Vascular tumors in infants and adolescents

Congenital hemangiomas are extremely rare; the exact prevalence however is unknown. They can resemble infantile hemangiomas both clinically as well as on imaging studies, but they are biologically a different entity. Clinically, they are recognized directly after delivery and appear rather bluish-red with less-well defined margins and may have a ‘pale-rim,’ as part of the adjacent skin is less well perfused due to a steal effect. Congenital hemangiomas are fully developed at birth (Fig. 3) and do not proliferate any more thereafter [10]. Typically, congenital hemangiomas are immunohistochemically negative for GLUT-1 in comparison to infantile hemangiomas. RICH are at or beyond their maximum extension at birth and regress rapidly in the months thereafter; regression is frequently complete with the first year of life [9, 33]. NICH instead persist without signs of regression, while rapid involution in PICH can occur and stop at any time, transforming PICH into NICH. Congenital hemangiomas, especially due to their extension already at birth, can cause significant complications such as high-output cardiac failure or thrombocytopenia, requiring early therapy.

Spindle cell and epitheloid hemangiomas are benign vascular tumors, typically lesions involving the skin and subcutis only and mostly do not require radiologic imaging [34]. In rare cases, epitheloid hemangioma can develop as a reactive process following local trauma or pregnancy within the bone, presenting as lytic, well-circumscribed lesions in the metaphysis and diaphysis of long bones of the extremities [35, 36]. In such cases, lesions should be differentiated from intraosseous epitheloid hemangioendothelioma, which requires biopsy. There is no standard of therapy established and treatment may involve surgical curettage, complete resection, or sclerotherapy [34].

Pyogenic granuloma can be a potential differential diagnosis of hemangioma. The prevalence is about 0.5–1% and thus represents a quite common acquired vascular tumor [37, 38]. Differing from infantile or congenital hemangioma, pyogenic granuloma rarely manifest before the age of 4 months. After minor injury, for example following insect bites, small vascular papules form up to 1 cm in size as red, exophytic lesions with high perfusion, primarily localized in the craniofacial region [9] (Fig. 5). However, pyogenic granuloma can also manifest within the intestines and parenchymal organs, which questions the formation out of minor injuries. Pyogenic granulomas, frequently also referred to as intravenous lobular capillary hemangioma, tend to bleed and are then best treated by surgical curettage or excision. Imaging is rarely indicated und thus no comprehensive data about presentation of pyogenic granuloma on US or MRI exists. Case reports describing MRI in pyogenic granuloma describe the morphology of pyogenic granuloma with those of hemangiomas, specifically an isointense signal of the lesion compared to the muscle and a homogenous enhancement after contrast agent administration [39]. Similarly, only rare evidence exists regarding interventional treatment of pyogenic granuloma, which may be reserved either for large tumors or for cases of severe hemorrhage [40, 41]. In general, although pyogenic granulomas can regress spontaneously, surgical excision is recommended to prevent bleeding complications and improve visible deformity.

Rather than being two distinct entities, tufted angioma (TA) and kaposiform hemangioendothelioma (KHE) are nowadays understood as a spectrum of the same disease. Both are locally aggressive tumors that can be accompanied by life-threatening consumptive coagulopathy consisting specifically of severe thrombocytopenia and hyperfibrinogenemia with diffuse intravascular coagulation, referred to as Kasabach-Merritt phenomenon (KMP) [22, 34, 42]. In general, tufted angioma is seen as a more superficial and milder form of the borderline vascular tumor compared to KHE. Interestingly, both tumors present distinct lymphatic antigens which support the hypothesis that both entities have at least a partial lymphatic phenotype [42‐44]. Of note, KHE and TA are negative for infantile hemangioma markers such as GLUT-1 [18, 42]. In case of diagnostic uncertainty, biopsy is recommended and histopathological evaluation is required from highly experienced pathologists with knowledge of these distinct pheno- and genotypes. The incidence of KHE is estimated to be below 1 in a million and most frequently KHE occur within the first weeks of life (60%), but can already be observed in utero or develop later in early adulthood [45]. KHE most frequently manifests along the extremities and less frequently along the trunk, the retroperitoneum, or the head-neck region. The clinical appearance is rather characteristic with a highly vascularized reddish-blueish mass without sharp margins. The skin is almost always involved with various degrees of purpura and ecchymoses (Fig. 6a). Larger KHE present as bulky mass with tense swelling of the affected extremity and frequently accompanied by massive lymphedema (Fig. 6a).

