Clinical presentation and diagnosis of prostate cancer

INTRODUCTION — Prostate cancer is among the most common cancers in males worldwide, with an estimated 1,600,000 cases and 366,000 deaths annually [1]. In the United States, 11 percent of males are diagnosed with prostate cancer over their lifetime, with the incidence generally rising with age [2]; there are an estimated 268,490 cases and 34,500 deaths annually [3]. The overall five-year survival rate is over 98 percent.

An overview of the clinical presentation and initial diagnosis of males with prostate cancer is presented here.

Screening, risk factors, and chemoprevention of prostate cancer are described separately:

●(See "Screening for prostate cancer".)

●(See "Risk factors for prostate cancer".)

●(See "Genetic risk factors for prostate cancer".)

●(See "Chemoprevention strategies in prostate cancer".)

Laboratory, radiologic, and pathologic testing of the prostate are described separately:

●(See "Measurement of prostate-specific antigen".)

●(See "The role of magnetic resonance imaging in prostate cancer".)

●(See "Prostate biopsy".)

●(See "Interpretation of prostate biopsy".)

●(See "Molecular prognostic tests for prostate cancer".)

The prostate cancer staging system, initial staging evaluation, and management approaches based upon risk are presented separately:

●(See "Initial staging and evaluation of males with newly diagnosed prostate cancer", section on 'Introduction'.)

●(See "Localized prostate cancer: Risk stratification and choice of initial treatment".)

●(See "Initial approach to low- and very low-risk clinically localized prostate cancer".)

●(See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement".)

●(See "Prostate cancer in older males".)

CLINICAL PRESENTATION

Spectrum of disease at detection — Clinical manifestations of prostate cancer are frequently absent at the time of diagnosis. The clinical behavior of prostate cancer ranges from a screen-detected, asymptomatic, microscopic, well-differentiated tumor that may never become clinically significant to the rarer, screen-detected or clinically symptomatic, aggressive, high-grade cancer that causes metastases, morbidity, and death.

At the time of diagnosis, 78 percent of patients have localized cancer, regional lymph node involvement is present in 12 percent, and 6 percent have distant metastases [2]. This distribution is likely to change with the increasing update of more sensitive positron emission tomography (PET)-based diagnostic studies, such as prostate-specific membrane antigen (PSMA) PET. (See "Screening for prostate cancer", section on 'Introduction' and "Initial staging and evaluation of males with newly diagnosed prostate cancer", section on 'PET imaging using PSMA-based radiotracers'.)

Symptoms — Most prostate cancers are diagnosed in the localized stage and are asymptomatic.

Uncommonly, prostate cancer may present with nonspecific lower urinary tract symptoms (LUTS), hematuria, or hematospermia; however, these symptoms are more commonly due to nonmalignant conditions [4]. In particular, LUTS such as frequency, urgency, nocturia, and hesitancy are more often related to a benign etiology such as benign prostate hyperplasia (BPH) rather than to prostate cancer. Such symptoms may also be due to bladder outlet obstruction, urinary tract infection, prostatitis, interstitial cystitis, or chronic pelvic pain syndrome. However, patients may be concerned that these or other symptoms due to anatomic, infectious, or irritative etiologies could indicate the presence of prostate cancer. (See "Lower urinary tract symptoms in males", section on 'Symptoms' and "Etiology and evaluation of hematuria in adults" and "Hematospermia".)

Among the 6 percent of patients whose prostate cancer is metastatic at the time of diagnosis, bone pain may be the presenting symptom. Bone is the predominant site of disseminated prostate cancer, and pain is the most common manifestation of bone metastases. An initial diagnosis of prostate cancer after bone metastases have already occurred has become unusual [5]. (See "Bone metastases in advanced prostate cancer: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

Other symptoms that may occur in patients with metastatic disease include hematuria, inability to void, urinary incontinence, erectile dysfunction, weight loss, weakness or back pain due to spinal cord compression, pain due to pathologic fractures, fatigue caused by anemia, or symptoms associated with chronic kidney disease. (See "Initial staging and evaluation of males with newly diagnosed prostate cancer", section on 'Evaluation for distant metastases'.)

Signs — Clinical signs that may be associated with prostate cancer include an elevated prostate-specific antigen (PSA) on laboratory testing and an abnormal prostate finding on digital rectal examination (DRE), although an abnormal prostate examination is only present in some patients with prostate cancer.

PSA testing — PSA is the most commonly used and most valuable test for early detection of prostate cancer. The likelihood of prostate cancer increases with more elevated PSA values. PSA testing in a man without a history of prostate cancer is most often done for screening purposes, but testing is sometimes performed as part of an evaluation of symptoms. (See "Screening for prostate cancer", section on 'Approach to screening'.)

