The relationship between recurrence and lung metastasis in giant cell tumor of bone Kemiğin dev hücreli tümörlerinde rekürrens ve akciğer metastazı arasındaki ilişki

Aim: The aim of this study is to evaluate the relationship between recurrence and lung metastasis in patients diagnosed with giant cell tumor of bone treated in our clinic and to present the other factors affecting the recurrence. Material and Methods: The patients who were treated and followed up for a giant cell tumor of the bone between 2002 and 2018 were retrospectively reviewed. A total of 114 patients with a mean age of 31.6 ± 13.3 were included in the study. Results: The mean follow-up period was 63.1 ± 33.4 months. Recurrence occurred in 26.3% (30 patients) of the patients in a mean of 17.1 months, while metastasis in the lung was found in 4.4% (5 patients). When the patients were evaluated according to their recurrence status, lung metastasis was observed in 13.3% of the patients with recurrence, while lung metastasis was observed in 1.2% of the patients without recurrence. Lung metastasis was found to be significantly higher in patients with recurrence than in the group without recurrence (p = 0.017). For lung metastasis, Hazard Ratio (HR) was calculated as 12.8 (95% CI: 1.4-119.5; p = 0.026). Conclusion: Giant cell tumors of the bone are locally aggressive tumors with unpredictable behavior. In our study, when the patients were evaluated according to their recurrence status, lung metastasis was observed in 13.3% of the patients with recurrence, and 1.2% of the patients without recurrence. Lung metastasis was found to be significantly higher in patients with recurrence than in the group without recurrence. Akciğer metastazının rekürrense kadar geçen süreler dikkate alınarak rekürrens gelişmesi üzerine olan etkisi Cox Regresyon analizi ile incelenmiştir. Akciğer metastazı için hesaplanan Hazard Ratio (HR): 12,8 (%95 GA:1,4-119,5; p=0,026) bulunmuştur. olan % 13,3' rekürrensi % 1.2' metastazı gözlendi. Akciğer metastazı, rekürrens göre derecede


Introduction
Giant cell tumor of bone is a benign but locally aggressive neoplasm involving epiphysometaphyseal junction of long bones. It consists of undifferentiated cells and a large number of multinucleated giant cells are seen. [1,2] Although histogenesis remains unclear, it is one of the most researched tumors.
It is most commonly seen in young adults aged 20-40 years.
It is rare before epiphysis closes. It is slightly more common in women than in men. [3,4] In general, it constitutes 5% of all bone tumors. [5] It is most commonly located in distal femur, proximal tibia, and distal radius. [2] The most common complaint is pain. Swelling, increased temperature, and limited range of motion in the affected joint may be associated with pain. Surrounding soft tissue involvement is also present in Campanacci grade 3 lesions.
Pathological fracture is also among the most common complaints. [6] Direct radiography is important in diagnosis. That indicates pathological fracture. The most common direct X-ray findings in the epiphysometaphyseal region are expansive mass appearance, fluid-fluid levels, geographic pattern and cortex destruction. Magnetic Resonance Imaging (MRI) is valuable in differential diagnosis and especially in Campanacci grade 3 lesions with soft tissue involvement. [7] Treatment varies according to grade and location of the tumor. The most important goal in the treatment is to provide local control. The most commonly used treatment method is curettage [8,9]. Despite an effective curettage, recurrence has been reported in the literature by 5% for grade 1 lesions, 30% for grade 2 lesions, and 80% for grade 3 lesions. [10] Giant cell bone tumor is a borderline neoplasm and metastasizes 1-9%. Publications have associated metastasis with local recurrence. [11] This reveals the importance of providing local control in primary treatment.
Giant cell tumors of the bone are metastasize to the lungs in rare cases. Previous studies tried to identify risk factors for lung metastasis by giant cell bone tumors. Those studies reported different results due to a small number of patients.
[12] The aim of this study is to evaluate the relationship between recurrence and lung metastasis in patients diagnosed with giant cell tumor of bone treated in our clinic and to present the other factors affecting the recurrence.

