Prostate Cancer Workup

Updated: Feb 02, 2021
  • Author: Chad R Tracy, MD; Chief Editor: Edward David Kim, MD, FACS  more...
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Approach Considerations

Currently, most cases of prostate cancer are identified by screening in asymptomatic men. Digital rectal examination (DRE) and prostate-specific antigen (PSA) evaluation are the two components used in prostate cancer screening. Transrectal ultrasonography (TRUS) has been associated with a high false-positive rate, making it unsuitable as a screening tool, but it has an established role in directing prostatic biopsies.

Needle biopsy of the prostate is indicated for tissue diagnosis in patients whose screening shows elevated PSA levels or abnormal DRE findings. Pathologic evaluation of the biopsy specimen permits calculation of the Gleason score, which is used to help determine prognosis.

Blood studies beyond PSA offer little useful information for men with newly diagnosed early-stage prostate cancer. For men with advanced disease, a chemistry profile (including serum creatinine and liver function tests) is warranted. Acid and alkaline phosphatase measurements do not provide helpful information in most cases.

Urinalysis should be performed. If results are abnormal (ie, indicating the presence of hematuria or infection), further workup is warranted before planning cancer therapy.

Computed tomography (CT) and/or MRI of the abdomen/pelvis are performed in a risk-stratified approach. Chest radiography is no longer a routinely advisable staging test for prostate cancer, though it may be of use in patients with prostatic ductal adenocarcinoma. 

In patients with a family history of high-risk germline mutations (eg, BRCA 1/2, Lynch mutation), a suspicious family history, or intraductal carcinoma on prostate biopsy, National Comprehensive Cancer Network (NCCN) guidelines recommend germline testing, preferably with pre-test genetic counseling. If a genetic mutation is identified, the NCCN recommends post-test genetic counseling. [41]


Prostate Cancer Screening

Prostate-specific antigen (PSA) testing with or without digital rectal examination (DRE) are the two components used in prostate cancer screening. Transrectal ultrasonography (TRUS) has been associated with a high false-positive rate, making it unsuitable as a screening tool, although it has an established role in directing prostatic biopsies.

A systematic review and meta-analysis that included 7 studies with 9,241 patients who underwent both DRE and prostate biopsy found that DRE performed by primary care physicians has poor diagnostic accuracy in screening for prostate cancer. The sensitivity of DRE in that setting was estimated to be 0.51, with a specificity of 0.59 and a positive predictive value of 0.41. [42]

The screening debate

Since the introduction and widespread adoption of screening men for prostate cancer using PSA, the rate of metastatic disease at presentation (de novo) has declined by 50%, and the rate of death from prostate cancer has declined by 70%. [43] However, PSA screening also led to the increased detection and the somewhat exuberant treatment of prostate cancer at increasingly early stages, and it became abundantly clear that the benefit of early prostate cancer detection must be balanced with the risk for the potential overtreatment of early-stage prostate cancer.

Both surgery and radiation therapy are associated with morbidity, including diminished erectile function and incontinence. This has prompted multiple evaluations of prostate cancer screening, including the Prostate, Colorectal, Lung, and Ovarian (PLCO) screening trial, [44] the European Randomized Study of Screening for Prostate Cancer (ERSPC), [45] and the Göteborg trial. [46]

The PLCO was conducted in the United States. Patients were randomized between 1993-2001 to either annual PSA screening with a DRE for 6 years or usual care. The screening cohort included 38,340 men and the usual care cohort included 38,343 men. After a median of 15 years of follow-up, there was no reduction in prostate cancer mortality. [44] Only 2.7% of men died from prostate cancer. Of note, this study was plagued by crossover. Overall, the rate of screening for at least one PSA test during the study was 99% for the intervention arm and 86% for the control arm. Many have argued that this study demonstrates no difference between screening and opportunistic screening; however, the difference between the two has questionable clinical significance, and this study really just evaluated screening compared with screening.

