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Desmoplastic Small Round Cell Tumor

The Value of Cytology, Immunohistochemistry, and Molecular Features in the Diagnosis of This Challenging Diagnostic Entity

Bernieh, Anas, MD*; Joyner, David, MD; Saad, Ali G., MD*‡

doi: 10.1097/PCR.0000000000000314
Case Reviews
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Desmoplastic small round cell tumor is a rare malignant neoplasm that usually occurs in adolescents and young adult males and typically presents as a large, often multinodular, intra-abdominal mass. The peritoneal cavity is the most common location of the tumor with multiple satellite nodules often noted at presentation. Extra-abdominal locations, such as the lung, kidney, middle ear, stomach, pancreas, pleura, bone, and the central nervous system, have been described. Distant metastases commonly involve the lymph nodes, liver, and lungs. Desmoplastic small round cell tumor is relatively rare, and only few cytologic descriptions are available. We present the case of a 16-year-old boy with unusually rapidly fatal desmoplastic small round cell tumor of the peritoneum with emphasis on the cytologic features. Recent advances in imaging techniques have resulted in increased number of cytologic preparations from unusual tumors or tumors in unusual locations. Morphologically, these tumors often display a divergent phenotype and immunophenotype. Immunohistochemistry plays a pivotal role in the characterization of these tumors and discrimination from other mimickers, particularly other “blue cell tumors.” Once suspected, identification of the characteristic translocation in these tumors confirms the diagnosis. Therefore, awareness of the cytologic features and the divergence of the immunophenotype of this tumor are crucial in order to arrive to the correct diagnosis and to ensure proper management plans of these often difficult-to-treat tumors.

From the Departments of *Pathology and

Radiology, University of Mississippi Medical Center, Jackson MS; and

Department of Pathology, Methodist Le Bonheur Healthcare, Memphis TN.

Reprints: Ali G. Saad, MD, Methodist Le Bonheur Healthcare, 50 N Dunlap St, Memphis, TN 38103. E-mail: ali.saad@lebonheur.org.

The authors have no funding or conflicts to declare.

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CASE REPORT

We present the case of a 16-year-old boy who presented with emesis and weight loss. A computed tomography (CT) scan of the abdomen (Fig. 1) showed a large heterogeneous intraperitoneal mass in the left midabdomen anterior to the descending colon measuring 8.9 cm in largest dimension with mixed internal serpiginous hyperdensities suggestive of feeding vessels and calcifications. Numerous heterogeneous enhancing masses were also present in the right lower quadrant and pelvis. The liver showed multiple metastatic foci, some with internal calcifications. Multiple enlarged retroperitoneal lymph nodes were present. Imaging of the thorax demonstrated enlarged superior mediastinal lymph nodes and bilateral pleural effusions.

FIGURE 1

FIGURE 1

A peritoneal lavage and biopsy of the tumor were performed via laparoscopy. Upon visualization of the abdominal cavity, it was clear that the patient had peritoneal “carcinomatosis” with extensive involvement of the peritoneum, diaphragm, and liver by multiple tumoral nodules. The omentum was very firm and extensively involved by tumor. Seven liters of clear serous ascites was removed and sent for cytologic examination. A biopsy of the omentum was performed. The family elected not to pursue any therapy, and the patient was sent to hospice, where he died 1 month after diagnosis.

Cytologic preparations (Fig. 2) showed rare small clusters or individual cells scattered in a background of abundant reactive mesothelial cells and mononuclear inflammatory cells. The tumor cells showed significant atypia and pleomorphism with very hyperchromatic nuclei and irregular nuclear contours. Nucleoli were absent to inconspicuous. Nuclear molding was evident. Of particular interest, the Papanicolaou stain disclosed intracytoplasmic densities corresponding to paranuclear intermediate filaments. These globules were further highlighted by a desmin immunostain.

FIGURE 2

FIGURE 2

Histological sections showed a “blue cell” tumor with large, dense fibrotic/desmoplastic bands between sheets of tumor cells. The tumor cells had hyperchromatic nuclei and scant to absent cytoplasm. They were immunopositive for desmin, in a dot-like pattern, and WT-1.

