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Prostate Cancer Pathology: Gleason Score and Tumor Stages

Guidelines and review literature: (EAU Guidelines Prostate Cancer) (S3-Leitlinie Prostatakarzinom) (Walsh-Campbell Urology 11th Edition).

TNM Staging [UICC 2025]

T1:

Nonpalpable tumor.

T1a: Prostate cancer in less than 5 % of resected tissue after TURP.
T1b: Prostate cancer in more than 5 % of resected tissue after TURP.
T1c: Prostate cancer in a needle biopsy with a nonpalpable tumor.

T2:

Palpable tumor confined to the prostate.

T2a: Tumor involves less than 50 % of one lobe.
T2b: Tumor involves more than 50 % of one lobe.
T2c: Tumor involves both lobes.

T3:

Tumor with extraprostatic extension.

T3a: Tumor extends through the prostatic capsule or microscopically invades the bladder neck.
T3b: Seminal vesicle invasion.

T4:

Tumor is fixed or invades adjacent organs: bladder, rectum, sphincter, or pelvic wall.

N:

Lymph node involvement.

N0: No lymph node involvement.
N1: Regional lymph node involvement.

M:

Presence of metastases.

M0: No distant metastases.
M1a: Nonregional lymph node metastases.
M1b: Bone metastases.
M1c: Other distant metastases.

G:

ISUP grading based on the Gleason score was introduced in 2014; see ISUP grade groups.

Clinical UICC Stage Grouping

Stage I: cT1 or cT2a cN0 cM0
Stage II: cT2b–cT2c cN0 cM0
Stage III: cT3–cT4 cN0 cM0
Stage IV: any cT with cN1 or cM1

Pathological UICC Stage Grouping

Stage I: does not exist.
Stage II: pT2 pN0 cM0
Stage III: pT3–pT4 pN0 cM0
Stage IV: any pT with pN1, cM1, or pM1

Adenocarcinoma of the Prostate

Histologic criteria:

The diagnosis of prostatic adenocarcinoma requires architectural distortion of prostatic tissue, nuclear atypia, and exclusion of benign mimics. If only two of these three diagnostic criteria are present, the diagnosis is atypical glands or atypical small acinar proliferation (ASAP). In equivocal cases, immunohistochemical studies with, for example, p63, cytokeratin, AMACR, PSA, NKX3.1, androgen receptor, chromogranin, synaptophysin, S100, and actin are helpful.

Prostatic intraepithelial neoplasia (PIN):

PIN consists of structurally normal prostatic glands lined by dysplastic cells. Depending on the degree of dysplasia, low-grade and high-grade PIN are distinguished. High-grade PIN is considered a possible precursor lesion and a risk marker for detecting prostate cancer in the same prostate.

Growth pattern of adenocarcinoma:

Most localized adenocarcinomas arise multifocally in the peripheral zone; a smaller proportion arise in the transition zone. Tumor growth in the central zone is rare. Extraprostatic extension frequently occurs apically or posterolaterally along the neurovascular bundles, where there is no sharply defined prostatic capsule. Less commonly, prostate cancer invades the seminal vesicles or rectum. Tumor volume correlates with disease extent: extraprostatic extension is rare when tumor volume is less than 0.5 cm³; lymph node metastases or seminal vesicle invasion are rare in tumors smaller than 4 cm³.

Gleason grading:

Gleason grading assesses glandular morphology at relatively low magnification. Cytologic features of the cells, such as nuclear size and shape, are not assessed. The observed glandular architectures are assigned Gleason grades (Gleason patterns) from 1–5.

