Staging Systems for Prostate Cancer

Alison M. Lake

Sam S. Chang

Cancer staging has historically depended on an anatomic evaluation of the extent of the cancer being diagnosed and treated. The ideal cancer staging system would provide clinicians with a tool for patient risk stratification according to critical disease characteristics, prognostication of disease progression and death, and guidance toward the most appropriate treatments. No longer is a solely anatomic staging system adequate as numerous nonanatomic factors provide important information that can influence treatment effectiveness. Attempts are being made to wed traditional anatomic staging parameters with these factors to provide critical information to the practicing physician. Agreement of a staging classification between nations and different organizations allows comparisons of clinical experience regardless of locale but is becoming increasingly difficult with the variety of schemes being utilized. This chapter reviews current methods of prostate cancer staging, both clinical and pathologic, existing staging systems, and future directions for improvement.

As information amasses and knowledge progresses with regard to a specific malignancy, periodic revision of a staging classification scheme is warranted and occurs with the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC). Not only is accurate staging necessary for appropriate classification of disease severity and treatment guidance, but it also facilitates communication among clinicians, performance of clinical trials, and evaluation of current treatment outcomes. Clinical staging is defined as determination of the extent of disease prior to any treatment and prior to availability of information from surgical resection. Clinical staging may include history and physical examination, laboratory data, and imaging results. Pathologic staging relies on the aforementioned information and is supplemented by information from surgical pathology after resection. The evolution of staging systems, particularly the widely used AJCC-based Tumor, Nodes, Metastases (TNMs) system, has resulted in the incorporation of clinically informative and significant, nonanatomic values, such as serum tumor marker levels. The TNM staging system follows certain principles and has at its core, anatomic findings. As the T, N, or M score increases, tumor severity increases, with lower stages denoting small, localized tumors, and higher stages denoting a progressive increase in size and “spread” of the tumor. Staging of all malignancies should include an accurate microscopic pathologic diagnosis (1).

CLINICAL STAGING OF PROSTATE CANCER

The primary goal of clinical staging of prostate cancer is to predict the extent of disease as accurately as possible. This provides guidance and directs the most appropriate treatment. The three main components of today’s clinical staging of prostate cancer are digital rectal examination (DRE), prostatespecific antigen (PSA) level, and tumor grade (Gleason score). Additional efforts to detect extraprostatic spread of disease may include imaging modalities and pelvic lymphadenectomy that provide clinical and pathologic staging information.

PROSTATE-SPECIFIC ANTIGEN

Prostate-specific antigen is a serine protease that is secreted in high levels in seminal fluid and functions as a liquefactive agent of the seminal coagulum, which is often elevated by prostatic disease (inflammation, infection, cancer, BPH). Prostate cancers diagnosed due to PSA abnormalities tend to have more favorable pathologic features than those diagnosed without PSA testing (2). A higher PSA level portends worse disease. Despite the confounding contribution of BPH and other prostatic disease, approximately 85% of men with a PSA <4 ng/mL will have organ confined disease at the time of prostatectomy, while only 59% of those with a PSA >4 ng/mL have organ confined disease (3). Among men who participated in the Prostate Cancer Prevention Trial, the prevalence of highgrade cancers increased from 12.5% of cancers associated with a PSA level of 0.5 ng/mL or less to 25.0% of cancers associated with a PSA level of 3.1 to 4.0 ng/mL (4).

DRE is a mainstay of the initial clinical evaluation of any prostate cancer patient. The presence, size, and location of a palpable nodule on DRE provide information regarding the extent of disease and are the key components of the TNM clinical staging system. Despite its prominence in the clinical staging of prostate cancer, the limitations of the DRE are widely accepted, particularly for detecting extracapsular extension. Several historical studies have demonstrated poor sensitivity and lack of reproducibility for DRE alone, with a reported sensitivity of 52% and specificity of 81% for prediction of organ confined disease (5). Anatomic evaluation of the T stage by DRE, however, has been the basis of numerous trials and serves as an important point of reference and evaluation. In the current PSA era, DRE partnered with PSA testing provides the highest cancer detection rate as opposed to either test individually.

TRANSRECTAL ULTRASOUND

The introduction of transrectal ultrasound (TRUS) for prostate imaging brought with it hope for a better method of not only identifying cancer but also delineating the extent of local disease. TRUS of the prostate may reveal hypoechoic foci; unfortunately the initial expectations for cancer detection by ultrasound have waned as its accuracy has been disappointingly low. Hypoechoic areas may be more likely to contain malignancy and should be sampled at the time of biopsy (6); however, the majority of hypoechoic areas found on TRUS are not malignant, and most cancers found on TRUS are, in fact, not visible with ultrasound (7). Prostate cancers can be hypoechoic, isoechoic, or hyperechoic (8). An additional limitation of TRUS is its dependence on operator skill level that can influence diagnostic capability. As a result, currently, the primary role of TRUS is imageguidance to ensure thorough sampling of the prostate at the time of biopsy.

