Monostotic chronic nonbacterial osteomyelitis/chronic recurrent multifocal osteomyelitis of clavicle mimicking malignant bone tumor: A case report and review of literature

Abstract

BACKGROUND

Bone tumors and tumor-like lesions are rare in children and adolescents and usually benign, while malignancies cannot be excluded. Rare entities such as chronic recurrent multifocal osteomyelitis (CRMO)/chronic nonbacterial osteomyelitis (CNO) should be also considered. CNO is a rare, non-infectious autoinflammatory bone disease that primarily affects children and adolescents. The clinically severe type is CRMO with multiple sites and waxing-waning course. The monostotic presentation of CNO as a solitary bone lesion may pose significant diagnostic challenges.

CASE SUMMARY

We present the case of a 13-year-old male athlete with a painful swelling of the left clavicle. Imaging studies revealed a morphologically aggressive lytic lesion indicative of primary malignant bone tumor. Histopathological analysis, however, excluded malignancy and supported a diagnosis of inflammatory osteomyelitis. Whole-body magnetic resonance imaging confirmed the monostotic nature of the lesion. Based on clinical, radiologic, and histological findings, a diagnosis of solitary CNO of the clavicle was established. The patient was treated conservatively with non-steroidal anti-inflammatory drugs and referred to a paediatric rheumatologist.

CONCLUSION

Including unusual entities as monostotic CRMO/CNO in the differential diagnosis of bone tumors avoids unnecessary surgical procedures or antibiotic use.

Key Words: Bone tumors; Chronic recurrent multifocal osteomyelitis; Chronic nonbacterial osteomyelitis; Whole body imaging; Differential diagnosis; Case report

Core Tip: Monostotic chronic recurrent multifocal osteomyelitis/chronic nonbacterial osteomyelitis represents a diagnostic challenge, as its clinical and radiological features frequently overlap with those of aggressive osseous malignancies or infectious osteomyelitis. This case report underscores the necessity of a multifaceted diagnostic approach of bone tumors, integrating histopathological analysis and Whole-body magnetic resonance imaging to confirm a non-infectious inflammatory etiology. Recognizing this underestimated entity, is essential for clinicians to ensure accurate diagnosis, preclude unnecessary invasive surgical interventions, and implement effective conservative management strategies.

INTRODUCTION

Bone tumors and tumor-like lesions are rare in children and adolescents and usually benign. The most common benign lesions include nonossifying fibromas, fibrous dysplasias, simple and aneurysmal bone cysts, and osteochondromas, whereas the most common malignancies include osteosarcomas and Ewing Sarcomas[1,2]. Although rare entities may perplex the treating physician, they should be considered in the differential diagnosis to improve the diagnostic accuracy and avoid therapeutic errors or overtreatment.

Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory disorder, predominantly affecting children and adolescents, with a slight female preponderance[3]. The clinical range of CNO varies from localized, self-limited monofocal lesions to recurrent multifocal bone inflammation, in the form of chronic recurrent multifocal osteomyelitis (CRMO), that usually results in fractures and bone deformities[4,5]. It can appear in every part of the skeleton except the neurocranium, with a preference for the metaphysis of long bones, the clavicles and the vertebrae[6]. Clinical manifestations of bone lesions usually appear with pain, high temperature, local oedema and fever. In some cases, mostly in adults, it may be combined with sinusitis, severe acne, palmoplantar pustulosis, hyperostosis and osteosis, a symptom complex called synovitis acne pustulosis hyperostosis osteitis (SAPHO)[7].

