Study of the efficacy of the elastic intramedullary nails in the treatment of primary aneurysmal bone cysts in extremities

Background The main treatment method of the primary aneurysmal bone cyst (ABC) in extremities is to curettage and bone grafts with high-speed burring, radiotherapy, sclerotherapy, arterial embolism and hormone therapy can be used for the lesions whose location cannot be easily exposed by the surgery. Regardless of the method, high recurrence rates are a common problem. Purpose To explore and compare the effect and efficacy of the elastic intramedullary nails in the treatment of primary ABC in extremities. Method 26 patients with primary ABC admitted and treated from 2010 to 2016 were studied retrospectively. 26 patients were divided into 2 groups according to the treatment plan: the patients of the control group received curettage and bone grafts with high-speed burring; the patients of the study group received curettage and bone grafts with high-speed burring + elastic intramedullary nail (ESIN). According to the imaging results (Neer grading) and MSTS(musculoskeletal tumor society)functional evaluation, the curative effect of the children of the 2 groups were analyzed statistically. Results A total of 10 patients of the control group received curettage and bone grafts with high-speed burring and a total of 16 patients of the study group received curettage and bone grafts with high-speed burring + ESIN. All of the patients were followed up for more than 2 years. 9 of the 26 patients recurred. According to the imaging results and MSTS function evaluation, there was statistically significant difference in the curative effect between the 2 groups ( P < 0.05).The recurrence cases in the study group have a better MSTS functioncal recovery. Conclusion Curettage and bone grafts with high-speed burring + ESIN can significantly reduce the recurrence rate of primary ABC in extremities. The using of ESIN has a good curative effect and efficacy.

Results A total of 10 patients of the control group received curettage and bone grafts with high-speed burring and a total of 16 patients of the study group received curettage and bone grafts with highspeed burring + ESIN. All of the patients were followed up for more than 2 years. 9 of the 26 patients recurred. According to the imaging results and MSTS function evaluation, there was statistically significant difference in the curative effect between the 2 groups ( P < 0.05).The recurrence cases in the study group have a better MSTS functioncal recovery.
Conclusion Curettage and bone grafts with high-speed burring + ESIN can significantly reduce the recurrence rate of primary ABC in extremities. The using of ESIN has a good curative effect and efficacy.

Background
Aneurysmal bone cyst (ABC) was original described by Jaffee and Lichtenstein in 1942, which has a low morbidity (about 1.4-3.2/a million people) [1] . A large amount of literature and clinical data indicated that ABC is a clinically rare benign bone tumor. However, some researchers presented that ABC is a malignant tumor, an intermediate tumor with malignant tendency. The imaging of ABC shows 3 that ABC is a polycystic and expansile osteolytic disorder, 70% of which are primary, and 30% are secondary. Up to now, the causes and pathogenic mechanisms of the ABC are still unknown, which leads to the diversified treatment methods of ABC. Currently, the main treatment method of ABC is curettage and bone grafts with high-speed burring. However, the high recurrence rate of ABC is still a worldwide recognized challenge. The recurrence rate of ABC was 11.8-20%, and the interval time between the surgery and the recurrence is 10 months. Some other reports revealed that the recurrence rate was generally higher in young patients than adults, which might be correlated to the location of focus in epiphysis or near epiphysis [2][3][4] .
This study retrospectively analyzed the clinical data of children with primary ABC in extremities and explored the effectiveness of ESIN in the treatment of primary ABC in extremities.

I. Case screening
The clinical data of the patients who have received surgical treatment after being diagnosed with primary ABC in our Hospital, 2010 to June, 2016 were recorded.
Inclusion criteria: The age of the patients was between 2-14 years old, with foci in the long bones of extremities, who have been followed up for more than 2 years, the surgeons who gave them surgical treatment had at least 10 years experience. All the participatences have complete clinical and imaging follow-up data.
Exclusion criteria: patients whose tumor foci were located in the flat bones or short bones, patients who received only plaster immobilization, but not surgical treatment due to pathological bone fracture; patients with secondary ABC.

