International Wound Journal ISSN 1742-4801
ORIGINAL ARTICLE
Cutaneous malakoplakia masquerading as pyoderma gangrenosum Mariam Smith-Pliego1 , Jose Contreras-Ruiz1 , Siobhan Ryan3 , R Gary Sibbald3 , Wedad Hanna4 & Rodrigo Roldan-Marin1,2 1 Department of Dermatology, “Dr. Manuel Gea Gonzalez” General Hospital, Mexico City, Mexico 2 Faculty of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico 3 International Interdisciplinary Wound and Ostomy Care Center, Sunnybrook & Women’s College Health Sciences Centre, Toronto, Canada 4 Department of Pathology, Sunnybrook & Women’s College Health Sciences Centre, Toronto, Canada Key words Cutaneous malakoplakia; Michaelis–Gutmann bodies; Pyoderma gangrenosum; Skin ulcer Correspondence to Roldan-Marin, MD Facultad de Medicina División de Investigación Circuito Interior Ciudad Universitaria Av. Universidad 3000 Mexico City 04510 Mexico E-mail:
[email protected]
Smith-Pliego M, Roldan-Marin R, Ryan S, Sibbald RG, Hanna W, Contreras-Ruiz J. Cutaneous malakoplakia masquerading as pyoderma gangrenosum. Int Wound J 2016; doi: 10.1111/iwj.12661 Abstract Cutaneous malakoplakia is a rare infection-related granulomatous disease frequently associated with immunocompromised states. Foamy macrophages containing basophilic granules, called the Michaelis–Gutman bodies, are pathognomonic. We report a case of cutaneous malakoplakia in a 77-year-old male with pyoderma gangrenosum and a 2-year history of a non-healing malleolar ulcer treated successfully with cotrimoxazole.
CASE REPORT
A 77-year-old male with a history of recurrent ulcerations presented with a 2-year-old non-healing wound. A 6⋅5 cm × 4 cm plaque was located on the right medial malleolus, characterised by multiple small draining ulcerated sinuses with exophytic granulation tissue alternating with skin-coloured to yellow and pink papules surrounded by scarred skin. (Figure 1A) The plaque was soft and almost fluctuant to the touch. The patient had a previous history of pyoderma gangrenosum (PG) and had therefore received unsuccessful treatment with oral mycofenolate mofetil (MFM), topical 0⋅1% tacrolimus ointment and intralesional steroids. At the time of consultation, the patient was on a topical silver-releasing foam, compression bandages, oral prednisone 15 mg per day, cefalexin 500 mg every 6 hours and intralesional triamcinolone around the wound edge (3 cc of 20 mg/mL) every 5 weeks without any progress. Other comorbidities included coronary artery disease, diabetes mellitus, hypertension, hypercholesterolaemia and multiple scars from previous pyoderma gangrenosum ulcers without any other association. Laboratory work-up revealed an elevated erythrocyte sedimentation rate (ESR) 55 mm/h, a C-reactive protein value of 19 and leukocytosis with neutrophilia. A plain X-ray of the foot did © 2016 Medicalhelplines.com Inc and John Wiley & Sons Ltd doi: 10.1111/iwj.12661
not show any signs of osteomyelitis. Wound culture revealed recurrent growth of Escherichia coli. Given that the patient was not responding and because of the unusual clinical presentation, a 4-mm punch skin biopsy was performed on a newly developed sinus.
MICROSCOPIC FINDINGS AND CLINICAL COURSE
The biopsy specimen revealed a diffuse histiocytic infiltrate and focal areas with abscess formation. These were formed by the
Key Messages • malakoplakia is a rare infection-related granulomatous disease frequently associated with immunocompromised states • foamy macrophages containing basophilic granules, called the Michaelis–Gutmann bodies, are pathognomonic • effective treatment requires discontinuation of immunosuppressive drug therapy and adequate use of antibiotics that concentrate within macrophages • cutaneous involvement is rare
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Cutaneous malakoplakia masquerading as pyoderma gangrenosum
M. Smith-Pliego et al.
Figure 1 (A) Multiple draining sinuses alternating with yellow to skin-coloured papules on the medial malleolus of the right ankle. (B and C) Typical features containing closely packed macrophages PAS-positive diastase-resistant inclusions or Von Hansemann cells. (D) Von Kossa stain showing small intracellular concentrically calcified structures (Michaelis–Gutman bodies).