Fluorescence in situ hybridization, performed on paraffin-embedded tissue section, confirmed the presence of t(11:22) involving the WT1 and EWS genes (Figs. 3 and 4).

FIGURE 3

FIGURE 3

FIGURE 4

FIGURE 4

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DISCUSSION

Desmoplastic small round cell tumor (DSRCT) is a rare malignant neoplasm that usually occurs in adolescent and young adults. About 80% are males. It typically presents as a large, often multinodular, intra-abdominal mass. Multiple smaller peritoneal implants are often found intraoperatively.1 This highly aggressive tumor was first described in 1989 by Gerald and Rosai2 as clusters of poorly differentiated small round blue cells embedded within a dense fibrosclerotic stroma. The peritoneal cavity is the most common location of the tumor, but unusual extra-abdominal locations including the lung,3 kidney,4,5 middle ear,6 stomach,7 pancreas,8 pleura,9 bone,10 and the central nervous system11 have been described. Distant metastases commonly involve the lymph nodes, liver, and lungs.12–14 Desmoplastic small round cell tumor is relatively rare, with fewer than 500 cases reported in the literature1,13,15 and only few cytologic descriptions.16–18 Awareness of the cytologic features and divergence of the immunophenotype is crucial in order to arrive at the correct diagnosis. This is particularly true when the tumor occurs in unusual, that is, extra-abdominal locations.

Desmoplastic small round cell tumor is a very rare sarcoma with predilection for the abdominopelvic peritoneal surfaces. Despite recent advances in therapeutic strategies, the prognosis remains poor. The tumor often comes to attention at an advanced stage when the tumor burden is already large. Characteristically, the tumor consists of multiple tumoral nodules imparting a multinodular appearance. Multiple satellite peritoneal nodules are frequently present.

Recent advances in imaging techniques have resulted in an increased number of cytologic preparations of neoplasms. With perhaps the exception of the central nervous system, imaging-guided fine-needle aspiration has the potential of being performed on practically any tumor in any anatomic location. As such, familiarity with cytologic features, particularly of those of rare entities, is required. Such awareness provides proper preoperative planning. As we discuss below, the best prognostic indicator of DSRCT remains an attempt to excise the tumor in its entirety. Because DSRCT often presents as multiple nodules spread along the peritoneal surface of the abdomen and pelvis, this tumor requires vigorous surgical planning and, not infrequently, involvement of multiple surgeons of various skills. Therefore, accurate preoperative cytologic diagnosis is paramount.

Awareness of the cytologic features of rare entities allows for the diagnosis with very small amounts of cells and tissue, facilitating proper surgical planning. Very few reports have addressed the preoperative diagnosis of DSRCT, perhaps related to a lack of familiarity with cytologic attributes.

The cytologic features of DSRCT can be challenging, given the frequent morphologic divergence of the tumor. Limited reports on the cytologic features of DSRCT are available.17–22 Review of the literature shows that nuclear grooves, infolding of nuclear membranes, and nuclear molding are common features.20–22 Necrosis, previously reported in few cases,20,21 was not encountered in our case. Similar to the report by Insabato et al,16 our specimen had intermediate filament buttons, which appear to be of particular importance in the cytologic differential diagnosis of DSRCT. The cytologic differential diagnosis revolves around the small round “blue” cell category. In this age group, a number of neoplastic entities enter this realm. As the tumor cells in this patient's fluid specimen have more than scant cytoplasm with eccentrically placed nuclei, which at times are bowed or indented, the major tumor consideration is embryonal rhabdomyosarcoma. This is further enhanced with the positive desmin reaction. The positivity for epithelial markers and the genetic alteration are highly valuable in this setting. Although the differential diagnosis also includes other neoplasms, for example, neuroblastoma, the patient's age, the radiological and clinical exams, and the lack of typical cytologic features, for example, rosettes and higher nucleus-to-cytoplasm ratios, aid in their exclusion.

