Sweet Syndrome Imitating Cutaneous Cryptococcal Disease

Abstract

Cryptococcoid Sweet syndrome is a rare histologic variant of the neutrophilic dermatosis presenting clinically with skin lesions typical of classical Sweet syndrome but with yeast-like structures suggestive of Cryptococcus on histopathology. Histochemical stains for fungus and cultures are negative whereas staining for myeloperoxidase is positive. We present 2 cases of cryptococcoid Sweet syndrome with atypical skin manifestations, including hemorrhagic bullae and plaques, and provide a brief review of the literature. Clinicians should be aware that this variant of Sweet syndrome can present with uncommon clinical findings and has histopathologic findings suggestive of Cryptococcus species.

Acute febrile neutrophilic dermatosis, also known as Sweet syndrome, is typically characterized by painful erythematous plaques or nodules but has a variety of atypical presentations including those mimicking an alkali burn [1], secondary syphilis [2], or cutaneous cryptococcal infection. We report 2 cases of cryptococcoid Sweet syndrome presenting with hemorrhagic bullae and plaques and histologic findings suggestive of fungal organisms. To our knowledge, only 13 cases of cryptococcoid Sweet syndrome have been reported in the literature to date, many of which presented with typical clinical findings [3–10]. Awareness of this unusual presentation of Sweet syndrome is important for clinicians to avoid misdiagnosis and inappropriate treatment.

CASE 1

An 81-year-old woman with a history of well-controlled diabetes mellitus (hemoglobin A1c 5%) and recently diagnosed recurrent metastatic breast cancer presented to the hospital with a 2-week history of bullae on the bilateral feet as well as facial and upper extremity ulcers and bullae. She took oral trimethoprim-sulfamethoxazole for several days as an outpatient without improvement. Treatment for the breast cancer had not been initiated. At the admitting hospital, vancomycin and valacyclovir were given for 3 days. She developed shock and was transferred to our hospital, where she required mechanical ventilation. Physical examination was notable for numerous hemorrhagic vesicles and plaques around the eyes, face, and neck involving mucous membranes, purpuric plaques across the chest and back, large ulcerations on the dorsolateral surfaces of the feet, and numerous hemorrhagic vesicles and bullae on the arms and anterior surfaces of the legs (Figure 1). Empiric intravenous acyclovir was started due to concern for zoster involving the face. Laboratory studies were notable for a leukocyte count of 13.1 × 10³_­cells/µL with 94% neutrophils. Initial platelet count was 118 × 10⁹/L (reference range, 150–450 × 10⁹/L), creatinine was 1.5 mg/dL, calcium was 8.4 mg/dL (reference range, 8.9–10.3 mg/dL), and albumin was 2.3 g/dL (reference range, 3.5–5.0 g/dL). Blood cultures were without growth, though antecedent antibiotics had been given at the previous hospital. Respiratory cultures grew Candida albicans. A screening test for the human immunodeficiency virus and rapid plasma reagin were nonreactive, and an antinuclear antibody screen was negative. Samples of exudate from the arm and chest showed numerous leukocytes on Gram stain but no organisms and no growth on culture. A culture for herpes simplex virus (HSV) and varicella zoster virus (VZV) from a back lesion was negative. Polymerase chain reaction testing for HSV and VZV was requested but unavailable. Computed tomography scan of the chest demonstrated a loculated pleural effusion and diffuse osseous lytic lesions including associated vertebral compression deformities. Pleural fluid sampling demonstrated malignant cells and bone biopsy of the pelvis did not identify metastatic disease. Skin biopsies for hematoxylin and eosin, tissue culture, and direct immunofluorescence were performed.

Figure 1.

Physical examination findings in case 1. Hemorrhagic vesicles and bullae on the legs (A), purpuric plaques on the chest (B) and hand (C), and hemorrhagic bullae on the hand (D).

Skin biopsy showed abundant vacuolated cells in the dermis and occasional ovoid to round structures suggestive of fungal organisms similar in appearance to Cryptococcus species (Figure 2). However, periodic-acid Schiff (PAS), and mucicarmine stains were negative (Figure 3), as was Grocott methenamine silver (GMS) stain. Empiric liposomal amphotericin B and flucytosine were initiated pending further evaluation. Serum cryptococcal antigen testing was negative on both latex agglutination and lateral flow assays, including after dilution. Histoplasma antigen in the urine and Blastomyces antigen in the urine and bronchoalveolar lavage fluid were negative. Direct immunofluorescence was also negative. Intravenous hydrocortisone was administered for 5 days for refractory shock. The patient's systemic and cutaneous manifestations continued to worsen despite antifungal therapy and supportive care, and she developed gram-negative septicemia. The patient's family requested she be transferred to hospice care. The skin biopsy was sent to the Centers for Disease Control and Prevention Infectious Diseases Pathology Branch to further evaluate for an infectious etiology. An immunohistochemistry assay for Cryptococcus and a polyfungal immunohistochemistry assay did not identify fungi. The report described the diagnosis as “pyogranulomatous dermatitis” and raised the possibility of the cryptococcoid variant of Sweet syndrome. Myeloperoxidase staining of the biopsy slides was positive, supporting the diagnosis of cryptococcoid Sweet syndrome (Figure 3).

