Pediatr Blood Cancer 2015;62:1555–1561
Primary Cutaneous and Subcutaneous Ewing Sarcoma Angela Di Giannatale, MD,1 Anna Maria Frezza, MD,2 Marie-Cecile Le Deley, MD, PhD,3 Perrine Marec-Berard, MD,4 Charlotte Benson, MD,2 Jean-Yves Blay, MD, PhD,5 Binh Bui, MD,6 Ian Judson, MD,2 Odile Oberlin, MD,1 Jeremy Whelan, MD,7 and Nathalie Gaspar, MD, PhD1* Background. Primary cutaneous/subcutaneous Ewing sarcoma (scEWS) is extremely rare. We describe clinical features, treatment, and outcome of this Ewing localization. Procedure. Retrospective study (1996–2012) on 56 patients. Results. Most primary scEWS occurred in late adolescent/young adult females (F/M ¼ 1.9; median age 21.5 years), with primary tumor in the extremity/trunk (48.5%/ 39%). Only 35/56 samples had Real-Time-Polymerase-Chain-Reaction/Fluorescent-In-Situ-Hybridization analysis, 32/35 had EWStranslocation. Most of them exhibited known favorable prognostic factors: localized disease (54/56), initial tumor volume < 200 ml (51/ 53). Thirty and 25 patients received chemotherapy according to EuroEwing99 or a shorter/less intense chemotherapy regimen associated with milder toxicity. One patient had not received chemotherapy. Surgery was performed at diagnosis in 37 patients (18/37 marginal/ intra-lesional resections) followed by secondary surgery in 8/37 (three remained marginal). Nineteen other patients had an initial biopsy followed by chemotherapy, 15/19 underwent late surgery (4/
15 marginal/intra-lesional resections). Overall, 27/56 patients received radiotherapy. Median follow-up was six years (1–15). Two patients with metastatic disease progressed at metastatic sites. Four patients with localized disease experienced progression/relapse (local n ¼ 3, metastatic n ¼ 1). Survival was excellent: 5y-OS and 5yEFS were 93.8% (95%CI ¼ 83–98%) and 88.5% (95%CI–¼ 77–95), respectively. Conclusions. Unplanned primary surgery should be avoided to try to minimize potential long term sequels due to secondary surgery or radiotherapy. Biopsy with molecular analysis and staging should be performed at diagnosis to inform treatment recommendations. Patients with metastases should be treated aggressively as for other metastatic EWS. Further studies are necessary to clarify whether a less intensive chemotherapy regimen could be safely used in localized disease to minimize acute/late toxicities. Pediatr Blood Cancer 2015;62:1555–1561. # 2015 Wiley Periodicals, Inc.
Key words: adolescent; cutaneous; ewing sarcoma; subcutaneous; young adults
INTRODUCTION Extraskeletal Ewing sarcoma (EES) was first described in 1969,[1] as a paravertebral “round cell” tumor histologically resembling Ewing sarcoma (EWS) but not arising from bone. The first large series of 39 EES cases was published in 1975.[2] Cytogenetic studies later confirmed that these tumors belong to the same family as EWS arising from bone which is commonly called Ewing sarcoma family tumors (ESFT).[3] In the first study mentioned, three patients with a tumor limited to cutaneous/subcutaneous sites were described and later, 88 other cases were published.[2,5–9]
We retrospectively investigated the clinical features, treatment strategies, and outcomes of 56 patients with primary scEWS treated in French and British centers and compared them to the previously published cases.
