Desmoplastic small round cell tumor pathology outlines

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Desmoplastic Small Round Cell Tumor

Desmoplastic small round cell tumor (DSRCT) is a very rare and aggressive mesenchymal tumor that occurs predominantly in adolescent and young adult males. It is associated with a diagnostic chromosomal translocation between the Ewing tumor gene and the Wilms tumor gene, t(11;22)(p13;q12), creating a chimeric gene (EWS-WT1) that encodes a chimeric protein with oncogenic properties. Patients typically present at advanced stage with a bulky abdominal mass, multiple peritoneal and omental implants, and symptoms of abdominal sarcomatosis, including pain, ascites, intestinal obstruction, hydronephrosis, and weight loss. DSRCT mainly involves the abdominal cavity but can spread to the lymph nodes, liver, lungs, and bones. There is no standard treatment approach. Aggressive treatment with combination chemotherapy, debulking surgery, and whole abdominopelvic irradiation results almost universally in a poor outcome. Median survival ranges between 17 and 25 mo, and the 5 yr overall survival remains <20%. Although high-dose chemotherapy and autologous stem cell rescue demonstrated some benefit, this approach has been abandoned because of significant toxicity. Alternative treatment options currently under investigation include hyperthermic intraperitoneal chemotherapy and radioimmunotherapy with monoclonal antibodies targeting different surface antigens on tumor cells.

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Desmoplastic Small Round Cell Tumors

Another translocation-associated sarcoma, these morphologically small round cell tumors are characterized by the t(11;22)(p13;q12)WT1-EWSR1 gene fusion protein. Occurring mostly in young males, these tumors present with multifocal peritoneal implantations of tumor. Abdominal pain and distention is the most common complaint. Imaging often reveals heterogeneous enhancement of the mass with central necrosis being common (Pickhardt et al., 1999). The presence of abdominal ascites is typical, given the predilection for liver involvement. Histologic staining of the EWSR1-WT1 fusion product is diagnostic for these tumors. Prognosis is universally poor, despite multimodal therapy to address widespread disease.

Desmoplastic Small Round Cell Tumor

Desmoplastic Small Round Cell Tumor (DSRCT) is a neoplasm of uncertain histogenesis with a striking predilection for forming large and small tumor masses on the serosal surfaces. Most cases are intra-abdominal, but the tumor can involve the pelvis, retroperitoneum, scrotum, and pleura. DSRCT affects mainly male adolescents and young adults between the ages of 15 and 35 years.

CYTOMORPHOLOGY OF DESMOPLASTIC SMALL ROUND CELL TUMOR:

sheets and clusters of small to intermediate-sized cells

fragments of desmoplastic stroma

uniformly round to oval cells

nuclear molding

Smears are variably cellular, with sheets and clusters of loosely cohesive, small to intermediate-sized cells. The groups often recapitulate the irregular shapes of the nests and islands seen in histologic sections. Occasional isolated cells are present among fragments of variably cellular and collagenous (“desmoplastic”) stroma. The tumor cells are uniformly undifferentiated and predominantly round to oval, with rare polygonal or spindled forms (Fig. 16.29). Nuclei are hyperchromatic, with finely granular chromatin and inconspicuous nucleoli. Nuclear molding can be striking, particularly at the edges of groups. The scanty cytoplasm stains palely amphophilic to eosinophilic, and occasional “rhabdoid” cells are present. Tumor cells in postchemotherapy cases can have a different cytomorphology, with isolated larger cells with conspicuous nucleoli.122

The differential diagnosis is similar to that for ES/PNET. DSRCT cells demonstrate a peculiar but characteristic polyphenotypic differentiation, with positive immunoreactivity for low-molecular-weight cytokeratins, EMA, neuroendocrine markers, and desmin, the latter in a characteristic dotlike pattern. They are also positive for Wilms tumor (WT1) and variably positive for CD99. DSRCT demonstrates a specific cytogenetic abnormality with t(11;22)(p13;q12) involving the EWS gene on 22q12 and the WT1 gene on 11p13 (Fig. 16.28).32,122–124

Intraabdominal Desmoplastic Small Round Cell Tumor

Desmoplastic Small Round Cell Tumor

DSRCT is an aggressive malignant neoplasm of uncertain histogenesis with a striking predilection for forming large and small tumor masses on the serosal surfaces. Most cases are intra-abdominal, but the tumor can involve the pelvis, retroperitoneum, scrotum, and pleura. DSRCT affects mainly male adolescents and young adults between the ages of 15 and 35 years.

