Microwave in situ inactivation in the treatment of bone giant cell tumor: a mid-term descriptive study

To evaluate the mid-term clinical efficacy of microwave in situ inactivation combined with bone grafting or polymethyl methacrylate (PMMA) filling in the treatment of giant cell tumor of bone (GCTB). This is a retrospective, descriptive, and analytical study. A total of 30 GCTB patients received microwave in situ inactivation from January 2012 to January 2020, whose clinical recurrence rate was evaluated at the last follow-up after microwave in situ inactivation surgery. The Musculoskeletal Tumor Society (MSTS) function score was used to evaluate the postoperative clinical panoramic results. All patients were followed up for 21 to 110 months, with an average of 63.79 months. Distal femur (40%) and proximal tibia (28%) had a higher rate of GCTB incidence. Seventeen percent of tumor patients suffered from associated pathologic fracture. The rate of Campanacci classification stage III was 60%. The average MSTS score was evaluated as 27.53 points overall at the last follow-up. In terms of complications, three, two, two and one cases developed fat liquefaction, controllable tissue rejection reaction, incision infection and degenerative changes around lesion joint, respectively, without in situ recurrences and reoperation as well as distant lung metastasis. The method of microwave in situ inactivation combined with bone grafting or PMMA filling is prudently recommended as one of the options for the limb salvage treatment of giant cell tumor of long and periarticular bone. IV: case series.


Introduction
Traditional focus curettage and bone graft fixation is an effective method of treating benign bone tumors. However, intracapsular resection is not enough for invasive neoplasms, which may cause a large number of local recurrences greatly affecting the prognosis (van et al. 2017;Zheng et al. 2020). An en-bloc resection is more likely to achieve a wide no-tumor margin, but the loss of function is often unacceptable. Nowadays, the technology of microwave in situ inactivation tries to achieve the same effect with a lower cost. Preserving the fully inactivated cortical bone structure serving as the basis and skeleton for structural reconstruction, this technique makes reconstruction easier and more durable (Fan et al. 2016). As a typical limb salvage heat treatment of giant cell tumor of long and periarticular bone, microwave inactivation has been used in a variety of bone tumors with satisfactory Xiang Jiang and Jianan Chen have contributed equally to this work. outcomes (Basile et al. 2014;De Marini et al. 2020;Han et al. 2017;Ke et al. 2021;Yu et al. 2017). However, enough medium-and long-term observation reports are still lacking in sufficient support. The author retrospected and described the mid-term efficacy of using microwave in situ inactivation combined with bone grafting or polymethyl methacrylate (PMMA) filling in the treatment of giant cell tumor of bone (GCTB). The report is as follows.

Preoperative demographic characteristics
This study has a total of 30 GCTB patients who received microwave in situ inactivation surgery in the General Hospital of Central Theater Command from January 2012 to January 2020. All the patients were evaluated by preoperative three-dimensional computed tomography (3D-CT) and magnetic resonance imaging (MRI) examination.
Imaging shows the existence of support on the compression stress side of the lesion area. Lung and emission CT (ECT) examinations were performed to exclude distant metastasis. Campanacci stages were assessed as I-III and classified by three senior oncology specialists (Table 1). All the patients underwent pathological examination and were followed up for 21 to 110 months, with an average of 63.79 months (Table 2).

Inclusion and exclusion
The inclusion criteria for the present study were: a retrospective study was designed, (i) Patients with GCTB in the extremities; (ii) Patients receiving curettage with adjuvant microwave therapy from 2012 to 2020. The exclusion criteria were as follows: (i) Patients with GCTB in the spine and pelvis; (ii) Patients found to have any form of distant metastatic lesions before surgery; (iii) Patients without receiving microwave ablation adjuvant curettage therapy; (iv) The loss of follow-ups.

