A niche within NICH

By Warren R. Heymann, MD
February 26, 2020
Vol. 2, No. 8

Just when I thought I grasped the concept of congenital hemangiomas, new data raises novel questions.

Compared to infantile hemangiomas that grow rapidly after birth and then involute, congenital hemangiomas arise and proliferate in utero. Although two major subtypes of congenital hemangiomas are well-known, rapidly involuting congenital hemangioma (RICH) and noninvoluting congenital hemangioma (NICH), Nasseri et al introduced partially involuting congenital hemangiomas (PICH) in a series of 8 full-term infants. RICH involutes completely within the first 6 to 14 months of life, NICH grows proportionally with the child and does not regress, and PICH evolves from RICH to persistent NICH-like lesions. (1)

Enjolras et al proposed the term NICH in their study of 53 patients. NICH was further defined in the review of 30 cases by Lee et al. All patients had fully formed vascular lesions at birth that demonstrated a nonprogressive course. The trunk and lower extremities were preferred sites. There was a female predominance, compared to Enjolras et al, where a slight male predominance was observed. Thirteen of 30 patients reported pain. Focal necrosis and scarring were observed in a minority of cases. Doppler studies, when performed, confirmed high vascular flow. Microscopic evaluation of four excised lesions showed lobular areas of endothelial cell proliferation directly adjacent to ectatic malformed vessels.

Immunohistochemical studies demonstrated an absence of glucose transporter-1 (GLUT-1) protein expression in all cases. Wilms tumor-1 (WT-1) positivity was observed in lobular areas. The larger vessels did not stain with WT-1, but some displayed D2-40 positivity, suggesting a lymphatic lineage of some malformed vessels. In the 10 patients who had several follow-visits, one demonstrated a slight increase in prominence and size of adjacent superficial veins, and another patient’s lesion became slightly more protuberant. (3)

New reports suggest that a subset of NICH lesions may actually grow postnatally (beyond expected proportional growth).

Cossio et al retrospectively analyzed 80 cases of NICH. Nine presented with atypical postnatal growth after a stable period, at ages from 2 to 10 years (mean: 5.3 years). Two patients had associated pain; five patients showed new red papules on the surface of the lesion; two reported bleeding from the papules; and one developed a pyogenic granuloma. All patients had Doppler ultrasound and/or MRI findings compatible with NICH, and a confirmatory biopsy was performed in four cases. In treatment, two patients received endovascular embolization, and one required further surgery. The authors concluded that NICH may develop significant postnatal growth over time requiring closer follow-up for longer periods. (4).

Knöpfel et al described two cases of NICH that demonstrated subtle postnatal growth over time: a 6-week-old girl with a right arm NICH which grew with increasing telangiectasia and a full-term 4-week-old boy whose NICH became elevated and darker. The authors suggest that postnatal growth of NICH may be more common than previously thought. (5)

The pathogenesis of congenital hemangiomas remains to be defined. Ayturk hypothesized that congenital hemangiomas arise due to somatic mutations and performed massively parallel mRNA sequencing on affected tissue from eight participants. The authors identified mutually exclusive, mosaic missense mutations that alter glutamine at amino acid 209 (Gln209) in GNAQ or GNA11 in all tested samples, at variant allele frequencies (VAF) ranging from 3% to 33%. The same mutations occurred in RICH and NICH, implying that other genetic, epigenetic, and/or environmental factors probably influence these lesions’ postnatal behavior. (6)

Therapeutically, most NICH do not require treatment. Surgical resection is an option if the lesion is discrete, within the subcutaneous tissue, and in a surgically amenable location. (3) Moreno-Ramirez et al opine that surgery should be offered as early as the diagnosis to achieve the best cosmetic and functional results in adult life. (7) A multidisciplinary consultative approach is recommended before embarking on other therapies (embolization, sclerotherapy, laser) until good evidence for these modalities is available. (3)

The observation that a subset of NICH may continue to grow postnatally is important for several reasons. On a practical level, parents must be told of this potential to avoid undue angst. On a theoretical basis, understanding this phenomenon could yield potential therapeutic medications not only for NICH, but also other lesions where GNAQ and GNA11 mutations have influence — phakomatosis pigmentovascularis, extensive dermal melanocytosis, and uveal melanoma. This niche within NICH warrants clinical recognition and basic research. Perhaps this variant should be called NICHE (noninvoluting congenital hemangioma evolving).

Point to Remember: It is important to recognize that some NICH lesions may demonstrate postnatal growth.

Our Expert’s Viewpoint

James Treat, MD
Associate Professor of Clinical Pediatrics and Dermatology
Perelman School of Medicine at the University of Pennsylvania

The recognition of congenital hemangiomas (CH) has defined a new category of vascular tumors and helped clarify the behavior or infantile hemangiomas (IH). Previously, multiple characteristics of CH such as their congenital presentation and rapid or complete lack of involution were inaccurately ascribed to IH. Dividing up CH to include partially involuting CH (PICH) has been helpful as PICH may represent a large proportion of all rapidly involuting CH (RICH). Further, the recognition that NICH can continue to grow helps inform prognosis and conversations about the pros and cons of surgery or interventional radiology. CH unfortunately have no medical therapy but clarifying the genetics of CH may lead to a future targeted therapeutic.

1. Nasseri E, Piram M, McCuaig CC, Kokta V, et al. Partially involuting congenital hemangiomas: A report of 8 cases and review of the literature. J Am Acad Dermatol 2014; 70: 75-79.

2. Enjolras O, Mulliken JB, Boon LM, Wassef M, et. Noninvoluting congenital hemangioma: A rare cutaneous vascular anomaly. Plast Recontr Surg 2001; 107: 1647-1654.

3. Lee PW, Frieden IJ, Streicher JL, McCalmont T, Haggstrom AN. Characteristics of noninvoluting congenital hemangioma: A retrospective review. J Am Acad Dermatol 2014; 70: 899-903.

4. Cossio ML, Dubois J, McCuaig CC, Coulombe J, et al. Non-involuting congenital hemangiomas (NICH with postnatal atypical growth: A case series. Pediatr Dermatol 2019; 36: 466-70.

5. Knöpfel N, Wälchli R, Luchsinger I, Theiler M, et al. Congenital hemangioma exhibiting postnatal growth. Pediatr Dermatol 2019; 36: 548-549.

6. Ayturk UM, Couto JA, Hann S, Mulliken JB, et al. Somatic activating mutations in GNAQ and GNA11 are associated with congenital hemangioma. Am J Hum Genet 2016; 98: 789-795.

7. Moreno-Ramirez D, Toledo-Pastrana T, Rios-Martin JJ, Ferrándiz L. Surgical removal of a noninvoluting congenital hemangioma using a modified sub-brow flap. JAAD Case Rep 2016; 2: 199-201.