Expression of Angiopoietin-TIE System Components in Angiosarcoma
Identifieur interne : 004706 ( Pmc/Corpus ); précédent : 004705; suivant : 004707Expression of Angiopoietin-TIE System Components in Angiosarcoma
Auteurs : Darya Buehler ; Patrick Rush ; Jason R. Hasenstein ; Stephanie R. Rice ; Gholam Reza Hafez ; B. Jack Longley ; Kevin R. KozakSource :
- Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc [ 0893-3952 ] ; 2013.
Abstract
Angiosarcoma is an aggressive malignancy of endothelial differentiation. Potential roles of the endothelial angiopoietin-tunica internal endothelial cell kinase (ANGPT-TIE) system in angiosarcoma diagnosis, pathogenesis, prognosis and treatment are undefined. To examine the expression and prognostic significance of angiopoietin-1, angiopoietin-2, TIE1 and TEK (TIE2) proteins in angiosarcoma, we immunohistochemically evaluated clinically annotated human angiosarcoma samples. Correlations of protein expression with overall survival and pathologic features were explored. The cohort included 51 patients diagnosed with angiosarcoma at age 30-86 years old (median 67). The 5-year overall survival was 45% with a median of 26 months. Moderate to strong expression of angiopoietin-1, TIE1 and TEK (TIE2) was identified in the majority of angiosarcomas and moderate to strong expression of angiopoietin-2 was observed in 42% of angiosarcomas. Increased angiopoietin-1 expression correlated with improved survival. Non-significant trends toward longer survival were also observed with increased TIE1 and TEK (TIE2) expression. Increased expression of angiopoietin-2, TIE1 and TEK (TIE2) was associated with vasoformative architecture. No differences in expression of these proteins were observed when patients were segregated by age, gender, presence or absence of metastases at diagnosis, primary tumor location, radiation association or the presence of necrosis. We conclude that components of the ANGPT-TIE system are commonly expressed in angiosarcomas. Reduced expression of these proteins is associated with non-vasoformative and clinically more aggressive lesions.
Url:
DOI: 10.1038/modpathol.2013.43
PubMed: 23558570
PubMed Central: 3706492
Links to Exploration step
PMC:3706492Le document en format XML
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<front><div type="abstract" xml:lang="en"><p id="P1">Angiosarcoma is an aggressive malignancy of endothelial differentiation. Potential roles of the endothelial angiopoietin-tunica internal endothelial cell kinase (ANGPT-TIE) system in angiosarcoma diagnosis, pathogenesis, prognosis and treatment are undefined. To examine the expression and prognostic significance of angiopoietin-1, angiopoietin-2, TIE1 and TEK (TIE2) proteins in angiosarcoma, we immunohistochemically evaluated clinically annotated human angiosarcoma samples. Correlations of protein expression with overall survival and pathologic features were explored. The cohort included 51 patients diagnosed with angiosarcoma at age 30-86 years old (median 67). The 5-year overall survival was 45% with a median of 26 months. Moderate to strong expression of angiopoietin-1, TIE1 and TEK (TIE2) was identified in the majority of angiosarcomas and moderate to strong expression of angiopoietin-2 was observed in 42% of angiosarcomas. Increased angiopoietin-1 expression correlated with improved survival. Non-significant trends toward longer survival were also observed with increased TIE1 and TEK (TIE2) expression. Increased expression of angiopoietin-2, TIE1 and TEK (TIE2) was associated with vasoformative architecture. No differences in expression of these proteins were observed when patients were segregated by age, gender, presence or absence of metastases at diagnosis, primary tumor location, radiation association or the presence of necrosis. We conclude that components of the ANGPT-TIE system are commonly expressed in angiosarcomas. Reduced expression of these proteins is associated with non-vasoformative and clinically more aggressive lesions.</p>
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</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">8806605</journal-id>
<journal-id journal-id-type="pubmed-jr-id">6644</journal-id>
<journal-id journal-id-type="nlm-ta">Mod Pathol</journal-id>
<journal-id journal-id-type="iso-abbrev">Mod. Pathol.</journal-id>
<journal-title-group><journal-title>Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc</journal-title>
</journal-title-group>
<issn pub-type="ppub">0893-3952</issn>
<issn pub-type="epub">1530-0285</issn>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">23558570</article-id>
<article-id pub-id-type="pmc">3706492</article-id>
<article-id pub-id-type="doi">10.1038/modpathol.2013.43</article-id>
<article-id pub-id-type="manuscript">NIHMS434148</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Expression of Angiopoietin-TIE System Components in Angiosarcoma</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Buehler</surname>
<given-names>Darya</given-names>
</name>
<degrees>M.D.</degrees>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rush</surname>
<given-names>Patrick</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hasenstein</surname>
<given-names>Jason R.</given-names>
</name>
<degrees>Ph.D.</degrees>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rice</surname>
<given-names>Stephanie R.</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hafez</surname>
<given-names>Gholam Reza</given-names>
</name>
<degrees>M.D.</degrees>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Longley</surname>
<given-names>B. Jack</given-names>
</name>
<degrees>M.D.</degrees>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kozak</surname>
<given-names>Kevin R</given-names>
</name>
<degrees>M.D., Ph.D.</degrees>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Department of Pathology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin</aff>
<aff id="A2"><label>2</label>
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin</aff>
<aff id="A3"><label>3</label>
Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin</aff>
<author-notes><corresp id="FN1">Correspondence to: Kevin R. Kozak, M.D., Ph.D., Wisconsin Institute for Medical Research, 1111 Highland Avenue Madison, WI 53705, Telephone: 608-263-8500, Fax Number: 608-262-7224, <email>kozak@humonc.wisc.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>20</day>
