Blastomycosis Presenting with Prostatic Involvement: Report of 2 Cases and Review of the Literature

0022-5347/ 83/ 1301-0160$02.00/ 0 Vol. 130, July

THE JOURNAL OF UROLOGY

Printed in U.S.A .

Copyright© 1983 by The Williams & Wilkins Co.

BLASTOMYCOSIS PRESENTING WITH PROSTATIC INVOLVEMENT: REPORT OF 2 CASES AND REVIEW OF THE LITERATURE TSUYOSHI INOSHITA, GEORGE A. YOUNGBERG, LOUIS J. BOELEN

AND

JAMES LANGSTON

From the Departments of Pathology and Surgery (Urology), East Tennessee State University College of Medicine, Johnson City and Veterans Administration Medical Center, Mountain Home, Tennessee ABSTRACT

We report on 2 patients who presented with prostatic involvement as the first prominent clinical manifestation of systemic blastomycosis. The clinical symptoms of both patients began with dysuria and urinary retention. In 1 patient skin lesions developed 4 weeks later and the initial chest x-ray findings were positive. The other patient became aware of skin lesions concurrently with the urinary symptoms and had negative chest x-ray findings. Successful treatment consisted of amphotericin B in 1 case and ketoconazole in the other case. A review of the literature revealed 8 well documented cases of blastomycosis with the initial presenting symptom of prostatic involvement. A summary of the previously reported cases is presented and the importance of recognition of skin lesions in such patients is stressed. Blastomycosis is a fungal disease caused by Blastomyces dermatitidis. The skin and lungs are affected most frequently and skin lesions as well as pulmonary symptoms, such as cough, chest pain and hemoptysis, are the most frequent causes for seeking medical attention in patients with blastomycosis. 1• 2 Genitourinary involvement also is known to occur, being diagnosed clinically in about 15 to 30 per cent of the cases with systemic blastomycosis. 1• 2 Of 25 patients who died of blastomycosis 14 (56 per cent) had genitourinary involvement on autopsy, according to a review of blastomycosis cases in Veterans Administration Hospitals.1 The genitourinary organs involved in order of frequency are the kidneys, prostate, epididymides, testes, seminal vesicles and bladder. 1 However, it appears that only a small fraction of patients have a genitourinary problem as the first prominent symptom of systemic blastomycosis. Some patients present with scrotal swelling due to involvement of the testes and/or epididymides, while others present with dysuria and urinary retention due to the involvement of the prostate. In 1948 Moore and Halpern reported on 2 patients whose presenting symptoms were due to prostatic involvement. 3 This was apparently the first report of such cases, although they found in the literature 12 instances of prostatic involvement developing during the course of disseminated blastomycosis. Since then, there have been reports of 6 additional well documented cases of blastomycosis with the first prominent clinical manifestation of prostatic involvement. Herein we report 2 cases of blastomycosis. In 1 patient the presenting symptoms were dysuria and frequency of urination, and diagnosis was prostatic blastomycosis. In the other case the initial manifestation of blastomycosis also was prostatitis. In both patients cutaneous manifestations of blastomycosis also developed. Similar cases reported previously are reviewed and the importance of recognition of rather typical skin lesions in these patients with prostatic symptoms is stressed. CASE REPORTS

Case 1. A 43-year-old white man had dysuria, hesitancy and weakness of the urinary stream 2 weeks in duration in May 1969. He was admitted to the Urology Service of the Veterans Administration Medical Center with acute urinary retention. On physical examination the patient was afebrile and the prostate was 3 to 4 times the normal size. Urinalysis showed 35 to 40 white and many red blood cells per high power field. Laboratory tests were unremarkable except for a white blood count Accepted for publication November 5, 1982.

