—  SHORT COURSE #13  —

Interpretation of Prostate Needle Biopsies

Case 13, 14, 15, 16 - Contemporary Approach to Gleason Grading and Discussion of Other Important Prognostic Markers in the Needle Biopsy Setting

Rajal Shah and Ming Zhou


Case 13
A 65 year old African American with a strong family history of prostate cancer underwent serum PSA test with value of PSA of 5.5 ng/ml. The patient subsequently underwent an extended biopsy of 12 cores .

Diagnosis:
Adenocarcinoma of the prostate, Gleason score 4+3=7, involving 20% of the core.

Case 14
A 60 year old African American men, underwent prostate biopsies for rising PSA.

Diagnosis:
Adenocarcinoma of the prostate, Gleason score 3+4=7.

Case 15:
A 58 year old male with PSA of 15 ng/ml, and prostate nodule.

Diagnosis:
Adenocarcinoma of the prostate, Gleason score 4+4=8, with large duct differentiation.

Case 16:
A 70 year-old male with rising PSA.

Diagnosis:
Adenocarcinoma of the prostate, Gleason score 3+5=8 (pattern 4 is secondary and pattern 5 is tertiary).

Contemporary approach to Gleason grading of Prostate Cancer

Donald F. Gleason in 1966, based on architectural features of prostate cancer created the Gleason grading system [1, 2]. The original description of this system was based on a study of 270 patients from the Minneapolis Veterans Administration Hospital. Later in 1974, study was expanded to include 1032 men [3]. Based on additional experience Gleason made further refinements to the system in 1974 and 1977. Using this architectural system, all tumors are fit into a 5-grade system representing a continuum of progressively complex morphologies. Another unique aspect of the system is that rather than assigning a worst grade to tumor, an average grade comprising of most prevalent and second most prevalent pattern (Gleason score= Primary + Secondary pattern) is assigned. Of many proposed systems for the grading of prostate cancer over the years, currently the most widely accepted and utilized system is the Gleason system. Most recently the system has been endorsed by the World Heath Organization [4].

Significance of Gleason grading
Numerous reports have confirmed the significance of Gleason score in predicting outcome after no treatment, treatment with radical prostatectomy and radiation therapy [5, 6, 7, 8]. In patients receiving neoadjuvant or adjuvant hormonal therapy Gleason grade has been found to be an independent predictor of biochemical failure [9]. Several groups have developed nomograms for predicting pathologic stage based on clinical stage, serum PSA and biopsy Gleason score [10, 11, 12]. The best known of these nomograms are "Partin tables" and "Kattan nomograms". Similarly, models for predicting risk of progression in patients treated with radiation therapy and other therapy settings have been proposed [13].

Why the need for a contemporary approach on Gleason grading?
Despite its inception almost 40 years ago, Gleason grading system has remained as most powerful and accepted grading system throughout the world. Nonetheless, the profile of prostate cancer and its treatment parameters has changed dramatically since the late 1960s, when Gleason grading system was first introduced. There are several arguments in favor of need for a contemporary approach to the Gleason grading prostate cancer [14]: 1) In late 1960s when Gleason grading was introduced there was no PSA screening. Digital rectal examination (DRE) was the primary form of clinical examination. In Gleason's original study the vast majority of men had advanced disease with either local extension outside prostate on clinical examination or distant metastases. Diagnosis of non-palpable tumor was rare [3]. 2) The use of 18-guage thin needle biopsies and the concept of sextant biopsy sampling approach were not practiced until the late 1980s [15]. Limited biopsy sampling of the palpable nodule or TURP was primary sampling approaches. Consequently, the grading in NBXs, particularly in multiple cores of different sites of the prostate cancer were not issues in Gleason's era. 3) The creation of Gleason system predated the use of immunohistochemistry. It became only realized after use of immunostaining for the basal cells that most of so called Gleason grade 1+1=2 were in fact adenosis (atypical adenomatous hyperplasia). Similarly, the concept of cribriform HGPIN was better appreciated after use of basal markers [16]. 4) There is no information in the original Gleason system, how to grade newly described variants or patterns of adenocarcinoma of the prostate. 5) The original Gleason system did not address issue of how to deal with tertiary patterns Contemporary application of Gleason grading with criteria and pitfalls for the diagnosis of each Gleason grade (Excerpts from the 2005 International Society of Urologic Pathology (ISUP) Consensus conference on Gleason grading of prostate carcinoma) [1, 2, 4, 14, 17, 18] The ISUP Gleason committee recommendations are based on combinations of scientific data where it is available and on personal and institutional experience where there is currently lack of sufficient scientific data. In the latter instance the recommendations are purely based on achievement of consensus amongst group of urological pathologists.

