Clin Exp Metastasis (2015) 32:345–351 DOI 10.1007/s10585-015-9713-6
RESEARCH PAPER
Postoperative brain metastases in soft tissue sarcomas Hiroshi Urakawa1 • Satoshi Tsukushi1 • Eiji Kozawa1 • Kunihiro Ikuta1 Shunsuke Hamada1 • Naoki Ishiguro1 • Yoshihiro Nishida1
•
Received: 12 November 2014 / Accepted: 5 March 2015 / Published online: 21 March 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Brain metastases (BMs) from soft tissue sarcoma (STS) are rare but lethal. We reviewed 187 consecutive patients with STS treated with definitive surgery in Nagoya University Hospital from 2004 to 2014. There were 10 patients with neurofibromatosis-1 (NF-1). We investigated estimated brain metastasis free survival (BMFS) after surgery and overall survival (OS) after BMs in STS. The factors that affected BMFS were also investigated. Eight of 187 patients (4.3 %) developed BM with a median period of 18.2 (range 8.8–42.6) months after surgery. Seven of 8 BM patients had metastases at other sites. Estimated 5 year BMFS rate after surgery was 95.2 %, and 3 month OS rate after BM was 25.0 %. NF-1 (p \ 0.0001), histological subtype of MPNST (p = 0.008), and primary tumor size C5 cm (p = 0.021) were significantly associated with increasing incidence of BM. In this study, postoperative BMs were common in patients with NF-1, MPNST, and large tumors. Considering the impact of NF-1 on BMFS, careful follow up for BM is necessary for NF-1 patients with metastases at other sites. Keywords Brain metastasis Soft tissue sarcoma Malignant peripheral nerve sheath tumor Neurofibromatosis-1 Survival Abbreviations BM Brain metastases STS Soft tissue sarcoma
& Hiroshi Urakawa [email protected] 1
Department of Orthopedic Surgery, Nagoya University Graduate School and School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, Aichi 466-8550, Japan
NF-1 BMFS OS MRI CT MFH MPNST ASPS PNET DFS
Neurofibromatosis-1 Brain metastasis free survival Overall survival Magnetic resonance image Computed tomography Malignant fibrous histiocytoma Malignant peripheral nerve sheath tumor Alveolar soft part sarcoma Primitive neuroectodermal tumor Disease free survival
Introduction Soft tissue sarcoma (STS) is a rare malignant tumor, with an annual incidence in the United States of approximately 12,000 new cases [1]. STSs comprise a heterogeneous group with a wide spectrum in terms of anatomic location and histologic type. The incidence of brain metastases (BMs) has been reported to be 1.0–7.2 % of STS patients [2–5]. Brain imaging is not performed routinely after definitive surgery in STS patients [6], and the optimal follow up method and/or period for STS brain recurrence have not been established. The prognosis after BMs has been reported as dismal in STS patients, but metastasectomy has been associated with an improved median post BM survival [3, 4]. In one study, favorable survival rates of 40 % at 1 year and 16 % at 2 years were reported after metastasectomy in sarcoma patients [7]. Early detection of BMs may contribute to increasing metastasectomy and improvement of post BM survival. The first aim of this study was to identify estimated brain metastasis free survival (BMFS) after surgery and
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346
estimated overall survival (OS) after BMs in STS patients. The second purpose was to identify the factors influencing postoperative BMFS and the clinical features of STS patients with BMs.
Clin Exp Metastasis (2015) 32:345–351 Table 1 Patient demographics Characteristics
Value (range) or no. of patients (%)
Sex
Patients and methods
Male
96 (51.3 %)
Female
91 (48.7 %)
Age, years
Patients
Median (range)
57 (0–92)
Tumor status
We reviewed 285 patients with STS treated with definitive surgery in Nagoya University Hospital from 2004 to 2014. Patients with well differentiated liposarcoma (n = 30), or dermatofibrosarcoma protuberans (n = 26) were excluded. Patients followed for less than 1 year postoperatively unless they had an early BM event were excluded from analysis (n = 42). We analyzed 187 consecutive patients (Table 1). This study was approved by the ethics committee of Nagoya University Graduate School and School of Medicine (Nagoya, Japan) in October 2014. After obtaining a waiver of patient informed consent requirements from the institutional review board, 187 consecutive patients with STS were retrospectively reviewed.
Primary Unplanned excision Recurrence
Usually, following diagnosis and staging, the primary management aimed to excise the tumor with wide margins from the tumor rim wherever possible. In cases subjected to unplanned initial excision requiring secondary definitive surgery, definitive surgery was undertaken within 2 months of the unplanned procedure to secure a wide margin from the site of the previous surgical manipulations wherever possible. Amputation was reserved for large tumors, which could only be surgically removed safely by such a procedure. Postoperative radiotherapy was administered selectively only to cases with microscopically positive or partially inadequate margins. Adjuvant chemotherapy was performed in the case of small round cell and synovial sarcomas. High grade, large and deep sarcomas are relative indications for adjuvant chemotherapy.
