Pulmonary Infantile Hemangioma: Clinical and Histopathological Review of Eight Cases

Abstract Introduction Infantile hemangioma (IH) is the most common benign vascular tumor of childhood. It typically appears as a single cutaneous mass in the head, neck, and trunk area. IH that does not arise in the skin most commonly presents in the liver. The lesion emerges shortly after birth, rapidly enlarges within the first six months of life, and then spontaneously involutes by 5-10 years of age. Risk factors associated with IH complications include lesional size, location, and growth characteristics. Pulmonary IH is rare with limited reports of clinical presentations and outcomes. Methods An IRB-approved, retrospective review of pediatric patients with a diagnosis of pulmonary IH was conducted. Cases were identified within the Department of Pathology at Boston Children's Hospital from surgical or autoptic specimens evaluated between 1918 and 2021. Analysis of histopathological slides confirmed pulmonary IH in eight infants. We describe the diagnostic workup, radiological, and histopathological findings of these eight patients. Results All patients presented with symptoms of respiratory distress, including tachypnea, subcostal retractions, and hypoxia. The median age at initial symptoms was 1.5 months (range, birth to 12 months). Five patients had a single pulmonary hemangioma ranging in size from 0.2 to 8.0 cm; three patients had multiple pulmonary hemangiomas. Four patients had co-occurrence of multifocal hepatic IH. The median age at histologic diagnosis of pulmonary IH was 6.5 months (range, 5 weeks to 16 months). Glucose transporter-1 (GLUT-1) immunostaining was positive in seven cases. Chest radiography demonstrated nonhomogeneous, mass-like consolidative opacities or rounded nodules. Treatment was primarily supportive. Three patients received medical therapy; two were treated with interferon, and one received propranolol. The infant treated with propranolol responded well with decreased lesional size and resolution of respiratory symptoms. Half of the patients in the cohort died; causes of death included cardiac failure from hepatic involvement, sepsis, hemorrhage, and liver failure. Conclusions Although IH is a common childhood tumor, IH of the lung is rare. Most (80%) IHs are focal, with hepatic co-involvement in 50-60% cases (Zavras et al. Eur J Pediatr, 2020; Hinen et al. Front Pediatr, 2020). Given that all patients who had concomitant hepatic hemangiomas died-albeit before the widespread availability of medical therapy-the presence of hepatic hemangiomas may confer high risk of complications. Patients with hepatic hemangiomas presented with pulmonary symptoms. Biopsy may be necessary to confirm the diagnosis of pulmonary IH and inform treatment. In this series, only treatment with propranolol or surgical resection was curative. Pulmonary IH should be considered in the differential diagnosis of infants with unexplained pulmonary masses, especially when accompanied by hepatic IH. Early recognition is critical for patients to receive proper and potentially life-saving treatment. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Pulmonary Infantile Hemangioma Mimicking a Congenital Cystic Adenomatoid Malformation

Pediatric and Developmental Pathology ◽

10.1177/1093526619838743 ◽

2019 ◽

Vol 22 (5) ◽

pp. 480-485 ◽

Cited By ~ 1

Author(s):

Coralie Dauge ◽

Tanguy Fenouil ◽

Thierry Petit ◽

Corinne Jeanne-Pasquier ◽

Sophie Collardeau-Frachon

Keyword(s):

Glucose Transporter ◽

Beta Blockers ◽

Infantile Hemangioma ◽

Vascular Tumor ◽

Cystic Mass ◽

Congenital Cystic Adenomatoid Malformation ◽

Glucose Transporter 1 ◽

Glut 1 ◽

Renal Malformations ◽

Rare Lesion

Infantile hemangioma (IH) is the most common benign vascular tumor of infancy, occurring predominantly in the head and neck. It is characterized by specific endothelial expression of glucose transporter-1 (GLUT-1) and involution with time, spontaneous or on beta-blockers treatment. Although some predisposing factors are known, the exact pathogenesis remains unclear. We report a case of pulmonary IH GLUT-1 positive, initially suspected as a cystic pulmonary airway malformation, in a child presenting with both cardiac and renal malformations. The clinical, radiological, pathological, and genetics findings are discussed with a review of the literature. Although pulmonary IH is a rare lesion, it should be suspected when facing a pulmonary cystic mass in a child.

