Prostate Cancer: Diagnosis and Staging

Prostate cancer is the most common noncutaneous cancer among men,^[1] accounting for an estimated 233,000 new cancer cases (14% of all new cancer cases) in 2014, with an estimated 29,480 cancer deaths in the same year (5% of all cancers).^[2] Therefore, the diagnosis and staging of prostate cancer are critically important. Test your knowledge on the current diagnostic and treatment approaches for prostate cancer. This image shows a transrectal ultrasound study (TRUS) with a hypoechoic area (arrow) along the left peripheral zone of the prostate, which is suggestive of prostate cancer.

The anatomy of the human male is shown. Which of the following statements is false with regard to the human prostate gland?

1. It is located inferior to the bladder and anterior to the rectum.
2. It functions as part of the male reproductive system and aids in the formation of spermatozoa.
3. It consists partly of smooth muscles, which aid in the expulsion of semen during ejaculation.
4. It is homologous to the Skene glands or paraurethral glands found in women.
5. Aside from nonmelanoma skin cancer, cancer of the prostate gland is the second leading cause of cancer-related deaths in American men.

Image courtesy of the National Cancer Institute (NCI).

Answer: B. It functions as part of the male reproductive system and aids in the formation of spermatozoa.

The prostate is a part of the human male reproductive system^[3]; however, spermatogenesis occurs in the seminiferous tubules of the testes.^[3,4] The prostate manufactures approximately 20-30% of the volume of the semen,^[5] and the semen assists in carrying sperm from the testes through the penis during the ejaculatory phase.^[4] In this image, a clinician inserts a gloved and lubricated finger into the rectum during a digital rectal examination (DRE) to palpate the prostate for any unusual lumps or irregularities. A prostate nodule is an indication for biopsy.

Image courtesy of the NCI.

In your clinic, a male patient notices the graphs of estimated prostate cancer cases and deaths (shown). He asks you what the lifetime incidence of prostate cancer is for a male from the general population. Which of the following statistics is your response?

1. Between 1 in 3 and 1 in 5
2. 1 in 5
3. Between 1 in 6 and 1 in 7
4. 1 in 10
5. 1 in 42

Image courtesy of the NCI.

Answer: C. Between 1 in 6 and 1 in 7.

The graph from the previous slide shows the 1990-2010 estimated incidence of and mortality from prostate cancer per 100,000 men per year.^[7] On the basis of 2008-2010 data, in the general male population, the lifetime risk of prostate cancer is about 15.3% (1 in 6.5).^[2] The incidence of prostate cancer increases with age (most common in males aged 65-74 y [36.3%]) and in men with a family history of prostate cancer; black men are also affected more often compared with males of other races (223.9 new cases per 100,000 men). Prostate cancer is the fifth leading cause of cancer death (most common in males aged 75-84 y [37.6%]); death rates are also higher in black men relative to males of other races (50.9 deaths per 100,000 men).^[2]

Image courtesy of the Centers for Disease Control and Prevention (CDC).

A 59-year-old male patient undergoing TRUS is found to have an extensive hypoechoic area (arrows) in the right peripheral zone (shown). Before proceeding further, the clinician discusses the risks and benefits of obtaining a prostate biopsy with him. Which of the following is not a common complication of a prostate biopsy?

1. Fever and pain
2. Hematospermia
3. Hematuria
4. Urinary tract infection
5. All of the above are potential complications.

Answer: E. All of the above are potential complications.

Fever, pain, hematospermia, hematuria, and urinary tract infection are all potential complications of a prostate biopsy.^[8] In TRUS (shown), an ultrasound probe is inserted into the rectum to assess the prostate when prostate-specific antigen (PSA) levels are elevated or irregular nodules are noted on the DRE.^[6] The standard PSA reference range is 0.0-4.0 ng/mL; normal age-specific PSA levels are 0-2.5 ng/mL for age 40-49 years; 0-3.5 ng/mL for age 50-59 years; 0-4.5 ng/mL for age 60-69 years; and 0-6.5 ng/mL for age 70-79 years.^[9] TRUS can also reveal prostatitis and benign prostatic hyperplasia.