14 (7.5 %)
Size, cm B5
70 (37.4 %)
[5
117 (62.6 %)
Anatomic site Extremity Trunk
147 (78.6 %) 40 (21.4 %)
Depth Superficial
94 (50.3 %)
Deep
93 (49.7 %)
Histological grade Low
Treatment
137 (73.3 %) 36 (19.3 %)
7 (3.7 %)
High-intermediate
180 (96.3 %)
Histological subtype MFH
56 (29.9 %)
Liposarcoma
31 (16.6 %)
MPNST
18 (9.6 %)
Myxofibrosarcoma
13 (7.0 %)
Synovial sarcoma
12 (6.4 %)
Fibromyxoid sarcoma
9 (4.8 %)
Leiomyosarcoma
6 (3.2 %)
Others
42 (22.5 %)
NF-1 Yes
10 (5.3 %)
No
177 (94.7 %)
Follow-up, months Median (range)
52.4 (11.3–129.6)
MFH, malignant fibrous histiocytoma, MPNST, malignant peripheral nerve sheath tumor, NF-1, neurofibromatosis-1
Follow up Patients with high and intermediate grade STS were followed every 3 months by physical examination to detect any local recurrence, by magnetic resonance image (MRI) of the primary site every 6 months, and by computed tomography (CT) of the chest every 3 months until 2 years after surgery and every 6 months thereafter. Patients with low grade STS were followed every 6 months by physical examination to detect any local recurrence, by MRI of the primary site every 6 or 12 months, and chest CT in some
123
cases. Imaging of brain was not performed routinely, but was performed in symptomatic cases or when judged advisable by the attending physician. Statistics Clinical data were collected from the patients’ clinical records. BMFS and OS rates were calculated using Kaplan–Meier product limit methods. BM free period was counted (months) from the date of the definitive surgery for
Clin Exp Metastasis (2015) 32:345–351
local control to the date of BM, and survival periods were counted (months) from the date of BM to the date of death or last follow-up time before study closure. Clinical factors such as sex, age (C50, \50), primary tumor size (C5 cm, \5 cm), sites (trunk, extremity), tumor depth (superficial, deep), histological grade (high-intermediate, low), histological subtype, and neurofibromatosis type 1 (NF-1) were analyzed for postoperative BMFS by log-rank test. Superficial tumor was defined to be located exclusively above the superficial fascia without invasion of the fascia. p values of \0.05 were considered significant.
Results There were 96 males and 91 females with a median age of 57 (range 0–92) years. Patients and tumor characteristics are summarized in Table 1. Ten patients with NF-1 were included in this study. In terms of histological subtypes, please see Table 1. Forty-two others included extraskeletal Ewing sarcoma (n = 7), solitary fibrous tumor (n = 6), fibrosarcoma (n = 6), rhabdomyosarcoma (n = 3), angiosarcoma (n = 2), alveolar soft part sarcoma (ASPS) (n = 2), clear cell sarcoma (n = 2), granular cell tumor (n = 2), inflammatory myofibroblastic tumor (n = 2), epithelioid sarcoma (n = 1), extraskeletal osteosarcoma (n = 1), extraskeletal myxoid chondrosarcoma (n = 1), and sarcoma, not otherwise specified (n = 7). Surgical treatments were performed in all cases, 179 resections and 8 amputations. 155 cases achieved negative margins excluding close margins. Perioperative radiotherapy was administered to 22, and chemotherapy to 42 of the total cases. The median follow-up period after surgery was 52.4 (range 11.3–129.6) months. Forty-nine of 187 patients (26.2 %) developed distant metastases after surgery with a median period of 9.1 (range 0.3-49.4) months. Distant metastases included lung (n = 31), bone (n = 13), muscle/soft tissue/skin (n = 13), lymph node (n = 10), liver (n = 7), and other viscera (n = 4). Eight of 187 patients (4.3 %) developed BM at a median period of 18.2 (range 8.8–42.6) months after surgery (Table 2). The histologic subtypes of 8 BMs were malignant peripheral nerve sheath tumor (MPNST) (n = 3), liposarcoma (n = 2), malignant fibrous histiovcytoma (MFH) (n = 1), clear cell sarcoma (n = 1), and primitive neuroectodermal tumor (PNET) (n = 1). Seven of 8 patients had metastases at other sites at diagnosis of BMs, and the median period from first metastases at other sites to BMs was 19.4 (7.5–37.4) months. Estimated 5 year BMFS rate after surgery was 95.2 % (Fig. 1). In univariate analysis, NF-1 (p \ 0.0001, Fig. 2a), histological subtype of MPNST (p = 0.008, Fig. 2b), and primary tumor size C5 cm (p = 0.021, Fig. 2c) were significantly associated with increasing BM incidence after surgery (Table 3).
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Of 8 BM patients, 7 were symptomatic, and one asymptomatic. One case was unexpectedly diagnosed by brain MRI. Of the 7 symptomatic BM patients, 3 were paralyzed, and the remaining patients had symptoms of vomiting, consciousness disorder, convulsion, and headache, respectively. Three patients had a single BM, and 5 had multiple ones. The three single BMs occurred in the cerebrum (n = 2) and cerebellum (n = 1). Seven of the 8 BM patients died during the follow up period, and the estimated 3 month OS rate and median survival after BM were 25.0 % and 1.8 months respectively (Fig. 3) in 8 the patients with BMs. Three BMs occurred in MPNST patients with other metastases, and aggressive tumor behavior was observed in these patients (Fig. 4).
