Primary Desmoplastic Small Round Cell Tumor of the Mandible: A Case Report and Literature Review


 Background: Desmoplastic small round cell tumor (DSRCT) is a sporadic, highly malignant tumor with a poor prognosis. The abdomen and pelvis have been reported as the primary localization sites. However, to the best of our knowledge, there are few reports on primary DSRCT in the mandible.Case presentation: We have reported a case of a 26-year-old Chinese man who presented with a mass in the right mandible. Imaging studies showed a hypoechoic mass in the right mandibular region. Intraoperative pathology revealed that the tumor tissue was composed of small round tumor cells and a dense desmoplastic stroma. On immunostaining, the tumor cells showed markers of epithelial, mesenchymal, myogenic, and neural differentiation. The EWSR1 gene rearrangement was detected by fluorescence in situ hybridization. Based on the overall morphological features and immunohistochemical findings, a final diagnosis of DSRCT was made. The patient was treated with comprehensive anti-tumor therapy mainly based on radiotherapy and chemotherapy.Conclusions: DSRCT is a very uncommon disease in which mandibular involvement is rare. Considering DSRCT in the differential diagnosis of small round blue cell tumors, even in extraperitoneal locations, is beneficial for a precise diagnosis. Full recognition of the clinicopathological features will help to better diagnose this disease.


Background
Desmoplastic small round cell tumor (DSRCT) is an extremely rare and aggressive neoplasm that most commonly affects adolescents and young adults and has a male predominance [1,2,[43][44][45]. DSRCT preferentially involves the abdominal and pelvic cavities. DSRCT in the pleura, lung, eye, ear, and testis has been reported in only a few cases (<5%) [3][4][5][6][7], but it is not consistently associated with any speci c organ. DSRCT has no speci c clinical symptoms. It can metastasize in the early stage and quickly recurs despite treatment [18,36,38,39]. Hence, its prognosis is poor. Here, we have presented a rare case of primary DSRCT in the mandible. In addition, we have described and summarized the clinicopathological features of DSRCT and discussed its diagnosis and treatment based on literature review.

Case Presentation
Clinical history A 26-year-old Chinese man with a chief complaint of a mass in the right mandible for 1 year was admitted to Xiangya Hospital, Central South University, Hunan, China. He had no signi cant past medical or family history. Routine physical and laboratory examinations were performed. Ultrasonography revealed a hypoechoic mass measuring approximately 28 mm×18 mm in the right mandibular region, with irregular shape, clear boundary (Fig. 1). Abdominal computer tomography (CT) scan revealed no other lesion elsewhere. There was no evidence of metastasis to the local or distant organs. Hence, lumpectomy was performed under general anesthesia.
Moreover, the Ki-67 proliferation index was estimated as 50%. The tumor cells were negative for Epstein-Barr virus-encoded small RNA (EBER) on uorescence in situ hybridization (FISH). And FISH analysis with a break-apart probe proved that the EWSR1 gene spilt in the neoplastic cells (Fig.4). However, EWSR1-WT1 fusion by RT-PCR was not performed due to limited conditions. Based on the above ndings and imaging ndings, primary lesions in the abdominal cavity and pelvic cavity were excluded, and a nal diagnosis of mandibular DSRCT was made.

Follow-up
Comprehensive anti-tumor therapy mainly based on chemotherapy and radiotherapy was rst proposed.
However, synchronous chemotherapy was not performed because of bone marrow suppression.
Therefore, cyclophosphamide combined with doxorubicin and vincristine chemotherapy was used for maintenance treatment. The patient is currently alive and well with no evidence of recurrence.

