This is a descriptive category describing a large number of malignant tumors that tend to occur in childhood. They are united by having a similar histologic appearance, that is, small round blue cells. Subtle clues may be present to distinguish between the tumors. The pathologist is assisted by immunohistochemistry, electron microscopy, and molecular analysis for chromosomal abnormalities. A list of the most common tumors placed in this category is found below.
Desmoplastic small round blue cell tumor
Mesothelioma, small cell
Primitive neuroectodermal tumor
Clinical Variants Special Stains/
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CLINICAL VARIANTS CHARACTERIZATION BONE
- Small round cell tumors of bone.
Surgical Pathology, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA.
- Arch Pathol Lab Med. 2007 Feb;131(2):192-204. Abstract quote
CONTEXT: Primary small round cell tumors of the bone are a heterogeneous group of malignant neoplasms presenting predominantly in children and adolescents. They include Ewing sarcoma/peripheral neuroectodermal tumor or Ewing family tumors, lymphoma, mesenchymal chondrosarcoma, and small cell osteosarcoma. Even though they share many morphological similarities, their unique biological and genetic characteristics have provided substantial insights into the pathology of these diverse neoplasms.
OBJECTIVE: To provide an overview of the clinical, radiologic, pathologic, and genetic characteristics of these tumors along with a pertinent review of the literature.
DATA SOURCES: A literature search using PubMed and Ovid MEDLINE was performed, and data were obtained from various articles pertaining to clinicopathologic, biological, and genetic findings in these tumors. Additionally, findings from rare cases have been included from author's subspecialty experience.
CONCLUSION: The diagnosis of small round cell tumors can be made accurately by applying clinicopathologic criteria, as well as a panel of immunohistochemical and genetic studies in appropriate cases. Molecular genetic studies may provide further insight into the biology, histogenesis, and prognosis of these tumors.
- Association of the t(12;22)(q13;q12) EWS/ATF1 Rearrangement With Polyphenotypic Round Cell Sarcoma of Bone: A Case Report.
Somers GR, Viero S, Nathan PC, Teshima I, Pereira C, Zielenska M.
From the Departments of *Paediatric Laboratory Medicine and daggerPaediatrics, Hospital for Sick Children, Toronto, Ontario, Canada; and double daggerDepartment of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Am J Surg Pathol. 2005 Dec;29(12):1673-1679. Abstract quote
The t(12;22)(q13;q12) chromosomal rearrangement results in an EWS/ATF1 fusion transcript and is associated with clear cell sarcoma (CCS). CCS is an uncommon tumor arising in tendons and aponeuroses of the extremities and shows evidence of melanocytic differentiation at the light microscopic, immunohistochemical, and/or ultrastructural level. Only 5 cases have been reported to arise in bone, none of which had molecular confirmation of the diagnosis.
The current report describes a 7-year-old girl with a primary round cell sarcoma of the left humerus showing polyphenotypic differentiation on immunohistochemical analysis. Antibodies directed at melanocytic antigens were negative, and there was no evidence of melanocytic differentiation by light microscopy or ultrastructural analysis.
Cytogenetic analysis revealed rearrangement of the EWS locus within 22q12. RT-PCR and sequence analysis revealed the presence of a fusion transcript bringing together exon 7 of EWS with exon 5 of ATF1, consistent with a type 2 transcript reported in association with CCS. However, given the lack of morphologic features usually present in CCS, a diagnosis of polyphenotypic round cell sarcoma was made.
This tumor thus expands the spectrum of neoplasms associated with the t(12;22)(q13;q12) rearrangement.
IMMUNOPEROXIDASE KEY DIFFERENTIATING FEATURES CD56
CD56 positive small round cell tumors. Differential diagnosis of hematological, neurogenic, and myogenic neoplasms.
Liu Q, Ohshima K, Sumie A, Suzushima H, Iwasaki H, Kikuchi M.
Department of Pathology, School of Medicine, Fukuoka University, Nanakuma 7-45-1, Jonanku, Fukuoka 814-01, Japan.
Virchows Arch 2001 Mar;438(3):271-9 Abstract quote
CD56-positive nasal and nasal-type natural killer (NK)/T-cell lymphoma is now a well-defined disease entity. Rare cases of blastic NK-cell lymphoma positive for CD56 have been recently reported. However, CD56 expression is also identified in several types of non-hematopoietic small round cell tumors in which lymphoma is included as a differential consideration.
