An unusual case of primary splenic soft part alveolar sarcoma: case report and review of the literature with emphasis on the spectrum of TFE3-associated neoplasms.

BACKGROUND: Alveolar soft part sarcoma is a rare tumour of soft tissues, mostly localized in muscles or deep soft tissues of the extremities. In rare occasions, this tumour develops in deep tissues of the abdomen or pelvis. CASE PRESENTATION: In this case report, we described the case of a 46 year old man who developed a primary splenic alveolar soft part sarcoma. The tumour displayed typical morphological alveolar aspect, as well as immunohistochemical profile notably TFE3 nuclear staining. Detection of ASPSCR1 Exon 7::TFE3 Exon 6 fusion transcript in molecular biology and TFE3 rearrangement in FISH confirmed the diagnosis. CONCLUSION: We described the first case of primary splenic alveolar soft part sarcoma, which questions once again the cell of origin of this rare tumour.

How to develop new systemic treatments in ultra-rare cancers with high unmet needs? The case of alveolar soft-part sarcoma.

Developing new drugs or generating evidence for existing drugs in new indications for ultra-rare cancers is complex and carries a high-risk of failure. This gets even harder in ultra-rare tumours, which have an annual incidence of 1 per 1,000,000 population or less. Here, we illustrate the problem of adequate evidence generation in ultra-rare tumours, using Alveolar Soft-Part Sarcomas (ASPS) - an ultra-rare sarcoma newly diagnosed in approximately 60 persons a year in the European Union - as an exemplar case showing challenges in development despite being potentially relevant for classes of agents. We discuss some possible approaches for addressing such challenges, especially focussing on constructive collaboration between academic groups, patients and advocates, drug manufacturers, and regulators to optimise drug development in ultra-rare cancers. This article, written by various European stakeholders, proposes a way forward to ultimately get better options for patients with ultra-rare cancers.

Establishment and characterization of NCC-ASPS2-C1: a novel patient-derived cell line of alveolar soft part sarcoma.

Alveolar soft part sarcoma (ASPS) is a rare mesenchymal tumor characterized by rearrangement of the ASPSCR1 and TFE3 genes and a histologically distinctive pseudoalveolar pattern. ASPS progresses slowly, but is prone to late metastasis. As ASPS is refractory to conventional chemotherapy, the only curative treatment is complete surgical resection. The prognosis of advanced and metastatic cases is poor, highlighting the need for preclinical research to develop appropriate treatment options. However, ASPS is extremely rare, accounting for < 1% of all soft tissue sarcomas, and only one patient-derived ASPS cell line is available from public cell banks worldwide for research. This study reports the establishment of a novel ASPS cell line derived from the primary tumor tissue of an ASPS patient, named NCC-ASPS2-C1. This cell line retains the ASPSCR1-TFE3 fusion gene, which is characteristic of ASPS. The characterization of this cell line revealed stable growth, spheroid formation, and invasive properties. By screening a drug library using NCC-ASPS2-C1, we identified several drugs that inhibited the proliferation of ASPS cells. In conclusion, the establishment of NCC-ASPS2-C1 provides a valuable resource for advancing ASPS research and developing novel treatments for this challenging disease.

Mimicking angiogenic microenvironment of alveolar soft-part sarcoma in a microfluidic coculture vasculature chip.

Alveolar soft-part sarcoma (ASPS) is a slow-growing soft tissue sarcoma with high mortality rates that affects adolescents and young adults. ASPS resists conventional chemotherapy; thus, decades of research have elucidated pathogenic mechanisms driving the disease, particularly its angiogenic capacities. Integrated blood vessels that are rich in pericytes (PCs) and metastatic potential are distinctive of ASPS. To mimic ASPS angiogenic microenvironment, a microfluidic coculture vasculature chip has been developed as a three-dimensional (3D) spheroid composed of mouse ASPS, a layer of PCs, and endothelial cells (ECs). This ASPS-on-a-chip provided functional and morphological similarity as the in vivo mouse model to elucidate the cellular crosstalk within the tumor vasculature before metastasis. We successfully reproduce ASPS spheroid and leaky vessels representing the unique tumor vasculature to assess effective drug delivery into the core of a solid tumor. Furthermore, this ASPS angiogenesis model enabled us to investigate the role of proteins in the intracellular trafficking of bioactive signals from ASPS to PCs and ECs during angiogenesis, including Rab27a and Sytl2. The results can help to develop drugs targeting the crosstalk between ASPS and the adjacent cells in the tumoral microenvironment.

