View source for Epithelioid sarcoma pathophysiology

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{{Epithelioid sarcoma}}
{{CMG}}; {{AE}} {{Ammu}}
==Overview==
Mutations in the ''SMARCB1'' gene cause epithelioid sarcoma. On gross pathology, solid, multinodular mass, glistening gray tan appearance, and multiple areas of hemorrhage and necrosis are characteristic findings of epithelioid sarcoma. On microscopic histopathological analysis, central necrosis surrounded by bland, polygonal cells with eosinophilic cytoplasm and peripheral spindling, desmoplasia, focal calcification, or metaplastic ossification are characteristic findings of epithelioid sarcoma.
==Pathogenesis==
* Epithelioid sarcoma is the second most common soft tissue sarcoma in hand. Epithelioid sarcoma is also sixth most common soft tissue sarcoma in upper extremity.
* Primary site of epithelioid sarcoma is upper distal extremities. Other rare sites of epithelioid sarcoma are:
:* [[Vulva]]
:* [[Penis]]
:* [[Spine]]
* Epithelioid sarcoma is a rare [[soft tissue sarcoma]] arising from mesenchymal tissue and characterized by [[Epithelioid cell|epithelioid]]-like features. 
* Epithelioid sarcoma accounts for less than 1% of all [[soft tissue sarcomas]]. Epithelioid sarcoma commonly presents itself in the [[distal]] limbs (fingers, hands, forearms, or feet) of young adults as a small, soft mass or a series of bumps. A [[proximal]] version has also been described, frequently occurring in the upper extremities.<ref>{{cite journal |last1=Guillou |first1=L |last2=Wadden |first2=C |last3=Coindre |first3=JM |last4=Krausz |first4=T |last5=Fletcher |first5=CD |title='Proximal-type' epithelioid sarcoma, a distinctive aggressive neoplasm showing rhabdoid features. Clinicopathologic, immunohistochemical, and ultrastructural study of a series |journal=The American Journal of Surgical Pathology |volume=21 |issue=2 |pages=130–46 |year=1997 |pmid=9042279 |doi=10.1097/00000478-199702000-00002}}</ref> Rare cases have been reported in the pelvis, vulva, penis, and spine.
* Epithelioid sarcoma most commonly strikes young adults, yet no age group is immune. The disease has a tendency to develop local recurrences and [[metastasis]] thereafter to regional lymph nodes, lung, bone, brain, and other locations, including the scalp.<ref name=pmid19415960/> Generally speaking, epithelioid sarcoma has a high rate of relapse after initial treatment and tends to recur locally (at or near the original tumor site). Epithelioid sarcoma also demonstrates lymphatic spread (in 22-48% of cases), and metastasis (in 21-63% of cases).<ref name=pmid24046109>{{cite journal |last1=Levy |first1=Antonin |last2=Le Péchoux |first2=Cécile |last3=Terrier |first3=Philippe |last4=Bouaita |first4=Ryan |last5=Domont |first5=Julien |last6=Mir |first6=Olivier |last7=Coppola |first7=Sarah |last8=Honoré |first8=Charles |last9=Le Cesne |first9=Axel |last10=Bonvalot |first10=Sylvie |title=Epithelioid Sarcoma: Need for a Multimodal Approach to Maximize the Chances of Curative Conservative Treatment |journal=Annals of Surgical Oncology |volume=21 |issue=1 |pages=269–76 |year=2014 |pmid=24046109 |doi=10.1245/s10434-013-3247-4 }}</ref> These events, as well as advanced stage (progression) and grade (aggressiveness), are predictive of an overall worse outcome. The overall five-year survival rate for epithelioid sarcoma is anywhere from 25 to 78%. Importantly, the 10-year and 15-year survival rate drops off significantly.<ref name=LevDina>{{cite web |last1=Lev |first1=Dina |title=Epigenetic reprogramming of epitheliold sarcoma: a role for INI1-HDAC crosstalk |url=https://ofur.rice.edu/content.aspx?id=4294967475 }}{{dead link|date=October 2015}}</ref><ref name=pmid16353216>{{cite journal |last1=Casanova |first1=Michela |last2=Ferrari |first2=Andrea |last3=Collini |first3=Paola |last4=Bisogno |first4=Gianni |last5=Alaggio |first5=Rita |last6=Cecchetto |first6=Giovanni |last7=Gronchi |first7=Alessandro |last8=Meazza |first8=Cristina |last9=Garaventa |first9=Alberto |last10=Di Cataldo |first10=Andrea |last11=Carli |first11=Modesto |title=Epithelioid sarcoma in children and adolescents |journal=Cancer |volume=106 |issue=3 |pages=708–17 |year=2006 |pmid=16353216 |doi=10.1002/cncr.21630 }}</ref> Associated with a more positive outcome are younger age, female vs. male sex, distal vs. proximal location, smaller tumor size, and negative margins upon tumor resection.<ref>{{cite journal |last1=Jawad |first1=Muhammad Umar |last2=Extein |first2=Jason |last3=Min |first3=Elijah S. |last4=Scully |first4=Sean P. |title=Prognostic Factors for Survival in Patients with Epithelioid Sarcoma: 441 Cases from the SEER Database |journal=Clinical Orthopaedics and Related Research |volume=467 |issue=11 |pages=2939–48 |year=2009 |pmid=19224301 |pmc=2758965 |doi=10.1007/s11999-009-0749-2 }}</ref><ref name=pmid16353216/>