There is no single threshold for defining an abnormal PSA value; there is considerable variability in normal PSA, and studies do not conclusively identify a single approach applicable to every patient. In deciding which patients with an elevated PSA require further evaluation (ie, urologic referral), we compare the patient's PSA result with the age-specific reference range, as well as with the prior year's PSA, if available.

Age-specific reference ranges are:

●40 to 49 years – 0 to 2.5 ng/mL

●50 to 59 years – 0 to 3.5 ng/mL

●60 to 69 years – 0 to 4.5 ng/mL

●70 to 79 years – 0 to 6.5 ng/mL

Some contributors to this topic evaluate further if the PSA is above the upper value for the age range, whereas others evaluate if the PSA is above the midpoint. We also evaluate if the PSA increased by more than 0.75 ng/mL in one year, even if the PSA value is not above the age-specific range.

Importantly, an elevated PSA can occur in a number of benign conditions, and a PSA result in the normal range does not rule out the possibility of prostate cancer. The differential diagnosis of an elevated PSA includes both transient (eg, prostatitis, perineal trauma) and persistent causes (eg, BPH). These causes, as well as mechanisms to assess and sometimes limit their impact on PSA measurement, are described separately. (See "Measurement of prostate-specific antigen", section on 'Causes of an elevated serum PSA'.)

These issues limit the specificity of an elevated PSA level, particularly among males with LUTS [6].

PSA levels may also be reduced by the use of some medications, especially 5-alpha-reductase inhibitors, limiting sensitivity for diagnosing prostate cancer. (See "Measurement of prostate-specific antigen", section on 'Medications'.)

Issues related to measurement of PSA and recommendations regarding PSA screening for prostate cancer are discussed in detail separately. (See "Measurement of prostate-specific antigen" and "Screening for prostate cancer", section on 'Approach to screening'.)

Repeating the PSA — Prior to urologic referral, we repeat an elevated or increased PSA test in a few weeks to confirm that the level remains elevated. If modifiable factors that can temporarily raise PSA are present (long-distance bicycle riding, ejaculation within 48 hours of the test), these factors should be addressed prior to repeating the PSA. If the repeated PSA is within the normal expected values for age and is not increased more than 0.75 ng/mL compared with the prior year value, no further evaluation is necessary, unless there is a palpable nodule, induration, or asymmetry on DRE.

Studies have found considerable variability in PSA results over the short term and in year-to-year comparisons. One-third of patients will have a decrease to baseline levels if PSA is repeated a month or so later, even in the absence of any treatment (eg, use of antibiotics for prostatitis). A retrospective analysis of stored serum from 972 males found substantial year-to-year fluctuations with 44 percent of males with a PSA above 4.0 ng/mL having normal PSA findings at subsequent annual visits [7-9]. (See "Acute bacterial prostatitis".)

Some factors (eg, long-distance bicycle riding, ejaculation within 48 hours of the PSA assay) may lead to transient elevations in the serum PSA [10-12]. Some benign factors can raise PSA persistently (eg, BPH), rather than transiently. Even if benign factors that can elevate PSA are present, urologic evaluation is still warranted. (See 'Who needs referral?' below.)

Digital rectal examination — On physical examination, DRE may detect prostate nodules, induration, or asymmetry that can occur with prostate cancer. However, prostate cancer is often not detectable by DRE because DRE can only detect tumors in the posterior and lateral aspects of the prostate gland, which are the portions of the prostate that are palpable via the rectum. Tumors not detected by DRE include the 25 to 35 percent that are not reachable because they occur in other parts of the gland and the small, stage T1 cancers that are not palpable (table 1). (See "Initial staging and evaluation of males with newly diagnosed prostate cancer", section on 'Staging system'.)

Many males have symmetric enlargement and firmness of the prostate. These findings are more frequent in males with BPH rather than cancer of the prostate. Notably, BPH and prostate cancer may coexist. (See "Clinical manifestations and diagnostic evaluation of benign prostatic hyperplasia".)

DRE is generally not recommended as a routine screening test for evaluation of the prostate or rectal area in the absence of symptoms (urinary or rectal). However, when an abnormality suggestive of prostate cancer is detected on DRE, further evaluation is warranted. (See 'Urologic evaluation' below.)

