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• W3205288669 abstract "Desmoplastic small round cell tumour (DSRCT) is an aggressive, paediatric mesenchymal neoplasm that predominantly involves the abdominal or pelvic peritoneum and often presents with widespread abdominal/peritoneal implants or metastases. Histologically, DSRCT has a characteristic appearance of nests of fairly uniform small round cells setting in variable amounts of desmoplastic stroma and immunohistochemically it exhibits a polyphenotypic multi-directional differentiation, with co-expression of epithelial, neural, and muscle markers.1Agaram N.P. Antonescu C.R. Ladanyi M. Desmoplastic small round cell tumour.In: WHO Classification of Tumours Editorial Board. WHO Classification of Tumours of Soft Tissue and Bone. 5th ed. IARC Press, Lyon2020: 306-308Google Scholar,2Gerald W.L. Miller H.K. Battifora H. et al.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: 499-513Crossref PubMed Scopus (547) Google Scholar Cytogenetically, DSRCT is characterised by a recurrent t(11;22)(p13;q12) translocation, leading to formation of the EWSR1-WT1 fusion transcripts that are composed mainly of the first 7 exons of the EWSR1 gene and the last three exons (exons 8–10) of the WT1 gene.3Gerald W.L. 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: 3028-3036Crossref PubMed Scopus (354) Google Scholar The diagnosis of DSRCT is relatively straightforward if the tumour arises in typical locations, exhibiting both its characteristic morphological and immunohistochemical features. However, DSRCT can occur more rarely in extra-abdominal/peritoneal sites either as primary or metastatic tumour and can display a broad spectrum of both morphological features and immunoprofiles, which may cause diagnostic confusion with other small round cell tumours.1Agaram N.P. Antonescu C.R. Ladanyi M. Desmoplastic small round cell tumour.In: WHO Classification of Tumours Editorial Board. WHO Classification of Tumours of Soft Tissue and Bone. 5th ed. IARC Press, Lyon2020: 306-308Google Scholar In these contexts, detection of the EWSR1-WT1 fusion represents a very useful tool for the differential diagnosis of DSRCT from its mimics. We report a unique case of DSRCT that presented as cervical lymph nodes metastases, which showed solid morphology with minimal or no desmoplastic stroma and harboured a novel EWSR1-WT1 fusion gene detected by targeted next generation sequencing (NGS) with confirmation by fluorescence in situ hybridisation (FISH) studies. The patient was a 25-year-old, previously healthy Chinese male who presented with enlargement of a left neck mass of 2 months duration. Physical examination identified a 2.0 cm, firm, rubbery, unfixed mass with multiple mobile small nodules in the left anterior upper neck, which were indicated as abnormal lymph nodes by ultrasonography. A core needle biopsy was performed as an initial workup, which revealed sheets of round and epithelioid neoplastic cells with atypical nuclei and brisk mitoses, admixed with a few mature-appearing lymphoid tissues; the neoplastic cells were positive for cytokeratin (CK) AE1/3 and CK7 and negative for p40, LCA, and EBER in situ hybridisation, and a diagnosis suggesting ‘lymph node metastatic malignancy, highly suspicious for poorly differentiated carcinoma’ was rendered. A subsequent positron emission tomography computed tomography (PET-CT) scan showed multiple solid and cystic masses located in the neck and body of the pancreas with widespread metastases to lymph nodes in hilar, hepatogastric space, retroperitoneal cavity and left upper neck region. Incisional biopsy of the largest cervical lymph node showed almost complete effacement of nodal architecture by an infiltrate of malignant cells, with only a few residual lymphoid follicles identified (Fig. 1A). At lower power, the neoplastic cells were arranged predominantly in large, solid sheets with little or no intervening stroma, and multiple foci of tumour necrosis resembling comedo-necrosis seen in breast carcinoma were noted (Fig. 1B). Upon close observation, a focal area showing vague nests of neoplastic cells separated by thin fibrocollagenous bands was identified at