Download Full-text

Neonatal Abdominal Hemangiomatosis: Propranolol beyond Infantile Hemangioma

Case Reports in Pediatrics ◽

10.1155/2016/9803975 ◽

2016 ◽

Vol 2016 ◽

pp. 1-4 ◽

Cited By ~ 1

Author(s):

Siu Ying Angel Nip ◽

Kam Lun Hon ◽

Wing Kwan Alex Leung ◽

Alexander K. C. Leung ◽

Paul C. L. Choi

Keyword(s):

Cardiac Failure ◽

Rare Case ◽

Male Infant ◽

Infantile Hemangioma ◽

Vascular Tumor ◽

Life Threatening ◽

Cutaneous Hemangioma ◽

Benign Course ◽

Hepatic Hemangiomas ◽

High Output

Hemangioma is the most common vascular tumor of infancy; presentation is often as cutaneous infantile hemangioma (IH). Cutaneous hemangioma is a clinical diagnosis. Most IHs follow a benign course, with complete involution without treatment in the majority of cases. Visceral hemangioma often involves the liver and manifests as a life-threatening disorder. Hepatic hemangiomas may be associated with high output cardiac failure, coagulopathy, and hepatomegaly which generally develop between 1 and 16 weeks of age. Mortality has been reportedly high without treatment. We report a rare case of a male infant with neonatal hemangiomatosis with diffuse peritoneal involvement, which mimicked a malignant-looking tumor on imaging, and discuss therapeutic options and efficacy. Propranolol is efficacious for IH but generally not useful for other forms of vascular hemangiomas, tumors, and malformations. In our case of neonatal peritoneal hemangiomatosis, propranolol appears to have halted the growth and possibly expedite the involution of the hemangiomatosis without other treatments.

Download Full-text

Reduced Chemosensitivity of FLT3/ITD Mutated Cells to Cytarabine and Quizartinib Under Hypoxic Conditions

Blood ◽

10.1182/blood.v128.22.1579.1579 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1579-1579

Author(s):

Heiko Konig ◽

Adriana L Rogozea ◽

Garrett H Kinnebrew ◽

Mircea Ivan

Keyword(s):