Discussion This is the first report to have focused on postoperative BM in STS. There have been some clinical series of BMs in bone and/or STS [2–5, 8], but these series included both bone and soft tissue or selected for patients with metastases diagnosed at either the first or subsequent visits. In our study, 8 of 187 patients (4.3 %) developed BMs, with the incidence of BM being similar to that previously reported [2–4]. There are some limitations in our study. First, the detection of BMs depended on the patients’ symptoms since brain imaging was not performed routinely, meaning that we could not detect all cases of asymptomatic BM. Second, this study included various types of STS, small cell and non-small cell sarcoma, both pediatric and adult cases, but most cases were non-small round STSs in adults. Third, we could not perform multivariate analysis because of the small number of BMs and lack of statistical power. There were a relatively small number of patients with NF-1 and MPNST in our study, and so the number of BMs in our series was much fewer than would have been expected otherwise, and a small change of even one or two events may have affected our results. In a report of 40 BMs in STS, the most frequent histological subtypes of STS metastasizing to the brain were leiomyosarcoma (n = 8), liposarcoma (n = 5), rhabdomyosarcoma (n = 4), and MFH (n = 4) [3]. Another series of 35 bone and STS BMs, also reported leiomyosarcoma as the most frequent STS histology (n = 7), followed by ASPS (n = 3), rhabdomyosarcomas (n = 2), and liposarcoma (n = 1) [8]. Whereas a third series of 20 bone and STS BMs reported a slightly different distribution of frequencies for the STS, including MFH (n = 5), ASPS (n = 3), rhabdomyosarcomas (n = 2), Ewing sarcomas/PNET (n = 2), and one each MPNST, liposarcoma, and hemangiopericytoma [2]. MPNST was the most common histology to develop BM in our series. A previous report described BM in 2 of 30
123
123
51/M
38/F
32/F
38/F
55/M
59/F
73/M
80/M
1
2
3
4
5
6
7
8
III
III
III
III
III
IIB
III
III
Stagea at diagnosis
PNET
Clear cell sarcoma
MFH
Liposarcoma
Liposarcoma
MPNST
MPNST
MPNST
Histological subtype
No
No
No
No
Yes
No
Yes
Yes
NF-1
Thigh
Thigh
Buttock
Thigh
Back
Back
Neck
Neck
Site of primary tumor
14
6
16
14
10
6
6
10
Size of primary tumor, cm
Chemotherapy
–
–
–
Chemotherapy
–
Chemotherapy
Chemotherapy, radiation
Adjuvant treatments
16.5
8.8
24.0
19.8
20.2
42.6
13.9
15.8
Time to BMs, months
No
Yes
Yes
Yes
Yes
Yes
No
No
Multiple BMs
Lung, liver, pancreas
–
Lung
Lung, lymph node
Lung
Lung, skin
Lung
Lung, bone
Presence of other metastases
–
–
Radiotherapy
-
Radiotherapy
Radiotherapy, metasectomy
Radiotherapy
–
Treatment for BMs
1.2
2.5
2.9
1.8
0.3
49.7
4.5
1.0
Follow up duration, months
DOD
DOD
DOD
DOD
DOD
AWD
DOD
DOD
Final status
MPNST malignant peripheral nerve sheath tumor, MFH malignant fibrous histiocytoma, PNET primitive neurectodermal tumors, NF-1 neurofibromatosis-1, BM brain metastasis, DOD dead of disease, AWD alive with disease a Stage, AJCC staging manual (7th edition)
Age/sex
Case
Table 2 Patients with brain metastases
348 Clin Exp Metastasis (2015) 32:345–351
Clin Exp Metastasis (2015) 32:345–351
349
Fig. 1 Postoperative brain metastasis free survival. The graph shows the cumulative postoperative brain metastasis free survival rate of soft tissue sarcoma patients (n = 187) using the Kaplan–Meier method
MPNST patients (5.3 %) [5]. Our series included 9 MPNST patients related to NF-1; two of them developed BMs after surgery. A worse outcome has been reported in MPNST patients with NF-1 compared to sporadic MPNST patients [9, 10]. Previous reports showed that the rate of NF-1 in MPNST patients was 22–52 % [9–11], but, in our study, 9 of 18 (50.0 %) MPNSTs were NF-1 related. Even though previous studies on BM in STS patients did not mention the proportion of NF-1 patients [2, 3, 5], the relatively high proportion of NF-1 patients in our study may have affected the high frequency of BMs in MPNSTs. Past reports noted some histological subtypes that are associated with an increased incidence of BMs in STS. Concurrent BMs were reported in 19 % of stage IV patients with ASPS [12], and 4 of 13 (30.8 %) ASPS patients were reported to have BMs [4]. Another report noted that 3 of 4 (75 %) ASPS cases had BMs [2], but no postoperative BMs developed in 2 patients of ASPS in our study. Univariate analysis revealed that MPNST had a significant impact on increasing the incidence of BM after surgery, and 3 of 18 (16.7 %) MPNST patients had BMs in our study. A review article focused on 21 reported MPNST patients with BMs from 1963 to 2012 [13]. MPNST patients with BM were noted to have an average age of 36.6 years, which is younger than that of other STSs and similar to that of our patients. Distant metastasis was reported to have occurred in 39 % of patients with NF-1, and 16 % without NF-1, most commonly to lung, and also to soft tissue, bone, liver, abdominal cavity, adrenal glands, diaphragm, mediastinum, brain, ovaries, kidneys, and retroperitoneum [10]. In our previous study, OS and disease free survival (DFS) rate at 5 years were 83 and 63 % respectively in patients with MPNST from 1986 to 2011 [14]. Large tumor size was an independent prognostic factor for survival and/
