RESEARCH ARTICLE
Dedifferentiated chondrosarcoma: Radiological features, prognostic factors and survival statistics in 23 patients Chenglei Liu1, Yan Xi1, Mei Li1, Qiong Jiao2, Huizhen Zhang2, Qingcheng Yang3, Weiwu Yao1*
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1 Department of Radiology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China, 2 Department of Pathology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China, 3 Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China * [email protected]
Abstract Background
OPEN ACCESS Citation: Liu C, Xi Y, Li M, Jiao Q, Zhang H, Yang Q, et al. (2017) Dedifferentiated chondrosarcoma: Radiological features, prognostic factors and survival statistics in 23 patients. PLoS ONE 12(3): e0173665. https://doi.org/10.1371/journal. pone.0173665 Editor: Dominique Heymann, Universite de Nantes, FRANCE
Dedifferentiated chondrosarcoma is a rare, highly malignant tumor with a poor survival. There are many confusing issues concerning the imaging feature that can facilitate early diagnosis and the factors that might be related to outcomes.
Methods Twenty-three patients with dedifferentiated chondrosarcoma confirmed by pathology were retrospectively reviewed from 2008 to 2015. The patients’ clinical information, images from radiographs (n = 17), CT (n = 19), and MRI (n = 17), histological features, treatment and prognosis were analyzed.
Received: October 9, 2016 Accepted: February 25, 2017 Published: March 16, 2017 Copyright: © 2017 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and within the Supporting Information files. Funding: This research was supported by the Scientific Research Plan Project of Shanghai (Grant # 16511101100, Funding Institution: Shanghai Science and Technology, url: http://www.stcsm. gov.cn/) and the Major Project Fund of Minister of Science and Technology (Grant # 2016YFC0106802, Funding Institution: Ministry of Science and Technology of the People’s Republic
Results There were 12 males and 11 females, and the mean age was 50.39 years old. Fourteen cases affected the axial bone (pelvis, spine), and 9 cases involved the appendicular bone. Seven (41.17%), 9 (47.36), and 12 (66.66%) lesions showed a biphasic nature on radiograph, CT and MRI, respectively. Of the lesions, 17.39% (4/23) were accompanied by pathological fractures. Histologically, the cartilage component was considered histological Grade1 in 12 patients and Grade 2 in 11 patients. The dedifferentiated component showed features of osteosarcoma in 8 cases, malignant fibrous histiocytoma in3 cases, myofibroblastic sarcoma in 1 case and spindle cell sarcoma in 11cases. Twenty-two cases were treated with surgical resection, and 17 cases achieved adequate (wide or radical) surgical margin. In 8 cases, surgery was combined with adjuvant chemotherapy. The overall median survival time was nine months; 17.4% of patients survived to five years.
Conclusion Axial bone location, lung metastasis at diagnosis, inadequate surgical margin, incorrect diagnosis before surgery and pathological fractures was related to poorer outcome. Pre- or postoperative chemotherapy had no definitively effect on improved survival.
PLOS ONE | https://doi.org/10.1371/journal.pone.0173665 March 16, 2017
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Dedifferentiated chondrosarcoma
of China, URL: http://www.most.gov.cn/). All external funding was secured by WY. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist.