II. Treatment Method
Surgery was performed under general anesthesia.
Control group: curettage and bone grafts with high-speed burring,plaster immobilization in the upper limbs for 6-8 weeks, and in the lower limbs for 8-12 weeks.
Study group: curettage and bone grafts with high-speed burring and ESIN was used under fluoroscopic guidance in an ascending matter (2-C-configuration). The diameter of the ESIN (2.0 to 3.0 mm) was decided on the basis of the preoperative anterior-posterior radiograph (digitally measured), plaster immobilization in the upper limbs for 4 weeks, and in the lower limbs for 6 weeks.

III. Follow-up and efficacy evaluation
All patients were reviewed with clinical examination, X-rays and functional evaluation four to eight weeks after the operation, then every three months until complete bone mineralization occurred and removal of the nails was possible. In order to makesure the long-term effectiveness, we arranged a further evaluation one year after the nails were removed.
Treatment results were classified according to the scheme used by Neer [5] : -Grade 1 = no response -the cyst showed no evidence of response to the treatment.
-Grade 2 = recurrence -the cyst initially consolidated with bone, but large areas of osteolysis and cortical thinning subsequently recurred.
-Grade 3 = healed with residual cyst -the cyst was consolidated with bone and the cortical margin thickened but there were still residual cyst parts.
-Grade 4 = healed -the cyst was completely filled in with bone and the cortical margin thickened.
Functional evaluation was performed by MSTS scoring [6] . MSTS and radiographic evaluation in the last follow-up time were conducted for both of the treatment group IV. Statistical analysis SPSS 20.0 (SPSS company, USA) statistical software package was used for statistical processing.
Among them, χ 2 test was used to compare the recurrence rate between the control group and the study group,R × C contingency table χ 2 test was used to compare the prognosis of the two groups, and t test of two independent samples was used to compare the MSTS score. Kaplan Meier survival curve was used to analyze the prognosis of the two groups and the relationship between the prognosis and the anatomical position, and the test level α value was 0.05 on both sides.

I. General Data
A total of 26 primary ABC patients were included in the study, and all conformed to the characteristics of typical pathologic histology of ABC (following figure) (Fig. 1).
Histological evaluation is mandatory for the accurate diagnosis of ABC. Grossly, ABC is spongy, hemorrhagic masses covered by a thin shell of the reactive bone. Microscopically, red blood cells and pale brown hemosiderin are abundant, filling cyst-like spaces bounded by septal proliferations of fibroblasts, mitotically active spindle cells, osteoid, calcifications, and scattered multi-nucleated giant cells [7] . Table 1 showed the specific focus distribution. The content includes 16 cases of the study group and 10 cases of control group; the mean age for the patients of the 2 groups were 5.94 (2-14) years old and 7.20 (2-12) years old, with no statistically significant difference between the 2 groups (P 0.05).

II. Prognostic Analysis
For the patients in the study group, 3 cases for grade I, 0 case for grade II, 1 case for grade III, and 12 cases for grade IV; for the patients in the control group, the prognostic evaluation results of Neer grading were 2 cases for grade I, 4 cases for grade II, 3 cases for grade III, and 1 case for grade IV. In addition, there were 2 cases of postoperative pathological fracture in the control group, and 1 case of skin irritation in the study group; none had severe infection, scar formation, or postoperative pathological fracture.
During follow-up period, postoperative MSTS functional scoring was performed for the patients of the 2 groups, and the results showed that the functional score of the patients in ESIN treatment group (28.88 ± 2.22) was statistical significantly higher than that of the control group (19.3 ± 7.83)(P < 0.001). According to the postoperative MSTS functional evaluation, we found that patients in the study group were still able to participate physical exercises eventhough the foci recurring, and no pathological fracture happened, and the postoperative life quality of the patients in the study group was greatly improved (Fig,2) .

