Fibro-adipose Vascular Anomaly Research Articles

Dermato-Radiological Evaluation of Congenital Limb Overgrowth Vascular Syndromes

Abstract International Society for the Study of Vascular Anomalies classification defines Congenital Limb Overgrowth Vascular Syndromes (CLOS) as a subset of vascular syndromes with other abnormalities that present with unilateral limb overgrowth. It includes Klippel–Trenaunay Syndrome, Parkes–Weber Syndrome, CLOVES (Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Spinal/Skeletal Anomalies/Scoliosis) Syndrome, Proteus Syndrome, PTEN Hamartomatous Syndrome, and Fibroadipose Vascular Anomaly. Due to their rare and complex nature, a multidisciplinary approach to diagnosis and treatment is required. A thorough clinical and radiological workup can go miles in reflecting on the patient’s outcome. Here we report five cases of CLOS with their detailed dermato-radiological profiles.

Ultrasonography-guided radiofrequency ablation of vascular malformations-The moving shot technique.

To describe a novel ultrasound-guided technique for percutaneous radiofrequency ablation of vascular malformations-the "moving shot technique." Preliminary observational cohort study, conducted from June 1, 2019, to January 31, 2021, including all consecutive patients diagnosed with vascular malformations who were treated with ultrasound-guided radiofrequency ablation using the moving shot technique. Only patients who had undergone at least one unsuccessful previous treatment were included (sclerotherapy with ethanol/aethoxysklerol or embolization/surgery). Eight patients with a median age of 22 years (interquartile range, 13-31) were included. Patients had different vascular malformations consisting of 1 arteriovenous malformation, 4 venous malformations, and 1 each a mixed venous-lymphatic malformation, a glomuvenous malformation and a FAVA (fibroadipose vascular anomaly). Malformations were located at the limbs in 5 patients (62.5%), the subcutaneous/intramuscular tissue of the body in 2 patients (25%) and at the chin in 1 patient (12.5%). Clinical symptoms were pain in 8 patients (100%), swelling in 6 patients (75%), and partial immobility in 4 patients (50%). All patients showed an improvement of clinical symptoms after treatment with 7 (87.5%) being completely asymptomatic and 1 (12.5%) showing improvement of immobility and pain. No procedural complications, such as nerve damage or skin burns occurred. The moving shot technique using ultrasonography-guided radiofrequency ablation is a promising technique for the interventional treatment of vascular malformations and should be validated in multicenter-approaches.

Summary of the application value of ultrasound imaging features in the clinical differential diagnosis of intramuscular capillary-type hemangioma and fibro-adipose vascular anomaly.

To investigate the value of ultrasonography as a diagnostic aid in differentiating intramuscular capillary-type hemangioma (ICTH) from fibro-adipose vascular anomaly (FAVA). A retrospective analysis was conducted of the clinical and ultrasound imaging data of 20 patients with ICTH and 45 patients with FAVA who were admitted to and pathologically confirmed in hospital between January 2013 and April 2023. The clinical and ultrasonographic appearances of the lesions in the two groups were compared and analyzed. A stepwise regression analysis was performed, and a joint diagnostic equation was constructed using the final variables selected. The receiver operating characteristic (ROC) curve and indicators, including sensitivity and specificity, were used to evaluate the efficacy of the joint diagnostic model. The two groups of patients suffering from ICTH and FAVA presented a statistically significant difference (P< 0.05) in terms of 'age', 'lesion size', 'fascial tail sign', 'presence of a fatty-tissue-like hyperecho around the lesion', 'blood flow' and 'presence of straight blood capillaries within the lesion'. Finally, the variables 'fascial tail sign' and 'presence of straight blood capillaries within the lesion' were selected to construct the model. The constructed joint diagnostic model had a sensitivity value of 70.0% (95% CI: 59.00-81.00), a specificity value of 98.0% (95% CI: 94.70-100.00) and a ROC curve value of 0.908, indicating the high efficacy of the combined diagnosis method. Ultrasonography can be utilized to differentiate ICTH from FAVA, and the combined diagnosis method can further improve the technique's diagnostic efficacy.

