Heat treatment for giant cell tumors of bone: A systematic review

Abstract

This systematic review evaluates the effects of heat treatments in de novo, residual and recurrent giant cell tumors of bone (GCTB). Studies were eligible for inclusion if one of the following treatments was administered: radiofrequency ablation (RFA), microwave ablation, argon cauterization, electrocauterization and hot liquid treatment. The primary outcome was recurrence. Secondary outcomes were complications, pain, function, and quality of life. Recurrence rates for microwave ablation as an adjuvant to intralesional curettage were 0%, 4% and 10% (3 retrospective single-group studies); for argon cauterization 4%, 8% and 26% (3 cohort studies); electrocauterization 0% to 33% (8 cohort studies); and hot liquid 9.5% and 24% (2 cohort studies). Follow-up was generally ≥24 months. Data on pain, function and quality of life were scarce. Complications included infection and secondary osteoarthritis. Current evidence does not demonstrate or exclude an effect of heat treatments on recurrence in GCTB. Further research should objectify if (subgroups of) patients benefit from these treatments.

Keywords

ablation techniques bone tissue cautery giant cell tumors of bone neoplasms recurrence thermal treatments

Introduction

Giant Cell Tumors of Bone (GCTB) comprise 4–9.5% of primary bone neoplasms.¹ Although they are benign, they can be locally aggressive, causing pain, functional impairment and/or pathological fractures. In rare cases, benign pulmonary metastases develop or it dedifferentiates to a malignant form. Giant Cell Tumors of Bone can be classified by radiographic appearance with the Campanacci grading system. There are several treatment options depending on location and extent of disease. Plain intralesional curettage is least extensive, and it is associated with a high recurrence rate of 47% (range 27%–82%). Burring of the cavity leads to lower recurrence rates, which can be further reduced to 12% (range 0%–26%) by using adjuvants: phenol, hydrogen peroxide, cryotherapy or cementation.² In severe cases with joint involvement, cortex destruction and/or soft tissue involvement, en bloc resection is indicated at the expense of the native joint.³ There is a need to further reduce GCTB recurrence rates and expand the palette of treatment options for challenging cases.

It is hypothesized that thermal techniques can reduce recurrence rates by causing death of (residual) tumor cells with heat.⁴ In radiofrequency ablation (RFA), heat is generated from a radiofrequency current which can be administered percutaneously or during surgery via a probe.⁵ Electromagnetic microwave ablation, via an inserted needle tip, causes water molecules in tissue to oscillate, generating heat.⁶ Coagulation with electrocautery produces heat through an electrical current. Argon coagulation uses an electrical current too, which is sent into a beam of argon gas that is “sprayed” at the tissue, cauterizing it. Hot liquid can be applied intraoperatively to the residual bone cavity after curettage. It is unknown if these treatments reduce recurrence rates in de novo, residual or recurrent GCTB. To our knowledge, there is no prior research that reviewed the effect of any heat treatment on recurrence rates, or any other clinical outcomes, in GCTB. This systematic review aims to evaluate the effect of heat treatments in patients with de novo, residual or recurrent GCTB. The primary outcome is recurrence rate. Secondary outcome measures are complications, pain, function and quality of life.

Methods

On December 13^th, 2022 a literature search was conducted across PubMed, Web of Science, and Embase using the main term “giant cell tumor of bone” with various terms for “heat treatments” (Addendum A). Titles, abstracts, and finally full-text articles were screened to include studies. One author performed the initial assessment; all authors resolved ambiguity via discussion and consensus. The study received a waiver from the Institutional Review Board, was registered on PROSPERO with ID CRD42022296749 and can be accessed in full at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=296749. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used.⁷

Eligibility criteria

Studies were required to meet the following criteria. The population included patients with de novo, residual or recurrent GCTB, regardless of age and anatomical site. The intervention involved heat treatment; eligible treatment forms were radiofrequency ablation, microwave ablation, argon beam coagulation, and field cauterization by electrocoagulation. Based on pilot search results, the protocol was revised to include treatments with hot liquid. Studies reporting on GCTBs as a separate subset of a larger population were partially included. Publications in the English language only were included. There were no limits placed on publication date or follow-up time, in order to maximize relevant search results. Randomized controlled trials, prospective or retrospective cohort studies (defined as n ≥ 11), case series (defined as n ≤ 10), and case reports were included to maximize capture of any relevant data. Studies without original data were excluded.

