Abstract
Cryptococcosis is an invasive mycosis and can disseminate an infection in immunocompromised hosts. The main sites of infection include the central nervous system and lungs; skeletal infections are rarely reported. We describe the case of a Chinese man in his early 40s with a 1-year history of dermatomyositis and prolonged use of corticosteroids and immunosuppressants. During re-examination of a previously discovered pulmonary nodule, lung computed tomography revealed that the nodule had grown in size, and a bone scan revealed local bone abnormalities and mass formation in the left scapula. The initial diagnosis was lung cancer with bone metastasis; therefore, both lesions were resected. The final histopathological diagnosis was disseminated cryptococcosis. This case presents a rare and atypical manifestation of pulmonary and skeletal cryptococcosis. Thus, cryptococcal infection should be considered in the differential diagnosis in patients presenting with immune insufficiency.
Keywords
Introduction
Cryptococcus, an opportunistic pathogenic fungus, commonly leads to infection in immunocompromised patients. It can infect nearly any organ of the human body and predominantly affects the nervous and respiratory systems.1–3 Although skeletal cryptococcosis can affect any bone, the vertebrae are the most frequently involved site, possibly due to their sufficient blood supply. After the vertebrae, the skull and femur are the subsequent most commonly affected sites.4–6 Disseminated cryptococcosis affecting the scapula is exceedingly rare.2,4,7 Herein, we present a unique and unusual case of a patient initially diagnosed with lung cancer with bone metastasis preoperatively and a final surgical pathological diagnosis of disseminated cryptococcosis. The reporting of this study conforms to the Case Report (CARE) guidelines. 8
Case description
In December 2023, the patient presented to the Affiliated Hospital of Southwest Medical University (Luzhou, Sichuan, China). The patient, a man in his early 40s, was diagnosed with dermatomyositis by the Department of Rheumatology 1 year ago. He was on an immunosuppressive regimen, which included tofacitinib and prednisone (25 mg/day). Ten months ago, due to the patient’s dyspnea symptoms, lung computed tomography (CT) was performed, revealing a solitary solid nodule in the lower lobe of the right lung, which was initially presumed to be infectious but was not treated with anti-infective therapy. Re-examination revealed that the lung nodule had increased in size since the previous imaging. CT revealed that the lobulated pulmonary nodule exhibited pleural indentation and spiculation sign; however, no halo signs were observed. The enhanced scan demonstrated moderate uneven enhancement (Figure 1(a)). Consequently, he was initially diagnosed with lung cancer, leading to his referral for thoracic surgery for further management. Laboratory investigations revealed a white blood cell count of 8.8 × 109/L (normal range: 3.5–9.5 × 109/L), 79.4% neutrophils (normal range: 40%–75%), 6.1% lymphocytes (normal range: 20%–50%), and 0.3% eosinophils (normal range: 0.4%–8%). All other test results were within normal limits.
(a) CT scan showing a solitary solid nodule in the lower lobe of the right lung. (b) Radiograph: bone defect lesions in the left scapula with clear boundary. CT scans of (c) soft-tissue window and (d) bone window show osteolytic lesions in the left scapula characterized by well-defined borders and the absence of sclerotic reaction. Red arrows point to the lesions. CT: computed tomography.
On examination, the patient only presented with the symptom of difficulty in breathing following physical activity. There was no evidence of weight loss or any other associated symptoms. His limb joint movements were normal.
Due to concerns regarding metastasis of the lung cancer, a bone scan was prescribed (Figure 2). The results revealed increased tracer uptake in the left scapula and evidence of bone destruction, along with a soft tissue mass. Radiography revealed lytic bone lesions in the left scapula with no sclerotic reaction (Figure 1(b)). CT demonstrated osteolytic destruction in the left scapula characterized by well-defined borders and the absence of sclerotic reaction (Figure 1(c) and (d)). Magnetic resonance imaging (MRI) revealed bone destruction and a soft tissue mass measuring 3.5 × 2.6 × 2.6 cm in the left scapula. Edema was also observed in the bone and surrounding soft tissue (Figure 3). All these imaging studies indicated that the lesion in the left scapula was consistent with metastatic disease. Considering the patient’s condition, conservative treatment was ineffective. The patient and his family also strongly advocated for surgical intervention. Therefore, the patient underwent surgery for the right lung and then for the left shoulder blade. Histopathological examinations of lung and bone tissue revealed granulomatous lesions, and Cryptococcus was confirmed using hematoxylin and eosin (HE), periodic acid-silver methenamine (PASM) and periodic acid-Schiff’s (PAS) staining (Figure 4). The final clinical diagnosis was disseminated cryptococcosis.