Cytomorphology of desmoplastic small round cell tumor

sheets and clusters of small to intermediate-sized cells

fragments of desmoplastic stroma

uniformly round, oval, or slightly angulated cells

nuclear molding

vague, small acinar structures

Smears are variably cellular, with sheets and clusters of loosely cohesive, small to intermediate-sized cells. The groups often recapitulate the irregular shapes of the nests and islands seen in histologic sections. Occasional isolated cells are present among fragments of variably cellular and collagenous (desmoplastic) stroma. The tumor cells are uniformly undifferentiated and predominantly round to oval, with rare polygonal or spindled forms (Fig. 17.35). Nuclei are hyperchromatic, with finely granular chromatin and inconspicuous nucleoli. Nuclear molding can be striking, particularly at the edges of groups. The scant cytoplasm is pale and amphophilic to eosinophilic, and occasional rhabdoid cells are present. Tumors in postchemotherapy cases can have isolated larger cells with conspicuous nucleoli.145,146

The differential diagnosis is similar to that for Ewing sarcoma. DSRCT cells demonstrate a peculiar but characteristic polyphenotypic differentiation, with positive immunoreactivity for low-molecular-weight cytokeratins, EMA, neuroendocrine markers, and desmin, the latter in a characteristic dotlike pattern. They are also positive for Wilms tumor (WT1) (antibody against C-terminal of WT1) and variably positive for CD99 (cytoplasmic). DSRCT demonstrates a specific cytogenetic abnormality: a t(11;22)(p13;q12) translocation involving the EWS gene on 22q12 and the WT1 gene on 11p13 (see Fig. 17.34 and Table 17.1).35,145,147,148

Desmoplastic small round cell tumor

DSRCT is a rare aggressive tumor that predominantly arises in children and adolescent males. Tumors typically arise in the abdomen and show extensive intra-abdominal growth. Approximately 5% of tumors arise outside the abdominal cavity. Histologically, DSRCT is composed of nests of small round cells within a desmoplastic stroma (Figure 15). Rarely, glandular differentiation or rosette formation is seen. The tumor cells typically show polyphenotypic differentiation, with expression of epithelial, muscle, and neural markers (keratin, epithelial membrane antigen, desmin, and neuron-specific enolase, Figure 15). CD99 may show cytoplasmic positivity in tumor cells, unlike the typical membranous staining pattern of ES.

DSRCT characteristically harbors a t(11;22)(p13;q12), fusing EWSR1 and WT1 genes. As in many other sarcoma types, the resultant chimeric protein acts as an aberrant transcription factor. Immunohistochemistry using antibodies directed against the C-terminus of WT1 may be helpful, but the available antibodies yield inconsistent results, and therefore molecular testing is more reliable if additional tests are needed to confirm the diagnosis of DSRCT.

Desmoplastic small round cell tumor

Desmoplastic small round cell tumor (DSRCT) is a highly malignant neoplasm that was first described in 1989 by Gerald and Rosai. It usually affects young persons during the second decade of life with a striking male predilection (male to female ratio >5:1). The tumor occurs most commonly in the peritoneal cavity, causing abdominal pain, distention, and occasionally ascites.

DSRCT can also occur in the paratesticular region.225,226 In this location, it characteristically presents as a scrotal mass in a young man. The mean age of men with paratesticular DSRCT is 28 years. Gross and microscopic examination reveals that the tumor may involve the paratesticular soft tissue, the tunics, and epididymis.