CNO/CRMO incidence is between 1:250.000 and 1:1.000.000[8,9], usually presenting in children after the age of 2, with peak onset between ages of 7 and 12[4]. Although the etiology is unclear, it is believed that there is a genetic and autoinflammatory basis behind this entity, since it is associated with other autoinflammatory disorders such as inflammatory bowel disease and psoriasis[4,10]. The diagnosis is based on clinical manifestations, radiological evidence and bone biopsy; however, it can be really challenging due to insufficient clinical evidence and inconclusive radiology. Crucially, while multifocal presentations prompt clinicians toward autoinflammatory diseases, monostotic CNO creates a critical diagnostic pitfall. When localized aggressively in a single bone like the clavicle, it directly mimics benign and malignant bone tumors, such as osteosarcoma and Ewing’s sarcoma as well as septic osteomyelitis, frequently misleading the initial differential diagnosis[10]. In this case report we describe a case of CNO/CRMO in 13-year-old male adolescent, whose clinical presentation in combination to the initial radiological examination led primarily to the diagnostic consideration of malignant diseases. This case emphasizes the need to correlate the patient’s history with the clinical and radiological findings including unusual clinical entities.

CASE PRESENTATION

Chief complaints

A 13-year-old male swimming-athlete presented with a painful lesion at the sternal end of his left clavicle.

History of present illness

The symptoms were of 2 weeks duration, which started during swimming competitions. Pain was exacerbated by upper limb exertion during athletic activity, with no reported nocturnal symptoms.

History of past illness

The patient had an unremarkable past medical history with no prior hospitalizations, chronic illnesses or musculoskeletal injuries.

Personal and family history

The patient was an active competitive swimming athlete with a non-contributory family medical history.

Physical examination

Clinical examination revealed swelling of the left clavicle, with pain elicited by applying pressure to the mid-clavicle. No enlarged lymph nodes were found in the supraclavicular space, cervix or axilla, with no evidence of dilated veins, redness or fever.

Laboratory examinations

Comprehensive laboratory evaluations were initiated to delineate the differential diagnosis. Initial laboratory investigations i.e. blood test, biochemical and microbiological tests did not reveal any significant findings [C-reactive protein (CRP) was 0.3 (normal values < 0.5) and erythrocyte sedimentation rate (ESR) was 12].

Imaging examinations

The chest X-ray of the patient was unremarkable apart from a mild expansion at the medial aspect of the left clavicle. Subsequently, the boy underwent a detailed imaging workup with computed tomography (CT) and magnetic resonance imaging (MRI) focused on the left clavicle (Table 1).

Table 1 The boy underwent a detailed imaging workup on the left clavicle.

Imaging modality	Key findings
X-ray	Initial identification of bone abnormality
CT	Detailed appreciation of osseous lesions
MRI	Locoregional mapping of bone marrow and soft tissue involvement
WB-MRI	Biomarker of disease activity and treatment response without radiation exposure

CT: Computed tomography; MRI: Magnetic resonance imaging; WB-MRI: Whole body magnetic resonance imaging.

CT images showed a lytic lesion (4 cm × 2 cm) on the sternal side of the left clavicle, causing widening of diaphysis and reaching the inner surface of the sternoclavicular joint, with clear thinning and focal cortical disruption, as well as mild periosteal reaction (Figure 1).

Figure 1 Axial computed tomography and coronal computed tomography chest. A: Axial computed tomography (CT) chest shows a lytic lesion (asterisk, 4 cm × 2 cm) that affects the medial aspect of the left clavicle with cortical diaphyseal expansion (thick arrow) reaching the inner surface of the sternoclavicular joint; B: Coronal CT chest shows perilesional cortical thinning (asterisk) with focal cortical disruption (slim arrow) and mild periosteal reaction.

MRI images revealed a rather aggressive bone lesion with extensive bone marrow involvement of the medial aspect of the clavicle, marked periosteal reaction and soft tissue edema surrounding the clavicle with vivid contrast enhancement. However, no clear soft tissue mass was detected (Figure 2).

Figure 2 Magnetic resonance imaging at the level of the clavicle. A and B: Coronal synth short-tau inversion recovery (STIR) (A) and axial STIR (B) images show an intramedullary lesion (asterisk) with abnormal high signal (asterisk) in the anatomical site of the medial aspect of the left clavicle with marked reaction from the surrounding periosteum and adjacent muscles without soft tissue component.

