54-Year-Old Woman with Clitoromegaly

CASE SCENARIO 54-Year-Old Woman with Clitoromegaly Joseph A. Veys, MD,* Ryan Payne, BS,† Dean G. Assimos, MD* *Wake Forest University School of Medicine and Department of Urology, Baptist Medical Center, Winston-Salem, NC; † Kansas University Medical Center, Kansas City, KS [Rev Urol. 2004;6(3):161-165] © 2004 MedReviews, LLC CASE REPORT 54-year-old African American woman is referred for evaluation of clitoromegaly. Review of systems is normal. The patient is taking no medications, including exogenous steroids. She does not use alcohol, tobacco, or illicit drugs. Two of her sisters had thyroid goiters; family history otherwise is unremarkable. Physical examination demonstrates a body weight of 198 lb (90 kg), normal vital signs, and no abnormalities except an enlarged clitoris. Complete blood count; blood urea nitrogen, serum creatinine, glucose, and electrolyte levels; and urinalysis are normal. Serum testosterone level is 152 ng/dL (normal, 8–61 ng/dL in postmenopausal women). Serum calcium level is 10.8 mg/dL (normal, 8.5–10.5 ng/dL). Serum intact parathyroid hormone level is 135 pg/mL (normal, 12–72 pg/mL). Serum follicle-stimulating hormone, luteinizing hormone, and prolactin; plasma catecholamine; and adrenocorticotropic hormone levels are normal. Twenty-four-hour urinary excretion of free cortisol and ketosteroids is normal. Chest radiograph, pelvic and thyroid ultrasound studies, and magnetic resonance image (MRI) of the brain are normal. An uninfused computed tomography scan of the abdomen and pelvis demonstrates a 2 cm right adrenal mass with an attenuation coefficient of 5 Hounsfield units. Pertinent MRI images of the adrenal glands are shown in Figures 1 and 2. A Figure 1. T2-weighted, single-shot, coronal image showing a right adrenal mass. Figure 2. Left, T1-weighted in-phase axial image showing a right adrenal mass. Right, T1-weighted, out-of-phase, axial image showing the same adrenal mass. MANAGEMENT OPTIONS Select the best option for the management of this patient: ❑ ❑ ❑ ❑ ❑ 1. 2. 3. 4. 5. Repeat imaging studies in 3 months Dexamethasone suppression test Percutaneous biopsy of the right adrenal gland Right adrenalectomy Bilateral adrenalectomy Vote online at www.medreviews.com; fax your response to MedReviews at (212) 971-4047; or e-mail your selection to dgern@medreviews.com. VOL. 6 NO. 3 2004 REVIEWS IN UROLOGY 161 Case Scenario continued Discussion of Last Issue’s Case Scenario IN THE LAST ISSUE, DRS KELLA AND A 57-year-old man was referred to his urologist after a routine serum prostate-specific antigen (PSA) test revealed a level of 9.4 ng/mL. The patient denied any significant lower urinary tract voiding symptoms. He was sexually potent and denied any family history of prostate cancer. Urine dip analysis showed no evidence of hematuria or urinary tract infection. Digital rectal examination revealed a 30-g prostate without induration or nodularity. Because of the elevated serum PSA level, the patient underwent transrectal, systematic sextant, ultrasoundguided prostate biopsies at an outside urologist’s clinic. The biopsies were sent for pathologic analysis as sitespecifically labeled samples. Of the 6 cores obtained, the right-sided cores at the mid-prostate and apical prostate revealed Gleason 8 (4 + 4) adenocarcinoma. The maximum length of cancer was 6 mm, or 50% of the apical core. Following the biopsy results, computed tomography (CT) of the pelvis and a bone scan demonstrated no evidence of lymphadenopathy or bone metastasis. The patient discussed various options with his urologist, who referred him to us for further evaluation and treatment. After consultation with us, including review of the pathology, which confirmed the original findings, the patient opted for a radical retropubic prostatectomy and bilateral pelvic lymph node dissection. A repeat PSA measurement during his consultation 1 month after the biopsy revealed a level of 15.7 ng/mL, although the results were obtained from a different laboratory and manufacturer’s assay. Tumor SLAWIN PRESENTED THIS CASE REPORT: Table 1 Ultrasensitive Prostate-Specific Antigen (uPSA) Assay Results Date 1/22/2003 Postoperative Day uPSA Level (ng/mL) 42 0.034 3/13/2003 93 0.047 4/29/2003 140 0.057 6/10/2003 182 0.068 markers drawn per a research protocol showed interleukin–soluble receptor and transforming growth factor ß levels of 38.3 ng/mL and 1.1 ng/mL, respectively. An open, mini-incision, left, unilateral, nerve-sparing radical retropubic prostatectomy with contralateral neurovascular bundle resection and sural nerve grafting was performed without complications. Final pathology revealed a Gleason 8 (4 + 4) adenocarcinoma with focal extracapsular extension and negative surgical margins. Lymph nodes were negative (pT3aN0M0). Postoperatively, the patient was monitored with an ultrasensitive PSA assay (uPSA) (Clinical Pathology Laboratories, Austin, Tex, using the Third-Generation Immulite PSA assay, DPC) beginning 6 weeks (42 days) after surgery and every 3 months thereafter. The results are shown in Table 1. THE FOLLOWING QUESTIONS REGARDING PATIENT MANAGEMENT WERE ASKED: The next appropriate step is: 1. 