Intracranial Metastasis of Extracranial Chondrosarcoma: Systematic Review With Illustrative Case

Charles E. Mackel; Harry Rosenberg; Hemant Varma; Erik J. Uhlmann; Rafael A. Vega; Ron L. Alterman

doi:10.14791/btrt.2023.0003

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Mackel, Rosenberg, Varma, Uhlmann, Vega, and Alterman: Intracranial Metastasis of Extracranial Chondrosarcoma: Systematic Review With Illustrative Case

Original Article

Brain Tumor Research and Treatment 2023; 11(2): 103-113.

Published online: 27 April 2023

DOI: https://doi.org/10.14791/btrt.2023.0003

Intracranial Metastasis of Extracranial Chondrosarcoma: Systematic Review With Illustrative Case

Charles E. Mackel¹

, Harry Rosenberg²

, Hemant Varma²

, Erik J. Uhlmann³

, Rafael A. Vega¹

, Ron L. Alterman¹

¹Department of Neurosurgery, Beth Israel Deaconess Hospital and Harvard Medical School, Boston, MA, USA.

²Department of Pathology, Beth Israel Deaconess Hospital and Harvard Medical School, Boston, MA, USA.

³Department of Neurology, Beth Israel Deaconess Hospital and Harvard Medical School, Boston, MA, USA.

Correspondence: Charles E. Mackel. Department of Neurosurgery, Beth Israel Deaconess Medical Center, 110 Francis St, Suite 9B, Boston, MA 02215, USA. Tel: +1-617-632-9511, Fax: +1-617-632-7424, cmackel@bidmc.harvard.edu

Received 16 January 2023 Revised 22 February 2023 Accepted 23 February 2023

The Korean Brain Tumor Society, The Korean Society for Neuro-Oncology, and The Korean Society for Pediatric Neuro-Oncology

https://creativecommons.org/licenses/by-nc/4.0/

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Cerebral chondrosarcoma metastases are rare and aggressive neoplasms. The rarity of presentation has precluded rigorous analysis of diagnosis, risk factors, treatment, and survival. We analyzed every reported case through exhaustive literature review. We further present the first case with Maffucci syndrome.

Methods

Three databases, PubMed, Embase, and Google Scholar, and crossed references were queried for cerebral chondrosarcoma metastases. Extracted variables included demographics, risk factors, tumor characteristics, interventions, and outcomes. Univariate and multivariate analyses were performed.

Results

Fifty-six patients were included from 1,489 literature results. The average age at brain metastasis was 46.6±17.6 years and occurred at a median of 24±2.8 months from primary diagnosis. Primary tumor histology (dedifferentiated 5.0±1.5 months, mesenchymal 24±3.0 months, conventional 41±7.4 months, p<0.05) and grade (low grade 54±16.7 months vs. high-grade 10±6.4 months, p<0.001) correlated with time interval until brain metastasis. A multiple enchondromatosis syndrome occurred in 13.2% of cases. At time of brain metastases diagnosis, extracranial metastases were identified in 76.2% of cases. Median survival after the development of brain metastasis was 2.0±0.78 months with a 1-year survival of 10.0%. On regression analysis, surgery reduced brain metastasis mortality risk and radiation trended towards reduced mortality risk (surgery: hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.064–0.763, p=0.017; radiation: HR 0.31, 95% CI 0.091–1.072, p=0.064).

Conclusion

We present a systematic review of cerebral chondrosarcoma metastases. Primary tumor histology and grade correlate with time until cerebral metastasis. Following cerebral metastasis, these tumors have poor prognosis and modestly benefit from surgery.

Keywords: Cerebral, Chondrosarcoma, Maffucci syndrome, Metastases

INTRODUCTION

Chondrosarcomas are a group of neoplasms comprised of tumors cells that produce a cartilage matrix [1]. They have an annual incidence of approximately 1 per 200,000 [2], and the majority (83%) are low grade [2]. Metastases occur in 10%–21% of grade II and 60%–71% of grade III chondrosarcomas, most commonly to the lung [3 4]. The 5-year overall survival of patients who develop metastatic chondrosarcoma is 28.6% [5].

While 1%–8% of all sarcoma patients develop brain metastases [6], intracranial metastasis in chondrosarcoma is exceedingly rare. A prior review reported only 9 cases of chondrosarcoma brain metastases [7]. Large retrospective reviews estimate that chondrosarcoma metastatic to the brain accounts for 0.0%–5.6% of sarcoma patients with brain metastases [8 9 10 11 12 13], 0.0%–0.24% of all sarcoma patients [6 8 9 13 14], and 0.17% of brain metastases [15]. A 6-year surveillance, epidemiology, and end results (SEER) analysis found only 3 out of 1,533 chondrosarcoma patients had brain metastases (0.2%) [16]. These prior retrospective studies each enfold just a few chondrosarcoma patients into a larger analysis of sarcomas without chondrosarcoma subset analysis [6 8 9 10 11 12 13 14]. Consequently, the nature of chondrosarcoma metastatic to the brain is poorly understood.

