"Aneurysmal Bone Cyst of the Pelvis: A Systematic Literature Review"

Background: Aneurysmal bone cysts (ABC) are rare benign, vascular, osteolytic bone lesions. Pelvic ABCs account for 8 -12% of these tumors and no clear guidelines for their treatment are available. To our knowledge, this is the rst systematic literature review regarding pelvic ABCs. Our primary objective was to identify treatment modalities and to assess the bone healing, measured as the degree of radiological ossication. Secondary objectives were to describe demographics, tumor characteristics, clinical and functional outcomes and recurrence. Methods: Searches were conducted in PubMed, Cochrane Library, and Web of Science. Based on the scarcity of reports, inclusion criteria were kept broad and comprised primary or recurrent pelvic ABCs, with a minimum follow up of one year and available information on radiological ossication. Data was extracted on the individual patient-level and grouped according to treatment modality. Forty-nine studies reporting on 194 patients were included. The level of evidence was low (29 case reports and 20 retrospective case series) and the reporting of outcomes inconsistent. Patients had a median age of 15 years and 52% were male. Five major treatment groups were identied and divided into 11 subgroups. The largest subgroup was curettage (23%) followed by selective arterial embolization (20%). Most ABCs were located in the ilium. Variations in mean tumor size (4.5-22.2cm) and degree of ossication (60-100%) depended on the treatment modality. Overall, in 77% cases the cyst ossied completely. Recurrence was reported in 22 patients (11%) and 2 patients (1%) died during the course of the treatment. Despite the low quality of reporting, this systematic review provides the rst comprehensive overview of pelvic ABC treatment modalities and their radiological and clinical outcomes. Neoadjuvant sclero-embolic treatments appear to be used most in recent years, but further comparative studies and better quality of reporting are needed to determine their effectiveness. Quality of reporting should be improved by following reporting guidelines.

Individual patient data was aggregated according to treatment received and descriptive statistics were applied using "StataCorp 2017".

Results
A total of 143 records were identi ed through database searching and cross referencing retrieved articles. After removing duplicates, 123 records were screened for eligibility (Fig 1). After reviewing the title and abstracts, 55 records were excluded. From the remaining 68 records, full-text articles were reviewed for eligibility and further 19 were omitted. Amongst the 19 excluded articles, 16 did not report on any outcomes for speci c treatment of pelvic ABC and 3 had a follow up of less than one year.
The nal number of studies included in the systematic review was 49, of which 29 were case reports and 20 were case series, spanning from 1979 to 2017. From the 49 studies, data of 194 patients was extracted into an excel sheet.

Treatment groups and patients included per study
A large number of treatment options was identi ed and grouped into 5 major treatment groups: observation, adjuvant, minor surgery, major surgery and combined. These major treatment groups were further subdivided into eleven distinct treatment subgroups. The number of studies and patients included in each treatment group are described in Table 1. Some studies appear in more than one treatment group.
Amongst the latter, 18 (47%) patients had only one SAE session, 10 (26%) patients had two and further 10 patients had three sessions of SAE. Diverse biomaterial like gel foam, latex particles, biospheres, Isobutyl 2 cyanoacrylate (IBCA), polyvinyl alcohol (PVA) and stainless-steel coils were used for the embolization.
Marginal excision was the third most commonly used treatment 27/194 (14%) whereas wide excision was used only in 5 cases. The terms marginal and wide derive from the 'Enneking classi cation of surgical margins' which is a standard reported measurement of surgical margins in osseous and soft tissue tumor surgery [25]. Various materials have been described to ll the bony voids after major or minor surgery like autologous bone grafts, allografts, bone cement, bioactive glass, plexur M biocomposite, arthrodesis with plating and vascularized bular graft.
The combined treatment groups included any type of surgery along with either SAE, sclerotherapy or radiotherapy. The combined group minor surgery + adjuvant was the fourth most used treatment (26/194). Most of these patients received SAE as neoadjuvant treatment.
Extended curettage was used in 11/194 cases and reportedly done through high speed burr, phenol, or ethanol washes. Sclerotherapy (10/194 cases) was either performed percutaneous or through a mini open approach under uoroscopy and general anesthesia. The sclerosants used were ethibloc, demineralized bone matrix (DBM) combined with autologous bone graft, 32 P chromic phosphate and polidocanal. The least used methods included radiotherapy (5/194), wide excision (5/194) and SAE with sclerotherapy (4/194). Radiotherapy has been used as neoadjuvant but also as adjuvant and treatment for recurrence. The maximum dosage received by any patient was 6000 Gy (Gray).
Demographics, radiological and functional outcomes were summarized according to the treatment subgroup.

