Enlarging Scalp Lesion in Pediatric Patient

A 13-year-old female presented with an enlarging lesion on the right frontal scalp, present for 1 year. Physical examination revealed an asymptomatic 7 × 6 mm polypoid papule with variable epidermal papillomatosis and an overlying hyperkeratotic scale and crust (Figure 1). A tangential shave biopsy specimen was taken for diagnostic purposes (Figures 2 and 3). Past medical history was notable for seizures which began 2 years previously. Initial brain magnetic resonance imaging (MRI) revealed subcortical edema and gyral enlargement of the right posterior parietal lobe with an adjacent focus of blooming artifact consistent with hemorrhage into a cavernous malformation (CM), a type of venous malformation. Subsequent MRIs over the next 2 years were consistent with accumulation of new CMs with surrounding edema bilaterally in the occipital lobes. Histopathologic examination of the skin biopsy revealed an intradermal proliferation of plump epithelioid cells with abundant, lightly eosinophilic cytoplasm (Figure 2, H&E 10×; Figure 3, H&E 20×). Markedly ectatic, variably sized, and partially congested vascular spaces were seen (Figure 3, H&E 20×). Fibrosclerotic stroma surrounded extravasated erythrocytes and a mixed inflammatory infiltrate included occasional scattered eosinophils. Immunohistochemical staining was notable for diffuse positivity for CD31, CD34, ETS-related gene (ERG), and CD10. Negative immunohistochemical staining was seen for p16, SOX10, Factor XIIIa, CD68, CD162, S100, and SMA. Staining with Ki-67 showed a low proliferative index throughout the tumor. Fluorescence in situ hybridization (FISH) of the skin biopsy demonstrated a transcription factor binding to IGHM enhancer 3 (TFE3) rearrangement. Histopathology and genetic testing confirmed the diagnosis of EHE with fusion of yes-associated protein 1 (YAP1)-TFE3. Positron emission tomography (PET)/computerized tomography (CT) scans revealed involvement of the CNS, scalp, lungs, and inguinal nodes. Epithelioid hemangioendothelioma (EHE) is a rare vascular sarcoma with a prevalence of 1 in 1,000,000 and 4:1 female predilection [1, 2]. It typically affects individuals between the ages of 30–50, but has been diagnosed in children and geriatric patients [1, 2]. EHE may present primarily in the skin, lung, liver, bone, retroperitoneum, lymph node, or ovary and may remain indolent or metastasize aggressively [1, 2]. A retrospective case series reported presentations of EHE in pediatric patients [3]. The ages of the patients ranged from 2 to 25 years old and there was a 1:1 ratio of females to males [3]. Locations of lesions were widespread including the lungs, liver, and scalp [3]. Ninety percent of EHE harbor a pathognomic WW domain-containing transcription regulator protein 1 (WWTR1) (3q25.1)-Calmodulin binding transcription activator 1 (CAMTA1) (1p36.23) gene fusion leading to the WWTR1 promotor having transcriptional control and constitutive activation of CAMTA1 [1, 2, 4]. A less common YAP1-TFE3 gene fusion has also been described in a subset of tumors and leads to overexpression of the protein TFE3, a transcription factor of the microphthalmia (MiT) family [5, 6]. Histopathologically, EHE is characterized by endothelial cells arranged in nests and cords with variable presence of mature lumens [1, 2, 4]. Intracytoplasmic vacuoles can sometimes be identified and chondroid, myxoid, or hyalinized stromal change may be seen. Ninety percent of tumors stain positive for CD31 and CD34 [2]. Friend leukemia integration 1 transcription factor (Fli-1) staining is often positive. The differential diagnosis of EHE includes epithelioid angiomatous nodule, epithelioid angiosarcoma, pyogenic granuloma, and bacillary angiomatosis [7]. Epithelioid angiomatous nodule is benign and does not extend into the subcutis, but does involve epithelioid vascular proliferation as seen in EHE [7]. Angiosarcomas show dermal collagen dissection by vascular channels, necrosis, and typical mitoses [7]. Pyogenic granulomas reveal lobular arrangements of capillaries in the dermis typically without mitoses. Bacillary angiomatosis shows a lobular vascular proliferation with a dense neutrophilic infiltrate [7]. In this case, previous medical history, histopathological examination, and confirmatory YAP1-TFE3 fusion were specific for the diagnosis of EHE. Due to the rarity of EHE, large, randomized trials are not available to guide treatment. EHE has an unpredictable natural course. Spontaneous regression without intervention has been described [8, 9]. In one study, 5-year progression-free survival was 86% for EHE harboring the YAP1-TFE3 fusion compared to 59% for EHE harboring the WWRT1-CAMTA1 fusion [10]. Tumor multifocality, presence of metastasis, and pleural involvement were predictive of shorter overall survival [10]. Treatment options include watchful waiting, surgical excision, embolization, radiation, chemotherapy, and immunotherapy [1, 2, 4]. Sirolimus has proven to effectively treat EHE without serosal effusions [11, 12]. Oncogenic fusions involving either WWRT (also known as TAZ) or YAP, seen in most EHE are involved in the activation of mammalian target of rapamycin (mTOR) complexes, making sirolimus an option for treatment [11, 13]. Pazopanib, a multi tyrosine kinase inhibitor has also shown efficacy in a case of metastatic pulmonary EHE [14]. Likewise, trametinib, a MEK inhibitor has shown a median progression-free survival for 6 months in patients with advanced EHE [15]. In our patient, the intracranial vascular lesions, initially considered CMs on prior MRIs, were subsequently favored to be the primary lesions of EHE with secondary metastasis to the scalp, lungs, and inguinal nodes. Given widespread involvement including metastatic pulmonary disease, systemic therapy was initiated with pazopanib and trametinib. Treatment was complicated by trametinib-induced acneiform eruption and periungual pyogenic granulomas. Follow-up full body PET/CT after 3 months of therapy revealed increased metabolic activity of pulmonary and inguinal nodules. Subsequently, the patient was switched to sirolimus monotherapy and treatment is ongoing. The authors declare no conflicts of interest.