Clin Transl Oncol (2015) 17:803–809 DOI 10.1007/s12094-015-1308-9
RESEARCH ARTICLE
A retrospective analysis of lung metastasis in 64 patients with alveolar soft part sarcoma Y.-P. Liu1 • J. Jin1 • W.-H. Wang1 • S.-L. Wang1 • Y.-W. Song1 H. Fang1 • H. Ren1 • X.-F. Liu1 • Z.-H. Yu1 • Y.-X. Li1
•
Received: 17 January 2015 / Accepted: 22 May 2015 / Published online: 3 June 2015 Ó Federacio´n de Sociedades Espan˜olas de Oncologı´a (FESEO) 2015
Abstract Objectives To analyse the lung metastasis and possible factors influencing lung metastasis in alveolar soft part sarcoma (ASPS) patients. Methods The medical records of 64 consecutive ASPS patients were reviewed to analyse their treatments, features of lung metastasis, and possible factors influencing lung metastasis. Results Thirty-six females and 28 males with a median age of 27 years were included. The primary disease sites were the extremities in 51 patients and other locations in 13 patients. The median primary tumour size was 5 cm. Wide local excision of the primary tumour was performed on 56 patients (87.5 %). Thirteen patients (20.3 %) received postoperative adjuvant radiotherapy, and nine patients (14.1 %) underwent adjuvant chemotherapy. Twelve patients (18.8 %) presented with metastatic lung disease. Twenty-nine patients (45.3 %) developed metastatic lung disease during follow-up. Lung metastasis occurred in 64.1 % of the patients. Lung metastasis was detected at a median interval of 20 months after primary ASPS diagnosis. Being male, [20 years of age, having a primary tumour size C5 cm, and local recurrence were associated with a greater rate of lung metastasis. Median survival after the diagnosis of lung metastasis was 34 months. The 5-year survival rates were 64.1 and 95.2 % for patients with and without lung metastasis (P \ 0.001). Thirty-seven patients
& Y.-X. Li [email protected] 1
Department of Radiation Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021 Beijing, People’s Republic of China
with metastatic lung disease received anthracycline- and ifosfamide-based chemotherapy. One patient experienced a partial remission. Conclusions ASPS patients have a high prevalence of lung metastasis. Sex, age, primary tumour size, and local recurrence are major factors influencing lung metastasis. Chemotherapy is not efficacious in ASPS patients with lung metastasis. Keywords Alveolar soft part sarcoma Lung metastasis Correlative factor Chemotherapy
Introduction Alveolar soft part sarcoma (ASPS) is a rare, high-grade but clinically and morphologically distinct sarcoma that accounts for approximately 0.5–1 % of all soft tissue sarcomas [1–4]. The origin of ASPS is unclear [3, 4]. ASPS exhibits an unbalanced chromosomal translocation der(17)t(X;17)(p11;25) resulting in the ASPL-TFE3 fusion gene and overexpression of TFE3 (transcription factor binding to immunoglobulin heavy constant enhancer 3) [5, 6]. Lately, TFE3 has been utilised as a diagnostic marker for ASPS [7, 8]. Complete surgical excision is the mainstay of therapy, the benefit of adjuvant chemotherapy and radiotherapy remains to be seen. Targeted therapies such as multiple tyrosine kinase receptor inhibitors (RTKs) or antiangiogenic therapy may be effective in some ASPS patients [9–11]. The hypervascularity, the propensity of vascular invasion, and the lack of capsule may account for the high rate of metastasis in ASPS [3, 6, 12, 13], and the lungs are the most common metastatic sites [3, 6, 14, 15]. Due to the rarity of ASPS, reports on the features of lung metastasis and the possible factors related to lung
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metastasis in large series of ASPS patients are scarce. We retrospectively reviewed 64 consecutive ASPS patients with an emphasis on lung metastasis and factors that possibly influenced the development of lung metastasis.
Materials and methods From May 1962 to August 2012, 64 consecutive patients with pathologically confirmed ASPS were treated at our institution. Data regarding their clinical characteristics, treatments, and lung metastasis were reviewed. The possible factors influencing lung metastasis were analysed. Follow-up data were collected from notes in the medical records or from direct contact with the patient or the patient’s family. Wide local excision of the primary tumour in an attempt to achieve complete resection was the mainstay of treatment in these patients. For the value of adjuvant chemotherapy and radiotherapy was not established, adjuvant radiotherapy and chemotherapy were applied at the discretion of the doctors. Chemotherapeutic regimens used to treat general soft tissue sarcomas (anthracycline-, ifosfamide-based regimens) were adopted as 3–6 cycles of therapy. Radiotherapy was delivered to the primary tumour location and the surgical scar plus a 1–2 cm margin with a median dose of 60 Gy (range 50–66 Gy) 4–6 weeks after surgery. Patients with unresectable or disseminated diseases at presentation received individualised therapy, such as chemotherapy, palliative radiotherapy, resection of metastases, and supportive care. Chemotherapy was also administered to patients who developed metastatic lung disease during follow-up. A variety of regimens (mainly anthracycline- and ifosfamide-containing regimens) were adopted for 2–8 cycles of therapy (median 4 cycles). Tumour response was evaluated according to the response evaluation criteria in solid tumours (RECIST) [16]. Patients with solitary or oligometastatic lung diseases without extrapulmonary involvement also underwent metastasectomy of their pulmonary metastases. The maximum diameter of the tumour was recorded according to the pathologic description after extended resection of the primary tumour. If this was not possible, the tumour size was recorded based upon pre-treatment imaging methods, such as computed tomography or magnetic resonance imaging. The endpoints for analysis were lung metastasis and survival. The time to lung metastasis and surviving time were calculated from the time of surgery (for patients who underwent surgical resection) or initial presentation (for patients who had advanced unresectable disease). All patients were followed for a median term of 66 months (range 14–205 months).
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Patient age (B20 or[20 years), gender, tumour size (\5 or C5 cm), tumour location (extremities or other locations), and local recurrence were reviewed to determine their prognostic value for lung metastasis. The lung metastasis rates and survival were computed using the Kaplan–Meier method. Univariate comparisons were performed by log-rank analysis. The multivariate analysis was performed using the Cox regression analysis. Differences at P \ 0.05 were considered significant.
Results Clinical features and primary treatment The clinical characteristics for the entire cohort of 64 patients were outlined in Table 1. The median age was 27 years, with one-third of the patients being younger than 20 years. There were slightly more females than males in this series. The majority of the patients’ primary tumours (79.7 %) were located in the extremities. Other tumour origins included the trunk in nine patients, the head and neck in two patients, the breast in 1 patient, and the uterus in one patient. The median maximum diameter of the primary tumour was 5 cm. Thirteen patients (20.3 %) had metastatic disease at the time of original diagnosis. Upon diagnosis, 87.5 % of these patients received wide resection of their primary tumours with clear margin. Four of them underwent primary tumour and lung metastatic tumour resection concurrently. Adjuvant radiotherapy and chemotherapy were administered to 13 (20.3 %) and 9 Table 1 Distribution of clinical features in 64 alveolar soft part sarcoma patients Feature
No.