The ERSPC trial, conducted across centers in 8 European countries and similar in design to the PLCO trial, enrolled 72,891 men in the PSA screening arm and 89,352 men in the control arm. After 13 years of follow-up, there was a significant reduction in prostate cancer-related mortality for the PSA screening; the number needed to invite for screening to prevent 1 death was 781 men and the number needed to treat was 27. [45] Some elements of PSA screening existed prior to trial enrollment and at several centers. The extrapolated PSA testing contamination (ie, testing of asymptomatic men in the control arm) in this study was significantly lower than in the PLCO trial (30%). [47]

Finally, the Göteborg screening study represents the smallest population of men with the least amount of PSA contamination and the longest follow-up. Men aged 50-64 who had not had prior PSA testing were randomized to PSA screening or standard care. At 18 years of follow-up, to prevent one prostate cancer-related mortality,  the number needed to invite was 231 and the number needed to diagnose was 10. [46] For perspective, the number needed to treat to prevent one death from breast cancer is around 414 and the number needed to invite for screening is around 1200 for which the United States Preventive Services Task Force (USPSTF) has granted a grade B recommendation. [48, 49] ,

In May 2012, the USPSTF recommended against all prostate cancer screening, on the basis of less mature data from PSA screening trials. [50] Many primary care societies amended their prostate cancer screening guidelines to reflect the USPSTF decision; thus, screening decreased among access points to urology clinics.

This recommendation resulted in a significant decrease in the annual incidence of prostate cancer diagnosed and an increase in the incidence of metastatic disease at the time of diagnosis in men older than 50 years of age. Decreasing incidence has been observed for patients with low risk as well as high-risk disease. [51] Emerging evidence suggests that these trends are also associated with worse survival. [52] The USPSTF guidance was amended in May, 2018, such that the USPSTF now provides a grade C recommendation for individualized prostate cancer screening for men aged 55-69 and a grade D rating for prostate cancer screening for men 70 years or older. [53]

Currently, the American Cancer Society (ACS), [54] American Urological Association (AUA), European Association of Urology, [55] and the National Comprehensive Cancer Network (NCCN) [56]  provide authoritative guidelines regarding prostate cancer screening. The specifics are addressed in the table below. Each body recommends an estimation of life expectancy as a component of both screening and treatment. Earlier screening is generally recommended in men with a family history of prostate cancer, those of African-American ancestry, and those with a personal or family history of high-risk germline mutations such as those associated with DNA damage repair, including BRCA1/2 and ATM. DRE is not as sensitive as PSA and is not mandated by many of the guidelines panels.

Repeated PSA testing occurs at differing intervals and the PSA threshold for biopsy is generally considered on a continuum. Of note, there is no PSA value threshold that can be used to rule out prostate cancer, and PSA should be repeated at least once after initial elevation

Evaluation of the competing risks for patient comorbidity and shared decision regarding both screening and treatment is of paramount importance. Shared decisions require collaboration between the care provider and patient to ensure that patient preference is accounted for in the decision-making process. This is especially important in patients with comorbid conditions and limited life expectancy.

In a cohort study evaluating survival 10 years after prostate cancer diagnosis, prostate cancer–specific mortality occurred in only 3% and 7% of patients with low and intermediate-risk disease, respectively, and in 18% of those with high-risk disease. However, 10-year mortality for men with more than three comorbid conditions was 26%, 40%, and 71% for age groups < 60, 61-74, and >75 years, respectively. [57] Similar associations were noted in the PIVOT trial (see Treatment) and exemplify the need to balance cancer treatment, personal preference, and life expectancy. [52]


Table 2. Prostate cancer screening recommendations from 4 major organizations (Open Table in a new window)


Screening Tools

Ages to Screen

Repeat Testing Interval

Indication for Prostate Biopsy

NCCN (2018)



>75 (only in very healthy men)

PSA* < 1 ng/mL, 2-4 years

PSA* 1-3 ng/mL, 1-2 years

PSA > 3 ng/mL or

Suspicious DRE

AUA (2018)


-Not indicated in men < 40

-Not recommended in men 40-54**

-After shared decision making for men      


-Not recommended for men >70 or

 men with life expectancy < 10-15 yrs

2 or more years

Consider PSA >3, however with additional consideration of factors affecting PSA***

EAU (2016)


Risk adapted model after shared decision making for men with a life-expectancy >10-15 years

-Men >50

-Men >45 with a family history

-African American men >45

-Men with PSA >1 ng/mL at age 40

-Men with PSA >2 ng/mL at age 60

Risk adapted:

-every 2 years for:

Men with PSA >1 ng/mL at age 40 or PSA >2 ng/mL at age 60

Every 8 years for those not at risk

-PSA should be addressed continuously

- Consider the addition of novel risk assays

ACS (2019)


Risk adapted model after shared decision making

-Men> 50, life expectancy > 10 years

-Men >45 at high risk

-Men>40 at very high risk¥

PSA*< 2.5 ng/mLà2 yrs

PSA* >2.5ng/ mLà1 yr

Not discussed

*assumes normal DRE

**Screening should be individualized for men aged 40-54 and those at higher risk, such as African-American men, men with a family history of metastatic or lethal adenocarcinoma (including prostate, breast, ovarian, and pancreatic cancers), multiple affected first-degree relatives of affected generations, and family members with cancer detected at younger ages.

***A second confirmatory PSA should be obtained prior to biopsy

ǂ African-American men or men with a first-degree relative with prostate cancer diagnosed at < 65 years of age

¥ More than one first-degree relative with prostate cancer at an early age


Prostate-Specific Antigen

When PSA testing was first developed, the upper limit of normal for PSA was thought to be 4 ng/mL. However, subsequent studies have shown that no PSA level guarantees the absence of prostate cancer. As the PSA level increases, so does the risk of this disease. When the PSA is 1 ng/mL, cancer can be detected in about 8% of men if a biopsy is performed. With a PSA level of 4-10 ng/mL, the likelihood of finding prostate cancer is about 25%; with a level above 10 ng/mL, the likelihood is much higher. [58]

Although cancer may be present even when the PSA level is less than 1 ng/mL, experts do not recommend a biopsy unless the PSA is higher (unless there is a suspicion on DRE or other modality). Some use 2.5 ng/mL as the cutoff, while others wait until it is 3 ng/mL or greater.

The European Randomized Study of Screening for Prostate Cancer (ERSPC) applied a PSA cutoff value of 3 ng/mL or higher as an indication for lateralized sextant biopsy. [59] For men with an initial PSA value of less than 3 ng/mL, the risk of developing aggressive prostate cancer and death has been found to significantly increase with PSA values in the 2-2.9 ng/mL range, although the overall risk of aggressive prostate cancer–related death remains limited. [60]

A review of data from the Surveillance, Epidemiology, and End Results (SEER) system of men with newly diagnosed prostate cancer from 2004 to 2006 by Shao et al found that most patients with a PSA threshold below 4.0 ng/mL had low-risk disease but underwent aggressive local therapy. Shao et al suggested that in the absence of the ability to distinguish indolent from aggressive cancers, lowering the biopsy threshold might increase the risk of overdiagnosis and overtreatment. [61]

A review by Preston and colleagues concluded that PSA levels in midlife correlate with future risk of lethal prostate cancer. The study population consisted of men who had PSA levels measured on enrollment in Physicians' Health Study, when they were 40-59 years old. In men with baseline PSA levels in the >90th percentile, versus those with levels at or below the median, the odds ratios for developing lethal prostate cancer (by age at baseline measurement) were as follows [62] :

  • Age 40-49 years: 8.7
  • Age 50-54 years: 12.6
  • Age 55-59 years: 6.9

A variety of approaches have been proposed for improving the accuracy of PSA for detecting prostate cancer. These include assessment of the velocity of PSA level increase and the percentage of free PSA.

See Prostate-Specific Antigen Testing for a complete discussion of this topic.

PSA velocity

PSA velocity is an important concept. To calculate velocity, at least 3 consecutive measurements on specimens drawn over at least 18-24 months should be used. Guidelines from the NCCN suggest that PSA velocity be considered in the context of the PSA level. [63] The following PSA velocities are suspicious for cancer:

  • PSA velocity of 0.35 ng/mL/y, when the PSA is ≤2.5 ng/mL
  • PSA velocity of 0.75 ng/mL/y, when the PSA is 4–10 ng/mL

However, a study by Vickers et al in 2011 called into question the concept of PSA velocity. In this study, PSA velocity cut points with a comparable specificity to PSA level cut points had a lower sensitivity, particularly for high-grade and clinically significant prostate cancer. The researchers concluded that “PSA velocity added little to the predictive accuracy of high PSA levels or positive DRE and would substantially increase the number of men recommended for a biopsy.” [64] This controversy has not been resolved.