Discussion
Desmoplastic small round cell tumor (DSRCT), which was rst described as a speci c disease by Gerald and Rosai [8,9], is a rare and aggressive soft-tissue sarcoma. Generally, DSRCT originates from the serosal surface of the abdominal cavity [30][31][32][33], but it can also be found in the lung, sinus, bone, and mediastinum [3,[12][13][14][49][50][51][52][53]. Clinical symptoms are usually associated with the tumor sites and lack speci city. Most patients have the initial symptoms of abdominal mass, constipation, ascites, and vomiting [18, 32,33,[35][36][37][38]. It can be accompanied by the manifestations of cachexia, such as fatigue and emaciation. Patients may develop intestinal obstruction, hydronephrosis, and urinary tract irritation owing to tumor compression [15]. The clinical features of previously published DSRCT cases in the last 5 years are summarized in Supplementary Table 2, Additional File 1. In our patient, a right mandibular mass without apparent clinical manifestations was detected incidentally. DSRCT is often widely disseminated throughout the peritoneal cavity, and some patients may present with metastasis to the lymph nodes, liver, and occasionally the lungs [16,18,30]. Hence, its prognosis is exceedingly poor.
Imaging examinations of DSRCT lack characteristic features. Ultrasound examination usually shows a lobulated soft tissue mass with an uneven internal echo [17]. Computed tomography (CT) usually reveals single or multiple lobular nodules or lumpy soft tissue masses, with an uneven density of the tumor body and multiple spotted calci cations [32]. The lesions tend to crowd out, surround and invade the surrounding tissues [43]. DSRCT is usually accompanied by akes of low intensity when there is a necrotic area in the tumor. Enhanced CT presents mild uneven enhancement, and edge enhancement may be observed in some larger masses. Moreover, positron emission tomography (PET)-CT have the potential to monitor residual disease and detect relapse or tumor progression at the early stages [14]. Imaging ndings are non-speci c, but they can indicate the location, size, and the number of tumors, thereby contributing to biopsy, surgery, and radiotherapy.  [30,[39][40][41]. This multiple antigen expression pro le is a characteristic of DSRCT and can be used to distinguish DSRCT from the other histologically related small round cell tumors. Further, para nuclear dot-like desmin positivity has important diagnostic signi cance. However, in our case, immunohistochemical staining showed a diffuse perinuclear staining pattern with desmin, but characteristic dot positivity was not prominent. Almost all cases of DSRCT are positive for WT1 and show cytoplasmic and paranuclear staining. Although the immunohistochemical analysis of classic cases of DSRCT tend reveal WT1 positivity, N-and C-terminals may be useful as a form of "molecular immunohistochemistry" to identify the EWS-WT1 transcript as the immunostaining pattern may be altered by variant transcripts and WT1 immunostaining may be negative (as in our case) [46-48]. To establish a DSRCT diagnosis, the interpretation of WT1 immunostaining requires knowledge of antibody target epitopes and correlations with clinical, morphological, and molecular ndings.
In the present case, the tumor was composed of nests of small to medium-sized cells, which might be misdiagnosed as small cell carcinoma. Small cell carcinoma can also show the immunoreactivity for epithelial and neuroendocrine markers. But in our case, immunohistochemical analysis of the coexpression of epithelial, mesenchymal, and neural markers by tumor cells, strongly support a diagnosis of DSRCT. DSRCT should also be distinguished from other carcinomas such as malignant melanoma, malignant lymphoma and metastatic neuroblastoma. However, the current case was negative for Melan-A and S100, which made malignant melanoma unlikely. And the positivity for epithelial markers helped to rule out the possibility of malignant lymphoma, which often involves lymph nodes, bone marrow and peripheral blood. In addition, stroma of massive nerve ber network is a characteristic feature in neuroblastoma, which might be a diagnostic clue. Due to the histological features of small round cells in the present tumor, it must be distinguished from other small round cell tumors such as rhabdomyosarcoma, primitive neuroectodermal tumor (PNET) and Ewing sarcoma (EWS). Rhabdomyosarcoma is more common in children; the tumor cells are commonly positive for myogenic markers (such as MYOD1, myogenin), but negative for epithelial and neuroendocrine markers. Morphologically, DSRCT and PNET can revealed chrysanthemum-like structure, and both of them have positive expression of CD99 and NSE. In our case, immunohistochemical results show the positivity for desmin and epithelial markers, which strongly favors a diagnosis of DSRCT over that of PNET. EWS shares histological and immunophenotypic similarities with DSRCT. The diffuse membranous positivity of CD99 is typical of EWS, and desmin positivity is exceedingly rare. Both EWS and DSRCT harbor EWSR1 rearrangements, the break-apart FISH assay for EWSR1 will not be helpful in the differential diagnosis between them. But characteristic translocation of EWS involves EWSR1 and the ETS family of transcription factors, not WT1. Convincingly, documentation of EWSR1-WT1 fusion is the "gold standard" for the diagnosis of DSRCT [35,39,40]. It was not performed in our case due to limited conditions. But immunohistochemically, a distinctive pattern of multi-phenotypic differentiation is useful and important for the diagnosis of DSRCT.
DSRCT is distinguished by the t (11;22) (p13; q12) chromosomal translocation involving a fusion between the transcriptional activating domain of EWSR1 and the WT1 gene [19][20][21]. Studies have also suggested that the EWSR1-WT1 fusion protein can induce the expression of PDGFA. PDGFA can induce the growth and proliferation of broblasts and the production of collagenous stroma, which may explain the characteristic reactive brosis of DSRCT [22]. Downstream activation of EWSR1-WT1 gene fusion includes signaling pathways of vascular endothelial growth factor (VEGF), IL2RB, and insulin growth factor (IGF)-1 [23][24][25]. A better understanding of the effects of these target genes will provide avenues for future treatment.
Despite multimodality treatment, DSRCT is highly aggressive and has a poor prognosis. The overall survival in patients is <3-5 years after diagnosis, and the 5-year survival rate is <20% [18,26,39,48]. There is no standardized approach for the treatment of this malignant disease. Effective cytoreduction combined with comprehensive therapies, as the best treatment strategy presented in most studies, may prolong patient survival [27,[37][38][39][40][41]. With the in-depth analysis of molecular genetics of DSRCT, targeted therapy, immunotherapy, and other methods have been used for the treatment of DSRCT in recent years [28,29].

Conclusions
In summary, DSRCT is a poorly understood malignant tumor with characteristic morphology, immunophenotype, and cytogenetic features. The disease does not present with speci c clinical signs or symptoms. PET-CT may help diagnose recurrent disease at an earlier stage. The EWSR1-WT1 fusion by RT-PCR is the gold standard for the diagnosis of DSRCT. When it is not feasible, de nitive diagnosis mainly depends on histological and immunohistochemical studies. The mandible is an unusual site for DSRCT, suggesting that the tumor may not have a site-speci c predilection. Further studies are needed to investigate this disease in future studies. Keda Yang designed and organized the study. All authors read and approved the nal manuscript. Figure 1 Cervical US: A hypoechoic, well-de ned mass measuring 28 mm ×18 mm located in the right mandibular region; no obvious blood ow signal was observed in the lesion.   Dual Color Break Apart speci c locus FISH probe targeting EWSR1 gene; green and red signals mark the 5′ and 3′ ends of the gene respectively.