Lymphatic malformations (LM) represent a serious, rare disease of the lymphatic system characterized by development of abnormal vessels, outpouchings, or cysts filled with lymphatic fluid. The distinguishing feature of this disease is the aberrant cellular growth that creates cysts of varying size and location. According to the International Society for the Study of Vascular Anomalies (ISSVA), there are three morphologic types of LMs based on the size of the individual cysts (as opposed to the overall size of the LM): macrocystic (typically > 2 cm), microcystic (generally < 2 cm), and mixed (includes aspects of both) . Macrocystic LMs typically exist beneath the skin and often can involve vascular components and/or organs. Microcystic LMs often have a cutaneous component and clinically present with lymphorrhea, bleeding, pain, itching, malodor, and functional deficits. Infections of malformations can occur and may lead to cellulitis of surrounding tissues or severe, life-threatening infections.
There are no treatments approved by the US Food and Drug Administration (FDA) for either macrocystic or microcystic lymphatic malformations. The current standard of care treatment options are mainly limited to procedural interventions such as surgery and sclerotherapy . Treatment success rates for surgery vary, especially for large infiltrative disease . Sclerotherapy, which involves injection of a sclerosant into the vascular structure, is associated with a higher response rate of up to 75% in macrocystic LM but much less successful in microcystic LM . Its use is limited by safety concerns including pulmonary fibrosis . However, a small study by Chaudry and colleagues (n = 34) found that treatment with the sclerosant bleomycin for microcystic LM was relatively safe and effective . Therefore, microcystic LM represents a high unmet need and serious genetic disease for which novel therapies should advance with a sense of urgency.
Within the past 10 years, researchers have identified that somatic activating mutations in phosphatidylinositol 3-kinase (PIK3CA) result in increased activation of the PIK3CA/AKT/mTOR signaling pathway, leading to increased lymphangiogenesis . This discovery has allowed researchers to consider potential new therapies that target this cellular pathway. One therapy in particular that has shown promise in a clinical setting is the mTOR inhibitor sirolimus, which is not FDA-approved for lymphatic malformations [7, 8].
Because LM is a congenital disease, diagnosis and treatment often occur early in life at specialized vascular malformation or vascular anomaly treatment centers. Given the complexity of the disease, patients are cared for by a multi-disciplinary team of specialists at these centers, which may include providers from dermatology, hematology/oncology, plastic or general surgery, otolaryngology, radiology and interventional radiology, orthopedics, and genetics, among others.
The research to fully understand the prevalence of LM is sparse and does not differentiate between macrocystic and microcystic LM. The totality of the epidemiologic literature for LM (inclusive of macro and microcystic) is limited to the incidence of the disease among various birth cohorts. Although both macrocystic and microcystic LM are chronic diseases, macrocystic lesions have better responses to treatments with surgery or sclerotherapy. As microcystic lesions do not respond as well to these treatments, they tend to be more persistent; therefore indicating the need to study the prevalence of each LM subtype.
Previous studies report a birth incidence ranging from 1/250 live births to as few as 1/4000 live births [9, 10]. Applying these rates to the provisional 2020 US Centers for Disease Control and Prevention birth data would yield about 900–14,400 new incident cases in 2020 . These studies and data are further challenged by the fact that the disease classification and nomenclature have gone through a number of iterations over the years and disease definitions across studies may not be aligned . Given the different treatment approaches for macrocystic and microcystic LM, including the different success rates of therapy and outcomes, it is important to distinguish the prevalence of microcystic LM from macrocystic LM. The current data estimates of LM incidence fail to capture the prevalence of microcystic LM, as people with this disease continue to age and require chronic care and treatment. By better understanding the total prevalence of people living with microcystic LM in the United States, efforts to identify underserved populations in need of potential new treatments can be better focused.
The purpose of the present study was to obtain an accurate estimate of the national prevalence for patients with microcystic LM or combined LM managed annually across physician specialties likely to treat this condition. In our survey, we defined lymphatic malformations with a cutaneous component (LMC) as patients with either microcystic LM or mixed type LM.
This is the first study using a methodology designed to estimate the national prevalence of annually managed LMC. It was not designed to estimate the total national prevalence of LMC, but rather the prevalence of a particular subset—patients whose LMC is being managed by a physician in a target specialty.
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