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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="PDQ Cancer Information Summaries [Internet]" /><meta name="citation_title" content="Childhood Vascular Tumors Treatment (PDQ®)" /><meta name="citation_publisher" content="National Cancer Institute (US)" /><meta name="citation_date" content="2016/01/28" /><meta name="citation_author" content="PDQ Pediatric Treatment Editorial Board" /><meta name="citation_pmid" content="26844334" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK343452/" /><meta name="citation_keywords" content="childhood vascular neoplasm" /><meta name="citation_keywords" content="benign childhood vascular tumor" /><meta name="citation_keywords" content="childhood locally aggressive or borderline vascular tumor" /><meta name="citation_keywords" content="childhood malignant vascular tumor" /><meta name="citation_keywords" content="childhood angiosarcoma" /><meta name="citation_keywords" content="childhood epithelioid hemangioendothelioma" /><meta name="citation_keywords" content="childhood vascular neoplasm" /><meta name="citation_keywords" content="benign childhood vascular tumor" /><meta name="citation_keywords" content="childhood locally aggressive or borderline vascular tumor" /><meta name="citation_keywords" content="childhood malignant vascular tumor" /><meta name="citation_keywords" content="childhood angiosarcoma" /><meta name="citation_keywords" content="childhood epithelioid hemangioendothelioma" /><meta name="citation_keywords" content="congenital hemangioma" /><meta name="citation_keywords" content="infantile hemangioma" /><meta name="citation_keywords" content="childhood angiofibroma" /><meta name="citation_keywords" content="childhood epithelioid hemangioma" /><meta name="citation_keywords" content="childhood pyogenic granuloma" /><meta name="citation_keywords" content="childhood spindle cell hemangioma" /><meta name="citation_keywords" content="juvenile nasopharyngeal angiofibroma" /><meta name="citation_keywords" content="childhood benign vascular tumor of the liver" /><meta name="citation_keywords" content="non-involuting congenital hemangioma" /><meta name="citation_keywords" content="partially involuting congenital hemangioma" /><meta name="citation_keywords" content="rapidly involuting congenital hemangioma" /><meta name="citation_keywords" content="Kaposiform hemangioendothelioma" /><meta name="citation_keywords" content="childhood composite hemangioendothelioma" /><meta name="citation_keywords" content="childhood papillary intralymphatic angioendothelioma" /><meta name="citation_keywords" content="childhood pseudomyogenic hemangioendothelioma" /><meta name="citation_keywords" content="childhood retiform hemangioendothelioma" /><meta name="citation_keywords" content="childhood tufted angioma" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Childhood Vascular Tumors Treatment (PDQ®)" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="National Cancer Institute (US)" /><meta name="DC.Contributor" content="PDQ Pediatric Treatment Editorial Board" /><meta name="DC.Date" content="2016/01/28" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK343452/" /><meta name="description" content="Treatment options for children with vascular tumors are limited and efficacy has not been validated in prospective clinical trials. 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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/pdqcis/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-pdqcis-lrg.png" alt="Cover of PDQ Cancer Information Summaries" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>PDQ Cancer Information Summaries [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK343452_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK343452_dtls__"><div>Bethesda (MD): <a href="http://www.cancer.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Cancer Institute (US)</a>; 2002-.</div></div><div class="half_rhythm"></div><div class="bk_noprnt"><form method="get" action="/books/n/pdqcis/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK343452_"><span class="title" itemprop="name">Childhood Vascular Tumors Treatment (PDQ®)</span></h1><div class="subtitle whole_rhythm">Health Professional Version</div><p class="contrib-group"><span itemprop="author">PDQ Pediatric Treatment Editorial Board</span>.</p><p class="small">Published online: November 8, 2018.</p><p class="small">Created: <span itemprop="datePublished">January 28, 2016</span>.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p id="CDR0000774170__126">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood vascular tumors. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.</p><p id="CDR0000774170__127">This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).</p></div><div id="CDR0000774170__1"><h2 id="_CDR0000774170__1_">General Information About Childhood Vascular Tumors</h2><p id="CDR0000774170__301">Vascular anomalies are a spectrum of rare diseases classified as vascular tumors or malformations. An updated classification system was adopted at the General Assembly of the International Society for the Study of Vascular Anomalies (<a href="http://www.issva.org/classification" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ISSVA</a>, April 2014) and recently published.[<a class="bk_pop" href="#CDR0000774170_rl_1_1">1</a>] Generally, vascular tumors are proliferative, while malformations enlarge through expansion of a developmental anomaly without underlying proliferation. </p><p id="CDR0000774170__2">Growth and/or expansion of vascular anomalies can cause clinical problems such as disfigurement, chronic pain, recurrent infections, coagulopathies (thrombotic and hemorrhagic), organ dysfunction, and death. Individuals often experience progressive clinical symptoms with worsening quality of life.</p><p id="CDR0000774170__302">Limited treatment options are available; their efficacy has not been validated in prospective clinical trials. Historically, therapies have been mostly interventional and surgical to palliate symptoms. New drugs such as propranolol and sirolimus are now available for the treatment of patients with some of these complex conditions. The first prospective clinical trial using propranolol for infantile hemangioma has been published, as well as the first prospective clinical trial that studied the effectiveness of sirolimus for complicated vascular anomalies.[<a class="bk_pop" href="#CDR0000774170_rl_1_2">2</a>,<a class="bk_pop" href="#CDR0000774170_rl_1_3">3</a>]</p><p id="CDR0000774170__8">With a prevalence of 4% to 5%, infantile hemangiomas are the most common benign tumors of infancy. Other vascular tumors are rare. The classification of these tumors has been difficult, especially in the pediatric population, because of their rarity, unusual morphologic appearance, diverse clinical behavior, and the lack of independent stratification for pediatric tumors. In 2013, The World Health Organization (WHO) updated the classification of soft tissue vascular tumors. Pediatric tumors were not independently stratified and the terminology was mostly left unchanged, but the intermediate category of tumors was divided into locally aggressive and rarely metastasizing. The ISSVA classification of tumors is based on the WHO classification (refer to Tables <a class="figpopup" href="/books/NBK343452.13/table/CDR0000774170__125/?report=objectonly" target="object" rid-figpopup="figCDR0000774170125" rid-ob="figobCDR0000774170125">1</a> and <a class="figpopup" href="/books/NBK343452.13/table/CDR0000774170__142/?report=objectonly" target="object" rid-figpopup="figCDR0000774170142" rid-ob="figobCDR0000774170142">2</a>) but the ISSVA classification uses more precise terminology and phenotypes that have been agreed upon by the members of ISSVA.</p><div id="CDR0000774170__125" class="table"><h3><span class="title">Table 1. 2013 World Health Organization Classification of Vascular Tumors</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK343452.13/table/CDR0000774170__125/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000774170__125_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Category </th><th colspan="1" rowspan="1" style="vertical-align:top;">Vascular Tumor Type</th></tr></thead><tbody><tr><td colspan="1" rowspan="4" style="vertical-align:top;"><b>Benign</b></td><td colspan="1" rowspan="1" style="vertical-align:top;">Hemangioma
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Epithelioid hemangioma</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Angiomatosis</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Lymphangioma
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"><b>Intermediate (locally aggressive)</b></td><td colspan="1" rowspan="1" style="vertical-align:top;"> Kaposiform hemangioendothelioma</td></tr><tr><td colspan="1" rowspan="4" style="vertical-align:top;"><b>Intermediate (rarely metastasizing)</b></td><td colspan="1" rowspan="1" style="vertical-align:top;">Retiform hemangioendothelioma
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Papillary intralymphatic angioendothelioma</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Composite hemangioendothelioma</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Kaposi sarcoma</td></tr><tr><td colspan="1" rowspan="2" style="vertical-align:top;"><b>Malignant</b></td><td colspan="1" rowspan="1" style="vertical-align:top;">Epithelioid hemangioendothelioma
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Angiosarcoma of soft tissue
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</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Adapted from Fletcher et al.[<a class="bk_pop" href="#CDR0000774170_rl_1_4">4</a>]</p></div></dd></dl></div></div></div><div id="CDR0000774170__142" class="table"><h3><span class="title">Table 2. 2014 International Society for the Study of Vascular Anomalies (ISSVA) Classification of Vascular Tumors<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK343452.13/table/CDR0000774170__142/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000774170__142_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Category </th><th colspan="1" rowspan="1" style="vertical-align:top;">Vascular Tumor Type </th></tr></thead><tbody><tr><td colspan="1" rowspan="9" style="vertical-align:top;"><b>Benign</b></td><td colspan="1" rowspan="1" style="vertical-align:top;">Infantile hemangioma/hemangioma of infancy</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Congenital hemangioma
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">—Rapidly involuting (RICH)</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">—Non-involuting (NICH)</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">—Involuting (PICH)
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Tufted angioma
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Spindle cell hemangioma</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Pyogenic granuloma (also known as lobular capillary hemangioma)
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Others</td></tr><tr><td colspan="1" rowspan="6" style="vertical-align:top;"><b>Locally aggressive or borderline</b></td><td colspan="1" rowspan="1" style="vertical-align:top;">Kaposiform hemangioendothelioma
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Retiform hemangioendothelioma</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Papillary intralymphatic angioendothelioma (PILA), Dabska tumor</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Composite hemangioendothelioma</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Kaposi sarcoma</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Others</td></tr><tr><td colspan="1" rowspan="3" style="vertical-align:top;"><b>Malignant </b></td><td colspan="1" rowspan="1" style="vertical-align:top;">Epithelioid hemangioendothelioma
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Angiosarcoma
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Others</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Adapted from ISSVA Classification of Vascular Anomalies. ©2014 International Society for the Study of Vascular Anomalies.
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Available at "<a href="http://www.issva.org/classification" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">issva<wbr style="display:inline-block"></wbr>.org/classification</a>." Accessed January 2016.[<a class="bk_pop" href="#CDR0000774170_rl_1_5">5</a>] </p></div></dd></dl></div></div></div><p id="CDR0000774170__303">The quality of evidence regarding childhood vascular tumors is limited by retrospective data collection, small sample size, cohort selection and participation bias, and heterogeneity of the disorders.</p><div id="CDR0000774170_rl_1"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000774170_rl_1_1">Wassef M, Blei F, Adams D, et al.: Vascular Anomalies Classification: Recommendations From the International Society for the Study of Vascular Anomalies. Pediatrics 136 (1): e203-14, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/26055853" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26055853</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_1_2">Léauté-Labrèze C, Hoeger P, Mazereeuw-Hautier J, et al.: A randomized, controlled trial of oral propranolol in infantile hemangioma. N Engl J Med 372 (8): 735-46, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25693013" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25693013</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_1_3">Adams DM, Trenor CC 3rd, Hammill AM, et al.: Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies. Pediatrics 137 (2): e20153257, 2016. [<a href="/pmc/articles/PMC4732362/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4732362</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26783326" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26783326</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_1_4">Fletcher CDM, Bridge JA, Hogendoorn P, et al., eds.: WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon, France: IARC Press, 2013.</div></li><li><div class="bk_ref" id="CDR0000774170_rl_1_5">International Society for the Study of Vascular Anomalies: ISSVA Classification for Vascular Anomalies. Melbourne, Australia: International Society for the Study of Vascular Anomalies, 2014. <a href="http://issva.org/content.aspx?page_id=22&club_id=298433&module_id=152904" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed November 08, 2018.</div></li></ol></div></div><div id="CDR0000774170__3"><h2 id="_CDR0000774170__3_">Benign Tumors</h2><p id="CDR0000774170__315">Benign vascular tumors include the following:</p><ul id="CDR0000774170__316"><li class="half_rhythm"><div><a href="#CDR0000774170__9">Infantile hemangioma</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000774170__131">Congenital hemangiomas</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000774170__134">Benign vascular tumors of the liver</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000774170__43">Spindle cell hemangioma</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000774170__48">Epithelioid hemangioma</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000774170__54">Pyogenic granuloma (lobular capillary hemangioma)</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000774170__60">Angiofibroma</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000774170__65">Juvenile nasopharyngeal angiofibroma</a>.</div></li></ul><div id="CDR0000774170__9"><h3>Infantile Hemangioma</h3><div id="CDR0000774170__10"><h4>Incidence and epidemiology</h4><p id="CDR0000774170__11">Infantile hemangiomas (IH) are the most common benign vascular tumor of infancy, occurring in 4% to 5% of infants. They are not usually present at birth and are diagnosed most commonly at age 3 to 6 weeks.[<a class="bk_pop" href="#CDR0000774170_rl_3_1">1</a>-<a class="bk_pop" href="#CDR0000774170_rl_3_3">3</a>] The lesion proliferates for an average of 5 months, stabilizes, and then involutes over several years.</p><p id="CDR0000774170__304">Infantile hemangiomas are more common in females, non-Hispanic white patients, and premature infants. Multiple hemangiomas are more common in infants who are the product of multiple gestations.[<a class="bk_pop" href="#CDR0000774170_rl_3_1">1</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_4">4</a>] Infantile hemangiomas are associated with advanced maternal age and placental complications.[<a class="bk_pop" href="#CDR0000774170_rl_3_1">1</a>] </p></div><div id="CDR0000774170__34"><h4>Biology</h4><p id="CDR0000774170__35">Most infantile hemangiomas occur sporadically. However, they may rarely be caused by an abnormality of chromosome 5 and present in an autosomal dominant pattern.[<a class="bk_pop" href="#CDR0000774170_rl_3_5">5</a>] In a study that evaluated inheritance patterns of infantile hemangiomas, 34% of patients had a family history of infantile hemangioma, most commonly in a first-degree relative.[<a class="bk_pop" href="#CDR0000774170_rl_3_6">6</a>]</p><p id="CDR0000774170__254">Infantile hemangioma endothelial cells have proven to be clonal in nature.[<a class="bk_pop" href="#CDR0000774170_rl_3_7">7</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_8">8</a>] Infantile hemangioma proliferation occurs during vasculogenesis (the formation of new blood vessels from angioblasts), as opposed to angiogenesis (the formation of new blood vessels from existing blood vessels). During proliferation, provasculogenic factors are expressed, such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), CD34, CD31, CD133, LYVE-1, and insulin-like growth factor (IGF)-2.[<a class="bk_pop" href="#CDR0000774170_rl_3_9">9</a>-<a class="bk_pop" href="#CDR0000774170_rl_3_12">12</a>] In involution, infantile hemangiomas express increased apoptosis.[<a class="bk_pop" href="#CDR0000774170_rl_3_12">12</a>] During this phase, there are also increased mast cells and levels of metalloproteinase, as well as upregulation of interferon and decreased basic FGF (bFGF).[<a class="bk_pop" href="#CDR0000774170_rl_3_12">12</a>-<a class="bk_pop" href="#CDR0000774170_rl_3_14">14</a>] Throughout their development, endothelial cells in infantile hemangioma express a particular phenotype showing positive staining for glucose transporter (GLUT1). GLUT1 is also expressed on placental endothelial cells but is absent in other vascular tumors such as congenital hemangioma and vascular malformations.[<a class="bk_pop" href="#CDR0000774170_rl_3_15">15</a>]</p><p id="CDR0000774170__255">Hypoxia may have a role in the pathogenesis of hemangiomas. As described above, hemangiomas are associated with conditions related to placental hypoxia,[<a class="bk_pop" href="#CDR0000774170_rl_3_1">1</a>] and multiple targets of hypoxia [<a class="bk_pop" href="#CDR0000774170_rl_3_16">16</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_17">17</a>] are demonstrated in proliferating hemangiomas such as VEGF-A, GLUT1, and IGF-2.[<a class="bk_pop" href="#CDR0000774170_rl_3_9">9</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_11">11</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_15">15</a>] The hypotheses suggest that a proliferating hemangioma is an attempt to normalize hypoxic tissue that occurred <i>in utero</i>.</p></div><div id="CDR0000774170__12"><h4>Clinical presentation</h4><p id="CDR0000774170__13">Most infantile hemangiomas are not present at birth but precursor lesions such as telangiectasia or faint discoloration of the skin or hypopigmentation can often be seen. The lesion can be mistaken as a bruise from birth trauma or as a capillary malformation (port wine stain) (refer to <a class="figpopup" href="/books/NBK343452.13/figure/CDR0000774170__245/?report=objectonly" target="object" rid-figpopup="figCDR0000774170245" rid-ob="figobCDR0000774170245">Figure 1</a>).[<a class="bk_pop" href="#CDR0000774170_rl_3_18">18</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_19">19</a>]</p><a id="CDR0000774170__244"></a><div id="CDR0000774170__245" class="figure bk_fig"><div class="graphic"><img src="/books/NBK343452.13/bin/CDR0000787423.jpg" alt="Photos showing an infantile hemangioma premonitory mark; the photos on the left show a precursor lesion (faint color with halo). The photos on the right show a hemangioma after proliferation (slightly raised with a brighter central color)." /></div><div class="caption"><p>Figure 1. The photos on the left depict the precursor lesion (faint color with <i>halo</i>). The photos on the right depict the hemangioma after proliferation (slightly raised with a brighter central color). Credit: Israel Fernandez-Pineda, M.D.</p></div></div><p id="CDR0000774170__243">Infantile hemangiomas can be superficial in the dermis, deep in the subcutaneous tissue, combined, or in the viscera. Combined lesions are common. They are most common in the head and neck but can be anywhere on the body. They can be localized, segmental, or multiple in nature. </p><p id="CDR0000774170__290">The cutaneous appearance of infantile hemangiomas is usually red to crimson, firm, and warm in the proliferative phase. The lesion then lightens centrally and becomes less warm and softer; it then flattens and loses its color. The process of involution can take several years and once involution has occurred, regrowth is uncommon. In two patients treated with growth hormone, regrowth after involution was noted.[<a class="bk_pop" href="#CDR0000774170_rl_3_20">20</a>] On further investigation, growth hormone receptors were found on the infantile hemangioma cells. Although preliminary, this may advance the research into the etiology of hemangioma growth.</p><p id="CDR0000774170__329">Permanent sequelae, such as telangiectasia, anetodermal skin, redundant skin, and a persistent superficial component, can occur after hemangioma involution (refer to <a class="figpopup" href="/books/NBK343452.13/figure/CDR0000774170__341/?report=objectonly" target="object" rid-figpopup="figCDR0000774170341" rid-ob="figobCDR0000774170341">Figure 2</a>). In a retrospective cohort study of 184 hemangiomas, the overall incidence of significant sequelae was 54.9%. Sequelae were more common in combined hemangiomas, hemangiomas with a step or abrupt border, and cobblestone surface hemangiomas. Furthermore, this study revealed that the average age to hemangioma involution was 3.5 years.