Angiosarcoma: Difference between revisions

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{{CMG}} {{shyam}}; {{AE}} {{M.B}}
{{CMG}} {{shyam}}; {{AE}} {{M.B}}
{{SK}}  Hemangiosarcoma; Pulmonary angiosarcoma; Vascular sarcoma  
{{SK}}  Hemangiosarcoma; Pulmonary angiosarcoma; Vascular sarcoma  
==Overview==
==Overview==
'''Angiosarcoma''' is a rare [[malignant]] vascular [[neoplasm]] of [[endothelial]]-type cells that line vessel walls. The peak age of incidence appears to be the 7th decade, and men are affected more than women.  Angiosarcoma was first described by Dr. Juan Rosai, in 1976. The pathogenesis of angiosarcoma is characterized by a rapid and extensively infiltrating overgrowth of vascular [[epithelial]] cells. Angiosarcoma may arise in any part of the body, but is more common in soft tissue than in bone. Common angiosarcoma locations include the  head and neck area, [[kidney]], [[liver]], [[lung]], and and the most common site of radiation-induced angiosarcoma development is the breast.  The [[PTPRB]]/[[Phospholipase C|PLCG1]] [[genes]] are associated with the development of angiosarcoma; [[mutation]] of these genes result in aberrant [[angiogenesis]]. The imaging modality of choice for diagnosing angiosarcoma will depend on the location. For [[pulmonary]] angiosarcoma, the imaging modality of choice is enhanced CT scan. For other types angiosarcoma, the imaging modality of choice is MRI. On CT scan, findings suggestive of angiosarcoma may include vascular invasion, nodular enhancement (common), and a hypoattenuating mass. The mainstay [[adjuvant therapy]] for angiosarcoma is a [[doxorubicin]]-based regimen. The response rate for [[chemotherapy]] in patients with angiosarcoma is poor.
'''Angiosarcoma''' is a rare [[malignant]] vascular [[neoplasm]] of [[endothelial]]-type cells that line vessel walls. The peak age of incidence appears to be the 7th decade, and men are affected more than women.  Angiosarcoma was first described by Dr. Juan Rosai, in 1976. The pathogenesis of angiosarcoma is characterized by a rapid and extensively infiltrating overgrowth of vascular [[epithelial]] cells. Angiosarcoma may arise in any part of the body, but is more common in soft tissue than in bone. Common angiosarcoma locations include the  head and neck area, [[kidney]], [[liver]], [[lung]], and and the most common site of radiation-induced angiosarcoma development is the breast.  The [[PTPRB]]/[[Phospholipase C|PLCG1]] [[genes]] are associated with the development of angiosarcoma; [[mutation]] of these genes result in aberrant [[angiogenesis]]. The imaging modality of choice for diagnosing angiosarcoma will depend on the location. For [[pulmonary]] angiosarcoma, the imaging modality of choice is enhanced CT scan. For other types angiosarcoma, the imaging modality of choice is MRI. On CT scan, findings suggestive of angiosarcoma may include vascular invasion, nodular enhancement (common), and a hypoattenuating mass. The mainstay [[adjuvant therapy]] for angiosarcoma is a [[doxorubicin]]-based regimen. The response rate for [[chemotherapy]] in patients with angiosarcoma is poor.
==Historical Perspective==
==Historical Perspective==
[[Angiosarcoma]] was first discovered by Dr. Juan Rosai, M.D. and colleagues in 1976.<ref name="pmid24946325">{{cite journal |vauthors=Barber W, Scriven P, Turner D, Hughes D, Wyld D |title=Epithelioid angiosarcoma: Use of angiographic embolisation and radiotherapy to control recurrent haemorrhage |journal=J Surg Case Rep |volume=2010 |issue=5 |pages=7 |year=2010 |pmid=24946325 |pmc=3649120 |doi=10.1093/jscr/2010.5.7 |url=}}</ref>  
[[Angiosarcoma]] was first discovered by Dr. Juan Rosai, M.D. and colleagues in 1976.<ref name="pmid24946325">{{cite journal |vauthors=Barber W, Scriven P, Turner D, Hughes D, Wyld D |title=Epithelioid angiosarcoma: Use of angiographic embolisation and radiotherapy to control recurrent haemorrhage |journal=J Surg Case Rep |volume=2010 |issue=5 |pages=7 |year=2010 |pmid=24946325 |pmc=3649120 |doi=10.1093/jscr/2010.5.7 |url=}}</ref>  
==Classification==
==Classification==
Angiosarcoma may be classified according to the clinical heterogeneity into two main groups, and every group can be subdivided into subtypes according to the anatomical location and etiology:<ref>{{Cite journal
*Angiosarcoma may be [[classification|classified]] according to the clinical heterogeneity into two main groups, and every group can be subdivided into subtypes according to the anatomical location and etiology:<ref>{{Cite journal
  | author = [[Matthew G. Fury]], [[Cristina R. Antonescu]], [[Kimberly J. Van Zee]], [[Murray F. Brennan]] & [[Robert G. Maki]]
  | author = [[Matthew G. Fury]], [[Cristina R. Antonescu]], [[Kimberly J. Van Zee]], [[Murray F. Brennan]] & [[Robert G. Maki]]
  | title = A 14-year retrospective review of angiosarcoma: clinical characteristics, prognostic factors, and treatment outcomes with surgery and chemotherapy
  | title = A 14-year retrospective review of angiosarcoma: clinical characteristics, prognostic factors, and treatment outcomes with surgery and chemotherapy
Line 47: Line 42:
  | pmid = 25532684
  | pmid = 25532684
}}</ref>  
}}</ref>  
{| {{table}} cellpadding="4" cellspacing="0" style="border:#c9c9c9 1px solid; margin: 1em 1em 1em 0; border-collapse: collapse;"
{| {{table}} cellpadding="4" cellspacing="0" style="border:#c9c9c9 1px solid; margin: 1em 1em 1em 0; border-collapse: collapse;"
| colspan="2" align="center" style="background-color: #0080FF; font-weight: bold;" | Angiosarcoma   
| colspan="2" align="center" style="background-color: #0080FF; font-weight: bold;" | Angiosarcoma   
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=== Pathophysiology ===
=== Pathophysiology ===
The pathogenesis of angiosarcoma is characterized by a rapid and extensive infiltrating overgrowth of vascular [[epithelial cells]].<ref name="pmid20537949">{{cite journal |vauthors=Young RJ, Brown NJ, Reed MW, Hughes D, Woll PJ |title=Angiosarcoma |journal=Lancet Oncol. |volume=11 |issue=10 |pages=983–91 |year=2010 |pmid=20537949 |doi=10.1016/S1470-2045(10)70023-1 |url=}}</ref> Angiosarcoma is a  locally aggressive [[tumor]] with a high rate of [[lymph node]] infiltration and [[metastases]].
*The pathogenesis of angiosarcoma is characterized by a rapid and extensive infiltrating overgrowth of [[vascular]] [[epithelial cells]].<ref name="pmid20537949">{{cite journal |vauthors=Young RJ, Brown NJ, Reed MW, Hughes D, Woll PJ |title=Angiosarcoma |journal=Lancet Oncol. |volume=11 |issue=10 |pages=983–91 |date=October 2010 |pmid=20537949 |doi=10.1016/S1470-2045(10)70023-1 |url=}}</ref>
 