<month>1</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="epub"><day>05</day>
<month>4</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="ppub"><month>8</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>01</day>
<month>2</month>
<year>2014</year>
</pub-date>
<volume>26</volume>
<issue>8</issue>
<fpage>1032</fpage>
<lpage>1040</lpage>
<pmc-comment>elocation-id from pubmed: 10.1038/modpathol.2013.43</pmc-comment>
<permissions><license xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms"><license-p>Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:<ext-link ext-link-type="uri" xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms">http://www.nature.com/authors/editorial_policies/license.html#terms</ext-link>
</license-p>
</license>
</permissions>
<abstract><p id="P1">Angiosarcoma is an aggressive malignancy of endothelial differentiation. Potential roles of the endothelial angiopoietin-tunica internal endothelial cell kinase (ANGPT-TIE) system in angiosarcoma diagnosis, pathogenesis, prognosis and treatment are undefined. To examine the expression and prognostic significance of angiopoietin-1, angiopoietin-2, TIE1 and TEK (TIE2) proteins in angiosarcoma, we immunohistochemically evaluated clinically annotated human angiosarcoma samples. Correlations of protein expression with overall survival and pathologic features were explored. The cohort included 51 patients diagnosed with angiosarcoma at age 30-86 years old (median 67). The 5-year overall survival was 45% with a median of 26 months. Moderate to strong expression of angiopoietin-1, TIE1 and TEK (TIE2) was identified in the majority of angiosarcomas and moderate to strong expression of angiopoietin-2 was observed in 42% of angiosarcomas. Increased angiopoietin-1 expression correlated with improved survival. Non-significant trends toward longer survival were also observed with increased TIE1 and TEK (TIE2) expression. Increased expression of angiopoietin-2, TIE1 and TEK (TIE2) was associated with vasoformative architecture. No differences in expression of these proteins were observed when patients were segregated by age, gender, presence or absence of metastases at diagnosis, primary tumor location, radiation association or the presence of necrosis. We conclude that components of the ANGPT-TIE system are commonly expressed in angiosarcomas. Reduced expression of these proteins is associated with non-vasoformative and clinically more aggressive lesions.</p>
</abstract>
<kwd-group><kwd>Angiosarcoma</kwd>
<kwd>angiopoietin</kwd>
<kwd>sarcoma</kwd>
<kwd>TEK</kwd>
<kwd>TIE</kwd>
</kwd-group>
</article-meta>
</front>
<body><sec sec-type="intro" id="S1"><title>INTRODUCTION</title>
<p id="P2">Angiosarcoma is an aggressive soft tissue sarcoma of endothelial differentiation. Current therapies are woefully inadequate. Patients presenting with localized disease have a 5 year overall survival of less than 60%. Those presenting with metastatic disease fare far worse with median survival generally less than one year <sup><xref rid="R1" ref-type="bibr">1</xref>
-<xref rid="R5" ref-type="bibr">5</xref>
</sup>
. The poor survival of patients with metastatic disease is largely attributable to limited systemic therapy options. Reported response rates with conventional cytotoxic chemotherapy are highly variable, however, they are generally similar to the disappointing response rates seen in other soft tissue sarcomas (<italic>i.e.</italic>
20-30%) <sup><xref rid="R6" ref-type="bibr">6</xref>
</sup>
.</p>
<p id="P3">Given the vascular differentiation of angiosarcomas, recent interest has turned to therapies that target endothelium-restricted signaling pathways. Vascular endothelial growth factors (VEGFs) and their receptors are expressed in angiosarcoma <sup><xref rid="R7" ref-type="bibr">7</xref>
-<xref rid="R14" ref-type="bibr">14</xref>
</sup>
. Moreover, activating mutations in KDR (VEGFR-2), the major pro-angiogenic VEGF receptor, have been reported in a small subset of angiosarcomas <sup><xref rid="R15" ref-type="bibr">15</xref>
</sup>
. Consequently, the therapeutic use of anti-VEGF agents has been explored in this disease. The pan-VEGF receptor tyrosine kinase inhibitor, sorafenib, has modest single agent activity in angiosarcoma <sup><xref rid="R16" ref-type="bibr">16</xref>
, <xref rid="R17" ref-type="bibr">17</xref>
</sup>
Similarly, the humanized anti-VEGF monoclonal antibody, bevacizumab, elicits objective responses in a minority of angiosarcoma patients <sup><xref rid="R18" ref-type="bibr">18</xref>
, <xref rid="R19" ref-type="bibr">19</xref>
</sup>
.</p>
<p id="P4">The ANGPT TIE pathway is largely confined to vasculature and consists of two tyrosine kinase receptors, TIE1 and TEK (TIE2), and three corresponding ligands, angiopoietins-1, -2 and -4. Although considerable context-dependent alterations in function have been observed, generally, angiopoietin-1 acts as a TEK (TIE2) receptor agonist and angiopoietin-2 as a TEK (TIE2) receptor antagonist. The TIE1 receptor has no known ligand and appears to function primarily as a TEK (TIE2) receptor antagonist through interference of angiopoietin-1 receptor interaction <sup><xref rid="R20" ref-type="bibr">20</xref>
</sup>
. Angiopoietin-1 plays a key role in maintaining the integrity of existing vessels and enhances endothelial cell survival, proliferation and migration in some settings <sup><xref rid="R21" ref-type="bibr">21</xref>
-<xref rid="R25" ref-type="bibr">25</xref>
</sup>
. Angiopoietin-2 appears to play a critical role in vascular remodeling and angiogenesis <sup><xref rid="R26" ref-type="bibr">26</xref>
</sup>
. The functions of the more recently described ligand, angiopoietin-4, are less well understood and its expression is largely limited to the lung <sup><xref rid="R27" ref-type="bibr">27</xref>
</sup>
.</p>
<p id="P5">Little information is available regarding the expression of ANGPT-TIE pathway components in human angiosarcoma samples <sup><xref rid="R12" ref-type="bibr">12</xref>
, <xref rid="R15" ref-type="bibr">15</xref>
, <xref rid="R28" ref-type="bibr">28</xref>
</sup>
. Recently, after identifying TEK (TIE2) expression in 11 human angiosarcomas, we reported that TEK (TIE2) inhibition delayed angiosarcoma growth in two murine models of the disease <sup><xref rid="R29" ref-type="bibr">29</xref>
