ORIGINAL ARTICLE

Extraskeletal Ewing sarcoma in children and adolescents:impact of narrow but negative surgical margin

Sajid S. Qureshi • Siddharth Laskar • Seema Kembhavi • Sanjay Talole •

Girish Chinnaswamy • Tushar Vora • Mukta Ramadwar • Saral Desai •

Nehal Khanna • Mary Ann Muckaden • Purna Kurkure

Accepted: 19 August 2013 / Published online: 28 August 2013

� Springer-Verlag Berlin Heidelberg 2013

Abstract

Purpose The aim of the study was to determine the

impact of negative but close resection margins on local

recurrence in children with extraskeletal Ewing sarcoma

(EES).

Method We reviewed records of 32 patients with EES

treated between March 2005 and March 2013. All patients

except one underwent surgical excision either upfront or

after induction chemotherapy. Patients with viable tumor

and negative surgical margins, which were categorized as

less than or greater than 1 cm, were selected. Local control

and survival analysis were performed for patients in both

the groups.

Results The 5-year event-free and overall survival rates

of entire cohort is 68 and 77 %, respectively. Surgical

margins were negative in 23/26 (90.3 %) patients. There

were no local recurrences in any of the patients with

margins of less than 1 cm. Only one patient with a margin

greater than 1 cm had a local recurrence along with distant

metastases. A tumor-free margin of more than 1 cm did not

affect overall or event-free survival (p = NS).

Conclusion Optimal local control is feasible in children

with EES regardless of the quantitative extent of negative

margins. Achieving a three-dimensional tumor-free margin

should be the goal of surgical resection.

Keywords Ewing sarcoma � Extraskeletal �Surgery � Surgical margin � Chemotherapy �Radiotherapy

Introduction

Tefft et al. introduced the term extraskeletal Ewing sar-

coma (EES) in 1969 [1]. EES account for 20–30 % of all

ES that may develop in soft tissues at any location [2, 3].

Although, more common in older age group, EES display a

bimodal distribution, with increased incidence in patients

older than 35 years and less than 5 years as compared to

skeletal Ewing sarcoma (SES) [4].

The systemic treatment of EES has evolved from che-

motherapy regimens similar to rhabdomyosarcomas to SES

protocols; however, the most advantageous local control

measure, surgery or radiotherapy, has not been established

due to paucity of trials comparing the two modalities [4, 5].

Although, the surgical recommendations include a wide

resection margin, there is no specific guideline defined

regarding the quantitative surgical margin [6–10]. The

characterization of margins is important especially, in sit-

uations where the liberties of wider margins are limited and

S. S. Qureshi (&)

Division of Pediatric Surgical Oncology, Department of Surgical

Oncology, Tata Memorial Centre, Ernest Borges Road, Parel,

400012 Bombay, India

e-mail: sajidshafiques@hotmail.com

S. Laskar � N. Khanna � M. A. Muckaden

Department of Radiation Oncology, Tata Memorial Centre,

Bombay, India

S. Kembhavi

Department of Radiology, Tata Memorial Centre, Bombay, India

S. Talole

Department of Biostatistics, Tata Memorial Centre, Bombay,

India

G. Chinnaswamy � T. Vora � P. Kurkure

Division of Pediatric Oncology, Department of Medical

Oncology, Tata Memorial Centre, Bombay, India

M. Ramadwar � S. Desai

Department of Pathology, Tata Memorial Centre, Bombay, India

123

Pediatr Surg Int (2013) 29:1303–1309

DOI 10.1007/s00383-013-3409-2

the surgical decision for resection with narrow margins will

be the difference between organ/limb preservation and

ablation.

With this question, our main aim was to determine

whether a narrow quantitative negative margin increases

the risk of local recurrence. Secondly, our data of

homogenous population of children and adolescents below

20 years will add to the limited data on non-metastatic EES

describing the clinical course, therapeutic approaches and

prognostic factors in patients of this age group.

