Complex vascular tumors and vascular malformations can be difficult to diagnose with accuracy especially in early infancy and childhood. We present a challenging case of a child who presented with an extensive infiltrating bilateral vascular lesion of the head and neck that appeared phenotypically as a Kaposiform hemangioendothelioma (KHE), but by histopathology and eventual genetic mutation testing, was more consistent with a congenital hemangioma (CH).
Using the International Society for the Study of Vascular Anomalies (ISSVA) classification of vascular anomalies,1 the terms infantile hemangioma (IH) and CH refer to distinct pathologies—both benign but with important immunohistochemical and clinical differences.2 GLUT-1 is almost never positive in CH, and these lesions are fully formed at birth and may rapidly involute (rapidly involuting CH—RICH) or grow proportionally with the patient (noninvoluting CH—NICH). Kaposiform hemangioendotheliomas (KHE) are nonhemangioma vascular tumors that may be locally aggressive.2 Histologically, these neoplasms are GLUT-1 negative, D2-40 positive hypercellular tufts of capillaries.3 KHE is distinguished by deep spindle cells and has a locally aggressive behavior. Clinically, both CHs and KHEs may present with Kasabach-Merritt phenomenon—a consumptive coagulopathy characterized by severe thrombocytopenia and microangiopathic hemolytic anemia.3 We describe a challenging case that helps further refine the diagnosis of vascular tumors.
An infant girl was noted to have bruising and fullness around her neck after a C-section delivery for a nuchal cord. At 5 weeks of age, she presented with persistent discoloration of the right neck and labored breathing. Ultrasound revealed a subcutaneous mass extending from the right shoulder to the right nasal bridge. PHACE (Posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, and eye anomalies) syndrome was considered. Echocardiogram, ophthalmic evaluation, CBC, fibrinogen, and D-dimer were all normal. Magnetic resonance imaging (MRI/MRA) showed no evidence of PHACE syndrome findings and a deep IH was suspected; propranolol therapy was initiated (Fig 1). (Informed written consent for use of photography was obtained from the parent.)
Due to nonresponse to propranolol therapy, at 3 months of age, she returned for biopsy of the lesion. Histopathology revealed deep dermal proliferation of numerous endothelial-lined vascular spaces. The endothelial nuclei stained positive for CD31, CD34, and WT-1, and negative for GLUT-1, LYVE-1, and D2-40 (Fig 2). The cellularity and negative lymphatic staining suggested an atypical hemangioma. Propranolol therapy was stopped. At 18 months of age, an MRI with and without contrast (WWO) was performed and revealed a T2-intense transpatial mass extending from the skull base to the supraclavicular soft tissues involving the bilateral carotid, masticator, retropharyngeal, and parapharyngeal spaces, encircling the aerodigestive tract but without any significant mass effect (Fig 3).
At age 5, the patient underwent uneventful tonsillectomy and adenoidectomy for obstructive sleep apnea and repeat biopsy of the vascular tumor for genetic testing of the somatic mutation in the lesion. Three weeks after the procedure, the patient was admitted for fever and swelling of the right face and periorbital region (Figure 4). Computed tomography (CT) with contrast revealed a retropharyngeal phlegmon and partial right cavernous sinus thrombosis. MRI WWO contrast redemonstrated the vascular tumor as an extensive infiltrating T2 hyperintensity involving the bilateral parotid and submandibular spaces, retropharyngeal and perispinal soft tissues, the carotid and parapharyngeal spaces, involvement of most cervical neural foramina, extension into the epidural spaces of the cervical spine, the bilateral suprasternal and supraclavicular regions, bilateral pterygopalatine fossae, masticator spaces and right orbit (Figure 5). Blood cultures grew Streptococcus anginosus. The patient improved with a 3-week course of intravenous antibiotics and 3 month course of anticoagulation (SQ Enoxaparin).
After further review of the pathologic specimen and tissue genetic testing that revealed GNAQ 209 high frequency allele mutation (14% variant allele fraction, c.627A>C, p.GIn209His, chr9:80409487T>G (GRCh37); RefSeq Accession NM_002072.4), diagnosis of a CH was favored rather than a KHE.
Diagnosis of vascular lesions has been standardized using the ISSVA classification.1 However, given the rarity of these tumors, classification is still challenging as demonstrated in the case reported here in which the patient was initially thought to have a KHE by clinical presentation but after further testing, consensus was to classify this tumor as a CH. Genetic testing was not available at the time of the child’s first biopsy in infancy but became available at the time of her second biopsy.
Genetic testing of involved tissue is especially useful in complex lesions of indeterminate phenotypic appearance. Both CH and KHE have been found to have G protein mutations: CH have GNAQ and GNA11 mutations, whereas KHE have GNA14 mutations.4 The spectrum of GNAQ 209 positive lesions is expanding.
In this case, MRI results were most consistent with KHE, showing avidly enhancing and infiltrating T2 hyperintensities throughout the soft tissues of the neck and face. However, on genetic evaluation, the presence of a GNAQ mutation led to a diagnosis of a CH.4 This case demonstrates significant overlap in clinical, pathologic, and radiographic findings that challenges classification of vascular tumors but also highlights the important role of genetic and molecular testing in facilitating diagnosis.
The nomenclature of vascular tumors continues to evolve to better capture and correlate pathophysiological and clinical characteristics. Atypical cases, such as the one presented here, challenge the existing nomenclature and provide opportunities to further refine classification. This tumor demonstrated genetic, molecular, and cellular traits more consistent with CH, but the clinical and radiographic findings appeared more consistent with a KHE. This supports extending the clinical phenotype of CH and refine the heterogeneity captured in this term.
Complex vascular tumors of the head and neck may present with significant clinical phenotypic overlap. The emergence of somatic genetic mutation testing has allowed us to differentiate between vascular tumor types and direct therapy appropriately. The case illustrates that even lesions quiescent for months to years, can rapidly become life-threatening in their complications with minor surgical interventions or infectious complications such as seen in this case. Genetic testing of the involved tissue in our patient allowed for a definitive diagnosis and will help direct therapy in the future.
1. International Society for the Study of Vascular Anomalies. ISSVA classification for vascular anomalies. 2014 July 2017. Available at: https://www.issva.org/UserFiles/file/ISSVA-Classification-2018.pdf
2. Steiner JE, Drolet BA. Vascular anomalies: classification of vascular anomalies: an update. Semin Intervent Radiol. 2017;34:225–232.
3. Kunimoto K, Yamamoto Y, Jinnin M. ISSVA Classification of vascular anomalies and molecular biology. Int J Mol Sci. 2022;23:2358.
4. Hinen HB, Trenor CC, Wine Lee L. Childhood vascular tumors. Front Pediatr. 2020;8:642.