Systemic radionuclide bone-scanning reveals active metabolism of left scapula and bone destruction along with a soft-tissue mass. Red arrows point to the lesions.
MRI (left scapula): (a) coronal T1-weighted, (b) coronal T2-weighted, (c) coronal fat-suppressed T2-weighted, (d) coronal enhanced T1-weighted, (e) sagittal enhanced T1-weighted, (f) transversal enhanced T1-weighted show bone destruction with enhanced soft-tissue mass. Red arrows point to the lesions.
Postoperative histopathological examination (a–c) lung tissue and (d–f) bone tissue. Periodic acid-Schiff reveals large number of spheroids with varying sizes and red outer membranes.
The patient was prescribed a 2-month course of fluconazole (oral fluconazole, 400 mg/day) postoperatively to address the antifungal infection. Four months later, the patient underwent re-examination at the hospital. His left shoulder was in good condition with no swelling detected, and he did not report any pain or dyspnea symptoms. Re-examination using chest CT and radiography of the left scapula revealed no radiological evidence of relapse (Figure 5). However, partial defects in the bone and right lung tissue persisted.
After 4 months of follow-up, the radiological images show no signs of recurrence. (a) chest CT and (b) radiograph of the left scapula. CT: computed tomography.
Discussion and conclusions
Cryptococcosis is a common fungal infection with wide global prevalence.1,3 Disseminated cryptococcosis is defined based on a positive culture from at least two different sites or a positive blood culture. 9 Immunosuppression, malignancy, corticosteroid treatment, and connective tissue disorders increase the risk of disseminated cryptococcosis.10–13 Cryptococcosis predominantly affects the nervous and respiratory systems. Lesions have also been reported in the skin, prostate, eyes, bone and joints. 1 Disseminated cryptococcosis rarely manifests as skeletal cryptococcosis, affecting <10% of patients; scapula involvement is particularly uncommon.7,14 A review of all English language reports of cryptococcosis involving the scapula since 1997 revealed only four related cases (Table 1).15–18
Main characteristics of four published cases of scapula cryptococcosis.
AMB: amphotericin B; Flu: fluconazole; 5-FC: 5-fluorocytosine; NA: not available.
Typical symptoms of skeletal cryptococcosis include pain and swelling.7,10,19 However, the patient was asymptomatic in the left shoulder. This may be attributed to the early stage of the lesion or the patient’s lack of awareness.
The radiological features of skeletal cryptococcosis are often nonspecific and may resemble those of other skeletal lesions. Based on radiological features, skeletal cryptococcosis may also be associated with other differential diagnoses, such as Staphylococcus aureus and tuberculosis infections as well as bone neoplasms such as Ewing’s sarcoma and osteogenic sarcoma.20–22 In our case, radiographic evidence revealed bone destruction and a soft-tissue mass in the left scapula as well as edema of the bone and surrounding soft tissues. The patient was initially suspected to have malignancy with metastases. Given the high suspicion of malignancy based on imaging and the need for a definitive diagnosis, tissue confirmation was pursued through surgical sampling. When stage IV non-small cell lung cancer (NSCLC) is suspected (e.g. a lung nodule with a suspected bone metastasis), the standard diagnostic pathway generally prioritizes biopsy-based histopathological confirmation (from the lung lesion and/or bone lesion), comprehensive staging, and multidisciplinary evaluation before definitive treatment decisions are made. 23 In the present case, surgery was performed before a definitive preoperative pathological diagnosis was established. This represents a limitation of the present study and underscores the importance of guideline-concordant diagnostic workup to prevent potentially unnecessary interventions and delays in optimal management.
