Correspondence *Department of Radiology, 2nd Floor, Rockefeller Outpatient Pavilion, Memorial Sloan-Kettering 53rd Street, 160 East 53rd Street, New York, NY 10022, USA

Email gersts@mskcc.org

The case

A 59-year-old man on exogenous androgen-replacement therapy was found to have a serum PROSTATE-SPECIFIC ANTIGEN (PSA) level of 3.4 ng/ml during a routine outpatient follow-up appointment with his urologist. The patient had a negative review of systems and was asymptomatic. He was otherwise healthy, with no history of serious illness. Digital rectal examination revealed induration of the left side of the prostate, mid-gland to apex, with a palpable firm nodule at the left apex. The patient was clinically staged as T2a.

Ultrasound-guided biopsy revealed prostate adenocarcinoma in three out of six cores with GLEASON SCORE 7 (4 + 3) tumor in the left mid and apical cores. The predominant tumor volume was in the left apex, where 70% of submitted cores were involved.

The patient had a baseline CT examination and bone scan which were unremarkable for evidence of metastatic disease. The patient then underwent ENDORECTAL MRI (with concomitant surface phased-array coil imaging) for more precise tumor staging, with a plan to proceed to laparoscopic prostatectomy pending the MRI findings. MRI revealed extensive tumor, predominantly within the anterior gland, which was not palpable on clinical examination, as well as the diffuse apical tumor (Figure 1A). In addition, there was evidence of tumor extension beyond the gland, including anterior invasion through the fibromuscular stroma, and anterior and superior extension into the bladder neck (Figures 1B and 1C). Right obturator adenopathy was also noted (Figure 1D), in addition to borderline enlargement of left external iliac and subcentimeter perivesicular nodes.

Figure 1 MRI scans of the prostate obtained before treatment start.

(A) Baseline axial T2-weighted image demonstrating a low-signal area of tumor within the apex and posterolateral gross extracapsular extension. (B) Axial T2-weighted image demonstrating tumor invasion into the left bladder neck and posterolateral bladder wall. (C) Coronal T2-weighted axial image demonstrating tumor involving the bladder wall. (D) Baseline axial T1-weighted image demonstrating right obturator adenophathy (outlined in box). t, tumor; ^*, bladder lumen.

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Urine cytology was performed and was negative. Subsequent cystoscopy revealed extrinsic mass effect compressing the left bladder neck, with suspected invasion. Bladder-neck biopsy confirmed a poorly differentiated adenocarcinoma of prostate origin (Figure 2A) with positive immunohistochemical studies for PSA and PROSTATIC ACID PHOSPHATASE (Figure 2B). The tumor cells were negative for high-molecular-weight keratin 34bE12 and cytokeratins CK7 and CK20, which are typical of urothelial carcinoma.

Figure 2 Histopathology of the prostate.

(A) Photomicrograph taken from a biopsy of the bladder neck, showing a poorly differentiated neoplasm with a solid growth pattern, rare gland formation, marked nuclear pleomorphism and prominent nucleoli. (B) Immunohistochemistry results: the tumor cells are immunoreactive with prostate-specific antigen and prostatic acid phosphatase. The tumor cells are negative for high-molecular-weight keratin 34bE12 and cytokeratins CK7 and CK20.

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Prostatectomy was subsequently canceled, and the patient received neoadjuvant hormonal therapy with oral bicalutamide and leuprolide by intramuscular injection, followed by consolidative radiation therapy with INTENSITY-MODULATED RADIATION THERAPY (IMRT) at a total dose of 81 Gy. Subsequent endorectal MRI examinations 12 months later showed a marked decrease in prostate tumor volume and near-resolution of the bladder-neck involvement (Figures 3A–3C). The adenopathy had also resolved (Figure 3D).

Figure 3 MRI scans of the prostate obtained following radiation and hormonal therapy.

(A) Marked reduction in tumor volume with associated poor zonal anatomy. (B) and (C) Near-resolution of the tumor involving the bladder neck. (D) Interval resolution of the adenopathy.

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Discussion of diagnosis

Initial diagnosis

There will be an estimated 232,000 cases of prostate cancer diagnosed in the US in 2005, with over 30,000 deaths due to the disease.¹ Although prostate cancer is predominantly found in older men, routine PSA screening has increased the detection of tumors in younger men, and permitted detection of cancers that are indolent or nonlethal, and at a lower stage.² The American Cancer Society currently recommends that all men aged 50 and older, or those aged 45 or older who are of African descent or have a history of a first-degree relative with prostate cancer, should undergo annual serum PSA screening and digital rectal examination.³ These should only be performed after discussion of the benefits and limitations of testing. Transrectal ultrasound is typically performed in men whose PSA density (PSA value divided by gland volume) is greater than 0.15, or whose test results are abnormal, with subsequent biopsy of any detectable or palpable lesions.⁴ Dysuria, diminished stream, hematuria or painful ejaculation might all be associated with prostate cancer; however, patients are often asymptomatic, and similar symptoms might be associated with benign prostatic hyperplasia or prostatitis.

