Abdomen

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2020, Case 24, and is desmoplastic small round cell tumor in the abdomen.

The information provided in this case was accurate and correct at the time of publication in 2020.

Any changes in terminology since the time of publication may not be reflected in this case.

The biopsy reveals a small round cell tumor composed of round cells with irregular nuclei and variable amounts of eosinophilic cytoplasm. Some of the tumor cells have a rhabdoid appearance characterized by eosinophilic cytoplasm and eccentric vesicular nuclei. Necrosis is present. Desmoplasia is not apparent. Immunohistochemical studies reveal the tumor to be positive for AE1/AE3 and neuron-specific enolase (NSE). Also, it is focally positive for desmin in a dot-like pattern and it shows nuclear expression of WT1 (C-terminus). The tumor retains expression of INI1 and is negative for S100, MyoD1, CD99 (membranous), CD45, and CD20. Molecular analysis reveals a reciprocal translocation involving the EWSR1 gene located on chromosome 22q12 and WT1 located on 11p13. The overall findings are consistent with a diagnosis of desmoplastic small round cell tumor (DSRCT).  

DSRCT is a rare, aggressive round cell tumor, initially described by William Gerald and Juan Rosai in 1991. It can arise in a broad age range, including young children and older adults, but has a predilection for male adolescents and young adults with a mean age of 22. The tumor typically occurs in the abdominopelvic cavity in the omentum, retroperitoneum, and mesentery and often shows widespread serosal involvement. Rare cases have been described in the head and neck, visceral organs, intrathoracically, intrascrotally, and paratesticularly. The tumors are highly aggressive. Metastases typically occur in the lung, liver, and distant lymph nodes. Bone and bone marrow involvement is rare. The treatment of choice is often intensive chemotherapy followed by aggressive debulking surgery and radiation therapy.  

The majority of cases have a distinctive histology from which the tumor derives its name — well-defined nests and islands of tumor cells embedded in a highly vascular desmoplastic stroma. The nuclei vary from uniform to pleomorphic to rhabdoid. Mitoses and areas of necrosis are common. Less commonly, the tumor may show a solid growth pattern without desmoplasia, papillary or single cell patterns, and epithelioid nuclear features. Multiple histologies may be seen within one tumor. The histologic appearance of the tumor mimics other undifferentiated round cell tumors, many of which also show a predilection for this age group. Focused panels of immunostains and molecular analysis are important to arrive at a correct diagnosis.  

Immunohistochemically, DSRCT is characterized by polyphenotypic differentiation with the expression of epithelial markers (EMA, CK8/18, and AE1/AE3), neural markers (NSE and CD57), and desmin (classically in a distinctive paranuclear dot-like pattern). Sixty-five percent to 95% of tumors are also immunoreactive with antibodies directed against the carboxy-terminus of the WT1 protein. This nuclear staining pattern reflects the WT1 transcripts in most of the tumors, which contain the carboxy terminal of the WT1 protein. However, depending on the translocation, unusual immunohistochemical staining patterns have been seen. Rarely, the amino-terminus (N-terminus) portion of the Wilms tumor protein is the one present. In these cases, the tumor will only stain with antibodies containing the N-terminus. Negative results for WT1 must therefore be carefully interpreted, and trying a different antibody directed at  different epitopes can be useful. Expression of WT1 is not specific for DSRCT and can be seen in CIC-rearranged sarcomas, Wilms tumor, mesothelioma, and serous carcinoma of the ovary. There is variable expression of actin, CD99, S100, synaptophysin, chromogranin, and S100. Myogenin, MyoD1, CK20, and CK5/6 are negative. The potential for cases to exhibit aberrant immunohistochemical staining patterns can lead to confusion with other small round blue cell tumors. 

Molecularly, DSRCT has a distinct and diagnostic molecular alteration consisting of a reciprocal translocation t(11;22)(p13;q12) resulting in the fusion of EWSR1 (22q12) to WT1 (11p13). RT-PCR and fluorescence in situ hybridization (FISH) can both identify the EWSR1::WT1 fusion on either frozen or formalin-fixed tissue. Therefore, DSRCT, along with Ewing sarcoma, clear cell sarcoma, a subset of myoepithelial carcinomas, hyalinizing clear cell carcinoma, and other tumors, fall into the category of tumors with an EWSR1 alteration. Identifying the fusion partner can separate DSRCT from histologically similar tumors harboring EWSR1 rearrangements. 

Rhabdomyosarcoma (RMS) is subclassified into four groups: embryonal, alveolar, pleomorphic, and spindle cell/sclerosing subtypes. Abdominal tumors may occur due to metastatic spread of an alveolar subtype or a primary embryonal tumor arising in the retroperitoneum. RMS can cause confusion with DSRCT morphologically, as it also shows nests of discohesive round cells surrounded by fibrovascular septa yielding a pseudoalveolar pattern or a solid pattern. Multinucleated giant cells called wreath cells are often present and can be a helpful clue to the diagnosis. Rhabdoid nuclear features may be present. Alveolar and embryonal RMS can be separated from DSRCT by positive expression of muscle markers myogenin and MyoD1, which are negative in DSRCT. Eighty percent of alveolar RMS harbor a diagnostic translocation fusion between PAX3 gene (at 2q36.1) (most common) or the PAX7 gene (at 1p36.13) with the FOXO1 gene (at 13q14.11), designated as fusion-positive tumors. Identification of the PAX3/PAX7::FOXO1 gene fusion allows for definitive diagnosis of an alveolar RMS.  

