Stesura Seveso Archivio Italiano di Urologia e Andrologia 2022; 94, 3350 REVIEW No conflict of interest declared. It usually occurs in the genitourinary tract [commonly the bladder (40%), renal parenchyma (16%), prostate and rarely the ureter (11%)], but it can affect all body organs (2, 3). Bladder malakoplakia can manifest as nodules, plaques, or ulcers with voiding symptoms and it can mimic cysti- tis or bladder tumor (4). At cystoscopy it appears as a yel- low soft tiny plaque or ulcer (1). The exact etiology is unknown, but it seems to be caused by a defect of phagocytic or degradative functions of his- tiocytes in response to E. coli or Proteus infection resulting in a chronic inflammatory process (5). The lesions are characterized by presence of large macrophages; foamy histiocytes (known as von Hansemann cells) containing Michaelis-Gutmann bodies (6). The gold standard for diagnosis and treatment has not yet been decided. Only case reports about vesical malako- plakia can be found in the literature, hence there is a lack of a review of this disease. For this reason the aim of our study was to review all the case reports about bladder malacoplakia in order to compare them. MATERIALS AND METHODS We searched articles on the PUBMED web-literature data- base with the following keywords: “vesical malakoplakia” and “bladder malakoplakia”. The including criteria for our study were: case report and primary bladder malako- plakia as central topic. In the literature we found 254 arti- cles. Of this, we excluded 172 articles because they did not respected the including criteria. So we selected 82 case reports. Furthermore 47 articles have been dis- charged because articles were unavailable or subject of the paper was off topic. At final we have included in our study 35 articles. RESULTS From the 35 articles analyzed, we obtained 36 case reports. The major problem was to find all the information considering that many case reports were incomplete or unclear in their writing, in particular regarding follow-up. The main characteristics of the patients and the patholo- gy are shown in Table 1. Objective: The aim of the study is to make a review of the literature about bladder malakoplakia. Material and Methods: We searched articles on the PUBMED web-literature database with the following keywords: “vesical malakoplakia” and “bladder malakoplakia”. In the literature we found 254 articles. At final we have excluded 219 articles, including in our study only 35 articles. Results: The overall average age found was 50.85 years. The average age of men was 43.22 years, while that of women was 53.37 years. 75% of the patient cases were women and 25% were men. Regarding comorbidities, in 5.55% of the cases were missing whereas 47.22% of the patients suffered from recurrent urinary tract infection (UTI) and 19.44% from immune system disorders. Urine culture was positive in 69.44% with E.coli being isolated in 92% of cases. Hydroureteronephrosis was present in 44.44% of the cases: left in 6.25% of cases, right in 18.75% and bilateral in 75%. The mean serum creatinine of patients with hydroureteronephrosis was 5.11 (1-21) mg/dl. The most fre- quent site of the lesion was the vesicoureteral junction (VUJ) (42.31%), followed by the trigone (38.46%). 