%
Age (years)
Median (range) 27 (9–60)
B20
20
31.3
[20
44
68.7
Gender Male
28
43.8
Female
36
56.2
Primary location Extremities
51
79.7
Other locations
13
20.3
\5
24
37.5
C5
40
62.5
Localised
51
79.7
Disseminated
13
20.3
Lung metastasis only
12
18.8
Tumour diameter (cm)
5 (1.0–18.0)
Disease at presentation
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(14.1 %) patients, respectively. Eight patients who presented with unresectable or disseminated diseases were individually treated with chemotherapy, palliative radiotherapy, resection of selected metastases, and supportive care, alone or in combination. Lung metastasis and factors influencing lung metastasis Twelve patients (18.8 %) presented with metastatic lung diseases. Twenty-nine patients (45.3 %) developed lung metastasis during follow-up. Lung metastasis occurred in 64.1 % of all patients and 95.2 % of patients with metastatic diseases. Other favoured metastatic sites included brain (15.6 %) and bone (6.3 %). Lung metastasis was detected at a median interval of 20 months (range 4–110 months) after the primary ASPS diagnosis. Three patients exhibited solitary lung metastasis and six patients exhibited lung metastasis more than 5 years after their initial treatment. The longest interval of time between primary tumour resection and lung metastasis was 110 months. After a median follow-up period of 37.5 months (range 0–191 months), the 2- and 3-year lung metastasis rates were 43.8 and 47.1 %, respectively (Fig. 1). Sex, age, primary tumour size, and tumour location were closely associated with lung metastasis by univariate analysis. Being male, [20 years of age, having a tumour size C5 cm, and a tumour origin in the extremities were positively correlated with lung metastasis. Sex, age, and primary tumour size were valuable prognostic risk factors for lung metastasis in the multivariable model analysis (Table 2). In addition, five patients recurred locally. All these patients developed lung metastasis at some point. Excepting the patients without primary tumour resection or presented with metastatic diseases, the lung metastasis rates differed significantly between patients with
Fig. 1 Lung metastasis in 64 ASPS patients
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and without local recurrence: 100.0 and 54.8 %, respectively, P = 0.038. Treatment of lung metastasis and survival Chemotherapy was administered to 90.2 % of patients (37/ 41) who developed lung metastasis. A variety of regimens (mainly anthracycline- and ifosfamide-containing regimens) were applied: Anthracycline and Ifosfamide based combination in 24 patients, Anthracycline or Ifosfamide based combination in five patients, Gemcitabine based combination in four patients, and chemotherapy regimens unknown in four patients. Of the 32 chemotherapy response evaluable patients, one experienced a partial response, 17 had stable disease, and 14 had progressive disease. The median survival time following diagnosis of lung metastasis was 34 months (range 8–145 months). The 5-year overall survival rates were 64.1 and 95.2 % for patients with and without lung metastasis (P \ 0.001, median follow-up period of 66 months after surgery or diagnosis) (Fig. 2). Eight patients with only solitary or oligometastatic diseases (B3 metastases) confined to the lung underwent metastasectomy of their pulmonary metastases, and 5 of those 8 received subsequent chemotherapy. After a median follow-up period of 36 months (range 4–110 months), five of those eight patients survived and three survived longer than 7 years.
Discussion ASPS is characterized by greater vascularity and evident vascular invasion both on imaging and pathology [3, 6, 12, 13, 17, 18]. Thus, a high rate of metastasis is seen in ASPS [6, 17]. Many reports have identified the lungs to be the most common metastatic sites for ASPS [6, 13, 17]. Due to the limited number of patients with ASPS, prospective studies to identify the features of lung metastasis and the factors influencing lung metastasis are impossible. The current study was a retrospective analysis of a relatively large ASPS cohort focused on lung metastasis. Our findings confirm that ASPS has a high propensity for lung metastasis and indicate that sex, age, primary tumour size, and local control are important prognostic risk factors for lung metastasis. We recognise that anthracycline- and ifosfamide-based chemotherapy is not efficacious in ASPS patients with lung metastasis and those patients manifest with an indolent clinical course. The lung was the most common site of metastasis in this group of patients. Lung metastasis occurred in about twothirds of the patients and was more frequent than any other metastatic sites. A high rate of lung metastasis (over 60 %) in ASPS was presented throughout the literature (Table 3).
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806 Table 2 Lung metastasis according to potential risk factors in 64 alveolar soft part sarcoma patients
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Risk factors
Univariate analysis
Multivariate analysis
No.
3-year lung metastasis (%)
P value
Hazard ratio
P value
B20
20
25.3
0.001
2.69
0.022
[20
44
57.0
Male
28
61.5
0.002
2.00
0.04
Female
36
36.1
51
52.9
0.022
2.41
0.155
13
23.1 0.002
2.74
0.008
Age (years)
Gender
Primary location Extremities Others
Tumour diameter (cm) \5
24
25.2
C5
40
61.3
Fig. 2 Survival differences of 64 ASPS patients with and without lung metastasis (surviving time was calculated from the time of initial diagnosis)
In a study of 48 stage IV (M1) ASPS patients, Portera et al. [19] reported 44 patients with lung metastasis. In Kayton’s study, 60.0 % of patients developed lung metastasis at some point [20]. Sood et al’s report showed that lung metastasis occurred in all patients with metastatic disease
Table 3 Summary of studies reporting lung metastasis in ASPS
References
[17]. Cho et al. [21] also found that the lung was the most common metastatic site in ASPS patients. Lung metastasis accounted for 95.2 % of the patients with metastatic diseases in our study. As thus, the lungs are definitely the most common metastatic sites in ASPS. The higher incidence of lung metastasis in ASPS is likely due to its hypervascularity and prominent intravascular tumour extension [3, 17]. Furthermore, pulmonary circulation is the filter of the blood from vena cava, and the pulmonary circulation pressure is lower than the systemic circulation, so the lungs are the most easily implanting sites for metastatic tumour cells. Because of the high prevalence of lung metastasis, it would be appropriate to analyse the possible clinical factors associated with lung metastasis, and we recommended regular screening via chest CT at diagnosis and during follow-up for patients with ASPS. The utility of PET-CT in ASPS would be informative as well when it’s indicated. Lung metastasis has an adverse effect on survival in our study. This is in accordance with the reports from Lieberman and Portera. Lieberman et al. [14] reported that the median survival dropped to 3 years with metastasis as opposed to 11 years without metastasis. Similarly, 5-year survival rates of 20 and 87 % were presented for patients
No. of patients
Lung metastasis (%)
Portera et al. [19]
48 (M1)
NA
92.0
Kayton et al. [20]
20
36
60.0
Sood et al. [17]
25
75
92.0 (100 % in M1)
Cho et al. [21]
19
54 (mean)
63.2
Rekhi et al. [5]
29
27.5
62.1
Ogura et al. [26]
26
71 (average)
76.9
Van Ruth et al. [31]
15
170
66.7
NA not available, M1 with metastatic diseases
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Median follow-up (months)
