Intraosseous Venous Malformation of the Rib With EWSR1-NFATC1 Fusion Mimicking Malignancy: A Pediatric Case Report

Abstract

Background:

Intraosseous venous malformations are rare, benign vascular bone lesions that may mimic malignant sarcomas on imaging.

Observations:

A 14-year-old male presented with fever and cough. Imaging revealed an incidental ossified rib mass with aggressive features. CT-guided biopsy was nondiagnostic, whereas open biopsy demonstrated a vascular lesion positive for CD31, FLI-1, and ERG. Molecular testing identified an EWSR1-NFATC1 fusion. Gross total resection was achieved, followed by prolonged disease-free survival, and the patient resumed full athletic activity 7 months after surgery.

Conclusions:

This case highlights the value of open biopsy and molecular testing to prevent misdiagnosis and overtreatment of intraosseous venous malformations.

Intraosseous vascular tumors, particularly intraosseous venous malformations, are rare, benign lesions that can be difficult to distinguish from malignant bone tumors such as osteosarcoma and Ewing sarcoma because of overlapping radiographic features.^1–3 Radiographically, they often present as expansile, well-defined lesions with a characteristic “honeycomb,” “soap-bubble,” or “sunburst” appearance due to osteolytic activity of the vascular malformation.⁴ Cortical destruction and soft-tissue involvement are also common.⁴ Affected bones include the pelvis, long bones, vertebrae, ribs, and craniofacial sites.^4,5 They account for a small but meaningful fraction of bone tumors.⁶ Despite their benign nature, these tumors are often mistaken for malignancy in children. Nondiagnostic needle biopsies are common due to their vascular heterogeneity, creating diagnostic uncertainty.^7–12 Open biopsy and surgical excision are often required for definitive diagnosis.^9–12

Molecular analysis has expanded the understanding of these tumors. Investigators have identified EWSR1-NFATC1 and EWSR1-NFATC2 fusions in benign vascular bone lesions.^3,4,13–16 Molecular testing is a valuable diagnostic adjunct when histology is nondiagnostic.

Here, we describe a pediatric case of an intraosseous venous malformation of the rib—initially concerning for malignancy on imaging—with the diagnosis confirmed by histology, immunohistochemistry, and molecular testing.

CASE PRESENTATION

A 14-year-old male with a past medical history of asthma presented to the emergency department with 2 weeks of low-grade fever, persistent cough, and malaise. He denied weight loss, night sweats, or chest pain. On examination, he was afebrile and in no respiratory distress. Breath sounds were decreased at the right lung base. There was no palpable chest mass or lymphadenopathy.

Laboratory evaluation revealed a white blood cell count of 12.2×10⁹/L (reference 4.5 to 11×10⁹/L) with neutrophil predominance, consistent with mild leukocytosis suggestive of an inflammatory or infectious process. Hemoglobin was normal at 12.9 g/dL (reference 12.5 to 16 g/dL). Platelet count was normal at 244×10⁹/L (reference 150 to 450×10⁹/L). C-reactive protein was elevated at 8.8 mg/dL (reference <0.5 mg/dL), and erythrocyte sedimentation rate was elevated at 63 mm/h (reference <20 mm/h), both consistent with systemic inflammation. Albumin was mildly decreased at 3.5 g/dL (reference 3.7 to 4.7 g/dL). Laboratory evidence of inflammation was felt to be secondary to a concurrent respiratory infection. Elevated inflammatory markers subsequently normalized on outpatient follow-up.

Chest radiograph demonstrated a right lower chest opacity with associated rib abnormality (Fig. 1A). Contrast-enhanced CT confirmed bilateral lower lobe opacities consistent with infection and revealed a large, ossified lesion of the right 10th rib with a spiculated, sunburst periosteal pattern, suspicious for malignancy (Fig. 1B). MRI demonstrated a heterogeneous, lobulated lesion with spiculated margins, diffusion-bright signal and soft-tissue extension (Figs. 1C, 2A–C). Axial postcontrast T1-weighted images with fat suppression further highlighted the lesion’s heterogeneous enhancement pattern (Figs. 2D, E). CT angiography and 3D reconstruction confirmed prominent intralesional vascularity with expansile cortical remodeling, confirming intraosseous origin of the lesion and aiding in surgical planning (Figs. 2D–F).