Methods

We reviewed the records of patients with EES treated

between March 2005 and March 2013 at a single tertiary

cancer centre. Of the 35 patients identified from the hos-

pital database, we selected 32 patients with non-metastatic

disease for analysis. Of the three patients excluded, two

had pulmonary metastases and one patient presented with

EES as a second malignant neoplasm.

All patients had comprehensive clinical evaluation and a

core biopsy for confirmation of the diagnosis. Patients who

underwent a surgical exploration elsewhere had their

biopsy result reviewed at our centre. Translocation studies

were not performed routinely. Every patient was discussed

in the multidisciplinary tumor board meeting for treatment

planning.

Radiology

Magnetic resonance imaging (MRI) was performed in all

patients with extremity primary and computed tomography

(CT) scan for evaluation of primary tumor on the trunk or

abdomen. A large volume tumor was defined as a neoplasm

equal to or more than 5 cm in greatest dimension and a

small volume tumor with greatest dimensions of less than

5 cm [4, 5].

All patients underwent investigations to exclude the

presence of metastatic disease including whole-body

technetium bone scan, chest CT scan, bone marrow aspi-

ration, and biopsy. Whole-body positron emission tomog-

raphy scan was also performed in some patients.

Chemotherapy

All patients were treated on the institutional chemotherapy

protocol for Ewing sarcoma family of tumors (ESFT)

which included two courses of VIE couplet (vincristine,

ifosfamide and etoposide) followed by two courses of VAC

couplet (vincristine, doxorubicin and cyclophosphamide)

administered every 3 weeks as neoadjuvant/induction

chemotherapy [11]. Maintenance therapy was administered

following local therapy to the primary tumor and consisted

of ten courses of chemotherapy administered every

3 weeks (VAC, 4 courses; VIE, 2 courses and VCD, 4

courses with actinomycin D substituted for doxorubicin

after a total dose of 360 mg/m2). Vincristine was admin-

istered weekly through the chemotherapy schedule.

Surgery

Wide resection of the tumor beyond the visible and pal-

pable limits ensuring an adequate surrounding margin of

uninvolved tissue or an intact fascial plane and without

sacrificing critical normal structures or causing unaccept-

able loss of function or cosmesis was the goal. Previous

biopsy needle tracts and incisions were included in the en

bloc resection specimen. Local anatomical extent of the

lesion guided the extent of excision rather than a fixed rule

of resection of entire muscle compartment. Lesions adja-

cent to bone with no apparent bony involvement were

resected with stripping of the periosteum, without resecting

the bone. Amputation was performed when there was

extensive invasion of neurovascular structures making limb

salvage unfeasible. Vascularized flaps, polypropylene mesh

or skin grafts were used for soft tissue coverage, rein-

forcement or preventing dead space. The tumor specimen

was oriented with sutures before sending it to the pathology

department.

Pathology

On gross examination of the specimen, closest surgical

margin was determined. The entire external surface of the

specimen was inked and the specimen cut perpendicularly

to the inked margin. Under microscopic examination, the

distance between the tumor and the inked margin was

measured. The surgical margins were recorded as positive

for tumor present at the inked border of the specimen;

negative surgical margins were categorized as less than

1 cm and greater than 1 cm.

For assessing the response to chemotherapy, a slice of

tumor with the largest surface area was entirely sampled in

a ‘grid’ fashion. Each of the tumor sections thus obtained

was evaluated for tumor response. Percentage of viable

tumor was assessed in the given cross-sectional area by a

semi-quantitative method wherein, percentage of viable

tumor cells and percentage of necrotic areas was calcu-

lated. Final score of percentage necrosis was a result of

average score on all tumor sections studied [12]. Tumors

were assigned to one of the two categories: good response

when there was no identifiable viable tumor or less than

5 % identifiable residual tumor cells and poor response

when the surgical specimen contained more than 5 %

residual tumor cells.

