CASE REPORT Year : 2022  |  Volume : 26  |  Issue : 3  |  Page : 11-14

A case of topical rapamycin effective for postsurgical hypertrophic scar of superficial lymphatic malformation with possible quality-of-life improvement

Yuki Isozaki, Motoi Kato, Naoko Fujita, Shota Tojo, Masahide Fujiki, Azusa Watanabe, Shoji Watanabe
Saitama Children's Medical Center, Chuo-ku, Saitama, Japan

Date of Submission17-Apr-2021Date of Acceptance31-May-2021Date of Web Publication22-Aug-2022

Correspondence Address:
Dr. Yuki Isozaki
Saitama Children's Medical Center, 1-2, Shintoshin, Chuo-ku, Saitama 330-0081
Japan

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jdds.jdds_38_21

Lymphatic malformation (LM) of the body surface causes symptoms such as bleeding, pain, lymphatic leakage, or infection of the lesion, usually treated with surgical resection and sclerotherapy, with limited efficacy. The vesicles of the body surface tend to recur after surgical resection and may cause lymphatic leakage, which could be long term a burden for patients, eventually decreasing their quality of life. In recent years, the efficacy of orally administered mammalian target of rapamycin inhibitor (rapamycin) has been reported for LM and other vascular anomalies but few are reported in the East Asian population. We report the case of a Japanese female with intractable gluteal LM that was successfully treated with topical rapamycin for postoperative recurrence and hypertrophic scarring.

Keywords: Lymphatic malformation, quality of life, rapamycin, scar/keloid, therapy (topical)

How to cite this article:
Isozaki Y, Kato M, Fujita N, Tojo S, Fujiki M, Watanabe A, Watanabe S. A case of topical rapamycin effective for postsurgical hypertrophic scar of superficial lymphatic malformation with possible quality-of-life improvement. J Dermatol Dermatol Surg 2022;26, Suppl S1:11-4
How to cite this URL:
Isozaki Y, Kato M, Fujita N, Tojo S, Fujiki M, Watanabe A, Watanabe S. A case of topical rapamycin effective for postsurgical hypertrophic scar of superficial lymphatic malformation with possible quality-of-life improvement. J Dermatol Dermatol Surg [serial online] 2022 [cited 2022 Aug 23];26, Suppl S1:11-4. Available from: https://www.jddsjournal.org/text.asp?2022/26/3/11/354311   Introduction 

Lymphatic malformation (LM) can cause bleeding, pain, lymphatic leakage, or infection of the lesion.[1] Microcystic type with surface vesicles, also known as lymphangioma circumscriptum, could be intractable because of its limited response to classical treatments, such as surgical resection, which causes lymphatic leakage from recurred vesicles.[2] In such cases, patients have to live with the lesion for a long time.

In recent years, the mechanistic target of rapamycin, also known as the mammalian target of rapamycin (mTOR) pathway, has also been implicated not only in the generation and propagation of vascular anomalies but also in the elevated levels of fibronectin and collagen in keloid.[3],[4],[5],[6] The efficacy of the mTOR inhibitor ramapycin (sirolimus) in the treatment of LM and other vascular anomalies has been reported.[7],[8] However, reports on topical rapamycin are rare. Thus, we report a case of effective use of topical rapamycin in postoperative scarring on the body surface, with a review of the literature.

  Case Report 

A 12-year-old female patient presented with no relevant medical history except extensive microcystic-type LM, which had appeared in the left gluteal region during infancy and was confirmed by magnetic resonance imaging and biopsy. She had previously undergone sclerotherapy (OK-432) five times since she was 6 years old, with no effect. The lesion had slowly increased with the appearance of vesicles on the skin surface, and she experienced pain and lymphatic drainage from the vesicles during the next 4 years. To relieve the symptoms, partial resection of the skin lesion was conducted when she was 10 years of age. After surgical resection, the symptoms were relieved, but the vesicle recurred from the surgical scar 1 year later. Following a ½-year observation, the vesicle had not disappeared, but the surgical scar became hypertrophic.

Surgical intervention would evoke the recurrence of the symptom; we decided to treat the LM with topical rapamycin which were reported of the efficacy of both hypertrophic scar in vitro and lymphatic vesicles. The ointment was applied following the drug information for tuberous sclerosis complex (TSC), topically twice daily on the lesion by parents. The patient was followed up regularly, and side effects and quality of life (QoL) were measured using the PedQL4.0®. The efficacy, side effects, and QoL were monitored. All procedures were approved by the Ethics Committee of Saitama Children's Medical Center, and informed consent was obtained from the patient.

The lesion improved gradually, vesicle volume decreased, and lymphatic drainage from vesicles disappeared after a month. The hypertrophic scar flattened after a month and reduced attenuation of color at 3 months [Figure 1]. The treatment was discontinued after 4 months because the patient was satisfied with the lesion improvement.

The patient felt mild irritation locally at the 1st month examination, but it disappeared spontaneously after a few months. No other local nor systemic side effects detectable by blood examinations were observed.

