Introduction

Malakoplakia is a chronic granulomatous inflammatory disorder characterized by lesions exhibiting von Hansemann macrophages in which the cytoplasm contains numerous periodic acid-Schiff (PAS)-positive cytoplasmic granules.¹ Basophilic targetoid intracytoplasmic von Kossa–positive inclusion bodies, called Michaelis-Gutmann (MG) bodies, are considered pathognomonic for this condition.¹

Although clinical signs of malakoplakia vary greatly, as virtually any organ can be affected, the genitourinary system (especially the bladder) and the gastrointestinal tract are the sites most commonly involved in humans.² In human medicine, urinary bladder (UB) malakoplakia is typically described as multiple, yellow to brown plaques with central umbilication or nodules usually <1 cm but ranging up to 4 cm in length.^1,3,4 This condition is usually associated with recurrent bacterial infection (affecting up to 80% of patients), most frequently caused by Escherichia coli.^1,2,5 A concurrent condition associated with poor immune function has been identified in 40% of cases.^1,2 Finally, a defective macrophage function is thought to alter normal bacteria digestion. The formation of pathognomonic MG bodies may be as result of the accumulation and mineralization of partially degraded bacteria.^1,2

Antibiotics with intracellular action are the main treatment (i.e., quinolones, sulfamethoxazole-trimethoprim [TMS]). A prolonged course of treatment (at least 2 mo) is typically recommended, although no clear recommendation can be drawn from the literature.^2,6 Quinolones are associated with a positive outcome in 80–90% of reported cases.^1,7 Extensive lesions have the highest chance of cure when surgery is combined with prolonged antibiotic therapy.^1,7

Malakoplakia of the urogenital tract has recently been described in cats.^8,9 We present the first description of urinary malakoplakia in a dog, in whom the disease affected the UB and was associated with lower urinary tract signs and recurrent E coli cystitis.

Case Report

A 4 mo old female Staffordshire bull terrier was referred to the Alliance Small Animal Clinic Internal Medicine service for a 2 mo history of hematuria and dysuria. A urinary tract infection caused by E coli had been identified by the referring veterinarian and, because of the culture and sensitivity testing results, cephalexin^a was prescribed (15 mg/kg orally q 12 hr). Dysuria abated, but hematuria persisted despite prolonged antibiotic therapy (7 wk). Apart from hematuria, the puppy appeared healthy. Antibiotic therapy had been stopped 3 days prior to referral.

The physical examination did not reveal any abnormality. The complete blood count demonstrated mild microcytic, normochromic, nonregenerative anemia {packed cell volume 31.8% [reference interval (RI): 37.3–61.7%]; hemoglobin 11.8g/dL [RI: 13.1–20.5 g/dL]; mean cell volume 60.3 fL [RI: 61.6–73.5 fL]; and mean corpuscular hemoglobin concentration 35.8 g/dL [RI: 32.0–37.9 g/dL]}. The complete serum biochemical profile was normal. Urinalysis (urine collected by cystocentesis) indicated a urine specific gravity (USG) of 1.036 and a pH of 6.5, with hematuria (4+) and proteinuria (3+) as determined by urine dipstick tests. Microscopic examination of the urine sediment showed numerous red blood cells (RBCs) (>25/high-power field [hpf]), leukocytes (>25/hpf), and bacilli. Urine culture yielded a pure growth of E coli (10⁶ colony-forming unit/mL) susceptible to all tested antibiotics.

Abdominal ultrasonography revealed echoic urine in the bladder, a thickened bladder wall, and numerous finger-like intraluminal lesions arising from the dorsal bladder wall and filling almost all of the bladder lumen (Figure 1A). Cystoscopy^b showed innumerable intraluminal masses of varying size, occupying most of the bladder lumen (Figure 1B). The origin of some of these masses could be observed craniodorsally and appeared pedunculated. The surface of these masses was pale in color and slightly irregular, with some erythematous and depressed areas. Less than 20% of the bladder wall remained visible laterally and ventrally and was covered by smooth, pale-colored plaques. Histologic evaluation of biopsies of the masses performed during cystoscopy using a 5 Fr flexible biopsy forceps showed marked infiltration of the submucosa by round cells with a large granular cytoplasm staining positive for PAS, consistent with macrophages. Small amounts of degenerate neutrophils, isolated lymphocytes, and plasmocytes were also observed. These findings were suggestive of granulomatous cystitis without signs of malignancy.