Drug Resistance ◽

Growth Inhibition ◽

Oxygen Tension ◽

Glucose Transporter ◽

Conflicts Of Interest ◽

Unmet Need ◽

Leukemic Cells ◽

Primary Cells ◽

Glucose Transporter 1 ◽

Hypoxic Conditions

Abstract Background: FLT3/ITD mutated AML is characterized by short remission duration and high relapse rates due to the survival of a small fraction of leukemic cells (LCs) that outlive initial therapy. There is compelling evidence that the hypoxic niche in the bone marrow (BM) provides a sanctuary where subpopulations of LCs evade cytotoxic therapy and acquire drug resistance. In order to define the mechanisms involved in this process, multiple studies have focused on the interactions between LCs and the BM microenvironment but less is known about to the role of hypoxia as a modulator of drug resistance. Hence, the effects of standard and investigational therapies under hypoxic conditions are largely unknown. Here, we investigated the cytotoxic response of FLT3/ITD-mutated cells to conventional and targeted therapy under normoxic (21% O2) and hypoxic (1% O2) conditions. Methods: Molm14 (M14) cells and primary cells from relapsed/refractory FLT3/ITD mutated AML patients were incubated in culture medium under normoxic and hypoxic conditions. Cytarabine (Cy) or Quizartinib (Quiz) were added as single agents at the indicated concentrations. After 48 hours proliferation and apoptosis assays were performed using MTT assays, annexin V/PI staining and FACS analysis (M14). Cells were also assessed for FLT3 protein and Hypoxia inducible factor (HIF) target gene expression by western blotting and PCR arrays (RT2 ProfilerTM PCR Array, Human Hypoxia Signaling Pathway Plus, Qiagen) (M14 and primary cells), respectively. Results: We found that M14 cells were significantly less susceptible to treatment under hypoxic conditions, both when exposed to Cy and targeted FLT3 inhibition with Quiz (Growth inhibition, 0.25nM Quiz: 8.5±4.2% (1% O2) vs. 22±2.5% (21% O2), p<.05; 49.6±2.5% (1% O2) vs. 58.1±2.3% (21% O2), n=8, p<.05; 0.25µM Cy: 3.7±2.5% (1% O2) vs. 14.4±1.5% (21% O2), p<.01; 1 µM Cy: 26.3±4.1% (1% O2) vs. 53.3±3.8% (21% O2), n=10-12, p<.001). In line with these findings, the apoptotic response of M14 cells to Cy treatment was significantly blunted under hypoxic conditions (Fold increase in apoptotic cells vs. untreated control, 1 µM: 5.7±0.8 fold [21% O2] vs. 2.7±0.5 fold [1% O2], n=4, p<.05). While not reaching the significance threshold, the trend was similar for the Quiz-treated cells. This effect was extended to primary, relapsed/refractory FLT3/ITD-mutated cells derived from patients (n=2) treated at our institution, where growth inhibition was consistently decreased in hypoxia at all doses of Cy and Quiz tested. Not unexpectedly, these primary cells required significantly higher doses compared to the established M14 cell line (1-10µM for Cy, and 50-200nM for Quiz). Importantly, Quiz appeared to be similarly effective in inactivating FLT3 activity under low and high oxygen tension. Therefore identifying tractable pro-survival genes induced by the low oxygen microenvironment should represent a viable strategy to increase the effectiveness of anti-leukemic agents. In order to identify such target candidates, we surveyed the effects of Quiz and Cy on a panel of 84 hypoxia-regulated genes using PCR arrays. Our preliminary studies revealed that while HIF pathway remains largely functional in the presence of Quiz or Cy, these agents severely blunt induction of several hypoxia genes (including Glucose transporter 1 [Glut1] and Carbonic Anhydrase 9 [CA9]) in both primary cells and M14 cells. Conclusions: 1.Hypoxia limits the cytotoxic effects of conventional and targeted therapeutic agents in primary and established FLT3/ITD mutated AML cells. 2. Quizartinib effectively abrogates FLT3 signaling under both normoxic and hypoxic conditions, indicating that other signaling pathways are critical for leukemic cell survival under reduced oxygen tension. 3. The induction of several potentially druggable HIF targets is disrupted by anti-AML agents, warranting the further investigation of combinational approaches between standard anti-AML agents and HIF targeted strategies. 4. Such therapeutic combinations are likely to be particularly effective undermicro-environmental stress conditions (e.g. severe hypoxia) thus addressing an unmet need in AML therapy. Disclosures No relevant conflicts of interest to declare.

Download Full-text

The Tibetan PHD2 Polymorphism Asp4Glu Is Associated with Hypersensitivity of Erythroid Progenitors to EPO and Upregulation of HIF-1 Regulated Genes Hexokinase (HK1) and Glucose Transporter 1 (SLC2A/GLUT1),

Blood ◽

10.1182/blood.v118.21.3388.3388 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3388-3388 ◽

Cited By ~ 2

Author(s):

Felipe R Lorenzo ◽

Sabina Swierczek ◽

Chad Daniel Huff ◽

Josef T. Prchal

Keyword(s):

