Malacoplakia: A 25-Year Experience with a Review of the Literature

0022-534 7/89/1416-1328$02.00/0 Vol. 141, June

THE JOURNAL OF UROLOGY

Copyright © 1989 by Williams & Wilkins

Printed in U.S.A.

MALACOPLAKIA: A 25-YEAR EXPERIENCE WITH A REVIEW OF THE LITERATURE JOHN P. LONG, JR. AND ALEX F. ALTHAUSEN From the Urological Service and Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts

ABSTRACT

Our experience with 9 cases of genitourinary malacoplakia is reviewed. The bladder was 'involved in 4 patients, ureter in 2, prostate in 1, testis in 1 and a combination of prostate, bladder, rectum and pelvic adnexae in 1. The female-to-male ratio was 2:1. Escherichia coli was present in 7 of 8 available urine cultures. Of 9 patients 2 had associated immunocompromised conditions. A variety of therapeutic approaches were chosen, depending mainly on location and extent of disease. These varying combinations of medical and surgical therapies produced resolution of disease in 8 of 9 patients. Generally, upper tract involvement requires surgical intervention, while most cases of lower tract involvement can be managed with antibiotics and endoscopic resection. Rare cases of extensive lower tract malacoplakia may require extirpation for cure. (J. Ural., 141: 1328-1331, 1989) Malacoplakia is a rare granulomatous disorder of unclear etiology. To date, approximately 200 cases of this disease have been reported in the world literature. In nearly 75 per cent of the reported cases malacoplakia has involved the genitourinary tract primarily. 1 Less frequently it occurs in the gastrointestinal tract and retroperitoneum, and it also has been reported involving the lung, brain, conjunctiva, pancreas, skin, tonsils and adrenal gland. 2 Early descriptions of this disease generally considered malacoplakia to be a benign, self-limiting process. However, it now is clear that in selected cases malacoplakia is associated with significant morbidity and mortality. The pathogenesis has yet to be established clearly and, consequently, the clinical course of malacoplakia often can pose genuine difficulties in management. The experience with malacoplakia at our institution during a 25-year period is presented. METHODS OF STUDY

The pathological index and medical records files from our hospital between 1962 and 1986 were reviewed and 10 cases of malacoplakia were found. Only 9 records were available for examination. One record had been lost and could not be re'trieved. Of the remaining 9 cases 1 has been reported previously.3 PATIENTS AND RESULTS

There were 6 women and 3 men in this series, with a ratio of 2:1. Patient age ranged from 10 to 64 years, with a mean age of 45 years. The primary sites of involvement, with associated clinical findings, are presented in table 1. In 8 of 9 patients the disease process was limited to 1 organ. The exception was a 54year-old man with extensive disease progressively involving the bladder, prostate, rectosigmoid and pelvic side wall (fig. 1). Gross or microscopic hematuria occurred in 4 of 5 cases involving the bladder, and in both cases involving the ureter. All patients with bladder, ureteral or prostatic involvement presented with lower tract irritative symptoms (frequency, urgency or dysuria). The only significant radiographic findings were those of unilateral ureteral obstruction on excretory urograms (IVPs) in both cases of ureteral malacoplakia. Urine culture data were available for 8 of the 9 patients: 7 were positive for pan-sensitive strains of Escherichia coli and in 1 (a 62-year old man with prostatic carcinoma) a focus of testicular malacoplakia was found incidentally at orchiectomy. Accepted for publication November 11, 1988.