III. Statistical Analysis
The results of the Chi-square test revealed that there was statistical difference in postoperative NEER grading between the patients of the 2 groups (P = 0.003), and the NEER grading prognosis of the patients in the study group was significantly better than that of the control group. According to the literature, the grades I-II of NEER grading were defined as recurrence, and the grades III-IV were 6 defined as cured. Grades III and IV were defined as success, whereas grades I and II represented a failure in treatment. The results of Kaplan-Meier curve and statistical analysis of Log-rank test revealed that there was statistically significant difference between the 2 groups (P = 0.028) (Fig. 3).
According to the statistical analysis of the relationship between the recurrence rate and the lesion site in the study group, there was no significant correlation between the lesion site and the recurrence rate (P = 0.092) (Fig. 4).

Discussion
The standard treatment of ABC is curettage with or without bone-graft. Despite the best efforts at curettage, postoperative highly variable recurrence rates have been shown. As a result, various auxiliary methods have been evolved to reduce the recurrence including the use of cement, highspeed burr, argon beam, phenol, and cryotherapy. Most of our patients had disabilities because of the tumor and their treatment, although none of them died or required amputation. It is difficult to treat ABC in the stage of aggressive period. Lesions that occur in the proximal femur should be treated more aggressively, partly because of the high rate of local recurrence and the high risk of fracture.
The most appropriate techniques for some of these tumors are curettage surgery and allograft implantation. However, the living quality of the recurred patients significantly reduced.
Up to now, the cause of ABC is still unknown. Traditionally, the current consensus believed that it is associated with the pressure increase in local blood vessels. In 1950, Lichtenstein et al [8] . proposed that the ABC should not been defined as a bone tumor, but a reactive disease of increased intraosseous pressure caused by intraosseous vasogenic disorder (intraosseous phlebemphraxis or arteriovenous fistula). In 1995, Kransdorf et al [9] . described the ABC foci as a formation of hemorrhage, and they proposed that continuous bleeding from intraosseous blood capillary created a cavity. Osteolytic change could be a result of rapid expansion of the sclerotin in the lesion area bone cysts formed. According to Mirra et al [10] .the so-called aneurysmal bone cyst is not a cyst nor a neoplasm; rather, it is probably a periosteal to arteriovenous malformation in bone, not uncommonly seen in association with other well-known benign and even malignant lesions. In the last 10 years, however, many researchers proposed that the formation of ABC was correlated with gene mutation, 7 and believed that the ABC was a bone tumor, not a disease caused by local bleeding.
Ye Y et al [11] . believed that primary ABC has now been identified as an independent neoplasm. The oncogenes responsible for ABC is formed secondary to gain-of-function translocations of t(16;17) (q22;p13) involving a gain-of-function of TRE17/USP6 (ubiquitin-specificprotease USP6 gene). In ABC, this mutation causes the induction of matrix metallopro-teinase (MMP) activity via NF-kB. They think that ABC has no malignant potential although the USP6 gene activatied. Oliveira et al. [12−13] believed that primary ABC was a tumor originated from mesenchymal cells, and they found that there was rearrangement of one or two oncogenes in USP6 (ubiquitin-specific protease 6) and CDH11 (cadherin 11 gene) in the patients with primary ABC, and that there was chromosome translocation in T (16;17) (q22;p1). They also found that the oncogene USP6 was in a very active state under the regulation of CDH11 promoter, but there was no translocation of CDH11 or USP6 in the patients with secondary ABC.
In this study, all of the patients had primary ABC, with good health status evaluated by each system, and without manifestations of malignant tumor. All of the patients of the 2 groups achieved satisfactory efficacies after receiving different treatment protocols, but the efficacy of the study group was superior to that of the control group.
Curettage and bone grafts with high-speed burring is the main treatment of ABC. At present, there were few literatures reported the theoretical basis for the application of ESIN in primary ABC. In 2015, Erol B et al [14] . proposed to take the curettage and bone grafts with high-speed burring assisted by the fixation with steel plate, ESIN or Kirschner wire, etc. as the treatment method of primary ABC.
They found that internal fixation in specific locations can promote healing rate in most of the ABC cases. Classified postoperative NEER grading of the children into 2 classes, namely the recurrence (grade I and II) and cured (grade III and IV).Our data showed that the recurrence rate of the patients in the study group(18.75%) was significantly lower than that of the control group(60%),This result indicated that the use of ESIN could reduce the recurrence rate (P < 0.05). However, the molecular mechanism of which should be further studied in patients with primary ABC. Meanwhile, we also 8 found that the time of postoperative plaster immobilization of the patients in the study group was significantly shorter than that of the control group. Additionally, the patients in the study group did not have pathological bone fracture after recurrence and the result of MSTS functional evaluation of recurrenced cases indicated satisfactory efficacy. According to above data, we could find