Fibro-adipose Vascular Anomaly Research Articles

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.

Percutaneous Cryoablation for Treatment of Biopsy-proven Fibroadipose Vascular Anomaly

Objective: To evaluate the clinical outcomes of patients with fibroadipose vascular anomaly (FAVA) treated via percutaneous cryoablation. Design: A 14-month retrospective study identified patients (<21 years old) with biopsy-proven diagnoses of FAVA. Appropriate evaluation in the vascular anomalies clinic preceded imaging, biopsy, and ablation therapy. Studied parameters included postablation MRI findings, pain, motor function, and complications of ablation therapy. Setting: A single, tertiary care pediatric hospital. Patients: Nine patients (median 12 years, range 8–16 years; 8 females, 1 male) met inclusion criteria. Interventions: Percutaneous cryoablation. Primary Outcome Measurement: Clinical success of cryoablation, defined as improvement of patient symptoms, including pain, functional restriction, and swelling. Results: Percutaneous biopsy demonstrated histological consistency with FAVA for all lesions. All patients underwent technically successful cryoablation therapy. One patient required repeat ablation. Symptoms resolved in 5 patients and improved in 4 patients. There were 5 minor complications and no major complications. Conclusions: These findings further validate previously published cohorts and demonstrate that percutaneous cryoablation is a potentially efficacious treatment option for FAVA with a favorable safety profile.

Hybrid treatment of fibroadipose vascular anomaly: A case report.

BackgroundFirst identified in 2014, fibroadipose vascular anomaly (FAVA) is a very rare type of venous and lymphatic malformation. Marked by tough fibrofatty tissue in the extremities overtaking portions of the muscles, it is associated with constant pain and contracture of the affected extremity. There is a paucity of literature, and no guidelines on treatment procedure are available. This case highlights the role of hybrid treatment with primary ethanol percutaneous ethanol embolization and additional surgery for radicality in excision of FAVA lesions.Case summaryA 9-year-old girl with FAVA underwent the hybrid treatment. The achievements of complete excision, clinical response, and patient satisfaction in long-term follow-up were assessed. Following the hybrid treatment, the patient experienced significant improvement in pain. Concurrent symptoms of physical limitation, leg swelling, and skin hyperesthesia also improved. The clinical benefit, supported by postoperative physiotherapy, was well stabilized at 6-month follow-up, resulting in complete patient satisfaction at 12- and 36-month follow-ups. No major complications were encountered.ConclusionEthanol embolization plus surgery is a safe, effective, and long-term hybrid treatment of symptomatic FAVA lesions.

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

BackgroundFibro-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 presentationCase 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.ConclusionsWe 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.

Surgical Management of Fibroadipose Vascular Anomaly of the Lower Extremities

Fibroadipose vascular anomaly (FAVA) is a recently-defined vascular malformation often involving the extremities and presenting in childhood. Patients may present to orthopaedic surgeons with pain, swelling, joint contractures, and leg length discrepancy. There is no established therapy or treatment paradigm. We report on outcomes following surgical excision for patients with this condition. Between 2007 and 2016, all 35 patients that underwent excision of lower-extremity FAVA were retrospectively reviewed using a combination of medical records, radiologic findings, and telemedicine reviews. Mean age at initial presentation was 12.3±6.8 years. Mean follow-up from time of definitive diagnosis at our institution was 66 months (range: 12 to 161 mo). Mean follow-up after surgery was 35 months (range: 6 to 138 mo). Females were affected more than males (71% vs. 29%). The most common location of FAVA was in the calf (49%), followed by the thigh (40%). The most commonly involved muscle was gastrocnemius (29%), followed by the quadriceps (26%). At latest follow-up after surgery, there was an improvement in the proportion of patients with pain at rest (63% vs. 29%), pain with activity (100% vs. 60%), as well as analgesia use (94% vs. 37%). Fourteen patients (40%) had symptomatic residual disease or recurrence of FAVA requiring further treatment. Six patients (17%) required further surgery and 6 (17%) required further interventional radiologic procedures. Three patients (9%) required eventual amputation for intractable pain and loss of function. Lesions with direct nerve involvement were associated with persistent neuropathic symptoms at latest follow-up (P=0.002) as well as symptomatic residual disease and/or recurrence requiring further treatment (P=0.01). Seventeen patients (49%) had 19 preoperative joint contractures. Eighteen of the 19 contractures (95%) had sustained improvement at latest follow-up. In carefully selected patients, surgical excision of FAVA results in improvement of symptoms. However, symptomatic residual disease and/or recurrence are not uncommon. Direct nerve involvement is associated with a worse outcome. Level IV-case series.