Bound versus free PSA

The measurement of bound and free PSA can help to differentiate mildly elevated PSA levels due to cancer from elevated levels due to benign prostatic hyperplasia. Free PSA is calculated as a percentage of total PSA; the lower the percentage of free PSA, the higher the likelihood of cancer. For example, cancer is found at prostate biopsy in only 8% of men with greater than 25% free PSA, but in more than half of those with less than 10% free PSA.

The percentage of free PSA is generally used as an additional factor in making an informed recommendation for or against biopsy in patients with a PSA level of 4-10 ng/mL. Typically, a free PSA above 25% is considered normal. Some experts recommend a biopsy when the free PSA is less than 18%; others advise a cutoff of 12%.

Free PSA percentage is most useful in men with very large glands and in patients in whom 1 biopsy result has already been negative. In healthy men with a PSA level of 4-10 ng/mL, many experts recommend biopsy without the additional free-PSA test. 



Prostate Biopsy

The diagnosis of screening-detected prostate cancer is confirmed by prostate biopsy. For several decades, prostate biopsy has been performed via a transrectal approach utilizing ultrasound guidance (TRUS). Initial prostate biopsies followed a sextant (6 core) protocol and were utilized in the many of the early studies regarding prostate cancer screening. However, over time, it became apparent that the sensitivity of a 6-core prostate biopsy was suboptimal. Optimization of prostate biopsy protocols demonstrated the value of obtaining 12 cores of prostate tissue in predetermined prostatic regions primarily targeting the peripheral zone, where most prostate cancers arise. [65]

In spite of these improvements, ultrasound-guided prostate biopsies fail to identify 20-30% of cancers and undergrade others. [66] Transrectal prostate biopsy is associated with several potential drawbacks. Complications include rectal bleeding, hematuria, hematospermia, pain, urinary tract infection (UTI), lower urinary tract symptoms, acute urinary retention, and transient erectile dysfunction. Most notably, sepsis requiring hospitalization occurs in 0.5-4% of cases, depending on antimicrobial administration practices. [67]

Recently, transperineal prostate biopsy has demonstrated promise in reducing several of the risks associated with transrectal biopsy. In a cohort of 1,287 patients undergoing transperineal prostate biopsies under local anesthesia, the rate of complications was notably low, with only 1.6% of patients developing urinary retention, one patient with a culture-confirmed UTI, and no episodes of sepsis. Cancer was detected in 49.8% of patients, with 30% of patients overall harboring clinically significant prostate cancer; moreover, 9.7% of cancers detected were located only in the anterior zone, a zone not normally sampled in transrectal biopsy templates. [68]

A similar study in 3,000 men undergoing transperineal biopsy demonstrated similar rates of complications, including UTI in < 1% of patients and acute urinary retention in 6.7% of patients, with complication rates increasing when the number of biopsies increased from 12 to 24. [69] Overall, detection rates for clinically significant prostate cancer are similar between TRUS and transperineal biopsies. [70]

Finally, the utilization of magnetic resonance imaging (MRI) to assess for lesions concerning for prostate cancer has recently gained significant traction in several clinical scenarios, including the following:

  • Prior to prostate biopsy
  • Active surveillance
  • Surgical or local therapy planning
  • Patients with a prior negative prostate biopsy and persistently elevated PSA

Lesions in the prostate that are detected on MRI are assigned Prostate Imaging–Reporting and Data System (PI-RADS) scores, based on location within the prostatic zones utilizing multiple MRI sequences. The images from the MRI are then overlaid on the images obtained using the ultrasound probe and the lesions of interest are targeted for biopsy. Each PI-RADS score is associated with the probability of detecting clinically significant ande role of prostate MRI and MRI-targeted biopsy in patients with a negative biopsy. [71, 72]

For men with an elevated PSA and no prior biopsy, the detection rates of clinically significant prostate cancer do not significantly vary with MRI-guided biopsy compared with TRUS biopsy alone; however, the omission of a biopsy for patients with a negative MRI might lead to decreased detection of clinically insignificant prostate cancer and low rates of missing clinically significant prostate cancer. [73]

These findings have been further confirmed in the PRECISION trial, in which MRI at the time of initial prostate biopsy demonstrated noninferiority to standard TRUS biopsy, with findings suggestive of superiority. [74] The role of MRI in the surveillance of men with low-risk prostate cancer is currently being evaluated, with mixed results and a consistent suggestion that a targeted biopsy should not be omitted. [75, 76, 77]

See Transrectal Ultrasonography of the Prostate for a discussion of TRUS and prostate biopsy, as well as Imaging in Prostate Carcinoma and Techniques of Local Anesthesia for Prostate Procedures and Biopsies.