The tumor is composed of nests and islands of small uniform cells divided into multiple nodules by desmoplastic stroma. They show immunohistochemical evidence of multilineage differentiation, including epithelial, mesenchymal, and neuronal features. The tumor cells are positive for cytokeratin, vimentin, desmin, and neuron-specific enolase, and negative for HBA-71. DSRCT belong to the Ewing's sarcoma (ES) family of tumors and share morphologic and immunohistochemical features with primitive neuroectodermal tumors or PNET. PNETs and ES are characteristically positive for CD99, which is also known as O13.

Some studies have found that DSRCTs can be reliably differentiated from PNET with antibodies to WT1. DSRCTs stain with WT1 antibody while PNETs do not. However, rhabdomyosarcomas also stain with WT1 antibody.227

Other tumors which enter into the differential diagnosis of DSRCT are embryonal rhabdomyosarcoma, malignant lymphoma, and retinal anlage tumor, which are also all composed of ‘small round blue cells.’ Embryonal rhabdomyosarcoma has myxoid stroma and occurs at a much younger age. Rhabdomyoblasts with densely eosinophilic abundant cytoplasm and cross-striations, when present, are helpful in diagnosing rhabdomyosarcoma. Myogenin, a marker for early muscle differentiation, can be used to differentiate rhabdomyoblastoma from DSRCT in difficult cases.

Malignant lymphomas lack the nests and clusters formed by the tumor cells in DSRCT. They also lack the sclerotic stroma and the immunohistochemical profile of DSRCT. In challenging cases, reverse transcriptase-polymerase chain reaction analysis of paraffin sections for demonstration of ES/WT1 chimeric mRNA is conclusive for DSRCT, since DSRCTs are characterized this gene fusion transcript t(11;22)(p13;q12) caused by a reciprocal translocation.

A recent study has found that DSRCTs overexpress connective tissue growth factor, CCN2, raising the possibility that CCN2 may be responsible for the characteristic desmoplasia of these tumors. Using immunohistochemistry and in situ hybridization, researchers found that CCN2 mRNA and protein were colocalized both to the tumor itself and to adjacent stromal fibroblasts and vascular endothelial cells.228 The diagnostic utility of this finding is, however, questionable.

Intra-abdominal Desmoplastic Small-Cell Tumor

Desmoplastic small-cell tumor (DSCT) is a malignant small-cell neoplasm characterized by diffuse involvement of the abdominal or pelvic peritoneum without a definite primary organ site of origin. DSCT occurs predominantly in young men with a mean age of 18.6 years. Patients present with symptoms related to the presence of large infiltrative or compressing mass lesions, including severe abdominal pain, incontinence of urine, constipation, and abdominal distention. The tumor is associated with an aggressive clinical course, and death usually occurs within 2 years after diagnosis. Caraway and associates described the cytologic appearance of DSCT in specimens procured by FNA from four young men aged 17–27 years, from abdominal or liver masses or from supraclavicular lymph nodes.162 The tumors were composed of small cells that tended to cluster and that contained round to oval nuclei, fine chromatin, and inconspicuous nucleoli (Fig. 27.65A). By histology, the cells evidence nesting with a prominent desmoplastic stromal reaction and frequent mitosis. The cells were positive for both keratin and desmin, the former distributed in a paranuclear dot-like pattern (Fig. 27.65B). By ultrastructural examination, the tumor cells had small junctions, scant cytoplasm, and paranuclear bundles of intermediate filaments and showed neither neuroendocrine nor rhabdomyosarcomatous differentiation. DSCT should be differentiated from other small round cell tumors that occur in this age group and location. Table 27.11 lists the differential diagnosis and typical immunocytochemical profiles of the different entities.

