Correspondence *Department of Uro-Neurology (Internal Box 71), The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK

Email snd999@gmail.com

The case

A 38-year-old West Indian man who was the father of one child, presented with a 3-month history of bilateral testicular swelling, night sweats and weight loss. His past medical history included mild asthma, and cessation of smoking 1 year previously. He had a parental history of renal failure. His primary-care physician prescribed three courses of antibiotics, with some improvement in symptoms, but persistent testicular swelling remained.

He was referred to the local urology service, whereupon physical examination revealed multiple, palpable, small scrotal masses arising from the testes, with associated inguinal and cervical lymphadenopathy. An ultrasound examination revealed several small, intratesticular, hypoechoic, space-occupying lesions with high vascularity (Figure 1), although abdominal ultrasonography and chest radiography findings were normal. Relevant blood results are reported in Table 1. Testicular tumor markers including -fetoprotein and -human chorionic gonadotropin were normal. Three early morning urine samples showed no abnormality on microscopy and culture. A CT scan of the chest, abdomen and pelvis revealed pretracheal, hilar, aortocaval, inguinal, iliac and gross para-aortic lymphadenopathies. A Heaf (tuberculin) skin test was negative.

Figure 1 Ultrasound scan of testicle that shows multiple, hypoechoic lesions present within the testicular body

 

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Table 1 The patient's blood-test results at his initial referral to the urology clinic

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The patient underwent left-testicular biopsy through an inguinal incision. The testis biopsy showed florid, well-formed, giant-cell epithelioid granulomata, some of which showed central necrosis (Figures 2 and 3). No acid-fast bacilli were seen when biopsy samples were subjected to special stains, and cultures exhibited no growth of organisms.

Figure 2 Photomicrograph of testicular biopsy specimen

Some normal testicular tubules are present as well as epithelioid granulomata, some of which exhibit central necrosis.

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Figure 3 Photomicrograph of epididymal biopsy specimen that shows a high-power view of an epithelioid granuloma with incipient central necrosis

 

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A diagnosis of tuberculosis was nonetheless made on the basis of the patient's medical history and histologic findings. After consultation with respiratory physicians, he was started on isoniazid 300 mg, pyrazinamide 1800 mg, rifampicin 720 mg and ethambutol 1000 mg daily. After 3 months of this therapy, however, the patient was symptomatically worse and had experienced further weight loss. There were no clinical or objective improvements noted on repeat ultrasound and CT scans, his serum angiotensin-converting-enzyme (ACE) level was 120 U/l (normal range 10–70 U/l), and his calcium levels and erythrocyte sedimentation rate remained elevated.

Antitubercular treatment was discontinued, which resulted in some symptomatic improvement. This lack of response to antitubercular therapy and the elevated serum ACE and calcium levels led to a diagnosis of sarcoidosis; consequently, the patient was started on daily prednisolone 40 mg, alendronic acid 5mg and lansoprazole 30mg with the aim of inhibiting the inflammatory process, reducing granuloma formation and complications from steroid therapy.

Within 1 month, the patient's systemic lymphadenopathy had regressed and his testicular swelling had subsided; both eventually normalized completely. He regained 8 kg, and by 2 months was able to undertake all of his normal activities. Repeat CT and ultrasound scans at 2 months after initial presentation showed complete resolution of all lymphadenopathy and testicular masses. His serum ACE level fell to 28 U/l, well within the normal range. Steroid therapy was tapered to nothing over the following 4 months, and the patient has not experienced any recurrence of sarcoidosis in 3 years of follow-up. The patient was, however, found to be oligospermic at 3 years of follow up.

Discussion of diagnosis

Sarcoidosis is an idiopathic, multisystem disease that is typically characterized by the presence of non-necrotizing epithelioid granulomata. The disease process can affect any organ system, and causes abnormal immune function. In the US, there is a 3.8-fold greater annual incidence of sarcoidosis among black African Americans compared to the white population.¹

As a result of the diversity of signs and symptoms, and the lack of a specific test, the diagnosis of sarcoidosis is dependent on three criteria: typical radiographic findings; histological findings of noncaseous granulomata; and exclusion of all possible alternative diagnoses. Classically, the diagnosis is made by a finding of bilateral hilar lymphadenopathy on a chest radiograph and characteristic findings on biopsy. In the majority of patients with sarcoidosis, disease is localized to the lungs; involvement of the genitourinary tract is rare, and affects only 0.2% of cases.² Cases of sarcoidosis have been misdiagnosed as testicular tumors, and have resulted in orchidectomy.^{3, 4}

In some sarcoid lesions, however, there may be focal necrosis within some of the granulomata, which mimics features usually seen in tuberculosis.⁵ To the best of our knowledge, necrosis within granulomata has not previously been described in sarcoidosis of the testes.