UROLOGIC EVALUATION

Who needs referral? — Males who have a clinical suspicion for prostate cancer either because of a high prostate-specific antigen (PSA) or an abnormal digital rectal examination (DRE) should be referred for urologic evaluation. Males with a known genetic predisposition to developing prostate cancer (eg, those with a pathogenic variant in a cancer predisposing gene such as BRCA2) should also be referred to urology for recommendations about screening. (See "Genetic risk factors for prostate cancer", section on 'Screening implications of increased genetic risk'.)

The objective of urologic evaluation is to determine whether a prostate biopsy is warranted, whether additional testing may obviate the need for biopsy at the time, and the appropriate timing for reevaluation. (See 'Signs' above.)

Decision to biopsy — Results of PSA testing, DRE, and any adjunctive tests and imaging are used to inform the clinical likelihood for harboring significant disease and thus guide the decision about whether a biopsy is needed to obtain tissue for histologic diagnosis. (See "Prostate biopsy".)

After shared decision making with the patient, we usually proceed to biopsy if:

●Life expectancy is at least 10 years (some contributors will perform a biopsy if life expectancy is >5 years)

And

●PSA is elevated above the range for the patient's age cohort, or PSA has increased more than 0.75 ng/mL over one year, or there is a palpable concerning abnormality on DRE

Not pursuing prostate biopsy, even if PSA is elevated or increased, may be appropriate in older patients or patients who have significant comorbidities that limit their life expectancy when the patient's goals are aligned with less aggressive diagnostics and interventions.

For males whose PSA is elevated but does not meet the above thresholds, urologic evaluation may include certain adjunctive PSA tests or prostate imaging in an attempt to better estimate the likelihood of prostate cancer.

●Potential adjunctive laboratory testing – Examples of adjunctive laboratory testing for equivocal PSA results include:

•PSA density – PSA density is determined by comparing the PSA level with the prostate size, measured typically by transrectal ultrasound (TRUS) or by prostate magnetic resonance imaging (MRI). PSA is expressed by both benign and malignant prostate tissue. Thus, an elevated PSA level may be more worrisome in a small prostate than in a larger-volume prostate in which higher levels of PSA may be expected. PSA density <0.15 ng/mL/cc is considered favorable. (See "Measurement of prostate-specific antigen", section on 'PSA density'.)

•Free or bound PSA – Free PSA can be measured and used to calculate the ratio of free to total PSA (f/t PSA). Prostate cancer is associated with a lower percentage of free PSA in the serum as compared with benign conditions. An f/t PSA <10 to 15 percent is highly suspect for prostate cancer, whereas an f/t PSA >25 percent is highly likely to be due to benign prostate hyperplasia (BPH). F/t PSA ratios are of most value when deciding whether a repeat biopsy is necessary in an older patient who has a prior negative biopsy, but a PSA level that is still suspicious. (See "Measurement of prostate-specific antigen", section on 'Serum free and bound PSA'.)

•Other tests, including molecular and genomic analysis – We do not suggest, for general use, the multiple other PSA-related analyses (eg, p2PSA) or other urine and blood-based molecular and genomic methods developed to attempt to increase the accuracy of PSA testing, including the 4K score, the Prostate Health Index (PHI), SelectMDx, PCA3, or EPI [13]. While these tests may provide information that is complementary to PSA and PSA density as well as MRI findings, there is no consensus about the ultimate clinical utility of these tests; however, some experts do use them. The tests are described in detail separately. (See "Measurement of prostate-specific antigen", section on 'Advances in PSA testing'.)

●Imaging – Prostate MRI is increasingly being used as an adjunctive tool in refining risk status for clinically meaningful prostatic disease and to inform decisions for performing biopsies. The role of MRI in prostate cancer is discussed in detail elsewhere. (See "The role of magnetic resonance imaging in prostate cancer", section on 'Initial presentation with no prior biopsy'.)

MRI can be used to image the prostate and help determine a need for biopsy. It is used more commonly for this purpose in Europe and Australia but is increasingly being used in the United States. A normal MRI does not rule out a clinically significant prostate cancer but makes it less likely. MRI is used more commonly as part of a fusion biopsy technique to allow targeting of specific areas or in patients with known prostate cancer on surveillance. (See "The role of magnetic resonance imaging in prostate cancer", section on 'Prostate imaging reporting and data system (PI-RADS)'.)

TRUS is often used to evaluate abnormalities detected on DRE. However, even if TRUS does not show concerning findings, prostate biopsy is warranted if indicated based on other factors (eg, PSA results or DRE) because TRUS misses a substantial number of tumors [14,15]. Cancers typically appear hypoechoic, but some may be hyperechoic or isoechoic, leading to false negative studies. (See "Prostate biopsy", section on 'Ultrasound'.)