Fibro-adipose vascular anomaly (FAVA) - diagnosis, staging and management

BackgroundThe diagnosis and treatment of fibro-adipose vascular anomaly (FAVA) of the limb remains challenging since this entity is rare and complex. This paper is aimed to describe the clinical and imaging features, staging and management of this underrecognized disease of the limb.Material and methodPatients diagnosed with FAVA and managed between September 2019 and May 2022 in department of pediatric surgery & vascular anomalies of Xi’an international medical center hospital were retrospectively reviewed. Data extracted include age at presentation, previous diagnosis, affected muscles, symptoms, previous treatment, our management, and follow-up.ResultsThirty-two patients with FAVA were diagnosed and managed in our center. There was a female sex predominance, with 23 female (72%) and 9 male (28%) in the cohort. Only one lesion was noticed during infancy; the remaining presented at age 1 to 20 years (median, 7 years). The most commonly involved muscles were gastrocnemius (14/32, 44%) and soleus (13/32, 40%). Swelling (mass), pain and contractures were the most common presentations. MRI featured a heterogeneous and ill-defined intramuscular high signal intensity. Diseases were staged according to clinical features: stage I (pain stage, n = 4), stage II (contracture stage, n = 20) and stage III (deformity stage, n = 8). Patients with stage I disease underwent radical resection and obtained a cure. Patients with stage II disease received radical resection and possible Achilles lengthening, having an outcome of cure. Personalized treatment was required in patients with stage III disease, including radical/partial/staged resection, Achilles lengthening/tenotomy, joint capsulotomy, neurolysis/neurectomy, tendon transfer, stretching exercises, and oral sirolimus/alpelisib. Significant improvement of symptoms was achieved in most.ConclusionThe most distinct features of FAVA include enlarging mass, severe pain and contracture. Based on distinct clinical and radiologic features, it is not difficult to make the diagnosis of FAVA. Earlier awareness of this disease can reduce misdiagnoses. Surgery-based comprehensive management can typically improve pain and contracture. Oral sirolimus or alpelisib plays an important role in treatment of unresectable lesions and major nerve involvement. Surgery alone can be curative in early stage FAVA.

Fibroadipose vascular anomaly successfully treated with sirolimus: experience in 3 children

PurposeFibro-adipose vascular anomaly (FAVA) is a unique lesion composed of dense fibro-fatty tissue and slow-flow vascular malformations and is associated with somatic PIK3CA mutations. The patient usually presents with pain, swelling, functional restriction, and skin hyperesthesia. Therapeutic armamentarium includes cryoablation, sirolimus, and surgical debulking/excision. Sirolimus is highly effective for treatment of FAVA and is well tolerated. Here, we report our experience of treating FAVA with sirolimus in 3 patients.MethodsWe retrospectively reviewed data of 3 patients with FAVA who were treated with sirolimus at our institution.ResultsA total of 3 patients with FAVA being managed with sirolimus were assessed. Two out of 3 were male. The ages of the patients were 2, 12, and 17 years respectively. Sirolimus was started at a dose of 0.8 mg/m2/dose two times a day, and patients were treated for a mean of 10.6 months (range 10–11 months). Dose adjustments were made to keep trough serum levels between 5 and 12 ng/ml. All of them had reduction in pain, and 1 of them experienced it within 4 days of therapy initiation. Follow-up MRI revealed reduction in size in all 3 patients. Sirolimus was well tolerated with mild acne and dyslipidaemia being the only side effects observed.ConclusionSirolimus is quite an effective treatment for patients with FAVA and is well-tolerated without any major adverse effects. Given the rapid responses and a favourable safety profile, we believe that sirolimus can be considered for all patients with FAVA as a first-line therapy, but long-term follow-up data from well-designed clinical trials are required.

Fibro-Adipose Vascular Anomaly (FAVA): Not Another Vascular Anagram.

Background. Fibro-adipose vascular anomaly (FAVA) is a rare benign mesenchymal lesion. Characterized primarily by intramuscular vascular malformation with secondary overgrowth of other mesenchymal elements, particularly fibro-adipose tissue, the condition is sometimes complicated by nonspecific clinical and imaging features, causing diagnostic dilemma. Herein, we attempted to outline and correlate the clinical characteristics, imaging findings, and histopathological features of this unusual entity. Method. The study design was retrospective in nature. Computerized database of our institute was searched for tumors, and archived slides were reviewed. Pertinent clinical data including imaging findings and treatment details were also recovered for correlation. Result. Among total of 24 patients identified, mean age was approximately 16 years, with the presence of nearly equal gender distribution. Pain along with swelling was most common symptoms with the presence of movement limitation, in few. Most lesions were long-standing and anatomically confined to lower limb with no side predilection. Using imaging, the majority of the lesions were identified as vascular anomaly or venous malformation, with FAVA being a differential diagnosis in few lesions. However, in a couple of patients, likelihood of mesenchymal tumors was also suggested, radiologically. On histology, the lesions showed the presence of clustered back to back, abnormal thin-walled, variably dilated, blood-filled sac-like vessels amid skeletal muscle bundles, along with extensive fibro-adipose tissue and variably atrophic skeletal muscle bundles, at the periphery, diagnostic of FAVA. Conclusion. Owing to the presence of overlapping clinical and imaging features, FAVA is often misdiagnosed, causing dilemma in clinical management. Clinical, radiological, and histopathological correlation is thereby warranted for clinching the correct diagnosis.