Histologically, the tumor is characterized by nests of tumor cells embedded within a dense sclerotic/desmoplastic stroma. The tumor cells commonly display a primitive appearance, but epithelial or rhabdoid features may be present. Mitoses and tumor necrosis are often present. Occasionally, large necrotic areas impart a pseudocystic appearance to the tumor. As described below, this tumor may show a wide spectrum of morphological and immunophenotypical features. Rosette formation is occasionally present. One case of paratesticular DSRCT with psammoma bodies has been reported.23

By immunohistochemistry, the tumor shows a distinctive multiphenotypic differentiation as demonstrated by the frequent expression by the tumor cells of markers associated with epithelial, neural, and muscular differentiation. The majority of cases are immunoreactive for epithelial membrane antigen, CD99, keratins, vimentin, neuron-specific enolase, and desmin. The latter has a characteristic cytoplasmic dot-like positivity with the latter. WT-1 immunopositivity is often encountered using antibodies to the carboxy-terminus but not the amino-terminus.24 Positivity for neurofilament has also been reported.16 This divergent differentiation, at least at the immunophenotypic level, is a major cause of concern for diagnostic purposes, particularly when dealing with cytologic preparations or biopsies from non–mesothelium-associated locations, such as the central nervous system, the ocular region, and so on, hence the importance of the detection of the EWSR1-WT1 gene fusion in cases with unusual anatomic or morphological features.

Desmoplastic small round cell tumors harbor a specific reciprocal chromosomal abnormality, t(11, 22)(p13, q12).25,26 Although this translocation is unique and results in rearrangement and fusion in DSRCT, the breakpoints involve 2 chromosomal regions previously described in other malignancies. As well recognized, 22q12 is the site of EWS, a gene involved in translocation and associated with the Ewing sarcoma family, whereas 11p13 is the site of WT1, the Wilms tumor gene. The most common chimeric transcript comprises an in-frame fusion of the first 7 exons of EWSR1 and exons 8 to 10 of WT1.

Despite recent advances, the cell of origin of DSRCT remains enigmatic. The frequent occurrence of DSRCT in serous cavities has led Gerald et al1 and Parkash et al9 to introduce the concept that DSRCT is a primitive tumor histogenetically related to mesothelium, that is, mesothelioblastoma. In support of this concept is the presence in this tumor of chromosomal translocation involving the Wilms tumor gene, which is involved in developing mesothelium.9 However, since the first report of DSRCT not occurring in a mesothelium-lined cavity,11 several additional reports have emerged,3,4,6,8,11,27 questioning this concept and raising more questions about the origin of this tumor.

The management of these tumors has been largely anecdotal; however, in the last few decades, there have been multiple attempts at treating these challenging tumors taking advantage of new systemic therapeutic protocols. In a recent study,28 Honore et al28 identified 4 good prognostic factors: absence of extraperitoneal metastases, gross total resection of the peritoneal tumor, postoperative whole abdominopelvic radiotherapy, and postoperative chemotherapy. The same study showed no benefit of surgery in patients with extraperitoneal metastases. The overall survival rate remains dismal with 5-year survival estimated at only 15% to 30%.29–31

In summary, DSRCT may display a wide variety of morphological and immunophenotypical features rendering the diagnosis challenging. Desmoplastic small round cell tumors may occur in unusual location, that is, locations not associated with mesothelial lining, adding to the complexity of the diagnosis. With the tremendous advances in imaging techniques, we are increasingly dealing with cytologic preparations with or without core biopsies. It is in these particular instances that categorizing the unique phenotype and identifying the characteristic chromosomal translocation become key importance to an accurate diagnosis and developing treatment strategies.

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CONCLUSIONS

We have described a rapidly fatal case of DSRCT along with its cytologic features. These relatively rare tumors with divergent phenotype and immunophenotype may result in diagnostic pitfalls. Awareness of the cytologic features of these tumors is pivotal in order to render the correct diagnosis and properly plan for surgical management.

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REFERENCES

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Keywords:

children; cytology; desmoplastic round cell tumor; molecular

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