==Genetics==
* ''SMARCB1'' gene is involved in the pathogenesis of epithelioid sarcoma.
==Genetics==
* The most common genetic mutation (found in 80-90% of epithelioid sarcomas) is the inactivation of the [[SMARCB1]] gene, or the loss of INI-1 function,<ref name=pmid19033866>{{cite journal |last1=Hornick |first1=Jason L. |last2=Dal Cin |first2=Paola |last3=Fletcher |first3=Christopher D.M. |title=Loss of INI1 Expression is Characteristic of Both Conventional and Proximal-type Epithelioid Sarcoma |journal=The American Journal of Surgical Pathology |volume=33 |issue=4 |pages=542–50 |year=2009 |pmid=19033866 |doi=10.1097/PAS.0b013e3181882c54 }}</ref><ref name=pmid15899790>{{cite journal |last1=Modena |first1=Piergiorgio |last2=Lualdi |first2=Elena |last3=Facchinetti |first3=Federica |last4=Galli |first4=Lisa |last5=Teixeira |first5=Manuel R. |last6=Pilotti |first6=Silvana |last7=Sozzi |first7=Gabriella |title=''SMARCB1/INI1'' Tumor Suppressor Gene Is Frequently Inactivated in Epithelioid Sarcomas |journal=Cancer Research |volume=65 |issue=10 |pages=4012–9 |year=2005 |pmid=15899790 |doi=10.1158/0008-5472.CAN-04-3050 }}</ref> which is thought to be a major contributor to disease progression. Epithelioid sarcoma typically contains chromosome 22q11.2 mutations or deletions and 8q gains, particularly i(8) (>q10). Aberrations of 18q and 8q, as well as recurrent gains at 11q13, have also been observed.<ref>{{cite journal |last1=Lushnikova |first1=Tamara |last2=Knuutila |first2=Sakari |last3=Miettinen |first3=Markku |title=DNA Copy Number Changes in Epithelioid Sarcoma and Its Variants: A Comparative Genomic Hybridization Study |journal=Modern Pathology |volume=13 |issue=10 |pages=1092–6 |year=2000 |pmid=11048803 |doi=10.1038/modpathol.3880203 }}</ref><ref>{{cite journal |last1=Nishio |first1=Jun |last2=Iwasaki |first2=Hiroshi |last3=Nabeshima |first3=Kazuki |last4=Ishiguro |first4=Masako |last5=Naumann |first5=Sabine |last6=Isayama |first6=Teruto |last7=Naito |first7=Masatoshi |last8=Kaneko |first8=Yasuhiko |last9=Kikuchi |first9=Masahiro |last10=Bridge |first10=Julia |title=Establishment of a new human epithelioid sarcoma cell line, FU-EPS-1: Molecular cytogenetic characterization by use of spectral karyotyping and comparative genomic hybridization |journal=International Journal of Oncology |volume=27 |issue=2 |pages=361–9 |year=2005 |pmid=16010416 |doi=10.3892/ijo.27.2.361 }}</ref><ref name=pmid15578074>{{cite journal |last1=Lin |first1=Lin |last2=Hicks |first2=David |last3=Xu |first3=Bo |last4=Sigel |first4=Jessica E |last5=Bergfeld |first5=Wilma F |last6=Montgomery |first6=Elizabeth |last7=Fisher |first7=Cyril |last8=Hartke |first8=Marybeth |last9=Tubbs |first9=Raymond |last10=Goldblum |first10=John R |title=Expression profile and molecular genetic regulation of cyclin D1 expression in epithelioid sarcoma |journal=Modern Pathology |volume=18 |issue=5 |pages=705–9 |year=2005 |pmid=15578074 |doi=10.1038/modpathol.3800349 }}</ref>
* The ''SMARCB1'' gene (also termed BAF47, INI1, or hSNF5) is located on chromosome [[22q11.2]]<ref name=pmid19033866/> and codes for a member of the [[SWI/SNF]] chromatin remodeling complex. Loss of SMARCB1 function is the most common genetic mutation observed in epithelioid sarcoma, and this dysfunction is likely a major driver of disease progression. SMARCB1 is a core protein subunit of the 15 subunit SWI/SNF (or BAF) complex involved in regulating the nucleosome architecture of our genome<ref name=pmid19033866/> and has been shown to be a potent [[tumor suppressor gene]],<ref>{{cite journal |last1=Kahali |first1=Bhaskar |last2=Yu |first2=Jinlong |last3=Marquez |first3=Stefanie B. |last4=Thompson |first4=Kenneth W. |last5=Liang |first5=Shermi Y. |last6=Lu |first6=Li |last7=Reisman |first7=David |title=The silencing of the SWI/SNF subunit and anticancer gene BRM in Rhabdoid tumors |journal=Oncotarget |volume=5 |issue=10 |pages=3316–32 |year=2014 |pmid=24913006 |pmc=4102812 |doi=10.18632/oncotarget.1945 }}</ref><ref name=pmid15899790/> meaning that its primary role is to control cell division and to even halt division under appropriate circumstances (i.e. signals to over-replicate). As this tumor suppressor is commonly inactivated in epithelioid sarcoma, cell division can fail to appropriately halt, resulting in unregulated cellular growth and the formation of cancer tumors. Several research teams are currently developing techniques to reverse this loss of genetic function characteristic of epithelioid sarcoma.<ref name=LevDina/>

