomas in a large study of mucinous carcinoma at radical prostatectomy supports grading mucinous prostate carcinomas based on the underlying architectural pattern rather than assuming that all of these tumors are aggressive [20].
Small cell carcinoma

It was the consensus that small cell carcinoma of the prostate has unique histological, immunohistochemical, and clinical features [21]. Comparable to its more common pulmonary counterpart, chemotherapy is the mainstay of therapy for prostatic small cell carcinomas. These clinicopathologic features differ from those associated with Gleason pattern 5 prostatic acinar carcinoma, such that small cell carcinoma should not be assigned a Gleason grade.
Adenocarcinoma with focal mucin extravasation

There was consensus amongst the group that adenocarcinomas of the prostate with focal mucinous extravasation should not be by default graded as Gleason score 4+4=8. Rather, one should ignore focal mucinous extravasation and grade the tumor based on the underlying architecture of the glands. The distinction between focal mucinous extravasation and colloid carcinoma is the presence of epithelial elements floating within the mucinous matrix within the latter whereas with mucinous extravasation there is only focal acellular mucin adjacent to cancer.
Mucinous fibroplasia (collagenous micronodules)

The delicate ingrowth of fibrous tissue seen with mucinous fibroplasia can result in glands appearing to be fused resembling cribriform structures although the underlying architecture is really that of individual discrete rounded glands invested by loose collagen. The tumor should be graded on the underlying glandular architecture, whereby the majority are graded as Gleason score 3+3=6 [22]. Only when there are distinct cribriform glands in areas of mucinous fibroplasias does this author diagnose Gleason pattern 4.
Glomeruloid structures

Glomeruloid glands in prostatic adenocarcinoma are characterized by dilated glands containing intraluminal cribriform structures with a single point of attachment, resembling a renal glomerulus [22]. On prostate biopsy, glomeruloid glands are exclusively associated with carcinoma and not associated with benign mimickers. The grading of such glomeruloid structures is controversial. Some urological pathologists do not assign a grade to glomeruloid patterns and rather just grade the surrounding tumor. According to some experts for the rare case where the entire tumor is composed of glomeruloid glands, a grade of 3+3=6 is assigned as long as the glomeruloid structures are small. Larger glomeruloid structures are uniformly accepted by urological pathologists as Gleason pattern 4. Other experts in the field feel that all glomeruloid structures should be assigned a Gleason pattern 4. A study of ours, subsequent to the consensus conference, indicated that glomerulations were overwhelmingly associated with concurrent Gleason pattern 4 or higher-grade carcinoma [23]. In several cases, transition could be seen among small glomerulations, large glomeruloid structures, and cribriform pattern 4 cancer. These data suggest that glomerulations represent an early stage of cribriform pattern 4 cancer and are best graded as Gleason pattern 4.
Pseudohyperplastic adenocarcinoma

Uncommonly, adenocarcinomas of the prostate share some architectural features with benign glands, including larger size, branching, and papillary infolding. These cancers should be graded as Gleason score 3+3=6 with pseudohyperplastic features [24, 25]. This convention is in large part based on the recognition that they are most often accompanied by more ordinary Gleason score 3+3=6 adenocarcinoma.

Reporting secondary patterns of lower grade when present to a limited extent

It was the consensus of the group that 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. For example, a needle biopsy core that is 100% involved by cancer, with 98% Gleason pattern 4 and 2% Gleason pattern 3 would be diagnosed as Gleason score 4+4=8. These cases with extensive pattern 4 cancer, where a significant amount of tumor is available for examination, should be considered as high grade (Gleason score>8). At the other extreme, one can occasionally see small foci of Gleason pattern 4 on needle biopsy with a few glands of pattern 3. In the setting of very limited cancer on needle biopsy, the few glands of pattern 3 would typically occupy over 5% of the area of the tumor focus, and one would grade these tumors as Gleason score 4+3=7. Given the significant potential in this scenario of a sampling error resulting from only limited cancer on biopsy, the presence of a relatively small amount of pattern 3 would most likely correspond to a Gleason score 7 tumor in the corresponding prostate. The same 5% cut off rule for excluding lower grade cancer also applies for TURPs and radical prostatectomy specimens, which in most cases would relate to extensive cancer with more than 95% Gleason pattern 4 tumor.

Reporting secondary patterns of higher grade when present to a limited extent

It was the consensus of the group that high-grade tumor of any quantity on needle biopsy, as long as it was identified at low to medium magnification (see General applications of the Gleason grading system) should be included within the Gleason score. Any amount of high grade tumor sampled on needle biopsy most likely indicates a more significant amount of high grade tumor within the prostate due to the correlation of grade and volume and the problems inherent with needle biopsy sampling. Consequently, a needle biopsy which is entirely involved by cancer with 98% Gleason pattern 3 and 2% Gleason pattern 4 would be diagnosed as Gleason score 3+4=7.