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with or without metastasis in Portera’s study [19]. Solitary metastasis and oligometastasis to the lung were not commonly seen in our patients. Most lung metastasis occurred within 2 years after primary ASPS diagnosis, but lung metastasis can continue to develop many years after the initial treatment. Falkenstern-Ge et al. [22] reported a lung metastasis that occurred 20 years after surgical resection of primary ASPS. Lillehei and co-workers reported an interval of 21 years between primary presentation and development of lung metastasis [23]. Late metastasis to the lung in ASPS has been frequently reported previously [2, 20, 21]. In our study, a few patients exhibited lung metastasis more than 5 years after initial treatment. We propose that longer than 5 years of follow-up is necessary for ASPS patients after radical resection. Our results demonstrated that sex, age, and primary tumour size were closely associated with lung metastasis. Being male and [20 years of age and having a tumour size C5cm were positively correlated with lung metastasis. Age and primary tumour size have been extensively reported in other reports to be important prognostic factors for survival [6, 14, 15, 20, 24–27]. Younger age at diagnosis and small tumour size has always been shown to be associated with good survival. Daigeler’s report [13] showed a favourable outcome in female patients. Metastatic disease was predictive of poor survival in both our group of patients and other reports [10, 14, 19, 21, 24]. It is reasonable that the factors affecting the incidence of lung metastasis also affect the survival, because distant metastasis is the main cause of ASPS fatality, while lung metastasis is the most commonly involved sites. Casanova et al. [24] presented a lower rate of metastatic spread in children (21 %). Kayton et al. [20] observed early stage
disease more frequently in patients B16 years of age than in older (70 and 40 %, respectively). Lieberban et al’s data indicated that the dependence of survival on age is due to the increased occurrence of metastasis in older people [14]. The lower rate of metastatic spread in younger patients is probably due to a less aggressive behaviour and different biological features of ASPS in those patients and an earlier diagnosis in paediatric ASPS patients [24]. Tumour size is closely related to metastatic spread in ASPS patients. This is understandable. Large size tumour growth needs longer time, which brings the tumour more chance to spread as well. Both Casanova et al. [24] and Lieberman et al. [14] showed that patients with a maximum tumour diameter [10 cm presented with metastatic disease. In Evans’s report, 1 in 5 patients with a tumour size \5 cm and 6 in 7 patients with a tumour size C5 cm developed lung metastasis [28]. Our observations confirm that a larger primary tumour size is positively correlated with lung metastasis. Of note, in our study, all the locally recurred patients developed lung metastasis. This suggests that complete excision of the primary tumour to achieve satisfactory local control is essential in reducing the risk of lung metastasis. In addition, the patients with ASPS originating in the extremities had a higher probability of lung metastasis than those originating in other locations. This may be due to the limitation of axial resection in the extremities. However, the difference was only significant by univariate analysis. Other reports have not observed this tendency [13, 24], thus, further studies are warranted. Active chemotherapy regimens have not been identified for ASPS patients with lung metastasis. Reports regarding chemotherapy in ASPS patients with metastatic disease
Table 4 Summary of studies reporting chemotherapy response for metastatic diseases in ASPS References
No. of patients
Regimen and cycles
Chemotherapy response (%)
Reichardt et al. [15]
68
Anthracycline-containing or ifosfamide-containing regimen, cycles: NA
CR 4 PR 3 SD 41 PD 51
Kayton et al. [20]
11
Ogura et al. [26]
9
Ogose et al. [25]
27
A vast assortment of chemotherapeutic and biologic agents were administered, cycles: NA
No CR
Mainly anthracycline-containing regimens. cycles: NA
No objective response
Based on cisplatin, ifosfamide, doxorubicin, and biologic response modifiers, cycles: NA
No clinical response
No PR
Orbach et al. [10]
18
Ifosfamide-doxorubicin-based regimens, evaluated after 3 cycles
CR ? PR 17
Portera et al. [19]
26
1. Vincristine and/or cyclophosphamide, 2. doxorubicin-based chemotherapy, median, 4 cycles (2–8 cycles)
Only 1 CR (3 %), no PR
NA not available, CR complete response, PR partial response, SD stable disease, PD progressive disease
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(mainly with lung metastasis) failed to demonstrate any promising results (Table 4). Reichardt et al. [15] analysed the response to first-line chemotherapy in 68 ASPS patients with measurable diseases. Anthracycline- or ifosfamidecontaining regimens were adopted. The responses were as follows: complete remission: 4 %, partial remission: 3 %, stable disease: 41 %, and progressive disease: 51 %. They concluded that ASPS patients should not be treated with chemotherapy outside of controlled clinical trials. Though most of the patients with lung metastasis in our study received 2–8 cycles of chemotherapy with anthracyclineor ifosfamide-based regimens, none experienced a complete remission and only one experienced a partial remission. Therefore, ASPS with metastatic lung disease is invariably chemoresistant to schemes used to treat general soft tissue sarcomas. Effective chemotherapeutic agents or alternative therapeutic options (such as targeted therapies) for ASPS with metastatic lung disease need to be developed. Some authors have reported prolonged survival following excision of metastases in the lungs [6, 14, 20]. For ASPS patients with lung metastasis alone, Lieberman et al. [14] reported a median survival of 218 months in five patients receiving excision of lung metastases and 63.5 months for patients without lung metastases excision. After resection of lung metastases, survivals longer than 10 years were also presented in Kayton’s series [20]. Surviving time longer than 7 years was observed in our series that underwent excision of the pulmonary metastases. The longterm survivors observed in this series and in other reports may justify metastasectomy for patients who have a medically resectable solitary metastasis or oligometastasis confined to the lung and a good performance status [6, 13, 14, 19, 27]. Although at present, there is no effective system treatment for ASPS patients with metastatic lung disease, those patients can survive a relatively long time, with a median survival of 34 months in our series. Portera [19] and Lieberman [14] also reported prolonged survival for ASPS patients who developed lung metastasis alone. A median survival of 40 and 63.5 months, respectively, were reported in their studies. This is much longer than most other soft tissue sarcomas [29, 30].
Conclusions This is a retrospective analysis of ASPS with metastatic lung disease that spanned half a century. Our results confirmed that lung metastasis is common in ASPS. Sex, age, primary tumour size at the time of original diagnosis, and local control greatly influence the occurrence of lung metastasis. Regular chemotherapy lacks efficacy in ASPS with metastatic lung disease. Metastasectomy may be justified for patients with medically resectable and lung confined
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metastasis. ASPS with metastatic lung disease manifests with an indolent clinical course. In the absence of effective drug for the treatment of lung metastasis from ASPS, an international, multi-centre clinical trial from the United Kingdom, Australia and Spain are collaboratively exploring the ability of cediranib to halt disease progression in patients with metastatic ASPS [cediranib: a highly potent VEGFR (Vascular Endothelial Growth Factor Receptor) inhibitor] [32]. This study possibly will bring us new information. Conflict of interest
We declare that we have no conflict of interest.