==Molecular Biology==

===VEGF===
[[VEGF]] (vascular endothelial growth factor) is often over-expressed in epithelioid sarcoma.<ref name=pmid10782895>{{cite journal |last1=Kuhnen |first1=Cornelius |last2=Lehnhardt |first2=Marcus |last3=Tolnay |first3=Edina |last4=Muehlberger |first4=Thomas |last5=Vogt |first5=Peter M. |last6=Müller |first6=Klaus-Michael |title=Patterns of expression and secretion of vascular endothelial growth factor in malignant soft-tissue tumours |journal=Journal of Cancer Research and Clinical Oncology |volume=126 |issue=4 |pages=219–25 |year=2000 |pmid=10782895 |doi=10.1007/s004320050036 }}</ref> This is a critical pathway in [[angiogenesis]], a process that cancer cells use to form new blood vessels, which provide necessary elements to the [[tumor]] for tumor survival. Anti-VEGF agents such as [[pazopanib]] have shown promise across several different carcinomas and in soft tissue sarcomas.<ref name=pmid22701332>{{cite journal |last1=Martín Liberal |first1=Juan |last2=Lagares-Tena |first2=Laura |last3=Sáinz-Jaspeado |first3=Miguel |last4=Mateo-Lozano |first4=Silvia |last5=García del Muro |first5=Xavier |last6=Tirado |first6=Oscar M. |title=Targeted Therapies in Sarcomas: Challenging the Challenge |journal=Sarcoma |volume=2012 |issue= |pages=626094 |year=2012 |pmid=22701332 |pmc=3372278 |doi=10.1155/2012/626094 }}</ref> In one case study, a patient with advanced metastatic vulvar epithelioid sarcoma showed a partial resolution of both lung and pleural metastases when pazopanib was administered, whereas all other therapies had failed<ref>{{cite web |last1=Chung |first1=Hye Won |title=The treatment of pazopanib on vulvar epithelioid sarcoma: A case report and review of literature |url=http://www.papersearch.net/view/detail.asp?detail_key=40327863 }}{{MEDRS|date=October 2015}}</ref>