High Altitude ◽

Glucose Transporter ◽

Conflicts Of Interest ◽

Negative Regulator ◽

Molecular Defect ◽

Mrna Levels ◽

Erythroid Progenitors ◽

Glucose Transporter 1 ◽

Exon 1 ◽

Functional Consequences

Abstract Abstract 3388 The hypoxic response, mediated by hypoxia inducible transcription factors (HIFs), is central to the control and development of many essential biological functions, including erythropoiesis. As a high-altitude population, many Tibetans have developed a remarkable ability to protect against several hypoxic complications, including polycythemia and other harmful responses exhibited by non-adapted populations upon exposure to severe hypoxia. We have identified 10 genes involved in high-altitude adaptation in Tibetans, including a principal negative regulator of HIF-1a and HIF-2 a peptides, i.e. PHD2 (EGLN1), as well as HIF2A (EPAS1) (Simonson, Science 2010). At this meeting last year (Lorenzo, Abstract# 2602 ASH 2010), we reported a novel PHD2 Asp4Glu mutation that we found in 57 of 94 Tibetan, 2 of 88 Asian and 0 of 38 Caucasian chromosomes. In most Tibetan samples, this variant is associated with a previously reported, unvalidated PHD2 polymorphism, Cys127Ser (found in 70 of 94 Tibetan, 27 of 88 Asian and 4 of 38 Caucasian chromosomes). To study the functional consequences of this PHD2 Asp4Glu mutation, we recruited five Tibetan volunteers living in Utah, four of whom were homozygous and 1 heterozygous for PHD2 Asp4Glu and Cys127Ser. We unexpectedly found that homozygotes for the exon 1 PHD2 mutation had markedly hypersensitive erythroid BFU-E (Fig.1) compared to the range of normal controls we have standardized over several decades. Interestingly, erythroid progenitors from individuals with Chuvash polycythemia or a HIF-2a gain-of-function mutation also have hypersensitive BFU-E. To determine if the Tibetan erythroid hypersensitivity data may be explained by increased HIF activity, we have quantified HIF target gene expression in subject granulocytes and found a significant increase in hexokinase (HK1) and glucose transporter (GLUT1/SLC2A) mRNA levels. These data report the first molecular defect with functional consequences that is associated with the complex Tibetan adaptation to extreme hypoxia. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Rapidly Involuting Congenital Hemangioma: Clinical and Histopathologic Features

Pediatric and Developmental Pathology ◽

10.1007/s10024-003-2134-6 ◽

2003 ◽

Vol 6 (6) ◽

pp. 495-510 ◽

Cited By ~ 227

Author(s):

Beatriz Berenguer ◽

John B. Mulliken ◽

Odile Enjolras ◽

Lawrence M. Boon ◽

Michel Wassef ◽

...

Keyword(s):

Endothelial Cells ◽

Glucose Transporter ◽

Fibrous Tissue ◽

Cyst Formation ◽

Infantile Hemangioma ◽

Vascular Tumors ◽

Glucose Transporter 1 ◽

Pathologic Features ◽

Congenital Hemangioma ◽

Rapidly Involuting Congenital Hemangioma

We define the histopathologic findings and review the clinical and radiologic characteristics of rapidly involuting congenital hemangioma (RICH). The features of RICH are compared to the equally uncommon noninvoluting congenital hemangioma (NICH) and common infantile hemangioma. RICH and NICH had many similarities, such as appearance, location, size, and sex distribution. The obvious differences in behavior served to differentiate RICH, NICH, and common infantile hemangioma. Magnetic resonance imaging (MRI) of the three tumors is quite similar, but some RICH also had areas of inhomogeneity and larger flow voids on MRI and arterial aneurysms on angiography. The histologic appearance of RICH differed from NICH and common infantile hemangioma, but some overlap was noted among the three lesions. RICH was composed of small-to-large lobules of capillaries with moderately plump endothelial cells and pericytes; the lobules were surrounded by abundant fibrous tissue. One-half of the specimens had a central involuting zone(s) characterized by lobular loss, fibrous tissue, and draining channels that were often large and abnormal. Ancillary features commonly found were hemosiderin, thrombosis, cyst formation, focal calcification, and extramedullary hematopoiesis. With one exception, endothelial cells in RICH (as in NICH) did not express glucose transporter-1 protein, as does common infantile hemangioma. One RICH exhibited 50% postnatal involution during the 1st year, stopped regressing, was resected at 18 months, and was histologically indistinguishable from NICH. In addition, several RICH, resected in early infancy, also had some histologic features suggestive of NICH. Furthermore, NICH removed early (2–4 years), showed some histologic findings of RICH or were indistinguishable from RICH. We conclude that RICH, NICH, and common infantile hemangioma have overlapping clinical and pathologic features. These observations support the hypothesis that these vascular tumors may be variations of a single entity ab initio. It is unknown whether the progenitor cell for these uncommon congenital vascular tumors is the same as for common infantile hemangioma.

