This Article Full Text (PDF) From JCO 1983 Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zagar, T. M. Articles by Kinsella, T. J. Search for Related Content PubMed PubMed Citation Articles by Zagar, T. M. Articles by Kinsella, T. J. Social Bookmarking                            What's this?

Extraosseous Ewing's Sarcoma: 25 Years Later

Department of Radiation Oncology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH

Timothy J. Triche

Department of Pathology, Los Angeles Children's Hospital, University of Southern California School of Medicine, Los Angeles, CA

Timothy J. Kinsella

Department of Radiation Oncology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH

Twenty-five years ago in Journal of Clinical Oncology, a retrospective review of patients with extraosseous Ewing's sarcoma (EES) treated at the National Cancer Institute in the early to mid 1970s with standard combined-modality therapy was published.¹ Much has changed since then, particularly in the methodology of diagnosis and molecular characterization of this rare malignancy. Unfortunately, however, we find ourselves using many of the same treatments we did almost three decades ago, without a substantial increase in the cure rate.

We now know that EES is not just defined by Ewing's sarcoma of bone by routine microscopic findings. Perhaps the largest area of advancement in EES over the past three decades has been in the field of molecular and cytogenetics. Along with Ewing's sarcoma of bone, primitive neuroectodermal tumor, peripheral neuroepithelioma, and Askin's tumor, EES belongs to the newly recognized Ewing's family of tumors (EFTs). What makes these tumors a common group is the almost universal presence of common genetic translocations involving chromosome 22. This gives credence to the idea that they all share a common cell of origin. Although agreement for what cell that may be is still not universal, most believe it is a mesenchymal cell that is reprogrammed to a neuroectodermal phenotype.^2-4 In addition to these laboratory investigations, observations of primary human rhabdomyosarcomas that harbor an EWS-FLI1 translocation and show a mixed myogenic and neuroectodermal phenotype supports this contention as well.⁵

Pathologic diagnosis of EES used to require standard light and electron microscopy, looking for small, round, blue cells with abundant glycogen and absent cytoplasmic filaments.⁶ Because of the lack of any specific morphologic features, the misdiagnosis rate was exceptionally high, for lack of a diagnostic histopathology. Now, with the advent of sophisticated staining and genomic techniques, we are able to confidently identify EES and all members of the EFTs that display the same immunohistochemical and molecular features. Although not as specific as it is sensitive for EES, immunohistochemical staining for CD99 (MIC2), a cell surface glycoprotein, can help aid in the diagnosis.^7,8 The recognition in 1992 by Zucman et al⁹ of a tumor-specific chimeric gene, resulting from the previously known common cytogenetics translocations, ushered in a new era of highly specific molecular diagnostics. The most common chromosomal translocation found in approximately 85% of EFTs, is a t(11;22)(q24;q12), which forms EWSR1-FLI1, a fusion transcription factor.^4,10 Many other translocations have been reported, virtually all involving the EWS gene on chromosome 22 and all resulting in the formation of an expressed fusion transcription factor. EWS is a normal protein transcription factor found in cells, whose function and downstream targets have yet to be fully elucidated. It is known, however, that EWS is an RNA binding protein that may facilitate interaction with RNA or single-stranded DNA.¹¹ The FLI1 gene, the most common gene to be fused with EWS, is a member of the ets family of developmentally regulated genes and encodes for a DNA binding transcription factor implicated in cellular proliferation, development, response to growth stimuli, and tumorigenesis.^12,13 It has also been shown in vitro that EWS-FLI1 is a potent inhibitor of apoptosis, a factor that can lead to unbalanced tumor growth.¹⁴ Finally, telomerase activity is upregulated by EWS fusion transcription factors in vitro, which helps promote cell immortality.¹⁵ Despite some ambiguity as to its exact role in the malignant character of EFT, the uniform presence of an EWS-ets chimeric gene in virtually all cases of EFTs has led to the development of two highly specific and reliable molecular diagnostics for the presence of the chimeric EWS gene, using either polymerase chain reaction (targeting EWS 5' and the common ets domain found in all ets family genes 3') or fluorescent in situ hybridization using an EWS-specific split-apart probe that flanks the common EWS translocations.¹⁶

As with any other site of cancer, to reliably test new treatments for diseases, large numbers of patients must be studied on randomized controlled clinical trials. Obviously, this poses a significant problem in trying to improve treatments for diseases that are uncommon; EES is no exception. Most of the reported literature regarding EES stems from single-institution retrospective case reviews. The only prospective, randomized data that are available for treatment of EES stems from the Intergroup Rhabdomyosarcoma Studies (IRS).

