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Sirolimus for microcystic lymphatic malformations: Caviar for frog spawn

DII small banner By Warren R. Heymann, MD
Jan. 23, 2017

Recently, our understanding of lymphatic malformations (LMs) has vastly expanded. Genetic advances have focused on the PI3K/AKT/mTOR pathway allowing the use of mTOR inhibitors for those lesions involved in this pathway. As noted in a previous post (Rapalogs for vascular lesions: Caveat mTOR; September 21, 2016), the mTOR protein is a serine-threonine kinase involved in complex intracellular signaling pathways affecting the key processes of cell growth, cell proliferation, angiogenesis, cellular metabolism, autophagy and apoptosis. Vascular endothelial growth factor (VEGF) is a vital regulator in lymphangiogenesis and angiogenesis acting both as a potential upstream stimulator of, and downstream effector in, the mTOR-signaling pathway. The mTOR inhibitors decrease VEGF secretion by tumors and reduce the sensitivity of endothelial cells to VEGF, thereby preventing neovascularization (1).

Of the rapalogs, sirolimus (rapamycin) has been used most frequently for managing vascular malformations and tumors. Topical use of sirolimus has been most prevalent for treating the angiofibromas of tuberous sclerosus, where it has proven safe and effective (2).

LMs are low-flow vascular anomalies of the lymphatic system. The International Society for the Study of Vascular Anomalies (ISSVA) has classified LMs as: 1) Common (cystic) LM [microcystic < 1cm, macrocystic > 1 cm, or mixed]; 2) Generalized lymphatic anomaly; 3) LM in Gorham-Stout disease; 4) Channel type LM; 5) Primary lymphedema, and; 6) Others. Histologically LMs are composed of thin-walled irregular vascular spaces lined by lymphatic endothelial cells (3).

LMs are usually congenital. They may have devastating complications such as respiratory failure, dyspnea, dysphagia, organ compression, and nerve compression. Although surgical excision of LMs is the preferred treatment, it is not always feasible because of the anatomic location of the lesion (4). Other therapeutic options have included expectant observation, sclerotherapy, radiofrequency ablation, laser therapy, sildenafil, propranolol, and sirolimus (3).

If you’re a skeptic about the use of systemic sirolimus for LMs, I encourage you to look at the dramatic rapid improvement displayed in patients with Gorham-Stout disease (5), diffuse lymphangiomatosis (6), and macroglossia due to LM (7). This is not fake news!

Ivars and Redondo detail the case of a 20+ year-old man with a biopsy-proven microcystic LM of the root of his penis extending on the scrotum. This was accompanied by lymphorrhea, and complicated by episodes of lymphangitis, with resultant penoscrotal deformity and lymphedema. After using 0.8% rapamycin petrolatum for 3 months, the patient displayed a marked reduction of the lesional size with virtual elimination lymphorrhea (8).

Microcystic LMs were formerly known as “lymphangioma circumscriptum”, although I still use the term. Their appearance has been likened to frog spawn (not that I can recall the appearance frog spawn). Why it was not compared to the far more elegant roe of sturgeon — caviar — defies explanation. Was it because the term “caviar spots” was already reserved for sublingual varicosities? Regardless, pending further confirmatory studies, topical sirolimus may ultimately prove to be the treatment of choice for microcystic LMs when surgery is not a viable option.

1. Nadal M, et al. Efficacy and safety of mammalian target of rapamycin inhibitors in vascular anomalies: A systematic review. Acta Derm Venereol 2016; 96: 448-52.
2. Wataya-Kaneda M, 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.
3. Defnet AM, et al . Pediatric lymphatic malformations: evolving understanding and therapeutic options. Pediatr Surg Int 2016; 32: 425-33.
4. Berger R. Nursing implications for the management of lymphatic malformation in children. J Pediatr Oncol Nurs 2016; June 5 [Epub ahead of print].
5. Cramer SL, et al. Gorham-Stout disease successfully treated with sirolimus and zolendronic acid therapy. J Pediatr Hematol Oncol 2016; 38: e129-32.
6. Laforgia N, et al. Lymphatic malformation in newborns as the first sign diffuse lymphangiomatosis: successful treatment with sirolimus. Neonatology 2016; 109: 52-5.
7. Yesil S, et al. Successful treatment of macroglossia due to lymphatic malformation with sirolimus. Ann Otol Rhinol Laryngol 2015; 124: 820-3.
8. Ivars M, Redondo P. Efficacy of topical sirolimus (rapamycin) for the treatment of microcystic lymphatic malformations. JAMA Dermatol 2017; 153: 103-5.

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