Download Full-text

Early orbital infantile hemangioma that emphasizes the importance of glucose-transporter-1 (GLUT-1)

Canadian Journal of Ophthalmology ◽

10.1016/j.jcjo.2017.07.003 ◽

2018 ◽

Vol 53 (2) ◽

pp. e58-e60 ◽

Cited By ~ 2

Author(s):

Joshua R. Ford ◽

Joaquín Gonzalez-Barlatay ◽

Alejandra A. Valenzuela

Keyword(s):

Glucose Transporter ◽

Infantile Hemangioma ◽

Glucose Transporter 1 ◽

Glut 1

Download Full-text

Erythrocyte Dematin Regulates Glucose Transport Via Akt Phosphorylation and 14-3-3zeta Association.

Blood ◽

10.1182/blood.v114.22.1990.1990 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1990-1990

Author(s):

Morvarid Mohseni ◽

Anwar Khan ◽

Athar H. Chishti

Keyword(s):

Plasma Membrane ◽

Protein Kinase ◽

Glucose Transport ◽

Cell Biology ◽

Glucose Transporter ◽

Conflicts Of Interest ◽

Adaptor Protein ◽

Degradation Pathway ◽

Actin Binding ◽

Glucose Transporter 1

Abstract Abstract 1990 Poster Board I-1012 Erythrocyte dematin is a widely expressed actin-binding and bundling protein, and functions as a suppressor of RhoA signaling in fibroblasts (Mohseni and Chishti, Molecular Cell Biology 28: 4712-4718, 2008). Dematin is a substrate of multiple protein kinases, and its actin bundling activity is regulated by cAMP dependent protein kinase. Recently, we identified a novel interaction between dematin and glucose transporter-1 (GLUT1) that is critically important for erythrocyte shape and membrane mechanical properties (Khan et al., Journal of Biological Chemistry 283:14600-14609, 2008). Since homologues of dematin and GLUT1 exist in many non-erythroid cells, we proposed that a conserved mechanism might couple related sugar transporters, such as the insulin-responsive glucose transporter-4 (GLUT4), to the actin cytoskeleton via dematin. Immunocytochemistry established the presence of dematin in 3T3-L1 adipocytes, and a small pool of dematin and GLUT4-containing vesicles co-localized in 3T3-L1 cells under both basal and insulin-stimulated conditions. Plasma membrane sheet assays indicate that upon insulin stimulation, dematin translocates to the plasma membrane along with GLUT4, resulting in partial co-localization at the plasma membrane. Furthermore, dematin RNAi treated 3T3-L1 cells show reduced GLUT4 protein expression, suggesting that dematin may regulate a sub-population of GLUT4 via the lysosomal degradation pathway in adipocytes. Importantly, glucose transport was reduced by ∼28% in 3T3-L1 adipocytes depleted of dematin, and by ∼15% in the dematin headpiece knockout (HPKO) mouse primary adipocytes. Since a significant amount of dematin did not co-localize with GLUT4 in the cytosol and plasma membrane, biochemical interaction between dematin and GLUT4 could not be verified using immunoprecipitation and transfection assays. Although dematin does not bind directly to GLUT4 under these conditions, a possibility existed that this interaction may be transient and mediated through an adaptor protein. Interestingly, dematin contains seven 14-3-3 binding sites, and 14-3-3 adaptor has been shown to be functionally involved in GLUT4 trafficking. We demonstrate that phosphorylated dematin binds to 14-3-3 in 3T3-L1 adipocytes under both basal and insulin stimulated conditions. Mutagenesis studies identify serine-85 on dematin as the primary phospho-binding site for 14-3-3zeta. Furthermore, using pharmacological inhibitors, Akt is identified as the likely protein kinase that phosphorylates dematin to mediate the biochemical interactions between dematin and 14-3-3zeta. Together, our results identify erythrocyte dematin as a potential regulator of glucose transporter trafficking and degradation pathways in adipocytes with functional implications for glucose homeostasis, diabetes, and obesity. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Verrucous venous malformations of the hand