Gleason Pattern 1 (Score 1+1=2)

Original Gleason description: 1966 and modifications in 1974 & 1977
Very well differentiated, small, closely packed, uniform, glands in essentially circumscribed masses.
Old-1

2005 ISUP committee recommendations
Circumscribed nodule of closely packed but separate, uniform, round to oval, medium-sized acini (larger glands than pattern 3)

Applications in clinical practice:
Most cases which were diagnosed as Gleason score 1+1=2 in the era of Gleason today would refer to as adenosis (AAH) with use of basal cell immunohistochemistry. This is a grade that should not be diagnosed regardless type of the specimen, with extremely rare exception.


Gleason Pattern 2 (Score of 3-4)

Original Gleason description: 1966 and modifications in 1974 & 1977
Similar to pattern 1 but with moderate variation in size and shape of glands and more atypia in the individual cells; cribriform pattern may be present, still essentially circumscribed, but more loosely arranged.
old-2

2005 ISUP committee recommendations
Like pattern 1, fairly circumscribed yet at the edge of tumor nodule there may be minimal infiltration. Glands are more loosely arranged and not quite as uniform as Gleason pattern 1. Cribriform patterns are not allowed in within Gleason pattern 2.


Applications in clinical practice:
This pattern occasionally exists on TURP and in multifocal low-grade tumors within the radical prostatectomy specimens. Due to poor reproducibility, lack of good correlation with prostatectomy grade, sampling issues, and potentially misleading clinical implications, Gleason score of 3-4 on needle biopsy should "rarely, if ever" be made when all classic criteria exists and diagnosis of adenosis is excluded [19, 20]. The major limitation of a diagnosis of Gleason score 4 on needle biopsy is that one may not see the edge of entire lesion. Therefore most of such lesions in NBX are diagnosed as 3+2=5 or 2+3=5 with a comment that almost always corresponding prostatectomy will have higher grade.

Gleason Pattern 3

Original Gleason description: 1966 and modifications in 1974 & 1977
Similar to pattern 2 but marked irregularity in size and shape of glands, with tiny glands or individual cells invading stroma away from circumscribed masses, or solid cords and masses with easily identifiable glandular differentiation within most of them. In 1974 and 1977 modifications, papillary or cribriform (1974) tumor which may vary in size and may be quite large, but the essential feature is the smooth and usually rounded edge around all the circumscribed masses of tumor (1977)


2005 ISUP committee recommendations
Discrete glandular units, typically smaller glands than seen in Gleason pattern 1 or 2, infiltrates in and amongst non-neoplastic prostate acini. Glands typically have marked variation in size and shape. Only smooth circumscribed small cribriform nodules of same size as normal glands should be diagnosed as 3. "Individual cells" would not be allowed within Gleason pattern 3.


Applications in clinical practice:
This is the most common grade encountered in needle biopsy specimens. Minute foci of individual, infiltrating tumor glands seen frequently in NBXs are pattern 3+3=6. It is now consensus that the vast majority of cribriform patterns should be diagnosed as Gleason pattern 4 with only rare cribriform lesions satisfying diagnostic criteria for cribriform pattern 3. Cribrifrom Gleason pattern 3 morphologically resemble high-grade cribriforming PIN but is diagnostic of cancer due to 1) large number of glands are negative for basal cell markers; 2) there are specific features of cancer such as perineural invasion or extraprostatic extension or 3) based on the presence of adjacent conventional carcinoma.

Gleason Pattern 4

Original Gleason description: 1966 and modifications in 1974 & 1977
Large clear cells growing in a diffuse pattern resembling hypernephroma; may show gland formation (1966) Raggedly infiltrating, fused-glandular tumor (1974). Glands are not single and separate, but coalesce and branch (1977)


2005 ISUP committee recommendations
Fused glands Ill-defined glands with poorly formed glandular lumina where tangentially sectioning is ruled out Large cribriform glands Irregular cribriforming glands Hypernephroid morphology


Applications in clinical practice:
In the most recent Partin tables Gleason score 7 (3+4) and Gleason score 7 (4+3) are considered separately [10]. This emphasizes on the importance of determining the primary pattern. Gleason pattern 4 constitute an important clinical decision making process. Presence of any Gleason pattern 4 typically is considered clinically significant prostate cancer. Caution should be advised for poorly formed gland criteria. Poorly formed glands seen randomly within a focus or only at the edge likely represents a tangential sectioning of Gleason 3 pattern.