*Angiosarcoma is a  locally aggressive [[tumor]] with a high rate of [[lymph node]] infiltration and [[metastases]].
* Angiosarcomas demonstrate obvious unregulated vascular-specific receptor tyrosine kinases containing TIE1, KDR, TEK and FLT.The up-regulation of these genes and over-expression of vascular endothelial growth factor receptors can cause endothelial cell expansion, angiogenesis, and also vascular leaks in the structure of vessels. <ref>{{Cite journal
*Angiosarcomas demonstrate obvious unregulated vascular-specific [[receptor tyrosine kinases]] containing [[TIE1]], [[KDR]], [[TEK]] and [[FLT]].
| author = [[Y. Amo]], [[M. Masuzawa]], [[Y. Hamada]] & [[K. Katsuoka]]
*The up-regulation of these [[genes]] and [[over-expression]] of [[vascular]] [[endothelial]] [[growth factor receptors]] can cause [[endothelial cell]] expansion, [[angiogenesis]], and also vascular leaks in the structure of vessels. <ref name="pmid14746640">{{cite journal |vauthors=Amo Y, Masuzawa M, Hamada Y, Katsuoka K |title=Serum concentrations of vascular endothelial growth factor-D in angiosarcoma patients |journal=Br. J. Dermatol. |volume=150 |issue=1 |pages=160–1 |date=January 2004 |pmid=14746640 |doi=10.1111/j.1365-2133.2004.05751.x |url=}}</ref><ref name="pmid20008140">{{cite journal |vauthors=Manner J, Radlwimmer B, Hohenberger P, Mössinger K, Küffer S, Sauer C, Belharazem D, Zettl A, Coindre JM, Hallermann C, Hartmann JT, Katenkamp D, Katenkamp K, Schöffski P, Sciot R, Wozniak A, Lichter P, Marx A, Ströbel P |title=MYC high level gene amplification is a distinctive feature of angiosarcomas after irradiation or chronic lymphedema |journal=Am. J. Pathol. |volume=176 |issue=1 |pages=34–9 |date=January 2010 |pmid=20008140 |pmc=2797867 |doi=10.2353/ajpath.2010.090637 |url=}}</ref><ref name="pmid20949568">{{cite journal |vauthors=Guo T, Zhang L, Chang NE, Singer S, Maki RG, Antonescu CR |title=Consistent MYC and FLT4 gene amplification in radiation-induced angiosarcoma but not in other radiation-associated atypical vascular lesions |journal=Genes Chromosomes Cancer |volume=50 |issue=1 |pages=25–33 |date=January 2011 |pmid=20949568 |pmc=3150534 |doi=10.1002/gcc.20827 |url=}}</ref><ref name="pmid22121953">{{cite journal |vauthors=Fernandez AP, Sun Y, Tubbs RR, Goldblum JR, Billings SD |title=FISH for MYC amplification and anti-MYC immunohistochemistry: useful diagnostic tools in the assessment of secondary angiosarcoma and atypical vascular proliferations |journal=J. Cutan. Pathol. |volume=39 |issue=2 |pages=234–42 |date=February 2012 |pmid=22121953 |doi=10.1111/j.1600-0560.2011.01843.x |url=}}</ref>
| title = Serum concentrations of vascular endothelial growth factor-D in angiosarcoma patients
** [[KDR]] [[mutations]] are seen in primary breast angiosarcoma regardless of exposure to [[radiation]].
| journal = [[The British journal of dermatology]]
** High level [[MYC]] amplification is seen is seen in radiation-induced and lymphedema-associated angiosarcoma.
| volume = 150
** [[FLT4]] amplification  has been detected in 25% of secondary angiosarcomas.
| issue = 1
* On [[gross pathology]], characteristic findings of angiosarcoma may include red/dark tan [[papules]] or [[noduls]], which are ytpically poorly circumscribed with central earas of [[necrosis]] and hemoorrhage.<ref name="pmid20537949">{{cite journal |vauthors=Young RJ, Brown NJ, Reed MW, Hughes D, Woll PJ |title=Angiosarcoma |journal=Lancet Oncol. |volume=11 |issue=10 |pages=983–91 |year=2010 |pmid=20537949 |doi=10.1016/S1470-2045(10)70023-1 |url=}}</ref>
| pages = 160–161
| year = 2004
| month = January
| pmid = 14746640
}}</ref><ref>{{Cite journal
| author = [[Johanna Manner]], [[Bernhard Radlwimmer]], [[Peter Hohenberger]], [[Katharina Mossinger]], [[Stefan Kuffer]], [[Christian Sauer]], [[Djeda Belharazem]], [[Andreas Zettl]], [[Jean-Michel Coindre]], [[Christian Hallermann]], [[Jorg Thomas Hartmann]], [[Detlef Katenkamp]], [[Kathrin Katenkamp]], [[Patrick Schoffski]], [[Raf Sciot]], [[Agnieszka Wozniak]], [[Peter Lichter]], [[Alexander Marx]] & [[Philipp Strobel]]
| title = MYC high level gene amplification is a distinctive feature of angiosarcomas after irradiation or chronic lymphedema
| journal = [[The American journal of pathology]]
| volume = 176
| issue = 1
| pages = 34–39
| year = 2010
| month = January
| doi = 10.2353/ajpath.2010.090637
| pmid = 20008140
}}</ref><ref>{{Cite journal
| author = [[Tianhua Guo]], [[Lei Zhang]], [[Ning-En Chang]], [[Samuel Singer]], [[Robert G. Maki]] & [[Cristina R. Antonescu]]
| title = Consistent MYC and FLT4 gene amplification in radiation-induced angiosarcoma but not in other radiation-associated atypical vascular lesions
| journal = [[Genes, chromosomes & cancer]]
| volume = 50
| issue = 1
| pages = 25–33
| year = 2011
| month = January
| doi = 10.1002/gcc.20827
| pmid = 20949568
}}</ref><ref>{{Cite journal
| author = [[Anthony P. Fernandez]], [[Yang Sun]], [[Raymond R. Tubbs]], [[John R. Goldblum]] & [[Steven D. Billings]]
| title = FISH for MYC amplification and anti-MYC immunohistochemistry: useful diagnostic tools in the assessment of secondary angiosarcoma and atypical vascular proliferations
| journal = [[Journal of cutaneous pathology]]
| volume = 39
| issue = 2
| pages = 234–242
| year = 2012
| month = February
| doi = 10.1111/j.1600-0560.2011.01843.x
| pmid = 22121953
}}</ref>
** KDR mutations are seen in primary breast angiosarcoma regardless of exposure to radiation.
** High level MYC amplification is seen is seen in radiation- induced and lymphedema-associated angiosarcoma.
** FLT4 amplification  has been detected in 25% of secondary angiosarcomas.
 