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that can be separated into three variants depending on the clinical setting: an endemic variant, a sporadic variant, and an HIV-associated variant. The sporadic variant predominantly affects young men (mean age of 30 years) and typically arises in the ileo-cecum. The tumor cells are uniform, of intermediate size with round nuclei, and often have multiple dark nucleoli and basophilic cytoplasm. The tumor has a high mitotic/apoptotic rate and interspersed tingible body macrophages, which gives rise to a starry sky pattern on low power. The tumor cells are positive for B-cell markers CD20, CD19, CD22, and CD79a, as well as germinal center markers CD10 and BCL6. The tumor is negative for epithelial antigens, S100, and desmin. Almost all cases of BL harbor a MYC translocation typically between the long arm of chromosome 8 (the site of the MYC gene on 8q24) and one of the three immunoglobulin genes.  

Ewing sarcoma (ES) is the prototypic small round cell tumor of bone and soft tissue and has a predilection for adolescents and young adults. The classic histology is that of an undifferentiated small blue cell tumor with light and dark areas. The tumor cells have a high nuclear to cytoplasm ratio, often with abundant glycogen and occasional rosette formation. Necrosis and mitoses are common. Rare tumors can show a nested pattern with intervening desmoplasia, mimicking a DSRCT. ES is defined by the reciprocal translocation of the EWSR1 gene and members of the Ewing family of transcription factors, most frequently FLI1 and ERG. Immunohistochemically, ES differs from DSRCT by diffuse membranous staining with CD99 in 90% of tumors and nuclear FLI1 in 67% of tumors. NKX2.2 is a sensitive but not specific marker. Variable expression of cytokeratins, S100, chromogranin, synaptophysin, and NSE can be seen. Desmin is usually negative. 

CIC::DUX4 sarcoma is an aggressive undifferentiated round cell sarcoma with a predilection for young adults. The tumors most commonly arise in the deep soft tissue of the trunk or extremities. The most common histologic appearance is that of solid sheets of round to oval tumor cells. By immunohistochemistry the tumor can show nuclear expression of WT1 and can focally express CD99 in a membranous pattern. Molecular analysis is diagnostic revealing a CIC::DUX4 gene fusion. 

1. Which of the following immunohistochemical results would be most supportive of a diagnosis of desmoplastic small round cell tumor (DSRCT)?
   
   
   1. CD99 in a membranous pattern, desmin negative, cytokeratin negative
   2. Cytoplasmic expression of WT1 C-terminal antibody
   3. Cytoplasmic expression of WT1 N-terminal antibody
   4. Nuclear expression of WT1 C-terminal antibody
   5. Nuclear staining with myogenin
2. Which of the following translocations is unique for DSRCT?
   
   
   1. EWSR1::ERG
   2. EWSR1::FLI1
   3. EWSR1::WT1
   4. MYC::IGH
   5. PAX3::FOXO1
3. The identification of an ESWR1 gene rearrangement would exclude which of the following tumors from the differential diagnosis?
   
   
   1. Clear cell sarcoma
   2. DSRCT
   3. Ewing sarcoma
   4. Hyalinizing clear cell carcinoma
   5. Rhabdomyosarcoma

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2. Anderson WJ, Hornick JL. Immunohistochemical correlates of recurrent genetic alterations in sarcomas. Genes Chromosomes Cancer. 2019;58(2):111-123.
3. Chougule A, Talyor MS, Nardi V, et al. Spindle and round cell sarcoma with EWSR1-PATZ1 gene fusion: a sarcoma with polyphenotypic differentiation. Am J Surg Pathol. 2019;43(2):220-228.
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5. Gerald WL, Miller HK, Battifora H, Miettinen M, Silva EG, Rosai J. Intra-abdominal desmoplastic small round cell tumor. Report of 19 cases of a distinctive type of high-grade polyphenotypic malignancy affecting young individuals. Am J Surg Pathol. 1991;15(6):499-513.
6. Mora J, Modak S, Cheung NK, et al. Desmoplastic small round cell tumor 20 years after its discovery. Future Oncol. 2015;11(7):1071-1081.
7. Murphy AJ, Bishop K, Pereira C, et al. A new molecular variant of desmoplastic small round cell tumor: significance of WT1 immunostaining in this entity. Hum Pathol. 2008;39(12):1763-1770.
8. Specht K, Sung YS, Zhang L, Richter GH, Fletcher CD, Antonescu CR. Distinct transcriptional signature and immunoprofile of CIC-DUX4 fusion-positive round cell tumors compared to EWSR1-rearranged Ewing sarcomas: further evidence toward distinct entities. Genes Chromosomes Cancer. 2014;53(7):622-633.

1. Nuclear expression of WT1 C-terminal antibody (d)
2. EWSR1::WT1 (c)
3. Rhabdomyosarcoma (e)