AbstractEpithelioid hemangioendothelioma (EHE) is a rare benign vascular tumor, affecting fewer than one in a million individuals. Spinal EHE is exceptionally rare. This case report presents a case of recurrent spinal EHE, focusing on its clinical manifestation and providing a brief overview of its genetic characteristics. Seven years prior, a patient underwent subtotal resection of a lumbar and retroperitoneal EHE. Due to severe intraoperative bleeding, part of the lumbar spine mass was left unresected and subsequently treated with a moderate dose of radiation therapy. More recently, the patient presented with bilateral lower extremity weakness and urinary incontinence. Imaging studies revealed metastases in the thoracic and sacral bones, along with regrowth in the anterior portion of the previously treated spinal EHE. The patient underwent a series of operations to address both the regrowth and metastases, followed by intensity-modulated radiation therapy to target the remaining tumor tissue while minimizing damage to surrounding structures. Although EHE is generally considered benign, this indolent tumor has a tendency for persistent regrowth and metastasis. This case highlights the importance of radical resection and the potential role of higher radiation doses in preventing recurrence. Molecular testing may aid in achieving an accurate diagnosis and guiding effective treatment strategies.
INTRODUCTIONEpithelioid hemangioendothelioma (EHE) is a rare vascular tumor that exhibits characteristics of both hemangioma and angiosarcoma2,4,15). It occurs in fewer than one in a million people and accounts for less than 1% of vascular neoplasms4). EHE of osseous origin is particularly uncommon, with vertebral involvement being even rarer, reported in under 10% of these cases4,10). Recent advances in next-generation sequencing (NGS) have identified mutations in EHE, offering insights into its biology and the dysregulated signaling pathways, suggesting new therapeutic strategies17). Fusion genes such as WWTR1-CAMTA1 and YAP1-TFE3 are recognized as critical drivers of tumorigenesis3,6,7,13,15-17). Despite its generally indolent nature, EHE can display aggressive behavior, particularly in cases of metastasis15).
Given the extreme rarity of EHE, comprehensive data on its clinical course, treatment outcomes, and prognosis remain insufficient. This case report contributes to the limited body of knowledge by presenting an exceptionally rare instance of recurrent spinal EHE. By documenting this case, we aim to enhance our understanding of the disease’s clinical behavior and provide insights to guide therapeutic strategies.
This case report also highlights the importance of aggressive surgical resection combined with curative dose intensity-modulated radiation therapy (IMRT) in the management of spinal EHE.
CASE REPORTA 49-year-old woman presented to our outpatient clinic with severe lower back pain and sensory disturbances below both knees. The patient was an active smoker with a long-standing history of diabetes and a significant family history of cancer, including her mother, who died of brain cancer. The patient had previously undergone posterior lumbar interbody fusion following a fall 15 years ago. Magnetic resonance imaging (MRI) and computed tomography (CT) scans revealed 12 × 9 × 11 cm lobulated mass in the vertebral body, with extraosseous paravertebral soft tissue extension and posterior element involvement, causing severe canal and neural foramen encroachment from the 3rd to the 5th lumbar spine. Additionally, two paraspinal masses (11 × 8 cm and 6.6 × 5 cm) were identified in the left psoas muscle and probable small bowel mesentery (Fig. 1).
Spinal angiography and tumor embolization were performed to prevent intraoperative bleeding due to the densely developed peritumoral vasculature. Although a substantial portion of the abdominal mass was removed, the vertebral fungating mass remained unresected due to massive intraoperative bleeding. Postoperative pathological examination confirmed the diagnosis of EHE.
After one month, the patient experienced worsening lower back pain and right leg weakness (motor grade 4+/5). Two-stage operations were performed following tumor embolization. Initially, the fungating mass at L3-5 was resected to decompress the spinal canal, and extensive vertebral fixation from T11 to S2 was completed. Two weeks later, L3-5 corpectomy and tumor removal were performed via a retroperitoneal approach (Fig. 2).
One month later, IMRT was administered to the residual mass, delivering a total of 40 Gy over 20 fractions. Three months after radiotherapy (RT), the motor weakness improved, and the patient remained free of neurological problems up to the 6-year postoperative follow-up (Fig. 3).
However, paresthesia below the L2 sensory dermatome level and bilateral lower extremity weakness (motor grade 4/5) developed seven years after the first surgery. The patient also experienced dysuria and abnormal cold sensations below the knees. MRI and CT revealed a large mass at the L2-5 level, with multiple bone metastases in the T9, T11, S2 vertebrae, as well as the left 4th rib and bilateral clavicles (Fig. 4).
Although immediate RT targeting the L2 to S2 region was initiated, it was eventually discontinued after delivering a total of 14 Gy over 7 fractions, owing to poor compliance resulting from the patient’s general weakness and abdominal pain. Upon discharge, the patient’s bilateral lower extremity weakness improved to the extent that she could walk unaided.