**Current Gleason grading**, modified according to the International Society of Urological Pathology (ISUP) Consensus Conferences of 2005 and 2014 (Epstein et al., 2016).
Gleason	Histologic criteria
1–2	Circumscribed nodules of densely packed but well-defined, medium-sized, round to oval glands. No stromal invasion. With current immunohistochemical methods, patterns 1–2 are virtually no longer diagnosed.
3	Discrete glandular units with marked variation in size and shape. Tumor cells infiltrate stroma and nonneoplastic glands, with smooth borders. Very small circumscribed cribriform tumor nodules may occur.
4	Fused microacinar glands; poorly differentiated glands with poorly formed lumina; glomeruloid, cribriform, or poorly formed glands. Tumor cell infiltrates have ill-defined borders.
5	No definite gland formation; instead, solid epithelial cords, cell clusters, or single cells. Central glandular necrosis, corresponding to comedocarcinoma, may be surrounded by papillary, cribriform, or solid tumor masses.

Gleason score in a needle biopsy:

The predominant and worst differentiated Gleason grades are combined to form the Gleason score. Theoretically, this ranges from 2 (1+1) to 10 (5+5). The Gleason score correlates with tumor prognosis. If only a very small carcinoma fragment is present, only one Gleason grade may be reported.

Gleason score in a prostatectomy specimen:

The predominant and second most common Gleason grades are combined to form the Gleason score. If the specimen also contains small proportions of more poorly differentiated Gleason grades, the highest Gleason grade is reported as a tertiary pattern, for example Gleason score 3+3, tertiary pattern 5.

ISUP grading of the Gleason score:

ISUP grading of prostate cancer was introduced in 2014 to facilitate comparison of the Gleason score with grading systems of other tumors. Of particular clinical relevance is the distinction between Gleason scores 3+4 and 4+3.

**ISUP grading of prostate cancer** according to the Gleason score (Epstein et al., 2016).
Gleason score	ISUP grade group
2–6	1
7 (3+4)	2
7 (4+3)	3
8	4
9–10	5

Other Subtypes of Prostate Cancer

Small-cell carcinoma of the prostate:

Rare, highly aggressive neuroendocrine carcinoma of the prostate with biologic similarities to small-cell lung carcinoma. Typical features include low PSA expression despite a high tumor burden, expression of neuroendocrine markers, early metastasis, and poor prognosis.

Mucinous adenocarcinoma:

Rare mucin-producing variant of adenocarcinoma with large pools of extracellular mucin and a similar prognosis.

Ductal prostate cancer:

Rare tumor arising from prostatic ductal epithelium. Combined ductal and acinar differentiation is more common. Exophytic growth into the urethra causes hematuria or obstructive voiding symptoms. With peripheral growth, diagnosis is often delayed because PSA does not rise substantially. Ductal prostate cancer has a less favorable prognosis than acinar prostate cancer.

Urothelial carcinoma of the prostate:

Primary urothelial carcinomas of the prostate are rare and must be distinguished from involvement of the prostatic urethra by urothelial carcinoma of the bladder. Noninvasive urothelial carcinoma can be treated with organ preservation. Stromal invasion is prognostically unfavorable and requires cystoprostatectomy, often with urethrectomy.

Squamous cell carcinoma of the prostate:

Rare carcinoma with pure squamous or, more commonly, mixed adenosquamous differentiation. Prognosis is poor; osteolytic bone metastases, normal or only mildly elevated PSA concentrations, and lack of response to androgen deprivation are typical. Secondary involvement from the bladder, urethra, or rectum must be excluded. Squamous transformation of adenocarcinoma may rarely occur during androgen deprivation therapy.

Rhabdomyosarcoma of the prostate:

Malignant mesenchymal tumor, predominantly in children; see prostatic sarcoma.

Leiomyosarcoma of the prostate:

Malignant mesenchymal tumor, predominantly in adults; see prostatic sarcoma.

Assessment of Prostate Needle Biopsies

Technique:

See prostate biopsy. Core specimens are obtained from defined areas of the prostate and submitted separately.

Prognostic prediction:

Signs of an unfavorable prognosis in a needle biopsy are:

High Gleason score (8–10) or Gleason pattern (4–5).
High proportion of tumor-positive cores, high tumor involvement per core, or high tumor involvement in the complete biopsy specimen.
Perineural invasion.