Notably, the patient had had no prior urinary symptoms whatsoever. An associated intercurrent immunodeficient state existed in 2 patients (a 39-year-old woman with metastatic malignant lymphoma and the patient with extensive pelvic disease mentioned previously who also had a progressive idiopathic restrictive lung process). Both patients were taking steroids at diagnosis. In all of our patients the preoperative diagnosis was either unknown or inaccurate. The ultimate diagnosis of malacoplakia was made only by pathological examination of adequate amounts of resected tissue. Intraoperatively, the cystoscopic appearance of these lesions was confused with neoplasms (4 cases) or condylomata (1). Both ureteral lesions were considered carcinomas preoperatively and were believed to be con sistent with carcinoma intraoperatively. Furthermore, a needle biopsy of prostate nodules in the patient with prostatic malacoplakia was interpreted initially as granulomatous prostatitis. The final diagnosis was made upon pathological examination of chips from transurethral resection. The forms of therapy and results of each case are presented in table 2. Followup ranged from 1 to 11 years, with a mean duration of 49 months. Open resection was done in patients 6, 7 and 9, endoscopic resection in conjunction with long-term antibiotics was used in patients 1 to 4 and 8, and both approaches were used in patient 5. Among the first 3 patients surgical resection constituted the principal form of therapy: 2 also were given short courses of routine postoperative antibiotics and 1 had no additional therapy. These 3 patients were rendered free of disease, with no recurrences. Among the remaining 6 patients 4 noticed progressive improvement with conservative therapy. Followup cystoscopy studies were performed in 2 of these 4 patients, with markedly diminished numbers of intravesical plaques found in both cases. However, in the remaining 2 patients malacoplakia clearly progressed despite attempts at conservative therapy. Curiously, these were the 2 patients with associated immunocompromised conditions: patient 5 failed an additional 8-month course of bethanechol (100 to 200 mg. per day) and ultimately required pelvic exenteration to control disease, while patient 1 had diffuse metastases from a malignant lymphoma that eventually caused death. Cystoscopy several months before death showed persistent plaques throughout the bladder. DISCUSSION

Malacoplakia was reported first in 1902 by Michaelis and Gutmann, who described the dense, lamellar inclusion bodies 1328

1329

MALACOFLAKIA TABLE

Pt. No.

Site of Involvement

L Sites of involvement with associated clinical findings in malacoplakia Urine Culture

Irritative Symptoms

Hematuria

Other

Bladder Bladder Bladder Bladder

E.coli E.coli None available E.coli

Gross Gross Microscopic Microscopic

Present Present Absent Present

E.coli

Microscopic

Present

Perinea! abcesses

6

Bladder, prostate, sigmoid, rectum, pelvic side wall Ureter

E.coli

Microscopic

Present

Pyuria on urinalysis

7

Ureter

E.coli

Microscopic

Present

8

Prostate

E.coli

Absent

Present

9

Testis

No growth

Absent

Absent

2

3

4

5

Multiple nodules on examination

TABLE 2.

Pt. No.

Therapy

30 mos.

Repeated transurethral resection of bladder tumors, prolonged courses of trimethoprim-sulfamethoxazole and ampicillin Transurethral resection of bladder tumors, daily trimethoprimsulfamethoxazole thereafter Transurethral resection of bladder tumors (2) and daily tetracycline Transurethral resection of bladder tumors (2), daily sulfisoxazole Repeated transurethral resection of bladder tumors, multiple antibiotics, bethanechol, pelvic exenteration Distal ureterectomy, and postop. tetracycline for 1 mo. Distal ureterectomy and postop. trimethoprim-sulfamethoxazole for 1 mo. Transurethral prostatectomy, ampicillin for 1 mo. Orchiectomy (incidental finding)

FIG. L A, pelvic CT scan shows malacoplakia involving right posterior wall of bladder and rectosigmoid, and extending to right pelvic side wall. B, similar study after 8 months ofbethanechol therapy reveals essentially no change in extent of disease.

characteristic of this disease. The term malacoplakia was introduced a year later by von Hansemann. The largest clinical experience from a single institution appeared in 1977 and consisted of 10 cases, all involving the bladder, collected during a 25-year period.4 Malacoplakia occurs rarely; in a. series of 20,000 autopsy examinations only 2 cases were found. 2 Moreover, a postmortem study of 232 bladders from patients with histories of cystitis and pyuria revealed no case of malacoplakia. 1 Nevertheless, several investigators note that malacoplakia may be much more prevalent than currently is recognized. 1 · 5 When presented with slides of malacoplakia at pathology seminars 5 of 61 pathologists made accurate diagnoses in 1956, compared to only 10 per

3

3 yrs.

