Prostate gland & seminal vesicles

Acinar / ductal adenocarcinoma

Gleason grading


Editorial Board Member: Bonnie Choy, M.D.
Editor-in-Chief: Debra L. Zynger, M.D.
Kenneth A. Iczkowski, M.D.

Topic Completed: 20 August 2021

Minor changes: 20 August 2021

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PubMed Search: Gleason grading[TI] "free full text"[sb]

Kenneth A. Iczkowski, M.D.
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Cite this page: Iczkowski KA. Gleason grading. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/prostategrading.html. Accessed December 7th, 2021.
Definition / general
  • In 1966, Dr. Donald Gleason devised grades of 1 - 5 based on glandular architecture and microscopic appearance using a 4x - 10x objective eyepiece that were shown to predict an outcome in prostate cancer (Cancer Chemother Rep 1966;50:125)
Terminology
  • Gleason score is the sum of the 2 most prevalent Gleason grades: primary and secondary, designated according to separate rules for biopsy and prostatectomy
  • If only 1 pattern is present, the primary and secondary patterns are given the same grade (ex: 3+3=6)
  • Systematic needle biopsy sets contain cores from different anatomically designated sites
    • Gleason score should be assigned separately for each anatomically designated site
    • Highest score may serve as a basis to determine treatment
    • Additional reporting of a global (case level) Gleason score is optional and global scoring may show a marginal benefit over using highest score according to Trpkov et al. (Am J Surg Pathol 2020;44:e87, Am J Surg Pathol 2018;42:1522)
  • Any glands showing perineural invasion must be excluded in assigning Gleason grading because perineural invasion distorts gland morphology such that Gleason 3 glands resemble Gleason 4
  • Grading rules:
  • In radical prostatectomy:
    • Gleason score should be based on the primary and secondary patterns; if a minor pattern constitutes < 5%, the pattern should be mentioned as a minor (tertiary) pattern; any higher grade minor pattern ≥ 5% should be incorporated into the Gleason score and ISUP group as the secondary pattern (2019 consensus) (Eur Urol 2018;73:674)
    • Ex: Gleason pattern 3=96% and pattern 4=4%, Gleason score=3+3=6 with minor (tertiary) 4
    • Ex: Gleason pattern 3=95% and pattern 4=5%, Gleason score=3+4=7
  • In needle biopsy:
    • Most prevalent pattern is graded as primary and any amount of a worst pattern is graded as secondary
    • Ex: Gleason pattern 3=96% and pattern 4=4%, Gleason score=3+4=7
    • Ex: Gleason pattern 3=95% and pattern 4=5%, Gleason score=3+4=7
  • For multiparametric MRI targeted biopsies:
    • Gleason scores should be given for the aggregate of cores from each individual biopsy site but not for each core (2019 consensus)
    • This method of reporting is by research by Gordetsky et al. (Hum Pathol 2018;76:68)
    • Benign histologic changes (chronic inflammation, acute inflammation, atrophy) should be reported in high suspicion lesions (PI-RADS 4 and 5) that are negative for cancer (Am J Surg Pathol 2020;44:e87)
Epidemiology
  • In 2014, the ISUP and World Health Organization adopted a simplified patient centric grading system composed of 5 prognostic grade groups as proposed in 2013 based on data and subsequently validated by biochemical recurrence hazard ratios on cases from 5 large academic centers (Am J Surg Pathol 2016;40:244, Prostate 2016;76:427, BJU Int 2013;111:753, Eur Urol 2016;69:428)
  • Grade groups are as follows:
    1. Gleason score 3+3=6
    2. Gleason score 3+4=7
    3. Gleason score 4+3=7
    4. Gleason score 8 (4+4=8, 3+5=8, 5+3=8)
    5. Gleason score ≥ 9 (4+5=9, 5+4=9, 5+5=10)
  • Note that Gleason grades 1 and 2 are no longer recommended for use, since those patterns of cancer have an outcome no different from grade 3; moreover, pure grade 3 cancer almost never metastasizes and is reasonable to treat by active surveillance, which has sparked speculation about whether it should even be labeled cancer (Oncology (Williston Park) 2014;28:22, Curr Opin Urol 2015;25:238)
  • Divisions of Gleason score 3+4=7 from 4+3=7 and of 8 from 9-10, which had often been bundled together for prognostic and research purposes, are supported by studies showing significantly different outcomes (J Clin Oncol 2009;27:3459, World J Urol 2014;32:1067, J Urol 2015;194:91)
    • Percentage of grade 4 or 5, when heterogeneous grades are present, should be mentioned in all specimens, although biopsy and prostatectomy have different rules for scoring (Am J Surg Pathol 2020;44:e87)
  • Grade group 4 is heterogeneous as it includes 4+4=8, 3+5=8 and 5+3=8, with recent data showing no or minimal long term outcome difference when present as the highest score in biopsy sampling; instead, the presence or absence of cribriform growth of cancer was a significant prognosticator (J Urol 2016;196:1076)
  • If tumor is minimal on biopsy (≤ 1 mm), Gleason score does not predict tumor stage and this can be noted on the report (ex: in a minimal focus with pattern 4, rather than doubling to 4+4=8, tumor can be designated on the report as too small for scoring) (Am J Surg Pathol 2000;24:1634)
  • Targeted biopsies detect a higher percentage of pattern 4 than systemic ones and are less likely to be upgraded on prostatectomy (Arch Pathol Lab Med 2019;143:86)
Diagrams / tables