Introduction Dedifferentiated chondrosarcoma is a rare, highly malignant variant of chondrosarcoma, comprising up to 11% of all chondrosarcomas[1]. This term was first described by Dahlin and Beabout in 1971[2]. It is characterized by a high-grade, non-cartilaginous sarcoma juxtaposed with a low or intermediate chondrosarcoma with an abrupt interface between these two components [3]. The dedifferentiated component can demonstrate various features, such as osteosarcoma, malignant fibrous histiocytoma(MFH), angiosarcoma, fibrosarcoma, rhabdomyosarcoma, leiomyosarcoma, anaplastic spindle cell sarcoma, and giant cell tumor [4]. The age of onset most frequently ranges from 50 to 60 years old with a slight predominance of men, and the most commonly involved sites are the femur, pelvis, and humerus [2, 5]. It exhibits aggressive behavior and generates a high mortality rate compared with conventional chondrosarcoma or non-cartilaginous sarcomatous component alone, with which 5-year survival rates have been less than 20% [6, 7]. It was believed that the improved survival would be attained by prompt, correct pretreatment diagnosis and surgical resection with wide or radical margin[8]. Clinically, the doctor is suspicious of this disease based on careful analysis of radiographic features and the clinical course[9]. Dedifferentiated chondrosarcoma can have a wide range of imaging features. Identifying these imaging features is not only essential to raise suspicious of this lesion, but also to help guide choice of preoperative biopsy site or multifocal sampling at initial diagnosis. Because the dedifferentiated component determines the growth of lesion, metastasis, and prognosis of patients[4], it is particularly important to identify imaging features of dedifferentiation underlying chondroid lesion. Radiographs demonstrating aggressive osseous destruction or cortical infiltration, large unmineralized soft tissue mass, pathological fracture, area with osteoid matrix and rapid progression were suggestive of dedifferentiation[10]. Mercuri et al further described its radiographic features and classified into three types for convenience of description and diagnosis [11]. However, not commonly, radiographs may be no evidence of chondral matrix mineralization and dedifferentiation. Some authors had been reported the MRI feature of dedifferentiated chondrosarcoma, who noted that region of reduced signal intensity compared with hyper intensity chondral component was corresponded to dedifferentiation on T2 weighted spin echo or short T1 inversion recovery sequences based on small series [12–14]. Some arthors also reported that the biphasic nature (i.e., distinctly diverse tumor features juxtaposed with chondroid lesions) may be a special and typical feature for dedifferentiated chondrosarcoma [15–17]. However, the tumor showed a biphasic nature on only one-third of radiographs, one-third of MRI images and one-half of CT scans [16]. Currently, surgical resection with disease-free margins and limb salvage remain a preferred treatment for dedifferentiated chondrosarcoma[18]. Authors reported that the outcome was favorable with a radical resection, and local recurrence was related to inadequate surgical margin [6–8, 18]. However, it is rather difficult to implement wide surgical resection for dedifferentiated chondrosarcoma because of pathological fractures, lesion permeability, skip lesions and frequent secondary lung metastasis[15]. Grimer RJ et al noted that 27% cases fail to have adequate (wide or radical) surgical margin, and patients with axial tumors had an apparent increase in inadequate margins as opposed to patients with appendicular lesions [7]. Usually, the behavior of chondrosarcoma was resistant to available chemotherapy and radiation. The presence of dedifferentiated component raised the possibility of neo-adjuvant or adjuvant chemotherapy and radiation[8]. Radiation is associated with several side effect and long term complication, which may increase the risk of developing undifferentiated sarcoma[19, 20]. So, palliative radiation was usually available for patients with chondrosarcoma that are not resectable and cause complaints, especially mesenchymal chondrosarcoma.