Here, we present nine cases of CD56+ small round cell tumors of histological origin unrelated to nasal NK/T-cell lymphoma. Eight of the nine cases presented as solid tumors of the sinonasal region. Clinical, histological, ultrastructural, and immunohistochemical examination and gene analysis for T-cell receptor (TcR) and immunoglobulin heavy chain (IgH) genes and in situ hybridization (ISH) for Epstein-Barr virus (EBV) were performed. Two cases presented with features consistent with blastic NK-cell lymphoma or lymphoblastic lymphoma of NK-cell phenotype. These cases showed features of lymphoblastic lymphoma, phenotypes of sCD3-, cCD3+, CD45+, CD56+, TdT+, and human leukocyte antigen (HLA)-DR+, germline of IgH and TcR genes, and EBV negative reactivity. One case had myeloid/NK-precursor acute leukemia/lymphoma with a phenotype of CD13+, CD33+, CD34+, CD56+, and MPO-. Three cases were neurogenic, including one case of olfactory neuroblastoma and two of primitive neuroectodermal tumors (PNET). It was difficult to differentiate CD56+ PNET from blastic NK-cell lymphoma, especially when only paraffin-embedded sections were available. Myogenic markers, such as HHF35, alpha-sarcomeric actin, and desmin, were positive in three cases of rhabdomyosarcomas.
Our findings suggest that as CD56 is used more routinely as a marker in immunohistochemical staining, the differential diagnosis of extranodal lymphohematological malignancies and small round cell tumors will become more complicated.
c-kit Expression in Pediatric Solid Tumors: A Comparative Immunohistochemical Study.
Smithey BE, Pappo AS, Hill DA.
Department of Pathology (B.E.S.), University of Tennessee Medical Center, and the Departments of Hematology-Oncology (A.S.P.) and Pathology (D.A.H.), St. Jude Children's Research Hospital, Memphis, Tennessee, U.S.A.
Am J Surg Pathol 2002 Apr;26(4):486-92 Abstract quote
The stem cell factor/c-kit tyrosine kinase receptor pathway has been shown to be important for tumor growth and progression in several cancers, including mast cell diseases, gastrointestinal stromal tumor, acute myeloid leukemia, small cell lung carcinoma, and Ewing sarcoma.
Studies using the oral agent STI-571 (Gleevec, Novartis), an inhibitor of the tyrosine kinases bcr-abl, c-kit, and PDGFR, have shown significant responses in patients with chronic myelogenous leukemia and gastrointestinal stromal tumor. With the aim of identifying additional groups of tumors that may use the stem cell factor/c-kit pathway and secondarily may be responsive to STI-571 treatment, this study surveyed 151 primary tumors from patients treated at St. Jude Children's Research Hospital for immunohistochemical expression of c-kit.
Formalin-fixed, paraffin-embedded sections were stained with rabbit polyclonal anti-human c-kit (CD117, Dako) using standard avidin-biotin-peroxidase complex technique, antigen retrieval, and an automated stainer. Strong, diffuse staining for c-kit was seen in a proportion of synovial sarcomas, osteosarcomas, and Ewing sarcomas. Strong, diffuse staining was less common in neuroblastomas, Wilms' tumors, and rhabdomyosarcomas and was negative in alveolar soft part sarcomas and desmoplastic small round cell tumors. Tumors with strong, diffuse staining for c-kit in a pattern similar to gastrointestinal stromal tumor may represent suitable targets for new therapeutic agents.
FLI-1 Utility of the immunohistochemical detection of FLI-1 expression in round cell and vascular neoplasm using a monoclonal antibody.
Rossi S, Orvieto E, Furlanetto A, Laurino L, Ninfo V, Dei Tos AP.
Department of Pathology, Regional Hospital, Treviso, Italy.
Mod Pathol. 2004 May;17(5):547-52. Abstract quote
FLI-1 nuclear transcription factor has been proposed as a useful tool in the differential diagnosis of small round cell sarcomas. Recently, FLI-1 has been reported as the first nuclear marker of endothelial differentiation. However, its clinical use has been hampered by major interpretation problems, due to the presence of background staining as well as staining variation between different lots of the same antiserum.