The differential diagnosis included benign and malignant primary bone tumors such as osteoblastoma, fibrous dysplasia, Ewing sarcoma and lymphoma, and septic osteomyelitis. The possibility of an unusual entity, such as autoimmune osteomyelitis was raised initially, although considered highly unlikely, based on the location of the lesion. Therefore, based on the location of the lesion and the age of the patient, an incisional biopsy was recommended by a specialized orthopedic surgeon. After obtaining informed consent from the parents, the adolescent patient underwent an open biopsy of the sternal tip of the clavicle, under general anesthesia and fluoroscopic control (Figure 3).

Figure 3  Image-guided open biopsy procedure.

Histopathological examination: This revealed a lesion characterized by myofibroblastic spindle stromal cells, without remarkable cellular atypia or mitotic activity, as well as cells of moderate chronic inflammation, predominantly lymphocytes. Neoplastic processes were excluded via immunohistochemistry, which demonstrated strict negativity for the Ewing sarcoma-associated markers CD99 and NKX2.2, the Langerhans cell histiocytosis marker CD1a, and the neural marker S100. Conversely, diffuse positivity for the myofibroblastic marker SMA and the osteoblastic differentiation marker SATB2 confirmed the benign nature of the lesion. Chronic inflammation was further highlighted by positivity for the CD45/LCA common leukocyte antigen.

Consequently, both the radiological features and the biopsy result suggested an inflammatory and reactive lesion, probably in the context of some type of chronic osteomyelitis. The patient underwent a baseline whole body-MRI (WB-MRI) scan after the biopsy, in order to investigate potential multifocal involvement of other anatomic locations that would be clinically occult, without the burden of ionizing radiation. WB-MRI confirmed the monostotic nature of the lesion.

FINAL DIAGNOSIS

The diagnosis of CNO as a monostotic lesion of the medial aspect of the left clavicle was reached by the correlation of clinical and radiological findings, while histological findings excluded neoplastic and septic entities.

TREATMENT

The young patient was treated non-surgically with non-steroidal anti-inflammatory drugs and was referred to a pediatric rheumatologist for further investigation and follow-up. WB-MRI did not reveal other sites of the lesion.

OUTCOME AND FOLLOW-UP

The young patient was treated non-surgically.

DISCUSSION

Unlike previously reported CNO/CRMO cases, our patient had unremarkable personal and family history and presented with an aggressive lytic lesion with cortical disruption mimicking primary malignancy. This case raises awareness for inclusion of CNO in the differential diagnosis of isolated lytic bone lesions[11-14]. CNO, also known as CRMO when chronically active with multiple sites of involvement, is a rare autoinflammatory bone disease of unknown cause that mainly affects children and young adults, with predominance in girls, leading to persistent bone pain and/or bone destruction, functional impairment and fractures[4]. The lesion can occur in almost any part of the skeleton, with a preference for the metaphysis of the long bones, the pelvis, the vertebral column and the clavicles. The disease may be single or multifocal, with symmetrical or asymmetrical lesions and with or without recurrence. Indeed, CNO covers a clinical spectrum with sometimes mild and self-limited monofocal lesions at one end, and chronically active or recurrent multifocal disease at the other end, that is most appropriately characterized as CRMO. In addition to bone manifestations, CNO often occurs with extraosseous manifestations from the gastrointestinal system and skin, and is associated with autoimmune diseases such as inflammatory arthritis and SAPHO[15]. CNO is a diagnosis by exclusion, because there are no specific biomarkers for the disease, or universally recognized diagnostic criteria. It often remains under-recognized as the clinical picture and laboratory tests are non-specific, while the radiological picture is similar to that of more serious conditions such as bacterial osteomyelitis and Ewing’s sarcoma[10,16]. In this clinical context, the meticulous evaluation of the patient’s age, alongside the precise onset and duration of symptoms, and the location of the lesion is considered of paramount importance for diagnostic accuracy[17].