PLOS ONE | https://doi.org/10.1371/journal.pone.0173665 March 16, 2017
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Dedifferentiated chondrosarcoma
Chemotherapy may be an adjunctive therapeutic strategy for dedifferentiated chondrosarcoma. However, because there have not been many reports about this rare disease, the role and effect of chemotherapy in dedifferentiated chondrosarcoma remain uncertainty [6, 8, 18, 21, 22]. A report from Mitchell et al noted that six patients underwent postoperative chemotherapy, the survival at five year was about 36%, whereas, additional six patients underwent only resection, without chemotherapy, all of them died within one year. The patients who received chemotherapy had a favorable outcome than those who did not [8]. However, Dickey et al noted that patients received adjuvant therapy whose median survival time was 7.5 months, and the five year rate of disease–free survival was 7.1%. There was no significant difference in the five year rate of disease–free survival concerning the use of chemotherapy [22]. Additionally, there was no papers documenting many cases received preoperative neoadjuvant chemotherapy achieved a good histological response. Mitchell et al noted that five patients underwent preoperative cytotoxic chemotherapy, only one achieved significant necrosis (>90%) [8]; Staals et al had no good responder in four patients [6], and Dickey et al reported poor chemotherapy response in 21patients who received preoperative neoadjuvant chemotherapy [22]. Identifying the potential prognostic factors of dedifferentiated chondrosarcoma was very important to patients themselves and doctors due to limited treatment options, which may help doctors to make decisions concerning treatment with future perspective. However, the potential prognostic factors remain unclear until now. Staals EL et al. reported that the factors, such as metastatic disease at diagnosis, MFH dedifferentiation, and a high proportion of dedifferentiated components in lesions, were associated with poor survival rates [6]. However, Grimer RJ et al showed that poor prognostic factors were the presence of a pathological fracture at diagnosis, a pelvic location and increasing age, whereas the histological subtype did not significantly affect outcome [7]. To increase recognition of this rare disease, we reported our experience of diagnosing and treating dedifferentiated chondrosarcoma in 23 patients, and we have attempt to further determine which factors that might be related to the outcomes.
Materials and methods Our retrospective study was approved by the hospital institutional review board (Shanghai No. 6 People’s Hospital), and the need for written informed consent was waived because the study was a retrospective study using a datum from which the patients’ identification had been removed. A total of 31 patients with a definitive diagnosis of dedifferentiated chondrosarcoma at our institution between 2008 and 2015 were reviewed. Of these cases, 8 patients were excluded due to lack of detailed clinical records and images. Finally, 23 patients were enrolled in our study. All of the patients were treated and followed up in our Department of Orthopedic Oncology. Clinical and follow-up data were obtained from the medical records and the patients themselves. Patients underwent standard radiographic examinations on a DR (Siemens, Erlangen, Germany). CT scans were performed on a 16-row CT scanner (Siemens Medical Solutions, Erlangen, Germany) or 64-row CT scanner (Light Speed VCT; GE Healthcare, Waukesha, WI) with both bone and soft tissue windows at 2-mm thicknesses and sagittal and coronal reformatted images. MR imaging was performed on 3.0-T superconducting MR scanner (Koninklijke Philips NV, Amsterdam, the Netherlands). All of the imaging findings were reviewed by two musculoskeletal radiologists who had 20 years of image diagnostic experience and complete knowledge of this tumor (Weiwu Yao, Mei li). If the diagnostic outcome was different between the two observers, an agreement was
PLOS ONE | https://doi.org/10.1371/journal.pone.0173665 March 16, 2017
3 / 15
Dedifferentiated chondrosarcoma
reached by consultation. The radiographic studies included the following: patterns of bone destruction; the presence and pattern of periosteal reaction; pathologic fracture; matrix mineralization; the presence and features of soft-tissue masses; pattern of enhancement and signal intensity characteristics on MR imaging; and the presence of biphasic nature. The biphasic nature was defined as demonstrating distinctly diverse tumor features adjacent to chondroid lesions, such as dominant lytic area within a mineralized tumor, a large unmineralized soft tissue mass, and a region with osteoid matrix[16]. The histologic slides were stained with hematoxylin and eosin, and when indicated, phosphotungstic acid hematoxylin (PTAH) and periodic acid-Schiff (PAS) were used. The histological features, including the histologic grade of the cartilaginous component and histologic subtype of the dedifferentiated component, were reviewed by two pathologists with more than 20 years of experience to ensure reliability in classification and grading (Huizhen Zhang, Qiong Jiao). The histological subtype depended on immunohistochemistry. All of the patients were followed up to death or at least for 12 months. For survival analysis, Kaplan-Meier survival analysis was used. Differences between groups were analyzed using the log-rank test. All of the statistical tests were 2-sided, and P values
Dedifferentiated chondrosarcoma: Radiological features, prognostic factors and survival statistics in 23 patients Chenglei Liu1, Yan Xi1, Mei Li1, Qiong Jiao2, Huizhen Zhang2, Qingcheng Yang3, Weiwu Yao1*
a1111111111 a1111111111 a1111111111 a1111111111 a1111111111
1 Department of Radiology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China, 2 Department of Pathology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China, 3 Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China * [email protected]
Abstract Background
OPEN ACCESS Citation: Liu C, Xi Y, Li M, Jiao Q, Zhang H, Yang Q, et al. (2017) Dedifferentiated chondrosarcoma: Radiological features, prognostic factors and survival statistics in 23 patients. PLoS ONE 12(3): e0173665. https://doi.org/10.1371/journal. pone.0173665 Editor: Dominique Heymann, Universite de Nantes, FRANCE
Dedifferentiated chondrosarcoma is a rare, highly malignant tumor with a poor survival. There are many confusing issues concerning the imaging feature that can facilitate early diagnosis and the factors that might be related to outcomes.