</sup>
. To examine potential roles for ANGPT-TIE pathway components in angiosarcoma diagnosis, pathogenesis, prognosis and treatment, we assessed the expression of angiopoietin-1, angiopoietin-2, TIE1 and TEK (TIE2) by immunohistochemistry in 51 clinically annotated human angiosarcoma samples.</p>
</sec>
<sec sec-type="materials|methods" id="S2"><title>MATERIALS AND METHODS</title>
<sec id="S3" sec-type="subjects"><title>Patients and Angiosarcoma Specimens</title>
<p id="P6">The study was approved by the Institutional Review Board. Patients were identified using a surgical pathology database that spanned the years 1987-2012. Candidate paraffin blocks were collected and the angiosarcoma diagnosis was confirmed by a pathologist with specific interest in soft tissue and skin tumors (G.R.H. and B.J.L.). The presence or absence of necrosis was noted. Tumor architectural pattern was assessed according to Shon et al. as follows: vasoformative (> 75% of tumor forming vascular channels with identifiable lumina), non-vasoformative (> 75% of tumor demonstrating architecturally solid epithelioid or spindle cell morphology without vascular channels) or mixed <sup><xref rid="R30" ref-type="bibr">30</xref>
</sup>
. Patient records were accessed for age at diagnosis, sex, disease distribution at diagnosis, date of last follow up or death, primary site and tumor size. Clinical notes and radiation records were reviewed. Angiosarcomas were deemed radiation associated if they occurred within or adjacent to prior radiation fields.</p>
</sec>
<sec id="S4"><title>Tissue Microarray Construction</title>
<p id="P7">Fifty-one paraffin blocks from angiosarcoma surgical specimens were identified. No specimen was obtained following neoadjuvant radiation or chemotherapy. After confirmation of the diagnosis, the most representative viable areas of the formalin-fixed paraffin embedded angiosarcomas were formatted into a 4.5 × 2 × 1 cm recipient tissue microarray in triplicate 1.0 mm cores using the MTA-1 manual tissue microarrayer (Beecher Instruments, Sun Prairie, WI).</p>
<p id="P8">The eleven angiosarcoma cases previously reported to express TEK (TIE2) in whole mount tissue sections were included in the tissue microarray <sup><xref rid="R29" ref-type="bibr">29</xref>
</sup>
. In five cases (two breast, two head and neck, and one Stewart-Treves), limited tumor tissue necessitated use of only two tissue cores. Sections were cut (5 μm) and standard H&E and CD31 stained slides were examined to verify the presence of viable angiosarcoma.</p>
</sec>
<sec id="S5"><title>Immunohistochemistry</title>
<p id="P9">Tissue sections (5 μm) were cut using traditional water bath technique and dried overnight at room temperature. Slides were deparaffinized in subsequent xylene and ethanol incubations followed by heat induced epitope retrieval using the Lab Vision PT module (Thermo Fisher Scientific, Fremont, CA) with Lab Vision citrate buffer pH 6.0 at 98 °C for 20 minutes without boiling. All staining was performed at room temperature using the Lab Vision 360 automated staining system. Biocare Medical (Concord, CA) reagents were used except where noted. Endogenous peroxidase was blocked for 5 min with Peroxidazed 1. Nonspecific protein binding was inhibited by a 10 min (angiopoietin-2, TIE1, TEK (TIE2)) or 30 min (angiopoietin-1) block with Sniper. For angiopoietin-1, nonspecific avidin binding was blocked using the Avidin Biotin kit, incubating 15 min for each reagent. Primary antibodies were diluted with DaVinci Green Antibody Diluent (angiopoietin-2, TIE1, TEK (TIE2)) or Renaissance Background Reducing Diluent (angiopoietin-1). Slides were incubated with primary antibodies for 60 min as follows: angiopoietin-1 (goat anti-angiopoietin-1 IgG, 1:50, R&D Systems, Minneapolis, MN), angiopoietin-2 (mouse anti-angiopoietin-2 IgG, 1:50, Santa Cruz Biotechnology, Santa Cruz, CA), TIE1 (mouse anti-TIE1 IgG, 1:300, R&D Systems), TEK (goat anti-TEK IgG, 1:50, R&D Systems).</p>
<p id="P10">For angiopoietin-2 and TIE1 stains, slides were subsequently incubated for 20 min with probe and HRP-polymer from mouse HRP-Polymer kit. For TEK (TIE2), similar incubations were performed with the goat HRP-polymer kit. For angiopoietin-1, primary incubation was followed by incubation for 15 min with biotinylated swine anti-goat IgG (1:50, Invitrogen, Carlsbad, CA) followed by a 15 min streptavidin-HRP treatment. Betazoid DAB and Mayer’s hematoxylin were each incubated for 1 min. Slides were washed with Tris-buffered saline-Tween between steps. For CD31 immunolabeling, the heat induced epitope retrieval was performed using Dako’s FLEX Target Retrieval Solution, Low pH (pH 6.0) for 45 min in a decloaker. Endogenous peroxidase was blocked with 300 μL of Dako’s peroxidase blocking reagent for 5 min. Slides were then incubated on Dako Autostainer with Dako FLEX Ready-to-Use CD31 antibody (mouse anti-CD31 IgG, Dako, Carpinteria, CA) at room temperature for 20 min followed by a Mouse LINKER for 15 min and Dako’s FLEX detection reagent for 15 min. DAB reagent was then applied for 5 min followed by hematoxylin counterstain. Immunoreactivity was scored by a pathologist blinded to patient outcomes using conventional brightfield microscopy. Cytoplasmic and membranous staining was interpreted as follows: 0, no staining; 1, weak staining; 2, moderate staining; 3, strong staining. For each patient, a single immunohistochemical score was generated by averaging the scores of all represented cores.</p>
</sec>
<sec id="S6"><title>Statistical Analysis</title>
<p id="P11">Five-year overall survival comparisons were performed using the Kaplan-Meier method. Statistical significance was calculated by log rank test. Survival curves were generated using GraphPad Prism software (Version 5.0, La Jolla, California). Fisher’s exact test was used to assess differences in protein expression between patient subgroups.</p>
</sec>
</sec>
<sec sec-type="results" id="S7"><title>RESULTS</title>
<sec id="S8" sec-type="intro"><title>Patient and Tumor Characteristics</title>
<p id="P12">Patient and tumor characteristics are presented in <xref rid="T1" ref-type="table">Table 1</xref>