Outcome measures

The primary outcome measure was recurrence. Secondary outcomes measures were complications, pain, function, and quality of life.

Data collection

Data items collected were: authors, publication year, journal, study type, number of subjects, tumor grade, site, primary or recurrent status, presence of pathological fracture, intervention, control, duration of follow-up, local recurrence, complications, pain, function, and quality of life. The data were managed using Microsoft Excel.

Risk of bias

The methodological quality was assessed for all included studies. Cohort studies were graded using the validated methodological index for non-randomized studies (MINORS) criteria.^8,9 Case reports were scored using the Joanna Briggs Institute (JBI) Critical Appraisal checklist.¹⁰ Unpublished work was searched on www.clinicaltrials.gov and from readily available conference data.

Summary measures and synthesis of results

Results were presented descriptively. No meta-analysis or pooling was performed due to the heterogeneous nature of interventions and patients.

Results

Search and elimination

The search process is summarized in Figure 1. 389 articles were found from PubMed, Web of Science, Embase and other sources (reference lists). 259 remained after removal of duplicates. 93 passed screening by title and abstract, 31 of which matched the inclusion criteria.

Figure 1.

Flow chart summarizing study search and selection.

Study characteristics and main findings

Study characteristics and main findings are listed in Table 1. Articles covered radiofrequency ablation (3), microwave ablation (4), argon cauterization (10), electrocauterization (11) and hot liquid (2). The methodological quality assessment is found in Addendum B.

Table 1.

Study characteristics and main findings.

