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Ewing's Sarcoma of the Rectum: Can We Afford Not to Use Molecular Pathology?

Medical Oncology Department, Institut Curie, Paris, France

Jorge S. Reis-Filho

The Breakthrough Toby Robins Breast Cancer Research Centre, London, United Kingdom

To the Editor:

Vardy et al¹ reported in the February 1, 2005, issue of the Journal of Clinical Oncology a case of extraosseous Ewing's sarcoma (EOE) of the rectum. The authors described a fungating, ulcerated, posterior wall rectal lesion, which was histologically characterized by a proliferation of undifferentiated small round blue cells with a high mitotic rate and extensive areas of necrosis. Histochemical staining with periodic acid Schiff before and after diastase treatment and immunohistochemistry with antibodies for MIC-2 (CD99), vimentin, cytokeratins (clones CAM 5.2 and AE1/AE3), S-100 protein, chromogranin, desmin, smooth muscle actin, and neuron-specific enolase were performed. Based on the presence of abundant glycogen and positivity for MIC-2, vimentin, and cytokeratin CAM 5.2, the authors made a diagnosis of EOE.

Although we agree that the morphologic, histochemical, and immunohistochemical findings described above are consistent with the diagnosis the authors made, a word of caution should be voiced. The features described by Vardy et al¹ are not sufficient for ruling out important differential diagnoses.^2-4 As elegantly described by Ozdemirli et al,² when dealing with small round blue cell tumors, the combination of light microscopy with a limited panel of immunohistochemical markers may lead to misdiagnoses. Lymphoblastic lymphoma, small-cell carcinoma, and EOE can show exceedingly similar morphologic, histochemical, and immunohistochemical features.^2,4 In fact, MIC-2 is now known to be frequently positive in both B and T lymphoblastic lymphomas.² Expression of MIC-2, although first described as specific for Ewing's sarcoma (ES), has been identified in 10% of the cases of 88 different tumor types (http://www.immunoquery.com).^2-4 Moreover, positive staining for vimentin and focal reactivity for cytokeratin CAM 5.2 cannot rule out either lymphoma or small-cell neuroendocrine carcinoma.^2-4 In a recent review of 143 cases of primary gastrointestinal lymphoma, patients' median age was 54 years, and, interestingly, 9% of all cases affected the rectum.⁵ In addition, a lymphoblastic lymphoma presenting as a rectal mass in a middle age male would be rare, but not as unexpected as an EOE in the same setting. It is noteworthy that the chemotherapy regimen that was used would also be effective in lymphoma.

ESs and primitive neuroectodermal tumors (PNETs) consistently harbor recurrent chromosomal translocations, including t(11;22)(q24,q12) EWS/FLI-1, t(21;22)(q22;q12) EWS/ERG, t(7;22)(p22;q12) EWS/ETV-1, and t(17;22)(q12;q12) EWS/E1AF, to name a few.^2,6 The EWS/FLI-1 is found in up to 85% of all EWS/PNETs and is reported to be specific for this family of tumors.^2,6 In recent years, it has become standard practice to confirm the diagnosis of ES/PNETs and differentiate them from their histologic mimickers by coupling immunohistochemistry with simple molecular pathology methods; namely, reverse transcriptase polymerase chain reaction (RT-PCR) for the fusion transcripts, which can be performed from fresh or formalin-fixed samples, or fluorescent in situ hybridization, which can be carried out on paraffin-embedded tissue sections.⁶

Last but not least, the authors missed in their MEDLINE and CANCERLIT review a recent and very comprehensive report of a PNET/ES/EOE affecting the rectum of a 17-year-old boy, confirmed by the identification of the EWS/FLI-1 transcript by RT-PCR.⁷

In conclusion, with molecular tools that are increasingly available to most pathology laboratories, when reporting on odd clinical presentations of PNET/ES and other tumors with known recurrent translocations, one has to confirm the diagnosis by RT-PCR or flourescent in situ hybridization, or at least make use of an extended immunohistochemical panel.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Vardy J, Joshua AM, Clarke SJ, et al: Small blue cell tumors of the rectum, CASE 1: Ewing's Sarcoma of the Rectum. J Clin Oncol 23:910-912, 2005[Free Full Text]

2. Ozdemirli M, Fanburg-Smith JC, Hartmann DP, et al: Differentiating lymphoblastic lymphoma and Ewing's sarcoma: Lymphocyte markers and gene rearrangement. Mod Pathol 14:1175-1182, 2001[CrossRef][Medline]

3. Pelosi G, Fraggetta F, Sonzogni A, et al: CD99 immunoreactivity in gastrointestinal and pulmonary neuroendocrine tumors. Virchows Arch 437:270-274, 2000[CrossRef][Medline]

4. Rosai J: Rosai and Ackerman's Surgical Pathology (ed 9). New York, NY, Mosby, 2004

5. Kohno S, Ohshima K, Yoneda S, et al: Clinicopathological analysis of 143 primary malignant lymphomas in the small and large intestines based on the new WHO classification. Histopathology 43:135-143, 2003[Medline]

6. Burchill SA: Ewing's sarcoma: Diagnostic, prognostic, and therapeutic implications of molecular abnormalities. J Clin Pathol 56:96-102, 2003[Abstract/Free Full Text]

7. Drut R, Drut M, Muller C, et al: Rectal primitive neuroectodermal tumor. Pediatr Pathol Mol Med 22:391-398, 2003[Medline]

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