===Gross Pathology===
On gross pathology, characteristic findings of angiosarcoma may include:<ref name="pmid20537949">{{cite journal |vauthors=Young RJ, Brown NJ, Reed MW, Hughes D, Woll PJ |title=Angiosarcoma |journal=Lancet Oncol. |volume=11 |issue=10 |pages=983–91 |year=2010 |pmid=20537949 |doi=10.1016/S1470-2045(10)70023-1 |url=}}</ref>
*Red/dark tan papules or noduls
*Typically poorly circumscribed
*Central earas of necrosis and hemoorrhage are common
{|
{|
|
|
[[File:AngiosarcomaGross.jpg|500px|thumb|none|Source:Wikimedia commons]]
[[File:AngiosarcomaGross.jpg|500px|thumb|none|Source:Wikimedia commons]]
|}
|}
 
* On microscopic [[histopathological]] analysis, characteristic findings of angiosarcoma may include irregular anastomosing [[vascular]] spaces lined by endothelial cells.<ref name="pmid17998731">{{cite journal |vauthors=Mittal S, Goswami C, Kanoria N, Bhattacharya A |title=Post-irradiation angiosarcoma of bone |journal=J Cancer Res Ther |volume=3 |issue=2 |pages=96–9 |date=2007 |pmid=17998731 |doi= |url=}}</ref>
On microscopic histopathological analysis, characteristic findings of angiosarcoma may include:
*[[Endothelial cells]] have hyperchromatic or vesicular nuclei with fast mitotic activity and necrotic spots.<ref name="pmid7569134">{{cite journal |vauthors=Murphey MD, Fairbairn KJ, Parman LM, Baxter KG, Parsa MB, Smith WS |title=From the archives of the AFIP. Musculoskeletal angiomatous lesions: radiologic-pathologic correlation |journal=Radiographics |volume=15 |issue=4 |pages=893–917 |date=July 1995 |pmid=7569134 |doi=10.1148/radiographics.15.4.7569134 |url=}}</ref>
*Irregular anastomosing vascular spaces lined by endothelial cells<ref>{{Cite journal
*The tumor cells in solid area are characterized by a spindled appearance and contain Weibel-Palade bodies.<ref name="pmid28477885">{{cite journal |vauthors=Marušić Z, Billings SD |title=Histopathology of Spindle Cell Vascular Tumors |journal=Surg Pathol Clin |volume=10 |issue=2 |pages=345–366 |date=June 2017 |pmid=28477885 |doi=10.1016/j.path.2017.01.006 |url=}}</ref>
| author = [[Srabani Mittal]], [[Chanchal Goswami]], [[Nandini Kanoria]] & [[Aniruddha Bhattacharya]]
*Immunohistochemical staining of spindle cells highlights [[CD31]], [[CD34]] and [[von-Willebrand factor]] related antigens which define the [[vascular]] origin of [[tumor]] cells.<ref name="pmid12150140">{{cite journal |vauthors=Kiyohara T, Kumakiri M, Kobayashl H, Itoh K, Lao LM, Ohkawara A, Nakmura H |title=Spindle cell angiosarcoma following irradiation therapy for cervical carcinoma |journal=J. Cutan. Pathol. |volume=29 |issue=2 |pages=96–100 |date=February 2002 |pmid=12150140 |doi=10.1034/j.1600-0560.2002.290206.x |url=}}</ref>
| title = Post-irradiation angiosarcoma of bone
| journal = [[Journal of cancer research and therapeutics]]
| volume = 3
| issue = 2
| pages = 96–99
| year = 2007
| month = April-June
| pmid = 17998731
}}</ref>
*Endothelial cells have hyperchromatic or vesicular nuclei with fast mitotic activity and necrotic spots<ref>{{Cite journal
| author = [[M. D. Murphey]], [[K. J. Fairbairn]], [[L. M. Parman]], [[K. G. Baxter]], [[M. B. Parsa]] & [[W. S. Smith]]
| title = From the archives of the AFIP. Musculoskeletal angiomatous lesions: radiologic-pathologic correlation
| journal = [[Radiographics : a review publication of the Radiological Society of North America, Inc]]
| volume = 15
| issue = 4
| pages = 893–917
| year = 1995
| month = July
| doi = 10.1148/radiographics.15.4.7569134
| pmid = 7569134
}}</ref>
*The tumor cells in solid area are characterized by a spindled appearance and contain Weibel-Palade bodies<ref>{{Cite journal
| author = [[Zlatko Marusic]] & [[Steven D. Billings]]
| title = Histopathology of Spindle Cell Vascular Tumors
| journal = [[Surgical pathology clinics]]
| volume = 10
| issue = 2
| pages = 345–366
| year = 2017
| month = June
| doi = 10.1016/j.path.2017.01.006
| pmid = 28477885
}}</ref>
**Immunohistochemical staining of spindle cells highlights CD31, CD34 and von-Willebrand factor related antigens which define the vascular origin of tumor cells.<ref>{{Cite journal
| author = [[Takahiro Kiyohara]], [[Masanobu Kumakiri]], [[Hitoshi Kobayashl]], [[Kei Itoh]], [[Li-Min Lao]], [[Akira Ohkawara]] & [[Hideki Nakmura]]
| title = Spindle cell angiosarcoma following irradiation therapy for cervical carcinoma
| journal = [[Journal of cutaneous pathology]]
| volume = 29
| issue = 2
| pages = 96–100
| year = 2002
| month = February
| pmid = 12150140
}}</ref>
 
*Lesion biopsy findings associated with angiosarcoma include:
**Irregular anastomosing vascular spaces lined by endothelial cells<ref>{{Cite journal
| author = [[Srabani Mittal]], [[Chanchal Goswami]], [[Nandini Kanoria]] & [[Aniruddha Bhattacharya]]
| title = Post-irradiation angiosarcoma of bone
| journal = [[Journal of cancer research and therapeutics]]
| volume = 3
| issue = 2
| pages = 96–99
| year = 2007
| month = April-June
| pmid = 17998731
}}</ref>
**Endothelial cells have hyperchromatic or vesicular nuclei with fast mitotic activity and necrotic spots<ref>{{Cite journal
| author = [[M. D. Murphey]], [[K. J. Fairbairn]], [[L. M. Parman]], [[K. G. Baxter]], [[M. B. Parsa]] & [[W. S. Smith]]
| title = From the archives of the AFIP. Musculoskeletal angiomatous lesions: radiologic-pathologic correlation
| journal = [[Radiographics : a review publication of the Radiological Society of North America, Inc]]
| volume = 15
| issue = 4
| pages = 893–917
| year = 1995
| month = July
| doi = 10.1148/radiographics.15.4.7569134
| pmid = 7569134
}}</ref>
**The tumor cells in solid area are characterized by a spindled appearance and contain Weibel-Palade bodies<ref>{{Cite journal
| author = [[Zlatko Marusic]] & [[Steven D. Billings]]
| title = Histopathology of Spindle Cell Vascular Tumors
| journal = [[Surgical pathology clinics]]
| volume = 10
| issue = 2
| pages = 345–366
| year = 2017
| month = June
| doi = 10.1016/j.path.2017.01.006
| pmid = 28477885
}}</ref>
**Immunohistochemical staining of spindle cells highlights CD31, CD34 and von-Willebrand factor related antigens which define the vascular origin of tumor cells.<ref>{{Cite journal
| author = [[Takahiro Kiyohara]], [[Masanobu Kumakiri]], [[Hitoshi Kobayashl]], [[Kei Itoh]], [[Li-Min Lao]], [[Akira Ohkawara]] & [[Hideki Nakmura]]
| title = Spindle cell angiosarcoma following irradiation therapy for cervical carcinoma
| journal = [[Journal of cutaneous pathology]]
| volume = 29
| issue = 2
| pages = 96–100
| year = 2002
| month = February
| pmid = 12150140
}}</ref>
 
