|Year : 2020 | Volume
| Issue : 5 | Page : 1020-1026
Comprehensive treatment for multicentric giant cell tumors of the pelvis and spine using apatinib: A case report and literature review
Jun Li1, Jun Zhou2, Yuntong Liu3, Xiaogang Sun2, Wei Song2
1 Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University; Li Chengli Innovation Studio, Jinan, China
2 Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
3 Department of Chemistry and Biochemistry, University of California, Santa Barbara, California, USA
|Date of Submission||20-Oct-2019|
|Date of Decision||12-May-2020|
|Date of Acceptance||21-Jul-2020|
|Date of Web Publication||29-Sep-2020|
Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021
Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021
Source of Support: None, Conflict of Interest: None
Background: There are no standardized treatments for giant cell tumors of the bone (GCTB) in rare locations such as the spine and pelvis or for those that are inoperable and recurrent, let alone for multicentric GCTB. This study reports a novel case of multicentric GCTB treated with a promising antiangiogenic drug, apatinib, a small-molecule tyrosine kinase inhibitor. The efficacy of apatinib in the treatment of GCTB has not been reported previously.
Patients and Methods: A 27-year-old female presented with two giant cell tumors of the spine and sacrum–ilium diagnosed on December 15, 2016. Surgery and selective arterial embolization (SAE) were not reasonable options for this patient, and denosumab was unavailable; therefore, the antiangiogenic drug apatinib and the osteoclast inhibitor zoledronic acid were administered. Apatinib was initially administered at a dose of 850 mg daily, which was decreased to 425 mg daily after 7 months, and then increased again to 635 mg after 11 months. The patient was prescribed a maintenance dose of 500 mg daily after 16 months. The patient reported side effects of Grades I–III nausea, vomiting, and Grades II–III hand–foot syndrome. The patient underwent SAE at 26 months, and at that time, she was switched to denosumab instead of zoledronic acid.
Results: The patient showed noticeable symptomatic improvement and visibly reduced tumor size after the first month of treatment. Computed tomography in the 4th month identified a partial response based on the RECIST criteria. The patient has achieved an objective reduction in tumor size at 32 months.
Conclusions: Comprehensive treatment including apatinib represents a potential new treatment strategy for inoperable GCTB, with tolerable side effects. However, further clinical trials are now necessary to confirm an effective dose and determine the efficacy and safety of apatinib in the treatment of GCTB.
Keywords: Apatinib, denosumab, multicentric giant cell tumor of the bone, selective arterial embolization, zoledronic acid
|How to cite this article:|
Li J, Zhou J, Liu Y, Sun X, Song W. Comprehensive treatment for multicentric giant cell tumors of the pelvis and spine using apatinib: A case report and literature review. J Can Res Ther 2020;16:1020-6
|How to cite this URL:|
Li J, Zhou J, Liu Y, Sun X, Song W. Comprehensive treatment for multicentric giant cell tumors of the pelvis and spine using apatinib: A case report and literature review. J Can Res Ther [serial online] 2020 [cited 2020 Oct 30];16:1020-6. Available from: https://www.cancerjournal.net/text.asp?2020/16/5/1020/296452
| > Introduction|| |
The nature of giant cell tumor of the bone (GCTB) remains controversial. This tumor was originally described as a malignant myeloid sarcoma and subsequently reclassified as a benign tumor because metastasis and associated death are rare. As defined by Jaffe in 1940, GCTB is a neoplasia in the supporting connective tissue of the marrow comprising ovoid stromal or spindle-shaped cells, interspersed with multinuclear cells. Compared with common benign tumors, GCTB is locally aggressive, destroying bone as well as overlying soft tissue. GCTB can metastasize to other parts of the body, particularly the lung, although this is rare. Furthermore, GCTB has a high recurrence rate after surgical removal. Refractory and unresectable GCTB can undergo malignant transformation, particularly in patients undergoing radiotherapy.
