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Home , Cryptococcosis, Sporotrichosis

Primary Capsule-Deficient Cutaneous in a Sporotrichoid Pattern in an Immunocompetent Host

Nathan Andrew Merl Jackson, DO; Daniel B. Herring, MD

Practice Points  neoformans is an encapsulated that is ubiquitous in the environment and is especially abundant in soil enriched with pigeon droppings.  Immunocompetent hosts often are asymptomatic or have only mild pulmonary disease, while disseminated disease affects the , , , and in immunocompromised hosts.  Diagnostic tests include india ink or mucicarmine staining to highlight characteristic capsules or the latex agglutination test to measure circulating capsular . copy not

Cryptococcosis is an opportunistic yeast infectionDo ryptococcosis is an opportunistic yeast infection caused by that remains caused by Cryptococcus neoformans that remains the most common systemic fungal infection in Cthe most common systemic fungal infection in immunosuppressed patients and often pres- immunosuppressed patients and often presents with ents with signs of . Primary cutaneous signs of meningitis. Cutaneous cryptococcosis occurs cryptococcosis (PCC) is a more rare clinical iden- in 10% to 20% of systemic Cryptococcus infections and tity that is characterized by skin lesions confined usually is secondary to hematogenous dissemination in to 1 body region, often presenting as a whitlow or patients with an underlying disease, particularly human phlegmon with positive cultureCUTIS for C neoformans immunodeficiency virus. Primary cutaneous crypto- and no evidence of simultaneous dissemination. coccosis (PCC) is a more rare clinical identity that We report a rare case of PCC in a 73-year-old man is characterized by skin lesions confined to 1 body with intact cell-mediated immunity. region, often presenting as a whitlow or phlegmon Cutis. 2015;96:E26-E29. with positive culture for C neoformans and no evi- dence of simultaneous dissemination. We report a rare case of PCC in a 73-year-old man with intact cell-mediated immunity.

Case Report A 73-year-old man who was a beef farmer presented on primary care referral with multiple red nodules and ulcers on the right third and fourth digits and Dr. Jackson is from West Virginia School of Osteopathic Medicine, distal forearm following abrasion to the region. The Lewisburg. Dr. Herring is from McCagh, Roberts & Herring patient reported that the lesions had started as pain- Dermatology, Cumberland, Maryland. The authors report no conflict of interest. ful nodules that would open and drain. He had been Correspondence: Nathan Andrew Merl Jackson, DO, 11007 Blan taking oral ciprofloxacin and oral ketoconazole for Avon Rd, Midlothian, MD 21543 ([email protected]). 3 days as prescribed by his primary care physician but

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had not begun to see results. He denied any travel did not reveal dark red capsules characteristic of or exposure to roses, fish tanks, or any sick contacts. Cryptococcus (Figure 4). The pathology report indi- A review of systems was negative for , night cated that the findings may represent sweats, malaise, , or any other systemic in the appropriate clinical setting, but GMS staining symptoms. Physical examination revealed multiple could not definitively classify or 2- to 6-mm nodules and ulcers distributed in a sporo- rule out other fungal infections without tissue cul- trichoid pattern on the right hand (Figure 1) and arm ture. Before culture results could be obtained, the (Figure 2). Lymphadenopathy was absent and the patient returned 2 weeks later for suture removal at rest of the examination revealed no abnormalities. which point the prior were stopped and Initially, 4 punch of the right hand 200 mg once daily was initiated. and arm were obtained and sent for Gram stain- Upon receiving the culture results, a diagnosis of ing, tissue culture (bacterial and fungal), and his- primary capsule-deficient cutaneous cryptococcosis topathologic review. A presumptive diagnosis of was made. The lesions showed clinical improvement sporotrichosis was made, with change of treatment at 1-month follow-up, and treatment with itracon- pending culture. On routine hematoxylin and eosin azole was continued with monthly liver function staining, marked acute and chronic - tests. After 5 months of continued improvement, the tous inflammation with microabscesses was noted. Acid-fast bacilli staining was negative. Follow-up Gomori methenamine-silver (GMS) staining showed numerous fungal spores with narrow base bud- ding (Figure 3). Subsequent mucicarmine staining copy not Do

Figure 3. Numerous fungal spores with narrow base budding on Gomori methenamine-silver staining (original magnification 100). CUTIS

Figure 1. Ulceration of the right fourth digit and palm.