[<a class="bk_pop" href="#CDR0000774170_rl_3_21">21</a>]</p><a id="CDR0000774170__340"></a><div id="CDR0000774170__341" class="figure bk_fig"><div class="graphic"><img src="/books/NBK343452.13/bin/CDR0000791441.jpg" alt="Photographs showing different types of hemangioma sequelae, pre-progression and post-progression." /></div><div class="caption"><p>Figure 2. Examples of different types of sequelae. A, deep hemangioma that regressed without sequelae; B, superficial hemangioma that left only telangiectasia; C, mixed hemangioma that left anetodermic skin; D, mixed hemangioma that left redundant skin; and E, mixed hemangioma that left fibrofatty tissue. Reproduced with permission from JAMA Dermatology. 2016. 152 (11): 1239–1243. Copyright © (2016) American Medical Association. All rights reserved.</p></div></div></div><div id="CDR0000774170__14"><h4>Diagnostic and staging evaluation</h4><p id="CDR0000774170__15">Infantile hemangiomas are usually diagnosed by the history and clinical appearance. Biopsy is rarely needed and performed only if there is an atypical appearance and/or atypical history and presentation. Imaging is not usually necessary, but if there is a deeper lesion without a cutaneous component, ultrasound imaging is beneficial for diagnosis because it reveals a high flow lesion with a typical Doppler wave characteristic.[<a class="bk_pop" href="#CDR0000774170_rl_3_22">22</a>]</p><div id="CDR0000774170__344"><h5>Infantile hemangioma with minimal or arrested growth</h5><p id="CDR0000774170__345">Infantile hemangioma with minimal or arrested growth (IH-MAG) is a variant of hemangioma that can be confused with capillary malformation or other syndromic hemangioma, such as <a href="/books/NBK343452.13/#CDR0000774170__18">PHACE syndrome</a>, because of their unusual characteristics. These hemangiomas are mostly fully formed at birth and are characterized by telangiectasia and venules with light and dark areas of skin coloration (refer to <a class="figpopup" href="/books/NBK343452.13/figure/CDR0000774170__347/?report=objectonly" target="object" rid-figpopup="figCDR0000774170347" rid-ob="figobCDR0000774170347">Figure 3</a>). They resolve spontaneously and are pathologically GLUT1 positive.[<a class="bk_pop" href="#CDR0000774170_rl_3_23">23</a>]</p><a id="CDR0000774170__346"></a><div id="CDR0000774170__347" class="figure bk_fig"><div class="graphic"><img src="/books/NBK343452.13/bin/CDR0000791733.jpg" alt="Photographs showing (A) presentation and (B) resolution of an infantile hemangioma in patient 4 (upper left and right photos), and (C) presentation and (D) resolution of an infantile hemangioma in patient 5 (bottom left and right photos)." /></div><div class="caption"><p>Figure 3. Patient 4 at (A) presentation and (B) resolution. Patient 5 at (C) presentation and (D) resolution. Ma, E. H., Robertson, S. J., Chow, C. W., and Bekhor, P. S. (2017), Infantile Hemangioma with Minimal or Arrested Growth: Further Observations on Clinical and Histopathologic Findings of this Unique but Underrecognized Entity. Pediatr Dermatol, 34: 64–71. doi:10.1111/pde.13022. Used with permission.</p></div></div></div><div id="CDR0000774170__291"><h5>Airway infantile hemangioma</h5><p id="CDR0000774170__292">Airway infantile hemangiomas are usually associated with segmental hemangiomas in a bearded distribution, which may include all or some of the following—the preauricular skin, mandible, lower lip, chin, or anterior neck. Airway infantile hemangioma can occur without skin lesions. It is important for an otolaryngologist to proactively assess lesions in this distribution before signs of stridor occur. The incidence of an airway infantile hemangioma increases with increased area of bearded involvement.[<a class="bk_pop" href="#CDR0000774170_rl_3_24">24</a>]</p></div><div id="CDR0000774170__293"><h5>Ophthalmologic involvement of hemangiomas</h5><p id="CDR0000774170__294">Periorbital hemangiomas can cause visual compromise.[<a class="bk_pop" href="#CDR0000774170_rl_3_25">25</a>] This usually occurs with hemangiomas of the upper medial eyelid but any hemangioma around the eye that is large enough can obstruct the visual axis. The clinician should be aware of subcutaneous periocular hemangiomas, as these lesions can extend into the orbit, causing exophthalmos or globe displacement with only limited cutaneous manifestations. Issues with these lesions include astigmatism from direct pressure of the growing hemangioma, ptosis, proptosis, and strabismus. One of the leading causes of preventable blindness in children is stimulus-deprivation amblyopia caused by hemangioma obstruction. All periorbital hemangiomas or those with any possibility of potential visual impairment should have an ophthalmologic evaluation.</p><p id="CDR0000774170__350">Infantile hemangiomas can occur in the conjunctiva. These hemangiomas can be associated with other ophthalmologic abnormalities and are treated with oral or topical beta-blockers.[<a class="bk_pop" href="#CDR0000774170_rl_3_26">26</a>]</p></div></div><div id="CDR0000774170__16"><h4>Syndromes associated with infantile hemangioma</h4><p id="CDR0000774170__17">Syndromes associated with infantile hemangioma include the following:</p><ul id="CDR0000774170__18"><li class="half_rhythm"><div class="half_rhythm"><b>PHACE syndrome:</b>
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<a href="http://omim.org/entry/606519" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PHACE syndrome</a> represents a spectrum of diseases and is defined by the presence of a large segmental infantile hemangioma, usually on the face or head, in association with one or more congenital malformations (refer to <a class="figpopup" href="/books/NBK343452.13/figure/CDR0000774170__166/?report=objectonly" target="object" rid-figpopup="figCDR0000774170166" rid-ob="figobCDR0000774170166">Figure 4</a>). PHACE syndrome is more common in girls and in full-term, normal birth weight and singleton infants.[<a class="bk_pop" href="#CDR0000774170_rl_3_27">27</a>-<a class="bk_pop" href="#CDR0000774170_rl_3_32">32</a>] The syndrome is not rare among patients with infantile hemangiomas. A prospective study of 108 infants with large facial hemangiomas observed that 31% of patients had PHACE syndrome.[<a class="bk_pop" href="#CDR0000774170_rl_3_33">33</a>] </div><div class="half_rhythm"><div id="CDR0000774170__166" class="figure bk_fig"><div class="graphic"><img src="/books/NBK343452.13/bin/CDR0000779667.jpg" alt="Photograph showing a large segmental hemangioma (plaque-like) in a bearded distribution on the right side of the face." /></div><div class="caption"><p>Figure 4. A large segmental infantile hemangioma (plaque-like) in a bearded distribution. This patient has an increased risk of PHACE syndrome, airway infantile hemangioma, and ulceration. A tracheostomy was placed secondary to a very diffuse airway hemangioma. Credit: Denise Adams, M.D.</p></div></div>
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</div><div class="half_rhythm">Consensus criteria for definite and possible PHACE syndrome were developed at an expert panel meeting, as follows:[<a class="bk_pop" href="#CDR0000774170_rl_3_29">29</a>]<h5><span class="title">PHACE</span></h5><dl id="CDR0000774170__36" class="temp-labeled-list"><dt>-</dt><dd><p class="no_top_margin"><b>P</b>osterior fossa abnormalities. Anomalies include posterior fossa malformations, including Dandy-Walker complex, cerebellar hypoplasia, atrophy, and dysgenesis/agenesis of the vermis. Effects of these anomalies include developmental delays and pituitary dysfunction.[<a class="bk_pop" href="#CDR0000774170_rl_3_34">34</a>]</p></dd><dt>-</dt><dd><p class="no_top_margin"><b>H</b>emangioma. A large segmental hemangioma over the face, neck, and rarely, the chest and shoulder area.</p></dd><dt>-</dt><dd><p class="no_top_margin"><b>A</b>rterial abnormalities. Cerebrovascular anomalies can include carotid artery abnormalities and absence, dilation, or narrowing of cerebral vessels. These anomalies, especially the carotid anomalies, can lead to progressive arterial occlusion and even stroke. Other neurological issues are noted in infancy and childhood.[<a class="bk_pop" href="#CDR0000774170_rl_3_31">31</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_32">32</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_35">35</a>-<a class="bk_pop" href="#CDR0000774170_rl_3_37">37</a>]</p></dd><dt>-</dt><dd><p class="no_top_margin"><b>C</b>ardiac abnormalities. Cardiac anomalies are most commonly coarctation of the aorta (coarctation is more proximal and affects longer segments), complex aortic arch anomalies, and ventricular and atrial septal defects. </p></dd><dt>-</dt><dd><p class="no_top_margin"><b>E</b>ye abnormalities.
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Ophthalmologic anomalies can include microphthalmos, retinal vascular abnormalities, persistent fetal retinal vessels, exophthalmos, coloboma, and optic nerve atrophy. </p></dd></dl></div><div class="half_rhythm">Diagnosis of PHACE requires clinical examination, cardiac evaluation with echocardiogram, ophthalmologic evaluation, and magnetic resonance imaging (MRI)/magnetic resonance angiogram (MRA) of the head, neck, and mediastinum. Patients need to be monitored for short- and long-term effects as noted above. Other issues include speech and language delay, swallowing dysfunction, hearing loss (conductive and sensorineural), and early-onset migraines.[<a class="bk_pop" href="#CDR0000774170_rl_3_38">38</a>-<a class="bk_pop" href="#CDR0000774170_rl_3_40">40</a>]</div><div class="half_rhythm">A report of two patients with retro-orbital infantile hemangioma and arteriopathy suggested a possible new presentation of PHACE syndrome.[<a class="bk_pop" href="#CDR0000774170_rl_3_41">41</a>] For patients with proptosis, globe deviation, and strabismus, an MRI/MRA is recommended. Further workup for PHACE may be needed on the basis of central nervous system (CNS) findings.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>LUMBAR/PELVIS/SACRAL syndrome:</b> Infantile hemangiomas located over the lumbar or sacral spine may be associated with genitourinary, anorectal anomalies, or neurological issues such as tethered cord.[<a class="bk_pop" href="#CDR0000774170_rl_3_42">42</a>-<a class="bk_pop" href="#CDR0000774170_rl_3_44">44</a>] The following criteria have been used to describe segmental infantile hemangioma syndrome in the lumbar, pelvic, and sacral areas. This syndrome has been described in the literature using several acronyms.<h5><span class="title">LUMBAR</span></h5><dl id="CDR0000774170__38" class="temp-labeled-list"><dt>-</dt><dd><p class="no_top_margin"><b>L</b>ower-body hemangioma and other cutaneous defects.</p></dd><dt>-</dt><dd><p class="no_top_margin"><b>U</b>rogenital anomalies or ulceration.</p></dd><dt>-</dt><dd><p class="no_top_margin"><b>M</b>yelopathy.</p></dd><dt>-</dt><dd><p class="no_top_margin"><b>B</b>ony deformities.</p></dd><dt>-</dt><dd><p class="no_top_margin"><b>A</b>norectal malformations or arterial anomalies.</p></dd><dt>-</dt><dd><p class="no_top_margin"><b>R</b>enal anomalies.</p></dd></dl><h5><span class="title">PELVIS</span></h5><dl id="CDR0000774170__39" class="temp-labeled-list"><dt>-</dt><dd><p class="no_top_margin"><b>P</b>erineal hemangioma.</p></dd><dt>-</dt><dd><p class="no_top_margin"><b>E</b>xternal genital malformations.</p></dd><dt>-</dt><dd><p class="no_top_margin"><b>L</b>ipomyelomeningocele.</p></dd><dt>-</dt><dd><p class="no_top_margin"><b>V</b>esicorenal abnormalities.</p></dd><dt>-</dt><dd><p class="no_top_margin"><b>I</b>mperforate anus.</p></dd><dt>-</dt><dd><p class="no_top_margin"><b>S</b>kin tag.</p></dd></dl><h5><span class="title">SACRAL</span></h5><dl id="CDR0000774170__40" class="temp-labeled-list"><dt>-</dt><dd><p class="no_top_margin"><b>S</b>pinal dysraphism.</p></dd><dt>-</dt><dd><p class="no_top_margin"><b>A</b>nogenital.</p></dd><dt>-</dt><dd><p class="no_top_margin"><b>C</b>utaneous.</p></dd><dt>-</dt><dd><p class="no_top_margin"><b>R</b>enal and urologic anomalies <b>A</b>ssociated with an angioma of <b>L</b>umbosacral localization.</p></dd></dl></div><div class="half_rhythm">Segmental lesions over the gluteal cleft and lumbar spine need to be evaluated with either ultrasound or MRI, depending on the age of the patient.</div></li></ul><p id="CDR0000774170__197">Infants with more than five infantile hemangiomas need to be evaluated for visceral hemangiomas. The most common site of involvement is the liver, in which multiple or diffuse lesions can be noted.[<a class="bk_pop" href="#CDR0000774170_rl_3_45">45</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_46">46</a>] Often these lesions are asymptomatic, but in a minority of cases, symptoms such as heart failure secondary to large vessel shunts, compartment syndrome, or profound hypothyroidism can occur due to the expression of iodothyronine deiodinase.[<a class="bk_pop" href="#CDR0000774170_rl_3_47">47</a>] Multiple or diffuse liver hemangiomas can occur in the absence of skin lesions. (Refer to the <a href="#CDR0000774170__134">Benign Vascular Tumors of the Liver</a> section of this summary for more information.)
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Other rare potential complications of visceral hemangiomas, dependent on specific organ involvement, include gastrointestinal hemorrhage, obstructive jaundice, and CNS sequelae, caused by mass effects.
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</p></div><div id="CDR0000774170__19"><h4>Treatment of infantile hemangioma</h4><p id="CDR0000774170__20">Treatment options for infantile hemangioma include the following:</p><ol id="CDR0000774170__21"><li class="half_rhythm"><div><a href="#CDR0000774170__128">Propranolol therapy</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000774170__129">Other selective beta-blocker therapy</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000774170__213">Corticosteroid therapy</a>.</div></li><li class="half_rhythm"><div>Pulsed dye laser therapy. Usually used for ulcerated infantile hemangiomas and residual lesions, such as telangiectasia after the proliferative period.[<a class="bk_pop" href="#CDR0000774170_rl_3_48">48</a>] Pulsed dye laser therapy helps with pain from ulcerative infantile hemangiomas. The use of pulsed dye laser therapy as upfront treatment for infantile hemangiomas is controversial.</div></li><li class="half_rhythm"><div>Excisional surgery. With the advent of new medical treatments, the use of surgery is reserved for ulcerated lesions, residual lesions, large periocular lesions that interfere with vision, and facial lesions with aesthetic impact that do not respond to medical therapy.[<a class="bk_pop" href="#CDR0000774170_rl_3_49">49</a>]</div></li><li class="half_rhythm"><div><a href="#CDR0000774170__239">Topical beta-blocker therapy</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000774170__229">Combined therapy for complicated hemangiomas</a>.</div></li></ol><div id="CDR0000774170__128"><h5>Propranolol therapy</h5><p id="CDR0000774170__22">Propranolol, a nonselective beta-blocker, is the first-line therapy for infantile hemangiomas. Potential mechanisms of action include vasoconstriction and/or decreased expression of VEGF and bFGF, leading to apoptosis.[<a class="bk_pop" href="#CDR0000774170_rl_3_50">50</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_51">51</a>] Specific mechanisms of action are under investigation.</p><p id="CDR0000774170__23">The use of propranolol was first noted in two infants treated for cardiac issues in Europe. A change in color, softening, and decrease in hemangioma size was noted. Since that time, the results of a randomized controlled trial have been reported.[<a class="bk_pop" href="#CDR0000774170_rl_3_52">52</a>] In 2014, the U.S. Food and Drug Administration (FDA) approved the drug propranolol hydrochloride for the treatment of proliferating infantile hemangioma.</p><p id="CDR0000774170__27">There are many other published reports about the efficacy and safety of propranolol.[<a class="bk_pop" href="#CDR0000774170_rl_3_53">53</a>-<a class="bk_pop" href="#CDR0000774170_rl_3_57">57</a>] Lack of response to treatment is rare. Propranolol therapy is usually used during the proliferative phase but has been effective in patients older than 12 months with infantile hemangiomas.[<a class="bk_pop" href="#CDR0000774170_rl_3_58">58</a>]</p><p id="CDR0000774170__24">Evidence (propranolol therapy):</p><ol id="CDR0000774170__25"><li class="half_rhythm"><div>In a large industry-sponsored randomized trial, 456 infants aged 5 weeks to 5 months with a proliferating infantile hemangioma of at least 1.5 cm received either a placebo or propranolol (1 mg/kg per day or 3 mg/kg per day) for 3 or 6 months. After interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg/kg per day for 6 months was selected for the final efficacy analysis.[<a class="bk_pop" href="#CDR0000774170_rl_3_52">52</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587981/" class="def">Level of evidence: 1iDiv</a>]<ul id="CDR0000774170__26"><li class="half_rhythm"><div>Of patients who received the selected regimen, 88% showed improvement by week 5, compared with 5% of patients who received the placebo.</div></li><li class="half_rhythm"><div>Adverse events occurred infrequently.</div></li></ul></div></li><li class="half_rhythm"><div>In 635 infants with infantile hemangioma, the overall response rate was 91% after 2 mg/kg per day, with most patients showing regression and only 2% with side effects, none of which were severe.[<a class="bk_pop" href="#CDR0000774170_rl_3_57">57</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587991/" class="def">Level of evidence: 3iiiDiv</a>] </div></li><li class="half_rhythm"><div>A meta-analysis that evaluated 5,130 patients from 61 studies concluded that propranolol was more effective and safer than were other treatments for infantile hemangioma.[<a class="bk_pop" href="#CDR0000774170_rl_3_59">59</a>]</div></li><li class="half_rhythm"><div>Airway infantile hemangioma lesions are rare; thus, there are limited prospective studies. A meta-analysis of 61 patients noted a trend of decreased treatment failure with increased dosing strategies, which is consistent with the use of higher doses of propranolol in these patients (3 mg/kg/day). The analysis also suggested that the concurrent use of steroids and propranolol may have reduced efficacy in patients with segmental airway hemangiomas, but previous treatment with steroids had no deleterious effect.[<a class="bk_pop" href="#CDR0000774170_rl_3_60">60</a>] Additional prospective studies are needed to validate these findings.</div></li></ol><p id="CDR0000774170__28">Based on expert consensus panel recommendations and updated reviews, considerations for the administration of propranolol therapy include the following:[<a class="bk_pop" href="#CDR0000774170_rl_3_61">61</a>-<a class="bk_pop" href="#CDR0000774170_rl_3_63">63</a>]</p><ul id="CDR0000774170__29"><li class="half_rhythm"><div class="half_rhythm"><b>Initiation of treatment:</b> Treatment should be undertaken in consultation with a pediatric vascular anomaly specialist with expertise in the diagnosis and treatment of pediatric vascular tumors and in the use of propranolol in children. In accord with an expert consensus panel, it is suggested that hospitalization for initiation of oral propranolol be considered in the following circumstances:[<a class="bk_pop" href="#CDR0000774170_rl_3_61">61</a>]<dl id="CDR0000774170__30" class="temp-labeled-list"><dt>-</dt><dd><p class="no_top_margin">Infant aged 5 weeks or younger (corrected for gestational age).</p></dd><dt>-</dt><dd><p class="no_top_margin">Infant of any age with inadequate social support.</p></dd><dt>-</dt><dd><p class="no_top_margin">Infant of any age with comorbid conditions affecting the cardiovascular or respiratory system, including symptomatic airway infantile hemangiomas.</p></dd><dt>-</dt><dd><p class="no_top_margin">Infant of any age with conditions affecting blood glucose maintenance.</p></dd></dl></div><div class="half_rhythm">The pretreatment evaluation (inpatient or outpatient) includes the following:<dl id="CDR0000774170__31" class="temp-labeled-list"><dt>-</dt><dd><p class="no_top_margin">History, with focus on cardiovascular and respiratory abnormalities (e.g., poor feeding, dyspnea, tachypnea, diaphoresis, wheezing, heart murmur) and family history of heart block or arrhythmia.</p></dd><dt>-</dt><dd><p class="no_top_margin">Physical examination including cardiac and pulmonary assessment and measurement of heart rate and blood pressure.</p></dd><dt>-</dt><dd><p class="no_top_margin">Consideration of an electrocardiogram, especially in children with heart rate lower than normal for age and history of arrhythmia or arrhythmia detected during examination.</p></dd><dt>-</dt><dd><p class="no_top_margin">Family history of congenital heart disease or maternal history of connective tissue disease.</p></dd></dl></div></li><li class="half_rhythm"><div class="half_rhythm"><b>Dosing:</b> The dosing used is generally 1 mg/kg per day to 3 mg/kg per day divided into two or three doses. Patients are initially started at a dose of 0.5 mg/kg per day to 1 mg/kg per day and increased over time. Initially, dosing of three times per day is recommended for infants younger than 8 weeks and for patients with PHACE syndrome.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Monitoring:</b> Monitoring varies depending on the institution. However, oral propranolol peaks at 1 to 3 hours after administration and most centers measure heart rate and blood pressure 1 and 2 hours after each dose with initiation and then when the dose is increased by at least 0.5 mg/kg per day. Parent and patient education includes when to hold the medication, signs of hypoglycemia, feeding necessity through the night, and when to call the physician with issues, such as illness, that may interfere with oral intake or lead to dehydration or respiratory problems.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Contraindications:</b> Propranolol treatment is contraindicated in infants and children with the following:<dl id="CDR0000774170__32" class="temp-labeled-list"><dt>-</dt><dd><p class="no_top_margin">Sinus bradycardia.</p></dd><dt>-</dt><dd><p class="no_top_margin">Hypotension.</p></dd><dt>-</dt><dd><p class="no_top_margin">Heart block greater than first degree.</p></dd><dt>-</dt><dd><p class="no_top_margin">Heart failure.</p></dd><dt>-</dt><dd><p class="no_top_margin">Asthma.</p></dd><dt>-</dt><dd><p class="no_top_margin">Hypersensitivity.</p></dd><dt>-</dt><dd><p class="no_top_margin">PHACE syndrome. PHACE syndrome with CNS arterial disease and/or coarctation of the aorta may be a relative contraindication. A decision to treat should be made in consultation with neurology and cardiology.