FIBRO-ADIPOSE VASCULAR ANOMALY IS A NEW DIAGNOSIS IN THE PRACTICE OF A PEDIATRIC VASCULAR SURGEON. EXPERIENCE IN DIAGNOSTICS AND TREATMENT

The article discusses results of surgical treatment of 25 children, aged 1 to 14, with fibro-adipose vascular anomaly (FAVA) of lower extremities. The patients were treated in Pirogov Russian Pediatric Clinical Hospital in 2015-2019. Diagnostic findings are presented; basic features of the discussed pathology are described. As the obtained results have shown, in the authors’ opinion, the discussed surgical approach turned to be quite effective, since it significantly improves the quality of life, and in some cases brings complete disappearance of complaints and symptoms in patients with FAVA.

Fibro-adipose vascular malformation (FAVA) in forearm: a successful surgical approach and literature review

Fibro-adipose vascular anomaly (FAVA) is a new entity characterized by fibro-adipose infiltration of muscle, pain, and contracture. The main differential diagnosis includes venous malformation and intramuscular hemangioma. Early treatment and physical therapy are of paramount importance to prevent severe contractures, muscle fibrosis, and limb atrophy. We present a case report of a 24-year-old female patient with FAVA in the volar aspect of left arm, presented with limitation to pronation and supination and pain. The patient was operated in 2017 in our center, performing a total resection of the mass and 2-year follow-up. We describe the criteria that we performed to diagnose the left forearm FAVA in this patient, based on the history; the magnetic resonance imaging, which demonstrated muscle replaced by heterogeneous soft tissue, intramuscular phlebolit, and dilated vessels; and histological images that showed a vascular proliferation associated with adipocytes and dense fibrous tissue replacing and infiltrating the skeletal muscle. En bloc resection of the mass was performed successfully, and it gave excellent results with recovery of limitation and improvement of pain and swelling that were maintained at 2-year follow-up. Surgery is a reliable and curative option in FAVA and could be the only one for long-term control of this entity. Level of evidence: Level V, therapeutic; diagnostic study.

Clinical and imaging features in fibro-adipose vascular anomaly (FAVA)

Fibro-adipose vascular anomaly (FAVA) is a rare and recently described complex vascular malformation. The clinical and imaging features and morphology can be confusing and often overlap with features of other vascular malformations and tumors. To present the imaging characterization of FAVA in association with clinical features. We retrospectively evaluated clinical and imaging (MRI, sonography and venography) findings in FAVA. We documented the clinical presentation, lesion morphology, imaging characteristics, tissue distribution, pattern of contrast enhancement and vascular characteristics. Thirty-eight people (31 female, 7 male) ages 1-30years (mean 12years) were diagnosed with FAVA based on clinical findings combined with imaging or histopathological findings (n=17). Most lesions were in the lower extremity (n=36). Three patterns were noticed: focal, focal infiltrative and diffuse. Fibro-adipose vascular anomaly, a rare and complex vascular malformation, has distinct clinical and imaging features that a radiologist should be familiar with to avoid delay in diagnosis and to direct appropriate management.