In this paper, we report a case of 66-year-old male patient with Maffucci syndrome who developed a cerebral chondrosarcoma metastasis as well as the results of a systematic literature review through which we identified sixfold more cases than previously accounted for. Combining our case with those in the literature, we analyzed patient demographics, tumor characteristics, treatment modalities, and outcomes to identify factors that impact patient survival.

METHODS

Ethics statement

This report was conducted according to the guidelines of the Declaration of Helsinki for biomedical research, and was deemed exempt by the Institutional Review Board for individual patient consent (2021P000600).

Search method

A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using the electronic databases of PubMed/MEDLINE, Embase, and Google Scholar for publications through April 2022 by the first author (CM). Titles and abstracts were reviewed; duplicates and results not matching search objectives were excluded. Full-text articles were reviewed for relevant references/citations. Inclusion criteria were 1) a peer-reviewed article or conference presentation 2) with at minimum an abstract in English 3) describing a remote, secondary intracranial chondrosarcoma. Extracted variables included patient demographic, tumor characteristics, and outcomes.

Statistics

SPSS Statistics Version 25 (IBM Corp., Armonk, NY, USA) was used for statistical calculations. The nonparametric Mann-Whitney U-test was used for continuous variables and chi-square or Fisher’s exact test for categorical variables. Generated Kaplan-Meier survival curves were compared using log-rank tests for univariate analysis. A stepwise multivariate Cox proportional hazards model was created for the time-dependent outcome of mortality. Median survival was listed as median± standard error. A p≤0.05 was considered to be significant.

RESULTS

Illustrative case

A 66-year-old male patient presented in May 2020 following 2 months of left thigh pain. His medical history was significant for multiple enchondromatosis misdiagnosed in childhood as fibrous dysplasia. A 2010 bone scan demonstrated enchondromas of the bilateral femurs, tibias, fibulas, and right hallux, and an MRI calf showed a subcutaneous calf hemangioma consistent with Maffucci syndrome (Fig. 1). Interval imaging demonstrated stable disease burden until a fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan obtained in the setting of new symptoms demonstrated a 12-cm signal abnormality of the distal femur with cortical destruction and soft tissue mass (Fig. 2). The remainder of the FDG was negative for malignancy.

Biopsy of the lesion revealed dedifferentiated chondrosarcoma, and he underwent wide resection with reconstruction endoprosthesis in July 2020. After 4 cycles of doxorubicin-cisplatin chemotherapy, a re-staging chest CT in October 2020 demonstrated multiple pulmonary nodules. Two weeks later, he developed partial seizures involving the left arm. An MRI revealed an enhancing 2.8-cm right parietal mass with edema (Fig. 3). Gross total resection of the mass was achieved, and he underwent hypofractioned stereotactic radiation (3×8 Gy). However, he was readmitted 2 weeks post-resection in status epilepticus. Repeat MRI excluded an acute process. He was discharged on 3 anti-epileptic drugs and initiation of gemcitabine-docetaxel. Three days after discharge, he returned with somnolence, confusion, and left hemiparesis. Interval head CT showed worsening hemispheric edema without an underlying mass. Chest CT showed significant progression of his pulmonary disease. He was transitioned to comfort measures and passed away in December 2020 at age 67.

Histopathology

On gross examination, the femoral lesion was an ill-defined, tan-white gelatinous mass extending from the diaphysis into soft tissue. Microscopy revealed a low-grade cartilaginous tumor juxtaposed to a high-grade, spindle cell neoplasm with a mitotic rate of 24 per 10 high-power field (HPF) in tumor-rich areas (Fig. 4). Margins were negative. Immunohistochemistry included positive staining for MLH1, MSH2, MSH6 and PMS2, and negative staining of S100, MNF116, SMA, desmin, and GFAP. FoundationOne analysis showed mutations of CHEK2 S428F, IDH1 R132C, and TERT promoter-124C>T as well as amplification of CDK4 and MDM2. A diagnosis of femoral grade 3 dedifferentiated chondrosarcoma was made. The brain metastasis demonstrated focal GFAP positivity but was architecturally similar to the femoral lesion. Since GFAP is a marker of cartilaginous differentiation [17] and the sample otherwise resembled the primary lesion, a diagnosis of high-grade dedifferentiated chondrosarcoma metastatic to the brain was rendered.

