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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 tumour 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:

Tumor is fixed or invades adjacent structures other than seminal vesicles: external sphincter, rectum, levator muscles, and/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 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:

To diagnose adenocarcinoma of the prostate, the following criteria are necessary: structural disturbances of the prostate tissue, nuclear atypia and the exclusion of 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/or actin will help to diagnose or differentiate.

Prostatic intraepithelial neoplasia (PIN):

Prostatic intraepithelial neoplasia (PIN) consists of 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 the prostatic intraepithelial neoplasia is a precursor of prostate cancer.

Growth pattern:

The majority (85%) of 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 limitating 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 that are smaller than 4 cm³.

Gleason Grading

Gleason grading is based on the assessment of the glandular morphology at a relatively low magnification. The cytological properties of the cells (nuclear size and shape) will not be judged. The various existing glands architectures are assigned to a Gleason pattern with values between 1–5 [Tab. current Gleason grading according to ISUP 2014].

**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 nodule 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, typically smaller glands than seen in Gleason pattern 1 or 2. Infiltrates in and amongst nonneoplastic prostate acini. Marked variation in size and shape. Smoothly circumscribed small cribriform nodules of 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 no glandular differentiation, 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 pattern 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 pattern are summarized to become a Gleason score. If small proportions of poor differentiated Gleason pattern are present in the specimen, the worst Gleason grade is honored by mentioning a tertiary pattern (example: Gleason score 3 + 4, tertiary pattern 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 the small cell lung cancer. Often pathology is mixed with small cell carcinoma and classical adenocarcinoma. Clinically relevant ACTH or ADH secretion is rarely found, 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). Prognosis has been considered to be more aggressive, although this has been challenged. The 2005 ISUP Consensus Conference suggests that these tumors should be classified as Gleason score 8 (4 + 4).

Ductal prostate cancer:

Pure ductal prostate cancer is rare (0.4%), more common are both ductal and acinar differentiation in the specimen. Ductal prostate cancer arrises from the prostatic ducts and shows often an exophytic growth into the urethra causing hematuria or obstructive micturition disorders. Since ductal prostate cancer show a decreased secretion of PSA, diagnosis is often made too late. In addition, ductal adenocarcinomas are more likely to be poorly differentiated with an unfavorable prognosis.

Urothelial carcinoma of the prostate:

1–4% of prostate cancers present as primary urothelial cancer of the prostatic urethra without manifestation of the bladder. Urothelial carcinoma of the prostate with stromal invasion harbour a poor prognosis, 20% have metastasized. 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 with poor prognosis, 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 they should be submitted 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 high proportion of tumor 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 Gleason score 5 or 6 in the needle biopsy specimen have a higher Gleason score in surgical specimen (upgrading). 40% of patients with only one positive core have extraprostatic tumor growth (T3). The combined consideration of 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 most accurate staging, the bounderies of the specimen after radical prostatectomy are marked with ink before whole- mount sectioning of the prostate. Alternatively, representative areas (Apex, pedicles, bladder neck ...) are sampled and embedded.

Prognostic factors in the specimen after prostatectomy:

Independent prognostic factors for prostate cancer are the Gleason score, margin status and and extraprostatic growth. The following data indicate the 10 years 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 lack of evaluability of the remaining 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/guideline/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, http://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