Congenital hepatic hemangiomas: Clinical, histologic, and genetic correlation.

BACKGROUND: The guide for monitoring and treatment of congenital hepatic hemangiomas (CHH) will depend on the subtype and the postnatal clinical behavior. Our aim is to present a series of CHH and characterize its clinical, histologic and genetic correlation, compared to cutaneous congenital hemangiomas (CCH). MATERIAL AND METHODS: A retrospective review of CHH patients diagnosed between 1991 and 2018 was performed. Clinical, morphological and histological data were analyzed and deep high-throughput sequencing was performed. MAIN RESULTS: Sixteen patients with CHH were included. Five patients were followed up with serial ultrasounds while pharmacological treatment (corticosteroids and propranolol) was decided in five. Surgical resection was performed in five owing to hemorrhage and suspicion of malignancy, and the last patient underwent embolization. Histologic analysis was available in 7 patients and confirmed CHH, showing two different histological patterns that could be associated with the presence of somatic pathogenic variants in GNAQ and/or PIK3CA detected in the genetic testing. Review of 7 samples of CCH revealed some histologic differences compared to CHH. CONCLUSION: CHH resemble its cutaneous homonym with similar clinical behavior. Histologic analysis can differentiate two subgroups while genetic testing can confirm mutations in GNAQ and in PIK3CA in a subset of CHH. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: IV.

Constitutional mosaicism in RASA1-related capillary malformation-arteriovenous malformation.

Capillary malformation-arteriovenous malformation (CM-AVM) is caused by germline RASA1 and EPHB4 alterations. RASA1 intralesional second hits have also been reported. Here we report RASA1 constitutional mosaicism, defined here as the presence of a mosaic variant in all cell types of an individual, in two patients with CM-AVM. High-throughput sequencing was used to search for RASA1 pathogenic variants in blood samples from two unrelated patients with CM-AVM. An affected tissue sample from one of the patients was also analyzed. Both patients showed different nonsense RASA1 variants in mosaic, ranging from 7% to 21.5%, in blood samples and in the corresponding affected tissue sample from one of the patients. In conclusion, we report for the first time the presence of RASA1 constitutional mosaicism in CM-AVM. Constitutional mosaicism has implications for accurate molecular diagnosis and recurrence risk and helps to explain the great phenotypic variability in CM-AVM.

Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly.

Generalized lymphatic anomaly (GLA) is a vascular disorder characterized by diffuse or multifocal lymphatic malformations (LMs). The etiology of GLA is poorly understood. We identified four distinct somatic PIK3CA variants (Glu542Lys, Gln546Lys, His1047Arg, and His1047Leu) in tissue samples from five out of nine patients with GLA. These same PIK3CA variants occur in PIK3CA-related overgrowth spectrum and cause hyperactivation of the PI3K-AKT-mTOR pathway. We found that the mTOR inhibitor, rapamycin, prevented lymphatic hyperplasia and dysfunction in mice that expressed an active form of PIK3CA (His1047Arg) in their lymphatics. We also found that rapamycin reduced pain in patients with GLA. In conclusion, we report that somatic activating PIK3CA mutations can cause GLA, and we provide preclinical and clinical evidence to support the use of rapamycin for the treatment of this disabling and deadly disease.

Current Management of Vascular Tumors in the Neonate.

Neonatal vascular tumours present particular difficulties in their diagnosis and treatment. The special behaviour of neonatal hemangioma and the aggressive but benign nature of kaposiform hemangioendothelioma provide examples of a modern need for a conservative approach. Recent advances in their pharmacological management have dramatically changed the therapeutical scope of this group of tumors with surgery playing a minor role in their treatment. Multidisciplinary teams management involving neonatology, pediatric surgery, dermatology, pathology, genetics and radiology specialists among others remains the best option for an optimal outcome.

Chylothorax and chylous ascites: management and pitfalls.

Leakage of lymph from the lymphatic ducts causes chylothorax (CT) or chylous ascitis (CA). This may happen for unknown reasons during fetal life or after birth and may also be caused by trauma after thoracic surgery or by other conditions. Fetal CT and CA may be lethal particularly in cases with fetal hydrops that sometimes benefit of intra-uterine instrumentation. After birth, symptoms are related to the amount of accumulated fluid. Sometimes, severe cardio-respiratory compromise prompts active therapy. Most patients with CT or CA benefit from observation, rest, and supportive measures alone. Drainage of the fluid may be necessary, but then loss of protein, fat, and lymphoid cells introduce new risks and require careful replacement. Low-fat diets with MCT and parenteral nutrition decrease fluid production while allowing adequate nutritional input. If lymph leakage does not stop, secretion inhibitors like somatostatin or octreotide are prescribed, although there is only weak evidence of their benefits. Imaging of the lymphatic system is indicated when the leaks persist, but this is technically demanding in children. Shunting of the lymph from one body space to another by means of valved catheters, embolization of the thoracic duct, and/or ligation of the major lymphatics may occasionally be indicated in cases refractory to all other treatments.

Invasive lymphatic malformation (gorham-stout) of the pelvis with prominent skin involvement.

Gorham-Stout syndrome is a rare disease characterized by progressive osteolysis leading to disappearance of the bone. Vascular proliferations have been implicated in the pathogenesis of this syndrome. The case of a 7-year-old girl with a prominent invasive lymphatic malformation on the lumbosacral area and massive osteolysis of the pelvic girdle is reported.

Osteolysis and lymphatic anomalies: a review of 54 consecutive cases.

