Epithelioid sarcoma in children and adolescents

A report from the Italian Soft Tissue Sarcoma Committee




Epithelioid sarcoma (ES) is an uncommon malignant soft tissue tumor. To the authors' knowledge, little information is available to date concerning its clinical features and management in children and adolescents, particularly with regard to the recently described proximal-type variant. The current study concerns 30 patients age < 18 years who were enrolled in the Italian Soft Tissue Sarcoma Committee protocols.


Histopathologic specimens, clinical data, and treatment modalities were reviewed for the current analysis. Nineteen patients had classic ES and 11 had proximal-type ES. Surgery was the mainstay of treatment; radiotherapy was given to six patients considered to be at risk of local disease recurrence due to incomplete resection, and chemotherapy was administered to eight patients.


With a median follow-up of 66 months, the 5-year event-free survival (EFS) and overall survival (OS) rates were 61.7% and 92.4%, respectively, but the OS rate dropped to 86.9% and 72.4%, respectively, at 10 years and 15 years. Local disease recurrence was the major cause of treatment failure. The most significant finding influencing both EFS and OS was tumor site, with a tumor location in the extremities predicting a favorable outcome. Initially unfavorable clinical findings and a worse outcome were associated with the proximal-type variant of ES. A response to chemotherapy was noted in three of the seven patients with measurable disease.


The current study confirms some typical features of ES (i.e., the peculiar superficial distal location [i.e., the hand, fingers], indolent growth, and a tendency to recur locally). The current study data do not clearly confirm the strong tendency for the lymph node involvement described in adult ES patients. Further studies are needed to better define the clinical behavior and biology of the proximal-type variant of ES. Cancer 2006. © 2005 American Cancer Society.

Epithelioid sarcoma (ES) was first described by Enzinger in 1970.1 It is an uncommon, malignant soft tissue tumor that generally presents in fascial planes, aponeuroses, and tendon sheaths of the extremities, particularly in the hand (the fingers) and foot. The tumor is most prevalent in young adults ages 20–40 years. It rarely is found in children and older people, but no age group is exempt.1–3

Pediatric oncologists usually classify ES within the heterogeneous group of nonrhabdomyosarcoma soft tissue sarcomas (NRSTS); in particular, ES recently has been included in the subset of so-called adult-type NRSTS.4 In what to our knowledge are two of the largest reported series on NRSTS, ES is reported to represent 5-8% of cases.4, 5

Histologically, in its classic form, the tumor has a distinctive nodular, granuloma-like pattern, with spindle and epithelioid cells circumscribing areas of central degeneration and necrosis.1, 6, 7 A subtype characterized by a more aggressive behavior and worse outcome recently was described in rare cases, mostly occurring as a deep-seated soft tissue mass at proximal body sites, hence the definition of proximal-type ES.8, 9 It is characterized histologically by sheets of large, atypical, epithelioid cells with vesicular nuclei and prominent nucleoli, with a rhabdoid phenotype. Despite the differences in clinical presentation and behavior, classic ES and proximal-type ES share a similar immunophenotypic profile (although peculiar alterations of chromosome 22 with deletions of the SMARCB1/INI1 gene recently were described in the proximal-type variant10), suggesting that they represent different variants of a distinctive tumor entity.8, 11

To our knowledge, few reports have been published to date and little information currently is available regarding the clinical features and management of ES in children and adolescents,6, 12–14 and no data at all are available concerning the clinical history of proximal-type ES in pediatric patients.

To contribute information regarding the natural history and management of ES in children and adolescents, the Italian Soft Tissue Sarcoma Committee (which is affiliated with the Associazione Italiana Ematologia Oncologia Pediatrica– [AIEOP]) reviewed their experience with children and adolescents diagnosed with ES.


Between January 1978 and December 2004, 30 consecutive, previously untreated patients age < 18 years with a diagnosis of ES were registered at AIEOP centers. Half of these patients were enrolled prospectively in the RMS'88 and RMS'96 AIEOP cooperative protocols for soft tissue sarcomas, whereas the other half were treated at the Istituto Nazionale Tumori of Milan (INT), which only joined the national protocols in 1996. The 30 patients represented approximately 7% of all NRSTS cases registered during the study period (n = 404 cases). Complete information regarding clinical data, treatment modalities, and outcome was available for all patients and was reviewed for the current analysis. Fourteen patients treated at the INT were included in the recently reported single-institutional series of adult-type NRSTS.4 Informed consent was provided by all patients or their guardians, according to the rules established by the study institutions.