Evaluation of TRIM63 RNA in situ hybridization (RNA-ISH) as a potential biomarker for alveolar soft-part sarcoma (ASPS).

Alveolar soft-part sarcoma (ASPS) is a rare soft tissue tumor with a broad morphologic differential diagnosis. While histology and immunohistochemistry can be suggestive, diagnosis often requires exclusion of other entities followed by confirmatory molecular analysis for its characteristic ASPSCR1-TFE3 fusion. Current stain-based biomarkers (such as immunohistochemistry for cathepsin K and TFE3) show relatively high sensitivity but may lack specificity, often showing staining in multiple other entities under diagnostic consideration. Given the discovery of RNA in situ hybridization (RNA-ISH) for TRIM63 as a sensitive and specific marker of MiTF-family aberration renal cell carcinomas, we sought to evaluate its utility in the workup of ASPS. TRIM63 RNA-ISH demonstrated high levels (H-score greater than 200) of expression in 19/20 (95%) cases of ASPS (average H-score 330) and was weak or negative in cases of paraganglioma, clear cell sarcoma, rhabdomyosarcoma, malignant epithelioid hemangioendothelioma, as well as hepatocellular and adrenal cortical carcinomas. Staining was also identified in tumors with known subsets characterized by TFE3 alterations such as perivascular epithelioid cell neoplasm (PEComa, average H-score 228), while tumors known to exhibit overexpression of TFE3 protein without cytogenetic alterations, such as melanoma and granular cell tumor, generally showed less TRIM63 ISH staining (average H-scores 147 and 96, respectively). Quantitative assessment of TRIM63 staining by RNA-ISH is potentially a helpful biomarker for tumors with molecular TFE3 alterations such as ASPS.

[Analysis of ultrasound images features and diagnostic model establishment of alveolar soft part sarcoma and intramuscular capillary-type hemangiomas].

Objective: The ultrasonography features of alveolar soft part sarcoma (ASPS) and intramuscular capillary-type hemangiomas (ICTH) were analyzed, and the diagnostic model of ASPS was established. Methods: A cross-sectional study was carried out. The clinical data of 52 patients [28 males and 24 females, aged (20.7±15.1) years] with pathologically confirmed ASPS and ICTH admitted to People's Hospital of Henan Province from January 2005 to February 2023 were included in the study. According to pathological types, the patients were divided into ASPS group and ICTH group. Clinical data of patients were retrospectively collected, and meaningful indicators in the univariate analysis were included in the regression analysis for screening. After comprehensive consideration of clinical significance and statistical significance, eligible indicators were selected for inclusion in the regression analysis. Binary logistic regression analysis was used to screen the factors that distinguished the pathological types of ASPS and ICTH, and the diagnostic model was established. The area under receiver operating characteristic (ROC) curve (AUC) was used to evaluate the diagnostic effectiveness of the diagnostic model in distinguishing ASPS from ICTH. Results: There were 20 patients in ASPS group, 10 males and 10 females, aged (26.9±13.5) years, and 32 patients in ICTH group, 18 males and 14 females, aged (16.8±15.0) years. The age difference between the ASPS group and the ICTH group was statistically significant (P<0.05), and there were statistically significant differences in the ultrasound imaging features of "clear boundary" "peripheral lobe" "thin blood vessels inside the lesion are straight and out of shape" "intra-lesion liquification" "peripheral thick blood vessels" and "peripheral muscle fiber disruption" between the two groups (all P<0.001).Variables with clinical and statistical significance were selected as independent variables. Binary logistic regression analysis showed that peripheral muscle fiber interruption (OR=97.358, 95%CI:6.833-1 387.249) and internal thin blood vessels were flat and out of shape (OR=0.052, 95%CI:0.003-0.921) was the correlation factor to distinguish the pathological types of ASPS and ICTH. Two ultrasonic image features of "peripheral muscle fiber interruption" and "internal thin blood vessels are straight and out of shape" were used to establish the diagnostic model. The sensitivity of "peripheral muscle fiber interruption" diagnostic model was 81.3%, and the specificity was 95.0%. The AUC was 0.811(95%CI: 0.761-0.954). The sensitivity, specificity and AUC of the diagnosis model of "internal thin vessels with flat misshape" were 90.0%, 96.9% and 0.934(95%CI: 0.830-0.984). The sensitivity, specificity and AUC of the combined diagnosis model of "peripheral muscle fiber interruption" and "internal thin blood vessel straight out of shape" were 96.9%, 90.0% and 0.974(95%CI:0.877-0.999). Conclusion: Ultrasonography can be used to distinguish ASPS from ICTH, and the combined diagnostic model based on the two ultrasonic imaging features of "peripheral muscle fiber interruption" and "internal thin blood vessel straight out of shape" can further improve the diagnostic efficiency.

