Genitourinary Sarcoidosis

8. RIU0419_07-13.qxd 7/13/09 8:00 PM Page 108 CASE REVIEW Genitourinary Sarcoidosis Pravin K. Rao, MD, Edmund S. Sabanegh, Jr, MD Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH Genitourinary involvement of sarcoidosis can mimic many common urologic conditions. Although sarcoidosis is a benign inflammatory condition, it can present much like malignant or infectious conditions; thus, failed diagnosis can lead to unnecessary medications or surgical procedures. In addition, management choices for patients with scrotal findings have important implications for future fertility. Thus, this uncommon condition should be on the differential diagnosis for any urologic patient. The authors report on a patient with a scrotal mass as his presenting symptom of sarcoidosis and review the diagnosis, implications, and management of sarcoidosis involving all potential sites in the urinary tract. [Rev Urol. 2009;11(2):108-113] © 2009 MedReviews®, LLC Key words: Sarcoidosis • Genitourinary • Scrotal mass • Urology crotal masses comprise a wide differential diagnosis. Although the vast majority of isolated epididymal masses are benign, solid testicular masses in adults are generally considered malignant until proven otherwise. Benign sarcoid lesions can occur in the testis, epididymis, or any other scrotal structure. In fact, sarcoidosis can involve many organs of the genitourinary (GU) system, commonly masquerading as other, more common conditions, including malignancy and infection. S 108 VOL. 11 NO. 2 2009 REVIEWS IN UROLOGY 8. RIU0419_07-13.qxd 7/13/09 11:06 PM Page 109 Genitourinary Sarcoidosis We present a patient with a scrotal mass as his presenting manifestation of sarcoidosis. This is followed by a concise review of the diagnosis and management of sarcoidosis, and a review of the limited literature available specifically pertaining to sarcoidosis of the GU tract. Finally, we provide initial management recommendations for each GU site of disease. Case Report A 42-year-old African American man presented with a 1-month history of a stable, painless area of swelling in his right hemiscrotum. Past medical history included psoriasis and dyslipidemia. For these conditions his treatments had included methotrexate, acitretin, calcipotriene, folate, and phototherapy. There was no history of any past surgery. He had no other complaints, and results from a review of systems were normal. He was in a monogamous relationship, did not use any tobacco, alcohol, or illicit drugs, and denied any history of genitourinary infections, including sexually transmitted diseases. He did state that he and his wife were trying to conceive a child. On physical examination, the scrotal skin was normal. The patient had bilateral descended, nontender testes of normal size and consistency. No intratesticular lesions were palpable, but there was a distinct mass in the right epididymal head that was 2 cm in diameter and did not transilluminate. The spermatic cord was normal without clinical varicocele or hernia. Findings from the rest of the physical examination were normal, including in the cardiorespiratory system. Scrotal ultrasound revealed an enlarged and hyperemic right epididymis, as well as a focal rounded hypoechoic noncystic 5-mm nodule in the right testicle (Figure 1). Testicular cancer markers, including fetoprotein, lactate dehydrogenase, and  human chorionic gonadotropin, were all normal. Options for management, including surgical exploration, were reviewed, but the patient refused any intervention. Within 1 month the patient complained that the epididymal mass was enlarging. He also reported a monthlong history of a steadily worsening nonproductive cough with nasal congestion. Results on physical examination remained unchanged, but a chest radiograph revealed bilateral hilar and mediastinal lymphadenopathy associated with interstitial changes Figure 1. Ultrasound images of right scrotal contents. Left images show enlarged, hyperemic right epididymis. Right upper and lower images show testicular mass and varicocele, respectively. in the lower lung zones. Computed tomography of the chest showed a 2.4-cm node in the right peritracheal region, as well as subcarinal, hilar, and retrocrural lymphadenopathy. There were no foci of cavitation or consolidation. A pulmonary consultation was obtained, and