Histopathologic Review

The histopathologic specimens and slides were reviewed for all patients by two of the authors (P.C. and R.A.) to confirm the diagnosis (using the revised World Health Organization [WHO] criteria),15 and in particular to identify cases of proximal-type ES. The criteria for the diagnosis of the proximal-type variant was the presence of large, epithelioid cells; marked nuclear atypia; frequently rhabdoid features; and the lack of a granulomatous-like pattern.8 Immunoreactivity for cytokeratins, epithelial membrane antigen, and CD34 helped to confirm the diagnosis. The grading system of the French Federation of Cancer Centers Sarcoma Group (FNCLCC)16 was tentatively applied to assign a histologic grade, although this practice is not recommended by the latest WHO classification.15 We decided to tentatively evaluate tumor grade because it is one of main factors used to predict patient prognosis and to determine the indication for adjuvant therapies in patients with NRSTS. The FNCLCC is a 3-grade system that defines a score in relation to tumor differentiation (for ES, a value of 3 is given by default), mitotic index (score of 1–3, according to the number of mitoses present in 10 high-power fields), and tumor necrosis (score of 0–2).16 This system was chosen for its great reproducibility and because it enables a valid comparison with adult patient series.

Clinical Grouping

At the time of diagnosis, local tumor extent was assessed using computed tomography (CT) and/or magnetic resonance imaging (MRI); pretreatment investigations included chest X-ray and/or chest CT scan, abdominal ultrasound, and whole-body bone scan in the majority of patients. Regional lymph nodes were assessed radiologically (by ultrasound) in the majority of patients (e.g., axillary ultrasound for tumors of the upper extremity). Lymph nodes were assessed surgically in two patients with no clinical signs of lymph node spread (both biopsies proved negative); one patient with clinically involved lymph nodes underwent lymphadenectomy.

Disease stage was assessed according to both the clinical TNM pretreatment staging system17 and the Intergroup Rhabdomyosarcoma Study (IRS) postsurgical grouping system.18 The TNM definition of T1 refers to tumors that are confined to the organ or tissue of origin, whereas T2 lesions invade contiguous structures; the T1 and T2 tumor groups are classified further as “a” or “b” according to whether they have a greatest tumor dimension of ≤ 5 cm or > 5 cm, respectively. Regional lymph node involvement is designated as N1 (no lymph node involvement– [N0]) and distant metastases at the time of disease onset is classified as M1 (no metastases– [M0]).17 The IRS system categorizes patients into four groups based on the amount and extent of residual tumor after initial surgery: Group I includes patients with completely excised tumors with negative microscopic margins; Group II indicates patients with macroscopically resected tumors with microscopic residual disease and/or resected involved regional lymph nodes; Group III patients have macroscopic residual disease after incomplete surgical resection or biopsy; and Group IV patients have metastases at the baseline.18


Patients were treated using multimodality approaches including surgery, chemotherapy, and radiotherapy, based on the ongoing protocols at the time of diagnosis. Overall treatment strategies did not change substantially over the years. Surgery was the mainstay of treatment. In principle, primary excision was attempted when complete, nonmutilating resection was considered feasible; otherwise a biopsy was performed and chemotherapy was administered to shrink the tumor and make it more amenable to subsequent surgery. Primary reexcision was recommended before any other treatment when microscopic residual disease was suspected, particularly in those patients who had undergone inadequate surgery initially based on the clinical assumption of a benign lesion. Surgery was defined as complete (IRS Group I) when histologic margins were free of disease, and therefore included ablative surgery, compartment resections (en bloc resection of the tumor and the entire compartment of origin in which the tumor was anatomically confined), and wide excisions (en bloc excisions through normal tissue, beyond the reactive zone but within the muscular compartment, removing the tumor together with its pseudocapsule). Marginal surgical resection (IRS Group II) was a resection performed just outside the pseudocapsule, with suspected microscopic residual disease (marginal resection according to Enneking's criteria), and cases of microscopically infiltrated margins (considered by Enneking to be intralesional).19

Radiotherapy was given to patients considered to be at risk of local disease recurrence because of microscopically or macroscopically incomplete surgical resection. It was delivered using megavoltage photon or electron beam energies, using conventional fractionation (200 centigrays [cGy] daily for 5 days per week) or hyperfractionated accelerated radiotherapy (HART) (2 daily fractions of 160 cGy, with a 6–8-hr interval), according to protocols in use at the time.