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</p></dd></dl></div></li><li class="half_rhythm"><div class="half_rhythm"><b>Adverse effects:</b> Adverse effects of propranolol include the following:[<a class="bk_pop" href="#CDR0000774170_rl_3_64">64</a>]<dl id="CDR0000774170__33" class="temp-labeled-list"><dt>-</dt><dd><p class="no_top_margin">Hypoglycemia.</p></dd><dt>-</dt><dd><p class="no_top_margin">Hypotension.</p></dd><dt>-</dt><dd><p class="no_top_margin">Bradycardia.</p></dd><dt>-</dt><dd><p class="no_top_margin">Sleep disturbance.</p></dd><dt>-</dt><dd><p class="no_top_margin">Diarrhea/constipation.</p></dd><dt>-</dt><dd><p class="no_top_margin">Cold extremities.
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</p></dd></dl></div><div class="half_rhythm">These complications have been reported in several studies, and severe complications have been rare.[<a class="bk_pop" href="#CDR0000774170_rl_3_64">64</a>] The risk of these complications is increased in patients with comorbidities and concomitant diseases, including diarrhea, vomiting, and respiratory infections. The need for close monitoring and possible periods of drug discontinuation should be considered during periods of illness.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Rebound growth after propranolol therapy:</b> Rebound refers to the growth of infantile hemangiomas after propranolol cessation. A multi-institutional, retrospective review of 997 patients with infantile hemangiomas found a rebound rate of 25.3% in 912 patients with adequate data. On univariate analysis, the factors associated with rebound included discontinuation of treatment before age 9 months, female sex, location on head/neck, segmental pattern, and deep or mixed skin involvement. On multivariate analysis, only deep infantile hemangiomas and female sex were significantly related.[<a class="bk_pop" href="#CDR0000774170_rl_3_65">65</a>]</div></li></ul></div><div id="CDR0000774170__129"><h5>Other selective beta-blocker therapy</h5><p id="CDR0000774170__130">Because of the nonselective and lipophilic nature of propranolol with the ability to cross the blood-brain barrier, other beta-blockers are being used for the treatment of infantile hemangiomas. In two small comparison studies, there was no difference in efficacy between propranolol and atenolol.[<a class="bk_pop" href="#CDR0000774170_rl_3_66">66</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_67">67</a>] In a retrospective study using nadolol, similar results were seen.[<a class="bk_pop" href="#CDR0000774170_rl_3_68">68</a>] A prospective study of 76 infants treated with atenolol noted efficacy and safety similar to propranolol.[<a class="bk_pop" href="#CDR0000774170_rl_3_69">69</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587990/" class="def">Level of evidence: 3iiDiv</a>] Additional studies are needed to assess differences between the toxicities of these agents and the toxicities of propranolol. There is some suggestion that the more selective beta-blockers have fewer side effects.[<a class="bk_pop" href="#CDR0000774170_rl_3_70">70</a>]</p></div><div id="CDR0000774170__213"><h5>Corticosteroid therapy</h5><p id="CDR0000774170__214">Before propranolol, corticosteroids were the first line of treatment for infantile hemangiomas. They were first used in the late 1950s but were never approved by the U.S. FDA. Corticosteroid therapy has become less popular secondary to the acute and long-term side effects of steroids (gastrointestinal irritability, immunosuppression, adrenocortical suppression, cushingoid features, and growth failure). </p><p id="CDR0000774170__215">Corticosteroids (prednisone or methylprednisolone) are used at times when there is a contraindication to beta-blocker therapy or as initial treatment while a patient is started on beta-blocker therapy.[<a class="bk_pop" href="#CDR0000774170_rl_3_71">71</a>]</p></div><div id="CDR0000774170__239"><h5>Topical beta-blocker therapy</h5><p id="CDR0000774170__257">Topical beta-blockers are used mainly for the treatment of small, localized, superficial hemangiomas as an alternative to observation. They have also been used in combination with systemic therapy in complicated hemangiomas or to prevent rebound in a hemangioma being tapered off of systemic treatment.[<a class="bk_pop" href="#CDR0000774170_rl_3_72">72</a>-<a class="bk_pop" href="#CDR0000774170_rl_3_74">74</a>]</p><p id="CDR0000774170__305">The topical timolol that is used is the ophthalmic gel-forming solution 0.5%. One drop is applied to the hemangioma two to three times per day until stable response is achieved.</p><p id="CDR0000774170__240">This treatment has limited side effects, but infants with a postmenstrual age of younger than 44 weeks and weight at treatment initiation of less than 2,500 grams may be at risk of adverse events, including bradycardia, hypotension, apnea, and hypothermia.[<a class="bk_pop" href="#CDR0000774170_rl_3_75">75</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_76">76</a>] Close monitoring of temperature, blood pressure, and heart rate in premature and low birth weight infants with infantile hemangiomas at initiation of and during therapy with topical timolol is necessary.</p><p id="CDR0000774170__241">Evidence (topical beta-blocker therapy):</p><ol id="CDR0000774170__242"><li class="half_rhythm"><div>In a multicenter, retrospective, cohort study, 731 children with predominantly superficial hemangiomas were treated with topical timolol 0.5% twice daily. Ninety-two percent of patients showed significant improvement in color and 77% showed improvement in size, extent, and volume. Topical timolol is generally well tolerated. However, data on its safety are limited.[<a class="bk_pop" href="#CDR0000774170_rl_3_74">74</a>]</div></li></ol></div><div id="CDR0000774170__229"><h5>Combined therapy for complicated hemangiomas</h5><p id="CDR0000774170__258">Combined therapy is considered either at initiation of treatment in complicated lesions in which there is functional impairment or organ compromise or used at the end of systemic therapy to prevent regrowth of the hemangioma <i>rebound</i>. Further investigation of efficacy and safety is needed for these regimens.</p><p id="CDR0000774170__259">Evidence (combined therapy for complicated hemangiomas):</p><ol id="CDR0000774170__260"><li class="half_rhythm"><div>A prospective randomized study that compared propranolol and 2 weeks of steroid therapy with propranolol alone revealed a decrease in the size of the hemangioma at 2, 4, and 8 weeks but no statistical difference in the size at 6 months.[<a class="bk_pop" href="#CDR0000774170_rl_3_77">77</a>]</div></li><li class="half_rhythm"><div> A prospective randomized study that compared timolol and propranolol with propranolol alone reported a decrease in color of the infantile hemangioma in the timolol group but no difference in overall size of the infantile hemangioma between the two treatment groups.[<a class="bk_pop" href="#CDR0000774170_rl_3_78">78</a>]</div></li><li class="half_rhythm"><div>Topical therapy with timolol combined with oral propranolol has been used.[<a class="bk_pop" href="#CDR0000774170_rl_3_79">79</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_80">80</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587990/" class="def">Level of evidence: 3iiDiv</a>]</div></li></ol></div></div><div id="CDR0000774170__261"><h4>Treatment options under clinical evaluation for infantile hemangiomas</h4><p id="CDR0000774170__262">Information about National Cancer Institute (NCI)–supported clinical trials can be found on the <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>. For information about clinical trials sponsored by other organizations, refer to the <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov website</a>.</p><p id="CDR0000774170__330">The following are examples of national and/or institutional clinical trials that are currently being conducted:</p><ol id="CDR0000774170__285"><li class="half_rhythm"><div><b><a href="https://clinicaltrials.gov/ct2/show/NCT02505971" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT02505971</a></b> (Nadolol Versus Propranolol in Children With Infantile Hemangioma)<b>:</b> This randomized, controlled, double-blinded study at Toronto Sick Kids is evaluating the efficacy and safety of both groups (nadolol and propranolol). Inclusion is for patients with hemangiomas that require systemic treatment.</div></li><li class="half_rhythm"><div><b><a href="https://clinicaltrials.gov/ct2/show/NCT02913612" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT02913612</a></b> (Efficacy, Safety, and Pharmacokinetics of Topical Timolol in Infants With Infantile Hemangioma [TIM01])<b>:</b> This is a multicenter, double-masked, randomized, efficacy, safety, and pharmacokinetic study. Timolol maleate 0.25% is being compared with timolol maleate 0.5%.</div></li></ol><div id="CDR0000774170__TrialSearch_261_sid_8"><h5>Current Clinical Trials</h5><p id="CDR0000774170__TrialSearch_261_22">Use our <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/advanced-search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">advanced clinical trial search</a> to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">General information</a> about clinical trials is also available.</p></div></div></div><div id="CDR0000774170__131"><h3>Congenital Hemangiomas</h3><p id="CDR0000774170__132">Congenital hemangiomas are benign vascular tumors that proliferate <i>in utero</i>. Development of these lesions is complete at birth. Histologically, these lesions are GLUT1 negative, unlike infantile hemangiomas. They are usually cutaneous, but can be found in the viscera. Complications include hemorrhage, transient heart failure, and transient coagulopathy.[<a class="bk_pop" href="#CDR0000774170_rl_3_81">81</a>]</p><p id="CDR0000774170__297">To the clinician unfamiliar with these lesions, congenital hemangiomas can be difficult to diagnose. Diagnostic criteria include a purpuric lesion fully formed at birth, frequently with a <i>halo</i> around the lesion, with high flow noted on ultrasound imaging. Essential to the diagnosis is observation of decrease in size over time or stability. These lesions do not enlarge unless there is hemorrhage into the tumor.</p><p id="CDR0000774170__264">Somatic activating mutations of <i>GNAQ</i> and <i>GNA11</i> have been found to be associated with congenital hemangiomas.[<a class="bk_pop" href="#CDR0000774170_rl_3_82">82</a>] Additional research is necessary to assess the significance of these findings, as this may aid in diagnosis and pathophysiology.</p><p id="CDR0000774170__160">Congenital hemangiomas are divided into the following three forms:</p><ul id="CDR0000774170__133"><li class="half_rhythm"><div class="half_rhythm"><b>Rapidly Involuting Congenital Hemangiomas (RICH).</b> These lesions are large high-flow lesions that are completely formed at birth but rapidly involute by 12 to 15 months. They can ulcerate and bleed and can cause transient heart failure and mild coagulopathy. After involution, usually some residual changes in the skin are present (refer to <a class="figpopup" href="/books/NBK343452.13/figure/CDR0000774170__167/?report=objectonly" target="object" rid-figpopup="figCDR0000774170167" rid-ob="figobCDR0000774170167">Figure 5</a>).[<a class="bk_pop" href="#CDR0000774170_rl_3_83">83</a>-<a class="bk_pop" href="#CDR0000774170_rl_3_86">86</a>]</div><div class="half_rhythm"><div id="CDR0000774170__167" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%205&p=BOOKS&id=532832_CDR0000779670.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK343452.13/bin/CDR0000779670.jpg" alt="Photographs showing a cutaneous congenital hemangioma on the inner right thigh at birth (left panel), 1 month (middle panel), and 1 year (right panel)." class="tileshop" title="Click on image to zoom" /></a></div><div class="caption"><p>Figure 5. Typical appearance of a cutaneous congenital hemangioma at birth. Note the pedunculated mass. This RICH lesion involuted over time but some residual skin changes remained. Credit: Denise Adams, M.D.</p></div></div></div></li><li class="half_rhythm"><div class="half_rhythm"><b>Partial Involuting Congenital Hemangiomas (PICH).</b> These lesions are completely formed at birth and involute only partially.[<a class="bk_pop" href="#CDR0000774170_rl_3_87">87</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Non-Involuting Congenital Hemangiomas (NICH).</b> These lesions are formed at birth and never involute. Depending on the location of the lesions and whether they cause functional impairment, the lesions may need to be removed surgically.[<a class="bk_pop" href="#CDR0000774170_rl_3_88">88</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_89">89</a>]</div></li></ul></div><div id="CDR0000774170__134"><h3>Benign Vascular Tumors of the Liver</h3><p id="CDR0000774170__135">In the literature, vascular liver tumors are usually classified as liver hemangioendotheliomas, <i>a broad classification no longer in use</i>. These tumors are classified according to their clinical characteristics and radiologic assessment.</p><p id="CDR0000774170__136">Lesions are usually divided into the following three categories:[<a class="bk_pop" href="#CDR0000774170_rl_3_46">46</a>]</p><ul id="CDR0000774170__137"><li class="half_rhythm"><div><a href="#CDR0000774170__161">Focal vascular lesions (congenital hemangiomas)</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000774170__266">Multiple liver lesions (infantile hemangiomas)</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000774170__298">Diffuse liver lesions (infantile hemangiomas)</a>.</div></li></ul><p id="CDR0000774170__138">On MRI, vascular liver tumors are hyperintense on T2 imaging and hypointense on T1 imaging, with postcontrast imaging demonstrating early peripheral enhancement with eventual diffuse enhancement.[<a class="bk_pop" href="#CDR0000774170_rl_3_46">46</a>]</p><div id="CDR0000774170__161"><h4>Focal vascular lesions (congenital hemangiomas)</h4><p id="CDR0000774170__139">Focal lesions of the liver are usually congenital hemangiomas (RICH or NICH) (refer to <a class="figpopup" href="/books/NBK343452.13/figure/CDR0000774170__169/?report=objectonly" target="object" rid-figpopup="figCDR0000774170169" rid-ob="figobCDR0000774170169">Figure 6</a>). RICH can present with symptoms of heart failure and mild to moderate coagulopathy.</p><p id="CDR0000774170__295">Treatment options for focal vascular lesions include the following:</p><ol id="CDR0000774170__296"><li class="half_rhythm"><div>Supportive management.</div></li><li class="half_rhythm"><div>Embolization for symptomatic shunting. These procedures need to be performed by interventional radiologists with expertise in vascular anomalies.[<a class="bk_pop" href="#CDR0000774170_rl_3_90">90</a>]</div></li><li class="half_rhythm"><div>Surgery. Patients with focal symptomatic hepatic congenital hemangioma unresponsive to supportive management or radiological intervention may be surgical candidates for resection. This is a rare circumstance and needs to be evaluated by an interdisciplinary vascular anomaly team.</div></li></ol><p id="CDR0000774170__265">No medication has proven to be an effective treatment for these lesions, and infants need to be supported during this initial period until involution begins.[<a class="bk_pop" href="#CDR0000774170_rl_3_46">46</a>] These lesions may be diagnosed prenatally. In rare situations, maternal treatment with medications such as steroids appeared to be effective but, more likely, natural involution may have been responsible.[<a class="bk_pop" href="#CDR0000774170_rl_3_91">91</a>]</p><a id="CDR0000774170__168"></a><div id="CDR0000774170__169" class="figure bk_fig"><div class="graphic"><img src="/books/NBK343452.13/bin/CDR0000779672.jpg" alt="MRI image of a single liver lesion (intrahepatic congenital hemangioma)." /></div><div class="caption"><p>Figure 6. Single liver lesion (intrahepatic congenital hemangioma). MRI image of a congenital hemangioma. Note the central enhancement, which is typical for an intrahepatic congenital hemangioma. Credit: Denise Adams, M.D.</p></div></div></div><div id="CDR0000774170__266"><h4>Multiple liver lesions (infantile hemangiomas)</h4><p id="CDR0000774170__140">Multifocal hepatic lesions are infantile hemangiomas. Multifocal lesions may not need to be treated if the patient is asymptomatic, and they typically follow the same proliferative and involution course as cutaneous hemangiomas.[<a class="bk_pop" href="#CDR0000774170_rl_3_46">46</a>] These lesions are monitored closely and if there is growth, propranolol therapy should be considered. If propranolol is needed, doses of up to 2 mg/kg per day are effective.</p></div><div id="CDR0000774170__298"><h4>Diffuse liver lesions (infantile hemangiomas)</h4><p id="CDR0000774170__159">Diffuse liver lesions can be very serious (refer to <a class="figpopup" href="/books/NBK343452.13/figure/CDR0000774170__171/?report=objectonly" target="object" rid-figpopup="figCDR0000774170171" rid-ob="figobCDR0000774170171">Figure 7</a>). Complications include hypothyroidism caused by the expression of iodothyronine deiodinase, congestive heart failure, and compartment syndrome.[<a class="bk_pop" href="#CDR0000774170_rl_3_45">45</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_46">46</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_92">92</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_93">93</a>]</p><a id="CDR0000774170__170"></a><div id="CDR0000774170__171" class="figure bk_fig"><div class="graphic"><img src="/books/NBK343452.13/bin/CDR0000779669.jpg" alt="CT image of diffuse liver lesions." /></div><div class="caption"><p>Figure 7. Diffuse liver lesions with classical imaging on CT. Note the peripheral enhancement in early contrast phase. Credit: Denise Adams, M.D.</p></div></div><p id="CDR0000774170__162">Treatment options for diffuse liver lesions may include the following:</p><ol id="CDR0000774170__144"><li class="half_rhythm"><div><b>Propranolol:</b> Beta-blockers are the most common treatment for diffuse and some multifocal infantile hemangiomas of the liver. Treatment doses of 2 to 3 mg/kg per day are indicated.[<a class="bk_pop" href="#CDR0000774170_rl_3_52">52</a>]</div></li><li class="half_rhythm"><div><b>Chemotherapy:</b> Steroids, cyclophosphamide, and vincristine have been used to treat diffuse liver infantile hemangioma.[<a class="bk_pop" href="#CDR0000774170_rl_3_46">46</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_94">94</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_95">95</a>]</div></li><li class="half_rhythm"><div><b>Transplant:</b> If a patient does not respond to medical management, a transplant may be indicated.[<a class="bk_pop" href="#CDR0000774170_rl_3_96">96</a>] Transplantation is considered only for patients with severe diffuse lesions who have multisystem organ failure and there is insufficient time for effective pharmacologic therapy.</div></li></ol><p id="CDR0000774170__145">There have been isolated reports of malignancy in patients with diffuse hepatic infantile hemangiomas.[<a class="bk_pop" href="#CDR0000774170_rl_3_97">97</a>] It is not clear if all cases were transformation of a benign lesion to a malignant phenotype; however, if the lesion does not respond to standard therapy, biopsy should be considered. Further evaluation and consensus is needed to assess whether these patients need to be monitored over a longer period of time with liver ultrasound. (Refer to the <a href="#CDR0000774170__192">Angiosarcoma of the Soft Tissue</a> section of this summary for more information.)</p><p id="CDR0000774170__267">The differential diagnosis of vascular liver lesions always includes malignant liver tumors; thus, alpha-fetoprotein (AFP) should be included in the initial lab work. AFP can be elevated above baseline in congenital and infantile hemangiomas of the liver, but will rapidly fall to normal levels in 1 to 2 months, although there are no prospective studies investigating AFP elevation.[<a class="bk_pop" href="#CDR0000774170_rl_3_98">98</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_99">99</a>] Some hypervascular hepatoblastomas in neonates with congestive heart failure have been mistaken for infantile hemangiomas. Other tumors in the differential diagnosis include angiosarcoma, metastatic neuroblastoma, and mesenchymal hamartomas. If there is any question about the diagnosis, a biopsy is recommended, although bleeding is a risk of the procedure.