Demographics:
Patient demographics per treatment subgroup are described in Table 2. From the 194 patients, 91 (47%) were females, 101 (52%) were males and gender was not reported for 2 (1%) patients. The overall median age was 15 years, ranging from 1.5 to 64 years old. The median age among the different treatment subgroups was very similar and within the second decade of life except for the wide excision group.
The mean time from the start of the symptoms to diagnosis was 10 months with a range from 2 weeks to 10 years. The median follow up was 3 years, with the longest follow up of 53 years in a 10-year-old with stage 2 ABC in the sacrum treated with extended curettage and radiotherapy [10].
Tumor characteristics: Main tumor characteristics in terms of size, anatomic location within the pelvis and Enneking staging according to treatment group and subgroup are described in Table 3. Only 8 (4%) patients presented with a recurring ABC and the rest were all primary de novo lesions.
The information on tumor size for individual patients was available for only 50/194 patients (25%); but for 22 (11%) patients, tumor size was described in categories of less than, up to, or greater than 5 cm [17]. The minimum reported tumor size was 3 cm and the maximum 30 cm. Treatment groups with an average size above 15 cm were all surgical (either as standalone treatment or combined with adjuvant therapy) whereas tumors in the observation group were on average 4.5 cm and were followed up with a median of 2.8 years.

Outcomes:
Radiological and clinical outcomes per treatment group are detailed in Table 4. Given that the radiological and functional outcomes reported in the retrieved studies were remarkably inconsistent, heterogenous and in occasions extremely vague, we tried to categorize the outcomes following our best interpretation and understanding of what was reported by the authors. Only one study [11] described the outcomes using the musculoskeletal tumor rating scale (MSTS), Toronto extremity salvage score (TESS) and the 36 item short form health survey (SF-36).
Our primary outcome focused in the ossi cation. In total,116 patients (60%) had complete ossi cation, 19 patients (10%) had partial and 5 patients (2%) had no evidence of ossi cation. The ossi cation status was not available in 20/194 cases: in 18 patients (9%) it was not reported, and two patients died during or shortly after surgery.
At the end of the follow up, 112 patients (58%) had reportedly no pain, whereas mild pain was mentioned in 16 (8%) patients, moderate pain in 5 (2%) patients, and in 50 patients (30%) pain was not reported.
Overall, the incidence of recurrence was low. Recurrence was reported in 21 (10.8%) patients and not reported in 15 patients (8%), whereas the remaining patients had no recurrence at the time of the last follow up. The longest time to recurrence was 6 years in a 13-year-old male patient with an ABC in the pubis extending to acetabulum treated with extended curettage [10]. Recurrence was treated mostly by curettage or excision and autologous bone grafting. Few recurrent cases were managed with sclero-embolic treatments instead of surgery [22] and 3 cases were treated with radiotherapy [23,24]. Curettage had a relatively high number of recurrences compared to the other treatments, however the unbalanced group size and low number of patients in some subgroups precludes a proper statistical analysis.
The number of reported complications is low. Hemorrhage was reported in 6 (3%) patients who were treated with surgery (5 patients) and sclerotherapy (1 patient). Of these, one patient died secondary to massive bleeding. Neurological complications were described in 13 (7%) patients and include hypoesthesia, bowel and bladder dysfunction or residual loss of bowel, bladder control, neuroma formations, and involvement of sacral roots, sciatic nerve, obturator nerve and caudal sac. 11 (6%) patients with neurological complications had ABC located in zone 4 (sacral) while in the remaining 2 were in zones 2 and 3. One patient with a tumor in zone 2 and 3 had partial encasement of the bladder with the ABC mass resulting in subtotal cystectomy. Leg length discrepancy (0.6 -3cm) was reported in 4 patients (2%) after marginal resection of ABC. Curettage in the sacrum (pelvic zone 4) was performed in 12 (26%) cases and had frequent reports of hemorrhage, bowel injury, dural tear and loss of bowel bladder control. 9/21(42%) patients had complications after treatment for recurrence. Capana et al reported 3 of these cases in which the primary treatment was radiotherapy or combination of radiotherapy with surgery, recurrence was observed and treated with curettage or radiotherapy. These patients were left with residual complications of crural nerve palsy, quadriceps, psoas de cit and femoral head necrosis [19].
In this series of 194 cases reported in the literature, two patients died of treatment-related complications. A 51-year-old female with a 25 x 25 x 20 cm ABC in the right ilium extending into the ischium. The patient was treated surgically and died of profuse perioperative bleeding [25]. The second case was a 48-yearold female with a 27.6 x 22.4 x 15.9 cm lesion in the left ilium with a history of embolization, sclerotherapy and repeated surgery. The authors performed preoperative embolization and percutaneous intralesional alcohol injection followed by staged near total resection combined with cryosurgery and off label systemic treatment with bevacizumab, a monoclonal anti-vascular endothelial growth factor (VEGF) antibody, to reduce bleeding. The patient developed clinical heart failure, prompting discontinuation of bevacizumab followed by a rapid regrowth of the pelvic lesion. After seven surgical sessions, the patient's condition no longer allowed further interventions and she was treated with radiotherapy. The patient died 2 years after ABC was rst diagnosed [26].
Aneurysmal bone cyst in the pelvis has also been described in 2 pregnant women. A pelvic bone lesion in pregnancy can be a di cult situation for the obstetrician to determine the effect of parturition on the pelvic bone [27]. The rst reported case was in 1986 of a right iliac aneurysmal bone cyst measuring 15 cm in a 19-year-old primigravida. At the time of the elective caesarian, the mass was excised through a separate lumbar approach. No recurrence or complication was reported [28]. The second reported case was a 6.1 x 2.9 x 6 cm lesion in the left ilium of a 26-year-old primigravida who had a successful elective caesarian section and the ABC was observed until the last follow-up [27].
We further analyzed tumor characteristics, clinical and radiological outcomes according to their pelvic zone location and the results are summarized in Table  5. While zone 3 was overall the most common tumor location 48/194 (25%), when taking in consideration tumors with overlapping zones as well, most patients 74/194 (38%) had affection of zone 1 -ilium; of these 14 had partial ossi cation and the functional outcome was not reported in half of them.

