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Microphthalmia-Associated Transcription Family Translocation Renal Cell Cancer
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Xp11 tRCC (also known as TFE3-rearranged RCC) is a brownish-yellow solid mass with an occasional gray-white cut surface (resembling papillary RCC), frequent necrosis, and hemorrhage. It is responsible for 20%–40% of pediatric RCC and only 1% of adult RCC (with an average onset age of 50 years). Histologically, Xp11 tRCC has large epithelioid cells in papillary and nested growth pattern and containing clear to eosinophilic cytoplasm, prominent nucleoli, and psammoma bodies (Figure 34.1). Cytogenetically, Xp11 tRCC contains a fusion of TFE3 in Xp11 with ASPSCR1 (also known as ASPL), PRCC, SFPQ (also known as PSF), CLTC, NONO, RBM10, PARP14, LUC7L3, KHSRP, DVL2, MED15, or GRIPAP1 in 1q22, resulting in chromosome translocation t(X;1)(p11.2;q21). Interestingly, Xp11 tRCC with a PRCC-TFE3 fusion shows a smaller structure of nested or papillary cells, less abundant cytoplasm, and less conspicuous nuclei than Xp11 tRCC with an ASPSCR1-TFE3 fusion, but the latter (which also occurs in alveolar soft part sarcoma) has a worse prognosis than the former. Due to its frequent lymph node metastasis, Xp11 tRCC confers a similar prognosis to clear cell RCC and a worse prognosis than papillary RCC [2].
What’s the latest with investigational drugs for soft tissue sarcoma?
Published in Expert Opinion on Investigational Drugs, 2022
Elena Cojocaru, Andrea Napolitano, Cyril Fisher, Paul Huang, Robin L Jones, Khin Thway
Alveolar soft part sarcoma (ASPS) is one of the rarest sarcoma subtypes and is molecularly characterized by ASPSCR1(ASPL)-TFE3 fusion [87,88]. The conserved translocation of the ASPSCR1-TFE3 fusion gene in ASPS leads to aberrant transcription of downstream target genes including HIF-1α, which upregulates proangiogenic factors including VEGF [89]. Inhibitors of the VEGF pathway, including sunitinib, pazopanib, and cediranib, have shown substantial antitumoral activity in ASPS [90–92]. It is well documented that VEGF promotes tumor progression through angiogenesis but also impairs the tumoral immune response [93]. Therefore, the double inhibition of the VEGF pathway and the immune checkpoints was investigated in a phase 2 trial enrolling patients with advanced sarcomas, including ASPS [94]. The results of this study were published in 2019 and the combination of the VEGF inhibitor axitinib with the PD-1 inhibitor pembrolizumab has shown significant antitumor activity in the ASPS population, with a PFS of 12.4 months compared to the non-ASPS patients where the median PFS was only 3 months [94].
Individualizing systemic therapy for advanced soft tissue sarcomas based on tumor histology and biology
Published in Expert Review of Anticancer Therapy, 2020
Candace L Haddox, Richard F Riedel
There are ongoing efforts to enhance the activity of ICI in STS through predictive biomarker development and combination therapies, including multimodality approaches. For example, radiation therapy increases pro-inflammatory cytokines and neoantigens, suggesting possible synergy with ICI [27,28]. SARC032 is an ongoing randomized phase II trial investigating neoadjuvant pembrolizumab in combination with preoperative radiation therapy and surgery in patients with localized UPS and ddLPS. Additionally, the combination of PD-1/programmed death-ligand 1 (PDL1) inhibitors with inhibition of other immune regulatory molecules such as CD40, lymphocyte-activating gene 3 (LAG-3), and semaphorin 4D are also being explored in preclinical studies and clinical trials. ICIs combined with TKIs have also shown promise, particularly in alveolar soft part sarcoma (ASPS), possibly owing to its characteristic molecular aberration. In this subtype, the ASPSCR1-TFE3 fusion gene leads to the upregulation of vascular endothelial growth factor (VEGF), which can promote tumor immune evasion. Based on these biological underpinnings, a phase II trial enrolled 33 patients with STS, enriched for ASPS (36%), exploring the combination of pembrolizumab with the VEGF receptor inhibitor, axitinib. Clinical benefit was observed in 53% of the patients enrolled and in 73% of the ASPS cohort [29]. Atezolizumab, a monoclonal antibody targeting PD-L1, is currently under investigation in a phase II trial of unresectable ASPS (NCT03141684).
A Review of the Role of Cytogenetics in the Diagnosis of Orbital Rhabdomyosarcoma
Published in Seminars in Ophthalmology, 2019
Paula Cortes Barrantes, Frederick A. Jakobiec, Thaddeus P. Dryja
Another tumor to be considered in the differential diagnosis of ARMS is alveolar soft part sarcoma (ASPS).43 Although it is rare (representing 0.2% to 0.9% of all soft tissue sarcomas), it involves the head and neck region with greatest frequency in children and infants and is most commonly located in the orbit and tongue.44 The cell of origin of the ASPS is as yet unknown. Hypotheses have postulated a relationship to granular cell tumor, renal cell carcinoma, and myogenic tumors, but they have by now been discarded.33 Histopathologically, ASPS displays an organoid pattern subdivided by thin fibrous septa containing fine vascular channels. Similar to ARMS, it can also manifest as a solid variant lacking the alveolar or nested patterns.43,44 Among the features that set these two tumors apart is the greater acidophilic and polygonal cytoplasm of the alveolar soft part sarcoma, which contains distinctive PAS-positive/diastase-resistant crystalloids.42,43 When employing immunohistochemistry for assistance in the differential diagnosis between ASPS and ARMS, the pathologist must take into consideration the fact that ASPS can be positive for skeletal muscle markers such as desmin, muscle-specific actin, myogenin and MyoD1 due to cross-reactivity with an unknown cytoplasmic constituent. Transcription factor E3 (TFE3) and cathepsin K are sensitive markers but not specific for ASPS. ASPS displays an unbalanced translocation, der(17)t(X:17)(p11:q25), resulting in the fusion of the alveolar soft part sarcoma critical region 1 (ASPSCR1) gene at 17q25 with the TFE3 transcription factor E3 gene at Xp11. The presence of this translocation by FISH or RT-PCR is diagnostic of ASPS44 and invaluable in separating it from ARMS.