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How I Treat Alveolar Soft Part Sarcoma? The Therapeutic Journey from Nihilism to Cautious Optimism…
CC BY 4.0 · Indian J Med Paediatr Oncol 2024; 45(01): 068-073
DOI: DOI: 10.1055/s-0042-1758540
Introduction
Alveolar soft part sarcoma (ASPS) is a very rare subtype, constituting less than 0.5% of malignant Soft tissue sarcoma.[1] It is an orphan disease affecting adolescents and young adults, predominantly females.[2] The rarity of the disease, with its indolent but relentless natural history and enigmatic line of differentiation, makes its diagnosis a challenge. Despite being a chemoresistant disease, it is known for prolonged survival even in a few metastatic patients with spontaneous disease stabilization and indolent disease behavior. Targeted therapy with antiangiogenic agents and immunotherapy is the way forward for this rare disease. In this review, we aim to give an overview of the approach to diagnosis and management of this orphan disease in 2022 in the Indian setting, which is widely applicable in other low-middle income countries (LMIC) as well.
Publication History
Article published online:
03 December 2022
© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
Introduction
Alveolar soft part sarcoma (ASPS) is a very rare subtype, constituting less than 0.5%-of malignant Soft tissue sarcoma.[1] It is an orphan disease affecting adolescents and young adults, predominantly females.[2] The rarity of the disease, with its indolent but relentless natural history and enigmatic line of differentiation, makes its diagnosis a challenge. Despite being a chemoresistant disease, it is known for prolonged survival even in a few metastatic patients with spontaneous disease stabilization and indolent disease behavior. Targeted therapy with antiangiogenic agents and immunotherapy is the way forward for this rare disease. In this review, we aim to give an overview of the approach to diagnosis and management of this orphan disease in 2022 in the Indian setting, which is widely applicable in other low-middle income countries (LMIC) as well.
Case history
A 25-years-old lady, a housewife, presented to our outpatient department (OPD) with a 2-year history of discomfort in her right thigh. Six months after the onset of symptoms, she felt a vague mass in the lateral aspect of the proximal right thigh with a doubtful gradual increase in the size of the swelling. There was no associated pain, fever, or weight loss. In view of the COVID pandemic, she reassured herself and had delayed any evaluation of this symptom. Now in view of increased anxiety and insistence of family, she has come to our OPD for evaluation.
How do I Evaluate her to Reach a Diagnosis?
The diagnostic evaluation will be C.R.P
C linical evaluation: history and physical examination
R adiological evaluation
P athological evaluation
Clinical Evaluation
History and examination reveal an indolent, slow-growing, painless soft tissue mass of 3 × 3 cm in the lateral aspect of right thigh, with no constitutional symptoms and no local compressive symptoms. In view of the above clinical presentation, one may misinterpret it to be a benign disease such as hemangioma.
Radiological evaluation
X-ray of the right thigh [antero-posterior/lateral views]: soft tissue mass in the right thigh, with no bony erosion and no calcification.
MRI: Radiological evaluation is to be completed before planning a biopsy.[3] [4] [5]
Flow voids due to intra and peri-tumoral vessels.
Hyperintense to muscle in T1 images
Moderate to intense contrast enhancement.
Pathological Evaluation
Core needle biopsy of the lesion classically shows[2]:
Pseudo-alveolar pattern [which gives it the name]
Intracytoplasmic rod-shaped crystals [PAS/diastase resistant]
Intravascular extension
Immunohistochemistry: TFE-3 and Cathepsin-K are highly sensitive, though not specific for ASPS. It is consistently negative for cytokeratin, epithelial membrane antigen (EMA), human melanoma black (HMB-45), synaptophysin, and chromogranin.
[When the clinicopathological features of ASPS were initially described in 1952,[1] Christopherson noted that “the most striking feature of the alveolar soft-part sarcoma is the basic uniformity throughout a given tumor and the similarity of one tumor to another.”]
The highly characteristic histopathology leads us to the diagnosis of ASPS.
Molecular studies
ASTS is a translocation-associated STS, with unbalanced non-reciprocal t(X,17) leading to ASPSCR1-TFE3 fusion gene on der (17) and ASPSCR1-TFE3 chimeric transcript, which is seen in almost all cases. In pathologically challenging cases, RT-PCR for the fusion transcript or FISH for TFE3 rearrangement will be helpful in making a definitive diagnosis.[6] [7]
The low incidence, lack of unique clinical features, indolent behavior with the small primary in metastatic disease and atypical sites [adults most common in thigh/gluteal region and in children in head and neck] may lead to misdiagnosis.
