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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 2017]

T1:

Clinically inapparent tumor not palpable or visible by imaging

T1a: Tumor was incidentally found in 5% or less of tissue resected
T1b: Tumor was incidentally found in more than 5% of tissue resected
T1c: Tumor identified by needle biopsy (e.g., because of elevated PSA level)

T2:

Tumor confined within the prostate

T2a: Tumor involves one-half of one lobe or less
T2b: Tumor involves more than half of one lobe, but not both lobes
T2c: Tumor involves both lobes

T3:

Tumor extends through the prostatic capsule

T3a: Extracapsular extension (unilateral or bilateral) including microscopic bladder neck involvement
T3b: Tumor invades seminal vesicle(s)

T4:

The tumor is fixed or invades adjacent structures other than seminal vesicles: external sphincter, rectum, levator muscles, or pelvic wall.

N:

Regional lymph nodes

N0: No regional lymph node metastasis
N1: Regional lymph node metastasis

M:

Distant metastasis

M0: No distant metastasis
M1a: Non-regional lymph node(s) metastasis
M1b: Bone metastasis
M1c: Other site(s)

G:

Grading: the grading of the Gleason score was introduced in 2014; see table grading of Gleason score.

UICC Tumor Stages

Stage I: T1 und T2a N0 M0
Stage II: T2b--T2c N0 M0
Stage: T3 N0 M0
Stage IV: T4 N0 M0 or Tx N1 or Tx M1

Adenocarcinoma of the Prostate

Histological criteria:

The following criteria are necessary for the pathological diagnosis of prostate cancer: structural disturbances of the prostate tissue, nuclear atypia, and excluding a benign lesion. If only two of the three diagnostic criteria are present, the diagnosis is "atypical glands" or "atypical small acinar proliferation" (=ASAP). In doubt, immunohistochemistry with p63, PSA, androgen receptor, chromogranin, synaptophysin, S100, and actin will help to diagnose or differentiate.

Prostatic intraepithelial neoplasia (PIN):

Prostatic intraepithelial neoplasia (PIN) comprises normal-built prostate glands with dysplastic cells. "Low-grade" and "high-grade" PIN is assigned depending on the grade of dysplasia. An alternative classification is PIN1, PIN2, and PIN 3, wherein PIN2 and PIN 3 correspond to "high-grade" PIN. Many molecular and clinical studies show that prostatic intraepithelial neoplasia is a precursor of prostate cancer.

Growth pattern:

Most (85%) localized prostate cancers grow multifocal in the peripheral prostate zone. The rest of the tumors grow in the transition zone. Tumor growth in the central zone is a rarity. Extraprostatic growth occurs most often apical or posterolateral along the prostatic pedicles (perineural infiltration), where there is no limiting prostate capsule. Advanced prostate cancers may infiltrate the seminal vesicles or the rectum. The tumor volume correlates with the extent of the disease: extraprostatic growth is rare for tumors less than 0.5 cm³ tumor volume. Lymph node metastasis or seminal vesicle infiltration is rare for tumors smaller than 4 cm³.

Gleason Grading

Gleason grading is based on assessing the glandular morphology at a relatively low magnification. The cytological properties of the cells (nuclear size and shape) are not judged. The various existing gland architectures are assigned to a Gleason pattern with values between 1–5 [Tab. Current Gleason grading].

**Current Gleason grading**, modified by the International Society of Urological Pathology (ISUP) Consensus Conference 2004 (Epstein et al., 2005) (among others Helpap , 2011).
Gleason	Histological criteria
1–2	Circumscribed nodules of closely packed but separate, uniform, rounded to oval, medium-sized acini (larger glands than pattern 3). With current methods of immunohistochemistry, grade 1–2 is rarely assigned.
3	Discrete glandular units with a marked variation in size and shape, typically smaller glands than seen in Gleason pattern 1 or 2. Infiltrates in and amongst nonneoplastic prostate acini. Smoothly circumscribed small cribriform nodules of the tumor.
4	Fused microacinar glands. Ill-defined glands with poorly formed glandular lumina. Large cribriform glands. Cribriform glands with an irregular border. Hypernephromatoid (resembling renal cell carcinoma).
5	Essentially, there is no glandular differentiation; the tumor is composed of solid sheets, cords, or single cells. Comedocarcinoma with central necrosis surrounded by papillary, cribriform, or solid masses.

Gleason score for a core biopsy:

The dominant and the worst differentiated Gleason patterns are summarized to become a Gleason score. This can theoretically be 2 (1 + 1) to 10 (5 + 5). The Gleason score correlates well with the prognosis of the tumor. If only a tiny fragment of prostate cancer can be seen, only a Gleason pattern can be determined. Beware of confusion between Gleason pattern and Gleason score.

Gleason score for a prostatectomy specimen:

The most common and second most common Gleason patterns are summarized to become a Gleason score. If small proportions of poor differentiated Gleason patterns are present in the specimen, the worst Gleason grade is honored by mentioning a tertiary pattern (e.g., Gleason score 3 + 4, tertiary pattern 5).