Figure 4. Mucicarmine staining showed an absence of Figure 2. Multiple nodules and ulcers distributed in a characteristic red Cryptococcus neoformans capsules sporotrichoid pattern on the right arm. (original magnification 100).

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itraconazole dose was decreased to 100 mg once daily characteristically measures 3 to 20 μm in diam- for 1 month. The patient was free of lesions and any eter and stains well with periodic acid–Schiff stain sequelae at 6-month and 1-year follow-up. and GMS.4,5 Therefore, the lack of capsule broad- ened our early differential to include Histoplasma Comment capsulatum, S schenckii, Paracoccidioides brasiliensis, Cryptococcosis is caused by C neoformans, an oppor- and even Blastomyces dermatitidis. tunistic, basidiomycetous, yeastlike fungus1 that Neuville et al1 proposed the following criteria presents as a yeast in both the environment and tis- for the diagnosis of PCC: the absence of dissemina- sue and normally is associated with immunocompro- tion and predominantly a solitary skin lesion on mised host infection, especially in individuals with unclothed areas presenting as a whitlow or phleg- human immunodeficiency virus. The most common mon, a history of skin injury or damage leading to route of infection is through the lungs as respiratory direct inoculation, participation in outdoor activi- droplets followed by hematogenous dissemination to ties, exposure to bird droppings, and isolation of the central nervous system and skin, with meningitis C neoformans serotype D. Other factors that strongly being the most common clinical manifestation and support PCC diagnosis over squamous cell carci- Cryptococcus being the most common cause of fun- noma (based on a review of the literature) are rural gal meningitis worldwide.2 Cutaneous involvement residential environment, older age, equal prevalence after hematogenous spread (secondary cutaneous among men and women, and lack of underlying cryptococcosis) is reported in 10% to 20% of systemic disease. Presence of these factors seem to favor PCC Cryptococcus cases, while PCC is limited to rare cases over squamous cell carcinoma, as some still consider in which trauma or abrasions to the affected site are the existence of PCC in general to be controversial notable risk factors.2,3 because skin manifestations represent a sentinel Cryptococcus can produce a myriad of skin mani- finding indicativecopy of disseminated disease.1,3 festations including but not limited to nodules, The can be found worldwide as an ubiq- ulcers, plaques, pustules, vesicobullous lesions, and uitous saprophyte of soil, especially if the soil is draining sinuses. Neuville et al1 found that , enriched with pigeon droppings. A link between cutaneous ulcers, and whitlows were the most com- C neoformansnot and pigeons has been suggested, with mon presenting clinical features in PCC. Whitlows dried avian excreta allowing the yeast to abundantly also have been reported as a rare presentation in grow because of its high nitrogen content.5,6 Other secondary cutaneous cryptococcosis yielding to the possible sites include decaying wood, fruits, veg- much more prevalent presentation of umbilicatedDo etables, and dust.1 There are 4 main serotypes and papules resembling .1 This 3 varieties of C neoformans: C neoformans var grubii polymorphic identity can therefore mimic not only (serotype A; worldwide distribution), C neoformans other dermatoses and neoplasms but other infections var gattii (serotypes B and C; more circumscribed such as bacterial cellulitis, herpes simplex virus, and diffusion and distribution including subtropical molluscum contagiosum, especially in disseminated regions of Australia, Central Africa, South Asia, cryptococcosis, making microscopic assessment cru- and California), and C neoformans var neoformans cial for the diagnostic confirmationCUTIS of cutaneous (serotype D; worldwide distribution).3,7 A litera- cryptococcosis. The differential diagnosis includes ture review indicated that known cases of sero- sporotrichosis and Mycobacterium marinum due to type D (global incidence, 9%) tended to produce the lymphatic distribution of the lesions as well as cutaneous lesions without systemic involvement.7 squamous cell carcinoma. Our initial diagnosis of Microscopically, the most important characteristic sporotrichosis was assumptive until mycological data feature found in all serotypes is the polysaccha- could be obtained. ride capsule, which normally acts as an important The histopathology patterns characteristic of virulence factor.6 This capsule as well as detection C neoformans infection fall into either a paucireac- of the budding yeast can be visualized with india ink tive pattern with myriads of densely packed organ- (), methylene blue, or mucicar- isms with mucoid gelatinous capsules that cause mine staining. The latex agglutination test for cryp- minimal tissue reaction or a mixed suppurative and tococcal antigen has been used as a serologic test for granulomatous reaction with varying degrees of cerebrospinal fluid, blood, and urine with a sensitiv- necrosis.4 The granulomatous form can affect histio- ity of 86% to 95%.8 cytes, giant cells, lymphocytes, and fibroblasts. These Treatment of cryptococcal disease depends on findings along with the characteristic carminophilic location and severity of lesions. Many cases of PCC capsule of C neoformans allows for a prompt diag- spontaneously resolve, but it is a recommended nosis. However, the C neoformans spore somewhat practice to treat the lesions via incision, local

