# Very Late Local Relapse of Ewing's Sarcoma of the Head  and Neck treated with Aggressive Multimodal Therapy

Authors: J. Thariat; A. Italiano; F. Peyrade; I. Birtwisle-Peyrottes; L. Gastaud; O. Dassonville; A. Thyss
Journal: Sarcoma
 (2008)

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## Abstract

Ewing's sarcoma's relapse rarely occurs more than two years after the initial diagnosis. We report the case of a 26-year-old man with a history of Ewing's sarcoma of the left maxillary sinus at the age of 10 who presented with a very late local relapse, 16 years after the first occurrence of disease. Ultimate control was achieved after multimodal therapy including surgery, high-dose chemotherapy, and radiotherapy. This report indicates that local relapses of Ewing's sarcoma can be treated with curative intent in selected cases.


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## Body

## 1. Introduction

Ewing's
sarcoma usually occurs before 30 with a peak incidence at 15 years of age. It
represents 5% of all primary bone tumors and is the second most common
malignant bone tumor in children. It is extremely rare in the head and neck as
it represents 3% of osseous Ewing’s sarcoma (OES) [1]. The mandible is most frequently affected. Only six
cases of maxillary sinus OES have been reported to date [2]. Children are usually omitted radiation therapy as
long as complete resection can be achieved to avoid radiation-induced growth
defects and the risk of radiation-induced sarcomas [3]. Late relapses have seldom been described [4–6]. We report here an observation corresponding, to the
best of our knowledge, to the longest period of complete remission followed by
local relapse thus far described and discussed its clinical implications.Case 1.
A 26-year-old man self-referred for isolated moderately paced painless swelling
of the left nasal ala with no physical status deterioration. His past medical
history was remarkable for Ewing’s sarcoma of the left maxillary sinus at the
age of 10 (stage T2N0M0 and IIA with radical margins according to the American
Joint Committee on Cancer (AJCC) and Musculoskeletal Tumor Society (MSTS)
staging systems, resp.). The patient had been treated according to the
Société Française d’Oncologie Pédiatrique (SFOP’s) protocol with chemotherapy,
hemimaxillectomy and palatine prosthetic reconstruction, and postoperative
chemotherapy without radiation therapy because of the absence of residual
viable tumor cells in the tumor resection specimen. The protocol was
adapted from the SFOP guidelines and consisted of (1) initial chemotherapy with
cyclophosphamide-doxorubicin, (2)
radical surgery if possible (children were stratified for chemotherapy and
radiation on histological response: patients with less than 10% tumor cells on
resection specimen and clear margins (complete resection) were considered good
responders and were omitted local radiotherapy), and (3) maintenance chemotherapy
(for up to 9 months) with actinomycin-vincristine.
Swelling had worsened over the past three months and
discharge appeared over the past month.  Examination was consistent with a large mucocele of the left nose area. On computerized tomography (CT) scan, a 19-mL contrast-enhanced
lesion with central sunburst pattern and calcifications (Figure1) was noted in
the para-nasal and cheek soft-tissues. It extended medially into the
surrounding nasal bone structures and posteriorly into the left maxillary sinus
and nasal fossa. Caldwell Luc operation revealed a fleshy purple lesion. The
lesion was easily resectable from subcutaneous soft tissues but was largely
extending into the frontal process of the surrounding maxillary bone. Resection
was therefore suboptimal (macroscopically incomplete). Grossly, the lesion
appeared as a purple matter with areas of hemorrhage and necrosis (Figure 2).
Histologically, it was a small-round-blue-cell tumor with homogenous highly
cellular areas spread apart by conjonctival septa and hemorrhagic lakes. Cells
had round hyperchromatic nuclei and scant cytoplasm. Histology was consistent
with the diagnostic of Ewing's
sarcoma. A
molecular cytogenetic analysis was performed. R-banded metaphase cells showed a
characteristic t(11;22)(q24;q12) translocation. A rearrangement of the EWSR1
(22q12) gene was detected by fluorescence in situ hybridization with a specific
locus probe. These findings confirmed the histological diagnosis of Ewing's
sarcoma. Whole body workup including thoracic and
abdominal CT scan, multiple bone marrow biopsies, and aspirates showed no
additional abnormality (stage rT1N0M0 at relapse). Chemotherapy consisted of
four cycles of doxorubicin
ifosfamide followed by intensification with high-dose busulfan-cyclophosphamide with autologous
peripheral-blood stem cell rescue. Complete response to chemotherapy was
achieved. Conformational radiation therapy (54 Gy) was prescribed according to
Euro Ewing 99 protocol [7] due to both suboptimal resection at relapse and
recurrent disease in the adulthood. The patient is alive and well with no
evidence of disease 15 months after diagnosis of relapse.CT scan showing a
contrast-enhanced lesion with central sunburst pattern and calcifications black
asterisk (upper (axial view), lower (sagittal view)) was noted in the para-nasal
and cheek soft-tissues. It extended medially into the surrounding nasal bone
structures and posteriorly into the left maxillary sinus and nasal fossa. It
extended superiorly to palatine prosthesis black square. Insert on Figure1(a)
shows conformational radiotherapy plan (according to Euro-Ewing 99
recommendations). Initial tumor volume was treated with a 2 cm margin and included
posttherapeutic scar tissue area white asterisk.
(a)(b)Figure 2
(Histological examination) HES× 600
small-round-blue-cell arrow head tumor with highly cellular areas. Insert (gross
examination) showed a pseudoencapsulated fleshy tumor mass.