the patient underwent transbronchial biopsies and bronchoalveolar lavage (BAL) with cultures. Pathologic evaluation showed nonnecrotizing granulomas (Figure 2). Results from Ziehl-Neelsen stain (for acid-fast organisms) were negative, as were results on cultures and stains of BAL samples. On the basis of the biopsy, evaluation, and clinical presentation, the patient was diagnosed with sarcoidosis. The patient was given inhaled steroids for his pulmonary symptoms and then was initiated on oral prednisone with methotrexate as a steroid-sparing agent. Follow-up chest radiograph after 6 months of treatment showed nearly complete resolution of the hilar lymphadenopathy. However, his physical examination showed progression of his epididymal masses, and his right testicle was firm. It was recommended that the patient follow up within 2 weeks Figure 2. Histopathologic examination of lung biopsy showing non-necrotizing granuloma amidst normal alveoli. VOL. 11 NO. 2 2009 REVIEWS IN UROLOGY 109 8. RIU0419_07-13.qxd 7/13/09 5:58 PM Page 110 Genitourinary Sarcoidosis continued with a repeat tumor markers evaluation and scrotal ultrasound. He was again counseled for surgical exploration, but he refused any further intervention. Sarcoidosis Basics Sarcoidosis is a chronic disorder of unknown etiology that is characterized by the development of lesions in multiple organ systems that histopathologically demonstrate noncaseating granulomas. The condition generally nonspecific and may include hepatomegaly, superficial lymphadenopathy, and subcutaneous nodules or reactive erythema nodosum. In the setting of a high clinical suspicion of sarcoidosis and normal results on chest radiograph, gallium-67 scanning may aid in detection by accumulating in areas of inflammation.5 Sarcoidosis remains a diagnosis of exclusion. Before a definitive diagnosis can be made, multiple other condi- The suspicion of sarcoidosis usually results from an incidental chest radiograph finding of bilateral hilar lymphadenopathy, which is present in 90% of sarcoidosis patients. affects 1 to 6 of every 1000 people worldwide, whereas the incidence in the United States is approximately 1 in 10,000.1 African Americans are affected at a rate 3- to 20-fold higher than whites, and women are affected approximately 10 times as frequently as men.2,3 The suspicion of sarcoidosis usually results from an incidental chest radiograph finding of bilateral hilar lymphadenopathy, which is present in 90% of sarcoidosis patients.4 Although most patients are asymptomatic, the most common presenting symptoms include dyspnea, cough, chest pains, and weight loss. Eightyfour percent of patients present with intrathoracic conditions5; however, an analysis of patients with sarcoidosis predicted that 30% of patients might actually present with extrapulmonary disease.6 In cases of extrapulmonary disease, clinical presentation usually relates to the organ systems involved, which can include the skin, liver, spleen, eyes, lymph nodes, central nervous system, salivary glands, mucosae, joints, heart, bone marrow, muscles, and kidneys.7 Unless a patient has specific complaints, physical examination findings are 110 VOL. 11 NO. 2 2009 tions that can share similar symptomatology and pathologic findings must be ruled out. These include tuberculosis, syphilis, sperm granuloma, filarial granuloma, lymphogranuloma venereum, granuloma inguinale, blastomycosis, coccidioidomycosis, actinomycosis, schistosomiasis, and Wegener’s granulomatosis.8 Certain tests can help rule out other diagnoses or can raise the suspicion of sarcoidosis. Staining of pathologic tissues with Gomori’s methenamine silver, Kinyoun’s acid-fast stain, and Warthin-Starry stain can be used to rule out fungi, acid-fast bacilli, and spirochetes, respectively.9 Laboratory test findings that are suggestive of sarcoidosis include hypercalcuria (which is found more commonly than hypercalcemia) and elevated levels of angiotensin-converting enzyme (ACE) and/or interleukin-2. Elevated ACE levels are nonspecific for sarcoid disease and can also be seen with diabetes, silicosis, cirrhosis, or hypersensitivity pneumonitis.7 Parathyroid hormone levels are often low or low normal. The etiology of sarcoidosis remains unclear. Certain human leukocyte antigen subtypes have been associ- REVIEWS IN UROLOGY ated with the disease, but