Review of Fibroadipose Vascular Anomaly Cases at a Multidisciplinary Vascular Anomalies Centre: Clinical Characteristics, Histopathological and Image Findings and Management

Review of Fibroadipose Vascular Anomaly Cases at a Multidisciplinary Vascular Anomalies Centre: Clinical Characteristics, Histopathological and Image Findings and Management

Fibroadipose Vascular Anomaly in the Upper Extremity: A Distinct Entity With Characteristic Clinical, Radiological, and Histopathological Findings

Fibroadipose vascular anomaly (FAVA) is an intramuscular vascular malformation that has been recently described as a distinct clinical entity. The clinical, radiological, and histopathological characteristics of FAVA in the upper extremity are reviewed. This was a retrospective case series of upper-extremity FAVA lesions. We reviewed 19 patients with FAVA of the upper limb. Pain, stiffness, swelling, and flexion contractures were the most common presentations. Except for one lesion confined to the hand, all lesions either presented with or developed a contracture within 10 years. Ten patients underwent surgical debulking. Six required tendon transfer reconstruction and 3 necessitated a free functional muscle transfer. Fibroadipose vascular anomaly in the upper extremity requires an accurate diagnosis and may benefit from early referral to a multidisciplinary vascular anomaly center with experienced hand surgeons. Compression garments, propranolol, and sclerotherapy seem to be ineffective. Surgical resection focused on symptomatic regions with appropriate reconstruction may have benefit in salvage of limbs with compromised function. Therapeutic IV.

Cryoablation of low-flow vascular malformations.

We aimed to evaluate the safety and effectiveness of cryoablation in the treatment of low-flow malformations, specifically venous malformation (VM) and fibroadipose vascular anomaly (FAVA). We conducted a retrospective review of 11 consecutive patients with low-flow malformations (14 lesions; 9 VM, 5 FAVA), median lesion volume 10.8 cm3, (range, 1.8-55.6 cm3) with a median age of 19 years (range, 10-50 years) who underwent cryoablation to achieve symptomatic control. Average follow-up was at a median of 207 days postprocedure (range, 120-886 days). Indications for treatment included focal pain and swelling. Technical success was achieved if the cryoablation ice ball covered the region of the malformation that corresponded to the patient's symptoms. Clinical success was considered complete if all symptoms resolved and partial if some symptoms persisted but did not necessitate further treatment. The technical success rate was 100%. At 1-month follow-up, 13 of 14 lesions (93%) had a complete response and one (7%) had a partial response. At 6-month follow-up 12 of 13 (92%) had a complete response and 1 (8%) had a partial response. A total of 6 patients underwent primary cryoablation. Out of 9 VM cases, 7 had prior sclerotherapy and 2 had primary cryoablation. Out of the 5 FAVA cases, 1 had prior sclerotherapy and the remaining 4 cases underwent primary cryoablation. There were 3 minor complications following cryoablation including 2 cases of skin blisters and 1 case of transient numbness. These complications resolved with conservative management. Cryoablation is safe and effective in the treatment of low-flow vascular malformations, either after sclerotherapy or as primary treatment.

Congenital Limb Overgrowth Syndromes Associated with Vascular Anomalies.

Congenital limb length discrepancy disorders are frequently associated with a variety of vascular anomalies and have unique genetic and phenotypic features. Many of these syndromes have been linked to sporadic somatic mosaicism involving mutations of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway, which has an important role in tissue growth and angiogenesis. Radiologists who are aware of congenital limb length discrepancies can make specific diagnoses based on imaging findings. Although genetic confirmation is necessary for a definitive diagnosis, the radiologist serves as a central figure in the identification and treatment of these disorders. The clinical presentations, diagnostic and imaging workups, and treatment options available for patients with Klippel-Trenaunay syndrome, CLOVES (congenital lipomatous overgrowth, vascular anomalies, epidermal nevi, and scoliosis/spinal deformities) syndrome, fibroadipose vascular anomaly, phosphatase and tensin homolog mutation spectrum, Parkes-Weber syndrome, and Proteus syndrome are reviewed. ©RSNA, 2019.

