Case report Cutaneous cryptococcosis Cumneous cryptococcosis N. Quartarolo, I. Thomas, H. Li, M. Wiederkehr, R. A. Schwartz and W. C. Lambert SUMMAR Y Cutaneous cryptococcosis, caused by the encapsulated yeast, Cryptococcus neoformans, is generally associated with concomitant systemic infection. The authors report a case of a man with isolated cuta- neous cryptococcosis of his right foot without obvious systemic manifestations. A review of the clinical aspects, pathogenesis and management of cutaneous cryptococcosis is also presented. Introduction Cryptococcosis is a systemic infection caused by the encapsulated yeast, Cryptococcus neo,:/ormans. Cryp- tococcus is ubiquitously found in the soil, in pigeon droppings and in their nesting places. In the non-hu- man environment it is not encapsulated and measures less than 2 µm . Its usual route of entry into humans is via inhalation of this non- or poorly encapsulated form of the organism. In the lungs, the organism develops its polysaccharide capsule, which is responsible for most of its virnlence. Even though the lungs are the site of inoculation, pulmonary infection, even in the immuno- compromised, tends to be asymptomatic. Immunocom- petent hosts tend to remain asymptomatic, but reacti- vation or spread to the lymph nodes, blood, central nervous system and any other tissue may occur in im- munosuppressecl indivicluals or those with low CD4 counts. (1 ,2,3) The most common manifestation of disseminated cryptococcosis is infection of the central nervous sys- tem, which produces meningitis or encephalitis . How- ever, systemic spreacl can cause almost any organ to become infected. The skin is the most common extraneural site of infection, affc;cting 10-20% of those with systemic involvement. (2) Cutaneous lesions are an ominous sign as they are often the first presenting symptom of systemic disease . However, rare cases of primary inoculatecl cutaneous lesions, without evidence of disseminated disease, have been reportecl. Case report A 48-year-olcl male presented with a 1 month his- to1y of an enlarging noclule on his right foot near the Acta Dermatoven APA Vol 11, 2002, No 4 - - ----------------~2f Cutaneous cryptococcosis Figure 1 . Solitary erythematous nodule on the medial aspect of the foot. Figure 2. Hematoxylin and eosin staining from shave biopsy of the lesion showing ulceration and pseudoepitheliomatous hyperplasia of the epidermis and granulomatous inflammation in the dermis. base of his big toe. The patient denied any history of trauma to the site and did not report any bleeding asso- ciated with this lesion. The patient was seen by a po- diatrist who diagnosed the lesion as cellulitis and initi- ated treatment with ciprofloxacin without improvement. The patient had a medica! history significant for diabe- tes mellitus as well as a !iver transplant seconda1y to cirrhosis 3 years prior to presentation for which he was being maintained on both tacrolimus and prednisone. Cutaneous examination revealed a 1.5 cm circular glis- tening erythematous nodule on the medial aspect of the foot near the base of the hallux (Figure 1). Histopathologic exam (shown in Figure 2) revealed ulceration and pseudoepitheliomatous hyperplasia of the epidermis. In the dermis, there was granulomatous inflammation composed of multinucleated giant cells, lymphocytes, histiocytes, eosinophils, neutrophils, and plasma cells. Numerous yeast-like organisms in small clear spaces were present both freely and in the histio- cytes and giant cells. The organisms mostly ranged from 5 to15 µmin diameter and had refractile walls. Periodic acid-Schiff (PAS) and Gomori's methenamine-silver ni- Figure 3. Gomori's methenamine-silver stain revealing numerous yeast-like organisms. Figure 4. Cryptococcal capsules stained positively with mucicarmine. Case report 126 -----------------------------------Acta Dermatoven APA Vol 11, 2002, No 4 Case report trate (GMS) stains were both positive for the organisms (GMS stain shown in Figure 3). Mucicarmine stained positively for the capsules of the organisms (Figure 4). These findings are characteristic for c1yptococcosis. After positive identification ofthe organism, a search for signs of systemic infection was initiated. Chest roentegram demonstrated a 1.6 cm nodule in the right upper lung field, however, a biopsy of this lesion was deferred. Blood and cerebral spina! fluid (CSF) cultures were negative for c1yptococcus. The patient was started on IV amphotericin B for 6 days, however, it was dis- continued due to elevated blood urea nitrogen and crea- tinine levels and was replaced with fluconazole. The patient was discharged and is being followed up as an outpatient. Discussion Prima1y cutaneous cryptococcosis is a rare occur- rence, as skin lesions are generally accompanied by sys- temic infection. However, there is evidence that some cases of primary cutaneous c1yptococcus occur by di- rect inoculation of the organism into sites of injury or trauma but in most instances there is metastatic spread from other parts of the body-usually the lung. Our patient had an isolated skin lesion without CSF or he- matologic evidence of disseminated