Current treatment strategies of GCTB are based on retrospective studies rather than on randomized clinical trials. The first choice of treatment in the extremities is intralesional excision. Nonsurgical treatments of GCTB can include external beam irradiation (EBI), selective arterial embolization (SAE), bisphosphonates, and denosumab. Owing to radiation-induced malignant transformation, the currently preferred treatment option is SAE whenever surgery is not possible. However, there is no consensus regarding the treatment of GCTB in rare locations, such as the small bones, pelvis, or spine as well as multicentric GCTB, most likely because of its rarity, limited surgical accessibility, and proximity of the tumor to nerve roots. Multicentric GCTB is defined as two or more separate giant cell tumor bone lesions confirmed by histopathology. From 1950 to 2002, only 48 cases of multicentric GCTB were documented as case reports or small case series,
Here, we report a case of multicentric cell tumor of the spine and sacrum–ilium diagnosed on December 15, 2016, for which surgery and SAE were not feasible options and denosumab was unavailable. Comprehensive treatment for this patient included an oral antiangiogenic drug, apatinib, and an osteoclast inhibitor, zoledronic acid. The patient had 26 months of progression-free survival (PFS) prior to a shift in the treatment strategy to SAE and denosumab. Currently, the patient demonstrates 32 months of PFS at the time of writing this manuscript. To the best of our knowledge, this is the first known case of GCTB that responded to comprehensive treatment including apatinib.
| > Case Report|| |
We report the case of a 25-year-old female who was admitted progressive chest pain on December 15, 2016. Computed tomography (CT) showed a large, heterogeneously enhanced mass lesion with small pieces of bone density in the thoracic cavity, which originated from the vertebral body and accessories of the 8th thoracic vertebra. The size of the mass was 17.17 cm × 16 cm × 18.5 cm. Several small necrotic areas within the mass diverged from the thoracic vertebra. Some pleural effusion was identified around the mass [Figure 1]a and [Figure 1]b. Whole-body CT revealed another large, heterogeneously enhanced mass lesion in the region of the left sacrum–ilium [Figure 1]c. Emission CT confirmed radioactive concentrations limited to the bones identified above. Biopsy subsequently confirmed the diagnosis of GCTB. Immunohistochemical staining results were CD68+ (multinuclear cells), P63+ (mononuclear cells), SMA+ (mononuclear cells), and Ki-67+ (active proliferation, approximately 5%). Multidisciplinary team consultations with a bone oncologist, a thoracic surgeon, and a vertebral surgeon did not recommend surgical treatment. An angiogram showed a rich blood supply within the lesion but failed to detect significant tumor-feeding arteries; consequently, SAE was not feasible [Figure 1]d. Furthermore, denosumab was not approved for use in the geographical region of the patient (mainland China). Because the antiangiogenic drugs endostatin and sorafenib have been shown to prevent the recurrence of osteosarcoma and metastasis and this GCTB demonstrated a rich blood supply similar to that of osteosarcoma, we decided to initiate antivascular therapy. However, the patient refused sorafenib and sunitinib for financial reasons.
|Figure 1: (a and b) A large heterogeneously enhanced mass lesion with small pieces of bone density in the thoracic cavity. Several small necrotic areas within the mass diverged from the thoracic vertebra. Some pleural effusion was identified around the mass. (c) Another large heterogeneously enhanced mass lesion in the left sacrum–ilium region. (d) Angiogram showing a rich blood supply within the lesion without main tumor-feeding arteries|
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Apatinib is a novel, potent, oral small-molecule tyrosine kinase inhibitor that targets the intracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2). Furthermore, apatinib may also be active on Ret, c-Kit, and c-Src tyrosine kinases. In clinical trials, apatinib has exhibited survival benefit for patients with gastric and non-small-cell lung cancer and is under investigation in multiple tumor types including breast cancers and liver cancers.,, The use of apatinib for the treatment of several tumors, including pleomorphic liposarcoma and melanoma, has been reported.