central necrotic area and neutrophils surrounded by sheets of histiocytes. The latter had abundant eosinophilic and granular cytoplasm (von Hansemann cells) and basophilic intracytoplasmatic laminated inclusions with targetoid appearance in many of the histiocytes, also known as Michaelis–Gutmann bodies, pathognomonic of malakoplakia. These were clearly delineated using special iron and calcium stains (Figure 1B–D). The patient was started on cotrimoxazole; intralesional steroids were stopped, and oral steroids were slowly tapered. The wound healed after 8 weeks of therapy, although tapering the steroids caused flaring of already healed areas of pyoderma gangrenosum. DISCUSSION
Malakoplakia was first described by Michaelis and Gutmann in 1902 (1,2) and later by von Hansemann in 1903, who named the lesion after the Greek words ‘malako’ meaning soft and ’plakia’ meaning plaque (3–5). It is an inflammatory granulomatous condition that usually affects the genitourinary tract in 60–70% percent of the cases (6), but it has also been described in other anatomic locations, including the gastrointestinal and respiratory tract (1), prostate, thyroid gland, lymph nodes, bones and joints, middle ear, oropharynx, eyes and brain (5,7). Cutaneous involvement is rare, with fewer than 50 cases reported in the literature (5,8,9), the first being described by Leclerc and 2
Bernier in 1972 (1,7,10) in a 64-year-old man with rheumatoid arthritis and a perianal lesion (8). The most commonly reported affected sites include the perianal area in 41% of cases (including vulva, inguinal, scrotum area) (5), followed by the abdominal wall and thorax in 20% (related to surgical scars or drainage sites) (8), head and neck with equal percentage (including forehead, eyelid) and finally the extremities in 10% (5,8). It occurs with a male/female ratio of 2⋅3:1, although there are few reports in which prevalence among women is higher (6). The median age at time of presentation is 53 years, ranging from 2 months to 81 years, more commonly affecting adults (2,7,8). Although the pathogenesis of the disease is poorly understood, its occurrence is associated more commonly with the presence of an immunocompromised (1) state affecting macrophage function rather than with age. Recent data report that it may occur even in healthy patients. Risk factors for the development of malakoplakia include organ transplantation (23%) (8), especially in kidney transplant recipients; connective tissue disorders (15%); neoplasm (10%) (5,8); diabetes mellitus (10%); and chronic immunodeficiency disorders, such as HIV, sarcoidosis, hepatitis C, rheumatoid arthritis and haematological malignancies (4,10). Prolonged therapy with systemic corticosteroids and the use of azathioprine and cyclophosphamide also contribute in this manner (5). The conditions leading to malakoplakia in most cases appear to reflect an acquired defect in cellular immunity (3,6), resulting © 2016 Medicalhelplines.com Inc and John Wiley & Sons Ltd
M. Smith-Pliego et al.
Cutaneous malakoplakia masquerading as pyoderma gangrenosum
in a defective lysosomal degradation of phagocytised bacteria (1,6). Clinically, lesions may vary, but they usually have gross appearance (8) and may be misdiagnosed; thereby, a biopsy is usually required for the diagnosis. The lesions may present as yellow-to-pink papules, but they can also appear as nodules, draining sinuses or ulcerations (7,8). Culture of the lesions can yield bacteria, most commonly coliform bacilli such as Escherichia coli (isolated in a 93%) (5,8), but also Klebsiella, Proteus, Pseudomonas, Mycobacterium avium, Mycobacterium tuberculosis, Shigella sp, Staphylococcus auereus, Enterococcus sp and Rhodococcus equi in HIV patients (1–3). Malakoplakia, according to Thorning and Vracko (3), is believed to result from the inadequate killing of bacteria by macrophages because of defective phagolysosomal activity (1). In vitro studies have suggested the presence of low levels of cyclic guanosine monophosphate (cGMP) leading to inadequate microtubular function and poor release of lysosomal enzymes required for an effective bacterial elimination from macrophages (11). Microscopically, cutaneous malakoplakia consists of dermal sheets of large macrophages with abundant cytoplasm containing fine eosinophilic granules, the von Hansemann cells (6,8), with a variable inflammatory infiltrate of lymphocytes, plasma cells and neutrophils (7), and the partially digested bacteria that accumulate in macrophages leading to deposition of calcium and iron (7,11). The resulting presence of a basophilic intracytoplasmic inclusion (6), the Michaelis–Gutmann bodies, is considered pathognomonic for the diagnosis of malakoplakia (11). Biopsy specimens should be processed using routine haematoxylin and eosin stain, periodic acid-Schiff stain (PAS), von Kossa stain for calcium (5,6) and Perls Prussian blue stain for iron. Michaelis–Gutmann bodies that stain positive with periodic acid-Schiff may be mistaken with fungal spores (10). There are two case reports of staining with anti-mycobacterium bovis (BCG) as a technique for screening of bacterial, mycobacteria and fungal organisms, useful in differentiating the negative staining Michaelis–Gutmann bodies from positive-staining bacteria within the histiocytic cells (10). The histiocytic cell stain for alpha-1 antitrypsin, lysozyme and CD-68 confirms their histiocytic nature (12). Malakoplakia with negative culture results has been reported in 7–19%, presumably secondary to prior use of antibiotics. Differential diagnoses to be considered are infectious, neoplastic and reactive processes. Infectious causes include lepromatous leprosy, actinomycosis, Whipple disease, Cryptococcus infection and leishmaniasis. Among the neoplastic and reactive causes, we may consider sarcoidosis, squamous cell carcinoma, Langerhans cell histiocytosis, malignant lymphoma,
histiocytoma, granular cell tumour, skin abscess, botryomycosis and pyoderma gangrenosum (1,8). Effective treatment requires the discontinuation of immunosupresive drug therapy and adequate use of antibiotics that concentrate in macrophages: gyrase inhibitors (9) and sulfonamide-diaminopyrimidina (e.g., quinolones, trimethoprim-sulfamethoxazole) (5,7,8). Therapy should be directed against E. coli and continued until skin lesions resolve clinically. Bethanechol chloride, a acetycholine agonist (6,8), has been used in combination with antibiotics as it may correct the decreased cGMP levels (7) that are believed to interfere with complete bacterial killing. The best results are achieved with surgical intervention, either excision or curettage (5,6), and overlapping antibiotic therapy. Complications include local disfigurement and organ dysfunction with visceral involvement. Prognosis is usually good as the clinical course tends to be benign (7).
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