. The cohort consisted of 30 females and 21 males, with a median age of 67 years at diagnosis (range, 30-86 years). The majority (69%) of patients presented with localized disease. Sixteen patients (31%) had distant metastases at diagnosis. Nearly 80% of patients presented with visceral/deep soft tissue, head and neck or cutaneous primaries. Visceral/deep soft tissue sites included liver (<italic>N</italic>
= 3), bone (<italic>N</italic>
= 3), bladder (<italic>N</italic>
= 3), lung (<italic>N</italic>
= 2), pelvic soft tissue (<italic>N</italic>
= 2), bowel (<italic>N</italic>
= 2), and one each of the following: spleen, ovary, seminal vesicle, adrenal, and aorta. Twelve cases (24%) were considered to be radiation associated, with the majority (7/12, 58%) being related to radiation therapy for breast cancer. Two-thirds of primary lesions were 5 cm or less in greatest dimension. The most common histologic pattern was vasoformative; 43% of tumors displayed necrosis. Considering the entire cohort, 5-year overall survival was 45% with a median of 26 months.</p>
</sec>
<sec id="S9"><title>Angiopoietin-1, Angiopoietin-2, TIE1, and TEK (TIE2) Expression</title>
<p id="P13">Angiopoietin-1 immunoreactivity was found in the vast majority of angiosarcomas; 3 (6%), 4 (8%), 26 (51%) and 18 (35%) of 51 lesions displayed no (0+), weak (1+), moderate (2+), and strong (3+) staining, respectively (<xref rid="F1" ref-type="fig">Figure 1</xref>
, rows 1 & 2). Among the 7 specimens with no-to-weak angiopoietin-1 immunoreactivity, 3 demonstrated weak, 3 demonstrated moderate and 1 demonstrated strong TEK (TIE2) expression (data not shown). Angiopoietin-2 staining was more heterogeneous with 19 (38%), 10 (20%), 10 (20%) and 11 (22%) of 50 specimens showing no, weak, moderate, and strong immunoreactivity, respectively (<xref rid="F1" ref-type="fig">Figure 1</xref>
, rows 3 & 4). A single specimen, represented by two cores, was lost from the tissue microarray during the angiopoietin-2 immunostaining procedure. TIE1 and TEK (TIE2) immunoreactivity largely paralleled angiopoietin-1 staining with the majority of samples displaying moderate to strong expression of these receptors. For TIE1, absent, weak, moderate, and strong staining was observed in 5 (10%), 11 (22%), 15 (29%), and 20 (39%) of 51 angiosarcomas, respectively (<xref rid="F2" ref-type="fig">Figure 2</xref>
, rows 1 & 2). TEK (TIE2) immunoreactivity was not observed in only one sample. In the remaining 50 specimens, TEK (TIE2) expression was found to be weak, moderate, and strong in 9 (18%), 20 (39%), and 21 (41%) cases, respectively (<xref rid="F2" ref-type="fig">Figure 2</xref>
, rows 3 & 4).</p>
</sec>
<sec id="S10"><title>ANGPT-TIE System Proteins and Overall Survival</title>
<p id="P14">Correlations between angiopoietin-1, angiopoietin-2, TIE1 and TEK (TIE2) immunostaining and overall survival are shown in <xref rid="F3" ref-type="fig">Figure 3</xref>
and <xref rid="T2" ref-type="table">Table 2</xref>
. Generally, expression of angiopoietin-1, TIE1 and TEK (TIE2) was associated with improved overall survival. However, this reached statistical significance only with angiopoietin-1. Among the 7 patients with no or low angiopoietin-1 immunoreactivity, none survived three years. In contrast, among patients with moderate to strong expression of angiopoietin-1, median overall survival approached 4 years.</p>
</sec>
<sec id="S11" sec-type="intro"><title>Correlations of Angiopoietin and TIE Expression with Patient and Tumor Characteristics</title>
<p id="P15">To identify potential correlations between angiopoietin-1, angiopoietin-2, TIE1, and TEK (TIE2) immunoreactivity and angiosarcoma patient and tumor characteristics, the samples were segregated by clinical and pathological variables (<xref rid="T3" ref-type="table">Table 3</xref>
). Expression patterns did not differ by age, gender, metastatic disease at presentation, radiation association or tumor size. Increased TIE receptor immunoreactivity was strongly associated with vasoformative histology. Similarly, increased angiopoietin staining was observed in vasoformative angiosarcomas; however, this did not reach statistical significance for angiopoietin-1. Breast angiosarcomas and the three angiosarcomas arising in the background of chronic lymphedema (Stewart-Treves syndrome) were associated with near-universal moderate-to-strong immunoreactivity for angiopoietin-1, TIE1 and TEK (TIE2). However, this did not differ in a statistically significant way when compared to more common primary sites. Notably, all breast angiosarcomas and the three angiosarcomas associated with Stewart-Treves syndrome displayed vasoformative architecture.</p>
</sec>
</sec>
<sec sec-type="discussion" id="S12"><title>DISCUSSION</title>
<p id="P16">The ANGPT-TIE system has an essential role in developmental angiogenesis <sup><xref rid="R31" ref-type="bibr">31</xref>
-<xref rid="R36" ref-type="bibr">36</xref>
</sup>
. Additionally, this complex vascular signaling architecture has been implicated in tumor progression. Elevated angiopoietin-1 expression has been correlated with improved disease-free survival in head and neck squamous cell carcinomas although it appears to have little prognostic significance in most solid tumors <sup><xref rid="R37" ref-type="bibr">37</xref>
-<xref rid="R40" ref-type="bibr">40</xref>
</sup>
. In contrast, overexpression of angiopoietin-2 and elevated angiopoietin-2/angiopoietin-1 ratios correlate with worse survival in an array of malignancies <sup><xref rid="R41" ref-type="bibr">41</xref>
-<xref rid="R48" ref-type="bibr">48</xref>
</sup>
. Importantly, agents targeting the ANGPT-TIE system are in active clinical development <sup><xref rid="R49" ref-type="bibr">49</xref>
-<xref rid="R52" ref-type="bibr">52</xref>
</sup>
.</p>
<p id="P17">Despite considerable examination of the roles of the ANGPT-TIE system in solid tumors, little information is available regarding the significance of this predominantly endothelium-limited signaling pathway in angiosarcoma. In our series of 51 angiosarcoma patients, we observed moderate-to-strong angiopoietin-1 immunoreactivity in 86% of cases. Angiopoietin-1 is not expressed in cultured human endothelial cells nor in the vasculature of developing mouse embryos <sup><xref rid="R25" ref-type="bibr">25</xref>
, <xref rid="R53" ref-type="bibr">53</xref>