METHODS Patients of any age, diagnosed between 1996 and 2012, were included in this study if they had a histological and/or molecular cytogenetic (FISH/RT-PCR) diagnosis of a EWS/Primitive
Additional supporting information may be found in the online version of this article at the publisher’s web-site
CONTICABASE, French national pathology soft tissue sarcoma database; CT, Computed Tomography; GSF-GETO, French Sarcoma Group-Bone Tumor Study Group; EE99, Euro Ewing 99; EES, Extraskeletal Ewing Sarcoma; EFS, Event-Free Survival; ESFT, Ewing Sarcoma Family Tumors; EVAIA/ VAIA, (Etoposide), Vincristine, Dactinomycin, Ifosfamide, Doxorubicin; EWS, Ewing Sarcoma; EWSR1, Ewing sarcoma breakpoint region 1; FDG-PET, Fluorodeoxyglucose-Positron Emission Tomography; FISH, Fluorescent In Situ Hybridization; HDT/SCT, High-Dose chemotherapy with autologous Stem Cell Transplantation; IVAD/IE, Ifosfamide, Vincristine, Dactinomycin, Doxorubicine/ Ifosfamide, Etoposide; MRI, Magnetic Resonance Imaging; Neo-AI, Neoadjuvante-Adriamycin, Ifosfamide; OS, Overall Survival; PNET, Primitive Neuroectodermal Tumor; R0/R1/R2, Quality of Resection 0/1/2 (wide, marginal, intralesional); RT-PCR, Real-Time Polymerase Chain Reaction; scEWS, Cutaneous/subcutaneous Ewing sarcoma; VAC/VAI, Vincristine, Dactinomycin, Cyclophosphamide/ Ifosfamide; VDC, Vincristine, Doxorubicin, Cyclophosphamide; VID/VIDE, Vincristine, Ifosfamide, Doxorubicin, (Etoposide) 1 MD, Pediatric and Adolescent Oncology, Gustave Roussy, 114 Rue Eduard Vaillant 94805, Villejuif, France; 2MD, Royal Marsden Fulham Road, SW3 6JJ,, London, UK; 3Biostatistics Department, Institut Gustave Roussy, Paris-Sud University, 114 Rue Eduard Vaillant 94805, Villejuif, France; 4Pediatric Onco-Hematology Institute, Centre Leon Berard, 28 Rue Laennec 69008, Lyon, France; 5Department of Medical Oncology, Centre Leon Berard, 28 Rue Laennec 69008, Lyon, France; 6Department of Medical Oncology, Institut Bergonie, 229 cours de l’Argonne 33076, Bordeaux Cedex, France; 7University College Hospital London NHS Foundation Trust, 1st Floor Central, 250 Euston Road, London NW1 2PG, UK
Conflict of interest: Nothing to declare.
Correspondence to: Nathalie Gaspar, MD, PhD, Pediatric and Adolescent Oncology, Gustave Roussy, 114 Rue Eduard Vaillant, 94805 Villejuif, France. E-mail: [email protected] Received 28 October 2014; Accepted 3 March 2015
C 2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25535 Published online 20 April 2015 in Wiley Online Library (wileyonlinelibrary.com).
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Giannatale et al.
Neuroectodermal Tumor (PNET) with a primary tumor limited to the dermis and/or hypodermis without muscle, bone, or deep organ involvement. French patients with primary scEWS were selected from the Euro-Ewing99 (EE99) [4] database, from the French national pathology soft tissue sarcoma database (CONTICABASE) or reported by French GSF-GETO investigators (Groupe sarcome franSc ais-groupe d’etude des tumeurs osseuses). Patients treated in two London institutions between 1996 and 2012 were also included in the study (University College of London Hospital NHS Foundation Trust; Royal Marsden Hospital). Patient clinical details (age, sex, tumor location, and size), histopathology, biology, therapeutic data (surgery, chemotherapy, radiotherapy) and follow-up information were collected. We reviewed the literature for English, French, and Italian papers (case reports and series), using PubMed and the following combinations: EWS, PNET, Ewing family, and cutaneous/ subcutaneous/superficial/soft tissue/extraskeletal or skin. Only primary dermal–hypodermal sites were considered. Overall survival (OS) and event-free survival (EFS) were calculated from the initiation of treatment (surgery or chemotherapy) and estimated by the Kaplan–Meier method. Patients who had failed to achieve an event-free status were considered as having progressive disease since the first day of therapy. All patients were included in the EFS curves. The statistical significance of prognostic variables was tested by the log-rank test. The distribution of variables were compared between patient groups using Fisher’s exact tests. A P value < 0.05 was considered significant.