of 15,650/mm. 3 with 90 per cent neutrophils. A chest x-ray revealed ill-defined hazy infiltrations in both apices. A fluctuant area was noted in the prostate 2 weeks later, and incision and drainage were done. The material was sent for routine culture and histological examination. The culture was negative, and the histological material revealed giant cells and was signed out as granulomatous prostatitis. Pustular and then scaly, skin lesions developed on the face, neck, arms, thighs and feet 2 weeks later. A biopsy of 1 of the lesions revealed a granulomatous process with thick-walled yeasts, some of which had a single broad-based bud. A review of the original material from the prostate revealed similar organisms. Blastomycosis was suspected, and subsequent culture of the material from the skin, urine and sputum yielded Blastomyces dermatitidis. The patient responded well to the administration of a total of 1 gm. intravenous amphotericin B during 3 months. He has been well without any recurrence for 13 years. Case 2. A 63-year-old white man had frequency and burning on urination for about 3 weeks in duration, for which he selfprescribed penicillin. He also noticed skin lesions on the hands and buttock. The patient was admitted to the Urology Service of the Veterans Administration Medical Center with the tentative diagnosis of benign prostatic hyperplasia in June 1982. On physical examination the prostate was tender and enlarged. A chest x-ray was clear. Laboratory tests were unremarkable except for numerous white blood cells on urinalysis. More cutaneous lesions appeared on the face, arms, legs and feet (fig. 1). A retropubic prostatectomy was performed and convalescence was uneventful. Histological examination of the prostatectomy specimen revealed a widespread granulomatous reaction with a large number of giant cells and neutrophils within and between the gland spaces (fig. 2). Periodic acid-Schiff and Grocott's methenamine silver stains revealed numerous thickwalled yeasts, some with a single broad-based bud (fig. 2). Two small foci of well differentiated adenocarcinoma were found incidentally. Because of the presence of fungal organisms in the prostate an association between the prostate problem and cutaneous lesions was suspected, and a punch biopsy of 1 of the cutaneous lesions on the left buttock was done. Touch impressions of the specimen stained with hematoxylin and eosin revealed organisms similar to those found in the prostate (fig. 3). Histology of the specimen also revealed such organisms in granulomatous areas (fig. 3). Pus underneath the crust of 1 of the lesions was submitted for culture, which subsequently yielded Blastomyces dermatitidis. The skin lesions were completely resolved after 1 month of therapy with 400 mg. oral 160

...

PROSTATIC BLASTOMYCOSIS

FIG. 1. Case 2. Crusted cutaneous lesion on forearm with erythematous border surrounding crusted central area (arrows) .

FIG. 2. Case 2. Prostate shows granulomatous reaction. H & E, reduced from x74. Inset reveals thick-walled yeasts (Blastomyces dermatitidis). Grocott's methenamine silver, reduced from X740.

ketoconazole daily. The patient is doing well on maintenance therapy of 400 mg. oral ketoconazole. DISCUSSION

We could find in the literature 8 well documented cases of blastomycosis whose predominant presenting manifestation was prostatic involvement (see table). 2- 7 Our 2 cases bring the total number to 10. All of these patients presented with symptoms referable to vesical neck obstruction or irritation. Of these patients the skin lesions appeared concurrently in 1 and after the urinary symptoms in 6 ("shortly thereafter" to 13 months later). The location of the cutaneous lesions more or less corresponds to their distribution in cases of usual cutaneous blastomycosis, the face being involved most frequently. The initial chest x-ray findings were positive in 6 cases, negative in 2 and not stated in 2. However, in 1 of the 2 patients with negative findings the chest x-ray later demonstrated positive findings. Diagnosis was made in all 10 cases by microscopic examination of prostatic secretion or pus, or histologic examination of a tissue specimen. Blastomyces dermatitidis is by far the most frequent causative agent of mycotic prostatitis, although mycotic involvement of the prostate by other fungi, such as Histoplasma capsulatum,6 Cryptococcus neoformans6 • 8 and Coccidioides immitis,9 has been reported. Blastomycosis occurs in 2 forms, primary cutaneous inoculation blastomycosis and systemic blastomycosis. 10 The former form is rare, occurring only in people who accidentally inoculate themselves during autopsies or microbiological laboratory procedures. This is believed not to lead to systemic blastomycosis. The second form is believed to begin as a pulmonary infection after inhalation of the causative agent, and