Different chemotherapeutic regimens were adopted over the years, and were the same as those used to treat rhabdomyosarcoma. The VACA regimen was comprised of vincristine at a dose of 1.5 mg/m2 given at Weeks 1, 4, and 7; doxorubicin at a dose of 30 mg/m2/day given for 2 days at Weeks 1 and 7; cyclophosphamide at a dose of 1200 mg/m2 given at Weeks 1, 4, and 7; and actinomycin D at a dose of 0.5 mg/m2/day given for 3 days at Week 4, for a total of either 37 weeks or 46 weeks. Ifosfamide replaced cyclophosphamide in the VAIA regimen (vincristine at a dose of 1.5 mg/m2 on Weeks 1–7; actinomycin D at a dose of 1.5 mg/m2 at Weeks 1 and 7; ifosfamide at a dose of 3 g/m2/day for 2 days at Weeks 1, 4, and 7; and doxorubicin at a dose of 40 mg/m2/day given for 2 days at Week 4, for a total of 27 weeks). Carboplatin and etoposide were included in the CEVAIE schedule, which was comprised of carboplatin at a dose of 500 mg/m2 given at Week 1; epirubicin at a dose of 150 mg/m2 given at Week 1; vincristine at a dose of 1.5 mg/m2 given at Weeks 1–7; actinomycin D at a dose of 1.5 mg/m2 given at Week 4; ifosfamide at a dose of 3 g/m2/day given for 3 days at Weeks 4 and 7; and etoposide at a dose of 150 mg/m2/day given for 3 days at Week 7, for a total of 27 weeks (in all regimens, the maximum dose of vincristine and actinomycin D administered was 2 mg). One patient with metastases at the time of disease onset received high-dose chemotherapy (comprised of thiotepa, cyclophosphamide, and melphalan) with stem cell rescue. In those patients who received primary chemotherapy, response was evaluated after 3 cycles (at Week 9 or 10) and was based on a reduction in the sum of the products of the perpendicular dimensions of all measurable lesions, defined as follows: a complete response (CR) indicated a complete disappearance of tumor, a partial response (PR) indicated a tumor reduction > 50%; and a minor response (MR) indicated a reduction of > 25%. Stable disease or a reduction in tumor of < 25% was recorded as no response (NR), whereas an increase in tumor size or the detection of new lesions was considered to be progressive disease.

Isolated limb perfusion (with the administration of doxorubicin) was performed in one patient.

Statistical Methods

Event-free survival (EFS) and overall survival (OS) were estimated according to the Kaplan–Meier method.20 Patients were evaluated from the date of histologic diagnosis until the most recent uneventful follow-up or disease progression, recurrence, or death from any cause (whichever occurred first) for EFS, and until to death for OS. The local recurrence-free survival (LRFS) rate was calculated from the time of diagnosis until local disease progression or recurrence. Patients who died of their tumor after distant failure occurring before any local disease progression/recurrence were censored at the time of death in the analysis of LRFS. The metastasis-free survival (MFS) rate was calculated from the time of diagnosis until the onset of distant metastases.

The log-rank test was used to compare the survival curves for the different subgroups of patients to establish the potential value of prognostic factors.21 The duration of patient follow-up (as of April 2005) ranged from 3–180 months (median, 66 mos).


Clinical Characteristics

The ages of the patients ranged from 4–18 years (median, 12 yrs); 17 patients were male and 13 were female. The time elapsing between the first symptoms (generally a swelling or a lump) and the correct diagnosis was 1–36 months (median latency period of 10 mos; the latency period was > 12 mos in 13 patients).