Although the patient's age at the time of diagnosis and comorbidities affect their prognosis, staging by clinical and imaging examinations, Gleason score, overall tumor volume and PSA levels together provide the most important prognostic indicators. Currently, a modified tumor-node-metastasis staging system is used for prostate cancer in the US (Tables 1 and 2).⁵ Patients with organ-confined disease have the best prognosis after radical prostatectomy, followed by those with extracapsular extension (ECE), extension to the seminal vesicles, or nodal involvement. Current guidelines for staging and work-up before definitive therapy are also under investigation. The US National Comprehensive Cancer Network provides regularly updated guidelines for practice in oncology, available either online or in CD-ROM format (Figure 4). For men whose life expectancy is less than 5 years and who are asymptomatic, no further work-up is required unless the patient is deemed at high risk. High-risk patients include those in whom complications such as hydronephrosis or metastasis can be expected to occur within 5 years without therapy.⁷ For all other patients, current recommendations vary; bone scan and pelvic CT or MRI are suggested for those with serum PSA >20 ng/ml or Gleason score 8, or for stage T3 or T4 disease. In addition, nomogram tables have been developed to predict disease recurrence, so that patients can be better counseled about their therapeutic options. At our institution, we routinely utilize a nomogram that is readily available to clinicians and patients on our institutional website for guidance after initial staging and work-up before beginning definitive therapy, or proceeding with observation and follow-up.⁸

Figure 4 National Comprehensive Cancer Network guidelines.

This figure has been reproduced with permission The NCCN 1.2005 Prostate Cancer Guideline, The Complete Library of NCCN Clinical Practice Guidelines in Oncology [CD-ROM]. Jenkintown, Pennsylvania: © National Comprehensive Cancer Network, May 2005. The most recent and complete version of the guideline can be seen online.⁷ These Guidelines are a work in progress that will be refined as often as new significant data becomes available. The NCCN Guidelines are a statement of consensus of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN guideline is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. These Guidelines are copyrighted by the National Comprehensive Cancer Network. All rights reserved. These Guidelines and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN.

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Table 1 Tumor-node-metastasis staging system for prostate cancer.

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Table 2 Histopathologic grades for prostate cancer.

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This patient had a Gleason score of 7 (4 + 3) and a palpable tumor, as well as three positive biopsy cores. Therefore, endorectal MRI with concomitant surface phased-array coil imaging was performed for further evaluation of the tumor stage. The importance of the number of positive biopsy specimens has been previously emphasized in studies involving patients with intermediate risk for pT3 tumors.⁹ An endorectal MRI could therefore be justified for this patient. At our institution, endorectal MRI has become routine practice in the preoperative staging work-up for patients with elevated PSA, a palpable abnormality, multiple positive biopsy cores or a Gleason score of 6 or higher. Independent variables are also considered, including the patient's age, a history of first-degree relatives with prostate cancer, and comorbidities. An elevated PSA with negative biopsy results often prompts a confirmatory MRI scan to localize discrete peripheral-zone lesions or anterior, nonpalpable, transition-zone lesions. We typically use focused small-field-of-view axial, coronal and sagittal T2-weighted sequences without fat saturation, covering the entire prostate and seminal vesicles, as well as a larger-field-of-view axial T1-weighted sequence through the entire pelvis to evaluate for adenopathy. Additional MR spectroscopy has also been used with increasing frequency at our institution, as diminished citrate and elevated choline levels—resulting in an increased ratio of choline to citrate—have been shown to increase the sensitivity and specificity of detection of prostate cancer.¹⁰ Elevated ratios of choline plus creatine to citrate have also been described, as well as other metabolic alterations. In general, endorectal MRI should be delayed until at least 3 weeks after biopsy to improve staging accuracy and to avoid suboptimal imaging from post-biopsy hemorrhage.¹¹