[<a class="bk_pop" href="#CDR0000774170_rl_3_100">100</a>]</p></div></div><div id="CDR0000774170__43"><h3>Spindle Cell Hemangioma</h3><div id="CDR0000774170__44"><h4>Clinical presentation</h4><p id="CDR0000774170__45">Spindle cell hemangiomas, initially called spindle cell hemangioendotheliomas, often occur as superficial (skin and subcutis), painful lesions involving distal extremities in children and adults.[<a class="bk_pop" href="#CDR0000774170_rl_3_101">101</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_102">102</a>] The tumors appear as red-brown or bluish lesions that can begin as a single nodule and develop into multifocal painful lesions over years. The lesions can be seen in Maffucci syndrome (cutaneous spindle cell hemangiomas occurring with cartilaginous tumors, enchondromas) and Klippel-Trenaunay syndrome (capillary/lymphatic/venous malformations), generalized lymphatic anomalies, lymphedema, and organized thrombus.[<a class="bk_pop" href="#CDR0000774170_rl_3_103">103</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_104">104</a>]</p><p id="CDR0000774170__199">These tumors are well circumscribed, occasionally contain phleboliths, and consist of cavernous blood spaces alternating with areas of nodular spindle cell proliferation. A significant percentage of spindle cell hemangiomas are completely intravascular. The vein containing the tumor is abnormal, as are blood vessels apart from the tumor mass.[<a class="bk_pop" href="#CDR0000774170_rl_3_103">103</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_104">104</a>]</p></div><div id="CDR0000774170__46"><h4>Treatment of spindle cell hemangioma</h4><p id="CDR0000774170__47">There is no standard treatment for spindle cell hemangioma because it has not been studied in clinical trials. Surgical removal is usually curative, although there is a risk of recurrence.[<a class="bk_pop" href="#CDR0000774170_rl_3_103">103</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_104">104</a>]</p></div></div><div id="CDR0000774170__48"><h3>Epithelioid Hemangioma</h3><div id="CDR0000774170__49"><h4>Clinical presentation</h4><p id="CDR0000774170__50">Epithelioid hemangiomas are benign lesions that usually occur in the skin and subcutis but can occur in other areas such as the bone, with focal and multifocal lesions.[<a class="bk_pop" href="#CDR0000774170_rl_3_103">103</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_105">105</a>] Epithelioid hemangiomas may be a reactive process, as they can be associated with local trauma and can develop in pregnancy. Patients usually present with local swelling and pain at the involved site. In the bone, they present as well-defined lytic lesions that involve the metaphysis and diaphysis of long bones.[<a class="bk_pop" href="#CDR0000774170_rl_3_103">103</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_106">106</a>] They can have a mixed lytic and sclerotic pattern of bone destruction. </p><p id="CDR0000774170__51">On pathologic evaluation, they have small caliber capillaries with eosinophilic, vacuolated cytoplasm and large oval, grooved, and lobulated nuclei. The endothelial cells are plump and are mature, well-formed vessels surrounded by multiple epithelioid endothelial cells within abundant cytoplasm. They lack cellular atypia and mitotic activity.[<a class="bk_pop" href="#CDR0000774170_rl_3_103">103</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_105">105</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_106">106</a>]</p></div><div id="CDR0000774170__52"><h4>Treatment of epithelioid hemangioma</h4><p id="CDR0000774170__53">There is no standard treatment for epithelioid hemangioma because it has not been studied in clinical trials. Treatment consists of curettage, sclerotherapy, and resection, or rarely, radiation therapy.[<a class="bk_pop" href="#CDR0000774170_rl_3_103">103</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_106">106</a>]</p></div></div><div id="CDR0000774170__54"><h3>Pyogenic Granuloma (Lobular Capillary Hemangioma)</h3><div id="CDR0000774170__55"><h4>Clinical presentation</h4><p id="CDR0000774170__56">Pyogenic granuloma, known as lobular capillary hemangioma, is a benign reactive lesion that can present at any age, including infancy, although it is most common in older children and young adults. They can present as single or multiple lesions.[<a class="bk_pop" href="#CDR0000774170_rl_3_107">107</a>-<a class="bk_pop" href="#CDR0000774170_rl_3_110">110</a>] These lesions can arise spontaneously, in sites of trauma, or within capillary and arteriovenous malformations. Pyogenic granulomas have also been associated with medications including oral contraceptives and retinoids. Most occur as solitary growths, but multiple (grouped) or rarely disseminated lesions have been described. These lesions appear as small or large, smooth or lobulated vascular nodules that can grow rapidly, sometimes over weeks to months and have a tendency to bleed profusely. These lesions are usually cutaneous, but deep-seated/subcutaneous pyogenic granulomas are noted and mimic other vascular lesions.[<a class="bk_pop" href="#CDR0000774170_rl_3_111">111</a>]</p><p id="CDR0000774170__57">Histologically, these lesions are composed of capillaries and venules with plump endothelial cells separated into lobules by fibromyxoid stroma. Some untreated lesions eventually atrophy, become fibromatous, and slowly regress.</p></div><div id="CDR0000774170__58"><h4>Treatment of pyogenic granuloma</h4><p id="CDR0000774170__59">Treatment often consists of full-thickness excision, curettage, or laser photocoagulation, but recurrence is common.[<a class="bk_pop" href="#CDR0000774170_rl_3_112">112</a>] A small case series of four patients with acquired ocular surface pyogenic granulomas were treated with topical timolol 0.5% twice daily for 21 days. In all cases, complete resolution with no recurrence occurred for at least 3 months. More studies are needed to validate these findings.[<a class="bk_pop" href="#CDR0000774170_rl_3_113">113</a>] A study of 22 patients with pyogenic granuloma who were treated with topical 1% propranolol ointment with occlusion found that 59% of patients achieved a complete response (mean, 66 days), 18% of patients had stable disease, and 22% of patients did not respond to the treatment.[<a class="bk_pop" href="#CDR0000774170_rl_3_114">114</a>] In this study, only skin toxicity was assessed. The authors did not comment on the penetrance of the propranolol formulation or include a safety evaluation of the side effects such as hypoglycemia and the effects on heart rate or blood pressure.</p></div></div><div id="CDR0000774170__60"><h3>Angiofibroma</h3><div id="CDR0000774170__61"><h4>Clinical presentation</h4><p id="CDR0000774170__62">Angiofibromas are rare, benign neoplasms in the pediatric population. Typically, they are cutaneous lesions associated with tuberous sclerosis, appearing as red papules on the face.</p></div><div id="CDR0000774170__63"><h4>Treatment of angiofibroma</h4><p id="CDR0000774170__64">Excision of the tumor, laser treatments, and topical treatments, such as sirolimus, have been used.[<a class="bk_pop" href="#CDR0000774170_rl_3_115">115</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_116">116</a>]</p></div></div><div id="CDR0000774170__65"><h3>Juvenile Nasopharyngeal Angiofibroma</h3><div id="CDR0000774170__66"><h4>Clinical presentation</h4><p id="CDR0000774170__67">Juvenile nasopharyngeal angiofibromas (JNA) account for 0.5% of all head and neck tumors.[<a class="bk_pop" href="#CDR0000774170_rl_3_117">117</a>] Histologically, juvenile nasopharyngeal angiofibromas are benign vascular tumors but they can be locally destructive, spreading from the nasal cavity to the nasopharynx, paranasal sinuses, and orbit skull base, with intracranial extension. Some publications have suggested a hormonal influence on juvenile nasopharyngeal angiofibroma, with emphasis on the molecular mechanisms involved.[<a class="bk_pop" href="#CDR0000774170_rl_3_118">118</a>,<a class="bk_pop" href="#CDR0000774170_rl_3_119">119</a>]</p></div><div id="CDR0000774170__68"><h4>Treatment of juvenile nasopharyngeal angiofibroma</h4><p id="CDR0000774170__69">Surgical excision is the treatment of choice but this can be challenging because of the extent of the lesion. A single-institution retrospective review of juvenile nasopharyngeal angiofibromas identified 37 patients with lateral extension.[<a class="bk_pop" href="#CDR0000774170_rl_3_120">120</a>] Anterior lateral extension to the pterygopalatine fossa occurred in 36 patients (97%) and further to the infratemporal fossa in 20 patients (54%). In 16 patients (43%), posterior lateral spread was observed (posterior to the pterygoid process and/or between its plates). The recurrence rate was 29.7% (11 of 37 patients). The recurrence rate in patients with anterior and/or posterior lateral extension was significantly higher than in patients with anterior lateral extension only. </p><p id="CDR0000774170__200">Juvenile nasopharyngeal angiofibromas have also been treated with radiation therapy, chemotherapy, alpha-interferon therapy, and sirolimus.[<a class="bk_pop" href="#CDR0000774170_rl_3_121">121</a>-<a class="bk_pop" href="#CDR0000774170_rl_3_124">124</a>]</p></div></div><div id="CDR0000774170_rl_3"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000774170_rl_3_1">Munden A, Butschek R, Tom WL, et al.: Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies. Br J Dermatol 170 (4): 907-13, 2014. [<a href="/pmc/articles/PMC4410180/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4410180</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24641194" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24641194</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_3_2">Darrow DH, Greene AK, Mancini AJ, et al.: Diagnosis and Management of Infantile Hemangioma. Pediatrics 136 (4): e1060-104, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/26416931" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26416931</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_3_3">Darrow DH, Greene AK, Mancini AJ, et al.: Diagnosis and Management of Infantile Hemangioma: Executive Summary. Pediatrics 136 (4): 786-91, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/26416928" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26416928</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_3_4">Haggstrom AN, Drolet BA, Baselga E, et al.: Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics. J Pediatr 150 (3): 291-4, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17307549" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17307549</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_3_5">Blei F, Walter J, Orlow SJ, et al.: Familial segregation of hemangiomas and vascular malformations as an autosomal dominant trait. Arch Dermatol 134 (6): 718-22, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9645641" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9645641</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_3_6">Castrén E, Salminen P, Vikkula M, et al.: Inheritance Patterns of Infantile Hemangioma. Pediatrics 138 (5): , 2016. [<a href="https://pubmed.ncbi.nlm.nih.gov/27940781" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27940781</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_3_7">Boye E, Yu Y, Paranya G, et al.: Clonality and altered behavior of endothelial cells from hemangiomas. J Clin Invest 107 (6): 745-52, 2001. [<a href="/pmc/articles/PMC208946/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC208946</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11254674" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11254674</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_3_8">Yu Y, Flint AF, Mulliken JB, et al.: Endothelial progenitor cells in infantile hemangioma. Blood 103 (4): 1373-5, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/14576053" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14576053</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_3_9">Barnés CM, Huang S, Kaipainen A, et al.: Evidence by molecular profiling for a placental origin of infantile hemangioma. Proc Natl Acad Sci U S A 102 (52): 19097-102, 2005. 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[<a href="https://pubmed.ncbi.nlm.nih.gov/25818498" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25818498</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_3_113">Oke I, Alkharashi M, Petersen RA, et al.: Treatment of Ocular Pyogenic Granuloma With Topical Timolol. JAMA Ophthalmol 135 (4): 383-385, 2017. [<a href="https://pubmed.ncbi.nlm.nih.gov/28301661" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28301661</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_3_114">Neri I, Baraldi C, Balestri R, et al.: Topical 1% propranolol ointment with occlusion in treatment of pyogenic granulomas: An open-label study in 22 children. Pediatr Dermatol 35 (1): 117-120, 2018. [<a href="https://pubmed.ncbi.nlm.nih.gov/29266656" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29266656</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_3_115">Haemel AK, O'Brian AL, Teng JM: Topical rapamycin: a novel approach to facial angiofibromas in tuberous sclerosis. Arch Dermatol 146 (7): 715-8, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20644030" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20644030</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_3_116">Pignatti M, Spaggiari A, Sala P, et al.: Laser treatment of angiofibromas in tuberous sclerosis. Minerva Pediatr 66 (6): 585-6, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/25336102" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25336102</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_3_117">Coutinho-Camillo CM, Brentani MM, Nagai MA: Genetic alterations in juvenile nasopharyngeal angiofibromas. Head Neck 30 (3): 390-400, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18228521" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18228521</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_3_118">Riggs S, Orlandi RR: Juvenile nasopharyngeal angiofibroma recurrence associated with exogenous testosterone therapy. Head Neck 32 (6): 812-5, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/19626637" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19626637</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_3_119">Liu Z, Wang J, Wang H, et al.: Hormonal receptors and vascular endothelial growth factor in juvenile nasopharyngeal angiofibroma: immunohistochemical and tissue microarray analysis. Acta Otolaryngol 135 (1): 51-7, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25384380" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25384380</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_3_120">Szymańska A, Szymański M, Czekajska-Chehab E, et al.: Two types of lateral extension in juvenile nasopharyngeal angiofibroma: diagnostic and therapeutic management. Eur Arch Otorhinolaryngol 272 (1): 159-66, 2015. [<a href="/pmc/articles/PMC4282713/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4282713</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24599598" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24599598</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_3_121">Samanta D: Topical mTOR (mechanistic target of rapamycin) inhibitor therapy in facial angiofibroma. Indian J Dermatol Venereol Leprol 81 (5): 540-1, 2015 Sep-Oct. [<a href="https://pubmed.ncbi.nlm.nih.gov/26323682" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26323682</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_3_122">Krakowski AC, Nguyen TA: Inhibition of Angiofibromas in a Tuberous Sclerosis Patient Using Topical Timolol 0.5% Gel. Pediatrics 136 (3): e709-13, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/26304829" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26304829</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_3_123">Mallick S, Benson R, Bhasker S, et al.: Long-term treatment outcomes of juvenile nasopharyngeal angiofibroma treated with radiotherapy. Acta Otorhinolaryngol Ital 35 (2): 75-9, 2015. [<a href="/pmc/articles/PMC4443565/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4443565</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26019389" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26019389</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_3_124">Peters T, Traboulsi D, Tibbles LA, et al.: Sirolimus: a therapeutic advance for dermatologic disease. Skin Therapy Lett 19 (4): 1-4, 2014 Jul-Aug. [<a href="https://pubmed.ncbi.nlm.nih.gov/25188522" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25188522</span></a>]</div></li></ol></div></div><div id="CDR0000774170__70"><h2 id="_CDR0000774170__70_">Intermediate Tumors (Locally Aggressive) </h2><div id="CDR0000774170__71"><h3>Kaposiform Hemangioendothelioma and Tufted Angioma</h3><p id="CDR0000774170__72">Kaposiform hemangioendothelioma (KHE) and tufted angioma are rare vascular tumors that typically occur during infancy or early childhood but have been reported in adults. Both tumors are thought to be a spectrum of the same disease, because both can be locally aggressive and cause Kasabach-Merritt phenomenon, a serious life-threatening coagulopathy characterized by profound thrombocytopenia and hypofibrinogenemia. They are discussed here as a single entity, kaposiform hemangioendothelioma.</p><div id="CDR0000774170__73"><h4>Incidence</h4><p id="CDR0000774170__74">The exact incidence of kaposiform hemangioendothelioma is unknown but is estimated to be 0.07 cases per 100,000 children per year.[<a class="bk_pop" href="#CDR0000774170_rl_70_1">1</a>-<a class="bk_pop" href="#CDR0000774170_rl_70_3">3</a>] The lesions affect both sexes equally, with most developing in the neonatal period, one-half presenting at birth, and others presenting during childhood or adulthood.[<a class="bk_pop" href="#CDR0000774170_rl_70_4">4</a>]</p></div><div id="CDR0000774170__75"><h4>Pathology</h4><p id="CDR0000774170__76">Kaposiform hemangioendothelioma is characterized by sheets of spindle cells with an infiltrative pattern in the dermis, subcutaneous fat, and muscle. There are often areas of fibrosis, with dilated thin-walled vessels infiltrated around the areas of spindle cells. Mixed with these areas are nests of rounded epithelioid cells of vascular origin and aggregates of capillaries with round or irregularly shaped lumens containing platelet-rich fibrin thrombi. There is usually the presence of abnormal lymphatic spaces, either within or at the periphery of the lesion. The rate of mitosis is variable but usually low. Tufted angioma is characterized by multiple, discrete lobules of tightly packed capillaries (tufts) scattered in the dermis and sometimes in the subcutis, so called <i>cannonball</i> pattern.[<a class="bk_pop" href="#CDR0000774170_rl_70_5">5</a>] Mitoses are rare.</p><p id="CDR0000774170__77">The pathogenesis is poorly understood. There is some evidence that kaposiform hemangioendothelioma may be derived from lymphatic endothelium, as the spindle cell expresses the vascular markers CD31 and CD34, the vascular endothelial growth factor receptor-3, a receptor required for lymphangiogenesis, and the lymphatic markers D2-40 and PROX1.[<a class="bk_pop" href="#CDR0000774170_rl_70_5">5</a>-<a class="bk_pop" href="#CDR0000774170_rl_70_7">7</a>] There is no evidence of association with human herpesvirus 8 infection as is present in Kaposi sarcoma.[<a class="bk_pop" href="#CDR0000774170_rl_70_7">7</a>]</p></div><div id="CDR0000774170__78"><h4>Clinical presentation</h4><p id="CDR0000774170__79">Kaposiform hemangioendothelioma most frequently involves the extremities and less frequently involves the trunk and head and neck area.[<a class="bk_pop" href="#CDR0000774170_rl_70_3">3</a>] Most lesions involve the skin (refer to <a class="figpopup" href="/books/NBK343452.13/figure/CDR0000774170__173/?report=objectonly" target="object" rid-figpopup="figCDR0000774170173" rid-ob="figobCDR0000774170173">Figure 8</a>). Deeper lesions (retroperitoneum, thoracic cavity, and muscle) can appear as a bluish-purpuric hue on the skin, whereas superficial lesions can be firm, purpuric or ecchymotic, and painful. Lesions are usually unifocal and growth is contiguous. Local lymph nodes may be involved, but they never metastasize. Rare multifocal presentations have been reported mostly in the bone.[<a class="bk_pop" href="#CDR0000774170_rl_70_1">1</a>-<a class="bk_pop" href="#CDR0000774170_rl_70_3">3</a>]</p><a id="CDR0000774170__172"></a><div id="CDR0000774170__173" class="figure bk_fig"><div class="graphic"><img src="/books/NBK343452.13/bin/CDR0000779673.jpg" alt="Photograph showing a Kaposiform hemangioendothelioma lesion on the right side of the face and neck." /></div><div class="caption"><p>Figure 8. Kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon. The lesion is indurated, firm, and warm with petechiae and purpura. Credit: Denise Adams, M.D.</p></div></div><p id="CDR0000774170__80">Seventy percent of patients with kaposiform hemangioendothelioma develop Kasabach-Merritt phenomenon, which is a life-threatening complication characterized by profound thrombocytopenia (range, 3,000/µL–60,000/µL) and profound hypofibrinogenemia (<1 g/L). D-dimer and fibrin degradation products are elevated. Severe anemia can occur secondary to tumor sequestration. Severe hemorrhage is rare; however, trauma (biopsy, surgical procedure), ulceration, infection, or delay in initiating treatment may induce progression to disseminated intravascular coagulation and serious bleeding and death can occur. Aggressive replacement of blood products, especially platelets, can increase the size of the lesion, causing significant pain and should only be considered with active bleeding and under the direction of a vascular anomaly specialist.[<a class="bk_pop" href="#CDR0000774170_rl_70_3">3</a>]</p></div><div id="CDR0000774170__81"><h4>Diagnostic evaluation</h4><p id="CDR0000774170__82">The diagnosis is based on the combination of clinical, histologic, and imaging features. Laboratory evaluation is essential for the diagnosis of Kasabach-Merritt phenomenon.