In this study, a novel monoclonal antibody raised against the carboxyl terminal of the FLI-1 protein (clone GI146-222, BD Pharmingen) was tested in a series of small round cell and vascular neoplasms. Furthermore, in order to assess FLI-1 specificity, we analyzed its expression in a series of common epithelial and nonepithelial malignancies. In total, 15 Ewing's sarcomas, 10 rhabdomyosarcomas, 5 desmoplastic small round cell tumors, 10 synovial sarcomas, 10 high-grade pleomorphic sarcomas, 10 malignant melanomas, 5 Merkel's carcinomas, 10 colonic adenocarcinomas, 10 breast carcinomas, 10 lung adenocarcinomas, 20 angiosarcomas, 5 epithelioid hemangioendotheliomas, 10 Kaposi's sarcomas and 10 benign hemangiomas, were stained.
A strong FLI-1 immunoreactivity was detected in all Ewing's sarcomas and vascular neoplasms, highlighting the high sensitivity of FLI-1 monoclonal antibody. However, 2/5 Merkel's carcinomas and 1/10 malignant melanomas showed a strong nuclear immunostaining, suggesting that FLI-1 may not be so helpful in the differential diagnosis of cutaneous Ewing's sarcoma. In addition, a weak immunoreactivity was found in 3/5 Merkel cell carcinomas, 3/10 synovial sarcomas, 5/10 malignant melanomas, 6/10 lung adenocarcinomas and in 1/10 breast carcinomas.
In contrast, all the rhabdomyosarcomas, desmoplastic small round cell tumors, high-grade pleomorphic sarcomas and colonic adenocarcinomas tested were negative. Importantly, in contrast with previous studies, no background staining was observed.
Our results indicate that FLI-1 monoclonal antibody can be reliably applied to the differential diagnosis of small round cell neoplasms of soft tissue, and confirm its important role as nuclear marker of endothelial differentiation, mainly helpful in those cases in which technical artifacts are seen by using the traditional membranous and cytoplasmic endothelial markers.
The Expression of WT1 in the Differentiation of Rhabdomyosarcoma from Other Pediatric Small Round Blue Cell Tumors.
Carpentieri DF, Nichols K, Chou PM, Matthews M, Pawel B, Huff D.
Departments of Pathology (DFC, MM, BP, DH) and Oncology (KN), The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Mod Pathol 2002 Oct;15(10):1080-6 Abstract quote
The WT1 gene encodes a transcription factor implicated in normal and neoplastic development.
The purpose of this study was to evaluate the diagnostic utility of a commercial WT1 antibody on a variety of pediatric small round blue cell tumors (SRBCT). A mouse monoclonal antibody (clone: 6F-H2, DAKO) raised against the N-terminal amino acids 1-181 of the human WT1 protein was tested. Microscopic sections from 66 specimens were stained using an antigen retrieval protocol with trypsin. The tumors included peripheral neuroectodermal tumors (PNET/Ewing's), neuroblastomas, desmoplastic small round cell tumors (DSRCT), lymphomas, Wilms' tumors, and rhabdomyosarcomas (RMS). One RMS case was investigated by Western blot analysis and RT-PCR to confirm the antibody specificity. A strong cytoplasmic staining was demonstrated in all RMS (11/11).
The Western blot analysis confirmed the WT1 protein in the tissue, and the RT-PCR confirmed the presence of WT1 mRNA in the peripheral blood and tissue of one RMS patient. The Wilms' tumors had a variable nuclear and/or cytoplasmic positivity in most (17/24) cases. All PNET/Ewing's were negative. The nuclei of two lymphoblastic lymphomas stained strongly. A weak nuclear or cytoplasmic staining was reported in a few DSRCT (3/5), lymphomas (2/10), and neuroblastomas (2/8).
This is a useful antibody in the differentiation of RMS from other SRBCTs. A strong cytoplasmic staining favors an RMS, and a strong nuclear staining is suggestive of a Wilms' tumor. A role for WT1 in the pathogenesis of rhabdomyosarcomas is raised. The limited sampling precludes any conclusions regarding the value of tissue or peripheral blood analysis for WT1 mRNA in patients with rhabdomyosarcoma.
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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.
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