Bilateral Testicular Infarction and Orchiectomy as a Complication of Polyarteritis Nodosa
Case Review
RIU0366_12-12.qxd 12/12/07 8:37 PM Page 235 CASE REVIEW Bilateral Testicular Infarction and Orchiectomy as a Complication of Polyarteritis Nodosa Sean P. Stroup, MD, Shannon R. Herrera, MD, Donald S. Crain, MD Department of Urology, Naval Medical Center San Diego, San Diego, CA We report an unusual case of a 28-year-old male with constitutional symptoms and bilateral testicular pain. After diagnosis of cytomegalovirus (CMV) hepatitis, his constitutional symptoms and testicular pain worsened despite treatment for epididymoorchitis. Ultrasound was concerning for infarction. Exploration in the operating room revealed bilateral testicular infarction requiring bilateral orchiectomy with subsequent androgen hormone replacement. Pathologic diagnosis was polyarteritis nodosa (PAN). PAN is a rare systemic vasculitis that affects multiple organs. There are no previous reports of PAN-induced vasculitis leading to bilateral testicular infarction and bilateral orchiectomy. [Rev Urol. 2007;9(4):235-238] © 2007 MedReviews, LLC Key words: Testicular infarction • Polyarteritis nodosa • Androgen replacement therapy olyarteritis nodosa (PAN) is a rare, systemic vasculitis that results in necrotizing inflammation of small- and medium-sized arteries. PAN may affect multiple organs, including the skin, kidneys, and gastrointestinal tract as well as the peripheral and central nervous systems.1 Testicles are involved in 38%-86% of cases but are generally asymptomatic.2 The need for orchiectomy is rare. We report an unusual case of a 28-year-old male who presented with constitutional symptoms and bilateral testicular pain. Exploration in the operating room after failure of antibiotic therapy for presumed epididymitis and worsening P VOL. 9 NO. 4 2007 REVIEWS IN UROLOGY 235 RIU0366_12-12.qxd 12/12/07 8:37 PM Page 236 Bilateral Testicular Infarction continued ultrasound findings revealed bilateral testicular infarction requiring bilateral orchiectomy. The pathologic diagnosis was polyarteritis nodosa (PAN). No reports of PAN-induced vasculitis resulting in bilateral testicular infarction and orchiectomy are found in the current literature. Case Presentation and Management A 28-year-old Latino male presented to the emergency department with a 10-day history of chills, night sweats, headaches, arthralgias, fevers to 104° F, and weight loss of 10 pounds. After admission, his symptoms progressed with diffuse joint pain and swelling involving elbows, knees, wrists, and ankles. Additionally, he developed a maculopapular rash over lower extremities. He had no significant past medical or surgical history, no allergies, and no recent travel, alcohol abuse, or tobacco use. He had previously fathered one child and had no history of sexual dysfunction. On examination, he was tachycardic with a heart rate of 110 beats per minute, had tender cervical lymphadenopathy, faint bilateral scleral icterus and hepatosplenomegaly with a mildly tender right upper quadrant abdominal exam, and a liver edge 3 cm below the costal margin. Initial laboratory evaluation included a white blood cell count of 4.0 K/L (84% neutrophils), a hemoglobin of 11.1 g/dL, and 141 K/L platelets. Urine analysis indicated 1520 white blood cells per high-power field and mild proteinuria. Serum chemistries were normal except for a creatinine of 1.3 mg/dL. Modest elevation in serum aminotransaminases was apparent with an alkaline phosphatase of 235, ALT 533, and AST of 323. Other studies included an erythrocyte sedimentation rate of 57 mm/hr, Creactive protein of 17.9 mg/dL (normal 0 to 0.8 mg/dL), and negative HIV, 236 VOL. 9 NO. 4 2007 RPR, and GC/Chlamydia probe. Hepatitis titers indicated adequate immunization for hepatitis A and hepatitis B; he was hepatitis B surface antibody negative. Coccidioides, Epstein Barr virus, and parvovirus serologies were also negative. Vancomycin and ceftriaxone were started initially and discontinued once cultures remained negative. Empiric prednisone was also started, and his myalgias and arthralgias improved, with complete resolution of his maculopapular rash. Cytomegalovirus (CMV) titers eventually indicated acute infection with concomitant elevation in liver function studies consistent with CMV hepatitis. One week later, while recovering in another location, he had new onset of bilateral testicular pain. A duplex ultrasound indicated increased vascular flow and was consistent with a Figure 1. Gross photograph showing thrombosis of spermatic cord and testicular vessels with bilateral testicular infarction. Pathologic analysis confirmed bilateral testicular ischemia and necrotizing vasculitis with thrombosis consistent with a diagnosis of PAN. Cross-sections of the spermatic cord indicated thrombosis of the spermatic artery and veins (Figure 1), and microscopy confirmed