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Whenever possible, histologic confirmation should be obtained, because prolonged therapy is often needed. However, if clinical and imaging findings are highly suggestive of the diagnosis, deferring biopsy is an option but needs to be planned with an interdisciplinary approach.</p><p id="CDR0000774170__207">
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Magnetic resonance imaging is the imaging preference. T1-weighted sequences typically show a poorly circumscribed soft tissue mass with soft tissue and dermal thickening and diffuse enhancement with gadolinium. T2-weighted sequences show a diffuse increased signal, with stranding in the subcutaneous fat. Gradient sequences show mildly dilated vessels in and around the soft-tissue mass.[<a class="bk_pop" href="#CDR0000774170_rl_70_3">3</a>]</p></div><div id="CDR0000774170__83"><h4>Treatment of kaposiform hemangioendothelioma and tufted angioma</h4><p id="CDR0000774170__84">Treatment varies according to severity; there is no evidence-based standard of care. An American and Canadian multidisciplinary expert panel published guidelines for the management of complicated kaposiform hemangioendothelioma.[<a class="bk_pop" href="#CDR0000774170_rl_70_8">8</a>] A number of treatment therapies have been reported but none have been uniformly effective.[<a class="bk_pop" href="#CDR0000774170_rl_70_9">9</a>,<a class="bk_pop" href="#CDR0000774170_rl_70_10">10</a>]</p><p id="CDR0000774170__85">Treatment options for kaposiform hemangioendothelioma include the following:[<a class="bk_pop" href="#CDR0000774170_rl_70_8">8</a>-<a class="bk_pop" href="#CDR0000774170_rl_70_17">17</a>]</p><ol id="CDR0000774170__86"><li class="half_rhythm"><div>Steroid therapy.</div></li><li class="half_rhythm"><div>Antiplatelet agent (aspirin) therapy.</div></li><li class="half_rhythm"><div>Alpha-interferon.</div></li><li class="half_rhythm"><div>Antifibrinolytic agent therapy.</div></li><li class="half_rhythm"><div>Chemotherapy, including vincristine, cyclophosphamide, actinomycin, and methotrexate used alone or in combination.</div></li><li class="half_rhythm"><div>Propranolol therapy.</div></li><li class="half_rhythm"><div>Surgical excision with or without embolization.</div></li><li class="half_rhythm"><div>Sirolimus as a single agent or in combination with steroids.</div></li></ol><p id="CDR0000774170__87">Initial treatment is most commonly steroids followed by vincristine. A retrospective review identified 37 children with kaposiform hemangioendothelioma whose lesions did not respond to steroids.[<a class="bk_pop" href="#CDR0000774170_rl_70_11">11</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000587991/" class="def">Level of evidence: 3iiiDiv</a>] Twenty-six kaposiform hemangioendothelioma lesions achieved complete remission, with platelet counts reaching normal levels within 7.6 ± 5.2 weeks after vincristine treatment.</p><p id="CDR0000774170__268">Propranolol therapy has been reported as a treatment option for kaposiform hemangioendothelioma. Its use is based on the positive results of propranolol for other more benign vascular tumors. Results have been mixed, with a report of improved effectiveness using higher doses of propranolol.[<a class="bk_pop" href="#CDR0000774170_rl_70_18">18</a>,<a class="bk_pop" href="#CDR0000774170_rl_70_19">19</a>] Preliminary results indicate that propranolol should be reserved for patients with kaposiform hemangioendothelioma without Kasabach-Merritt phenomenon and with smaller, less complicated lesions.</p><p id="CDR0000774170__306">Secondary to promising case reports, case series and a prospective clinical trial, sirolimus may be considered an alternative first-line therapy for kaposiform hemangioendothelioma.[<a class="bk_pop" href="#CDR0000774170_rl_70_14">14</a>,<a class="bk_pop" href="#CDR0000774170_rl_70_15">15</a>,<a class="bk_pop" href="#CDR0000774170_rl_70_20">20</a>] There are limited studies investigating its effect on kaposiform hemangioendothelioma/tufted angioma without Kasabach-Merritt phenomenon.</p><p id="CDR0000774170__307">Reports that support the use of sirolimus include the following:</p><ol id="CDR0000774170__308"><li class="half_rhythm"><div>In a prospective study that assessed the efficacy and safety of sirolimus for the treatment of complicated vascular anomalies, 13 patients with kaposiform hemangioendothelioma were treated.[<a class="bk_pop" href="#CDR0000774170_rl_70_21">21</a>] <ul id="CDR0000774170__309"><li class="half_rhythm"><div>In patients with kaposiform hemangioendothelioma and Kasabach-Merritt phenomenon, ten of ten patients had a partial response, with normalization of their platelet count and fibrinogen at the end of six and 12 courses.</div></li><li class="half_rhythm"><div>In three of three patients with kaposiform hemangioendothelioma without Kasabach-Merritt phenomenon, one patient with multifocal bony disease had disease progression while the other two patients revealed a partial response at the end of course 12. Side effects were minimal in this group of young patients and no patient with kaposiform hemangioendothelioma required a dose adjustment or was removed from study secondary to toxicity.</div></li></ul></div></li><li class="half_rhythm"><div>A single case report of a child with kaposiform hemangioendothelioma who developed recurrence of pain and fibrosis years after initial therapy and was treated with sirolimus for 26 months observed the following:[<a class="bk_pop" href="#CDR0000774170_rl_70_20">20</a>]<ul id="CDR0000774170__310"><li class="half_rhythm"><div>The patient's contracture and range of motion improved, the lesion shrank, and the child was well 2 years later.</div></li></ul>
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</div></li><li class="half_rhythm"><div>In a multicenter, retrospective cohort study, 52 Chinese patients with progressive kaposiform hemangioendothelioma were analyzed. Thirty-seven patients (71%) had Kasabach-Merritt phenomenon. Those without Kasabach-Merritt phenomenon received sirolimus alone, and 21 of the patients with Kasabach-Merritt phenomenon received a combination of sirolimus and prednisone.[<a class="bk_pop" href="#CDR0000774170_rl_70_22">22</a>]<ul id="CDR0000774170__342"><li class="half_rhythm"><div> Overall, 96% and 98% of patients demonstrated improvement in notable symptoms and/or had improved complications at 6 and 12 months, respectively.</div></li></ul></div></li></ol><p id="CDR0000774170__208">Additional studies are needed to determine the long-term efficacy and safety of sirolimus for the treatment of vascular tumors associated with Kasabach-Merritt phenomenon.</p><p id="CDR0000774170__209">Surgical excision may be possible for lesions that are smaller, have failed medical management, or are life threatening. Embolization may be performed in conjunction with surgery or medical therapy; usually it is a temporizing measure.</p><p id="CDR0000774170__269">The mortality associated with this tumor is primarily from the extensive coagulopathy associated with Kasabach-Merritt phenomenon.</p><p id="CDR0000774170__88">Even with therapy, these lesions do not fully regress and can recur; worsened symptomatology (pain, inflammation) can occur with age, especially around the time of puberty.[<a class="bk_pop" href="#CDR0000774170_rl_70_23">23</a>] </p><p id="CDR0000774170__89">Long-term effects include chronic pain, lymphedema, heart failure, and orthopedic issues.[<a class="bk_pop" href="#CDR0000774170_rl_70_23">23</a>] These lesions prove to be a difficult dilemma for the practitioner because they have a varied clinical spectrum and response to therapy.</p></div><div id="CDR0000774170__270"><h4>Treatment options under clinical evaluation for kaposiform hemangioendothelioma</h4><p id="CDR0000774170__271">Information about National Cancer Institute (NCI)–supported clinical trials can be found on the <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>. For information about clinical trials sponsored by other organizations, refer to the <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov website</a>.</p><p id="CDR0000774170__331">The following is an example of a national and/or institutional clinical trial that is currently being conducted:</p><ol id="CDR0000774170__287"><li class="half_rhythm"><div><b><a href="https://clinicaltrials.gov/ct2/show/NCT02110069" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT02110069</a></b> (A Study to Compare Vincristine to Sirolimus for Treatment of High-Risk Vascular Tumors)<b>:</b> This is a study comparing vincristine with sirolimus for the treatment of high-risk kaposiform hemangioendothelioma. A multicenter adaptive study design determining efficacy (initially defined as the time to hematologic response) by comparing vincristine with sirolimus therapy while patients are on a steroid wean.</div></li></ol></div></div><div id="CDR0000774170_rl_70"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000774170_rl_70_1">Rodriguez V, Lee A, Witman PM, et al.: Kasabach-merritt phenomenon: case series and retrospective review of the mayo clinic experience. J Pediatr Hematol Oncol 31 (7): 522-6, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19564750" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19564750</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_2">Ryan C, Price V, John P, et al.: Kasabach-Merritt phenomenon: a single centre experience. Eur J Haematol 84 (2): 97-104, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/19889011" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19889011</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_3">Croteau SE, Liang MG, Kozakewich HP, et al.: Kaposiform hemangioendothelioma: atypical features and risks of Kasabach-Merritt phenomenon in 107 referrals. J Pediatr 162 (1): 142-7, 2013. [<a href="/pmc/articles/PMC3494787/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3494787</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22871490" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22871490</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_4">Lee B, Chiu M, Soriano T, et al.: Adult-onset tufted angioma: a case report and review of the literature. Cutis 78 (5): 341-5, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/17186794" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17186794</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_5">Enjolras O, Soupre V, Picard A: Uncommon benign infantile vascular tumors. Adv Dermatol 24: 105-24, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/19263597" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19263597</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_6">Zukerberg LR, Nickoloff BJ, Weiss SW: Kaposiform hemangioendothelioma of infancy and childhood. An aggressive neoplasm associated with Kasabach-Merritt syndrome and lymphangiomatosis. Am J Surg Pathol 17 (4): 321-8, 1993. [<a href="https://pubmed.ncbi.nlm.nih.gov/8494101" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8494101</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_7">Arai E, Kuramochi A, Tsuchida T, et al.: Usefulness of D2-40 immunohistochemistry for differentiation between kaposiform hemangioendothelioma and tufted angioma. J Cutan Pathol 33 (7): 492-7, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16872472" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16872472</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_8">Drolet BA, Trenor CC 3rd, Brandão LR, et al.: Consensus-derived practice standards plan for complicated Kaposiform hemangioendothelioma. J Pediatr 163 (1): 285-91, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23796341" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23796341</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_9">Haisley-Royster C, Enjolras O, Frieden IJ, et al.: Kasabach-merritt phenomenon: a retrospective study of treatment with vincristine. J Pediatr Hematol Oncol 24 (6): 459-62, 2002 Aug-Sep. [<a href="https://pubmed.ncbi.nlm.nih.gov/12218593" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12218593</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_10">Hauer J, Graubner U, Konstantopoulos N, et al.: Effective treatment of kaposiform hemangioendotheliomas associated with Kasabach-Merritt phenomenon using four-drug regimen. Pediatr Blood Cancer 49 (6): 852-4, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/16411198" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16411198</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_11">Wang Z, Li K, Yao W, et al.: Steroid-resistant kaposiform hemangioendothelioma: a retrospective study of 37 patients treated with vincristine and long-term follow-up. Pediatr Blood Cancer 62 (4): 577-80, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25346262" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25346262</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_12">Fernandez-Pineda I, Lopez-Gutierrez JC, Ramirez G, et al.: Vincristine-ticlopidine-aspirin: an effective therapy in children with Kasabach-Merritt phenomenon associated with vascular tumors. Pediatr Hematol Oncol 27 (8): 641-5, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20863161" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20863161</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_13">Kai L, Wang Z, Yao W, et al.: Sirolimus, a promising treatment for refractory Kaposiform hemangioendothelioma. J Cancer Res Clin Oncol 140 (3): 471-6, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24464150" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24464150</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_14">Hammill AM, Wentzel M, Gupta A, et al.: Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer 57 (6): 1018-24, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21445948" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21445948</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_15">Blatt J, Stavas J, Moats-Staats B, et al.: Treatment of childhood kaposiform hemangioendothelioma with sirolimus. Pediatr Blood Cancer 55 (7): 1396-8, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20730884" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20730884</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_16">Fernandez-Pineda I, Lopez-Gutierrez JC, Chocarro G, et al.: Long-term outcome of vincristine-aspirin-ticlopidine (VAT) therapy for vascular tumors associated with Kasabach-Merritt phenomenon. Pediatr Blood Cancer 60 (9): 1478-81, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23609996" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23609996</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_17">Chiu YE, Drolet BA, Blei F, et al.: Variable response to propranolol treatment of kaposiform hemangioendothelioma, tufted angioma, and Kasabach-Merritt phenomenon. Pediatr Blood Cancer 59 (5): 934-8, 2012. [<a href="/pmc/articles/PMC3528889/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3528889</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22648868" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22648868</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_18">Filippi L, Tamburini A, Berti E, et al.: Successful Propranolol Treatment of a Kaposiform Hemangioendothelioma Apparently Resistant to Propranolol. Pediatr Blood Cancer 63 (7): 1290-2, 2016. [<a href="https://pubmed.ncbi.nlm.nih.gov/27100060" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27100060</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_19">Wang Z, Li K, Dong K, et al.: Variable response to propranolol treatment of kaposiform hemangioendothelioma, tufted angioma, and Kasabach-Merritt phenomenon. Pediatr Blood Cancer 61 (8): 1518-9, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24482015" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24482015</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_20">Oza VS, Mamlouk MD, Hess CP, et al.: Role of Sirolimus in Advanced Kaposiform Hemangioendothelioma. Pediatr Dermatol 33 (2): e88-92, 2016 Mar-Apr. [<a href="https://pubmed.ncbi.nlm.nih.gov/26864138" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26864138</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_21">Adams DM, Trenor CC 3rd, Hammill AM, et al.: Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies. Pediatrics 137 (2): e20153257, 2016. [<a href="/pmc/articles/PMC4732362/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4732362</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26783326" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26783326</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_22">Ji Y, Chen S, Xiang B, et al.: Sirolimus for the treatment of progressive kaposiform hemangioendothelioma: A multicenter retrospective study. Int J Cancer 141 (4): 848-855, 2017. [<a href="https://pubmed.ncbi.nlm.nih.gov/28486787" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28486787</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_70_23">Schaefer BA, Wang D, Merrow AC, et al.: Long-term outcome for kaposiform hemangioendothelioma: A report of two cases. Pediatr Blood Cancer 64 (2): 284-286, 2017. [<a href="https://pubmed.ncbi.nlm.nih.gov/27701822" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27701822</span></a>]</div></li></ol></div></div><div id="CDR0000774170__90"><h2 id="_CDR0000774170__90_">Intermediate Tumors (Rarely Metastasizing)</h2><p id="CDR0000774170__317">Intermediate vascular tumors (rarely metastasizing) include the following:</p><ul id="CDR0000774170__318"><li class="half_rhythm"><div><a href="#CDR0000774170__319">Pseudomyogenic hemangioendothelioma</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000774170__91">Retiform hemangioendothelioma</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000774170__98">Papillary intralymphatic angioendothelioma</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000774170__146">Composite hemangioendothelioma</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000774170__153">Kaposi sarcoma</a>.</div></li></ul><div id="CDR0000774170__319"><h3>Pseudomyogenic Hemangioendothelioma</h3><div id="CDR0000774170__320"><h4>Incidence and outcome</h4><p id="CDR0000774170__321">Pseudomyogenic hemangioendothelioma is a rare, newly designated, distinct vascular tumor. It is characterized as an intermediate-grade tumor with moderately aggressive local spread and rare distant metastatic disease.</p></div><div id="CDR0000774170__322"><h4>Pathology and biology</h4><p id="CDR0000774170__323">Pseudomyogenic hemangioendothelioma is characterized by loose fascicles of plump spindle and epithelioid cells with abundant eosinophils, cytoplasm, and coexpression of keratins and endothelial markers.[<a class="bk_pop" href="#CDR0000774170_rl_90_1">1</a>-<a class="bk_pop" href="#CDR0000774170_rl_90_3">3</a>]
