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Epithelioid Sarcoma—From Genetics to Clinical Practice

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Epithelioid Sarcoma—From Genetics to Clinical Practice cancers Review Epithelioid Sarcoma—From Genetics to Clinical Practice Anna M. Czarnecka 1,2,* , Pawel Sobczuk 1,3,* , Michal Kostrzanowski 1,4 , Mateusz Spalek 1 , Marzanna Chojnacka 5, Anna Szumera-Cieckiewicz 6,7 and Piotr Rutkowski 1 1 Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; [email protected] (M.K.); [email protected] (M.S.); [email protected] (P.R.) 2 Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland 3 Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, 02-097 Warsaw, Poland 4 Faculty of Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland 5 Department of Radiotherapy, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; [email protected] 6 Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; [email protected] 7 Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, 02-776 Warsaw, Poland * Correspondence: [email protected] (A.M.C.); [email protected] (P.S.) Received: 29 June 2020; Accepted: 24 July 2020; Published: 29 July 2020 Abstract: Epithelioid sarcoma is a mesenchymal soft tissue sarcoma often arising in the extremities, usually in young adults with a pick of incidence at 35 years of age. Epithelioid sarcoma (ES) is characterized by the loss of SMARCB1/INI1 (integrase interactor 1) or other proteins of the SWI/SNF complex. Two distinct types, proximal and distal, with varying biology and treatment outcomes, are distinguished. ES is known for aggressive behavior, including a high recurrence rate and regional lymph node metastases. An optimal long-term management strategy is still to be defined. The best treatment of localized ES is wide surgical resection. Neo-adjuvant or adjuvant radiotherapy may be recommended, as it reduces the local recurrence rate. Sentinel lymph node biopsy should be considered in ES patients. Patients with metastatic ES have a poor prognosis with an expected median overall survival of about a year. Doxorubicin-based regimens are recommended for advanced ES. Tazemetostat, an EZH2 methyltransferase, has shown promising results in ES patients. Novel therapies, including immunotherapy, are still needed. Keywords: epithelioid sarcoma; SMARCB1; EZH2; surgery; radiotherapy; chemotherapy; tazemetostat 1. Introduction Epithelioid sarcoma (ES) is a rare, slow-growing neoplasm that was first well-characterized by F.M. Enzinger in 1970 [1]. ES is a soft tissue sarcomas (STS) subtype that is recognized in less than 1% of STS patients [2]. However, it is the second most common STS of the hand and the sixth STS of the upper extremity [2,3]. In a study of 16,500 subsequent STS patients, only 23 ES were reported, but it was the most common STS: of the hand [4]. The ES incidence rate is 0.03/100,000 in the European Union and 0.05/10,000 in the USA as per RARECAREnet and the SEER18 cancer registries. Age-adjusted rate Cancers 2020, 12, 2112; doi:10.3390/cancers12082112 www.mdpi.com/journal/cancers Cancers 2020,, 12,, 2112x FOR PEER REVIEW 2 of 1921 young to middle-aged adults (20–40 years of age group) [6,7]. Distal subtype occurs mostly in young inadults, EU and while USA proximal is 0.02 /is100,000 more common and 0.05 /in100,000, a slightly respectively older population, [5]. ES usuallywith a median develops age in of young 40 years to middle-agedat the time of adultsdiagnosis (20–40 [6,8]. years ES is of very age unlikely group) [to6,7 occur]. Distal in children; subtype occurshowever, mostly a series in youngof cases adults, were whilereported, proximal as described is more commonbelow [9–11]. in a slightly Males oldersuffer population, from ES more with often a median than agefemales, of 40 with years ratio at the of time 2:1 of[2,12,13]. diagnosis [6,8]. ES is very unlikely to occur in children; however, a series of cases were reported, as describedTwo ES below subtypes—distal [9–11]. Males suandffer proximal—are from ES more know oftenn. than These females, subtypes with vary ratio in of morphology 2:1 [2,12,13]. and prognosisTwo ESbut subtypes—distal occur at a similar and rate. proximal—are The distal ES subtype known. is These the canonical subtypes subtype vary in of morphology the disease, and prognosisit most often but presents occur at as a similara deep rate.dermal The or distal subcutaneous ES subtype tumor is the with canonical lymphatic subtype node of metastases. the disease, andProximal it most ES often develops presents mostly as a in deep the dermalproximal or limbs, subcutaneous pelvis, perineum, tumor with and lymphatic genital tract node [14] metastases. (Figure Proximal1A). Each ES of developsthe subtypes mostly develops in the proximal both in proximal limbs, pelvis, and perineum,distal locations and genital [6,15]. tractIn general, [14] (Figure the most1A). Eachcommon of the ES subtypeslocalization develops is in the both extremities. in proximal Still, and few distal cases locationswith atypical [6,15 ES]. Inlocalization general,the in small most commonbowel, penis, ES localization vulva, tongue, is in thebuttocks, extremities. parotid Still, gland, few casespalate, with or atypicalintraocular ES localizationare known in[16–18]. small bowel,Around penis, a quarter vulva, of tongue, cases occur buttocks, in the parotid location gland, prev palate,iously oraffected intraocular by trauma are known or in [ 16the–18 scar]. Around tissues a[19]. quarter of cases occur in the location previously affected by trauma or in the scar tissues [19]. 5cm 5cm Figure 1. EpithelioidEpithelioid sarcoma—perineal area. ( A)) Locally Locally advanced advanced primary primary tumor tumor (delineated, black contour); (B) Metastases to regional lymphlymph nodesnodes inin thethe samesame patientpatient (delineated,(delineated, blackblack contour).contour). At presentation, thethe diseasedisease typicallytypically manifests manifests as as a a painless, painless, slow-growing, slow-growing, firm firm nodule nodule deep deep in softin soft tissues tissues with with a glistening a glistening and gray-tan and gray-tan appearance appearance characterized characterized by superficial by superficial bleeding, bleeding, necrosis, andnecrosis, ulcerations and ulcerations [14]. Pain [14]. is reported Pain is by reported some patients, by some mainly patients, if tumors mainly localize if tumors in proximity localize toin joints.proximity Various to joints. morphology, Various morphology, symptoms, andsymptoms, signs lead and tosigns diffi leadculties to difficul in ES diagnosticsties in ES diagnostics and often delayand often appropriate delay appropriate treatment. treatment. Due to the Due ulceration to the diulcerationfferential, differential, diagnosis should diagnosis include should non-healing include woundsnon-healing and wartswounds [20 ].and ES iswarts also often[20]. initiallyES is also recognized often initially as inflammatory recognized or granulomatous as inflammatory lesions or orgranulomatous other benign conditionslesions or [other21]. At benign the time conditions of diagnosis, [21]. ES At tumors the time are usuallyof diagnosis, small withES tumors a diameter are belowusually 5 small cm [13 with,22]; a however,diameter inbelow some 5 cases,cm [13,22]; mostly however, in proximal in some variant, cases, ES mostly tumors in proximal reach over variant, 20 cm dimensionES tumors reach [1,23]. over In 10–20%, 20 cm dimension ES is multifocal. [1,23]. In Tumors 10–20%, with ES deepis multifocal. tissue location Tumors spread with deep via tendon tissue sheathslocation andspread aponeuroses via tendon [13 sheaths,19,24]. and ES oftenaponeurose metastasizes [13,19,24]. to lymph ES often nodes me (uptastasize to 30%). to Patients lymph nodes suffer from(up to in-transit 30%). Patients metastases suffer and from lymphatic in-transit spread metastases (Figure and1B). [lymphatic22,24]. Distant spread metastases (Figure 1B). most [22,24]. often developDistant metastases in the lungs, most bones, often and develop brain. in Lessthe lung commons, bones, metastases and brain. are Less found common in the scalp,metastases kidneys, are musculoskeletalfound in the scalp, system, kidneys, and musculoskeletal digestive tract, including system, and the digestive liver [25]. tract, ES metastatic including spread the liver is reported [25]. ES inmetastatic the course spread of the is diseasereported in in 20% the to course 50% of of patients the disease [19, 22in ,20%26]. Aroundto 50% of 20% patients of patients [19,22,26]. present Around with distant20% of patients metastases present already with at distant the primary metast diagnosisases already [27]. at the primary diagnosis [27]. 2. Pathology 2. Pathology Microscopically ES is typically multinodular, often with a tendency to central necrosis Microscopically ES is typically multinodular, often with a tendency to central necrosis and and degeneration. With the hematoxylin–eosin staining, the deep acidophilia is observed. The nodular degeneration. With the hematoxylin–eosin staining, the deep acidophilia is observed. The nodular pattern could be variable—in some cases, the nodules are well-circumscribed, while in others, they pattern could be variable—in some cases, the nodules are well-circumscribed, while in
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