Abstract No. 656 Percutaneous cryoablation of fibro-adipose vascular anomaly: safe and effective therapy

Fibro-adipose vascular anomalies (FAVAs) are complex vascular malformations typically presenting with lifestyle limiting pain and at times contractures. FAVAs are difficult to treat typically with poor response to sclerotherapy. Recently a small series of pediatric patients was published showing percutaneous cryoablation to be a safe and effective treatment. The purpose of our study was to evaluate the efficacy and clinical outcomes of image-guided cryoablation in pediatric and adult patients with FAVA either as primary therapy or after prior failed interventions. A retrospective review was performed of all patients undergoing percutaneous image-guided cryoablation with preprocedure imaging or biopsy consistent with FAVA from 10/2014 to 9/2017 at two institutions. There were 10 patients’ ages 9-40 (mean age 22.2 years) and 13 ablations. Pre-procedure, intraprocedural, and, when available, follow-up imaging was reviewed. EMR review was performed to determine demographics, indication, prior treatments both interventional and surgical, symptoms, and clinical response after the procedure and at any subsequent follow-up visits, as well as any complications. Response was categorized as complete resolution of pain, marked improvement (now able to perform activities previously limited by pain or no longer requiring pain medication), minimal improvement, and no improvement. The indication for all primary procedures was pain. The indications for repeat ablation was residual pain (n = 2) and ablation of another site (n = 1). Cryoablation was performed under ultrasound (n = 4), CT (n = 8), or combined ultrasound and CT guidance (n = 1). Five of the 10 patients had prior surgical resection, sclerotherapy, or embolization with recurrence of symptoms. Three patients had a complete response, 6 patients had marked improvement, and 1 patient was lost to follow-up. There were 6 minor complications including temporary numbness, scab at the access site, hematoma, and skin discoloration that resolved. There were no major complications. Cryoablation is safe and effective for treatment of adult and pediatric FAVA lesions either as primary therapy or after failed prior interventions.

Clinical and sonographic features of pediatric soft-tissue vascular anomalies part 2: vascular malformations.

Vascular malformations are a heterogeneous group of entities, many of which present in the pediatric age group. Sonography plays a major role in the management of children with these vascular anomalies by providing information that helps in diagnosing them, in assessing lesion extent and complications, and in monitoring response to therapy. The interpretation of sonographic findings requires correlation with clinical findings, some of which can be easily obtained at the time of scanning. This has to be combined with the use of appropriate nomenclature and the most updated classification in order to categorize these patients into the appropriate management pathway. Some vascular malformations are part of combined vascular anomalies or are associated with syndromes that include other disorders, frequently limb overgrowth, and these are now being reclassified based on their underlying genetic mutation. Sonography has limitations in the evaluation of some vascular malformations and in these cases MR imaging might be considered the imaging modality of choice, particularly for lesions that are large, that involve multiple compartments or are associated with other soft-tissue and bone abnormalities. In this article, which is part 2 of a two-part series, the authors review the most relevant clinical and sonographic features of arteriovenous, capillary, venous and lymphatic malformations as well as vascular malformations that are part of more complex conditions or associated with syndromes, including Parkes-Weber syndrome, phosphatase and tensin homologue (PTEN) hamartoma tumor syndromes, Klippel-Trénaunay syndrome, CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi and skeletal anomalies) syndrome, fibro-adipose vascular anomaly and Proteus syndrome.

Fat-containing soft-tissue masses in children.

The diagnosis of soft-tissue masses in children can be difficult because of the frequently nonspecific clinical and imaging characteristics of these lesions. However key findings on imaging can aid in diagnosis. The identification of macroscopic fat within a soft-tissue mass narrows the differential diagnosis considerably and suggests a high likelihood of a benign etiology in children. Fat can be difficult to detect with sonography because of the variable appearance of fat using this modality. Fat is easier to recognize using MRI, particularly with the aid of fat-suppression techniques. Although a large portion of fat-containing masses in children are adipocytic tumors, a variety of other tumors and mass-like conditions that contain fat should be considered by the radiologist confronted with a fat-containing mass in a child. In this article we review the sonographic and MRI findings in the most relevant fat-containing soft-tissue masses in the pediatric age group, including adipocytic tumors (lipoma, angiolipoma, lipomatosis, lipoblastoma, lipomatosis of nerve, and liposarcoma); fibroblastic/myofibroblastic tumors (fibrous hamartoma of infancy and lipofibromatosis); vascular anomalies (involuting hemangioma, intramuscular capillary hemangioma, phosphate and tensin homologue (PTEN) hamartoma of soft tissue, fibro-adipose vascular anomaly), and other miscellaneous entities, such as fat necrosis and epigastric hernia.