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can remain as a subclinical pulmonary infection or become symptomatic. The original pulmonary focus can be insignificant in its appearance on a chest x-ray. Dissemination to the skin occurs primarily through hematogenous routes. Dissemination to other organs, such as the bones, liver, adrenal glands and genitourinary tract, also can occur. Both of our patients presented with prostatic involvement as the first prominent clinical manifestation of systemic blastomycosis. Case 1 had positive chest x-ray findings, while case 2 had negative findings. Both patients had fairly typical skin lesions of blastomycosis, beginning as small papules with gradual progression to elevated, verrucous, crusted lesions. The gross appearance of these lesions is characteristic of but not specific for blastomycosis and could be found in conditions such as other mycoses, tuberculosis, tertiary syphilis, drug eruptions, leishmaniasis, granuloma inguinale and cutaneous neoplasms. 10 However, the importance of the recognition of such skin lesions in patients with genitourinary symptoms should be emphasized. Manipulation, such as prostatic massage, and surgical procedures, such as prostatectomy, could potentially disseminate the organisms further and accelerate the. clinical course of the patients, as reported by Moore and Halpern. 3 Therefore, it is beneficial to make a diagnosis of blastomycosis on the basis of the skin lesions. Direct microscopic examination of pus from the skin using 15 per cent potassium hydroxide is a useful technique.10 In case 2 we took a punch biopsy of 1 of the skin lesions, which was used for making touch impressions that were then immediately stained with hematoxylin and eosin. By this method we could demonstrate the organisms immediately following the biopsy and later confirm the finding with histological examination of paraffin sections. The stained touch impressions may be easier to interpret than direct microscopic examination of the pus. Pus from a cutaneous lesion also was used for culture of the organisms. Although this is necessary for a definitive diagnosis it takes at least 10 to 14 days to obtain results. 10 A review of the literature revealed that of 10 patients with prostatic involvement as the primary manifestation of systemic blastomycosis 7 eventually had cutaneous lesions. In 5 of these 7 patients skin lesions were already present at the time of diagnosis. Treatment consisted of intravenous aipphotericin B, a conventional antifungal agent, in case 1 and oral ketoconazole, a newer antifungal agent, 11 • 12 in case 2. Both patients responded well. Amphotericin B has been the most reliable and effective drug for treatment of systemic fungal infections. 13 Its disadvantages are intravenous administration, poor tolerance by many patients and nephrotoxicity. Flucytosine, which can be admin-

FIG. 3. Case 2. Skin shows pseudo-epitheliomatous hyperplasia of epidermis with granulomatous inflammation in dermis. H & E, reduced from X74. Inset reveals yeasts on touch impression. Reduced from X470.

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INOSHITA AND ASSOCIATES

Reported cases of blastomycosis presenting with prostatic involvement Reference

Age

Presenting Symptoms

Moore and Halpern"

56 64

Bunge and Harness' Burr and Huffines'' Witorsch and Utz'

57 55 44

Urinary retention Urinary frequency, urgency and burning Painful and frequent urination Vesical neck obstruction Intermittent dysuria, urinary frequency and gross pyuria

64

Orr and associatesn

45

Bissada and associates' Case I

79 43

Case 2

63

Interval Between Urinary and Skin Manifestations

Urinary hesitancy, nocturia, incontinence, perineal pain and gross pyuria Hesitancy, dysuria and weakened urinary stream Burning on urination Dysuria, hesitancy and weakness of urinary stream Frequency and burning on urination

istered orally, has a narrow spectrum of activity and can cause marrow depression. 13 Recently, ketoconazole, a synthetic imidazole derivative, has become available. 11 • 12 This is a highly efficacious, broad-spectrum, oral antifungal agent. It has therapeutic efficacy in candidiasis, histoplasmosis, coccidioidomycosis and paracoccidioidomycosis. Although there are less data for blastomycosis in vivo as well as in vitro studies show efficacy of this drug 11 and its clinical application was successful in our case 2. Ketoconazole is less toxic and better tolerated than other antifungal agents. Minor adverse reactions include nausea, vomiting, headache, dizziness and pruritus. The most notable adverse reactions are hepatitis and gynecomastia. 12 However, the frequency of these major reactions is still unclear. Because of its oral administration and apparent lower toxicity, ketoconazole may be preferred as an initial agent. However, more studies are needed to establish clearly its relative efficacy, especially compared to amphotericin B, and the clinical importance of serious liver damage, which has been noticed in some patients treated with this drug, including 3 fatal cases. 14 Mr. George Musil and Ms. Judy Lewis provided photographic assistance.