Some of the clinical features of the 30 patients are presented in Table 1, comparing classic ES patients (19 patients) with patients with proximal-type ES (11 patients). Overall, 6 patients were classified as having FNCLCC Grade 3 tumors, and 24 patients were classified as having FNCLCC Grade 2 tumors. In the majority of cases, the primary tumor sites were in the extremities, and were distal in several patients (5 cases of a tumor arising in a finger). The median tumor size was 3 cm, and the majority of tumors measured < 5 cm, with no local invasion reported.

Table 1. Clinical Features
HistologyEntire series (n = 30 patients)Classic ES (n = 19 patients)Proximal-type ES (n = 11 patients)
  1. ES: epithelioid sarcoma; FNCLCC: French Federation of Cancer Centers Sarcoma Group; IRS: Intergroup Rhabdomyosarcoma Study.

FNCLCC gradeGrade 2 (24 patients) Grade 3 (6 patients)Grade 3 (2 patients)Grade 3 (4 patients)
Primary tumor siteExtremities (23 patients)  
 Upper (16 patients [arm in 2 patients, forearm in 6 patients, hand in 3 patients, and finger in 5 patients])  
 Lower (7 patients [gluteus/thigh in 4 patients, leg in 2 patients, and foot in 1 patient])  
 Head and neck (3 patients [head in 1 patient, oral cavity in 1 patient, and tongue in 1 patient])Proximal site (nonextremities) (2 patients)Proximal site (nonextremities) (6 patients)
 Trunk (3 patients)  
 Intraabdomen (omentum) (1 patient)  
Tumor size1-11 cm (median, 3 cm)  
 ≤ 5 cm (22 patients))> 5 cm (3 patients)> 5 cm (5 patients)
 > 5 cm (8 patients  
TNM classificationT1a (20 patients)T2b (1 patient)T2b (4 patients)
 T1b (3 patients)  
 T2a (2 patients)  
 T2b (5 patients_  
 N1 (3 patients)N1 (2 patients)N1 (1 patient)
 M1 (2 patients)M1 (1 patient)M1 (1 patient)
IRS groupingGroup I (18 patients)Group III (2 patients)Group III (4 patients)
 Group II (4 patients)  
 Group III (6 patients)  
 Group IV (2 patients)  

Three patients had regional lymph node involvement and two patients had distant metastases (one patient in the lung and one patient in soft tissue).

With regard to the 11 patients with the proximal-type ES variant, 6 tumors arose at a proximal site (4 in the trunk, 1 in the head and neck area, and there was 1 case of intraabdominal disease). High-grade (FNCLCC Grade 3 disease), large (measuring > 5 cm), and unresectable tumors were more common among those patients with proximal-type ES compared with the patients with classic ES (the difference was not found to be statistically significant, but it should be noted that the number of patients in each group was small).


Complete surgical resection was the only treatment in the 18 IRS Group I patients (no adjuvant treatments were given); of these 18 patients, 11 achieved histologically free surgical margins after undergoing a primary reexcision performed within 8 weeks of initial inadequate surgery. In other words, 11 patients who were classified as Group II were downstaged to Group I after primary reexcision, thereby avoiding radiotherapy. Fingers were amputated in three patients.

Four patients were classified as IRS Group II because of surgical margin excisions (not amenable to resurgery) in three patients and regional lymph node involvement in one patient (both the primary forearm tumor and the enlarged axillary lymph nodes were completely resected).

With regard to the eight patients with advanced disease (six of whom were in IRS Group III and two of whom were classified as Group IV), the first surgical approach was a biopsy in six patients and a macroscopically incomplete resection in two patients. Six of these patients subsequently underwent delayed surgery (achieving histologically clear surgical margins in three patients). One patient was treated with radiotherapy and chemotherapy (with no further surgery performed). One 18-year-old patient with a large tumor of the upper limb received isolated limb perfusion, but experienced severe local side effects (cutaneous and soft tissue necrosis) that subsequently made emergency amputation necessary.

Overall, radiotherapy was administered to 6 patients (2 patients in IRS Group II, 3 patients in IRS Group III, and 1 patient in IRS Group IV), with conventional fractionation used in 1 patient (a dose of 70 grays [Gy]) and HART administered to 5 patients (doses ranged from 40–50 Gy).