A systematic clinical + radiological + pathological evaluation leads us to a definite diagnosis of ASPS.
Now the Definitive Diagnosis of ASPS is Made. How do we Stage the Patient?
The natural history of ASPS is unique with an extremely indolent behavior with late metastasis becoming symptomatic months to years after diagnosis. The most common sites of metastasis are lungs, bone, and brain. Brain metastasis in ASPS is more than in other soft tissue sarcomas.[8]
a) NCCT chest: multiple bilateral lung metastases.
b) MRI Brain: normal.
c) PET-CT: not recommended as initial staging in NCCN/ESMO guidelines.
We have reached a final diagnosis of metastatic ASPS.
ASPS is unique among STS, to have a small primary with an indolent behavior with late metastasis in the lungs. It is one of the few STS, with a high risk of brain metastasis.
How do we Treat Patients with ASPS?
Goals of Treatment
▪ Minimize local recurrence.
▪ Minimize perioperative morbidity and mortality.
▪ Maximize functionality and QOL.
▪ Maximize overall survival.
The overview of the management plan of ASPS is depicted in the [Fig. 1].
Localized Disease
Localized disease is treated with wide local excision followed by adjuvant radiotherapy if there is evidence of microscopic or macroscopic residual disease or if the margin status is questionable.[9]
Metastatic Disease
Is there a role for surgical excision of primary in metastatic disease with resectable primary?
In the pre-targeted-therapy era, if complete resection was feasible, with limited postoperative morbidity then surgery of the primary, followed by systematic treatment was adopted, the rationale being the indolent disease biology. SEER retrospective data of 25 patients with 58% having a metastatic disease with primary resections, showed an improvement in the overall survival. The role remains questionable and controversial in the present targeted therapy era.[9]
Metastatic Disease, Limited Disease Burden:
Patients with the limited disease who are asymptomatic may be observed with close follow-up, considering the indolent behavior. Brain metastasis [symptomatic/asymptomatic] should be treated with CNS-directed therapy.
Metastatic Disease with Heavy disease burden/Symptomatic/Rapidly progressive Disease:
ASPS is a relatively chemo-resistant disease. Hence, in both adjuvant and metastatic settings, chemotherapy is not offered.[2] [10]
First-line therapy includes targeted therapy with anti-angiogenic [VEGF] agents pazopanib and sunitinib and immunotherapy with immune checkpoint inhibitors and combinations of both.
In view of the rarity of the disease, evidence for treatment options comes from small retrospective case series and recent prospective studies. So, it is difficult to draw definite conclusions. The best treatment happens to be a lot of educated guesses.
Recommended Treatment Agents for Metastatic Disease
NCCN recommendation 2021 [Evidence blocks of therapy is shown in [Table 1]].
|
Sunitinib |
|||||
|
3/5 |
3/5 |
2/5 |
3/5 |
2/5 |
|
|
Efficacy |
Safety |
Quality of evidence |
Consistency of evidence |
Affordability |
|
|
Pazopanib |
|||||
|
3/5 |
3/5 |
2/5 |
3/5 |
2/5 |
|
|
Efficacy |
Safety |
Quality of evidence |
Consistency of evidence |
Affordability |
|
|
Pembrolizumab |
|||||
|
3/5 |
3/5 |
2/5 |
2/5 |
1/5 |
|
|
Efficacy |
Safety |
Quality of evidence |
Consistency of evidence |
Affordability |
|
Sunitinib |
|||
|---|---|---|---|
|
Author |
Year |
Number of patients |
Outcomes |
|
Stacchiotti[11] |
2011 |
9 |
5PR/3SD/1PD Median TTP: 17months |
|
Li[12] |
2016 |
14 |
4PR/10SD Median PFS:41months |
|
Jagodzinska[13] |
2017 |
15 |
6PR/8SD/1PD MedianPFS:19months Median OS:56months |
|
Pazopanib |
|||
|
Year |
Author |
Number of patients |
Outcomes |
|
Stacchiotti[14] |
2018 |
30 |
1CR/7PR/17SD/4PD/1NE Median PFS:13.6months |
|
Kim[15] |
2019 |
6 |
ORR:17% Median PFS:5.5 months |
|
Cediranib |
|||
|
Kummar[16] |
2013 |
43 |
ORR:35% |
|
Judson[17] |
2014 |
6 |
2PR/4SD |
|
Judson [RCT, Ph2] CASPS[18] |
