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Prostate Cancer Staging

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

Of crucial importance for any therapeutic decision is both the assessment of the tumor stage and the evaluation of the biological aggressiveness of the prostate cancer. Staging includes digital-rectal examination (DRE), PSA concentration, results of the prostate needle biopsy, laboratory tests, imaging and/or pelvic lymphadenectomy.

Clinical Staging of Prostate Cancer

Clinical staging is done with digital-rectal examination, PSA concentration and Gleason score of the prostate biopsy. Each parameter has a good statistical correlation with the pathologic tumor stage. The prediction accuracy of a single parameter is too low in individual patients. The prediction of the clinical risk (prostate cancer mortality) is accurate with the combined consideration [see table risk stratification of prostate cancer].

**D’Amico risk classification for prostate cancer:** clinical risk (mortality) for localized prostate cancer before definitive treatment (D'Amico et al., 2003). (*) Figures represent cancer-specific mortality. EBRT: external beam radiotherapy. RPE: radical prostatectomy
Risk	Criteria	10-year mortality after EBRT (*)	10-year risk of PSA Prgression after RPE	10-year mortality after RPE (*)
Low	PSA <10 ng/ml and Gleason score ≤6	2%	17%	1%
Intermediate	PSA 10–20 ng/ml or Gleason score 7	8%	54%	4%
High	PSA >20 ng/ml or Gleason score >7	24%	71%	11%

Another important risk factor is PSA velocity in the year before treatment, unfavorable is a rise of more than 2 ng/ml (D'Amico et al., 2006). With additional consideration of the tumor burden in the prostate biopsy, the prediction accuracy will be even better. With additional consideration of the tumor burden in the prostate biopsy, the prediction accuracy will be even better (CAPRA score), see table \ref{pca_capra_score}]. CAPRA stands for Cancer of the Prostate Risk Assessment and was developed by the University of California, San Francisco based on data from the CaPSURE study (Cooperberg et al., 2009). See table \ref{pca_capra_prognose} for pathologic outcomes and prognosis after radical prostatectomy as a function of the CAPRA score.

The Partin tables use the combination of local tumor stage, PSA level and Gleason score to predict pathology results after radical prostatectomy. The tables are based on the pathological results at the James Buchanan Brady Urological Institute. Some authors are of the opinion that the Partin tables underestimate the risk of lymph node metastasis. The reason may be the limited dissection field used in this clinical series.

The Kattan nomogram also uses the combination of local tumor stage, PSA concentration and Gleason score (https://www.mskcc.org/nomograms/prostate). The result of the nomogram estimates the 5-year progression-free survival rate after radical prostatectomy (Kattan et al., 1998). Kattan nomograms are now also available for predicting the progression-free survival after radiotherapy (Kattan et al., 2003), brachytherapy (Kattan et al., 2001) and overall survival with hormone therapy in the metastatic disease (Smaletz et al., 2002).

Bone Scintigraphy

Bone scan is used to diagnose bone metastases of prostate cancer. It has a relatively high sensitivity with poor specificity [figure prostate cancer bone metastasis]. Suspect lesions need further diagnostic workup with X-rays, CT, MRI or bone biopsy.

For PSA concentration below 10 ng/ml, the rate of bone metastases in prostate cancer is very low (1.3%) at a constant rate of false-positive findings. In patients with an organ-confined tumor, PSA less than 10 ng/ml, a Gleason score below 8 and missing bone pain, bone scintigraphy can be safely omitted before curative treatment.

**Bone scintigraphie in a patient with prostate cancer and PSA of 100 ng/ml.** Multiple lesions can be seen in the spine, sacrum and ribs. With kind permission, Dr. G. Antes, Kempten.

Computed Tomography

A CT scan is able to identify enlarged lymph nodes, hydronephrosis, bone metastases and infiltration of neighboring organs of the primary tumor. In patients with a PSA below 20 ng/ml and a Gleason score below 8, above mentioned pathologies are rare. The significance of enlarged lymph nodes is limited (not specific and may be false-positive). A CT scan is an option only in high-risk prostate carcinoma before curative therapy, especially in combination with PET (see next section).

Positron Emission Tomography

PET (in combination with a CT or MRI) yields a high diagnostic accuracy and is superior to the combination of bone scintigraphy and CT (Hofman u.a., 2020). ⁶⁸Ga-PSMA is used as tracer. Indications for PSMA-PET-CT include high-risk prostate cancer prior to curative therapy, biochemical recurrence after curative therapy, or progression with systemic therapy for metastatic prostate cancer.