Cryoablation in fibro-adipose vascular anomaly (FAVA): a minimally invasive treatment option.

Fibro-adipose vascular anomaly (FAVA) is a complex vascular malformation that typically presents with persistent pain, discomfort, contracture and other disabling symptoms. There are no minimally invasive treatment options to effectively control these symptoms. Image-guided percutaneous cryoablation, which has been used to control pain in people with cancer, could be used for similar indications in FAVA. To assess the role of image-guided percutaneous cryoablation for control of symptoms in FAVA lesions. We conducted a retrospective cohort study of 20 children and young adults with FAVA who underwent percutaneous cryoablation at 26 sites, from September 2013 to August 2015. The outcome was based on the brief pain inventory scoring (BPI), concurrent symptoms, clinical response and patient satisfaction. After cryoablation there was significant improvement in pain, which dropped by 3 points (pain now) to 3.7 points (pain in the last 24h). Most patients indicated that pain interfered less in their everyday social life. Concurrent symptoms like swelling, physical limitations and skin hyperesthesia also improved. Clinical response was greatest at 2-5months follow-up after cryoablation, with acceptable patient satisfaction thereafter. Technical response was 100%. There were no major complications. Image-guided percutaneous cryoablation is a safe and effective option for treatment of symptomatic FAVA lesions.

Combined and complex vascular malformations

The correct diagnosis of vascular malformations is obtainable by clinical assessment and patient history in the majority of cases. Nonetheless, confusion in nomenclature, existence of multiple classifications and rarity of these lesions leads to misdiagnosis and related wrong treatment. This is especially the case in combined or complex vascular malformations or vascular malformations that are part of syndromes as these have overlapping clinical and imaging features. New entities in the field of vascular anomalies have been described recently like fibro-adipose vascular anomaly or central conducting lymphatic anomalies.

Lymphatic and Other Vascular Malformative/Overgrowth Disorders Are Caused by Somatic Mutations in PIK3CA

To test the hypothesis that somatic phosphatidylinositol-4,5-bisphospate 3-kinase, catalytic subunit alpha (PIK3CA) mutations would be found in patients with more common disorders including isolated lymphatic malformation (LM) and Klippel-Trenaunay syndrome (KTS). We used next generation sequencing, droplet digital polymerase chain reaction, and single molecule molecular inversion probes to search for somatic PIK3CA mutations in affected tissue from patients seen at Boston Children's Hospital who had an isolated LM (n = 17), KTS (n = 21), fibro-adipose vascular anomaly (n = 8), or congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (n = 33), the disorder for which we first identified somatic PIK3CA mutations. We also screened 5 of the more common PIK3CA mutations in a second cohort of patients with LM (n = 31) from Seattle Children's Hospital. Most individuals from Boston Children's Hospital who had isolated LM (16/17) or LM as part of a syndrome, such as KTS (19/21), fibro-adipose vascular anomaly (5/8), and congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (31/33) were somatic mosaic for PIK3CA mutations, with 5 specific PIK3CA mutations accounting for ∼ 80% of cases. Seventy-four percent of patients with LM from Seattle Children's Hospital also were somatic mosaic for 1 of 5 specific PIK3CA mutations. Many affected tissue specimens from both cohorts contained fewer than 10% mutant cells. Somatic PIK3CA mutations are the most common cause of isolated LMs and disorders in which LM is a component feature. Five PIK3CA mutations account for most cases. The search for causal mutations requires sampling of affected tissues and techniques that are capable of detecting low-level somatic mosaicism because the abundance of mutant cells in a malformed tissue can be low.