(American Journal of Pathology. 1999;155:2181-2182.)
© 1999 American Society for Investigative Pathology
Diagnosis and Classification of Small Round-Cell Tumors of Childhood
Marc Ladanyi
Memorial Sloan-Kettering Cancer Center New York, New York
To the Editor-in-Chief:
I read with interest the recent Commentary on the diagnosis and
classification of small round-cell tumors of childhood that appeared in
the July 1999 issue of the Journal.1
However,
two statements made in this Commentary warrant further analysis. First,
the author states that "although several subtly different
EWS-FLI1 and EWS fusion transcripts have been
identified to date, significant correlations between different chimeric
EWS transcripts and clinical parameters have not been
identified." This statement is not supported by a review of the
literature. Since 1996, two independent groups have published data
showing that EWS-FLI1 fusion transcript structure is indeed
prognostically significant in Ewing’s sarcoma.2,3
Analogous observations have incidentally also been reported in
alveolar rhabdomyosarcoma4
and synovial
sarcoma.5,6
The second statement that warrants further comment is that "the
t(11;22) is not specific for the Ewing’s family of tumors" because
"recent studies have demonstrated that the t(11;22) translocation can
be identified in some cases of neuroblastoma and rhabdomyosarcoma."
This echoes a similar statement in the accompanying
article.7
However, these two examples of the apparent
nonspecificity of EWS-FLI1 for Ewing’s sarcoma require
critical analysis. Regarding the report of EWS-FLI1 in
neuroblastoma,8
it should be noted that these results have
not been independently reproduced and that they were demonstrated only
by reverse transcriptase-polymerase chain reaction (RT-PCR), not by
conventional cytogenetics, contrary to what is implied by the authors’
sentence. The reported incidence of 17% is in fact difficult to
reconcile with almost two decades of conventional cytogenetic analysis
of neuroblastoma which has not detected the t(11;22) translocation in
this tumor. Other groups have also failed to detect EWS-FLI1
by RT-PCR in larger series of neuroblastomas.9
In
reference to the report of EWS-FLI1 in
rhabdomyosarcoma,10
this also remains an isolated report
of two cases of apparently typical primitive rhabdomyosarcoma, which
were found to contain the translocation by RT-PCR (and in one case also
by fluorescence in situ hybridization). However, other
RT-PCR studies including a total of 92 rhabdomyosarcomas have failed to
detect a single EWS-FLI1-positive case.9,11,12
These two rhabdomyosarcoma-like tumors containing
EWS-FLI110
may therefore be more closely
related to the rare mixed phenotype tumors, which have been reported to
contain EWS-FLI1 by several groups.13–16
In summary, I would suggest that isolated reports such as
these8,10
be presented critically and with appropriate
context provided. Studies that present unexpected
findings inconsistent with the rest of the literature should always be
carefully evaluated. The issues involved raise more than simply a
question of specificity or nonspecificity of a given test. Rather, they
impact fundamental concepts of the biology and nosology of these
tumors. It is only through the critical analysis of our own data and
those of other investigators that we can hope to make sense of these
often puzzling tumors.
References
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Cohn S: Diagnosis and classification of the small round-cell tumors of childhood. Am J Pathol 1999, 155:11-15[Free Full Text]
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Zoubek A, Dockhorn-Dworniczak B, Delattre O, Christiansen H, Niggli F, Gatterer-Menz I, Smith TL, Jurgens H, Gadner H, Kovar H: Does expression of different EWS chimeric transcripts define clinically distinct risk groups of Ewing tumor patients? J Clin Oncol 1996, 14:1245-1251[Abstract/Free Full Text]
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de Alava E, Kawai A, Healey JH, Fligman I, Meyers P, Huvos AG, Gerald WL, Jhanwar SC, Argani P, Antonescu CR, Pardo-Mindan FJ, Ginsberg J, Womer R, Lawlor ER, Wunder J, Andrulis I, Sorensen PHB, Barr FG, Ladanyi M: EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing’s sarcoma. J Clin Oncol 1998, 16:1248-1255[Abstract/Free Full Text]
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Kelly KM, Womer RB, Sorensen PHB, Xiong Q-B, Barr FG: Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma. J Clin Oncol 1997, 15:1831-1836[Abstract/Free Full Text]
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Kawai A, Woodruff J, Healey JH, Brennan MF, Antonescu CR, Ladanyi M: SYT-SSX gene fusion as a determinant of morphology, and prognosis in synovial sarcoma. N Engl J Med 1998, 338:153-160[Abstract/Free Full Text]
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Nilsson G, Skytting B, Xie Y, Brodin B, Perfekt R, Mandahl N, Lundeberg J, Uhlen M, Larsson O: The SYT-SSX1 variant of synovial sarcoma is associated with a high rate of tumor cell proliferation, and poor clinical outcome. Cancer Res 1999, 59:3180-3184[Abstract/Free Full Text]
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Gilbert J, Haber M, Bordow SB, Marshall GM, Norris MD: Use of tumor-specific gene expression for the differential diagnosis of neuroblastoma from other pediatric small round-cell malignancies. Am J Pathol 1999, 155:17-21[Abstract/Free Full Text]
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Burchill SA, Wheeldon J, Cullinane C, Lewis IJ: EWS-FLI1 fusion transcripts identified in patients with typical neuroblastoma. Eur J Cancer 1997, 33:239-243
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Dockhorn-Dworniczak B, Schafer KL, Blasius S, Christiansen H, Koscielniak E, Ritter J, Winkelmann W, Jurgens H, Bocker W: Assessment of molecular genetic detection of chromosome translocations in the differential diagnosis of pediatric sarcomas. Klin Padiatr 1997, 209:156-164[Medline]
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Thorner P, Squire J, Chilton-MacNeil S, Marrano P, Bayani J, Malkin D, Greenberg M, Lorenzana A, Zielenska M: 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. Am J Pathol 1996, 148:1125-1138[Abstract]
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Barr FG, Chatten J, D’Cruz CM, Wilson AE, Nauta LE, Nycum LM, Biegel JA, Womer RB: Molecular assays for chromosomal translocations in the diagnosis of pediatric soft tissue sarcomas. JAMA 1995, 273:553-557[Abstract]
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de Alava E, Ladanyi M, Rosai J, Gerald WL: Detection of chimeric transcripts in desmoplastic small round cell tumor and related developmental tumors by reverse transcriptase polymerase chain reaction: a specific diagnostic assay. Am J Pathol 1995, 147:1584-1591[Abstract]
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Whang-Peng J, Knutsen T, Theil K, Horowitz ME, Triche T: Cytogenetic studies in subgroups of rhabdomyosarcoma. Genes Chromosomes Cancer 1992, 5:299-310[Medline]
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Sorensen PHB, Shimada H, Liu XF, Lim JF, Thomas G, Triche TJ: Biphenotypic sarcomas with myogenic and neural differentiation express the Ewing’s sarcoma EWS/FLI1 fusion gene. Cancer Res 1995, 55:1385-1392[Abstract/Free Full Text]
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Katz RL, Quezado M, Senderowicz AM, Villalba L, Laskin WB, Tsokos M: An intra-abdominal small round cell neoplasm with features of primitive neuroectodermal and desmoplastic round cell tumor and a EWS/FLI-1 fusion transcript. Hum Pathol 1997, 28:502-509[Medline]
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Ordi J, de Alava E, Torne A, Mellado B, Pardo-Mindan J, Iglesias X, Cardesa A: Intra-abdominal desmoplastic small round cell tumor with EWS/ERG fusion transcript. Am J Surg Pathol 1998, 22:1026-1032[Medline]