References 1. Anderson ME, Hornicek FJ, Gebhardet MC, Raskin KA. Alveolar soft part sarcoma: a rare and enigmatic entity. Clin Orthop Relat Res. 2005;438:144–8. 2. Enzinger FM, Weiss SW. Malignant tumors of uncertain type. In: Enzinger FM, Weiss SW, editors. Soft tissue tumors. 3rd ed. St. Louis: Mosby; 1995. p. 1067–74. 3. Folpe AL, Deyrup AT. Alveolar soft-part sarcoma: a review and update. J Clin Pathol. 2006;59:1127–32. 4. Weiss SW. Alveolar soft part sarcoma, are we at the end or just the beginning of our quest? AJP. 2002;160:1197–9. 5. Rekhi B, Ingle A, Agarwal M, Puri A, Laskar S, Jambhekar NA. Alveolar soft part sarcoma ‘revisited’: clinicopathological review of 47 cases from a tertiary cancer referral centre, including immunohistochemical expression of TFE3 in 22 cases and 21 other tumours. Pathology. 2012;44:11–7. 6. Zarrin-Khameh N, Kaye KS. Alveolar Soft Part Sarcoma. Arch Pathol Lab Med. 2007;131:488–91. 7. Pang LJ, Chang B, Zou H, Qi Y, Jiang JF, Li HA, et al. Alveolar soft part sarcoma: a bimarker diagnostic strategy using TFE3 immunoassay and ASPLTFE3 fusion transcripts in paraffin-embedded tumor tissues. Diagn Mol Pathol. 2008;17:245–52. 8. Williams A, Bartle G, Sumathi VP, Meis JM, Mangham DC, Grimer RJ, et al. Detection of ASPL/TFE3 fusion transcripts and the TFE3 antigen in formalinfixed, paraffin-embedded tissue in a series of 18 cases of alveolar soft part sarcoma: useful diagnostic tools in cases with unusual histological features. Virchows Arch. 2011;458:291–300. 9. Kummar S, Allen D, Monks A, Polley EC, Hose CD, Ivy SP, et al. Cediranib for metastatic alveolar soft part sarcoma. J Clin Oncol. 2013;31:2296–302. 10. Orbach D, Brennan B, Casanova M, Bergeron C, Mosseri V, Francotte N, et al. Paediatric and adolescent alveolar soft part sarcoma: a joint series from European cooperative groups. Pediatric Blood Cancer. 2013;60:1826–32. 11. Hilbert M, Mary P, Larroquet M, Serinet MO, Helfre S, Brisse H, et al. Alveolar soft part sarcoma in childhood: is Sunitinib-Sutent(R) treatment an effective approach? Pediatric Blood Cancer. 2012;58:475–6. 12. Christopherson WM, Foote FW, Stewart FW. Alveolar soft-part sarcomas: structurally characteristic tumors of uncertain histogenesis. Cancer. 1952;5:100–11. 13. Daigeler A, Kuhnen C, Hauser J, Goertz O, Tilkorn D, Steinstraesser L, et al. Alveolar soft part sarcoma: clinicopathological findings in a series of 11 cases. World J Surg Oncol. 2008;6:71–8. 14. Lieberman PH, Brennan MF, Kimmel M, Erlandson RA, Garin-Chesa P, Flehinger BY. Alveolar soft-part sarcoma: a clinico-pathologic study of half a century. Cancer. 1989;63:1–13. 15. Reichardt P, Lindner T, Pink D, Thuss-Patience PC, Kretzschmar A, Dorken B. Chemotherapy in alveolar soft part sarcomas: what do we know? European J Cancer. 2003;39:1511–6. 16. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47. 17. Sood S, Baheti AD, Shinagare AB, Jagannathan JP, Hornick JL, Ramaiya NH, et al. Imaging features of primary and metastatic alveolar soft part sarcoma: single institute experience in 25 patients. British J Radiol. 2014. doi:10.1259/bjr. 20130719. 18. Lorigan JG, O’Keeffe FN, Evans HL, Wallace S. The radiologic manifestations of alveolar soft-part sarcoma. Am J Roentgenol. 1989;153:335–9. 19. Portera CA, Ho V, Patel SR, Hunt KK, Feig BW, Respondek PM, et al. Alveolar soft part sarcoma: clinical course and patterns of metastasis in 70 patients treated at a single institution. Cancer. 2001;91:585–91. 20. Kayton ML, Meyers P, Wexler LH, Gerald WL, Laquaglia MP. Clinical presentation, treatment, and outcome of alveolar soft part sarcoma in children, adolescents, and young adults. J Pediatr Surg. 2006;41:187–93.
Clin Transl Oncol (2015) 17:803–809 21. Cho YJ, Kim JY. Alveolar soft part sarcoma: clinical presentation, treatment and outcome in a series of 19 patients. Clin Orthopedic Surg. 2014;6:80–6. 22. Falkenstern-Ge RF, Kimmich M, Wohlleber M, Grabner A, Friedel G, Ott G, et al. Lung metastasis of primary alveolar soft-part sarcoma occurring 20 years after initial treatment. Case Rep Oncolog Med. 2013. doi:10.1155/2013/690520. 23. Lillehei KO, Kleinschmidt-DeMasters B, Mitchell DH, Spector E, Kruse CA. Alveolar soft part sarcoma: an unusually long interval between presentation and brain metastasis. Human Pathol. 1993;24:1030–4. 24. Casanova M, Ferrari A, Bisogno G, Cecchetto G, Basso E, Bernardi BD, et al. Alveolar soft part sarcoma in children and adolescents: a report from the SoftTissue Sarcoma Italian Cooperative Group. Ann Oncol. 2000;11:1445–9. 25. Ogose A, Yazawa Y, Ueda T, Hotta T, Kawashima H, Hatano H, et al. Alveolar soft part sarcoma in japan: multi-institutional study of 57 patients from the Japanese Musculoskeletal Oncology Group. Oncology. 2003;65:7–13. 26. Ogura K, Beppu Y, Chuman H, Yoshida A, Yamamoto N, Sumi M, et al. Alveolar soft part sarcoma: a single-center 26-patient case series and review of the literature. Sarcoma. 2012. doi:10.1155/2012/907179.
809 27. Pennacchioli E, Fiore M, Collini P, Radaelli S, Dileo P, Stacchiotti S, et al. Alveolar soft part sarcoma: clinical presentation, treatment, and outcome in a 33 patients at a single institution. Ann Surg Oncol. 2010;7:3229–33. 28. Evans HL. Alveolar soft-part sarcoma. A study of 13 typical examples and one with a histologically atypical component. Cancer. 1985;55:912–7. 29. Ferguson PC, Deheshi BM, Chung P, Catton CN, O’Sullivan B, Gupta A, et al. Soft tissue sarcoma presenting with metastatic disease: outcome with primary surgical resection. Cancer. 2011;117:372–9. 30. Kane JM, Finley JW, Driscoll D, Kraybill WG, Gibbs JF. The treatment and outcome of patients with soft tissue sarcomas and synchronous metastases. Sarcoma. 2002;6:69–73. 31. van Ruth S, van Coevorden F, Peterse JL, Kroon BB. Alveolar soft part sarcoma: a report of 15 cases. Eur J Cancer. 2002;38:1324–8. 32. Institute of Cancer Research, United Kingdom. A Phase II Trial of Cediranib in the Treatment of Patients with Alveolar Soft Part Sarcoma (CASPS). 2014. ClinicalTrials.gov Identifier: NCT01337401. Available from: https://clinicaltrials.gov/ ct2/show/NCT01337401?term=cediranib&rank=11. Accessed 21 May 2015.
