|Year : 2020 | Volume
| Issue : 4 | Page : 240-241
Cutaneous cryptococcoma in association with CD4 lymphocytopenia: A patient with multiple sclerosis treated with fingolimod
Tzu-Kun Lo, Julia Yu-Yun Lee
Department of Dermatology, National Cheng Kung University Hospital, Tainan, Taiwan
|Date of Submission||23-Mar-2020|
|Date of Decision||15-Apr-2020|
|Date of Acceptance||19-Apr-2020|
|Date of Web Publication||24-Jun-2020|
Dr. Julia Yu-Yun Lee
Department of Dermatology, National Cheng Kung University Hospital, Tainan
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Lo TK, Lee JY. Cutaneous cryptococcoma in association with CD4 lymphocytopenia: A patient with multiple sclerosis treated with fingolimod. Dermatol Sin 2020;38:240-1
|How to cite this URL:|
Lo TK, Lee JY. Cutaneous cryptococcoma in association with CD4 lymphocytopenia: A patient with multiple sclerosis treated with fingolimod. Dermatol Sin [serial online] 2020 [cited 2022 Sep 26];38:240-1. Available from: https://www.dermsinica.org/text.asp?2020/38/4/240/291280
Cryptococcal infection is an uncommon infection, mainly affecting the lung and central nervous system in immunocompromised patients. Other organs such as the skin can be affected, usually by the hematogeneous spread. Fingolimod, an immunosuppressant for multiple sclerosis (MS), sequesters lymphocytes in lymph nodes, resulting in peripheral lymphopenia. Although the initial trials of fingolimod did not observe a significantly increased risk of infections, recent data show an association of fingolimod with progressive multifocal leukoencephalopathy, Varicella-Zoster, and cryptococcal infections. Fingolimod is also associated with other fungal infections such as histoplasmosis.
We are aware of nine cases of Cryptococcus infection associated with fingolimod therapy reported to date. We report an unusual case presenting with a solitary, fungating ulcerated cryptococcoma in the setting of fingolimod therapy for MS.
| Case Report|| |
A 52-year-old male with a 6-year history of MS on fingolimod therapy in the past 2 years and psoriasis for >10 years was referred to our department for the evaluation of a 3-month history of an enlarging, fungating ulcerated tumor on the right waist. Initially, the nodule was about 0.5–1 cm in diameter, with mild swelling, and erythema. He denied any trauma history, recent travel, or close contact with birds. No medication or surgical treatments was given in these 3 months before referral.
Examination revealed a 3 cm × 3 cm erythematous fungating ulcerated tumor on his right waist [Figure 1]. A biopsy specimen from the tumor revealed numerous yeasts with narrow-based budding in the subcutaneous tissue. Mucicarmine staining was positive for these organisms [Figure 2]. The findings were consistent with granulomatous lobular panniculitis caused by Cryptococcus infection (cryptococcoma). Culture for fungi revealed whitish yeast colony with a creamy appearance on the Remel inhibitory mold agar, whose microscopic features showed encapsulated budding blastoconidia, features of Cryptococcus neoformans. Tissue culture was negative for Mycobacterium tuberculosis.
|Figure 1: The patient presenting with a 3 cm × 3 cm erythematous fungating, ulcerated tumor on the right waist|
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|Figure 2: The skin biopsy specimen showing numerous mucicarmine-positive yeast cells with narrow-based budding in the subcutaneous tissue (a) Scanning view (left upper), H and E, ×40; and lesion site, H and E, ×100 (b) Mucicarmine stain, ×400|
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A chest X-ray revealed no active lung lesion. Images of the brain magnetic resonance imaging showed persistent MS, cortical atrophy with ventriculomegaly, and periventricular white matter changes with no interval change. Cerebrospinal fluid (CSF) examination revealed normal white blood cell count (1/mm3) and protein (61 mg/dL), and negative for cryptococcal antigen. CSF and blood cultures yielded no growth of bacteria or fungus. Other relevant laboratory findings included a serum cryptococcal antigen titer of 1:8 (negative, 1:2 [−]) and a white blood cell count of 7500/μL (range, 4000–11,000/μL) with neutrophils 72.5%, lymphocytes 9.7%, monocytes 15.5% with an absolute lymphocyte count of 727.5/μL (range, 1000–5000/μL), and CD4+ lymphocytes counts 91.7/μL (range, 560–1840/μL), CD8+ lymphocytes 195/μL (range, 260–1230/μL) with a CD4/CD8 ratio of 0.47. Antigen and antibody tests for HIV showed negative results.