DISCUSSIONThis case involves an exceptionally rare instance of spinal EHE with recurrent and metastatic behavior, which is particularly significant given the limited data on the natural history and progression of this tumor type. The aggressive recurrence and metastasis observed underscore the unpredictable clinical course of EHE and the challenges in managing it, highlighting the need for optimized treatment strategies and the integration of emerging molecular diagnostics.
1. Differential DiagnosisSpinal EHE closely mimics several other conditions, making precise differential diagnosis critical2). Conditions such as metastatic carcinoma, angiosarcoma, and hemangiomas can present similarly but require distinct therapeutic strategies5). The diagnostic approach must consider both the patient’s age and the extent of disease involvement1,2). For patients with multifocal disease, differential diagnoses should consider metastatic carcinoma, lymphoma, and myeloma, especially when disease progression aligns with characteristics of more advanced age1,2). Conversely, multifocal disease in cases presenting earlier in life may suggest conditions such as Langerhans cell histiocytosis and fibrous dysplasia1,2). For solitary lesions, the differential must encompass fibrous dysplasia, Ewing's sarcoma, osteosarcoma, and fibrosarcoma, requiring detailed clinical and radiological evaluation1,2).
2. Comparative AnalysisGiven the rarity of spinal EHE, a comparative analysis of cases in the literature offers valuable insights into its clinical behavior. A summary of patient demographics, tumor characteristics, treatments, and outcomes is presented in Table 1.
3. Treatment ApproachIn the treatment of EHE, surgical resection remains the primary modality, aiming for maximal tumor removal while preserving spinal stability and neurological function4,10). Contemporary treatment typically integrates RT with function-preserving surgery18). Although RT is increasingly utilized for non-resectable primary tumors, and advancements in image-guided RT have expanded therapeutic options, there is no consensus on the optimal dose and fractionation for palliative or curative purposes12,14). Conventionally, curative RT doses for sarcomas range from 50 to 75 Gy, with a median of 60 Gy9). In this case, the patient received 40 Gy of IMRT, a palliative dose aimed at local tumor control. Although initially effective, with stable disease for over seven years, an aggressive recurrence later developed, suggesting that this dose was insufficient for sustained tumor suppression and long-term metastasis prevention. This finding suggests that higher radiation doses may be necessary for sustained tumor control and long-term metastasis prevention and draws attention to the importance of aggressive treatment approaches, including curative doses of IMRT and maximal surgical resection. Further research is required to establish definitive treatment guidelines for this rare and challenging tumor.
4. Clinical CourseThis tumor exhibited a peculiar clinical course, remaining well-controlled for seven years before recurring aggressively with distant metastasis. This unusual pattern of progression raises important considerations regarding the adequacy of the initial treatment approach. It suggests that a curative dose of IMRT and maximal resection may be necessary for prolonged disease control and the prevention of late recurrences. This case emphasizes the need for continuous vigilance and potentially more aggressive initial treatment in managing EHE to mitigate the risk of future metastasis.
5. NGS in EHENGS is a cutting-edge technique for genetic analysis, but its application remains restricted to specialized centers due to limited availability and high costs. In this case, NGS testing was planned but could not be conducted due to financial and logistical barriers. Despite these challenges, NGS plays a crucial role in identifying the key mutations in EHE, most notably the WWTR1(TAZ)-CAMTA1 and YAP1-TFE3 fusions.
The WWTR1(TAZ)-CAMTA1 fusion reprograms endothelial cells, promoting aggressive tumor behavior, while the YAP1-TFE3 fusion leads to abnormal gene regulation and enhanced oncogenic properties4,15). Patients with the YAP1-TFE3 fusion, though less common, are reported to have a better 5-year overall survival rate (86% vs. 59%) and tend to be younger than those with the WWTR1(TAZ)-CAMTA1 fusion4,6,15,19). Additionally, the recurrence rate for spinal EHE is approximately 13%19).
6. Multidisciplinary ManagementManaging spinal EHE requires a multidisciplinary approach involving neurosurgeons, radiologists, and oncologists. Postoperative monitoring of spinal stability and neurological function is critical, with imaging studies indispensable for planning, follow-up, and detecting recurrence or metastasis. This case underscores the importance of administering curative-dose IMRT and performing aggressive surgical resection. Molecular diagnostics play a vital role in achieving a good prognosis and guiding future strategies based on the disease's unique characteristics.
Effective management of EHE, especially when it involves the spine, demands a comprehensive multidisciplinary approach to ensure optimal outcomes. The role of genetic profiling in understanding EHE behavior cannot be overstated, as it provides insights into potential therapeutic targets and prognostic indicators. Future studies should focus on optimizing RT dosing strategies and exploring the benefits of combining novel targeted therapies with conventional treatment modalities.
NotesACKNOWLEDGEMENTS We sincerely thank Professor Jiha Kim for his invaluable support during the preparation of this case report. NotesINFORMED CONSENT This case study was approved by our institutional ethics committee, with a waiver of informed consent granted (IRB no. 2024-07-016). Table 1.
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