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

Fibro-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. We retrospectively reviewed data of 3 patients with FAVA who were treated with sirolimus at our institution. A 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. Sirolimus 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.


Introduction
Fibro-adipose vascular anomaly came into picture as a new entity when a group of patients with a unique lesion composed of dense fibro-fatty tissue and slow-flow vascular malformations involving muscles of the extremities was initially described by Alomari and colleagues in 2014.
The acronym FAVA (fibro-adipose vascular anomaly) was given to this new entity and is histologically characterized by fibro-adipose infiltration of the muscle and unusual fusiform dilatation of veins [1].Other additional findings include lymphoplasmacytic aggregates, neural involvement by the anomaly, small foci of microcystic lymphatic malformations, clusters of thick-walled muscular channels, myxoid stroma, elastosis, and woven or lamellar pattern of the affected bone.In ISSVA (International Society for the Study of Vascular Anomalies) classification FAVA is currently placed under category of provisionally unclassified vascular anomaly [2].Females are more commonly affected than males in a ratio of 3:1 to 4.4:1 [3,4].FAVA often affects younger individuals, and in a recent case series involving 38 patients with FAVA, the mean age at diagnosis was 12 years [3].Muscles of lower extremity are most commonly involved followed by upper extremity and rarely trunk [3,4].Pain, functional restriction, and skin hyperesthesia are present in almost every patient at initial encounter; they may additionally show up with swelling, phlebectasia, and contractures [3].Pain can occur due to multitude of reasons which include fibrofatty infiltration of muscles, venous stasis in abnormally dilated veins, and neural involvement [4].The clinical and imaging features are often confusing and may overlap with other malformations of the vessels.In contrast to venous malformations, FAVA lesions are painful lesions in the extremities of young adults.They appear solid on ultrasound, usually limited to the intramuscular compartment, have fat signal on MRI within and surrounding the lesion, and are associated with phlebectasia.They may also show mild vascularity on the early phase angiography images.
Studies performed in vitro have demonstrated that PIK3CA mutation leads to excessive activation of mTOR pathway [7,8].Moreover, the antiproliferative effect on various vascular anomalies including FAVA has been seen with use of sirolimus an m-TOR inhibitor [9][10][11].Based on these findings, activated PI3K/AKT/mTOR signalling pathway appears to play a key role in pathogenesis of vascular anomaly in FAVA.
Treatment paradigms for FAVA are evolving depending upon initial size, location, and pace of growth.Sclerotherapy is usually considered as a first-line treatment option for slow-flow vascular anomaly, but FAVA lesions are less responsive to it owing to its dominant solid fibrofatty component.Current treatment options include cryoablation, sirolimus, and surgical debulking/excision [4].Here, we report our experience of treating FAVA with sirolimus in 3 patients.

Methods
Written consent was obtained from parents for the inclusion of patient's information in this report.We retrospectively reviewed medical records of 3 patients diagnosed with FAVA at our centre between March 2021 and January 2022.Data on clinical characteristics, imaging, laboratory testing, demographics, treatment, response, and side effects was collected.
Each case was discussed in a multidisciplinary meeting, and a diagnosis of FAVA was only made after consensus agreement was reached following the review of patients clinical, radiological, and histopathological details (Fig. 1).Available treatment options included medical management or surgical excision as cryoablation was not available at our centre.None of the patients was found to be a candidate for surgical excision after multidisciplinary discussion, so all the three were offered medical therapy with sirolimus.
Sirolimus was initially started at a dose of 0.8 mg/ m 2 /dose given twice a day.After treatment initiation, patients were followed up every 2-3 weeks for first 2 visits and then monthly.At each follow-up, clinical response and toxicity assessment was done; also, sirolimus trough level and lipid profile were checked.A trough level of 5-15 ng/ml [12,13] was targeted, and sirolimus doses were adjusted accordingly provided there were no adverse effects.Edmonton symptom assessment scale (ESAS) [14] was used to assess the severity of pain, where zero denoted no pain and 10 denoted worst pain possible.Pain rating in all 3 patients was done by a trained nursing staff.First imaging (MRI) was performed after 5-6 months of therapy.We did linear measurements and took the improvement in longest dimension for response assessment, though we agree that volumetric measurement would have been ideal.The soft tissue and the vascular components are usually intermingled in FAVA, and thus the measurements include both.Assessment of both these components separately was not done.The MRI results were interpreted blinded to the clinical response.Though FAVA is associated with PIK3CA mutation, the same was not checked in our patients, and the responses were not correlated with laboratory parameters like d-dimer or fibrinogen levels.

