Bone and Soft Tissue Pathology
Case 3 -
Memorial Hospital for Cancer
New York, NY
Click on each slide thumbnail image for an enlarged view
Ewing sarcoma is a malignant tumor of small round cells arising in bone. The exact nature
and origin of the cells has been a matter of much debate.
Ewing, who is credited with
bringing attention to the disorder, preferred to call it "diffuse endothelioma of bone." 
Others believed it was derived from skeletal mesenchyme.  Still others proposed that it was
merely a form of metastatic neuroblastoma. As a result of recent cytogenetic and molecular studies,
Ewing sarcoma is now thought to be a member of a family of tumors that includes primitive neuroectodermal
tumors (PNET), peripheral neuroepithelioma, Askin's tumor of the chest wall, and extraosseous Ewing
sarcoma.  These tumors probably arise from a neuroectodermal stem cell rather than mesenchymal
tissue, but definitive proof is still lacking.
Ewing sarcoma is one half to one third as common as osteogenic sarcoma in the U.S., but
among patients less than 15 years of age, Ewing sarcoma is nearly as common as osteogenic
sarcoma.  This reflects the fact that Ewing sarcoma has a sharper peak incidence in younger
patients than osteogenic sarcoma and is rare beyond the third decade. However, the development of new
cytogenetic and molecular diagnostic tools may allow the detection of more cases in the elderly that
previously were ascribed to poorly differentiated round cell tumors.
The disease usually affects Caucasians and is distinctly uncommon in blacks and Asians. The
male to female ratio is approximately 3:2.  The pelvis and femur are favored locations, but
many other bones may be involved, including the humerus, tibia, and fibula. Primary soft tissue
involvement has a predilection for the paravertebral muscles.
The etiology is related to a chromosomal translocation. In over 90% of cases, there is a
reciprocal t(11;22)(q24;q12) translocation that results in a fusion of the EWS gene to the Fli1 gene. In
approximately 5% of cases there is a 21;22 translocation that fuses the EWS gene to the ERG gene, and in
rare cases the EWS gene may be fused to other genes such as the E1A gene and the ETV1 gene.
The chimaeric proteins function as aberrant transcription factors. It is believed that the
fusion proteins activate and/or repress a set of genes which result in neoplastic transformation of the
cell, but the critical target genes have yet to be identified.
Most patients complain of pain and swelling at the affected site. Growth of the tumor is
rapid, and symptoms are typically present for only weeks to months. In most cases, a substantial firm
mass is present, and its sudden appearance and enlargement may cause alarm in the patient. The
presentation can simulate acute osteomyelitis, and some patients have constitutional symptoms of fevers,
malaise, and lethargy. Pathologic fractures occasionally occur.
Radiographic Differential Diagnosis
Ewing sarcoma has protean radiographic manifestations and is notorious for its ability to
masquerade as other disorders. The most well-known finding — onionskin formation — is not consistently
present. Moreover, it is not a unique attribute and can be produced by numerous other diseases,
including osteomyelitis, Langerhans cell granuloma, and osteogenic sarcoma. Onionskin formation is one
form of reactive periosteal bone formation. Other forms include the sunburst pattern ("hair-on-end"
bone) and Codman's triangle. In all of these variations, the new bone is not made by the tumor but by
the periosteum, which is elevated off the cortical bone by a rapidly expanding mass. In Codman's
triangle, the mass erodes through the central portion of the onionskin laminations, leaving only the
triangular ends on the bone. In a sunburst pattern, the central portion is filled in by spicules of new
bone radiating outward perpendicular to the shaft.
Ewing sarcoma usually produces an ill-defined, lytic defect that permeates up and down the
medullary canal, giving the bone a moth-eaten appearance. However, in approximately 10% of cases, the
tumor may have a predominantly blastic appearance as a result of exuberant reactive bone formation. This
can cause it to be confused with osteogenic sarcoma, particularly the small cell variant. 
An important clue that suggests the possibility of Ewing sarcoma is the presence of a large
soft tissue mass adjacent to the bone. This may be subtle and difficult to appreciate on plain
radiographs but becomes apparent with CT or MRI scans. In certain bones such as the pelvis, periosteal
reaction is often absent radiographically, and the soft tissue mass becomes more important to making the
Laboratory tests may show leukocytosis with a left shift, and the erythrocyte sedimentation
rate may be elevated. These findings, along with the history, examination, and radiographs, can easily
deceive the clinician into thinking that the diagnosis is osteomyelitis. The serum lactate dehydrogenase
(LDH) is important to note since it is correlated to the disease burden, and it has prognostic
Pathologic Differential Diagnosis
The tumor is composed of sheets of small round blue cells with hyperchromatic nuclei. There
is scant cytoplasm and little extracellular matrix. The cells are usually glycogen positive. Neural
markers are occasionally present, and these can include neuron-specific enolase, CD57, neurofilaments,
S100 protein, and Homer-Wright rosettes. 