Unfavorable prognostic signs in a needle biopsy are usually also present in the surgical specimen. Underestimation of tumor extent is clinically relevant: some patients with a Gleason score of 6 in the needle biopsy show a higher grade or stage in the prostatectomy specimen. Combined assessment of needle biopsy, PSA level, digital rectal examination, and MRI improves predictive accuracy.

Atypical glands:

Atypical prostatic glands that do not appear unequivocally malignant (atypical small acinar proliferation) present a diagnostic challenge. The likelihood of prostate cancer on subsequent evaluation is increased; consider repeat targeted and systematic biopsy depending on the PSA course, MRI findings, and prior biopsy.

Assessment of the Surgical Specimen

The resection margins of the surgical specimen after radical prostatectomy are inked. The prostate is then serially sectioned into transverse slices and embedded.

Prognostic factors in the pathologic specimen:

Independent prognostic factors after radical prostatectomy are ISUP grade group, pT stage, seminal vesicle invasion, lymph node status, and margin status. Modern postoperative nomograms and scores, such as the MSKCC nomogram or CAPRA-S score, combine these parameters with the PSA level and provide a reliable estimate of biochemical recurrence risk after surgery.

Positive surgical margins (R1):

The Gleason score is more important for prognosis than margin status alone. Not every patient with an R1 resection develops biochemical recurrence. This may be explained by minimal, tangentially sectioned, or artifactual positive margins and by tumor biology.

Pattern of Metastasis

Prostate cancer preferentially metastasizes to lymph nodes and bone; other sites of metastasis include lung, liver, bladder, adrenal gland, and rarely the testis.

Prostate cancer etiology

Index

Prostate cancer symptoms

Index: 1–9 A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

References

N. Mottet (Chair), J. Bellmunt, E. Briers (Patient Representative), R.C.N. van den Bergh (Guidelines Associate), M. Bolla, N.J. van Casteren (Guidelines Associate), P. Cornford, S. Culine, S. Joniau, T. Lam, M.D. Mason, V. Matveev, H. van der Poel, T.H. van der Kwast, O. Rouvière, T. Wiegel Guidelines on Prostate Cancer of the European Association of Urology (EAU), https://uroweb.org/guidelines/prostate-cancer/.

Epstein u.a. 1993 EPSTEIN, J. I. ; PIZOV, G. ; WALSH, P. C.: Correlation of pathologic findings with progression after radical retropubic prostatectomy.
In: Cancer
71 (1993), Nr. 11, S. 3582–93

Epstein, J. I.; Allsbrook, W. C.; Amin, M. B.; Egevad, L. L. & Committee, I. S. U. P. G. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma.
Am J Surg Pathol, 2005, 29, 1228-1242.

Epstein, J. I.; Egevad, L.; Amin, M. B.; Delahunt, B.; Srigley, J. R.; Humphrey, P. A. & , G. C. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: Definition of Grading Patterns and Proposal for a New Grading System.
Am J Surg Pathol, 2016, 40, 244-252

Hammerer und Huland 1994 HAMMERER, P. ; HULAND, H.: Systematic sextant biopsies in 651 patients referred for prostate evaluation.
In: J Urol
151 (1994), Nr. 1, S. 99–102Helpap, B.; Hartmann, A. & Wernert, N. Anleitung zur pathologisch-anatomischen Diagnostik von Prostatatumoren des Bundesverbandes Deutscher Pathologen e. V. und der Deutschen Gesellschaft für Pathologie e. V.
2011.

Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): Interdisziplinäre Leitlinie der Qualität S3 zur Früherkennung, Diagnose und Therapie der verschiedenen Stadien des Prostatakarzinoms, https://www.leitlinienprogramm-onkologie.de/leitlinien/prostatakarzinom

Wein, A. J.; Kavoussi, L. R.; Partin, A. P. & Peters, C. A. Campbell-Walsh Urology
. Elsevier, 2015. ISBN 978-1455775675.

Deutsche Version: Prostatakarzinom

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