MRI is the imaging modality of choice to demonstrate disease extension [46, 47]. The mass is poorly circumscribed and diffusely permeates soft tissues without reference to defined tissue planes with potential destruction of adjacent bones. The lesions are highly vascularized and frequently hypertrophic arterial feeders can be identified on MRA (Fig. 6b). In the early phase, a massive arterial tumor blush occurs around the center of the lesion (Fig. 6b, c). Flow-voids can be observed, in contrary KHE never exhibit arterio-venous shunting which is a common feature of arteriovenous malformations. Imaging depicts the associated lymphedema with characteristic septa perpendicular to the skin surface (Fig. 6d, e), that show prominent enhancement after gadolinium administration (Fig. 6f). Dilated draining veins are frequently observed (Fig. 6g). The diagnosis is made clinically together with MR imaging and, most importantly, laboratory values. As > 70% of KHE develop a KMP, where activated metaplastic tumor endothelium activates thrombocytes and destroying them within the lesion, thereby causing massive thrombocytopenia and life-threatening consumptive coagulopathy [11].

Treatment of KHE, especially with associated KMP is complex and always needs dedicated specialized care within an interdisciplinary setting. In 2013, a consensus-derived standard of practices was published. In this report, intravenous treatment with vincristine and prednisolone has been advocated. Embolization therapy was suggested as a bridging therapy using either small-sized particles or liquid embolics, especially in life-threatening situations, providing additional time for medical therapy to become effective [34, 48]. Surgery may be performed but requires extensive tumor resection, is often incomplete or impossible due to the accompanying coagulation disorder, and is associated with substantial morbidity. A recent meta-analysis evaluated the treatment of 244 patients with KHE, which consisted of systemic corticosteroids, interferon, radiotherapy, embolization, aspirin/ticlopidin for inhibiting thrombocyte aggregation, chemotherapy, and sirolimus. Up to now, there is no consensus on the optimal therapeutic regime for KHE with or without KMP but several novel approaches are being discussed including the use of mTOR inhibitors [11]. The authors of this review have encouraging clinical results in a combined interdisciplinary treatment of KHE with life-threatening KMP. We propose to immediately initiate treatment with acetylsalicylate acid in a weight-adapted dose of 1–2 mg per kg/body weight. Subsequently, we perform transarterial embolization using alcohol vinyl copolymer (Fig. 6h–j) to reduce the contact of thrombocytes to the activated endothelium and rescue the patient form the consumptive coagulopathy. Following embolization, we initiate treatment with sirolimus, a well-established mTOR inhibitor, which has proven effective in the treatment of vascular malformations with a high proliferation rate and has similarly been used in treatment of KHE [48‐50]. We start sirolimus with a dose of 0.8 mg/m² with the goal to achieve a trough level of 7–9 ng/ml in the early morning. In the cases we have treated so far, KMP resolved within the first 2 weeks of treatment eliminating the risk of life-threatening bleeding, and with the combination of embolization and sirolimus substantial regression of the size of the mass, reduction of discoloration and skin tension was achieved (Fig. 6k, l). Medical treatment with acetylsalicylate acid and sirolimus is continued for 6–12 months. Again, we would like to emphasize that especially in cases of KHE and KMP, tight cooperation between radiologists, pediatric hematooncologists, pediatric surgeons, hemostasiologists, and pathologists is absolutely mandatory, also with respect to the fact that all therapy approaches discussed are being performed as off-label use in the absence of published clinical data in this extremely rare tumor entity.

Retiform hemangioendothelioma is a superficially located tumor that is frequently encountered in adults, less frequent in small children, and has been named due to its net-like vascular composition [51]. Retiform hemangioendothelioma are closely related to PILA/Dapka tumors and have an overlapping pathological background. Composite hemangioendothelioma is another rare vascular tumor entity, similar as retiform hemangioendothelioma with almost no malignant potential or tendency to metastasize [52]. Imaging appearance is heterogeneous [53] so that diagnosis has to be based regularly on biopsy.

Kaposi sarcoma (KS) is considered a low-grade malignant vascular tumor. Four different subtypes are classified: classical, iatrogenic, AIDS-related, and African/endemic [42], while all subtypes share human herpesvirus 8 infection as their common origin. Infection of vascular endothelial cells by the HHV8 virus induces their lymphatic reprogramming and similar downregulation of classical vascular genes. Cutaneous manifestations are heterogeneous such as dermal patches, plaques, or nodules. Compared to adults, cervical and oropharyngeal lymphadenopathy as well as visceral involvement are more common in children than cutaneous manifestations. All tissues and organs can be affected, leading to a wide variety of presentations on radiological imaging best reviewed by O’Mahony [54] and Restrepo [55]. Mass-like lesions in deeper tissue show marked contrast enhancement and can even show high FDG uptake in PET/CT imaging. Lesions can result in progressive bone destruction and metastasis-like osteolytic lesions [56, 57]. Lymphatic manifestation over the entire body as well as characteristic perihilar bronchovascular infiltrates of KS are frequently encountered in imaging of KS. While iatrogenic type of Kaposi sarcoma frequently regresses spontaneously after ending immunosuppression, the other types require systemic therapy or/and local radiotherapy. Topical treatments such as cryotherapy or intralesional injection of Bleomycin or interferon have been reported.