Primary site

Fifty-six cases met the inclusion criteria, including the present case (Fig. 5, Tables 1 and 2) [4 6 8 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64]. The mean age at diagnosis of the primary chondrosarcoma was 43.1±18.6 years with an even distribution between the sexes. The most common primary site, histology, and grade were the appendicular skeleton (27/55 cases, 49.1%), conventional chondrosarcoma (19/40 cases, 47.5%), and grade 3 (21/33, 63.6%), respectively. Surgery was pursued as initial primary site treatment in 89.1% of cases (41/46) with 23/27 cases documenting clean resection margins. Radiation and chemotherapy were utilized in a quarter of cases. A third of cases had local recurrence (14/43) at a median of 12±2.8 months from initial diagnosis, and 82.2% of cases developed extracranial metastases at a median interval of 12±2.2 months from the time of initial diagnosis. The median survival from primary diagnosis was 29±9.1 months (Table 1).

Development of brain metastasis

The average age at brain metastasis was 46.6±17.6 years. At the time brain metastases were diagnosed, extracranial metastases were already identified in 76.2% of cases (32/42). Brain metastasis occurred at a median of 24±2.8 months from primary diagnosis (Table 3). Primary histology and grade were correlated with the time to brain metastasis with dedifferentiated and high-grade chondrosarcomas demonstrating earlier median times to brain metastasis (dedifferentiated 5±1.5 months, mesenchymal 24±3.0 months, conventional 41±7.4 months, p<0.05; low grade 54±16.7 months vs. high-grade 10±6.4 months, p<0.001) (Table 3).

Survival from brain metastasis

Median survival after the development of brain metastasis was 2.0±0.78 months with a 1-year survival of 10.0% (4/40) (Table 4). Surgery for a single or symptomatic metastases was performed in 55.5% of cases (20/36). Radiation therapy was used in 34.6% of cases (9/26). One third of patients received supportive care only (9/26). Surgery was associated improved median survival (4.0±1.4 months vs. 1.0±0.24, p=0.024) (Fig. 6). On multivariate Cox regression analysis controlling for sex, age, extracranial tumor burden at the time of intracranial metastasis, and treatment modality, surgery demonstrated reduced brain metastasis mortality risk (hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.064–0.763, p=0.017) and radiation trended towards reduced mortality risk (HR 0.31, 95% CI 0.091–1.072, p=0.064).

DISCUSSION

Here, we present the largest systematic review of intracranial metastatic chondrosarcoma to date. Our analysis indicates that most chondrosarcomas metastatic to the brain occur in the fifth decade of life (46.6±17.6 years), evenly distributed between the sexes, have pre-existing extracranial metastases at presentation (76.2%), and arise at a median of 24±2.8 months after primary chondrosarcoma diagnosis. The development of chondrosarcoma brain metastases is a particularly grim event. Although chondrosarcoma metastases in general yield a median survival of 14.0±2.5 months and a 5-year overall survival of 28.4% [5], our data suggest that when chondrosarcoma metastasizes to the brain that the median survival is only 2.0±0.78 months with a 1-year survival of 10.0%.

The overall 5-year survival for chondrosarcomas across grade and location is 75.2% [65]. Tumor- and patient-specific factors impacting survival include patient age [66], tumor histology [2 67] and grade [2 66 67], molecular profile [68], primary location [1 66 69], primary site surgery [1 5 37 66], and primary site radiation [1 69]. Although local recurrence shortens survival, metastatic spread particularly impacts mortality [1 66 67]. In a long-term study of primary central chondrosarcomas, Andreou et al. [69] noted a 5-year overall survival among nonmetastatic tumors of 89% compared to 23% for those with metastases. Wang et al. [5] reported high grade chondrosarcomas with metastases at presentation (grade 3) had worse median survival than low grade (grade 1 or 2) chondrosarcomas presenting with metastases (9.0±1.7 vs. 49±15.7 months). Amer et al. [67] observed that 19.8% of dedifferentiated and 10.6% of mesenchymal chondrosarcomas present with metastases.

We observed significantly shorter intervals to brain metastasis among higher grade primary tumors than lower grade tumors (10±6.4 vs. 54±16.7 months). Dedifferentiated tumors (5.0±1.5 months) have the shortest interval from primary to metastatic diagnosis followed by mesenchymal (24±3.0 months) and conventional chondrosarcomas (41±7.0 months). Accounting for brain metastasis, primary tumor histology or grade did not impact survival, which likely reflected interval progression of primary low-grade tumors to higher grade tumors at metastasis as one-third of low-grade primaries (4/12) [20 26 27 38 59] demonstrated progression on tissue obtained after recurrence. While primary site surgery exhibited a trend towards longer interval in the development of brain metastases (27±6.6 vs. 4.0±4.4 months, p=0.12), the rarity of nonsurgical primary site management (n=5) restricted this analysis. In light of the dismal prognosis of metastatic chondrosarcoma, high clinical suspicion for malignant progression of low-grade primaries and systemic surveillance of high-grade primaries is warranted.

