CLINICAL
AND
LABORATORY OBSERVATIONS
An Unusual Case of Ewing Sarcoma: A Middle-aged Woman
With Multiple Recurrences Over 36 Years
Max J. Gordon, BA,* J. Carlos Manivel, MD,w Edward Y. Cheng, MD,z and Keith M. Skubitz, MD*
Summary: Ewing sarcoma (EWS) is a primary bone tumor that
most often occurs in the long bones of young patients. EWS is
typically an aggressive tumor that is highly sensitive to radiation
therapy; recurrences often occur, usually within a year of treatment. We present a case of EWS that first presented in a patient at
the age of 40 with extraosseous disease. The patient was treated
initially with radiation and surgery. Over the following 36-year
period, the tumor recurred once and metastasized twice. The
morphologic, immunohistochemical, and cytogenetic features of
this tumor were typical of EWS, and the tumor was highly
responsive to radiation therapy. The unusually prolonged course in
this patient demonstrates significant heterogeneity in the biological
behavior of EWS, and the importance of randomized trials in
cancer therapy.
study demonstrated a t(11;22) translocation. Bilateral bone marrow
biopsy was negative. She received 3 months of preoperative chemotherapy with alternating cycles of cyclophosphamide, doxorubicin, and vincristine (CAV) alternating with ifosfamide and
etoposide (IE), followed by wide local resection. The resected
specimen had <5% viable cells. She had an additional 5 months of
postoperative chemotherapy with the same agents.
In 2012, she presented with low back pain and a large, tender,
buttock mass. MRI revealed an 11.3 11.4 6.8 cm mass centered
on the left posterior iliac crest. PET-CT showed a metabolically
active, lytic mass with adjacent soft-tissue extension and enlarged,
metabolically active lymph nodes, with no evidence of distant
metastases.
Biopsy of the iliac crest mass revealed EWS (Fig. 1). The
tumor cells were immunoreactive for CD99, and negative for
Key Words: Ewing sarcoma, tumor biology, late recurrence
(J Pediatr Hematol Oncol 2014;36:e463–e464)
BACKGROUND
Ewing’s1 original report described a highly radiosensitive primary bone tumor that typically recurred within
a year of surgery. Ewing sarcoma (EWS) typically occurs in
the long bones in the second and third decades, but can
arise in the soft tissues and in older patients as well.2,3 It is
an aggressive, rapidly growing neoplasm, and spreads most
often to the lungs, bones, and marrow.4 Most recurrences
occur within a few years of treatment.5 Survival has
improved since the addition of chemotherapy, from B10%
for localized disease, to B60% to 70% today.6 Despite
excellent initial response, 5-year survival in patients with
recurrent disease remains <10%.7 We present a case of a
woman who presented at the age of 40 with an extraosseous
EWS that recurred locally once and metastasized twice over
36 years.
CASE REPORT
A 40-year-old woman presented in 1976 with a soft-tissue
mass in her right pharynx; biopsy reviewed at our institution
revealed extraskeletal EWS. She was treated with resection and
postoperative radiation, and did well for 18 years, but in 1994 had a
recurrence in the posterior oropharyngeal space, hypopharynx, and
right pyriform fossa. She was treated with resection and postoperative radiation. She did well until 2000 when a tumor was
noted in the left humerus. Biopsy demonstrated EWS; karyotype
Received for publication June 10, 2013; accepted January 27, 2014.
From the *Department of Medicine; wDepartment of Pathology and
Laboratory Medicine, Veterans Administration Medical Center;
and zDepartment of Orthopaedic Surgery, University of Minnesota Medical School, Minneapolis, MN.
The authors declare no conflict of interest.
Reprints: Keith M. Skubitz, MD, Department of Medicine—
Hematology, Oncology and Transplant, University of Minnesota,
Office Mayo Mail Code 480, 420 Delaware St. SE, Minneapolis,
MN 55455 (e-mail: [email protected]).