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) scanning is become more widely available in the United States and is more sensitive and specific than other PET scan techniques to detect soft tissue and distant metastases. Local disease within the prostate can be demonstrated on PSMA PET in some cases. However, imaging with PSMA PET is not currently used to diagnose local disease or to direct prostate biopsy. (See "Initial staging and evaluation of males with newly diagnosed prostate cancer", section on 'PET imaging using PSMA-based radiotracers'.)

Use of adjunctive laboratory testing to inform the decision to biopsy varies among experts, including among contributors to this topic, and some contributors use MRI more frequently than others.

Attempts have been made to create risk models to determine the likelihood of prostate cancer based on multiple variables (eg, PSA, age, family history, DRE result, prostate volume, previous negative biopsies, PSA velocity, free PSA). A meta-analysis concluded that some models improved the predictive value of PSA for detecting prostate cancer, with areas under the receiver operating characteristic curve (AUC) ranging from 0.66 to 0.79 [16]. Only one model was used to predict clinically significant (high-grade) cancer, with an overall AUC 0.71 (95% CI 0.67-0.75); however, estimates showed a high degree of heterogeneity. Until such models have undergone additional study for clinical effectiveness, we do not recommend using them to inform the decision to biopsy. A diagnostic strategy involving blood-based risk prediction combined with MRI-targeted biopsy has also been evaluated [17].

Biopsy technique — A transrectal biopsy is typically performed with imaging guidance (ie, TRUS or MRI). MRI targeting may be performed with initial biopsy and is a common practice in the United Kingdom, Australia, and the United States. After a negative biopsy with TRUS, if there is ongoing concern because of further increase in PSA or abnormalities on examination, a repeat biopsy with MRI targeting increases the cancer detection rate. MRI-targeted prostate biopsy is being evaluated as a method to improve accuracy, either alone or used with TRUS to do a MRI/US-fusion biopsy [18,19]. The use of imaging to guide biopsy is described separately. (See "The role of magnetic resonance imaging in prostate cancer", section on 'Clinical applications' and "The role of magnetic resonance imaging in prostate cancer", section on 'Elevated serum PSA with a prior negative TRUS biopsy' and "Prostate biopsy", section on 'Transrectal biopsy'.)

The transrectal route for biopsy remains the most common, but transperineal biopsy is being performed increasingly. The transperineal route may require more sedation or anesthesia than the transrectal route but is associated with a lower risk of infection. (See "Prostate biopsy", section on 'Anatomic approaches'.)

MRI targeting may be considered to facilitate the diagnosis, with some experts recommending that biopsy may be avoided if the MRI is normal. If the MRI shows an abnormality, the use of registration or fusion software can allow a lesion targeted on MRI to be identified again during a later TRUS-guided biopsy procedure, and this may improve the accuracy of biopsy.

The techniques involved in prostate biopsy, including preparation, extent of sampling, and complications, are discussed separately. (See "Prostate biopsy".)

DIAGNOSIS

Nonmetastatic disease — The diagnosis of prostate cancer requires histologic examination of tissue obtained on prostate biopsy. Prostate cancer cannot be diagnosed on the basis of a prostate-specific antigen (PSA) result, physical examination, adjunctive laboratory testing, imaging studies, or symptoms.

A biopsy may show prostate cancer, precancerous, or benign findings. Histologic features and interpretation of a prostate biopsy are described separately. (See "Interpretation of prostate biopsy", section on 'Histologic features'.)

If the biopsy indicates prostate cancer, architectural patterns of the cells in the biopsy specimen are used to generate a primary and secondary Gleason score that is then used to define the grade group, a five-tier grading system for prostate cancer (GRADE groups from 1 to 5 (table 2)), which correlates with prognosis and is used to determine treatment approaches for localized disease based on risk stratification (table 3). (See "Interpretation of prostate biopsy", section on 'Gleason grading system' and "Localized prostate cancer: Risk stratification and choice of initial treatment".)

The biopsy may indicate a precancerous histologic finding. Clinical implications of precancerous results on prostate biopsy are described separately. (See "Precancerous lesions of the prostate: Pathology and clinical implications".)

A prostate biopsy that does not show cancer does not exclude the possibility of prostate cancer. The biopsy may indicate benign findings even if prostate cancer is present because a prostate biopsy uses a sampling technique with a substantial potential for missing cancerous tissue, even when imaging is used to guide biopsy. Thus, repeat biopsy may be indicated if the PSA level increases further, or if findings on digital rectal examination or prostate imaging warrant rebiopsy. This is described in detail separately. (See "Interpretation of prostate biopsy", section on 'Issues related to sampling error' and "Prostate biopsy", section on 'Patient follow-up'.)