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123

Radiotherapy

Radiotherapy was recommended in patients with positive

surgical margins, poor response to chemotherapy and in

patients with large primary tumors at presentation. Inter-

stitial brachytherapy whenever feasible was offered, espe-

cially for primary sites in the extremity. External beam

radiotherapy was delivered using conformal portals to a

dose of 45–50 Gy/25–28 fractions/5–6 weeks based on the

status of surgical margins.

Follow-up

Patients were followed every 3 months for 2 years, and

then every 6 months for 3 years. Imaging re-evaluation

was performed at the end of all chemotherapy and there-

after at least every 6 months during the first 3 years off

therapy. Additional studies, including biopsy were added

when indicated by clinical and radiological evaluation.

Patients not following up at the hospital were contacted by

telephone or mail. Follow-up was completed until June

2013.

Statistical analysis

Overall survival (OS), event-free survival (EFS) and local

control (LC) were calculated using Kaplan–Meier method.

Overall survival was calculated from the date of diagnosis

to the date of death or last follow-up. EFS was calculated

from the date of diagnosis to the date of relapse at any site

or death from any reason. LC was defined by any local

failure, regardless of metastatic disease status at the time in

order to better characterize our ability to control gross

disease. Chi-square test was used to compare proportions

and prognostic factors were compared using the log-rank

test.

Following factors were studied to determine prognosis:

gender, age (less or more than 10 years), tumor site, size,

depth, surgical margins and histological response to pre-

operative chemotherapy. SPSS software (version 18.0 for

windows) was used for statistical analysis.

Results

The median age of the patients was 10 years (range

11 months to 19 years) and 18 patients were less than

10 years. The most common site was the extremity

(n = 19). The other sites included the trunk (n = 4), head

and neck (n = 3), intra-abdominal (n = 5) and perineum

(n = 1). Regional lymph node metastasis was present in

three patients. Majority of the lesions were in the deep soft

issue (n = 27) and five patients had a tumor in the sub-

cutaneous tissue. The characteristics of all 32 patients are

detailed in Table 1.

Table 1 Event-free survival

(EFS) and overall survival (OS)

by each characteristic of the

non-metastatic patients

Characteristics No.

n = 32

5-year EFS

(%)

p value 5-year OS

(%)

p value

Gender

Male 23 61.9 0.37 74.8 0.90

Female 9 85.7 85.7

Age at diagnosis (years)

\10 18 78.7 0.43 80.4 0.54

[10 14 60.6 74

Location

Extremity 19 60.9 0.39 67.5 0.35

Central 13 80.8 90.9

(Trunk, head and neck,

intra-abdominal, perineum)

Tumor size (cm)

\5 14 71.4 0.40 89 0.12

[5 18 66 64.0

Depth

Superficial 5 40 0.23 80 0.84

Deep 27 77.8 77.6

Histology response

Poor 12 62.3 0.69 40.9 0.35

Good 9 68.6 85.7

Pediatr Surg Int (2013) 29:1303–1309 1305

123

Treatment

All but one patient underwent surgical excision for local

control. Ten patients underwent resection without induc-

tion chemotherapy, six of them being a re-excision after an

initial unplanned excision elsewhere, and 21 patients

underwent resection after 9 weeks of induction chemo-

therapy. One patient had received chemotherapy and

radiation prior to resection. Amputation was performed in

one patient; wide excision was achieved in remaining 30

patients. Polypropylene mesh was used for reconstruction

of chest wall in one patient, vascularized flap in two

patients and skin graft in one patient.

The median duration of surgery was 1.50 h (range

30 min to 5 h) and the median blood loss was 50 ml (range

10–900 ml). The median postoperative hospital stay was

6 days (range 2–13 days). There was no postoperative

mortality.

Definitive radiotherapy was used in one patient. Post-

operative radiotherapy was administered to 19 patients;

four of these patients received interstitial brachytherapy.