Various technical modifications in transrectal ultrasonography may contribute to prostate cancer staging; however,
data to support their use remain inconclusive. Employing Power Doppler ultrasonography, one study reported a significant association between the detection of perforating vessels at the posterior prostatic capsule and extraprostatic extension (pT3 disease) at radical prostatectomy (9). Another advanced technique, color Doppler ultrasonography is gaining more proponents, but changes in vascular flow may be nonspecific (10). A study of 47 men with clinically localized prostate cancer, evaluated the contribution of color Doppler TRUS (CD-TRUS)-guided neurovascular bundle-adjacent biopsies in predicting the presence of perineural invasion and extraprostatic extension (pT3 disease) in subsequent radical prostatectomy specimens. Although accurate in predicting perineural invasion, CD-TRUS-guided biopsies had a low positive predictive value (24%) for extraprostatic disease (11). Elastography during prostate biopsy is a technique that measures the elasticity of the prostate tissue during ultrasound. Just as with DRE, firmer areas are more suspicious for cancer. The authors of one study compared standard gray-scale technique with CD-TRUS and elastography and concluded that although they are promising adjuncts to the standard sextant TRUS biopsy, these techniques are not adequate to replace it at this time (12). Currently, despite ongoing research advances, most maintain that the contribution of TRUS imaging to the clinical staging of prostate cancer patients is limited at best (13).

TRUS BIOPSY

Clinical staging for prostate cancer depends on a biologic diagnosis of prostate cancer that most commonly is determined by TRUS biopsy. Although a variety of methods and equipment exist, an appropriate biopsy technique modifies the original sextant biopsy pattern by obtaining at least 8 to 12 tissue cores using an 18-G needle and focusing the biopsies toward the lateral areas of the gland. A six-core or less biopsy is no longer considered adequate for standard cancer detection (14,15). The most important information provided by TRUS biopsy is cancer diagnosis and histologic grade that helps to risk stratify patients.

There is a growing body of evidence that supports prostate biopsy tumor volume as a useful surrogate for primary tumor size, and as a result, quantification of tumor on prostate needle biopsy has been proposed as an important adjunct to contemporary staging practices (16,17,18,19). Many studies have demonstrated a consistent relationship between various adverse pathologic and survival outcomes and greater volumes of cancer in the biopsy specimen (19). Several measures of biopsy tumor volume have been evaluated and applied clinically, including the number or percentage of cores involved with cancer, the percentage of cancer in each core, the total percentage of cancer in the entire biopsy specimen, and the number of (linear) millimeters of carcinoma (16). On the basis of each of these parameters, a correlation has been reported between increased biopsy tumor volume and a greater risk of one or more adverse outcomes (extraprostatic extension, lymph node involvement, seminal vesicle invasion, and biochemical recurrence) (16,17,18,19,20). Unfortunately, there remains no consensus regarding the most feasible, reproducible, and valid method for quantifying biopsy tumor volume. Additional study is necessary to establish the most discriminatory measurement of biopsy tumor volume prior to the incorporation of such data into routine staging practices. Future directions may include genomic and proteomic analysis of prostate biopsy tissue to identify subsets of genes or proteins that provide valuable prognostic information and could revolutionize our current approach to clinical and pathologic staging (21,22).

GLEASON GRADING

The Gleason grading system is the most commonly used histologic grading system for prostate cancer and is based on a low magnification view of prostate tissue and recognition and categorization of various abnormal patterns of gland architecture. Gleason grade is an independent predictor of disease extent and is used in many risk stratification schema and predictive models for prostate cancer (23). In the seventh edition of the AJCC Staging, this histopathologic grading system has become the standard evaluation scheme for prostate cancer grade.

There are five patterns of gland architecture designated by this system (labeled numbers 1 through 5). A Gleason score of a prostate biopsy specimen consists of the sum of the primary (most common) and the secondary (second most common) pattern on biopsy. Thus, in theory it is possible to have a Gleason score of 2 through 10. In practice, however, it is the consensus of the International Society of Urologic Pathology Grading Committee that Gleason score 2 should not be diagnosed, with extremely rare exception, and Gleason scores 3 and 4 should be diagnosed “rarely, if ever.” Notable histologic variants include ductal adenocarcinoma which is always considered Gleason sum 4 + 4 = 8, colloid (mucinous) carcinoma (also Gleason sum 4 + 4 = 8), and small cell carcinoma, which is not assigned a Gleason grade.

On needle biopsy cores, lower grade patterns are ignored if they occupy <5% of the area of tumor. Thus, a biopsy core that contains 98% pattern 4 and 2% pattern 3 is given a Gleason score of 4 + 4 = 8. Contrarily, a higher grade pattern is included in the biopsy score even if it is <5% of the area of tumor. Tertiary patterns are not awarded to needle biopsy specimens. For instance, a specimen that has patterns 3, 4, and 5 within it, where pattern 3 and 4 are the most common and second most common, is not recorded as a Gleason 3 + 4 = 7, tertiary pattern 5. Rather, on a needle biopsy specimen, this is reported as Gleason 3 + 5 = 8. On radical prostatectomy specimens, a tertiary pattern is assigned when it is present (24).

