A 20-Year-Old Woman with Metachronous Polyostotic Simple (Unicameral) Bone Cysts in 9 Sites: A Case Report

Introduction

First described by Virchow in 1876, simple bone cysts (SBCs), also known as unicameral or solitary bone cysts, are benign, fluid-filled bone lesions that occur most often within long bones [1–3]. SBCs typically present in the first 2 decades of life, with a slight male predominance, and are most commonly found in the proximal humerus (50%) and femur [4]. Cysts are often discovered incidentally during imaging studies performed for other reasons or following a pathologic fracture [5]. In fact, SBCs are the most common benign intraosseous lesions in children, accounting for approximately 3% of all biopsied bone tumors [1,6]. The diagnosis is typically straightforward on imaging, including plain radiograph, magnetic resonance imaging (MRI), and/or computed tomography (CT) [7]. In some cases, histologic examination may be necessary to confirm the diagnosis and rule out other entities such as aneurysmal bone cysts (ABCs) or fibrous dysplasia [8]. Treatment can be non-surgical or surgical, with surgical interventions that include intralesional injections, decompression, curettage with or without bone grafting, or some combination of techniques [9].

The pathogenesis of SBCs is unclear, although several hypotheses have been proposed, including developmental anomalies, trauma, and venous obstruction leading to intraosseous fluid accumulation [4]. Recently, a small subset of SBCs have been shown to harbor EWSR1/FUS::NFATc2 gene rearrangements [10–12]. Multifocal SBCs, although rare, involve the presence of multiple simple bone cysts in different bones simultaneously. This condition poses unique diagnostic and therapeutic challenges because of its uncommon presentation and potential for substantial skeletal morbidity [1]. Here, we report an exceptional case of a 20-year-old woman with multifocal SBCs affecting 9 known anatomical sites, and we discuss the unique diagnostic and therapeutic challenges.

Case Report

CLINICAL PRESENTATION:

The patient initially presented to our clinic with pain in the proximal anteromedial right tibia and ankle after a fall down the stairs. The pain was described as 7/10 on the visual analog scale (VAS) and was exacerbated with weightbearing. Notably, she reported bruising and swelling in the proximal leg after the fall, which had since resolved. On physical examination, there was a fullness in the proximal anteromedial leg which was tender without increased warmth or erythema.

DIAGNOSIS:

Radiographs of the right tibia and fibula revealed 3 expansile radiolucencies with internal septations located in the proximal tibia, the distal tibial metaphysis, and distal fibula meta-diaphysis (Figure 1). MRI was performed to better characterize the cysts and whole-body technetium-99m bone scintigraphy was performed to assess for any other sites of involvement. MRI of the right lower extremity identified 2 lesions in the tibia and 1 in the fibula, showing a single fluid-filled osseous cavity with a single fluid-fluid level and areas of cortical thinning without frank disruption, periosteal edema, or an associated soft tissue component (Figure 2). Despite these findings being suggestive of SBCs, the differential diagnosis remained broad, including multifocal ABCs, polyostotic fibrous dysplasia, or giant cell tumor. Complete blood count and comprehensive metabolic panel lab results were all within normal limits.

Whole-body technetium-99m bone scintigraphy revealed increased radiotracer uptake activity within the previously identified lesions, as well as the left proximal and distal tibia, left proximal humerus, right proximal and distal femur, and pelvis, raising concern for additional lesions (Figure 3). Subsequent radiographs of these sites demonstrated expansile radiolucencies with internal septations in the patient’s left proximal humerus, left pubic ramus, and left proximal and distal tibia, but did not identify lesions in either the right proximal or distal femur (Figure 4). An MRI of the pelvis found a lesion in the right iliac bone.

Despite the strong suspicion of multifocal SBCs suggested by imaging studies, tissue diagnosis was recommended using a CT-guided core-needle biopsy. The right proximal tibia revealed benign cyst contents and scant fragments of woven bone in a hemorrhagic background. However, these findings were insufficient to differentiate definitively between SBCs and ABCs, necessitating further histologic evaluation.