Results
A total of 3 patients with FAVA being managed with sirolimus were assessed (Table 1).Two out of 3 were male.The ages of the patients were 2, 12, and 17 years, respectively.All the patients presented with pain and swelling; 2 out of 3 had skin hyperesthesia (could not be assessed in the 3rd case as she was a 2-year-old child), and 1 out of 3 had functional impairment.Two had involvement of the lower limb (gluteal region in both), and 1 had lesion in the forearm.One of the children underwent angioembolisation of the lesion (before being diagnosed as FAVA) and had no benefit from it.Sirolimus was started in all 3 patients at a dose of 0.8 mg/m 2 /dose two times a day.The solution form was used for the 2-year-old child.Patients were treated with sirolimus for a mean of 10.6 months (range 10-11 months).Sirolimus was very well tolerated by all with dyslipidaemia and acne which was seen in 1 patient being the only side effect observed.Dose increment was done in all patients at follow-up, and trough levels throughout were maintained between 5 and 12 ng/ml.Although higher doses initially were targeted, benefit was seen at lower trough levels so that doses were not always increased.
Responses to sirolimus were marked and rapid with ESAS score decreasing from 6/10 to 1/10 within 4 days in one case and from 5/10 to 0/10 after 7 days in the second case.ESAS scoring could not be done in the third case in view of younger age, but as reported by the parent, the child used to wince and cry upon touching the swelling and avoided moving the affected limb before treatment initiation, but after 15-20 days of taking sirolimus, the swelling became non-tender, and the child also started moving the affected limb.A decrease in the size of the swelling was seen in all 3 patients.Two out of three patients presented with skin hyperaesthesia and had complete resolution at follow-up.One patient who had functional impairment in the form of limping was able to walk normally after 2 weeks of therapy.
One of the patients discontinued treatment on his own after 3 months of initiation as he had marked clinical improvement but had recurrence of pain (ESAS 4/10) merely 10 days after it.Sirolimus was then restarted, and he was again pain free (ESAS-0/10) just after 1 week.
Repeat MRI was done after 5-6 months of treatment; all the patients had reduction in the size of the lesion; case 1 had < 20% reduction, case 2 had 20% reduction, and case 3 had a 40% reduction in size (Figs. 2 and 3).