30.56% of patients were treated with antibiotic and surgery (transurethral resec- tion of bladder, partial or radical cystectomy), less frequent options were antibiotics alone and surgery alone. The recur- rence rate was 15%. Conclusions: Malakoplakia is a disorder usually related to other affections, like UTI and immunodepression, and it seem to be caused by an abnormal macrophage function. In almost half of the described cases of isolated bladder malako- plakia, hydroureteronephrosis and renal failure were present.Treatment is not standardized, but both medical and surgical therapies are effective to avoid recurrence. KEY WORDS: Malakoplakia; Rare disorder; Urinary tract infection. Submitted 9 June 2022; Accepted 23 June 2022 INTRODUCTION Malakoplakia is a rare disorder which was described for the first time in 1902 by Michaelis and Gutmann. It affects both sexes, mostly people over 40 years old, patients with immunosuppression, diabetes mellitus, renal transplanta- tion, long-term therapy with systemic corticosteroids and patients with a prior infection of E. coli (1). Malakoplakia of the urinary bladder: A review of the literature Giordano Polisini 1, Rocco Francesco Delle Fave 1, Camilla Capretti 2, Angelo Marronaro 2, Alessia Mariagrazia Costa 2, Luigi Quaresima 2, Daniele Mazzaferro 2, Andrea Benedetto Galosi 1 1 Division of Urology, University Hospital “Ospedali Riuniti”, School of Medicine, Department of Clinical, Special and Dental Sciences, Marche Polytechnic University, Ancona, Italy; 2 Department of Urology, Civitanova Marche Hospital, Civitanova Marche, Italy. DOI: 10.4081/aiua.2022.3.350 Summary 351Archivio Italiano di Urologia e Andrologia 2022; 94, 3 Malakoplakia of the urinary bladder Data considered and collected were: age, sex, comorbidi- ty, serum creatinine, presence of bacteria in urine, hydroureteronephrosis, site of injury, treatment and fol- low-up. The presence or absence of hydronephrosis was derived from imaging examinations: ultrasound, computerized tomography (CT), intravenous pyelography (IVP), etc. As shown in the Table 2, the antibiotics used for the treat- ment were quinolones, Trimethoprim-sulfamethoxazole and b-lactams. As not all the articles reported the antibi- otic used, we decided to analyze the data by generally referring to the use of antibiotics or not and the same applies to the type of intervention performed. The overall average age found was 50.85 years. The aver- age age of men was 43.22 years, while that of women was 53.37. 75% of the patient cases were women and 25% were men. Regarding comorbidities, in 5.55% of the cases they were missing whereas 47.22% of the patients suffered from recurrent urinary tract infections (UTI) and 19.44% from immune system disorders (such as diabetes). Urine culture was positive in 69.44%. The infection was sustained in 92% of cases by E. coli. Missing or negative culture are reported in 30%. On the other hand Corynebacterium was occasionally reported. Corynebacterium urealyticum is the cause of encrusting cystitis. It is usually missed in routine urine cultures since it does not grow after an overnight incubation. It grows in special media on longer incubation period in special medias. Inaccurate search for it could explain the high rate of negative cultures. Of the patients with negative urine culture, 85.71% had no history of recurrent UTI. Of the patients with positive urine culture, 60% had a history of recurrent UTI. Table 1. Characteristics of the patients and the pathology. Article Age Sex Comorbility Serum Urine Presence of Site of lesion (years) creatinine culture/ ohydro-Nephrosis levels (mg/dl) bacteria at imaging Hina S et al. JCPSP 2019 (5) 55 Female Recurrent UTI, diabetes 1.1 E. coli Right Right VUJ Rabani S et al. Urol J 2019 (6) 1.7 Female Recurrent UTI Normal E. coli None Right lateral wall Sirithanaphol W et al. JECR 2018 (2) 66 Female Panniculitis, sistemic sclerosis, pulmonar fibrosis Normal Negative None \ Parkin CJ et al. BJ 2020 (15) 82 Female Recurrent UTI, diabetes, LNH 2.66 E. coli Bilateral Right and left VUJ and the trigone Gao P et al. JIMR 2021 (4) 48 Male Diabetes 1.4 E. coli Right Right lateral wall involving right VUJ Shah A et al. PSI 2005 (8) 11 Male Recurrent UTI, megalo-urethra and PUJ Normal