Fig. 2 Postoperative brain metastasis free survival in different groups. The graph shows the cumulative postoperative brain metastasis free survival rate of soft tissue sarcoma patients with two different groups (n = 187) of a with or without neurofibromatosis-1, b MPNST or non MPNST, and c primary tumor size more than 5 cm or within 5 cm using the Kaplan–Meier method
or DFS in STS patients [14–16]. Large tumor size is associated with biological aggressiveness and highly metastatic potential of the tumor. Large tumor size was
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350
Clin Exp Metastasis (2015) 32:345–351
Table 3 Univariate analysis of clinical variables for brain metastasis Variable
5-years estimated brain metastasis free survival, (%)
p*
Sex Male
95.6
Female
94.9
0.996
Age, years C50
96.1
\50
94.0
Primary tumor size, cm C5 92.1 \5
0.595
0.021
100
Site Trunk
92.2
Extremity
96.1
0.246
Tumor depth Superficial
97.7
Deep
92.5
0.131
Fig. 3 Overall survival after brain metastasis. The graph shows the cumulative overall survival rate of soft tissue sarcoma patients after the diagnosis of brain metastases (n = 8) using the Kaplan–Meier method
Histological grade High-intermediate
95.0
Low
100
0.555
Histological subtype MFH
98.0
Others
94.1
0.265
Liposarcoma Others
92.9 95.7
0.451
MPNST
82.1
0.008
Others
96.8
NF-1 Yes
70.0
No
96.7
\0.0001
MFH malignant fibrous histiocytoma, MPNST malignant peripheral nerve sheath tumor, NF-1 neurofibromatosis-1 * Log-rank test
also associated with an increased morbidity from BMs after surgery in our study. As shown in Table 2, all primary tumors were more than 5 cm in patients with BMs, and potential aggressiveness of large tumor strongly affected the occurrence of BMs. Histological tumor grade is a known prognostic factor for metastasis in STS patients [15, 17]. In our study, there was no patient with BM who had low grade STS, but no statistical significance was observed between the histological tumor grade and BMFS. Our study included only 9 cases of low grade tumor, and there was a lack of statistical power for determination of the relationship between histological tumor grade and BMFS. Median OS from craniotomy has been reported as 7 months in BM patients of bone and STS [7]. Another retrospective study showed that metastasectomy for BM of STS was associated with an improved postmetastasis
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Fig. 4 A case of brain metastasis in NF-1 related MPNST. Magnetic resonance T2-weighted image at diagnosis of brain metastasis in NF-1 related MPNST (a) and T2-weighted image of brain metastasis after 6 days (b)
Clin Exp Metastasis (2015) 32:345–351
survival (9.6 months compared with 2.7 months for those patients who did not undergo resection) [3]. Prognostic factors associated with better post BM survival have been reported to include ASPS histology, initial surgical treatment, and brain irradiation for non-surgical treatment patients [4]. In our study, metastasectomy for BM was performed in only 1 of 8 patients with BM, and the median OS after BM was 1.8 months and dismal in our study. Interestingly, however, that one patient treated by metastasectomy and radiation for BM was still alive at 49.7 months after BM, underlining that surgical treatment for selected BM patients can result in long survival. The number of BMs has been reported as one of the prognostic factors in patients with BMs [18]. It can affect resectability of BMs, but there was no tendency between the number of BMs and prognosis in our study. There is a possibility that early detection of BM may improve the prognosis after BM detection. In our series, 7 of 8 BM patients had lung metastases with or without other metastatic site involvement. Other reports also showed a high incidence of other site metastases in BM patients with STS [2–5]. Since blood from the lungs flows directly to the brain, lung cancer is capable of spreading to the brain [19], and lung metastasis can cause BM in STS. Routine brain imaging may not be indicated for all STS patients after definitive surgery because of cost. In our study, NF-1, histological subtype of MPNST, and primary tumor size C5 cm were significantly associated with increasing incidence of BMs after surgery. It is reasonable to perform brain imaging for metastatic STS patients when these risk factors are present. In our study, the median interval from first metastases at other sites to BMs was 19.4 (7.5–37.4) months in 7 patients, but it is difficult to determine the adequate follow up interval of brain imaging from our results. In conclusion, BMs from STS are rare but lethal. Postoperative BMs were common in patients with NF-1, MPNST, and large tumor. Considering the impact of NF-1 on BMFS, careful follow up for BM is necessary for STS patients with NF-1 after metastases at other sites. Acknowledgment assistance.
We thank Miss Eri Ishihara for secretarial
Conflict of interest All the authors declare that they have no financial and personal relationships with any other persons or organizations that could potentially and inappropriately influence their work and conclusion. Funding One or more of the authors (H.U.) has received research funding from the Ministry of Education, Culture, Sports, Science and
