Cryptococcal osteomyelitis of the humeral head initially diagnosed as avascular necrosis.
Key Words: cryptococcosis, Cryptococcus, osteomyelitis
A 19-year-old female was admitted to the hospital with complaints of progressively increasing left shoulder pain for six months. One month earlier, at another hospital, magnetic resonance imaging (MRI) showed a lytic lesion with minimal periosteal reaction in the left humerus. Her past medical history was significant for sarcoidosis, treated with prednisone for the past five years. She denied trauma, recent travel, or illicit drug use. The lesion was diagnosed as an avascular necrosis of the humeral head, and the patient was treated with nonsteroidal anti-inflammatory medications. A urine sample sent for culture grew Cryptococcus neoformans, and the patient was referred to the hospital for further evaluation.
At admission, the patient was awake and alert. The temperature was 98.7[degrees]F, heart rate was 106/min, and blood pressure was 133/101 mm Hg. The physical examination was remarkable for significantly restricted range of motion in the left shoulder joint, and the presence of redness, swelling, and marked pain on palpation over the anterior aspect.
MRI of the left shoulder demonstrated a lytic lesion in the left humeral head (Fig.). The chest x-ray was unremarkable. The peripheral blood white cell count was 5,200 [mm.sup.3] with 73% neutrophils. The initial erythrocyte sedimentation rate (ESR) was 28 m/h, and serum cryptococcus antigen was 1:100. According to an analysis of the cerebrospinal fluid, meningitis seemed unlikely.
The patient underwent biopsy of the lesion under fluoroscopic guidance. Smear and a culture of the material obtained during biopsy showed fungi, identified as Cryptococcus neoformans, which was also isolated from the blood culture. The patient was treated with liposomal formulation of amphotericin B at 5 mg/kg/d for 25 days, and then fluconazole 400 mg/d orally for 4 weeks. A repeat serum cryptococcal antigen was 1:16, ESR 12, and CRP was 0.3. The pain gradually subsided, and one month later, MRI confirmed a decrease in the size of the lesion.
Cryptococcosis is a systemic mycosis caused by an encapsulated yeast-like fungus with a common reservoir in soil and pigeon feces. It usually occurs in immunocompromised patients, particularly those with defective cellular immunity. Although the lungs and the central nervous system are the most likely sites, any organ can become affected.
The incidence of skeletal involvement in disseminated cryptococcosis is estimated at 5%. The presumed pathogenesis of cryptococcal osteomyelitis is via hematogenous spread from the pulmonary focus or the lymph node, but direct inoculation through the skin and contiguous spread are also possible. (1,2) In the review of 40 cases of cryptococcal osteomyelitis by Liu, (3) sarcoidosis is the most frequently reported underlying condition, followed by tuberculosis, steroid therapy, and diabetes mellitus. In 75% of cases, there was a single skeletal focus with vertebrae being the most common site. Humerus lesions were described in 6 of 40 cases (15%).
The majority of patients with skeletal cryptococcal infections present with soft tissue swelling and tenderness. In a review of 39 cases by Behrman et al, only 7 patients were febrile. Median duration of symptoms before diagnosis was 3 months (range 2 weeks to 33 months). (1)
Typical radiological presentation of cryptococcal osteomyelitis is a lytic lesion with mild or absent periosteal reaction. (4) The differential diagnosis includes neoplasms and infectious agents, such as other fungi, Actinomyces, mycobacteria, and Brucella.