## 2. Discussion

Multimodality therapy for Ewing's
sarcoma is associated with markedly improved survival rates. Surgery followed
by adjuvant radiotherapy and multiagent chemotherapy has dramatically improved five
years survival rates to 70%, compared with single—or even dual—modality
therapy [8]. In our case, the patient had not been treated with
radiotherapy at initial diagnosis because of the absence of residual disease following
surgical resection. The choice of local control treatment modalities depends on
several factors including tumor site, tumor size, and age [9]. Survival rates in patients with Ewing’s sarcoma of
the head and neck may be better than those of patients with tumors in other
locations but vary depending on the bone involved [10] and the possibility to perform surgery. Complete
surgical excision is undertaken whenever possible as nonsurgical treatment is
associated with a poorer long-term survival rate than that of a treatment
regimen that includes surgery. Radiotherapy has been used historically for the
treatment of Ewing’s sarcomas, as those sarcomas are relatively radiosensitive [11]. However, a significant proportion of children
treated with radiotherapy develop late toxicity, including growth defects and
occurrence of second malignancies [3]. Therefore, radiotherapy is not recommended for
children in whom surgical resection can be performed with clear margins.
However, most treatment failures in patients who do not have distant metastases
at presentation result from local recurrence. Moreover, adjuvant radiotherapy
has been associated with improved local control and improves survival when
compared to surgery or radiotherapy alone [9, 12]. Finally, it might be questioned whether radiotherapy
should have been advocated initially in our patient. As there was no evidence
for any microscopic disease after dose-intense chemotherapy and complete
surgery, it was estimated that the benefit of increased local control in this
case would have exceeded the risk of toxicity.Early metastatic relapse has the poorest prognosis [13]. Collins' law states [14] that for mesenchymal tumors of the childhood, the
period of risk for tumor recurrence is the age of the child at diagnosis plus
nine months. On the other hand, 85% of the relapses occur within three years [13, 15]. However, some relapses occur later than five years
after initial diagnosis. Of those, metastatic relapses are by far the most
common [4–6, 16]. One case only of regional relapse has been described
17 years after diagnosis in one series [5]. To our knowledge, no such late strictly local
relapse in the head and neck area as in our case has been reported so far. Such
rare occurrences may be misdiagnosed. Had our patient not been particularly
aware of his past medical history and given the mucocele-like aspect of his relapse in the head
and neck area, he might have not been treated adequately in nonspecialized centers. Such late local relapse might question
whether the patient had in fact a late relapse of his initial tumor or a
clonally distinct recurrence. The most reliable method to answer this question
would have been to analyze the fusion gene sequence in both the primary and
relapsed tumor pathologic specimens. Unfortunately, initial pathologic
specimens were not available in our case.Five-year survival after relapse is less than 10% but
selected patients benefit from aggressive salvage treatment [13]. In particular, late relapses may be treated with
curative intent as in our case. Indeed, patients with longer time to first
recurrence represent the subset of patients most likely to survive following
recurrence [15] provided that the diagnosis is not delayed to a point,
where disease is no longer manageable with optimal maximum dose-intensity
treatment.Finally, the patient is well and free of disease 15
months after relapse. While followup following treatment of relapse is still
short, intensive salvage multimodality treatment including radiotherapy for
local relapse was feasible and ultimate tumor control was achieved.


## 3. Conclusion

Such past
medical history as Ewing's
sarcoma must not be
overlooked when facing apparently benign tumor since very late local relapse is
possible. Ultimate control can be achieved for local relapses of Ewing's
sarcoma in the adulthood with aggressive salvage
treatment protocols. Further data are needed to assess the role of aggressive
local treatment.



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*Source: 854141-2008-05-29.xml*