	Study design	n	FU in mo (range)	Site (n)	Grade I/II/III %	# %	Disease status (%)	Intervention	Recur %	Complication % (n and type)
Percutaneous RFA
Koo and Chung, 2021	R	1	42	NR	NR	0	Recurrent	Percutaneous RFA	N/A	0
Santiago et al. 2009	CR	1	24	Sacrum (1)	0/0/100	0	NR	Percutaneous RFA, cement	N/A	NR
Zhao et al. 2014	CR	1	20	Femur (1)	0/0/100	0	De novo	Percutaneous RFA. 2 weeks later: Curettage, autograft, allograft, ethanol, internal fixation	0	0
Microwave ablation
Jiao et al. 2020	R	10	29 (19 - 53)	Radius (10)	0/NR/NR	NR	NR	Curettage with MWA, electrocautery, cement	10	NR
Ke et al. 2021	R	54	60 (24 - 126)	Femur (17), tibia (16), radius (8), humerus (5), other (8)	0/44/56	15	De novo (81) recurrent (9)	Curettage with MWA, cement or allograft	4	9 (2 femoral head necrosis, 1 inf, 1 subluxation, 1 #)
Jiang et al. 2022	R	30	64 (21 - 110)	Femur (12), tibia (10), radius (3), other (5)	10/30/60	17	NR	Curettage with MWA, allo-autograft (n = 16) or cement (n = 14). In some: internal fixation	0	27 (3 fat liquefaction, 2 rejection, 2 inf, 1 oa)
Luna et al. 2020	CS	2	30	Pelvis (2)	NR	0	De novo	Percutaneous MWA, bisphosphonate, cement. 3 – 5 sessions	0	NR
Argon cauterization
Lewis et al. 2006	R	37	73 (1 - 108)	Tibia (16), femur (11), radius (6), other (4)	5/89/5	16	De novo (92) Recurrent (8)	Argon beam cauterization, curettage, burr. In few: internal fixation	8.3	27 (4 #, 4 inf, 1 nerve palsy, 1 tendon rupture)
Ofluoglu, 2008	R	24	34 (14 - 70)	Femur (8), tibia (6), other (10)	8/25/71*	4	De novo (87) recurrent (13)	Argon plasma cauterization, curettage, burr, cement, phenol. In some: internal fixation	4	17 (3 delayed wound healing, 1 oa)
Benevenia et al. 2017	R	42	56 (12 - 234)	Tibia (20), femur (19), other (3)	0/0/100	NR	NR	Argon beam coagulation, curettage, burr, H₂O₂, cement in most, allograft in some. Most: Internal fixation	26	29 (6 #, 6 oa)
Takeda, et al. 2009	CR	2	60; 74	Sacrum (1), spine (1)	NR	0	De novo	Curettage, burr, argon beam coagulation, re-curettage, auto- or allograft, internal fixation	0	50 (1 transient nerve palsy)
Bibbo et al. 2010	CR	2	27; 33	Metatarsal (2)	0/100/0	0	De novo	Cycles of curettage, burr, H₂O₂, argon beam photocoagulation plus autograft	0	NR
Menon et al. 2016	CR	1	15	Femur (1)	0/0/100	0	De novo	Denosumab pretreatment, curettage, burr, argon laser cautery, autograft, cement, denosumab posttreatment	0	NR
Futani et al. 2018	CS	5	58 (24 - 126)	Fibula (5)	0/80/20	0	De novo	Osteoscopic curettage, argon plasma coagulation, cement. In one: denosumab pretreatment	0	NR
Chen et al. 2018	CR	1	20	Tibia periprosthetic (1)	0/0/100	0	De novo	Curettage, burr, argon beam coagulation, cement, internal fixation. Posttreatment denosumab, bisphosphonate	0	NR
Donigian et al. 2022	CR	1	10	Femur (1)	0/0/100	0	De novo	Intralesional excision, burr, phenol, argon laser treatment, bone grafting	100	100 (1 malignancy and metastasis)
Sukpanichying-yong et al. 2022	CS	6	35 (24 ‐ 46)	Femur (5), tibia (1)	0/33/67	0	De novo	Curettage, burr in most, H₂O₂, argon beam coagulation, cement, autologous bone graft in some. (n = 6)	17	0
Electrocauterization
Ward Sr. and Li, 2002	R	24	59 (12 - 115)	Tibia (9), femur (7), radius (3), humerus (3), other (2)	0/50/50*	NR	NR	Curettage, burr, electrocautery, phenol, cement (63%), autograft (63%), internal fixation (38%)	8	41 (4 graft or cement failures, 1 burn, 3 oa, 1 delayed union)
Saiz et al. 2003	R	40	76 (26 - 178)	Femur (17), tibia (14), radius (5), other (4)	0/90/10*	NR	NR	Curettage, burr, electrocauterization, phenol, cement. In some: internal fixation	12.5	7,5 (2 oa, 1 #)
Suzuki et al. 2007	R	30	57 (24 - 120)	Femur (17), tibia (13)	33/33/33	NR	De novo	Cycles of curettage, burr, electrocauterization. Plus autograft (90%) and/or cement (40%)	33	46 (10 oa, 4 #)
Xing et al. 2013	R	162	64 (25 - 80)	Femur (80), tibia (57), calcaneus (7), radius (5), other (13)	4/51/40^†	19	De novo (89) Recurrent (11)	Intervention: Curettage, electrocautery (n = 48). Control: Curettage (n = 114) Concomitant: Burr (63%), cement (8%), liquid N₂ (41%)	8 and 21 (p= .051)	NR
Moon et al. 2013	R	23	68 (30 - 121)	Femur (14), tibia (9)	9/78/13	0	De novo (90) Recurrent (10)	Curettage, electrocautery, burr, phenol, cement	0	4 (1 oa)
Zheng et al. 2017	R	136	87 (24 - 192)	Tibia (69), femur (67)	11/46/42	NR	NR	Curettage, burr, electrocautery, allograft (63%) or cement (37%), internal fixation (59%)	19	8,8 (8 inf, 2 #, 1 graft rejection, 1 joint fluid leakage)
Şirin et al. 2019	R	79	47 (24 - 96)	Femur (29), tibia (25), radius (9), humerus (5), pelvis (5), other (6)	13/40/47		De novo (66)Recurrent (34)	Cycles of curettage, burr, electrocautery. Cement. Internal fixation (14%)	5	3 (2 inf)
Tuntarattana-pong et al. 2021	R	28	40 (10 - 156)	Femur (12), tibia (8), other (8)	0/0/100*	46	NR	Cycles of curettage, burr, electrocauteryCement. In some: internal fixation	11	7 (1 oa, 1 inf)
Adams et al. 2010	CR	1	6	Femur (1)	0/100/0	0	De novo	Curettage, burr, electrocautery, allograft	0	0
Silva et al. 2016	CR	1	12	Femur (1)	0/100/0	0	De novo	Curettage, electrocautery, autograft, cement	100	NR
Oba et al. 2016	CR	1	96	Femur (1)	0/0/100	0	Twice recurrent	Curettage, electrocautery	100	100 (1 physeal arrest)
Conti et al. 2020	CR	1	50	Femur (1)	NR	0	De novo	Curettage, burr, electrocautery, phenol, cement, plate	0	1 (oa)
Hot liquid
Morii et al. 2008	R	29	52 (24 - 120)	Femur (13), tibia (8), radius (4), pelvis (3), humerus (1)	21/66/14	NR	NR	Curettage, burr, electrocautery, hot water (60°C, 5 min), allograft (90%)	24	10 (3 #)
Waikakul et al. 2015	R	21	55 (50 - 71)	Radius (5), tibia (4), femur (3), sacrum (2), other (7)	52/38/100	71	De novo (62)Recurrent (38)	Curettage, burr, electrocautery, hot ringer lactate (50°C, 20 min). Autograft, cement (24%), internal fixation (57%)	9.5	5 (1 hematoma requiring surgery)

