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Malakoplakia
Introduction
Malakoplakia is a rare inflammatory condition that typically occurs in immunocompromised individuals. It was first described by Michaelis and Gutmann in 1902 after identifying the Michaelis-Gutmann bodies that are pathognomonic for this condition.[1] In 1903, von Hansemann coined the term “malakoplakia,” meaning “soft plaque.”[2] This condition typically affects the urinary tract, but the involvement of nearly every organ system has been reported to include the pulmonary, gastrointestinal, endocrine, musculoskeletal, lymphatic, integumentary, and central nervous systems.[3][4] While the exact etiology is unknown, Escherichia coli is the most common organism associated with this condition, although several others have been implicated.[3][4][5] Common treatment approaches include a combination of surgical excision and oral antibiotics or oral antibiotics as monotherapy.[1][3][6][7]
Etiology
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Etiology
The exact pathogenesis of malakoplakia is poorly understood. It is thought to be due to an acquired bactericidal defect in macrophages. Beta-glucuronidase and cyclic guanosine monophosphate (cGMP) are required for normal microtubular function and phagolysosomal activity. Diminished beta-glucuronidase release and decreased cGMP levels have been demonstrated in patients with malakoplakia. This is believed to lead to decreased clearance of pathogenic organisms due to the persistence of phagolysosomes. The pathognomonic Michaelis-Gutman bodies (calcified intracytoplasmic inclusions) are thought to represent the phagolysosomes that have not been exocytosed.[3][8] The disease process is typically associated with acquired immunosuppression. It has been described in patients with human immunodeficiency virus (HIV), organ transplants, malignancy, diabetes mellitus, connective tissue diseases, hepatitis C, and sarcoidosis.[4][5][9] While the disease process is rare in children, there have been cases associated with X-linked agammaglobulinemia, common variable immunodeficiency, and severe combined immunodeficiency.[5][10] Malakoplakia is typically caused by gram-negative rods. The most common causative species of bacteria is Escherichia coli. Still, many other bacterial organisms have been implicated, including Klebsiella, Proteus, Corynebacterium, Pseudomonas, Acinetobacter, Staphylococcus, Streptococcus, Enterococcus, Aerobacter, Rhodococcus, Mycobacterium, Salmonella, and Burkholderia species.[3][4][9][11]
Epidemiology
Malakoplakia of the genitourinary tract is more prevalent in females, with an approximate ratio of 4 to 1. However, this ratio is lost in cases of malakoplakia found outside the genitourinary tract. There is an increased risk of cutaneous malakoplakia in males, with an approximate ratio of 2 to 1. Malakoplakia is most common in older patients, with a peak incidence in those over 50 years of age but with a reported range of 6 weeks to 85 years of age.[3][12][13][14]
Pathophysiology
The exact pathogenesis of malakoplakia is not well defined. It has been demonstrated that the bactericidal capacity of macrophages is defective in malakoplakia. It is thought to be due to deficiencies in beta-glucuronidase and intracellular cGMP, which results in inadequate microtubular function and phagolysosomal activity and accumulates partially digested bacteria in macrophages.[3][4][6][15]
Histopathology
On histology, the examination of affected tissue reveals dermal sheets of von Hansemann cells and a variable mixed inflammatory infiltrate consisting of neutrophils, lymphocytes, and plasma cells. Von Hansemann cells are enlarged foamy histiocytes with an eccentric, hyperchromatic nucleus and eosinophilic granules. Michaelis-Gutmann bodies are intracytoplasmic laminated concretions representing accumulations of calcified, iron-containing phagolysosomes considered partially degraded bacterial organisms. Michaelis-Gutmann bodies are pathognomonic for this condition. They can stain positive with periodic acid-Schiff, Perls, and von Kossa stains.[1][2][3][5][9]
History and Physical
Patients often report a history of immunosuppression, which may be iatrogenic or medical. The clinical presentation of cutaneous malakoplakia is variable, with lesions that can appear as tender ulcerations, nodules, papules, and plaques or as fungating masses with perianal and genital skin being commonly involved. However, other organ systems can be involved, such as thorax, abdominal wall, head, neck, and extremities masses. It is important to keep malakoplakia on the differential diagnosis in individuals with a history of immunosuppression and recurrent infections.[1][4][6][9]
Evaluation
The evaluation of cutaneous malakoplakia is guided by the patient's history and physical examination. A skin biopsy of a suspicious lesion is essential to diagnose cutaneous malakoplakia and exclude other neoplastic, inflammatory, or infectious processes. Michaelis-Gutmann bodies and von Hansemann cells characterize histologic findings for cutaneous malakoplakia. Cultures of the lesions may help further guide antibiotic treatment.[4][6]