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||
The etiology for this tumor is unclear, although a balanced translocation t(7;19) resulting in the <i>SERPINE1-FOSB</i> fusion gene was reported.[<a class="bk_pop" href="#CDR0000774170_rl_90_4">4</a>]</p></div><div id="CDR0000774170__324"><h4>Clinical presentation and diagnostic evaluation</h4><p id="CDR0000774170__325">The tumor usually presents in young men aged 20 to 50 years.[<a class="bk_pop" href="#CDR0000774170_rl_90_1">1</a>,<a class="bk_pop" href="#CDR0000774170_rl_90_2">2</a>] Multifocal disease occurs in 70% of patients. Sites of involvement include the dermis, subcutis, and bones. Patients usually present with pain or a soft tissue mass.[<a class="bk_pop" href="#CDR0000774170_rl_90_1">1</a>,<a class="bk_pop" href="#CDR0000774170_rl_90_5">5</a>]</p></div><div id="CDR0000774170__326"><h4>Treatment of pseudomyogenic hemangioendothelioma</h4><p id="CDR0000774170__327">Most patients are treated with surgery, including amputation with multifocal bony disease.[<a class="bk_pop" href="#CDR0000774170_rl_90_1">1</a>] In reported cases, chemotherapy has had limited response. Recently, the mammalian target of rapamycin (mTOR) inhibitors have been considered as treatment options.[<a class="bk_pop" href="#CDR0000774170_rl_90_6">6</a>,<a class="bk_pop" href="#CDR0000774170_rl_90_7">7</a>]</p></div></div><div id="CDR0000774170__91"><h3>Retiform Hemangioendothelioma</h3><div id="CDR0000774170__92"><h4>Pathology and clinical presentation</h4><p id="CDR0000774170__93">Retiform hemangioendotheliomas are slow growing, exophytic, flat tumors found in young adults and occasionally children.[<a class="bk_pop" href="#CDR0000774170_rl_90_8">8</a>] They are usually located in the limbs and trunk. Histologically, they are located in the dermis and subcutaneous tissue. Vessels exhibit a pattern resembling the rete testis and are lined by protruding endothelial cells. They do not express lymphatic markers but stain positive for endothelial markers.[<a class="bk_pop" href="#CDR0000774170_rl_90_9">9</a>]</p></div><div id="CDR0000774170__94"><h4>Prognostic factors</h4><p id="CDR0000774170__95">Local recurrences are common, but distinct metastases are extremely rare.[<a class="bk_pop" href="#CDR0000774170_rl_90_9">9</a>]</p></div><div id="CDR0000774170__96"><h4>Treatment of retiform hemangioendothelioma</h4><p id="CDR0000774170__97">Surgical excision with adequate surgical tumor margins and monitoring for local recurrence is the treatment for this tumor. There are case reports of the use of radiation therapy and chemotherapy for inoperable and recurrent tumors.[<a class="bk_pop" href="#CDR0000774170_rl_90_10">10</a>-<a class="bk_pop" href="#CDR0000774170_rl_90_13">13</a>]</p></div></div><div id="CDR0000774170__98"><h3>Papillary Intralymphatic Angioendothelioma</h3><div id="CDR0000774170__99"><h4>Pathology and clinical presentation</h4><p id="CDR0000774170__100">Papillary intralymphatic angioendothelioma, also known as Dabska tumor, can occur in the adult and pediatric population.[<a class="bk_pop" href="#CDR0000774170_rl_90_14">14</a>] The lesions occur in the dermis and subcutis on all body parts and there have been some reports of lymph node involvement. They can be large or small raised purplish firm nodules.</p><p id="CDR0000774170__101">Pathologically, they reveal intravascular growth of well-differentiated endothelial cells in a columnar configuration. They have thickened hyaline walls with hobnailed endothelium. Vascular endothelial growth factor receptor type 3, a marker for lymphatic endothelium, is positive in most cases. There is minimal cytologic atypia.[<a class="bk_pop" href="#CDR0000774170_rl_90_15">15</a>] Some are associated with vascular malformations.</p></div><div id="CDR0000774170__102"><h4>Treatment of papillary intralymphatic angioendothelioma</h4><p id="CDR0000774170__103">Surgical excision is the treatment of choice.[<a class="bk_pop" href="#CDR0000774170_rl_90_16">16</a>]</p></div></div><div id="CDR0000774170__146"><h3>Composite Hemangioendothelioma</h3><div id="CDR0000774170__147"><h4>Pathology and clinical presentation</h4><p id="CDR0000774170__148">Composite hemangioendothelioma is a very rare vascular tumor classified because of the combined benign and malignant vascular components. Usually, combined epithelioid and retiform variants are noted but some tumors have three components (epithelioid, retiform, and spindle cell).[<a class="bk_pop" href="#CDR0000774170_rl_90_17">17</a>] Angiosarcoma foci have been noted. Pathology reveals positivity for CD31, factor VIII, and vimentin.[<a class="bk_pop" href="#CDR0000774170_rl_90_17">17</a>,<a class="bk_pop" href="#CDR0000774170_rl_90_18">18</a>] Rarely, D-240 is positive with a Ki-67 index of approximately 20%.[<a class="bk_pop" href="#CDR0000774170_rl_90_17">17</a>]</p><p id="CDR0000774170__210">This tumor usually occurs in the dermis and subcutis of the distal extremities but has been found in other areas such as the head, neck, and mediastinum.[<a class="bk_pop" href="#CDR0000774170_rl_90_17">17</a>] They have been reported in all age groups.[<a class="bk_pop" href="#CDR0000774170_rl_90_17">17</a>] </p></div><div id="CDR0000774170__149"><h4>Prognostic factors</h4><p id="CDR0000774170__150">Composite hemangioendotheliomas recur locally and rarely metastasize.[<a class="bk_pop" href="#CDR0000774170_rl_90_17">17</a>,<a class="bk_pop" href="#CDR0000774170_rl_90_18">18</a>] Regional lymph nodes are the most likely site of metastasis and need imaging evaluation.[<a class="bk_pop" href="#CDR0000774170_rl_90_17">17</a>]</p></div><div id="CDR0000774170__151"><h4>Treatment of composite hemangioendothelioma</h4><p id="CDR0000774170__152">Surgical removal is the treatment of choice, although radiation therapy and chemotherapy have been used for metastatic disease.[<a class="bk_pop" href="#CDR0000774170_rl_90_19">19</a>,<a class="bk_pop" href="#CDR0000774170_rl_90_20">20</a>]</p></div></div><div id="CDR0000774170__153"><h3>Kaposi Sarcoma</h3><div id="CDR0000774170__154"><h4>Pathology and clinical presentation</h4><p id="CDR0000774170__155">Kaposi sarcoma (KS) is a rare malignant vascular tumor associated with a viral etiology (human herpesvirus 8).[<a class="bk_pop" href="#CDR0000774170_rl_90_21">21</a>] The skin lesions were first described in 1872 by Moritz Kaposi. The incidence has increased worldwide secondary to the HIV-AIDS epidemic. It is an extremely rare diagnosis in children. Epidemic and iatrogenic forms of Kaposi sarcoma in children result from profound acquired T-cell deficiency that results from HIV infection and rare immune disorders.</p><p id="CDR0000774170__156">A retrospective study has investigated the presentation of Kaposi sarcoma in children in endemic areas of Africa. Children usually present with cutaneous lesions, lymphadenopathy, and intrathoracic and oral lesions. Cutaneous lesions initially appear as red, purple, or brown macules, later developing into plaques and then nodules.[<a class="bk_pop" href="#CDR0000774170_rl_90_22">22</a>-<a class="bk_pop" href="#CDR0000774170_rl_90_24">24</a>]</p><p id="CDR0000774170__299">Kaposi sarcoma is exceedingly rare in the pediatric population and is usually associated with immunocompromised states such as HIV infection or solid organ transplant.</p></div><div id="CDR0000774170__157"><h4>Treatment of Kaposi sarcoma</h4><p id="CDR0000774170__158">Children with Kaposi sarcoma have responded to treatment with chemotherapy regimens, including bleomycin, vincristine, and taxanes, although there are no prospective clinical trials. Other treatment options have been based on adult studies (see below).</p><p id="CDR0000774170__288">Because Kaposi sarcoma is rare in the pediatric population, there are no evidence-based studies. Even in adults, the evidence and quality of studies is inferior and it is difficult to recommend particular treatment regimens. Fifty-six Malawian children aged 3 to 12 years with Kaposi sarcoma were treated with six courses of vincristine, bleomycin, and oral etoposide. This was a high-risk population because 48 of the patients (86%) were HIV positive, of whom 36 (77%) were on antiretroviral therapy. Quality of life improved in 45 patients (80%). Eighteen patients (32%) had a complete remission. At 12 months, the overall survival rate was 71%, and the event-free survival rate was 50%.[<a class="bk_pop" href="#CDR0000774170_rl_90_25">25</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>]</p><p id="CDR0000774170__314">In a systematic review of treatment for classic Kaposi sarcoma, 26 articles published from 1980 to 2010 were reviewed; articles describing populations at high risk secondary to previous transplantation and endemic and epidemic Kaposi sarcoma were excluded.[<a class="bk_pop" href="#CDR0000774170_rl_90_26">26</a>] All articles had a minimum of five patients per intervention. A greater than 50% decrease in the size of the lesions or lymphedema was considered a response. The quality of the articles was considered poor, primarily because of lack of uniform staging criteria and variable means of assessing response. The following response rates for systemic treatments were noted:</p><ul id="CDR0000774170__311"><li class="half_rhythm"><div> Pegylated doxorubicin—71% to 100%.</div></li><li class="half_rhythm"><div>Vinca alkaloids—58% to 90%.</div></li><li class="half_rhythm"><div> Etoposide—74% to 76%.</div></li><li class="half_rhythm"><div> Taxanes—93% to 100%.</div></li><li class="half_rhythm"><div> Gemcitabine—100%.</div></li><li class="half_rhythm"><div>Vinblastine and bleomycin—97%.</div></li><li class="half_rhythm"><div>Interferon alfa-2—71% to 100%.</div></li></ul><p id="CDR0000774170__312">For local therapies, the following response rates were reported: </p><ul id="CDR0000774170__313"><li class="half_rhythm"><div> Intralesional vincristine—62%.</div></li><li class="half_rhythm"><div> Intralesional interferon alfa-2—50% to 90%.</div></li><li class="half_rhythm"><div> Imiquimod—56%.</div></li><li class="half_rhythm"><div> Radiation therapy—63% to 93%.</div></li></ul><p id="CDR0000774170__289"> (Refer to the PDQ summary on <a href="/books/n/pdqcis/CDR0000062914/">Kaposi Sarcoma Treatment</a> for information about the treatment of Kaposi sarcoma in adults.)</p></div></div><div id="CDR0000774170_rl_90"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000774170_rl_90_1">Hornick JL, Fletcher CD: Pseudomyogenic hemangioendothelioma: a distinctive, often multicentric tumor with indolent behavior. Am J Surg Pathol 35 (2): 190-201, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21263239" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21263239</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_2">Billings SD, Folpe AL, Weiss SW: Epithelioid sarcoma-like hemangioendothelioma. Am J Surg Pathol 27 (1): 48-57, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12502927" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12502927</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_3">Mirra JM, Kessler S, Bhuta S, et al.: The fibroma-like variant of epithelioid sarcoma. A fibrohistiocytic/myoid cell lesion often confused with benign and malignant spindle cell tumors. Cancer 69 (6): 1382-95, 1992. [<a href="https://pubmed.ncbi.nlm.nih.gov/1371711" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1371711</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_4">Walther C, Tayebwa J, Lilljebjörn H, et al.: A novel SERPINE1-FOSB fusion gene results in transcriptional up-regulation of FOSB in pseudomyogenic haemangioendothelioma. J Pathol 232 (5): 534-40, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24374978" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24374978</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_5">Amary MF, O'Donnell P, Berisha F, et al.: Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma: characterization of five cases. Skeletal Radiol 42 (7): 947-57, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23381465" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23381465</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_6">Joseph J, Wang WL, Patnana M, et al.: Cytotoxic and targeted therapy for treatment of pseudomyogenic hemangioendothelioma. Clin Sarcoma Res 5: 22, 2015. [<a href="/pmc/articles/PMC4615364/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4615364</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26500758" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26500758</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_7">Ozeki M, Nozawa A, Kanda K, et al.: Everolimus for Treatment of Pseudomyogenic Hemangioendothelioma. J Pediatr Hematol Oncol 39 (6): e328-e331, 2017. [<a href="https://pubmed.ncbi.nlm.nih.gov/28121744" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28121744</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_8">El Darouti M, Marzouk SA, Sobhi RM, et al.: Retiform hemangioendothelioma. Int J Dermatol 39 (5): 365-8, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10849129" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10849129</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_9">Colmenero I, Hoeger PH: Vascular tumours in infants. Part II: vascular tumours of intermediate malignancy [corrected] and malignant tumours. Br J Dermatol 171 (3): 474-84, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24965196" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24965196</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_10">Keiler SA, Honda K, Bordeaux JS: Retiform hemangioendothelioma treated with Mohs micrographic surgery. J Am Acad Dermatol 65 (1): 233-5, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21679834" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21679834</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_11">Hirsh AZ, Yan W, Wei L, et al.: Unresectable retiform hemangioendothelioma treated with external beam radiation therapy and chemotherapy: a case report and review of the literature. Sarcoma 2010: , 2010. [<a href="/pmc/articles/PMC2948930/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2948930</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20936126" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20936126</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_12">Enjolras O, Mulliken JB, Kozakewich HPW: Vascular tumors and tumor-like lesions. In: Mulliken JB, Burrows PE, Fishman SJ, eds.: Mulliken & Young's Vascular Anomalies: Hemangiomas and Malformations. 2nd ed. New York, NY: Oxford University Press, 2013, pp 259-324.</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_13">Tamhankar AS, Vaidya A, Pai P: Retiform hemangioendothelioma over forehead: A rare tumor treated with chemoradiation and a review of literature. J Cancer Res Ther 11 (3): 657, 2015 Jul-Sep. [<a href="https://pubmed.ncbi.nlm.nih.gov/26458658" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26458658</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_14">Dabska M: Malignant endovascular papillary angioendothelioma of the skin in childhood. Clinicopathologic study of 6 cases. Cancer 24 (3): 503-10, 1969. [<a href="https://pubmed.ncbi.nlm.nih.gov/5343389" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 5343389</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_15">Fanburr-Smith JC: Papillary intralymphatic angioendothelioma. In: Fletcher CDM, Bridge JA, Hogendoorn P, et al., eds.: WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon, France: IARC Press, 2013, pp 148.</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_16">Neves RI, Stevenson J, Hancey MJ, et al.: Endovascular papillary angioendothelioma (Dabska tumor): underrecognized malignant tumor in childhood. J Pediatr Surg 46 (1): e25-8, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21238627" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21238627</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_17">Shang Leen SL, Fisher C, Thway K: Composite hemangioendothelioma: clinical and histologic features of an enigmatic entity. Adv Anat Pathol 22 (4): 254-9, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/26050262" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26050262</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_18">Mahmoudizad R, Samrao A, Bentow JJ, et al.: Composite hemangioendothelioma: An unusual presentation of a rare vascular tumor. Am J Clin Pathol 141 (5): 732-6, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24713748" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24713748</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_19">Tateishi J, Saeki H, Ito K, et al.: Cutaneous composite hemangioendothelioma on the nose treated with electron beam. Int J Dermatol 52 (12): 1618-9, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/22998114" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22998114</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_20">Soldado F, Fontecha CG, Haddad S, et al.: Composite vascularized fibular epiphyseo-osteo-periosteal transfer for hip reconstruction after proximal femoral tumoral resection in a 4-year-old child. Microsurgery 32 (6): 489-92, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22511340" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22511340</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_21">Jackson CC, Dickson MA, Sadjadi M, et al.: Kaposi Sarcoma of Childhood: Inborn or Acquired Immunodeficiency to Oncogenic HHV-8. Pediatr Blood Cancer 63 (3): 392-7, 2016. [<a href="/pmc/articles/PMC4984265/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4984265</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26469702" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26469702</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_22">Dow DE, Cunningham CK, Buchanan AM: A Review of Human Herpesvirus 8, the Kaposi's Sarcoma-Associated Herpesvirus, in the Pediatric Population. J Pediatric Infect Dis Soc 3 (1): 66-76, 2014. [<a href="/pmc/articles/PMC3933043/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3933043</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24567845" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24567845</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_23">El-Mallawany NK, Kamiyango W, Slone JS, et al.: Clinical Factors Associated with Long-Term Complete Remission versus Poor Response to Chemotherapy in HIV-Infected Children and Adolescents with Kaposi Sarcoma Receiving Bleomycin and Vincristine: A Retrospective Observational Study. PLoS One 11 (4): e0153335, 2016. [<a href="/pmc/articles/PMC4833299/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4833299</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27082863" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27082863</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_24">Rees CA, Keating EM, Lukolyo H, et al.: Mapping the Epidemiology of Kaposi Sarcoma and Non-Hodgkin Lymphoma Among Children in Sub-Saharan Africa: A Review. Pediatr Blood Cancer 63 (8): 1325-31, 2016. [<a href="/pmc/articles/PMC7340190/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7340190</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27082516" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27082516</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_25">Macken M, Dale H, Moyo D, et al.: Triple therapy of vincristine, bleomycin and etoposide for children with Kaposi sarcoma: Results of a study in Malawian children. Pediatr Blood Cancer 65 (2): , 2018. [<a href="https://pubmed.ncbi.nlm.nih.gov/28988435" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28988435</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_90_26">Régnier-Rosencher E, Guillot B, Dupin N: Treatments for classic Kaposi sarcoma: a systematic review of the literature. J Am Acad Dermatol 68 (2): 313-31, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/22695100" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22695100</span></a>]</div></li></ol></div></div><div id="CDR0000774170__104"><h2 id="_CDR0000774170__104_">Malignant Tumors</h2><p id="CDR0000774170__273">Malignant vascular tumors include the following:</p><ul id="CDR0000774170__274"><li class="half_rhythm"><div><a href="#CDR0000774170__191">Epithelioid hemangioendothelioma</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000774170__192">Angiosarcoma of the soft tissue</a>.