==Causes==
==Causes==
The most common cause of angiosarcoma appears to be therapeutic radiation, which was a well-recognized cause of hepatic angiosarcoma in the era when the thorium containing contrast agent Thorotrast was employed. Presently, the breast is the most common anatomic site affected by radiation-induced angiosarcoma.
The most common cause of angiosarcoma appears to be therapeutic radiation, which was a well-recognized cause of hepatic angiosarcoma in the era when the thorium containing contrast agent Thorotrast was employed. Presently, the breast is the most common anatomic site affected by radiation-induced angiosarcoma.
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| style="background: #F5F5F5; " |Metastasis (M1)
| style="background: #F5F5F5; " |Metastasis (M1)
|}
|}
=== Symptoms ===
=== Symptoms ===
*Angiosarcomas occur at different anatomic sites and grow insidiously, then they can present with various misleading symptoms.<ref name="YoungBrown2010">{{cite journal|last1=Young|first1=Robin J|last2=Brown|first2=Nicola J|last3=Reed|first3=Malcolm W|last4=Hughes|first4=David|last5=Woll|first5=Penella J|title=Angiosarcoma|journal=The Lancet Oncology|volume=11|issue=10|year=2010|pages=983–991|issn=14702045|doi=10.1016/S1470-2045(10)70023-1}}</ref> The most common clinical manifestation is a gradually enlarging, painless mass. <ref>{{Cite journal
*Angiosarcomas occur at different anatomic sites and grow insidiously, then they can present with various misleading symptoms.<ref name="YoungBrown2010">{{cite journal|last1=Young|first1=Robin J|last2=Brown|first2=Nicola J|last3=Reed|first3=Malcolm W|last4=Hughes|first4=David|last5=Woll|first5=Penella J|title=Angiosarcoma|journal=The Lancet Oncology|volume=11|issue=10|year=2010|pages=983–991|issn=14702045|doi=10.1016/S1470-2045(10)70023-1}}</ref> The most common clinical manifestation is a gradually enlarging, painless mass. <ref>{{Cite journal
Line 519: Line 372:
  | pmid = 26617830
  | pmid = 26617830
}}</ref>
}}</ref>
=== Physical Examination ===
=== Physical Examination ===
Patients with angiosarcoma may appear [[Cachexia|cachectic]] or normal. In cutaneous angiosarcoma, physical examination findings may include:
Patients with angiosarcoma may appear [[Cachexia|cachectic]] or normal. In cutaneous angiosarcoma, physical examination findings may include:
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*Blushed purple-red [[papule]]  
*Blushed purple-red [[papule]]  
=== Laboratory Findings ===
=== Laboratory Findings ===
There are no specific laboratory findings associated with angiosarcoma.
*There are no specific laboratory findings associated with angiosarcoma.
===Electrocardiogram===
*There are no ECG findings associated with angiosarcoma.
===Echocardiography or Ultrasound===
*On ultrasound imaging, angiosarcoma may have variable features according to the location of the tumor. It may appear as an echogenic, nodular, or lobulated mass.<ref name="BendelMaleszewski2011">{{cite journal|last1=Bendel|first1=Emily C.|last2=Maleszewski|first2=Joseph J.|last3=Araoz|first3=Philip A.|title=Imaging Sarcomas of the Great Vessels and Heart|journal=Seminars in Ultrasound, CT and MRI|volume=32|issue=5|year=2011|pages=377–404|issn=08872171|doi=10.1053/j.sult.2011.06.001}}</ref>
===X-ray===
*There are no x-ray findings associated with angiosarcoma.
===Imaging Findings===
===Imaging Findings===
*The imaging modality of choice for angiosarcoma will depend on the location.
*The imaging modality of choice for angiosarcoma will depend on the location.
*For pulmonary angiosarcoma, the imaging modality of choice is enhanced CT scan.<ref name="angio">Sturgis EM, Potter BO. Sarcomas of the head and neck region. Curr Opin Oncol. 2003 May. 15(3):239-52</ref> For other types angiosarcoma, the imaging modality of choice is MRI.
*For pulmonary angiosarcoma, the imaging modality of choice is enhanced CT scan.<ref name="angio">Sturgis EM, Potter BO. Sarcomas of the head and neck region. Curr Opin Oncol. 2003 May. 15(3):239-52</ref> For other types angiosarcoma, the imaging modality of choice is MRI.
====CT====
===CT Scan===
On CT, findings of angiosarcoma may include:<ref name="angio">Sturgis EM, Potter BO. Sarcomas of the head and neck region. Curr Opin Oncol. 2003 May. 15(3):239-52</ref>
On CT, findings of angiosarcoma may include:<ref name="angio">Sturgis EM, Potter BO. Sarcomas of the head and neck region. Curr Opin Oncol. 2003 May. 15(3):239-52</ref>
*Vascular invasion  
*Vascular invasion  
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*Hypoattenuating mass
*Hypoattenuating mass
*Multicentric lesions
*Multicentric lesions
 
===MRI===
====MRI====
On MRI, findings of angiosarcoma may include:<ref>{{Cite journal
On MRI, findings of angiosarcoma may include:<ref>{{Cite journal
  | author = [[Ayman H. Gaballah]], [[Corey T. Jensen]], [[Sarah Palmquist]], [[Perry J. Pickhardt]], [[Alper Duran]], [[Gregory Broering]] & [[Khaled M. Elsayes]]
  | author = [[Ayman H. Gaballah]], [[Corey T. Jensen]], [[Sarah Palmquist]], [[Perry J. Pickhardt]], [[Alper Duran]], [[Gregory Broering]] & [[Khaled M. Elsayes]]
Line 551: Line 408:
*T1/T2: heterogeneous areas of hyperintensity suggestive of a mixed tumour and [[hemorrhage]]
*T1/T2: heterogeneous areas of hyperintensity suggestive of a mixed tumour and [[hemorrhage]]
*T1 C+ (Gd): heterogeneous enhancement
*T1 C+ (Gd): heterogeneous enhancement
 