Fibroadipose vascular anomaly: a clinicopathological study of 75 cases.

Fibroadipose vascular anomaly (FAVA) is a complex vascular malformation that is likely to be under-recognised. In this study we aimed to report the pathological features and somatic PIK3CA mutations associated with the most common clinicopathological features. Cases were identified by reviewing the lesions resected from patients with FAVA registered at our Haemangioma Surgery Centre and unusual intramuscular vascular anomalies in our pathology database. There were 23 males and 52 females, who ranged in age from 1 to 51 years. Most cases occurred in the lower extremities (n = 62). The majority of the lesions were intramuscular, with a few disrupting the overlying fascia and involving subcutaneous fat (19 of 75), and a minority of the cases had cutaneous vascular stains (13 of 75). Histopathologically, the lesion was composed of anomalous vascular components that were intertwined with mature adipocytic and dense fibrous tissues and vascular components with: (a) clusters of thin-walled channels, some with blood-filled nodules and others with thin walls resembling pulmonary alveoli; (b) numerous small vessels (arteries, veins and indeterminate channels) - proliferative small blood vessels were often mixed with adipose tissue; (c) larger abnormal venous channels usually irregularly and sometimes excessively muscularised; (d) lymphoid aggregates or lymphoplasmacytic aggregates were usually observed; and (e) lymphatic malformations were sometimes seen as minor elements. All patients had their lessons subjected to PCR, and 53 patients had somatic PIK3CA mutations (53 of 75). FAVA is a slow-flow vascular malformation with specific clinicopathological and molecular characteristics. Its recognition is fundamental for its clinical/prognostic implications and for targeted therapy.

Endoscopic Resection for Vascular Anomalies in Children: A New Standard.

To report an innovative endoscopic surgery for subcutaneous vascular malformations and intramuscular fibro-adipose vascular anomaly (FAVA) at our center. Historically, open surgical resection has been the treatment of choice. Recent advances in minimally invasive surgery have led to the successful application of endoscopic resection techniques for the surgical management of diseases of soft tissue. Patients who underwent endoscopic resection of vascular anomalies were included in this retrospective review. Data were extracted from our Vascular Anomalies Center database between September 2019 and October 2022, including sex, age, symptoms, diagnosis, sites of surgery, previous treatment, surgery, and follow-up. There were 13 females and 15 males in the current study, with ages ranging from 1 to 17 years. The diagnoses included microcystic lymphatic malformation (LM) (n = 8), Klippel-Trénaunay syndrome (n = 7), venous malformation (n = 6), FAVA (n = 6), and mixed cystic LM (n = 1). Surgical sites included the lower extremity (n = 24), abdominal wall (n = 2), upper extremity (n = 1), and thoracic wall (n = 1). Five patients had an intramuscular lesion (FAVA). The endoscopic technique used 2 or 3 small ports in a gas inflation manner. Surgery included thrombectomy, radical resection, and debulking of vascular anomalies. Postoperative sclerotherapy with bleomycin was performed through a drainage tube in 6 patients with microcystic LM. Technical success was obtained in 27 patients. The conversion to open surgery was performed in one patient owing to the deep location of the lesion. No wound-related complication was observed. Endoscopic surgery is a minimally invasive, effective, and safe treatment for subcutaneous vascular malformations and intramuscular FAVA. This approach can set a new standard that minimizes wound complications and reduces recovery time in patients undergoing resection for benign soft-tissue lesions.