Given the tolerable side effects and remarkable therapeutic efficacy of apatinib, it may serve as a novel treatment strategy for other types of tumors. Based on these attributes, lower financial burden that it represented, and potential for long-term survival of the patient with GCTB, apatinib was considered superior to other antiangiogenic drugs for this patient. Oral apatinib (850 mg/day) and zoledronic acid (venous inflow, 4 mg/21–28 days) were administered. This treatment was approved by the Ethics Committee of Shandong Provincial Hospital Affiliated with Shandong University. Written informed consent was obtained from the patient. Apatinib was initiated orally at 850 mg per day on the December 21, 2016. As determined using CT scan after 29 days, tumor volume decreased by approximately 22%, with inner liquid density areas suggesting increased necrosis and enlarged necrotic lesions. A CT scan at the 4th month of treatment identified a partial response according to the response evaluation criteria in solid tumors. However, the patient reported side effects of grades I–III nausea, vomiting, and grades II–III hand–foot syndrome. The dose of apatinib was subsequently reduced to 635 mg in the 6th month and further to 425 mg in the 7th month. The dose was increased again to 725 mg in the 11th month, after detection of a slight enlargement of the mass. The size of the tumor was significantly reduced in the 14th and 16th months [Figure 2]a, [Figure 2]b, [Figure 2]c. The dose was then reverted to 500 mg after the 16th month, and the tumor cancer was evaluated as stable disease by CT review in the 18th month (April 2018). Re-examination of angiography showed a decreased blood supply and many necrotic areas within the mass. No significant tumor-feeding arteries were detected [Figure 2]d. After 26 months of PFS with apatinib and zoledronic acid, the patient was eager to undergo operation, but no surgeon answered her. The patient underwent an unsuccessful SAE procedure (data not shown) on February 8, 2019. From that time, the patient began taking denosumab instead of zoledronic acid; a slight reduction of the thoracic mass (9.2 cm × 9.5 cm on June 25, 2019, almost 25% of the primary volume) and stable state of sacrum–ilium lesion [Figure 3] were observed. Subsequently, the patient effectively achieved a state of tumor reduction for 32 months, but, and currently, she still struggles with GCTB.
|Figure 2: CT scan after 16 months of Apatinib treatment. (2A and 2B) the previous large, heterogeneously enhancing mass lesion with small pieces of bone density in the thoracic cavity was greatly reduced to 10cm*10cm*11cm in size. Most of them were necrotic areas in the mass. No pleural effusion was found around the mass. (Fig. 2C) another large, heterogeneously enhancing mass lesion in left sacrum-ilium region was not changed much. (Fig. 2D) an angiogram showed not as rich blood supply as before in the lesion and failed again to detect the main tumor-feeding arteries into the mass. 2D 1-5 showed arteries surrounded the lesion without entering the lesion.|
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|Figure 3: (a) The patient's thoracic mass is 9.22 cm × 9.55 cm on June 25, 2019, a reduction of almost 75% of initial volume. (b) The lesion in the sacrum–ilium remains in a stable state|
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| > Discussion|| |
Although deemed pathologically benign, GCTB can be locally aggressive and destroy bone as well as overlying soft tissue. In addition, it can metastasize to other parts of the body, especially the lung. This type of tumor is also associated with a high recurrence rate after surgical operation. Therefore, it is evident clear that the histopathological features of GCTB may not clearly predict clinical behavior, including the risk of recurrence or metastasis.
When possible, intralesional excision is the treatment of first choice for GCTB. Systemic therapy has been used to facilitate intralesional surgery in more complex cases to minimize mutilating surgery at a later stage. However, recurrence of disease mostly depends on the thoroughness of surgery. Nonsurgical treatment options include EBI, SAE, bisphosphonates, and denosumab. However, recommendations for the treatment of GCTB in the extremities are based on retrospective reports rather than on randomized clinical trials. Currently, only denosumab has been assessed in open-label, phase II prospective clinical studies, and based on promising results in these trials, denosumab has been marketed for the treatment of GCTB. In contrast, use of other therapeutic methods including surgery, SAE, and zoledronic acid is solely based on retrospective studies. There is currently no uniform standardized treatment for GCTB. Therefore, a comprehensive strategy for the treatment of GCTB that reduces local recurrence and preserves the native joint must be a priority.