2019 |
32/16 |
3PR/14SD Median PFS:10.8months |
|
Dasatinib |
|||
|
Schurtze[19] |
2017 |
12 |
Median PFS:11months 5yr OS:30% |
|
Crizotinib |
|||
|
Schoffski[20] |
2018 |
45 |
1PR/35SD 1year PFS:38% |
|
Tivantinib |
|||
|
Wagner[21] |
2012 |
27 |
21SD/5PD/1NE Median PFS:5.5 months |
|
Combination of targeted therapy |
|||
|
Flores[22] |
2018 |
69 [11 targetted/ 15chemo/ 6observation] |
2PR/6SD/3PD Median TTP: - Targetted:12months Chemo:7months Observation:4months |
|
J.Bajpai[23] |
2019 |
54[6 with sunitinib/pazopanib] |
2CR/2PR Median PFS:23 months |
|
Year |
Author |
Number |
Outcome localized disease |
Outcome metastatic disease |
|---|---|---|---|---|
|
1989 |
Lieberman[28] |
91 [69/22] |
Median OS = 11 y OS at 2 y-77% OS at 5 y-60% OS at 10 y-38% OS at 20 y-15% |
Median OS = 3 y |
|
2018 |
Flores[22] |
69 [31/38] |
OS at 5 y-87% |
OS at 5 y-61% |
Conflict of Interest
None declared.
References
- Christopherson WM, Foote Jr FW, Stewart FW. Alveolar soft-part sarcomas; structurally characteristic tumors of uncertain histogenesis. Cancer 1952; 5 (01) 100-111
- Reichardt P, Lindner T, Pink D, Thuss-Patience PC, Kretzschmar A, Dörken B. Chemotherapy in alveolar soft part sarcomas. What do we know?. Eur J Cancer 2003; 39 (11) 1511-1516
- McCarville MB, Muzzafar S, Kao SC. et al. Imaging features of alveolar soft-part sarcoma: a report from Children's Oncology Group Study ARST0332. AJR Am J Roentgenol 2014; 203 (06) 1345-1352
- Li X, Ye Z. Magnetic resonance imaging features of alveolar soft part sarcoma: report of 14 cases. World J Surg Oncol 2014; 12: 36
- Cui JF, Chen HS, Hao DP, Liu JH, Hou F, Xu WJ. Magnetic resonance features and characteristic vascular pattern of alveolar soft part sarcoma. Oncol Res Treat 2017; 40 (10) 580-585
- Ladanyi M, Lui MY, Antonescu CR. et al. The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene 2001; 20 (01) 48-57
- Williams A, Bartle G, Sumathi VP. et al. Detection of ASPL/TFE3 fusion transcripts and the TFE3 antigen in formalin-fixed, 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 (03) 291-300
- Wang Y, Cui J, Yan X, Jin R, Hong X. Alveolar soft part sarcoma with multiple brain and lung metastases in pregnancy: a case report and literature review. Medicine (Baltimore) 2017; 96 (46) e8790
- Wang H, Jacobson A, Harmon DC. et al. Prognostic factors in alveolar soft part sarcoma: A SEER analysis. J Surg Oncol 2016; 113 (05) 581-586
- Ogura K, Beppu Y, Chuman H. et al. Alveolar soft part sarcoma: a single-center 26-patient case series and review of the literature. Sarcoma 2012; 2012: 907179
- Stacchiotti S, Negri T, Zaffaroni N. et al. Sunitinib in advanced alveolar soft part sarcoma: evidence of a direct antitumor effect. Ann Oncol 2011; 22 (07) 1682-1690
- Li T, Wang L, Wang H. et al. A retrospective analysis of 14 consecutive Chinese patients with unresectable or metastatic alveolar soft part sarcoma treated with sunitinib. Invest New Drugs 2016; 34 (06) 701-706
- Jagodzińska-Mucha P, Świtaj T, Kozak K. et al. Long-term results of therapy with sunitinib in metastatic alveolar soft part sarcoma. Tumori 2017; 103 (03) 231-235
- Stacchiotti S, Mir O, Le Cesne A. et al. Activity of pazopanib and trabectedin in advanced alveolar soft part sarcoma. Oncologist 2018; 23 (01) 62-70
- Kim M, Kim TM, Keam B. et al. A Phase II trial of pazopanib in patients with metastatic alveolar soft part sarcoma. Oncologist 2019; 24 (01) 20-e29
- Kummar S, Allen D, Monks A. et al. Cediranib for metastatic alveolar soft part sarcoma. J Clin Oncol 2013; 31 (18) 2296-2302
- Judson I, Scurr M, Gardner K. et al. Phase II study of cediranib in patients with advanced gastrointestinal stromal tumors or soft-tissue sarcoma. Clin Cancer Res 2014; 20 (13) 3603-3612
- Judson I, Morden JP, Leahy MG. et al. Activity of cediranib in alveolar soft part sarcoma (ASPS) confirmed by CASPS (cediranib in ASPS), an international, randomized phase II trial [abstract 11004]. Proc ASCO. 2017;35(15).
