Desmoplastic small round cell tumor

* An extra-abdominal desmoplastic small round cell tumor (DSRCT) of the lung with immunohistochemical, ultrastructural, and cytogenetic evidence of multidirectional differentiation is reported. We demonstrate that DSRCTs of the lung and pleura show morphologic, molecular, genetic, and ultrastructural features similar to DSRCTs arising in other sites. The tumor showed coexpression of cytokeratins (AEI/3, epithelial membrane antigen, CAM 5.2) and mesenchymal markers (vimentin, desmin, neuron-specific enolase), as well as WT1. Ultrastructurally, intracytoplasmic whorls of intermediate filaments, similar to previous descriptions of DSRCT in nonthoracic sites, were also demonstrated in this case. EWS-WT1 gene fusion characteristic of DSRCT with the t(11;22)(q13;q12) translocation was demonstrated in this tumor.

(Arch Pathol Lab Med. 2002;126:1226-1228)

desmoplastic small round cell tumor (DSRCT) was first described by Gerald and Rosai in 19891 as a distinct tumor with specific histologic and immunohistochemical patterns and chromosomal translocation.1-3 Most of the cases have been reported in male patients in the second or third decade of life.1,4 The characteristic translocation has not been described in the lung/pleura.4,5 In this article, we report an extra-abdominal DSRCT of the lung with the histochemical, immunohistochemical, and ultrastructural features diagnostic of this entity and the characteristic EWS-WTI gene fusion.

REPORT OF A CASE

A 22-year-old white man presented with shortness of breath on exertion, dry cough, and weakness of 2 weeks' duration and a history of wheezing and joint pains for 3 months. There was no history of weight loss, fever, or night sweats. The patient had smoked half a pack of cigarettes per day for less than 1 year. He did not have a history of exposure to any known toxin, and he denied any alcohol or substance abuse. Tuberculin skin test was nonreactive. Chest radiography revealed diffuse reticulonodular infiltrates bilaterally. Computed tomography revealed multiple bilateral reticulonodular densities in the right lung and mediastinum, as well as bilateral hilar and mediastinal lymphadenopathy, suggesting the diagnosis of metastatic tumor (Figure 1). Bronchoalveolar lavage yielded malignant cells, which were initially considered to be consistent with either a carcinoma or a germ cell neoplasm. A transbronchial biopsy of the right lower lobe showed poorly differentiated neoplastic cells, which reacted positively for cytokeratin AEl/3 and vimentin, and produced no reaction for 5100 protein. Cultures for bacterial, mycobacterial, and fungal organisms were negative. A thorough clinical workup failed to reveal other lesions. The patient underwent video-assisted thoracoscopic wedge resection of the left lower lobe.

Grossly, the external surface of the resected specimen was studded with multiple tan-white, firm, smooth-surfaced nodules, ranging from 1.2 to 1.4 cm with tan-white cut surface. Histologically, nests of uniform round to polygonal small tumor cells were seen in pleura, extending along the septa into the lung parenchyma (Figure 2, A). Nests of neoplastic cells with central necrosis were also found in alveolar spaces and some were noted in vascular spaces. No rosettes or pseudorosettes were seen. The tumor cells were surrounded by fibroblastic stroma and showed eosinophilic cytoplasm and slightly pleomorphic, hyperchromatic nuclei, with focal nuclear indentations, nuclear vacuolation, and multilobation (Figure 2, B). Nucleoli were inconspicuous, but there were more than 3 mitoses per 10 high-power fields. Immunohistochemical staining revealed coexpression of cytokeratins, vimentin, desmin, and neuron-specific enolase in the tumor cells (Figure 3). Desmin showed a dotlike or globoid expression in the perinuclear region, with no expression in stromal tissue (Figure 4, A). Neuron-specific enolase immunostaining showed strong cytoplasmic positivity. WT1, a polyclonal immunostain developed against the amino terminus of the WT1 protein, showed nuclear dotlike positivity (Figure 4, B).6 Immunostaining results are summarized in the Table. Ultrastructural examination showed moderately preserved tumor cells with irregular nuclear outlines and small nucleoli. Many tumor cells contained scattered cytoplasmic particles consistent with glycogen, mitochondria, and rough endoplasmic reticulum. No cell junctions or neurosecretory granules were found. A few cells showed intracytoplasmic whorls of intermediate filaments and recognizable intermediate filaments, consistent with published descriptions of DSRCT (Figure 5). The tumor was analyzed for the t(11;22)(q13;q12) translocation, using EWS- and WT1-specific primers and complementary DNA derived from tumor tissue RNA as a template, in the reverse transcription-polymerase chain reaction. The presence of amplifiable RNA was confirmed using primers specific for [3-actin. Polymerase chain reaction products were blotted onto a nylon membrane and probed with an internal end-labeled oligonucleotide with a sequence specific for WTI or EWS.13 The control was a positive patient specimen with the molecular rearrangement confirmed by sequencing the specific EWS/WT1 transcript, which was demonstrated in the tumor from our case (Figure 6).

Following the diagnosis of DSRCT, the patient was treated with 4 courses of doxorubicin, cisplatin, and ifosfamide. Six months after completion of chemotherapy, the patient was reported to be doing well.