the periphery of the lesion (Fig. 1C). At high magnification, the neoplastic cells were monomorphic with scant to moderate amounts of lightly eosinophilic cytoplasm; the nuclei were uniform, round, and sometimes eccentrically placed, with vesicular or coarse chromatin (Fig. 1D). Numerous apoptotic neoplastic cells and 35 mitoses per 10 high power fields were noted. By immunohistochemistry, the neoplastic cells in the resected lymph node were positive diffusely and strongly for CK AE1/3 (Fig. 1E) and epithelial membrane antigen (EMA) (Fig. 1F). Staining for desmin showed a typical diffuse and perinuclear dot-like pattern (Fig. 1G). Neural markers such as synaptophysin and neuron specific enolase (NSE) were not expressed in any cells, and insulinoma-associated protein 1 (INSM-1), a zinc-finger transcription factor related to neuroendocrine differentiation,4Rosenbaum J.N. Guo Z. Baus R.M. et al.INSM1: a novel immunohistochemical and molecular marker for neuroendocrine and neuroepithelial neoplasms.Am J Clin Pathol. 2015; 144: 579-591Crossref PubMed Scopus (123) Google Scholar was expressed in very few neoplastic cells (Fig. 1H). Staining with antibodies against smooth muscle actin (SMA), MyoD1, myogenin, CD99, NKX2.2, TLE-1, CD34, CD30, CD3, CD20 and ALK (1A4) were all negative in the neoplastic cells. The expression of SMARCB1/INI1 was retained and the Ki-67 proliferation index was approximately 70%. Genetic testing was performed using targeted NGS for 425 cancer-relevant genes (Geneseeq Prime; Geneseeq Technology, Canada), which revealed a fusion gene between EWSR1 exon 7 and WT1 exon 7 with a variant allele frequency (VAF) of 31.1% (Fig. 2A). FISH analyses using the break-apart probe sets demonstrated positive rearrangements of both the EWSR1 (Fig. 2B) and WT1 (Fig. 2C) loci, thus confirming the NGS results. On the basis of the morphological, immunophenotypic, and molecular genetic features, a diagnosis of metastatic solid variant DSRCT was rendered for this lymph node lesion. The imaging findings suggested that the primary site was located in the abdominal cavity, which was in line with the typical clinical manifestations of DSRCT. The patient was treated by 24 weeks of chemotherapy with doxorubicin and cisplatin, without surgical resection of the main masses, and his status was stable 9 months following diagnosis. DSRCT mostly arises in the abdominopelvic cavity, often with widespread serosal involvement, and rarely presents outside the abdominopelvic cavity, mainly in the thoracic cavity and paratesticular region.1Agaram N.P. Antonescu C.R. Ladanyi M. Desmoplastic small round cell tumour.In: WHO Classification of Tumours Editorial Board. WHO Classification of Tumours of Soft Tissue and Bone. 5th ed. IARC Press, Lyon2020: 306-308Google Scholar,5Thway K. Noujaim J. Zaidi S. et al.Desmoplastic small round cell tumor: pathology, genetics, and potential therapeutic strategies.Int J Surg Pathol. 2016; 24: 672-684Crossref PubMed Scopus (41) Google Scholar Clinically, it typically presents symptoms related to the primary site, such as painful abdominal masses with abdominal distension, acute abdomen, ascites, and organ obstruction.1Agaram N.P. Antonescu C.R. Ladanyi M. Desmoplastic small round cell tumour.In: WHO Classification of Tumours Editorial Board. WHO Classification of Tumours of Soft Tissue and Bone. 5th ed. IARC Press, Lyon2020: 306-308Google Scholar,5Thway K. Noujaim J. Zaidi S. et al.Desmoplastic small round cell tumor: pathology, genetics, and potential therapeutic strategies.Int J Surg Pathol. 2016; 24: 672-684Crossref PubMed Scopus (41) Google Scholar However, DSRCT can present initially as disseminated metastases, which are often intra-abdominally confined, with the most common location being liver.5Thway K. Noujaim J. Zaidi S. et al.Desmoplastic small round cell tumor: pathology, genetics, and potential therapeutic strategies.Int J Surg Pathol. 