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Malignant Gastrointestinal Neuroectodermal Tumor: Clinicopathologic, Immunohistochemical, Ultrastructural, and Molecular Analysis of 16 Cases With a Reappraisal of Clear Cell Sarcoma-like Tumors of the Gastrointestinal Tract

Stockman, David L. MD*; Miettinen, Markku MD; Suster, Saul MD*; Spagnolo, Dominic MBBS, FRCPA, MD‡,§; Dominguez-Malagon, Hugo MD; Hornick, Jason L. MD, PhD; Adsay, Volkan MD#; Chou, Pauline M. MD, PhD**; Amanuel, Benhur MBBS, FRCPA‡,§; VanTuinen, Peter PhD*; Zambrano, Eduardo V. MD*

The American Journal of Surgical Pathology: June 2012 - Volume 36 - Issue 6 - p 857–868
doi: 10.1097/PAS.0b013e31824644ac
Original Articles

The clinical, histologic, immunophenotypic, ultrastructural, and molecular features of a distinctive gastrointestinal tumor are described. Sixteen patients, 8 women and 8 men aged 17 to 77 years (mean age, 42 y; 63% less than 40 y) presented with abdominal pain, intestinal obstruction, and an abdominal mass. Mean tumor size was 5.2 cm (range, 2.4 to 15.0 cm). The tumors arose in the small bowel (10), stomach (4), and colon (2) and were histologically characterized by a sheet-like or nested population of epithelioid or oval-to-spindle cells with small nucleoli and scattered mitoses. Five cases showed focal clearing of the cytoplasm. Scattered osteoclast-type multinucleated giant cells were present in 8 cases. The tumor cells were positive for S-100 protein, SOX10, and vimentin in 100% of cases, for CD56 in 70%, for synaptophysin in 56%, for NB84 in 50%, for NSE in 45%, and for neurofilament protein in 14% of cases. All cases tested were negative for specific melanocytic, gastrointestinal stromal tumors, epithelial, and myoid markers. Ultrastructural examination of 5 cases showed features of primitive neuroectodermal cells with clear secretory vesicles, dense-core granules, occasional gap junctions, and no evidence of melanogenesis. EWSR1 gene rearrangement was assessed by fluorescence in situ hybridization in 14 cases. Twelve cases (86%) showed split EWSR1 signal consistent with a chromosomal translocation involving EWSR1. One case showed extra intact signals, indicating that the nuclei possessed either extra copies of the EWSR1 gene or chromosome 22 polysomy. Only 1 case showed no involvement of the EWSR1 gene. Six cases demonstrated rearrangement of the partner fusion gene ATF1 (46%), and 3 showed rearrangement of CREB1 (23%); 2 cases lacked rearrangement of either partner gene. Clinical follow-up was available in 12 patients and ranged from 1.5 to 106 months. Six patients died of their tumors (mean survival, 32 mo; 83% less than 24 mo). At last follow-up, 4 patients were alive with regional, lymph node, and liver metastases, and 2 patients were alive with no evidence of disease. The tumor described here is an aggressive form of neuroectodermal tumor that should be separated from other primitive epithelioid and spindle cell tumors of the gastrointestinal tract. The distinctive ultrastructural features and absence of melanocytic differentiation serve to separate them from soft tissue clear cell sarcomas involving the gastrointestinal tract. The designation “malignant gastrointestinal neuroectodermal tumor” is proposed for this tumor type.

*Department of Pathology, The Medical College of Wisconsin, Milwaukee, WI

Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC

PathWest Laboratory Medicine WA

§School of PALM, University of Western Australia, Nedlands, WA, Australia

The National Cancer Institute of Mexico, Mexico City, Mexico

Department of Pathology, Brigham and Women’s Hospital, Boston, MA

#Emory University Hospital, Atlanta, GA

**Children’s Hospital Memorial Hospital, Chicago, IL

Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Eduardo V. Zambrano, MD, Department of Pathology, Medical College of Wisconsin, 9200W. Wisconsin Ave., Milwaukee, WI 53226 (e-mail:

© 2012 Lippincott Williams & Wilkins, Inc.