Cryptococcoid Sweet syndrome: A case report and literature review

A man in his 50s with a past medical history notable for hypertension, diabetes mellitus, former polysubstance use disorder (cocaine, LSD, and marijuana), and psoriasis was transferred from an outside hospital for acute on chronic renal failure, hypoxic respiratory failure, and progressive, painful rash. The patient's home medications included hydralazine, amlodipine, losartan, aspirin, carvedilol, finasteride, metoprolol, insulin, glimepiride, and tamsulosin. He first developed painful sores on his back 2 days prior to transfer, which rapidly spread to involve his face and lower extremities. He also endorsed arthralgias, ocular pain, diarrhea, and anuria. Examination revealed numerous erythematous to violaceous indurated papules and plaques with thick hemorrhagic crusting on the forehead and back and hemorrhagic bullae on the bilateral upper and lower extremities – including peripheral IV sites (Figure 1). Oral ulceration and confluent hemorrhagic crusting of his lips were also noted. Two punch biopsies from lesions on his arm and leg demonstrated a dense neutrophilic dermal infiltrate, papillary edema, focal vasculitis, and vacuolar spaces with small basophilic nuclei (Figure 2). Immunohistochemical staining was diffusely positive for myeloperoxidase (MPO) and lysozyme. Direct immunofluorescence, HSV immunostaining, periodic acid Schiff (PAS), acid-fast bacillus (AFB), Grocott methenamine silver (GMS), and gram stains were all unremarkable. A broad infectious work-up was performed including screening for hepatitis B and C, viral PCRs (HSV, VZV, CMV and EBV), HIV, RPR, beta-D glucan, screening for endemic fungi (Cryptococcus, Coccidioidomycosis, and Blastomyces), Mycoplasma pneumoniae and Chlamydia pneumoniae, strongyloides serologies, extended respiratory viral panel, aerobic, anaerobic, and fungal cultures, tissue culture of skin biopsy and culture of bronchiolar alveolar lavage, all of which were unremarkable. Inflammatory markers were elevated. Complete blood count was unremarkable and without leukocytosis or hypereosinophilia. Serologic testing revealed elevated perinuclear antineutrophil cytoplasmic antibodies (pANCA >1:10,240), antinuclear antibodies (ANA, 1:1,280), anti-histone antibodies (4.4 AU/ml), anti-chromatin (1.7), positive cryoglobulins, serine proteinase 3 antibody (33 AU/ml), and MPO antibodies (28 AU/ml). Antibodies against Jo-1, SCL-70, Smith, SSA, and SSB were negative. Echocardiogram was without vegetations. Given these results, the patient was diagnosed with cryptococcoid Sweet syndrome. Medications were reviewed to identify possible culprits, and hydralazine was subsequently discontinued. The patient was treated with intravenous methylprednisolone and dapsone, which was continued along with an oral prednisone taper upon discharge. He experienced gradual resolution in skin manifestations over the course of 2 months without recurrence upon discontinuation of therapy (Figure 3). Cryptococcoid Sweet syndrome was first described by Ko et al.1 in 2013 as a histological variant of Sweet syndrome. Histopathologically, this condition is characterized by cytoplasmic vacuolization and acellular, basophilic bodies, resembling the clear capsule of Cryptococcus organisms and yeast forms, respectively.2 PAS and other fungal stains are characteristically negative for fungal elements, and the cutaneous lesions do not remit with antifungal therapy.2 Cryptococcoid Sweet syndrome was first formally recognized as a variant of Sweet syndrome in a 2017 literature review by Wilson et al.,1, 2 which included eight cases. Since this time, seven additional cases have been reported, plus this case for a total of 16 cases to date. Table 1 outlines the clinical, laboratory, and histopathologic findings as well as the treatment course for these cases.1-9 From this collated data, the average age of presentation was 71 years and there was a female predominance (75%). Clinical features were similar among cases and mirrored those associated with classic Sweet syndrome – namely, the acute onset of tender, sharply demarcated, edematous, erythematous to violaceous papules, plaques, and nodules favoring the head, neck, and upper extremities. In contrast to classic Sweet syndrome, however, involvement of the oral mucosa manifesting as erosions or ulcerations was more common in the cryptococcoid variant and reported in six cases (38%), including our patient.1, 3-5 Hemorrhagic bullae, erosion, ulceration, and/or crusting were often present, with several cases demonstrating concurrent, striking purpura that correlated with histologic evidence of vasculitis. With regard to serologic studies, approximately half of the cases reported positive pANCA antibodies, and several were notable for dual MPO and PR3 positivity – a finding that should raise suspicion for an underlying infectious or drug trigger when present. Additionally, many cases demonstrated ANA and anti-histone antibody positivity consistent with drug-induced lupus. Histopathologic features were similar to those described above, and all were negative for PAS and/or other fungal stains. The vacuolated spaces on histopathology are thought to represent ballooning degenerating autolyzed inflammatory cells.1 Eight of the nine cases (89%) reporting MPO staining were diffusely positive. Sweet syndrome is characteristically a reactive phenomenon and can occur in the setting of infection, underlying malignancy, or medication exposures. Two cases included in this review report an associated hematologic malignancy, and two cases report concurrent cocaine use.1, 2 The association between cocaine use and cryptococcoid Sweet syndrome was initially described by Wilson et al.2 and theorized to represent levamisole toxicity triggering an ANCA-associated autoimmune disorder, manifesting as Sweet syndrome. In the case presented, the patient had only remote cocaine exposure and consultation with state agencies near the time of diagnosis indicated that rates of levamisole contamination regionally were minimal at the time. Hydralazine is a frequently utilized antihypertensive medication that has been associated with both drug-induced lupus erythematosus and cutaneous vasculitis.10 It is postulated that hydralazine accumulates in neutrophils, leading to apoptosis, exposure of sequestered antigens, and resultant autoantibodies, including ANA, anti-dsDNA, anti-histone, and ANCA.11 Recent reports have identified an association between cryptococcoid Sweet syndrome and hydralazine use, including several cases with overlapping features of neutrophilic dermatitis, drug-induced lupus, and vasculitis similar to the case presented.3, 6 Additionally, while many of the published cases of cryptococcoid Sweet syndrome do not detail medication history, past medical history of hypertension was common (33% of cases reporting medical history), raising the question of potential hydralazine use in these cases. Differentiating between true cryptococcosis and cryptococcoid Sweet syndrome can be challenging, particularly in cases that lack a dense neutrophil-predominant infiltrate.2, 7 A high index of suspicion is essential to allow for timely diagnosis and initiation of appropriate treatment. Immunohistochemical staining can be utilized to distinguish between cryptococcal infection and cryptococcoid Sweet syndrome. Beyond characteristic negative fungal staining, a diagnosis of cryptococcoid Sweet syndrome is supported by strong MPO staining. In summary, this study outlines a case of cryptococcoid Sweet syndrome associated with hydralazine use and prior cocaine exposure. In the creation of this report, an updated literature review was performed to collate clinical, laboratory, and histopathological findings described in available reports to date. Most notably, the presence of multiple positive autoantibodies, mucosal involvement, concurrent vasculitis, and the presence of a classic exposure should raise clinical suspicion for this entity. Given the rarity of cryptococcoid Sweet syndrome, additional evidence of this disease and its potential precipitating factors is needed.