4

30 mos.

5

2 yrs.

6

12 mos.

7

8 yrs.

8

7 yrs.

9

15 mos.

Normal !VP Normal IVP Normal IVP Normal IVP, thickened bladder on voiding cystourethrogram Normal IVP

Ureteral obstruction on IVP Ureteral obstruction on !VP Mild trabeculation on IVP NormalIVP

Treatment and results

Followup

11 yrs.

X-Ray Findings

Results Persistent lesions at multiple cystoscopies, pt. died of liver failure 30 mos. after presentation Remained asymptomatic, with neg. urine cultures

Resolution of symptoms, with no recurrence Became asymptomatic, with diminished number of lesions at fo!lowup cystoscopy Continued progression of malacoplakia until exenteration, prompt resolution of symptoms postop. with no recurrence Resolution of symptoms, IVP normal at 12 mos. Resolution of symptoms, IVP normal at 15 mos. Became asymptomatic, with neg. urine cultures No recurrence during followup

cent in 1966. 6 Difficulties in making the clinical diagnosis of malacoplakia also are well documented 1 · 4 and confirmed by our experience in this series. The first case of malacoplakia occurring outside the urinary tract was reported in 1958. Although this predominance of malacoplakia in the urinary tract remains well recognized, its occurrence at many diverse sites has prompted some investigators to suggest that malacoplakia may be a systemic disease. Urinary tract malacoplakia usually occurs in women in the fourth or fifth decade. The female-to-male ratio approaches nearly 4:1. Within the urinary tract itself malacoplakia is found most frequently in the bladder, which is involved in 70 per cent of the cases. Isolated upper tract lesions are uncommon (15 per cent of the cases), as is combined upper and lower tract involvement (15 per cent). 2 The clinical presentation of malacoplakia varies depending on its site of origin. The predominance of hematuria and

1330

LONG AND ALTHAUSEN

irritative symptoms in malacoplakia of the bladder is well documented, 1 • 5 • 7 and supported by our experience (table 1). Upper tract lesions may present with varying degrees of colic. Fever, especially with a flank mass, usually inciicates renal parenchymal involvement, which is bilateral in nearly 50 per cent of the cases. 8 With parenchymal involvement IVPs usually demonstrate enlarged, odd-appearing kidneys, delayed function or an overt mass. When involvement is limited to the collecting system, however, often no radiographic findings are identified. 9 Prostatic malacoplakia typically presents either with prostatomegaly and bladder outlet obstruction, or with hard nodules simulating carcinoma. 1° Consideration of malacoplakia in the differential diagnosis of prostate nodules seems to be particularly important in that 4 of the 22 reported cases of prostate malacoplakia have been interpreted initially as carcinoma, usually of the clear cell type. 11 Testicular involvement usually is heralded by progressive, unilateral pain and swelling that are refractory to 7 to 10 days of antibiotics. Diagnosis is made invariably at orchiectomy. 12 Grossly, malacoplakia consists of submucosal aggregates of macrophages that appear as soft tan-yellow colored plaques. These raised lesions often have targetoid centers and areas of hyperremia around the bases (fig. 2). Histologically, malacoplakia is characterized by collections of plump, frothy macrophages (von Hansemann macrophages) with a varying amount of plasma cell infiltration (fig. 3). The sine qua non of malacoplakia remains the demonstration of Michaelis-Gutmann bodies on microscopic section. These distinct inclusion bodies invariably are located within macrophages, are 5 to 10 J.lm. in diameter and have a dense matrix core, usually containing many myelin-like lamellations.13 These cores appear to be composed primarily of calcium hydroxyapatite, with variable amounts of iron; they stain positive with periodic acid, Schiff, von Kossa and prussian blue stains. A clear association between malacoplakia and urinary tract infection currently is widely recognized. Recent reviews note

FIG. 2. Patient 7. Distal ureterectomy specimen shows raised plaques of malacoplakia within ureteral mucosa.