Figure 2.

Skin biopsy specimen from case 1 at ×100 (A) and ×400 (B) magnification. Hematoxylin and eosin staining demonstrates a dense dermal infiltrate composed of neutrophilic inflammation, debris, and numerous rounded structures with some located in cleared-out spaces. These structures are seen singly, in apparent doublets, and some appear to display budding.

Figure 3.

Stains of skin biopsy specimen from case 1. Periodic-acid Schiff (A) and mucicarmine (B) staining did not demonstrate fungal organisms. Myeloperoxidase stain was positive, supporting the diagnosis of Sweet syndrome (C).

CASE 2

An 87-year-old woman with diabetes mellitus, hypertension, and stage 3 chronic kidney disease presented to the hospital with a 3-day history of acute pruritic, painful ulcers, and bullae on her extremities and chest and a chronic progressive ulcer near the left ankle. Physical examination on admission was significant for >20 edematous round plaques and nodules with central ulceration affecting the bilateral upper and lower extremities, chest (Figure 4), and face as well as a 5-cm ulcer with a hemorrhagic base superior to the left medial malleolus. The patient was suspected to have a neutrophilic dermatosis, potentially Sweet syndrome and/or pyoderma gangrenosum. Laboratory studies were notable for a leukocyte count of 11.3 × 10³ cells/µL with 85% neutrophils and a creatinine of 1.9 g/dL. Blood cultures were drawn, and skin biopsy of a left arm nodule was performed for hematoxylin and eosin, tissue culture, and direct immunofluorescence; while awaiting results, the patient was started on empiric vancomycin and cefepime and high-dose prednisone.

Figure 4.

Physical examination findings in case 2. Multiple edematous round plaques and nodules with central ulceration on the arm (A), chest (B), and leg (C).

Skin biopsy showed numerous yeast-like forms in the dermis surrounded by vacuolated spaces, suspicious for Cryptococcus (Figure 5). The GMS stain weakly highlighted the yeast-like cells, but PAS stain was negative. Blood, tissue, and stool cultures were negative for bacterial, fungal, and viral etiologies. Direct immunofluorescence was also negative. Antimicrobial therapy was discontinued following biopsy results, and cutaneous manifestations began improving on prednisone therapy. The patient was discharged on an oral prednisone taper along with oral dapsone, topical clobetasol, and wound care instructions for the chronic lower extremity ulcer. At the 1-month dermatology follow-up, the more nodular lesions, particularly in the upper extremities, were continuing to resolve as the patient completed the prednisone taper while the lower extremity ulcer was weeping and requiring ongoing wound care. A subsequent positron emission tomography/computed tomography scan did not identify hypermetabolic foci. The acute rash was deemed to be due to idiopathic cryptococcoid Sweet syndrome while the chronic leg ulcer was ultimately attributed to pyoderma gangrenosum.

Figure 5.

Skin biopsy specimen from case 2 at ×400 magnification. Hematoxylin and eosin staining demonstrates round forms in the dermis surrounded by vacuolated spaces.

DISCUSSION

Sweet syndrome is an acute febrile neutrophilic dermatosis characterized by painful erythematous plaques or nodules. It generally occurs in 3 clinical contexts: classical, malignancy-associated, or drug-associated [11]. Classical Sweet syndrome typically presents in women 30–50 years of age and is often associated with infection, autoimmune disease, or pregnancy. Malignancy-associated Sweet syndrome can occur with hematologic or solid tumor malignancy, but the estimated frequency varies widely [12]. In a recent single-center review, malignancy was associated with 67% of cases of Sweet syndrome; of these, acute myeloid leukemia was the most common (24/56 [43%]), followed by myelodysplastic syndrome and solid tumors (10/56 [18%] each) [13]. Medications were associated with 27% of all cases, with filgrastim being most common (8/22 [36%]) followed by other drugs such as cytotoxic agents and antimicrobials such as trimethoprim-sulfamethoxazole. However, a variety of medication classes have been implicated in drug-associated Sweet syndrome, including antibiotics, antivirals, antihypertensives, and nonsteroidal anti-inflammatory drugs [11]. While the pathogenesis of Sweet syndrome is not fully defined, it is hypothesized that a trigger such as infection, inflammatory condition, malignancy, or medication promotes an inflammatory state with proliferation of neutrophils while a lymphocytic cytokine response encourages dermal localization [14].