#: fracture at baseline; *: Enneking Grade instead of Campanacci; ^†: Remainder of tumor grades unknown; CR: case report; CS: case series; FU: duration of follow-up; Grade: Campanacci grade I/grade II/grade III; inf: infection; Min: minutes; mo: months; MWA: microwave ablation; n: number of subjects; N/A: not applicable; NR: not reported; oa: osteoarthritis; R: retrospective cohort study; Recur: local recurrence.

Microwave ablation

On microwave ablation, three retrospective cohort studies were found. Jiao et al. inserted microwave needles into GCTB and ablated for 3 to 5 min at 100 W, followed by intralesional curettage and electrocauterization.¹¹ Ke et al. inserted a microwave antenna into the tumor and heated the tissue to 100°C before performing curettage as well.¹² Jiang et al. used microwave ablation during curettage surgeries, aiming for 70°C, adjusting power up to 100 W to achieve visually fully burned tissue.¹³ Local recurrence rates were 10%, 4% and 0% respectively after a mean follow-up of 29, 60 and 64 months. Musculoskeletal Tumor Society scores (MSTS, a function measure, only taken postoperatively) were mean 24, median 27.7 and mean 27.5 out of a maximum of 30.^11–13 Complications, listed in Table 1, included fat liquefaction, osteonecrosis of the femoral head, tissue rejection reactions, fracture and infection. None of the studies reported data on the secondary outcomes ‘pain’ and ‘quality of life’.

One case series was published on percutaneous microwave ablation without curettage. Two patients with pelvic GCTB were treated with three to five sessions, where bisphosphonate and cement were percutaneously inserted through a cannula as well. No recurrences were seen after 30 months. Surgery was avoided and pain reduction was achieved.¹⁴

Percutaneous RFA

The literature search yielded three articles on the use of percutaneous RFA: two case reports on de novo GCTB and one retrospective cohort study with one case of recurrent GCTB, among other diagnoses. Percutaneous RFA was done for pain relief in unresectable sacral GCTB.^15,16 A probe was inserted into the tumor under computed tomography (CT) guidance and the tissue was ablated at 90°C for 6 min followed by cement insertion through a cannula. Pain reduction of ≥4 points on a Visual Analogue Scale (VAS) was achieved after two sessions. The duration of follow-up was 24 months.