Among 38 cases for which there was sufficient clinical history, an underlying benign cartilaginous lesion transformed to a chondrosarcoma in 23.7%. In 5 of 8 cases, the cartilaginous lesion was part of a multiple enchondromatoses syndrome. Four cases had a diagnosis of Ollier disease; ours represented the first probable case of Maffucci syndrome. Ollier disease has a prevalence of 1 per 100,000 people and is differentiated from the rarer Maffucci syndrome by the presence of concurrent hemangiomas in the latter [70]. While malignant conversion is rare (<1%) among non-syndromic enchondromas [71], conversion to chondrosarcoma ranges from 20%–45.8% in Ollier disease and 30.5%–57.1% in Maffucci syndrome [72]. In our review, the time from syndromic diagnosis to diagnosis of chondrosarcoma ranged from 10–63 years with brain metastasis occurring 2 months to 8 years after malignant conversion [43 55 64]. Although the sarcomatous transformation may take years to occur, once it happens the resulting lesion is as metastatically aggressive as primary chondrosarcomas. With fewer than 200 cases of Maffucci syndrome in the literature [70], our patient is the first to have intracranial chondrosarcoma metastasis described.

Chondrosarcomas subdivide into five categories: 1) grade 1–3 primary or secondary, central or peripheral conventional; 2) grade 3 dedifferentiated; 3) grade 1 clear cell; 4) grade 3 skeletal or extra-skeletal mesenchymal; and 5) periosteal [73]. The presence of cartilaginous matrix on histopathology is a critical diagnostic marker [1]. We excluded 6 cases of “extraskeletal myxoid chondrosarcomas” from analysis [74 75 76 77 78 79] because they lack cartilaginous differentiation and are not considered to be true “chondrosarcomas” [80]. Although chondrosarcomas do not have a specific molecular marker, somatic mutations of IDH1/IDH2 help differentiate chondromas/chondrosarcomas from other mesenchymal bone tumors. Since mesenchymal IDH1/IDH2 mutations promote chondrogenic differentiation over osteogenic differentiation, it is unsurprising that nearly 80% of chondrosarcomas arising in multiple enchondromatosis syndromes demonstrate this mutation [81]. Although the importance of IDH1/IDH2 mutations in chondrosarcoma prognosis is unsettled, some studies have evinced its negative impact on survival [68]. Because of its relative recency as a marker, an IDH1 mutation was formally reported in only 2 other cases in addition to ours [18].

A third of metastatic intracranial chondrosarcoma patients were managed with supportive care only, which reflects the aggressiveness of the disease and its systemic burden with 82% of cases with intracranial metastases ultimately developing extracranial metastases. Both surgery and radiation of intracranial metastases improved median survival by 3–4 months, which suggests that patients with single or symptomatic brain metastases and reasonable systemic burden may benefit from intracranial treatment. Multivariate analysis further suggested reduced mortality risk following surgery (HR 0.22, p=0.017). Radiation therapy had a nonsignificant association with improved mortality (HR 0.31, p=0.064). Chemotherapy for intracranial disease burden was not associated with survival benefit. Although ours is the first study to specifically examine management of chondrosarcoma brain metastases, it has been previously shown that metastasectomy generally confers survival benefit in metastatic chondrosarcoma [69 82]. The modest benefit of surgery or radiation in appropriately selected patients with chondrosarcoma brain metastases reflect treatment outcomes of sarcomatous brain metastases more generally [7 12].

Limitations

This systematic review has several limitations. First, it combines case reviews and series; therefore, it is highly susceptible to publication and retrospective-study biases. Second, techniques of radiation, surgery, and chemotherapy continue to improve, confounding treatment comparisons. Third, study heterogeneity complicates analysis, including differences in treatment approaches, patient characteristics, and histologic reports. Finally, outcome data remains significantly limited by small sample size and lack of long-term follow-up.

Conclusion

Metastatic cerebral chondrosarcomas are rare but aggressive neoplasms. On average, they arise 24±2.8 months after primary chondrosarcoma diagnosis. Following their development, median survival is 2.0±0.78 months with a 1-year survival of 10%. Primary lesion histology and grade influence the interval between initial diagnosis and the identification of a brain metastasis. Where feasible, surgical resection improves survival. Multiple enchondromatoses syndrome underlie 13.2% (5/38) of cases of chondrosarcomatous brain metastases and warrant high clinical suspicion.

