Prostate
Prostatic carcinoma
Grading (Gleason)

Author: Kenneth Iczkowski, M.D. (see Authors page)

Revised: 27 June 2016, last major update June 2016

Copyright: (c) 2003-2016, PathologyOutlines.com, Inc.

PubMed Search: Gleason grading [title]
Definition / General
  • In 1966, Donald Gleason (Cancer Chemother Rep 1966;50:125) devised grades of 1 to 5, based on glandular architecture at low to medium power, that were shown to predict outcome in prostate cancer
Terminology
  • Gleason score is potentially 2 to 10, the sum of the two most prevalent Gleason patterns: primary and secondary patterns
  • If only one pattern is present, the primary and secondary patterns are given the same grade
  • Needle biopsy sets contain cores from different anatomically designated sites
  • It is recommended that the Gleason score be assigned separately for each anatomically designated site, since information is lost if only a global score is given
    • The highest score of tumor will represent the entire case as the basis to determine treatment
  • Any glands showing perineural invasion must be excluded in assigning Gleason grading
    • This is because perineural invasion distorts gland morphology such that Gleason 3 glands resemble Gleason 4
  • Assignment of patterns:
    • Recommendations are based on 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading (Am J Surg Pathol 2005;29:1228; reviewed, J Urol 2010;183:433)
    • Some specimens may show a pattern that is the third most prevalent, and this is called a tertiary pattern
  • Needle biopsy: the most prevalent pattern is graded as primary, and the worst pattern (even if it is third most prevalent) is graded as secondary
  • Radical prostatectomy: Gleason score should be based on the primary and secondary patterns
Epidemiology
  • The International Society for Urologic Pathology's (ISUP) and World Health Organization, in 2014, adopted a simplified patient-centric grading system composed of 5 prognostic Grade Groups (Am J Surg Pathol 2016;40:244, Prostate 2016;76:427) as proposed in 2013 based on data from Johns Hopkins (BJU Int 2013;111:753) and subsequently validated by biochemical recurrence hazard ratios on cases from 5 large academic centers (Eur Urol 2016;69:428)
  • Grade Groups 1 through 5 were designated as Gleason Score (GS) 3+3=6, GS 3+4=7, GS 4+3=7, GS 8 and GS 9-10 respectively
  • Note that Gleason grades 1 and 2 are no longer recommended for use, since cancer with those patterns has 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 a debate about whether it should even be labeled cancer (Oncology (Williston Park) 2014;28:22, 24, 29, Curr Opin Urol 2015;25:238)
  • The divisions of GS 3+4=7 from GS 4+3=7 (J Clin Oncol 2009;27:3459) and of GS 8 from GS 9-10, which had often been bundled together for prognostic and research purposes, are supported by studies showing significantly different outcomes (World J Urol 2014;32:1067, J Urol 2015;194:91).
  • Grade Group 4 is heterogeneous as it includes GS 4+4=8, GS 3+5=8 and GS 5+3=8
    • However, we have recently shown no or minimal long-term outcome difference between these various GS when present as the highest GS in biopsy sampling
    • Instead, GS 8 was significantly stratified by the presence or absence of cribriform growth of cancer (J Urol 2016 Jun 2 [Epub ahead of print])
    • For reporting purposes, we comment on cribriform growth when it is present in any high grade cancer
    • Upgrading is seen in 1/3 of prostatectomy specimens after biopsy; downgrading in 5%
    • 1/3 of Gleason 8's at biopsy are Gleason 7 at radical prostatectomy
  • If tumor is minimal on biopsy (1 mm or less), Gleason score does not predict tumor stage; and this can be noted on the report (Am J Surg Pathol 2000;24:1634)
Micro Description
  • Gleason grade 1
    • Gleason score of 1+1=2 is extremely rare
    • Most cases that were diagnosed as Gleason score 1+1=2 in the era of Gleason would today be referred to as atypical adenomatous hyperplasia (AAH; adenosis)
    • Originally described as single, separate, closely packed, uniform round glands arranged in a circumscribed nodule with pushing borders
    • Separation of glands at the periphery from the main collection by more than one gland diameter indicates a component of at least grade 2
    • Should not be diagnosed on needle biopsy

