Congenital vascular lesions, could MAPK and PI3K inhibitors pave the way to new therapies?

PURPOSE OF REVIEW: Superficial vascular anomalies are a heterogeneous group of malformative and tumoral lesions, developed from various types of abnormal lymphatic and/or blood vessels. They are mostly benign but their clinical evolution can lead to dramatic cosmetic concern, functional impairment and even life-threatening conditions. Until recently, treatments relied on invasive procedures such as embotherapy/sclerotherapy and/or surgery. Recent molecular findings pave the way of new medical therapies. RECENT FINDINGS: Two main signaling pathways PI3K-AKT-mTOR and RAS-MAPK-ERK are now identified to encounter for the causative pathogenic genetic variants of most vascular anomalies. Involved genes are also responsible for several common neoplasms for which targeted therapies are already available or under development. Repurposing treatment strategy is considered for vascular anomalies treatment with promising results. SUMMARY: The mTOR inhibitor sirolimus is the most used targeted therapy so far but new molecules are tested currently.

Atypical presentations of congenital hemangiomas: Extending the clinical phenotype.

BACKGROUND/OBJECTIVES: Congenital hemangiomas (CH) are a group of benign vascular tumors that are present at birth and exhibit variable involution during infancy. Congenital hemangiomas that do not involute are typically solitary patch or plaque-type tumors that grow proportionally with somatic growth. We report a case series of 9 patients with persistent CH, which exhibited uncommon features including segmental involvement, recurrent or severe pain, or growth via volumetric increase in size or apparent increased extent of anatomic involvement over time. METHODS: Via retrospective chart review, we included patients with persistent CH and atypical presentations. Available data regarding clinical characteristics, natural history, histopathology, imaging, and genetic tests were collected. RESULTS: Data on 9 patients were collected, including 7 noninvoluting CH and 2 partially involuting CH. Three of the 9 cases had segmental distribution, 6 had apparent growth or clinical evolution, and 4 were symptomatic with pain. One also had marked localized intravascular coagulopathy. CONCLUSIONS: Ongoing or recurrent pain and large extent of anatomic involvement can be features of CH, albeit uncommon ones, and can pose both diagnostic and management challenges. Tissue genomic studies can offer a novel tool for CH diagnosis.

Congenital cutaneous pyogenic granuloma: Report of two cases and review of the literature.

Congenital cutaneous pyogenic granuloma is a rare benign vascular tumor with clinical and histopathological features similar to infantile hemangioma. It usually presents as a red, pedunculated and highly friable papule. On histopathological analysis, one can see a capillary vessel proliferation with lobular pattern and endothelial proliferation. The differential diagnosis is based on negativity of glucose transporter 1 (GLUT1) immunochemistry studies. We report two infants with congenital pyogenic granuloma, one with a unique cutaneous lesion and the other with multiple lesions affecting both skin and mucosal surfaces. These two cases highlight the importance of the differential diagnosis based on the GLUT1 immunochemistry analysis considering the distinct treatments required to these infant vascular tumors.

Rapidly involuting congenital hemangioma

Abstract: Rapidly involuting congenital hemangioma is a rare vascular tumor that generally has a good prognosis. The authors describe a case of a newborn girl with a left cervical vascular lesion. Image exams were performed, and the lesion slowly decreased, leaving redundant skin. Considering all of the findings, a final diagnosis of a rapidly involuting congenital hemangiomas was suspected.

Rapidly involuting congenital hemangioma.

Rapidly involuting congenital hemangioma is a rare vascular tumor that generally has a good prognosis. The authors describe a case of a newborn girl with a left cervical vascular lesion. Image exams were performed, and the lesion slowly decreased, leaving redundant skin. Considering all of the findings, a final diagnosis of a rapidly involuting congenital hemangiomas was suspected.

GNA14 Somatic Mutation Causes Congenital and Sporadic Vascular Tumors by MAPK Activation.

Vascular tumors are among the most common neoplasms in infants and children; 5%-10% of newborns present with or develop lesions within the first 3 months of life. Most are benign infantile hemangiomas that typically regress by 5 years of age; other vascular tumors include congenital tufted angiomas (TAs), kaposiform hemangioendotheliomas (KHEs), and childhood lobular capillary hemangiomas (LCHs). Some of these lesions can become locally invasive and unresponsive to pharmacologic intervention, leading to significant complications. Recent investigation has revealed that activating mutations in HRAS, KRAS, NRAS, GNAQ, and GNA11 can cause certain types of rare childhood vascular tumors, and we have now identified causal recurrent somatic activating mutations in GNA14 by whole-exome and targeted sequencing. We found somatic activating GNA14 c.614A>T (p.Gln205Leu) mutations in one KHE, one TA, and one LCH and a GNA11 c.547C>T (p.Arg183Cys) mutation in two LCH lesions. We examined mutation pathobiology via expression of mutant GNA14 or GNA11 in primary human endothelial cells and melanocytes. GNA14 and GNA11 mutations induced changes in cellular morphology and rendered cells growth-factor independent by upregulating the MAPK pathway. Our findings identify GNA14 mutations as a cause of childhood vascular tumors, offer insight into mechanisms of oncogenic transformation by mutations affecting Gaq family members, and identify potential targets for therapeutic intervention.