- Schuetze SM, Bolejack V, Choy E. et al. Phase 2 study of dasatinib in patients with alveolar soft part sarcoma, chondrosarcoma, chordoma, epithelioid sarcoma, or solitary fibrous tumor. Cancer 2017; 123 (01) 90-97
- Schöffski P, Wozniak A, Kasper B. et al. Activity and safety of crizotinib in patients with alveolar soft part sarcoma with rearrangement of TFE3: European Organization for Research and Treatment of Cancer (EORTC) phase II trial 90101 ‘CREATE’. Ann Oncol 2018; 29 (03) 758-765
- Wagner AJ, Goldberg JM, Dubois SG. et al. Tivantinib (ARQ 197), a selective inhibitor of MET, in patients with microphthalmia transcription factor-associated tumors: results of a multicenter phase 2 trial. Cancer 2012; 118 (23) 5894-5902
- Flores RJ, Harrison DJ, Federman NC. et al. Alveolar soft part sarcoma in children and young adults: a report of 69 cases. Pediatr Blood Cancer 2018; 65 (05) e26953
- Simha V, Bajpai J. Alveolar Soft Part Sarcomas(ASPS): A tertiary cancer care center experience from India. Journal of Clinical Oncology 2019; 37 (15) e22553
- Groisberg R, Hong DS, Behrang A. et al. Characteristics and outcomes of patients with advanced sarcoma enrolled in early phase immunotherapy trials. J Immunother Cancer 2017; 5 (01) 100
- Naqash AR, Coyne GHO, Moore N. et al. Phase II study of atezolizumab in advanced alveolar soft part sarcoma (ASPS). Journal of Clinical Oncology 2021; 39 (15) ,suppl. 11519
- Wilky BA, Trucco MM, Subhawong TK. et al. Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial. Lancet Oncol 2019; 20 (06) 837-848
- Saerens M, Brusselaers N, Rottey S, Decruyenaere A, Creytens D, Lapeire L. Immune checkpoint inhibitors in treatment of soft-tissue sarcoma: A systematic review and meta-analysis. Eur J Cancer 2021; 152: 165-182
- 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 (01) 1-13
Address for correspondence
Publication History
Article published online:
03 December 2022
© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
References
- Christopherson WM, Foote Jr FW, Stewart FW. Alveolar soft-part sarcomas; structurally characteristic tumors of uncertain histogenesis. Cancer 1952; 5 (01) 100-111
- Reichardt P, Lindner T, Pink D, Thuss-Patience PC, Kretzschmar A, Dörken B. Chemotherapy in alveolar soft part sarcomas. What do we know?. Eur J Cancer 2003; 39 (11) 1511-1516
- McCarville MB, Muzzafar S, Kao SC. et al. Imaging features of alveolar soft-part sarcoma: a report from Children's Oncology Group Study ARST0332. AJR Am J Roentgenol 2014; 203 (06) 1345-1352
- Li X, Ye Z. Magnetic resonance imaging features of alveolar soft part sarcoma: report of 14 cases. World J Surg Oncol 2014; 12: 36
- Cui JF, Chen HS, Hao DP, Liu JH, Hou F, Xu WJ. Magnetic resonance features and characteristic vascular pattern of alveolar soft part sarcoma. Oncol Res Treat 2017; 40 (10) 580-585
- Ladanyi M, Lui MY, Antonescu CR. et al. The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene 2001; 20 (01) 48-57
- Williams A, Bartle G, Sumathi VP. et al. Detection of ASPL/TFE3 fusion transcripts and the TFE3 antigen in formalin-fixed, 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 (03) 291-300
- Wang Y, Cui J, Yan X, Jin R, Hong X. Alveolar soft part sarcoma with multiple brain and lung metastases in pregnancy: a case report and literature review. Medicine (Baltimore) 2017; 96 (46) e8790
- Wang H, Jacobson A, Harmon DC. et al. Prognostic factors in alveolar soft part sarcoma: A SEER analysis. J Surg Oncol 2016; 113 (05) 581-586