Ewing sarcoma may be morphologically indistinguishable from other small round cell tumors,
such as lymphoma of bone and metastatic neuroblastoma. Differentiation from these other entities has
been facilitated in recent years by the development of the monoclonal antibodies HBA71 and O13 against
Ewing sarcoma.  The antibodies recognizes the p30/32 MIC2 protein, which was originally
described as a cell surface marker of T lymphocytes.  The function of the MIC2 protein is
not completely understood, but in T cells it is thought to be involved in cell adhesion.
Immunohistochemistry with the O13 antibody is positive in most cases of Ewing sarcoma.
In a large study of 244 cases, the antibody was found to be 91% sensitive.  However, the
antibody is not 100% specific, and it occasionally cross-reacts with lymphomas and other
tumors.  This is not surprising since the MIC2 protein has been detected by another antibody
12E7 on most lymphoblastic lymphomas and T cell acute lymphocytic leukemias.  Other tumors
that occasionally bind O13 include astrocytomas, neuroectodermal tumors, mesenchymal chondrosarcoma,
embryonal rhabdomyosarcomas, and carcinomas.
It is notable that neuroblastomas have not
been found to react with O13.
The development of reverse transcriptase-polymerase chain reaction (RT-PCR) has also aided
the diagnosis of Ewing sarcoma by facilitating the detection of specific chromosomal
translocations.  RT-PCR is a powerful test, and one study reported 100% sensitivity and
specificity in detecting the 11;22 translocation.  However, other tumors besides Ewing
sarcoma occasionally possess the same translocation, and one study found it in two polyphenotypic tumors
and two mixed rhabdomyosarcomas.  Thus, like the O13 antibody, RT-PCR cannot be relied
upon exclusively to make the diagnosis, and it is still important to consider all of the histologic and
The staging system for Ewing sarcoma differs from the system used for most sarcomas of bone.
This seems appropriate since the histogenesis of Ewing sarcoma may not be mesenchymally derived and the
clinical behavior seems to differ from most sarcomas. Enneking suggested four stages: stage I, solitary
intraosseous tumor; stage II, solitary tumor with extraosseous extension; stage III, multicentric
skeletal involvement; and stage IV, distant metastases. 
The staging system reflects the propensity of Ewing sarcoma to disseminate widely and early
in the course of the disease. Lungs and other bones are the usual sites of metastases. A distinctive
feature of Ewing sarcoma is its predilection for bone marrow involvement, which is uncommon in other
sarcomas.  The finding carries a poor prognosis, and Meyers et al found no survivors when
it was present.  Bone marrow biopsy should be part of the standard staging studies for
Treatment of the primary tumor consists of radiation therapy,
surgery, or a combination of both modalities. Historically, radiation therapy has been used most often.
It was recognized by Ewing and others that the tumors are sensitive to radiation. However, survival with
radiation alone was less than 10%, reflecting the presence of microscopic disseminated disease at the
time of diagnosis. Surgery, which usually involved amputation, produced equally poor results, and
consequently, many authors condemned the use of surgery for Ewing sarcoma.
Radiation has produced rates of local control ranging from 60-90%. There are a number of
explanations for the wide variation in results. Techniques of radiation therapy have improved over time.
Radiation in older trials may have been hampered by inadequate equipment as well as poor imaging
techniques. The advent of CT and MRI has led to more accurate depiction of the tumor and better
selection of radiation fields. Yet despite the advances in radiation therapy, a number of recent reports
have continued to show disappointing results. A POG study found only 76% local control at three
years  while a CESS study reported only 77% local control at five years. 
Recurrences have been noted to occur within radiation fields, and autopsies have demonstrated viable
malignant cells in irradiated tumors. Tepper et al found live neoplastic cells in 11 of 28 primary
tumors,  and Telles et al found recurrent disease in 13 of 26 tumors.  A certain
amount of selection bias was inherent in these autopsy studies since only patients who failed treatment
were analyzed. Nevertheless, the studies clearly demonstrate that many tumors are not completely
eradicated by radiation.
Local recurrence after radiation is associated with a number of factors. The size of the
tumor is important. Large tumors (greater than 100 ml in volume) are much more likely to harbor a focus
of radioresistant cells than small tumors.  The location of the tumor is also important.
Central and pelvic tumors have much higher rates of local recurrence than distal tumors. 
This may reflect the difficulty in achieving adequate radiation doses around vital organs.
The response to chemotherapy also affects the likelihood of local recurrence. It was first
noted that patients who received chemotherapy had lower overall rates of local recurrence than patients
who did not receive chemotherapy.
Arai et al subsequently found that patients who
responded well to chemotherapy had significantly better local control than patients who responded
poorly.  In this study, patients who had an objective response to chemotherapy and a tumor
less than 8 cm long achieved 90% local control, despite being given a low radiation dose (35 Gy).