, <xref rid="R54" ref-type="bibr">54</xref>
</sup>
. Rather, angiopoietin-1 is thought to be expressed primarily by mural cells and signal through TEK (TIE2) in a paracrine fashion <sup><xref rid="R25" ref-type="bibr">25</xref>
</sup>
. Thus, our observations raise the possibility that, in contrast to cultured and fetal endothelial cells, angiosarcoma cells express angiopoietin-1. This is consistent with the findings of Brown and colleagues who detected angiopoietin-1 mRNA in 2 of 2 angiosarcomas studied <sup><xref rid="R28" ref-type="bibr">28</xref>
</sup>
. Alternatively, angiopoietin-1 immunoreactivity may be attributable to detection of receptor-bound angiopoietin-1. Consistent with this possibility is the observation that angiopoietin-1 protein is observed in the vessels of unwounded skin <sup><xref rid="R55" ref-type="bibr">55</xref>
</sup>
.</p>
<p id="P18">Our observation that 4 of 7 angiosarcomas with no-to-weak angiopoietin-1 staining demonstrated moderate-to-strong TEK (TIE2) expression suggests that detection of bound angiopoietin-1 does not entirely explain the near universal angiopoietin-1 immunoreactivity seen in angiosarcomas. Further investigation of the cellular source of angiopoietin-1 in angiosarcomas is warranted.</p>
<p id="P19">Our observation that 62% of angiosarcomas express at least low levels of angiopoietin-2 is consistent with the endothelial differentiation of this malignancy and the scant available data regarding angiopoietin-2 expression in angiosarcoma. Brown and colleagues detected strong angiopoietin-2 mRNA expression in 2 of 2 examined angiosarcomas <sup><xref rid="R28" ref-type="bibr">28</xref>
</sup>
. Angiopoietin-2 mRNA was also found to be upregulated in angiosarcomas when compared to other soft tissue sarcomas <sup><xref rid="R15" ref-type="bibr">15</xref>
</sup>
. Amo and colleagues observed elevated serum levels of angiopoietin-2 in 11 patients with pathologically proven angiosarcoma of the face and scalp compared to healthy volunteers <sup><xref rid="R53" ref-type="bibr">53</xref>
</sup>
. In this study, serum angiopoietin-2 was found to correlate with disease burden. The high rates of TIE1 and TEK (TIE2) expression in our patient cohort are also consistent with endothelial differentiation and the limited evidence of TIE receptor expression in angiosarcoma. Strong TIE1 and TEK (TIE2) mRNA expression has been observed in 2 of 2 angiosarcomas <sup><xref rid="R28" ref-type="bibr">28</xref>
</sup>
. Furthermore, levels of TIE1 and TEK (TIE2) mRNA were found to be elevated in angiosarcomas compared to other soft tissue sarcomas <sup><xref rid="R15" ref-type="bibr">15</xref>
</sup>
. Additionally, TEK (TIE2) expression was identified immunohistochemically in 7 of 10 examined pulmonary epithelioid angiosarcomas <sup><xref rid="R12" ref-type="bibr">12</xref>
</sup>
.</p>
<p id="P20">Our observation that increased expression of ANGPT-TIE system components is associated with both the more favorable vasoformative histologic pattern and improved overall survival is consistent with a loss of endothelial markers with progression to more aggressive disease <sup><xref rid="R30" ref-type="bibr">30</xref>
</sup>
. Consistent with this model is the observation that loss of vascular endothelial growth factor receptor 2 is associated with worse survival in angiosarcoma patients <sup><xref rid="R9" ref-type="bibr">9</xref>
</sup>
. The correlation between increased angiopoietin-1 expression and overall survival is not simply explained by correlations with other known prognostic factors. The dominant, negative prognostic factor in this patient population is the presence of metastatic disease at diagnosis. The fact that angiopoietin-1 expression did not vary when patients were segregated by the presence or absence of metastases at diagnosis (nor any other examined clinical or pathological variable) suggests it may be a novel prognostic factor in this disease. Larger studies are required to confirm this observation and define the potential utility of using angiopoietin-1 immunoreactivity in clinical testing.</p>
<p id="P21">TEK (TIE2) inhibitor therapy has recently been reported to inhibit angiosarcoma growth in two distinct murine models of this disease <sup><xref rid="R29" ref-type="bibr">29</xref>
</sup>
. Coupled with our observation that ANGPT-TIE system components are commonly expressed in angiosarcoma, these findings raise the possibility that manipulation of the ANGPT-TIE system may have therapeutic utility in this poor prognosis malignancy. Thus, immunohistochemical evaluation of these proteins in angiosarcoma could potentially be used as a part of therapeutic decision making. Further studies on the mechanistic roles for this critical vascular signaling pathway in angiosarcomagenesis are certainly merited.</p>
</sec>
</body>
<back><ack id="S13"><p>Support provided by NIH Grant 1UL1RR025011 (KRK)</p>
</ack>
<fn-group><fn id="FN2" fn-type="conflict"><p><bold>DISCLOSURE/CONFLICT OF INTEREST</bold>
</p>
<p>There are no financial disclosures to report.</p>
</fn>
</fn-group>
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<floats-group><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label>
<caption><title>Representative images displaying the spectrum of angiopoietin-1 and angiopoietin-2 immunoreactivity in human angiosarcomas</title>
<p>Corresponding H&E stained images are also displayed (original magnification 400x).</p>
</caption>
<graphic xlink:href="nihms434148f1"></graphic>
</fig>
<fig id="F2" orientation="portrait" position="float"><label>Figure 2</label>
<caption><title>Representative images displaying the spectrum of TIE1 and TEK (TIE2) immunoreactivity in human angiosarcomas</title>
<p>Corresponding H&E stained images are also displayed (original magnification 400x).</p>
</caption>
<graphic xlink:href="nihms434148f2"></graphic>
</fig>
<fig id="F3" orientation="portrait" position="float"><label>Figure 3</label>
<caption><title>Overall survival of angiosarcoma patients segregated by tumor expression of angiopoietin-1 (A), angiopoietin-2 (B), TIE1 (C) and TEK (TIE2) (D)</title>
</caption>
<graphic xlink:href="nihms434148f3"></graphic>
</fig>
<table-wrap id="T1" position="float" orientation="portrait"><label>Table 1</label>
<caption><p>Patient and tumor characteristics</p>
</caption>