RESULTS Between 1999 and 2012, 1,005 patients were registered in the EE99 database; 134 patients with soft tissue EWS, and among them 24 had scEWS (2.7% of the all EE99 population). During the same period, 13 additional French patients not included in the EE99 trial were identified through two French sarcoma databases (CONTICABASE and GSF-GETO). Nineteen patients from London institutions not enrolled in EE99 were included from 1996. From the literature we identified 27 papers describing 91 patients with scEWS.[2,5–9]
Patient characteristics in this series and in the literature are described in Table I. Patients were predominantly female (sex ratio F/M1.9). The median age at diagnosis was 21.5 years (range 1.5– 82). Patients treated in the EE99 trial were younger than those with other chemotherapy regimens (median age 15 and 30 years, P < 0.001; 21/28 and 6/28 were 20 years, respectively). Only two patients (3.5%) had metastatic disease at diagnosis (lung metastases). Most of the lesions were small volume tumors
Primary Cutaneous and Subcutaneous Ewing Sarcoma Angela Di Giannatale, MD,1 Anna Maria Frezza, MD,2 Marie-Cecile Le Deley, MD, PhD,3 Perrine Marec-Berard, MD,4 Charlotte Benson, MD,2 Jean-Yves Blay, MD, PhD,5 Binh Bui, MD,6 Ian Judson, MD,2 Odile Oberlin, MD,1 Jeremy Whelan, MD,7 and Nathalie Gaspar, MD, PhD1* Background. Primary cutaneous/subcutaneous Ewing sarcoma (scEWS) is extremely rare. We describe clinical features, treatment, and outcome of this Ewing localization. Procedure. Retrospective study (1996–2012) on 56 patients. Results. Most primary scEWS occurred in late adolescent/young adult females (F/M ¼ 1.9; median age 21.5 years), with primary tumor in the extremity/trunk (48.5%/ 39%). Only 35/56 samples had Real-Time-Polymerase-Chain-Reaction/Fluorescent-In-Situ-Hybridization analysis, 32/35 had EWStranslocation. Most of them exhibited known favorable prognostic factors: localized disease (54/56), initial tumor volume < 200 ml (51/ 53). Thirty and 25 patients received chemotherapy according to EuroEwing99 or a shorter/less intense chemotherapy regimen associated with milder toxicity. One patient had not received chemotherapy. Surgery was performed at diagnosis in 37 patients (18/37 marginal/ intra-lesional resections) followed by secondary surgery in 8/37 (three remained marginal). Nineteen other patients had an initial biopsy followed by chemotherapy, 15/19 underwent late surgery (4/
15 marginal/intra-lesional resections). Overall, 27/56 patients received radiotherapy. Median follow-up was six years (1–15). Two patients with metastatic disease progressed at metastatic sites. Four patients with localized disease experienced progression/relapse (local n ¼ 3, metastatic n ¼ 1). Survival was excellent: 5y-OS and 5yEFS were 93.8% (95%CI ¼ 83–98%) and 88.5% (95%CI–¼ 77–95), respectively. Conclusions. Unplanned primary surgery should be avoided to try to minimize potential long term sequels due to secondary surgery or radiotherapy. Biopsy with molecular analysis and staging should be performed at diagnosis to inform treatment recommendations. Patients with metastases should be treated aggressively as for other metastatic EWS. Further studies are necessary to clarify whether a less intensive chemotherapy regimen could be safely used in localized disease to minimize acute/late toxicities. Pediatr Blood Cancer 2015;62:1555–1561. # 2015 Wiley Periodicals, Inc.
Key words: adolescent; cutaneous; ewing sarcoma; subcutaneous; young adults
INTRODUCTION Extraskeletal Ewing sarcoma (EES) was first described in 1969,[1] as a paravertebral “round cell” tumor histologically resembling Ewing sarcoma (EWS) but not arising from bone. The first large series of 39 EES cases was published in 1975.[2] Cytogenetic studies later confirmed that these tumors belong to the same family as EWS arising from bone which is commonly called Ewing sarcoma family tumors (ESFT).[3] In the first study mentioned, three patients with a tumor limited to cutaneous/subcutaneous sites were described and later, 88 other cases were published.[2,5–9]
We retrospectively investigated the clinical features, treatment strategies, and outcomes of 56 patients with primary scEWS treated in French and British centers and compared them to the previously published cases.
