 |
|
|
|
|
|
|
|
|
|
 |
 |
 |
 |
 |
 |
 |
 |
|
Background
Ewing's sarcoma is a sarcoma of the bone classically described under small round blue cell tumors (SRBCT). There is considerable clinical and histologic overlap between this tumor and the primitive neuroectodermal tumor (PNET). For many years, pathologists struggled to make a diagnostic distinction. Now with sophisticated molecular biological analysis, it turns out that both tumors share a common and unique chromosomal translocation. Most investigators now believe that Ewing's sarcoma and PNET are different morphological expressions of one tumor type. In general, Ewing's sarcoma arises within the bone while PNET arises within soft tissues. However, there are overlap cases of Ewing's sarcoma arising within soft tissue (Extraosseous Ewing's Sarcoma) and PNET arising within the bone. Under the microscope, the tumors share a considerable homology though there are usually more neuroendocrine features with PNET. Ewing's sarcoma is thought to be a more undifferentiated tumor. Though data is conflicting, some investigators believe ES to have a slightly better prognosis.
These bone tumors usuallypresent with localized pain and a mass, present for several months. There may be generalized symptoms such as fever, anemia, and malaise, and these findings are more common in patients with disseminated disease.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION AGE RANGE-MEDIAN Median age of 13 years
80% occur within first 2 decades of lifeMales favored Uncommon in blacks
LABORATORY/
RADIOLOGIC/
OTHER TESTSCHARACTERIZATION Radiographs Onionskin or sunburst periosteal reaction and an extraosseous component
Pathologic fractures are uncommon occurring in about 5% of cases
Serum LDH May be helpful to predict recurrence, especially multifocal recurrence with 80% sensitivity FISH
- Molecular diagnosis of Ewing sarcoma/primitive neuroectodermal tumor in routinely processed tissue: a comparison of two FISH strategies and RT-PCR in malignant round cell tumors.
Bridge RS, Rajaram V, Dehner LP, Pfeifer JD, Perry A.
1Department of Pathology and Immunology, Lauren V Ackerman Laboratory of Surgical Pathology, Barnes-Jewish and St Louis Children's Hospitals, Washington University Medical Center, St Louis, MO, USA.
Mod Pathol. 2006 Jan;19(1):1-8. Abstract quote
Ewing sarcoma/primitive neuroectodermal tumor (EWS/PNET) is a diagnostically challenging malignant round cell tumor with signature translocations involving the EWS gene. These translocations are detectable with both reverse transcriptase-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) in formalin-fixed paraffin-embedded tissue. However, RT-PCR is less sensitive in formalin-fixed paraffin-embedded than frozen tissue. Similarly, commercial FISH probes have recently become available, but have yet to be rigorously tested in the clinical setting.
Therefore, we have compared RT-PCR with FISH using 'home brew' fusion probes for Ewing sarcoma (EWS)-FLI1 and a commercial EWS break apart probe set in 67 archival round cell tumors, including 27 EWS/PNETs. Sensitivities and specificities for both FISH assays were 91 and 100%, respectively, whereas RT-PCR had a sensitivity of 54% and a specificity of 85%. The break apart strategy was easier to interpret than probe fusion approach.
We conclude that FISH is a more sensitive and reliable ancillary technique than RT-PCR for the diagnosis of EWS/PNET in formalin-fixed paraffin-embedded tissue, although the latter provides additional information regarding fusion transcript subtype and prognosis. The commercial break apart probe set is both readily available and easy to interpret, making it particularly attractive. Nonetheless, complex round cell tumors often benefit from molecular testing with multiple methods.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION General 10% present with multiple bone involvement, usually representing metastasis
70% present with disseminated disease
- Ewing sarcoma family of tumors.
Khoury JD.
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Adv Anat Pathol. 2005 Jul;12(4):212-20. Abstract quote
The Ewing sarcoma family of tumors (ESFT) comprises morphologically heterogeneous tumors that are characterized by nonrandom chromosomal translocations involving the EWS gene and one of several members of the ETS family of transcription factors. The translocation t(11;22)(q24;q12) is the most common and leads to the formation of the EWS-FLI1 fusion protein, which contributes to ESFT pathogenesis by modulating the expression of target genes.
Tumors may be composed of small uniform cells with minimal morphologic evidence of differentiation, or they may be composed of larger, less uniform cells with varying degrees of neuroectodermal differentiation. CD99 expression is identified in nearly all ESFT and constitutes a useful positive marker when used as part of a panel of immunostains that can help rule out other differential diagnostic considerations. Molecular diagnostic tests commonly used to detect the presence of ESFT-specific translocations include RT-PCR and fluorescence in situ hybridization.