<table frame="hsides" rules="none"><thead><tr><th align="left" rowspan="1" colspan="1"></th>
<th align="left" rowspan="1" colspan="1"></th>
<th align="center" rowspan="1" colspan="1">N (% total)</th>
</tr>
</thead>
<tbody><tr><td align="left" rowspan="9" colspan="1"><italic><bold>Patient Characteristics</bold>
</italic>
</td>
<td align="left" rowspan="1" colspan="1">Age, Median (range, years)</td>
<td align="center" rowspan="1" colspan="1">67 (range, 30-86)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Gender</td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> male</td>
<td align="center" rowspan="1" colspan="1">21 (41%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> female</td>
<td align="center" rowspan="1" colspan="1">30 (59%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Localized Disease</td>
<td align="center" rowspan="1" colspan="1">35 (69%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Metastatic Disease</td>
<td align="center" rowspan="1" colspan="1">16 (31%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Vital Status</td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> alive</td>
<td align="center" rowspan="1" colspan="1">19 (37%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> deceased</td>
<td align="center" rowspan="1" colspan="1">32 (63%)</td>
</tr>
<tr><td align="left" rowspan="23" colspan="1"><italic><bold>Tumor Characteristics</bold>
</italic>
</td>
<td align="left" rowspan="1" colspan="1">Primary Site</td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> visceral/deep soft tissue</td>
<td align="center" rowspan="1" colspan="1">20 (39%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> head and neck/cutaneous</td>
<td align="center" rowspan="1" colspan="1">20 (39%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> breast</td>
<td align="center" rowspan="1" colspan="1">8 (16%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> Stewart-Treves</td>
<td align="center" rowspan="1" colspan="1">3 (6%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Radiation Associated</td>
<td align="center" rowspan="1" colspan="1">12 (24%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> breast</td>
<td align="center" rowspan="1" colspan="1">7 (58%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> bladder</td>
<td align="center" rowspan="1" colspan="1">2 (17%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> liver</td>
<td align="center" rowspan="1" colspan="1">1 (8%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> sternum</td>
<td align="center" rowspan="1" colspan="1">1 (8%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> scalp</td>
<td align="center" rowspan="1" colspan="1">1 (8%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Primary tumor size:</td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> Total available</td>
<td align="center" rowspan="1" colspan="1">45</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> ≤ 5 cm</td>
<td align="center" rowspan="1" colspan="1">30 (67%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> > 5 cm</td>
<td align="center" rowspan="1" colspan="1">15 (33%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Histologic pattern</td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> vasoformative</td>
<td align="center" rowspan="1" colspan="1">30 (59%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> epithelioid</td>
<td align="center" rowspan="1" colspan="1">6 (12%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> spindle</td>
<td align="center" rowspan="1" colspan="1">2 (4%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> mixed</td>
<td align="center" rowspan="1" colspan="1">13 (25%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Necrosis</td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> absent</td>
<td align="center" rowspan="1" colspan="1">29 (57%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> present</td>
<td align="center" rowspan="1" colspan="1">22 (43%)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"><italic><bold>Total</bold>
</italic>
</td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">51</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="T2" position="float" orientation="landscape"><label>Table 2</label>
<caption><p>Overall survival based on angiopoietin and TIE expression</p>
</caption>
<table frame="hsides" rules="none"><thead><tr><th align="center" rowspan="1" colspan="1"></th>
<th align="center" colspan="2" rowspan="1">Angiopoietin-1</th>
<th align="center" colspan="2" rowspan="1">Angiopoietin-2</th>
<th align="center" colspan="2" rowspan="1">TIE1</th>
<th align="center" colspan="2" rowspan="1">TEK (TIE2)</th>
</tr>
<tr><th align="center" rowspan="1" colspan="1"></th>
<th align="center" rowspan="1" colspan="1">0-1</th>
<th align="center" rowspan="1" colspan="1">2-3</th>
<th align="center" rowspan="1" colspan="1">0-1</th>
<th align="center" rowspan="1" colspan="1">2-3</th>
<th align="center" rowspan="1" colspan="1">0-1</th>
<th align="center" rowspan="1" colspan="1">2-3</th>
<th align="center" rowspan="1" colspan="1">0-1</th>
<th align="center" rowspan="1" colspan="1">2-3</th>
</tr>
<tr><th align="center" rowspan="1" colspan="1"></th>
<th align="center" valign="bottom" colspan="8" rowspan="1"><hr></hr>
</th>
</tr>
</thead>
<tbody><tr><td align="left" rowspan="1" colspan="1"><italic><bold>Median OS (mo)</bold>
</italic>
</td>
<td align="center" rowspan="1" colspan="1">5</td>
<td align="center" rowspan="1" colspan="1">47</td>
<td align="center" rowspan="1" colspan="1">26</td>
<td align="center" rowspan="1" colspan="1">28</td>
<td align="center" rowspan="1" colspan="1">11</td>
<td align="center" rowspan="1" colspan="1">33</td>
<td align="center" rowspan="1" colspan="1">8</td>
<td align="center" rowspan="1" colspan="1">33</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"><italic><bold>3 yr OS (%)</bold>
</italic>
</td>
<td align="center" rowspan="1" colspan="1">0</td>
<td align="center" rowspan="1" colspan="1">52</td>
<td align="center" rowspan="1" colspan="1">45</td>
<td align="center" rowspan="1" colspan="1">48</td>
<td align="center" rowspan="1" colspan="1">38</td>
<td align="center" rowspan="1" colspan="1">51</td>
<td align="center" rowspan="1" colspan="1">30</td>