Desmoplastic Small Round Cell Tumor

Desmoplastic small round cell tumor (DSRT) typically arises in intra-abdominal soft tissues and has a strong predilection for males. Although its most common site is the peritoneum, DSRT can arise in kidney, testes, ovaries, pleura, scalp, ethmoid sinuses, and pancreas.468-472 DSRT usually presents with abdominal pain and weight loss and is commonly locally or distantly metastatic at the time of diagnosis. The diffuse paraserosal spread of DSRT may prevent resection with negative margins. A high tumor response rate in untreated DSRT and previously treated DSRT to high-dose cyclophosphamide, doxorubicin, and vincristine alternating with ifosfamide and etoposide may reduce bulky disease, permitting surgical resection and radiotherapy, if necessary.473 Although the results are mixed, patients with high-risk disease may benefit from consolidation by high-dose chemotherapy and autologous stem cell rescue.474,475 Relapsed disease may respond to irinotecan and temozolomide or low-dose cyclophosphamide and vinorelbine.476,477 DSRT tends to develop and spread widely in the peritoneum, so based on its efficacy in peritoneal carcinomatosis, the use of continuous hyperthermic peritoneal infusion of chemotherapy is being studied, although initial results do not appear promising.476,478 Multimodality therapy, consisting of aggressive surgical debulking, chemotherapy, and external beam radiotherapy, was associated with a 3-year survival rate of 55% compared to 27% when all three modalities were not used. Gross tumor resection was associated with a 58% 3-year survival rate compared to no survivors in the nonresected control group.479 However, despite multimodality therapy, long-term survival rates remain very low.

As the name implies, DSRT appears histologically as malignant, undifferentiated, small round cells that are typically associated with a prominent desmoplastic reaction (Fig. 20-28).480 Desmoplastic stroma, however, is not always present, and the location of the tumor may play a role in this regard. For example, desmoplastic small round cell tumor originating in the kidney characteristically lacks desmoplastic stroma.468 Some tumors have glandular or rosette-like epithelial differentiation. Nuclei are usually hyperchromatic with little pleomorphism and with dispersed chromatin and small nucleoli. The scant cytoplasm is poorly outlined. A rhabdoid-type cytoplasmic inclusion can be observed focally in about half of cases. Areas of necrosis and frequent mitoses are common. Multiphenotypic differentiation is characteristic immunohistochemically. Most cases show immunoreactivity for cytokeratin, EMA, vimentin, and desmin. Desmin and vimentin commonly show a dotlike intracytoplasmic pattern corresponding to the rhabdoid-type inclusion. Nuclear WT1 expression with antibodies to the carboxy terminus is usually observed. Ultrastructurally, tumor cells are primitive and organelle-poor and may show paranuclear whorls of intermediate filaments (see Fig. 20-28C). Cell junctions including desmosomes may be observed focally.

Molecularly, DSRT is characterized by t(11;22)(p13;q12), which fuses the Ewing's sarcoma gene EWS with WT1.481-484 Although there is variability in the structure of the resulting chimera, the most common fusion includes EWS exons 1 through 7 and WT1 exons 8 through 10.484,485 WT1 is a Cys2-His2 zinc finger DNA-binding protein that shares a high degree of homology and DNA recognition motif with the growth factor stimulated zinc finger DNA-binding protein EGR1.486-489 The most common translocations result in EWS-WT1 chimeras that preserve three of the four zinc finger motifs. However, because of molecular heterogeneity, chimeras may lack other EWS or WT1 exons.485 The EWS-WT1 fusion has been detected in two intra-abdominal tumors that had histologic features of epithelioid leiomyosarcoma but lacked desmoplastic stroma, suggesting either a variant DSRT or another tumor type marked by EWS-WT1.490 Based on the paradigm of the other transcription factors fused to the Ewing's sarcoma gene, EWS-WT1 is thought to exert its oncogenic activity through transcriptional mechanisms, and several putative transcriptional targets have been identified. The EWS-WT1 fusion activates platelet-derived growth factor alpha (PDGFA), T cell acute lymphoblastic leukemia-associated antigen 1 (TALLA-1), and interleukin-2/15 receptor expression.491-493 DSRTs stain positive for PDGF and for insulin-like growth factor II.494 As a mitogen potentially acting on tumor-associated fibroblasts, PDGF seems to be a plausible cause for the desmoplastic reaction characteristic of these tumors. However, immunohistochemical analysis demonstrates an inverse correlation of PDGF expression with desmoplasia.495 Although PDGF expression might suggest therapeutic PDGFR inhibition, imatinib mesylate demonstrates little to no activity as a single agent for DSRT.496 About one third of DSRTs stain positive for androgen receptor, and androgen blockade may result in some response.497