Histopathology

Five patients had no residual tumor noted in the specimen

after neoadjuvant therapy (n = 4) or wide re-excision

(n = 1) after outside incomplete excisions. Surgical mar-

gins in the remaining 26 patients were negative in 23

(90.3 %) and positive in three (9.6 %). Of the 23 patients

with negative margins, 19 patients had a margin of less

than 1 cm and four were more than 1 cm. Of the 21

specimens evaluated for tumor response to chemotherapy,

9 (42.8 %) had good response and 12 (57.1 %) had poor

response.

Complications

Wound infection occurred in three patients and one patient

developed deep venous thrombosis. Significant delay in

initiating adjuvant treatment occurred in the patient with

deep venous thrombosis who eventually missed the plan-

ned postoperative radiotherapy. There were no complica-

tions related to the use of polypropylene mesh.

Outcome and survivals

The median follow-up time was 40 months (range

2–93 months). There were seven relapses (23 %). The

median time to relapse was 18 months (range

11–34 months) with five of them appearing before

20 months. The relapses were local only in one, both local

and distant in one and distant only in five patients. The sites

of metastases were lungs, bone and brain in three, two and

one patient, respectively. The patient with isolated local

recurrence had received definitive radiotherapy for local

control. The patient was successfully salvaged with wide

excision of recurrence and brachytherapy and is disease

free at 65 months following completion of treatment.

Of the remaining six patients who relapsed, two patients

received best supportive care and four received palliative

chemotherapy (one of them also received radiation). Sur-

gery for resection of pulmonary metastases was performed

in one patient. Four patients died after relapse and two are

alive with disease. The projected 5 year OS, EFS and LC

were 77 % [95 % confidence interval (CI) 58–96), 68.4 %

(95 % CI 50–87) and 92 % (95 % CI 81–100)] (see Fig. 1).

Relapse according to extent of resection

Five patients with no residual tumor and three with positive

margins were excluded. The remaining 23 patients with

negative margins were analyzed. Of the 19/23 patients with

a margin of less than 1 cm, 11 received postoperative

radiotherapy. There was no local recurrence in this group.

Distant relapse occurred in two patients not receiving

radiotherapy and three patients receiving radiotherapy. Of

the 4/23 patients with a margin of more than 1 cm, two

patients also received postoperative radiotherapy. There

was one relapse (local and distant) in the patient who did

not receive radiotherapy. The 5-year OS and EFS was 67.2

and 67.6 % in patients with a margin of less than 1 cm

versus 66.7 and 66.7 % for a margin of more than 1 cm

(p = NS).

Prognostic factors

On univariate analysis (see Table 1) age, gender, location

of tumor, tumor size and depth was not found to be sig-

nificant prognostic factors. The histological response to

chemotherapy showed a trend towards better overall sur-

vival only, although it was not statistically significant

(41 % for poor response versus 86 % for good response,

p = 0.3).

Discussion

The conventional wide margin of resection for sarcoma

described by Enneking et al. [13] includes the pseudo

capsule and a cuff of normal tissue surrounding the tumor.

As for any other sarcoma, this is also applicable for EES;

however, neither a quantitative margin nor a tumor-free

qualitative margin has been established for EES. Although,

few reports have considered margins as a prognostic factor;

however, there is no uniformity in the inclusion and

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exclusion criteria and the categorization of quantitative

margin in these studies (Table 2).

The local recurrence rate for EES ranged between 5 and

46 % in previous reports [4, 6–10]. The overall local

recurrence rate in our series was 6.4 % (2/32). There was

no local recurrence in the patients with a negative margin

of less than 1 cm. In patients with a margin of more than

1 cm, there was only one local recurrence along with dis-

tant metastases to the lung. This patient had not received

postoperative radiotherapy due to complications of deep

venous thrombosis and relapsed within 1 month of com-

pletion of chemotherapy. The apprehension of negative but

narrow margin being associated with higher local recur-

rence rate is dispelled from the results of our study.