Surgical technique
All operations were performed by the same group of senior bone oncology surgeons. Adopting conventional tumor extensive resection entry, they paid attention to the boundary between normal tissue and tumor edge   (Ke et al. 2021;Kawaguchi et al. 2013;Knavel et al. 2017;Leon et al. 1993). During the operation, the purpose of fully burning the tumor could be realized by changing the position of the antenna array, and the power size of the microwave needle could be accurately controlled to focus on burning. The microwave inactivation area needed to cross the boundary of 2 cm to achieve the extensive resection of the envelope and reaction area according to Li et al. (2015). With regard to inactivation close to important peripheral nerve vessels, local protection could be performed by cold saline package isolation. As for tumor treatment involving subarticular cartilage, the purpose was to adequately remove the tumor to avoid recurrence instead of sticking to retain 1-2 cm bone subarticular. During inactivation, cold saline was continuously injected into the joint cavity to maintain a low temperature to protect the articular cartilage surface, and the low point of the joint cavity could retain an empty needle so that excess liquid could be sustainably discharged ( Fig. 1).
After the application of the microwave inactivation technique to heat treatment in the cystic capsule and reaction area, traditional tumor scraping technique was used for removing tumor tissue and managing capsule boundary. Furthermore, mixed allograft and autologous bone grafting or polymethyl methacrylate (PMMA) filling was performed. For patients with insufficient bone under the joint surface, large autoiliac bone transplantation stabilized under the joint surface and internal fixation could be performed to achieve added support (Figs. 2 and 3).

Outcome measure
Intraoperative time consumption and bleeding volume were recorded. After the last postoperative follow-up, the Musculoskeletal Tumor Society (MSTS) function score formulated by Enneking (Enneking et al. 1993) was adopted to evaluate the postoperative clinical panoramic results (Table 3). The score is out of 30 points: More than 24, 18-24, 12-18 and less than 12 points are rated as excellent, good, medium and poor, respectively. The tumor and internal fixation and joint surface were evaluated by using X-ray, 3D-CT reconstruction and MRI.

Statistical analysis
Campanacci classification was graded by three orthopedic and bone tumor surgeons (A, B and C) who followed the blind method according to the conformity rate of observers. Consistency check data were evaluated by Cohen's Kappa coefficient by using Statistical Product Service Solutions (SPSS) statistics software version 25.0 (International Business Machines Corporation (IBM Corp.), Armonk, New York, the United States of America (USA)). MSTS scores were group-compared according to the final surgical procedure.

Clinical results
For all the patients, the estimated mean blood loss was 177.67 ± 88.85 ml, of which the most was 275.00 ml on the proximal humerus, followed by 204.56 and 177.78 ml on the distal femur and proximal tibial successively. The mean operation time was 205.96 ± 66.85 min, of which 309 and 245.78 min were for proximal humerus and proximal tibial, respectively (Fig. 4). According to the Campanacci grading system, 60.0% of patients presented with grade III (Fig. 5). The average MSTS functional evaluation score of all 30 patients was 27.53 points (ranging from 22 to 30) at the last postoperative follow-up, with an overall excellent rate of 80%. Mixed allograft and autologous bone grafting were performed in 16 cases, with a mean score of 27.86. PMMA filling was performed in 14 cases, with a mean score of 27.25. The comparison of patients undergoing bone grafting and PMMA filling showed no significant difference in the MSTS functional score (Fig. 6). These results were similar  to other studies of microwave ablation treatment (Fan et al. 2016;Ke et al. 2021).

Complications and recurrence
Three, two, two and one cases (10.0%, 6.7%, 6.7% and 3.3%) had the complication of fat liquefaction, tissue rejection reaction, incision infection and degenerative changes around the joint, without in situ recurrences, and reoperation as well as distant lung metastasis. No one died among all the cases (Table 2).