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RESEARCH ARTICLE
A retrospective analysis of lung metastasis in 64 patients with alveolar soft part sarcoma Y.-P. Liu1 • J. Jin1 • W.-H. Wang1 • S.-L. Wang1 • Y.-W. Song1 H. Fang1 • H. Ren1 • X.-F. Liu1 • Z.-H. Yu1 • Y.-X. Li1
•
Received: 17 January 2015 / Accepted: 22 May 2015 / Published online: 3 June 2015 Ó Federacio´n de Sociedades Espan˜olas de Oncologı´a (FESEO) 2015
Abstract Objectives To analyse the lung metastasis and possible factors influencing lung metastasis in alveolar soft part sarcoma (ASPS) patients. Methods The medical records of 64 consecutive ASPS patients were reviewed to analyse their treatments, features of lung metastasis, and possible factors influencing lung metastasis. Results Thirty-six females and 28 males with a median age of 27 years were included. The primary disease sites were the extremities in 51 patients and other locations in 13 patients. The median primary tumour size was 5 cm. Wide local excision of the primary tumour was performed on 56 patients (87.5 %). Thirteen patients (20.3 %) received postoperative adjuvant radiotherapy, and nine patients (14.1 %) underwent adjuvant chemotherapy. Twelve patients (18.8 %) presented with metastatic lung disease. Twenty-nine patients (45.3 %) developed metastatic lung disease during follow-up. Lung metastasis occurred in 64.1 % of the patients. Lung metastasis was detected at a median interval of 20 months after primary ASPS diagnosis. Being male, [20 years of age, having a primary tumour size C5 cm, and local recurrence were associated with a greater rate of lung metastasis. Median survival after the diagnosis of lung metastasis was 34 months. The 5-year survival rates were 64.1 and 95.2 % for patients with and without lung metastasis (P \ 0.001). Thirty-seven patients
& Y.-X. Li [email protected] 1
Department of Radiation Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021 Beijing, People’s Republic of China
with metastatic lung disease received anthracycline- and ifosfamide-based chemotherapy. One patient experienced a partial remission. Conclusions ASPS patients have a high prevalence of lung metastasis. Sex, age, primary tumour size, and local recurrence are major factors influencing lung metastasis. Chemotherapy is not efficacious in ASPS patients with lung metastasis. Keywords Alveolar soft part sarcoma Lung metastasis Correlative factor Chemotherapy
Introduction Alveolar soft part sarcoma (ASPS) is a rare, high-grade but clinically and morphologically distinct sarcoma that accounts for approximately 0.5–1 % of all soft tissue sarcomas [1–4]. The origin of ASPS is unclear [3, 4]. ASPS exhibits an unbalanced chromosomal translocation der(17)t(X;17)(p11;25) resulting in the ASPL-TFE3 fusion gene and overexpression of TFE3 (transcription factor binding to immunoglobulin heavy constant enhancer 3) [5, 6]. Lately, TFE3 has been utilised as a diagnostic marker for ASPS [7, 8]. Complete surgical excision is the mainstay of therapy, the benefit of adjuvant chemotherapy and radiotherapy remains to be seen. Targeted therapies such as multiple tyrosine kinase receptor inhibitors (RTKs) or antiangiogenic therapy may be effective in some ASPS patients [9–11]. The hypervascularity, the propensity of vascular invasion, and the lack of capsule may account for the high rate of metastasis in ASPS [3, 6, 12, 13], and the lungs are the most common metastatic sites [3, 6, 14, 15]. Due to the rarity of ASPS, reports on the features of lung metastasis and the possible factors related to lung
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metastasis in large series of ASPS patients are scarce. We retrospectively reviewed 64 consecutive ASPS patients with an emphasis on lung metastasis and factors that possibly influenced the development of lung metastasis.
Materials and methods From May 1962 to August 2012, 64 consecutive patients with pathologically confirmed ASPS were treated at our institution. Data regarding their clinical characteristics, treatments, and lung metastasis were reviewed. The possible factors influencing lung metastasis were analysed. Follow-up data were collected from notes in the medical records or from direct contact with the patient or the patient’s family. Wide local excision of the primary tumour in an attempt to achieve complete resection was the mainstay of treatment in these patients. For the value of adjuvant chemotherapy and radiotherapy was not established, adjuvant radiotherapy and chemotherapy were applied at the discretion of the doctors. Chemotherapeutic regimens used to treat general soft tissue sarcomas (anthracycline-, ifosfamide-based regimens) were adopted as 3–6 cycles of therapy. Radiotherapy was delivered to the primary tumour location and the surgical scar plus a 1–2 cm margin with a median dose of 60 Gy (range 50–66 Gy) 4–6 weeks after surgery. Patients with unresectable or disseminated diseases at presentation received individualised therapy, such as chemotherapy, palliative radiotherapy, resection of metastases, and supportive care. Chemotherapy was also administered to patients who developed metastatic lung disease during follow-up. A variety of regimens (mainly anthracycline- and ifosfamide-containing regimens) were adopted for 2–8 cycles of therapy (median 4 cycles). Tumour response was evaluated according to the response evaluation criteria in solid tumours (RECIST) [16]. Patients with solitary or oligometastatic lung diseases without extrapulmonary involvement also underwent metastasectomy of their pulmonary metastases. The maximum diameter of the tumour was recorded according to the pathologic description after extended resection of the primary tumour. If this was not possible, the tumour size was recorded based upon pre-treatment imaging methods, such as computed tomography or magnetic resonance imaging. The endpoints for analysis were lung metastasis and survival. The time to lung metastasis and surviving time were calculated from the time of surgery (for patients who underwent surgical resection) or initial presentation (for patients who had advanced unresectable disease). All patients were followed for a median term of 66 months (range 14–205 months).
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Patient age (B20 or[20 years), gender, tumour size (\5 or C5 cm), tumour location (extremities or other locations), and local recurrence were reviewed to determine their prognostic value for lung metastasis. The lung metastasis rates and survival were computed using the Kaplan–Meier method. Univariate comparisons were performed by log-rank analysis. The multivariate analysis was performed using the Cox regression analysis. Differences at P \ 0.05 were considered significant.
Results Clinical features and primary treatment The clinical characteristics for the entire cohort of 64 patients were outlined in Table 1. The median age was 27 years, with one-third of the patients being younger than 20 years. There were slightly more females than males in this series. The majority of the patients’ primary tumours (79.7 %) were located in the extremities. Other tumour origins included the trunk in nine patients, the head and neck in two patients, the breast in 1 patient, and the uterus in one patient. The median maximum diameter of the primary tumour was 5 cm. Thirteen patients (20.3 %) had metastatic disease at the time of original diagnosis. Upon diagnosis, 87.5 % of these patients received wide resection of their primary tumours with clear margin. Four of them underwent primary tumour and lung metastatic tumour resection concurrently. Adjuvant radiotherapy and chemotherapy were administered to 13 (20.3 %) and 9 Table 1 Distribution of clinical features in 64 alveolar soft part sarcoma patients Feature
No.