Notes

Author Contributions:

Conceptualization: Charles E. Mackel, Rafael A. Vega, Ron L. Alterman.
Data curation: Charles E. Mackel.
Formal analysis: Charles E. Mackel.
Investigation: Charles E. Mackel, Harry Rosenberg, Hemant Varma.
Methodology: Charles E. Mackel.
Resources: Hemant Varma.
Supervision: Rafael A. Vega, Ron L. Alterman.
Visualization: Harry Rosenberg.
Writing—original draft: Charles E. Mackel.
Writing—review & editing: Charles E. Mackel, Harry Rosenberg, Erik J. Uhlmann, Rafael A. Vega, Ron L. Alterman.

Conflicts of Interest: The authors have no potential conflicts of interest to disclose.

Funding Statement: None

Availability of Data and Material

The datasets generated or analyzed during the study may be available from the corresponding author on reasonable request.

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Fig. 1

Axial fat-suppressed post-gadolinium of the calf. Soft tissue hemangioma (arrow) in the lateral head of the left gastrocnemius in the presence of enchondromas consistent with Maffucci syndrome.

Fig. 2

Imaging of the left distal femur over time, demonstrating a soft tissue mass with cortical destruction. A: Left femoral enchondroma on axial CT 2 years prior to malignant conversion with avidity of 2.6 on associated FDG-PET. B: Same femoral enchondroma on axial CT at time of dedifferentiation demonstrating cortical thinning and breakthrough. C: FDG-PET avidity in femoral chondrosarcoma increased to 17.6. Remainder of body scan negative.

Fig. 3

Axial T1 post-gadolinium MRI demonstrating heterogeneously enhancing, intra-axial right parietal brain metastasis and surrounding vasogenic edema 4 months after primary diagnosis.

Fig. 4

Histochemistry of malignant tissue from femoral (A and B) and cerebral (C) tumor sites (hematoxylin and eosin stain). A: At low power (×10), high-grade chondrosarcoma on the right with areas of tumor necrosis on the left. B: Higher power (×20) highlights striking nuclear pleomorphism, prominent nucleoli, and mitotic activity. C: Malignant neoplasm in the brain (×20) with similar morphological features as femoral biopsy and nuclear pleomorphism, prominent nucleoli, abundant mitoses.

Fig. 5

PRISMA flow chart of search results for articles.

Fig. 6

Survival following extracranial chondrosarcoma metastatic to brain. A: Kaplan-Meier survival graph for chondrosarcomas following brain metastasis. B: Comparison of survival between patients with surgical resection versus non-surgical management of brain metastases with significantly different survival outcomes on log-rank test (p=0.024).

Table 1

Compilation of clinical characteristics of patients who subsequently developed chondrosarcoma brain metastases

Characteristic			Value (n=56)
Age at primary (yr)			43.1±18.6 (n=52)
Age at brain metastasis (yr)			46.6±17.6 (n=50)
Time to death from primary (mo), median±SE			29.0±9.1
Sex (n=55)
	Male		28 (50.9)
Origin
	Secondary chondrosarcoma		8/38 (23.7)
Primary location (n=55)
	Appendicular		27 (49.1)
	Axial^*		18 (32.7)
	Soft tissue		10 (18.2)
Primary histology (n=40)
	Conventional		19 (47.5)
	Mesenchymal		7 (17.5)
	Dedifferentiated		11 (27.5)
	Clear cell		2 (5.0)
	Periosteal		1 (2.5)
Primary grade (n=33)
	Low grade (1/2)		12 (36.4)
		1	5 (15.6)
		2	7 (21.9)
	High grade (3)		21 (63.6)
Initial primary treatment (n=46)
	Surgery		41 (89.1)
		Negative margins	23/27 (85.2)
	Radiation		11 (23.9)
	Chemotherapy		12 (26.1)
	None		2 (4.3)
Local recurrence			14/43 (32.6)
	Time to recurrence (mo), median±SE		12.0±2.8
Extracranial metastases			37/45 (82.2)
	Time to ECM (mo), median±SE		12.0±2.2
	ECM at brain metastasis Dx		32/42 (76.2)
Initial brain metastasis treatment
	Surgery		20/36 (55.5)
		Surgery only	7/26 (26.9)
		With radiation	1/26 (3.8)
		With radiation and chemotherapy	4/26 (15.4)
		With chemotherapy	1/26 (3.8)
	Radiation		9/26 (34.6)
		Radiation only	3/26 (11.5)
		With chemotherapy	1/26 (3.8)
	Chemotherapy		6/26 (23.1)
	Supportive care		9/26 (34.6)