FIG. 3. Typical histological appearance of malacoplakia with dense inclusions (Michaelis-Gutmann bodies) evident within large, frothy macrophages (von Hansemann macrophages). Reduced from X363.

that 80 to 90 per cent of urine cultures from patients with malacoplakia were positive for bacilliform organisms. Of these positive cultures 70 to 75 per cent yielded E. coli, invariably of a common strain.'· 14 Our experience with 7 of 8 available cultures positive for E. coli is consistent with these observations. The pathogenesis of malacoplakia may be related to this prevalence of bacilliform infections. Electron microscopic evidence suggests that Michaelis-Gutmann bodies originate from phagolysosomes containing partially digested bacterial debris. Abdou and associates studied the macrophages of a patient with retroperitoneal malacoplakia and demonstrated diminished monocytic bactericidal activity versus E. coli. 15 The administration of bethanechol returned this activity to normal levels in vitro and in vivo. Two additional reports also documented decreased bactericidal activity in malacoplakia macrophages, 16' 17 although a separate report showed no impairment of bacterial killing capacity in macrophages from a patient with malacoplakia. 18 Moreover, McClure found no difference in monocytic bactericidal activity to either E. coli or Staphylococcus aureus between a group of 6 patients with biopsy proved malacoplakia, and a group of age and sex-matched controls.2 Interestingly, bethanechol had no effect on the killing capacity of macrophages from either group. Obviously, further investigation is needed to clarify these conflicting data. Selection of therapy depends chiefly on whether the disease involves primarily the upper or lower urinary tract. Malacoplakia of the upper tracts often is an aggressive process, associated with significant mortality. Renal parenchymal malacoplakia exists in 2 forms, unifocal or multifocal. The multifocal form occurs in 75 per cent of the cases. 9 Bilateral renal involvement occurs in 50 per cent of these cases. To date 8 of 8 reported patients with bilateral renal parenchymal malacoplakia have died within 6 months of diagnosis, regardless of medical therapy chosen. 8 Bilateral involvement of the proximal collecting system has been reported in only 2 cases; 1 patient died of progressive disease, 19 while 1 survived after bilateral pyelotomy and excision of all visible disease. 20 However, a review of unilateral upper tract involvement showed that 7 patients with either renal parenchymal malacoplakia (4) or pelvic disease (3) limited to 1 side all survived when treated with nephrectomy. 19 Isolated lesions in the proximal ureter are extremely rare. Malacoplakia has been reported in the proximal or mid ureter in only 4 patients, all of whom had simultaneous, ipsilateral renal parenchymal malacoplakia. 19 • 21 N ephroureterectomy was done in 1 of these patients but no followup was reported. Both of our cases of ureter al malacoplakia involved the distal ureter, 1 of which was reported previously. 3 In each case there was no

'FP l vu.I.