Chemotherapy was given to eight patients (the one patient in IRS Group II with N1 disease, five of the six patients in IRS Group III, and the two patients in IRS Group IV). The chemotherapy regimen used was VACA in two patients, VAIA in three patients, CEVAIE in two patients, and CEVAIE followed by high-dose chemotherapy with stem cell rescue in one patient. The response to primary chemotherapy was evaluable in seven patients and was a CR in two patients, a PR in one patient, and NR in four patients (for an overall response rate 43%). With regard to the regimen administered, responses were observed in one of the two patients treated with VAIA (the other patient was not evaluable), two of the three patients treated with CEVAIE, and neither of the two patients treated with VACA. All three patients who responded to chemotherapy had received regimens including ifosfamide and anthracyclines.


At the time of last follow-up, the EFS for the entire series of patients was 61.7% at 5 years, and did not change significantly at either 10 years or 15 years. The OS was 92.4% at 5 years, but decreased to 86.9% and 72.4%, respectively, at 10 years and 15 years (1 patient died of tumor 132 mos after diagnosis).

Seventeen patients were alive in first complete disease remission and 1 patient was alive with stable disease. Twelve patients developed a disease recurrence 3–112 months after diagnosis (median time to disease recurrence was 11 mos). The first disease recurrence was local in 9 patients, in the regional lymph nodes in 1 patient, and at distant sites (lung) in 2 patients (associated with local recurrence in 1 patient), for 5-year LRFS and MFS rates of 65.0% and 82.1%, respectively. Among the 12 patients with recurrent disease, 4 died of their tumor and 3 were alive with progressive disease at the time of last follow-up. Five patients (who developed local recurrence) were able to achieve further complete disease remission thanks to salvage treatments (mutilating surgery in 3 patients) and were alive without evidence of disease at a range of 54–120 months (median of 100 mos) after their last disease recurrence (2 patients experienced only 1 disease recurrence, and 3 patients developed several subsequent disease recurrences, with features resembling in-transit metastases noted in 2 of these patients).

Table 2 shows the results of univariate analysis (considering the variables usually significant for NRSTS). The most significant factor found to influence both EFS and OS was the site of the tumor, with a location in the extremities predicting a favorable outcome. Tumor size (considering the usual cutoff value of 5 cm) appeared to be less significant. However, because the median tumor size in this series was 3 cm, the analysis also was performed considering a cutoff value of 3 cm; the 5-year EFS was reported to be 88.9% in patients with tumors measuring ≤ 3 cm and 47.4% in those patients with tumors measuring > 3 cm. This difference was statistically significant (P = 0.0140).

Table 2. Univariate Analysis
Risk factorValue5-yr OS rate, %5-yr EFS rate, %
  1. OS: overall survival; EFS: event-free survival; IRS: Intergroup Rhabdomyosarcoma Study; FNCLCC: French Federation of Cancer Centers Sarcoma Group.

Size≤ 5 cm (n = 22)95.2P = 0.123566.1P = 0.3930
 > 5 cm (n = 8)64.3 50.0 
IRS groupI (n = 18)94.1 76.7 
 II (n = 4)100 25.0 
 III (n = 6)53.3P value not evaluable33.3P value not evaluable
 IV (n = 2)100 100 
HistologyClassic (n = 19)100P = 0.281965.7P = 0.6016
 Proximal-type (n = 11)79.5 54.9 
Tumor siteExtremities (n = 23)100P = 0.005473.9P = 0.0121
 Other (n = 7)55.6 16.7 
Age< 10 yrs (n = 11)90.0P = 0.912072.7P = 0.5285
 ≥ 10 yrs (n = 19)85.0 55.2 
T classificationT1 (n = 23)95.5P = 0.067272.3P = 0.0405
 T2 (n = 7)55.6 28.6 
N classificationN0 (n = 27)91.3P = 0.027061.1P = 0.4504
 N1 (n = 3)50.0 66.7 
FNCLCC tumor gradeGrade 2 (n = 24)94.7P = 0.032169.0P = 0.0233
 Grade 3 (n = 6)55.6 33.3 

The proximal-type variant of ES was associated with unfavorable survival curves (P value was not significant): It is interesting to note that the combination of proximal-type variant and high grade (FNCLCC Grade 3 disease) was found to be associated with a poor prognosis (four patients with a total of three cases of disease recurrence and two deaths).