===MET===
[[Mesenchymal–epithelial transition|MET]] (mesenchymal to epithelial transition) is another biological pathway that is likely involved in the development and progression of epithelioid sarcoma.<ref>{{cite journal |last1=Kuhnen |first1=C. |last2=Tolnay |first2=Edina |last3=Steinau |first3=Hans Ulrich |last4=Voss |first4=Bruno |last5=Müller |first5=Klaus-Michael |title=Expression of c-Met receptor and hepatocyte growth factor/scatter factor in synovial sarcoma and epithelioid sarcoma |journal=Virchows Archiv |volume=432 |issue=4 |pages=337–42 |year=1998 |pmid=9565343 |doi=10.1007/s004280050175 }}</ref><ref name=pmid25098767>{{cite journal |last1=Imura |first1=Yoshinori |last2=Yasui |first2=Hirohiko |last3=Outani |first3=Hidetatsu |last4=Wakamatsu |first4=Toru |last5=Hamada |first5=Kenichiro |last6=Nakai |first6=Takaaki |last7=Yamada |first7=Shutaro |last8=Myoui |first8=Akira |last9=Araki |first9=Nobuhito |last10=Ueda |first10=Takafumi |last11=Itoh |first11=Kazuyuki |last12=Yoshikawa |first12=Hideki |last13=Naka |first13=Norifumi |title=Combined targeting of mTOR and c-MET signaling pathways for effective management of epithelioid sarcoma |journal=Molecular Cancer |volume=13 |issue= |pages=185 |year=2014 |pmid=25098767 |pmc=4249599 |doi=10.1186/1476-4598-13-185 }}</ref> c-MET is a [[tyrosine kinase]] [[oncogene]], and its signaling pathway has been implicated in a variety of malignancies, including many cancers.

===Sonic hedgehog and Notch===
The [[Sonic hedgehog]] and [[Notch signaling pathway]]s are also suspected to be up-regulated in epithelioid sarcoma. These cell signaling pathways control cellular proliferation and differentiation. They are also involved in [[cancer stem cell]] coordination and disease invasiveness and metastasis. Hhat inhibitors (such as RU-SKI 43) block the Sonic hedgehog signaling pathway by inhibiting hedgehog palmitoyl acytl-transferase. Current trials are investigating Notch inhibitors against epithelioid sarcoma.<ref>{{ClinicalTrialsGov|NCT01154452|Vismodegib and Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced or Metastatic Sarcoma}}</ref>

===mTOR===
The frequent hyperactivation of [[mTOR]] (mammalian target of rapamycin) signaling has also been observed in epithelioid sarcoma.<ref name=pmid25098767/><ref name=pmid21821699>{{cite journal |last1=Xie |first1=X. |last2=Ghadimi |first2=M. P. H. |last3=Young |first3=E. D. |last4=Belousov |first4=R. |last5=Zhu |first5=Q.-s. |last6=Liu |first6=J. |last7=Lopez |first7=G. |last8=Colombo |first8=C. |last9=Peng |first9=T. |last10=Reynoso |first10=D. |last11=Hornick |first11=J. L. |last12=Lazar |first12=A. J. |last13=Lev |first13=D. |title=Combining EGFR and mTOR Blockade for the Treatment of Epithelioid Sarcoma |journal=Clinical Cancer Research |volume=17 |issue=18 |pages=5901–12 |year=2011 |pmid=21821699 |pmc=3176924 |doi=10.1158/1078-0432.CCR-11-0660 }}</ref> The mTOR pathway has been described as a “master switch” for cellular [[catabolism]] and [[anabolism]], and it can enhance [[cell cycle progression]], cell survival, and block normal cell death ([[apoptosis]]).<ref name=pmid22701332/> Interestingly, it has been demonstrated that simply blocking mTOR signaling can result in the reactivation of the [[AKT]] pathway, negating much of the anti-mTOR’s efficacy.<ref name=pmid25098767/> This reactivation of AKT has been shown to be c-MET-dependent,<ref name=pmid25098767/> resulting in the rationale that blocking both mTOR and c-MET concurrently would show increased efficacy.

