Introduction

Primary Cutaneous Cryptococcosis (PCC) is an opportunistic fungal infection that was first described and distinguished from systemic cryptococcal infection in 1928 [1]. It is defined as skin lesions localized to a circumscribed body region with a positive skin culture for Cryptococcus neoformans and no evidence of concurrent dissemination.

Pigeon contact, trauma, and inoculation have been recognized as risk factors for cryptococcosis [2]. Secondary cutaneous cryptococcosis is always seen in disseminated cryptococcosis or secondary to cerebral or pulmonary cryptococcosis. In recent years, there has been a marked increase in the number of reports of cryptococcosis. Cutaneous cryptococcosis maybe present as blister, nodular, or acne-like eruptions. However, ulcers are uncommon in cutaneous cryptococcosis. Here, we report a case of PCC presenting as ulcers that rapidly expanded. We also reviewed articles of cutaneous cryptococcosis and found that ulcerated type of cutaneous cryptococcosis may have a high death rate and require early recognition and adequate antifungal treatment.

Case Report

A 67-year-old female appeared with erythema and ulcers on the extensor portion of her right thigh for one month. She had been treated with ceftriaxone for four weeks and then voriconazole plus fluconazole for one week while the lesions increased rapidly in size with significant pain. The patient had hepatitis B infection since 2010 and undifferentiated arthritis since 1990. She was treated with 5 mg of prednisone every other day for the underlying illness. Physical examination revealed two ulcers measuring nearly 13×8 cm and 10×4 cm on the extensor side of the right thigh, with marked edematous erythema at the edges of the ulcers and purulent discharge on the surface of the ulcers (Figure1a).

Figure 1a: Physical examination revealed two ulcers on the extensor side of the right thigh with marked edematous erythema at the edge of the ulcers and purulent discharge on the surface of the ulcers. There were also some satellite opacities around the ulcers. Figure 1b: After four months of antifungal treatment, the ulcers gradually decreased in size with only residual atrophic hypopigmentation.

The results of laboratory tests, including a complete blood cell count and absolute lymphocytes, were normal. The levels of complete reactive protein (23.03 mg/dL; normal range 0-5) and the sedimentation rate (51 mm/h; normal range 0-20) were both elevated. The human immunocompromised virus test was negative. Hepatitis B DNA quantities were 9.67x10⁴ IU/ ml. Histological analysis revealed numerous yeast-like fungi, indicating cryptococcosis (Figure 2). The biochemical and genetic identification of purulent skin secretions proved that the isolated pathogen was C. neoformans. The serum cryptococcal antigen titer test was positive. Blood culture results were normal. Systemic involvement was ruled out by chest computed tomography (CT) and cerebrospinal fluid examination.

Figure 2: Histological analysis revealed an inflammatory granulomatous reaction formation in the dermis and subcutis with lymphocytes, histiocytes, neutrophils, plasma cells, and local necrosis, with capsuled spores and hyphae.

For the treatment, due to the severe ulcer, it was suspected to be pyoderma gangrenosum at first, and we prescribed methylprednisolone 40 mg daily for one week. However, the purulent discharge was more frequent. The diagnosis of PCC was confirmed after the biopsy result and laboratory findings. Methylprednisolone was discontinued. The patient received flucytosine 100 mg/kg/day for six weeks and fluconazole 800 mg/day for two weeks, after which fluconazole was reduced to 400 mg/day. The patient was also given entecavir and hydroxychloroquine for hepatitis B and rheumatoid arthritis. After four months of antifungal treatment, the ulcers gradually decreased in size with only residual atrophic hypopigmentation (Figure 1b).

Discussion

C. neoformans and C. gattii are the common culprits of cryptococcosis. Infections with C. neoformans are more common in immunosuppressive persons [3]. The most common sites of infection are extremities. Manifestations of cutaneous cryptococcosis are diverse, such as rash, pustules, purpura, vesicles, nodules, ulcers, sometimes mimicking herpes zoster, cellulitis, or pyoderma gangrenosum. Lesions may be single or multiple and often accompanied with pain.

Our patient was immune dysregulation and developed rapidly enlarged ulcers. The patient was treated with voriconazole for one week with a poor response, suggesting the possibility of pyoderma gangrenosum or tumors. Finally, biopsy and blood cryptococcal antigen tests confirmed cryptococcal infection. Fortunately, body tests excluded the systemic involvement. The patient received intensive antifungal medication promptly, and the ulcers healed after four months treatment.

Our patient is a clear case of cryptococcal infection. To date, a review of literature identified 20 patients presenting ulcerated cutaneous cryptococcosis (supplemental material). Summary of the cases, most cases (65%) were in the extremities and half cases were immunosuppressive. What’s more, nearly a third of cases had systemic involvement and a fourth of cases died, which indicated that ulcerated cutaneous cryptococcosis might be more dangerous than other types [4,5] (Table 1).

A skin biopsy is necessary for diagnosis. Screening for systemic involvement, including pneumonia and cerebrospinal, is required after diagnosing cutaneous cryptococcosis. Chest CT and lumbar puncture are necessary, and bronchoalveolar lavage may be needed in some cases.

The high mortality rate of ulcerated cutaneous cryptococcosis needs to be validated by further clinical investigation. However, early recognition and treatment are essential to achieve a better prognosis. Current guidelines recommend fungicidal treatment with amphotericin B (0.7-1 mg/kg/day) and flucytosine (100 mg/kg/day) for at least four weeks, followed by consolidation therapy with fluconazole (400–800 mg/day) for eight weeks and maintenance therapy with fluconazole (200 mg/day) for 6-12 months for multiple organ involvement. For single-site infections, fluconazole (400 mg/day) is recommended for 6-12 months [6]. However, there is no standard treatment regimen for multiple sites skin lesions. For elderly patients, drug side effects such as myelosuppression and electrolyte disturbances must be noted. In conclusion, cutaneous cryptococcosis should be considered when rapid progressive ulcers are present in immunosuppressed population, and early intervention is critical.

Statement of Ethics

Ethics approval was not required for this study in accordance with local or national guidelines. Patient have given their written informed consent to publish their case (including publication of images).

Author Contributions

Tian meng Yan undertook the academic writing. Suchun Hou revised the article. Fanfan Xing and Ruiping Zhang made a contribution to the diagnosis of the patient. Li Ma and Xiaoming Liu helped make the antifungal regimen to the patient.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its supplementary material files. Further enquiries can be directed to the corresponding author.

References

1. Castellani A (1928) Notes on Blastomycosis: Its AEtiology and Clinical Varieties. Proc R Soc Med 21: 447-462.
2. Christianson JC, Engber W, Andes D (2003) Primary cutaneous cryptococcosis in immunocompetent and immunocompromised hosts. Med Mycol 41:177-188.
3. Du L, Yang Y, Gu J, Chen J, Liao W, et al. (2015) Systemic Review of Published Reports on Primary Cutaneous Cryptococcosis in Immunocompetent Patients. Mycopathologia. 180: 19-25.
4. Kikuchi N, Hiraiwa T, Ishikawa M, Mori T, Igari S, et al. (2016) Cutaneous Cryptococcosis Mimicking Pyoderma Gangrenosum: A Report of Four Cases. Acta Derm Venereol 96:116-117.
5. Liu Y, Qunpeng H, Shutian X, Honglang X (2016) Fatal primary cutaneous cryptococcosis: case report and review of published literature. Ir J Med Sci 185: 959-963.
6. Noguchi H, Matsumoto T, Kimura U, Hiruma M, Kusuhara M, et al. (2019) Cutaneous Cryptococcosis. Med Mycol J 60:101-107.