Metastatic disease — Individuals who present with symptomatic metastatic disease with a metastatic pattern typical for prostate cancer (ie, bone metastases) and an elevated PSA usually do not need a prostate biopsy. For patients presenting with de novo metastatic disease, if confirmation of the diagnosis is clinically indicated, this can generally be obtained from histologic examination of a biopsy specimen from a metastatic focus, which is less invasive than a transrectal ultrasound (TRUS)-guided prostate biopsy. The evaluation of prostate cancer that initially presents after becoming metastatic to bone is described separately. (See "Bone metastases in advanced prostate cancer: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Prostate cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Prostate cancer screening (PSA tests) (The Basics)" and "Patient education: Prostate cancer screening (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical presentation

•The clinical behavior of prostate cancer ranges from a screen-detected, asymptomatic, microscopic, well-differentiated tumor that may never become clinically significant to the rarer, screen-detected or clinically symptomatic, aggressive, high-grade cancer that can cause metastases, morbidity, and death. (See 'Spectrum of disease at detection' above.)

•Most prostate cancers are diagnosed in the localized stage and are asymptomatic. Uncommonly, prostate cancer may present with nonspecific lower urinary tract symptoms (LUTS), or more rarely, hematuria, hematospermia, or bone pain. For most males, LUTS are usually due to nonmalignant conditions. (See 'Symptoms' above.)

•Prostate-specific antigen (PSA) is the most commonly used and most valuable test for early detection of prostate cancer. The likelihood of prostate cancer increases with more elevated PSA values, although there is no specific numerical threshold that accurately determines the presence of prostate cancer. PSA testing in a man without a history of prostate cancer is most often done for screening purposes, but testing is sometimes performed as part of an evaluation of symptoms. (See 'PSA testing' above.)

If the PSA is elevated, decision making about who needs further evaluation (ie, urologic referral) is based on the patient's PSA result, as well as the prior year's PSA, if available. Some contributors to this topic evaluate further if the PSA is above the upper value for the age range, whereas others evaluate if the PSA is above the midpoint. We also evaluate if the PSA increased by more than 0.75 ng/mL in one year, even if the PSA value is not above the age-specific range.

Prior to urologic referral, we repeat an elevated or increased PSA test in a few weeks to confirm that the level remains elevated. If modifiable factors that may temporarily raise PSA are present (eg, recent ejaculation, long-distance bicycle riding), these factors should be addressed prior to repeating the PSA. (See 'Repeating the PSA' above.)

•Prostate cancer may also be suspected in patients who have an abnormal digital rectal examination (DRE). Although DRE is not recommended for screening, if DRE is performed, asymmetry, nodularity, or induration raise suspicion for prostate cancer. (See 'Digital rectal examination' above.)

●Urologic evaluation

•Individuals who have a clinical suspicion for prostate cancer either because of a high PSA or an abnormal DRE should be referred for urologic evaluation. The objective of urologic evaluation is to determine whether a prostate biopsy is warranted, whether additional testing may obviate the need for biopsy at the time, and the appropriate timing for reevaluation. (See 'Who needs referral?' above.)

•After shared decision making with the patient, biopsy may be warranted if the patient has a life expectancy of at least 10 years (some contributors biopsy if life expectancy is >5 years) and one of the following: an elevated PSA above the range for the patient's age cohort; an increase in the PSA of more than 0.75 ng/mL over one year; or a nodule, induration, or asymmetry on DRE. If the PSA results are equivocal, adjunctive testing (eg, PSA density, PSA doubling time, MRI) can be useful to better estimate the likelihood of prostate cancer. If the patient has significant comorbidities that limit life expectancy, a prostate biopsy to evaluate for the possibility of asymptomatic prostate cancer is usually not warranted. (See 'Decision to biopsy' above.)

●Diagnosis – The diagnosis of prostate cancer requires histologic examination of tissue obtained on prostate biopsy. Individuals who present with symptomatic metastatic disease usually do not need a prostate biopsy, and a metastatic focus is typically biopsied to confirm the diagnosis, if clinically indicated. (See 'Diagnosis' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Philip Kantoff, MD, who contributed to an earlier version of this topic review.

We are saddened by the death of Nicholas Vogelzang, MD, who passed away in September 2022. UpToDate gratefully acknowledges Dr. Vogelzang's role as Section Editor on this topic, and his dedicated and longstanding involvement with the UpToDate program.