Another case report described percutaneous RFA as a neoadjuvant treatment 2 weeks prior to curettage. Ablation was performed with an inserted electrode for four cycles of 3 min at 150 W at about 100°C, under ultrasound monitoring instead of CT. No recurrences or complications were reported after 20 months.¹⁷

Another study reported percutaneous RFA in one case of unresectable recurrent GCTB. An electrode was used to apply 100 W for 30 s at a time. Total time and target temperature were not reported. Pain score was reduced from a VAS 7 preoperatively to 3 post-procedurally and 1.6 at final 42-months follow-up, without complications. Tumor size was reduced and stable.¹⁸ None of the studies reported function or quality of life. Kaur et al. reported treating five recurrent GCTB cases with RFA, however, the results were not published.¹⁹

Argon cauterization

Three uncontrolled cohort studies used argon cauterization to treat the cavity lining during intralesional treatment of CGTB. Lewis et al. combined this with burring and cement injection in 37 patients resulting in an 8.3% recurrence rate after a mean follow-up of 73 months.²⁰ Ofluoglu did the same with the addition of phenol (n = 24), reporting a recurrence rate of 4% after a mean follow-up of 34 months.²¹ Benevenia et al. treated 42 patients with argon beam photocoagulation and burring, hydrogen peroxide lavage, and reconstructed with cement and/or allograft. A recurrence rate of 26% was found after a mean follow-up of 56 months.²² Tissue temperature was not reported in these studies. However, with argon cauterization a maximum of 205°C can be reached.²³ Complication rates were 17%–29%: primarily fractures, delayed wound healing, infection, and secondary osteoarthritis. Mean MSTS scores, only measured postoperatively, ranged from 25.7 to 28.

Seven case reports and case series were found, as follows. Argon beam coagulation was used after curettage for one sacral and one lumbar vertebral GCTB without causing permanent neurological damage and without recurrence after 60 and 74 months, respectively.²³ Two cases of metatarsal GCTB were treated with cycles of argon beam coagulation and burring and hydrogen peroxide, without recurrences after 27 and 33 months.⁴ Argon cautery was used during curettage of a distal femoral GCTB in combination with (neo-)adjuvant denosumab; no recurrences had occurred after 15 months, without pain and with significant functional improvement.²⁴ Five proximal fibular GCTB cases were treated with minimally invasive osteoscopic surgeries including cycles of argon plasma cauterization; no recurrences were found after range 24–26 months follow-up.²⁵ Argon beam coagulation was used with curettage in a complex periprosthetic proximal tibia GCTB case without recurrence after 20 months.²⁶ A recurrence was seen in one femoral case where argon coagulation was also used in the initial intralesional treatment: it recurred after 12 weeks and became malignant and metastasized, necessitating amputation and palliative treatment.²⁷ One recurrence was also seen among six de novo cases that were treated with curettage including argon beam coagulation and H₂O₂, over a mean follow-up of 35 months.²⁸

Electrocautery

Eight retrospective studies reported on electrocautery during intralesional curettage. Only one study had a control group treated by curettage without electrocautery. However, these groups may not be comparable due to a variety of other adjuvants used. There was no statistically significant difference in recurrence rate (8% vs 21%, p = 0.51).²⁹ The other cohort studies, which were noncomparative, reported various procedure regimens.^30–36 Typically, cycles of burring and electrocauterization were followed by different combinations of other adjuvants, cement, and instrumentation. No target or actual temperature for the electrocauterization was reported by any of the authors: most reported visual endpoints such as blackening of tissue or normal appearance after cauterization and burring. Recurrence rates ranged from 0 to 46% after range 10–192 months follow-up. Complications included osteoarthritis, infection, and fractures. Limited data were reported on pain and function; none on quality of life.

