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The mysteries of malakoplakia

DII small banner By Warren R. Heymann, MD
May 24, 2017

A, Dermal nodule with confluent sheets of histiocytes containing abundant granular amphophilic cytoplasm (arrows) admixed with an inflammatory infiltrate and scattered collection of neutrophils. B, Histiocytic inclusions staining positively for calcium on a von Kossa stain. These findings were consistent with malakoplakia.
Credit: JAAD
Any dermatology resident preparing for their board exam will tell you that malakoplakia is defined by Michaelis-Gutmann bodies and von Hansemann cells. Somehow reciting those terms can give a person a false sense of understanding. My perspectives about malakoplakia are based solely on my reading — I have never seen a case in person or microscopically, at least knowingly.

I was intrigued by a case report of malakoplakia described in the Clinicopathological Challenge section of JAMA detailing a case of malakoplakia in a 60+ year-old woman presenting with eroded perianal and labial nodules. Her medical history was that she had chronic graft-versus-host disease following a bone marrow transplant for chronic lymphocytic leukemia, treated with tacrolimus, prednisone, and azathioprine (the lesions appeared prior to the administration of azathioprine). Histologically she demonstrated calcospherites (Michaelis-Gutmann bodies, PAS and von Kossa positive) within nodular inflammation of histiocytes and neutrophils. The bacterial culture was positive for heavy growth of Escherichia coli. The patient improved with ciprofloxacin and a reduction of prednisone; complete resolution followed discontinuation of azathioprine (1).

Malakoplakia (derived from the Greek for ‘soft plaque’) was first described in 1902. Multiple organ systems may be affected, most commonly the urinary (approximately 60%) and gastrointestinal tracts. Cutaneous malakoplakia is rare and clinically heterogeneous, presenting as papules, nodules, ulcers, intertriginous plaques or nonhealing surgical wounds (2). Cutaneous malakoplakia is most commonly seen in older men in the perineal region, although other sites may be involved, including the head and neck (4). Approximately 90% of patients with malakoplakia have evidence of coliform (most commonly E. coli) in the their blood, urine, or tissue (2). Bacteria such as Staphylococcus, Pseudomonas, Proteus, Klebsiella, and Rhodococcus have also been implicated (3).

The pathogenesis of malakoplakia is unknown. Although it may occur in healthy individuals, it is frequently associated with immunosuppression that affects macrophage function. Risk factors for the development of malakoplakia include organ transplantation (23%), especially in kidney transplant recipients; connective tissue disorders (15%); neoplasms (10%); diabetes mellitus (10%); and chronic immunodeficiency disorders, such as HIV, sarcoidosis, hepatitis C, rheumatoid arthritis and lymphoproliferative malignancies. Prolonged therapy with systemic corticosteroids and the use of azathioprine and cyclophosphamide may be responsible. The conditions leading to malakoplakia reflect an acquired defect in cellular immunity resulting in a defective lysosomal degradation of phagocytised bacteria. This may be related to low levels of cGMP, leading to inadequate microtubular function, and a poor release of lysosomal enzymes that are necessary to effectively eliminate bacteria from macrophages (5).

In addition to biopsies and cultures, evaluation of the patient may be aided by FDG-PET scans to determine the extent of disease. Medical management focuses on antibiotics that act intracellularly (i.e., quinolones, trimethoprim- sulfamethoxazole), and eliminating immunosuppressive factors, if possible. For certain lesions a surgical approach is appropriate (5).

According to Alvarez, “M-G [Michaelis-Gutmann] bodies are 5–15 µm targetoid inclusion bodies, described as “bird eyes” or “owl eyes,” located within and outside the cytoplasm of macrophages. The ultrastructure of M-G bodies shows the presence of a core surrounded by a concentric lamina and a finely granular peripheral zone. Calcium, phosphorus, and a variable amount of iron have been detected in the core and laminations. These findings indicate that M-G bodies are an accumulation of nonexocytosed phagolysosomes that have calcified. They stain positively with PAS, Von Kossa, and Giemsa. Bacterial fragments within the bodies have occasionally been reported.” (5)

Most articles refer to the Michaelis-Gutmann bodies as “pathognomonic” for malakoplakia, but are they really? In Nguyen’s histologic description, “calcospherites” were appreciated. A calcospherite is defined as a granular or laminated deposit of calcium salts. A PubMed search of the term demonstrates that calcospherites may be appreciated in diverse entities including pulmonary alveolar microlithiasis, psammomatous calcification in intestinal type gastric carcinoma, oligodendrogliomas, neurodegenerative disorders, testicular microlithiasis, and others.

I concur with Alvarez et al who believe that these calcified bodies, described under different names in the literature (Michaelis–Gutmann bodies in malakoplakia, Schaumann or “conchoidal” bodies in sarcoidosis, psammoma bodies in papillary thyroid cancer), may represent the unfinished job of our immune system in destroying and “taking out the garbage” (5). Learning why these macrophages fail to do so will provide a pathway toward making them truly functional, preventing lesional development.

1. Nguyen Y, et al. Cutaneous nodules in the genital area in a patient with chronic graft-versus-host disease. JAMA Dermatol 2017; 153: 465-6
2. Alwan W, et al. Nonhealing surgical wound site due to cutaneous malakoplakia. Clin Exp Dermatol 2017; 42: 123-5.
3. Alvarez P, et al. Calcified bodies in New World cutaneous leishmaniasis. Am J Dermatopathol 2011; 33: 827-30.
4. Coates M, et al. A case of cutaneous malakoplakia in the head and neck region and review of the literature. Head and Neck Pathol 2016; 10: 444-50.
5. Smith-Pliego M, et al. Cutaneous malakoplakia masquerading as pyoderma gangrenosum. Int Wound J; 2016 Aug 15 [Epub ahead of print].

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