===Other Imaging Findings===
<br />
*There are no other imaging findings associated with angiosarcoma.
===Other Diagnostic Studies===
*There are no other diagnostic studies associated with angiosarcoma.
== Treatment ==
== Treatment ==
=== Medical Therapy ===
=== Medical Therapy ===
* The role of adjuvant chemotherapy, is unclear. Adjuvant chemotherapy and/or radiotheray provide less mutilating surgery, and for patients with unresectable tumors or those who refuse surgery is an option.<ref>{{Cite journal
* The role of adjuvant chemotherapy, is unclear. Adjuvant chemotherapy and/or radiotheray provide less mutilating surgery, and for patients with unresectable tumors or those who refuse surgery is an option.<ref>{{Cite journal
  | author = [[Robin J. Young]], [[Nicola J. Brown]], [[Malcolm W. Reed]], [[David Hughes]] & [[Penella J. Woll]]
  | author = [[Robin J. Young]], [[Nicola J. Brown]], [[Malcolm W. Reed]], [[David Hughes]] & [[Penella J. Woll]]
Line 689: Line 547:
  | pmid = 22466664
  | pmid = 22466664
}}</ref>
}}</ref>
====Primary Prevention====
====Primary Prevention====
There are no [[Primary prevention|primary preventive]] measures available for angiosarcoma.
There are no [[Primary prevention|primary preventive]] measures available for angiosarcoma.
====Secondary Prevention====
====Secondary Prevention====
Once diagnosed and successfully treated, patients with angiosarcoma are followed-up every 3, 6, or 12 months depending on the stage at [[diagnosis]]. Follow-up testing for angiosarcoma may include:<ref name="pmid20537949">{{cite journal |vauthors=Young RJ, Brown NJ, Reed MW, Hughes D, Woll PJ |title=Angiosarcoma |journal=Lancet Oncol. |volume=11 |issue=10 |pages=983–91 |year=2010 |pmid=20537949 |doi=10.1016/S1470-2045(10)70023-1 |url=}}</ref>
Once diagnosed and successfully treated, patients with angiosarcoma are followed-up every 3, 6, or 12 months depending on the stage at [[diagnosis]]. Follow-up testing for angiosarcoma may include:<ref name="pmid20537949">{{cite journal |vauthors=Young RJ, Brown NJ, Reed MW, Hughes D, Woll PJ |title=Angiosarcoma |journal=Lancet Oncol. |volume=11 |issue=10 |pages=983–91 |year=2010 |pmid=20537949 |doi=10.1016/S1470-2045(10)70023-1 |url=}}</ref>
*Periodic [[imaging]]/[[angiography]] evaluation
*Periodic [[imaging]]/[[angiography]] evaluation
*Laboratory testing: [[complete blood count]] (e.g., [[anemia]])
*Laboratory testing: [[complete blood count]] (e.g., [[anemia]])
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
   
   
[[Category:Oncology]]
[[Category:Oncology]]
 
[[Category:Up-To-Date]]
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Revision as of 13:59, 15 October 2019


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]; Associate Editor(s)-in-Chief: Mohsen Basiri M.D. Synonyms and keywords: Hemangiosarcoma; Pulmonary angiosarcoma; Vascular sarcoma

Overview

Angiosarcoma is a rare malignant vascular neoplasm of endothelial-type cells that line vessel walls. The peak age of incidence appears to be the 7th decade, and men are affected more than women. Angiosarcoma was first described by Dr. Juan Rosai, in 1976. The pathogenesis of angiosarcoma is characterized by a rapid and extensively infiltrating overgrowth of vascular epithelial cells. Angiosarcoma may arise in any part of the body, but is more common in soft tissue than in bone. Common angiosarcoma locations include the head and neck area, kidney, liver, lung, and and the most common site of radiation-induced angiosarcoma development is the breast. The PTPRB/PLCG1 genes are associated with the development of angiosarcoma; mutation of these genes result in aberrant angiogenesis. The imaging modality of choice for diagnosing angiosarcoma will depend on the location. For pulmonary angiosarcoma, the imaging modality of choice is enhanced CT scan. For other types angiosarcoma, the imaging modality of choice is MRI. On CT scan, findings suggestive of angiosarcoma may include vascular invasion, nodular enhancement (common), and a hypoattenuating mass. The mainstay adjuvant therapy for angiosarcoma is a doxorubicin-based regimen. The response rate for chemotherapy in patients with angiosarcoma is poor.

Historical Perspective

Angiosarcoma was first discovered by Dr. Juan Rosai, M.D. and colleagues in 1976.[1]

Classification

  • Angiosarcoma may be classified according to the clinical heterogeneity into two main groups, and every group can be subdivided into subtypes according to the anatomical location and etiology:[2]

[3][4]

Angiosarcoma
Primary Secondary
Cutaneous Post Radiation Angiosarcoma
Breast Lymphedema-associated Angiosarcoma
Soft tissue and Bone Angiosarcoma due to exposure to mutatgens
Visceral

Pathophysiology

File:AngiosarcomaGross.jpg
Source:Wikimedia commons
  • On microscopic histopathological analysis, characteristic findings of angiosarcoma may include irregular anastomosing vascular spaces lined by endothelial cells.[10]
  • Endothelial cells have hyperchromatic or vesicular nuclei with fast mitotic activity and necrotic spots.[11]
  • The tumor cells in solid area are characterized by a spindled appearance and contain Weibel-Palade bodies.[12]
  • Immunohistochemical staining of spindle cells highlights CD31, CD34 and von-Willebrand factor related antigens which define the vascular origin of tumor cells.[13]

Causes

The most common cause of angiosarcoma appears to be therapeutic radiation, which was a well-recognized cause of hepatic angiosarcoma in the era when the thorium containing contrast agent Thorotrast was employed. Presently, the breast is the most common anatomic site affected by radiation-induced angiosarcoma. Angiosarcomas may arise after exposure to vinyl chloride, although they remain rare tumors even in an exposed population. Angiosarcomas are also observed after lymphedema from any cause, be it surgical, filarial, or congenital, and defined as Stewart-Treves syndrome. Common causes of angiosarcoma include:[5]

Differentiating Angiosarcoma from Other Diseases

Angiosarcoma must be differentiated from other diseases that cause a highly vascular mass or non-healing cutaneous ulcerations such as:

Differentials for Cutaneous Angiosarcoma

Cutaneous angiosarcoma must be differentiated from other diseases with non-healing cutaneous ulcerations such as:[14][15][16]

Differentials for Non-cutaneous Angiosarcoma

Angiosarcoma must be differentiated from other diseases that cause a highly vascular mass such as:[17]

Epidemiology and Demographics

  • In general 2% of soft tissue sarcomas are angiosarcomas, and the incidence of soft tissue sarcoma is about 6 per 100,000 person; on the other words,the incidence of angiosarcomas can be calculated approximately 1.2 per 1,000.000 person.[18][19]
  • Angiosarcoma is more commonly observed among patients aged between 40 to 75 years old.The peak age of incidence appears is the 7th decade,[20]
  • Males are more commonly affected with angiosarcoma than females.[20]
  • The male to female ratio is 2:1.[20]
  • There is no racial predilection for angiosarcoma. however, African-Americans in the U.S are rarely affected.[21]

Risk Factors

Common risk factors in the development of angiosarcoma include:[5]

Natural History, Complications and Prognosis

  • The majority of patients with angiosarcoma remain asymptomatic for years.[5]
  • Early clinical features may include nonspecific symptoms, such as pain, fatigue, malaise, and nausea.
  • If left untreated, the majority of patients with angiosarcoma may rapidly progress to develop metastases.[20]

Common complications of angiosarcoma include:[5]

  • Prognosis is generally poor; the 5-­year survival rate of patients with angiosarcoma is approximately 12-33%.
  • Poor prognostic factors include patient age (> 65 years), retroperitoneal location, and large tumor size.[20]

Diagnosis

Diagnostic Study of Choice

  • There is no single diagnostic study of choice for the diagnosis of angiosarcomas. The imaging modality of choice for angiosarcoma or use of punch biopsy of skin will depend on the anatomic location of lesions.
    • Magnetic resonance imaging (MRI) is the imaging modality of choice for evaluating of suspicious lesions of the extremities, retroperitoneum, or abdominal wall.[22]
    • CT scan is useful in for evaluating of lung, pleural, and mediastinal involvement.
    • An x-ray may be helpful in the diagnosis of bone angiosarcoma. Findings on an x-ray suggestive of diagnostic include solitary lytic lesion, with irregular borders or a mixed lytic-sclerotic pattern.[23]
    • Punch biopsy of cutaneous lsions accompanied with immunohistochemical staining provide accurate findings for diagnosis of cutaneous angiosarcoma. Findings associated with angiosarcoma include irregular anastomosing vascular spaces lined by endothelial cells, and immunohistochemical staining of tumor cells highlights CD31, CD34 and von-Willebrand factor related antigens which define the vascular origin of tumor cells.[24][25]