Successful Treatment of Fibro-Adipose Vascular Anomaly with Sirolimus

BackgroundThe purpose of this study was to present our initial experience in using sirolimus therapy to treat fibro-adipose vascular anomaly (FAVA). MethodsWe retrospectively reviewed the medical records of eight patients with FAVA who were treated with sirolimus at our hospital between July 2017 and October 2020. ResultsSix girls (75%) and two boys (25%) were included in the cohort; the average age was 8 years (range, 1–13 years). Vascular tumors developed mainly on the extremities, including the forearm (n = 2; 25.0%), calf (n = 4; 50.0%), and thigh (n = 2; 25.0%). The predominant symptoms included swelling of the lesion (n = 8; 100%), pain (n = 7; 87.5%), contracture (n = 3; 37.5%), and phlebectasia (n = 3; 37.5%). Magnetic resonance imaging was the primary method used for FAVA diagnosis, and all patients underwent enhanced MRI. All lesions were heterogeneous with hyperintense T1 signals. The fat-suppressed T2-weighted images also revealed heterogeneous hyperintense masses, thus indicating fibrofatty infiltration. All eight patients received a sirolimus treatment regimen after FAVA diagnosis. One patient underwent tumor resection but experienced recurrence, whereas the other six patients underwent biopsy. Histological examination revealed that the lesions consisted of fibrofatty tissue with abnormal venous channels and anomalous lymphatic vascular components. Sirolimus softened the masses and caused tumor shrinkage within 5.25 ± 2.6 weeks (range, 2–10 weeks) after treatment initiation. The tumors also involuted rapidly and became stable within 7.75 ± 2.25 months after treatment initiation (range, 6–12 months). All seven patients experiencing pain reported relief within 3.8 ± 1.8 weeks (range, 2–7 weeks) after initiation of sirolimus therapy. Sirolimus alleviated but did not fully resolve the contracture in three patients. Remarkably, five patients exhibited a complete response, and three patients exhibited a partial response. At the time of the last follow-up, three patients had begun to gradually taper off sirolimus after 24 months of treatment and maintained a low blood sirolimus concentration. No serious adverse effects were observed during treatment. ConclusionFAVA is a complex vascular malformation that appears to respond well to sirolimus treatment. Thus, sirolimus may be an effective and safe treatment for FAVA. Level of evidenceLEVEL IV.

Radiomics-based machine learning approach in differentiating fibro-adipose vascular anomaly from venous malformation.

As a complex vascular malformation, fibro-adipose vascular anomaly was first proposed in 2014. Its overlap with other vascular malformations regarding imaging and clinical features often leads to misdiagnosis and improper management. To construct a radiomics-based machine learning model to help radiologists differentiate fibro-adipose vascular anomaly from common venous malformations. We retrospectively analyzed 178 children, adolescents and young adults with vascular malformations (41 fibro-adipose vascular anomaly and 137 common vascular malformation cases) who underwent MRI before surgery between May 2012 to January 2021. We extracted radiomics features from T1-weighted images and fat-saturated (FS) T2-weighted images and further selected features through least absolute shrinkage and selection operator (LASSO) and Boruta methods. We established eight weighted logistic regression classification models based on various combinations of feature-selection strategies (LASSO or Boruta) and sequence types (single- or multi-sequence). Finally, we evaluated the performance of each model by the mean area under the receiver operating characteristics curve (ROC-AUC), sensitivity and specificity in 10 runs of repeated k-fold (k = 10) cross-validation. Two multi-sequence models based on axial FS T2-W, coronal FS T2-W and axial T1-W images showed promising performance. The LASSO-based multi-sequence model achieved an AUC of 97%±3.8, a sensitivity of 94%±12.4 and a specificity of 89%±9.0. The Boruta-based multi-sequence model achieved an AUC of 97%±3.7, a sensitivity of 95%±10.5 and a specificity of 87%±9.0. The radiomics-based machine learning model can provide a promising tool to help distinguish fibro-adipose vascular anomaly from common venous malformations.

Fibro-Adipose Vascular Anomaly: Characteristic Imaging Features on Sonography and Magnetic Resonance Imaging.

To analyse the image characteristics of fibro-adipose vascular anomaly (FAVA) and the value of ultrasound and magnetic resonance imaging (MRI) for its diagnosis. The clinical and imaging data characteristics of 10 patients with FAVA admitted to our hospital between January 2018 and December 2020 who underwent ultrasound and MRI diagnosis were retrospectively analysed. A total of 10 patients (six males and four females) with pathologically confirmed FAVA, aged from 3 to 27years (median: 13years), underwent ultrasound and MRI; of these, two patients underwent MRI-enhanced examinations. All lesions involved mainly muscle, with a few disruptions and involvements of subcutaneous fat. Five cases were located subcutaneously near the fascia; one case was adjacent to the periosteum. Ultrasound showed fascial tail in seven cases, and MRI showed fascial tail in six cases. Both ultrasound and MRI showed the lesions to be oval-shaped masses with blurred borders and a mean maximum diameter of 99.8 ± 48.7mm. Ultrasound showed a mass with a mixture of high and low echoic areas. Magnetic resonance imaging imaging showed a heterogeneous, mixed-signal intensity on T1-weighted images, probably influenced by the fibrous and fatty components of the lesion. T2-weighted images showed a mixed-high signal. Enhanced computed tomography scans showed significant heterogeneous enhancement of the lesions. Both ultrasound and MRI showed that fascial tail sign is an important imaging feature for FAVA disease; this provides a reliable basis for its diagnosis and can be used to distinguish it from venous malformations, which have no fascial tail signs. Therefore, fascial tail signs can be used as imaging features and require special attention in the diagnosis of FAVA disease.