2. 3. 4. 162 Continued observation until uPSA level is greater than 0.2 ng/mL Repeated bone scan, CT scan, and/or indium 111-capromab pendetide immunoscintigraphy (ProstaScint scan) Immediate or delayed androgen deprivation therapy Salvage radiotherapy VOL. 6 NO. 3 2004 REVIEWS IN UROLOGY Case Scenario AUTHOR’S DISCUSSION This case would likely generate passionate debate among urologists, academics, and non-academics alike, with each certain of the superiority of his or her preferred management choice. Furthermore, despite this lack of consensus, the scenario above affects more than 30,000 men per year,1 each faced with an array of choices, opinions, and conflicting advice. Serum PSA levels should rapidly become undetectable and remain so after surgery. The actual level that determines an “undetectable” level is likely to be influenced by both the technique of prostatectomy used and the assay itself. As the quality of PSA assays used in clinical laboratories has improved over the years, the level indicating undetectable PSA after surgery has steadily decreased from less than 0.4 to less than 0.2 to less than 0.1 ng/mL, a level commonly used now by many academic centers to indicate undetectable PSA after surgery. At the Baylor Prostate Center (BPC), we have been using the Third-Generation Immulite PSA assay (DPC) routinely after surgery for over 4 years. Among patients who have undergone surgery at the BPC, the overwhelming majority achieve a PSA level below 0.03 ng/mL within 6 weeks of surgery. PSA levels may fluctuate from visit to visit below this 0.03 ng/mL cutpoint, but the majority of patients who have a PSA level over 0.03 ng/mL either at the 6-week visit or at any point thereafter will experience an inexorable rise in PSA levels, although often at variable rates, as this patient demonstrates. Others have also demonstrated the utility of measuring ultrasensitive PSA (uPSA) values in men after radical prostatectomy.2 Yu and colleagues3 demonstrated that a rising uPSA in the range of 0.001 to 0.1 ng/mL correlated with factors associated with poorer prognosis, such as higher Gleason grade, positive margins, seminal vesicle invasion, and elevated preoperative PSA level. In a separate study, Yu and colleagues4 showed that the use of doubling times of uPSA level in the range below 0.1 ng/mL detected relapse after radical prostatectomy earlier. Haese and colleagues5 also demonstrated earlier detection of recurrence, establishing a nearly 300-day advantage over conventional PSA assays with the use of uPSA assays. However, lowering the cutoff point for undetectable PSA to an ultrasensitive level of 0.03 ng/mL without first performing analogous validation at other centers may lead to a significant number of patients without prostate cancer recurrence receiving a false diagnosis of recurrence. For example, one recent report from a different institution demonstrated that a single PSA elevation of less than 0.4 ng/mL after radical prostatectomy is associated with subsequent stable, nonprogressing disease in up to 50% of patients.6 What is the advantage of detecting a PSA rise after surgery so early in the course of disease? The reasons are becoming more compelling as our knowledge of the natural history of a rising PSA after surgery and the factors that determine response to salvage radiation therapy are becoming clearer. An estimated 65% of men with biochemical failure after radical prostatectomy will have bone metastases within 10 years in the absence of salvage therapy.7 In addition, numerous studies have demonstrated that a high pretreatment PSA level negatively impacts the effectiveness of salvage radiotherapy. Better outcomes with salvage radiotherapy occur when it is administered at the earliest evidence of biochemical recurrence. Once biochemical recurrence has been established, calculation of PSA doubling time (PSADT) can help in the management of recurrent prostate cancer. Shorter PSADT has been shown to be an ominous sign of rapidly aggressive disease recurrence that is more likely to lead to distant metastases and death due to prostate cancer. D’Amico Once biochemical recurrence has been established, calculation of PSA doubling time can help in the management of recurrent prostate cancer. and colleagues8 demonstrated posttreatment PSADT to be significantly associated with time to prostate cancer– specific mortality (P < .001) in a study of more than 8000 men undergoing radical