In radical prostatectomy specimens with the analogous situation of a tumor nodule having 98% Gleason pattern 3 and 2% pattern 4, there was no consensus within the group. Approximately half of the group would diagnose these foci in an analogous fashion to that done on needle biopsy and interpret the case as Gleason score 3+4=7 regardless of the percentage of pattern 4. The other half would note these tumors as Gleason score 3+3=6 with a minor component of Gleason pattern 4. The rationale for the latter method is based on radical prostatectomy data; cancers with more than 95% Gleason pattern 3 and less than 5% pattern 4 have pathological stages that are worse than a pure Gleason score 3+3=6 tumor yet not as adverse as a Gleason score 3+4=7 where pattern 4 occupies more than 5% of the tumor [26, 27].

Tertiary Gleason patterns

Needle biopsy

On needle biopsies with patterns 3, 4, and 5, both the primary pattern and the highest grade should be recorded, which is a departure from the original Gleason grading system [10]. For example, tumors with Gleason score 3+4 and a tertiary pattern 5 would be recorded as Gleason score 3+5=8. Men with biopsy Gleason score 7 with tertiary pattern 5 have a higher risk of PSA failure whether treated with radical prostatectomy or radiation therapy when compared to men with Gleason score 7 without tertiary grade 5 and have a comparable risk with men with Gleason score 8-10 [28, 29]. In cases where there are three patterns consisting of patterns 2, 3, and 4, pattern 2 is ignored and the biopsy is graded as Gleason score 3+4=7 or Gleason score 4+3=7, depending on whether pattern 3 or pattern 4 was more prevalent.

Radical prostatectomy

In radical prostatectomy specimens, tertiary Gleason patterns are associated with higher pathological stage and biochemical recurrence as compared to the same Gleason score cancers without tertiary patterns. [26, 27, 30, 31, 32, 33, 34, 35]. The presence of a tertiary higher grade component is associated with an increased risk of biochemical recurrence, typically raising the risk of recurrence to a level intermediate between those of cancers without a tertiary component in the same Gleason score category and cancers in the next higher Gleason score category. The one exception is Gleason score 4+3=7 with tertiary pattern 5, which has progression rates more comparable to Gleason score 8. Typically, the tertiary pattern is added to the Gleason score (i.e. 3+4=7 with tertiary pattern 5).

Radical prostatectomy specimens with separate tumor nodules

It was recommended that radical prostatectomy specimens should be processed in an organized fashion where one can make some assessment as to whether one is dealing with a dominant nodule or separate tumor nodules. This does not necessarily require serially sectioning and embedding a radical prostatectomy in its entirety. Rather, multiple sampling techniques have described how one can subtotally submit the prostate, yet still maintain orientation in order to distinguish between different tumor nodules [36, 37, 38]. This issue becomes critical in the situation where one has a higher-grade peripheral nodule and a smaller, typically transition zone, lower-grade nodule. One can have a nodule of Gleason score 4+4=8 within the peripheral zone and a Gleason score 2+2=4 nodule within the transition zone. Occasionally these Gleason score 2+2=4 transition zone tumors may even reach relatively sizable proportions although typically they are organ-confined. If one were to assign an overall score considering all of the tumor within the prostate as one lesion, the score of such a tumor would be Gleason score 4+2=6 or Gleason score 2+4=6. It was the consensus of the group that such a grade would be misleading as it is not logical to expect that the presence of a lower grade tumor that is discrete from a separate high grade tumor nodule could in some way mitigate the poor prognosis associated with the higher grade tumor nodule. It was also recognized that if a tumor was graded, for example, as Gleason score 4+2=6 or 2+4=6, the presence of pattern 4 within such a diagnosis would not be emphasized and the patient would typically merely be recorded as having a Gleason score 6 tumor, which would not accurately reflect the nature of his lesion. The recommendation of the consensus conference was that one should assign a separate Gleason score to each dominant tumor nodule(s). With only a couple of exceptions, pathologists within the consensus conference who were authors of large radical prostatectomy series had already adopted this method of grading and the prognostic impact of the Gleason score within these series already reflects this approach. Most often, the dominant nodule is the largest tumor, which is also the tumor associated with the highest stage and highest grade. In the unusual occurrence of a non-dominant nodule (i.e. smaller nodule) that is of higher stage, one should also assign a grade to that nodule. If one of the smaller nodules is the highest grade focus within the prostate, the grade of this smaller nodule should also be recorded. In general this will be the exception; in most cases, separate grades will be assigned to only one or at most two dominant nodules.