Evolution of grading of special prostate cancer patterns
Histologic pattern 2005 consensus 2014 consensus 2019 consensus
Branched / undulating glands Include as Gleason 3
Cribriform (under Gleason scheme: mostly 3, sometimes 4) 4 but can be 3 if much larger than benign gland, round and has loose cells Always 4 Always 4 and presence or absence should be specified for 3+4, 4+3 or 4+4
Glomeruloid variant No consensus, 3 versus 4 Always 4 --
Mucinous variant No consensus, some favored 4 Depends on growth pattern regardless of mucin; could be 3, 4 or 5 --
Small cell (pure) Do not grade -- --
Intraductal, pure form -- Do not grade Do not grade
Intraductal, associated with invasive cancer -- -- Include in estimating the percentage of grade 4, instead of keeping it separate
Ductal 4+4=8 -- --
Adenoid cystic / basal cell carcinoma -- Do not grade Do not grade
Microscopic (histologic) description
  • Discontinued Gleason grades 1 and 2
    • It was agreed at the 2014 consensus conference that Gleason grades 1 and 2 should be discontinued because grade 1 or 2 cancer in needle biopsy does not predict better prostatectomy findings than grade 3 and these grades show marked interpathologist variability
    • Gleason score of 1+1=2 was originally described as single, separate, closely packed, uniform round glands arranged in a circumscribed nodule with pushing borders; many of such cases would, with the benefit of today's immunostains, be referred to as atypical adenomatous hyperplasia (AAH or adenosis)
  • Gleason grade 3
    • Single, separate glands
    • May be either minute or large and cyst-like; glands have an irregularly separated, ragged, poorly defined edge, looser than a nodule and are infiltrative
    • Key feature is retention of at least a wisp of stroma intervening between neighboring glands
    • Tangentially cut glands may appear as if they are poorly formed but should not get graded as a 4 unless poorly formed and fused glands persist on several levels (J Urol 2011;186:465)
    • Patterns of Gleason grade 3 prostatic adenocarcinoma:
      1. Most common pattern is well formed, relatively uniform glands infiltrating between benign glands; glands may be angulated or compressed, separated by > 1 gland diameter
      2. Small glands with pinpoint lumina, glands still separate
      3. Medium sized glands with undulating luminal contours or large glands or branching
      4. Large glands with a pseudoatrophic appearance
    • Cribriform cancer no longer qualifies as Gleason 3, even if the glands are similar in size to normal glands (J Urol 2010;183:433)
  • Gleason grade 4
    • Key finding is coalescent or fused glands with > 1 lumen and absence of intervening stroma between adjacent glands
    • Patterns of Gleason grade 4 prostatic adenocarcinoma:
      1. Most common is small acinar structures, some with well formed lumina, fusing into cords or chains; may be undergraded as Gleason 3
      2. Cribriform (often merging with papillary, see Microscopic (histologic) images) by consensus has a confluent sheet of contiguous malignant epithelial cells with multiple glandular lumina that are easily visible at low power (objective magnification 10x); there should be no intervening stroma or mucin separating individual or fused glandular structures (Ann Diagn Pathol 2021;52:151733, Am J Surg Pathol 2021;45:1118)
        • Nodule of a cribriform gland should be larger than normal prostate gland
        • Large nodules of cribriform Gleason 4 lack supporting stroma and tend to fragment
        • Thus, fragments of cribriform glands on needle biopsy represent Gleason 4
      3. Hypernephroid pattern, with nests of clear cells resembling renal cell carcinoma; small, hyperchromatic nuclei; fusion of acini into more solid sheets with the appearance of back to back glands without intervening stroma
      4. Intraductal carcinoma, when admixed with invasive carcinoma, should be counted as Gleason 4 and not counted separately for quantitation purposes (Am J Surg Pathol 2020;44:e87)
        • Its presence and significance should be mentioned
        • This emphasizes the adverse influence which has a unique phenotype of certain driver mutations as shown by Khani et al. (J Pathol 2019;249:79)
      5. Glomeruloid pattern (2014 consensus), a rare small cribriform variant, contains a tuft of cells that is mostly detached from its surrounding duct space except for a single point of attachment (see Microscopic (histologic) images)
      6. Hypernephroid pattern, with nests of clear cells resembling renal cell carcinoma; small, hyperchromatic nuclei; fusion of acini into more solid sheets with the appearance of back to back glands without intervening stroma
    • Research and 2014 consensus support grading all cribriform cancer as Gleason 4 because the presence and amount of cribriform cancer carries a distinctly adverse prognosis for recurrence and for death from cancer (Am J Surg Pathol 2013;37:1855, Am J Clin Pathol 2011;136:98, Mod Pathol 2015;28:457, Adv Anat Pathol 2018;25:31, Surg Pathol Clinics 2018;11:687)
    • Note: patients with Gleason 8 at biopsy may have Gleason 7 at prostatectomy due to unsampled Gleason 3
    • Note: basal cell markers are crucial in distinguishing cribriform high grade prostatic intraepithelial neoplasia, cribriform intraductal carcinoma and invasive cribriform carcinoma
    • Rarely, pure intraductal carcinoma occurs in biopsy specimens
  • Gleason grade 5
    • Grade 5 has 2 patterns:
      • Comedonecrosis: central necrosis with intraluminal necrotic cells or karyorrhexis within papillary / cribriform spaces; caution should be exercised since many such foci have demonstrable basal cells, making them intraductal carcinoma instead; thus, immunostaining is recommended if this would alter the grade group (Histopathology 2019;74:1081, Am J Surg Pathol 2018;42:1036)
      • Single cells, possibly forming cords, possibly with vacuoles (signet ring cells) but without glandular lumens; this pattern may mimic lymphocytes at low power
    • Gleason 5 pattern has moderately good reproducibility, although certain patterns are more problematic (Am J Surg Pathol 2015;39:1242)
    • Gleason 5 cancer is often missed or underdiagnosed on needle biopsy (Int J Clin Exp Pathol 2011;4:468, Urology 2012;79:178)
    • Presence of Gleason grade 5 in prostate biopsy specimens predicts higher rates of metastasis and death compared with Gleason 4+4=8 cancer and even the smallest amounts of 5 predict outcome after prostatectomy (J Urol 2015;194:91, World J Urol 2014;32:1067, Eur Urol 2018;73:674)
Microscopic (histologic) images