Gleason score and ISUP Grading:

The grading of prostate cancer was introduced in 2014 by the International Society of Urological Pathology (ISUP) to compare the Gleason score with the grading of other tumors [table ISUP grading of prostate carcinoma]. Another advantage is acknowledging the significant difference between Gleason scores 3+4 and 4+3.

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

Other pathological subtypes of prostate cancer

Small-cell carcinoma of the prostate:

Small-cell carcinoma of the prostate is rare and highly aggressive; it is biologically identical to small-cell lung cancer. Often, pathology is mixed with small-cell carcinoma and classical adenocarcinoma. Clinically relevant ACTH or ADH secretion is rare, but neuroendocrine differentiation in immunohistochemistry is common. The average survival time is one year.

Mucinous adenocarcinoma:

Mucinous adenocarcinoma of the prostate is characterized by large pools of extracellular mucin (at least 25% of the tumor volume). The prognosis is controversial. The 2005 ISUP Consensus Conference suggests these tumors should be classified as Gleason score 8 (4 + 4).

Ductal prostate cancer:

Ductal prostate cancer arises from the prostatic ducts and often shows an exophytic growth into the urethra, causing hematuria or obstructive micturition disorders. Pure ductal prostate cancer is rare (0.4%); ductal and acinar differentiation in the specimen are more common. Ductal prostate cancer has a poor prognosis due to a low secretion of PSA, leading to late diagnosis. In addition, ductal adenocarcinomas are more likely to be poorly differentiated.

Urothelial carcinoma of the prostate:

1–4% of prostate cancers are primary urothelial cancer of the prostatic urethra without manifestation of the bladder. Urothelial carcinoma of the prostate with stromal invasion harbors a poor prognosis, 20% present with metastasis. More common and with better prognosis are superficial urothelial carcinomas of the prostatic urethra without stromal invasion, often as recurrence or progression from bladder carcinoma.

Squamous carcinoma of the prostate:

Primary squamous carcinoma of the prostate is rare and has a poor prognosis; the median survival time is around 24 months. Patients develop osteolytic bone metastases without rising PSA; hormone treatment is ineffective. More common and important for differential diagnosis is the squamous transformation of prostate cancer during hormone therapy.

Sarcoma of the prostate:

Malignant mesenchymal tumor, see section prostatic sarcoma.

Assessment of Needle Biopsy Specimens

See section prostatic biopsy for surgical detail in obtaining the tissue. Biopsy specimens should be taken from different areas of the prostate and sent to pathology in separate containers.

Prognostic signs:

Signs of poor prognosis in the needle biopsy specimen are:

High Gleason score (8–10) or Gleason pattern 4 or 5.
High number of positive cores or a high proportion of prostate carcinoma in the cores (tumor length).
Perineural invasion.

Accuracy of the prognostic signs in needle biopsy specimen:

Poor prognosis signs in the needle biopsy specimen are usually verified in the surgical specimen. More problematic is the underestimation of the disease: 40% of patients with a Gleason score of 5 or 6 in the needle biopsy specimen have a higher Gleason score in surgical specimens (upgrading). 40% of patients with only one positive core have extraprostatic tumor growth (T3). Combining prognostic signs in the needle biopsy specimen (Gleason score, number of positive cores, perineural invasion) with PSA concentration and clinical lokal tumor stage (DRE) improves the accuracy.

Assessment of the specimen

For the most accurate staging, the boundaries of the specimen after radical prostatectomy are marked with ink before whole-mount sectioning of the prostate. Representative areas (e.g., apex, pedicles, bladder neck) are also sampled and embedded.

Prognostic factors in the specimen after prostatectomy:

The Gleason score, margin status, and extraprostatic growth are independent prognostic factors for prostate cancer. The following data indicate the 10-year recurrence probabilities for patients with pN0 and without seminal vesicle infiltration (Epstein et al., 1993):

Gleason score: 2–4 (4%), 5–6 (19%), 7 (50%), 8–10 (66%)
Organ confined T2 (17%), extraprostatic growth T3 (43%)
Negative surgical margins (22%), positive surgical margins (46%)
Gleason 5–6 and negative surgical margins (8%), Gleason 5–6 and positive surgical margins (28%)
Gleason 7 and negative surgical margins (39%), Gleason 7 and positive surgical margins (67%)

The prognostic significance of positive surgical margins (R1):

The Gleason score is more important than margin status for prognosis (see above). A significant proportion of patients (around 50%) do not progress despite of positive surgical margins. This can be explained by the imprecise assessability of the removed tissue, the tumor was just completely removed. Furthermore, artificially positive surgical margins can arise from manipulation during surgery and sectioning.

Metastasis of prostate cancer

Location in descending order of frequency:

Lymph nodes
Bone
Lungs
Bladder
Liver
Adrenal gland
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, Langversion 3.1, 2014 AWMF Registernummer: 034/022OL, https://www.awmf.org//leitlinien/detail/ll/043-022OL.html (Zugriff am: 07.02.2016)

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

Deutsche Version: Prostatakarzinom