there have been no causal relationships defined. In addition, infectious agents including Mycobacterium tuberculosis and human herpes virus (subtype 8) have been implicated as etiologic factors.10 However, a definitive relationship has yet to be established. GU Manifestations of Sarcoidosis Genitourinary involvement of sarcoidosis is relatively uncommon, occurring in less than 0.2% of all clinically diagnosed cases, but it can occur in myriad sites (Table 1).11 In a study of 60 patients with reproductive tract involvement of sarcoidosis, the disease involved the epididymis in 73%, testis in 47%, spermatic cord in 8%, and the prostate in 3%.5 Rarely, the disease can cause scrotal and penile skin lesions or renal masses.10,12 Sarcoid disease can affect metabolic function through 2 main mechanisms that concern the urologist. First, sarcoidosis alters calcium balance, leading to nephrolithiasis in 10% of patients.12 In addition, rarely the sarcoid disease replaces normal suprarenal gland tissue, causing adrenal insufficiency.13 Epididymal sarcoid, the most frequently involved GU site of sarcoidosis, Table 1 Sarcoidosis: Genitourinary Organs of Involvement, in Decreasing Order of Incidence 1. Epididymis 2. Testis 3. Vas deferens 4. Prostate 5. Other scrotal or external genitalia 6. Kidney 7. Bladder 8. Adrenal 8. RIU0419_07-13.qxd 7/13/09 5:58 PM Page 111 Genitourinary Sarcoidosis usually presents as a unilateral painless mass, although bilateral masses may be present. Although these masses often regress with steroid treatment, these lesions can also develop or progress during steroid treatment.1 Tumors in the epididymis can also cause obstructive azoospermia that may be reversible with steroid administration.14 Possible findings on scrotal ultrasound include epididymal enlargement and/or heterogeneity.15 In equivocal cases of epididymal involvement, T2-weighted magnetic resonance imaging (MRI) may reveal a high signal intensity area on a background of normal epididymal tissue.5 Sarcoidosis of the testicle typically occurs in 20- to 40-year-old African American men.16 Ironically, this is the same age group most affected by testicular cancer; this condition, however, affects predominantly white men.17 Testicular sarcoid is usually associated with sarcoid disease in the epididymis, but may also be found as isolated testicular disease. Patients with testicular manifestation of sarcoidosis usually present with a nodu- solid tumor malignancies.18 However, it has been suggested that sarcoid reactions might occur as part of the body’s response to certain tumors and are not, in fact, the initiating event for neoplasm. Tumor-related sarcoid reactions have been found to occur in 4% of patients with sarcoma and with higher frequency in lymphoma patients.19 Interestingly, in patients with sarcoid and certain concomitant malignancies, sarcoid reactions are 4 times as likely to be found in tumorcell–free lymph nodes than in nodes containing malignant cells.19 Simultaneous testicular cancer and sarcoidosis have been demonstrated in multiple reports. A review of published cases in 1998 found 49 reported patients with testicular malignancy and sarcoidosis.19 Interestingly, in 37 of these patients the sarcoidosis was diagnosed on follow-up of testicular cancer, suggesting that it might have developed as a reaction to testicular malignancy. Rayson and colleagues20 found that among patients seen at the Mayo Clinic over a 46-year span, the incidence of sarcoidosis among patients with testicular cancer was more The unclear relationship between malignancy and sarcoidosis has been a cause for much debate with regard to the management of testicular masses in sarcoidosis. lar, diffuse, and painless mass in 1 testicle. On ultrasound examination, these masses most commonly appear as hypoechoic lesions,15 although they can also be hyperechoic. On MRI, they exhibit low signal intensity on T2-weighted images and enhance with contrast on T1 images.15 The unclear relationship between malignancy and sarcoidosis has been a cause for much debate with regard to the management of testicular masses in sarcoidosis. Sarcoidosis does confer an increased risk of lymphoproliferative disease and some than 6 per 10,000—approximately 100 times the baseline incidence observed in young white men. The details of the etiology and frequency of this