Histologic Findings

Although the change in glandular architecture represented by the Gleason score is currently the most widely used histologic parameter, it is not the only histologic change that can be observed in prostate cancers. Indeed, notable changes in cell and nuclear morphology, DNA ploidy, neuroendocrine differentiation, and vascularity can be observed and may have prognostic significance.

There is a continuum from normal prostatic epithelium to invasive carcinoma. Precursor lesions to carcinoma may include prostatic intraepithelial neoplasia (PIN) and atypical small acinar proliferation (ASAP). (See the images below.)

Prostate cancer. Micrograph of high-grade prostati Prostate cancer. Micrograph of high-grade prostatic intraepithelial neoplasia
Prostate cancer. Adenocarcinoma around a small ner Prostate cancer. Adenocarcinoma around a small nerve (center). Courtesy of Thomas M. Wheeler, MD.
Prostate cancer. Small focus of adenocarcinoma on Prostate cancer. Small focus of adenocarcinoma on needle biopsy on right side of slide (normal glands on left side). Courtesy of Thomas M. Wheeler, MD.
Prostate cancer. Immunohistochemical stains showin Prostate cancer. Immunohistochemical stains showing normal basal cells (brown) in a benign gland with no basal cells in malignant glands (on right side with no brown staining). Malignant glands show increased expression of racemase (red cytoplasmic stain). Courtesy of Thomas M. Wheeler, MD.

The architecture of the gland remains normal but the epithelial layers become multi-layered and crowded. At a cellular level, the nucleus becomes large and nucleoli are visible. The term PIN is becoming less used in favor of atypical small acinar proliferation (ASAP), which is proliferation of usually small acini with features suggestive of but not diagnostic of cancer.

Clinical studies suggested that PIN predates a carcinoma by 10 or more years. This concept is less accepted in the modern era. PIN as a precursor of cancer has been replaced by ASAP. The identification of ASAP in prostate biopsy specimens warrants further searching for concurrent invasive carcinoma, with up to 30% having cancer identified on subsequent biopsy specimens. Repeat biopsies within 3-6 months are recommended for patients with ASAP cases but PIN is treated as a benign finding.

See Precancerous Lesions of the Prostate for a complete discussion of this topic.

Transitional cell prostate carcinoma

Transitional cell carcinoma (TCC) of the prostate is carcinoma of urothelial origin with a pathology that involves prostatic tissue. Primary prostatic TCC is very rare and involves the entire prostatic urethra, particularly near the verumontanum, the large prostatic duct, and nearby acini. Secondary prostatic TCC mainly involves the bladder neck or posterior prostatic tissue; it results from direct pagetoid spread of urothelial cancer in situ (CIS) or direct pathologic invasion of bladder urothelial carcinoma.

Extensive involvement of the prostatic duct and acini may appear as areas of luminal necrosis and periductal fibrosis. In cases of prostatic stroma invasion, there are irregular areas of induration and fibrosis.

Primary prostatic papillary urothelium carcinoma is characterized by papillary growth lined by urothelial cells of multiple layers with mild to severe cytologic atypia. Endophytic growth pattern with involvement of superficial suburethral tissue and ductal spread may occur.

Urothelial cancer in situ (CIS) may involve the prostatic urethra, the prostatic duct, and the acini. The vast majority of cases arise synchronously with bladder urothelial neoplasia or from pagetoid spread from the bladder neck. CIS is characterized by partial or complete replacement of urethra or duct by highly atypical urothelial cells; these cells have pleomorphic nuclei, coarse chromatin, and frequent mitoses or apoptosis. There may be large areas of well-defined nests of CIS as a result of CIS's extension into prostatic acini. Periductal fibrosis or fibrosis of the acini, as well as chronic inflammation, may be evident. [256]

Invasion of urothelial carcinoma into prostatic stroma is characterized by irregular nests, clusters, or single atypical cells that infiltrate into dense prostatic tissue. Two well-recognized pathways of invasive carcinomas have been described: (1) invasive carcinoma arising from the prostatic urethra and duct, which is often associated with CIS within the prostatic duct or acini, and (2) prostatic stroma invasion, in which bladder cancer penetrates from posterior periprostatic soft tissue or the bladder neck. Focal invasion of superficial lamina propria has also been reported to occur in association with prostatic urethra CIS.