TREATMENT:

The patient underwent open biopsy, curettage, local adjuvant with argon beam and doxycycline, and bone grafting of the bilateral proximal tibias and left proximal humerus. Histologic evaluation from the surgical specimens provided definitive confirmation of SBCs, demonstrating classic features including cyst wall, cholesterol clefts, and fibrin-like deposits and debris (Figure 5). The histologic confirmation established the diagnosis of SBCs and excluded alternative considerations. To address the pelvic lesions as well as those in the distal fibula and tibia, CT-guided doxycycline sclerotherapy with injection of adjuvant acellular matrix was performed in 3 sessions over the course of 5 months.

EWSR1 and FUS fluorescence in situ hybridization (FISH) was performed to assess for the presence of an FUS/EWSR1::NFATc2 fusion, and that result was negative. Analysis via conventional cytogenetics revealed a normal karyotype; however, optical genome mapping (OGM) was also performed and demonstrated 1p-, 1q-, 2p-, inv(5q), dup(8), 22q-. No definitive pathogenic structural variant (SV) or copy number variation (CNV) was detected by OGM.

Fifteen months after the initial presentation, the patient presented with new right-hand pain. A radiograph revealed an expansile multiloculated radiolucency throughout the entirety of the third metacarpal (Figure 6). The patient opted for open biopsy, curettage, local adjuvant with argon beam and doxycycline, and bone grafting of the third metacarpal.

Radiographs of the patient’s pelvis, bilateral tibias and fibulas, and left humerus taken 17 months after her first procedure revealed postprocedural changes at the treated sites and continued progression of sclerosis, with near-complete resolution of the cysts (Figure 7). There has been no recurrence of lesions.

Discussion

This case report highlights a unique presentation of multifocal SBCs, differing from prior cases in its breadth, with 9 confirmed lesions across both tubular and non-tubular bones, and in its comprehensive diagnostic and therapeutic approach. The use of doxycycline sclerotherapy, a novel treatment for SBCs, alongside traditional surgical methods, underscores the potential for minimally invasive options in select cases [13]. Additionally, FISH and OGM were employed to investigate potential genetic contributions to the development of SBCs, but no pathogenic rearrangements were identified. This emphasizes the importance of exploring molecular mechanisms in rare presentations.

SBCs are the most common benign intraosseous lesions in children, accounting for approximately 3% of all biopsied bone tumors [1,6]. Although typically solitary, there have been reports of multiple SBCs occurring in a single patient, though these are exceedingly rare [1,3,14–19]. One review demonstrated the rate of multiple SBCs to be as low of 1.8% of all cases, with those patients often presenting at an older age compared to those with solitary lesions. The reviewed cases also showed a male predominance and were noted to have a less aggressive course with lower recurrence rates compared to classic metaphyseal SBCs [18].

Several prior reports of multiple SBCs have limitations that raise questions about definitive multifocality. For example, Jasan et al [14] presented a case involving a 22-year-old man diagnosed with bilateral SBCs of the hamate bones. However, SBCs are uncommon in the carpus, and the biopsy ultimately revealed foreign body giant cells, calling the initial diagnosis of SBCs into question. Oliver et al [15] described a 38-year-old woman with bilateral SBCs of the calcaneus identified via CT and MRI but, notably, no biopsy was performed, leaving the diagnosis unconfirmed. While Manafi-Rasi et al [1] reported on a similar patient with 4 lesions, the lack of radiograph for the tibial lesion raised questions about definitive diagnosis in that specific location. Ji et al [17] reported on a 34-year-old man presenting with 2 lesions. Unlike our case, their patient had Wilson’s disease accompanied by hepatic cirrhosis and the authors theorized that his underlying metabolic disorder contributed to the development of pseudocysts [17].

To the best of our knowledge, our patient represents an extremely rare case of metachronous multifocal (polyostotic) SBCs with the most lesions reported to date (9), confirmed through histologic sampling. Our patient underwent a multi-modal treatment approach that included doxycycline sclerotherapy in some lesions and curettage, local argon beam and doxycycline adjuvant, and bone grafting for others. In this case, diagnosis was particularly challenging because of the unusual presentation of multiple cysts and rarity of the underlying condition. Initial diagnosis of SBCs usually begins with plain radiographs that reveal a well-circumscribed radio-lucency characterized by internal septations and thin sclerotic borders. These lesions are often located in the metaphysis of long bones [2]. In more complex cases, or when multifocal lesions are suspected, additional imaging, including MRI and/or CT, can provide further detail [7].