Treatment and management

Current treatment strategies for prostate carcinoma include surgery, radiation therapy, adjuvant hormonal therapy, or watchful waiting. Despite attempts to establish a 'gold standard', the increased detection of prostate carcinoma, including tumors that might be nonlethal and those earlier in stage, has led to more complex treatment choices. Younger patients without serious medical illnesses are more likely to die of prostate cancer, and are therefore offered more definitive treatments than older patients or those with comorbidities. Recent reports in the literature have suggested that, particularly in younger patients, there might be a reduction in disease-specific and overall mortality, as well as a reduced risk of metastasis and local progression when radical prostatectomy is performed, as opposed to watchful waiting.¹² For patients pursuing definitive therapy, radical prostatectomy with pelvic-lymph-node dissection is typically reserved for those in whom the evidence suggests organ-confined disease, as well as negative bone scintigraphy; although it might also be offered to patients whose endorectal MRI results suggest possible local extension or ECE of the tumor, but show no evidence of pelvic adenopathy. Surgery and radiation therapy are both associated with significant side effects, including sexual and urinary dysfunction, and surgery carries the additional risk of morbidities that are associated with any operative procedure and general anesthesia.

Radiation therapy, including conventional external-beam or three-dimensional conformal radiotherapy and implanted brachytherapy seeds, also has morbidity risks. These include cystitis and acute urinary retention, proctitis, urethral stricture, enteritis and sexual dysfunction. IMRT shows significant promise as a more targeted therapeutic approach, maximizing the radiation dose to the tumor while minimizing the dose to surrounding healthy tissues.¹³

Hormonal therapy focuses on androgen deprivation or lowering serum testosterone, with side effects including impotence, hot flashes, and loss of libido. Gynecomastia and a negative psychologic impact are also considerations. Neoadjuvant hormonal therapy can be combined with radiation therapy; however, recent data suggest that long-term androgen deprivation of greater than 6 months' duration, combined with three-dimensional conformal radiation therapy, might increase the risk of radiation-related morbidity.¹⁴

Neoadjuvant hormonal therapy, followed by IMRT, was utilized in treating this patient. Subsequent endorectal MRI demonstrated a marked response to therapy within the first 12 months of treatment (Figures 3A–3C). Although imaging follow-up remains standard for those with more advanced disease, serum PSA is also typically monitored to evaluate recurrence, utilizing both the absolute value and PSA doubling time, or rate of rise. Guidelines for assessing post-treatment PSA failure have been issued by the American Society for Therapeutic Radiology and Oncology (ASTRO);¹⁵ however, calculation of the patient's absolute PSA nadir value and the characterization of local recurrence are two important issues which must be addressed when using these guidelines to assess disease recurrence.¹⁶ A short PSA doubling time (<3 months) or persistently elevated PSA might signify either persistent active disease or recurrence.¹⁷ In addition, hormonal therapy might suppress PSA levels despite the presence of viable tumor. Prostate biopsy, with confirmatory endorectal MRI in the case of positive results, has been advocated within 24–36 months for patients whose PSA level never drops to <1 ng/ml after radiation therapy, or for patients whose serum PSA rises.¹⁶

This patient's serum PSA level has shown a progressive decrease, most recently measured at 0.10 ng/ml. Any subsequent rise in PSA might warrant a repeat biopsy with confirmatory MRI. In the case of local tumor recurrence without adenopathy, the possibility of salvage radical cystoprostatectomy with pelvic-lymph-node dissection might be considered.

Conclusion

This case demonstrates the value of endorectal MRI of the prostate in the initial staging and work-up of prostate cancer. In this patient with a palpable tumor and Gleason score 7 (4 + 3) disease in at least three cores obtained by transrectal-ultrasound-guided biopsy, the MRI findings (of tumor extension into the bladder and lymphadenopathy) provided substantial and valuable information that altered the patient's management. At most academic centers, endorectal MRI has become routine practice in the work-up for patients with multiple positive cores, markedly elevated PSA, high Gleason score, or other indications of aggressive or advanced disease. This case provides an example in which the current guidelines from the National Comprehensive Cancer Network were not strictly adhered to, and the patient's work-up was individualized.

Endorectal MRI was performed in this patient as part of tumor staging. It has been the experience at our institution that endorectal MRI, particularly when combined with MR spectroscopy, can provide additional valuable information for the diagnosis and management of this disease.

Prostate cancer screening, staging and management protocols remain topics of much debate, and undergo continuous evaluation and review. Routine PSA screening accounts for the observed increase in the incidence of prostate cancer as well as the overall downward stage migration. The combined use of continuously updated guidelines, predictive nomograms, and future methods to help separate indolent from more aggressive tumors will refine current recommendations.

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Subject areas under which this article appears: Prostate cancer | Imaging and radiology