Patients who had an objective response to chemotherapy and a tumor more than 8 cm long were given a high
radiation dose (50-60 Gy), but these patients obtained only 52% local control. Finally, patients who
failed to show a response to chemotherapy were also given a high dose (50-60 Gy), but had only 17% local
In addition to improving local control with radiation, effective adjuvant chemotherapy has
made limb-sparing surgical excision possible. In fact, surgery may be a superior alternative to
radiation treatment. The most cogent argument in favor of surgery is that it can remove a focus of
radioresistant and chemoresistant cells that may reside within a large tumor. Another compelling
argument is that patients who undergo radiation are at a substantial risk for developing a second primary
tumor, particularly osteogenic sarcoma.
The cumulative risk increases with time and has
been estimated to be 8.6% at 20 years, with a mean latency of 7.6 years.  Patients who
receive a radiation dose of 60 Gy or greater seem to be at greatest risk.
Many clinicians have objected to surgery on the basis of its being invasive, destructive,
and disfiguring. They have preferred radiation since it seems to be non-invasive and limb-preserving.
This viewpoint may have had some merit in the past, but it is no longer completely valid. Surgical
reconstructive techniques have improved considerably, and function after limb-sparing surgery is
significantly better now than in the past. Surgery should no longer be reserved for "expendable" bones,
such as the ribs, clavicle, and fibula.  With modern surgical techniques, there are few, if
any, truly non-expendable bones, and reconstructive options exist for essentially all anatomic sites.
Furthermore, it is worth emphasizing that radiation produces a significant amount of damage to normal
tissue and can potentially cause serious functional impairment. Complications of radiation include skin
atrophy and breakdown, fibrosis of muscles, contracture of joints, vasculitis, neuropathy, growth plate
arrest, limb length inequality, osteonecrosis, and pathologic fractures.
Although it is important to compare radiation and surgery with respect to functional
outcome, the focus of the current debate should center on oncologic outcome. At present, the published
data seems to favor surgery but is not entirely conclusive. Several studies have shown that surgery
produces a higher rate of local control. Bacci et al found 36% local recurrence with radiation alone
compared to 8% local recurrence with either surgery alone or surgery with radiation.  Ozaki
reported 15% local recurrence with radiation therapy alone compared to 4% local recurrence with surgery
alone and 4% with surgery and radiation therapy.  The main criticism of these and other
studies is that they were not randomized trials, and there may have been a selection bias towards
surgical excision of relatively smaller and more distal tumors.
There is only limited data pertaining to large, centrally located tumors, which carry the
Some have recommended radiation therapy for these sites because it
is difficult to obtain negative surgical margins, and the rate of complications is high. However,
radiation treatment is also difficult in central locations because of their proximity to vital organs,
and these tumors are precisely the ones most likely to recur after radiation.
There is conflicting data on whether surgery may have a positive impact on pelvic tumors.
Scully et al found that there was no difference in survival between radiation therapy and surgery for
pelvic tumors.  The experience of the Rizzoli Institute was similar, and survival was not
improved by the addition of surgery to radiation.  In contrast to these findings, several
groups have reported more favorable results after surgical treatment of pelvic tumors.
In the study from Memorial Sloan-Kettering, nine of 12 cases of pelvic tumors were treated
surgically, and there were no local recurrences in these nine tumors.  At UCLA, Yang et al
obtained 51% cumulative 5-year survival in patients who had surgical resection compared to 18% survival
in patients who did not have surgery. 
Some have proposedthat a combination of surgery and radiation be
used to improve the rate of local control. Data on this subject is limited and confounded by a
significant selection bias for patients that receive both radiation and surgery. Often these are the
patients with the greatest perceived risk of recurrence — those with positive margins, large tumors, or
contamination by previous surgery. This may be the reason that some investigators have not found an
advantage to combining surgery with radiation.
More encouraging results were found by
Wunder et al at Memorial Sloan-Kettering. Among patients who had a complete
en bloc resection, the relative risk of local recurrence was 3.9 for patients who did not receive
radiation compared to those that did receive radiation.  All six patients with local
recurrence in this series subsequently died of disease. The results at UCLA also seem to indicate a
potential benefit of combined radiation and surgery in selected patients.  If indeed there
is an increase in both local control and survival, the benefits of combining the two modalities may
outweigh the increased risks of complications that would be expected from this aggressive approach.
Proposals to conduct randomized trials of radiation versus surgery fail to consider that many patients
may benefit from both modalities.
The issue of surgical treatment is further complicated by the choice of margins. Should the
margin be outside of the original tumor, outside of the tumor after induction chemotherapy, or outside of
the tumor after induction chemotherapy and radiation? Theoretically, it seems most prudent if the margin
around the original tumor is chosen, but this requires sacrificing the most tissue. A margin outside of
a tumor that has shrunk after induction chemotherapy and/or radiation is less optimal but may be chosen
to spare important structures such as major nerves.
