Fibro-adipose vascular anomaly (FAVA): three case reports with an emphasis on the mammalian target of rapamycin (mTOR) pathway

Abstract

Background Fibro-adipose vascular anomaly (FAVA) is a new entity of vascular anomalies with somatic and mosaic gain-of-function mutations of the phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA ). PIK3CA mutation excessively activates mammalian target of rapamycin (mTOR) pathway, which promotes angiogenesis and lymphangiogenesis. Histologically, FAVA is composed of intramuscular fibrous and adipose tissues with venous malformation (VM). Although sirolimus known as a mTOR inhibitor has good response to FAVA, expression pattern of the mTOR pathway was still unclear. Herein, we immunohistochemically investigated three novel FAVA patients with an emphasis on the mTOR pathway (p-S6K1, p-4EBP1 and p-AKT). Case presentation Case 1: A 10-year-old female had complained of pain in the left thigh since she was 6-year-old. Under the clinical diagnosis of VM, she underwent surgical resection for the lesion. Case 2: A 29-year-old female patient had complained of discomfort and mild pain in the left shoulder since she was 18-year-old. After childbirth, she had severe ongoing pain and contracture of the shoulder. Under clinical diagnosis of VM, surgical resection was performed. Case 3: A 53-year-old female had complained of pain and knee restriction after surgical treatment of a knee tumor at the age of 31. Under the clinical diagnosis of atypical lipomatous tumor or high grade liposarcoma, surgical resection was performed. Histologically, all three patients presented with characteristic features of fibrous and adipose tissues with abnormal vessels within the skeletal muscle, leading to diagnosis of FAVA. Although VM has been reported as an important finding in FAVA, immunohistological findings demonstrated that abnormal vessels comprised complex of VM and lymphatic malformation (LM) in all cases. Furthermore, besides vascular malformation, abnormal fibrous and adipose tissues of FAVA expressed mTOR pathway components. Conclusions We presented three new cases of FAVA. Histological and immunohistochemical analyses revealed that VM and LM complex was an important finding in FAVA, and that the mTOR pathway components were expressed in abnormal fibrous tissue, adipose tissue and vascular malformation. These findings suggested that FAVA might be a mesenchymal malformation caused by PI3K/AKT/mTOR pathway.

PIK3CA mutation correlates with mTOR pathway expression but not clinical and pathological features in Fibro-adipose vascular anomaly (FAVA)

“…2 C, G). The lymphatic phenotype was supported by endothelial D2-40 and/or Prox1 immunopositivity in consistent with our previous study [ 3 ]. In one PIK3CA-mutant case (case 2) and one PIK3CA-wt case (case 3), some nerves contained enlarged vessels (Fig.…”

“…Four FAVA cases with formalin-fixed paraffin-embedded (FFPE) tissues were retrieved from the pathology files of Osaka University Hospital from 2010 to 2020. A final diagnosis of FAVA was determined by consensus agreement after consideration of clinical, radiologic, and histological findings [ 1 – 3 ]. This study was approved by the Ethical Review Board of the Graduate School of Medicine, Osaka University (IBR No.…”

“…FAVA is extremely rare and occurs most commonly in the muscles of the lower extremities of young patients [ 1 , 2 ]. Histologically, FAVA is composed of venous malformation (VM), lymphatic malformation (LM), and the presence of fibro-adipose tissues with the atrophic skeletal muscle [ 1 , 3 ]. A recent study identified somatic and mosaic gain-of-function mutations of the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA ) gene in a subset of FAVAs (62.5%) [ 4 ].…”

Multiple congenital malformations arise from somatic mosaicism for constitutively active Pik3ca signaling

“…PI3K inhibitors have been very promising in clinical trials for these conditions (eg. Dill et al, 2014;Roy et al, 2015;Venot et al, 2018;Hori et al, 2020) Some patients develop supernumerary, hypertrophic muscles in the upper limbs; these are occasionally bilateral, indicating that the original somatic mutation may have developed in a cell whose progeny entered the paraxial mesoderm cell during gastrulation (Frisk et al, 2019). While nearly half of overgrowth PRD patients in one cohort presented vascular malformations, the congenital tissue overgrowth in the vast majority continued to evolve postnatally (Keppler-Noreuil et al, 2014).…”

“…Recent models for CCMs also feature upregulated PI3K activity and increased p-S6 in endothelial cells, unlike what we have initially observed in the vascular lesions induced before or after birth by increased PI3K signaling in mural cell progenitors with immunofluorescence. However, activation of pAkt, p-S6 and other pathway effectors in the connective tissues of patients with PIK3CA-mutated fibroadipose vascular anomalies (FAVA) indicate that the syndromic aspects are not dissociable from the vascular tumor-like malformations themselves (Hori et al, 2020). Further functional work will be needed to define the additional mediators and intracellular effectors of endothelial-mural paracrine exchanges in these new models NC cells are a minority but crucial lineage in cardiac function and development .…”