Abstract
Introduction
Chondroblastic osteosarcoma is an aggressive bone tumor characterized by chondroid matrix production with variable cellularity. This retrospective study is aimed to assess the demographic distribution, clinical behavior and oncological outcome of chondroblastic osteosarcoma.
Methods
27 patients (14 males, 13 females) with chondroblastic osteosarcoma were included. The site of involvement included: proximal tibia (41%), distal femur (26%) and distal tibia (15%).The mean age of patients was 17 years (S.D: 6.9 years) (range 6–45 years).
Results
Painful swelling was the main complaint in all cases. Two patients were classified as Enneking III (lung) stage and the remaining patients had Enneking IIB stage. Post-neoadjuvant chemotherapy limb sparing surgery was performed in 70% of cases while in 30% of cases limb amputation was done. On histopathological examination of specimens mean necrosis was 64% (20–95%). Disease free survival (DFS) at 2 years was 46.4% and at 4 years was 27.9%. Median disease free survival was 24 ± 10.30 months. Overall survival (OS) at 2 years was 53.3% and at 4 years was 16.6%. Median overall survival is 28 ± 5.93 months.
Conclusions
Chondroblastic osteosarcoma is associated with poor prognosis, high recurrence rate and metastatic potential with dismal long-term survival. Chondroblastic osteosarcoma is an aggressive histological variant of conventional osteosarcoma with frequent location around the knee joint, affecting young population. Chemotherapy with Methotrexate, Adriamycin, Cisplatin (MAP) regimen is a well-tolerated regimen, resulting in limb salvage surgery in majority of the cases.
Keywords: Chondroblastic osteosarcoma, Limb salvage, Chemotherapy, Amputation
Introduction
Osteosarcoma is the most common malignant bone tumor, accounting for 15–35% of all primary malignant bone tumor [1]. It is predominantly a disease that affects the young in the second and third decades of life, however it can affect any age population [2].
Chondroblastic osteosarcoma, characterized by chondroid matrix production with variable cellularity, is considered an aggressive histology with poor outcome accounting for 25% of cases of conventional osteosarcoma [4−9]. Numerous variables have been associated with an adverse prognosis in osteosarcoma including metastatic disease at presentation, non-osteoblastic histological subtype, tumor size, male gender, young age, tumor location, genetic variations, poor response to neoadjuvant chemotherapy, and inadequate surgical margins [3, 4]. In current medical literature are few studies considered demographic pattern, clinical nature and survival outcome of Chondroblastic osteosarcoma. This study was aimed to assess the demographic distribution, clinical behavior and oncological outcome of chondroblastic osteosarcoma.
Materials and Methods
From 2015 to 2019, 186 patients with osteosarcoma were surgically treated at our center and 27 patients were identified with chondroblastic osteosarcoma (Fig. 1). As per the departmental protocol, on presentation patients were investigated with X-ray and MRI of local part and CECT thorax. Biopsy confirmation was done in all the patients. All patients received neo adjuvant chemotherapy (MAP protocol) with Cisplatin, Adriamycin and high dose Methotrexate as per institutional protocol. As a part of treatment protocol all patients received MAP protocol, i.e. three drug regimen of cisplatin and Adriamycin for three cycles and high dose methotrexate for fourth cycle for a duration of 12 weeks before surgery. Dose of cisplatin (120 mg/m2) was divided over 2 days, Adriamycin (75 mg/m2) was divided over 3 days. High dose methotrexate with adequate hydration was given at (12 g/m2) and folinic acid rescue after 24 h of completion of methotrexate. Patients were evaluated with MRI after completion of neoadjuvant chemotherapy and underwent surgery. After surgery adjuvant chemotherapy was administered. Patients once discharged were kept under 3-monthly follow-up for the first 2 years and then 6 monthly afterwards. In follow-up, patients were evaluated for functional outcomes and disease control with local MRI and CECT thorax. Any recurrence was noted and investigated further with biopsy confirmation.
Fig. 1.
Flow chart of selection of patients with Chondroblastic osteosarcoma
Statistical analysis for Overall Survival (OS) and Disease Free Survival (DFS) was done using Kaplan–Meier curve analysis.
We collected demographic data, radiological and histopathological features, clinical course and management details of these 27 consecutive patients of the Chondroblastic osteosarcoma from the prospectively maintained database of the institute. We also collected the post treatment follow-up data of OPD visits; where we assessed the overall survival, disease free survival of these patients. As per institute protocol, prior written informed consent was obtained from all patients for future use of their data and the study was approved by the clinical ethics committee of the hospital.
Results
Clinico-Epidemiological Data
In this study were included 27 patients (14 males: 13 females). Age varies from 6–45 years old and median age was 16 years. Most of the patients (17) were younger than 18 years of age while the remaining (10) were > 18 years old (Table 1).
Table 1.