Needle biopsy with different cores showing different grades

In current practice within the United States, a minimum of ten to 12 cores are sampled for the initial biopsy to rule out prostate cancer. In cases where multiple cores are positive for cancer, different cores may have a different Gleason grade. What overall grade should be assigned to such a patient for purposes of treatment and prognosis? This issue assumes its greatest importance when one or more of the cores show pure high-grade cancer (i.e. Gleason score 4+4=8) and the other cores show pattern 3 (3+3=6, 3+4=7, 4+3=7) cancer. Should the overall grade be the core with the highest grade or does one assign the grade by mentally adding all the cancer together as if it was one long core. Assume a case with Gleason score 4+4=8 on one core with pattern 3 (3+3=6, 3+4=7, 4+3=7) on other cores. The “Global” score for the entire case, averaging all involved needle biopsies together as if they were one long positive core, would be 4+3=7 or 3+4=7 depending on whether pattern 4 or 3 predominated.

Several studies have demonstrated that in cases with different cores having different grades, the highest Gleason score on a given core correlates better with stage and Gleason score at radical prostatectomy than the average or most frequent grade amongst the cores [39, 40, 41]. Additional support for giving cores a separate grade rather than an overall score for the entire case is that all of the various tables (i.e. Partin tables) and nomograms that have been validated and proven to be prognostically useful have used the highest core grade in cases where there are multiple cores of different grades.

It is therefore incumbent on pathologists to report the grades of each core separately as long as the cores are submitted in separate containers or the cores are in the same container yet specified by the urologist as to their location (i.e. by different color inks). As a consequence, the core with the highest grade tumor can be selected by the clinician as the grade of the entire case to determine treatment [42, 43]. In addition to giving separate cores individual Gleason scores, it is an option for pathologists to also give an overall score at the end of the case.

There is no consensus how to grade different cores with different grades when the different cores are present within the same specimen container without a designation as to site [10]. For example, there may be two cores of tissue from the left base in one jar without further designation, or multiple cores divided into containers from the left and right side of the gland. If more than one core contains cancer in the setting of multiple cores per container, some urological pathologists still grade each core separately with the remaining experts in the field giving an overall grade for the involved cores per specimen container. A rationale for the latter approach is that it is implicit that clinicians submitting multiple cores together in one container do not value the specific information derived from the cores within a given container. On the other hand, assigning a Gleason score to each core even when there are multiple positive cores in a given jar provides the most accurate information for patient care.

In cases with multiple fragmented cores in a jar, only an overall Gleason score for that jar can be assigned. For example, diagnosing Gleason score 4+4=8 on a tiny tissue fragment where there are other fragments with Gleason score 3+3=6 could be in error; if the cores were intact and the tumor was all on one core, it would be assigned a Gleason score 3+4=7 or 4+3=7.

Prognostic Gleason grade grouping

A problem with the current system is that Gleason score 6 is typically recommended as the lowest grade assigned on biopsy material. However, the Gleason scale ranges from 2-10, such that patients are unduly concerned when told they have Gleason score 6 cancer on biopsy, logically but incorrectly assuming that their tumor is in mid-range of aggressiveness. Another problem is that Gleason score 7 tumor is often considered as one grade, without distinction of 3+4=7 and 4+3=7. Finally, most studies combine Gleason scores 8-10 as high grade cancer without differentiating Gleason score 9-10 from Gleason score 8.

Based on a series of 6,462 men treated by radical prostatectomy (RP) where both the needle biopsy and RP were graded using the current modified Gleason grading system, the 5-year biochemical free survival rates for men with 3+3, 3+4, 4+3, 8, and 9-10 at biopsy were 94.6%, 82.7%, 65.1%, 63.1%, and 34.5% respectively (p @<@0.001 for trend); and 96.6%, 88.1%, 69.7%, 63.7%, and 34.5% based on RP pathology respectively (p @<@0.001).

It has been proposed the following Gleason grade groups and reporting of grade that accurately reflects prognosis while incorporating descriptive terminology:

 Gleason score 2-6 (well-differentiated), prognostic grade group I/V;
 Gleason score 3+4=7 (moderately differentiated), prognostic grade group II/V;
 Gleason score 4+3=7 (moderately-poorly differentiated), prognostic grade group III/V;
 Gleason score 8 (poorly differentiated), prognostic grade group IV/V;
 Gleason score 9-10 (undifferentiated), Prognostic grade group V/V.

See also

 tumoral grade
 prostate cancer

• prostate adenocarcinoma
  • prostate acinar adenocarcinoma

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