Values are presented as mean±SD or n (%) unless otherwise specfied. ^*Axial includes pelvis/scapula. Dx, diagnosis; ECM, extracranial metastasis

Table 2

Literature review of clinical characteristics of patients with cerebral chondrosarcoma metastasis

Study	Age (primary, yr)/sex	Primary location	Primary histology/grade	Initial treatment of primary	Time to local recurrence (months)	Time to extracranial metastasis (months)	Extracranial metastases	Time to intracranial metastasis	Age (intracranial metastasis)	Initial CNS Tx resection/radiation/chemotherapy	Follow-up from primary/CNS (months)	Final status
Present case	66/M	Femur (skeletal)	Dedifferentiated/3	S (wide)+CT	None	3	Lung	3.5	67	GTR/GK/gemcitabine-docetaxel	5/1.5	Dead
Nakagawa et al. [18]	65/M	Radius (skeletal)	Conventional/2	NS	NS	41	Lung, kidney, spleen	41	68.5	-/-/-	42/1	Dead
Nakagawa et al. [18]	30/M	Tibia (skeletal)	Conventional/1	NS	NS	None	None	153	42.75	S/-/-	170/17	Alive
Shyamasunder et al. [19]	70/M	Scapula (skeletal)	NS/NS	None	None	0	Vertebrae	0	70	-/-/-	0.75/0.75	Dead
Flint et al. [20]	53/M	Femur (skeletal)	Clear cell/1	S (wide)	192	204	Lung, liver, spine	>204	NS	NS/NS/NS	NS/NS	Dead
Hussain and Ahmed [21]	NS/F	Femur (skeletal)	Conventional/NS	S (GTR)	None	NS, before brain	Lung	NS	51	S/-/Gliadel	NS/NS	Alive
Zoccali et al. [22]	60/F	Femur (skeletal)^*	Dedifferentiated/3	S (wide)+CT	None	12	Liver	6	60	S/-/-	8.0	Dead
Agarwal et al. [23]	46/F	Foot (skeletal)	Conventional/2	S (amputation)	None	None	None	72	52	STR/NS/NS	NS/NS	NS
Bekiesinska-Figatowska et al. [6]	12.5/M	Pelvis (skeletal)	Dedifferentiated/3	NS	NS	NS	NS	23	14.4	NS/NS/NS	38.4/15.4	Dead
Ghosh et al. [24]	33/M	Rib (skeletal)	NS/NS	S	NS	NS	NS	156	46	GTR/NS/NS	NS/NS	Alive
Lee et al. [25]	28/F	Lung (soft tissue)	Mesenchymal/3	S (GTR)	6	6	Liver, bone	31	31	-/RT/-	37/6	Dead
Lo et al. [26 27]	54/F	Scapula (skeletal)	Conventional/1	S (local)	9	12	Lung	24	56	S/RT/-	28/4	Alive
Niazi et al. [28]	NS/M	Femur (skeletal)	NS/NS	NS	NS	NS	Lung, heart, bone	NS	58	NS/NS/NS	NS/NS	NS
Chow [29]	25/F	Femur (skeletal)	Conventional/2	S (en bloc)	None	33	Ileum, lung	43	28.5	-/-/-	43/0	Dead
Jiang et al. [30]	38/M	Craniofacial (skeletal)	NS/NS	RT	NS	NS	NS	83	45	S/-/-	117.6/34.6	Alive
Francés-Muñoz et al. [31]	43/F	Rib (skeletal)	Conventional/2	S	None	NS, before brain	Lung, eye	120	53	NS/NS/NS	NS/NS	NS
Kawaguchi et al. [32]	70/F	Femur (skeletal)	NS/NS	S+RT	None	None	None	27	72	STR/-/-	29/2	Dead
Pontes et al. [33]	26/F	Mandible (skeletal)	Conventional/3	S (en bloc)	None	12	Spine	12	27	NS/NS/NS	24/12	Dead
Tseng et al. [34]	82/M	Cutaneous (soft tissue)	Mesenchymal/3	S	NS	NS	NS	24	84	S/NS/NS	NS/NS	NS
Tam et al. [35]	55/F	Scapula (skeletal)	Dedifferentiated/3	S (wide)+RT	None	12	Lung	16	56	-/WBRT/-	17/1	Dead
Flannery et al. [36]	13.5/M	Leg (skeletal)	NS/NS	NS	NS	NS	NS	6	14	S/GK/CT	10/4	Dead
Flannery et al. [36]	54.5/M	Pelvis (skeletal)	NS/NS	NS	NS	NS	NS	16	56	S/GK+WBRT/CT	21/5	Dead
Goda et al. [37]	39/M	Scapula (skeletal)	Conventional/1	S (positive margins)+RT	None	72	Lung, spine, soft tissue	>72	NS	NS/NS/NS	103/NS	Alive
Tsutsumi et al. [38]	60/M	Finger (skeletal)	Conventional/2	S (amputation)	None	48	Lung, heart, spleen	54	64	S/GK/Cisplatin	64/10	Alive
Bruns et al. [39]	36/M	Ileo-sacral (skeletal)	Dedifferentiated/3	S (with margins)+CT	None	3	Lung	3	36	NS/NS/NS	6/3	Dead
