Oy, another “Oid” to worry about: Cryptococcoid lesions

By Warren R. Heymann, MD
July 3, 2019
Vol. 1, No. 17

The suffix “oid” means “resembling.” There is a plethora of “oids” in dermatology — lichenoid, Pagetoid, rupioid, targetoid, to name a few. (My favorite is “oid-oid” disease, aka Sulzberger-Garbe disease, or exudative discoid and lichenoid chronic dermatosis; a likely a variant of severe nummular dermatitis, originally described in Jewish men. (1) Until I wrote this introduction I had assumed “oid-oid” was really meant to be “oy-oy” disease!) 

Clinical and histologic mimicry challenge even the most seasoned dermatologists. The latest “oid” that may compel clinicians to say “oy” is the cryptococcoid histologic appearance of neutrophilic dermatoses (ND). 

The clinical variability of ND runs the spectrum from urticarial lesions to Sweet syndrome, pyoderma gangrenosum, to resembling necrotizing fasciitis (so-called “necrotizing neutrophilic dermatoses”). (2) Cryptococcus neoformans infections present with a wide variety of cutaneous morphologies. Primary infections may be observed in immunocompetent or immunocompromised hosts, as an ulceronodular lesion or abscess. In immunosuppressed hosts, whether by HIV or iatrogenic immunosuppression, as seen in transplant patients, disseminated cryptococcosis is more likely. Cutaneous manifestations can be protean in disseminated disease, presenting as abscesses, molluscum contagiosum-like lesions, cellulitis, or panniculitis. (3) 

The histological diagnosis of cryptococcosis is based upon the identification of organisms, which are characteristically doubly refractile, measuring 5 to 15 μm in diameter, and containing a periodic acid‐Schiff (PAS)‐positive, Gomori methenamine silver (GMS)‐positive cell wall and a polysaccharide capsule that can be highlighted with mucicarmine and Alcian blue stains. Tissue diagnosis can be more difficult in the setting of capsule‐deficient organisms and phagocytosed organisms; mucicarmine and Alcian blue stains may not show capsules under these circumstances. (4)

Ko et al described three cases demonstrating a neutrophil-predominant dermal infiltrate admixed with abundant acellular bodies surrounded by capsule-like vacuolated spaces, which strikingly mimicked Cryptococcus. Two cases occurred within the setting of underlying hematologic malignancies; the third case was associated with immune dysregulation. Two patients were acutely ill in the medical intensive care unit. Fungal work-up, including cultures and multiple stains (PAS, GMS, and mucicarmine) were negative. Because of clinical deterioration in these two patients, transmission electron microscopy was performed, definitively ruling out a fungal infection. In both cases, characteristics most compatible with autolysing neutrophils, not Cryptococcus, were identified. The authors theorized that the degrading cells represented neutrophils undergoing autophagy-related programmed necrotic death, involving extensive cytosolic vacuolization. (5) A similar case of an 82-year-old woman with diabetes and chronic renal insufficiency presenting with ulcerative plaques on the trunk and extremities was reported by Bynekova et al. A similar histologic picture was detailed, and a FISH study, using a Cryptococcus specific probe, was negative. (6)

Fresco et al reported two cases of leukocytoclastic vasculitis with virtually identical cryptococccoid changes. The first case was a 73-year-old woman with end-stage renal disease on dialysis and the second was a 50-year-old woman with end-stage renal disease on dialysis, who had used cocaine (presumably leading to levamisole-induced vasculitis). Both patients had positive serum anti-myeloperoxidase antibodies. The former patient died whereas the latter improved following administration of intravenous methylprednisolone. (4)
Wilson et al detailed two cases histiocytoid Sweet syndrome, with cryptococcoid features, in which the cells stained positively for CD68 and myeloperoxidase. Interestingly, both patients had a history of cocaine use and positive antineutrophilic cytoplasmic antibodies, suggesting that these lesions were due to levamisole-contaminated cocaine. (7) 
Just to complicate matters further, Akabary et al reported the case of a 76-year-old man with pulmonary sarcoidosis, COPD, and Nocardia pneumonia; he was treated with prednisone and trimethoprim-sulfamethoxasole. He developed a cellulitic plaque on his left calf. A biopsy revealed a neutrophilic infiltrate with neutrophilic debris — on higher power encapsulated cells stained positively for PAS, GMS, and mucicarmine, confirming the diagnosis of cryptococcal cellulitis. In this case, the authors were initially suspecting a neutrophilic dermatosis, however the detailed histologic findings proved to be Cryptococcus, not cryptococcoid. (8) 