%
Age (years)
Median (range) 27 (9–60)
B20
20
31.3
[20
44
68.7
Gender Male
28
43.8
Female
36
56.2
Primary location Extremities
51
79.7
Other locations
13
20.3
\5
24
37.5
C5
40
62.5
Localised
51
79.7
Disseminated
13
20.3
Lung metastasis only
12
18.8
Tumour diameter (cm)
5 (1.0–18.0)
Disease at presentation
Clin Transl Oncol (2015) 17:803–809
(14.1 %) patients, respectively. Eight patients who presented with unresectable or disseminated diseases were individually treated with chemotherapy, palliative radiotherapy, resection of selected metastases, and supportive care, alone or in combination. Lung metastasis and factors influencing lung metastasis Twelve patients (18.8 %) presented with metastatic lung diseases. Twenty-nine patients (45.3 %) developed lung metastasis during follow-up. Lung metastasis occurred in 64.1 % of all patients and 95.2 % of patients with metastatic diseases. Other favoured metastatic sites included brain (15.6 %) and bone (6.3 %). Lung metastasis was detected at a median interval of 20 months (range 4–110 months) after the primary ASPS diagnosis. Three patients exhibited solitary lung metastasis and six patients exhibited lung metastasis more than 5 years after their initial treatment. The longest interval of time between primary tumour resection and lung metastasis was 110 months. After a median follow-up period of 37.5 months (range 0–191 months), the 2- and 3-year lung metastasis rates were 43.8 and 47.1 %, respectively (Fig. 1). Sex, age, primary tumour size, and tumour location were closely associated with lung metastasis by univariate analysis. Being male, [20 years of age, having a tumour size C5 cm, and a tumour origin in the extremities were positively correlated with lung metastasis. Sex, age, and primary tumour size were valuable prognostic risk factors for lung metastasis in the multivariable model analysis (Table 2). In addition, five patients recurred locally. All these patients developed lung metastasis at some point. Excepting the patients without primary tumour resection or presented with metastatic diseases, the lung metastasis rates differed significantly between patients with
Fig. 1 Lung metastasis in 64 ASPS patients
805
and without local recurrence: 100.0 and 54.8 %, respectively, P = 0.038. Treatment of lung metastasis and survival Chemotherapy was administered to 90.2 % of patients (37/ 41) who developed lung metastasis. A variety of regimens (mainly anthracycline- and ifosfamide-containing regimens) were applied: Anthracycline and Ifosfamide based combination in 24 patients, Anthracycline or Ifosfamide based combination in five patients, Gemcitabine based combination in four patients, and chemotherapy regimens unknown in four patients. Of the 32 chemotherapy response evaluable patients, one experienced a partial response, 17 had stable disease, and 14 had progressive disease. The median survival time following diagnosis of lung metastasis was 34 months (range 8–145 months). The 5-year overall survival rates were 64.1 and 95.2 % for patients with and without lung metastasis (P \ 0.001, median follow-up period of 66 months after surgery or diagnosis) (Fig. 2). Eight patients with only solitary or oligometastatic diseases (B3 metastases) confined to the lung underwent metastasectomy of their pulmonary metastases, and 5 of those 8 received subsequent chemotherapy. After a median follow-up period of 36 months (range 4–110 months), five of those eight patients survived and three survived longer than 7 years.
Discussion ASPS is characterized by greater vascularity and evident vascular invasion both on imaging and pathology [3, 6, 12, 13, 17, 18]. Thus, a high rate of metastasis is seen in ASPS [6, 17]. Many reports have identified the lungs to be the most common metastatic sites for ASPS [6, 13, 17]. Due to the limited number of patients with ASPS, prospective studies to identify the features of lung metastasis and the factors influencing lung metastasis are impossible. The current study was a retrospective analysis of a relatively large ASPS cohort focused on lung metastasis. Our findings confirm that ASPS has a high propensity for lung metastasis and indicate that sex, age, primary tumour size, and local control are important prognostic risk factors for lung metastasis. We recognise that anthracycline- and ifosfamide-based chemotherapy is not efficacious in ASPS patients with lung metastasis and those patients manifest with an indolent clinical course. The lung was the most common site of metastasis in this group of patients. Lung metastasis occurred in about twothirds of the patients and was more frequent than any other metastatic sites. A high rate of lung metastasis (over 60 %) in ASPS was presented throughout the literature (Table 3).
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806 Table 2 Lung metastasis according to potential risk factors in 64 alveolar soft part sarcoma patients
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Risk factors
Univariate analysis
Multivariate analysis
No.
3-year lung metastasis (%)
P value
Hazard ratio
P value
B20
20
25.3
0.001
2.69
0.022
[20
44
57.0
Male
28
61.5
0.002
2.00
0.04
Female
36
36.1
51
52.9
0.022
2.41
0.155
13
23.1 0.002
2.74
0.008
Age (years)
Gender
Primary location Extremities Others
Tumour diameter (cm) \5
24
25.2
C5
40
61.3
Fig. 2 Survival differences of 64 ASPS patients with and without lung metastasis (surviving time was calculated from the time of initial diagnosis)
In a study of 48 stage IV (M1) ASPS patients, Portera et al. [19] reported 44 patients with lung metastasis. In Kayton’s study, 60.0 % of patients developed lung metastasis at some point [20]. Sood et al’s report showed that lung metastasis occurred in all patients with metastatic disease
Table 3 Summary of studies reporting lung metastasis in ASPS
References
[17]. Cho et al. [21] also found that the lung was the most common metastatic site in ASPS patients. Lung metastasis accounted for 95.2 % of the patients with metastatic diseases in our study. As thus, the lungs are definitely the most common metastatic sites in ASPS. The higher incidence of lung metastasis in ASPS is likely due to its hypervascularity and prominent intravascular tumour extension [3, 17]. Furthermore, pulmonary circulation is the filter of the blood from vena cava, and the pulmonary circulation pressure is lower than the systemic circulation, so the lungs are the most easily implanting sites for metastatic tumour cells. Because of the high prevalence of lung metastasis, it would be appropriate to analyse the possible clinical factors associated with lung metastasis, and we recommended regular screening via chest CT at diagnosis and during follow-up for patients with ASPS. The utility of PET-CT in ASPS would be informative as well when it’s indicated. Lung metastasis has an adverse effect on survival in our study. This is in accordance with the reports from Lieberman and Portera. Lieberman et al. [14] reported that the median survival dropped to 3 years with metastasis as opposed to 11 years without metastasis. Similarly, 5-year survival rates of 20 and 87 % were presented for patients
No. of patients
Lung metastasis (%)
Portera et al. [19]
48 (M1)
NA
92.0
Kayton et al. [20]
20
36
60.0
Sood et al. [17]
25
75
92.0 (100 % in M1)
Cho et al. [21]
19
54 (mean)
63.2
Rekhi et al. [5]
29
27.5
62.1
Ogura et al. [26]
26
71 (average)
76.9
Van Ruth et al. [31]
15
170
66.7
NA not available, M1 with metastatic diseases
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Median follow-up (months)