STAGING SYSTEMS

The two most well-known staging systems for prostate cancer are the Whitmore-Jewett staging system and the TNM staging system. The Whitmore-Jewett staging system (Table 8.1) is the first staging system that was devised for prostate cancer in the 1950s. The AJCC/UICC endorses the TNM staging system. The most recent revision of this system, the seventh edition, was published in 2009 (Table 8.2). There are a few significant changes in this latest edition when compared to the 2002 sixth edition. Gleason score for the first time is recognized as the preferred grading system, thereby abolishing the scheme of poorly, moderately, and well-differentiated carcinoma. Extraprostatic extension with microscopic bladder neck invasion is now grouped as T3a instead of T4 disease due to evidence that clinical outcome is likely to be better than in cases with seminal vesicle invasion. Importantly, the clinical parameters of serum PSA level and Gleason score have now been incorporated as part of the anatomic stage/prognostic groups (Table 8.3). (1) This is the first time that these parameters have been formally included. Undoubtedly, this framework is not as sophisticated as other attempts to stage prostate cancer such as various nomograms and neural networks. But the anatomic stage/prognostic groups adhere to the overarching mantra of the AJCC staging, which is to base staging on the TNM anatomic classification.

TABLE 8.1 WHITMORE-JEWETT STAGING SYSTEM FOR PROSTATE CANCER

Stage A
Stage A is clinically undetectable tumor confined to the prostate gland and is an incidental finding at prostatic surgery.
	Substage A1: well differentiated with focal involvement and usually left untreated
	Substage A2: moderately or poorly differentiated or involves multiple foci in the gland
Stage B
Stage B is tumor confined to the prostate gland.
	Substage B0: nonpalpable and PSA detected
	Substage B1: single nodule in one lobe of the prostate
	Substage B2: more extensive involvement of one lobe or involvement of both lobes
Stage C
Stage C is tumor clinically localized to the periprostatic area but extending through the prostatic capsule; seminal vesicles may be involved.
	Substage C1: clinical extracapsular extension
	Substage C2: extracapsular tumor producing bladder outlet or ureteral obstruction
Stage D
Stage D is metastatic disease.
	Substage D0: clinically localized disease (prostate only) but persistently elevated enzymatic serum acid phosphatase titers
	Substage D1: regional lymph nodes only
	Substage D2: distant lymph nodes and metastases to bone or visceral organs
	Substage D3: D2 prostate cancer patients who relapsed after adequate endocrine therapy

TABLE 8.2 SEVENTH EDITION 2010 TNM STAGING SYSTEM FOR PROSTATE CANCER

TNM Clinical Staging System
Primary Tumor (T)
Clinical
	TX	Primary tumor cannot be assessed
	T0	No evidence of primary tumor
	T1	Clinically unapparent tumor neither palpable nor visible by imaging
	T1a	Tumor incidental histologic finding in 5% or less of tissue resected
	T1b	Tumor incidental histologic finding in more than 5% of tissue resected
	T1c	Tumor identified by needle biopsy (e.g., because of elevated PSA)
	T2	Tumor confined within prostate^a
	T2a	Tumor involves one half of one lobe or less
	T2b	Tumor involves more than one half of one lobe but not both lobes
	T2c	Tumor involves both lobes
	T3	Tumor extends through the prostate capsule^b
	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: such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall
Regional Lymph Nodes (N)
Clinical
	NX	Regional lymph nodes were not assessed
	N0	No regional lymph node metastasis
	N1	Metastasis in regional lymph node(s)
Distant Metastasis (M)
	M0	No distant metastasis
	M1	Distant metastasis
	M1a	Nonregional lymph node(s)
	M1b	Bone(s)
	M1c	Other site(s) with or without bone disease
TNM Pathologic Staging System
Primary Tumor (T)^c
Pathologic (pT)
	pT2	Organ confined
	pT2a	Unilateral, one half of one side or less
	pT2b	Unilateral, involving more than one half of side but not both sides
	pT2c	Bilateral disease
	pT3	Extraprostatic extension
	pT3a	Extraprostatic extension or microscopic invasion of bladder neck^d
	pT3b	Seminal vesicle invasion
	pT4	Invasion of rectum, levator muscles, and /or pelvic wall
Regional Lymph Nodes (N)
Pathologic
	pNX	Regional nodes not sampled
	pN0	No positive regional nodes
	pN1	Metastases in regional node(s)
Distant Metastasis (M)
	M0	No distant metastasis
	M1	Distant metastasis
	M1a	Nonregional lymph node(s)
	M1b	Bone(s)
	M1c	Other site(s) with or without bone disease
^aThere is no pathologic T1 classification. ^bPositive surgical margin should be indicated by an R1 descriptor (residual microscopic disease). ^cThere is no pathologic T1 classification. ^dPositive surgical margin should be indicated by an R1 descriptor (residual microscopic disease).