Pathologic fractures, especially those occurring after radiation, poses another surgical
dilemma. In the study by Terek et al, all femoral lesions treated initially with radiation eventually
required surgical treatment, either as a result of recurrence or pathologic fracture which failed to
unite.  Healing of these post-radiation fractures can occur but is often
It is likely that no single therapeutic strategy will be ideal for all patients. Surgery
may theoretically improve the chances for local control, but patients should be carefully selected, and
the lesion must be resectable with adequate margins. In patients at high risk of local recurrence,
surgery may be combined with radiation, but there may be an increase in wound complications. In the
rare, unresectable lesion, radiation alone may be the only choice, but it is possible that after
radiation and induction chemotherapy, the lesion may regress and become resectable.
The development of chemotherapy for Ewing sarcoma began in the 1960s, when phase II trials
in patients with metastatic disease showed promise for cyclophosphamide, actinomycin D, vincristine, and
other agents. Successful adjuvant chemotherapy for patients with non-metastatic disease was reported by
Hustu in 1968, who treated five patients with vincristine and cyclophosphamide.  It may be
more than mere coincidence that the chemotherapy was adapted from protocols for neuroblastoma, and the
neurotoxic agent vincristine was used.
The first Intergroup Ewing Sarcoma Study (IESS-1) began accrual of patients in
1973.  This involved 3 major study groups (CCSG, SWOG, and CALBG) and 84 participating
institutions. The chemotherapy was based on vincristine, actinomycin D, and cyclophosphamide (VAC), and
patients were randomized to three groups: VAC alone, VAC plus doxorubicin (VACA), and VAC plus whole
lung irradiation. Radiation was used to treat the primary tumor. The IESS-1 study firmly established
the effectiveness of adjuvant chemotherapy. Patients that received VAC plus doxorubicin had a 5 year
relapse-free survival of 60%, which was far superior to any historical control. Patients that received
only VAC had a survival of only 28%, which demonstrated the effectiveness of doxorubicin. Survival with
VAC + whole lung irradiation gave intermediate results with survival of 53%, which was better than VAC
alone, but was not as effective as the VACA combination.
In the follow-up IESS-2 trial, intermittent high dose chemotherapy was shown to be more
effective than continuous moderate dose chemotherapy.  Dose intensity, especially that of
doxorubicin, was found to be an important factor.  A 5 year disease-free survival of 68%
was achieved in the intermittent high dose chemotherapy group, but there was greater cardiotoxicity and
one cardiac-related death. 
Subsequent trials have corroborated the findings of IESS-1 and confirmed the effectiveness
of VACA. The results of selected major trials are shown in Table 4. The CESS 81 study obtained 55%
disease-free survival at 69 months  while the Rizzoli group found 54% disease-free survival
at 5 years.  Hayes et al used these four agents in a somewhat different protocol and
reported 3 year disease-free survival of 82% for tumors less than 8 cm and 64% for tumors greater than 8
Rosen at Memorial Sloan-Kettering reported a 10 year experience with a series of 67
consecutive patients from 1970-80.  The protocols evolved during this period from T2 to T6
to T9. The T2 protocol consisted of VACA, while the T6 and T9 protocols employed doxorubicin,
cyclophosphamide, high dose methotrexate, BCD (see osteogenic sarcoma above), and BCNU (T6). Although
excellent results were reported with 79% disease-free survival at 2 years, which was stable to 5 years,
the interpretation of the study is complicated by the variety of agents and protocols. Many of the early
patients received extremely high doses of doxorubicin in the range of 700-900 mg/m2, which is beyond the
doses allowed under current protocols. In a follow-up study of patients that received T9 and T11
chemotherapy at the same institution, Meyers found 53% event-free survival at 5 years.  This
study, however, included patients with metastatic and relapsed disease.
There is currently much interest in the use of ifosfamide and etoposide (VP16), which have
been shown to be effective in phase II trials.
However, addition of these agents to the
traditional four agent regimen VACA may produce only a small increase in survival. A large study from
the Rizzoli Institute found only a 4% increase in disease-free survival, which was not statistically
Preliminary data from a recent large, randomized CCG/POG study of 398
patients showed more encouraging results, and the five year event-free survival was increased
significantly from 52 to 69%. 
In recent years there has been an effort to stratify patients into high risk vs. standard
risk categories. The definition of high risk varies, but usually includes metastatic cases (lung, bone,
and/or bone marrow), relapsed cases, and primary tumors in unfavorable locations. The latter category is
comprised of axial and pelvic tumors, but many investigators have also included "proximal" tumors in the
humerus and femur. Large tumors have also been included in high risk categories, with criteria being
either >8 cm greatest dimension or >100 ml volume.
It seems that if all of the above tumors are considered "high risk" then only a small
percentage of cases would qualify as "standard risk." Not all of the high risk cases are at similarly
high risk. The prognosis in axial or pelvic locations is worse than the humerus or femur. Likewise, the
prognosis for patients that relapse while on chemotherapy is bleak, whereas the prognosis for patients
that present with metastatic disease may be somewhat better.