Discussion
With locally aggressive behavior and a slight tendency to metastasis, GCTB accounts for 5% of the incidence of bone tumors, and occurs mostly in skeletally mature patients who are generally at the age of 20 to 45 with a long predicting survival time and a desire to maximize the preservation of limbs and activity (Fan et al. 2016;Ambrosi et al. 2021). Therefore, the medical decision needs to preserve the limb, maintain joint function as more as possible, and ensure a decrease in the risk of tumor recurrence.
To date, the preferred treatment for GCTB has included extra sac wall curettage with or without local adjuvant, enbloc resection or amputation. However, no standard treatment modality was established (van Heijden et al. 2017;Basu et al. 2021). It has been reported that lesions after insac curettage have a recurrence rate of 27% to 65%, and curettage with cystic wall treatment technology including phenol or liquid nitrogen and PMMA has a recurrence rate of 12-27% (Arbeitsgemeinschaft et al. 2008;Balke et al. 2008;Klenke et al. 2011). Due to the higher odds of adverse events, the intra-cystic curettage of tumors has been deprecated. Nevertheless, some studies still show that a little bit less than 12% of GCTB after en-bloc resection may recur (Errani et al. 2010). Resection which sacrificed extensive bones around lesions may have the lowest recurrence rate, which, however, is also associated with worse functional results and often accompanied by tissue reconstruction function or alternative treatment for excised segments. Prosthesis-related complications must be of concern. The relationship between prosthesis service life and long-term patient survival remains noteworthy (Fan et al. 2016). Generally, prosthesis has advantages in early-stage application, especially in function (Wang et al. 2020). However, Ahlmann (Ahlmann et al. 2006) reported that 35 prostheses (16.6%) in 211 cases of tumor resection and prosthesis replacement encountered failure, of which infection, the rate of revision, amputation and prosthetic removal accounted for 5.2%, 13.8%, 2.4% and 0.5%, respectively. These issues cannot be ignored.  The ultimate goal is to seek more effective and thorough treatment and preserve more limb motor function. Experts tried a variety of schemes to achieve peripheral envelope extensive resection to remove the reaction zone and reduce the chance of recurrence. Current tumor limb-preserving treatment programs include tumor-type artificial prosthesis, tumor segment excised with inactivated bone replant back, 3D printing prosthesis reconstruction, microwave high-temperature inactivation and other methods (Wang et al. 2020). Various options have their rigorous selection of indications. Microwave heat treatment technology is favored by oncology surgeons because of being able to retain more bone and soft tissue structures. Microwave energy radiated by the antenna leads to the rapid rotation of water, proteins and other polar molecules in tissue, enabling faster heating (Fan et al. 2016). The ablation frequency of medical microwaves is generally 915 or 2450 MHz, of which the latter is widely applied because of its fast heat production with large power and ablation zones (Zheng et al. 2020;Lubner et al. 2010). In addition, microwave in situ inactivation could result in the necrosis of tumor blood vessels before curettage (Cornman-Homonoff et al. 2017). For bone tumors with a rich blood supply like GCTB, it could easily achieve a higher temperature and effectively block blood vessels, greatly reducing tumor bleeding and guaranteeing surgery safety (Zheng et al. 2020). Apart from that, microwave ablation could not only directly kill tumor cells in situ, but also activate the host immune system to fight against tumor and induce cytokine production to alter T-cell balance by increasing the systemic cytotoxic T-lymphocytes/regulatory T-cells ratio and remodeling the microenvironment to influence its outcome (Repasky et al. 2013;Takaki et al. 2017;Yu et al. 2014).
The main concern is tumor recurrence. Losing limitation effect by the cortex of bone, pathologic fracture is responsible for one way of contamination by tumor, which  can trigger off a higher risk of recurrence (O'Donnell et al. 1994;van Heijden et al. 2013a, b). In light of this consideration, the solution was adopted to gradually turn up power or increase the processing time of heat treatment on the basis of ensuring the safety of important nerves and blood vessels. This scheme should ensure that the microwave inactivation area is above 2 cm outside the contaminated zone to achieve the extensive resection of the envelope and reaction area, especially pathological fracture (Fan et al. 2016;Ke et al. 2021;Li et al. 2015). Accurate temperature-controlled microwave needles can make sure that the power set does not cause iatrogenic damage. Tumor scrape removal was performed after adequate heat treatment, which may reduce the contamination risk of surrounding soft tissues due to the inactivation of residual tumor tissue after microwave ablation (Ke et al. 2021). According to this interim study, no in situ recurrence and metastasis outcomes were observed in patients with high Campanacci stages and pathological fracture during the follow-up period.
No consensus was reached on the issue of which material is more effective in the reconstruction of the cavity after curettage (Takeuchi et al. 2018;Zheng et al. 2017). PMMA and bone grafting are two commonly adopted schemes at present. Bone grafting is recommended by virtue of its great structural support and biological background for bone healing, which, however, is unfit for filling in the large cavity and the strength of bones cannot be immediately restored (Vaishya et al. 2019). In comparison, bone cementing can provide immediate full weight-bearing after surgery and early defense. With cytotoxic and thermal effects on tumor cells in operation, bone cementation has better local tumor control and a lower recurrence rate compared with bone grafting (Zheng et al. 2017). However, adjacent cartilage damage and osteoarthritis after bone cementing could not be ignored in clinical treatment (Vaishya et al. 2019). It had been suggested that mechanical failure could be reduced by bone combined with cement grafting under the cartilage around the knee (Teng et al. 2019). Furthermore, it also may be a meaningful research direction for the prevention of thermal damage under the cartilage caused by cementation. The postoperative MSTS score of the patients is another focus deserving attention. In this series, the average MSTS functional evaluation score of all 30 patients was 27.53 points with a satisfactory functional outcome. No statistically significant difference was found though patients receiving PMMA filling had higher MSTS scores than those receiving bone grafting (Fig. 6). Assisted microwave inactivation technique in the treatment of GCTB appeared to obtain a satisfying functional result in the medium term.
Several studies demonstrated that microwave ablation will decrease bone stiffness but make no changes in breaking load, without serious effect on revascularization and new bone formation, maintaining the integrity of the joint to the utmost extent (Kawaguchi et al. 2013). In this study, one case of proximal tibia suffered joint degenerative changes after about 2 years of surgery. The reason for this complication was considered to be the thermal damage to the cartilage surface caused by the microwave (Zheng et al. 2017;van Heijden et al. 2013a, b). However, this phenomenon could not be deemed universal due to the possibility of external intervention in follow-up cases and the lack of enough positive samples.
In this series, a few complications were observed, such as fat liquefaction, tissue rejection reaction and infection. Three and two of 30 cases got fat liquefaction and postoperatively incisional infection, respectively, after surgery. It has been suggested that improving the level of preoperative cephalosporin antibiotics and minimizing operation time could reduce the incidence of infection (Ke et al. 2021). However, the authors urged that the placing of adequate drainage tubes in the wound area should be suggested. Two of 30 cases suffered rejection reaction with wound exudate, and massive bone grafting may have adverse factors for the occurrence of rejection reactions (Zheng et al. 2017;Vaishya et al. 2019;Teng et al. 2019). The short-term use of 5 mg dexamethasone could effectively limit the development of inflammation and greatly relieve symptoms.
Denosumab (RANKL inhibitor) and Zoledronic increase the treatment options for GCTB. Literature has pointed out that denosumab and Zoledronic are capable of inhibiting GCTB osteoclastic differentiation in vitro evaluation (Shibuya et al. 2019). It has been demonstrated that denosumab can lead to a significant reduction in tumor size, reducing pain and restoring bone stock (Traub et al. 2016). In addition, a calcified rim surrounding soft tissue often seen in denosumab treated GCTB could be a facility to curettage in previously uncurettable GCTB (van Heijden et al. 2017). Scholars have observed that denosumab can reduce tumor stage to easier curettage, whose separate use without other adjuvant therapies, however, is accompanied by a higher rate of local recurrence (Errani et al. 2018). Therefore, it is supposed that microwave inactivation combined with denosumab would generate animated discussions in the future.