351 Technology of Japan [Grant-in-Aid 24791533 for Scientific Research (C)].
References 1. Siegel R et al (2014) Cancer statistics, 2014. Cancer J Clin 64(1):9–29 2. Ogose A et al (1999) Brain metastases in musculoskeletal sarcomas. Jpn J Clin Oncol 29(5):245–247 3. Espat NJ et al (2002) Soft tissue sarcoma brain metastases. Prevalence in a cohort of 3829 patients. Cancer 94(10):2706–2711 4. Chou YS et al (2011) Brain, the last fortress of sarcoma: similar dismal outcome but discrepancy of timing of brain metastasis in bone and soft tissue sarcoma. J Surg Oncol 104(7):765–770 5. Yoshida S et al (2000) Brain metastasis in patients with sarcoma: an analysis of histological subtypes, clinical characteristics, and outcomes. Surg Neurol 54(2):160–164 6. von Mehren M et al (2012) Soft tissue sarcoma, version 2.2012: featured updates to the NCCN guidelines. J Nat Compr Cancer Netw 10(8):951–960 7. Wronski M et al (1995) Resection of brain metastases from sarcoma. Ann Surg Oncol 2(5):392–399 8. Salvati M et al (2010) Sarcoma metastatic to the brain: a series of 35 cases and considerations from 27 years of experience. J Neuro-oncol 98(3):373–377 9. Evans DG et al (2002) Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet 39(5):311–314 10. Ducatman BS et al (1986) Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer 57(10):2006–2021 11. Anghileri M et al (2006) Malignant peripheral nerve sheath tumors: prognostic factors and survival in a series of patients treated at a single institution. Cancer 107(5):1065–1074 12. Portera CA Jr et al (2001) Alveolar soft part sarcoma: clinical course and patterns of metastasis in 70 patients treated at a single institution. Cancer 91(3):585–591 13. Shweikeh F et al (2014) Brain metastasis in bone and soft tissue cancers: a review of incidence, interventions, and outcomes. Sarcoma 2014:475175 14. Ikuta K et al (2014) Hyaluronan expression as a significant prognostic factor in patients with malignant peripheral nerve sheath tumors. Clin Exp Metastasis 31(6):715–725 15. Gronchi A et al (2010) Extremity soft tissue sarcoma in a series of patients treated at a single institution: local control directly impacts survival. Ann Surg 251(3):506–511 16. Urakawa H, et al. (2013) Association of short duration from initial symptoms to specialist consultation with poor survival in soft-tissue sarcomas. Am J Clin Oncol. doi:10.1097/COC. 0b013e318295aea2 17. Coindre JM et al (2001) Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer 91(10):1914–1926 18. Barnholtz-Sloan JS et al (2012) A nomogram for individualized estimation of survival among patients with brain metastasis. Neuro-oncology 14(7):910–918 19. Rades D et al. (2013) Brain metastasis. Prognostic value of the number of involved extracranial organs. Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft [et al] 189(12):996–1000
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RESEARCH PAPER
Postoperative brain metastases in soft tissue sarcomas Hiroshi Urakawa1 • Satoshi Tsukushi1 • Eiji Kozawa1 • Kunihiro Ikuta1 Shunsuke Hamada1 • Naoki Ishiguro1 • Yoshihiro Nishida1
•
Received: 12 November 2014 / Accepted: 5 March 2015 / Published online: 21 March 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Brain metastases (BMs) from soft tissue sarcoma (STS) are rare but lethal. We reviewed 187 consecutive patients with STS treated with definitive surgery in Nagoya University Hospital from 2004 to 2014. There were 10 patients with neurofibromatosis-1 (NF-1). We investigated estimated brain metastasis free survival (BMFS) after surgery and overall survival (OS) after BMs in STS. The factors that affected BMFS were also investigated. Eight of 187 patients (4.3 %) developed BM with a median period of 18.2 (range 8.8–42.6) months after surgery. Seven of 8 BM patients had metastases at other sites. Estimated 5 year BMFS rate after surgery was 95.2 %, and 3 month OS rate after BM was 25.0 %. NF-1 (p \ 0.0001), histological subtype of MPNST (p = 0.008), and primary tumor size C5 cm (p = 0.021) were significantly associated with increasing incidence of BM. In this study, postoperative BMs were common in patients with NF-1, MPNST, and large tumors. Considering the impact of NF-1 on BMFS, careful follow up for BM is necessary for NF-1 patients with metastases at other sites. Keywords Brain metastasis Soft tissue sarcoma Malignant peripheral nerve sheath tumor Neurofibromatosis-1 Survival Abbreviations BM Brain metastases STS Soft tissue sarcoma
& Hiroshi Urakawa [email protected] 1
Department of Orthopedic Surgery, Nagoya University Graduate School and School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, Aichi 466-8550, Japan
NF-1 BMFS OS MRI CT MFH MPNST ASPS PNET DFS
Neurofibromatosis-1 Brain metastasis free survival Overall survival Magnetic resonance image Computed tomography Malignant fibrous histiocytoma Malignant peripheral nerve sheath tumor Alveolar soft part sarcoma Primitive neuroectodermal tumor Disease free survival
Introduction Soft tissue sarcoma (STS) is a rare malignant tumor, with an annual incidence in the United States of approximately 12,000 new cases [1]. STSs comprise a heterogeneous group with a wide spectrum in terms of anatomic location and histologic type. The incidence of brain metastases (BMs) has been reported to be 1.0–7.2 % of STS patients [2–5]. Brain imaging is not performed routinely after definitive surgery in STS patients [6], and the optimal follow up method and/or period for STS brain recurrence have not been established. The prognosis after BMs has been reported as dismal in STS patients, but metastasectomy has been associated with an improved median post BM survival [3, 4]. In one study, favorable survival rates of 40 % at 1 year and 16 % at 2 years were reported after metastasectomy in sarcoma patients [7]. Early detection of BMs may contribute to increasing metastasectomy and improvement of post BM survival. The first aim of this study was to identify estimated brain metastasis free survival (BMFS) after surgery and
123
346
estimated overall survival (OS) after BMs in STS patients. The second purpose was to identify the factors influencing postoperative BMFS and the clinical features of STS patients with BMs.
Clin Exp Metastasis (2015) 32:345–351 Table 1 Patient demographics Characteristics
Value (range) or no. of patients (%)
Sex
Patients and methods
Male
96 (51.3 %)
Female
91 (48.7 %)
Age, years
Patients
Median (range)
57 (0–92)
Tumor status
We reviewed 285 patients with STS treated with definitive surgery in Nagoya University Hospital from 2004 to 2014. Patients with well differentiated liposarcoma (n = 30), or dermatofibrosarcoma protuberans (n = 26) were excluded. Patients followed for less than 1 year postoperatively unless they had an early BM event were excluded from analysis (n = 42). We analyzed 187 consecutive patients (Table 1). This study was approved by the ethics committee of Nagoya University Graduate School and School of Medicine (Nagoya, Japan) in October 2014. After obtaining a waiver of patient informed consent requirements from the institutional review board, 187 consecutive patients with STS were retrospectively reviewed.