METHODS Patients of any age, diagnosed between 1996 and 2012, were included in this study if they had a histological and/or molecular cytogenetic (FISH/RT-PCR) diagnosis of a EWS/Primitive
Additional supporting information may be found in the online version of this article at the publisher’s web-site
CONTICABASE, French national pathology soft tissue sarcoma database; CT, Computed Tomography; GSF-GETO, French Sarcoma Group-Bone Tumor Study Group; EE99, Euro Ewing 99; EES, Extraskeletal Ewing Sarcoma; EFS, Event-Free Survival; ESFT, Ewing Sarcoma Family Tumors; EVAIA/ VAIA, (Etoposide), Vincristine, Dactinomycin, Ifosfamide, Doxorubicin; EWS, Ewing Sarcoma; EWSR1, Ewing sarcoma breakpoint region 1; FDG-PET, Fluorodeoxyglucose-Positron Emission Tomography; FISH, Fluorescent In Situ Hybridization; HDT/SCT, High-Dose chemotherapy with autologous Stem Cell Transplantation; IVAD/IE, Ifosfamide, Vincristine, Dactinomycin, Doxorubicine/ Ifosfamide, Etoposide; MRI, Magnetic Resonance Imaging; Neo-AI, Neoadjuvante-Adriamycin, Ifosfamide; OS, Overall Survival; PNET, Primitive Neuroectodermal Tumor; R0/R1/R2, Quality of Resection 0/1/2 (wide, marginal, intralesional); RT-PCR, Real-Time Polymerase Chain Reaction; scEWS, Cutaneous/subcutaneous Ewing sarcoma; VAC/VAI, Vincristine, Dactinomycin, Cyclophosphamide/ Ifosfamide; VDC, Vincristine, Doxorubicin, Cyclophosphamide; VID/VIDE, Vincristine, Ifosfamide, Doxorubicin, (Etoposide) 1 MD, Pediatric and Adolescent Oncology, Gustave Roussy, 114 Rue Eduard Vaillant 94805, Villejuif, France; 2MD, Royal Marsden Fulham Road, SW3 6JJ,, London, UK; 3Biostatistics Department, Institut Gustave Roussy, Paris-Sud University, 114 Rue Eduard Vaillant 94805, Villejuif, France; 4Pediatric Onco-Hematology Institute, Centre Leon Berard, 28 Rue Laennec 69008, Lyon, France; 5Department of Medical Oncology, Centre Leon Berard, 28 Rue Laennec 69008, Lyon, France; 6Department of Medical Oncology, Institut Bergonie, 229 cours de l’Argonne 33076, Bordeaux Cedex, France; 7University College Hospital London NHS Foundation Trust, 1st Floor Central, 250 Euston Road, London NW1 2PG, UK
Conflict of interest: Nothing to declare.
Correspondence to: Nathalie Gaspar, MD, PhD, Pediatric and Adolescent Oncology, Gustave Roussy, 114 Rue Eduard Vaillant, 94805 Villejuif, France. E-mail: [email protected] Received 28 October 2014; Accepted 3 March 2015
C 2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25535 Published online 20 April 2015 in Wiley Online Library (wileyonlinelibrary.com).
1556
Giannatale et al.
Neuroectodermal Tumor (PNET) with a primary tumor limited to the dermis and/or hypodermis without muscle, bone, or deep organ involvement. French patients with primary scEWS were selected from the Euro-Ewing99 (EE99) [4] database, from the French national pathology soft tissue sarcoma database (CONTICABASE) or reported by French GSF-GETO investigators (Groupe sarcome franSc ais-groupe d’etude des tumeurs osseuses). Patients treated in two London institutions between 1996 and 2012 were also included in the study (University College of London Hospital NHS Foundation Trust; Royal Marsden Hospital). Patient clinical details (age, sex, tumor location, and size), histopathology, biology, therapeutic data (surgery, chemotherapy, radiotherapy) and follow-up information were collected. We reviewed the literature for English, French, and Italian papers (case reports and series), using PubMed and the following combinations: EWS, PNET, Ewing family, and cutaneous/ subcutaneous/superficial/soft tissue/extraskeletal or skin. Only primary dermal–hypodermal sites were considered. Overall survival (OS) and event-free survival (EFS) were calculated from the initiation of treatment (surgery or chemotherapy) and estimated by the Kaplan–Meier method. Patients who had failed to achieve an event-free status were considered as having progressive disease since the first day of therapy. All patients were included in the EFS curves. The statistical significance of prognostic variables was tested by the log-rank test. The distribution of variables were compared between patient groups using Fisher’s exact tests. A P value < 0.05 was considered significant.
RESULTS Between 1999 and 2012, 1,005 patients were registered in the EE99 database; 134 patients with soft tissue EWS, and among them 24 had scEWS (2.7% of the all EE99 population). During the same period, 13 additional French patients not included in the EE99 trial were identified through two French sarcoma databases (CONTICABASE and GSF-GETO). Nineteen patients from London institutions not enrolled in EE99 were included from 1996. From the literature we identified 27 papers describing 91 patients with scEWS.[2,5–9]
Patient characteristics in this series and in the literature are described in Table I. Patients were predominantly female (sex ratio F/M1.9). The median age at diagnosis was 21.5 years (range 1.5– 82). Patients treated in the EE99 trial were younger than those with other chemotherapy regimens (median age 15 and 30 years, P < 0.001; 21/28 and 6/28 were 20 years, respectively). Only two patients (3.5%) had metastatic disease at diagnosis (lung metastases). Most of the lesions were small volume tumors