[Congenital hemangiomas: Report on ten patients]. / Hémangiomes congénitaux : à propos de dix cas.

INTRODUCTION: Congenital hemangiomas (CHs) are rare congenital vascular tumors seldom mentioned in the literature. MATERIALS AND METHODS: We carried out a retrospective study of all the cases of CH diagnosed and treated at Besançon Hospital from 2008 to 2014. The clinical, radiological, and histological data of each case were collected. All the children were seen again in 2014. RESULTS: Ten CHs (seven rapidly involuting CHs, RICH and three non-involuting CH, NICH), predominantly full-term eutrophic male infants, were enrolled. RICHs were located on the head (n=2), trunk (n=2), and lower limbs (n=3), and NICHs were found on the hands. Diagnosis was clinical for all ten infants. All CHs resembled "tumor" congenital lesions: single, oval-shaped, nonpulsatile, and well delimited, and their size did not increase after birth. Two RICHs were warm, one had phlebolites, and two had draining veins at the first visit. The mean age of the RICH involution onset was 1.7 months and the mean time to complete involution was 10.4 months. One CH was classified as a PICH (partially involuting CH) due to partial regression, two RICHs were still in the involution process at the age of 10 and 15 months, and one regressed very quickly within 7 days. No complications were observed in the NICH. Two RICHs presented benign complications (ulcerations and bleeding). Two RICHs regressed entirely, and five regressed with sequelae: lipoatrophy (n=3), cutaneous excess (n=2), dysplastic veins (n=3), a pigmented area (n=1), and an anemic halo (n=2). DISCUSSION: The small number of patients in our cohort, in spite of the length of the study, confirms the rarity of CH. The sex-ratio in favor of male infants and the location of NICH on the hands have not been reported. The most discriminating element remained the follow-up over 1 year. The initial clinical aspect of the NICH and the progression of one RICH into a NICH suggested possible overlapping forms between RICH and NICH. Some CHs, including one PICH, presented clinical and radiological criteria similar to those of vascular malformations (warm lesion, dysplastic veins, and echo-Doppler results in favor of vascular malformation). RICH regressed with sequelae in most cases. CONCLUSION: This study reveals a polymorphous clinical presentation of CH and provides a thorough description of their progression. It underlines the existence of overlapping phenomena between RICH and NICH, and between CH and vascular malformations, thus suggesting a possible link between proliferation and malformation phenomena at the origin of these lesions.

Mosaicismo tipo 2 en glomangiomatosis familiar / Type 2 Mosaicism in Familial Glomangiomatosis

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Rapidly involuting congenital hemangioma with pustules: two cases.

Rapidly involuting congenital hemangiomas (RICHs) are rare tumors that usually present as well-defined bluish or violaceous plaques or tumors with scattered telangiectasias and central or peripheral pallor. We report two previously unreported cases of RICH with associated pustules.

Rapidly involuting congenital hemangioma associated with profound, transient thrombocytopenia.

Rapidly involuting congenital hemangioma (RICH) is an uncommon, often high-flow vascular tumor that presents at birth and involutes within the first year of life. It is clinically and histologically distinct from infantile hemangioma, kaposiform hemangioendothelioma, and tufted angioma, the latter two being associated with Kasabach-Merritt phenomenon. We present a female infant with RICH and profound, transient thrombocytopenia and review the extent and clinical course of thrombocytopenia in the context of congenital vascular tumors.

Non-involuting congenital haemangioma of the eyelid: successful treatment with fluroscopic ultrasound guided sclerotherapy and surgical excision.

We present a case of non-involuting congenital haemangioma (NICH) of the right eyelid which was present at birth as a purpuric macule but increased in size to cause significant obstruction of vision. At four years of age the lesion was treated with fluroscopic ultrasound-guided sclerotherapy using 0.5% sodium tetradecyl suphate foam and surgically debulked 16 days later. Histopathology was negative for glucose transporter-1 stain confirming the diagnosis. The residual segments were subsequently treated in three further sessions of sclerotherapy in the ensuing three years. This treatment approach resulted in a good cosmetic and functional outcome with no associated complications. To our knowledge, this is the first published case of a histologically confirmed NICH treated primarily with sclerotherapy.

Masson tumor arising in a congenital vascular anomaly.