Primary Unplanned excision Recurrence
Usually, following diagnosis and staging, the primary management aimed to excise the tumor with wide margins from the tumor rim wherever possible. In cases subjected to unplanned initial excision requiring secondary definitive surgery, definitive surgery was undertaken within 2 months of the unplanned procedure to secure a wide margin from the site of the previous surgical manipulations wherever possible. Amputation was reserved for large tumors, which could only be surgically removed safely by such a procedure. Postoperative radiotherapy was administered selectively only to cases with microscopically positive or partially inadequate margins. Adjuvant chemotherapy was performed in the case of small round cell and synovial sarcomas. High grade, large and deep sarcomas are relative indications for adjuvant chemotherapy.
14 (7.5 %)
Size, cm B5
70 (37.4 %)
[5
117 (62.6 %)
Anatomic site Extremity Trunk
147 (78.6 %) 40 (21.4 %)
Depth Superficial
94 (50.3 %)
Deep
93 (49.7 %)
Histological grade Low
Treatment
137 (73.3 %) 36 (19.3 %)
7 (3.7 %)
High-intermediate
180 (96.3 %)
Histological subtype MFH
56 (29.9 %)
Liposarcoma
31 (16.6 %)
MPNST
18 (9.6 %)
Myxofibrosarcoma
13 (7.0 %)
Synovial sarcoma
12 (6.4 %)
Fibromyxoid sarcoma
9 (4.8 %)
Leiomyosarcoma
6 (3.2 %)
Others
42 (22.5 %)
NF-1 Yes
10 (5.3 %)
No
177 (94.7 %)
Follow-up, months Median (range)
52.4 (11.3–129.6)
MFH, malignant fibrous histiocytoma, MPNST, malignant peripheral nerve sheath tumor, NF-1, neurofibromatosis-1
Follow up Patients with high and intermediate grade STS were followed every 3 months by physical examination to detect any local recurrence, by magnetic resonance image (MRI) of the primary site every 6 months, and by computed tomography (CT) of the chest every 3 months until 2 years after surgery and every 6 months thereafter. Patients with low grade STS were followed every 6 months by physical examination to detect any local recurrence, by MRI of the primary site every 6 or 12 months, and chest CT in some
123
cases. Imaging of brain was not performed routinely, but was performed in symptomatic cases or when judged advisable by the attending physician. Statistics Clinical data were collected from the patients’ clinical records. BMFS and OS rates were calculated using Kaplan–Meier product limit methods. BM free period was counted (months) from the date of the definitive surgery for
Clin Exp Metastasis (2015) 32:345–351
local control to the date of BM, and survival periods were counted (months) from the date of BM to the date of death or last follow-up time before study closure. Clinical factors such as sex, age (C50, \50), primary tumor size (C5 cm, \5 cm), sites (trunk, extremity), tumor depth (superficial, deep), histological grade (high-intermediate, low), histological subtype, and neurofibromatosis type 1 (NF-1) were analyzed for postoperative BMFS by log-rank test. Superficial tumor was defined to be located exclusively above the superficial fascia without invasion of the fascia. p values of \0.05 were considered significant.
Results There were 96 males and 91 females with a median age of 57 (range 0–92) years. Patients and tumor characteristics are summarized in Table 1. Ten patients with NF-1 were included in this study. In terms of histological subtypes, please see Table 1. Forty-two others included extraskeletal Ewing sarcoma (n = 7), solitary fibrous tumor (n = 6), fibrosarcoma (n = 6), rhabdomyosarcoma (n = 3), angiosarcoma (n = 2), alveolar soft part sarcoma (ASPS) (n = 2), clear cell sarcoma (n = 2), granular cell tumor (n = 2), inflammatory myofibroblastic tumor (n = 2), epithelioid sarcoma (n = 1), extraskeletal osteosarcoma (n = 1), extraskeletal myxoid chondrosarcoma (n = 1), and sarcoma, not otherwise specified (n = 7). Surgical treatments were performed in all cases, 179 resections and 8 amputations. 155 cases achieved negative margins excluding close margins. Perioperative radiotherapy was administered to 22, and chemotherapy to 42 of the total cases. The median follow-up period after surgery was 52.4 (range 11.3–129.6) months. Forty-nine of 187 patients (26.2 %) developed distant metastases after surgery with a median period of 9.1 (range 0.3-49.4) months. Distant metastases included lung (n = 31), bone (n = 13), muscle/soft tissue/skin (n = 13), lymph node (n = 10), liver (n = 7), and other viscera (n = 4). Eight of 187 patients (4.3 %) developed BM at a median period of 18.2 (range 8.8–42.6) months after surgery (Table 2). The histologic subtypes of 8 BMs were malignant peripheral nerve sheath tumor (MPNST) (n = 3), liposarcoma (n = 2), malignant fibrous histiovcytoma (MFH) (n = 1), clear cell sarcoma (n = 1), and primitive neuroectodermal tumor (PNET) (n = 1). Seven of 8 patients had metastases at other sites at diagnosis of BMs, and the median period from first metastases at other sites to BMs was 19.4 (7.5–37.4) months. Estimated 5 year BMFS rate after surgery was 95.2 % (Fig. 1). In univariate analysis, NF-1 (p \ 0.0001, Fig. 2a), histological subtype of MPNST (p = 0.008, Fig. 2b), and primary tumor size C5 cm (p = 0.021, Fig. 2c) were significantly associated with increasing BM incidence after surgery (Table 3).