Methods Twenty-three patients with dedifferentiated chondrosarcoma confirmed by pathology were retrospectively reviewed from 2008 to 2015. The patients’ clinical information, images from radiographs (n = 17), CT (n = 19), and MRI (n = 17), histological features, treatment and prognosis were analyzed.
Received: October 9, 2016 Accepted: February 25, 2017 Published: March 16, 2017 Copyright: © 2017 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and within the Supporting Information files. Funding: This research was supported by the Scientific Research Plan Project of Shanghai (Grant # 16511101100, Funding Institution: Shanghai Science and Technology, url: http://www.stcsm. gov.cn/) and the Major Project Fund of Minister of Science and Technology (Grant # 2016YFC0106802, Funding Institution: Ministry of Science and Technology of the People’s Republic
Results There were 12 males and 11 females, and the mean age was 50.39 years old. Fourteen cases affected the axial bone (pelvis, spine), and 9 cases involved the appendicular bone. Seven (41.17%), 9 (47.36), and 12 (66.66%) lesions showed a biphasic nature on radiograph, CT and MRI, respectively. Of the lesions, 17.39% (4/23) were accompanied by pathological fractures. Histologically, the cartilage component was considered histological Grade1 in 12 patients and Grade 2 in 11 patients. The dedifferentiated component showed features of osteosarcoma in 8 cases, malignant fibrous histiocytoma in3 cases, myofibroblastic sarcoma in 1 case and spindle cell sarcoma in 11cases. Twenty-two cases were treated with surgical resection, and 17 cases achieved adequate (wide or radical) surgical margin. In 8 cases, surgery was combined with adjuvant chemotherapy. The overall median survival time was nine months; 17.4% of patients survived to five years.
Conclusion Axial bone location, lung metastasis at diagnosis, inadequate surgical margin, incorrect diagnosis before surgery and pathological fractures was related to poorer outcome. Pre- or postoperative chemotherapy had no definitively effect on improved survival.
PLOS ONE | https://doi.org/10.1371/journal.pone.0173665 March 16, 2017
1 / 15
Dedifferentiated chondrosarcoma
of China, URL: http://www.most.gov.cn/). All external funding was secured by WY. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist.