Fig. 1 Event-free survival and overall survival

Table 2 Literature review of

margin status and local

recurrence in EES

a Local recurrence along with

distant metastases

Authors/Ref. Period No. of patients/

operated

Margin category Local

recurrence (%)

Rud et al. [7] 1935–1985 42/34 Wide negative 46

Positive margin Insufficient data

Siebenbrock et al. [8] 1964–1991 34/32 Wide resection 20

Marginal resection 37.5

Raney et al. [4] 1972–1991 130/51 Negative margin 5

Microscopic residual 7

Ahmad et al. [9] 1977–1995 24/19 Wide resection 0

Suboptimal resection 10

Orr et al. [17] 1982–2009 46/39 Positive 12

Negative 15

El Weshi [6] 1995–2004 57/43 Wide resection 30

Suboptimal resection 40

Tural et al. [10] 1997–2010 27/15 Wide C1 cm 0

Positive 50

Qureshi et al. (present study) 2005–2013 32/31 Positive 0

Negative 4

B1 cm 0

C1 cm 25a

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However, the low number of recurrences and inadequate

power of the study prevent us from making conclusions

from our data regarding the appropriate quantitative margin

of resection for EES. Nevertheless, based on our findings

and those of other investigators, it is evident, that as long as

tumor-free margins are achieved and radiation is used

judiciously, close margins can be tolerated to minimize

morbidity and maximize function in terms of organ/limb

salvage [4].

Radiotherapy is an important component of local treat-

ment. There have been varying reports in the literature

concerning the primary or postoperative use of radiation

therapy in EES. Radiation alone as the primary treatment

was associated with progression of disease in one study in

contrast to another study reporting a 64 % disease-free

survival, which led the authors to question the need of a

wide surgical excision [14, 15]. In other studies, the high

incidence of local recurrence in patients who did not

receive radiation therapy led to investigators recommend-

ing use of adjuvant radiotherapy with all local resections

[6, 7]. Most of our patients (19/30) had at least one of the

indications for postoperative radiotherapy; hence, radio-

therapy was offered. The beneficial effect of postoperative

radiotherapy in reducing local failure rates in patients with

unclear surgical margins and poor histological response has

been demonstrated by both the CESS and EICESS trials.

Both these trials also reported a 50 % reduction in local

failure rates after postoperative radiotherapy for central

primaries [16]. Although, the low number of local recur-

rences and the small patient cohort prevents us from

drawing strong conclusions, the combination of organ and

function preserving surgery and adjuvant radiation therapy

seems to result in optimal local controls thus avoiding more

ablative procedures.

EES in children is uncommon and very limited data are

available pertaining to this age group [4, 5, 17]. Usually

the reports include retrospective case reviews of EES

clubbed with adult data. The largest series (130 patients)

of EES is from the IRS I, II, and III trials [4]. In this

study, the authors concluded that EES and RMS had a

similar response to multimodal therapy and EES should be

treated with RMS regime considering the fact that there

was no survival benefit when doxorubicin was added. In

contrast, Castex et al. [5] reported data on 63 non-meta-

static patients with EES and observed better outcomes for

patients treated with chemotherapy protocols of SES.

They attributed the better outcomes due to the use of

anthracyclines and recommended treatment of EES similar

to SES protocols. The St. Judes group showed similar

outcomes for patients with EES and SES treated with ES

protocols [17]. In our series, all the patients received

chemotherapy as per our institutional protocol for SES and

the OS and EFS of 77 and 68.4 % were comparable to the

69–77 and 58–67 % reported in the previous series.

However, our results may be an overestimate since the

median follow-up is 40 months only. The prognostic

factors identified in the above studies include the site,

size, depth and complete resection with negative margins.

The site, size and depth of the primary tumor were not a

predictor of OS or EFS in our study probably because of

small number and the favorable overall outcome in these

patients. In our study there was a trend towards better OS

with good response to chemotherapy; however, this was

not statistically significant.

In conclusion, good local control can be achieved

regardless of the quantitative extent of negative margins.

Tumor-free margins should be the goal of resection of EES.

However, the small number of patients and non-random-

ized nature of the study are the limitations to this finding.

This requires confirmation with further prospective studies.

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