Cryptococcal infection of the femur misdiagnosed as a primary bone tumor: A case report and literature review

Abstract

Cryptococcal infections are uncommon, and musculoskeletal involvement of the femur is extremely rare, often resulting in diagnostic challenges. A woman in her early 70s presented with a 20-day history of progressive left thigh pain that was aggravated by limb movement. Initial evaluation at a local hospital suspected a primary bone tumor based on radiographic findings of an osteolytic lesion in the midshaft of the left femur. Laboratory tests revealed elevated C-reactive protein level, erythrocyte sedimentation rate, and ferritin levels, but no malignant tumor markers were detected. Radiological assessment, including magnetic resonance imaging and whole-body scintigraphy, raised the suspicion of a primary bone tumor, with differential diagnoses including eosinophilic granuloma or Brodie’s abscess. An ultrasound-guided biopsy revealed spindle cell proliferation with multinucleated giant cells, with no evidence of malignancy. A multidisciplinary consultation attributed the finding to either an infectious etiology or a possible false-negative result of B-mode ultrasound-guided biopsy. The patient subsequently underwent debridement and biopsy of the affected bone in the left thigh. Although microbial cultures were negative, immunohistochemical analysis showed features consistent with cryptococcal infection. Special staining demonstrated the characteristic thick capsules of Cryptococcus spp., confirming the diagnosis of a cryptococcal granuloma in the left femur. Early diagnosis and timely treatment are important to effectively manage cryptococcal bone infections.

Introduction

Cryptococcal infections are caused by species of the Cryptococcus genus, primarily Cryptococcus neoformans and C. gattii.^1,2 These fungi are found in the environment, particularly in soils enriched with bird droppings, especially from pigeons. ³ The most common manifestation of cryptococcal infections is cryptococcal meningitis, which occurs when the fungi spread to the central nervous system and cause meningeal inflammation. This can result in symptoms such as headache, fever, neck stiffness, nausea, vomiting, and altered sensorium.^4,5 Pulmonary cryptococcosis is another common form in which the infection affects the lungs and presents with symptoms such as cough, chest pain, and dyspnea.^6,7 Musculoskeletal cryptococcosis is exceedingly rare, accounting for 5%–10% of disseminated cases, and is rarely reported in immunocompetent individuals. ⁸ Cryptococcal infections primarily affect immunocompromised individuals, such as patients with human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS), organ transplant recipients, and patients receiving immunosuppressive therapy.^9–12 The pathogenesis of cryptococcal infection involves hematogenous spread from a primary site, often the lungs, leading to fungal seeding in bone tissue. ¹³

Patients typically present with localized pain, swelling, and sometimes systemic symptoms such as fever. Diagnosis relies on a combination of imaging techniques (magnetic resonance imaging (MRI) or computed tomography), histopathological examination, microbial cultures, and cryptococcal antigen testing of bone biopsy specimens. ¹⁴ The clinical presentation of a cryptococcal bone infection often mimics that of a primary bone tumor, making early diagnosis difficult. In most cases, bone lesions caused by Cryptococcus spp. exhibit an insidious onset and subtle radiological features, often mistaken for more common conditions such as primary bone tumors, metastatic cancer, or inflammatory conditions. Here, we report a case of cryptococcal infection of the femur that was initially misdiagnosed as a primary bone tumor in an immunocompetent patient. This case may help clinicians achieve early diagnosis and initiate timely treatment of cryptococcal bone infection.

Case presentation

A woman in her early 70s presented with a 20-day history of persistent, dull pain in her left femur, which was exacerbated by movement. The pain began spontaneously, without trauma or identifiable precipitating factors, and worsened with activity. Initial evaluation at a local hospital revealed an osteolytic lesion in the midshaft of the left femur on radiography, suggestive of a bone tumor (Figure 1(a) and (b)). Curettage and bone grafting were therefore planned. However, the patient’s family requested a transfer to a tertiary hospital for further evaluation, and she was transferred to the Central Hospital of Yongzhou in May 2020.

Figure 1.

Preoperative and postoperative X-ray images. (a, b) Preoperative X-ray showing low-density osteolytic lesions (red arrows) with a slight periosteal reaction in the diaphyseal bone at the mid-distal shaft of the femur, with a swollen soft tissue shadow (red arrows). Preoperative MRI and whole-body bone scintigraphy. (c–f) Femur MRI ((c) coronal T1-weighted; (d) horizontal T1-weighted; (e) coronal T2-weighted; (f) horizontal T2-weighted) revealing abnormal signal changes in the midshaft bone, medullary cavity, and surrounding soft tissues (red arrows) and (g) whole-body bone scintigraphy showing active metabolism of the left femur (red arrows). MRI: magnetic resonance imaging.