Four case reports were found on curettage with electrocautery. A distal femoral GCTB - with unusual complete coagulative necrosis on histopathologic analysis - did not recur after 6 months of follow-up.³⁷ A femoral neck GCTB did recur after 1 year.³⁸ A 9-year-old child with two prior GCTB recurrences of the distal femur did not recur a third time after 96 months follow up. Premature physeal closure did occur.³⁹ One other distal femoral case also did not recur after 50 months follow-up.⁴⁰

Hot liquid

Hot liquid was used in two studies. Morii et al. let 60°C water sit in the cavity for 5 min after curettage, burring, electrocauterization and followed by allograft insertion. The recurrence rate was 10% after a mean follow-up of 52 months. Complications were reported in 10%: all postoperative fractures.⁴¹ Waikakul et al. used hot Ringer’s lactate solution as an adjuvant after curettage via continuous infusion into the cavity for 20 min at 50°C. This resulted in a 9.5% recurrence rate after median follow-up of 55 months, with 5% complications.⁴²

Discussion

This review evaluated the effect of heat treatments on recurrence in GCTB patients, as this rare condition has a tendency to recur despite the use of adjuvant treatments. This review identified various heat treatment methods; intralesional and percutaneous, with and without other concurrent interventions, in diverse groups of patients. Recurrence rates were similar to those in the general literature (0%–26% for intralesional treatment with various adjuvants).^2,43 In orphan diseases it is difficult to prove causality between treatment and outcome as studies are often small, retrospective, uncontrolled and heterogenous, as was the case in this review. As a result, an effect of heat treatments on the risk of recurrence in GCTB could not be demonstrated or excluded, and routine use in clinical practice is not supported by these findings.

Biologically, it is plausible that heat would lower the risk of recurrence by eliminating residual tumor cells from the cavity. For bone and for disease (GCTB), cell death begins at 47°C and the potential for regeneration is eliminated at 70°C.^44–47 Above 105°C, ablation becomes less effective due to tissue vaporization and carbonization.¹⁸ The extent of thermal damage depends on tissue, temperature and exposure time. All treatments studied reached the effective temperature range. The hot liquid techniques were on the low end, necessitating longer exposure time.

Thermal damage to surrounding tissues is a concern. Neural tissue can be permanently damaged above 45°C and chondrocytes above 50°C.^48,49 Ex vivo studies prove that intact bone does not conduct heat well, hence protecting surrounding structures.^50,51 Vascular flow nearby the target site can also lead to dissipation of thermal energy. Intra-articular or intralesional cooling and maintaining a safe distance can further mitigate risk.

Complications found in this review included no permanent neural damage. Osteoarthritis was seen in some cases. Notable complications of microwave ablation were fat liquefaction and femoral head necrosis. With argon and electrocauterization, the main postoperative complications were wound problems, infection, fractures and osteoarthritis. It is unclear if the described complications are attributable to the disease itself, the operation(s), the adjuvants, and/or the heat treatment. No complications of RFA were reported. With regard to the safety of RFA, it is reassuring that it is a well-established treatment for other osseous lesions. In osteoid osteoma, about 2% of patients have a complication (skin or muscle burn).⁵² In treatments with hot liquid, lower temperatures where used (50 – 60°C) than in other heat therapies, precluding some of the heat-related complication risks. Longer term complications can be missed by the short follow-up that was primarily focused on detecting recurrences. Adverse effects of heat should be weighed against the risks associated with other treatment forms: chemical damage from phenol, thermal damage from cryotherapy, and thermal damage from heat produced by cement as it polymerizes.

The secondary outcome measures pain, quality of life and physical function are important considerations in the setting of a benign, localized disease. Only a few studies reported adequate data on these clinically relevant outcomes. For unresectable GCTB, three case reports documented successful pain palliation with percutaneous RFA. These preliminary results are in keeping with the known beneficial effects of RFA on pain in metastatic bone disease and osteoid osteoma.^52,53 Overall, information regarding the effect of heat treatment on pain, physical function and quality of life was lacking and therefore could not be assessed.