- Ogura K, Beppu Y, Chuman H. et al. Alveolar soft part sarcoma: a single-center 26-patient case series and review of the literature. Sarcoma 2012; 2012: 907179
- Stacchiotti S, Negri T, Zaffaroni N. et al. Sunitinib in advanced alveolar soft part sarcoma: evidence of a direct antitumor effect. Ann Oncol 2011; 22 (07) 1682-1690
- Li T, Wang L, Wang H. et al. A retrospective analysis of 14 consecutive Chinese patients with unresectable or metastatic alveolar soft part sarcoma treated with sunitinib. Invest New Drugs 2016; 34 (06) 701-706
- Jagodzińska-Mucha P, Świtaj T, Kozak K. et al. Long-term results of therapy with sunitinib in metastatic alveolar soft part sarcoma. Tumori 2017; 103 (03) 231-235
- Stacchiotti S, Mir O, Le Cesne A. et al. Activity of pazopanib and trabectedin in advanced alveolar soft part sarcoma. Oncologist 2018; 23 (01) 62-70
- Kim M, Kim TM, Keam B. et al. A Phase II trial of pazopanib in patients with metastatic alveolar soft part sarcoma. Oncologist 2019; 24 (01) 20-e29
- Kummar S, Allen D, Monks A. et al. Cediranib for metastatic alveolar soft part sarcoma. J Clin Oncol 2013; 31 (18) 2296-2302
- Judson I, Scurr M, Gardner K. et al. Phase II study of cediranib in patients with advanced gastrointestinal stromal tumors or soft-tissue sarcoma. Clin Cancer Res 2014; 20 (13) 3603-3612
- Judson I, Morden JP, Leahy MG. et al. Activity of cediranib in alveolar soft part sarcoma (ASPS) confirmed by CASPS (cediranib in ASPS), an international, randomized phase II trial [abstract 11004]. Proc ASCO. 2017;35(15).
- Schuetze SM, Bolejack V, Choy E. et al. Phase 2 study of dasatinib in patients with alveolar soft part sarcoma, chondrosarcoma, chordoma, epithelioid sarcoma, or solitary fibrous tumor. Cancer 2017; 123 (01) 90-97
- Schöffski P, Wozniak A, Kasper B. et al. Activity and safety of crizotinib in patients with alveolar soft part sarcoma with rearrangement of TFE3: European Organization for Research and Treatment of Cancer (EORTC) phase II trial 90101 ‘CREATE’. Ann Oncol 2018; 29 (03) 758-765
- Wagner AJ, Goldberg JM, Dubois SG. et al. Tivantinib (ARQ 197), a selective inhibitor of MET, in patients with microphthalmia transcription factor-associated tumors: results of a multicenter phase 2 trial. Cancer 2012; 118 (23) 5894-5902
- Flores RJ, Harrison DJ, Federman NC. et al. Alveolar soft part sarcoma in children and young adults: a report of 69 cases. Pediatr Blood Cancer 2018; 65 (05) e26953
- Simha V, Bajpai J. Alveolar Soft Part Sarcomas(ASPS): A tertiary cancer care center experience from India. Journal of Clinical Oncology 2019; 37 (15) e22553
- Groisberg R, Hong DS, Behrang A. et al. Characteristics and outcomes of patients with advanced sarcoma enrolled in early phase immunotherapy trials. J Immunother Cancer 2017; 5 (01) 100
- Naqash AR, Coyne GHO, Moore N. et al. Phase II study of atezolizumab in advanced alveolar soft part sarcoma (ASPS). Journal of Clinical Oncology 2021; 39 (15) ,suppl. 11519
- Wilky BA, Trucco MM, Subhawong TK. et al. Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial. Lancet Oncol 2019; 20 (06) 837-848
- Saerens M, Brusselaers N, Rottey S, Decruyenaere A, Creytens D, Lapeire L. Immune checkpoint inhibitors in treatment of soft-tissue sarcoma: A systematic review and meta-analysis. Eur J Cancer 2021; 152: 165-182
- 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 (01) 1-13