On admission, it was discovered that the patient was a farmer with an overall healthy constitution, had no immune abnormalities, and had no history of long-term steroid use. She underwent cholecystectomy at a local hospital 3 years ago. Neither the patient nor her family had a history of viral hepatitis; tuberculosis; AIDS; diabetes; hypertension; or respiratory, cardiovascular, or neuropsychiatric diseases. Vital signs at admission included a blood pressure level of 138/78 mmHg, heart rate of 90 beats per minute, and temperature of 36.6°C. There were no significant abnormalities in urination or defecation, and the patient did not experience any notable weight loss in May 2020.

Physical examination revealed no abnormalities in the lungs or central nervous system. The left thigh had intact skin with a slightly elevated local temperature, but no ulceration or localized tenderness was noted. The right hip and knee joints demonstrated a normal range of motion. Laboratory tests revealed thrombocytosis with a platelet count of 393 × 10⁹/L (reference interval (RI): 125–350 × 10⁹/L), normal white blood cell count, and monocyte percentage elevated at 10% (RI: 3%–8%). Inflammatory marker levels were elevated: C-reactive protein (CRP) level was 70.3 (RI: 0–10) mg/L and erythrocyte sedimentation rate (ESR) was 71 (RI: 0–20) mm/h. Ferritin level was also elevated at 457.4 (RI: 4.63–204) ng/mL, while other tumor markers were normal. Liver and renal function tests, alkaline phosphatase, urinalysis, stool routine, and T-cell-based tuberculosis infection assays were all negative.

Chest and abdominal computed tomography findings were unremarkable. Plain radiography of the left femur revealed tumor-like changes in the midshaft. MRI revealed abnormal signals in the midshaft, medullary cavity, and surrounding soft tissues, suggestive of an eosinophilic granuloma or Brodie’s abscess (Figure 1(c) to (f)). Whole-body bone scintigraphy showed markedly increased metabolic activity in the midshaft of the left femur, suggesting a primary bone tumor (Figure 1(g)).

Based on the physical examination, laboratory tests, and radiologic examination, the patient was provisionally diagnosed with a primary bone tumor. Given her advanced age, brief symptom duration, and rapid disease progression, malignancy could not be ruled out. To confirm the diagnosis, an ultrasound-guided subcutaneous biopsy was performed. Pathological examination revealed spindle cell proliferation with neutrophil and lymphocyte infiltration in skeletal muscle under hematoxylin and eosin (H&E) staining and scattered multinucleated giant cells but no malignant cells (Figure 2(a) and (b)).

Figure 2.

Subcutaneous and resection biopsy tissues with staining methods. (a) H&E staining showing spindle cell proliferation with neutrophil and lymphocyte infiltration in the majority of the skeletal muscle tissue; (b) scattered multinucleated giant cells were observed (red arrows); (c) H&E staining revealing infiltration of neutrophils and lymphocytes in the tissue; (d) scattered multinucleated giant cells were observed (red arrows); (e) increased multinucleated giant cells were noted, along with vacuolar hyaline bodies in the cytoplasm and (f) PAS staining showing purple staining of numerous Cryptococcus thick capsules (red arrows). Magnifications: 20× and 40×. H&E: hematoxylin and eosin; PAS: periodic acid-Schiff.

The patient’s medical records were reviewed. Elevated CRP, ESR, and ferritin levels suggested inflammation. The biopsy findings showed no malignancy, and the level of alkaline phosphatase, a typical tumor marker, was within normal limits. Multidisciplinary consultation confirmed no pulmonary or central nervous system infections, supporting the possibility of an infectious etiology or false-negative biopsy. With patient and family consent, debridement and biopsy of the left thigh were performed. Although tissue culture was negative, immunohistochemical examination showed neutrophil and lymphocyte infiltration, along with multinucleated giant cells and vacuolar hyaline bodies suspected to contain Cryptococcus spp. (Figure 2(c) to (e)). Periodic acid-Schiff (PAS) staining demonstrated purple staining of numerous Cryptococcus capsules (Figure 2(f)). The pathological diagnosis confirmed cryptococcal granuloma, and the final diagnosis was cryptococcal infection of the left femur.

The patient was started on fluconazole with a loading dose of 400 mg once daily, followed by a maintenance dose of 200 mg daily. She was discharged on postoperative day 6 and continued oral fluconazole (200 mg daily) for 3–6 months. At 1- and 3-month follow-ups, routine blood, liver, and renal function tests were normal. At 1-month follow-up, the patient reported residual symptoms. Radiology showed a cystic radiolucency and periosteal reaction in the midshaft of the left femur (Figure 3(a) and (b)). At 3-month follow-up, the patient was asymptomatic. Imaging revealed notable bone resorption and satisfactory recovery (Figure 3(c) and (d)). The patient was subsequently lost to follow-up due to the resolution of symptoms and her decision to discontinue further evaluations.