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A cystotomy was performed 5 wk after the cystoscopy. The inner bladder mucosa was diffusely affected over the whole inside of the bladder and contained numerous white-to-yellow pedunculated proliferations up to 4 cm in length (Figure 1C). These proliferations were resected by peeling off the bladder mucosa until no more macroscopic lesions were observed and then were submitted for histological examination.

The bladder submucosa was diffusely thickened by a marked homogenous round-cell infiltration. The cells were ∼25 µm in diameter with distinct cytoplasmic borders, voluminous cytoplasm that was acidophilic PAS positive, and a round-to-ovoid, eccentric, euchromatic-to-hyperchromatic nucleus with small central nucleolus (von Hansemann macrophages) (Figures 2A, C). Rare cells showed round, poorly stained, basophilic targetoid cytoplasmic von Kossa–positive inclusion bodies, consistent with MG bodies (Figures 2B, D). Immunohistochemistry was positive for major histocompatibility complex class II and vimentine, confirming the macrophagic origin of the infiltrating cells (Figures 2E, F). A mild neutrophilic and lymphocytic infiltration was also observed. These findings were consistent with a diagnosis of bladder malakoplakia.

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Culture on a surgical bladder biopsy yielded a growth of E coli susceptible to doxycycline, cephalosporins, and TMS and intermediate to amoxicillin-clavulanate and quinolones. After surgery, the puppy was managed with IV Ringer’s Lactate, amoxicillin and clavulanic acid^c (12.5 mg/kg IV q 12 hr), and buprenorphine^d (20 µg/kg IV q 8 hr), and then discharged 2 days after surgery with amoxicillin and clavulanic acid^e (12.5 mg/kg PO [per os] q 12 hr) and tramadol^f (5m/kg PO q 12 h for 5 days). The antibiotherapy was modified to TMS^g (18 mg/kg PO q 12 hr) 3 wk after discharge following reception of the histopathological results. At the follow-up visit 6 wk after discharge, the puppy had been free of urinary signs since surgery. The serum biochemical profile was normal. Urinalysis (urine collected by cystocentesis) showed a USG of 1.038, a pH of 7, and hematuria (4+). Microscopic examination of the urinary sediment revealed slight hematuria (10 RBCs/hpf). Urine culture was negative. Ultrasonography showed persistent craniodorsal thickening of the UB wall with a maximum thickness of 13 mm. The treatment was continued for another 6 wk, and the dose of antibiotics was adjusted to the patient’s change in body weight.

At the second follow-up visit, after 9 wk of TMS therapy, the puppy was still free of urinary signs. Urinalysis (urine collected by cystocentesis) showed a USG > 1.050, a pH of 6.5, and hematuria (2+). Microscopic examination of the urinary sediment revealed epithelial cells (2/hpf) and rare RBCs (<1 RBC/hpf). Thickening (up to 18.4 mm) of the UB wall persisted. Urine culture yielded growth of E coli (10³ colony-forming unit/mL) resistant to potentiated sulfonamides and doxycycline but sensitive to quinolones, and with intermediate sensitivity to beta-lactams. The dog was switched to doxycycline^h (6.25 mg/kg PO q 12 hr) because of the good penetration of this antibiotic in tissues despite its low urinary concentration and to avoid the use of quinolones in an immature dog.

The puppy was lost to follow-up after this visit.

Discussion

Malakoplakia is an uncommon chronic granulomatous inflammatory disorder, well described in human medicine. The median age at presentation is 50 yr, although malakoplakia can occur in patients of any age.^1,2,5 Cases of bladder malakoplakia are often presented with voiding symptoms and hematuria.² When malakoplakia involves the ureters and the kidneys, ureteral obstruction, renal failure, or a large renal mass can develop.^3,5,10

Very few cases of malakoplakia have been reported in the veterinary literature. The first reports were postmortem descriptions of digestive, nodal, and systemic malakoplakia in breeding pigs.^11,12 In small animals, malakoplakia was first described in a 5 wk old kitten euthanized for recurrent lower urinary tract signs caused by a generalized bladder lesion.⁸ Another case was reported in a 4 mo old kitten presented with chronic lower urinary tract signs caused by bladder malakoplakia and successfully treated with prolonged antibiotic therapy.⁹ A case of vaginal malakoplakia was recently reported in a 3 yr old cat, who was successfully treated with per-endoscopic debridement of the lesions and a 6 wk course of enrofloxacin.¹³ The latter report mentioned an unpublished case of bladder malakoplakia in a 3 mo old kitten in New Zealand.