disease; however, the lung nodule found by chest roentegram indicates that his lesion probably resulted from pulmonary seed- ing. A high index of suspicion is mandatory because cryptococcal skin involvement is non-specific and pro- duces a wide variety of lesions. A wide variety of mor- phologies may be seen, including: papules, nodules, plaques, vesicles, bullae, pustules, abscesses, cellulitis, ulcers and purpura, as well as acneiform, herpetiform, Kaposi sarcoma or basal cell carcinoma-like nodules. (3,4) The lesions are most often confused with bacte- rial cellulitis and are erroneously treated with antibac- terial agents. Thus, any new skin lesion in a high risk individual should be evaluated. Biopsy specimens reveal one of 2 types of patho- logic reactions that are described as either gelatinous or granulomatous. Gelatinous lesions show numerous cryptococci and little if any inflammatory reaction REFER ENC ES Cutaneous cryptococcosis whereas granulomatous lesions show fewer cryptococci and marked inflammation consisting of lymphocytes, mononuclear cells, and occasionally giant cells. The gelatinous type of response is seen with cryptococci that have large capsules while cryptococci with thinner or no capsules are found with the granulomatous re- sponse. Although the organisms can generally be seen with hematoxylin and eosin stained tissue, special stains such as GMS, PAS and mucicarmine make them easier to see. GMS stains the organism black while PAS and mucicarmine stains the polysaccharide capsule red. Mucicarmine has the added advantage in that it does not stain pathogenic fungi other than cryptococcus.(1) Once a diagnosis of cutaneous cryptococcal infec- tion has been made it is imperative to initiate a search for systemic involvement including obtaining a chest X-ray, blood, urine, and CSF cultures, India ink stain of CSF from lumbar puncture, and testing for the presence of the c1yptococcal antigen in the serum and CSF. Chest X-ray may reveal signs of pulmonary infection includ- ing !obar consolidation or nodular lesions. Patients with cryptococcal meningitis generally have an elevated opening pressure during lumbar puncture and CSF analysis demonstrates a preponderance oflymphocyes, with a total leukocyte count of 40-400.(2,5) India Ink preparations are positive in only 50% of patients with CNS disease, latex agglutination is positive in about 93% of patients but CSF cultures are eventually positive in 95% of ali patients with cryptococcal meningitis.(1) The mainstay of treatment for cryptococcosis is amphotericin B with/without flucytosine. Unfortunately, it is highly toxic, has poor CSF penetration and has a substantial relapse rate. More recently, the azoles have emerged as alternate therapies in patients that cannot tolerate amphotericin B. Fluconzaole has been found to be particularly effective due to its high bioavailability, excellent CSF penetration and long half life. It is be- cause of these properties that it is now the drug of choice for prophylactic therapy. In addition, it has been asso- ciated with fewer relapses and less drug toxicity. The mortality of disseminated cryptococcosis is 70-80% in untreated patients compared with 17% treated with sys- temic anti-fungal agents.(4,6) Again, it is critical to com- mence a thorough investigation into any cutaneous le- sion in high risk individuals in order to initiate rapid therapy. l. Hernandez AD. Cutaneous cryptococcosis. Dermatol Clinics 1989; 7: 269-274. · 2. HaightDO, Esperanza LE, Greene JN, Sandin RL, DeGregorio R, and Spiers ASD. Case report: cutane- ous manifestations of cryptococcosis. AmJ Med Sci 1994; 308: 192-195. 3. Thomas I, Eng RHK, and Schwartz RA. Cutaneous manifestations of systemic cryptococcosis in immu- nosuppressed patients. J Med 2001; 32: 259-66. Acta Dermatoven APA Vol 11, 2002, No 4 ---- -----------------J27 Cutaneous c1yptococcosis 4. Yantsos VA, Carney J, and Greer DL. Review of the morphological variations in cutaneous cryptococcosis with a new case resembling varicella. Cutis 1994: 54:343-347. 5. Durden FM and Elewski B. Cutaneous involvement with Cryptococcus neoformans in AIDS. J Am Acad Derm 1994; 30: 844-848. 6. Hussain S, Wagener MW, and Singh N. Cryptococcus neoformans infection in organ transplant recipi- ents: variables influencing clinical characteristics and outcome. Emerg InfDiseases 2001; 7: 375-381. A U T H O R S ' Nicole Quartarolo, MSc, Dermatology, New Jersey Medica[ School, A D D R E S S E S Newark Isabelle Thomas, MD, same address, and Chief Dermatology Service, New Jersey Veterans Adminstration Health Care System, East Orange, New Jersey Hong Li, MD, Dermatology and Pathology, New Jersey Medical School, Newark,NJ Michael Wiederkehr, MD, pathologist, Dept Pathology, New Jersey Medical School, Newark, New Jersey W. Clark Lambert, MD, PhD, Professor and Associate Head, Dermatology, Professor oj Pathology, Chief, Dermatopathology New Jersey Medical School, Newark, NJ RobertA. Schwartz MD, MPH, Dermatology, New Jersey Medical School, 185 South OrangeAvenue, Newark, NewJersey07103 E-mail:rowchwar@umdnj.edu Case report .f 29 - ------------------------------Acta Dermatoven APA Vol 11, 2002, No 4