2016; 24: 672-684Crossref PubMed Scopus (41) Google Scholar The case of DSRCT currently reported is unique in that it presented as multiple cervical lymph nodes metastases, which led to the imaging discovery of multiple masses in the pancreas with extensive intra-abdominal lymph nodes metastases. Extra-abdominal metastasis for DSRCT is rare, with the reported incidence being less than 5%, and has been documented most frequently to the lung and brain.6Stiles Z.E. Dickson P.V. Glazer E.S. et al.Desmoplastic small round cell tumor: a nationwide study of a rare sarcoma.J Surg Oncol. 2018; 117: 1759-1767Crossref PubMed Scopus (35) Google Scholar Extra-abdominal lymph node metastasis as the initial clinical presentation for DSRCT is exceptional but has been sporadically documented in the literature. Backer et al.7Backer A. Mount S.L. Zarka M.A. et al.Desmoplastic small round cell tumour of unknown primary origin with lymph node and lung metastases: histological, cytological, ultrastructural, cytogenetic and molecular findings.Virchows Arch. 1998; 432: 135-141Crossref PubMed Scopus (21) Google Scholar in 1998 described a case of metastatic DSRCT of unknown origin that presented with supraclavicular and axillary lymph node deposits and multiple pulmonary and brain metastases. Lae et al.8Lae M.E. Roche P.C. Jin L. et al.Desmoplastic small round cell tumor: a clinicopathologic, immunohistochemical, and molecular study of 32 tumors.Am J Surg Pathol. 2002; 26: 823-835Crossref PubMed Scopus (269) Google Scholar in 2002 reported a series of 32 cases of DSRCT, one of which presented as an axillary lymph node metastasis, leading to the diagnosis of an abdominal and pelvic DSRCT with retroperitoneal lymph node metastasis. An additional case, reported by Mihok and Cha9Mihok N.A. Cha I. Desmoplastic small round cell tumor presenting as neck mass: a case report.Diagn Cytopathol. 2001; 25: 68-72Crossref PubMed Scopus (19) Google Scholar in 2001, presented as a supraclavicular neck mass that was found to be a metastatic lymph node from a primary abdominal DSRCT. Much more rarely, DSRCT can arise as primary disease in extra-abdominal lymph nodes and other anatomical sites that are uncovered by serosa, including bone and soft tissue in the limbs, head and neck region, and central nervous system.1Agaram N.P. Antonescu C.R. Ladanyi M. Desmoplastic small round cell tumour.In: WHO Classification of Tumours Editorial Board. WHO Classification of Tumours of Soft Tissue and Bone. 5th ed. IARC Press, Lyon2020: 306-308Google Scholar,5Thway K. Noujaim J. Zaidi S. et al.Desmoplastic small round cell tumor: pathology, genetics, and potential therapeutic strategies.Int J Surg Pathol. 2016; 24: 672-684Crossref PubMed Scopus (41) Google Scholar,8Lae M.E. Roche P.C. Jin L. et al.Desmoplastic small round cell tumor: a clinicopathologic, immunohistochemical, and molecular study of 32 tumors.Am J Surg Pathol. 2002; 26: 823-835Crossref PubMed Scopus (269) Google Scholar However, in these scenarios, extensive clinicopathological and radiological correlation to exclude metastasis from an abdominopelvic DSRCT is mandatory. In the current World Health Organization classification, DSRCT is defined as a malignant mesenchymal neoplasm composed of small round tumour cells associated with prominent stromal desmoplasia, polyphenotypic differentiation, and EWSR1-WTI gene fusion.1Agaram N.P. Antonescu C.R. Ladanyi M. Desmoplastic small round cell tumour.In: WHO Classification of Tumours Editorial Board. WHO Classification of Tumours of Soft Tissue and Bone. 5th ed. IARC Press, Lyon2020: 306-308Google Scholar However, a range of morphological appearances, such as spindle, rhabdoid and epithelioid cell morphology, the presence of epithelial features with glands or a rosette pattern, and the absence of desmoplastic stroma, have been rarely described.1Agaram N.P. Antonescu C.R. Ladanyi M. Desmoplastic small round cell tumour.In: WHO Classification of Tumours Editorial Board. WHO Classification of Tumours of Soft Tissue and Bone. 5th ed. IARC Press, Lyon2020: 306-308Google Scholar,5Thway K. Noujaim J. Zaidi S. et al.Desmoplastic small round cell tumor: pathology, genetics, and potential therapeutic strategies.Int J Surg Pathol. 2016; 24: 672-684Crossref PubMed Scopus (41) Google Scholar It has been proposed that the most diagnostically challenging features for DSRCT are related to the spindle cell morphology, or to the absence of desmoplastic stroma. Recently, Al-Ibraheemi et al.10Al-Ibraheemi A. Broehm C. Tanas M.R. et al.Desmoplastic small round cell tumors with atypical presentations: a report of 34 cases.Int J Surg Pathol. 