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with or without metastasis in Portera’s study [19]. Solitary metastasis and oligometastasis to the lung were not commonly seen in our patients. Most lung metastasis occurred within 2 years after primary ASPS diagnosis, but lung metastasis can continue to develop many years after the initial treatment. Falkenstern-Ge et al. [22] reported a lung metastasis that occurred 20 years after surgical resection of primary ASPS. Lillehei and co-workers reported an interval of 21 years between primary presentation and development of lung metastasis [23]. Late metastasis to the lung in ASPS has been frequently reported previously [2, 20, 21]. In our study, a few patients exhibited lung metastasis more than 5 years after initial treatment. We propose that longer than 5 years of follow-up is necessary for ASPS patients after radical resection. Our results demonstrated that sex, age, and primary tumour size were closely associated with lung metastasis. Being male and [20 years of age and having a tumour size C5cm were positively correlated with lung metastasis. Age and primary tumour size have been extensively reported in other reports to be important prognostic factors for survival [6, 14, 15, 20, 24–27]. Younger age at diagnosis and small tumour size has always been shown to be associated with good survival. Daigeler’s report [13] showed a favourable outcome in female patients. Metastatic disease was predictive of poor survival in both our group of patients and other reports [10, 14, 19, 21, 24]. It is reasonable that the factors affecting the incidence of lung metastasis also affect the survival, because distant metastasis is the main cause of ASPS fatality, while lung metastasis is the most commonly involved sites. Casanova et al. [24] presented a lower rate of metastatic spread in children (21 %). Kayton et al. [20] observed early stage
disease more frequently in patients B16 years of age than in older (70 and 40 %, respectively). Lieberban et al’s data indicated that the dependence of survival on age is due to the increased occurrence of metastasis in older people [14]. The lower rate of metastatic spread in younger patients is probably due to a less aggressive behaviour and different biological features of ASPS in those patients and an earlier diagnosis in paediatric ASPS patients [24]. Tumour size is closely related to metastatic spread in ASPS patients. This is understandable. Large size tumour growth needs longer time, which brings the tumour more chance to spread as well. Both Casanova et al. [24] and Lieberman et al. [14] showed that patients with a maximum tumour diameter [10 cm presented with metastatic disease. In Evans’s report, 1 in 5 patients with a tumour size \5 cm and 6 in 7 patients with a tumour size C5 cm developed lung metastasis [28]. Our observations confirm that a larger primary tumour size is positively correlated with lung metastasis. Of note, in our study, all the locally recurred patients developed lung metastasis. This suggests that complete excision of the primary tumour to achieve satisfactory local control is essential in reducing the risk of lung metastasis. In addition, the patients with ASPS originating in the extremities had a higher probability of lung metastasis than those originating in other locations. This may be due to the limitation of axial resection in the extremities. However, the difference was only significant by univariate analysis. Other reports have not observed this tendency [13, 24], thus, further studies are warranted. Active chemotherapy regimens have not been identified for ASPS patients with lung metastasis. Reports regarding chemotherapy in ASPS patients with metastatic disease
Table 4 Summary of studies reporting chemotherapy response for metastatic diseases in ASPS References
No. of patients
Regimen and cycles
Chemotherapy response (%)
Reichardt et al. [15]
68
Anthracycline-containing or ifosfamide-containing regimen, cycles: NA
CR 4 PR 3 SD 41 PD 51
Kayton et al. [20]
11
Ogura et al. [26]
9
Ogose et al. [25]
27
A vast assortment of chemotherapeutic and biologic agents were administered, cycles: NA
No CR
Mainly anthracycline-containing regimens. cycles: NA
No objective response
Based on cisplatin, ifosfamide, doxorubicin, and biologic response modifiers, cycles: NA
No clinical response
No PR
Orbach et al. [10]
18
Ifosfamide-doxorubicin-based regimens, evaluated after 3 cycles
CR ? PR 17
Portera et al. [19]
26
1. Vincristine and/or cyclophosphamide, 2. doxorubicin-based chemotherapy, median, 4 cycles (2–8 cycles)
Only 1 CR (3 %), no PR
NA not available, CR complete response, PR partial response, SD stable disease, PD progressive disease
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(mainly with lung metastasis) failed to demonstrate any promising results (Table 4). Reichardt et al. [15] analysed the response to first-line chemotherapy in 68 ASPS patients with measurable diseases. Anthracycline- or ifosfamidecontaining regimens were adopted. The responses were as follows: complete remission: 4 %, partial remission: 3 %, stable disease: 41 %, and progressive disease: 51 %. They concluded that ASPS patients should not be treated with chemotherapy outside of controlled clinical trials. Though most of the patients with lung metastasis in our study received 2–8 cycles of chemotherapy with anthracyclineor ifosfamide-based regimens, none experienced a complete remission and only one experienced a partial remission. Therefore, ASPS with metastatic lung disease is invariably chemoresistant to schemes used to treat general soft tissue sarcomas. Effective chemotherapeutic agents or alternative therapeutic options (such as targeted therapies) for ASPS with metastatic lung disease need to be developed. Some authors have reported prolonged survival following excision of metastases in the lungs [6, 14, 20]. For ASPS patients with lung metastasis alone, Lieberman et al. [14] reported a median survival of 218 months in five patients receiving excision of lung metastases and 63.5 months for patients without lung metastases excision. After resection of lung metastases, survivals longer than 10 years were also presented in Kayton’s series [20]. Surviving time longer than 7 years was observed in our series that underwent excision of the pulmonary metastases. The longterm survivors observed in this series and in other reports may justify metastasectomy for patients who have a medically resectable solitary metastasis or oligometastasis confined to the lung and a good performance status [6, 13, 14, 19, 27]. Although at present, there is no effective system treatment for ASPS patients with metastatic lung disease, those patients can survive a relatively long time, with a median survival of 34 months in our series. Portera [19] and Lieberman [14] also reported prolonged survival for ASPS patients who developed lung metastasis alone. A median survival of 40 and 63.5 months, respectively, were reported in their studies. This is much longer than most other soft tissue sarcomas [29, 30].
Conclusions This is a retrospective analysis of ASPS with metastatic lung disease that spanned half a century. Our results confirmed that lung metastasis is common in ASPS. Sex, age, primary tumour size at the time of original diagnosis, and local control greatly influence the occurrence of lung metastasis. Regular chemotherapy lacks efficacy in ASPS with metastatic lung disease. Metastasectomy may be justified for patients with medically resectable and lung confined
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metastasis. ASPS with metastatic lung disease manifests with an indolent clinical course. In the absence of effective drug for the treatment of lung metastasis from ASPS, an international, multi-centre clinical trial from the United Kingdom, Australia and Spain are collaboratively exploring the ability of cediranib to halt disease progression in patients with metastatic ASPS [cediranib: a highly potent VEGFR (Vascular Endothelial Growth Factor Receptor) inhibitor] [32]. This study possibly will bring us new information. Conflict of interest
We declare that we have no conflict of interest.