As a benign tumor, GCTB should be surgically removed as necessary. Ideally, all patients should be treated with intralesional excision along with local adjuvant therapy, e.g., phenol, liquid nitrogen, or polymethyl-methacrylate (PMMA) to salvage the joint, achieve optimal functional outcomes, and reduce recurrence rates, similar to results after en bloc resection. The current established treatment with acceptable recurrence rates is curettage with local adjuvant application involving either phenol and PMMA (3%–33%) or PMMA alone (0%–29%). Medical centers specializing in cryosurgery apply liquid nitrogen with bone grafts to the residual surgical cavity and report recurrence rates of 8%–42%. In general, curettage with PMMA can be repeated after recurrence, as this strategy achieves acceptable re-recurrence rates of 14%–22%. Considering the points mentioned above, en bloc resection should only be conducted in cases of multiple recurrent or unresectable GCTB, impossible joint salvage, extensive cortex destruction leaving insufficient cortex to curette, or extensive soft tissue invasion. En bloc resection requires reconstruction with a large segment allograft or prosthesis. In one report, aggressive curettage and cement filling using internal fixation of the distal femur to GCTB and oral bisphosphonates resulted in no recurrence after a median follow-up of 28 weeks. Aggressive curettage may be performed in limb GCTB cases with limited tumor localization and invasion but without pathological fracture. However, there remains a lack of uniform surgical recommendations regarding aggressive curettage.
Although the surgical treatment of limb GCTB can be successful, it is more challenging in the axial skeleton and sacrum (2%–8% of all GCTBs). In these areas, GCTBs are often discovered late, when the tumor is large in size, with spinal or pelvic instability and nerve root invasion. In these locations, local adjuvants such as bone cement, phenol, or cryotherapy have limited use owing to their toxic effects on nervous tissue. When this type of tumor affects the thoracic wall, the surgical procedure is technically more complex. The reported size of the largest thoracic GCTB successfully treated by surgery was 11 cm × 4 cm × 13 cm. En bloc resection is the gold standard for giant cell tumor of the spine and sacrum with a curative rate of 90%. However, the feasibility of intralesional surgery depends on the involvement of neurovascular structures and soft tissue extension. Even resection is difficult when the spinal cord and large vessels are involved. If en bloc resection is not applicable, poor resection, without disease-free margins of the tumor, reduces the curative rate to 50%. Furthermore, we cannot ignore the sacrifice of neurological function after this type of surgery, including loss of bowel and bladder control or sexual dysfunction. Systemic therapy can be used when surgery is not possible or as an adjunct during the perioperative period.
Selective arterial embolization
SAE has proved to be a reasonable treatment option for GCTB because it reduces tumor size and/or induces ossification, affording pain relief and further surgical opportunities. However, in most of the previously published reports, SAE was used as an adjuvant for preoperative treatment followed by surgery, with few patients receiving SAE as a major treatment modality.,
SAE treatment of limb GCTB is relatively simple compared with that of the spine and pelvis, in which the main blood supply vessels can be difficult to locate. Xiao et al. systematically reviewed the application of SAE for giant cell tumor of the sacrum and pelvis in 2017. This systematic review included 44 patients (34 females and 10 males) with a mean age of 34.4 years (range: 15–68 years). Further, 41 (93.2%) patients had lesions in the sacrum, whereas four had lesions in the ilium (1 had giant cell tumor of both the sacrum and pelvis). SAE was administered between one and ten times. During the follow-up period (mean: 85.8 months), the radiographic response rate was 81.8%, with an overall survival (OS) rate (81.8%) being slightly higher than that of local controls (75%). No incidences of bowel, bladder, or sexual dysfunction were observed. Three patients developed distant metastases and died. The results indicated that SAE may serve as an alternative treatment for GCTBGCT patients for whom surgery is not appropriate.
Bisphosphonates bind to bone minerals, inhibiting the proliferation and migration of GCTB-derived osteoclasts at sites of bone resorption and subsequently promoting the apoptosis of osteoclasts. For the past few decades, bisphosphonates have been used as a systemic therapy for GCTB. For most inoperable tumors, it is possible to achieve stabilization of localized bone. Tse et al. conducted a retrospective controlled study including 44 GCTB patients, of whom 24 received two courses of preoperative and three courses of postoperative intravenous pamidronate disodium or zoledronic acid, followed by 3 months of oral clodronate disodium. During the follow-up period of 48–115 months, the recurrence rates for drug treatment and control groups were 4.2% (1/24) and 30% (6/20), respectively. In a separate study, aggressive curettage with cement filling and internal fixation on the distal femur plus oral bisphosphonates resulted in no recurrence at follow-up (median: 28 weeks). Recently, Shi et al. performed a meta-analysis on the effect of bisphosphonates on local recurrence of GCTB, which confirmed that the effects of bisphosphonates on reducing the local recurrence of GCTB are not influenced by tumor grade. Currently, a phase II randomized study using postoperative zoledronic acid is on-going in high-risk GCTB patients.