Qualitative research with patients and caregivers of patients with PIK3CA related overgrowth spectrum: content validity of clinical outcome assessments

BackgroundPIK3CA-Related Overgrowth Spectrum (PROS) are rare syndromes caused by a mutation in the PIK3CA gene, including fibroadipose hyperplasia or overgrowth; congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal (CLOVES); megalencephaly-capillary malformation (MCAP or M-CM); fibro-adipose vascular anomaly (FAVA); Klippel-Trenaunay syndrome (KT; also known as, Klippel-Trenaunay-Weber syndrome); capillary, lymphatic, and venous malformations (CLVM); and lymphatic malformation (LM). Characterized by malformations and tissue overgrowth, PROS manifests at birth or in early childhood. Pain and functional limitations associated with these conditions may greatly impact the health-related quality of life (HRQoL) of persons with PROS including physical functioning, work/school, social functioning, and emotional well-being.ResultsSelected clinical outcome assessments (COAs), identified during a literature review, were tested with adults with PROS, and children with PROS and their caregivers to determine comprehensibility, relevance, and appropriateness for measuring symptom severity and HRQoL. Tested were the Patient Global Impression of Symptom Severity (PGI-S), Brief Pain Inventory (BPI), Wong-Baker FACES, Patient-Reported Outcomes Measurement Information System (PROMIS) Profile, PROMIS Pediatric Short Form Sleep Disturbance, and PROMIS Dyspnea Severity. Qualitative interviews tested the self-report adult, self-report pediatric, and observer-report COAs with adults with PROS, and children with PROS and their caregivers.Ten adults (≥ 18 years old) with PROS, and 20 children (6–17 years old) with PROS and their caregivers, participated. All reported positive feedback on item relevance. Adults and children over the age of 12 comprehended and responded to self-reported items. Secondary objectives examined the age children could self-report their conditions using pediatric versions and assessed available observer-report versions of the COAs with caregivers. Some participants under the age of 12 had trouble understanding some terminology. Further, adults and children with cognitive impairment associated with MCAP/M-CM sometimes had difficulty with self-report. Caregivers were able to report their child’s symptoms and impacts using observer-report COAs. Participant feedback prompted further consideration of the measurement of pain in this population, including variability of pain over time, location of pain, and type.ConclusionsThis study provided valuable information from patients about PROS, supporting the content validity of the COAs, with recommended revisions. COAs are easily understood by persons with PROS and caregivers and are appropriate for measuring symptoms and disease-related impacts across diverse PROS syndromes in clinical trials.

A Comparative Review of Fibroadipose Vascular Anomaly and PTEN Hamartoma Syndrome of the Soft Tissue

Fibroadipose vascular anomaly and PTEN hamartoma of the soft tissue are vascular anomalies that tend to present with similar clinical findings. These entities are often confused for other conditions, with patients regularly presenting to vascular anomalies specialists with incorrect diagnoses. As PTEN hamartoma of the soft tissue has been identified as a neoplastic syndrome, ensuring an accurate diagnosis is of paramount importance. The objective of this case review was to identify similarities and differences in the clinical, histologic, and radiologic findings between these 2 rare vascular anomalies.

MRI-based radiomics in distinguishing Kaposiform hemangioendothelioma (KHE) and fibro-adipose vascular anomaly (FAVA) in extremities: A preliminary retrospective study

ObjectiveTo investigate the pretreatment differentiation between Kaposiform hemangioendothelioma (KHE) and fibro-adipose vascular anomaly (FAVA) in extremities of pediatric patients. To build and validate an MRI-based radiomic model. MethodIn this retrospective study, we obtained imaging data from 43 patients. We collected and compared clinical information, sketched region of interest (ROI), and extracted radiomic features from fat-suppressed T2-weighted (T2FS) images of the two cohorts of 30 and 13 patients respectively (training versus testing cohort 7:3). To select features, we used two sample t-test and the least absolute shrinkage and selection operator (LASSO) regression. The support vector machine (SVM) classification was constructed and evaluated by receiver operating characteristic (ROC) analysis. ResultsThirty patients with KHE and 13 patients with FAVA in the extremities were included. Most lesions demonstrated low to intermediate signal intensity on T1-weighted images and hyperintense signals on T2-weighted ones. They also showed similar traits pathologically. Initially, 107 radiomic features were acquired and then three were finally selected. The support vector machine (SVM) model was able to differentiate the two anomalies from each other with an area under the curve (AUC) of 0.807 (95%CI 0.602–1.000) and 0.846 (95%CI 0.659–1.000) in training and testing cohort, respectively. ConclusionThe derived radiomic features were helpful in differentiating KHE from FAVA. A model which contained these features might further improve the performance and hopefully could serve as a potential tool for identification.