The QoL assessment showed that the physical health summary scores were 100% for both the patient and the parents since the beginning. However, the psychosocial health summary score of the patient was depressed before the treatment, which improved up to 100% after the present topical treatment [Figure 2].

  Discussion 

LM and lymphatic vesicles decrease QoL by pain, lymphatic drainage, bleeding, and infection. The microcystic type of LM, especially, is known for poor response to sclerotherapy; even after surgical resection, the recurrence and the risk of organ damage make it difficult to treat. Other new therapies have been explored. Topical rapamycin might be effective for both lymphatic and hypertrophic scars.

Rapamycin is an mTOR inhibitor that regulates cellular catabolism and anabolism. It has been used as an immunosuppressive agent, lymphangioleiomyomatosis, antineoplastic agent, and TSC. It is also known to inhibit angiogenesis and keloid fibroblasts and is expected to be effective in treating vascular malformations, hypertrophic scars, and keloids, and its use as an oral drug is widely accepted in Western countries.

The efficacy of topical application of TSC has been previously reported. The advantages of topical application are that it can be expected to produce high concentrations of pharmacological effects locally, and the side effects are localized (skin dryness, irritation, and folliculitis),[9],[10] thus avoiding the systemic side effects of oral treatment (drug-induced pneumonitis, infection, and hypercholesterolemia).[11]

Reports of topical rapamycin application for microcystic LM have gradually increased since 2017,[12],[13] with six case reports, one multicenter case series, and one randomized controlled trial (phase 2) reported a total of 30 cases.[12],[13],[14],[15],[16],[17],[18],[19],[20] Except for one case report from Turkey, all other cases were reported from Europe and the United States, and there were no cases reported from East Asia, including Japan [Table 1]. (PubMed keyword search “topical and ramapycin and lymphatic malformation” January 18, 2021).

Table 1: List of reports of topical rapamycin application for microcystic lymphatic malformation

Click here to view

The most frequent symptoms were vesicles/lymphatic drainage (49%), pain (18%), infection (14%), and bleeding (14%), and efficacy was reported in 28 of 30 cases (93%). It was also effective for patients who had received prior local treatment, such as excision, sclerotherapy, cryotherapy, and laser therapy, with a rate of 89% (8 of 9 patients).

Side effects were reported in seven (23%) of the 30 patients,[12],[14],[15],[16],[17],[18] local irritation and discomfort were reported in all cases with side effects, as well as additional symptoms of swelling in one case (3%),[12] local eczema in one case (3%),[14] and xerosis in one case (3%).[17] In our case, there were no systemic symptoms, and local skin irritation was observed, which disappeared after a few months.

In contrast, although no clinical cases of hypertrophic scars have been reported, it has been observed that the thickness and length of scars in mouse models treated with topical 0.2% rapamycin were significantly smaller than those in control groups.[21] In our case, 0.2% rapamycin was used for thickened scars, which showed some improvement.

QoL in patients with vascular malformations tends to decrease, especially in severe cases of mixed vascular malformations, and psychosocial aspects need to be considered.[22] However, there are still few reports on the QoL of patients with LM alone. According to the QoL assessment of patients with Klippel-Trenaunay syndrome (KTS), a congenital mixed vascular malformation, the physical and social aspects of patients with relatively severe vascular malformations were inferior to those of the general population. However, the psychological aspects were reported to be similar to those of the general population due to emotional coping from early childhood.[22],[23] In the present case, contrary to the case of KTS, only a decrease in the patient's mental QoL was observed. It might be that the disease is relatively mild in childhood, with new symptoms appearing in adolescence. The patient may have to cope with new emotional issues, unlike severe cases, and since the lesion is less likely to be seen by her parents, the patient may feel alone. The improvement in QoL by applying the ointment may have the advantage of being a source of reassurance to the patient because of the simplicity of starting treatment without hospital admission.

In this case, quantitative evaluation before and after treatment was not performed, and objective evaluation of the treatment effect was lacking. However, we observed improvement in the gross findings and subjective symptoms of the patient, suggesting that topical treatment was effective. There is no clear evaluation of relapse after drug discontinuation in the literature, and the timing of drug discontinuation and resumption should be carefully considered.

In conclusion, topical rapamycin may be a relatively safe and effective therapeutic option for superficial LMs with hypertrophic scars. It might also help improve the patients' psychosocial side.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 