Contributed by Kenneth A. Iczkowski, M.D.
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Gleason grade 3

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Gleason grade 3


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Gleason grade 4

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Gleason grade 4

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Gleason grade 4


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Gleason grade 5

Virtual slides

Images hosted on other servers:
Gleason 4+3=7 versus 3+4=7

Gleason 4+3=7 versus 3+4=7

Gleason 4+3=7, cytokeratin 34 beta E12

Gleason 4+3=7, cytokeratin 34 beta E12

Gleason 4+4=8, cribriform to solid

Gleason 4+4=8, cribriform to solid

Sample pathology report
  • Prostate, left lateral, prostate needle core biopsy:
    • Prostatic adenocarcinoma, Gleason score 4+3=7 (Grade group 3) involving 2 of 4 cores and 30% of the tissue (40%, 2 mm and 20%, 4 mm) (60% of the tumor is Gleason pattern 4, not cribriform)
  • Prostate, radical prostatectomy:
    • Prostatic adenocarcinoma, Gleason score 3+3=6 with tertiary 4 (Grade group 1) (Gleason pattern 3=96% and pattern 4=4%) (see synoptic report)
Board review style question #1
Per the 2019 ISUP consensus conference, a prostate biopsy report for high grade cancer must include

  1. A case level global Gleason score
  2. A grade if the entire cancer focus consists of perineural invasion
  3. Both a primary and secondary grade for tumor measuring less than 1 mm
  4. For Gleason grade 4, a mention of whether or not cribriform / large gland pattern is present
  5. Gleason grades 1 and 2, if present
Board review style answer #1
D. For Gleason grade 4, a mention of whether or not cribriform / large gland pattern is present. By consensus, the presence of cribriform carcinoma should be reported. Gleason grades 1 and 2 are discontinued. Grading is not recommended for perineural invasion because perineural invasion distorts gland morphology (grade 3 looks like 4). For tumor that is 1 mm or less, only 1 grade needs to be assigned, avoiding doubling Gleason 4 to 4+4=8, which would be misleading if cancer in other cores is mostly Gleason 3. A case level global score is optional.

Comment Here

Reference: Gleason grading
Board review style question #2

This field from a prostate biopsy shows

  1. Entirely Gleason 3 cancer
  2. Entirely Gleason 4 cancer
  3. Entirely Gleason 5 cancer
  4. Mixture of Gleason 3 and Gleason 4 cancer
  5. Mixture of Gleason 4 and Gleason 5 cancer
Board review style answer #2
B. Entirely Gleason 4 cancer. The tumor consists entirely of ragged and fused glands. Discrete, round to angulated gland spaces, separated by stroma, diagnostic of Gleason 3 are not present. Single cells without glandular lumen formation, diagnostic of Gleason 5 are not present.

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Reference: Gleason grading
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