association remain unknown.12 Sarcoidosis can also manifest as other scrotal masses, including granuloma of the vas deferens or scrotal skin. However, these are quite rare, and little is known about sarcoidosis of these sites. Urinary stone disease occurs in approximately 10% of sarcoidosis patients.12 In up to 4% of sarcoidosis patients, nephrolithiasis is the initial or only cause of symptoms.6,7 Hypercalcemia with or without hypercalcuria is due to the acquisition of  hydroxylase activity in mononuclear cells within sarcoid granulomas.21 This activity allows for increased conversion of vitamin D from its inactive to active form. Subsequently, an increased level of 1,25 dihydroxyvitamin D3 promotes bone resorption and intestinal absorption of calcium.12 Sarcoid-induced changes in calcium metabolism can also cause nephrocalcinosis with subsequent renal impairment, even in the absence of renal granulomas. Renal insufficiency develops slowly, and approximately 33% of patients will have changes of granulomatous interstitial nephritis with renal sarcoidosis.21 In the setting of interstitial nephritis, contrast imaging of affected kidneys can sometimes produce a characteristic striated nephrogram.15 A less-common renal manifestation of sarcoidosis is that of an apparent renal mass. On imaging, renal sarcoidosis can mimic lymphoma, but the differential diagnosis includes tuberculosis as well as primary or metastatic renal cancer.21 Treatment The treatment of sarcoidosis largely depends on its severity. Most patients will see spontaneous resolution of the disease within 2 years.19 However, for patients with unresolving sarcoidosis, severe or acute symptoms, or disease affecting function of a major organ system, medical treatment is usually initiated. In general, corticosteroids ameliorate radiographic, symptomatic, and metabolic manifestations of disease.12 Ketoconazole has also shown potential to lower vitamin D and calcium levels in patients with abnormalities of calcium metabolism.12 For sarcoidosis of the genitourinary tract, considerations of malignancy and fertility must also be considered. Because of the unpredictable nature VOL. 11 NO. 2 2009 REVIEWS IN UROLOGY 111 8. RIU0419_07-13.qxd 7/13/09 5:58 PM Page 112 Genitourinary Sarcoidosis continued of epididymal involvement, a screening semen analysis is recommended on diagnosis of sarcoidosis in patients concerned with future fertility, with a low threshold for repeat tests or sperm banking before or during treatment. In the setting of severe oligospermia or azoospermia, pulsed steroid therapy may allow improvement in sperm counts by causing regression of obstructive epididymal granulomas.14 Primary epididymal tumors are almost universally benign, so epididymal involvement of sarcoidosis does not require an aggressive diagnostic approach. The principal concerns pertain to patient symptoms and fertility. In addition to a screening semen analysis and possible sperm banking, proper documentation of size and location should be made with physical risk of malignancy than epididymal masses. In light of the possible etiologic link between testicular cancer and sarcoidosis, all patients with a testicular mass and sarcoidosis should Because sarcoidosis is a benign and usually self-limited condition, its management is often much different from that of most primary genitourinary conditions. be strongly encouraged to undergo an inguinal exploration. Whereas some advocate orchiectomy for all patients with unilateral masses,1,16 others believe that radical orchiectomy should be reserved for diffuse testicular disease, indeterminate pathologic findings, or failed organ preservation.4 At a minimum, an exploration with intraoperative ultrasound, biopsies, and When testicular sarcoid involvement is suspected, the paramount goals are ruling out malignancy and protecting the patient’s fertility if future conception is desired. examination and scrotal ultrasound. Subsequently, excisional biopsy should be considered if the mass causes bothersome symptoms or is unresponsive to medical treatment. When testicular sarcoid involvement is suspected, the paramount goals are ruling out malignancy and protecting the patient’s fertility if future conception is desired. Primary testicular masses carry a much higher should be considered. If bilateral masses are present or if