E. coli None Postero and left lateral walls Ristic-Petrovic A et al. VP 2013 (3) 53 Female Recurrent UTI \ E. coli \ Trigone, left VUJ, posterior wall Nabeshima A et al. J UOEH 2012 (16) 65 Female No significantpasthistory Normal E. coli \ Trigone Bruce R et al. UR 1990 (17) 86 Female Recurrent UTI, small cell carcinoma \ E. coli none Bladder dome Stamatiou K et al. NUM 2014 (1) 72 Male Recurrent UTI, diabetes, CVD 21 Positive Bilateral Trigone, left VUJ, posterior wall Mukha RP et al. IUN 2010 (18) 40 Male Recurrent UTI 2.8 \ Bilateral \ Jordaan HF et al. Clin Exp Dermatol 1990 (19) 68 Female Recurrent UTI, pemfigo and immunodeficiency \ E. coli Normal \ Minor L et al. J Urol 2013 (9) 16 Female \ 3 E. coli Bilateral \ Patniak R et al. Cases J 2009 (11) 18 Male No significantpasthistory 1.6 Negative Bilateral Trigone, left VUJ, bladder neck Berney DM et al. Histopathology 1996 (12) first case 72 Female No significantpasthistory \ Negative \ \ Berney DM et al. Histopathology 1996 (12) second case 57 Male Acute renal failure \ \ \ \ PozoMengual B et al. Actas Urol Esp 2003 (14) 76 Female No urological history Normal Negative None Postero wall and bladder dome Sulman A et al. Urology 2002 (20) 40 Female Recurrent UTI \ E. coli None Bladder neck and left lateral wall Billis A. Nephron 1994 (21) 27 Female CRI/ESDR \ Negative \ Trigone Nukui M et al. Hinyokika Kiyo, 1997 (22) 63 Female No significant past history 2.9 \ Bilateral Trigone and bilateral VUJ Batchelor JS. Br J Urol 1991 (23) 63 Female Recurrent UTI \ \ \ Posteriorwall Bylund J et al. Nat Clin Pract Urol 2008 (24) 51 Female Recurrent UTI, blood hypertension 3.4 E. coli Bilateral \ Feldman S et al. J Urol 1980 (25) 50 Female Recurrent UTI 3.8 E. coli Bilateral Ureteral orifices were not visualized Stanton MJ. J Urol 1983 (13) 48 Female Recurrent UTI \ E. coli None Right hemitrigone, right lateral wall and bladder neck Fariña Perez LA. Actas Urol Esp 1999 (26) 69 Male CVD, TBC \ Corynebacteriumurealyticum None Postero and bilateralwall Kohda N Hinyokika K et al. 1984 (27) 44 Female Recurrent UTI 0.7 Negative None Posterior, left and right wall Zornox DH et al. J Urol. 1979 (28) 69 Female No significantpasthistory Normal E. coli None Right lateralwall Kato T et al. Hinyokika K 2001(29) 70 Female Recent pyelonephritis, HCV Normal E. coli Right Trigone, bilteral VUJ and neck Stripling JR et al. South Med J 1979 (30) 38 Male No significantpasthistory 15 E. coli Bilateral Trigoneoblitering the ureteral orifices Cavallone B, et al. Urologia 2018 (31) 65 Female Recurrent UTI, diabetes, obesity 9.3 E. coli Bilateral Anterior and left lateral wall Tsai R et al. AJR Am J Roentgenol 2016 (32) 31 Female \ \ Negative None Left wall Steele B et al. Pediatr Radiol 2003 (33) 16 Female CRI, VUR 2.8 E. coli Bilateral \ Tsung SH. Urology 1982 (34) 50 Female No significantpasthistory Normal E. coli \ \ Cowie AG et al. Br J Surg 1970 (35) 50 Female Recurrent UTI Normal E. coli None Internal meatus Andress MR et al. Br J Radiol 1968 (36) 36 Male Dystrophia myotonica \ E. coli Bilateral Widely distributed, with bilateral involvment of VUJ Melicow MM. J Urol 1957 (37) 64 Female Cholecystectomy \ E. coli Left \ Archivio Italiano di Urologia e Andrologia 2022; 94, 3 G. Polisini, R.F. Delle Fave, C. Capretti, A. Marronaro, A.M. Costa, L. Quaresima, D. Mazzaferro, A.B. Galosi 352 Hydroureteronephrosis was present in 44.44% of the cases, was absent in 36.11%, and was missing in 19.44%. In the patients with hydroureteronephrosis, 6.25% had left, 18.75% right and 75% bilateral hydroureteronephro- sis.. The mean serum creatinine of patients with hydroureteronephrosis was 5.11 (1-21) mg/dl. Regarding the site of the lesion, this information was missing in 10 cases (27.78%). In most of the remaining 