Current therapy for patients with ESFT includes chemotherapy and surgery with or without radiation therapy. At present, the most significant prognostic factor for patients with ESFT is whether the disease is localized or metastatic.Sites Femur most common site with predilection for long tubular bones
Classically diaphyseal but may be metaphyseal
Rarely epiphysealFlat bone sites include the pelvis and ribs
Appearance Firm gray white intraosseous tumor with a softer more friable extraosseous component DURA Primary Peripheral PNET/Ewing's Sarcoma of the Dura: a Clinicopathologic Entity Distinct from Central PNET.
Dedeurwaerdere F, Giannini C, Sciot R, Rubin BP, Perilongo G, Borghi L, Ballotta ML, Cornips E, Demunter A, Maes B, Dei Tos AP.
Department of Pathology (FD, RS, AD, BM), Katholieke Universiteit Leuven, Leuven, Belgium.
Mod Pathol 2002 Jun;15(6):673-8 Abstract quote We describe two cases of peripheral primitive neuroectodermal tumor-Ewing's sarcoma (PNET-ES) arising intracranially in the leptomeninges. Both tumors exhibited a primitive undifferentiated round-cell morphology.
Immunohistochemical stains revealed strong membrane expression of CD99 in both cases. A t(11;22)(q24;q12) could be demonstrated with reverse transcriptase-polymerase chain reaction in one case, whereas fluorescence in situ hybridization analysis performed in the second case showed a rearrangement of the EWS gene.
The occurrence of PNET-ES at this site is very unusual. Immunophenotypical as well as genetic analysis play a key role in the diagnosis and the distinction from central PNET.
ESOPHAGUS Esophageal extraskeletal Ewing's sarcoma
Chihaya Maesawa, MD
Sin Iijima, MD
Nobuhiro Sato, MD
Noda Yoshinori, MD, etalHum Pathol 2002;33:130-132. Abstract quote
Extraskeletal Ewing's sarcoma is a rare tumor. The most common sites of occurrence are on the trunk, extremities, and retroperitoneum. This type of tumor is well characterized by recurrent chromosomal translocation such as t (11;22) (q24;q12) (EWSR1/FLI1) or t (21;22) (q22;q12) (EWSR1/ERG) and overexpression of MIC2/CD99 on tumor cell membrane.
We describe the first reported case of an esophageal extraskeletal Ewing's sarcoma with confirmation from immunohistochemical and molecular diagnoses. A 56-year-old man developed a polypoid tumor located in the lower part of the esophagus. The tumor was composed of small-sized round cells showing prominent fibrillar cytoplasmic processes. Intracytoplasmic glycogen was detected in all the tumor cells. Immunoreactivity for MIC2/CD99 was positive on the membrane of all tumor cells. A reverse transcriptase-polymerase chain reaction followed by sequencing revealed an EWSR1/ERG chimeric transcript, which combined EWSR1 exon 10 with ERG exon 6.
The present report added a new entity of esophageal small round cell tumor.
SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION PAS with diastase Glycogen present in 75% of cases IMMUNOPEROXIDASE
Intercellular junctions in Ewing sarcoma/primitive neuroectodermal tumor: additional evidence of epithelial differentiation.
Schuetz AN, Rubin BP, Goldblum JR, Shehata B, Weiss SW, Liu W, Wick MR, Folpe AL.
1Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
Mod Pathol. 2005 Nov;18(11):1403-10 Abstract quote.
Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) has recently been shown to frequently express cytokeratins, suggesting partial epithelial differentiation. Older ultrastructural studies have documented primitive cell-cell junctions in ES/PNET, reportedly resembling poorly formed desmosomes. Recently, paraffin-reactive antibodies have become available to proteins found in a variety of intercellular junctions indicative of epithelial differentiation, including tight junctions, desmosomes and adherens junctions.
We examined intercellular junction protein expression in a large number of genetically confirmed ES/PNET. Formalin-fixed, paraffin-embedded sections from 23 primary and seven recurrent or metastatic cases of genetically confirmed ES/PNET were immunostained for claudin-1 and occludin (tight junction structural proteins), zonula occludens-1 (ZO-1, tight junction linker protein), desmoglein 1/2 (desmosomal adherens protein), desmoplakin (desmosomal structural protein) and E-cadherin (epithelial adherens junction protein), using steam heat-induced epitope retrieval and the Dako Envision system. Cases with >5% positive cells were scored as 'positive'. Normal colonic epithelium and skin served as external positive controls. Claudin-1 was expressed by 19 of 30 specimens (63%), ZO-1 was expressed by 15 of 29 specimens (51%), and occludin was expressed by three of 28 specimens (11%). In 28 specimens all three tight junction markers were evaluable. In all, 15 samples (54%) expressed only one tight junction marker, and 10 samples (36%) expressed two tight junction markers. No case expressed all three tight junction markers. Desmoglein was expressed in one of 30 (3%) samples. Desmoplakin was expressed in two of 28 (7%) samples. E-cadherin was negative in all cases.