a mass does not respond to medical treatment of sarcoidosis, then biopsy should be performed. frozen-section analysis should be performed to rule out malignancy. We believe that both are acceptable approaches and that the risk factors for malignancy as well as the patient’s desires for future pregnancies should guide the diagnostic and treatment approach. Although sarcoidosis much more rarely causes an apparent renal mass on imaging studies, malignancy Conclusions Although involvement of the GU tract is rare in sarcoidosis, it can occur in nearly any site. Because sarcoidosis is a benign and usually self-limited condition, its management is often much different from that of most primary genitourinary conditions. For this reason, it is important to consider it in the differential diagnosis for many urologic lesions. The management of lesions in the GU tract should consider many factors, including risk of malignancy, response to medical treatment, tolerance for surgery, and fertility status. References 1. 2. 3. 4. 5. Wong JA, Grantmyre J. Sarcoid of the testis. Can J Urol. 2006;13:3201-3203. Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med. 2007;357:2153-2165. Naseem S, Lindley R, Mufti GR. Testicular sarcoid. Urol Int. 2001;67:100-101. Massarweh NN, Bhalani VK, Shaw KK, et al. Testicular presentation of sarcoidosis and organ preservation: case report and review of management strategies. Urology. 2006;67:200. Kodama K, Hasegawa T, Egawa M, et al. Bilateral epididymal sarcoidosis presenting without radiographic evidence of intrathoracic lesion: review Main Points • Sarcoidosis can affect any organ of the genitourinary tract. • Sarcoidosis can mimic many conditions that require aggressive or invasive treatments. • Sarcoidosis is generally a self-limited condition, and it is most commonly treated conservatively with anti-inflammatory medications. • Although sarcoidosis is rare in the genitourinary tract, it should commonly be on the differential diagnosis in urologic conditions. 112 VOL. 11 NO. 2 2009 REVIEWS IN UROLOGY 8. RIU0419_07-13.qxd 7/13/09 5:58 PM Page 113 Genitourinary Sarcoidosis 6. 7. 8. 9. 10. 11. of sarcoidosis involving the male reproductive tract. Int J Urol. 2004;11:345-348. Rizzato G. Extrapulmonary presentation of sarcoidosis. Curr Opin Pulm Med. 2001;7:295-297. Darabi K, Torres G, Chewaproug D. Nephrolithiasis as primary symptom in sarcoidosis. Scand J Urol Nephrol. 2005;39:173-175. Rudin L, Megalli M, Mesa-Tejada R. Genital sarcoidosis. Urology. 1974;3:750-754. Vahid B, Weibel S, Nguyen C. Scrotal swelling and sarcoidosis. Am J Med. 2006;119(11):e3. McLaughlin SS, Linquist AM, Burnett JW. Cutaneous sarcoidosis of the scrotum: a rare manifestation of systemic disease. Acta Derm Venereol. 2002;82:216-217. Ricker W, Clark M. Sarcoidosis: a clinicopathologic review of 300 cases, including 22 autopsies. Am J Clin Pathol. 1949;19:725-749. 12. 13. 14. 15. 16. Matlaga BR, Assimos DG. Urologic manifestations of nonurologic disease urolithiasis. Urol Clin North Am. 2003;30:91-99. Vaughan ED, Blumenfeld JD. Pathophysiology, evaluation, and medical management of adrenal disorders. In: Campbell MF, Wein AJ, Kavoussi LR, Novick AC, eds. Campbell-Walsh Urology. Vol 2. 9th ed. Philadelphia: W.B. Saunders; 2007:1821-1867. Svetec DA, Waguespack RL, Sabanegh ES Jr. Intermittent azoospermia associated with epididymal sarcoidosis. Fertil Steril. 1998;70: 777-779. Koyama T, Ueda H, Togashi K, et al. Radiologic manifestations of sarcoidosis in various organs. Radiographics. 2004;24:87-104. Singer AJ, Gavrell GJ, Leidich RB, Quinn AD. Genitourinary involvement of systemic sar- 17. 18. 19. 20. 21. coidosis confined to testicle. Urology. 1990;35: 442-444. Daniels JL Jr, Stutzman RE, McLeod DG. A comparison of testicular tumors in black and white patients. J Urol. 1981;125:341-342. Brincker H. Coexistence of sarcoidosis and malignant disease: causality or coincidence? Sarcoidosis. 1989;6:31-43. Tjan-Heijnen VC, Vlasveld LT, Pernet FP, et al. Coincidence of seminoma and sarcoidosis: a myth or fact? Ann Oncol. 1998;9:321-325. Rayson D, Burch PA, Richardson RL. Sarcoidosis and testicular carcinoma. Cancer. 1998;83: 337-343. Mizunoe S, Yamasaki T, Tokimatsu I, et al. Sarcoidosis associated with renal masses on computed tomography. Intern Med. 2006;45: 279-282. VOL. 11 NO. 2 2009 REVIEWS IN UROLOGY 113