Cangir et al, reporting
the IESS experience, found that the 5 year survival was 30% for patients that presented with metastases
(ie, patients who did not relapse during treatment).  Sandoval similarly found an overall
survival of 35% for cases that presented de novo with
metastases.  The type (location) and timing of metastases appear to be important. Meyers
found no survivors in patients with bone marrow involvement or patients that developed metastases while
on chemotherapy.  These considerations should be kept in mind when reviewing the literature
on high risk cases. The results that pertain to one set of "high risk" patients may very well not apply
to another group.
In contrast to osteogenic sarcoma and other sarcomas, there has not been much success with
surgical resection of metastases. Heij reported that all 12 patients who underwent thoracotomy for
metastases eventually died of the disease.  It is probable that the behavior of Ewing
sarcoma differs from osteogenic sarcoma, and Ewing sarcoma has a much greater propensity for widespread
Bone marrow transplant and stem cell rescue have been used for relapsed and high risk cases.
. This approach seems especially applicable to cases of bone marrow metastases,
which might respond to bone marrow ablation by total body irradiation and/or high-dose chemotherapy.
Total body irradiation has a additional appeal since Ewing sarcoma is radiosensitive. However, it should
be recalled that the responses below 30 Gy were unpredictable, and a significant percentage of cases do
not respond well to radiation therapy even at high doses. 
Cornbleet et al reported in 1981 on 3 patients with refractory Ewing sarcoma treated with
high dose melphalan and autologous bone marrow rescue.  Two patients had a complete
response and survived free of disease for 12 and 13 months. One patient had a partial response. A more
extensive study was performed at the NCI, where patients were treated with VACA, radiation therapy for
local control, 8 Gy total body irradiation, and autologous bone marrow rescue.  Early
results were impressive with 30/31 complete responses, but long-term results were less encouraging. Of
the 13 metastatic cases, 9 relapsed and the projected 6 year survival rate was only 10%. The
non-metastatic, high-risk cases fared better with only 5 of 18 cases relapsing. Burdach et al reported
more optimistic results in a group of 17 patients with metastatic disease (7 new cases, 10 relapsed
cases).  Treatment consisted of induction chemotherapy, local treatment, myeloablation with
melphalan/etoposide +/- carboplatin, 12 Gy total body irradiation, and finally bone marrow or stem cell
rescue. The 6 year relapse-free survival was 45%.
- Noguera R, Triche TJ, Navarro S, Tsokos M, Llombart-Bosch A: Dynamic model of differentiation in Ewing's sarcoma cells. Comparative analysis of morphologic, immunocytochemical, and oncogene expression parameters [see comments]. Laboratory Investigation 1992;66:143-151.
- Rettig WJ, Garin-Chesa P, Huvos AG: Ewing's sarcoma: new approaches to histogenesis and molecular plasticity [editorial; comment]. Laboratory Investigation 1992;66:133-137.
- Ewing J: Diffuse endothelioma of bone. Proceedings of the New York Pathological Society 1921;21:17
- Mirra JM: Bone tumors, Philadelphia, Lea & Febiger; 1989:
- Gurney JG, Davis S, Severson RK, Fang JY, Ross JA, Robison LL: Trends in cancer incidence among children in the U.S. Cancer 1996;78:532-541.
- Huvos AG: Bone Tumors, Philadelphia, W.B. Saunders; 1991:
- Urano F, Umezawa A, Hong W, Kikuchi H, Hata J: A novel chimera gene between EWS and E1A-F, encoding the adenovirus E1A enhancer-binding protein, in extraosseous Ewing's sarcoma. Biochemical & Biophysical Research Communications 1996;219:608-612.
- Jeon IS, Davis JN, Braun BS, et al: A variant Ewing's sarcoma translocation (7;22) fuses the EWS gene to the ETS gene ETV1. Oncogene 1995;10:1229-1234.
- Zelazny A, Reinus WR, Wilson AJ: Quantitative analysis of the plain radiographic appearance of Ewing's sarcoma of bone. Investigative Radiology 1997;32:59-65.
- Fellinger EJ, Garin-Chesa P, Glasser DB, Huvos AG, Rettig WJ: Comparison of cell surface antigen HBA71 (p30/32MIC2), neuron-specific enolase, and vimentin in the immunohistochemical analysis of Ewing's sarcoma of bone. American Journal of Surgical Pathology 1992;16:746-755.
- Hamilton G, Fellinger EJ, Schratter I, Fritsch A: Characterization of a human endocrine tissue and tumor-associated Ewing's sarcoma antigen. Cancer Research 1988;48:6127-6131.
- Fellinger EJ, Garin-Chesa P, Su SL, DeAngelis P, Lane JM, Rettig WJ: Biochemical and genetic characterization of the HBA71 Ewing's sarcoma cell surface antigen. Cancer Research 1991;51:336-340.
- Fellinger EJ, Garin-Chesa P, Triche TJ, Huvos AG, Rettig WJ: Immunohistochemical analysis of Ewing's sarcoma cell surface antigen p30/32MIC2. American Journal of Pathology 1991;139:317-325.