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

BackgroundFibro-adipose vascular anomaly (FAVA) is a rare and new entity of vascular anomaly. Activating mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene were identified at a frequency of 62.5% in FAVA cases. The PIK3CA mutations excessively activate mammalian target of rapamycin (mTOR) pathway, which promotes angiogenesis and lymphangiogenesis, implying that PIK3CA mutations may act as drivers of FAVAs. This study investigated the correlations between PIK3CA mutational status, clinicopathological features and immunohistochemical expression of the mTOR pathway in a series of FAVA.MethodsWe retrospectively evaluated the clinical and pathological findings of four FAVA cases. We performed next-generation sequencing (NGS) with a custom panel of genes associated with the mTOR pathway and genes responsible for other vascular anomalies; followed by direct sequencing and immunohistochemical analysis of the mTOR pathway.ResultsTwo PIK3CA-mutation cases and two PIK3CA-wild-type (wt) cases exhibited similar typical clinical features of FAVA. Histological analysis revealed venous malformation, lymphatic malformation, nerves containing enlarged abnormal vessels and fibrofatty tissue were observed regardless of PIK3CA mutational status. In contrast to clinical and histological findings, the immunohistochemical expression of activated AKT and mTOR that are upstream of the mTOR pathway was detected in abnormal vessels of PIK3CA-mutation cases but not in those of PIK3CA-wt cases. However, activated eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and ribosomal protein S6 kinase 1 (S6K1), both of which are downstream effectors of the mTOR pathway, were expressed in abnormal vessels of both PIK3CA-mutation and PIK3CA-wt cases. Furthermore, targeting NGS did not find any common genetic mutations involved in the mTOR pathway among PIK3CA-wt cases.ConclusionsThere was no significant association between the presence of PIK3CA mutations and the clinicopathological features of FAVA, suggesting that the PIK3CA gene is not necessarily involved in the onset of FAVA. FAVAs lacking PIK3CA mutations may be caused by other gene mutations that activate 4EBP1 and S6K1.

Sirolimus Leads to Rapid Improvement in Fibroadipose Vascular Anomalies

Purpose: Fibroadipose vascular anomaly (FAVA) is a complex vascular anomaly associated with postzygotic somatic PIK3CA mutations. FAVAs can cause significant pain, swelling, and musculoskeletal dysfunction. Treatment options are limited. Sirolimus is a well-tolerated and effective treatment for patients with FAVA. We report our experience of using sirolimus to treat 11 children with FAVAs. Methods: We conducted a retrospective review of all patients with FAVA treated with sirolimus in our institution. Results: Fourteen patients (10 females) were referred for sirolimus therapy for FAVA. Eleven patients were initiated on sirolimus at a mean age of 14 years (range: 9–17.9 years) and were then treated for a mean of 19 months (range: 1–46 months). Five had previously undergone sclerotherapy without benefit. Sirolimus was initiated at a dose of either 2.5 mg/m2 once daily or 0.8 mg/m2 twice daily. Doses were titrated to maintain sirolimus trough levels of 5–15 ng/L. Goals of treatment were improvement in pain and musculoskeletal dysfunction. All 11 patients reported reduced pain; 7 reporting this within 3 weeks of starting sirolimus. This allowed for discontinuation of analgesia. Function improved significantly in 9 of 11, leading to resumption of sports or work participation. Sirolimus side effects were similar to prior reports, most commonly mouth sores, mildly elevated lipids and acne. There was no grade III/IV toxicity. Conclusion: Sirolimus is a well-tolerated and effective treatment for patients with FAVA. Initial symptom improvement is rapid, with significantly reduced pain and improved function. We believe that sirolimus should be considered for all patients with FAVA as a first-line therapy before surgical/interventional approaches.