347
Of 8 BM patients, 7 were symptomatic, and one asymptomatic. One case was unexpectedly diagnosed by brain MRI. Of the 7 symptomatic BM patients, 3 were paralyzed, and the remaining patients had symptoms of vomiting, consciousness disorder, convulsion, and headache, respectively. Three patients had a single BM, and 5 had multiple ones. The three single BMs occurred in the cerebrum (n = 2) and cerebellum (n = 1). Seven of the 8 BM patients died during the follow up period, and the estimated 3 month OS rate and median survival after BM were 25.0 % and 1.8 months respectively (Fig. 3) in 8 the patients with BMs. Three BMs occurred in MPNST patients with other metastases, and aggressive tumor behavior was observed in these patients (Fig. 4).
Discussion This is the first report to have focused on postoperative BM in STS. There have been some clinical series of BMs in bone and/or STS [2–5, 8], but these series included both bone and soft tissue or selected for patients with metastases diagnosed at either the first or subsequent visits. In our study, 8 of 187 patients (4.3 %) developed BMs, with the incidence of BM being similar to that previously reported [2–4]. There are some limitations in our study. First, the detection of BMs depended on the patients’ symptoms since brain imaging was not performed routinely, meaning that we could not detect all cases of asymptomatic BM. Second, this study included various types of STS, small cell and non-small cell sarcoma, both pediatric and adult cases, but most cases were non-small round STSs in adults. Third, we could not perform multivariate analysis because of the small number of BMs and lack of statistical power. There were a relatively small number of patients with NF-1 and MPNST in our study, and so the number of BMs in our series was much fewer than would have been expected otherwise, and a small change of even one or two events may have affected our results. In a report of 40 BMs in STS, the most frequent histological subtypes of STS metastasizing to the brain were leiomyosarcoma (n = 8), liposarcoma (n = 5), rhabdomyosarcoma (n = 4), and MFH (n = 4) [3]. Another series of 35 bone and STS BMs, also reported leiomyosarcoma as the most frequent STS histology (n = 7), followed by ASPS (n = 3), rhabdomyosarcomas (n = 2), and liposarcoma (n = 1) [8]. Whereas a third series of 20 bone and STS BMs reported a slightly different distribution of frequencies for the STS, including MFH (n = 5), ASPS (n = 3), rhabdomyosarcomas (n = 2), Ewing sarcomas/PNET (n = 2), and one each MPNST, liposarcoma, and hemangiopericytoma [2]. MPNST was the most common histology to develop BM in our series. A previous report described BM in 2 of 30
123
123
51/M
38/F
32/F
38/F
55/M
59/F
73/M
80/M
1
2
3
4
5
6
7
8
III
III
III
III
III
IIB
III
III
Stagea at diagnosis
PNET
Clear cell sarcoma
MFH
Liposarcoma
Liposarcoma
MPNST
MPNST
MPNST
Histological subtype
No
No
No
No
Yes
No
Yes
Yes
NF-1
Thigh
Thigh
Buttock
Thigh
Back
Back
Neck
Neck
Site of primary tumor
14
6
16
14
10
6
6
10
Size of primary tumor, cm
Chemotherapy
–
–
–
Chemotherapy
–
Chemotherapy
Chemotherapy, radiation
Adjuvant treatments
16.5
8.8
24.0
19.8
20.2
42.6
13.9
15.8
Time to BMs, months
No
Yes
Yes
Yes
Yes
Yes
No
No
Multiple BMs
Lung, liver, pancreas
–
Lung
Lung, lymph node
Lung
Lung, skin
Lung
Lung, bone
Presence of other metastases
–
–
Radiotherapy
-
Radiotherapy
Radiotherapy, metasectomy
Radiotherapy
–
Treatment for BMs
1.2
2.5
2.9
1.8
0.3
49.7
4.5
1.0
Follow up duration, months
DOD
DOD
DOD
DOD
DOD
AWD
DOD
DOD
Final status
MPNST malignant peripheral nerve sheath tumor, MFH malignant fibrous histiocytoma, PNET primitive neurectodermal tumors, NF-1 neurofibromatosis-1, BM brain metastasis, DOD dead of disease, AWD alive with disease a Stage, AJCC staging manual (7th edition)
Age/sex
Case
Table 2 Patients with brain metastases
348 Clin Exp Metastasis (2015) 32:345–351
Clin Exp Metastasis (2015) 32:345–351
349
Fig. 1 Postoperative brain metastasis free survival. The graph shows the cumulative postoperative brain metastasis free survival rate of soft tissue sarcoma patients (n = 187) using the Kaplan–Meier method
MPNST patients (5.3 %) [5]. Our series included 9 MPNST patients related to NF-1; two of them developed BMs after surgery. A worse outcome has been reported in MPNST patients with NF-1 compared to sporadic MPNST patients [9, 10]. Previous reports showed that the rate of NF-1 in MPNST patients was 22–52 % [9–11], but, in our study, 9 of 18 (50.0 %) MPNSTs were NF-1 related. Even though previous studies on BM in STS patients did not mention the proportion of NF-1 patients [2, 3, 5], the relatively high proportion of NF-1 patients in our study may have affected the high frequency of BMs in MPNSTs. Past reports noted some histological subtypes that are associated with an increased incidence of BMs in STS. Concurrent BMs were reported in 19 % of stage IV patients with ASPS [12], and 4 of 13 (30.8 %) ASPS patients were reported to have BMs [4]. Another report noted that 3 of 4 (75 %) ASPS cases had BMs [2], but no postoperative BMs developed in 2 patients of ASPS in our study. Univariate analysis revealed that MPNST had a significant impact on increasing the incidence of BM after surgery, and 3 of 18 (16.7 %) MPNST patients had BMs in our study. A review article focused on 21 reported MPNST patients with BMs from 1963 to 2012 [13]. MPNST patients with BM were noted to have an average age of 36.6 years, which is younger than that of other STSs and similar to that of our patients. Distant metastasis was reported to have occurred in 39 % of patients with NF-1, and 16 % without NF-1, most commonly to lung, and also to soft tissue, bone, liver, abdominal cavity, adrenal glands, diaphragm, mediastinum, brain, ovaries, kidneys, and retroperitoneum [10]. In our previous study, OS and disease free survival (DFS) rate at 5 years were 83 and 63 % respectively in patients with MPNST from 1986 to 2011 [14]. Large tumor size was an independent prognostic factor for survival and/