===EGFR===
The over-expression of [[epidermal growth factor receptor]] (EGFR) has been reported in a majority of epithelioid sarcomas.<ref name=pmid21821699/><ref name=pmid20118913>{{cite journal |last1=Cascio |first1=Michael J |last2=O'Donnell |first2=Richard J |last3=Horvai |first3=Andrew E |title=Epithelioid sarcoma expresses epidermal growth factor receptor but gene amplification and kinase domain mutations are rare |journal=Modern Pathology |volume=23 |issue=4 |pages=574–80 |year=2010 |pmid=20118913 |doi=10.1038/modpathol.2010.2 }}</ref> EGFR is a member of the [[ErbB|HER receptor family]]. Upon [[ligand binding]], EGFR phosphorylation triggers the activation of downstream signaling pathways involved in critical cellular functions such as [[Cell growth|proliferation]], survival, and [[angiogenesis]].<ref>{{cite journal |last1=Yang |first1=J.-L. |last2=Hannan |first2=M.T. |last3=Russell |first3=P.J. |last4=Crowe |first4=P.J. |title=Expression of HER1/EGFR protein in human soft tissue sarcomas |journal=European Journal of Surgical Oncology |volume=32 |issue=4 |pages=466–8 |year=2006 |pmid=16524687 |doi=10.1016/j.ejso.2006.01.012 }}</ref> [[In-vitro]] and [[in-vivo]] laboratory experiments have demonstrated that the blockade of EGFR in epithelioid sarcoma results in decreased cell proliferation, increased apoptosis, and abrogated invasion and migration capacities.<ref name=pmid21821699/> Of interest, while the simple blockade of EGFR with a single agent has shown limited results in the clinical setting, when used as part of a combination regime (where an EGFR inhibitor is combined with an mTOR inhibitor), a [[Synergy|synergism]] has been observed, and superior tumor growth inhibition has been demonstrated.<ref name=pmid21821699/>

===CD109===
[[CD109]] is often expressed in advanced epithelioid sarcoma and is thought to mark the [[cancer stem cell]] (or cancer initiating cell) of the disease.<ref name=pmid24376795>{{cite journal |last1=Ahmad |first1=Aamir |last2=Emori |first2=Makoto |last3=Tsukahara |first3=Tomohide |last4=Murase |first4=Masaki |last5=Kano |first5=Masanobu |last6=Murata |first6=Kenji |last7=Takahashi |first7=Akari |last8=Kubo |first8=Terufumi |last9=Asanuma |first9=Hiroko |last10=Yasuda |first10=Kazuyo |last11=Kochin |first11=Vitaly |last12=Kaya |first12=Mitsunori |last13=Nagoya |first13=Satoshi |last14=Nishio |first14=Jun |last15=Iwasaki |first15=Hiroshi |last16=Sonoda |first16=Tomoko |last17=Hasegawa |first17=Tadashi |last18=Torigoe |first18=Toshihiko |last19=Wada |first19=Takuro |last20=Yamashita |first20=Toshihiko |last21=Sato |first21=Noriyuki |title=High Expression of CD109 Antigen Regulates the Phenotype of Cancer Stem-Like Cells/Cancer-Initiating Cells in the Novel Epithelioid Sarcoma Cell Line ESX and Is Related to Poor Prognosis of Soft Tissue Sarcoma |journal=PLoS ONE |volume=8 |issue=12 |pages=e84187 |year=2013 |pmid=24376795 |pmc=3869840 |doi=10.1371/journal.pone.0084187 }}</ref> Its level of expression has also been shown to be predictive of outcome. Cancer stem cells are a small population of tumor cells characterized by general chemo-resistance, the ability to self-renew, multi-differentiation potential, dormancy capabilities, and tumorigenesis. Therefore, cancer stem cells are thought to play key roles in the progression and relapse of cancer.