Grading, Assigning Stage, and Risk Stratification

Once detected on biopsy, prostate cancer is assigned a grade and stage followed by a risk group for consideration of further therapy. Prostate cancer grading has traditionally been performed according to the Gleason Grading system, a two-number system in which the first number is assigned to the predominant focus of tumor and the second assigned to the second more predominant pattern; each is graded on a scale of 1-5 and the sum of the two constitutes the overall grade. [78] Generally, the cut-off for prostate cancer starts with Gleason grade 3+3 cancer.

In 2010, the International Society of Urological Pathology (ISUP) modified the Gleason Grading system to a 5-grade system in which grade group 1 encompasses Gleason 3+3 disease, and Gleason 3+4 is stratified into a different grade than Gleason 4+3 (see the Table below). [79]

Table 3. International Society of Urological Pathology (ISUP) grading system (Open Table in a new window)

ISUP Grade

Gleason Score




Only individual discrete well-formed glands



Predominantly well-formed glands with lesser component of poorly formed/fused/cribriform glands



Predominantly poorly formed/fused/cribriform glands with lesser component of well-formed glands



Only poorly formed/fused/cribriform glands


Predominantly well-formed glands and lesser component lacking glands (or with necrosis)


Predominantly lacking glands (or with necrosis) and lesser component of well-formed glands



Lacking gland formation (or with necrosis) with or without poorly formed/fused

The tumor-node-metastasis (TNM) staging system of the American Joint Committee on Cancer (AJCC) is used to stage prostate cancer. The current revision of the AJCC system, which took effect in January 2018, also uses both the Gleason score and the grade group for staging. [80]  See Prostate Cancer Staging.

Clinical staging is combined with grading and clinical parameters (such as PSA, PSA density, and volume of cancer in biopsy cores) to formulate clinical risk groups. Many groups have assigned risk stratification tools in this area, however, the NCCN risk stratification is discussed in this article. In the NCCN approach, risk group is assigned on the basis of clinical and pathologic features; in turn, risk grouping guides additional evaluation with imaging studies, such as bone imaging and pelvic and/or abdominal imaging. Risk group and in some cases family history guide the use of germline testing, and risk group along with life expectancy guides the use of molecular biomarker analysis of the tumor. [41] In the NCCN guidelines, clinical risk calculators such as the PCPT or ERSPC calculators are utilized to determine the risk of lymph node involvement. [81]

Advanced imaging utilizing multiple radiotracers is currently being evaluated for localized prostate cancer staging, but it has not yet been standardized for clinical practice and staging and is beyond the scope of this article. [82]

Therapy is primarily determined by life expectancy and patient goals. For very low risk disease, therapy distinction is based on life expectancy < 10 years, 10-20 years, or > 20 years. For low risk and both categories of intermediate risk disease, this distinction is made at 10 years. For high and very high risk disease, this cut-point is 5 years or based on symptoms from advanced disease. NCCN guidelines provide initial therapy recommendations based on risk category and life expectancy. [41]

Transitional cell carcinoma (TCC)

TNM staging of TCC involving the prostate depends on the primary site.

Prostatic TCC secondary to bladder TCC

If prostatic stroma invasion is present, it is staged as pT4a bladder cancer, regardless of whether there is contiguous invasion of the prostatic urethra, prostatic duct, or acini or direct, penetrating invasion of the bladder. If the prostate is involved only by cancer in situ (CIS), the stage of bladder tumor depends on the depth of invasion into the bladder, independent of the amount and location of the CIS.

Primary prostatic urethra urothelial carcinoma

The tumor is staged according to the depth of invasion and the degree of involvement of the prostate, as follows:

  • Ta - Noninvasive, papillary carcinoma

  • Tis - Urethral CIS

  • T1 - Invasion of subepithelial connective tissue

  • T2 - Involvement of the prostatic stroma

  • T3 - Invasion beyond the prostatic capsule or bladder neck

  • T4 - Invasion of adjacent organs


Prediction Models

Models have been developed that combine the clinical stage (as determined by DRE findings), Gleason score, and PSA level in an attempt to better predict which men have organ-confined cancer, as opposed to those who may have local extension. In addition, these models can be used to predict the time to biochemical failure and the time to the development of clinical metastatic disease in patients with rising PSA levels.