The monostotic nature of the rather morphologically aggressive clavicular lesion in the present case and its location provided a useful hint indicative of CNO. It has been reported that typical sites of bone involvement in CNO are the mandible, the sternal aspect of the clavicle with or without involvement of the sternoclavicular joint and the vertebral bodies[18].

Chandola et al[19] provided a comprehensive analysis of CRMO mimics, delineating the overlapping clinical and radiologic features that complicate the diagnostic process. This classification encompasses a broad spectrum of pathologies, including infectious diseases, malignancies, autoimmune conditions, metabolic and other distinct entities, while highlighting the key imaging findings essential for their differentiation.

The radiological appearance of CRMO varies, depending on the radiological imaging method used. Plain radiography serves as the initial imaging modality; however, it remains non-diagnostic and is associated with a high rate of false-negative results, particularly in the early stages of the disease[20]. The utilization of CT, bone scintigraphy and positron emission tomography is declining, particularly within the pediatric population, to prevent ionizing radiation exposure[21]. MRI plays an important role in the diagnosis of the disease. Lesions appear mainly in the metaphysis, with lytic or sclerotic changes, depending on the stage of the disease, periosteal reaction, swelling of the bone marrow and/or surrounding soft tissue inflammation. However, given the inherently multifocal nature of the disease, WB-MRI has emerged as the imaging gold standard. The role of WB-MRI has been well documented not only in oncologic patients but also in various musculoskeletal disorders, including CNO. The radiation free nature of WB-MRI is ideal for pediatric population in order to investigate multiple sites of active lesions and may serve as a radiation-free imaging tool for assessment of treatment response. WB-MRI offers the distinct advantage of identifying the total lesion burden and potential complications in a single study, while maintaining a superior safety profile[22], which is very advantageous since CNO is a bone disorder that most frequently affects children and adolescents. In certain cases, features in favor of an inflammatory process, such as the absence of a soft tissue mass or the presence of multifocal lesions, remove the suspicion of malignancy. In other cases, as in the present case, the possibility of malignancy cannot be excluded, and a biopsy is considered necessary[23,24].

Laboratory tests are often normal, but in some cases, elevated inflammation markers such as CRP and ESR are present[25]. In numerous studies specific serum biomarkers and high cytokine levels have been associated with the occurrence of CRMO, but further research is needed to establish their validity[26].

The histopathological findings are extremely important for the diagnosis of CNO/CRMO, especially with the demonstration of acute or chronic inflammatory cells and the absence of malignant cells or microorganisms suggestive of infection[27].

In difficult cases, diagnostic criteria can be used, although they are not universally established in the diagnosis of CNO/CRMO. The most widely used are Jansson and Bristol criteria, which are based on the exclusion of other diseases, the presence of characteristic clinical, laboratory, imaging and/or histological findings[28,29], while European Alliance of Associations for Rheumatology/American College of Rheumatology established recently, classification criteria for pediatric CNO, using a weighted scoring system that contributes to a more accurate categorization of patients with CNO/CRMO[30].

CONCLUSION

This case highlights the diagnostic complexity of CNO/CRMO, particularly in monostotic cases and in the absence of systemic or recurrent symptoms. The overlap in radiologic features with malignant bone lesions underscores the importance of a multidisciplinary approach, including correlation of clinical, laboratory and imaging evaluation before performing biopsy for definitive histopathological evaluation. Consideration of rare entities such as CNO that may be included in the differential diagnosis can prevent unnecessary invasive procedures and facilitate appropriate management. Increased awareness among clinicians is essential to recognize this underdiagnosed autoinflammatory entity and initiate timely, conservative treatment that can lead to symptom resolution and disease control[31].