While the initial plain radiograph of our patient’s tibia did raise suspicion for SBC, the discovery of multiple lesions complicated the diagnosis, as there are few documented cases of multifocal SBC in the literature and no documented cases involving as many as 9 sites. Consequently, the patient underwent an MRI of the right lower extremity, which was non-diagnostic and expanded the differential to include multifocal SBC, multifocal ABC, polyostotic fibrous dysplasia, or giant cell tumor. Whole-body technetium-99m scintigraphy was helpful in identifying additional lesions in the patient’s left proximal and distal tibia, left proximal humerus, and left pubic ramus. However, it missed a lesion in the right iliac wing, later identified on pelvic MRI, and another in the right third meta-carpal, discovered 15 months after the initial lesions were detected and treated. The bone scans also raised suspicion for lesions in both the right proximal and distal femurs that were ultimately not present. Given the low sensitivity and specificity of the bone scan in our patient, we propose considering a skeletal survey in future cases where multifocal SBCs are suspected. Ultimately, histologic sampling secured the diagnosis of multifocal SBC, effectively ruling out other potential diagnoses.

The etiology of SBCs remains largely speculative, with multiple theories proposed. Historically, SBCs were thought to be a developmental anomaly or a result of trauma. More recent hypotheses suggest that venous obstruction may contribute by increasing intramedullary pressure, leading to interstitial fluid accumulation [4,19]. Genetic factors may also play a role in the pathology of SBCs, as specific genetic fusions characteristic of aggressive round cell sarcomas, including FUS/EWSR1::NFATC2, have been detected in SBCs [10–12]. However, these fusions are extremely rare and were ultimately not detected in our patient. Interestingly, these same fusions have also been detected in a subset of epithelioid vascular neoplasms and vascular malformations of bone.

In the case of multifocal SBCs, the treatment approach must be tailored to each patient, considering the number, size, and location of the cysts, as well as the patient’s symptoms and overall health status. Asymptomatic and small cysts may be observed with regular follow-up and imaging [2]. For symptomatic cysts, those causing significant bone weakening, or recurrent fractures, a more aggressive approach may be necessary. This may include intralesional injections, decompression, curettage with or without bone grafting, or some combination of techniques [9].

The criterion standard surgical treatment for SBC is curettage with or without bone grafting [1]. Depending on the size and location of the lesion, internal fixation may also be required, and in severe cases, resection of the affected bone segment may be necessary [9]. Minimally invasive procedures such as injection of corticosteroids, bone marrow, or bone graft substitutes aim to promote cyst healing and reduce the risk of recurrence [6]. However, Sung et al [9] reported that corticosteroid injections alone have a failure rate of almost 84%, advocating for a combination of corticosteroids and curettage.

Recent studies have explored the use of doxycycline injections for the treatment of ABCs due to their sclerosing effects [13,20,21]. Doxycycline inhibits matrix metalloproteinases (MMPs), which are involved in the degradation of bone and extracellular matrix, although its precise effects on MMPs remains a topic of debate. Additionally, it inhibits vascular endothelial growth factor (VEGF), which promotes angiogenesis crucial for growth and maintenance of ABCs [22]. Although doxycycline use is cautioned in children younger than 8 years old because of its potential to cause enamel pigmentation, the safety profile of doxycycline injections for SBCs has shown promise [23]. To date, only 1 study has evaluated the use of doxycycline in SBCs; Wong et al [24] treated 77 patients, aged 3–34 years, with ABCs (n=50) and SBCs (n=27) with doxycycline sclerotherapy. Only 1 lesion failed sclerotherapy and required surgical excision. The authors observed high levels of patient satisfaction, with little to no pain, almost no functional impairment, and low rates of adverse events. Similarly, our patient showed promising early-stage results in lesions treated with both doxycycline sclerotherapy and doxycycline combined with curettage.

Conclusions

This report presented a rare case of a young woman with multiple SBCs across 9 anatomical sites. Overall, the management of multifocal SBCs requires a multidisciplinary approach, involving orthopaedic surgeons, radiologists, and pathologists for optimal outcomes.