ischemic necrosis of the testicle (Figures 2 and 3). Polyarteritis nodosa is a rare autoimmune systemic vasculitis leading to necrotizing inflammation of small- and medium-sized arteries. diagnosis of bilateral epididymoorchitis. Upon return to our institution several days thereafter, he had worsening constitutional symptoms. He was started on broad-spectrum antibiotics and intravenous ganciclovir due to confirmed CMV infection. Repeat testicular ultrasound at admission demonstrated a diffuse hypoechoic and heterogenous appearance to both testes as well as bilateral absence of blood flow. He was taken to the operating room for exploration; no evidence of torsion was found, and intraoperative Doppler ultrasound confirmed absence of blood flow to both testes. Based on gross inspection and incision of the tunica and seminiferous tubules, which showed only coagulated blood throughout and no demonstrable bleeding, bilateral orchiectomy was performed. REVIEWS IN UROLOGY Androgen replacement therapy was initiated immediately and consisted of daily application of 50 mg of 1% testosterone transdermal gel. Discussion PAN is a rare autoimmune systemic vasculitis leading to necrotizing inflammation of small- and mediumsized arteries. PAN was first described by Kussmaul and Maier in 1866 and has been known to affect multiple areas, including the skin, kidney, gastrointestinal tract, and peripheral and central nervous systems. In 1990, the American College of Rheumatology established 10 criteria for the diagnosis of PAN in a patient with vasculitis (Table 1). Testalgia unrelated to trauma or infection is important in these criteria. PAN may be diagnosed if 3 out of 10 criteria are present with RIU0366_12-12.qxd 12/12/07 8:37 PM Page 237 Bilateral Testicular Infarction Figure 2. Low-power view showing vasculitis and thrombosis affecting a vessel within the spermatic cord (hematoxylin-eosin, original magnification 40). Figure 3. High-power view of inflammatory cells and thrombosis within the testicle, (hematoxylin-eosin, original magnification 400). a sensitivity and specificity of 82% and 87%, respectively.3 Retrospectively, our patient appears to have had only 2 of these 10 criteria, including testicular pain not due to infection or trauma and diffuse myalgias and weakness of leg muscles. He did present with 5-7 lbs of weight loss, but this did not quite meet criteria for PAN. When suspicion is high and the testicles are viable, biopsy may be used to confirm diagnosis. In this case, however, ultrasound did not indicate viability of the testicles, which was confirmed intraoperatively. Progression to infarction and need for orchiectomy are rare, and the need for bilateral orchiectomy as a result of PAN has not been previously reported. In autopsy studies, the kidneys are the most commonly involved organ. Renal involvement frequently leads to renal infarctions, insufficiency, and hypertension. Rupture of renal arterial aneurysms can cause perirenal hematomas. Affected ureters can occasionally stricture and obstruct. Testicular involvement is reported in 38%-86% of those with PAN, based on autopsy studies, but only 2%-18% of patients are symptomatic.2,4 Epididymitis, orchitis, and pain from ischemia are common presentations for PAN, whereas isolated testicular involvement as the initial site of PAN and bilateral infarction are less common.5 Several studies have reported testicular masses suspicious for tumor that have proven to be PAN.6 Fraenkel-Rubin and colleagues described limited PAN of the reproductive system affecting the testicles of a 26-year-old man and the adnexa and uterus of a female.1 Untreated patients have a high mortality of 30% at 1 year and 88% at 5 years. The cornerstones of current therapy are cyclophosphamide and prednisone with a 5-year survival of nearly 80%.7 Table 1 American College of Rheumatology Criteria for the Classification of Polyarteritis Nodosa • Weight loss of greater than 4 kg • Livedo reticularis • Testicular pain or tenderness that is not due to infection, trauma, or other causes • Diffuse myalgias or weakness of muscles or tenderness of leg muscles • Mononeuropathy, multiple mononeuropathies, or polyneuropathy • Hypertension (with diastolic blood pressure 90 mm Hg) • Elevation of BUN ( 40 mg/dL) or creatinine ( 1.5 mg/dL) • Presence of HBAg or HBsAb in serum • Arteriogram demonstrating aneurysms or occlusions of the visceral arteries not due to noninflammatory causes • Biopsy of small-sized or medium-sized artery containing granulocytes VOL. 9 NO. 4 2007 REVIEWS IN UROLOGY 237 RIU0366_12-12.qxd 12/12/07 8:37 PM Page 238 Bilateral Testicular Infarction continued The pathogenesis of PAN is poorly understood. Most cases are idiopathic but may be associated with immune complex deposition, especially in the 7%-10% of cases associated with hepatitis B infection.8 Only a limited number of case reports describe