- Lee CS, Southey MC, Waters K, et al: EWS/FLI-1 fusion transcript detection and MIC2 immunohistochemical staining in the diagnosis of Ewing's sarcoma. Pediatric Pathology & Laboratory Medicine 1996;16:379-392.
- Devaney K, Abbondanzo SL, Shekitka KM, Wolov RB, Sweet DE: MIC2 detection in tumors of bone and adjacent soft tissues. Clinical Orthopaedics & Related Research 1995;176-187.
- Weidner N, Tjoe J: Immunohistochemical profile of monoclonal antibody O13: antibody that recognizes glycoprotein p30/32MIC2 and is useful in diagnosing Ewing's sarcoma and peripheral neuroepithelioma [see comments]. American Journal of Surgical Pathology 1994;18:486-494.
- Perlman EJ, Dickman PS, Askin FB, Grier HE, Miser JS, Link MP: Ewing's sarcoma--routine diagnostic utilization of MIC2 analysis: a Pediatric Oncology Group/Children's Cancer Group Intergroup Study. Human Pathology 1994;25:304-307.
- Riopel M, Dickman PS, Link MP, Perlman EJ: MIC2 analysis in pediatric lymphomas and leukemias. Human Pathology 1994;25:396-399.
- MacEwen EG, Kurzman ID, Rosenthal RC, et al: Therapy for osteosarcoma in dogs with intravenous injection of liposome-encapsulated muramyl tripeptide. Journal of the National Cancer Institute 1989;81:935-938.
- Scotlandi K, Serra M, Manara MC, et al: Immunostaining of the p30/32MIC2 antigen and molecular detection of EWS rearrangements for the diagnosis of Ewing's sarcoma and peripheral neuroectodermal tumor. Human Pathology 1996;27:408-416.
- Thorner P, Squire J, Chilton-MacNeil S, et al: Is the EWS/FLI-1 fusion transcript specific for Ewing sarcoma and peripheral primitive neuroectodermal tumor? A report of four cases showing this transcript in a wider range of tumor types. American Journal of Pathology 1996;148:1125-1138.
- Enneking WF: Musculoskeletal Tumor Surgery, New York, Churchill Livingstone Inc. 1983:1351.
- Oberlin O, Bayle C, Hartmann O, Terrier-Lacombe MJ, Lemerle J: Incidence of bone marrow involvement in Ewing's sarcoma: value of extensive investigation of the bone marrow. Medical & Pediatric Oncology 1995;24:343-346.
- Meyers PA, Wunder J, Healey J, Paulian G, Huvos A: Ewing's sarcoma (ES)/primitive neuroectodermal tumor (PNET) of bone: histological response (HR) to pre-operative chemotherapy (CT) predicts event free survival (EFS) (Meeting abstract). Proc Annu Meet Am Soc Clin Oncol 1995;14:A1407
- Falk S, Alpert M: Five-year survival of patients with Ewing's sarcoma. Surgery, Gynecology & Obstetrics 1967;124:319-324.
- Boyer CW, Jr., Brickner TJ, Jr., Perry RH: Ewing's sarcoma: case against surgery. Cancer 1967;20:1602-1606.
- Donaldson S, Shuster J, Andreozzi C: The Pediatric Oncology Group (POG) experience in Ewing's sarcoma of bone. Medical and Pediatric Oncology 1989;17:283
- Jurgens H, Exner U, Gadner H, et al: Multidisciplinary treatment of primary Ewing's sarcoma of bone. A 6-year experience of a European Cooperative Trial. Cancer 1988;61:23-32.
- Tepper J, Glaubiger D, Lichter A, Wackenhut J, Glatstein E: Local control of Ewing's sarcoma of bone with radiotherapy and combination chemotherapy. Cancer 1980;46:1969-1973.
- Telles NC, Rabson AS, Pomeroy TC: Ewing's sarcoma: an autopsy study. Cancer 1978;41:2321-2329.
- Razek A, Perez CA, Tefft M, et al: Intergroup Ewing's Sarcoma Study: local control related to radiation dose, volume, and site of primary lesion in Ewing's sarcoma. Cancer 1980;46:516-521.
- Chan RC, Sutow WW, Lindberg RD, Samuels ML, Murray JA, Johnston DA: Management and results of localized Ewing's sarcoma. Cancer 1979;43:1001-1006.
- Fernandez CH, Lindberg RD, Sutow WW, Samuels ML: Localized Ewing's sarcoma--treatment and results. Cancer 1974;34:143-148.
- Arai Y, Kun LE, Brooks MT, et al: Ewing's sarcoma: local tumor control and patterns of failure following limited-volume radiation therapy. International Journal of Radiation Oncology, Biology, Physics 1991;21:1501-1508.
- Kuttesch JF, Jr., Wexler LH, Marcus RB, et al: Second malignancies after Ewing's sarcoma: radiation dose-dependency of secondary sarcomas. Journal of Clinical Oncology 1996;14:2818-2825.