Discussion
Pelvic aneurysmal bone cyst is a treatment challenge. Most cases have been managed with individualized treatment plans tailored to their size, stage, location, behavior, available clinical resources and surgical expertise. In this systematic literature review we were able to successfully categorize these varied treatments for 194 patients of pelvic ABC in 5 groups and 11 sub-groups which is not only a useful overview of existing therapeutic modalities but also suggests the variability that exists about choosing best treatment modality.
We were able to identify only 194 patients of pelvic ABC ful lling our inclusion criteria since 1979, which emphasizes the rarity of the problem. The gender distribution of pelvic ABC in our study had a slight male predominance with 52% of the cases, which is contrary to previous reports which had a higher prevalence in women. The median age was 15 years although the range was quite wide from 1.5 years to 65 years. Most lesions grow signi cant size, become stage 3 and remain asymptomatic before being diagnosed. Amongst the 194 reported in literature 60% show complete radiological ossi cation, 72% were reported functional and 10.8% had a recurrence. These results indicate that most pelvic ABC have a good prognosis.
Curettage with bone grafting is the most preferred treatment method followed by selective arterial embolization either alone or in combination with surgery. In the curettage treatment group 75% had radiological ossi cation with no pain and 88% were 'functional' after treatment [10,11,29,19,18]. It was used in all pelvic zones and for any tumor stage. The maximum reported size for a lesion treated with curettage was 30 x 30 x 20 cm in zone 4 in a 14 year old [24]. Selective arterial embolization is described in the literature as a simpler, cheap, easily repeatable, a less invasive or risky procedure. It has been used in patients at extreme ages, the youngest being 1.5 and oldest 64 years. Surgery and radiotherapy were the main treatment modalities for ABC until the introduction of SAE [30]. The earliest records of selective arterial embolization (SAE) for pelvic ABC come from Wallace et al (1979) in 2 patients. They reported 15% reduction in size and pain free status after one year in one 27 year old female patient with an ABC in ilium. The second patient, a 38 year old male, was reported to have a surgery and cordotomy followed by SAE. The patient remained pain free at 5 years follow-up but had a recurrence later [31].
Varshney et al did a comparative study to determine the healing rate and functional score between two groups treated either with sclerotherapy (polidocanal) or with intralesional curettage. They concluded, that "although the healing rates were similar, we found higher rates of clinically important complications, worse functional outcomes, and higher hospital burden associated with intralesional excision". They called it a preliminary study and recommended larger studies to con rm their ndings [32]. In this review comparison of the two groups is not possible due to large discrepancy in patient number 45 in curettage vs.
10 in sclerotherapy group. Moreover due to poor quality of reporting outcomes, the reliability of the results is questionable.
In most recent studies reviewed, sclero-embolic procedures are used as adjuncts or combined with major surgical procedures in large pelvic tumors [33,32,34,35]. Papagelopoulos et al set 5 cm as a cut off for performing a curettage or excisional surgery [10]. We observed in the systematic review that tumors > 15 cm were all treated surgically either alone or combined with adjuvants. However we cannot say if this is the best treatment in such cases. Following an excisional surgery some major mechanical complications are reported, like hip dislocation/subluxation, protusio acetabuli, limb length discrepancy etc [10]. but according to the reports, the key to overcome these issues is to get a near anatomic reconstruction of the pelvic defects. Currently triradiate iliac crest grafts, vascularized or non-vascularized bular grafts, allografts, custom-made mega prosthesis, extracorporeal irradiated pelvic bone and re-implantation have all been described [20,18,[36][37][38]. Zidzislaw et al predicts that the future for pelvic defects is statistical shape model (SSM) reconstruction method using mirroring approach.
Since the anatomic location of the tumor in uences the treatment strategy and prognosis, we analyzed the results by pelvic zone. Patients with tumors in zone 4 accounted for most of the neurological complications reported whereas half of the cases with hemorrhage, including a deadly case were located in zone 1.
In their series of 13 pelvic ABC in children Novais et al observed higher recurrence rates in open physis and suggested that destructive lesions in triradiate cartilage can lead to long term complications [11]. In our results we observed that 3/4 patients with leg length discrepancy were near the triradiate cartilage ie zones 2 and 3. In summary, the particular neighboring structures and their involvement require modi ed treatment methods for better outcome as Papagelopolus concludes [10].
The minimum average tumor size per treatment group was 4.5 cm (observation), whereas the maximum average size was 22.5 cm (curettage); however when the results are grouped by pelvic zones the average diameter ranges only from 7.5 to15.5 cm. This might suggest that in addition to the anatomic location, the tumor size also has some in uence on the treatment method since the average size by pelvic zone is similar. However given that tumor size was only available for 25% patients these results should be interpreted with great caution.
The limitations of our systematic literature review are mainly due to the low evidence found, which was mostly restricted to retrospective case reports and case series. This was further hampered given the heterogeneous reporting and inconsistent outcome measurements which precluded a metaanalysis.