Alveolar soft part sarcoma: a clinicopathological and immunohistochemical analysis of 26 cases emphasizing risk factors and prognosis.

OBJECTIVE: This study aimed to investigate the clinicopathological features and prognostic indicators of alveolar soft part sarcoma (ASPS). METHODS: The characteristics of 26 ASPS patients diagnosed at our hospital between January 2011 and January 2019 were retrospectively analysed. RESULTS: The data for 12 male and 14 female patients, with a median age of 27.5 years, were assessed. The clinical symptoms mainly included painless enlarged masses in deep soft tissues. ASPS had a characteristic pathological morphology. Twenty-four patients were positive for TFE3, and TFE3 gene rearrangement was detected in 12 patients. Among the 26 patients who completed follow-up, 14 had metastasis, 1 had local recurrence, and 7 died. Kaplan-Meier survival analysis revealed that prognosis was significantly correlated with sex, tumour size and metastasis (P < 0.05). Multivariate Cox regression analysis revealed that sex and metastasis were independent prognostic risk factors for patients with ASPS (P < 0.05). CONCLUSION: ASPS is a rare soft tissue sarcoma of unknown origin that occurs in young people, has a slow but metastatic course, and is associated with a poor 5-year survival rate among patients with metastasis. ASPS has character TFE3 protein and gene expression, and the diagnosis is relatively specific. The diagnosis requires comprehensive analysis of clinical history, histological morphology, and immunohistochemistry.

PEComa with ASPSCR1::TFE3 fusion: expanding the molecular genetic spectrum of TFE3-rearranged PEComa with an emphasis on overlap with alveolar soft part sarcoma.

AIMS: Mesenchymal neoplasms involving TFE3 gene fusions are diverse, mainly include alveolar soft part sarcoma (ASPS) that is characterised by ASPSCR1::TFE3 fusion, and a small subset of perivascular epithelioid cell tumours (PEComas) referred to as TFE3-rearranged PEComa, that most frequently harbours SFPQ::TFE3 fusion. Historically, ASPS and TFE3-rearranged PEComa are considered two distinctive entities despite their known morphological overlap. However, recent studies have suggested a potential histogenetic relationship between them, and several neoplasms that showed morphological features more closely fit PEComa rather than ASPS but harboured ASPSCR1::TFE3 fusion have been documented. In this study, we report three cases of PEComa with ASPSCR1::TFE3 fusion. METHODS AND RESULTS: Clinicopathological features were assessed and partner agnostic targeted next-generation sequencing on clinically validated platforms were performed. The patients are two females and one male with age at presentation ranging from 21 to 51 years. All three tumours were located in the viscera (rectum, kidney and cervix). On a relatively limited follow-up period (range = 9-15 months), all patients are alive without evidence of recurrent or metastatic disease. The neoplasms were composed of tight nested architecture of epithelioid clear cells separated by a delicate vascular network, two of which were associated with sheets of plump spindle cells, and none showed significant discohesive tumour morphology. Immunohistochemically, in addition to TFE3 protein, all three neoplasms demonstrated co-expression of melan-A and smooth muscle actin. RNA-sequencing identified ASPSCR1::TFE3 fusion in all three cases that were confirmed by subsequent fluorescence in-situ hybridisation analyses. CONCLUSIONS: Our study expands the molecular genetic spectrum of TFE3-rearranged PEComa and further indicates its close relationship to ASPS.

Efficacy of immune checkpoint inhibitors in alveolar soft-part sarcoma: results from a retrospective worldwide registry.

BACKGROUND: Conventional cytotoxic drugs are not effective in alveolar soft-part sarcoma (ASPS). Immune checkpoint (programmed cell death protein 1/programmed death-ligand 1) inhibitors (ICIs) are promising drugs in ASPS. A worldwide registry explored the efficacy of ICI in ASPS. MATERIALS AND METHODS: Data from adult patients diagnosed with ASPS and treated with ICI for advanced disease in expert sarcoma centers from Europe, Australia and North America were retrospectively collected, including demographics and data related to treatments and outcome. RESULTS: Seventy-six ASPS patients, with a median age at diagnosis of 25 years (range 3-61 years), were registered. All patients received ICI for metastatic disease. Immunotherapy regimens consisted of monotherapy in 38 patients (50%) and combination in 38 (50%) (23 with a tyrosine kinase inhibitor). Among the 68 assessable patients, there were 3 complete responses and 34 partial responses, translating into an overall response rate of 54.4%. After a median follow-up of 36 months [95% confidence interval (CI) 32-40 months] since the start of immunotherapy, 45 (59%) patients have progressed on ICI, with a median progression-free survival (PFS) of 16.3 months (95% CI 8-25 months). Receiving ICI in first line (P = 0.042) and achieving an objective response (P = 0.043) correlated with a better PFS. Median estimated overall survival (OS) from ICI initiation has not been reached. The 12-month and 24-month OS rates were 94% and 81%, respectively. CONCLUSIONS: This registry constitutes the largest available series of ASPS treated with ICI. Our results suggest that the ICI treatment provides long-lasting disease control and prolonged OS in patients with advanced ASPS, an ultra-rare entity with limited active therapeutic options.