  • Gleason grade 2
    • Like grade 1 but more variability in gland shape and more stroma separating glands, such that glands are separated by less than one gland's width
    • Less circumscribed at periphery, although no infiltration into stroma or between benign glands
    • Tends to be in transition zone (periurethral)
    • While it may be acceptable to diagnose Gleason 2 on prostatectomy or transurethral resection, it should not be diagnosed on needle biopsy (Histopathology 2007;50:683) since:
      1. Grade 2 cancer is uncommon in the peripheral zone
      2. Grade 2 is subject to marked inter-pathologist variability
      3. Grade 2, assigned by non-urologic pathologists, usually reflects undergrading compared with experts
      4. Grade 2 cancer in needle biopsy tissue does not predict better findings than grade 3 at radical prostatectomy

  • Gleason grade 3
    • Single, separate, much more variable glands, may be closely packed but usually irregularly separated, ragged, poorly defined edge, but still in circumscribed structure, looser than a nodule, slightly infiltrative, still has intervening stroma 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:
      • (a) Most common pattern is well formed, relatively uniform glands infiltrating between benign glands; glands may be angulated or compressed, separated by > 1 gland diameter
      • (b) Small glands with pinpoint lumina, glands still separate
      • (c) Medium sized glands with undulating luminal contours or 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
    • Coalescent or fused glands
    • Absence of intervening stroma between adjacent glands constitutes fusion
    • Patterns of Gleason grade 4 prostatic adenocarcinoma:
      • (a) Most common is small acinar structures, some with well formed lumina, fusing into cords or chains; may be undergraded as Gleason 3
      • (b) Papillary or cribriform tumors with irregular / invasive edges; includes many but not all endometrioid carcinomas; nodule of cribriform gland should be larger than normal prostate gland; large nodules of cribriform Gleason 4 lack supporting stroma and tend to fragment; thus large fragments of cribriform glands on needle biopsy represents Gleason 4
    • Contemporary research supports grading all cribriform cancer as Gleason 4 because the presence and amount of cribriform cancer carries a distinctly adverse prognosis for recurrence (Am J Surg Pathol 2013;37:1855, Am J Clin Pathol 2011;136:98) and for death from cancer (Mod Pathol 2015;28:457)
    • Note: basal cell markers are crucial in distinguishing cribriform high grade PIN, cribriform intraductal carcinoma (IDC) and invasive cribriform carcinoma
    • Note: patients with Gleason 8 at biopsy may have Gleason 7 at prostatectomy due to unsampled Gleason 3
      • (c) 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

  • Gleason grade 5
    • Grade 5: two patterns
      • 5a: Comedocarcinoma: papillary / cribriform carcinomas with central necrosis (must have intraluminal necrotic cells or karyorrhexis)
      • 5b: Single-celled cancer, possibly forming cords, possibly with vacuoles (signet ring cells) but without formation of a glandular lumen
        • 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)
    • The presence of Gleason grade 5 in prostate biopsy specimens predicts higher rates of metastasis and death (J Urol 2015 Jan 24, World J Urol 2014;32:1067) compared to Gleason 4+4=8 cancer
Micro Images

Scroll to see all images.


Images hosted on PathOut server, contributed by Kenneth Iczkowski, M.D.:

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Gleason grade 3 cancer consists of single pseudoacinar spaces, usually small or minute in size,
but sometimes medium or large. Although the pseudoacini may be crowded, at least a wisp of
stroma intervenes between each (Fig. 1).


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Pseudoacini that are relatively uniform in size and spaced less than a gland’s width apart are also graded
as Gleason 3. They were formerly called Gleason grade 2. However, after the ISUP 2005 consensus conference,
the use of grades 1 and 2 cancer was discouraged since the prognostic implications are identical to
Gleason grade 3 cancer (Fig. 2).


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Gleason grade 4 cancer typically consists of small pseudoacinar spaces that are fused or coalesced
into linear arrays, without intervening stroma (Fig. 3).


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Gleason grade 4 cancer also includes pseudoacinar spaces that are larger than a normal benign acinus.
These may take on a cribriform or sieve-like arrangement (Fig. 4).


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A papillary Grade 4 growth pattern with stromal cores (Fig. 5).


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Gleason grade 5 cancer is diagnosed when single cancer cells are perceptible in the stroma.
Note that they are almost always larger than lymphocytes (Fig. 6).


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The presence of luminal comedonecrosis in a cancer gland space is also sufficient to diagnose Gleason grade 5 (Fig. 7).



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Grade 2


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Grade 3+2


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Gleason pattern 3(a)


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Gleason pattern 4(a)


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Gleason pattern 4, various images

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Gleason pattern 4, various images


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Single cells with vacuoles (left) or forming linear cords