BACKGROUND: Progressive osteolysis caused by lympathic malformations is a rare condition that should be known by specialists involved in the study of lymphatic disorders because they are necessarily involved in the treatment. The purpose of the present study is to report on a large series of patients to illustrate the multiple clinical pictures and the wide range of therapeutic measures necessary for arresting bone destruction and lymphatic leak. METHODS AND RESULTS: Inclusion criteria were osteolysis associated with lymphatic malformation that required treatment. Diagnosis was based on history, plain X-rays, MRI, and demonstration of the lymphatic nature of the lesions with D2-40 immunohistochemistry. Treatment was based on resection of the bone lytic lesion or soft tissue lymphatic masses, control of chylothorax or chyloperitoneum, interferon, zoledronic acid, and radiotherapy. The study included 54 patients (25 females and 29 males) with a median age of 9 years (range 2 to 65). Eight patients had focal osteolysis without soft tissue lymphatic anomaly, 15 multifocal osteolysis without soft tissue lymphatic anomaly, 7 focal osteolysis associated with soft tissue lymphatic anomaly, and 24 multifocal osteolysis with soft tissue lymphatic anomaly. Among the wide variety of pharmacological therapies provided, only one protocol showed a consistent positive effect (end of ostelytic progression) in 17 patients who received a course of 6 to 15 months of interferon alpha-2B at 1.5 million units/m(2) body surface area/day in association with zoledronic acid at 0.05 mg/kg/month. Thirty-two patients underwent multiple surgical procedures in order to remove the soft tissue involved, correct orthopedic problems, or improve chylothorax, and three were treated with radiotherapy which was successful in one case. CONCLUSIONS: Osteolysis from lymphatic origin is a devastating surgical condition. Therapeutic options have to be considered separately if the disease is active or inactive and according to the targeted organ (skin, bone, or viscera). Total removal of the lymphatic anomaly is rarely possible, but its subtotal excision together with pharmacological antiangiogenic therapy in selected patients under surveillance of a multidisciplinary group familiarized with the disease, minimize the progression of both, lymphatic invasion, osteolysis, and their serious complications.

Macrocephaly-capillary malformation: Analysis of 13 patients and review of the diagnostic criteria.

Macrocephaly-capillary malformation (M-CM) is a genetic syndrome of unknown etiology characterized by an enlarged head circumference and patchy, reticular capillary malformation. We describe the clinical features of 13 cases, report on the genome-wide Copy Number Variation characterization of these patients, analyze the main clinical features of this syndrome and propose a modification of the current diagnostic criteria: the inclusion of both overgrowth/asymmetry and neuroimaging alterations as major criteria.

Major and minor arterial malformations in patients with cutaneous vascular abnormalities.

The association of persistent embryonic arteries and the absence of 1 carotid or vertebral arteries with facial or neck hemangioma or vascular malformation have been frequently described. The abnormalities can involve major or minor vessels. Of 22 patients of our series with this neurocutaneous syndrome, 20 had the origin of both anterior cerebral arteries from the same internal carotid artery. Thirteen patients showed absence or hypoplasia of 1 carotid artery and 10 of 1 vertebral artery; 10 showed persistence of the trigeminal artery; 3 had persistent proatlantal artery; 6 showed the absence of the posterior communicating artery; and 4 had hypoplastic posterior cerebral artery. Other less frequent abnormalities were found in 7 patients. Intellectual level of most patients was either borderline or below normal. Abnormalities in the vascularization and perfusion of the frontal lobes may contribute to the borderline or lower mental level of these patients.

The role of GLUT1 immunostaining in the diagnosis and classification of liver vascular tumors in children.

BACKGROUND/AIM: GLUT1 is an erythrocyte-type glucose transporter protein typically expressed in cutaneous proliferating hemangioma. Immunostaining for GLUT1 is becoming valuable for predicting the outcome of vascular skin tumors. Liver vascular tumors (LVTs) are a serious challenge for pediatric surgeons because of their often severe and sometimes unpredictable clinical course. To improve therapeutic strategies, we designed this study in which we tested in pathology specimens of LVT the hypothesis that GLUT1 expression could be useful to understand and classify LVT. MATERIAL AND METHODS: In the last 10 years, we treated 20 children with LVT. Pathology specimens from biopsy, excision, or autopsy were available in 11 of them. The paraffin sections were immunostained for GLUT1 and also for Ki-67 to assess the proportion of proliferating cells. Patients were divided into 2 groups: GLUT1-positive (n = 4) and GLUT1-negative (n = 7) that were compared for age at diagnosis, survival, and proportion of proliferating cells. Nonparametric and chi 2 tests were used for statistical analysis as appropriate. RESULTS: Mean age at diagnosis was higher in GLUT1-positive group, although not statistically significant in comparison with GLUT1-negative (308 +/- 515 vs 70 +/- 51 days, respectively). Three of 4 children in GLUT1-positive group died versus 1 of 7 in the GLUT1-negative group (not significant). All GLUT1-positive tumors were multicentric hemangiomata without central necrosis and only 1 with large vessels. Among GLUT1-negative tumors, 5 were solitary masses and 2 were multicentric (the value of the last 2 specimens was uncertain), 2 had central necrosis, and 2 had large vessels. Proliferation index was 18% +/- 1.42% and 1.42% +/- 0.97%, respectively, in each group ( P < .05). CONCLUSIONS: GLUT1-positive tumors have significantly higher proliferation rates than negative ones. Mortality tended to be higher in children with GLUT1-positive tumors. Positive GLUT1 immunostaining is likely specific for proliferating hemangioma, and it predicts the typical course of proliferation followed by involution.