Image courtesy of the NCI.

The TRUS-guided prostate biopsy from the patient revealed the histology shown (hematoxylin-eosin, ×300). Two distinct differentiations of prostatic tissues are noticeable when the slide is viewed from the right half to the left. Which of the following Gleason values (or scores) can be attributed to this tissue?

1. Gleason values 1 and 2
2. Gleason values 2 and 3
3. Gleason values 3 and 4
4. Gleason values 4 and 5
5. Gleason values 1 and 3

Image courtesy of the NCI/Otis Brawley, MD.

Answer: C. Gleason values 3 and 4.

The standard approach for grading prostate cancer depends on a Gleason value, which is determined on the basis of the pathologic evaluation of a prostatectomy specimen and is commonly estimated from prostate biopsy tissue.^[10] Prostate cancer patterns are assigned a number from 1 to 5 (well differentiated to very poorly differentiated); the Gleason value is created by adding the scores of the most common pattern grades present to those of the highest-grade patterns present. The histologic features on the previous slide revealed a Gleason value of 3 with moderately differentiated cancer on the right and a Gleason value of 4 with less well-differentiated cancer on the left. The patient's Gleason value is therefore 7 (3 + 4).

Image courtesy of NCI.

An 84-year-old asymptomatic man presents to his doctor for follow-up. A prostate biopsy performed by another physician 1 year ago revealed prostate cancer (Gleason 3 + 3 = 6) in 1 of 12 cores, occupying 5% of the core length. His PSA level is 5.9 ng/mL, essentially unchanged from 1 year ago. The patient denies experiencing any recent health changes. He has no recent urinary complaints, bone pain, or weight loss. His previous medical history consists of congestive heart failure (ejection fraction: 20%), persistent atrial fibrillation, and liver cirrhosis. He currently takes warfarin, metoprolol, aldactone, benazepril, furosemide, and lactulose. He is afebrile; his blood pressure is 132/82 mmHg, and his pulse is 65 beats/min and irregular. The physical examination is otherwise unremarkable. What is the appropriate next step in evaluating this patient?

1. Refer for radical prostatectomy.
2. Obtain a computed tomography (CT) scan of the abdomen.
3. Obtain a bone scan.
4. Repeat TRUS-guided biopsy.
5. Monitor this patient (surveillance).

Image courtesy of Wikimedia Commons.

Answer: E. Monitor this patient (surveillance).

The patient is an older man with multiple medical comorbidities whose life expectancy is likely less than 10 years. The 2012 US Preventive Services Task Force (USPSTF) recommendations note that screening and treatment trials have shown no benefit in men older than 70 years.^[11] The 2014 National Comprehensive Cancer Network (NCCN) guidelines note that very few men older than 75 years benefit from PSA testing; they suggest being cautious with screening tests in men older than 70 years and recommend such testing only in healthy men in this age group who have few or no comorbidities.^[6] The NCCN indicates that clinicians could consider a higher PSA cutoff level (>4 ng/mL) in men older than 70 years who may present with high-risk cancers or a cutoff of 3 ng/mL at 75 years.^[6] The image shows the 2014 NCCN guidelines for early detection of prostate cancer and indications for biopsy.^[6]

Source of image information: NCCN.^[6]

A 63-year-old man presents to his internist with a screening PSA level of 14.2 ng/mL. On DRE, the clinician notices a distinctly irregular prostatic border. Because of the potential for a prostatic malignancy, which of the following is the best next step for diagnosis?

1. Obtain a nuclear medicine bone scan.
2. Obtain an endorectal magnetic resonance image (MRI).
3. Perform TRUS-guided prostate biopsy.
4. Obtain a PSA doubling time.
5. Perform a radical prostatectomy.

Answer: C. Perform TRUS-guided prostate biopsy.