===Cyclin D1===
[[Cyclin D1]] is a protein requisite for cell cycle progression and has been shown to be up-regulated in epithelioid sarcoma.<ref name=pmid15578074/> Cyclin D-1 is a regulator of cyclin-dependent kinases ([[CDK4]] and [[CDK6]]). It has been shown to interact with the [[retinoblastoma protein]] (a tumor suppressor gene), CDK4 and CDK6, [[thyroid hormone receptor beta]], and [[nuclear receptor coactivator 1]], among others.<ref name=pmid15578074/> Cyclin D and CDKs promote cell cycle progression by releasing [[transcription factors]] that are important for the initiation of [[DNA replication]]. Abnormal levels of cyclin D-1 may promote rapid cell division in epithelioid sarcoma.
==Gross Pathology==
* Gross pathological features are:
:* Solid, multinodular mass
:* Glistening gray tan appearance
:* Multiple areas of hemorrhage and necrosis
==Microscopic Pathology==
* Histologically, epithelioid sarcoma forms nodules with central necrosis surrounded by bland, polygonal cells with eosinophilic cytoplasm and peripheral spindling.<ref name=pmid19415960>{{cite journal |last1=Armah |first1=Henry B. Armah |last2=Parwani |first2=Anil V. |title=Epithelioid sarcoma |journal=Archives of Pathology & Laboratory Medicine |volume=133 |issue=5 |pages=814–9 |year=2009 |pmid=19415960 |doi=10.1043/1543-2165-133.5.814 |doi-broken-date=October 6, 2015 |url=http://www.archivesofpathology.org/doi/10.1043/1543-2165-133.5.814?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed }}</ref> Epithelioid sarcomas typically express [[vimentin]], [[cytokeratins]], [[epithelial membrane antigen]], and [[CD34]], whereas they are usually negative for [[S100 protein|S100]], [[desmin]], and FLI-1.<ref name=pmid19415960/> They typically stain positive for [[CA125]].<ref>{{cite journal |last1=Kato |first1=Hiroshi |last2=Hatori |first2=Masahito |last3=Kokubun |first3=Shoichi |last4=Watanabe |first4=Mika |last5=Smith |first5=Richard A |last6=Hotta |first6=Tetsuo |last7=Ogose |first7=Akira |last8=Morita |first8=Tetsuro |last9=Murakami |first9=Takashi |last10=Aiba |first10=Setsuya |title=CA125 expression in epithelioid sarcoma |journal=Japanese Journal of Clinical Oncology |volume=34 |issue=3 |pages=149–54 |year=2004 |pmid=15078911 |doi=10.1093/jjco/hyh027 }}</ref>
* Desmoplasia, focal calcification, or metaplastic ossification
==Gallery==
<gallery>
Image:Epithelioid sarcoma - 01.jpg| Low magnification micrograph of epithelioid sarcoma<ref> Epithelioid sarcoma librepathology
(2015). http://librepathology.org/wiki/index.php/Epithelioid_sarcoma  Accessed on February 11, 2016</ref>
Image:Epithelioid sarcoma - high mag.jpg|Low magnification micrograph of epithelioid sarcoma<ref> Epithelioid sarcoma librepathology
(2015). http://librepathology.org/wiki/index.php/Epithelioid_sarcoma  Accessed on February 11, 2016</ref>
Image:Epithelioid sarcoma - intermed mag 02.jpg| Intermediate magnification micrograph of epithelioid sarcoma<ref> Epithelioid sarcoma librepathology
(2015). http://librepathology.org/wiki/index.php/Epithelioid_sarcoma  Accessed on February 11, 2016</ref>
Image:Epithelioid sarcoma - smarcb1 - intermed mag.jpg| High magnification micrograph of epithelioid sarcoma<ref> Epithelioid sarcoma librepathology
(2015). http://librepathology.org/wiki/index.php/Epithelioid_sarcoma  Accessed on February 11, 2016</ref>
Image:Epithelioid sarcoma - very high mag.jpg| Very high magnification micrograph of epithelioid sarcoma<ref> Epithelioid sarcoma librepathology
(2015). http://librepathology.org/wiki/index.php/Epithelioid_sarcoma  Accessed on February 11, 2016</ref>
Image:Epithelioid sarcoma - very high mag.jpg| Very high magnification micrograph of epithelioid sarcoma<ref> Epithelioid sarcoma librepathology
(2015). http://librepathology.org/wiki/index.php/Epithelioid_sarcoma  Accessed on February 11, 2016</ref>
</gallery>
==References==
{{reflist|2}}

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