Treatment / Management
Given that malakoplakia is rare, large prospective trials are lacking, and evidence reporting successful treatment is largely anecdotal, there are no standardized treatment guidelines. General treatment principles include systemic antibiotics, surgical excision, and limiting immunosuppression. Antibiotics that optimize the intracellular killing of bacteria by phagocytes have been successful in the treatment of malakoplakia. Such antibiotics include fluoroquinolones, trimethoprim/sulfamethoxazole, and rifampin.[3][12][14][16] The optimal treatment duration of antibiotic therapy is unknown, but successful treatment may require long-term antibiotic therapy.[17] Theoretically, adding bethanechol, an anticholinergic agent, and ascorbic acid may increase cellular levels of cGMP within phagocytes and lead to the improved intracellular killing of bacteria.[3][12][16] Surgical excision of malakoplakia lesions should be considered based on the site affected, complications, or if medical treatment fails. Malakoplakia of the upper urinary tract tends to be aggressive. If the renal parenchyma is affected, nephrectomy should be considered. Additionally, if there is urethral, bladder, or ureteral obstruction, surgical excision or resection should be considered.[12][17][18] Combining surgical therapy and quinolone antibiotic therapy may be the most effective treatment.[16](B3)
Malakoplakia is often associated with acquired immunosuppression, including regimens used for organ transplantation or connective tissue diseases. One case series suggested that the use of prednisone and azathioprine was associated with decreased bacterial killing by neutrophils and monocytes; malakoplakia improved with discontinuation of immunosuppression.[19] There have been other reports of successful treatment of malakoplakia after either discontinuing or reducing the dose of prednisone and azathioprine.[16] Per a review of 140 cases of malakoplakia comparing treatment modalities, van der Voort et al suggested the following treatment steps: “(1) If feasible, stop prednisone and azathioprine treatment in those cases where malakoplakia developed during the use of this medication. (2) Perform surgical resection and drainage in combination with ciprofloxacin administration. (3) give ciprofloxacin hydrochloride, 500 mg twice daily if surgery is impossible. (4) Whether adding bethanechol and ascorbic acid offers any advantage to the other treatment modalities remains to be proved.”[16](B3)
Differential Diagnosis
The differential diagnosis includes other infectious diseases, neoplastic, and reactive processes, including:
Prognosis
Cutaneous malakoplakia typically presents as a self-limited condition that rarely leads to death. Lesions can undergo spontaneous regression in immunocompetent individuals with a mean 4 to 6 months duration. In individuals treated with surgery with or without antibiotics, there has been a reported 81% cure rate. However, the course of the disease can be variable and can relapse, cause local disfigurement, or present with internal organ involvement despite medical and surgical management.[3][7][12][16][21][16]
Complications
The associated complications of malakoplakia are largely related to the location and severity of involvement. For example, malakoplakia of the urinary system may be a cause of acute kidney injury, recurrent urinary tract infections, and renal failure and is very rarely fatal.[22][23][24][25][26]
Deterrence and Patient Education
Patients with a history of immunosuppression, whether iatrogenic or secondary to another medical condition, should be warned about potential side effects or sequelae, such as malakoplakia. Patients should be instructed to inform their provider of any persistent, enlarging, or ulcerating skin lesions.
Enhancing Healthcare Team Outcomes
Malakoplakia is a very rare inflammatory condition that typically occurs in immunocompromised individuals. Case reports from the literature have reported successful treatment with antibiotics, surgical excision, or a combination of both. Large randomized controlled studies do not exist for any specific treatments. Because malakoplakia can affect nearly every organ system, this condition is best handled with an interprofessional team approach. Such a team may include the provider managing the immunosuppressive condition or regimen (such as an infectious disease specialist, rheumatologist, primary clinician, oncologist, or transplant clinician), dermatologist, surgeon, and pharmacist. The initial provider may coordinate with the pharmacist for the ideal immunosuppressive regimen. When malakoplakia is suspected, a dermatologist or surgeon may be consulted to perform a biopsy. Depending on the location and complexity of the lesion(s), an infectious disease specialist, dermatologist, and surgeon may be needed to maximize the management of the malakoplakia. Identifying and treating patients who are at risk early and keeping malakoplakia on the differential may reduce morbidity.
References
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