Fig. 2 Postoperative brain metastasis free survival in different groups. The graph shows the cumulative postoperative brain metastasis free survival rate of soft tissue sarcoma patients with two different groups (n = 187) of a with or without neurofibromatosis-1, b MPNST or non MPNST, and c primary tumor size more than 5 cm or within 5 cm using the Kaplan–Meier method
or DFS in STS patients [14–16]. Large tumor size is associated with biological aggressiveness and highly metastatic potential of the tumor. Large tumor size was
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350
Clin Exp Metastasis (2015) 32:345–351
Table 3 Univariate analysis of clinical variables for brain metastasis Variable
5-years estimated brain metastasis free survival, (%)
p*
Sex Male
95.6
Female
94.9
0.996
Age, years C50
96.1
\50
94.0
Primary tumor size, cm C5 92.1 \5
0.595
0.021
100
Site Trunk
92.2
Extremity
96.1
0.246
Tumor depth Superficial
97.7
Deep
92.5
0.131
Fig. 3 Overall survival after brain metastasis. The graph shows the cumulative overall survival rate of soft tissue sarcoma patients after the diagnosis of brain metastases (n = 8) using the Kaplan–Meier method
Histological grade High-intermediate
95.0
Low
100
0.555
Histological subtype MFH
98.0
Others
94.1
0.265
Liposarcoma Others
92.9 95.7
0.451
MPNST
82.1
0.008
Others
96.8
NF-1 Yes
70.0
No
96.7
\0.0001
MFH malignant fibrous histiocytoma, MPNST malignant peripheral nerve sheath tumor, NF-1 neurofibromatosis-1 * Log-rank test
also associated with an increased morbidity from BMs after surgery in our study. As shown in Table 2, all primary tumors were more than 5 cm in patients with BMs, and potential aggressiveness of large tumor strongly affected the occurrence of BMs. Histological tumor grade is a known prognostic factor for metastasis in STS patients [15, 17]. In our study, there was no patient with BM who had low grade STS, but no statistical significance was observed between the histological tumor grade and BMFS. Our study included only 9 cases of low grade tumor, and there was a lack of statistical power for determination of the relationship between histological tumor grade and BMFS. Median OS from craniotomy has been reported as 7 months in BM patients of bone and STS [7]. Another retrospective study showed that metastasectomy for BM of STS was associated with an improved postmetastasis
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Fig. 4 A case of brain metastasis in NF-1 related MPNST. Magnetic resonance T2-weighted image at diagnosis of brain metastasis in NF-1 related MPNST (a) and T2-weighted image of brain metastasis after 6 days (b)
Clin Exp Metastasis (2015) 32:345–351
survival (9.6 months compared with 2.7 months for those patients who did not undergo resection) [3]. Prognostic factors associated with better post BM survival have been reported to include ASPS histology, initial surgical treatment, and brain irradiation for non-surgical treatment patients [4]. In our study, metastasectomy for BM was performed in only 1 of 8 patients with BM, and the median OS after BM was 1.8 months and dismal in our study. Interestingly, however, that one patient treated by metastasectomy and radiation for BM was still alive at 49.7 months after BM, underlining that surgical treatment for selected BM patients can result in long survival. The number of BMs has been reported as one of the prognostic factors in patients with BMs [18]. It can affect resectability of BMs, but there was no tendency between the number of BMs and prognosis in our study. There is a possibility that early detection of BM may improve the prognosis after BM detection. In our series, 7 of 8 BM patients had lung metastases with or without other metastatic site involvement. Other reports also showed a high incidence of other site metastases in BM patients with STS [2–5]. Since blood from the lungs flows directly to the brain, lung cancer is capable of spreading to the brain [19], and lung metastasis can cause BM in STS. Routine brain imaging may not be indicated for all STS patients after definitive surgery because of cost. In our study, NF-1, histological subtype of MPNST, and primary tumor size C5 cm were significantly associated with increasing incidence of BMs after surgery. It is reasonable to perform brain imaging for metastatic STS patients when these risk factors are present. In our study, the median interval from first metastases at other sites to BMs was 19.4 (7.5–37.4) months in 7 patients, but it is difficult to determine the adequate follow up interval of brain imaging from our results. In conclusion, BMs from STS are rare but lethal. Postoperative BMs were common in patients with NF-1, MPNST, and large tumor. Considering the impact of NF-1 on BMFS, careful follow up for BM is necessary for STS patients with NF-1 after metastases at other sites. Acknowledgment assistance.
We thank Miss Eri Ishihara for secretarial
Conflict of interest All the authors declare that they have no financial and personal relationships with any other persons or organizations that could potentially and inappropriately influence their work and conclusion. Funding One or more of the authors (H.U.) has received research funding from the Ministry of Education, Culture, Sports, Science and
351 Technology of Japan [Grant-in-Aid 24791533 for Scientific Research (C)].
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