  References 
1.Khunger N. Lymphatic malformations: Current status. J Cutan Aesthet Surg 2010;3:137-8.  
[PUBMED]  [Full text]  2.Kim SW, Kavanagh K, Orbach DB, Alomari AI, Mulliken JB, Rahbar R. Long-term outcome of radiofrequency ablation for intraoral microcystic lymphatic malformation. Arch Otolaryngol Head Neck Surg 2011;137:1247-50.  
    3.Hammill AM, Wentzel M, Gupta A, Nelson S, Lucky A, Elluru R, et al. Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer 2011;57:1018-24.  
    4.Wataya-Kaneda M, Ohno Y, Fujita Y, Yokozeki H, Niizeki H, Ogai M, et al. Sirolimus gel treatment vs placebo for facial angiofibromas in patients with tuberous sclerosis complex: A randomized clinical trial. JAMA Dermatol 2018;154:781-8.  
    5.Chen J, Liu K, Liu Y, Wang X, Zhang Z. Targeting mTORC1/2 with OSI-027 inhibits proliferation and migration of keloid keratinocytes. Exp Dermatol 2019;28:270-5.  
    6.Ong CT, Khoo YT, Mukhopadhyay A, Do DV, Lim IJ, Aalami O, et al. mTOR as a potential therapeutic target for treatment of keloids and excessive scars. Exp Dermatol 2007;16:394-404.  
    7.Nadal M, Giraudeau B, Tavernier E, Jonville-Bera AP, Lorette G, Maruani A. Efficacy and safety of mammalian target of rapamycin inhibitors in vascular anomalies: A systematic review. Acta Derm Venereol 2016;96:448-52.  
    8.Freixo C, Ferreira V, Martins J, Almeida R, Caldeira D, Rosa M, et al. Efficacy and safety of sirolimus in the treatment of vascular anomalies: A systematic review. J Vasc Surg 2020;71:318-27.  
    9.Malissen N, Vergely L, Simon M, Roubertie A, Malinge MC, Bessis D. Long-term treatment of cutaneous manifestations of tuberous sclerosis complex with topical 1% sirolimus cream: A prospective study of 25 patients. J Am Acad Dermatol 2017;77:464-72.e3.  
    10.Wataya-Kaneda M, Nakamura A, Tanaka M, Hayashi M, Matsumoto S, Yamamoto K, et al. Efficacy and safety of topical sirolimus therapy for facial angiofibromas in the tuberous sclerosis complex: A randomized clinical trial. JAMA Dermatol 2017;153:39-48.  
    11.Takada T, Mikami A, Kitamura N, Seyama K, Inoue Y, Nagai K, et al. Efficacy and safety of long-term sirolimus therapy for asian patients with lymphangioleiomyomatosis. Ann Am Thorac Soc 2016;13:1912-22.  
    12.García-Montero P, Del Boz J, Sanchez-Martínez M, Escudero Santos IM, Baselga E. Microcystic lymphatic malformation successfully treated with topical rapamycin. Pediatrics 2017;139:e20162105.  
    13.Ivars M, Redondo P. Efficacy of topical sirolimus (Rapamycin) for the treatment of microcystic lymphatic malformations. JAMA Dermatol 2017;153:103-5.  
    14.Çalışkan E, Altunel CT, Özkan CK, Tunca M. A case of microcystic lymphatic malformation successfully treated with topical sirolimus. Dermatol Ther 2018;31:e12673.  
    15.Le Sage S, David M, Dubois J, Powell J, McCuaig CC, Théorêt Y, et al. Efficacy and absorption of topical sirolimus for the treatment of vascular anomalies in children: A case series. Pediatr Dermatol 2018;35:472-7.  
    16.García-Montero P, Del Boz J, Baselga-Torres E, Azaña-Defez JM, Alcaraz-Vera M, Tercedor-Sánchez J, et al. Use of topical rapamycin in the treatment of superficial lymphatic malformations. J Am Acad Dermatol 2019;80:508-15.  
    17.Dodds M, Tollefson M, Castelo-Soccio L, Garzon MC, Hogeling M, Hook K, et al. Treatment of superficial vascular anomalies with topical sirolimus: A multicenter case series. Pediatr Dermatol 2020;37:272-7.  
    18.Badia P, Ricci K, Gurria JP, Dasgupta R, Patel M, Hammill A. Topical sirolimus for the treatment of cutaneous manifestations of vascular anomalies: A case series. Pediatr Blood Cancer 2020;67:e28088.  
    19.Cai DR, Gu DH, Yu Z, Yang DX, Chen DH, Lin DX. Topical rapamycin in superficial lymphatic malformation: microcystic lymphatic malformation or verrucous venous malformation? J Am Acad Dermatol 2019;S0190-9622(19):30165-30163.  
    20.Leducq S, Caille A, Barbarot S, Bénéton N, Bessis D, Boccara O, et al. Topical sirolimus 0.1% for treating cutaneous microcystic lymphatic malformations in children and adults (TOPICAL): protocol for a multicenter phase 2, within-person, randomized, double-blind, vehicle-controlled clinical trial. Trials 2019;20:739.  
    21.Webber LP, Yip B, Nascimento Filho CH, Park HB, Castilho RM, Squarize CH. Topical delivery of mTOR inhibitor halts scarring. J Dermatol Sci 2019;95:76-9.  
    22.Oduber CE, Khemlani K, Sillevis Smitt JH, Hennekam RC, van der Horst CM. Baseline quality of life in patients with klippel-trenaunay syndrome. J Plast Reconstr Aesthet Surg 2010;63:603-9.  
    23.Breugem CC, Merkus MP, Smitt JH, Legemate DA, van der Horst CM. Quality of life in patients with vascular malformations of the lower extremity. Br J Plast Surg 2004;57:754-63.  
    
  [Figure 1], [Figure 2]
 
 
  [Table 1]