The moral of this saga is to keep an open mind regarding potential diagnostic pitfalls should you receive a biopsy report detailing cryptococcoid changes in the context of ND — while it may be an actual cryptococcal infection, it may also be non-infectious and reactive. Securing a precise diagnosis is crucial given the therapeutic differences and possible devastating consequences of misdiagnosis. Consider “oid” lesions to avoid an “oy vey” outcome. 

Point to remember: Histologic cryptococcoid changes may accompany neutrophilic dermatoses, including Sweet syndrome and leukocytoclastic vasculitis. It is incumbent on clinicians and dermatopathologists to perform appropriate studies (histologic stains, FISH, cryptococcal antigen testing in the CNS or serum) to ascertain if there is a true cryptococcal infection or mimicry at play.   

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Our expert’s viewpoint

Jason B. Lee, MD
Professor & Clinical Vice Chair
Department of Dermatology & Cutaneous Biology, Thomas Jefferson University

This is a timely topic for me as I have recently encountered 3 cases that had this histopathological finding. I have seen this pattern on several occasions in the setting of vasculitis and Sweet syndrome. As noted in Dr. Heymann’s commentary, this likely represents a reaction pattern seen in degenerative changes of dense neutrophilic infiltrate. The identity of these cryptococcoid ballooned cells has been postulated to be neutrophils undergoing degenerative changes, but recent reports of CD68 positivity of these cells suggest that they may represent ballooned histiocytes. Though cryptococcoid neutrophilic dermatosis and cryptococcal infection may appear strikingly similar on H&E, the two entities are easily differentiated by fungal stains.

1. Tabara K, Noweta M, Bienias W, Kaszuba-Bartkowiak K, Kaszuba A. A 6-year-old boy with Sulzberger and Garbe dermatosis: A case report and literature review. Postepy Dermatol Alergol. 2013; 30:403-8.
2. Sanchez IM, Lowenstein S, Johnson KA, Babik J, et al. Clinical features of neutrophilic dermatosis variants resembling necrotizing fasciitis. JAMA Dermatol 2019; 155: 79-84. 
3. Akram SM, Koirala J. Cryptococcus (Cryptococcosis), Cutaneous. StatPearls [Internet]. Treasure Island (Fl). StatPearls Publishing; 2019-2019 Jan 30.
4. Fresco A, Wang J, Krausz A, Chan A, et al. Cryptococcus-like changes in the setting of vasculitis. J Cutan Pathol 2019; 46: 143-147.  
5. Ko JS, Fernandez AP, Anderson KA, Burdick LM, et al. Morphologic mimickers of Cryptococcus occurring within inflammatory infiltrates in the setting of neutrophilic dermatitis: A series of three cases highlighting clinical dilemmas with a novel histologic pitfall. J Cutan Pathol 2013; 40: 38-45. 
6. Byekova YA, Shedd AD, Schiro JA, Barrett TL, Lewin M. An additional case of neutrophilic dermatosis histopathologically mimicking Cryptococcus in a patient with Sweet’ syndrome. J Cutan Pathol 2014; 41: 972-974. 
7. Wilson J, Gleghorn K, Kelly B. Cryptococcoid Sweet’s syndrome: Two reports of Sweet’s syndrome mimicking cutaneous cryptococcosis. J Cutan Pathol 2017; 44: 413-419.
8. Akbary S, Ramirez J, Fivenson D. Cryptococcal cellulitis: A rare entity histologically mimicking a neutrophilic dermatosis. J Cutan Pathol 2018; 45: 90-93.  

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