that the internal fixation with ESIN can not only increase the cure rate of the patients with primary ABC, reduce their recurrence rate, but also significantly reduce the time for postoperative plaster immobilization of the patients and the risk to have another pathological bone fracture, and also significantly improve postoperative life quality of the patients. Meanwhile, we also found that the recurrence factors may be correlated to the lesion location, but statistical analysis indicated no statistical significance. We believe that the use of ESIN in the treatment of primary ABC has following advantages: (1) With its good elasticity, each ESIN is able to form 3 supporting points in the medullary space; 2 nails are distributed in the medullary space to form double arches, which is a central -type internal splint fixation; the mechanical conduction after fixation is a stress sharing mode, which brings less interference to normal biomechanics of the limbs. The nails provide at least 4 kinds of stability of biomechanics, namely counter-bending stability of axial stability, lateral stability and counter-rotation stability, which can effectively prevent displacement, angulation and rotation after fixation, therefore, the nails can significantly reduce the time of postoperative plaster immobilization of the patients and improve postoperative life quality of the children.
(2) Based on the pathogenesis of the ABC, Biesecker et al [15] . supported the hypothesis that ABC was a secondary reactive lesion of bone occurring owing to hemodynamic disturbances based on the results of manometric pressure studies showing increased intracysticpressure. Marcove RCet al [16] . suggested that arresting this hemodynamic disturbance could induce healing and prevent recurrence. Healing therefore may occur either spontaneously or after biopsy or fracture. Therefore, we hypothesis that fixation ESIN can achieve the effect of continuous intracapsular drainage, and thus reduce intracapsular pressure, promote healing and reduce recurrence. Furthermore, compared with Kirschner wire, ESIN is located in the marrow cavity, and it brings less foreign body reaction to surrounding tissues and could reside 9 in body for a long term. (3) After long-term follow-up for the patients of both groups, it was found that all of the recurrenced cases in the study group had no pathological bone fracture, and we believe that when the recurrenced area is located in the stress bone (femur or tibia), the internal fixation with ESIN can provide protection and significantly reduce the risk of refracture.
In this study, most of the ABC located at the neck of the femur which is near the metaphysis and is a stress bone in both of the 2 groups. Some researches recommended to curettage and bone grafts with high-speed burring, assisted by internal fixation with steel plate, but local bone cortex of ABC was injured in an osteolytic manner, so it needs to be further discussed whether the internal fixation with steel plate can play a role on the prevention of pathological bone fracture and stabilization once there was a recurrence or expansion of the lesion (Fig. 5). Due to its poor stability, the kirschner wire can hardly play the role of secure internal fixation. Hutchinson PH, Wang x et al [17−18] believed that in the treatment of the fracture of the neck of humerus, the penetration of ESIN head through the epiphyseal plate of proximal humerus and placement of ESIN in the epiphysis would not cause epiphyseal premature closure and affect the growth. For example, we used ESIN less than 3 mm to penetrate the epiphyseal plate of proximal humerus in some cases, and no epiphyseal premature closure was found in the 3 years follow-up. Due to the mechanism of 4 biological stabilities, the ESIN can exert the effect of stability; the cross stress produced by the nails in the medullary space can attain the goal of supporting the longitudinal axis of the long bone, and avoid the risk of another pathological bone fracture due to weak sclerotin and lesions following focus recurrence (Fig. 6).
Furthermore, we found one of the patients had the lesion in proximal humerus, which was a active ABC. The patient received curettage and bone grafts with high-speed burring and ESIN. According to our 3 years imaging follow-up. we found that there was a focal recurrence, but the focal recurrence migrated away from the epiphysis as time goes on, and the patient had no obstacles in physical exercise so far, whose score of MSTS was 28. In 2008, Patrick et al [19] . retrospectively analyzed 53 patients with ABC, and found that the patients around 12 years old had a relatively high recurrence rate. 8 out of 19 patients with lesion near the epiphysis had recurrence after the surgery and the recurrence rate significantly higher than the patients with ABC in other locations. This study speculated that this might be correlated with insufficient curettage due to surgeon's concern of postoperative growth deformity during surgery. Therefore, we made a hypothesis that in case of postoperative recurrence, the ESIN in the medullary reduced the risk of pathological fracture, and the patient's postoperative functional score and life quality were significantly improved to an extent that he/she could even do physical exercise, and when the patient was older and the focus furtherly migrated away from the epiphysis, another surgical treatment was provided, which, according to our speculation, was able to reduce the recurrence rate and surgical difficulty. Furthermore, the patient's life quality in the recurrence period was greatly improved. This speculation, however, should be further proved by a large amount of clinical cases in the future study (Fig. 7).