Epithelioid hemangioendothelioma (EHE) in contrast to the aforementioned hemangioendotheliomas is a malignant tumor arising from the endothelium of medium to large blood vessels and can occur in the soft tissue of the extremities (rarely head and neck) as well as in liver, spleen, lung, and bone and lymphatic tissue [34]. The peak incidence (< 1/1 million) is in the fourth and fifth decade, but it can rarely occur also in children. Females under hormonal contraception seem to be affected more frequently as far as hepatic manifestations are concerned [58]. The degree of malignancy can vary and the overall survival has been reported to be 73% at 5 years. Frequently, EHE of the liver follows an indolent course, causing a continuous debate of immediate treatment is necessary or of benefit for the patient. There is no established tumor marker, and imaging findings are similarly heterogeneous, with moderate enhancement after contrast agent administration [59]. An example of hepatic EHE is shown in Fig. 7. Surgery is considered the treatment of choice for solitary lesions [60]. Once metastasized, the response to (angiosarcoma like) chemotherapy is poor [61]. Preoperative embolization has been reported either preoperatively or in cases of rupture [62, 63], chemoembolization either in case of inoperability or as bridge to liver transplant, with no clear evidence until today [64, 65].

Angiosarcomas are similarly rare (estimated incidence 2/1 Mio) and comprise 2% of all sarcomas. In general, they are tumors of high malignancy that can arise from vascular endothelial cells in any part of the body. Typically, angiosarcomas manifest in the sixth or seventh decade of life, rarely they can occur at childhood age [66]. Multiple risk factors are known, such as chronic lymphedema (Stewart-Treves syndrome), conditions post-surgery and radiotherapy, various exogenous toxins such as arsenic or vinyl chloride, as well as genetic predisposition such as neurofibromatosis NF-1, BRCA1/2 mutations, Mafucci syndrome, as well as Klippel-Trenaunay syndrome, the latter two being predominantly combined vascular malformations. Although most angiosarcomas occur spontaneously, a few reports of malignant transformation of benign vascular lesions exist [67]. Cutaneous angiosarcomas may present as local bruise or papule without sharp borders, typically occur multifocal and can be easily mistaken for benign vascular lesions. With increasing size, the infiltrating growth character becomes more obvious. Soft tissue or visceral organ manifestations present as expanding heterogeneous mass, which can grow rapidly up to 20 cm or more in size [66]. Metastasis typically occurs hematogeneously most frequently to the lungs. Both cutaneous lesions as well as visceral manifestations exhibit wide possible differential diagnosis and similarly hepatic manifestation of angiosarcoma is radiologically difficult to differentiate from other liver tumors such as hepatocellular carcinoma, liver metastasis, or even hemangioma [68], so that biopsy of suspect lesions is required for correct diagnosis.

Imaging of primary lesions is most frequently performed by MRI or CT; CT of the chest is necessary to rule out pulmonary metastasis. In case of angiosarcoma of the large vessel, the tumor can mimic atheroma or thrombotic material within the vessel [69] (Fig. 8a, b). In such cases, PET imaging can help in the differential diagnosis, as angiosarcomas typically exhibit a high metabolic activity (Fig. 8c, d). Treatment of vascular complications includes palliative approaches in case of vessel obstruction or thromboembolic complications [70] as well as emergency embolization in case of tumor bleeding. For hepatic manifestations, chemo- and radioembolization have been performed in cases of inoperability or metastasis, but their efficacy compared to chemotherapy has not been evaluated [68, 71, 72].

Besides the described tumors which are of endothelial origin, other vascular soft tissue tumors exist. Hemangiopericytoma is a distinct tumor entity arising from vascular pericytes. Several categories such as solitary fibrous tumors have been subcategorized as hemangiopericytoma-like neoplasms. Typically, hemangiopericytomas in childhood present as self-limiting lesions with malignant potential while tumor manifestation in adulthood is frequently malignant with high likelihood of metastasis, most commonly occurring in case of intracranial hemangiopericytomas. Hemangiopericytomas are hypervascular lesions. Treatment of these vascular soft tissue tumors is not standardized and involves surgery and/or radiosurgery for intracranial lesions in combination with systemic therapy. In rare cases, embolization can be performed preoperatively to reduce bleeding complications [73‐76].