Congenital and infantile Masson's tumors are rare. We report a case of Masson's tumors arising within a congenital vascular mass in an otherwise healthy infant. The diagnosis was made following surgical excision and supported by histologic staining. There has been no recurrence of the lesions to date.

[Glomangiomatosis on the hand. A case report]. / Glomangiomatose der Hand. Ein Fallbericht.

Glomus tumours are solitary benign lesions most frequently located subungually on fingers and toes. In the rare case of a glomangiomatosis, the typical glomus cells are found on the altered vessel wall of the angiomatosis. Due to the rarity of this disease, no therapeutic golden standard has been mentioned in the literature, and a conservative treatment is usually adopted. The case of a 20-year-old craftsman with congenital, painful glomangiomatosis on his left dominant hand, progressively limiting the functionality of this limb, is reported. Two years after unsuccessful partial tumour resection, a surgical treatment based on radical tumour resection in terms of a finger amputation was performed. The 1-year follow-up showed no signs of pain for the patient.

Uncommon benign infantile vascular tumors.

Significant progress in the diagnosis of infantile vascular tumors has been achieved during the past 2 decades because of improvements in the recognition of clinical characteristics, radiologic features, and histopathologic analysis, as well as the discovery of important immunophenotypic markers such as GLUT-1. These recent advances make it possible to define more clearly the distinct clinical entities with their variable prognoses and to improve the management of lesions that, although histologically benign, infrequently may be lethal because of their invasive potential.

[Congenital vascular leiomyosarcoma]. / Léiomyosarcome vasculaire congénital.

INTRODUCTION: Vascular leiomyosarcoma is a conjunctive tumor which develops in the smooth muscle cells of vessel walls. Proximal vascular leiomyosarcoma involving the large vessels and peripheral vascular leiomyosarcoma which develops in the vascular pedicles of the limbs and subcutaneous vessels are distinguished. OBSERVATION: We report the case of a 6-year-old child who presented from birth a peripheral vascular leiomyosarcoma. The immunohistochimic study revealed tumor cell expression vimentin, SMA and desmine. In spite of wide surgical resection with associated chemotherapy, the child's clinical status deteriorated. DISCUSSION: Vascular leiomyosarcoma is a rare tumor occurring exceptionally in children. Prognosis depends on the presence of local recurrence and metastatic spread.

[The impact of Glut-1 marker application on the diagnosis and treatment of congenital vascular anomalies]. / Impacto de la aplicación del marcador GLUT-1 en el diagnóstico y tratamiento de las anomalías vasculares congénitas.

Hemangiomas of infancy have a unique vascular phenotype demonstrated by glucose transporter 1 (GLUT-1) staining marker. Since its first description by P. E. North in 2000 its use has become widely spread by clinicians and researchers in the field of vascular anomalies. We prospectively and retrospectively used GLUT-1 marker on 90 patients divided in five groups over a two years period. Grupo I: Hemangiomas under 1 year of age. Grupo II: Hemangiomas between 1 and 15 years of age. Grupo III: Misdiagnosed angiomas in patients older than 15 years. Grupo IV: Patients with low and high flow vascular malformations Grupo V: Vascular tumors other than hemangiomas. As a result of the study, significant improvement has been noticed by the authors in appropiate vascular anomalies classification by primary care physicians involved in the study. Angioma is not anymore synonym of vascular birthmark. In addition the management of the newborn with a vascular tumour benefit from a more appropriate antiangiogenic therapy. Patients with RICH (rapidly involuting congenital hemangioma) or NICH (non involuting congenital hemangioma) pattern after biopsy and inmunohistochemical study did not receive any pharmacological agent as a part of their treatment. Finally GLUT-1 helped multidisciplinary vascular anomalies team development by promoting clinical, radiological and histopathologic correlations between different specialists.

Congenital hemangiomas and infantile hemangioma: missing links.

Rapid postnatal growth and slow involution in childhood characterize the common infantile hemangioma. There are other rare vascular tumors that present fully grown at birth and behave quite differently, as designated by the acronyms: rapidly involuting congenital hemangioma (RICH) and noninvoluting congenital hemangioma (NICH). RICH and NICH have similarities in appearance, location, size, equal sex ratio, and both have overlapping radiologic and histologic features with infantile hemangioma. However, neither type of congenital tumor immunostains for glucose transporter-1 protein, a marker of infantile hemangioma. This raises the question of whether these congenital vascular lesions are variations in a spectrum of hemangioma or are entirely different tumors. We describe two groups of patients that suggest a linkage between postnatal and congenital vascular tumors: Link I (n=5), children who had either RICH or NICH coexisting with infantile hemangioma, and Link II (n=10), children initially diagnosed as having RICH, but regression was incomplete and the residuum was that of NICH. We conclude that these infants exhibit "missing links" between the rare RICH and NICH, and the common infantile hemangioma.