Conclusion
In summary, according to this study, we believe that the treatment of the primary ABC in extremities with curettage and bone grafts with high-speed burring assisted by ESIN is a safe and effective treatment measure, which can effectively reduce the recurrence rate, prevent the occurrence of pathological fracture in recurred cases, reduce the time for postoperative plaster immobilization and improve the patient's life quality. However, the number of our cases was limited, further studies are needed based on more and multi-centerd cases to prove our conclusion, though statistically significant difference has been got in our study.

Ethics approval and consent to participate
The Medical Ethical Commission of the Shanghai Children's Hospital approved this study. Participants signed informed consent form before participation.

Consent for publication
All authors agree to publish in World Journal of Surgical Oncology

Availability of data and material
All the data used in the article can be obtained from the medical record information system of Shanghai Children's Hospital Shanghai jiao tong University. Any questions or enquiries regarding the present study can be directed to Li-hua Zhao, MD (18616771553@163.com), as the corresponding author.

Funding
The present study was supported by the National Natural Science Foundation of China (no. 12 Zhao revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.

Competing interests
The authors declare that they have no competing interests.     The results of Kaplan-Meier curve and statistical analysis of Log-rank test revealed that there was statistically significant difference between the 2 groups (P = 0.028).
18 Figure 3 The results of Kaplan-Meier curve and statistical analysis of Log-rank test revealed that there was statistically significant difference between the 2 groups (P = 0.028).
19 Figure 3 The results of Kaplan-Meier curve and statistical analysis of Log-rank test revealed that there was statistically significant difference between the 2 groups (P = 0.028).
20 Figure 4 According to the statistical analysis of the relationship between the recurrence rate and the lesion site in the study group, there was no significant correlation between the lesion site and the recurrence rate (P = 0.092) .
21 Figure 4 According to the statistical analysis of the relationship between the recurrence rate and the lesion site in the study group, there was no significant correlation between the lesion site and the recurrence rate (P = 0.092) .

Figure 4
According to the statistical analysis of the relationship between the recurrence rate and the lesion site in the study group, there was no significant correlation between the lesion site and the recurrence rate (P = 0.092) .