l\l[ALACOPLAKIA

evidence of renal involvement, either ra,11c1gr.aphH:aliy or at operation. Both patients were treated with ureterectomy and ureteroneocystostomy ,Nith excellent results (table An IVP was normal at 12 and 15 months, respectively. It appears that, although rare, lesions in the ureter occasionally can be solitary and may represent a form of malacoplakia that is not as aggressive as that which involves the proximal ureter. The therapy of choice for unilateral renal parenchymal malacoplakia remains nephrectomy, which should be done as soon as the diagnosis is made. Lesions in the proximal or mid ureter are perhaps managed most prudently with nephroureterectomy, given the high likelihood of simultaneous parenchymal involvement. However, if the lesion is in the distal ureter with no evidence of proximal disease radiographically, excision of the involved segment alone appears to be adequate. Unlike upper tract disease, malacoplakia of the lower urinary tract generally is a more benign, often self-limiting process, although rare cases of extensive pelvic spread have been reported. 22 There is no clear regimen of choice, although various combinations of endoscopic and medical therapies have been reported with equally successful results 1 • 2 • 17• 22 • 23 What most of these regimens seem to have in common is that they usually are successful once the urine has been rendered sterile for a prolonged period, regardless of the type of antibiotic used. Endoscopic resection of intravesical disease also has been reported but always in conjunction with antibiotic regimens. No data exist that demonstrate that the use of transurethral resection alone is more effective than antibiotic therapy in resolving these lesions. Despite initial enthusiasm for bethanechol, subsequent reports in the literature regarding its clinical efficacy are conflicting. 2 • 22 • 24 • 2 " Bethanechol had no effect on the course of malacoplakia in our patient who received it (table 2). The management of malacoplakia localized to the lower urinary tract generally is conservative. If initial urine cultures are positive the therapeutic approach of choice consists of a long course of appropriate antibiotics. However, if cultures are negative either a 3 to 4-month triai of bethanechol and/or similar courses of any broad-spectrum antibiotic are reasonable therapeutic alternatives. Adjunctive endoscopic resection of small numbers of plaques may be attempted but a complete transurethral resection of intravesical disease probably is not necessary, unless lesions subsequently persist despite medical therapy. If symptoms resolve, an extended cystoscopic followup with antibiotic prophylaxis seems to be prudent. In all patients close monitoring of urine cultures with aggressive use of antibiotics to keep the urine abacteriuric is mandatory. surveillance should be maintained until all plaques resolve. Extensive pelvic malacoplakia fortunately is rare. Only 2 cases of extravesical extension involving contiguous organs have been reported in the urological literature" In both in stances the disease was controlled with conservative therapy using bethanechol' 5 or c~,J;'i::",~i'<"v:"'~vHcc 22 Standard conservative therapy continuously failed in our patient with extensive pelvic malacoplakia. Total pelvic exenteration was done with subsequent resolution of disease. While not the primary treatment of choice, extirpation may be a responsible alternative in cases of progressive extravesical malacoplakia that have been refractory to conventional therapy. Our case of prostatic involvement represents case 23 reported in the literature. 11 Success has been reported with open resection, and with transurethral resection of prostatic malacoplakia. Transurethral resection with short-term antibiotics was adequate in our case. Recurrent testicular malacoplakia is rare after orchiectomy. This remains the definitive treatment for this form of the disease. Intercurrent immunodeficiency states have been reported in approximately 40 per cent of all cases of malacoplakia. 16 However, a clear causal link between systemic immunodeficiency and malacoplakia has yet to be demonstrated. Steroid use has been postulated to have a role in the pathogenesis of malaco-