On the basis of the clinical findings, the best next diagnostic step is to obtain a TRUS-guided prostate biopsy.^[6] This TRUS shows the prostate. The hypoechoic lesion, highlighted in blue in the peripheral zone of the gland, is suggestive of cancer. With the development of the PSA screening test in the early 1990s, prostate cancer has been diagnosed earlier in its course.^[12] Prostate cancer is most commonly suspected on the basis of elevations in the PSA screening test and/or abnormalities noted on DRE.^[6,12] Most prostate cancers are diagnosed without any abnormalities on examination.

A 62-year-old asymptomatic man has no past medical history and a smooth-surfaced prostate on DRE. However, his PSA level is 25 ng/mL. TRUS-guided biopsy revealed prostate carcinoma (shown) confined to the prostate with a Gleason value of 8. What is the best next test for this patient?

1. Obtain an MRI.
2. Obtain a CT scan.
3. Obtain a bone scan.
4. Monitor this patient (surveillance).

Answer: C. Obtain a bone scan.

The patient's clinical stage is IIA T1cNXMX, because the tumor was identified by needle biopsy that was obtained because of the high PSA level (>20 ng/mL), and nodal spread and distant metastasis cannot be assessed with the information given.^[10] He also does not have T2, T3, or T4 clinical disease. Therefore, a bone scan is the best next step for staging workup.^[13] The isotopic bone scans shown reveal diffuse metastases and demonstrate a "superscan" appearance (intense symmetric activity in the bones with diminished renal/soft-tissue activity^[14]); note the absence of renal excretion of the radioactive tracer. Almost all prostate cancer patients are initially diagnosed with T1c disease, and almost none have any symptoms related to the prostate or to prostate cancer.^[15]

The table shown lists issues associated with DRE and PSA screening.^[12] Annual PSA screening is common but highly controversial for asymptomatic men older than 50 years. Early surgery or radiation may lead to complications such as impotence, incontinence, and death from infection. Therefore, the USPSTF no longer recommends routine PSA screening.^[11] However, the American Cancer Society recommends that men discuss testing with their clinicians starting at age 50 years if they have an average risk of cancer and have a life expectancy of at least another 10 years (start discussions at age 45 y for high-risk patients: black men, men with a brother/father/son who was diagnosed with prostate cancer before age 65 y).^[12] The American Urological Association (AUA) recommends that men discuss testing with clinicians starting at age 55 years and does not recommend routine PSA screening in men older than 70 years or in any man whose life expectancy is less than 10-15 years.^[16]

Two years ago, a 69-year-old man presented with worsening complaints of urgency, incontinence, nocturia, and weak urinary stream. At that time, his PSA level was 3.3 ng/mL, and he was started on tamsulosin. Finasteride was recently added to help with controlling his symptoms; however, his symptoms persisted. A DRE did not reveal an enlarged prostate or any masses. A suprapubic transvesical prostatectomy was performed. Tissue analysis incidentally revealed prostate cancer in 2% of the prostate tissue with a Gleason value of 4. No lymph node involvement was found. Further imaging did not reveal any metastasis. Which stage is this patient's cancer?

1. Stage I
2. Stage II
3. Stage III
4. Stage IV

Image courtesy of Wikimedia Commons.

Answer: A. Stage I.

Clinicians use prostate cancer staging to not only categorize the risk of the cancer spreading beyond the prostate but also to evaluate the potential for administering local therapies, including surgery and/or radiation.^[3,10,12,17] Staging also employs the Gleason value for grading. In stage I disease, prostate cancer is confined to the prostate. The table shown details the tumor, node, metastasis (TNM) staging system for prostate cancer which evaluates the size of the tumor, involvement of lymph nodes, and the presence of any metastasis.^[3,10,12,17] A tumor that is not clinically apparent is staged T1; a tumor that is confined to the prostate is staged T2; a tumor that extends beyond the prostate capsule is staged T3.^[3,10,12,17]

Prostate cancer is categorized into 4 stages on the basis of the TNM staging system, a patient's PSA level, and the Gleason value, as shown.^[3,10,12,17]

Table adapted courtesy of NCI.

