Gleason grading system is based on the architectural patterns of the tumor, and taking in consideration of heterogeneity of prostate cancer, it includes the sum of the most common and the second most common patterns. The grading system encompasses grades from 1 to 5, from well circumscribed uniform glands (grade 1) to the poorly differentiated tumor composed of solid sheets and/or single cells or areas of central (comedo) necrosis (Fig. 10.1). Initial description of the system was based on a study of 270 patients from the Minneapolis Veterans Administration Hospital, and the study was expanded to 463 men in 1967 and 1032 men in 1974 [6–8]. These initial studies included men mostly with advanced disease with either extraprostatic extension or metastatic disease at the time of diagnosis. The strength of this grading system is that it is relatively simple and fairly easily applied with reasonable concordance (reproducibility). In addition, it is one of the most powerful prognostic predictors in Pca, predicting pathological findings in RP, biochemical failure, local and distant metastasis after therapy, and Pca-specific mortality, and is one of the key parameters used in therapy planning, especially for decisions regarding active surveillance versus definitive therapy.

The current guidelines of the Gleason grading system , including the most recent updates which were introduced in 2014 at a meeting attended by pathologists with expertise in prostate pathology and groups of oncologists and urologists, include elimination of GS 2 (1 + 1) regardless of the specimen type and limiting GS 2–4 diagnosis to rare cases in which the cancer is diagnosed in transurethral resection (TURP) specimens where the circumscription of the tumor nodules can be observed [6] (Fig. 10.2).

It also includes expansion and better definition of Gleason grade 4 category. In Gleason’s original descriptions, grade 4 group included only “large clear cells growing in a diffuse pattern resembling hypernephroma; may show gland formation” (Fig. 10.1). Later modifications included raggedly infiltrating fused glands and glands that are not single and separate but coalesce and branch. The 2005 consensus further expanded the category to include most cribriform glands (except “small cribriform glands with regular contour and round evenly distributed lumina” still regarded as Gleason grade 3) and ill-defined glands with poorly formed glandular lumens or “poorly formed” glands.

In 2014, all cribriform glands regardless of the shape and size and glands with glomeruloid architecture, considered a variant of cribriform architecture , were added to the Gleason grade 4 category (Figs. 10.2 and 10.4). When compared with all the different patterns that make up Gleason grade 4 group, cribriform growth pattern has been shown to predict adverse clinical outcome parameters such as postoperative metastasis and disease-specific death [12, 13].

Distinguishing tangentially sectioned Gleason grade 3 glands that appear poorly formed from the truly poorly formed glands has been a great challenge for pathologists (Figs. 10.3 and 10.4). Although it was noted that “more than occasional poorly formed glands” must be seen for a tumor to be classified as Gleason grade 4 in the latest consensus meeting to avoid overcalling of tangentially cut glands, attempts have been made to determine the morphologic and quantitative criteria to overcome the ambiguity of “poorly formed” definition. Zhou et al. [14] studied interobserver reproducibility of diagnosing “poorly formed glands” on core needle biopsies among urologic pathologists and came up with recommendations to consider only cancer glands with no or rare luminal formation as “poorly formed” and to have at least ten “poorly formed glands” that are not immediately adjacent to well-formed glands to be considered Gleason pattern 4. This issue is of utmost important since presence of Gleason grade 4 pattern is among the criteria used to make decisions, namely, if a patient is going to be included in active surveillance programs or offered a definitive therapy, such as prostatectomy or radiation therapy. In a recent multi-institutional study involving an active surveillance cohort [15], the reproducibility of assigning a Gleason pattern 3 vs 4 or higher was worst for small foci with glands where the interpretation varied between tangentially sectioned Gleason pattern 3 vs poorly formed glands of Gleason pattern 4. The best interobserver agreement was in cribriform and glomeruloid Gleason 4 patterns [16] in a recent study among genitourinary pathologists. In line with the previous study by McKenney, hardly any consensus was reached on ill-formed and fused glands. More recent attempts to further optimize histologic grading of prostatic adenocarcinoma to decrease interobserver variance and provide consistent and more accurate prognostic stratification for the individual patient include attempts of incorporating individual architectural patterns into the grading scheme and assessing their relative contribution to the prognostic strength [17].

Gleason grade 5 patterns include single cells, solid tumor sheets, and cords of cells without any glandular differentiation as well as central (comedo) necrosis (Fig. 10.5). They generally do not present diagnostic challenges, unless the amount of single cells/cords of cells is limited.

The most common practice is to give a Gleason score to each specimen of biopsy core(s) that is submitted in separate containers. For treatment algorithms, typically the highest Gleason score is used regardless of the volume of cancer in the particular core(s). In heterogeneous and multifocal tumors, this has the potential to overrepresent the high-grade component in the entire gland and place the patient in a higher-risk category. In a study by Aries-Stella et al., when using the highest biopsy Gleason score, the authors found that 60% of such patients had a downgraded Gleason score at prostatectomy [18]. As a result they concluded that a composite needle biopsy Gleason score combining relative proportions of each Gleason grade pattern in multiple contiguous positive biopsies correlated better with prostatectomy Gleason score in patients with heterogeneous needle biopsy Gleason scores (>2 different GSs or a two-step difference in GS between separate biopsies).