Limitations and conclusion
It should be acknowledged that this study has a number of limitations. For foreseeable tumor ethical considerations and due to geographical range limits and lower incidence impact, this study had no control group with a limited number of included studies. Thus, it is a single-center retrospective and descriptive analysis. Even if these factors were taken into consideration, overall MSTS excellence rate of 80% was still achieved, and this ratio in Campanacci III tumors is 83.33% (Table 3). According to the result of this retrospective study, the true effect can be prudently expected. This method can effectively reduce the recurrence rate and preserve limb function. However, more patients and longer follow-ups are required to further confirm this hypothesis. It indicates that the method of microwave local tissue inactivation combined with bone grafting or PMMA filling can be considered as one of the options for the limb salvage treatment of GCTB.
Author contributions PGX designed the study and performed the operations. FX and XML conducted experimental review and guidance. XJ and JNC involved in drafting the manuscript or revising critically for important intellectual content. JNC, WZ, CZ, GDW and DD collected the data. XJ, JNC and WZ analyzed the data and performed the statistics. All authors read and approved the final version of the manuscript.

Funding
The current study was subsidized by Joint Foundation project of Hubei Provincial Health and Family Planning Commission (No. WJ2018H0073).

Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Conflict of interest
The authors declare that they have no competing interests.
Ethical approval This study was performed according to the Helsinki Declaration and was approved by the Ethics Committee of General Hospital of Central Theater Command.

Consent for publication
Written informed consent for publication was obtained from all participants.