How I Treat Alveolar Soft Part Sarcoma? The Therapeutic Journey from Nihilism to Cautious Optimism …

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 raredisease. In this review,weaimtogiveanoverviewof the approach to diagnosis and management of this orphan disease in 2022 in the Indian setting, which iswidely applicable in other low-middle income countries (LMIC) as well.


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

Clinical Evaluation
History and examination reveal an indolent, slow-growing, painless soft tissue mass of 3 Â 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.
• Hyperintense to muscle in T1 images • Moderate to intense contrast enhancement.
The highly characteristic histopathology leads us to the diagnosis of ASPS.

Molecular studies
ASTS is a translocation-associated STS, with unbalanced nonreciprocal 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

Learning Point
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 þ radiological þ 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.

Learning Point
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. 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 antiangiogenic [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].

Rationale
ASPS is a translocation associated STS, with the ASPSCR1-TFE3 fusion as a hallmark. This fusion transcript leads to MET overexpression and increased angiogenesis in this highly vascular tumor. Hence antiangiogenic targeted therapy holds promise in this disease.

Combination Regimens
Immune checkpoint inhibitor with antiangiogenic targeted therapy:

Therapeutic Journey from Nihilism to Cautious Optimism
The progress in systemic therapy with targeted agents has led to improvement in survival as shown in ►Table 3. The 5 years overall survival of patients with the localized disease was 60%. Now over three decades later, patients with metastatic disease, treated with targeted therapy have the same survival. This clearly shows the progress in our therapeutic journey.
With many novel agents in the pipeline and pathway-driven basket trials and collaborative prospective clinical trials, the future of management of ASPS looks bright and promising.

Take Home Messages
• ASPS is a rare orphan disease, with an indolent yet relentless clinical course. • A detailed clinico-radio-pathological evaluation is the key to diagnosis. • It usually presents as a painless slow-growing vascular soft tissue mass in the lower limb of adolescents and young adults, predominantly females. • It has characteristic histopathology with Pseudo-alveolar patterns and intracytoplasmic crystals. IHC with TFE3 and Molecular studies for ASPSCR1-TFE3 help in challenging situations. • Metastatic disease to lung/bone/brain leads to poor prognosis. It is unique among STS to have brain metastasis. • Localized disease is managed with wide local excision followed by adjuvant radiotherapy if microscopic or macroscopic residual disease. • It is essentially a chemoresistant disease with an almost negligible role for Adjuvant chemotherapy. • Metastatic disease is treated with targeted anti-VEGF agents such as pazopanib/sunitinib and immunotherapy such as pembrolizumab or combination. • With many novel agents in the pipeline and pathwaydriven Basket trials with collaborative prospective clinical trials, the future of management of ASPS looks promising. It is truly a therapeutic journey from Nihilism to cautious optimism.