Gleason Pattern 5

Original Gleason description: 1966 and modifications in 1974 & 1977
Very poorly differentiated tumors; usually in solid masses or diffuse growth with little or no differentiation into glands (1966).
Can resemble comedocarcinoma of the breast (1977). Almost absent gland pattern with few tiny glands or signet cells (1977).


2005 ISUP committee recommendations
Essentially no glandular differentiation, composed of solid sheets, cords, or single cells Comedocarcinoma with central necrosis surrounded by papillary, cribriform, solid masses


Applications in clinical practice:
One must be stringent as to the definition of comedonecrosis, requiring intraluminal necrotic cells and/or karyorrhexis, especially in the setting of cribriform glands. The revised Gleason diagram by the 2005 ISUP Gleason grade committee, showing the contemporary approach to the Gleason grading of prostate cancer is summarized below [14].


Gleason grading in unusual subtypes and patterns of Prostate cancer

Table 1 Gleason Grading of Unusual Subtypes and Patterns

Histologic type or pattern Gleason grade
Foamy gland pattern Graded based on underlying architecture
Pseudohyperplastic Pattern 3
Atrophic Pattern 3
Large duct carcinoma Pattern 4, with necrosis 5
Signet-ring cell carcinoma Pattern 5
Small cell carcinoma Not graded
Adenosquamous and squamous carcinoma Not graded
Sarcomatoid carcinoma Not graded
Glomeruloid pattern 3 or 4
Collagenous micronodules Graded based on underlying architecture
Mucinous (colloid) carcinoma 3 or 4

Table 2 Gleason Grading of Cribriform Carcinomas

Histologic pattern* Gleason grade
1) Rounded, well-circumscribed cribriform glands of the same size of normal glands (resemble cribriform high-grade PIN) 3
2) Large cribriform glands 4
3) Cribriform glands with irregular borders 4
4) Cribriform carcinoma with ductal differentiation 4

* Vast majority of cribriform carcinoma patterns (>95%) fall into Gleason pattern 4 with only rare cribriform lesions satisfying criteria (#1) for pattern 3.

Reporting secondary pattern of lower grade when present to a limited extent
In the setting of high-grade cancer one should ignore lower grade patterns if they occupy <5% of the area of tumor. In the setting of very small focus of cancer, the few glands of lower grade should be recorded, as there is significant potential of sampling error resulting from limited cancer. An example in the needle biopsy situation is given in figure # 1.

Reporting secondary pattern of higher grade when present to a limited extent
High-grade tumor of any quantity on needle biopsy, as long as it was identified at low to medium magnification should be included within the Gleason score. This is based on any amount of high grade sampled in needle biopsy most likely indicates a more significant tumor (Fig #1). The guidelines for this parameter in the setting of radical prostatectomy are not clear, but majority agree that even limited higher-grade tumor should be reported in the context of either secondary or tertiary grade [21, 22].

Reporting Tertiary Gleason Pattern
The importance of tertiary Gleason pattern is typically when it is of higher grade than secondary pattern. The typical scenario with tertiary patterns on biopsy includes tumors with patterns 3, 4, and 5 in various proportions. It is now consensus that such tumors should be overall classified high-grade in NBX setting (Figure #1). NBX with patterns 3, 4, and 5, both the primary pattern and the highest grade should be recorded, i.e. 3+5=8. This recommendation is based on management decision issue. Majority clinicians use Partin tables or Nomogram to predict outcomes such as pathological stage or prognosis following radical prostatectomy or following radiation therapy. These algorithms typically use only primary and secondary pattern reported in the NBX and therefore tertiary pattern of higher grade would be dropped unless reported as secondary pattern. Tertiary pattern of lower grade can be ignored in the needle biopsy setting.