Denosumab is a fully human monoclonal antibody specific for the receptor activator of nuclear factor kappa B ligand (RANKL). The immature state of neoplastic stromal cells depends on the formation of giant cells, whereas the formation of giant cells reciprocally depends on RANKL signaling by stromal cells. Moreover, denosumab acts similarly to osteoprotegerin to eliminate giant cells, thus diminishing osteoclast activity and increasing sclerosis and reconstitution of cortical bone. Denosumab is approved to treat osteoporosis in postmenopausal women at risk for fracture, patients with prostate or breast cancer who have bone loss due to androgen deprivation therapy or aromatase inhibitor therapy, and to prevent skeletal related event in patients with bone metastases from solid tumors.
Denosumab is effective in GCTB disease prevention and progression in reducing tumor size, thus permitting further surgical opportunities. Denosumab directly binds to human RANKL and potently inhibits osteolysis driven by human RANKL. The first open-label, one-arm phase II study of denosumab for the treatment of recurrent or unresectable GCTB was conducted in 2010 and demonstrated clear clinical benefit. There was an objective response to denosumab therapy in 86% of patients (30 of 35) investigated, which was defined as 90% elimination of giant cells by histological evaluation (20 of 20 cases) or by the absence of radiographic progression of the lesion (10 of 15 cases). Only a minority of these patients underwent intralesional surgery after denosumab treatment. Using conventional radiographs and CT, sclerosis and reconstitution of cortical bone were observed after denosumab treatment. Furthermore, reduced uptake was observed by fluorodeoxyglucose-positron emission tomography (FDGFDG-PET), indicating that FDG-PET may also be a sensitive tool. It remains unclear whether local recurrence rates can be lowered by denosumab treatment, although data from longer follow-up assessments may address this issue. In 2012, an associated histological study was published, in which 20 of 20 patients (100%) showed a reduction of 90% or more in tumor giant cells and a reduction in tumor stromal cells by histopathological analysis. In addition, 13 (65%) patients were found to have an increased proportion of dense fibroosseous tissue and/or new woven bone, instead of proliferating RANKL-positive stromal cells.
An interim analysis of a second and larger study (n = 282) was published in 2013 and confirmed a high degree of efficacy of denosumab treatment for giant cell tumor of the long bones. Patients were divided into three cohorts: those with surgically unsalvageable GCTB (cohort 1); those with salvageable GCTB whose surgery was associated with severe morbidity (cohort 2); and those who transferred from a previous study of denosumab for GCTB (cohort 3). Analyzable patients in cohort 1 had no disease progression after a median follow-up of 13 (range: 5.8–21.0) months. In cohort 2, 74 of 100 (74%) analyzable patients with tumors requiring morbid surgery at study entry did not require surgery at the end of the trial. However, 16 (62%) of 26 patients who received surgery underwent a less morbid procedure than that initially planned. The median follow-up in cohort 2 was 9.2 months. Based on this study, denosumab was approved by the U. S. Food and Drug Administration for the treatment of adults and skeletally mature adolescents with GCTB that was inoperable or when surgical resection was likely to result in severe morbidity. At the time of writing this manuscript, denosumab was still not approved in Mainland China.
Other studies have investigated the use of denosumab as a neoadjuvant or adjuvant. Van et al. proposed that 3–44 months of neoadjuvant denosumab be incorporated in the standard multidisciplinary treatment of patients with advanced GCTB who are not candidates for primary curettage. Recently, the efficacy of preparative denosumab in achieving prospectively decided intention of therapy in operable GCTB patients and local recurrence-free survival was evaluated. Local control rates were found to be unlikely to improve with the use of preoperative denosumab; however, a short preoperative course of denosumab facilitated surgery in certain cases of operable GCTB, with a high risk of local recurrence making curettage or resection technically easier. Luengo-Alonso et al. reported that the use of denosumab as an adjuvant treatment in GCTB exerted a positive but variable histological response, with consistent radiological changes and several types of adverse effects.
