Japanese Journal of Clinical Oncology

Results

Of 480 patients with musculoskeletal sarcomas, 20 developed symptomatic brain metastases (4.2% of all sarcoma cases, 11.2% of cases with distant metastases). Alveolar soft part sarcoma (3/4), extraskeletal Ewing's sarcoma (2/8), rhabdomyosarcoma (2/13) and bone Ewing's sarcoma (2/18) tended to show relatively high incidences of brain metastases (Table 1).

Table 2 summarizes the clinical features of 20 patients with brain metastases. Age at diagnosis of brain metastasis ranged from 7 to 66 years. The interval between initial treatment of primary tumor and brain metastases ranged from 0 to 180 months (mean, 36 months). Presenting symptoms were headache in 10 cases, general convulsion in three cases and loss of consciousness, facial spasm, dementia, hemiplegia, visual disturbance, nausea and facial palsy in one case each. The locations of brain metastases were confirmed by computed tomography in 19 cases and by autopsy in one case. Twelve patients had solitary lesions and eight patients had multiple lesions.

Table 1. Incidence of brain metastases in muscoskeletal sarcomas

	No. of cases	No. of brain metastases
Soft tissue sarcomas	268	15
Malignant fibrous histiocytoma	69	5
Liposarcoma	54	1
Fibrosarcoma	35	0
Malignant peripheral nerve sheath tumor	27	1
Synovial sarcoma	15	0
Rhabdomyosarcoma	13	2
Angiosarcoma	11	0
Ewing's sarcoma/PNET*	8	2
Leiomyosarcoma	8	0
Hemangiopericytoma	6	1
Epithelioid sarcoma	6	0
Alveolar soft part sarcoma	4	3
Clear cell sarcoma	5	0
Extraskeletal myxoid chondrosarcoma	2	0
Mesenchymal chondrosarcoma	1	0
Unclassified	4	0
Bone sarcomas	212	5
Osteosarcoma	103	3
Chondrosarcoma	58	0
Ewing's sarcoma/PNET*	18	2
Malignant fibrous histiocytoma	14	0
Chordoma	12	0
Angiosarcoma	3	0
Fibrosarcoma	2	0
Mesenchymal chondrosarcoma	1	0
Hemangiopericytoma	1	0
Total	480	20

x*PNET, primitive neuroectodermal tumor.

Lung metastasis occurred in 16 patients (80%), four of which were synchronous and 15 metachronous with brain lesion. The time to brain metastases after lung metastases varied from 0 to 120 months. Although four patients had no lung metastasis, three of these patients had distant metastases in locations other than the lung (bone, soft tissue, retroperitoneal space). One patient had only brain metastasis. This patient had MFH of the axilla with four local recurrences (case 5).

Three patients underwent resection of brain metastases. One patient with alveolar soft part sarcoma and one patient with MFH died 24 and 16 months after craniotomy, respectively, and one patient with MFH committed suicide 4 months after craniotomy (mean survival, 14.7 months). All of them showed marked improvement of neurological symptoms and no evidence of recurrent brain tumors until their death. Five patients underwent external beam radiotherapy consisting of 30-55 Gy and their survival ranged from 1 to 8 months (mean, 3.8 months). Two of those four patients showed improved neurological symptoms and died of systemic problems and three patients died of brain metastasis. Thirteen patients received palliative steroid treatment with or without chemotherapy. Their survival ranged from 2 weeks to 8 months (mean, 2.7 months). Twelve of 13 patients died of systemic problems and one patient died of a neurological cause.

In all patients, the mean survival after diagnosis of brain metastasis was 5.1 months.

Discussion

There have been a few reports of series studying the incidence of cerebral metastasis of sarcomas ranging from 1.6 to 10% (1,2). However, these series included uterine, gastrointestinal and nasopharyngeal sarcomas. The true incidence of brain metastasis in sarcoma patients who present to orthopedic surgeons has not been well understood. Of 480 patients with sarcomas whom we reviewed, 20 (4.2%) developed brain metastases. In addition, it should be noted that among the advanced cases with distant metastases, over 10% had brain metastases.

Although it is well known that two thirds of all brain metastases are multiple (3), only eight of 20 cases were multiple in this series. Bouffet et al. (4) also reported that only three of seven sarcoma patients with brain metastases had multiple lesions.

Three of four alveolar soft tissue sarcomas developed brain metastases. Comparing our cases with the reports in the literature, this tumor most frequently metastasizes to the brain in sarcomas (2,5). The tumor sometimes presents with lung or brain metastases, which are the first manifestation of the disease (6). Skeletal metastasis, which is also rare in sarcomas, is frequent in this tumor (7). Therefore, special attention should be paid to the brain and skeletal metastases in patients with alveolar soft part sarcoma.

Various reports suggest that Ewing's sarcoma and rhabdomyosarcoma also tend to metastasize to the brain, as in our series. The introduction of effective chemotherapy for these tumors has resulted in prolonged survival and an increased incidence of intracranial metastasis (1,2,4).