<td align="center" rowspan="1" colspan="1">51</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="T3" position="float" orientation="landscape"><label>Table 3</label>
<caption><p>Angiopoietin and TIE expression in patient and tumor subsets</p>
</caption>
<table frame="hsides" rules="none"><thead><tr><th align="left" rowspan="1" colspan="1"></th>
<th align="center" colspan="3" rowspan="1">Angiopoietin-1</th>
<th align="center" colspan="3" rowspan="1">Angiopoietin-2</th>
<th align="center" colspan="3" rowspan="1">TIE1</th>
<th align="center" colspan="3" rowspan="1">TEK (TIE2)</th>
</tr>
<tr><th align="left" rowspan="1" colspan="1">Age</th>
<th align="center" rowspan="1" colspan="1">0-1</th>
<th align="center" rowspan="1" colspan="1">2-3</th>
<th align="center" rowspan="1" colspan="1">P</th>
<th align="center" rowspan="1" colspan="1">0-1</th>
<th align="center" rowspan="1" colspan="1">2-3</th>
<th align="center" rowspan="1" colspan="1">P</th>
<th align="center" rowspan="1" colspan="1">0-1</th>
<th align="center" rowspan="1" colspan="1">2-3</th>
<th align="center" rowspan="1" colspan="1">P</th>
<th align="center" rowspan="1" colspan="1">0-1</th>
<th align="center" rowspan="1" colspan="1">2-3</th>
<th align="center" rowspan="1" colspan="1">P</th>
</tr>
<tr><th align="left" rowspan="1" colspan="1"></th>
<th align="center" colspan="12" valign="bottom" rowspan="1"><hr></hr>
</th>
</tr>
</thead>
<tbody><tr><td align="left" rowspan="1" colspan="1"> ≤ 67 yo</td>
<td align="center" rowspan="1" colspan="1">3</td>
<td align="center" rowspan="1" colspan="1">26</td>
<td align="center" rowspan="1" colspan="1">0.45</td>
<td align="center" rowspan="1" colspan="1">15</td>
<td align="center" rowspan="1" colspan="1">13</td>
<td align="center" rowspan="1" colspan="1">0.57</td>
<td align="center" rowspan="1" colspan="1">8</td>
<td align="center" rowspan="1" colspan="1">21</td>
<td align="center" rowspan="1" colspan="1">0.55</td>
<td align="center" rowspan="1" colspan="1">5</td>
<td align="center" rowspan="1" colspan="1">24</td>
<td align="center" rowspan="1" colspan="1">0.73</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> > 67 yo</td>
<td align="center" rowspan="1" colspan="1">4</td>
<td align="center" rowspan="1" colspan="1">18</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">14</td>
<td align="center" rowspan="1" colspan="1">8</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">8</td>
<td align="center" rowspan="1" colspan="1">14</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">5</td>
<td align="center" rowspan="1" colspan="1">17</td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"><italic><bold>Gender</bold>
</italic>
</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> Male</td>
<td align="center" rowspan="1" colspan="1">3</td>
<td align="center" rowspan="1" colspan="1">18</td>
<td align="center" rowspan="1" colspan="1">1.0</td>
<td align="center" rowspan="1" colspan="1">13</td>
<td align="center" rowspan="1" colspan="1">8</td>
<td align="center" rowspan="1" colspan="1">0.77</td>
<td align="center" rowspan="1" colspan="1">7</td>
<td align="center" rowspan="1" colspan="1">14</td>
<td align="center" rowspan="1" colspan="1">1.0</td>
<td align="center" rowspan="1" colspan="1">6</td>
<td align="center" rowspan="1" colspan="1">15</td>
<td align="center" rowspan="1" colspan="1">0.28</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> Female</td>
<td align="center" rowspan="1" colspan="1">4</td>
<td align="center" rowspan="1" colspan="1">26</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">16</td>
<td align="center" rowspan="1" colspan="1">13</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">9</td>
<td align="center" rowspan="1" colspan="1">21</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">4</td>
<td align="center" rowspan="1" colspan="1">26</td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"><italic><bold>Stage at Diagnosis</bold>
</italic>
</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> Localized</td>
<td align="center" rowspan="1" colspan="1">5</td>
<td align="center" rowspan="1" colspan="1">30</td>
<td align="center" rowspan="1" colspan="1">1.0</td>
<td align="center" rowspan="1" colspan="1">19</td>
<td align="center" rowspan="1" colspan="1">15</td>
<td align="center" rowspan="1" colspan="1">0.76</td>
<td align="center" rowspan="1" colspan="1">8</td>
<td align="center" rowspan="1" colspan="1">27</td>
<td align="center" rowspan="1" colspan="1">0.10</td>
<td align="center" rowspan="1" colspan="1">6</td>
<td align="center" rowspan="1" colspan="1">29</td>
<td align="center" rowspan="1" colspan="1">0.71</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> Metastatic</td>
<td align="center" rowspan="1" colspan="1">2</td>
<td align="center" rowspan="1" colspan="1">14</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">10</td>
<td align="center" rowspan="1" colspan="1">6</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">8</td>
<td align="center" rowspan="1" colspan="1">8</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">4</td>
<td align="center" rowspan="1" colspan="1">12</td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"><italic><bold>Primary Site</bold>
</italic>
</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> Visceral/deep soft tissue</td>
<td align="center" rowspan="1" colspan="1">5</td>
<td align="center" rowspan="1" colspan="1">15</td>
<td align="center" rowspan="1" colspan="1">0.29</td>
<td align="center" rowspan="1" colspan="1">13</td>
<td align="center" rowspan="1" colspan="1">7</td>
<td align="center" rowspan="1" colspan="1">0.15</td>
<td align="center" rowspan="1" colspan="1">10</td>
<td align="center" rowspan="1" colspan="1">10</td>
<td align="center" rowspan="1" colspan="1">0.14</td>
<td align="center" rowspan="1" colspan="1">5</td>
<td align="center" rowspan="1" colspan="1">15</td>
<td align="center" rowspan="1" colspan="1">0.45</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> HN/cutaneous</td>
<td align="center" rowspan="1" colspan="1">1</td>
<td align="center" rowspan="1" colspan="1">19</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">13</td>
<td align="center" rowspan="1" colspan="1">7</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">5</td>
<td align="center" rowspan="1" colspan="1">15</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">5</td>