Bruns et al. [39]	58/M	Femur (skeletal)	Dedifferentiated/3	S (wide)+RT	None	10	Lung	10	58	NS/NS/NS	10/0	Dead
Kawanishi et al. [40]	NS/M	NS	NS/NS	NS	NS	NS	Lung, bone	NS	42	-/GK/-	NS/3.5	Alive
Patil et al. [41]	54/M	Foot (skeletal)	NS/NS	S (local curettage)	16	None	None	53	58.5	NS/NS/NS	54/1	Dead
Postovsky et al. [8]	24/F	Chest wall (soft tissue)	Mesenchymal/3	CT+RT+BMT	None	24	Lung, bone	24	26	-/RT/Cytoxan-topotecan	31.5/7.5	Dead
Yoshida et al. [42]	63/M	Sternum (skeletal)	NS/NS	S (with margins)	5	None	None	5	63.5	-/-/-	5/0	Dead
Bovée et al. [43]	46/M	Tibia (skeletal)^†	Conventional/3	S	NS	96	Lung	96	54	-/-/-	98/2	Dead
Kim et al. [44]	37/F	Heart (soft tissue)	Conventional/NS	S+CT+RT	None	None	None	20	39	S/NS/NS	NS/NS	NS
Ozaki et al. [4]	52/F	Femur (skeletal)	Conventional/3	S+CT	NS	4	Lung	4	52	-/NS/NS	14/10	Dead
Rushing et al. [45]	48/F	Caudal neuraxis (soft tissue)	Mesenchymal/3	S (GTR)+RT	24	NS	Lung	NS	NS	NS/NS/NS	84/NS	Dead
Sans et al. [46]	22/M	Foot (skeletal)	Mesenchymal/3	None	NS	0	Lung	0	22	-/-/-	0.625/0.625	Dead
Wroński et al. [47]	30/F	Hand (skeletal)	NS/NS	NS	NS	NS	Lung	35	33	S/NS/NS	39/4	Dead
Wroński et al. [47]	27/F	Craniofacial (skeletal)	NS/NS	NS	1.25	NS	No lung	11	27	S/NS/NS	12.75/1.75	Dead
Konishi et al. [48]	28/F	Knee (skeletal)	Periosteal/NS	S+CT	60	72	Lung, ovary, spleen, stomach	72	34	S/-/-	72/0	Alive
Moran et al. [49]	62/F	Larynx (soft tissue)	Conventional/NS	S (en bloc)	12	15	Lung, hypopharynx	15	63	-/-/-	NS/NS	Dead
Jallu et al. [50]	45/F	Femur (skeletal)	Conventional/2	S (wide)	None	None	None	8	45	GTR/-/-	NS/0.25	Alive
Salminen et al. [51]	68/M	Trachea (soft tissue)^*	Conventional/NS	S (local)	NS	12	Rib	36	71	NS/NS/NS	38/2	Dead
Bertoni et al. [52]	22/F	Tibia (skeletal)^*	Dedifferentiated/3	S (with margins)	7	NS	Lung, pelvis	NS	22	NS/NS/NS	12/NS	Dead
Perry et al. [53], Bertoni et al. [54]	51/F	Knee Cartilage (soft tissue)^*	Conventional/2	S (amputation)+CT	15	15	Lung	>15	53	NS/NS/NS	20/NS	Dead
Liu et al. [55]	13/F	Femur (skeletal)^†	NS/NS	S (amputation)+RT+CT	NS	NS	NS	NS	NS	NS/NS/NS	12/NS	Dead
Liu et al. [55]	64/F	Femur (skeletal)^†	Dedifferentiated/3	S (en bloc)	NS	NS	NS	NS	NS	NS/NS/NS	2/NS	Dead
Reif and Graf [56]	3/M	Caudal neuraxis (soft tissue)	Mesenchymal/3	S (GTR)+CT+RT	3	None	None	14	4	STR/-/-	15/1	Dead
Johnson et al. [57]	47/M	Pelvis	Dedifferentiated/3	S (wide)+CT	NS	5	Lung, liver, adrenal, lymph nodes, bone marrow	5	47	NS/NS/NS	6/1	Dead
ohnson et al. [57]	65/F	Pelvis (skeletal)	Dedifferentiated/3	S (wide)	3	3	Liver, lung	4	65	NS/NS/NS	4.5/0.5	Dead
Johnson et al. [57]	62/F	Femur (skeletal)	Dedifferentiated/3	CT+RT	NS	4	Lung	4	62	NS/NS/NS	6/2	Dead
Sherr et al. [58]	49/F	Pelvis (skeletal)	NS/NS	S (en bloc)	None	72	Lung, subcutaneous, oral cavity	77	57	S/-/-	81/4	Dead
Templeton et al. [59]	20/M	Mandible (skeletal)	Conventional/NS	S	NS	36	Lung	144	32	S/NS/NS	NS/NS	NS
Pialat et al. [60]	25/F	Arm (soft tissue)	Mesenchymal/3	NS	None	NS, after brain	Lung, bone, skin, muscle	24	27	NS/NS/NS	47/23	Dead
Unni et al. [61]	NS/NS	Femur (skeletal)	Clear cell/1	S	84	NS	Humerus, skull, lung, pelvis	144	NS	NS/NS/NS	156/12	Dead
Gercovich et al. [62]	54/M	Pelvis (skeletal)	NS/NS	S (en bloc)	None	43	Lung, subcutaneous	52	58	-/-/-	52.5/0.5	Dead
Talerman [63]	15/M	Tibia (skeletal)	Conventional/NS	S (amputation)	None	228	Kidney	228	34	-/-/-	228/0	Dead
Cowan [64]	28/M	Tibia (skeletal)^†	NS/NS	S (amputation)	NS	NS	NS	30	30	-/NS/NS	30/0	Dead