Journal of Hand Surgery (European Volume) ◽

10.1177/1753193419845271 ◽

2019 ◽

Vol 44 (8) ◽

pp. 850-855

Author(s):

Usha E.A. Beijnen ◽

Francesca Saldanha ◽

Ingrid Ganske ◽

Joseph Upton ◽

Amir H. Taghinia

Keyword(s):

Glucose Transporter ◽

Early Recognition ◽

Venous Malformation ◽

Vascular Anomaly ◽

Vascular Lesions ◽

Venous Malformations ◽

Level Of Evidence ◽

Glucose Transporter 1 ◽

Ablative Techniques ◽

Disease Free

Verrucous venous malformation is a rare vascular anomaly that presents as a deep purple skin stain and evolves into a larger scaly, keratotic lesion that can bleed and cause pain. Because of its similarity to other vascular lesions, it is often misdiagnosed and treated incorrectly. Ten patients with hand verrucous venous malformations evaluated between 1990 and 2017 were reviewed. Diagnosis was confirmed with histopathology. Six patients were initially misdiagnosed and two patients were incorrectly treated. Eight patients had excision procedures. Immunostaining for glucose transporter 1 protein was positive in all specimens that underwent staining. Most (three of four) of the patients with isolated small lesions remained disease free postoperatively, but those with larger lesions experienced recurrence or continued growth. Early recognition of verrucous venous malformation is important because nonsurgical ablative techniques are ineffective; the optimal treatment is surgery. Level of evidence: IV

Download Full-text

Solitary Pulmonary Infantile Hemangioma in an Infant with Atrial Septal Defect

Pediatric and Developmental Pathology ◽

10.2350/07-03-0249.1 ◽

2008 ◽

Vol 11 (6) ◽

pp. 465-468 ◽

Cited By ~ 2

Author(s):

Zsombor Melegh ◽

Yatin Patel ◽

Pramila Ramani

Keyword(s):

Atrial Septal Defect ◽

Glucose Transporter ◽

Septal Defect ◽

Infantile Hemangioma ◽

Lung Lesion ◽

Imaging Studies ◽

Glucose Transporter 1 ◽

Infancy And Childhood ◽

Right Ventricular Dilatation ◽

Parenchymal Lung

Pulmonary infantile hemangiomas are extremely rare in infancy and childhood. We describe a case of a 22-month-old infant who presented with repeated chest infections. Imaging studies revealed a solitary parenchymal lung lesion in the left upper lobe, an atrial septal defect, and mild right ventricular dilatation. Various investigations failed to delineate the precise nature of the lung lesion and it was resected. Histological examination of the lung lesion showed an infantile hemangioma, which expressed glucose transporter-1 protein, GLUT-1, a marker of infantile hemangiomas. This case represents a unique coexistence of 2 lesions, both of which resulted in right-sided overload, contributed to mainly by the atrial septal defect causing increased volume and, to a lesser extent, by the pulmonary hemangioma resulting in increased pressure. This case also emphasizes the fact that infantile hemangioma, although rare, should be considered as a differential diagnosis of solitary lung lesions.

Download Full-text