Conclusion
Pelvic ABC has been documented in medical literature as case reports or case series and with heterogeneous reporting. In this systematic literature review, individual patient data was extracted to give an overview regarding functional and radiological outcomes by treatment modality.
Although mostly benign, pelvic ABC has an unpredictable behavior. A clear trend is being adapted towards the use of neo adjuvant sclero-embolic treatments alone or combined with surgery for better radiological and functional outcome. Furthermore, we encourage reporting of surgical case reports following a standard reporting guideline like SCARE statement (http://www.scareguideline.com/) to strengthen the quality of reporting The authors declare that they have no known competing nancial interests or personal relationships that could have appeared to in uence the work reported in this paper.

-Funding
The present research work was supported by AOTrauma in the form of clinical research fellowship at AOCID granted to the rst author. The data collection and manuscript writing was done at AOCID with the help of the supervisor and staff.

-Authors' Contributions
Ayesha performed the literature review and extracted the data with the constant help of Elke and Anahi. The manuscript was written and edited by all three authors. All authors read and approved the nal manuscript.

-Acknowledgements
We are grateful to AOCID staff, and in particular to Vasiliki Kalampoki for her help in data analysis. We also acknowledge the contribution of Prof Syed Muhammad Awais Dean Faculty of Health Sciences, University of Punjab, Lahore Pakistan for his generous sharing of knowledge, constant support, and for being a source of inspiration.    Note: Rossi et al [17] grouped the age of patients as <10, 10-20, >20 yrs. Therefore, these data was excluded when calculating the median age for each treatment group.    *One patient died. Therefore, the sum of the outcomes is less than the total number of patients in these categories.