A 74-year-old patient presents to an urgent care clinic complaining about right-sided pelvic pain. He also complains about back pain that has been increasing in severity over the course of the past year. The patient's pelvic radiograph is shown. What type(s) of lesions is (are) evident on this pelvic radiograph?

1. Osteoblastic metastases
2. Sclerotic metastases
3. Osteolytic metastases
4. Both osteoblastic metastases and sclerotic metastases
5. None of the above

Answer: D. Both osteoblastic metastases and sclerotic metastases.

Prostate cancer bony metastasis is common; it presents as multiple osteoblastic lesions, as seen on the previous slide.^[18] Osteolytic prostate metastases can occur as well. Tumors from the prostate, breast, lung, thyroid, and kidney are the cancers that most commonly metastasize to bone.^[18,19] Metastases that present as mixed lytic/sclerotic lesions typically originate in the lung and breast. A radionuclide isotopic bone scan after injection of methylene diphosphonate (MDP) technetium-99m is shown; this is the standard imaging modality used to assess for potential bone metastases from prostate cancer.^[10] Multiple areas of increased radionuclide tracer activity from metastatic prostate cancer are present on this bone scan.

A DRE performed on a 73-year-old man reveals a normal-sized and mobile prostate, but a nodular mass within the borders of the prostate gland is palpable (shown). His PSA level is 15.5 ng/mL. Soon thereafter, he undergoes TRUS, and a biopsy reveals adenocarcinoma of the prostate with a Gleason value of 9. CT imaging does not reveal spread of the cancer outside of his prostate. What is the stage of this patient's prostate cancer?

1. Stage I
2. Stage II
3. Stage III
4. Stage IV

Image courtesy of the NCI.

Answer: B. Stage II.

In stage II prostate cancer (shown), the tumor has advanced and is of a higher grade compared with stage I disease. However, it does not extend beyond the prostate.^[3,10] The tumor can be palpated on DRE, and it can often be seen on TRUS. Stage III disease involves extension of the primary tumor outside of the prostate capsule.^[3,10]

Image courtesy of the NCI.

A 72-year-old man with a PSA level of 18.5 ng/mL undergoes a prostatic biopsy; histopathologic examination reveals prostate cancer with a Gleason value of 7. MRI performed to evaluate for further extracapsular invasion assessed the prostate in three views: (a) an axial T2-weighted image, (b) a coronal T2-weighted image, and (c) a diffusion coefficient map of a diffusion-weighted MRI. A lesion is noted on MRI across the three views (arrows). Definitive surgery shows seminal vesicle invasion by the cancer, but there is no further spread and no distant lymph node involvement. What is the stage of this patient's prostate cancer?

1. Stage I
2. Stage II
3. Stage III
4. Stage IV

Answer: C. Stage III.

The tumor on the previous slide shows a lesion in the left midanterior peripheral zone of the prostate with frank extracapsular extension. Because definitive surgery did not reveal any further extracapsular tumor spread, pathologic staging is T3N0, or stage III. Stage III prostate cancer involves extracapsular invasion that may involve the seminal vesicles but has not spread beyond the seminal vesicles.^[3,10] Stage IV disease (shown on this slide) involves extension of the disease beyond the prostate and seminal vesicles to nearby lymph nodes and/or to nearby structures, such as the bladder, rectum, and pelvic bones.^[3,10]

Image courtesy of the NCI.

A 70-year-old man presents with advanced prostate cancer with diffuse osteoblastic bony metastases (arrows) to the spine, pelvis, and femur, as shown in this anteroposterior abdominal radiograph. Which of the following are common symptoms of advanced or recurrent prostate cancer?

1. Loss of appetite and weight loss
2. Back pain and bony pain (without fractures)
3. Suppression of the bone marrow
4. Compression of the spinal cord
5. All of the above

Image courtesy of Wikimedia Commons.

Answer: E. All of the above

Advanced prostate cancer is often associated with loss of appetite, weight loss, back pain and bony pain (without fractures), suppression of the bone marrow, and compression of the spinal cord.^[20] This CT scan at the level of the kidneys indicates extensive para-aortic lymphadenopathy (arrows) secondary to advanced prostate cancer.