Staging

According to the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) and by Enneking classification, soft tissue sarcomas are classified to different stages based on the primary tumor characteristics, histological grading and the local or distant tumor involvement. Table below provides summarized information regarding staging of angiosarcoma:[26][27]

Stage Grade Site Metastasis
Ia Low grade (G1) Intracompartmental (T1) No metastasis (M0)
Ib Low grade (G1) Extracompartmental (T2) No metastasis (M0)
IIa High grade (G2) Intracompartmental (T1) No metastasis (M0)
IIb High grade (G2) Extracompartmental (T2) No metastasis (M0)
IIIa Low or High grade (G1-G2) Intracompartmental (T1) Metastasis (M1)
IIIb Low or High grade (G1-G2) Extracompartmental (T2) Metastasis (M1)

Symptoms

  • Angiosarcomas occur at different anatomic sites and grow insidiously, then they can present with various misleading symptoms.[28] The most common clinical manifestation is a gradually enlarging, painless mass. [29]Some patients complain of pain or symptoms due to compression of adjacent neurovascular structures that causes pain or edema in an extremity.
  • Primary cutaneous, head and neck and breast angiosarcoma may present with skin thickening, erythema, or skin discoloration.[30][31]
  • Secondary angiosarcomas include radiation-Induced and lymphedema-associated Angiosarcoma have a distinct feature, presenting as single or several ecchymotic maculopapular cutaneous lesions in the radiation field or in areas exposed to chronic lymphedema.[32]

Physical Examination

Patients with angiosarcoma may appear cachectic or normal. In cutaneous angiosarcoma, physical examination findings may include:

Laboratory Findings

  • There are no specific laboratory findings associated with angiosarcoma.

Electrocardiogram

  • There are no ECG findings associated with angiosarcoma.

Echocardiography or Ultrasound

  • On ultrasound imaging, angiosarcoma may have variable features according to the location of the tumor. It may appear as an echogenic, nodular, or lobulated mass.[33]

X-ray

  • There are no x-ray findings associated with angiosarcoma.

Imaging Findings

  • The imaging modality of choice for angiosarcoma will depend on the location.
  • For pulmonary angiosarcoma, the imaging modality of choice is enhanced CT scan.[20] For other types angiosarcoma, the imaging modality of choice is MRI.

CT Scan

On CT, findings of angiosarcoma may include:[20]

  • Vascular invasion
  • Nodular enhancement (common)
  • Hypoattenuating mass
  • Multicentric lesions

MRI

On MRI, findings of angiosarcoma may include:[34]

  • T1/T2: heterogeneous areas of hyperintensity suggestive of a mixed tumour and hemorrhage
  • T1 C+ (Gd): heterogeneous enhancement

Other Imaging Findings

  • There are no other imaging findings associated with angiosarcoma.

Other Diagnostic Studies

  • There are no other diagnostic studies associated with angiosarcoma.

Treatment

Medical Therapy

  • The role of adjuvant chemotherapy, is unclear. Adjuvant chemotherapy and/or radiotheray provide less mutilating surgery, and for patients with unresectable tumors or those who refuse surgery is an option.[35][36]
  • Since angiosarcomas are histologically anthracycline-sensitive, then initial systemic chemotherapy for unresectable and/or metastatic angiosarcomas include doxorubicin-based therapy with or without ifosfamide.[37]
  • However, taxane-based regimen may be preffered for initial therapy.Paclitaxel is effective for advanced angiosarcoma.[38]
  • Gemcitabine-based regimen is preferable to doxorubicin with or without ifosfamide for patients with significant clinical haert failure, due to heart-toxicity of doxorubicin.[39]
  • In addition, some vascular biologic molecules, with antiangiogenic characteristics including bevacizumab, sunitinib, and sorafenib, and with or without cytotoxic chemotherapy have shown dramatic responses in a small number of angiosarcoma patients.[40]

Surgery

  • The mainstay of treatment for angiosarcoma is complete surgical resection with wide margins for local and locoregional disease in combination with preoperative or postoperative radiotherapy.[41][42]
  • Surgical resection in combination with radiation therapy is the treatment of choice for small angiosarcomas.[5]
  • Complete surgical resection with wide margins is preferred for local and locoregional angiosarcoma.[5] Owing to the tendency for local infiltration, surgical resection should be associated with preoperative or postoperative radiotherapy.[43]
  • Surgery is not recommended on patients with large sized angiosarcomas. The recurrence rate of angiosarcoma after surgery is 80%.It usually occures after a median of six months locally or distantly and the three-year disease-free and overall survival rates both are low.[44][45]

Primary Prevention

There are no primary preventive measures available for angiosarcoma.

Secondary Prevention

Once diagnosed and successfully treated, patients with angiosarcoma are followed-up every 3, 6, or 12 months depending on the stage at diagnosis. Follow-up testing for angiosarcoma may include:[5]