In fact, the largest collection of patients studied to date with EES are from the IRS I, II, and III trials. Five percent of the nearly 3,000 patients on these three landmark trials (total of 130) had EES.¹⁷ Eighty-eight percent of patients with EES presented with localized disease, which is somewhat lower than that typically seen with primary Ewing's sarcoma of bone. All of the 114 patients with nonmetastatic EES received chemotherapy and some type of surgery, and most received radiation therapy—none received radiation as the sole modality for local control. Eighty-two percent achieved a complete response to treatment, and 10-year overall survival was 62%, 61%, and 77% for the patients in the IRS I, II, and III trials, respectively. On subset analysis, the authors concluded that patients with localized, gross residual EES did not achieve an overall survival benefit when doxorubicin was added—this is in contradistinction to the IESS 1 and 2 trials, which did show a benefit for doxorubicin.

It is difficult to say for certain whether we should be using the same therapeutic approach as with classic Ewing's sarcoma of bone. In light of the fact that it has been shown that they have a common genetic basis, it has been felt that they should get the same treatment. A group from St Jude's specifically looked at this question and confirmed that patients with EES fare well with the same treatment as with Ewing's, including alternating chemotherapy with ifosfamide and etoposide, as per the recommendation of IESS 3.¹⁸

It is widely recognized that EES and EFTs are, indeed, systemic diseases at presentation, even if documented metastases are not found. As such, chemotherapy has typically been the first treatment offered, but local control remains imperative. So, as was the case decades ago, EES cases are treated with combined-modality treatment, with chemotherapy, surgery, and/or radiation therapy. However, the question of optimal local control has not been definitively answered, because there have never been trials comparing radiotherapy with surgery. Currently, most protocols recommend surgical resection rather than radiation therapy if possible, using postoperative radiation for positive margins or residual disease. Some valid reasons arguing for the omission of radiotherapy include the avoidance of radiation-induced second malignancies (although chemotherapy-related leukemias/myelodysplastic syndromes occur commonly) and growth deformities. In addition, proponents of surgery without radiation therapy cite the ability to pathologically evaluate response to therapy and to potentially change systemic treatment if response is less than adequate. In some cases, surgery cannot be performed, and radiation therapy is used as the modality for local control. Examples of this include EESs located in the pelvis, shoulder region, and head and neck. The use of prophylactic lung irradiation has fallen somewhat out of favor, but in some patients who present with pulmonary metastases not amenable to surgical resection, radiation to these metastases can still provide a chance of cure.

Other new fronts in the treatment of EES have been borrowed from the developing radiation literature for lymphomas—the so-called less is more mentality. Whereas doses on the order of 45 to 55.8 Gy have traditionally been used in the past, groups at St Jude's and Memorial Sloan-Kettering have advocated using 30 to 36 Gy, with surprisingly high control rates. Proton therapy is also now approved by the Children's Oncology Group protocols to limit the dose to normal tissues and subsequent side effects, including induction of second malignancies.

With the aid of sophisticated imaging techniques, we are now better able to localize these lesions. In older trials, routine roentogram studies were the most sophisticated imaging modality available. Later, with the development of computed tomography scanning, more accurate staging of EES became possible, because the former is particularly sensitive to evaluate the chest for pulmonary metastases. The introduction of magnetic resonance imaging has substantially sharpened our diagnostic acumen, particularly with respect to characterizing soft tissue versus bony involvement. As is the trend for many other malignancies, positron emission tomography scanning may be incorporated into our staging and radiation therapy planning armamentarium in the future for EESs.

Although our knowledge of underlying genetic abnormalities of EES and EFTs has increased tremendously, we still have not successfully made the transition from the laboratory to the clinic with respect to targeted therapy approaches. Ultimately, the goal is to have the treatment of EES and EFTs mirror that of other malignancies such as chronic myeloid leukemia, in which discovery of a common translocation has led to a therapeutic target [t(9;22) with formation of bcr-abl and imatinib mesylate as therapy]. Another potential therapeutic approach would be to target the chimeric gene itself, which has been demonstrated in an animal model but is far from the clinic at this point.¹⁹ Current clinical trials are testing various new therapies that may interact with downstream elements that EWSR1 may help regulate. One example of this is a phase II trial at the National Cancer Institute, currently accruing patients, in which CP-751,871, a human monoclonal antibody directed toward the insulin-like growth factor type 1 receptor, is being tested in patients with EFTs. Immunoglobulin F is a known antiapoptotic molecule, and could, perhaps, be regulated at the transcriptional level by fusion transcription factors found in EES and EFTs. As time passes, and new targets of EWS-fusion transcription factors are found, as is a common theme with many other malignancies, molecular targeted therapy will increasingly become important.