These models have been adapted to personal-computer and handheld-computer platforms and can be used with ease in clinical practice. One such program can be downloaded free of charge from the Prostate Nomogram section of the Memorial Sloan-Kettering Cancer Center Web site. The Partin tables, updated by experts at Johns Hopkins in January 2013, are another excellent nomogram for predicting prostate cancer spread and prognosis. Updates to the tool were based on a study of 5629 men who underwent radical prostatectomy and staging lymphadenectomy between 2006 and 2011. The updated tables show that certain categories of men who were previously not thought to have a good prognosis (eg, those with a Gleason score of 8) actually can be cured with surgery. [83, 84]

The Cancer of the Prostate Risk Assessment (CAPRA) score is calculated from the PSA level, the Gleason score, the percentage of biopsy cores positive for cancer, the clinical tumor stage, and the patient age at diagnosis. In a large cohort of patients with clinically localized prostate cancer, the CAPRA score proved accurate for predicting metastases, cancer-specific mortality, and all-cause mortality. No patient with a CAPRA score of 0 reached either metastasis or mortality endpoints, but each single-point increase in the CAPRA score was associated with increasing risk. [85]

From the results of the Prostate Cancer Prevention Trial (PCPT), an online risk calculator was created. [6, 86] The information needed includes age, PSA score, ethnicity, family history, positive or negative DRE findings, and positive or negative prior biopsy findings. After those values are entered, the calculator predicts the chances for no, low-grade, and high-grade prostate cancer. The intent is to help guide treatment decision-making. See the PCPT prostate cancer risk calculator.

Whitmore-Jewett classification

The Whitmore-Jewett classification divides prostate cancer into 4 stages, A-D, as follows:

  • Stage A - Tumor is present, but not detectable clinically
  • Stage B - The tumor can be felt on physical examination but has not spread outside the prostatic capsule
  • Stage C - The tumor has extended through the capsule
  • Stage D- The tumor has spread to other organs

The Whitmore-Jewett classification is no longer widely used, as prostate cancer does not necessarily progress in a sequential manner. However, further stratification of stage D by Crawford and Blumenstein [87] has been thought to improve classification and understanding of a subset of patients who have hormone-insensitive prostate cancer. The staging is as follows:

  • Stage D1 - Involvement of pelvic lymph nodes
  • Stage D1.5 - Rising PSA level after failure of local therapy (ie, biochemical failure)
  • Stage D2 - Metastatic disease to bone and other organs
  • Stage D2.5 - Rising PSA after nadir level
  • Stage D3 - Castrate-resistant prostate cancer
  • Stage D3.5 - Sensitive to hormones
  • Stage D4 - Insensitive to hormones

Other Tests

Molecular/genetic characteristics

The molecular and genetic features of prostatic TCC are similar to those of bladder TCC. Common cytogenetic abnormalities are chromosomal losses (2q, 5q, 8p, 9p, 9q, 11p, 18q) and gains (1q, 5p, 8q, 17q). Many oncogenes (Her2/neu, H-ras, EGFR, cyclin, and MDM2) and tumor suppressor genes (p53RB, and PTEN) have been implicated in the tumorigenesis. [260]

In a review of 42 biopsies, Varinot and colleagues found HOXB13 expression was negative or weakly positive in individuals with carcinomas of urothelial origin, and positive in patients with prostatic carcinoma. They concluded that HOXB13 was a marker for prostatic origin of a carcinoma with good sensitivity (89%) and very good specificity (100%) and had the potential to be a diagnostic aide when poorly differentiated or neuroendocrine tumors were encountered. [259]


The immunoprofile of prostatic transitional cell carcinoma (TCC) is identical to that of bladder carcinoma. Tumors are positive for cytokeratin (CK) 7 (90%), p63 (87%), thrombomodulin (79%), CK20 (61%), high–molecular weight CK (HMWCK) 34βE12 (59%), CK5/6 (55%), and uroplakin III (55%). [258]