Our data suggest that many of the previously described cell-cell junctions in ES/PNET are poorly formed tight junctions, given the high frequency of claudin-1 and ZO-1 expression. This may underestimate the true frequency of tight junction protein expression in ES/PNET, as there are at least 20 different claudins and other ZO proteins. These tight junctions are almost certainly abnormal, given the absence of occludin expression in most cases. Desmosomal and adherens junction protein expression was rare to absent.
Our findings provide additional evidence that ES/PNET frequently show partial epithelial differentiation.
- Morphologic and Immunophenotypic Diversity in Ewing Family Tumors: A Study of 66 Genetically Confirmed Cases.
Folpe AL, Goldblum JR, Rubin BP, Shehata BM, Liu W, Dei Tos AP, Weiss SW.
From the *Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA; daggerDepartment of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH; double daggerDepartment of Pathology, University of Washington Medical Center, Seattle, WA; and section signDepartment of Pathology, Regional Hospital, Treviso, Italy.
Am J Surg Pathol. 2005 Aug;29(8):1025-1033. Abstract quote
More than 85% of Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET), or "Ewing family of tumors" (EFTs), have the translocation, t (11;22) (q24;q12), with others having variant translocations. Identification of these by cytogenetic and/or molecular genetic techniques is specific for EFT and is increasingly recognized as the "gold standard" for diagnosis. However, these techniques are not universally available.
We therefore studied a large group of genetically confirmed EFTs to more completely understand the morphologic and immunophenotypic spectrum of this rare sarcoma. Sixty-six cytogenetically, FISH or RT-PCR proven-EFTs were retrieved. In 56 cases, immunohistochemistry (IHC) was performed for pan-cytokeratins (PanCK), high molecular weight cytokeratins (HMWCK), desmin (DES), CD99, CD117, and FLI1 protein using heat-induced epitope retrieval and the Dako Envision system.
The cases arose chiefly in children and young adults (median 18 years; range, 3-65 years) of both sexes (male, 32; female, 31; unknown, 3) in a variety of bone (N = 39) and soft tissue (N = 27) sites. Histologically, 46 cases (73%) showed only typical features of ES, 9 cases (16%) showed features of PNET, 3 cases (5%) showed "adamantinoma-like" features, 3 cases (5%) corresponded to "atypical Ewing sarcoma," 3 cases (5%) showed principally intersecting fascicles of spindled cells, and 2 cases had abundant hyalinized matrix. IHC results were as follows: PanCK (18 of 56, 32%), HMWCK (3 of 55, 5%), DES (1 of 56, 2%), CD99 (52 of 52, 100%), CD117 (13 of 54, 24%), and FLI1 (44 of 47, 94%). HMWCK was expressed only in "adamantinoma-like" EFTs, none of which expressed DES.
In conclusion, most, but not all, EFTs can be accurately diagnosed using time-honored morphologic criteria and ancillary immunohistochemistry. However, genetic confirmation remains essential for the diagnosis of unusual morphologic variants of EFT, including "adamantinoma-like," spindled, sclerosing, and clear cell/anaplastic variants. Therefore, to exclude or confirm the diagnosis of Ewing's sarcoma in round cell sarcomas having a variety of patterns but not specifically conforming to a tumor of known lineage (eg, rhabdomyosarcoma), cytogenetics, and/or molecular analysis is required.FLI-1 Am J Surg Pathol 2000;24:1657-1662
FLI-1 protein is overepxressed as a result of the translocationSome cases of PNET are negative in spite of CD99 positivity
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES CHONDROSARCOMA, MESENCHYMAL LYMPHOMA Differentiating Lymphoblastic Lymphoma and Ewing’s Sarcoma: Lymphocyte Markers and Gene Rearrangement
Metin Ozdemirli, M.D, Ph.D., Julie C. Fanburg-Smith, M.D., Dan-Paul Hartmann, Ph.D., Norio Azumi, M.D., Ph.D. and Markku Miettinen, M.D.