The clinical presentation often includes fever and edematous skin lesions involving the head and neck, though other anatomic locations can be involved. Skin biopsy demonstrates a diffuse neutrophilic infiltrate with papillary dermal edema, and there is typically a rapid response to systemic corticosteroid therapy [11]. Some authors have suggested that the diagnostic criteria are no longer fully inclusive and should be expanded to atypical presentations such as blisters and pustules, and other histopathologic findings of Sweet syndrome should be considered, particularly the cryptococcoid variant [15]. Classical histopathologic findings of Sweet syndrome include papillary dermal edema with neutrophilic infiltrate. In the histiocytoid variant, the immature neutrophils appear similar to histiocytes [16]. As in the cases described here, vacuolated spaces may appear as a clear halo mimicking the capsule of Cryptococcus around nuclear segmentation that mimics a budding yeast form [6]. This is hypothesized to be due to degradation of neutrophils. As in case 1, myeloperoxidase staining can be used to differentiate Sweet syndrome from other inflammatory dermatoses [12].

Disease caused by Cryptococcus species is most commonly seen in immunocompromised hosts but may occur in apparently healthy individuals. The most frequent sites of cryptococcal disease include the skin, lungs, and central nervous system but can also involve other sites such as bones [17–19]. Cutaneous lesions may include ulcers, plaques, pustules, nodules, abscesses, cellulitis, umbilicated papules, or hemorrhagic bullae [20, 21]. Skin involvement reflects either a cutaneous manifestation of disseminated cryptococcosis, with antigenemia or other sites of infection identified, or localized cutaneous cryptococcosis, without antigenemia. Notably, lateral flow cryptococcal antigen assays used in the diagnosis of cryptococcosis have improved sensitivity over latex agglutination assays but may produce false-positive results [19, 22]. These assays are also susceptible to false-negative results consequent to the “hook” effect in the presence of excess antigen, as has been reported in both serum and cerebrospinal fluid samples [23, 24]. Serum samples in case 1 were diluted to examine for this effect and remained negative.

Special stains aid in the identification of Cryptococcus organisms in pathologic specimens. These include the GMS and PAS stains for sensitive detection of fungal cell walls, though these can stain species other than Cryptococcus [25]. Mucicarmine is more specific for mucins and can highlight the mucinous capsule of Cryptococcus, though it can be falsely negative with capsule deficient or previously treated organisms. The Fontana-Masson stain identifies melanin in cell walls and can assist in species identification, including in capsule-deficient Cryptococcus, but may still stain other fungi [26]. While fungal infection is less likely with negative special stains, it is not entirely ruled out. Therefore, structure morphology and clinical presentation remain essential for making a final diagnosis.

Previously published cases of the cryptococcoid variant of Sweet syndrome (Supplementary Table) suggest that this form of Sweet syndrome can be treated with high-dose steroids, similar to other forms [4, 6]. The patient in case 1 received intravenous hydrocortisone for several days for refractory shock in addition to empiric antifungal therapy, yet continued to deteriorate, similar to the cases presented by Ko et al [3], and subsequently developed gram-negative septicemia. However, the patient in case 2 improved with systemic steroid therapy. This is most likely due to the severity of their respective clinical conditions, but data are limited on the effectiveness of steroids for cryptococcoid Sweet syndrome.

CONCLUSIONS

These cases highlight that Sweet syndrome can present with clinical and histopathologic findings consistent with cutaneous cryptococcal disease. These cases also illustrate that Sweet syndrome can produce an array of cutaneous findings, including hemorrhagic bullae and plaques. It is important for clinicians to consider this infectious mimic in appropriate patients and particularly those with a history of malignancy or recent treatment with drugs known to be associated with Sweet syndrome.

Supplementary Data

Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Author contributions. Writing—original draft: A. A. J., D. S. G., S. N. G. Writing—review and editing: All authors. Resources: S. G. N., D. C. P., L. D. A., J. M. C.

Patient consent. The patient in case 2 provided written consent for publication. The patient in case 1 was deceased and family could not be reached for consent. Images and details have been de-identified.

Disclaimer. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Financial support. This work was supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health (Georgia Clinical and Translational Science Alliance, UL1TR002378 and TL1TR002382).

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.