- Bacci G, Toni A, Avella M, et al: Long-term results in 144 localized Ewing's sarcoma patients treated with combined therapy. Cancer 1989;63:1477-1486.
- Gasparini M, Lombardi F, Ballerini E, et al: Long-term outcome of patients with monostotic Ewing's sarcoma treated with combined modality. Medical & Pediatric Oncology 1994;23:406-412.
- Strong LC, Herson J, Osborne BM, Sutow WW: Risk of radiation-related subsequent malignant tumors in survivors of Ewing's sarcoma. Journal of the National Cancer Institute 1979;62:1401-1406.
- Smith LM, Cox RS, Donaldson SS: Second cancers in long-term survivors of Ewing's sarcoma. Clinical Orthopaedics & Related Research 1992;275-281.
- Novakovic B, Fears TR, Horowitz ME, Tucker MA, Wexler LH: Late effects of therapy in survivors of Ewing's sarcoma family tumors. Journal of Pediatric Hematology/Oncology 1997;19:220-225.
- Nicholson HS, Mulvihill JJ, Byrne J: Late effects of therapy in adult survivors of osteosarcoma and Ewing's sarcoma [see comments]. Medical & Pediatric Oncology 1992;20:6-12.
- Hawkins MM, Wilson LM, Burton HS, et al: Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer. Journal of the National Cancer Institute 1996;88:270-278.
- Tucker MA, D'Angio GJ, Boice JD, Jr., et al: Bone sarcomas linked to radiotherapy and chemotherapy in children. New England Journal of Medicine 1987;317:588-593.
- Neff JR: Nonmetastatic Ewing's sarcoma of bone: the role of surgical therapy. Clinical Orthopaedics & Related Research 1986;111-118.
- Jentzsch K, Binder H, Cramer H, et al: Leg function after radiotherapy for Ewing's sarcoma. Cancer 1981;47:1267-1278.
- Lewis RJ, Marcove RC, Rosen G: Ewing's sarcoma -- functional effects of radiation therapy. Journal of Bone & Joint Surgery - American Volume 1977;59:325-331.
- Ozaki T, Hillmann A, Hoffmann C, et al: Significance of surgical margin on the prognosis of patients with Ewing's sarcoma. A report from the Cooperative Ewing's Sarcoma Study. Cancer 1996;78:892-900.
- Nesbit ME, Jr., Gehan EA, Burgert EO, Jr., et al: Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: a long-term follow-up of the First Intergroup study. Journal of Clinical Oncology 1990;8:1664-1674.
- Wilkins RM, Pritchard DJ, Burgert EO, Jr., Unni KK: Ewing's sarcoma of bone. Experience with 140 patients. Cancer 1986;58:2551-2555.
- Scully SP, Temple HT, O'Keefe RJ, Scarborough MT, Mankin HJ, Gebhardt MC: Role of surgical resection in pelvic Ewing's sarcoma. Journal of Clinical Oncology 1995;13:2336-2341.
- Picci P, Sangiorgi L, Bahamonde L, et al: Outcome of patients with non-metastatic Ewing's sarcoma of the pelvis: results in 65 patients (Meeting abstract). Proc Annu Meet Am Soc Clin Oncol 1994;13:A1656
- Evans RG, Nesbit ME, Gehan EA, et al: Multimodal therapy for the management of localized Ewing's sarcoma of pelvic and sacral bones: a report from the second intergroup study. Journal of Clinical Oncology 1991;9:1173-1180.
- Rosen G, Caparros B, Nirenberg A, et al: Ewing's sarcoma: ten-year experience with adjuvant chemotherapy. Cancer 1981;47:2204-2213.
- Yang RS, Eckardt JJ, Eilber FR, et al: Surgical indications for Ewing's sarcoma of the pelvis. Cancer 1995;76:1388-1397.
- Frassica FJ, Frassica DA, Pritchard DJ, Schomberg PJ, Wold LE, Sim FH: Ewing sarcoma of the pelvis. Clinicopathological features and treatment. Journal of Bone & Joint Surgery - American Volume 1993;75:1457-1465.
- Wunder JS, Paulian G, Huvos AG, Heller G, Meyers PA, Healey JH: Histologic response to chemotherapy predicts oncologic outcome in surgically-treated Ewing sarcoma. Journal of Bone and Joint Surgery [Am] 1998;80:1020-1033.
- Terek RM, Brien EW, Marcove RC, Meyers PA, Lane JM, Healey JH: Treatment of femoral Ewing's sarcoma. Cancer 1996;78:70-78.
- Springfield DS, Pagliarulo C: Fractures of long bones previously treated for Ewing's sarcoma. Journal of Bone & Joint Surgery - American Volume 1985;67:477-481.
- Hustu HO, Holton C, James D, Jr., Pinkel D: Treatment of Ewing's sarcoma with concurrent radiotherapy and chemotherapy. Journal of Pediatrics 1968;73:249-251.