Multiparametric MRI of the Prostate

MRI of the prostate is indicated for imaging of locally advanced prostate cancer, if imaging results would change treatment decision.

Pelvic Lymphadenectomy

Pelvic lymphadenectomy is necessary for exact diagnosis of nodal metastasis. Any imaging technique can only detect lymph node enlargement and is therefore neither sensitive and nor specific. Surgical (laparoscopic) nodal staging as an isolated intervention is seldom indicated in patients with a higher risk of lymph node metastasis, particularly before perineal prostatectomy or brachytherapy. See section surgical techniques/pelvic lymphadenectomy for details of the procedure.

The dissection field of pelvic lymphadenectomy is debated (limited versus extended field). Bounderies for a limited dissection:

Lateral boundery: external iliac artery
Kaudal boundery: superior ramus of the pubis
Cranial boundery: bifurcation of the common iliac artery
Medial boundery: bladder, branches of the internal iliac artery
Dorsal boundery: obturator fossa

In low-risk tumors (Gleason score <7 and PSA < 10 ng/ml), the probability of lymph node metastasis is very low (< 5%). Pelvic lymphadenectomy is not necessary before curative treatment. In low-risk patients, the need for surgical lymph node staging even during retropubic prostatectomy is controversial and debated. Some authors have the opinion that the incidence of lymph node metastases is underestimated (e.g., in the Partin tables, see above). They demand that extended pelvic lymphadenectomy should be done, if radical prostatectomy is necessary.

As an alternative for extended lymphadenectomy in low risk patients, some centers perform sentinel lymphadenectomy. After injection of a radioactive tracer in the prostate, sentinel lymph nodes are intraoperatively detected with a gamma probe and removed. This limits the dissection field, sensitivity is higher than in standard lymphadenectomy (Wawroschek et al., 2003). Controlled trials for sentinal lymphadenectomy are not availabe, the procedure is time consuming and expensive.

Experimental Diagnostic Procedures

New Tumor Markers for Screening

PCA3 (prostate cancer antigen 3)

PCA3 is a non-protein-coding RNA, which is highly overexpressed in prostate cancer cells and can be detected in the urine after prostate massage (DRE). Initial studies indicate a better sensitivity and specificity for PCA3 in men with elevated PSA. In addition, PCA3 may play a role in future treatment algorithms, since tumor volume can be predicted (Auprich et al., 2011). In Germany, PCA3 tests cost around 300 Euro.

Analysis of Gene Expression

Prolaris is a diagnostic test from Myriad Genetics, which analyzes the RNA expression of cell cycle genes in prostate biopsy tissue. 30 genes of proliferation are examined, 15 housekeeping genes serve as control (Cuzick et al., 2012). The test claims to increase the safety for patients with low-risk cancer choosing active surveillance, but controlled studies are lacking. The test is very expensive (3400 dollars in 2013).

Other Methods:

Detection of micrometastases in bone marrow, RT-PCR for the detection of prostate cancer cells in the blood or lymph nodes.

New Techniques for Imaging

New methods and tracers improve imaging with PET, MRI or ultrasound.

MRI imaging:

MRI with magnetic nanoparticles or diffusion weighted imaging (DWI) increase the accuracy for the detection of lymph node metastases (Harisinghani et al., 2003).

Elastography:

The elasticity of the prostate tissue can be displayed in color with the help of an special ultrasonic probe and pressure on the prostate. Less elastic regions are suspicious for cancer. Elastography is better in prostate cancer detection than normal gray scale imaging. The sensitivity and specificity of elastography is 60–70%, but this not sufficient to omit prostate biopsy in patients with elevated PSA, if imaging appears normal (Brock et al., 2012). In addition, elastography is helpful for targeting prostate biopsy.

Analysis of the Ultrasonography Raw Data:

HistoScanning is Database-assisted analysis of the raw data from the ultrasound probes and is supposed to be better than conventional gray scale imaging to detect prostate cancer. HistoScanning is already available for a fee (per application 200–500 Euros). Independent trials could not confirm initial promising results (Schiffmann et al., 2014) (Javed et al., 2014).

Prostate cancer screening

Index

Prostate cancer treatment options

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

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Deutsche Version: Prostatakarzinom