FIGURE 1.

Chest imaging of right rib lesion. A, Chest radiograph demonstrating a right lower chest opacity with associated rib abnormality. B, Contrast-enhanced CT showing a large, ossified lesion of the right 10th rib with a spiculated, sunburst periosteal pattern. C, MRI of the chest with contrast demonstrating a heterogeneous, lobulated, diffusion-bright lesion with soft-tissue extension.

FIGURE 2.

MRI and CT angiography of the rib lesion. A–C, Coronal contrast-enhanced MRI sequences demonstrate a heterogeneous, spiculated mass arising from the right 10th rib with areas of diffusion-bright signal and soft-tissue extension. D and E, Axial postcontrast T1-weighted MRI with fat suppression highlights the lesion’s heterogeneous enhancement and lobulated morphology. F, Three-dimensional CT reconstruction reveals the expansile rib lesion with prominent cortical remodeling and associated vascularity, confirming the intraosseous origin and aiding surgical planning.

A CT-guided needle biopsy was performed, which was nondiagnostic. Because imaging was concerning for an aggressive malignant neoplasm, the patient underwent open biopsy of the right tenth rib mass. Intraoperatively, the lesion was noted to be highly vascular. The procedure was associated with brisk bleeding, which was controlled with Surgicel and pressure. Estimated intraoperative blood loss was 200 mL. Frozen section demonstrated an atypical vascular proliferation in a myxoid background, without evidence of a small round blue cell tumor. Permanent histology revealed thin-walled vessels of variable caliber within fibrous stroma, lined by flat-to-cuboidal endothelial cells with focal hobnail morphology and mild cytologic atypia. Mitotic figures were rare. Immunohistochemistry confirmed endothelial differentiation with diffuse positivity for CD31, FLI-1, and ERG (Figs. 3A–F).

FIGURE 3.

Histopathology and immunohistochemistry of the rib lesion. A, Low-power view showing a vascular lesion composed of irregular, thin-walled vessels embedded in fibrous stroma (H&E). B, Higher magnification highlighting vascular channels of variable caliber with erythrocyte-filled lumina (H&E). C, High-power field demonstrating endothelial cells with flat-to-cuboidal morphology, focal hobnailing, and mild cytologic atypia without significant mitotic activity (H&E). D, Strong staining of endothelial cells, confirming vascular differentiation (CD31). E, Nuclear positivity within endothelial cells, further supporting endothelial lineage (FLI-1). F, Nuclear staining consistent with vascular endothelial differentiation (ERG).

Molecular testing with FoundationOne CDx identified an in-frame EWSR1-NFATC1 fusion transcript, supporting the diagnosis of an intraosseous venous malformation rather than a malignant neoplasm. The fusion was detected by next-generation sequencing; however, the level of expression of the fusion transcript was not quantified. After multidisciplinary discussion and confirmation of normal coagulation studies (normal prothrombin time, activated partial thromboplastin time, and fibrinogen), the patient underwent right thoracotomy with complete excision of the rib lesion (Fig. 4). Surgical margins were negative. His postoperative course was uneventful, and he was discharged home on postoperative day 5. A follow-up chest radiograph showed no residual lesion. At subsequent outpatient visits, he reported no pain or functional limitations. At 7 months postoperatively, he was cleared by his surgeon to resume unrestricted physical activity.

FIGURE 4.

Gross specimen status postsurgical removal of the 10th rib mass.

DISCUSSION

This case illustrates the diagnostic challenge of distinguishing intraosseous venous malformations from malignant bone tumors in children. Radiographic features such as a sunburst pattern, periosteal reaction, and soft-tissue extension closely mimicked osteosarcoma and Ewing sarcoma.^1–4 MRI findings with heterogeneous spiculated or sunburst patterns, diffusion-bright signal, and soft-tissue extension further heightened concern for malignancy, underscoring the diagnostic limitations of imaging in isolation.^1,4–6

The initial CT-guided needle biopsy was nondiagnostic, which is consistent with prior reports, which noted that small biopsy samples often fail to capture the vascular and heterogeneous architecture of these lesions.^7–12 In this case, an open biopsy provided sufficient material for histologic and immunohistochemical evaluation, enabling accurate diagnosis. This highlights the importance of open surgical biopsy when initial sampling is inconclusive and the necessity of multidisciplinary collaboration among oncology, radiology, surgery, and pathology in evaluating atypical bone tumors.^9,11