The patient was initially diagnosed with tuberculosis and given antitubercular therapy because of his medical history and the presence of necrotizing granulomata in testicular biopsy samples, but no mycobacteria were either cultured from or detected in biopsy samples when special stains for acid-fast bacilli were used. His lack of response to therapy and clinical deterioration fortunately led to further investigations and a review of the diagnosis of tuberculosis. In this patient with sarcoidosis, morbidity resulted from the delay in final diagnosis and from side effects of the antitubercular therapy. This case highlights the importance of considering sarcoidosis even when biopsies show granulomata with patchy necrosis that mimics tuberculosis.

The differential diagnosis (i.e. tuberculous orchitis without involvement of the epididymis) is rare, because tuberculous orchitis is usually thought to result from a retrograde infection that initially affects the prostate and seminal vesicles. Testicular involvement occurs at an advanced stage of this tubercular infection, and fine-needle aspiration of the testis can be used to confirm this diagnosis.⁶

Treatment and management

A review of the literature on sarcoidosis of the male reproductive tract, published in 2004, identified 60 affected individuals with an average age of 33 years (range 2–67 years). Most (73%) patients were either black or Asian,³ and the most common structure involved was the epididymis. As sarcoidosis of the male reproductive tract most frequently occurs in young, black or Asian patients, sarcoidosis should be considered early in the differential diagnosis of such men who present with a testicular mass and have granulomatous changes that are evident on histology.

Scrotal granulomata can cause inflammation, ductal obstruction and fibrosis that leads to azoospermia,⁷ which might explain the development of oligospermia in this patient. Fertility is of concern in these young men, and can be impaired by the primary disease and also by surgical management. Of the 60 patients with scrotal sarcoidosis reviewed by Kodama et al.,³ 21 were treated with orchidectomy or epididymectomy. Although testicular malignancy is of concern, where there are bilateral lesions or a strong suspicion of sarcoidosis and negative testicular tumor markers, testis preservation should be considered and biopsy only performed to elicit the diagnosis.⁸

In this patient, a rapid clinical response to prednisolone therapy occurred; we speculate that the presence of caseous necrosis within granulomata might potentially be an indicator of a favorable response to steroid therapy.⁹ Previous case reports of scrotal sarcoidosis have also reported good outcomes with steroid therapy, with no requirement to use immunomodulatory drugs.^{4, 10, 11}

Serum ACE may be useful in cases when the differential diagnosis is in doubt, because levels of this enzyme have been reported to be raised in patients with active sarcoidosis but not in those with caseating tuberculosis.¹² This disparity is thought to be related to specific increases in ACE activity in sarcoid nodules.¹³ The clinician must be aware, however, that elevated ACE levels have limited diagnostic value, because this finding is not specific for sarcoidosis. Once the diagnosis of sarcoidosis is confirmed, serial measurement of serum ACE levels (for patients in whom they are initially elevated) is helpful to monitor the patient's response to therapy, and for detection of relapse after cessation of corticosteroids.¹²

MRI has been used to detect sarcoidosis of the epididymis, however, this technique can only detect characteristics of inflammatory change, and is not able to distinguish adequately between benign, malignant and inflammatory lesions.³

Surgery is only required where the diagnosis of sarcoidosis cannot be reliably confirmed, or for persistent pain. Steroid treatment might help to preserve affected patients' fertility, but these men should be advised to undergo semen analysis after sarcoidosis is diagnosed, and should be offered the option of sperm banking if oligospermia is present.⁷

Conclusion

We describe a case of sarcoidosis that presented as testicular granulomatosis with patchy necrosis. The patient was initially misdiagnosed as having tuberculosis, but continued to deteriorate despite antitubercular therapy. Sarcoidosis should, therefore, be included in the differential diagnosis of patients with granulomatous inflammation associated with focal necrosis on biopsy, especially when mycobacteria are not identified in biopsy specimens on acid-fast staining or culture. Testis-preserving surgery should be considered in such cases. This patient responded well to steroid therapy and made a good recovery, but may have developed oligospermia as a consequence of sarcoidosis.

References

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Subject areas under which this article appears: Infections, inflammation and prostatitis