The most important side effects of denosumab were headache and bone pain (1%–10% of cases), osteonecrosis of the jaw (1%–2% of cases), and hypocalcemia and hypophosphatemia (0.01% of cases). On the other hand, serious adverse effects were observed during high-dose denosumab therapy in young people with GCTB, which suggested that weight-adjusted dosing and safety monitoring during and after antiresorptive therapy are required in young patients.
Considering most cases involving malignant transformation of GCTB arise as a result of radiotherapy, moderate-dose radiotherapy (40–55 Gy) is restricted to rare cases and is only appropriate when surgery would lead to unacceptable morbidity or when RANKL inhibitors are contraindicated or unavailable.
Like osteosarcoma, large GCTB lesions exhibit a quality during surgery that suggests an abundant arterial blood supply; this provides a rationale for the use of SAE. A large degree of neovascularization within the lesion can also imply the potential usefulness of antivascular therapy. The endovascular inhibitor endostatin and multitarget inhibitor sorafenib are recommended for the treatment of osteosarcoma in China. However, no reports in the existing literature relate to the use of antiangiogenic treatment for GCTB.
VEGF plays a key role in the development of carcinoma via ligation of VEGFRs. Apatinib, a small-molecule antiangiogenic agent, exerts its inhibitory effect by binding to VEGFR-2 and inhibiting phosphorylation of the extracellular signal-regulated kinase. The inhibitory effect of apatinib is strong for VEGFR-2 and moderate for c-Kit and c-Src tyrosine kinases. Apatinib was first assessed in a randomized phase II trial in China for advanced or metastatic gastric cancer after the failure of chemotherapy. Patients were divided into three study groups: a placebo group and groups given 850 mg apatinib once daily or 425 mg twice daily. The median OS times were 2.50 (95% confidence interval [CI], 1.87–3.70) months, 4.83 (95% CI, 4.03–5.97) months, and 4.27 (95% CI, 3.83–4.77) months, respectively, and PFS times were 1.40 (95% CI, 1.20–1.83) months, 3.67 (95% CI, 2.17–6.80) months, and 3.20 (95% CI, 2.37–4.53) months, respectively. The PFS and OS of the two apatinib groups were significantly better than those of the placebo group. In the current clinical trials, apatinib is used either alone or in combination with chemotherapeutic agents for various solid tumors. The development of intrahepatic cholangiocarcinoma (ICC) relies on the interaction between VEGF and VEGFR-2, and this signaling pathway is targeted by apatinib. Treatment of metastatic triple-negative breast cancer (TNBC) is challenging owing to drug resistance. In a phase IIb prospective, open-label study, all 59 patients with TNBC were treated with apatinib at a dose of 500 mg/day. The mean PFS and OS were 3.3 and 10.6 months, respectively. Another study retrospectively assessed the efficacy and safety of apatinib in patients with advanced/metastatic NSCLC who failed more than two lines of treatment and apatinib reported that the objective response rate was 18.2% and the disease control rate was 95.5%. The median PFS and OS were 203 (95% CI, 120–269) days and 227 (95% CI, 146–294) days, respectively. A number of case reports have evaluated apatinib in various tumor types (pleomorphic liposarcoma, malignant glioma, and melanoma). However, in the case presented here, the patient refused sorafenib and sunitinib for financial reasons. Based on the known clinical effects and financial incentive to use the drug, apatinib was selected as the best option.
| > Conclusion|| |
To our knowledge, our study is the first to use apatinib for the treatment of a multicentric giant cell tumor of the pelvis and spine. We concluded that apatinib is a reasonable therapy with acceptable side effects for unresectable GCTB. However, further clinical trials are necessary to confirm an effective dose and to investigate the efficacy and safety of apatinib for GCTB treatment.
The work was supported by a grant from Shandong Provincial Medical and Health Technology Development Plan (2017WS286). The funding organization had no role in the design or conduct of this research.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]