Although the etiology of malakoplakia has not been fully characterized, bacteria seem to play a central role in its development. Indeed, ∼80% of humans with urinary tract malakoplakia suffer from recurrent bacterial infection, most commonly caused by E coli.^1,2,6 An abnormal immune response has also been implicated in the pathogenesis of malakoplakia because 40% of human cases are associated with poor immune function such as malignancy, autoimmunity, immunosuppressive therapy, chronic excessive alcohol consumption, or general debilitation.^2,5 Finally, a defective lysosomal function is suspected in patients suffering from malakoplakia. A decreased guanosine 3′,5′-cyclic monophosphate/adenosine 3′,5′-cyclic monophosphate ratio and abnormal release of ß-glucuronidase have been identified in macrophages from lesions of malakoplakia.² These features are thought to interfere with normal microtubular assembly, lysosome migration, and fusion with phagosomes.^1,2 This leads to cytoplasmic accumulation of partially degraded bacteria, which can subsequently mineralize to form the pathognomonic MG bodies.² This hypothesis is supported by the finding of partially degraded bacteria in MG bodies in some cases of human malakoplakia.¹ Furthermore, macrophages from one feline case exhibited intracytoplasmic bacterial rods that hybridized with an E coli/Shigella species probe during fluorescence in situ hybridization analysis.¹³ No evidence of immunodepression was observed in our case, although extensive testing was not carried out, nor was it in the three feline cases reported in the literature.^8,9,13 These four cases were all encountered in young animals, three of them immature. This supports the possibility of a congenital defect in macrophage function leading to the development of malakoplakia. The association of innate immune deficiency, granulomatous disease, and bacterial involvement has been previously described in granulomatous colitis of boxers and French bulldogs, which has been linked to malakoplakia by some authors.¹⁴ Granulomatous colitis is characterized by granulomatous inflammation associated with the presence of invasive E coli within the mucosa and macrophages.¹⁵ Granulomatous colitis is thought to result from a congenital impaired destruction of intramucosal and macrophage E coli caused by a decreased respiratory burst within the phagocytes. A genetic cause is highly suspected, and the gene neutrophil cytosolic factor encoding for a subunit of the nicotinamide adenine dinucleotide phosphate oxidase complex has recently been elected as a candidate gene in the development of granulomatous colitis.¹⁶ Another condition similar to malakoplakia was reported in seven laboratory beagles originating from two different litters from the same colony.¹⁷ Granulomatous lesions were found in the leptomeninges, with PAS-positive macrophages exhibiting a positive reaction to E coli antigen in their cytoplasm and evidence of abnormal lysosomal function on electron microscopy.¹⁷ MG bodies were not identified in the lesions, as they may occur in the early phase of malakoplakia.⁴ Although these conditions have not been clearly defined as malakoplakia, they share strong similarities with it and strengthen the hypothesis that malakoplakia in small animals could be of congenital origin.

The medical treatment of malakoplakia is based on antibiotic therapy. In human patients, antibiotics exhibiting intracellular penetration (i.e., ciprofloxacin and TMS) are advocated to aid in intracellular elimination of bacteria.^6,18 Duration of therapy is variable but generally exceeds 2 mo.⁶ The two cats reported to have been successfully treated received TMS for 22 wk or enrofloxacin for 6 wk.^9,13 TMS was initially selected in our case as the young age of the dog precluded the use of fluoroquinolones for a long period of time. When the second follow-up culture revealed resistance of the infection to TMS, the dog was switched to a boosted dose of doxycycline because this drug exhibits good intraparenchymatous diffusion despite its low urinary concentration. Unfortunately, the puppy was then lost to follow-up, and the effectiveness of the treatment could not be evaluated. Bethanechol increases the level of cyclic guanosine 3′,5′-cyclic monophosphate, and ascorbic acid decreases the level of adenosine 3′,5′-cyclic monophosphate, which subsequently enhances the bactericidal activity of the phagosomes.^1,5,19 Some authors therefore prescribe these compounds in the treatment of malakoplakia even though critical evaluations of their effects are lacking. Surgical treatment may be required in selected cases. In our case, surgery was elected to obtain a larger amount of biopsy material for diagnosis and because of the extensive nature of the lesions. Resection of the lesions associated with medical treatment was effective in improving urinary symptoms.

Conclusion

Malakoplakia is a rare disease in humans and only recently described in small animals. This case report is the first description of malakoplakia in a dog. Malakoplakia should be included in the differential diagnosis when a bladder mass is identified in a dog, particularly if the patient is immature. The main treatment consists of prolonged antibiotherapy, although surgical treatment may be required.