Demographic and clinical features of patients with Chondroblastic osteosarcoma
| Male | 14 (51.8%) |
| Female | 13 (48.2%) |
| Median age | 16 years |
| < 18 years | 17 (62.9%) |
| ≥ 18 years | 10 (37.1%) |
| Site involved | |
| Proximal tibia | 11 (40.7%) |
| Distal femur | 7 (25.9%) |
| Distal tibia | 4 (14.8%) |
| Proximal humerus | 2 (7.4%) |
| Scapula | 1 (3.7%) |
| Ileum | 2 (7.4%) |
| Clinical presentation | |
| Painful swelling | 27 |
| Functional disability | 27 |
| Pathological fracture | 1 |
| Metastasis | |
| Lung metastasis | 2 (7.40%) |
Proximal tibia being involved in 11 patients; distal femur was the second common site involved and distal tibia was involved in four patients and iliac bone involved in two patients.
Proximal humerus was involved in two patients and scapula was involved in one patient.
The presenting complaint was painful swelling in all cases. Two patients had lung metastases on presentation. Two patients had skip metastasis on ipsilateral side (tibia) on MRI imaging. One patient presented with pathological fracture. In total 19 cases, alkaline phosphatase was raised and mean alkaline phosphate level was 251 IU/L (S.D: 230 IU/L) (Range 74–1002 IU/L). Two patients were classifieds as Enneking III (lung) stage and the remaining patients had Enneking IIB stage.
Magnetic Resonance Imaging (MRI) was done in all cases and it has shown aggressive disease biology. In almost all cases, the tumoral lytic lesion has appeared to involve the marrow, in an extent greater than the tumor size per se. All were advanced enough to breach the cortex and extend into the adjacent soft tissue.
Post-Neoadjuvant Chemotherapy Data
Surgical resection was performed in all patients. Post-neoadjuvant chemotherapy limb sparing surgery was performed in 19 cases (70%) while in eight cases (30%) amputation needed to be done. Excision with mega prosthesis was done in nine cases, while excision with arthrodesis was done in two cases. Extracorporeal radiation and reimplantation (ECRT) were done in four cases. Rotationplasty was done in one case, internal hemipelvectomy was done in two cases. Modified Tikhoff–Linberg procedure was done in one case of osteosarcoma involving scapula (Table 2).
Table 2.
Management performed in patients with Chondroblastic osteosarcoma
| Limb sparing surgery | 19 (70.4%) |
| Excision + megaprosthesis | 9 |
| Excision + arthrodesis | 2 |
| Excision + rotationplasty | 1 |
| ECRT | 4 |
| Internal hemipelvectomy | 2 |
| Modified tikhoff–linberg procedure | 1 |
| Amputation | 8 (29.6%) |
| Above knee amputation | 5 |
| Below knee amputation | 1 |
| Hip disarticulation | 1 |
| Forequarter amputation | 1 |
Histopathological Data
In all cases a complete R0 resection (minimal margin 2 mm) was achieved. On final histopathological analysis, in 26 cases there was cortical breach present with infiltration into surrounding soft tissue. Post-neoadjuvant chemotherapy, pathological complete response was present in one case. On histopathological examination of specimens, mean percentage of viable tumor was 28% (range 10–80%) while mean necrosis was 64% (range 20–95%) (Table 3).
Table 3.
Histopathological features in patients with Chondroblastic osteosarcoma
| Histopathological findings | |
| Cortical breach | 26 (96.3%) |
| Soft tissue extension | 24 (88.9%) |
| Pathological complete response | 1 |
| Mean viable tumor | 28% (10–80%) |
| Mean necrosis | 64% (20–95%) |
Survival Data
Patients once discharged were kept under regular 3 monthly follow-up for the first 2 years and then every 6 months afterwards. All patients were subjected to adjuvant chemotherapy till 29th week. Out of the study population, six patients were lost to follow-up after a mean duration of 8 months post surgery. Of the remaining 21 patients, nine patients developed recurrent disease (Table 4). Of those nine patients, two had local recurrence of which one was treated with hip disarticulation and is still under follow-up while one resulted in mortality. Among the remaining seven patients two had both local recurrence and distant metastasis while five had distant metastasis. Most common site for distant metastasis was lung (n = 6) while one had solitary lytic metastasis in upper limb fourth finger for which patient underwent amputation. One patient with localized lung metastasis in one lobe was operated with VATS (Video Assisted Thoracic Surgery) Lobectomy.
Table 4.
Oncologic outcome in patients with Chondroblastic osteosarcoma
| Lost to follow-up | 6 (mean duration: 8 months) (22.2%) |
| Recurrence (out of 21) | 9 (42.85%) |
| Local recurrence | 2 |
| Local + distant metastasis | 2 |
| Distant metastasis | 5 |
| Mortality (out of 21) | 10 (47.61%) |
| Among recurrent patients (out of 9) | 6 (66.67%) (mean OS 27.5 months) |
| Median DFS | 24 ± 10.30 months |
| Median OS | 28 ± 5.93 months |
There were ten mortalities in follow-up period. Out of the nine recurrent cases, six resulted in mortality after mean Overall survival of 27.5 months. Among the recurrent cases, three were operated for disease control, and all those three patients are under follow-up.