^*Secondary, nonsyndromic chondrosarcoma; ^†Secondary, syndromic chondrosarcoma. CNS, central nervous system; Tx, treatment; S, surgery; CT, chemotherapy; GTR, gross total resection; GK, gamma knife; STR, subtotal resection; RT, radiation; NS, not specified; -, none; WBRT, whole brain radiation therapy; BMT, bone marrow transplant

Table 3

Factors associated with time to development of brain metastases among patients with extracalvarial chondrosarcomas

Variable		Time to brain metastasis (mo)	Log-rank
From primary diagnosis		24.0±2.8
Primary histology
	Conventional (n=18)	41.0±7.4	C vs. M, p=0.033^*
	Mesenchymal (n=6)	24.0±3.0	M vs. D, p=0.015^*
	Dedifferentiated (n=9)	5.0±1.5	C vs. D, p<0.001^*
Primary grade
	1 (n=5)	144.0±78.8	1 vs. 2, p=0.037^*
	2 (n=7)	43.0±2.6	2 vs. 3, p=0.019^*
	3 (n=18)	10.0±6.4	1 vs. 3, p=0.002^*
	Low vs. high grade	54.0±16.7 vs. 10.0±6.4	p<0.001^*
Primary treatment
	Surgery vs. none	27.0±6.6 vs. 4.0±4.4	p=0.12
	Radiation (HG) vs. none	14.0±4.4 vs. 5.0±1.0	p=0.85
	Chemotherapy (HG) vs. none	4.0±0.71 vs. 12.0±4.2	p=0.1

Values are presented as median±SE unless otherwise specfied.

^*Significant at p≤0.05. C, conventional; D, dedifferentiated; ECM, extracranial metastases; HG, high grade; M, mesenchymal

Table 4

Factors associated with overall survival following brain metastases among patients with extracalvarial chondrosarcomas

		Survival (mo)	Log-rank
From brain metastasis diagnosis		2.0±0.78
	Age ≤45	4.0±0.97 vs. 2.0±0.41	p=0.14
	ECM at brain metastasis Dx	2.0±1.3 vs. 1.5±0.43	p=0.17
	Primary LG vs. HG	12.0±8.3 vs. 2.0±1.0	p=0.14
Primary histology
	Conventional	10.0±4.4	C vs. M, p=0.78
	Mesenchymal	6.0±5.5	M vs. D, p=0.39
	Dedifferentiated	1.5±0.75	C vs. D, p=0.18
Treatment
	Surgery	4.0±1.4 vs. 1.0±0.24	p=0.024^*
	Radiation	5.0±1.2 vs. 1.0±0.23	p=0.14
	Chemotherapy	5.0±1.1 vs. 1.0±0.54	p=0.38
6-Month survival		11/40 (27.5%)
12-Month survival		4/40 (10.0%)

Values are presented as median±SE unless otherwise specfied.

^*Significant at p≤0.05. C, conventional; D, dedifferentiated; Dx, diagnosis; ECM, extracranial metastases; LG, low grade; HG, high grade; M, mesenchymal

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