26 cases the disease occurred in more than one area of the bladder. Location, in order of frequency, was vesicoureter- al junction (VUJ) in 42.31%, trigone in 38.46%, left later- al wall in 30.77%, right lateral wall in 26.92%, posterior wall in 26.92%, bladder neck in 15.38%, bladder floor in 7.69% and anterior wall in 3.85%. With regard to treatment, we excluded from the analy- sis nephrostomies, urinary shunts without cystectomy and ureteral stent placement aimed at treating hydroureteronephrosis and not bladder pathology. Treatment in 2.78% of cases was not reported. 30.56% of patients were treated with antibiotic and surgery (transurethral resection of bladder, partial or radical cys- tectomy). The remaining were treated as follows: 13.89% with antibiotics alone, 22.22% with surgery alone, 5.56% with antibiotic and bethanechol, 5.56% with antibiotic, bethanechol and ascorbic acid, 5.56% with antibiotic, bethanechol, ascorbic acid and surgery, 8.33% with antibiotic, ascorbic acid and surgery and 5.56% with fol- low-up only. In total, therefore, the two most frequently used treat- ments were antibiotic therapy (69.44%) and surgery (66.67%). Regarding surgery, 75% of operations were transurethral resection of the bladder (TURB), the remaining being partial or radical cystectomy. Regarding recurrences, they were missing in 12 case reports (33.33%). Out of the remaining 24 case reports, we excluded 2 cases because the patient had had a cys- tectomy and could not perform bladder follow-up and 2 other articles due to sudden death from other causes within about one month after diagnosis. In the remaining 20 reports, the recurrence rate was 15%. Cases treated with medical therapy alone (without surgical removal) that demonstrated a reduction of the bladder mass on fol- Table 2. Treatment and follow up. Article Treatment Follow up Hina S et al. JCPSP 2019 (5) Antibiotics, ascrorbic acid, TURB \ Rabani S et al. Urol J 2019 (6) Partial cystectomy, trimethoprim-sulfamethoxazole No recurrence after 9 years Sirithanaphol W et al. JECR 2018 (2) Ciprofloxacin, TURB No recurrence Parkin CJ et al. BJ 2020 (15) Amoxicillin-clavulanic acid, TURB No recurrence after 2 months Gao P et al. JIMR 2021 (4) TURB, tazobactam Bladder recurrence at 6 months with right idroureteronephrosis Shah A et al. PSI 2005 (8) Antibiotics Bladder recurrence 2 and 3 years later Ristic-Petrovic A et al. VP 2013 (3) TURB \ Nabeshima A et al. J UOEH 2012 (16) TURB \ Bruce R et al. UR, 1990 (17) Antibiotics \ Stamatiou K et al. NUM 2014 (1) Quinolones, TURB He died 8 months later after a further worsening of renal failure and complications of the cardiovascular system Mukha RP et al. IUN, 2010 (18) Radical cystectomy \ Jordaan HF et al. Clin Exp Dermatol 1990 (19) Trimethoprim-sulfamethoxazole, bethanechol, ascorbic acid No recurrence Minor L et al. J Urol 2013 (9) Quinolones, bethanechol No recurrence Patniak R et al. Cases J 2009 (11) Antibiotics No recurrence after 10 years Berney DM et al. Histopathology 1996 (12) first case Antibiotics, radical cystectomy The patient initially improved, but developed renal failure and died 3 months after cystectomy Berney DM et al. Histopathology 1996 (12) second case Radical cystectomy He died a month after radical cystectomy PozoMengual B et al. Actas Urol Esp 2003 (14) Ciprofloxacin, TURB At 15 day the patient developed a sepsis and she died after 48 hours Sulman A et al. Urology 2002 (20) Antibiotics, TURB \ Billis A. Nephron 1994 (21) \ \ Nukui M et al. Hinyokika Kiyo 1997 (22) TURB, trimethoprim sulfamethoxazole, bethanecol, ascorbic acid No recurrence after 20 months. Batchelor JS. Br J Urol 1991 (23) Follow up No recurrence after18 months but the patient developed LHN Bylund J et al. Nat Clin Pract Urol 2008 (24) Ciprofloxacin, ascorbic acid, bethanechol, TURB No recurrence after 6-9 months Feldman S et al. J Urol 1980 (25) Follow up Bladder recurrence after 2 months. The patient underwent total cystectomy Stanton MJ. J Urol 1983 (13) Trimethoprim-sulfamethoxazole, ascorbic acid, bethanechol No recurrence after 18 months Fariña Perez LA. Actas Urol Esp 1999 (26) TURB After 30 days, he died for heart failure Kohda N Hinyokika K et al. 1984 (27) TURB \ Zornox DH et al. J Urol 1979 (28) trimethoprim-sulfamethoxazole, ascorbic acid, TURB No recurrence after 12 month Kato T et al. Hinyokika K 2001(29) TURB No recurrence after 7 months Stripling JR et al. South Med J 1979 (30) Cephalosporin, TURB No recurrence Cavallone B et al. Urologia 2018 (31) Ciprofloxacin, ascorbic acid, TURB \ Tsai R et al. AJR Am J Roentgenol. 2016 (32) Bethanechol, rifampicin and trimethoprim-sulfamethoxazole No recurrence after 2 months Steele B et al. Pediatr Radiol 2003 (33) Ciprofloxacin No recurrence, decrease in the number and size of lesions Tsung SH. Urology 1982 (34) Antibiotics \ Cowie AG et al. Br J Surg 1970 (35) Antibiotics, cystotomy No recurrence, small residual nodule that was fulgurated. No further cystoscopic abnormality has developed Andress MR et al. Br J Radiol 1968 (36) TURB, antibiotics \ Melicow MM. J Urol 1957 (37) Cystectomy \ 353Archivio Italiano di Urologia e Andrologia 2022; 94, 3 Malakoplakia of the urinary bladder low-up imaging were not considered as recurrences. The shortest follow-up was 2 weeks and the longest was 10 years. The recurrence rate of patients treated with antibiotics alone was 1/3 (33.33%). The recurrence rate of patients treated with antibiotic and surgery was 1/7 (14.29%). The recurrence rate of patients treated with follow up was 1/2 (50%). On the other hand, according to the single treatment, the recurrence rate of antibiotic use was 11.76%, of surgery 9.09% and follow-up only 50%. DISCUSSION Malacoplakia is a rare inflammatory and granulomatous disease. It was first identified by Michaelis and Gutmann in 1902 and its histological features were described by Von Hansemann in 1903. The term 'malacoplakia' originates from the Greek 'malakos' and 'plakos' and means 'soft plaque' (7). According to recent literature, the age of onset is over 50 years with a prevalence four times higher in women. Malacoplakia mainly affects the urinary tract, particularly the bladder, followed by the kidney, the prostate and rarely the ureter (4, 5, 38). However, it may also affect other parts of the body including the conjunctiva, tonsils, adre- nal glands, spleen, pancreas, retroperitoneum, mesenteric lymph node, brain, lung, and skin and potentially any organ. In addition, urinary involvement is more frequent in women and extra urinary involvement in men (8). The exact etiology is still unclear. However, a close asso- ciation has been seen with recurrent urinary infections (especially from E. coli) and immunodepression (diabetes, kidney transplant) (7). In fact, Malakoplakia is believed to result from defective phagocytosis [due to reduced intracellular levels of cyclic guanosine monophosphate (cGMP)], resulting in inadequate killing of bacteria. It results in granulomatous reaction caused by an accumulation of bacterial degradation prod- ucts. Partially digested bacteria become calcified and accumulate in macrophages, forming the pathognomonic Michaelis-Gutmann bodies (9). In addition, the macrophages involved in malacoplakia contain high immunoreactive a1-antitrypsin levels unlike other inflammatory processes (except for tuberculosis and xanthogranulomatous pyelonephritis). Thus, immunohis- tochemical search for a1-antitrypsin can be useful for a dif- ferential diagnosis (10). Clinically, it presents with irritative lower