Recurrent peripartum alveolar soft-part sarcoma: Case report using CARE methodology.

INTRODUCTION: Alveolar soft-part sarcoma (ASPS) is a rare malignant sarcoma with only a few cases reported in the sinus and head and neck region. It shows strong female predominance. Hormone-dependent recurrence was never reported. CASE REPORT: A 35 year-old woman presented nasal cavity ASPS during her first pregnancy, middle-ear ASPS during the second, and a third ASPS in the sinus outside of any peripartum period, with unfavorable progression and metastasis, terminating in death. DISCUSSION: Pathology analysis of the tumors showed positive immunolabeling for progesterone receptors in the two peripartum episodes. This was thus the first report of peripartum recurrence of ASPS with strong progesterone sensitivity, reinforcing the suspected biological link between ASPS and progesterone. This case report may be a preliminary finding suggesting progesterone blockers as a novel treatment for recurrent ASPS.

ASPSCR1::TFE3 orchestrates the angiogenic program of alveolar soft part sarcoma.

Alveolar soft part sarcoma (ASPS) is a soft part malignancy affecting adolescents and young adults. ASPS is characterized by a highly integrated vascular network, and its high metastatic potential indicates the importance of ASPS's prominent angiogenic activity. Here, we find that the expression of ASPSCR1::TFE3, the fusion transcription factor causatively associated with ASPS, is dispensable for in vitro tumor maintenance; however, it is required for in vivo tumor development via angiogenesis. ASPSCR1::TFE3 is frequently associated with super-enhancers (SEs) upon its DNA binding, and the loss of its expression induces SE-distribution dynamic modification related to genes belonging to the angiogenesis pathway. Using epigenomic CRISPR/dCas9 screening, we identify Pdgfb, Rab27a, Sytl2, and Vwf as critical targets associated with reduced enhancer activities due to the ASPSCR1::TFE3 loss. Upregulation of Rab27a and Sytl2 promotes angiogenic factor-trafficking to facilitate ASPS vascular network construction. ASPSCR1::TFE3 thus orchestrates higher ordered angiogenesis via modulating the SE activity.

Primary Intracranial Alveolar Soft Part Sarcoma: A Report of 3 Cases.

Alveolar soft part sarcoma (ASPS) commonly involves extremities and head and neck regions. Primary intracranial ASPS is rare. We report a series of 3 primary intracranial ASPS. These were not suspected clinically and histopathology with immunohistochemistry proved to be diagnostic in all 3 tumors.

A case report and literature review on nephrogenic alveolar soft part sarcoma: clinicopathological manifestations and genetic features.

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare kind of malignant soft tissue tumor with undefined differentiation, of which the incidence rate accounts for only 0.5-1.0% among all kinds of soft tissue tumors. An even rarer ASPS occurs in kidney. CASE PRESENTATION: Here we reported a case of a 7-year-old girl diagnosed with nephrogenic ASPS, regarding the analyses of the incidence, clinical manifestation, pathology and genetic diagnosis, in order to deepen the recognition of the disease. CONCLUSIONS: ASPS is very rare, and tends to occur to young patients. It is very significant to precisely diagnose ASPS at an early stage, which will be the key point for the following treatment choices and prognosis.

Primary Alveolar Soft-Part Sarcoma of the Lung: A Case Report.