COMMENT

Desmoplastic small round cell tumor is characterized by nests of small tumor cells surrounded by a cellular and vascular collagenous stroma, hence the name desmoplastic small round cell tumor. The amount of stroma varies with the progression of the tumor, although the stroma is always seen.1,7 More than 100 cases of DSRCT of the peritoneum have been reported in the English literature.1,3,7 Other reported sites include the tunica vaginalis testis, skull, parotid gland, hand, uterine serosal surface, ovarian surface, and urogenital region.5,8 To date, 4 cases of DSRCT have been described in the thoracic cavity, although the tumor was confined to the thorax in only 1 of these cases.4,5,7

Desmoplastic small round cell tumor was first described as a mesothelioblastoma1,4 because these tumors were located in the peritoneum, tunica vaginalis, or pleura, and they expressed cytokeratins and epithelial membrane antigen. However, a mesothelial origin of this tumor has been questioned, since these tumors are seen in sites where mesothelium is not found. Also, they do not express thrombomodulin and calretinin proteins, and ultrastructurally long microvilli have been consistently absent?4

In most of the reported cases, epithelial membrane antigen, neuron-specific enolase, and desmin were expressed, the latter with characteristic dotlike perinuclear positivity.9 Recently, WT1, a polyclonal antibody against the amino terminus of the WT1 protein, has shown posiTive staining in more than 95% of cases, as was seen in our case.5,6 The presence of perinuclear whorls of intermediate filaments by electron microscopy, which correspond to the dotlike immunostaining with desmin, together with the absence of specialized cell junctions, neurosecretory granules, and long microvilli are pertinent negative findings that also support the diagnosis of DSRCT.1,9 The characteristic translocation t(11;22)(q13;q12) in DSRCT was first reported by Sawyer et al in 1992.3 Since then, several reports have confirmed this finding and established that this translocation is specific for DSRCT, regardless of its site.3,10-12

In summary, DSRCT should be considered in the differential diagnosis of undifferentiated small round cell tumors of the thorax. Immunostains for WT1 protein and the characteristic translocation are diagnostic of this tumor.

References

1. Gerald WL, Rosai J. Desmoplastic small round cell tumor with divergent differentiation. Pediatr Pathol. 1989;9:177-183.

2. Argatoff LH, O'Connell JX, Mathers JA, et al. Detection of the EWS-WT1 gene fusion by reverse transcriptase-polymerase chain reaction in the diagnosis of intra-abdominal desmoplastic small round cell tumor. Am J Surg Pathol. 1996; 20:406-412,

3. Sawyer JR, Tryka AF, Lewis JM. A novel reciprocal chromosome translocation t(11;22)(ql 3;12) in an intraabdominal desmoplastic small round cell tumor. Am J Surg Pathol. 1992; 16:411-416.

4. Ordonez NG. Desmoplastic small round cell tumor: a histopathologic study of 39 cases with emphasis on unusual histological patterns. Am J Surg PathoL 1998;22:1303-1313.

5. Parkash V, Gerald WL, Parma A, et al. Desmoplastic small round cell tumor of the pleura. Am] Surg Pathol. 1995;19:659-665.

6. Barnoud R, Sabourin IC, Pasquier D, et al. Immunohistochemical expression of WTI by desmoplastic small round cell tumor: a comparative study with other small round cell tumors. Am J Surg Pathol. 2000;24:830-836.

7. Gerald WL, Ladanyi M, de Alava E, et al. Clinical, pathologic, and molecular spectrum of tumors associated with t(11;22)(p13;q12): desmoplastic small round-cell tumor and its variants. J Clin Oncol. 1998;16:3028-3036.

8. Cummings OW, Ulbright TM, Young RH, et al. Desmoplastic small round cell tumors of the paratesticular region: a report of six cases. Am J Surg Pathol. 1997;21:219-225.

9. Ordonez NG. Desmoplastic small round cell tumor, II: an ultrastructural and immunohistochemical study with emphasis on new immunohistochemical markers. Am J Surg Pathol. 1998;22:1314-1327.

10. Ladanyi M, Gerald W, Fusion of the EWS and WTI genes in the desmoplastic small round cell tumor. Cancer Res. 1994;54:2837-2840.

11. Brodie SG, Stocker SI, Wardlaw JC, et al. EWS and WT-1 gene fusion in desmoplastic small round cell tumor of the abdomen. Hum Pathol. 1995;26: 1370-1374.

12. Roberts P, Burchill SA, Beddow RA, et al. A combined cytogenetic and molecular approach to diagnosis in a case of desmoplastic small round cell tumor with a complex translocation (11;22;21). Cancer Genet Cytogenet. 1999;108:1925.

Salahuddin Syed, MD; Abida K. Hague, MD; Hal K. Hawkins, MD, PhD; Poul H. B. Sorensen, MD, PhD; Daniel F Cowan, MD

Accepted for publication December 5, 2001.

From the Department of Pathology, University of Texas Medical Branch, Galveston, Tex (Drs Syed, Haque, Cowan, and Hawkins); and the Molecular Diagnostic Laboratory, Department of Pathology and Pediatrics, BC Research Institute for Children's and Women's Health, Vancouver, British Columbia, Canada (Dr Sorensen).

Reprints: Daniel F. Cowan, MD, Department of Pathology, University of Texas Medical Branch, 301 University Blvd, Route 0555, Galveston, TX 77555-5302 (e-mail: dcowan@utmb.edu).

Copyright College of American Pathologists Oct 2002
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