Introduction Dedifferentiated chondrosarcoma is a rare, highly malignant variant of chondrosarcoma, comprising up to 11% of all chondrosarcomas[1]. This term was first described by Dahlin and Beabout in 1971[2]. It is characterized by a high-grade, non-cartilaginous sarcoma juxtaposed with a low or intermediate chondrosarcoma with an abrupt interface between these two components [3]. The dedifferentiated component can demonstrate various features, such as osteosarcoma, malignant fibrous histiocytoma(MFH), angiosarcoma, fibrosarcoma, rhabdomyosarcoma, leiomyosarcoma, anaplastic spindle cell sarcoma, and giant cell tumor [4]. The age of onset most frequently ranges from 50 to 60 years old with a slight predominance of men, and the most commonly involved sites are the femur, pelvis, and humerus [2, 5]. It exhibits aggressive behavior and generates a high mortality rate compared with conventional chondrosarcoma or non-cartilaginous sarcomatous component alone, with which 5-year survival rates have been less than 20% [6, 7]. It was believed that the improved survival would be attained by prompt, correct pretreatment diagnosis and surgical resection with wide or radical margin[8]. Clinically, the doctor is suspicious of this disease based on careful analysis of radiographic features and the clinical course[9]. Dedifferentiated chondrosarcoma can have a wide range of imaging features. Identifying these imaging features is not only essential to raise suspicious of this lesion, but also to help guide choice of preoperative biopsy site or multifocal sampling at initial diagnosis. Because the dedifferentiated component determines the growth of lesion, metastasis, and prognosis of patients[4], it is particularly important to identify imaging features of dedifferentiation underlying chondroid lesion. Radiographs demonstrating aggressive osseous destruction or cortical infiltration, large unmineralized soft tissue mass, pathological fracture, area with osteoid matrix and rapid progression were suggestive of dedifferentiation[10]. Mercuri et al further described its radiographic features and classified into three types for convenience of description and diagnosis [11]. However, not commonly, radiographs may be no evidence of chondral matrix mineralization and dedifferentiation. Some authors had been reported the MRI feature of dedifferentiated chondrosarcoma, who noted that region of reduced signal intensity compared with hyper intensity chondral component was corresponded to dedifferentiation on T2 weighted spin echo or short T1 inversion recovery sequences based on small series [12–14]. Some arthors also reported that the biphasic nature (i.e., distinctly diverse tumor features juxtaposed with chondroid lesions) may be a special and typical feature for dedifferentiated chondrosarcoma [15–17]. However, the tumor showed a biphasic nature on only one-third of radiographs, one-third of MRI images and one-half of CT scans [16]. Currently, surgical resection with disease-free margins and limb salvage remain a preferred treatment for dedifferentiated chondrosarcoma[18]. Authors reported that the outcome was favorable with a radical resection, and local recurrence was related to inadequate surgical margin [6–8, 18]. However, it is rather difficult to implement wide surgical resection for dedifferentiated chondrosarcoma because of pathological fractures, lesion permeability, skip lesions and frequent secondary lung metastasis[15]. Grimer RJ et al noted that 27% cases fail to have adequate (wide or radical) surgical margin, and patients with axial tumors had an apparent increase in inadequate margins as opposed to patients with appendicular lesions [7]. Usually, the behavior of chondrosarcoma was resistant to available chemotherapy and radiation. The presence of dedifferentiated component raised the possibility of neo-adjuvant or adjuvant chemotherapy and radiation[8]. Radiation is associated with several side effect and long term complication, which may increase the risk of developing undifferentiated sarcoma[19, 20]. So, palliative radiation was usually available for patients with chondrosarcoma that are not resectable and cause complaints, especially mesenchymal chondrosarcoma.