With regard to the treatment administered as variables, it is difficult to establish any significant correlation with outcome. As expected, initial complete resection with histologically free surgical margins was associated with a good EFS; among the 18 patients in IRS Group I (all of whom were treated with surgery alone), 4 developed disease recurrence (all 4 locally, and 1 patient also had distant spread). Microscopically infiltrated surgical margins were associated with local recurrence. All three of the patients in IRS Group II (with the patient classified as Group II because of lymph node involvement being excluded from the analysis) had local disease recurrences. It is interesting to note that radiotherapy was administered in only one of these patients despite the guidelines of the protocols (however, the patient treated with radiotherapy also developed a disease recurrence).

Patients with tumors considered to be unresectable at the time of diagnosis (IRS Group III) were found to have a high risk of metastatic spread (5-year MFS rate of 33%); the only patient still alive in first disease remission at the time of last follow-up was the one who experienced a CR after primary chemotherapy.

The two patients with metastases at the time of diagnosis were alive without evidence of disease at the time of last follow-up, 20 months and 41 months, respectively, after diagnosis. The first patient was treated with chemotherapy (achieving a PR) and then complete surgery for the primary tumor and metastasis (of soft tissue); the second patient experienced a CR of both the primary tumor (histologically proven) and lung metastases, and then received radiotherapy for the primary tumor site (the knee) and the lungs.

With regard to those patients with lymph node involvement at the time of diagnosis, 1 patient was alive with disease 40 months from the time of diagnosis (he received radiotherapy for both the primary tumor, which was considered unresectable, and the lymph nodes), and 2 patients had died of metastatic disease 54 months and 132 months, respectively, from the time of diagnosis.


To the best of our knowledge, only scanty information is available in the literature regarding the clinical aspects and treatment of ES occurring in pediatric patients. Table 3 shows the very small number of reported cases.4–6, 12–14, 22 Therefore, to our knowledge, the current series is the largest group of children and adolescents with ES described to date. The main objective of the current study was to describe the clinical peculiarities of childhood ES (in relation to what we know regarding other pediatric NRSTS and adult ES) and to attempt to discuss the most suitable treatment strategies.

Table 3. Cases of Children and Adolescents with ES Reported in the Literature
Published series regarding childhood ESNo. of casesTumor siteOutcome
  • ES: epithelioid sarcoma; NED: no evidence of disease; DOD: dead of disease; AWD: alive with disease; NRSTS: nonrhabdomyosarcoma soft tissue sarcomas.

  • a

    Axial extremities are considered to be the head and neck, trunk, and pelvis.

Schmidt and Harms, 1987661 in the extremities 5 at axial sitesa5 alive with NED (at a follow-up of 6-14 mos) 1 DOD
De Vries et al., 19891444 in the extremities2 alive with NED (after regional disease recurrence) 2 DOD
Kodet et al. 199412117 in the extremities 4 at axial sites6 alive with NED (at a follow-up of 0-7 yrs) 1 AWD 3 DOD
Gross et al., 19961384 in the extremities 4 at axial sites6 alive with NED (at a follow-up of 12-126 mos) 2 DOD
Major published series regarding NRSTS   
Pratt et al., 1999223 ES/81 NRSTS (4%)  
Spunt et al., 199956 ES/121 NRSTS (5%)  
Ferrari et al., 2005414 ES/179 NRSTS (8%)  

The results of the current study confirm that ES has some typical clinical features, such as 1) location at superficial distal sites (e.g., the hand and fingers); 2) an indolent growth rate (it occasionally is diagnosed after the removal of a small swelling that has existed for several years, and disease recurrence can occur many years after the first diagnosis); and 3) a tendency toward locoregional recurrence, with nodules or plaques (often multiple, sometimes confluent) charting a course along an extremity (as in-transit-type metastases).2, 3, 23–25

With regard to other NRSTS,4, 5, 22 the extent of primary surgery (IRS group), tumor size, T and N status, tumor grade, and tumor site were all found to be significantly correlated with outcome in the current series, although the small number of patients in each subgroup severely limited the statistical significance of the analysis. The tumor's site of origin was found to be one of the most significant prognostic variables. ES arising in the extremities was found to have a more favorable prognosis than ES originating in the trunk and head and neck region. When tentatively applied to pediatric ES patients, the FNCLCC grading system appeared to be a statistically significant prognostic variable for both EFS and OS on univariate analysis.