Five patients with MFH was the largest number in this series. In other types of sarcomas, there seem to be no common histological types in brain metastasis. Probably almost all types of high-grade sarcomas can metastasize to the brain (1).

As in previous reports, all patients in this study had distant or local relapses, especially in the lung (1,4,5). When the patients have or had pulmonary metastases, the clinician should consider the possibility of brain metastasis.

Because most patients in this series had disseminated disease, the overall prognosis was poor. However, two of three patients who underwent total removal of the tumor survived over 1 year. Some reports indicate that complete removal of brain metastases for selected patients is associated with favorable prognosis (8,9). Of the 25 patients surgically treated in Wronski et al.'s series (8), six survived over 20 months. In particular, surgical treatment for alveolar soft part sarcoma can result in a good prognosis (8).

Table 2. Clinical summary of 20 patients with sarcoma metastatic to the brain

Patient No.	Histology	Primary site	Age, gender	Met. of other lesions	Interval lung-brain met. (months)	Symptoms	Location of met.	Treatment	Survival (months)	Cause of death
Soft tissue
1	MFH	R.thigh	43, F	Lung, bone	0	Headache	R. parietal	Conservative	3	Systemic
2	MFH	L. thigh	66, M	Lung	0	General convulsion	L. frontal	Conservative	2	Systemic
3	MFH	L. back	45, M	Lung, bowel	10	General convulsion	R. frontal	Surgery	4	Suicide
4	MFH	L. thigh	65, F	Lung	0	Headache	R. temporal	Surgery	16	Systemic
5	MFH	L. axilla	40, F	-	-	Loss of consciousness	L. frontal	Conservative	0.5	Neurological
6	ASPS	R. thigh	61, M	Lung, bone, bowel	84	Dementia	R. temporal	Surgery	24	Systemic
7	ASPS	R. calf	38, M	Lung, bone soft tissue,	120	Headache	L. temporal	Conservative	4	Systemic
8	ASPS	L. calf	20, F	Lung, bone, soft tissue	24	Headache	Multiple	Chemotherapy	4	Systemic
9	Rhabdomyosarcoma	L. forearm	7, F	Bone, soft tissue	-	Headache	Multiple	Chemotherapy	4	Systemic
10	Rhabdomyosarcoma	L. thigh	16, M	Lung	3	Hemiplesia	L. parietal	Radiation	1	Neurological
11	Ewing's sarcoma	L. thigh	44, M	Lung, bone	3	Headache	R.temporal	Conservative	1	Systemic
12	Ewing's sarcoma	R. buttock	17, F	Lung, bone	4	Headache	L. occipital	Conservative	6	Systemic
13	MPNST	R. forearm	61, M	Lung	2	Facial convulsion	Multiple	Radiation	4	Systemic
14	Myxoid liposarcoma	L. buttock	62, F	Lung, bone soft tissue,	2	Headache	Multiple	Radiation	4	Systemic
15	Hemangiopericytoma	L. thigh	46, M	Lung, bone, liver, soft tissue	10	General convulsion	Multiple	Conservative	1	Systemic
Bone
16	Osteosarcoma	L. tibia	52, M	Retroperitoneal	-	Visual disturbance	L. parietal	Radiation	8	Neurological
17	Osteosarcoma	L. femur	14, F	Lung	2	Nausea	L. temporal	Conservative	2	Systemic
18	Osteosarcoma	R. femur	11, F	Lung	12	Headache	Multiple	Chemotherapy	6	Systemic
19	Ewing's sarcoma	L. femur	15, M	Lung, bone	1	Headache	Multiple	Radiation	2	Neurological
20	Ewing's sarcoma	Sacrum	17, M	Bone, soft tissue	-	Facial palsy	Multiple	Chemotherapy	1	Neurological

MFH, malignant fibrous histiocytoma; ASPS, alveolar soft part sarcoma; MPNST, malignant peripheral nerve sheath tumor; met, metastases; L., left; R., right.

Radiation may benefit patients with multiple metastases or poor general condition (10). Five patients in this series underwent radiotherapy and two of them showed improved neurological symptoms and died of systemic disease. Recently, stereotactic radiosurgery has been used for some patients with metastatic brain tumors. Radiosurgery is an effective, safe treatment and appears to be beneficial for the patients with inoperable lesions (11).

Because most patients with metastatic brain sarcomas are in poor medical condition and have been pretreated heavily with chemotherapy, the effect of additional chemotherapy is generally poor (6). However, a few reports have described a complete response to chemotherapy in patients with metastatic brain sarcomas (10,12). These cases indicate that chemotherapy should be considered for patients with metastatic brain sarcomas.

In conclusion, brain metastases are not uncommon in advanced musculoskeletal sarcomas. Patients with alveolar soft part sarcoma, rhabdomyosarcoma, Ewing's sarcoma and pulmonary metastases have a high risk of brain involvement. Surgical treatment for selected patients can result in long survival.