PLOS ONE | https://doi.org/10.1371/journal.pone.0173665 March 16, 2017
2 / 15
Dedifferentiated chondrosarcoma
Chemotherapy may be an adjunctive therapeutic strategy for dedifferentiated chondrosarcoma. However, because there have not been many reports about this rare disease, the role and effect of chemotherapy in dedifferentiated chondrosarcoma remain uncertainty [6, 8, 18, 21, 22]. A report from Mitchell et al noted that six patients underwent postoperative chemotherapy, the survival at five year was about 36%, whereas, additional six patients underwent only resection, without chemotherapy, all of them died within one year. The patients who received chemotherapy had a favorable outcome than those who did not [8]. However, Dickey et al noted that patients received adjuvant therapy whose median survival time was 7.5 months, and the five year rate of disease–free survival was 7.1%. There was no significant difference in the five year rate of disease–free survival concerning the use of chemotherapy [22]. Additionally, there was no papers documenting many cases received preoperative neoadjuvant chemotherapy achieved a good histological response. Mitchell et al noted that five patients underwent preoperative cytotoxic chemotherapy, only one achieved significant necrosis (>90%) [8]; Staals et al had no good responder in four patients [6], and Dickey et al reported poor chemotherapy response in 21patients who received preoperative neoadjuvant chemotherapy [22]. Identifying the potential prognostic factors of dedifferentiated chondrosarcoma was very important to patients themselves and doctors due to limited treatment options, which may help doctors to make decisions concerning treatment with future perspective. However, the potential prognostic factors remain unclear until now. Staals EL et al. reported that the factors, such as metastatic disease at diagnosis, MFH dedifferentiation, and a high proportion of dedifferentiated components in lesions, were associated with poor survival rates [6]. However, Grimer RJ et al showed that poor prognostic factors were the presence of a pathological fracture at diagnosis, a pelvic location and increasing age, whereas the histological subtype did not significantly affect outcome [7]. To increase recognition of this rare disease, we reported our experience of diagnosing and treating dedifferentiated chondrosarcoma in 23 patients, and we have attempt to further determine which factors that might be related to the outcomes.
Materials and methods Our retrospective study was approved by the hospital institutional review board (Shanghai No. 6 People’s Hospital), and the need for written informed consent was waived because the study was a retrospective study using a datum from which the patients’ identification had been removed. A total of 31 patients with a definitive diagnosis of dedifferentiated chondrosarcoma at our institution between 2008 and 2015 were reviewed. Of these cases, 8 patients were excluded due to lack of detailed clinical records and images. Finally, 23 patients were enrolled in our study. All of the patients were treated and followed up in our Department of Orthopedic Oncology. Clinical and follow-up data were obtained from the medical records and the patients themselves. Patients underwent standard radiographic examinations on a DR (Siemens, Erlangen, Germany). CT scans were performed on a 16-row CT scanner (Siemens Medical Solutions, Erlangen, Germany) or 64-row CT scanner (Light Speed VCT; GE Healthcare, Waukesha, WI) with both bone and soft tissue windows at 2-mm thicknesses and sagittal and coronal reformatted images. MR imaging was performed on 3.0-T superconducting MR scanner (Koninklijke Philips NV, Amsterdam, the Netherlands). All of the imaging findings were reviewed by two musculoskeletal radiologists who had 20 years of image diagnostic experience and complete knowledge of this tumor (Weiwu Yao, Mei li). If the diagnostic outcome was different between the two observers, an agreement was
PLOS ONE | https://doi.org/10.1371/journal.pone.0173665 March 16, 2017
3 / 15
Dedifferentiated chondrosarcoma
reached by consultation. The radiographic studies included the following: patterns of bone destruction; the presence and pattern of periosteal reaction; pathologic fracture; matrix mineralization; the presence and features of soft-tissue masses; pattern of enhancement and signal intensity characteristics on MR imaging; and the presence of biphasic nature. The biphasic nature was defined as demonstrating distinctly diverse tumor features adjacent to chondroid lesions, such as dominant lytic area within a mineralized tumor, a large unmineralized soft tissue mass, and a region with osteoid matrix[16]. The histologic slides were stained with hematoxylin and eosin, and when indicated, phosphotungstic acid hematoxylin (PTAH) and periodic acid-Schiff (PAS) were used. The histological features, including the histologic grade of the cartilaginous component and histologic subtype of the dedifferentiated component, were reviewed by two pathologists with more than 20 years of experience to ensure reliability in classification and grading (Huizhen Zhang, Qiong Jiao). The histological subtype depended on immunohistochemistry. All of the patients were followed up to death or at least for 12 months. For survival analysis, Kaplan-Meier survival analysis was used. Differences between groups were analyzed using the log-rank test. All of the statistical tests were 2-sided, and P values