2019; 27: 236-243Crossref PubMed Scopus (23) Google Scholar reported a series of 34 cases of DSRCT with atypical presentations, six of which exhibited solid growth pattern, while the absence of stromal desmoplasia was found in two cases; both tumours were located outside the abdominopelvic cavity (with one each in the neck and thigh). Our case of pure solid morphology and lacking prominent desmoplastic stroma illustrates that its diagnosis can be difficult when there is variant morphology, especially when occurring at an unexpected location. Differential diagnoses mainly include primary high-grade lymphoma and other metastatic small round cell tumours, such as poorly differentiated carcinoma, synovial sarcoma, Ewing sarcoma, and solid pattern of alveolar rhabdomyosarcoma. Although immunohistochemical staining plays an important role in the histological diagnosis of DRSCT, molecular testing for the EWSR1-WT1 fusion is often required to confirm the diagnosis. Another intriguing finding of our case was that the chimeric transcripts found by NGS analysis were composed of an unusual in-frame junction of exon 7 of EWSR1 to exon 7 of WT1. Although the EWSR1-WT1 fusion transcript of DSRCT usually consists of the first 7 exons of the EWSR1 gene fused to the last 3 exons (exons 8–10) the WT1 gene, a range of non-classic breakpoints for the t(11;22)(p13;q12) translocation have been reported, including use of EWSR1 exons 8, 9, and 10, as well as variant transcripts due to aberrant splicing resulting in loss of EWSR1 exon 6 or WT1 exon 9.1Agaram N.P. Antonescu C.R. Ladanyi M. Desmoplastic small round cell tumour.In: WHO Classification of Tumours Editorial Board. WHO Classification of Tumours of Soft Tissue and Bone. 5th ed. IARC Press, Lyon2020: 306-308Google Scholar,3Gerald W.L. 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: 3028-3036Crossref PubMed Scopus (354) Google Scholar,5Thway K. Noujaim J. Zaidi S. et al.Desmoplastic small round cell tumor: pathology, genetics, and potential therapeutic strategies.Int J Surg Pathol. 2016; 24: 672-684Crossref PubMed Scopus (41) Google Scholar,6Stiles Z.E. Dickson P.V. Glazer E.S. et al.Desmoplastic small round cell tumor: a nationwide study of a rare sarcoma.J Surg Oncol. 2018; 117: 1759-1767Crossref PubMed Scopus (35) Google Scholar However, to our knowledge, the in-frame junction of exon 7 of EWSR1 to exon 7 of WT1 found in the present case has not been previously described in DSRCT. Most recently, Magro et al.11Magro G. Broggi G. Zin A. et al.Desmoplastic small round cell tumor with pure spindle cell morphology and novel EWS-WT1 fusion transcript: expanding the morphological and molecular spectrum of this rare entity.Diagnostics (Basel). 2021; 11: 545Crossref PubMed Scopus (5) Google Scholar documented an abdominal DSRCT that exhibited a wholly solid pattern of pure spindle cell morphology, absence of desmoplastic stroma and harboured a novel fusion transcript for exon 9 of EWSR1 to exon 7 of WT1. This case showed many features similar to those found in our case. It has been hypothesised that the over-expression of platelet-derived growth factor A (PDGFA), a potent fibroblast growth factor, induced by EWSR1-WT1 may contribute to the prominent desmoplasia in DSRCT.12Lee S.B. Kolquist K.A. Nichols K. et al.The EWS-WT1 translocation product induces PDGFA in desmoplastic small round-cell tumour.Nat Genet. 1997; 17: 309-313Crossref PubMed Scopus (151) Google Scholar Whether this variant of EWSR1-WT1 transcript (fusion of exon 7 of EWSR1 to exon 7 of WT1) is related to the desmoplasia-poor morphology in our case remained undetermined, which needs further functional studies to clarify. The authors state that there are no conflicts of interest to disclose." @default.
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• W3205288669 title "Desmoplastic small round cell tumour presenting as cervical lymph nodes metastases with solid pattern morphology and novel EWSR1-WT1 fusion transcript" @default.
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