Based on the histopathological and other laboratory findings, a diagnosis of cutaneous cryptococcoma in association with CD4 lymphocytopenia was made. The patient was admitted. Fingolimod was discontinued because of lymphocytopenia and was replaced by glatiramer acetate therapy. The tumor was excised. Amphotericin B 70 mg/day and flucytosine 8000 mg/day were initiated as induction therapy. However, acute kidney injury with hypokalemia was noted 9 days later. Amphotericin B was discontinued, and oral fluconazole 800 mg daily was administered for 6 months with flucytosine 8000 mg/day being continued for 2 months. Ten weeks after discontinuation of fingolimod and initiation of antifungal therapy, the absolute lymphocyte count returned to 1712/μL (CD4+ lymphocytes count 344.2/μL, CD8+ lymphocytes 419.6/μL, and CD4/CD8 ratio 0.82). The titer of serum cryptococcal antigen reduced to 1:2. At 1-year follow-up, the right waist wound was healing without recurrence, and he remained in good health.
| Discussion|| |
Fingolimod is a disease-modifying treatment for MS through downregulation of sphingosine-1-phosphate receptors on lymphocytes, ultimately preventing them from entering the central nervous system.
Cutaneous cryptococcosis or cryptococcoma manifesting as a large solitary tumor is rare. We are aware of three reported cases, and two of them were with MS under Fingolimod therapy.,,
To the best of our knowledge, only nine cases of cryptococcal infection associated with fingolimod treatment have been reported to date; only three manifested cutaneous infection. Although a causal link between fingolimod-induced CD4 lymphocytopenia and cryptococcosis has not been proven directly, the decreased CD4 cell counts might be a risk factor for acute cryptococcal infection or a reactivation of a latent infection.
The risk of fingolimod-associated cryptococcal infections appears to be higher with duration of treatment of at least 2 years and in patients of older age. If such a trend of increased risk is further confirmed in future, the need for cryptococcal antigen positivity surveillance pretherapy and perhaps yearly while on therapy may become important in predicting the risk of cryptococcal infection.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Grebenciucova E, Reder AT, Bernard JT. Immunologic mechanisms of fingolimod and the role of immunosenescence in the risk of cryptococcal infection: A case report and review of literature. Mult Scler Relat Disord 2016;9:158-62.
Veillet-Lemay GM, Sawchuk MA, Kanigsberg ND. Primary cutaneous histoplasma capsulatum infection in a patient treated with fingolimod: A case report. J Cutan Med Surg 2017;21:553-5.
Samudralwar RD, Spec A, Cross AH. Case report: Fingolimod and cryptococcosis: Collision of immunomodulation with infectious disease. Int J MS Care 2019;21:275-80.
Bryan AM, Del Poeta M. Sphingosine-1-phosphate receptors and innate immunity. Cell Microbiol 2018;20:e12836.
Amaral DM, Rocha RC, Carneiro LE, Vasconcelos DM, Abreu MA. Disseminated cryptococcosis manifested as a single tumor in an immunocompetent patient, similar to the cutaneous primary forms. An Bras Dermatol 2016;91:29-31.
Seto H, Nishimura M, Minamiji K, Miyoshi S, Mori H, Kanazawa K, et al
. Disseminated cryptococcosis in a 63-year-old patient with multiple sclerosis treated with fingolimod. Intern Med 2016;55:3383-6.
Forrestel AK, Modi BG, Longworth S, Wilck MB, Micheletti RG. Primary cutaneous cryptococcus in a patient with multiple sclerosis treated with fingolimod. JAMA Neurol 2016;73:355-6.
Mehling M, Brinkmann V, Antel J, BarOr A, Goebels N, Vedrine C, et al
. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis 71. Neurology 2008;14:1261-7.
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