association between CMV infection and PAN. Inflammation of the affected vessel wall leads to intimal proliferation, luminal narrowing, and reduced blood flow, and predisposes to thrombosis of affected vessels. Arterial bifurcations are most commonly affected. Inflammation may also lead to aneurysm formation with resultant life-threatening bleeding. Other processes leading to testicular infarction in the absence of trauma and torsion include infection and other vasculidities. Severe nonresolving epididymitis has been implicated in many unilateral cases and one bilateral case of testicular infarction.9 Henoch-Schönlein’s purpura is another hypersensitivity vasculitis that commonly affects the skin (palpable purpura), gastrointestinal tract, joints, kidneys, and, occasionally, the testes. It usually affects children and may be difficult to distinguish from testicular torsion if testes are involved. Androgen replacement therapy was started immediately after orchiectomy to maintain secondary sex characteristics and muscle strength, prevent osteoporosis, and maintain overall well-being.10 A number of testosterone preparations are available in the marketplace. Intramuscular injections of esterified testosterone preparations (enanthate and cypionate) have been used for many years to treat hypogonadism. Other preparations include buccal tablets and transdermal patches and gels. We generally recommend transdermal testosterone gel to most hypogonadal men because it produces normal serum testosterone concentrations, and most patients find it convenient. Among those using gel or patches, initial dosing is 50 mg per day, but dosing can be adjusted to reach therapeutic levels. During the first few months after the initiation of testosterone replacement therapy, some undesirable effects of normal puberty, such as acne and gynecomastia, can be seen. Because prostate cancer is thought to be testosterone dependent, hypogonadal men should be screened for prostate cancer before beginning testosterone replacement and monitored for prostate cancer during treatment. Vasculitidies may present as testicular pain. Careful clinical examination is needed to evaluate for these rare presentations. Early treatment with steroids and immunosuppressive agents may impact disease course. This case illustrates the diagnostic challenges of polyarteritis nodosa and strategies for postoperative management of hypogonadism. Acknowledgments: Thanks to Dr. Aaron Huber for providing pathologic images. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the US Government. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Fraenkel-Rubin M, Ergas D, Sthoeger ZM. Limited polyarteritis nodosa of the male and female reproductive systems: diagnostic and therapeutic approach. Ann Rheum Dis. 2002;61:362-364. Teichman JM, Mattrey RF, Demby AM, Schmidt JD. Polyarteritis nodosa presenting as acute orchitis: a case report and review of the literature. J Urol. 1993;149:1139-1140. Lightfoot RW Jr, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum. 1990;33:1088-1093. Dahl EV, Baggenstoss AH, Deweerd JH. Testicular lesions of periarteritis nodosa, with special reference to diagnosis. Am J Med. 1960;28:222-228. Susanto CR, Fedder G, Looijen-Salamon MG. Acute, painful, and swollen testicle as the presenting feature in polyarteritis nodosa. Eur J Intern Med. 2003;14:441-443. Huisman TK, Collins WT Jr, Voulgarakis GR. Polyarteritis nodosa masquerading as a primary testicular neoplasm: a case report and review of the literature. J Urol. 1990;144:1236-1238. Gayraud M, Guillevin L, le Toumelin P, et al. Longterm followup of polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: analysis of four prospective trials including 278 patients. Arthritis Rheum. 2001;44:666-675. Guillevin L, Lhote F, Cohen P, et al. Polyarteritis nodosa related to hepatitis B virus. A prospective study with long-term observation of 41 patients. Medicine (Baltimore). 1995;74:238-253. Bird K, Rosenfield AT. Testicular infarction secondary to acute inflammatory disease: demonstration by B-scan ultrasound. Radiology. 1984; 152:785-788. Snyder PJ, Peachey H, Berlin JA, et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab. 2000;85:2670-2677. Main Points • Pathologic diagnosis was polyarteritis nodosa (PAN). PAN is a rare systemic vasculitis that affects multiple organs. • Testicular involvement is reported in 38%-86% of those with PAN, based on autopsy studies, but only 2%-18% of patients are symptomatic. • Vasculitidies presenting as testicular pain require careful clinical examination. Early treatment with steroids and immunosuppressive agents may impact disease course. • Androgen replacement should be started immediately after development of an anorchic state to maintain secondary sex characteristics, muscle strength, prevent osteoporosis, and ensure overall well-being. 238 VOL. 9 NO. 4 2007 REVIEWS IN UROLOGY