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irrigation and debridement, and anti-inflammatory serotype D, low virulence of the capsule-deficient and agents.9 Antifungal therapy with strain, or perhaps some other immunologic mecha- with or without was the nism of defense. standard of therapy. The newer oral azole compounds (eg, ketoconazole, , itraconazole) are effec- References tive against Cryptococcus, making them the probable 1. Neuville S, Dromer F, Morin O, et al. Primary cutane- treatment in immunocompetent patients because of ous cryptococcosis: a distinct clinical entity [published fewer side effects. Nonetheless, these drugs should online ahead of print January 17, 2003]. Clin Infect Dis. be maintained for several weeks or even months to 2003;36:337-347. achieve complete resolution of PCC.10 2. Werchniak AE, Baughman RD. Primary cutaneous Our patient’s clinical presentation, physical find- cryptococcosis in an elderly man. Clin Exp Dermatol. ings, and treatment response seemed to fit well with 2004;29:159-160. a diagnosis of PCC, particularly the solitary skin 3. Pau M, Lallai C, Aste N, et al. Primary cutane- lesions on unclothed areas of the skin; history of ous cryptococcosis in an immunocompetent host skin injury, participation in farming, or exposure to [published online ahead of print March 14, 2009]. bird droppings (eg, contaminated soil, manure); iso- Mycoses. 2010;53:256-258. lation of C neoformans; and lack of evidence of dis- 4. Ramdial PK, Calonje E, Sing Y, et al. Molluscum- seminated disease. Once a diagnosis of PCC is made, like cutaneous cryptococcosis: a histopathological and however, evaluation of a patient’s pathogenetic appraisal [published online ahead of print and other systemic involvement must be performed, June 4, 2008]. J Cutan Pathol. 2008;35:1007-1013. as solitary skin lesions can be the only symptom and 5. Vogelaers D, Petrovic M, Deroo M, et al. A case of pri- an early marker of disseminated disease. Inclusion mary cutaneouscopy cryptococcosis. Eur J Clin Microbiol Infect of a in the absence of localizing Dis. 1997;16:150-152. signs is not required in the workup of PCC, with 6. Naka W, Masuda M, Konohana A, et al. Primary cutane- the emergence of more cases of PCC being required ous cryptococcosis and Cryptococcus neoformans serotype before conclusive recommendations can be made. A D. Clin Exp Dermatol. 1995;20:221-225. strong history and physical examination, including 7. not Xiujiao X, Ai’e X. Two cases of cutaneous cryptococcosis. pertinent details such as local trauma and exposure Mycoses. 2005;48:238-241. to bird droppings, along with the criteria provided 8. Murray PR, Rosenthal KS, Pfaller MA, eds. Medical by Neuville et al1 and laboratory information mayDo be Microbiology. 6th ed. Philadelphia, PA: Mosby sufficient to diagnose PCC; close monitoring should Elsevier; 2009. be continued.1 Luckily, of the reported cases of PCC 9. Moreno Castillo JL, Del Negro G, Heins-Vaccari E, in immunocompetent individuals, oral antifungal et al. Primary cutaneous cryptococcosis. Mycopathologia. therapy usually has been curative.2,3 The fact that 1986;96:25-28. our patient did not develop generalized disease 10. Joshi S, Wattal C, Duggal L, et al. Cutaneous cryptococ- could be explained by the presence of the possible cosis. J Assoc Physicians India. 2004;52:242-243. CUTIS

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