Targeted Next Generation Sequencing Expands Genotype in Patients with PIK3CA-Related Overgrowth Spectrum (PROS)

Background: Disorders of somatic mosaicism (DoSM) are caused by mutations that arise post-zygotically and are present in only a specific part of the body. These mutations alter the function and regulation of key genes in cell proliferation pathways, including the PI3K/AKT/mTOR pathway, and show significant overlap with mutations identified in cancer(McNulty et al. Am J Hum Genet, 2019). PIK3CA-Related Overgrowth Spectrum (PROS) is an umbrella term that encompasses a variety of overgrowth syndromes caused by post-zygotic, somatic gain-of-function PIK3CA mutations with low-level mosaicism (Luks et al. J Pediatr, 2015). The clinical phenotype of PROS is heterogeneous and many tissue types can be affected. This often makes clinical diagnosis challenging. The use of cancer genomics in patients with vascular anomalies may aid in establishing a genetic diagnosis and expand use of targeted medical therapies.Methods: Three patients who presented with clinical symptoms of PROS underwent targeted next generation sequencing of affected tissue using OncoPanel. Oncopanel is a genomic assay that detects somatic mutations, copy number variations and structural variants in 447 genes implicated in cancer.Results: Three patients with a PROS phenotype demonstrated somatic mutations in genes distinct from PIK3CA.Case 1: A 15-year-old female presented with a painful right leg mass, calf atrophy, contracture of the knee, leg-length discrepancy, and severe limp. Histology was consistent with fibroadipose vascular anomaly (FAVA) versus kaposiform hemangioendothelioma (KHE). Given her significant functional impairment, treatment with Sirolimus was initiated with significant improvement in appearance and functionality. OncoPanel testing revealed a PIK3C2B c.2881G>A (p.G961S) mutation.Case 2: A 12-month-old male was noted at birth to have a diffuse capillary malformation, multiple lymphatic malformations, macrodactyly of his bilateral hands and leg length-discrepancy, consistent with Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Spinal/Skeletal Anomalies/Scoliosis (CLOVES) syndrome. He underwent numerous surgical de-bulking procedures, epiphysiodesis, sclerotherapy, and laser therapy with continued disease progression. OncoPanel revealed a PIK3R1c.1731_1738delAGACCAATinsATGTAAGAAAG (p.D578_Y580delinsCKKD) mutation.Case 3: A 10-month-old female presented with a diffuse capillary malformation and leg-length discrepancy. She subsequently developed multiple painful and progressive lymphatic lesions over her left arm and chest which did not respond to sclerotherapy. Due to high clinical suspicion for PROS, she underwent targeted genetic testing via droplet digital PCR (ddPCR) to detect the five most common variants (C420R, E542K, E545K, H1047L, H1047R) in PIK3CA, but no hotspot mutations were identified. Over the next year and a half, the patient had two biopsies performed, PIK3CA ddPCR testing performed twice, and OncoPanel testing performed twice. OncoPanel testing of the second tissue biopsy ultimately resulted in the identification of a PIK3R1 c.1723-1731del p.K575_R577del mutation.Conclusion: The clinical diagnosis of DoSM is often challenging. While the use of cancer genomics for diagnostic purposes in vascular anomalies is uncommon, its use continues to broaden our understanding of syndromes related to alterations in the PI3K/AKT/mTOR pathway. PIK3CB encodes a catalytic subunit of PI3K, p110β, and is dysregulated in certain types of cancer. PIK3R1 encodes multiple regulatory subunits of PI3K and acts as a negative regulator of PIK3CA function. Both gain-of-function of PIK3CB or loss-of-function of PIK3R1 lead to inappropriate activation of PIK3CA, and our cases highlight that mutations in other genes can lead to the clinical phenotype of PROS. It is reasonable to expect that patients with alterations in genes that activate PIK3CA may benefit from medical treatment with direct PIK3CA inhibitors. Limiting diagnostic testing to evaluation of the PIK3CA gene alone may yield negative results and preclude patient eligibility for treatment with novel therapies. The use of next-generation sequencing (NGS) designed to detect somatic variations in cancer will likely play a pivotal role in detecting variants in vascular anomalies in the future and in expanding our understanding of genetic alterations involved in PROS. DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:Sirolimus is used off-label for the treatment of vascular anomalies.