References

  1. ↑ Barber W, Scriven P, Turner D, Hughes D, Wyld D (2010). "Epithelioid angiosarcoma: Use of angiographic embolisation and radiotherapy to control recurrent haemorrhage". J Surg Case Rep. 2010 (5): 7. doi:10.1093/jscr/2010.5.7. PMC 3649120. PMID 24946325.
  2. ↑ Matthew G. Fury, Cristina R. Antonescu, Kimberly J. Van Zee, Murray F. Brennan & Robert G. Maki (2005). "A 14-year retrospective review of angiosarcoma: clinical characteristics, prognostic factors, and treatment outcomes with surgery and chemotherapy". Cancer journal (Sudbury, Mass.). 11 (3): 241–247. PMID 16053668. Unknown parameter |month= ignored (help)
  3. ↑ M. Schlemmer, P. Reichardt, J. Verweij, J. T. Hartmann, I. Judson, A. Thyss, P. C. W. Hogendoorn, S. Marreaud, M. Van Glabbeke & J. Y. Blay (2008). "Paclitaxel in patients with advanced angiosarcomas of soft tissue: a retrospective study of the EORTC soft tissue and bone sarcoma group". European journal of cancer (Oxford, England : 1990). 44 (16): 2433–2436. doi:10.1016/j.ejca.2008.07.037. PMID 18771914. Unknown parameter |month= ignored (help)
  4. ↑ Marie Karanian & Jean-Michel Coindre (2015). "[Fourth edition of WHO classification tumours of soft tissue]". Annales de pathologie. 35 (1): 71–85. doi:10.1016/j.annpat.2014.11.003. PMID 25532684. Unknown parameter |month= ignored (help)
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 Young RJ, Brown NJ, Reed MW, Hughes D, Woll PJ (October 2010). "Angiosarcoma". Lancet Oncol. 11 (10): 983–91. doi:10.1016/S1470-2045(10)70023-1. PMID 20537949.
  6. ↑ Amo Y, Masuzawa M, Hamada Y, Katsuoka K (January 2004). "Serum concentrations of vascular endothelial growth factor-D in angiosarcoma patients". Br. J. Dermatol. 150 (1): 160–1. doi:10.1111/j.1365-2133.2004.05751.x. PMID 14746640.
  7. ↑ Manner J, Radlwimmer B, Hohenberger P, Mössinger K, Küffer S, Sauer C, Belharazem D, Zettl A, Coindre JM, Hallermann C, Hartmann JT, Katenkamp D, Katenkamp K, Schöffski P, Sciot R, Wozniak A, Lichter P, Marx A, Ströbel P (January 2010). "MYC high level gene amplification is a distinctive feature of angiosarcomas after irradiation or chronic lymphedema". Am. J. Pathol. 176 (1): 34–9. doi:10.2353/ajpath.2010.090637. PMC 2797867. PMID 20008140.
  8. ↑ Guo T, Zhang L, Chang NE, Singer S, Maki RG, Antonescu CR (January 2011). "Consistent MYC and FLT4 gene amplification in radiation-induced angiosarcoma but not in other radiation-associated atypical vascular lesions". Genes Chromosomes Cancer. 50 (1): 25–33. doi:10.1002/gcc.20827. PMC 3150534. PMID 20949568.
  9. ↑ Fernandez AP, Sun Y, Tubbs RR, Goldblum JR, Billings SD (February 2012). "FISH for MYC amplification and anti-MYC immunohistochemistry: useful diagnostic tools in the assessment of secondary angiosarcoma and atypical vascular proliferations". J. Cutan. Pathol. 39 (2): 234–42. doi:10.1111/j.1600-0560.2011.01843.x. PMID 22121953.
  10. ↑ Mittal S, Goswami C, Kanoria N, Bhattacharya A (2007). "Post-irradiation angiosarcoma of bone". J Cancer Res Ther. 3 (2): 96–9. PMID 17998731.
  11. ↑ Murphey MD, Fairbairn KJ, Parman LM, Baxter KG, Parsa MB, Smith WS (July 1995). "From the archives of the AFIP. Musculoskeletal angiomatous lesions: radiologic-pathologic correlation". Radiographics. 15 (4): 893–917. doi:10.1148/radiographics.15.4.7569134. PMID 7569134.
  12. ↑ Marušić Z, Billings SD (June 2017). "Histopathology of Spindle Cell Vascular Tumors". Surg Pathol Clin. 10 (2): 345–366. doi:10.1016/j.path.2017.01.006. PMID 28477885.
  13. ↑ Kiyohara T, Kumakiri M, Kobayashl H, Itoh K, Lao LM, Ohkawara A, Nakmura H (February 2002). "Spindle cell angiosarcoma following irradiation therapy for cervical carcinoma". J. Cutan. Pathol. 29 (2): 96–100. doi:10.1034/j.1600-0560.2002.290206.x. PMID 12150140.
  14. ↑ S. A. Sinclair, L. Sviland & S. Natarajan (1998). "Angiosarcoma arising in a chronically lymphoedematous leg". The British journal of dermatology. 138 (4): 692–694. PMID 9640382. Unknown parameter |month= ignored (help)
  15. ↑ R. J. W. de Keizer, D. de Wolff-Rouendaal & M. A. Nooy (2008). "Angiosarcoma of the eyelid and periorbital region. Experience in Leiden with iridium192 brachytherapy and low-dose doxorubicin chemotherapy". Orbit (Amsterdam, Netherlands). 27 (1): 5–12. doi:10.1080/01676830601168926. PMID 18307140.
  16. ↑ Rita Vora, Gopikrishnan Anjaneyan & Rajat Gupta (2014). "Cutaneous angiosarcoma of head and neck". Indian journal of dermatology. 59 (6): 632. doi:10.4103/0019-5154.143575. PMID 25484419. Unknown parameter |month= ignored (help)
  17. ↑ C. D. Fletcher, A. Beham, S. Bekir, A. M. Clarke & N. J. Marley (1991). "Epithelioid angiosarcoma of deep soft tissue: a distinctive tumor readily mistaken for an epithelial neoplasm". The American journal of surgical pathology. 15 (10): 915–924. PMID 1718176. Unknown parameter |month= ignored (help)
  18. ↑ Robin J. Young, Nicola J. Brown, Malcolm W. Reed, David Hughes & Penella J. Woll (2010). "Angiosarcoma". The Lancet. Oncology. 11 (10): 983–991. doi:10.1016/S1470-2045(10)70023-1. PMID 20537949. Unknown parameter |month= ignored (help)
  19. ↑ Andrea Ferrari, Iyad Sultan, Tseng Tien Huang, Carlos Rodriguez-Galindo, Ahmad Shehadeh, Cristina Meazza, Kirsten K. Ness, Michela Casanova & Sheri L. Spunt (2011). "Soft tissue sarcoma across the age spectrum: a population-based study from the Surveillance Epidemiology and End Results database". Pediatric blood & cancer. 57 (6): 943–949. doi:10.1002/pbc.23252. PMID 21793180. Unknown parameter |month= ignored (help)
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 20.6 Sturgis EM, Potter BO. Sarcomas of the head and neck region. Curr Opin Oncol. 2003 May. 15(3):239-52
  21. ↑ Erich M. Sturgis & Bryan O. Potter (2003). "Sarcomas of the head and neck region". Current opinion in oncology. 15 (3): 239–252. PMID 12778019. Unknown parameter |month= ignored (help)
  22. ↑ Ayman H. Gaballah, Corey T. Jensen, Sarah Palmquist, Perry J. Pickhardt, Alper Duran, Gregory Broering & Khaled M. Elsayes (2017). "Angiosarcoma: clinical and imaging features from head to toe". The British journal of radiology. 90 (1075): 20170039. doi:10.1259/bjr.20170039. PMID 28471264. Unknown parameter |month= ignored (help)
  23. ↑ D. E. Wenger & L. E. Wold (2000). "Malignant vascular lesions of bone: radiologic and pathologic features". Skeletal radiology. 29 (11): 619–631. PMID 11201031. Unknown parameter |month= ignored (help)
  24. ↑ Srabani Mittal, Chanchal Goswami, Nandini Kanoria & Aniruddha Bhattacharya (2007). "Post-irradiation angiosarcoma of bone". Journal of cancer research and therapeutics. 3 (2): 96–99. PMID 17998731. Unknown parameter |month= ignored (help)