Figure 3.

(a and b) One-month follow-up X-ray revealing a cystic light-permeable area in the local bone of the lateral middle part of the left femur, along with a slight periosteal reaction around it, which was roughly similar to that at preoperation (red arrows) and (c and d) three-month follow-up analysis demonstrated that the local intraosseous cystic light transmission area in the lateral middle of the left femur was smaller than before, and the periosteal reaction disappeared completely (red arrows).

Discussion

Cryptococcal infection is an opportunistic infection that predominantly affects immunocompromised individuals, such as those with HIV infection, malignancies, solid organ transplants, and connective tissue diseases as well as those receiving immunosuppressive therapy.^10,15 Cryptococcosis is uncommon in immunocompetent individuals, and isolated cases of cryptococcal osteomyelitis are particularly rare.^16,17 Cryptococcal bone infections typically affect the vertebrae, ribs, clavicles, pelvis, and humerus. ¹⁸

However, infections involving the femur are exceptionally rare, and their diagnosis and management can be complex and challenging. Diagnostic approaches for cryptococcal infections of the femur are nonspecific. Radiological features associated with cryptococcal bone infections, such as bone destruction, erosion, mixed lytic and sclerosing lesions, and joint space narrowing, are often inconclusive and may mimic imaging findings seen in conditions such as osteomyelitis or arthritis. ¹⁹ Additionally, serum biomarkers, including cryptococcal antigen, lack sufficient sensitivity, and microbial cultures and histopathologic investigation may fail to detect Cryptococcus. ²⁰ The gold standard for diagnosis remains direct histopathological investigation of tissue samples, wherein Grocott’s methenamine silver and PAS staining can reveal the mucopolysaccharide-rich capsules of Cryptococcus spp. As with other forms of fungal bone infections, optimal treatment involves a combination of appropriate antifungal therapy (e.g. fluconazole), reversal of immune suppression, and surgical intervention when indicated. ²¹

Interestingly, in this case, the older patient presented with an immunocompetent host for cryptococcosis, along with an initial tumor-like presentation with osteolytic destruction on imaging. This finding suggests that host factors beyond classical immunosuppression, such as age-related immune senescence or local tissue microenvironment alterations, may predispose individuals to infections. In addition, some cases of cryptococcal osteomyelitis may clinically resemble malignancy, underscoring the importance of timely and accurate diagnostic strategies.^22,23

The diagnostic process highlighted the key pitfalls in evaluating osteolytic bone lesions. The initial tumor-like imaging appearance, along with negative fungal cultures, demonstrated how easily cryptococcal osteomyelitis can closely mimic neoplastic or other granulomatous conditions. Notably, elevated inflammatory markers (CRP, ESR, and ferritin) serve as important indicators of an infectious process, despite the absence of systemic symptoms. C. neoformans infection has been associated with elevated CRP, ESR, and ferritin levels. ²⁴ Studies suggest that Cryptococcus spp. can use ferritin, a major iron storage protein in vertebrates, as the sole iron source, underscoring the potential role of inflammatory markers in assessing bone lesions. ²⁵

Histopathological investigation proved essential for a definitive diagnosis, particularly as the microbial cultures remained negative. This may have been due to a low fungal burden or prior partial treatment. Granulomatous inflammation with identifiable cryptococcal organisms on H&E and PAS staining was diagnostic. This reinforces the need to perform biopsy and special staining early when an infection is suspected. Cryptococcal osteomyelitis should be considered in patients with unexplained osteolytic lesions, regardless of their immune status. Inflammatory markers can aid in distinguishing infectious etiologies from neoplastic ones. Clinicians must maintain a high index of suspicion for this rare but treatable infection to prevent unnecessary interventions and delays in appropriate therapy. However, the limitations of our study include the lack of specific high-molecular assays, such as 5.8S polymerase chain reaction, and the relatively short follow-up period for patients.

Conclusion

Cryptococcal infection of the femur, although rare, should be considered in the differential diagnosis of patients presenting with bone lesions and elevated inflammatory markers, particularly when conventional tumor markers are negative. This case highlights the importance of a comprehensive diagnostic approach, including inflammatory markers, imaging studies, histopathologic investigation, and microbiological testing, to facilitate early diagnosis and prompt initiation of appropriate antifungal therapy. With timely intervention, favorable outcomes can still be achieved, even in atypical presentations of cryptococcal infections.