Discussion
We describe 3 children with FAVA who were treated with sirolimus.Our patients were consistent with prior reports of FAVA that it has propensity to affect young adolescents and mainly the lower limb.All the treated patients had pain (ESAS score 5/10-6/10) and swelling at the involved sites at presentation, and one also had functional impairment in the form of limping.Clinical responses were dramatic with significant improvement in pain and functional limitations and decrease in the size of swelling.Responses were quite rapid with pain decreasing as early as within 4 days of starting sirolimus in one of our patients.Radiologically, all 3 patients had a decrease in the size of the lesion.A favourable safety profile was found with sirolimus in clinical studies and case series which described its use in the treatment of vascular anomalies [10,15].However, some data is accumulating with concerns regarding infectious complications in the literature [16].Sirolimus was very well tolerated with dyslipidaemia and acne being the only side effects observed in 1/3 of our patients.All of them are still continuing the treatment.The duration for which sirolimus is to be continued in FAVA patients is still not clear.In a study, sirolimus was discontinued in 5 patients with vascular anomalies; however, of these, disease recurrence occurred in 3, and they were restarted on therapy.A good response was reported again fortunately once sirolimus was restarted [17]; a similar finding was also seen in 1 of our patients who discontinued treatment and had dramatic response on the reinstitution of therapy.This suggests that longer duration of therapy with sirolimus may be required.Sirolimus through levels of 10-15 ng/ml was suggested in initial studies which described its use in vascular anomalies [15,18].But we found in our patients that even lower levels were quite effective (levels of 5-12 ng/ml were maintained).
Results from our case series further support the use of sirolimus in FAVA.To the best of our knowledge, there are only 2 other published reports describing the benefit of sirolimus in FAVA.Erickson et al. reported promising outcomes in two children (ages: 12 and 15 years).Within 2 weeks, both had marked decrease in pain and resolution of functional impairment.At follow-up, one of them had 10% reduction in size, while the other had a dramatic 50% decrease.Sirolimus was largely tolerated well except that one patient who developed dyslipidaemia.Trough sirolimus levels were maintained between 2 and 8 ng/ml [9].
In another report by Ahmad Al-Huniti et al., a group of 11 children with FAVA was treated with sirolimus; females comprised 64% of the patients; in 91%, lower limbs were involved.The mean age at treatment initiation was 14 years (range: 9-17.9 years).The mean duration of treatment with sirolimus was 19 months (range: 4-46 months).The most common side effects were hyperlipidaemia (100%), mouth ulcers (73%), and mild acne (27%).Sirolimus was discontinued by 2 patients in this series, with reasons being oral ulcers in one and fatty liver and dyslipidaemia in the other.Improvement in pain was reported by all patients with 5/11 having complete resolution of pain.Improvement in musculoskeletal function was reported by 10/11 patients.Eighty percent of the patients who had a swelling prior to initiation of sirolimus reported at least some reduction in size clinically.Skin hyperesthesia was found in 6 patients at baseline, and with treatment, 3 had complete response and 1 had marked improvement.A follow-up MRI was done after 12 months of therapy in 7 patients, and of them, 6 had some decrease in lesion size, while 1 had a stable lesion A repeat MRI was performed in 3 of the 7 patients (~ 14 months from the first MRI) in which one patient had further decrease in size with stable disease in the other two [19].
Therapeutic options for FAVA have been mainly invasive until lately.In view of diffuse, infiltrative growth pattern and significant depth of involvement, surgical excision or debulking can be difficult.Whenever possible, surgical resection can be helpful, but recovery period required may be longer, and it carries a significant risk of morbidity; therefore, patient selection should be judicious.In a study, surgical resection was done in 35 patients, amputation was required for uncontrollable pain/loss of function in 3 of 35 patients, wound infections developed in 3/35 patients, while around 40% of them required further treatment for their symptomatic residual disease [20].
Cryoablation is now a part of the therapeutic armamentarium for FAVA patients and has been tried increasingly.There is retrospective data from four studies on the use of cryoablation in FAVA patients.There was a total of 40 patients, and of them, 80% had either partial or complete response (some required more than one cryoablation session) [4,22,23,25].However, in the 4 studies quoted above, considerable adverse effects were also noted with cryoablation: transient numbness (18%) being the most common, followed by skin blistering/ulceration (10%).Residual/recurring pain was reported in 33% of patients (most with FAVA) undergoing cryoablation from another study [25].The underlying pathophysiology/ genetics of FAVA is not addressed by cryoablation, and its long-term efficacy is unknown.
FDA has now approved alpelisib, a PIK3CA-alpha inhibitor for the management of PIK3CA-related overgrowth syndromes (PROS) in patients more than 2 years of age based on real-world evidence from EPIK-P1 [26], a retrospective chart review study.In this study, at week 24, 27% of patients (10/37) had a response defined as reduction in target lesion volume by > 20%, and no patients experienced disease progression.Additionally, at week 24, investigators observed patient improvements in pain (90%, 20/22), fatigue (76%, 32/42), vascular malformation (79%, 30/38), limb asymmetry (69%, 20/29), and disseminated intravascular coagulation (55%, 16/29).FAVA also belongs to the spectrum of PROS, and alpelisib is an option for its management, but data from randomised clinical trials is needed to further embrace its use into clinical practice.
To the best of our knowledge, we have in our series reported the youngest child (age 2 years) who had FAVA and was treated successfully with sirolimus.One of our patient before being diagnosed as FAVA was treated with angioembolisation of the feeding arteries of the lesion and had no benefit with it; also, the mean time from symptom initiation to confirmation of diagnosis was 2.6 years (range 1-5 years) in our series; these two points strongly highlight the importance of a multidisciplinary discussion for making a diagnosis of FAVA and for treatment planning, and hence, there should be an individualised approach for the treatment of FAVA after a multidisciplinary discussion.Based on the rapid response of FAVA to sirolimus in our series and the others published so far and considering the facts discussed above, sirolimus can be considered as a first-line therapy for FAVA.The optimal dosing and duration of therapy need to be determined, and continued long-term monitoring is required for the assessment of delayed adverse effects.

Conclusion
Sirolimus is an effective treatment for patients with FAVA and is well-tolerated without any major adverse effects.Responses are rapid and dramatic, with significant reduction in pain and improvement in function.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 to further support its use.

Fig. 1
Fig. 1 Low power histopathology image of the case 1 showing vessels of varying calibre and skeletal muscle surrounded by extensive fibrous and adipose tissue (H&E × 40)

Fig. 2 Fig. 3
Fig. 2 Case 3. Upper panel: axial, coronal, and sagittal T2W images (FS in a and b and non-fat suppressed in c) show large infiltrative intramuscular mass involving left gluteal muscle, arrow showing fatty replacement of the muscle fibres.Lower panel: post sirolimus (6 months) axial, coronal, and sagittal T2W images (FS) show approximately 40% reduction in the size of the mass

Table 1
Baseline demographics and presentation of patients and response to sirolimus