  25. ↑ Takahiro Kiyohara, Masanobu Kumakiri, Hitoshi Kobayashl, Kei Itoh, Li-Min Lao, Akira Ohkawara & Hideki Nakmura (2002). "Spindle cell angiosarcoma following irradiation therapy for cervical carcinoma". Journal of cutaneous pathology. 29 (2): 96–100. PMID 12150140. Unknown parameter |month= ignored (help)
  26. ↑ William M. Lydiatt, Snehal G. Patel, Brian O'Sullivan, Margaret S. Brandwein, John A. Ridge, Jocelyn C. Migliacci, Ashley M. Loomis & Jatin P. Shah (2017). "Head and Neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual". CA: a cancer journal for clinicians. 67 (2): 122–137. doi:10.3322/caac.21389. PMID 28128848. Unknown parameter |month= ignored (help)
  27. ↑ Muhammad Umar Jawad & Sean P. Scully (2010). "In brief: classifications in brief: enneking classification: benign and malignant tumors of the musculoskeletal system". Clinical orthopaedics and related research. 468 (7): 2000–2002. doi:10.1007/s11999-010-1315-7. PMID 20333492. Unknown parameter |month= ignored (help)
  28. ↑ Young, Robin J; Brown, Nicola J; Reed, Malcolm W; Hughes, David; Woll, Penella J (2010). "Angiosarcoma". The Lancet Oncology. 11 (10): 983–991. doi:10.1016/S1470-2045(10)70023-1. ISSN 1470-2045.
  29. ↑ Ayman H. Gaballah, Corey T. Jensen, Sarah Palmquist, Perry J. Pickhardt, Alper Duran, Gregory Broering & Khaled M. Elsayes (2017). "Angiosarcoma: clinical and imaging features from head to toe". The British journal of radiology. 90 (1075): 20170039. doi:10.1259/bjr.20170039. PMID 28471264. Unknown parameter |month= ignored (help)
  30. ↑ R. M. Donnell, P. P. Rosen, P. H. Lieberman, R. J. Kaufman, S. Kay, D. W. Jr Braun & D. W. Kinne (1981). "Angiosarcoma and other vascular tumors of the breast". The American journal of surgical pathology. 5 (7): 629–642. PMID 7199829. Unknown parameter |month= ignored (help)
  31. ↑ Ayman H. Gaballah, Corey T. Jensen, Sarah Palmquist, Perry J. Pickhardt, Alper Duran, Gregory Broering & Khaled M. Elsayes (2017). "Angiosarcoma: clinical and imaging features from head to toe". The British journal of radiology. 90 (1075): 20170039. doi:10.1259/bjr.20170039. PMID 28471264. Unknown parameter |month= ignored (help)
  32. ↑ Lifang Cui, Jixin Zhang, Xinmin Zhang, Hong Chang, Congling Qu, Jiangying Zhang & Dingrong Zhong (2015). "Angiosarcoma (Stewart-Treves syndrome) in postmastectomy patients: report of 10 cases and review of literature". International journal of clinical and experimental pathology. 8 (9): 11108–11115. PMID 26617830.
  33. ↑ Bendel, Emily C.; Maleszewski, Joseph J.; Araoz, Philip A. (2011). "Imaging Sarcomas of the Great Vessels and Heart". Seminars in Ultrasound, CT and MRI. 32 (5): 377–404. doi:10.1053/j.sult.2011.06.001. ISSN 0887-2171.
  34. ↑ Ayman H. Gaballah, Corey T. Jensen, Sarah Palmquist, Perry J. Pickhardt, Alper Duran, Gregory Broering & Khaled M. Elsayes (2017). "Angiosarcoma: clinical and imaging features from head to toe". The British journal of radiology. 90 (1075): 20170039. doi:10.1259/bjr.20170039. PMID 28471264. Unknown parameter |month= ignored (help)
  35. ↑ Robin J. Young, Nicola J. Brown, Malcolm W. Reed, David Hughes & Penella J. Woll (2010). "Angiosarcoma". The Lancet. Oncology. 11 (10): 983–991. doi:10.1016/S1470-2045(10)70023-1. PMID 20537949. Unknown parameter |month= ignored (help)
  36. ↑ Guy Lahat, Asha R. Dhuka, Hen Hallevi, Lianchun Xiao, Changye Zou, Kerrington D. Smith, Thuy L. Phung, Raphael E. Pollock, Robert Benjamin, Kelly K. Hunt, Alexander J. Lazar & Dina Lev (2010). "Angiosarcoma: clinical and molecular insights". Annals of surgery. 251 (6): 1098–1106. doi:10.1097/SLA.0b013e3181dbb75a. PMID 20485141. Unknown parameter |month= ignored (help)
  37. ↑ N. Penel, A. Italiano, I. Ray-Coquard, L. Chaigneau, C. Delcambre, Y. M. Robin, B. Bui, F. Bertucci, N. Isambert, D. Cupissol, E. Bompas, J. O. Bay, F. Duffaud, C. Guillemet & J. Y. Blay (2012). "Metastatic angiosarcomas: doxorubicin-based regimens, weekly paclitaxel and metastasectomy significantly improve the outcome". Annals of oncology : official journal of the European Society for Medical Oncology. 23 (2): 517–523. doi:10.1093/annonc/mdr138. PMID 21566149. Unknown parameter |month= ignored (help)
  38. ↑ Keith M. Skubitz & Philip A. Haddad (2005). "Paclitaxel and pegylated-liposomal doxorubicin are both active in angiosarcoma". Cancer. 104 (2): 361–366. doi:10.1002/cncr.21140. PMID 15948172. Unknown parameter |month= ignored (help)
  39. ↑ Gino K. In, James S. Hu & William W. Tseng (2017). "Treatment of advanced, metastatic soft tissue sarcoma: latest evidence and clinical considerations". Therapeutic advances in medical oncology. 9 (8): 533–550. doi:10.1177/1758834017712963. PMID 28794805. Unknown parameter |month= ignored (help)
  40. ↑ Kieuhoa T. Vo, Katherine K. Matthay & Steven G. DuBois (2016). "Targeted antiangiogenic agents in combination with cytotoxic chemotherapy in preclinical and clinical studies in sarcoma". Clinical sarcoma research. 6: 9. doi:10.1186/s13569-016-0049-z. PMID 27274393.
  41. ↑ W. M. Lydiatt, A. R. Shaha & J. P. Shah (1994). "Angiosarcoma of the head and neck". American journal of surgery. 168 (5): 451–454. PMID 7977971. Unknown parameter |month= ignored (help)
  42. ↑ Samia Arifi, Rhizlan Belbaraka, Rabie Rahhali & Nabil Ismaili (2015). "Treatment of Adult Soft Tissue Sarcomas: An Overview". Rare cancers and therapy. 3: 69–87. doi:10.1007/s40487-015-0011-x. PMID 27182479.
  43. ↑ B. Ashleigh Guadagnolo, Gunar K. Zagars, Dejka Araujo, Vinod Ravi, Thomas D. Shellenberger & Erich M. Sturgis (2011). "Outcomes after definitive treatment for cutaneous angiosarcoma of the face and scalp". Head & neck. 33 (5): 661–667. doi:10.1002/hed.21513. PMID 20960566. Unknown parameter |month= ignored (help)
  44. ↑ Darya Buehler, Stephanie R. Rice, John S. Moody, Patrick Rush, Gholam-Reza Hafez, Steven Attia, B. Jack Longley & Kevin R. Kozak (2014). "Angiosarcoma outcomes and prognostic factors: a 25-year single institution experience". American journal of clinical oncology. 37 (5): 473–479. doi:10.1097/COC.0b013e31827e4e7b. PMID 23428947. Unknown parameter |month= ignored (help)
  45. ↑ Jojanneke M. Seinen, Emelie Styring, Vincent Verstappen, Fredrik Vult von Steyern, Anders Rydholm, Albert J. H. Suurmeijer & Harald J. Hoekstra (2012). "Radiation-associated angiosarcoma after breast cancer: high recurrence rate and poor survival despite surgical treatment with R0 resection". Annals of surgical oncology. 19 (8): 2700–2706. doi:10.1245/s10434-012-2310-x. PMID 22466664. Unknown parameter |month= ignored (help)
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