- Nesbit ME, Jr., Perez CA, Tefft M, et al: Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: an Intergroup Study. National Cancer Institute Monographs 1981;255-262.
- Burgert EO, Jr., Nesbit ME, Garnsey LA, et al: Multimodal therapy for the management of nonpelvic, localized Ewing's sarcoma of bone: intergroup study IESS-II [see comments]. Journal of Clinical Oncology 1990;8:1514-1524.
- Smith MA, Ungerleider RS, Horowitz ME, Simon R: Influence of doxorubicin dose intensity on response and outcome for patients with osteogenic sarcoma and Ewing's sarcoma [see comments]. Journal of the National Cancer Institute 1991;83:1460-1470.
- Hayes FA, Thompson EI, Meyer WH, et al: Therapy for localized Ewing's sarcoma of bone. Journal of Clinical Oncology 1989;7:208-213.
- Meyer WH, Kun L, Marina N, et al: Ifosfamide plus etoposide in newly diagnosed Ewing's sarcoma of bone. Journal of Clinical Oncology 1992;10:1737-1742.
- Jurgens H, Exner U, Kuhl J, et al: High-dose ifosfamide with mesna uroprotection in Ewing's sarcoma. Cancer Chemotherapy & Pharmacology 1989;24:Suppl 1:S40-4.
- Wexler LH, DeLaney TF, Tsokos M, et al: Ifosfamide and etoposide plus vincristine, doxorubicin, and cyclophosphamide for newly diagnosed Ewing's sarcoma family of tumors. Cancer 1996;78:901-911.
- Jurgens H, Treuner J, Winkler K, Gobel U: Ifosfamide in pediatric malignancies. [Review] [19 refs]. Seminars in Oncology 1989;16:Suppl 3):46-50.
- Grier H, Krailo M, Link M, et al: Improved outcome in nonmetastatic Ewing's sarcoma (EWS) and PNET of bone with the addition of ifosfamide (I) and etoposide (E) to vincristine (V), Adriamycin (Ad), cyclophosphamide (C), and actinomycin (A): a Children's Cancer Group (CCG) and Pediatric Oncology Group (POG) report (Meeting abstract). Proc Annu Meet Am Soc Clin Oncol 1994;13:A1443
- Bacci G, Picci P, Ruggieri P, et al: No advantages in the addition of ifosfamide and VP-16 to the standard four-drug regimen in the maintenance phase of neoadjuvant chemotherapy of Ewing's sarcoma of bone: results of two sequential studies. Journal of Chemotherapy 1993;5:247-257.
- Bacci G, Picci P, Ferrari S, et al: Neoadjuvant chemotherapy for Ewing's sarcoma of bone. No benefit observed after adding ifosfamide and etoposide to vincristine, actinomycin, cyclophosphamide, and doxorubicin in the maintenance phase-results of two sequential studies. Cancer 1998;82:1174-1183.
- Dunst J, Jurgens H, Sauer R, et al: Radiation therapy in Ewing's sarcoma: an update of the CESS 86 trial [see comments]. International Journal of Radiation Oncology, Biology, Physics 1995;32:919-930.
- Cangir A, Vietti TJ, Gehan EA, et al: Ewing's sarcoma metastatic at diagnosis. Results and comparisons of two intergroup Ewing's sarcoma studies. Cancer 1990;66:887-893.
- Sandoval C, Meyer WH, Parham DM, et al: Outcome in 43 children presenting with metastatic Ewing sarcoma: the St. Jude Children's Research Hospital experience, 1962 to 1992. Medical & Pediatric Oncology 1996;26:180-185.
- Kushner BH, Meyers PA, Gerald WL, et al: Very-high-dose short-term chemotherapy for poor-risk peripheral primitive neuroectodermal tumors, including Ewing's sarcoma, in children and young adults. Journal of Clinical Oncology 1995;13:2796-2804.
- Heij HA, Vos A, De Kraker J, Voute PA: Prognostic factors in surgery for pulmonary metastases in children. Surgery 1994;115:687-693.
- Miser JS, Kinsella TJ, Triche TJ, et al: Preliminary results of treatment of Ewing's sarcoma of bone in children and young adults: six months of intensive combined modality therapy without maintenance. Journal of Clinical Oncology 1988;6:484-490.
- Bader JL, Horowitz ME, Dewan R, et al: Intensive combined modality therapy of small round cell and undifferentiated sarcomas in children and young adults: local control and patterns of failure. Radiotherapy & Oncology 1989;16:189-201.
- Burdach S, Jurgens H, Peters C, et al: Myeloablative radiochemotherapy and hematopoietic stem-cell rescue in poor-prognosis Ewing's sarcoma. Journal of Clinical Oncology 1993;11:1482-1488.
- Cornbleet MA, Corringham RE, Prentice HG, Boesen EM, McElwain TJ: Treatment of Ewing's sarcoma with high-dose melphalan and autologous bone marrow transplantation. Cancer Treatment Reports 1981;65:241-244.