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REFERENCES

1. Blastomycosis Cooperation Study of the Veterans Administration: Blastomycosis. I. A review of 198 collected cases in Veterans Administration Hospitals. Amer. Rev. Resp. Dis., 89: 659, 1964. 2. Witorsch, P . and Utz, J . P .: North American blastomycosis: a study of 40 patients. Medicine, 47: 169, 1968. 3. Moore, M . and Halpern, L. K.: Blastomycosis involving the prostate: report of two cases, one with and one without cutaneous lesions. J. Urol., 60: 612, 1948. 4. Bunge, R. G. and Harness, W. N.: Blastomycosis of the prostate: case report. J. Urol., 66: 263, 1951. 5. Burr, A. H. and Huffines, T. R.: Blastomycosis of the prostate with miliary dissemination treated by Stilbamidine. J. Urol., 71: 464, 1954. 6. Orr, W. A., Mulholland, S. G. and Walzak, M. P ., Jr.: Genitourinary

..

4 wks.

6 mos. 3 wks. 13 mos.

Location of Skin Lesions

Chest X-Ray Findings

Face and neck

Pos. Not stated

Not stated Face, arms, back and It. foot Face, upper posterior neck, post-auricular area and extremities

Pos. Neg. then pos. Pos. Pos.

"Shortly"

4 wks. Concurrently

7. 8. 9. 10. 11.

12. 13. 14.

Face, rt. forearm and It. foot Face, neck, arms, t highs and feet Face, arms, buttock, legs and feet

Not stated Pos. Pos. Neg.

tract involvement with systemic mycosis. J. Urol., 107: 1047, 1972. Bissada, N. K., Finkbeiner, A. F. and Redman, J. F.: Prostatic mycosis: nonsurgical diagnosis and management. Urology, 9: 327, 1977. Brock, D. J. and Grieco, M. H.: Cryptococcal prostatitis in a patient with sarcoidosis: response to 5-fluorocytosine. J. Urol., 107: 1017, 1972. Price, M. J., Lewis, E. L. and Carmalt, J.E.: Coccidioidomycosis of prostate gland. Urology, 19: 653, 1982. Harrell, E. R. and Curtis, A. C.: North American blastomycosis. Amer. J. Med., 27: 750, 1959. Heel, R. C., Brogden, R. N., Carmine, A., Morley, P . A., Speight, T. M . and Avery, G. S.: Ketoconazole: a review of its t herapeutic efficacy in superficial and systemic fungal infections. Drugs, 23: 1, 1982. Jones, H . E.: Ketoconazole. Arch. Dermatol., 118: 217, 1982. Medoff, G. and Kobayashi, G. S.: Strategies in the treatment of systemic fungal infections. New Engl. J. Med., 302: 145, 1980. Hepatotoxic potential of ketoconazole under investigation. FDA Drug Bull., 12: 11, 1982. EDITORIAL COMMENT

The authors have presented 2 cases of prostatic blastomycosis, which is certainly a rare urologic disorder. It is practically impossible for the clinician to be suspicious of this diagnosis before review of biopsy material. The authors stress the importance of cutaneous manifestations that may elevate the clinician's index of suspicion. Certainly, the diagnosis usually is made after t he biopsy material has been reviewed and the classic histological appearance of blastomycosis is seen. The urologist should be aware of multiple infectious diseases that can involve the genitourinary tract, their presentations and treatments. The authors present a good review of the literature with analysis of the other reported series. Treatment fortunately has become less toxic and better tolerated by the patient. S. Grant Mulholland Department of Urology Thomas J efferson Hospital Philadelphia, P ennsy lvania