Figure 5
The patients with recurrence of ABC. The figure indicated pathological bone fracture even with internal fixation with steel plate. In view of focal recurrence, osteolytic change of local bone cortex of the neck of femur and cystic change of medullary space, the efficacy of the internal fixation by the 3 nails should be discussed further, and meanwhile unclear fixation efficacy of proximal nail of steel plate led to stress bone fracture.
24 Figure 5 The patients with recurrence of ABC. The figure indicated pathological bone fracture even with internal fixation with steel plate. In view of focal recurrence, osteolytic change of local bone cortex of the neck of femur and cystic change of medullary space, the efficacy of the internal fixation by the 3 nails should be discussed further, and meanwhile unclear fixation efficacy of proximal nail of steel plate led to stress bone fracture.

Figure 5
The patients with recurrence of ABC. The figure indicated pathological bone fracture even with internal fixation with steel plate. In view of focal recurrence, osteolytic change of local bone cortex of the neck of femur and cystic change of medullary space, the efficacy of the internal fixation by the 3 nails should be discussed further, and meanwhile unclear fixation efficacy of proximal nail of steel plate led to stress bone fracture.
26 Figure 6 curettage and bone grafts with high-speed burring + ESIN for the foci of neck of femur. The x-rays are present in Month 1, 6, 18 and 40 after surgery respectively. The patients of this group had no pathological fracture even after focal recurrence, and no epiphyseal premature closure was observed in 4 years eventhough the penetration of ESIN into the epiphyseal plate (5-9 years old), and bilateral lower limbs were equal in length, and the score of MSTS (musculoskeletal tumor society) was 28.
28 Figure 6 curettage and bone grafts with high-speed burring + ESIN for the foci of neck of femur. The x-rays are present in Month 1, 6, 18 and 40 after surgery respectively. The patients of this group had no pathological fracture even after focal recurrence, and no epiphyseal premature closure was observed in 4 years eventhough the penetration of ESIN into the Figure 6 curettage and bone grafts with high-speed burring + ESIN for the foci of neck of femur. The x-rays are present in Month 1, 6, 18 and 40 after surgery respectively. The patients of this group had no pathological fracture even after focal recurrence, and no epiphyseal premature closure was observed in 4 years eventhough the penetration of ESIN into the epiphyseal plate (5-9 years old), and bilateral lower limbs were equal in length, and the score of MSTS (musculoskeletal tumor society) was 28.

Figure 7
A B and C showed the lesion in one year before surgery, preoperative and 4 years postoperation respectively, the patients had the lesion in proximal humerus, which was an active ABC. The patient received curettage and bone grafts with high-speed burring + ESIN.
According to our long-term imaging follow-ups, we found that there was a focal recurrence, but the focal recurrence migrated away from the epiphysis with the passage of time, and the patient had no obstacles in physical exercise so far, the score of MSTS (muscular skeletal tumor society) was 28. 34 Figure 7 35 A B and C showed the lesion in one year before surgery, preoperative and 4 years postoperation respectively, the patients had the lesion in proximal humerus, which was an active ABC. The patient received curettage and bone grafts with high-speed burring + ESIN.
According to our long-term imaging follow-ups, we found that there was a focal recurrence, but the focal recurrence migrated away from the epiphysis with the passage of time, and the patient had no obstacles in physical exercise so far, the score of MSTS (muscular skeletal tumor society) was 28.

Figure 7
A B and C showed the lesion in one year before surgery, preoperative and 4 years postoperation respectively, the patients had the lesion in proximal humerus, which was an active ABC. The patient received curettage and bone grafts with high-speed burring + ESIN.
According to our long-term imaging follow-ups, we found that there was a focal recurrence, but the focal recurrence migrated away from the epiphysis with the passage of time, and the patient had no obstacles in physical exercise so far, the score of MSTS (muscular skeletal tumor society) was 28.

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