</div></li></ul><div id="CDR0000774170__191"><h3>Epithelioid Hemangioendothelioma</h3><div id="CDR0000774170__sm_CDR0000779194_105"><h4>Incidence and outcome</h4><p id="CDR0000774170__sm_CDR0000779194_108">This tumor was first described in soft tissue by Weiss and Enzinger in 1982. Epithelioid hemangioendotheliomas can occur at younger ages, but the peak incidence is in the fourth and fifth decades of life. The tumors can have an indolent or very aggressive course, with overall survival of 73% at 5 years. There are case reports of patients with untreated multiple lesions who have a very benign course compared with other patients who have a very aggressive course. Some pathologists have tried to stratify patients to evaluate risks and adjust treatment, but more research is needed.[<a class="bk_pop" href="#CDR0000774170_rl_104_1">1</a>-<a class="bk_pop" href="#CDR0000774170_rl_104_7">7</a>]</p><p id="CDR0000774170__sm_CDR0000779194_124">The presence of effusions, tumor size larger than 3 cm, and a high mitotic index (>3 mitoses/50 high-power fields) have been associated with unfavorable outcomes.[<a class="bk_pop" href="#CDR0000774170_rl_104_3">3</a>]</p></div><div id="CDR0000774170__sm_CDR0000779194_109"><h4>Pathology and biology</h4><p id="CDR0000774170__sm_CDR0000779194_110">A <i>WWTR1-CAMTA1</i> gene fusion has been found in a large percentage of patients; less commonly, a <i>YAP1-TFE3</i> gene fusion has been reported.[<a class="bk_pop" href="#CDR0000774170_rl_104_1">1</a>] These fusions are not directly targetable with current medicines. Monoclonality has been described in multiple liver lesions, suggesting a metastatic process.</p><p id="CDR0000774170__sm_CDR0000779194_119">Histologically, these lesions are characterized as epithelioid lesions arranged in nests, strands, and trabecular patterns, with infrequent vascular spaces. Features that may be associated with aggressive clinical behavior include cellular atypia, one or more mitoses per 10 high-power fields, an increased proportion of spindled cells, focal necrosis, and metaplastic bone formation.[<a class="bk_pop" href="#CDR0000774170_rl_104_3">3</a>]</p><p id="CDR0000774170__sm_CDR0000779194_128">The number of pediatric patients reported in the literature is limited.</p></div><div id="CDR0000774170__sm_CDR0000779194_106"><h4>Clinical presentation and diagnostic evaluation</h4><p id="CDR0000774170__sm_CDR0000779194_107">Common sites of involvement are liver alone (21%), liver plus lung (18%), lung alone (12%), and bone alone (14%).[<a class="bk_pop" href="#CDR0000774170_rl_104_3">3</a>,<a class="bk_pop" href="#CDR0000774170_rl_104_8">8</a>,<a class="bk_pop" href="#CDR0000774170_rl_104_9">9</a>] Clinical presentation depends on site of involvement, as follows: </p><ul id="CDR0000774170__sm_CDR0000779194_113"><li class="half_rhythm"><div><b>Liver:</b> Hepatic nodules have central vascularity on ultrasound, contrast-enhancing lesions by computed tomography, and low T1 signal and moderate T2 signal on magnetic resonance imaging. </div></li><li class="half_rhythm"><div><b>Lung:</b> Pulmonary epithelioid hemangioendothelioma may be an asymptomatic finding on chest x-ray or be associated with pleuritic pain, hemoptysis, anemia, and fibrosis.</div></li><li class="half_rhythm"><div><b>Bone:</b> Bone metastasis may be associated with pathologic fracture. On x-rays, they are well-defined osteolytic lesions and can be multiple or solitary.</div></li><li class="half_rhythm"><div><b>Soft tissue:</b> Thirty percent of soft tissue cases are associated with metastases, and when present, can have a very aggressive course, with limited response to chemotherapy.</div></li><li class="half_rhythm"><div><b>Skin:</b> Cutaneous lesions can be raised and nodular or can be warm red-brown plaques.</div></li></ul></div><div id="CDR0000774170__sm_CDR0000779194_111"><h4>Treatment of epithelioid hemangioendothelioma</h4><p id="CDR0000774170__sm_CDR0000779194_115">Treatment options for epithelioid hemangioendothelioma include the following:</p><ol id="CDR0000774170__sm_CDR0000779194_116"><li class="half_rhythm"><div>Observation.</div></li><li class="half_rhythm"><div>Surgery.</div></li><li class="half_rhythm"><div>Immunotherapy.</div></li><li class="half_rhythm"><div>Targeted therapy.</div></li><li class="half_rhythm"><div>Chemotherapy.</div></li></ol><p id="CDR0000774170__sm_CDR0000779194_112">For indolent cases, observation is warranted. For more aggressive cases, multiple medications have been used, including interferon, thalidomide, sorafenib, pazopanib, and sirolimus.[<a class="bk_pop" href="#CDR0000774170_rl_104_10">10</a>] The most aggressive cases are treated with angiosarcoma-type chemotherapy. Surgery is used when possible. Liver transplantation has been used with aggressive liver lesions, both with and without metastases.[<a class="bk_pop" href="#CDR0000774170_rl_104_3">3</a>,<a class="bk_pop" href="#CDR0000774170_rl_104_11">11</a>-<a class="bk_pop" href="#CDR0000774170_rl_104_14">14</a>]</p></div><div id="CDR0000774170__sm_CDR0000779194_120"><h4>Treatment options under clinical evaluation for epithelioid hemangioendothelioma</h4><p id="CDR0000774170__sm_CDR0000779194_121">Information about National Cancer Institute (NCI)–supported clinical trials can be found on the <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>. For information about clinical trials sponsored by other organizations, refer to the <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov website</a>.</p><p id="CDR0000774170__sm_CDR0000779194_136">The following are examples of national and/or institutional clinical trials that are currently being conducted:</p><ol id="CDR0000774170__sm_CDR0000779194_123"><li class="half_rhythm"><div><b><a href="https://www.cancer.gov/clinicaltrials/NCT03148275" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT03148275</a></b> (Trametinib in Treating Patients with Epithelioid Hemangioendothelioma That Is Metastatic, Locally Advanced, or Cannot Be Removed by Surgery)<b>:</b> This is a phase II trial assessing the efficacy of trametinib, with patient-reported outcomes as secondary aims.</div></li><li class="half_rhythm"><div><b><a href="https://www.cancer.gov/clinicaltrials/NCT01532687" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT01532687</a></b> (Gemcitabine Hydrochloride With or Without Pazopanib Hydrochloride in Treating Patients With Refractory Soft Tissue Sarcoma)<b>:</b> This randomized phase II trial studies how well gemcitabine hydrochloride works with or without pazopanib hydrochloride in treating patients with refractory soft tissue sarcoma.
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</div></li></ol><div id="CDR0000774170__TrialSearch_sm_CDR0000779194_120_sid_7"><h5>Current Clinical Trials</h5><p id="CDR0000774170__TrialSearch_sm_CDR0000779194_120_22">Use our <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/advanced-search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">advanced clinical trial search</a> to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">General information</a> about clinical trials is also available.</p></div></div></div><div id="CDR0000774170__192"><h3>Angiosarcoma of the Soft Tissue</h3><div id="CDR0000774170__sm_CDR0000779195_114"><h4>Incidence</h4><p id="CDR0000774170__sm_CDR0000779195_115">Angiosarcoma is a rare (accounting for 2% of sarcomas), aggressive, vascular tumor that can arise in any part of the body, but is more common in the soft tissue. Angiosarcoma has an estimated incidence of 2 cases per 1 million people; in the United States, it annually affects approximately 600 people who are typically aged 60 to 70 years.[<a class="bk_pop" href="#CDR0000774170_rl_104_15">15</a>] </p><p id="CDR0000774170__sm_CDR0000779195_165">Angiosarcomas are extremely rare in children and it is unclear if the pathophysiology of this tumor is different in the pediatric population. Cases have been reported in neonates and toddlers, with presentation of multiple cutaneous lesions and liver lesions, some of which are <i>GLUT1</i> positive.[<a class="bk_pop" href="#CDR0000774170_rl_104_16">16</a>-<a class="bk_pop" href="#CDR0000774170_rl_104_19">19</a>] Most angiosarcomas involve the skin and superficial soft tissue, although the liver, spleen, and lung can be affected; bone is rarely affected.</p></div><div id="CDR0000774170__sm_CDR0000779195_116"><h4>Risk factors</h4><p id="CDR0000774170__sm_CDR0000779195_117">Established risk factors include vinyl chloride exposure, radiation exposure, and chronic lymphedema from any cause, including Stewart-Treves syndrome.[<a class="bk_pop" href="#CDR0000774170_rl_104_20">20</a>]</p></div><div id="CDR0000774170__sm_CDR0000779195_118"><h4>Pathology and biology</h4><p id="CDR0000774170__sm_CDR0000779195_119">Angiosarcomas are largely aneuploid tumors. The rare cases of angiosarcoma that arise from benign lesions such as hemangiomas have a distinct pathway that needs to be investigated. <i>MYC</i> amplification is seen in radiation-induced angiosarcoma. <i>KDR-VEGFR2</i> mutations and <i>FLT4-VEGFR3</i> amplifications have been seen with a frequency of less than 50%.[<a class="bk_pop" href="#CDR0000774170_rl_104_20">20</a>]</p><p id="CDR0000774170__sm_CDR0000779195_120">Histopathologic diagnosis can be very difficult because there can be areas of varied atypia. The common feature is an irregular network of channels in a dissective pattern along dermal collagen bundles. There is varied cellular shape, size, mitosis, endothelial multilayering, and papillary formation. Epithelioid cells can also be present. Necrosis and hemorrhage are common. Tumors stain for factor VIII, CD31, and CD34. Some liver lesions can mimic infantile hemangiomas and have focal <i>GLUT1</i> positivity. Nomenclature of these liver lesions has been difficult and confusing with use of terminology from 1971 (e.g., type I hemangioendothelioma: infantile hemangioma; type II hemangioendothelioma: low-grade angiosarcoma; type III hemangioendothelioma: high-grade angiosarcoma).[<a class="bk_pop" href="#CDR0000774170_rl_104_17">17</a>]</p></div><div id="CDR0000774170__sm_CDR0000779195_122"><h4>Treatment of angiosarcoma of the soft tissue</h4><p id="CDR0000774170__sm_CDR0000779195_167">Treatment options for angiosarcoma of the soft tissue include the following:</p><ol id="CDR0000774170__sm_CDR0000779195_173"><li class="half_rhythm"><div>Surgery (localized disease).</div></li><li class="half_rhythm"><div>Radiation therapy (localized cutaneous disease in adults).</div></li><li class="half_rhythm"><div>Surgery, chemotherapy, and radiation therapy (metastatic disease).</div></li></ol><p id="CDR0000774170__sm_CDR0000779195_163">Localized disease is cured by aggressive surgery. Complete surgical excision
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appears to be crucial for angiosarcomas and lymphangiosarcomas despite evidence
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of tumor shrinkage in some patients who were treated with local or systemic therapy.[<a class="bk_pop" href="#CDR0000774170_rl_104_18">18</a>,<a class="bk_pop" href="#CDR0000774170_rl_104_21">21</a>-<a class="bk_pop" href="#CDR0000774170_rl_104_23">23</a>] A review of 222 patients (median age, 62 years; range, age 15–90 years) showed an overall disease-specific survival (DSS) rate of 38% at 5 years. Five-year DSS was 44% in 138 patients with localized, resected tumors but only 16% in 43 patients with metastases at diagnosis.[<a class="bk_pop" href="#CDR0000774170_rl_104_23">23</a>] Data on liver transplantation for localized angiosarcoma are limited.[<a class="bk_pop" href="#CDR0000774170_rl_104_24">24</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000335144/" class="def">Level of evidence: 3iiA</a>]</p><p id="CDR0000774170__sm_CDR0000779195_181">Localized disease, especially cutaneous angiosarcoma, can be treated with radiation therapy. Most of these reported cases are in adults.[<a class="bk_pop" href="#CDR0000774170_rl_104_25">25</a>]</p><p id="CDR0000774170__sm_CDR0000779195_123">Multimodal treatment with surgery, systemic chemotherapy, and radiation therapy is used for metastatic disease, although it is rarely curative.[<a class="bk_pop" href="#CDR0000774170_rl_104_26">26</a>] Disease control is the objective in metastatic angiosarcoma, with published progression-free survival rates between 3 months and 7 months [<a class="bk_pop" href="#CDR0000774170_rl_104_27">27</a>] and a median overall survival (OS) rate of 14 months to 18 months.[<a class="bk_pop" href="#CDR0000774170_rl_104_28">28</a>] In both adults and children, 5-year OS rates between 20% and 35% are reported.[<a class="bk_pop" href="#CDR0000774170_rl_104_18">18</a>,<a class="bk_pop" href="#CDR0000774170_rl_104_19">19</a>,<a class="bk_pop" href="#CDR0000774170_rl_104_29">29</a>]
|
||
</p><p id="CDR0000774170__sm_CDR0000779195_169">In a child diagnosed with angiosarcoma secondary to malignant transformation from infantile hemangioma, response to treatment with bevacizumab, a monoclonal antibody against vascular endothelial growth factor, combined with systemic chemotherapy, has been reported.[<a class="bk_pop" href="#CDR0000774170_rl_104_16">16</a>,<a class="bk_pop" href="#CDR0000774170_rl_104_26">26</a>] A report of eight cases of liver angiosarcoma in children highlighted the misuse of the term <i>hemangioendothelioma</i> and the importance of early diagnosis and treatment of these tumors.[<a class="bk_pop" href="#CDR0000774170_rl_104_30">30</a>]</p><p id="CDR0000774170__sm_CDR0000779195_124">Biologic agents that inhibit angiogenesis have shown activity in adults with angiosarcoma.[<a class="bk_pop" href="#CDR0000774170_rl_104_17">17</a>,<a class="bk_pop" href="#CDR0000774170_rl_104_29">29</a>]</p></div><div id="CDR0000774170__sm_CDR0000779195_170"><h4>Treatment options under clinical evaluation for angiosarcoma of the soft tissue</h4><p id="CDR0000774170__sm_CDR0000779195_171">Information about National Cancer Institute (NCI)–supported clinical trials can be found on the <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>. For information about clinical trials sponsored by other organizations, refer to the <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov website</a>.</p><p id="CDR0000774170__sm_CDR0000779195_191">The following is an example of a national and/or institutional clinical trial that is currently being conducted:</p><ol id="CDR0000774170__sm_CDR0000779195_178"><li class="half_rhythm"><div><b><a href="https://www.cancer.gov/clinicaltrials/NCT01532687" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT01532687</a></b> (Gemcitabine Hydrochloride With or Without Pazopanib Hydrochloride in Treating Patients With Refractory Soft Tissue Sarcoma)<b>:</b> This randomized phase II trial studies how well gemcitabine hydrochloride works with or without pazopanib hydrochloride in treating patients with refractory soft tissue sarcoma. </div></li></ol><div id="CDR0000774170__TrialSearch_sm_CDR0000779195_170_sid_7"><h5>Current Clinical Trials</h5><p id="CDR0000774170__TrialSearch_sm_CDR0000779195_170_22">Use our <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/advanced-search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">advanced clinical trial search</a> to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">General information</a> about clinical trials is also available.</p></div></div></div><div id="CDR0000774170_rl_104"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000774170_rl_104_1">Mehrabi A, Kashfi A, Fonouni H, et al.: Primary malignant hepatic epithelioid hemangioendothelioma: a comprehensive review of the literature with emphasis on the surgical therapy. Cancer 107 (9): 2108-21, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/17019735" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17019735</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_2">Haro A, Saitoh G, Tamiya S, et al.: Four-year natural clinical course of pulmonary epithelioid hemangioendothelioma without therapy. Thorac Cancer 6 (4): 544-7, 2015. [<a href="/pmc/articles/PMC4511336/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4511336</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26273413" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26273413</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_3">Sardaro A, Bardoscia L, Petruzzelli MF, et al.: Epithelioid hemangioendothelioma: an overview and update on a rare vascular tumor. Oncol Rev 8 (2): 259, 2014. [<a href="/pmc/articles/PMC4419652/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4419652</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25992243" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25992243</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_4">Dong K, Wang XX, Feng JL, et al.: Pathological characteristics of liver biopsies in eight patients with hepatic epithelioid hemangioendothelioma. Int J Clin Exp Pathol 8 (9): 11015-23, 2015. [<a href="/pmc/articles/PMC4637634/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4637634</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26617819" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26617819</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_5">Adams DM, Hammill A: Other vascular tumors. Semin Pediatr Surg 23 (4): 173-7, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/25241094" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25241094</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_6">Xiao Y, Wang C, Song Y, et al.: Primary epithelioid hemangioendothelioma of the kidney: the first case report in a child and literature review. Urology 82 (4): 925-7, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23726166" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23726166</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_7">Reich S, Ringe H, Uhlenberg B, et al.: Epithelioid hemangioendothelioma of the lung presenting with pneumonia and heart rhythm disturbances in a teenage girl. J Pediatr Hematol Oncol 32 (4): 274-6, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20445417" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20445417</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_8">Daller JA, Bueno J, Gutierrez J, et al.: Hepatic hemangioendothelioma: clinical experience and management strategy. J Pediatr Surg 34 (1): 98-105; discussion 105-6, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10022152" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10022152</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_9">Ackermann O, Fabre M, Franchi S, et al.: Widening spectrum of liver angiosarcoma in children. J Pediatr Gastroenterol Nutr 53 (6): 615-9, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21832953" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21832953</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_10">Stacchiotti S, Provenzano S, Dagrada G, et al.: Sirolimus in Advanced Epithelioid Hemangioendothelioma: A Retrospective Case-Series Analysis from the Italian Rare Cancer Network Database. Ann Surg Oncol 23 (9): 2735-44, 2016. [<a href="https://pubmed.ncbi.nlm.nih.gov/27334221" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27334221</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_11">Semenisty V, Naroditsky I, Keidar Z, et al.: Pazopanib for metastatic pulmonary epithelioid hemangioendothelioma-a suitable treatment option: case report and review of anti-angiogenic treatment options. BMC Cancer 15: 402, 2015. [<a href="/pmc/articles/PMC4437555/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4437555</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25967676" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25967676</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_12">Raheja A, Suri A, Singh S, et al.: Multimodality management of a giant skull base hemangioendothelioma of the sphenopetroclival region. J Clin Neurosci 22 (9): 1495-8, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25986183" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25986183</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_13">Ahmad N, Adams DM, Wang J, et al.: Hepatic epithelioid hemangioendothelioma in a patient with hemochromatosis. J Natl Compr Canc Netw 12 (9): 1203-7, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/25190690" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25190690</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_14">Otte JB, Zimmerman A: The role of liver transplantation for pediatric epithelioid hemangioendothelioma. Pediatr Transplant 14 (3): 295-7, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20331517" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20331517</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_15">Cioffi A, Reichert S, Antonescu CR, et al.: Angiosarcomas and other sarcomas of endothelial origin. Hematol Oncol Clin North Am 27 (5): 975-88, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/24093171" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24093171</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_16">Jeng MR, Fuh B, Blatt J, et al.: Malignant transformation of infantile hemangioma to angiosarcoma: response to chemotherapy with bevacizumab. Pediatr Blood Cancer 61 (11): 2115-7, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24740626" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24740626</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_17">Dehner LP, Ishak KG: Vascular tumors of the liver in infants and children. A study of 30 cases and review of the literature. Arch Pathol 92 (2): 101-11, 1971. [<a href="https://pubmed.ncbi.nlm.nih.gov/5559952" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 5559952</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_18">Ferrari A, Casanova M, Bisogno G, et al.: Malignant vascular tumors in children and adolescents: a report from the Italian and German Soft Tissue Sarcoma Cooperative Group. Med Pediatr Oncol 39 (2): 109-14, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12116058" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12116058</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_19">Deyrup AT, Miettinen M, North PE, et al.: Pediatric cutaneous angiosarcomas: a clinicopathologic study of 10 cases. Am J Surg Pathol 35 (1): 70-5, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21164289" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21164289</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_20">Elliott P, Kleinschmidt I: Angiosarcoma of the liver in Great Britain in proximity to vinyl chloride sites. Occup Environ Med 54 (1): 14-8, 1997. [<a href="/pmc/articles/PMC1128629/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1128629</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/9072028" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9072028</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_21">Lezama-del Valle P, Gerald WL, Tsai J, et al.: Malignant vascular tumors in young patients. Cancer 83 (8): 1634-9, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9781959" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9781959</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_22">Fata F, O'Reilly E, Ilson D, et al.: Paclitaxel in the treatment of patients with angiosarcoma of the scalp or face. Cancer 86 (10): 2034-7, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10570428" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10570428</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_23">Lahat G, Dhuka AR, Hallevi H, et al.: Angiosarcoma: clinical and molecular insights. Ann Surg 251 (6): 1098-106, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20485141" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20485141</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_24">Orlando G, Adam R, Mirza D, et al.: Hepatic hemangiosarcoma: an absolute contraindication to liver transplantation--the European Liver Transplant Registry experience. Transplantation 95 (6): 872-7, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23354302" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23354302</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_25">Sanada T, Nakayama H, Irisawa R, et al.: Clinical outcome and dose volume evaluation in patients who undergo brachytherapy for angiosarcoma of the scalp and face. Mol Clin Oncol 6 (3): 334-340, 2017. [<a href="/pmc/articles/PMC5403362/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5403362</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28451409" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28451409</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_26">Dickson MA, D'Adamo DR, Keohan ML, et al.: Phase II Trial of Gemcitabine and Docetaxel with Bevacizumab in Soft Tissue Sarcoma. Sarcoma 2015: 532478, 2015. [<a href="/pmc/articles/PMC4446476/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4446476</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26074722" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26074722</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_27">North PE, Waner M, Mizeracki A, et al.: A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol 137 (5): 559-70, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11346333" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11346333</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_28">Boye E, Yu Y, Paranya G, et al.: Clonality and altered behavior of endothelial cells from hemangiomas. J Clin Invest 107 (6): 745-52, 2001. [<a href="/pmc/articles/PMC208946/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC208946</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11254674" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11254674</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_29">Ravi V, Patel S: Vascular sarcomas. Curr Oncol Rep 15 (4): 347-55, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23852636" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23852636</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_104_30">Grassia KL, Peterman CM, Iacobas I, et al.: Clinical case series of pediatric hepatic angiosarcoma. Pediatr Blood Cancer 64 (11): , 2017. [<a href="https://pubmed.ncbi.nlm.nih.gov/28521077" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28521077</span></a>]</div></li></ol></div></div><div id="CDR0000774170__193"><h2 id="_CDR0000774170__193_">Special Considerations for the Treatment of Children With Cancer</h2><p id="CDR0000774170__194">Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[<a class="bk_pop" href="#CDR0000774170_rl_193_1">1</a>] Children and adolescents with
|
||
cancer should be referred to medical centers that have a multidisciplinary team
|
||
of cancer specialists with experience treating the cancers that occur during
|
||
childhood and adolescence. This multidisciplinary team approach incorporates the skills
|
||
of the primary care physician, a surgeon experienced in vascular
|
||
tumors, a pathologist, radiation oncologists, pediatric oncologists,
|
||
rehabilitation specialists, pediatric nurse specialists, social workers, and
|
||
others to ensure that children receive treatment, supportive care, and
|
||
rehabilitation that will achieve optimal survival and quality of life.
|
||
(Refer to the PDQ summaries on <a href="https://www.cancer.gov/publications/pdq/information-summaries/supportive-care" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Supportive and Palliative Care</a> for specific information about supportive care for children and adolescents with cancer.) </p><p id="CDR0000774170__195">Guidelines for pediatric cancer centers and their role in the treatment of
|
||
pediatric patients with cancer have been outlined by the American Academy of
|
||
Pediatrics.[<a class="bk_pop" href="#CDR0000774170_rl_193_2">2</a>] At these pediatric cancer centers, clinical trials are
|
||
available for most types of cancer that occur in children and
|
||
adolescents, and the opportunity to participate in these trials is offered to
|
||
most patients and families. Clinical trials for children and adolescents with
|
||
cancer are generally designed to compare potentially better therapy with
|
||
therapy that is currently accepted as standard. Most of the progress
|
||
made in identifying curative therapies for childhood cancers has been achieved
|
||
through clinical trials. Information about ongoing clinical trials is
|
||
available from the <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p><p id="CDR0000774170__196">Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[<a class="bk_pop" href="#CDR0000774170_rl_193_1">1</a>] Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on <a href="/books/n/pdqcis/CDR0000343584/">Late Effects of Treatment for Childhood Cancer</a> for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)</p><div id="CDR0000774170_rl_193"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000774170_rl_193_1">Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [<a href="/pmc/articles/PMC4136455/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4136455</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24853691" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24853691</span></a>]</div></li><li><div class="bk_ref" id="CDR0000774170_rl_193_2">Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15173520" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15173520</span></a>]</div></li></ol></div></div><div id="CDR0000774170__5"><h2 id="_CDR0000774170__5_">Changes to This Summary (11/08/2018)</h2><p id="CDR0000774170__6">The PDQ cancer information summaries are reviewed regularly and updated as
|
||
new information becomes available. This section describes the latest
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changes made to this summary as of the date above.</p><p id="CDR0000774170__352"><b><a href="#CDR0000774170__3">Benign Tumors</a></b></p><p id="CDR0000774170__351">The <a href="#CDR0000774170__293">Ophthalmologic involvement of hemangiomas</a> subsection was renamed from Periorbital infantile hemangioma.</p><p id="CDR0000774170__353">Added <a href="#CDR0000774170__350">text</a> to state that infantile hemangiomas can occur in the conjunctiva. These hemangiomas can be associated with other ophthalmologic abnormalities and are treated with oral or topical beta-blockers (cited Theiler et al. as reference 26).</p><p id="CDR0000774170__354">Added <a href="#CDR0000774170__56">text</a> to state that pyogenic granulomas are usually cutaneous, but deep-seated/subcutaneous pyogenic granulomas are noted and mimic other vascular lesions (cited Putra et al. as reference 111).</p><p id="CDR0000774170__355">Added <a href="#CDR0000774170__59">text</a> to state that a study of 22 patients with pyogenic granuloma who were treated with topical 1% propranolol ointment with occlusion found that 59% of patients achieved a complete response, 18% of patients had stable disease, and 22% of patients did not respond to the treatment. In this study, only skin toxicity was assessed. The authors did not comment on the penetrance of the propranolol formulation or include a safety evaluation of the side effects such as hypoglycemia and the effects on heart rate or blood pressure (cited Neri et al. as reference 114).</p><p id="CDR0000774170__disclaimerHP_3">This summary is written and maintained by the <a href="https://www.cancer.gov/publications/pdq/editorial-boards/pediatric-treatment" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Pediatric Treatment Editorial Board</a>, which is
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editorially independent of NCI. The summary reflects an independent review of
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the literature and does not represent a policy statement of NCI or NIH. More
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information about summary policies and the role of the PDQ Editorial Boards in
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maintaining the PDQ summaries can be found on the <a href="#CDR0000774170__AboutThis_1">About This PDQ Summary</a> and <a href="https://www.cancer.gov/publications/pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ® - NCI's Comprehensive Cancer Database</a> pages.
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</p></div><div id="CDR0000774170__AboutThis_1"><h2 id="_CDR0000774170__AboutThis_1_">About This PDQ Summary</h2><div id="CDR0000774170__AboutThis_2"><h3>Purpose of This Summary</h3><p id="CDR0000774170__AboutThis_3">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood vascular tumors. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.</p></div><div id="CDR0000774170__AboutThis_4"><h3>Reviewers and Updates</h3><p id="CDR0000774170__AboutThis_5">This summary is reviewed regularly and updated as necessary by the <a href="https://www.cancer.gov/publications/pdq/editorial-boards/pediatric-treatment" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Pediatric Treatment Editorial Board</a>, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).</p><p id="CDR0000774170__AboutThis_22"> Board members review recently published articles each month to determine whether an article should:</p><ul id="CDR0000774170__AboutThis_6"><li class="half_rhythm"><div>be discussed at a meeting,</div></li><li class="half_rhythm"><div>be cited with text, or</div></li><li class="half_rhythm"><div>replace or update an existing article that is already cited.</div></li></ul><p id="CDR0000774170__AboutThis_7">Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.</p><p>The lead reviewers for Childhood Vascular Tumors Treatment are:</p><ul><li class="half_rhythm"><div>Denise Adams, MD (Children's Hospital Boston)</div></li><li class="half_rhythm"><div>Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)</div></li><li class="half_rhythm"><div>Holcombe Edwin Grier, MD</div></li><li class="half_rhythm"><div>Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)</div></li><li class="half_rhythm"><div>Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)</div></li><li class="half_rhythm"><div>Alberto S. Pappo, MD (St. Jude Children's Research Hospital)</div></li><li class="half_rhythm"><div>R Beverly Raney, MD (Consultant)</div></li><li class="half_rhythm"><div>Stephen J. Shochat, MD (St. Jude Children's Research Hospital)</div></li></ul><p id="CDR0000774170__AboutThis_9">Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's <a href="https://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.</p></div><div id="CDR0000774170__AboutThis_10"><h3>Levels of Evidence</h3><p id="CDR0000774170__AboutThis_11">Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a <a href="/books/n/pdqcis/CDR0000062796/">formal evidence ranking system</a> in developing its level-of-evidence designations.</p></div><div id="CDR0000774170__AboutThis_12"><h3>Permission to Use This Summary</h3><p id="CDR0000774170__AboutThis_13">PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”</p><p id="CDR0000774170__AboutThis_14">The preferred citation for this PDQ summary is:</p><p id="CDR0000774170__AboutThis_15">PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Vascular Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: <a href="https://www.cancer.gov/types/soft-tissue-sarcoma/hp/child-vascular-tumors-treatment-pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.cancer.gov/types/soft-tissue-sarcoma/hp/child-vascular-tumors-treatment-pdq</a>. Accessed <MM/DD/YYYY>. [PMID: 26844334]</p><p id="CDR0000774170__AboutThis_16">Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in <a href="https://visualsonline.cancer.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Visuals Online</a>, a collection of over 2,000 scientific images.
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</p></div><div id="CDR0000774170__AboutThis_17"><h3>Disclaimer</h3><p id="CDR0000774170__AboutThis_18">Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the <a href="https://www.cancer.gov/about-cancer/managing-care" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Managing Cancer Care</a> page.</p></div><div id="CDR0000774170__AboutThis_20"><h3>Contact Us</h3><p id="CDR0000774170__AboutThis_21">More information about contacting us or receiving help with the Cancer.gov website can be found on our <a href="https://www.cancer.gov/contact" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Contact Us for Help</a> page. Questions can also be submitted to Cancer.gov through the website’s <a href="https://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>.</p></div></div><div style="display:none"><div style="display:none" id="figCDR0000774170245"><img alt="Image CDR0000787423" src-large="/books/NBK343452.13/bin/CDR0000787423.jpg" /></div><div style="display:none" id="figCDR0000774170341"><img alt="Image CDR0000791441" src-large="/books/NBK343452.13/bin/CDR0000791441.jpg" /></div><div style="display:none" id="figCDR0000774170347"><img alt="Image CDR0000791733" src-large="/books/NBK343452.13/bin/CDR0000791733.jpg" /></div><div style="display:none" id="figCDR0000774170166"><img alt="Image CDR0000779667" src-large="/books/NBK343452.13/bin/CDR0000779667.jpg" /></div><div style="display:none" id="figCDR0000774170167"><img alt="Image CDR0000779670" src-large="/books/NBK343452.13/bin/CDR0000779670.jpg" /></div><div style="display:none" id="figCDR0000774170169"><img alt="Image CDR0000779672" src-large="/books/NBK343452.13/bin/CDR0000779672.jpg" /></div><div style="display:none" id="figCDR0000774170171"><img alt="Image CDR0000779669" src-large="/books/NBK343452.13/bin/CDR0000779669.jpg" /></div><div style="display:none" id="figCDR0000774170173"><img alt="Image CDR0000779673" src-large="/books/NBK343452.13/bin/CDR0000779673.jpg" /></div></div></div></div>
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2016</li><li><span class="bk_col_itm"><a href="/books/NBK343452.2/">NBK343452.2</a></span> March 31, 2016</li><li><span class="bk_col_itm"><a href="/books/NBK343452.1/">NBK343452.1</a></span> January 28, 2016</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this Page</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#CDR0000774170__1" ref="log$=inpage&link_id=inpage">General Information About Childhood Vascular Tumors</a></li><li><a href="#CDR0000774170__3" ref="log$=inpage&link_id=inpage">Benign Tumors</a></li><li><a href="#CDR0000774170__70" ref="log$=inpage&link_id=inpage">Intermediate Tumors (Locally Aggressive) </a></li><li><a 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class="simple-list"><li><a href="/books/NBK363066/">Patient Version</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/27253005" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Childhood Vascular Tumors Treatment (PDQ®): Patient Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Childhood Vascular Tumors Treatment (PDQ®): Patient Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Pediatric Treatment Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/26389232" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Childhood Liver Cancer Treatment (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Childhood Liver Cancer Treatment (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Pediatric Treatment Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/26389361" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Childhood Soft Tissue Sarcoma Treatment (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop 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class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Childhood Nasopharyngeal Cancer Treatment (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Pediatric Treatment Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/26389373" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Childhood Ependymoma Treatment (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Childhood Ependymoma Treatment (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Pediatric Treatment Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=26844334" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" 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