A specific comment concerning the role of tumor size in predicting outcome in ES patients may be warranted. With regard to the group of NRSTS patients as a whole, tumor size is one of the most significant prognostic factors, as confirmed by the recently reported series from the INT, in which the usual dimension of 5 cm was considered as a cutoff value with which to compare patient subsets (the 5-year EFS rate was 88% in patients with tumors measuring ≤ 5 cm and 41% in those patients with tumors measuring > 5 cm) and it is worth noting that the median tumor dimension was 6 cm.4 Conversely, in the current series of ES patients, tumor size appeared to be less important in predicting outcome when the cutoff value of 5 cm was considered, but it became significant if a cutoff of 3 cm was used (5-year EFS rate of 89% for patients with tumors measuring ≤ 3 cm and 47% for patients with tumors measuring > 3 cm; P = 0.0140). The 3-cm latter cutoff appeared to be more suitable (and therefore significant), considering that the median size of ES tumors in the current series was 3 cm (ES lesions at onset are usually smaller in size than other NRSTS).

The results of the current study suggest that the overall outcome for children and adolescents with ES is comparable to that in patients with other pediatric NRSTS (the 5-year EFS rate was 64% for the 182 patients at the INT).4 In other words, the ES histotype does not appear to have a worse outcome than other histotypes. Conversely, in the University of Texas M. D. Anderson Cancer Center study of a large series of 1225 adult patients with localized soft tissue sarcomas (including 29 cases of ES [2%]), Zagars et al. reported that, together with malignant fibrous histiocytoma and neurogenic sarcoma, the ES histotype was one of the factors found to be predictive of local and metastatic disease recurrence.26 The authors suggested that ES might be correlated with unfavorable survival rates because this histotype is “lymphogenous” (i.e., characterized by a tendency toward lymph node spread).26 In fact, adult patients with ES have been recognized as demonstrating lymph node involvement more frequently than patients with other soft tissue sarcomas.1, 27–30 This tendency, described largely in adult ES patients, appears to be less evident in pediatric patients; although de Vries et al.14 reported that all four ES patients in their study developed lymph node metastases,14 none of the eight patients in the St. Jude series13 were found to have lymph node spread, and none of the three patients in the same study who underwent lymph node dissection for staging purposes were found to have histologically positive lymph nodes.13 In the current series, 3 of 30 patients had lymph node involvement at the time of diagnosis, a percentage (10%) that is lower than that noted in adult series (up to 45%),1, 27–30 but higher than has been reported for pediatric NRSTS patients as a whole (approximately 5%).4, 5, 31 It is possible that the rate of lymph node involvement might actually be higher than we found because only two patients were sampled. However, other findings in the current series appear to suggest a weaker propensity for lymph node spread in pediatric ES patients compared with adults. In fact, surgical lymph node staging was performed in two cases, both of which were negative, and only one patient developed disease recurrence with lymph node metastases. It is difficult to speculate as to why children and adolescents with ES appear to be less likely to develop lymph node involvement compared with adults. Most likely, a combination of different factors (e.g., patient age, treatment, and tumor biology) might be hypothesized.