Alveolar soft-part sarcoma is a rare type of soft tissue malignant tumor. Although the tumor can occur in many parts of the body, primary alveolar soft-part sarcoma of the lung is extremely rare. According to previous literature, only 3 cases of primary alveolar soft-part sarcoma of the lung were reported, and no comprehensive analysis was conducted on these cases. Here, we describe another case of alveolar soft-part sarcoma in the lung, where the negative results of immunohistochemical staining cause extreme difficulty in distinguishing this lesion from other tumors. A 30-year-old Chinese male presented with chest pain and dyspnea. Computed tomography revealed a pulmonary mass, and biopsy results showed vacuolar tumor cells with abundant eosinophilic cytoplasm. A number of immunohistochemical markers were negative, but the tumor cells were positive for TFE3 and ASPSCR1::TFE3 fusion gene. No other tumor masses were found in the patient after whole-body scanning. The final diagnosis was primary alveolar soft-part sarcoma of the lung. Pathologists should consider the possibility of alveolar soft-part sarcoma in lung tumors with typical "organ like" or "acinar like" cell nests, where the tumor cells are large, vacuolated, and the nucleolus is obvious. After excluding metastasis from other sites, TFE3 immunohistochemical staining and ASPSCR1::TFE3 fusion gene detection are recommended for the diagnosis of primary alveolar soft-part sarcoma.

Treatment of metastatic alveolar soft part sarcoma with axitinib and pembrolizumab in an 80-year-old patient with a history of autoimmune disorders.

Alveolar soft part sarcoma (ASPS) is a rare malignancy with low sensitivity to chemotherapy. While localized ASPS has a very good prognosis after resection, the 5-year overall survival rate drops substantially in metastatic disease. We report the case of an 80-year-old male patient with ASPS of the left elbow and metastasis to the lung, lymph nodes and peritoneum. After weighing the benefits and risks, systemic treatment with the anti-PD-1 checkpoint inhibitor pembrolizumab combined with the vascular endothelial growth factor receptor tyrosinkinase inhibitor axitinib was initiated in this patient with a history of psoriasis and Crohn's disease. After only two cycles of therapy, a significant size reduction of the nodal cervical metastasis became apparent. A partial response of all metastases was then confirmed in the first computed tomography restaging. So far, side effects have remained manageable, especially with regard to the development or worsening of autoimmune adverse events. The patient continued to have a high quality of life, while also remaining in ongoing partial response for 15 months at the time of submission. While sarcomas generally have low sensitivity to immunotherapies, ASPS is an exception, and checkpoint inhibition is an integral part of its systemic therapy.

Randomized Phase II Trial of Sunitinib or Cediranib in Alveolar Soft Part Sarcoma.

PURPOSE: Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor with few treatment options. We designed a phase II randomized trial to determine the activity and tolerability of single-agent cediranib or sunitinib in patients with advanced metastatic ASPS. PATIENTS AND METHODS: Patients 16 years of age and older were randomized to receive cediranib (30 mg) or sunitinib (37.5 mg) in 28-day cycles. Patients could cross over to the other treatment arm at disease progression. The primary endpoint was to measure the objective response rate (ORR) for each agent. Median progression-free survival (mPFS) for the two arms was also determined. RESULTS: Twenty-nine of 34 enrolled patients were evaluable for response. One patient on each of the initial two treatment arms had a partial response (ORR: 6.7% and 7.1% for cediranib and sunitinib, respectively). Twenty-four patients had a best response of stable disease (86.7% and 78.6% for cediranib and sunitinib, respectively). There were no significant differences in mPFS for the two treatment arms. Clinical benefit (i.e., objective response or stable disease for a minimum of four or six cycles of therapy) on the first-line tyrosine kinase inhibitor (TKI) therapy did not predict benefit on the second-line TKI. Both drugs were well tolerated. As of August 2021, 1 patient (unevaluable for ORR) remains on study. CONCLUSIONS: The study did not meet its endpoints for ORR. Although both TKIs provided clinical benefit, the outcomes may have been attenuated in patients who had progressed ≤6 months before enrollment, potentially accounting for the low response rates. See related commentary by Wilky and Maleddu, p. 1163.

Primary intraosseous alveolar soft part sarcoma: Report of two cases with radiologic-pathologic correlation.

Alveolar soft part sarcoma (ASPS) accounts for less than 1 % of all soft tissue sarcomas. ASPS presents a poor prognosis and develops frequent metastases, especially in the lungs, brain and bones. Current therapies, such as surgery, radiotherapy and chemotherapy, are not fully effective and other alternative treatments are currently being studied. ASPS is predominantly found in the deep soft tissues of the lower extremities. To our knowledge, only thirteen primary intraosseous ASPS have been reported in the literature. In this study, we report two new cases of this exceedingly rare entity. Both cases already had multiple metastases since diagnosis; one of them represents the first case of a primary bone ASPS in the ulna and is also the primary intraosseous ASPS with the longest reported case of survival, after having maintained long periods of stabilization despite not having received any systemic treatment.