Material and Methods
The patients who were treated and followed up for a Confidence Interval (CI). According to Kaplan Meier method and Log-Rank test, the rates of lung metastasis development were evaluated association of the recurrence. In this study, statistical significance level was accepted as p <0.05.
In this study, 53.5% of tumors were on the right side. Other surgeries after recurrence; curettage + cryotherapy / cauterization + grafting / cementation, arthrodesis, biological reconstruction and amputation ( Table 1). Three of the lung metastases were proximal to the tibia and 2 were distal to the femur.
Complications were postoperative infection and pathological fracture. The most common postoperative complication was infection and was seen in 7% (8 patients).  Lung metastasis rates of patients according to recurrence status were also evaluated by Kaplan Meier method and Log-Rank test. Lung metastasis rates were observed to be higher in patients with recurrence than those without recurrence.

Discussion
In this study, in our orthopedic clinic specialized in cancer, we reviewed the 16-year data of patients treated with the diagnosis and treatment of giant cell tumors and analyzed the relationship between recurrence and lung metastasis. Lung metastasis was found to be significantly higher in patients with recurrence than in the group without recurrence. Accordingly, patients with recurrence have an increased 12.8 times risk of lung metastasis. Therefore, the risk factors that increase the recurrence should be well known and the local control in primary treatment should be provided.
Six different surgical procedures were performed according to the location and grade of the tumor. The most common surgical procedure was intralesional curettage. In our study, the recurrence rate was 26.3% and the complication rate was 9.6%.
In the literature, recurrence rates are reported in a wide spectrum ranging from 0% to 65% depending on the location of the tumor, size of the tumor, the stages of the patients and the types of treatment applied. While the highest recurrence rates are seen in patients undergoing only curettage, better results can be achieved by adding adjuvant therapies such as cauterization, high speed burr, phenol, liquid nitrogen, polymethylmethacrylate in addition to curettage. The best results can be obtained by en-block resection. Which patient should be treated aggressively, and which patient will be treated with curettage, this decision should be made specifically for each patient according to the location and localization of the tumor, and the surgical experience of the clinician. [13,14] Teixeira et al. investigated non-surgical factors associated with local recurrences Campanacci classification and tumor diameter increased postoperative recurrence rates. [15] In this study, the relationship between recurrence and lung metastasis was evaluated while evaluating the factors affecting recurrence. Lung metastasis was found to be high in patients with recurrence. Most studies showed that recurrence rate of giant cell tumor of bones is risk factor for lung metastasis. [16] Complication risk rates vary depending on the type of procedure being performed. Cases with pathological fractures have higher recurrence rates and lower functional outcomes. [17] The most common complication is infection and it occurs between 2% and 25% and the rate of infection after aggressive surgeries is higher. [18] In our study, the most common complication was also infection.
Giant cell tumor of bone is a disease of individuals whose epiphysis is closed; it is seen in 3% of children. An epiphyseal lesion detected in a patient with incomplete skeletal maturation is most likely chondroblastoma, while the diagnosis in the completed patient is probably a giant cell tumor. This tumor has been reported to be equal in men and women in some studies, although it is known to be a little more common in women. More than 75% of the lesions were seen in the long bones and more than 50% of all lesions were located around the knee. [14,18] In our study, the demographic data of the patients were consistent with the literature, the majority of cases were in adults (93%), the most common site was knee circumference (35%) and more frequent in women (54%).
Giant cell tumors of the bone are locally aggressive tumors with unpredictable behavior. They are local recurrenceprone tumors, rarely metastasize, and the most common metastasis is in the lungs.
Although various classifications have been described in the light of histological clinical or radiological findings related to giant cell tumors, none of them provide a prognostic idea. Jaffe et al. described a histological classification in 1940, while Campanacci et al. described a clinical and radiological classification in 1987. [19,20] We analyzed the patients according to gender, tumor direction and tumor location, and there were no significant findings.
Giant cell tumors of the bone may rarely malign, their prevalence is reported to be below 1%. [21] We did not find any patients with malignant transformation during the follow-up period.
Giant cell tumors can sometimes accompany Paget disease, especially in terms of orthopedic locations of giant cell tumors, pelvic and vertebral locations are associated with Paget disease. [22] In our data, only 5.3% of the patients were located in the pelvic / vertebral region and we did not find any Paget association.

Conclusion
Giant cell tumors of the bone are locally aggressive tumors with unpredictable behavior. In our study, when the patients were evaluated according to their recurrence status, lung metastasis was observed in 13.3% of the patients with recurrence, and 1.2% of the patients without recurrence. Lung metastasis was found to be significantly higher in patients with recurrence than in the group without recurrence. Therefore, the risk factors that increase the recurrence should be well known and careful follow-up of patients with recurrence is recommended in terms of lung metastasis.