A further issue for debate concerns the recently described proximal-type ES entity. This variant is characterized by large, epithelioid cells; marked nuclear atypia; frequently rhabdoid features; a lack of a granulomatous-like pattern; and a preference for proximal and axial regions (e.g., the pelvis and trunk) rather than the usual extremities.8 To our knowledge, it is not yet clear whether proximal-type ES is a different variant of ES (its immunophenotypic profile is quite similar to that of classic ES)8, 11, 32 or whether it should be considered to be a form of extrarenal rhabdoid tumor.9 Recently, studies have appeared that highlight a difference in the mechanisms of the alteration of the SMARCB1/INI1 gene between proximal-type ES and rhabdoid tumor because deletions were found in the former and inactivating mutations in the latter.10 This different genetic background, coupled with a morphologic heterogeneity described in proximal-type ES compared with rhabdoid tumor, suggests that they are two distinct entities.10 This issue goes beyond the objective of the current study, but the limited information available in the adult literature suggests a worse outcome for patients with this variant.8–11 It is difficult to state conclusively whether this unfavorable prognosis has to do with different biologic features, or simply with the well known classic prognostic factors (proximal location in particular, but also tumor size and depth) that affect this variant. To our knowledge, the current study is the first to describe the clinical features and outcome of proximal ES diagnosed in childhood. Far from being able to speculate on the biologic and clinical behavior of proximal-type ES in pediatric patients, we can only describe the clinical findings and outcome in the current series. Among the 11 patients with histologic features that were similar to those described as being peculiar to this variant, 6 tumors were in fact located at proximal sites (the trunk, head and neck, and abdomen). It should be noted that the characteristics that usually identify the clinically more aggressive sarcomas (i.e., high grade, large size, unresectability, and locally advanced disease) were represented more strongly in the 11 patients with proximal-type ES than in the other 19 patients with classic ES. Survival analysis demonstrated a worse outcome for the patients with proximal-type ES (5-year EFS and OS rates of 54.9% and 79.5%, respectively, vs. 65.7% and 100%, respectively), although the survival rates were found to correlate more with the proximal tumor site than the proximal-type histotype. It also must be said that these survival rates are distinctly higher than those reported for patients with extracranial rhabdoid tumors,33 suggesting that the clinical behavior of proximal-type ES (at least in the current series of pediatric patients) differs considerably from that of rhabdoid tumors.

The current study describes the clinical behavior after therapy of ES diagnosed in pediatric patients. With regard to the optimal treatment of ES, the small number of patients in the current study limits the possibility of reaching definite conclusions. Surgical resection clearly remains the mainstay of treatment, with clinicians striving to obtain histologically disease-free margins (primary reexcision was found to be helpful in 11 patients in the current study). Because distal sites often are affected, and the fingers in particular, finger amputation should be considered as an option, especially after a first local disease recurrence. Little could be inferred from the current series with regard to the role of adjuvant therapies. Patients who undergo marginal surgical resection, with microscopically infiltrated margins, are at a high risk of local disease recurrence and should, in principle, be given radiotherapy, but the data from the current study did not allow us to establish a clear role for radiotherapy. The possible benefit of chemotherapy remains to be determined, but it is worth emphasizing that three patients in the current study (of seven patients with measurable disease) responded well to chemotherapy (two of whom achieved CRs), and all had received chemotherapy regimens that included ifosfamide and anthracyclines.

ES is a rare subtype of soft tissue sarcoma with peculiar features, and to our knowledge little is known regarding its clinical behavior and management when it occurs in children. Although the large group of soft tissue sarcomas clearly includes an assortment of different diseases, the rarity of each histotype prevents the performance of clinical trials on a single tumor type; therefore, soft tissue sarcomas usually are analyzed as a group. The new European protocol for NRSTS (developed by the new European pediatric Soft Tissue Sarcoma Study Group [EpSSG]) includes ES within the group of “adult-type” soft tissue sarcomas (together with adult-type fibrosarcoma, malignant peripheral nerve sheath tumor, leiomyosarcoma, clear cell sarcoma of soft tissue, liposarcoma, and others).34 In the EpSSG NRSTS protocol, chemotherapy with the combination of ifosfamide and doxorubicin, followed by a local treatment strategy (surgery and/or radiotherapy), is recommended in the case of tumors considered to be unresectable at the time of diagnosis. Adjuvant therapies are recommended according to the risk of local and distant disease recurrence, as suggested by the presence of residual disease after initial surgery, tumor size, and tumor grade. ES patients consequently will receive adjuvant chemotherapy in the case of FNCLCC Grade 3 histology and a tumor size measuring >than 5 cm, whereas postoperative radiotherapy will be given to patients with completely resected ES measuring > 5 cm, and to patients who underwent an initial marginal resection.33 The need for surgical lymph nodes assessment remains an open issue; because experience in pediatric patients did not entirely confirm the high propensity toward lymph node spread suggested by the adult literature, lymph node biopsy is not required for ES patients in the EpSSG protocol.