Molecular testing identified an EWSR1-NFATC1 fusion, consistent with emerging literature describing NFATC1 and NFATC2 rearrangements in benign vascular bone tumors.^3,4,13–16 Identification of this fusion helped to confirm our patient’s histologic diagnosis of a benign venous malformation of the rib and rule out a malignant neoplasm. However, molecular findings must be interpreted in conjunction with histologic, immunohistochemical, and radiographic features, particularly given the association of EWSR1-NFATC2 fusions with malignant sarcomas, including Ewing sarcoma. This case highlights the growing role of genomics in bone tumor diagnostics.

Studies suggest NFATC family transcription factors regulate osteoclast differentiation and angiogenesis, providing a potential mechanism for their role in vascular tumor biology. Interestingly, additional studies have demonstrated that malignant sarcomas with NFATC2 fusions show amplification of the fusion and high transcript expression, whereas amplification is absent in benign bone lesions with NFATC2 fusions, including simple bone cysts and benign vascular bone tumors.^4,13

From a clinical perspective, the rib is an uncommon site for benign intraosseous vascular tumors in children. Historical reviews identified fewer than 50 reported rib cases, most in adults over 45; only isolated pediatric cases have been described.^5–9 The differential diagnosis of pediatric rib masses includes osteosarcoma, Ewing sarcoma, Langerhans cell histiocytosis, and metastatic disease such as neuroblastoma, all of which can demonstrate destructive rib lesions on imaging.^5–9 This wide differential often prompts extensive diagnostic evaluation, occasional overtreatment, and considerable anxiety for patients and families. Our case, therefore, adds to the limited pediatric literature and emphasizes the importance of accurate diagnosis.

Historically, intraosseous vascular bone lesions were often called “cavernous hemangiomas.” However, the current International Society for the Study of Vascular Anomalies (ISSVA) classification system uses the term “venous malformation” instead of “cavernous hemangioma” to accurately reflect that these lesions are congenital, slow-flow malformations, not proliferative vascular tumors, and to eliminate confusion with infantile hemangiomas, which grow rapidly and involute.

Management of intraosseous vascular tumors has historically ranged from observation of asymptomatic lesions to curettage, embolization, or complete resection, depending on location and symptoms.^17,18 In highly vascular lesions or those in complex anatomic sites, preoperative embolization can reduce operative blood loss.^18–20 Systemic therapy with the mTOR inhibitor sirolimus has been shown to be effective and safe for the treatment of complex venous malformations.²¹ Radiation therapy is sometimes considered for the treatment of complex and/or inoperable venous malformations. Because surgical resection was feasible for this patient, a multidisciplinary vascular anomalies team deferred systemic sirolimus therapy and radiation therapy. With surgical resection and without the need for preoperative embolization or adjuvant therapy, negative margins were achieved, which decreases the future risk for local recurrence. Our patient successfully resumed unrestricted physical activity seven months after surgery.

Optimal long-term surveillance remains an unanswered question. While recurrence is rare, local regrowth years after surgery has been documented, suggesting the need for at least periodic clinical follow-up.³ Future studies are needed to determine whether molecular characteristics, such as NFATC1 versus NFATC2 fusion status, predict recurrence risk. Similarly, standardized follow-up imaging guidelines are lacking, and management is often individualized based on symptoms, lesion location, and surgical margins.

Intraosseous venous malformations are rare, particularly in the pediatric population.^5–9 Their radiographic resemblance to aggressive malignancies, combined with the frequent nondiagnostic nature of needle biopsies,^7,8,10,11 creates a significant risk for misdiagnosis. Our case adds to the limited number of pediatric rib vascular lesions reported and highlights the value of open biopsy, immunohistochemistry, and molecular analysis to distinguish benign vascular lesions from malignant tumors. Complete surgical excision remains curative in most cases, although long-term follow-up is advised to monitor for rare recurrence.³ Finally, recognition of the association of EWSR1-NFATC1/2 fusions with benign vascular bone lesions may facilitate recognition of these lesions and prevent unnecessary treatment, preserve functional outcomes, and alleviate anxiety for patients and families.