Reliance on the degree of periosteal inflammation may be misleading. There are reports of cases when patients with cryptococcal osteomyelitis were initially diagnosed as having Ewing sarcoma or osteosarcoma. (5,6) In the case reported by Witte et al, a 68-year-old man with a history of diabetes and alcohol abuse presented with a lytic humeral lesion, and was thought to have a malignant neoplasm due to extensive periosteal reaction. Fine needle aspiration (FNA) of the lesion revealed C neoformans. (4)
The insidious course of the disease may lead to a delay in diagnosis and treatment. The possibility of cryptococcal infection should not be forgotten when immunocompromised patients present with persistent bone pain and lytic lesions, even though another diagnosis may seem obvious. Ganjei et al reported a case of a 71-year-old man with a history of multiple neoplasms and a new lytic lesion of the rib, which was thought to be due to metastatic disease. FNA biopsy revealed cryptococcal organisms, and the patient responded to antifungal chemotherapy. (7)
The most effective way to establish the diagnosis is by organism identification in the surgical biopsy material. In the review by Behrman et al., (1) the diagnosis was established by aspiration in 8 of 39 cases, by incision and drainage in 3, and by surgery in 26. Histologic findings typically include fibrohistiocytic and granulomatous inflammation with necrosis, multinucleate giant cells, and acute and chronic inflammation. The staining of the organism capsule with mucicarmine allows differentiation from other fungi. (4)
The treatment of cryptococcal osteomyelytis includes medications and surgical measures. Surgical debridement should always be considered. The patients are usually treated with amphotericin B and 5-flucytosine. Single agent therapy is generally avoided, since secondary drug resistance has been documented. (9) The duration of therapy is not well determined and should be based on clinical and radiological improvement.
Cryptococcal osteomyelitis should be in the differential diagnosis of lytic osseous lesions. The biopsy of the lesion with thorough microbiologic evaluation should be considered as early as possible to prevent increased morbidity and mortality due to delay in diagnosis and treatment.
1. Behrman RE, Masci JR, Nicholas P. Cryptococcal skeletal infections: case report and review. Rev Infect Dis 1990;12:181-190.
2. Raftopoulos I, Meller JL, Harris V, et al. Cryptococcal rib osteomyelitis in a pediatric patient. J Pediatr Surg 1998;33:771-773.
3. Liu PY. Cryptococcal osteomyelitis: case report and review. Diagn Microbiol Infect Dis 1998;30:33-35.
4. Witte DA, Chen I, Brady J, et al. Cryptococcal osteomyelitis. Report of a case with aspiration biopsy of a humeral lesion with radiologic features of malignancy. Acta Cytol 2000;44:815-818.
5. Zach TL, Penn RG. Localized cryptococcal osteomyelitis in an immunocompetent host. Pediatr Infect Dis 1986;5:601-603.
6. Fialk MA, Marcove RC, Armstrong D. Cryptococcal bone disease: a manifestation of disseminated cryptococcosis. Clin Orthop 1981;158:219-223.
7. Ganjei P, Evans DA, Fischer ML. Diagnosis of cryptococcal osteomyelitis by fine needle aspiration cytology. A case report. Acta Cytol 1982;26:224-226.
8. Hospenthal DR, Bennett JE. Flucytosine monotherapy for cryptococcosis. Clin Infect Dis 1998;27:260-264.
Natalya Goldshteyn, MD, Antonela Zanchi, MD, Kenneth Cooke, MD, and Rabia Agha, MD
From the Division of Pediatric and Adult Infectious Diseases and Department of Pathology, Beth Israel Medical Center and the Department of Radiology, Saint Luke's Medical Center, New York, NY.
Reprint requests to Dr. Rabia Agha, Division of Pediatric Infectious Diseases, Beth Israel Medical Center, 17 Street and 1st Avenue, BH7-14, New York, NY, 10003. Email: email@example.com
Accepted March 24, 2006.
RELATED ARTICLE: Key Points
* Disseminated cryptococcosis usually occurs in patients with defective cellular immunity. Incidence of skeletal involvement is estimated at 5%.
* Typical radiological presentation is a lytic lesion with mild or absent periosteal inflammation.
* Surgical biopsy is the most effective diagnostic modality.
* Cryptococcal skeletal infections should be considered in the differential diagnosis of lytic osseous lesions.
* Clinical and radiological resemblance of various disorders may lead to delayed start of treatment.