<td align="center" rowspan="1" colspan="1">15</td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> Breast</td>
<td align="center" rowspan="1" colspan="1">1</td>
<td align="center" rowspan="1" colspan="1">7</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">3</td>
<td align="center" rowspan="1" colspan="1">4</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">1</td>
<td align="center" rowspan="1" colspan="1">7</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">0</td>
<td align="center" rowspan="1" colspan="1">8</td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> Stewart-Treves</td>
<td align="center" rowspan="1" colspan="1">0</td>
<td align="center" rowspan="1" colspan="1">3</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">0</td>
<td align="center" rowspan="1" colspan="1">3</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">0</td>
<td align="center" rowspan="1" colspan="1">3</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">0</td>
<td align="center" rowspan="1" colspan="1">3</td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"><italic><bold>Radiation Associated</bold>
</italic>
</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> Yes</td>
<td align="center" rowspan="1" colspan="1">2</td>
<td align="center" rowspan="1" colspan="1">10</td>
<td align="center" rowspan="1" colspan="1">0.66</td>
<td align="center" rowspan="1" colspan="1">6</td>
<td align="center" rowspan="1" colspan="1">5</td>
<td align="center" rowspan="1" colspan="1">1.0</td>
<td align="center" rowspan="1" colspan="1">3</td>
<td align="center" rowspan="1" colspan="1">9</td>
<td align="center" rowspan="1" colspan="1">0.73</td>
<td align="center" rowspan="1" colspan="1">2</td>
<td align="center" rowspan="1" colspan="1">10</td>
<td align="center" rowspan="1" colspan="1">1.0</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> No</td>
<td align="center" rowspan="1" colspan="1">5</td>
<td align="center" rowspan="1" colspan="1">34</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">23</td>
<td align="center" rowspan="1" colspan="1">16</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">13</td>
<td align="center" rowspan="1" colspan="1">26</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">8</td>
<td align="center" rowspan="1" colspan="1">31</td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"><italic><bold>Tumor Size</bold>
</italic>
</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> ≤ 5 cm</td>
<td align="center" rowspan="1" colspan="1">5</td>
<td align="center" rowspan="1" colspan="1">25</td>
<td align="center" rowspan="1" colspan="1">0.69</td>
<td align="center" rowspan="1" colspan="1">19</td>
<td align="center" rowspan="1" colspan="1">10</td>
<td align="center" rowspan="1" colspan="1">0.25</td>
<td align="center" rowspan="1" colspan="1">8</td>
<td align="center" rowspan="1" colspan="1">22</td>
<td align="center" rowspan="1" colspan="1">0.54</td>
<td align="center" rowspan="1" colspan="1">4</td>
<td align="center" rowspan="1" colspan="1">26</td>
<td align="center" rowspan="1" colspan="1">0.28</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> > 5 cm</td>
<td align="center" rowspan="1" colspan="1">2</td>
<td align="center" rowspan="1" colspan="1">19</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">10</td>
<td align="center" rowspan="1" colspan="1">11</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">8</td>
<td align="center" rowspan="1" colspan="1">13</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">6</td>
<td align="center" rowspan="1" colspan="1">15</td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"><italic><bold>Histologic Pattern</bold>
</italic>
</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> Vasoformative</td>
<td align="center" rowspan="1" colspan="1">2</td>
<td align="center" rowspan="1" colspan="1">28</td>
<td align="center" rowspan="1" colspan="1">0.11</td>
<td align="center" rowspan="1" colspan="1">13</td>
<td align="center" rowspan="1" colspan="1">16</td>
<td align="center" rowspan="1" colspan="1"><bold>0.04</bold>
</td>
<td align="center" rowspan="1" colspan="1">3</td>
<td align="center" rowspan="1" colspan="1">27</td>
<td align="center" rowspan="1" colspan="1"><bold>0.0001</bold>
</td>
<td align="center" rowspan="1" colspan="1">2</td>
<td align="center" rowspan="1" colspan="1">28</td>
<td align="center" rowspan="1" colspan="1"><bold>0.01</bold>
</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> Non-vasoformative</td>
<td align="center" rowspan="1" colspan="1">5</td>
<td align="center" rowspan="1" colspan="1">16</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">16</td>
<td align="center" rowspan="1" colspan="1">5</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">13</td>
<td align="center" rowspan="1" colspan="1">8</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">8</td>
<td align="center" rowspan="1" colspan="1">13</td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"><italic><bold>Necrosis</bold>
</italic>
</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> Present</td>
<td align="center" rowspan="1" colspan="1">5</td>
<td align="center" rowspan="1" colspan="1">17</td>
<td align="center" rowspan="1" colspan="1">0.22</td>
<td align="center" rowspan="1" colspan="1">12</td>
<td align="center" rowspan="1" colspan="1">10</td>
<td align="center" rowspan="1" colspan="1">0.78</td>
<td align="center" rowspan="1" colspan="1">10</td>
<td align="center" rowspan="1" colspan="1">12</td>
<td align="center" rowspan="1" colspan="1">0.07</td>
<td align="center" rowspan="1" colspan="1">6</td>
<td align="center" rowspan="1" colspan="1">16</td>
<td align="center" rowspan="1" colspan="1">0.30</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1"> Absent</td>
<td align="center" rowspan="1" colspan="1">2</td>
<td align="center" rowspan="1" colspan="1">27</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">17</td>
<td align="center" rowspan="1" colspan="1">11</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">6</td>
<td align="center" rowspan="1" colspan="1">23</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">4</td>
<td align="center" rowspan="1" colspan="1">25</td>
<td align="center" rowspan="1" colspan="1"></td>
</tr>
</tbody>
</table>
</table-wrap>
</floats-group>
</pmc>
</record>
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