Grading of prostate cancer: a work in progress

Abstract

Grading of prostate cancer has evolved substantially over time, not least because of major changes in diagnostic approach and concomitant shifts from late- to early-stage detection since the adoption of PSA testing from the late 1980s. After the conception of the architecture-based nine-tier Gleason grading system more than 50 years ago, several changes were made in order to increase its prognostic impact, to reduce interobserver variation and to improve concordance between prostate needle biopsy and radical prostatectomy grading. This eventually resulted in the current five-tier grading system, with a much more detailed description of the individual architectural patterns constituting the remaining three Gleason patterns (i.e. grades 3-5). Nevertheless, there is room for improvement. For instance, distinction of common grade 4 subpatterns such as ill-formed and fused glands from the grade 3 pattern is challenging, blurring the division between low-risk patients who could be eligible for deferred therapy and those who need curative therapy. The last few years have witnessed the publication of several studies on the prognostic impact of individual architectural subpatterns showing that, in particular, the cribriform pattern exceeded the prognostic impact of other grade 4 subpatterns. This review provides an overview of the changes in prostate cancer grading over time and provides a thorough description of the various Gleason subpatterns, the current evidence of their prognostic impact and areas of contention. Potential practical ways for improvements of the current grading system are also put forward.

Keywords: Gleason pattern; grading; prognostic biomarker; prostate cancer; tumour architecture.

Figure 1

Gamut of Gleason grade 3 adenocarcinoma, including (A) densely packed medium‐sized well‐delineated tubules, typical of transition zone carcinoma, (B) ‘sparse’ carcinoma consisting of scattered acinar and tubular structures (arrows) widely separated from each other by intervening normal fibromuscular stroma and benign glands, (C) ‘stromogenic’ carcinoma showing well‐delineated small‐ to medium‐sized glands within a desmoplastic stroma, (D) atrophic variant carcinoma consisting of acini lined by flattened epithelial cells, (E) branching pattern carcinoma comprised of distinct medium‐sized glandular structures with branching outpouchings, not to be confused with fusing of glands, (F) pseudohyperplastic pattern adenocarcinoma with tumorous glands mirroring the architecture of normal benign glands, (G) PIN‐like adenocarcinoma, constituted of large‐sized glands lined by columnar neoplastic cells, lacking a layer of basal cells demonstrated by immunostaining, (H) miconodular collagenous nodule with entrapped acinar carcinoma cells with complex architecture and (I) mucinous carcinoma with distinct small‐sized neoplastic acini within extracellular mucin.

Figure 2

Depiction of grade 4 subpatterns: (A) haphazardly distributed poorly formed very small‐sized distinct glands showing some lumen‐formation, (B) fused small‐sized lumen‐containing glands in a retiform pattern, (C) focus of glomeruloid structures within small‐ to medium‐sized distinct glands, (D) expansile rounded tumour area with cribriform pattern lacking intervening stroma or capillaries, (E) abortive glands consisting of structures with glandular shape, but lacking a lumen, to be distinguished from solid pattern grade 5 carcinoma, (F) large‐sized glands which merge together, constituting the large‐fused pattern, (G) complex fused glands with irregular cribriform area, but with intervening stroma and capillaries, (H) large‐sized glands with glomeruloid features showing a cribriform pattern, adjacent to small‐sized glomeruloid glands and (I) papillary pattern lined by columnar tumour cells reminiscent of ductal adenocarcinoma.

Figure 3

Composite of prostatic adenocarcinomas with papillary architecture: (A) classical ductal (‘endometrioid’) carcinoma, characterised by papillary formations, lined by tall columnar neoplastic cells, (B) papillary formations lined by tumour cells resembling benign prostate glandular luminal cells in a pseudohyperplastic variant carcinoma, (C,D) papillary formations protruding into larger cystic spaces and lined by columnar luminal cells with round (basal) nuclei (C) or with apical nuclei (D) distinct from the ductal adenocarcinoma as shown in (A).

Figure 4

Most common grade 5 patterns, such as (A) comedocarcinoma, showing a necrotic central plug surrounded by fused glands, (B) single cells with vacuolisation with haphazard distribution between benign glands, (C) single file of tumour cells, lacking lumina, embedded in dense stroma, (D) smaller solid areas (upper right) with some acinar (pseudo‐rosetting) nuclear arrangement, but lacking lumen formation, (E) larger sheet of poorly differentiated tumour cells and (F) solid area of cells with signet ring‐like appearance.

Figure 5

Architectural patterns which may be challenging for grading: (A) well‐defined grade 3 medium‐sized glands transitioning to and intermingling with increasingly smaller‐sized glands, but still considered as grade 3, contrasting with (B) medium‐sized grade 3 glands with an abrupt transition to a cluster of ill‐formed (grade 4) glands and (C) medium‐sized well‐described grade 3 glands slowly transitioning into a larger field (>10 structures) of ill‐formed (grade 4) glands. In (D) small‐sized closely packed circumscribed glands surrounded by thin wisps of stroma, most consistent with grade 3 glands, (E) well‐circumscribed pale glands with flocculated eosinophilic lumen content and considerable cytonuclear atypia (compared to gland on the right side) and (F) pseudo‐rosetting pattern in an otherwise solid carcinoma field in a biopsy considered as grade 5 pattern at the ISUP 2014 consensus meeting.