New horizon for classifying and managing vascular anomalies

The diagnosis of vascular anomalies has been challenging for dermatologists. Fortunately, refined classification systems may help make an accurate diagnosis. In parallel, recent genetic research unravelled some of the underlying mechanisms of vascular anomalies, which allows the development of targeted treatment strategies for patients.

“Vascular anomalies are frequently congenital, may present themselves as red or blue discolourations, and may be progressive, stable, or regressive,” explained Dr Carine van der Vleuten (Radboud University Medical Center, the Netherlands) [1]. Early diagnosis is often challenging, particularly the discrimination between vascular malformations and vascular tumours. “Many of these vascular anomalies present similarly in the early stage, complicating the diagnosis,” she continued.

Accurate classification of vascular anomalies is essential for early diagnosis, prognosis, and adequate management. The first attempt to classify vascular anomalies was made by Mulliken and Glowacki, who based their classification system on endothelial characteristics [2]. Later, the International Society for the Study of Vascular Anomalies (ISSVA) included clinical, biological, and genetic characteristics to differentiate between vascular malformations and vascular tumours. “The presence of proliferative endothelium versus non-proliferative endothelium was an important discriminator between vascular tumours and vascular malformations,” said Dr van der Vleuten. Since 2014, the ISSVA classification for vascular anomalies has been available online, with the latest update released this year [3]. The classification system broadly discriminates between vascular tumours, malformations, and potentially unique vascular anomalies (PUVA). Vascular tumours are further divided into benign, borderline, and malignant types, whereas vascular malformations can be categorised as fast-flow or slow-flow (see Figure). Dr van der Vleuten mentioned that slow-flow malformations fall into 1 of 4 subtypes: capillary, lymphatic, venous, or combined. Most of the aforementioned categories encompass additional subcategories to determine the exact type of vascular anomaly. “The ISSVA classification system of vascular anomalies comprises multiple pages of information, with many subcategories for each main category,” Dr van der Vleuten emphasised. “In recent years, genetic causes of vascular malformations have gained increasing relevance and are also described in the ISSVA framework.”

Figure: ISSVA classification for vascular anomalies [3]



Dr van der Vleuten continued her presentation by explaining that the discrimination between vascular tumours and vascular malformations is not as dichotomous as once believed. Several elements in pathogenesis overlap, and various vascular malformations can also exhibit proliferative behaviour. According to her, genetic diagnosis plays a key role in identifying the precise nature of a vascular malformation.

When examining the genetic basis, many vascular malformations emerge as a sporadic expression of DNA mosaicism. However, some arise from a familial origin involving germline mutations, where an additional "second hit" is necessary for the malformation to become clinically apparent. Although genetics is a valuable tool for understanding vascular malformations, they have limitations. Various phenotypes share common molecular pathways. “For example, many conditions fall under the PIK3CA-related overgrowth spectrum (PROS) umbrella, linked through one single genetic defect, yet yielding similar phenotypes,” clarified Dr van der Vleuten.

Hereafter, Dr van der Vleuten gave an example to illustrate the differences between 2 types of haemangioma. Infantile haemangiomas, which are frequently reported, are characterised by disproportional growth, are not present at birth, and regress slowly over time. No specific mutation has been linked to this type. In contrast, congenital haemangiomas are present at birth and either regress rapidly or, in the case of non-involuting congenital haemangiomas, remain stable. “Congenital haemangiomas are associated with GNAQ or GNA11 mutations, which are also observed in children with port-wine stains. Therefore, these mutations may be a missing link between vascular malformations and vascular tumours,” argued Dr van der Vleuten.

Another example of genetics' expanding role in diagnosing vascular anomalies comes from PTEN mutations. Dr van der Vleuten noted that a subset of vascular malformations has been linked to a germline PTEN mutation, which is known to be responsible for PTEN Hamartoma Tumour Syndrome (PHTS). Malignancies associated with PHTS typically begin to appear around the age of 30. Since the same PTEN mutations cause benign hamartomas, they may serve as early indicators of PHTS. Dr van der Vleuten recommended being extra vigilant if vascular malformations are observed in combination with other clinical features.

In conclusion, clinical, radiological, histopathological, and genetic information should be used to classify vascular anomalies. “The genetic information provides additional clarity and offers a rationale to start specific treatment,” Dr van der Vleuten concluded.

1. Van der Vleuten C. Vascular anomalies, genetics, and semantics. Dermatologendagen 2025, 10–11 April, Apeldoorn, the Netherlands.
2. Mulliken JB and Glowacki J. Plastic and Reconstructive Surgery. 1982;69(3):412-420.
3. International Society for the Study of Vascular Anomalies. https://www.issva.org.

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Posted on 5 June 2025