plakia. However, the development and cure of malacoplakia in renal transplant patients do not appear to be influenced in any way by the use of steroidso 26 The role, if any, of immunodeficiency in either the clinical course or pathogenesis of malacoplakia is uncertain at best. REFERENCES 1. Stanton, M. J. and Maxted, W.: Malacop!akia: a study of the literature and current concepts of pathogenesis, diagnosis and treatment. J. Urol., 125: 139, 1981. , 2. McClure, J.: Malakoplakia. J. Path., 140: 275, 1983. 3. Nieh, P. T. and Althausen, A. F.: Malacoplakia of the ureter. J. Urol., 122: 701, 1979. 4. O'Dea, M. J., Malek, R. S. and Farrow, G. M.: Malacoplakia of the urinary tract: challenges and frustrations with 10 cases. J. Urol., ll8: 739, 1977. 5. Smith, B. H.: Malacoplakia of the urinary tract: a study oftwentyfour cases. Amer. J. Clin. Path., 43: 409, 1965. 6. Sanusi, I. D. and Tio, F. 0.: Gastrointestinal malacoplakia. Report of a case and review of the literature. Amer. J. Gastrol., 62: 356, 1974. 7. Qualman, S. J., Gupta, P. K. and Mendelsohn, G.: Intracellular Escherichia coli in urinary malakoplakia: a reservoir of infection and its therapeutic implications. Amer. J. Clin. Path., 81: 35, 1984. 8. Ho, K. L., Rassekh, Z. S. and Nam, S. H.: Bilateral renal malakoplakia. Urology, 13: 321, 1979. 9. Hartman, D. S., Davis, C. J., Lichtenstein, J. E. and Goldman, S. M.: Renal parenchymal malacoplakia. Radiology, 136: 33, 1980. 10. McClure, J.: Malacoplakia of the prostate: a report of two cases and a review of the literature. J. Clin. Path., 32: 629, 1979. 11. Koga, S., Arakaki, Y., Matsuoka, M. and Ohyama, C.: Malakoplakia of prostate. Urology, 27: 160, 1986. 12. Brown, R. C. and Smith, B. H.: Malacoplakia of the testis. Amer. J. Clin. Path., 47: 135, 1967. 13. Stevens, S. and McClure, J.: The histochemical features of the Michaelis-Gutmann body and a consideration of the pathophysiological mechanisms of its formation. J. Path., 137: 119, 1982. 14. Damjanov, I. and Katz, S. M.: Malakoplakia. Path. Ann., part 2, 16: 103, 1981. 15. Abdou, N. I., NaPombejara, C., Sagawa, A., Ragland, C., Stechschulte, D. J., Nilsson, U., Gourley, W., Watanabe, I., Lindsey, N. J. and Allen, M. S.: Malakoplakia: evidence for monocyte !ysosomal abnormality correctable by cholinergic agonist in vitro and in vivo. New Engl. J. Med., 297: 1413, 1977. 16. Witherington, R., Branan, W. J., Jr., Wray, B. B. and Best, G. K.: Malacoplakia associated with vesicoureteral reflux and selective immunoglobulin A deficiency. J. Urol., 132: 975, 1984. 17. Maderazo, E. G., Berlin, B. B. and Marhardt, C.: Treatment of malakoplakia with trimethoprim-sulfamethoxazole. Urology, 13: 70, 1979. 18. Lewin, K. J., Fair, W. R., Steigbigel, R. T., Winberg, C. D. and Droller, M. J.: Clinical and laboratory study into the pathogenesis of malakoplakia. J. Clin. Path., 29: 354, 1976. 19. Deridder, P.A., Koff, S. A., Gikas, P. W. and Heidelberger, K. P.: Renal malacop!akia. J. Urol., 117: 428, 1977. 20. Halpern, G. N., Kalies, D. W., Factor, S. and Wein, A. J.: Malacoplakia causing bilateral ureteropelvic junction obstruction. Urology, 3: 628, 1974. 21. Sexton, C. C., Lowman, R. M., Nyongo, A. 0. and Baskin, A. M.: Malacoplakia presenting as complete unilateral ureteral obstruction. J. Urol., 128: 139, 1982. 22. Matthews, P. N., Greenwood, R. N., Hendry, W. F. and Cattell, W. R.: Extensive pelvic malacoplakia: observations on management. J. Urol., 135: 132, 1986. 23. Miles, B. J. and Skoog, S.: Treatment of malakoplakia of bladder with intravesical neosporin irrigation. Urology, 27: 32, 1986. 24. Zornow, D. H., Landes, R.H., Morganstern, S. L. and Fried, F. A.: Malacoplakia of the bladder: efficacy of bethanechol chloride therapy. J. Urol., 122: 703, 1979. 25. Stanton, M. J., Lynch, J. H., Maxted, W. C. and Chun, B. K.: Malacoplakia of the bladder: a case report of resolution with bethanechol, trimethoprim-sulfamethoxazole and ascorbic acid. J. Urol., 130: 1174, 1983. 26. Streem, S. B.: Genitourinary malacoplakia in renal transplant recipients: pathogenic, prognostic and therapeutic considerations. J. Urol., 132: 10, 1984.