Department of Pathology (MO, DH, NA), Georgetown University Medical Center, Washington, D.C.; and Department of Soft Tissue Pathology (JCF-S, MM), Armed Forces Institute of Pathology, Washington, D.C
Mod Pathol 2001;14:1175-1182 Abstract quote
We encountered a child with an intraosseous small round cell tumor that was negative for LCA, CD20 (L26), and CD3 and positive for vimentin, CD99 (MIC-2), and periodic acid-Schiff. The tumor exhibited rosette-like formations.
This case was initially interpreted as Ewing’s sarcoma (ES); however, additional studies revealed positivity for CD79a, CD43, and TdT expression, and an immunoglobulin heavy chain gene rearrangement (IgH-R) by polymerase chain reaction (PCR) established this to be a precursor B-lymphoblastic lymphoma.
Because the differential diagnosis of ES and lymphoblastic lymphoma can be difficult and the differential diagnostic value of leukocyte antigens and immunoglobulin heavy chain gene rearrangement studies have not been fully evaluated, we conducted a more extensive investigation on 33 (21 soft tissue and 12 intraosseous) ES cases.
NEUROBLASTOMA OSTEOSARCOMA, SMALL CELL PNET SMALL ROUND BLUE CELL TUMOR
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS Usually determined by the outcome of the metastatic disease rather than the local control of the tumor <10 years of age
Distal extremity
Tumor volume<100 ml
Chemotherapy response prior to resection, <10% viable tumorPelvis
Tumor >8 cm
Elevated wbc and sedimentation rate
Microscopic filigree pattern
Chemotherapy response prior to resection, >10% viable tumorp53 and Ki67 Expression of p53 gene product and cell proliferation marker Ki-67 in Ewing's sarcoma: Correlation with clinical outcome.
Amir G, Issakov J, Meller I, Sucher E, Peyser A, Cohen IJ, Yaniv I, Ben Arush MW, Tavori U, Kollender Y, Ron N, Peylan-Ramu N.
Departments of Pathology, Orthopedic Surgery, and Oncology, Hadassah Medical Center and Hebrew University-Hadassah Medical School, Jerusalem, Israel; Unit of Bone and Soft Tissue Pathology and National Unit of Orthopedic Oncology, Sourasky Medical Center and Departments of Pediatric Hematology/Oncology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Rambam Medical Center, Technion Faculty of Medicine, Haifa, Israel; and Chaim Sheba Medical Center, Tel Hashomer, Israel.
Hum Pathol 2002 Feb;33(2):170-174 Abstract quote Overexpression of tumor suppressor gene p53, cell proliferation nuclear antigen Ki-67, and proto-oncogene HER-2/neu are associated with poor prognosis in some tumors.
We studied p53, Ki-67, and HER-2/neu immunohistochemical expression in archival biopsies of 37 patients with Ewing's sarcoma (ES). Patients with ES were treated at four Israeli hospitals between 1982 and 2000. Formalin-fixed paraffin-embedded tissue sections were stained by immunohistochemistry for p53, Ki-67, and HER-2/neu. More than 300 cells were counted on each slide, and the percentage of positively stained nuclei was computed. p53 overexpression was defined as nuclear staining of >2.3% of cells, Ki-67 overexpression as nuclear staining of >8.3% malignant cells. HER-2/neu staining was scored semiquantitatively on a scale of 0 to 4+. Twenty-two of 37 patients are alive and well, with mean follow-up time of 38 months. There was overexpression of p53 in 16 patients (43%) and of Ki-67 in 21 patients (57%). The correlation between p53 and Ki-67 overexpressions was 0.61.
We found no overexpression of HER-2/neu. Median relapse-free survival (RFS) was statistically significantly shorter for patients with p53 overexpression (25 months) than for patients with negative staining (>92 months). The prognostic value of p53 overexpression was also significant after adjusting for tumor location and age. Median RFS was shorter for patients with positive Ki-67 staining (40 months) than for patients with negative staining (80 months) but did not reach statistical significance.
Our study suggests that p53 is a predictor of RFS in patients with ES. More patients must be studied to assess the validity of this observation.
Survival 5 year survival with combination of surgery and chemotherapy is 74%
European Cooperative Trial utilizing a 4 drug chemotherapy prior to local control with either surgery or radiation resulted in overall disease free survival of 60% at 36 months and 55% at 69 months
Patients with metastatic disease have 5 year survival of 30%
If mets confined to lungs and these tumors are successfully resected, significantly improved survivalTREATMENT Preoperative chemotherapy followed by surgical resection
- Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study.
Miser JS, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Grier HE.
City of Hope National Medical Center, 1500 E Duarte Road, Duarte, CA 91010, USA.