prostatectomy or radiation therapy for prostate cancer. Specifically, a posttreatment PSADT of less than 3 months and the actual value of the posttreatment PSADT when it was 3 months or more were found to be surrogate end points for prostate cancer–specific mortality after surgery or radiation therapy. Our patient’s post-prostatectomy PSA rise from 0.034 to 0.068 ng/mL occurred over a 5-month interval, during which the PSADT was calculated to be 4.63 months. Despite this aggressive feature, a conventional assay with a lower limit of detection of 0.1 ng/mL would have resulted in “undetectable” levels of PSA. Interestingly, the short time frame to a detectable PSA level in the setting of negative surgical margins traditionally has been associated with metastatic disease rather than a local recurrence. With this in mind, our management has often focused on a systemic approach using hormonal therapy. Partin and colleagues9 found that 65% of all VOL. 6 NO. 3 2004 REVIEWS IN UROLOGY 163 Case Scenario continued patients with metastatic disease had PSA recurrence within 12 months of surgery. Patients who had local, biopsyproven recurrences and no evidence of metastasis on bone scan usually had recurrence after 1 year. However, ultrasensitive assays were not used in this study, and it is unclear if the same results would apply to detection of a rise in uPSA level. There appears to be little or no value to additional imaging studies in this setting, as the presumed volume of recurrent or persistent disease is too low and below the sensitivity of these modalities. Raj and colleagues10 investigated the ability of ProstaScint to detect biochemically recurrent prostate carcinoma with low serum PSA levels (mean, 1.1 ng/mL; range, 0.1-4 ng/mL). Nearly 75% of patients demonstrated uptake of the antibody. Almost one third of those with uptake had recurrence only in the prostatic fossa. Patients having recurrence within 1 year of radical prostatectomy had significantly lower rates of local uptake of the ProstaScint antibody, suggesting that early recurrence is more likely to be metastatic. However, certain limitations to ProstaScint exist. Interpretation of scans is highly operator-dependent. The monoclonal antibody currently used is specific for the intracellular prostate-specific membrane antigen (PSMA) in the prostate cancer cells, reducing its effectiveness. Research studies have demonstrated that the ProstaScint scan images primarily dying cells, which allows intracellular access of the imaging antibody.11 Other researchers have questioned ProstaScint’s usefulness. For example, Ponsky and colleagues12 investigated ProstaScint’s ability to predict metastatic lymph node disease preoperatively and found a high false-positive rate and low predictive value. Although recent data on an experimental new imaging antibody directed at the extracellular portion of the PSMA antibody look promising, this technique is not yet clinically available.13 The use of tumor markers transforming growth factor ß (TGF-ß) and interleukin-6–soluble receptor (IL-6sR), measured in blood obtained preoperatively, has demonstrated utility in calculating the risk of recurrence after radical prostatectomy and in distinguishing between local or metastatic disease.14-16 Elevated levels of IL-6sR have been associated with increased local tumor volume and Gleason score, whereas elevated levels of TGF-ß have been associated with invasive and metastatic disease. This patient had an elevated IL-6sR level but a low TGF-ß level before surgery, suggesting that the rise in uPSA level after surgery could be due to persistent or recurrent local disease. Recent data suggest that patients such as this one may benefit from salvage radiotherapy. A multicenter evaluation of more than 500 patients receiving treatment at 5 academic centers identified predictors of response to salvage radio- 164 VOL. 6 NO. 3 2004 REVIEWS IN UROLOGY therapy. For example, in patients receiving early salvage radiotherapy (pretreatment PSA ≤ 2.0 ng/mL), those with moderate-grade disease and a rapid PSADT had 4-year progression-free probabilities (PFPs) of 64% and 22% when the surgical margins were positive and negative, respectively. Patients with high-grade disease with positive margins receiving early salvage radiotherapy had a 4-year PFP of 81% when the PSADT was greater than 10 months and 37% when it was 10 months or less. Patients who received late salvage radiotherapy (pretreatment PSA > 2.0 ng/mL) had an overall 4-year PFP of 20%.17 In a recently submitted follow-up study, a nomogram to predict a durable response to salvage radiotherapy was developed and internally validated (unpublished data). Based on this nomogram, the current patient was told that he Salvage radiotherapy offers the patient a chance for local control of his