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. 2021 Aug 15;11(8):3990-4001.
eCollection 2021.

Diagnosis of "cribriform" prostatic adenocarcinoma: an interobserver reproducibility study among urologic pathologists with recommendations

Rajal B Shah  1 , Qi Cai  1 , Manju Aron  2 , Daniel M Berney  3 , John C Cheville  4 , Fang-Ming Deng  5 , Jonathan Epstein  6 , Samson W Fine  7 , Elizabeth M Genega  8 , Michelle S Hirsch  9 , Peter A Humphrey  10 , Jennifer Gordetsky  11 , Glen Kristiansen  12 , Lakshmi P Kunju  13 , Cristina Magi-Galluzzi  14 , Nilesh Gupta  15 , George J Netto  14 , Adeboye O Osunkoya  16 , Brian D Robinson  17 , Kiril Trpkov  18 , Lawrence D True  19 , Patricia Troncoso  20 , Murali Varma  21 , Thomas Wheeler  22 , Sean R Williamson  23 , Angela Wu  13 , Ming Zhou  8
Affiliations

Diagnosis of "cribriform" prostatic adenocarcinoma: an interobserver reproducibility study among urologic pathologists with recommendations

Rajal B Shah et al. Am J Cancer Res. .

Abstract

Accurate diagnosis of cribriform Gleason pattern 4 (CrP4) prostate adenocarcinoma (PCa) is important due to its independent association with adverse clinical outcomes and as a growing body of evidence suggests that it impacts clinical decision making in PCa management. To identify reproducible features for diagnosis of CrP4, we assessed interobserver agreement among 27 experienced urologic pathologists of 60 digital images from 44 radical prostatectomies (RP) that represented a broad spectrum of potential CrP4. The following morphologic features were correlated with the consensus diagnosis (defined as 75% agreement) for each image: partial vs. transluminal glandular bridging, intraglandular stroma, <12 vs. ≥12 lumina, well vs. poorly formed lumina, mucin (mucinous fibroplasia, extravasation, or extracellular pool), size (compared to benign glands and number of lumina), number of attachments with gland border by tumor cells forming a "glomeruloid-like" pattern, a clear luminal space along the periphery of gland occupying <50% of glandular circumference, central nerve, dense (cell mass occupying >50% of luminal space) vs. loose, and regular vs. irregular contour. Interobserver reproducibility for the overall diagnostic agreement was fair (k=0.40). Large CrP4 had better agreement (k=0.49) compared to small CrP4 (k=0.40). Transluminal bridging, dense cellular proliferation, a clear luminal space along the periphery of gland occupying <50% of gland circumference, lack of intraglandular mucin, and lack of contact between the majority of intraglandular cells with stroma were significantly associated with consensus for CrP4. In contrast, partial bridging, majority of intraglandular cells in contact with stroma, mucinous fibroplasia, only one attachment to the gland border by tumor cells forming a "glomeruloid-like" pattern, and a clear luminal space along the periphery of gland accounting for >50% of the glandular circumference were associated with consensus against CrP4. In summary, we identified reproducible morphological features for and against CrP4 diagnosis, which could be used to refine and standardize the diagnostic criteria for CrP4.

Keywords: Prostate adenocarcinoma; consensus; cribriform; gleason grade; grade group; reproducibility.

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Conflict of interest statement

None.

Figures

Figure 1
Figure 1
(A-C) Examples of cribriform lesions that achieved consensus for CrP4. (A) A large CrP4 showing dense cellular proliferation with numerous well-formed lumina (>12) and transluminal bridging, forming a “sieve-like” growth. There is no intraglandular stroma or blood vessels. (B) A large CrP4 with branching contour. Despite stoma between branching cribriform glands (arrows), there is no intraglandular stroma or vessels. (C) Small CrP4 that are the size of adjacent benign glands (insert) and have dense transluminal cellular proliferation with <12 well-formed lumina (A-C, Hematoxylin and eosin, original magnifications ×4 (A and B), ×10 (C)).
Figure 2
Figure 2
(A, B) Examples of unusual morphologic patterns that achieved consensus for CrP4. (A) An example of mucinous prostate adenocarcinoma (PCa) showing multiple complex confluent nests with well-formed lumina floating within pools of mucin. Seventy-four % of participants classified it as large CrP4, 4% as small CrP4, and the remaining 22% as non-cribriform pattern 4. (B) An example of dense transluminal proliferation with poorly formed “rosette-like” multiple lumina. Seventy-eight % of participants classified this example as CrP4 and the remaining 22% as pattern 5 (A, B, Hematoxylin and eosin, original magnification ×10 (A and B)).
Figure 3
Figure 3
(A-D) Examples of lesions that achieved consensus against CrP4. (A) Cancer glands showing loose cellular proliferation forming multiple incomplete (partial) bridging. Ninety % of participants classified this lesion as a non-cribriform pattern 4. (B) PCa exhibiting complex proliferation of interconnecting tumor cells with well-formed slit-like lumina. However, the majority of tumor cells are in contact with stroma of blood vessels, suggestive of a papillary process. Ninety-six % of participants classified this as a non-cribriform pattern 4. (C) Small to medium cancer glands showing glomeruloid morphology (arrows). Intraluminal proliferation is attached to the border of the gland with one attachment and a clear luminal space along gland periphery occupies >50% of gland circumference. Ninety-three % of participants classified this as an example of glomerulation pattern 4. (D) PCa with intraluminal mucinous fibroplasia (arrows), creating a complex architecture mimicking CrP4. 96% classified it as either pattern 3 (63%) or as non-cribriform pattern 4 (33%) (A-D, Hematoxylin, and eosin, original magnification ×4 (A) and ×10 (B-D)).
Figure 4
Figure 4
(A-C) Examples that did not achieve consensus for or against Crp4. (A) A PCa showing large gland “glomeruloid-like” architecture. There are multiple attachments to the gland border and a clear luminal space along the periphery occupy >50% of gland circumference. Fifty-two % of participants classified it as large CrP4, 11% as small CrP4, and 37% as glomerulation pattern 4. (B) A PCa forms complex dense cellular proliferation with multiple well-formed lumina around the nerve. Thirty-three % participants classified it as small CrP4, 26% large CrP4, 26% non-cribriform pattern 4 and 15% pattern 3. (C) A PCa with mucin extravasation. Sixty-three % of participants classified it as non-cribriform pattern 4, 11% as large CrP4, 22% as small CrP4, and 4% as pattern 3 (A-C, Hematoxylin, and eosin, original magnification ×10 (A) and ×20 (B, C)).
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