References 1. Anderson ME, Hornicek FJ, Gebhardet MC, Raskin KA. Alveolar soft part sarcoma: a rare and enigmatic entity. Clin Orthop Relat Res. 2005;438:144–8. 2. Enzinger FM, Weiss SW. Malignant tumors of uncertain type. In: Enzinger FM, Weiss SW, editors. Soft tissue tumors. 3rd ed. St. Louis: Mosby; 1995. p. 1067–74. 3. Folpe AL, Deyrup AT. Alveolar soft-part sarcoma: a review and update. J Clin Pathol. 2006;59:1127–32. 4. Weiss SW. Alveolar soft part sarcoma, are we at the end or just the beginning of our quest? AJP. 2002;160:1197–9. 5. Rekhi B, Ingle A, Agarwal M, Puri A, Laskar S, Jambhekar NA. Alveolar soft part sarcoma ‘revisited’: clinicopathological review of 47 cases from a tertiary cancer referral centre, including immunohistochemical expression of TFE3 in 22 cases and 21 other tumours. Pathology. 2012;44:11–7. 6. Zarrin-Khameh N, Kaye KS. Alveolar Soft Part Sarcoma. Arch Pathol Lab Med. 2007;131:488–91. 7. Pang LJ, Chang B, Zou H, Qi Y, Jiang JF, Li HA, et al. Alveolar soft part sarcoma: a bimarker diagnostic strategy using TFE3 immunoassay and ASPLTFE3 fusion transcripts in paraffin-embedded tumor tissues. Diagn Mol Pathol. 2008;17:245–52. 8. Williams A, Bartle G, Sumathi VP, Meis JM, Mangham DC, Grimer RJ, et al. Detection of ASPL/TFE3 fusion transcripts and the TFE3 antigen in formalinfixed, paraffin-embedded tissue in a series of 18 cases of alveolar soft part sarcoma: useful diagnostic tools in cases with unusual histological features. Virchows Arch. 2011;458:291–300. 9. Kummar S, Allen D, Monks A, Polley EC, Hose CD, Ivy SP, et al. Cediranib for metastatic alveolar soft part sarcoma. J Clin Oncol. 2013;31:2296–302. 10. Orbach D, Brennan B, Casanova M, Bergeron C, Mosseri V, Francotte N, et al. Paediatric and adolescent alveolar soft part sarcoma: a joint series from European cooperative groups. Pediatric Blood Cancer. 2013;60:1826–32. 11. Hilbert M, Mary P, Larroquet M, Serinet MO, Helfre S, Brisse H, et al. Alveolar soft part sarcoma in childhood: is Sunitinib-Sutent(R) treatment an effective approach? Pediatric Blood Cancer. 2012;58:475–6. 12. Christopherson WM, Foote FW, Stewart FW. Alveolar soft-part sarcomas: structurally characteristic tumors of uncertain histogenesis. Cancer. 1952;5:100–11. 13. Daigeler A, Kuhnen C, Hauser J, Goertz O, Tilkorn D, Steinstraesser L, et al. Alveolar soft part sarcoma: clinicopathological findings in a series of 11 cases. World J Surg Oncol. 2008;6:71–8. 14. Lieberman PH, Brennan MF, Kimmel M, Erlandson RA, Garin-Chesa P, Flehinger BY. Alveolar soft-part sarcoma: a clinico-pathologic study of half a century. Cancer. 1989;63:1–13. 15. Reichardt P, Lindner T, Pink D, Thuss-Patience PC, Kretzschmar A, Dorken B. Chemotherapy in alveolar soft part sarcomas: what do we know? European J Cancer. 2003;39:1511–6. 16. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47. 17. Sood S, Baheti AD, Shinagare AB, Jagannathan JP, Hornick JL, Ramaiya NH, et al. Imaging features of primary and metastatic alveolar soft part sarcoma: single institute experience in 25 patients. British J Radiol. 2014. doi:10.1259/bjr. 20130719. 18. Lorigan JG, O’Keeffe FN, Evans HL, Wallace S. The radiologic manifestations of alveolar soft-part sarcoma. Am J Roentgenol. 1989;153:335–9. 19. Portera CA, Ho V, Patel SR, Hunt KK, Feig BW, Respondek PM, et al. Alveolar soft part sarcoma: clinical course and patterns of metastasis in 70 patients treated at a single institution. Cancer. 2001;91:585–91. 20. Kayton ML, Meyers P, Wexler LH, Gerald WL, Laquaglia MP. Clinical presentation, treatment, and outcome of alveolar soft part sarcoma in children, adolescents, and young adults. J Pediatr Surg. 2006;41:187–93.
Clin Transl Oncol (2015) 17:803–809 21. Cho YJ, Kim JY. Alveolar soft part sarcoma: clinical presentation, treatment and outcome in a series of 19 patients. Clin Orthopedic Surg. 2014;6:80–6. 22. Falkenstern-Ge RF, Kimmich M, Wohlleber M, Grabner A, Friedel G, Ott G, et al. Lung metastasis of primary alveolar soft-part sarcoma occurring 20 years after initial treatment. Case Rep Oncolog Med. 2013. doi:10.1155/2013/690520. 23. Lillehei KO, Kleinschmidt-DeMasters B, Mitchell DH, Spector E, Kruse CA. Alveolar soft part sarcoma: an unusually long interval between presentation and brain metastasis. Human Pathol. 1993;24:1030–4. 24. Casanova M, Ferrari A, Bisogno G, Cecchetto G, Basso E, Bernardi BD, et al. Alveolar soft part sarcoma in children and adolescents: a report from the SoftTissue Sarcoma Italian Cooperative Group. Ann Oncol. 2000;11:1445–9. 25. Ogose A, Yazawa Y, Ueda T, Hotta T, Kawashima H, Hatano H, et al. Alveolar soft part sarcoma in japan: multi-institutional study of 57 patients from the Japanese Musculoskeletal Oncology Group. Oncology. 2003;65:7–13. 26. Ogura K, Beppu Y, Chuman H, Yoshida A, Yamamoto N, Sumi M, et al. Alveolar soft part sarcoma: a single-center 26-patient case series and review of the literature. Sarcoma. 2012. doi:10.1155/2012/907179.
809 27. Pennacchioli E, Fiore M, Collini P, Radaelli S, Dileo P, Stacchiotti S, et al. Alveolar soft part sarcoma: clinical presentation, treatment, and outcome in a 33 patients at a single institution. Ann Surg Oncol. 2010;7:3229–33. 28. Evans HL. Alveolar soft-part sarcoma. A study of 13 typical examples and one with a histologically atypical component. Cancer. 1985;55:912–7. 29. Ferguson PC, Deheshi BM, Chung P, Catton CN, O’Sullivan B, Gupta A, et al. Soft tissue sarcoma presenting with metastatic disease: outcome with primary surgical resection. Cancer. 2011;117:372–9. 30. Kane JM, Finley JW, Driscoll D, Kraybill WG, Gibbs JF. The treatment and outcome of patients with soft tissue sarcomas and synchronous metastases. Sarcoma. 2002;6:69–73. 31. van Ruth S, van Coevorden F, Peterse JL, Kroon BB. Alveolar soft part sarcoma: a report of 15 cases. Eur J Cancer. 2002;38:1324–8. 32. Institute of Cancer Research, United Kingdom. A Phase II Trial of Cediranib in the Treatment of Patients with Alveolar Soft Part Sarcoma (CASPS). 2014. ClinicalTrials.gov Identifier: NCT01337401. Available from: https://clinicaltrials.gov/ ct2/show/NCT01337401?term=cediranib&rank=11. Accessed 21 May 2015.
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