Copyright r 2014 by Lippincott Williams & Wilkins
J Pediatr Hematol Oncol
FIGURE 1. A, Recurrent extraskeletal Ewing sarcoma in hypopharynx. Small blue cells grow in loosely cohesive sheets (hematoxylin and eosin stain, 400). B, Metastatic Ewing sarcoma in
left iliac crest. Tumor cells are strongly reactive for CD99
(immunoperoxidase stain, 400).
Volume 36, Number 7, October 2014
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Gordon et al
J Pediatr Hematol Oncol
myogenin and CD45. Fluorescence in situ hybridization identified
an EWS gene translocation through a break-apart probe, which
was consistent with a t(11;22) translocation. Of the interphase cells
examined, 72.5% had a signal pattern indicative of rearrangement
of the EWS gene: 12.5% had a typical EWS rearrangement pattern, and an additional 60% had a complex signal pattern most
consistent with doubling of the stemline.
Treatment with CAV was begun. A good response was
obtained after 1 cycle, but was associated with unacceptable toxicity, primarily myelosuppression, likely due to her age and previous treatment. The regimen was changed to pegylated liposomal
doxorubicin and vincristine, but this modified regimen was also
overly myelosuppressive. Treatment with radiation therapy was
undertaken with a good symptomatic response. Tumor recurred
outside the radiation field shortly after the completion of therapy,
and she elected hospice.
transcription factors have been described; they have been
associated with different proliferative rates and prognoses.3
The specific exons involved in this case were not studied.
The initial response to radiation and chemotherapy is
typical of this tumor. However, the prolonged evolution
over many years is unusual. Long evolution, multiple
recurrences many years apart, and sustained response to
therapy indicate a less aggressive course than is usually seen
in EWS. This case demonstrates significant heterogeneity in
tumor biology within this category of usually highly
aggressive malignant tumors, and also demonstrates the
importance of randomized trials in cancer therapy.
DISCUSSION
One of the difficulties in treating malignant tumors is
their biological heterogeneity. Although most cases of EWS
arise in the bone in young patients, they can also occur in
extraskeletal sites, including the pharynx, and in older
patients. The microscopic, immunohistochemical, cytogenetic, and karyotypic features of our patient’s tumor are
typical of EWS. In this tumor the reciprocal translocation
t(11;22) (q24;q12) results in the fusion of the EWS gene at
22q12 with the FLI1 gene at 11q24. A less common translocation partner is the ERG gene at 21q22. This translocation was detected by karyotype in the patient’s humerus
metastasis, and by fluorescence in situ hybridization technique in the iliac crest metastasis. Different combinations of
exons from both partner genes result in different length and
composition of the chimeric protein. At least 13 EWS-FLI1
types and 4 EWS-ERG types of oncogenic aberrant
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Volume 36, Number 7, October 2014
REFERENCES
1. Ewing J. Diffuse endothelioma of bone. Proc NY Pathol Soc.
1921;12:17–24.
2. Lawlor ER, Mathers JA, Bainbridge T, et al. Peripheral
primitive neuroectodermal tumors in adults: documentation by
molecular analysis. J Clin Oncol. 1998;16:1150–1157.
3. deAlava E, Panizo A, Antonescu CR, et al. Association of
EWS-FLI1 type 1 fusion with lower proliferative rate in Ewing’s
sarcoma. Am J Pathol. 2000;156:849–855.
4. Skubitz KM, D’Adamo DR. Sarcoma. Mayo Clin Proc.
2007;82:1409–1432.
5. Bacci G, Longhi A, Ferrari S, et al. Pattern of relapse in 290
patients with nonmetastatic Ewing’s sarcoma family tumors
treated at a single institution with adjuvant and neoadjuvent
chemotherapy between 1972 and 1999. Eur J Surg Oncol.
2006;32:974–979.
6. Balamuth NJ, Womer RB. Ewing’s Sarcoma. Lancet Oncol.
2010;11:184–192.
7. Jedlicka P. Ewing sarcoma, an enigmatic malignancy of likely
progenitor cell origin, driven by transcription factor oncogenic
fusions. Int J Exp Clin Pathol. 2010;3:338–347.
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2014 Lippincott Williams & Wilkins