J Clin Oncol. 2004 Jul 15;22(14):2873-6. Abstract quote
PURPOSE: One hundred twenty patients with metastatic Ewing's sarcoma or primitive neuroectodermal tumor (PNET) of bone were entered onto a randomized trial evaluating whether the addition of ifosfamide and etoposide to vincristine, doxorubicin, cyclophosphamide, and dactinomycin improved outcomes.
METHODS: Thirty-two patients had metastases to lungs only, 12 patients had metastases to bone marrow or bones only, 64 patients had metastases in multiple sites, and five patients had metastases in other sites; seven patients could not be assessed precisely. Treatment comprised 9 weeks of chemotherapy before local control and 42 weeks of chemotherapy; thereafter, regimen A consisted of vincristine 2 mg/m(2), cyclophosphamide 1,200 mg/m(2), and either doxorubicin 75 mg/m(2) or dactinomycin 1.25 mg/m(2). Regimen B consisted of regimen A alternating every 3 weeks with ifosfamide 1,800 mg/m(2)/d for 5 days and etoposide 100 mg/m(2)/d for 5 days.
RESULTS: Patients treated on regimen B did not have significantly better survival than those treated on regimen A. The event-free survival (EFS) and survival (S) at 8 years were 20% (SE, 5%) and 32% (SE, 6%), respectively, for those treated on regimen A and 20% (SE, 6%) and 29% (SE, 6%), respectively, for those treated on regimen B. Patients who had only lung metastases had EFS and S of 32% (SE, 8%) and 41% (SE, 9%), respectively, at 8 years. There were six toxic deaths (5%), four from cardiac toxicity and two from sepsis (four treated on regimen B and two treated on regimen A). Two had second malignant neoplasms.
CONCLUSION: Adding ifosfamide and etoposide to standard therapy does not improve outcomes of patients with Ewing's sarcoma or PNET of bone with metastases at diagnosis.A Midkine Promoter-based Conditionally Replicative Adenovirus for Treatment of Pediatric Solid Tumors and Bone Marrow Tumor Purging.
Adachi Y, Reynolds PN, Yamamoto M, Wang M, Takayama K, Matsubara S, Muramatsu T, Curiel DT.
The Division of Human Gene Therapy, Departments of Medicine, Surgery, and Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294 [Y. A., P. N. R., M. Y., W. M., K. T., D. T. C.].
Cancer Res 2001 Nov 1;61(21):7882-8 Abstract quote
The treatment of advanced neuroblastoma (NB) or Ewing's sarcoma (ES) is one of the major challenges in pediatric oncology. Both malignancies are refractory to conventional therapies and have an extremely poor prognosis. High-dose myeloablative radiochemotherapy with autologous bone marrow or peripheral blood stem cell rescue is one of the most aggressive treatments attempted for these diseases but is often undermined by residual tumor cells contaminating the graft. Thus, in this approach, purging of tumor cells from the graft is key to the prevention of relapse after transplantation.
We investigated a novel approach to eliminate tumor cells from the bone marrow or peripheral blood stem cell graft without causing stem cell damage through the use of a conditionally replicative adenovirus (Ad).
ES and NB are sensitive to Ad infection, and advanced NBs express a high level of the growth/differentiation factor midkine (MK). We confirmed in this study that ES cell lines (SK-ES-1 and RD-ES) are also sensitive to Ad infection and express high levels of MK. In contrast, CD34(+) stem cells are refractory to Ad infection and express very little MK. A conditionally replicative Ad in which the expression of E1 is controlled by the MK promoter achieved good levels of viral replication in NB or ES and induced remarkable tumor cell killing. On the other hand, this virus caused no damage to CD34(+) cells even after 3 h of infection at a dose of 1000 multiplicity of infection.
We concluded that application of this replication-competent Ad to hematopoietic grafts could be a simple but effective procedure to achieve complete tumor cell purging.
Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
Primitive neuroectodermal tumor (PNET)
Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation
Commonly Used Terms
This is a glossary of terms often found in a pathology report.Diagnostic Process
Learn how a pathologist makes a diagnosis using a microscopeSurgical Pathology Report
Examine an actual biopsy report to understand what each section meansSpecial Stains
Understand the tools the pathologist utilizes to aid in the diagnosisHow Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurate
Got Path?
Recent teaching cases and lectures presented in conferences
Pathologists Who Make A Difference
Search for a Physician Specialist
Last Updated January 5, 2006
Send mail to The Doctor's Doctor with questions or comments about this web site.
Read the Medical Disclaimer.
Copyright © The Doctor's Doctor