Figure #1 representing scenario of above three situations:

For the radical prostatectomy specimen one assigns the Gleason score based on the primary and secondary patterns with a comment as to the tertiary pattern when it is of higher grade. Moose et al demonstrated that at radical prostatectomy Gleason score of 4+3=7 with a tertiary pattern 5, behaves worse than with Gleason score of 4+3=7 with out tertiary pattern 5, but have a lower incidence of seminal vesicle invasion and lymph node metastases compared to seen with Gleason score 4+5=9 [22].

Example: Figure #2


Needle Biopsy with multiple cores demonstrating different grades
It is not clear how different Gleason score on needle biopsies should be reported, that is, whether individual biopsy cores should be graded separately or whether the grade of multiple positive biopsies should be summarized as global Gleason score [23]. The recommendation of the ISUP Gleason grading committee is that one should assign individual Gleason scores to separate cores as long as the cores were submitted in the separate containers or the cores were in the same container yet specified by the Urologist as to their location. Giving an overall or gestalt Gleason grade is optional(Figure #3).


Global (Gestalt) Gleason score is optional
Kunz et al demonstrated that when one core with Gleason score of 4+4=8 with other cores having pattern 3, the pathological stage at radical prostatectomy is comparable to cases with all needle cores having Gleason score 4+4=8 [24]. In another study, the highest Gleason score and the biopsy core with the highest tumor volume correlated best with final Gleason score at radical prostatectomy [25]. In a recent survey Rubin et al demonstrated that, our surgical colleagues typically tend to pick out the highest grade of all cores and label the patient with that grade [26]. However, the scenarios where multiple cores are submitted in the same container without site identifiers or labeled "left/right" are common. To assess this scenario, we analyzed 110 extended biopsies containing different Gleason scores with corresponding radical prostatectomy for clinically significant differences. Scenario of multiple intact cores with different Gleason scores in the same container (s) was created by analyzing as if submitted in containers labeled "left/right". For each biopsy, a Global (all positive cores averaged as 1 long positive core), Worst, and Largest tumor volume Gleason score was determined and compared with radical prostatectomy Gleason score by kappa statistics. Overall, biopsy Worst Gleason score had the best correlation with radical prostatectomy Gleason grade (kappa agreement of 0.37). Clinically significant upgrading at radical prostatectomy was least with Worst (4%) and highest with Global Gleason score (37%). These results suggested that when multiple intact cores are submitted in the same container without specific identifiers, individual cores with cancer should be graded and or/worst Gleason score should be recorded (33) . In cases where cores are fragmented, and one cannot be sure if one is looking at an intact core, the consensus is that one should only give an overall score for that container.

Figure #4


Significance of Percent Gleason Pattern 4-5
Several studies have demonstrated importance of percentage pattern 4/5 [27]. This is particularly predictive of prognosis at the extreme of the percentages. However, the percent pattern 4/5 on NBX has not shown to correlate well with the percentage of 4/5 in the corresponding radical prostatectomy [28]. Reporting of this parameter is optional.

Limitations of Gleason grading
Gleason grading system is certainly not without limitations. The very concept of the histological patterns representing a continuum ensures that there will be gray zones and hence a problem of reproducibility. This limitation has been documented by several studies for both inter- and intra- observer variability. Major limitation of the system is poor agreement between biopsy and prostatectomy Gleason score [20, 29, 30]. Only in about 1/3 of cases such agreement is typically demonstrated with further 1/3 having a prostatectomy score within +/-1 of needle biopsy. In the remaining 1/3 the difference is 2 or more. Factors that contribute such discrepancy include tumor heterogeneity, sampling errors, inter- and intra-variability, and interpretive errors. Surgical pathologist typically have tendency to under grade the biopsies. Recent studies suggest that this discrepancy is reduced when more extended biopsy approach protocols are adopted [31, 32].

Important clues to the contemporary Gleason grading

Table 3 Gleason Grading: Take Home Messages

1) Small foci of cancer do not necessarily mean low-grade cancer.
2) Gleason score of 2-4 on NBX is almost always wrong.
3) Tumor of only few malignant glands located amongst benign glands is grade 3.
4) Fusion is Gleason pattern 4.
5) Well-formed fused glands pattern is grade 4.
6) Majority of cribriform carcinomas (>95%) represent grade 4.
7) Ill-defined glands cluster with poorly formed glandular lumina represent Gleason grade 4.
8) Many "special" types of prostate cancer are grade 4.
9) Comedonecrosis represents grade 5

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