Only a small number of pediatric hematologist oncologists and even fewer of our adult counterparts feel comfortable evaluating and treating vascular anomalies.
While admittedly rare, these conditions are still common enough that clinicians in many disciplines encounter them. Hematologist/oncologists are most likely to see vascular malformations, which often present as mass lesions. Complications of these disorders occur across the hematology-oncology spectrum and include clots, pulmonary emboli, cancer predisposition, and an array of functional and psychosocial disorders.
Vascular anomalies are broadly categorized as vascular tumors or malformations. The tumors include hemangiomas, locally aggressive lesions, and true cancers. Malformations can be isolated disorders of one or more blood vessel types (veins, arteries, capillaries or lymphatics), or they can be one part of syndromic disorders. Lymphedema also falls under the heading of vascular anomalies. To make the terminology less confusing, in 2018 the International Society for the Study of Vascular Anomalies refined its classification scheme.
Vascular malformations are thought to be congenital. Although some are obvious at birth, others aren’t apparent until adulthood. In most cases, they grow with a child and may do so disproportionately at puberty and with pregnancies. The fact that vascular malformations persist into adulthood is one reason why their care should be integral to medical hematology-oncology.
Although the cause of a vascular malformation is not always known, a wide range of genetic mutations thought to be pathogenic have been reported. These mutations are usually somatic (only within the involved tissues, not in the blood or germ cells and therefore, not heritable) and tend to cluster in the VEGF-PIK3CA and RAS-MAP signaling pathways.
These genes and pathways will be familiar to any oncologist who cares for patients with solid tumors, notably breast cancer or melanoma. However, unlike the clonal expansion seen in cancers, most vascular malformations will express pathogenic mutations in less than 20% of vascular endothelium within a malformation.
Since 2008, medical management has been limited to sirolimus (rapamycin), a mammalian target of rapamycin inhibitor, which can be effective even when mTOR mutations aren’t apparent. In a seminal phase 2 trial of 57 patients with complex vascular anomalies who were aged 0-29 years, 47 patients had a partial response, 3 patients had stable disease, and 7 patients had progressive disease. None had complete responses. These data highlight the need for more effective treatments.
Recently, vascular anomalists have begun to repurpose drugs from adult oncology that specifically target pathogenic mutations. Some studies underway include Novartis’ international Alpelisib (Piqray) clinical trial for adults and children with PIK3CA-related overgrowth syndromes (NCT04589650) and Merck’s follow-up study of the AKT inhibitor miransertib for PROS and Proteus syndrome. Doses tend to be lower than those used to treat cancers. To date, these have been generally well-tolerated, with sometimes striking but preliminary evidence of efficacy.
During the past 2 years, symposia on vascular anomalies at the annual meeting of the American Society of Hematology have launched what we are hoping is just the start of a broader discussion. In 2020, Fran Blei, MD, chaired Vascular Anomalies 101: Case-Based Discussion on the Diagnosis, Treatment and Lifelong Care of These Patients, and in 2021, Adrienne Hammill, MD, PhD, and Dr. Raj Kasthuri, MBBS, MD, chaired a more specialized symposium: Hereditary Hemorrhagic Telangiectasia (HHT): A Practical Guide to Management.
Dr. Blatt is in the division of pediatric hematology oncology at the University of North Carolina at Chapel Hill. She disclosed no relevant financial relationships.