No standardized treatment protocol exists for cryptococcal infections in specific anatomical locations, except for the lungs and central nervous system.3,24 Surgery in combination with antifungal agents and antifungal therapy alone have been demonstrated to be effective for treating infections at these sites. 25 Although surgery is an effective and rapid method of eliminating a fungal infection and preventing its spread to adjacent sites, its use may pose an increased risk of disseminating the infection; it is therefore not recommended for immunocompromised patients. 26 For patients diagnosed with disseminated cryptococcosis, combination therapy using amphotericin and 5-fluorocytosine (5-FC) is recommended initially, followed by consolidation and maintenance therapy with fluconazole.3,15 Since the patient had undergone surgical treatment, only fluconazole was used for consolidation therapy. In our patient, postoperative antifungal therapy consisted of oral fluconazole (400 mg/day) for approximately 2 months; after treatment completion, he was followed up for a further 4 months. At the most recent follow-up (approximately 6 months postoperatively), he was clinically stable with follow-up imaging showing no evidence of recurrence. In immunocompromised patients with disseminated cryptococcosis, a prolonged course of antifungal therapy is generally recommended (often 6–12 months). 3 We acknowledge that this treatment duration may be shorter than the common recommendation for disseminated disease and consider this a limitation of the present report.
Cryptococcal capsular antigen (CrAg) testing, although a recommended first-line assay in suspected cryptococcosis, 3 was not performed for this patient. The final diagnosis was established based on histopathological examination, with fungal organisms consistent with Cryptococcus identified on PAS staining of both pulmonary and left scapular lesion specimens. The absence of CrAg testing is a limitation and highlights the value of incorporating CrAg testing into a guideline-concordant diagnostic algorithm. 3
Importantly, lumbar puncture with cerebrospinal fluid (CSF) evaluation is recommended in immunocompromised patients with disseminated cryptococcosis to assess for concomitant cryptococcal meningitis. 3 In the present case, CSF analysis was not performed because the patient had no neurological symptoms or signs suggestive of central nervous system involvement during evaluation and follow-up and was unwilling to undergo lumbar puncture. This represents a limitation and underscores the importance of guideline-concordant evaluation (including CSF assessment when indicated) to prevent missed diagnosis of central nervous system disease and guide appropriate antifungal strategy and duration. 3
Table 2 summarizes reported radiographic and cross-sectional imaging findings of skeletal cryptococcosis across multiple skeletal sites (spine, skull, long bones, pelvis, ribs, and scapula). These findings are not pathognomonic, and definitive diagnosis typically requires microbiological and/or histopathological confirmation.
Imaging features of skeletal cryptococcosis across anatomical sites: a literature-based summary.
CT: computed tomography; MRI: magnetic resonance imaging; TB: tuberculosis.
Taken together, skeletal cryptococcosis is an uncommon clinical disease that lacks specific imaging and clinical findings and can mimic malignancy or other infections. We recommend that skeletal cryptococcosis be considered in the differential diagnosis of any patient presenting with bone lesions, especially those with immunodeficiency, as indicated by long-term use of corticosteroids or immunosuppressants. Early tissue confirmation and guideline-concordant evaluation may help reduce misdiagnosis, diagnostic delay, and potentially harmful management.
Footnotes
Acknowledgments
Not applicable.
Author contributions
Zeren Luo and Chuanyan Yang conceived the study, collected the clinical and imaging data, performed literature review, and drafted the manuscript. Pan Han participated in data collection and literature review. Dong Chen contributed to imaging interpretation and figure preparation. Pinxiong Li supervised the study and critically revised the manuscript for important intellectual content. All authors approved the final version of the manuscript.
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Consent to treatment
The patient provided written informed consent for the planned treatment/procedures as part of routine clinical care.
Data availability
Not applicable.
Declaration of conflicting interest
The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical considerations
All patient information in this case report has been fully deidentified to protect the patient’s privacy.
Funding
This work was supported by the Luzhou Science and Technology Program (2023RCX173), National Science Foundation for Young Scientists of China (82202143), Sichuan Science and Technology Program (2022YFS0616), and Doctoral Research Initiation Fund of the Affiliated Hospital of Southwest Medical University.