disease. could expect a 40% biochemical progression-free rate and a 5-year metastasis-free survival rate of 85%. After discussion of this and other options with the patient, including immediate or delayed hormonal therapy, the patient elected to proceed with local salvage radiotherapy, which was initiated 7 months after his initial surgery. His uPSA level dropped to 0.065 ng/mL when measured 2 months after completion of therapy, and his most recent uPSA level was 0.072 ng/mL, 4 months after his radiation treatment. PSADT after salvage therapy with external-beam radiation was calculated to be 15.81 months, indicating a marked reduction in this important surrogate marker for prostate cancer progression and future prostate cancer–specific morbidity and mortality. Although this marked reduction in PSADT may indicate a reduced risk of the development of future metastases, this is unproven and remains an area of investigation. We present a patient with early recurrence detected using an ultrasensitive assay. Recurrences detected as early as this case, with such low levels of serum PSA, are difficult to image for presence of local or metastatic disease. Conventionally, early recurrences have been assumed to be metastatic, especially in the presence of negative surgical margins. However, the treatment of metastatic disease would be hormonal therapy, which has not been proved to provide cure. Salvage radiotherapy offers the patient a chance for local control of his disease. Recent research demonstrates that patients thought destined for development of progressive metastatic disease may achieve a durable response to salvage radiotherapy. Case Scenario References 1. 2. 3. 4. 5. 6. 7. 8. Moul JW. Prostate specific antigen only progression of prostate cancer. J Urol. 2000;163:1632-1642. Ellis WJ, Vessella RL, Noteboom JL, et al. Early detection of recurrent prostate cancer with an ultrasensitive chemiluminescent prostate-specific antigen assay. Urology. 1997;50:573-579. Yu H, Diamandis EP, Wong PY, et al. Detection of prostate cancer relapse with prostate specific antigen monitoring at levels of 0.001 to 0.1 micro g./l. J Urol. 1997;157:913-918. Yu H, Diamandis EP, Prestigiacomo AF, et al. Ultrasensitive assay of prostatespecific antigen used for early detection of prostate cancer relapse and estimation of tumor-doubling time after radical prostatectomy. Clin Chem. 1995;41:430-434. Haese A, Huland E, Graefen M, et al. Ultrasensitive detection of prostate specific antigen in the followup of 422 patients after radical prostatectomy. J Urol. 1999;161:1206-1211. Amling CL, Bergstralh EJ, Blute ML, et al. Defining prostate specific antigen progression after radical prostatectomy: what is the most appropriate cut point? J Urol. 2001;165:1146-1151. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281:1591-1597. D’Amico AV, Moul JW, Carroll PR, et al. Surrogate end point for prostate cancerspecific mortality after radical prostatectomy or radiation therapy. J Natl Cancer Inst. 2003;95:1376-1383. 9. 10. 11. 12. 13. 14. 15. 16. 17. Partin AW, Pearson JD, Landis PK, et al. Evaluation of serum prostate-specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases. Urology. 1994;43:649-659. Raj GV, Partin AW, Polascik TJ. Clinical utility of indium 111-capromab pendetide immunoscintigraphy in the detection of early, recurrent prostate carcinoma after radical prostatectomy. Cancer. 2002;94:987-996. Troyer JK, Beckett ML, Wright GL Jr. Location of prostate-specific membrane antigen in the LNCaP prostate carcinoma cell line. Prostate. 1997;30:232-242. Ponsky LE, Cherullo EE, Starkey R, et al. Evaluation of preoperative ProstaScint scans in the prediction of nodal disease. Prostate Cancer Prostatic Dis. 2002;5:132-135. Bander NH, Trabulsi EJ, Kostakoglu L, et al. Targeting metastatic prostate cancer with radiolabeled monoclonal antibody J591 to the extracellular domain of prostate specific membrane antigen. J Urol. 2003;170:1717-1721. Shariat SF, Andrews B, Kattan MW, et al. Plasma levels of interleukin-6 and its soluble receptor are associated with prostate cancer progression and metastasis. Urology. 2001;58:1008-1015. Shariat SF, Shalev M, Menesses-Diaz A, et al. Preoperative plasma levels of transforming growth factor beta1 (TGF-ß1) strongly predict progression in patients undergoing radical prostatectomy. J Clin Oncol. 2001;19:2856-2864. Kattan MW, Shariat SF, Andrews B, et al. The addition of interleukin-6 soluble receptor and transforming growth factor beta1 improves a preoperative nomogram for predicting biochemical progression in patients with clinically localized prostate cancer. J Clin Oncol. 2003;21:3573-3579. Stephenson AJ, Shariat SF, Zelefsky MJ, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA. 2004;291:1325-1332. VOL. 6 NO. 3 2004 REVIEWS IN UROLOGY 165