Management of Fibro-adipose Vascular Anomalies (FAVA) in Paediatric Practice

Fibro-adipose vascular anomaly (FAVA) is a discrete type of vascular anomaly. We describe our experience managing FAVA at a tertiary level paediatric hospital and offer a treatment algorithm. MethodsA retrospective review of 27 patients with proven FAVA was undertaken. All patients had undergone MRI and USS evaluation. Patient demographics, presenting concerns, treatment methods, and outcomes were recorded and evaluation with the paediatric outcomes data collection instrument (PODCI) completed a minimum of 12 months after definitive treatment. ResultsMean age at presentation was 8.9 years (range: 9 m-17.4 y) and mean post-treatment follow-up was 7.4 y (range: 2 y-11.6 y). Twenty of 27 lesions affected the lower limb. Severe neurogenic-type pain was present in 23 cases and contractures across joints in 11 cases. Sclerotherapy with sodium tetradecyl sulphate was used in 11 cases, with no improvement in symptoms. Cryoablation provided pain relief in 3/4 cases, but contracture subsequently increased in one patient and pain recurred in another.Fourteen cases underwent surgery (four surgical excisions alone, 10 in combination with other procedures). Three patients required four further surgical procedures that include one amputation for intractable pain and poor function.PODCI evaluations suggest overall good function, with surgical management and interventional radiology that provide comparable results. Surgery did correct deformity. ConclusionIf conservative measures or cryoablation fail to achieve symptomatic control, surgical excision should be considered, combined with adjunctive procedures, to correct contractures and balance muscle forces.Relief of pain may compensate for the loss of muscle mass and overall improves function. Multidisciplinary team working is essential.

Abstract No. 547 Interventional outcomes in the management of fibroadipose vascular anomaly at a tertiary care pediatric hospital

Fibro-adipose vascular anomaly (FAVA) is a pediatric vascular malformation resulting in debilitating pain and reduced mobility in otherwise healthy children. Multidisciplinary assessment and treatment is vital for management, though there is minimal literature assessing postoperative outcomes or follow-up among FAVA patients. 22 patients with biopsy-proven FAVA between June 2013 to February 2020 were referred to our institution for evaluation. Lesions were classified by a typical (calf, arm) or atypical (foot, knee, thigh, gluteal, hand, thoracic, abdominal) location. Documentation of pre- and postprocedural pain at first follow-up visit, length of follow-up after intervention, number of repeat interventions, and development of an additional lesion was obtained. 16 patients (ages 3–15; mean, 10.3 years) with 20 separate lesions (8 typical location; 12 atypical location) pursued invasive treatment for FAVA to ameliorate their pain. Primary interventions performed included sclerotherapy (n = 15), cryoablation (n = 1), sclerotherapy and cryoablation (n = 1), or surgery (n = 3). Technical success for each intervention was 100%, and there were no major complications. Median initial follow-up time was 30 days. 2 patients were lost to follow-up. 10/14 (71%) of patients reported a decrease or absence of pain. 4/14 (28%) sclerotherapy patients required repeat intervention for pain and underwent repeat sclerotherapy (n = 2), cryoablation (n = 3), surgery (n = 1), or sirolimus therapy (n = 1). The two patients who were treated with repeat sclerotherapy required additional intervention and achieved pain relief after cryoablation and surgery, respectively. Median interval between repeat interventions was 484 days. 2/14 patients (14%) developed additional FAVA lesions that required treatment. Median interval for recurrent disease was 408 days. Virtually all patients achieved pain relief after initial intervention. A fraction of patients required reintervention within 18 months. Though a limited sample, cryoablation demonstrated 100% pain relief among the five patients who received cryoablation as either a primary or secondary treatment.

Cryoablation as Second-line Therapy for Fibroadipose Vascular Anomaly

Purpose: Fibroadipose vascular anomaly (FAVA) is a recently described intramuscular vascular anomaly that replaces normal skeletal muscle with fibrofatty proliferation and phlebectasia causing pain and contractures. Cryoablation has recently emerged as a means of treating FAVA with favorable outcomes. The purpose of our study was to examine our FAVA patients with failed prior interventions who underwent cryoablation as second-line treatment. Methods: A retrospective review was performed of all cases of cryoablation for FAVA (diagnosed on imaging or biopsy) who had undergone prior treatment from October 2014 to October 2020 at the adult and children’s hospital. Preprocedure, intraprocedural, and, when available, follow-up imaging was reviewed. Electronic medical record and imaging review was performed to determine demographics, indication, prior treatments both interventional and surgical, symptoms, and clinical response. Results: There were 9 patients with 11 ablation procedures; 8/9 patients had decrease in pain. One patient with diffuse FAVA had worsening pain after ablation and was subsequently treated with sirolimus. Conclusions: FAVA can be difficult to treat with traditional methods such as sclerotherapy or surgical resection. Cryoablation has recently emerged as a promising treatment. Our experience suggests FAVA with failed prior interventions may respond favorably to cryoablation.