In summary, a lot of progress has been made in the field of EESs in the past 25 years, but there is still a long way to go—hopefully some time soon, we will be analyzing molecular targeted therapies in randomized, controlled clinical trials.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Timothy J. Kinsella

Financial support: Timothy J. Kinsella

Administrative support: Timothy J. Kinsella

Provision of study materials or patients: Timothy J. Triche, Timothy J. Kinsella

Collection and assembly of data: Timothy M. Zagar, Timothy J. Kinsella

Data analysis and interpretation: Timothy M. Zagar, Timothy J. Triche, Timothy J. Kinsella

Manuscript writing: Timothy M. Zagar, Timothy J. Kinsella

Final approval of manuscript: Timothy J. Kinsella

REFERENCES

1. Kinsella TJ, Triche TJ, Dickman PS, et al: Extraskeletal Ewing's sarcoma: Results of combined modality treatment. J Clin Oncol 1:489-495, 1983[Abstract]

2. Hu-Lieskovan S, Zhang J, Wu L, et al: EWS-FLI1 fusion protein up-regulates critical genes in neural crest development and is responsible for the observed phenotype of Ewing's family of tumors. Cancer Res 65:4633-4644, 2005[Abstract/Free Full Text]

3. Lessnick SL, Dacwag CS, Golub TR: The Ewing's sarcoma oncoprotein EWS/FLI induces a p53-dependent growth arrest in primary human fibroblasts. Cancer Cell 1:393-401, 2002[CrossRef][Medline]

4. Delattre O, Zucman J, Melot T, et al: The Ewing family of tumors: A subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 331:294-299, 1994[Abstract/Free Full Text]

5. Sorensen PH, Shimada H, Liu XF, et al: Biphenotypic sarcomas with myogenic and neural differentiation express the Ewing's sarcoma EWS/FLI1 fusion gene. Cancer Res 55:1385-1392, 1995[Abstract/Free Full Text]

6. Triche TJ, Askin FB: Neuroblastoma and the differential diagnosis of small-, round-, blue-cell tumors. Hum Pathol 14:569-595, 1983[Medline]

7. Fellinger EJ, Garin-Chesa P, Triche TJ, et al: Immunohistochemical analysis of Ewing's sarcoma cell surface antigen p30/32MIC2. Am J Pathol 139:317-325, 1991[Abstract]

8. 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. Am J Surg Pathol 18:486-494, 1994[Medline]

9. Zucman J, Delattre O, Desmaze C, et al: Cloning and characterization of the Ewing's sarcoma and peripheral neuroepithelioma t(11;22) translocation breakpoints. Genes Chromosomes Cancer 5:271-277, 1992[Medline]

10. Helman LJ, Meltzer P: Mechanisms of sarcoma development. Nature Reviews: Cancer 3:685-694, 2003

11. Ohno T, Ouchida M, Lee L, et al: The EWS gene, involved in Ewing Family of tumors, malignant melanoma of soft parts and desmoplastic small round cell tumors, codes for an RNA binding protein with novel regulatory domains. Oncogene 9:3087-3097, 1994[Medline]

12. May WA, Gishizky ML, Lessnick SL, et al: Ewing sarcoma 11;22 translocation produces a chimeric transcription factor that requires the DNA-binding domain encoded by FLI1 for transformation. Proc Natl Acad Sci U S A 90:5752-5756, 1993[Abstract/Free Full Text]

13. Hromas R, Klemsz M: The ETS oncogene family in development, proliferation and neoplasia. Int J Hematol 59:257-265, 1994[Medline]

14. Yi H, Fujimura Y, Ouchida M, et al: Inhibition of apoptosis by normal and aberrant Fli-1 and erg proteins involved in human solid tumors and leukemias. Oncogene 14:1259-1268, 1997[CrossRef][Medline]

15. Takahashi A, Higashino F, Aoyagi M, et al: EWS/EWT fusions activate telomerase in Ewing's tumors. Cancer Res 63:8338-8344, 2003[Abstract/Free Full Text]

16. Monforte-Muñoz H, Lopez-Terrada D, Affendie H, et al: Documentation of EWS gene rearrangements by fluorescence in-situ hybridization (FISH) in frozen sections of Ewing's sarcoma-peripheral primitive neuroectodermal tumor. Am J Surg Pathol 23:309-315, 1999[CrossRef][Medline]

17. Raney RB, Asmar L, Newton WA Jr, et al: Ewing's sarcoma of soft tissues in childhood: A report from the Intergroup Rhabdomyosarcoma Study, 1972-1991. J Clin Oncol 15:574-582, 1997[Abstract/Free Full Text]

18. Gururangan S, Marina NM, Luo X, et al: Treatment of children with peripheral primitive neuroectodermal tumor or extraosseous Ewing's tumor with Ewing's-directed therapy. J Pediatr Hematol Oncol 20:55-61, 1998[CrossRef][Medline]

19. Hu-Lieskovan S, Heidel JD, Bartlett DW, et al: Sequence-specific knockdown of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing's sarcoma. Cancer Res 65:8984-8992, 2005[Abstract/Free Full Text]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This Article Full Text (PDF) From JCO 1983 Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zagar, T. M. Articles by Kinsella, T. J. Search for Related Content PubMed PubMed Citation Articles by Zagar, T. M. Articles by Kinsella, T. J. Social Bookmarking                            What's this?