urinary tract symptoms (LUTS) such as dysuria, pollakiuria, urinary urgency and haematuria. These symptoms may mimic cystitis and bladder cancer. Diagnosis is histological by biopsy of the visible mass on cystoscopy which as mentioned above, it appears as a yel- low soft tiny plaque or ulcer (11). It is characterized histologically by Von Hansemann oval histiocytes which contain basophilic lysosomal inclusion bodies called Michaelis Gutmann bodies (12). Imaging examinations (ultrasonography, CT and IVP) may be useful to identify concomitant hydroureteronephrosis and to identify minus defects of the upper urinary tract, indicating its involvement. Currently there are no validated guidelines regarding its treatment (5). Antibiotics are gener- ally administered to treat the underlying infection, such as quinolones, trimethoprim and rifampicin, in combination or not with ascorbic acid and/or bethanechol (4). Ascorbic acid and bethanechol (cholinergic agent) both seems to increase intracellular cyclic guanine monophos- phate levels increasing bactericidal phagocytosis function of macrophages (13). Surgical intervention is recommended when medical intervention fails (14). The results listed below are in agreement with the data described in the literature: - the average age was found to be around 50 years, - the disease is more frequent in women than in men, - malacoplakia seems to be associated with recurrent UTI and immune system disorders. - about 90% of positive urine cultures are sustained by E. coli. In our study of the epidemiology, we found a lower mean age of incidence in men than in women by about 10 years, with a women:men frequency ratio of 3:1, instead of 4:1 as reported in the literature. In our review, we decided to look at the site of the disease and found that the most frequently affected sites were the trigone and ureteral meatuses. For the first time in our analysis, we found that about one third of patients had hydronephrosis (mono or bilateral) and that this correlated with involvement of the trigone and/or VUJ. In the cases examined, hydronephrosis almost always led to renal failure with mean serum crea- tinine values of 5.1 mg/dL (the highest value found in a case of acute renal failure was 21 mg/dL). CONCLUSIONS Nowadays, malakoplakia is a disorder not well know, that seems related to other affections, like UTI and immun- odepression, and is thought to be the result of abnormal macrophage function. In accordance with the literature, it can present with a very-variable spectrum of symptoms although we have shown that in isolated bladder malakoplakia without ureteral involvement, hydroureteronephrosis and renal failure are very common (in almost half of the cases). Treatment is not standardized, but both medical and sur- gical therapies seem to be effective in curing the condition and avoiding recurrence, although we did not collect suf- ficient data to perform a statistical analysis. REFERENCES 1. Stamatiou K, Chelioti E, Tsavari A, et al. 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Correspondence Giordano Polisini, MD gio.pol.93@gmail.com (Corresponding Author) Rocco Francesco Delle Fave, MD dellefavefrancesco@alice.it Andrea Benedetto Galosi, MD a.b.galosi@univpm.it Division of Urology, University Hospital “Ospedali Riuniti”, School of Medicine, Department of Clinical, Special and Dental Sciences, Marche Polytechnic University, Ancona, Italy Camilla Capretti, MD camilla.capretti@sanita.marche.it Angelo Marronaro, MD angelo.marronaro@sanita.marche.it Alessia Mariagrazia Costa, MD alessia.costa@sanita.marche.it Luigi Quaresima, MD luigi.quaresima@sanita.marche.it Daniele Mazzaferro, MD daniele.mazzaferro@sanita.marche.it Department of Urology, Civitanova Marche Hospital, Civitanova Marche, Italy