Limitations of this study are suspected selective reporting and publication bias, selection bias, and loss to follow-up. Publication bias is suspected given the favorable outcomes in most case reports. Follow-up time was short, as only about 70% of GCTB recurrences happen in the first 24 months.⁵⁴

Despite the lack of definitive conclusions, findings of this review can serve as a starting point for the continued research into heat treatment for de novo, residual and recurrent GCTB. Treatment specifications such as optimal temperature, exposure time and frequency have so far been based on in vitro studies and need to be optimized.^40,41 Anecdotal evidence identified in this review suggests that heat treatments can be a suitable alternative or adjuvant to standard treatments in specific patient categories. Overall, the optimal choice of treatment regime for CGTB is multifactorial, including age, anatomical location, tumor size, progression, joint involvement, symptoms, and patient and provider preference.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Carlijn Schoutens

Floortje GM Verspoor

Addendum A

Search terms: (radiofrequen* OR ablation OR thermal OR microwave OR argon OR electrocauter* OR electrotome OR plasma beam OR coagulat* OR cauteriz* OR cauteris*) AND (giant cell tumor of bone OR giant cell tumour of bone OR giant cell tumor OR giant cell tumour OR osteoclastoma)

Addendum B

Table 2.

Appraisal of cohort studies using MINORS criteria.

Study by first author	Items for noncomparative and comparative studies								Sum	Additional items for comparative studies				Sum
Study by first author	1	2	3	4	5	6	7	8	Sum	9	10	11	12
Koo	2	2	1	2	0	2	2	0	11	-	-	-	-	-
Jiao	2	2	1	2	0	2	2	0	-	2	2	0	1	16
Ke	2	2	1	2	0	2	1	0	10	-	-	-	-	-
Jiang	1	1	1	1	1	1	2	0	8	-	-	-	-	-
Lewis	2	2	1	2	0	2	2	0	11	-	-	-	-	-
Ofluoglu	1	2	1	2	0	2	0	0	8	-	-	-	-	-
Benevenia	2	2	0	2	0	2	1	0	9	-	-	-	-	-
Ward Sr	2	2	1	2	0	2	1	0	10	-	-	-	-	-
Saiz	2	2	1	1	0	2	1	0	9	-	-	-	-	-
Suzuki	2	2	2	2	0	2	1	0	11	-	-	-	-	-
Xing	1	1	1	1	0	2	0	0	6	-	-	-	-	-
Moon	1	1	1	2	0	2	0	0	7	-	-	-	-	-
Zheng	2	1	2	2	0	2	2	0	11	-	-	-	-	-
Şirin	2	2	1	2	0	2	2	0	11	-	-	-	-	-
Tuntarattanapong	2	2	1	2	0	2	2	0	-	2	2	1	2	18
Morii	2	2	1	1	0	2	0	0	8	-	-	-	-	-
Waikakul	2	2	2	1	0	2	2	0	11	-	-	-	-	-

0: not reported; 1: reported but inadequate; 2: reported and adequate.

Table 3.

Appraisal of case reports and case series.

Study by first author	Items JBI checklist								Additional item
Study by first author	1	2	3	4	5	6	7	8	FU >24 months?
Santiago	N	N	N	N	Y	N	N	Y	Y
Zhao	Y	N	Y	Y	Y	Y	Y	Y	N
Luna	Y	N	Y	Y	Y	Y	U	Y	Y
Takeda	Y	N	Y	Y	Y	Y	Y	Y	Y
Bibbo	Y	Y	Y	Y	Y	Y	U	U	Y
Menon	Y	N	Y	Y	Y	Y	N	Y	N
Futani	Y	N	Y	Y	Y	Y	U	Y	Y
Chen	Y	Y	Y	Y	Y	Y	Y	Y	N
Donigian	Y	Y	Y	Y	N	Y	Y	Y	N
Sukpanichyingyong	Y	N	N	N	Y	Y	Y	N	Y
Adams	Y	Y	Y	Y	Y	Y	Y	Y	N
Silva	Y	N	Y	Y	Y	Y	Y	Y	N
Oba	Y	Y	Y	Y	N	N	Y	Y	Y
Conti	Y	N	N	Y	Y	Y	Y	Y	Y

FU: follow-up; Y: yes; N: no; U: unknown.

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