Statistical analysis for Disease Free Survival (DFS) and Overall Survival (OS) was done using Kaplan- Meier curve analysis. All lost to follow-up patients (n = 6) were considered as an event (mortality) for the sake of statistical analysis to avoid any selection bias. Due to less number of study population, subset analysis for individual variant was not done. Using Kaplan- Meier curve analysis, Disease Free Survival (DFS) at 2 years was 46.4% and at 4 years was 27.9%. Median Disease free survival was 24 ± 10.30 months (Fig. 2). Overall Survival (OS) at 2 years is 53.3% and at 4 years is 16.6%. Median Overall survival was 28 ± 5.93 months (Fig. 3).
Fig. 2.
Disease free survival (DFS) in patients with Chondroblastic osteosarcoma
Fig. 3.
Overall free survival (OS) in patients with Chondroblastic osteosarcoma
Discussion
Chondroblastic osteosarcoma is a rare tumor and accounts for 10–25% of all subtype of osteosarcoma [1, 8, 9]. Conventionally they are treated in similar line with conventional osteosarcoma with neoadjuvant chemotherapy followed by surgical treatment. In current medical literature are few studies considered on clinical, oncological and histopathological outcomes of Chondroblastic osteosarcoma [7–9].
Tsagozis et al. had analyzed clinical outcomes of Chondroblastic osteosarcoma and their incidence was 16% of all subtypes of osteosarcoma [9]. Sun et al. had analyzed prognostic factors for survival of patients with Chondroblastic osteosarcoma and their incidence was 12% of all subtypes of osteosarcoma [8]. The incidence of Chondroblastic osteosarcoma in current study was 15% of all subtypes of osteosarcoma.
Chemotherapy response is an important prognostic marker in patients with osteosarcoma. The effect of neoadjuvant chemotherapy was poor in patients with Chondroblastic osteosarcoma [2, 3, 8, 9]. Tsagozis et al. showed that 18% patients were good responders (necrosis > 90%) and 67% patients were poor responders [9]. The patients with good response to chemotherapy had major component of Chondroblastic elements on histopathological study. MAP protocol was used in the current study and one patient had 100% necrosis while mean necrosis was 64% (range 20–95%). Post neoadjuvant therapy limb salvage surgery was possible in majority of the cases (70.4%). Complete R0 resection was achieved in all the cases. There were no major complications post surgery, with no 30-days mortality. On final histology almost all cases have shown cortical breach (96.3%) with majority of the cases shown soft tissue extension (88.9%); suggesting aggressive histology of this malignancy. Once recovered following surgery, all patients took adjuvant therapy for completion of 29-weeks cycle.
In the current study, there was an equal distribution of cases between both sexes and the median age was 16 years, with the most common age group affected was less than 18 years (62.9%). The most common presenting complaint was painful swelling (100%), with various degrees of functional disability was seen in almost all cases. The most common site being involved was around the knee (66.6%), with proximal tibia (40.7%) being the most common bone of involvement.
Surgical treatment of osteosarcoma with wide margins is key step for complete excision of the tumor and this play major role in oncologic outcomes of patients. In current study limb sparing surgery was performed in 70% cases while in 30% cases limb amputation was done and histopathological study showed R0 margins in all patients. Role of surgical margin in Chondroblastic osteosarcoma is considered more important as chemotherapy response is poorer as compared to conventional osteosarcoma [9].
The study by Tsagozis et al. showed 47% patients developed metastases after primary treatment at a median interval of 21 months [9]. The Overall disease-specific survival (DSS) was 51% at five years and 42% at ten years [9]. According to Sun et al. the 5-years overall survival rates were 56.2% in patients with Chondroblastic osteosarcoma [8]. In current study almost half of the study patients developed recurrence within 2 years of treatment, resultant mortality was there in almost 2/3rd of them within one year of recurrence. The Disease Free Survival (DFS) at 2 years is 46.4% and at 4 years is 27.9%, while Overall Survival (OS) at 2 years is 53.3% and at 4 years is 16.6%. After 2 years there is a significant decline in both Disease free survival and Overall survival, suggesting poor long-term survival of this aggressive histology.
The limitation of the current study was its retrospective nature, and number of patients lost to follow-up during treatment course. We had not analyzed LDH at follow-up period of chemotherapy and we will keep this analysis in our next prospective study. We also suggest multi-institutional studies to further assess the oncological outcome and also to further advance the current standard of care to improvise management protocol, such as new chemotherapy regimen for better control of systemic disease.
Conclusion
Chondroblastic osteosarcoma is associated with poor prognosis, high recurrence rate and metastatic potential with dismal long-term survival. Chondroblastic Osteosarcoma is an aggressive histological variant of conventional osteosarcoma with frequent location around the knee joint, affecting young population. Chemotherapy with Methotrexate, Adriamycin, Cisplatin (MAP) regimen is a well-tolerated regimen, resulting in limb salvage surgery in majority of the cases.
Funding
None.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Ethical Standard Statement
This article does not contain any studies with human or animal subjects performed by the any of the authors.
Informed Consent
For this type of study informed consent is not required.
Footnotes
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