Malignant tumors of the atrium are uncommon and the most frequent primary cardiac sarcoma was intimal sarcoma and angiosarcomas [4]. However, tumors like the present case which shows the histological characterized by the solid sheet and pseudopapillary focally architectures, immunohistochemically positive for S100 and SOX-10 but negative for HMB-45, A103 and CD99, and appears EWSR1 gene rearrangement by FISH have never been reported in atrium. Based on the histological, immunophenotypical and molecular genetic characteristics, we considered the diagnostic of GNET which was exclusively occurred in the gastrointestinal tract in the past reported references. To test of our conjecture, FISH examination with the EWSR1-ATF1 dichromatic probe and whole transcriptome sequencing in paraffin embedded tissue of this tumor were performed respectively, and the results showed that the tumor cells were found to harbor the EWSR1-ATF1 fusion gene, and then to be confirmed by the whole transcriptome sequencing analysis with involving of exon 8 of EWSR1 and exon 4 of ATF1. These findings confirmed our hypothesis and supported the diagnosis of GNET although the extra-gastrointestinal GNET had never been reported. In the present case, the scattered osteoclast-like multinucleated giant cells, which were only reported in up to 50% of cases [1,5−8], were not found yet. Besides, no other suspicious mass was found by the full body CT scan examination, including at the abdomen and gastrointestinal tract, suggesting that this tumor was primary but not the secondary tumor at the atrium.
The major differential diagnostic consideration of the present case was clear cell sarcoma (CCS) of soft tissue, melanoma, malignant peripheral nerve sheath tumor (MPNST), Ewing sarcoma /primary neuroectodermal tumor (ES/PNET) and intimal sarcoma (IS). CCS and GNET may share some same histological and immunophenotypically features, and the two tumors can both harbor EWSR1-ATF1 fusion gene. However, CCS often shows melanocyte differentiation and is lack of neuroectodermal differentiation. Because of the accumulation of hemosiderin rather than melanin, and the absence of HMB45 and A103 immunostaining activity but positive for SOX10 in neoplasm cells, the diagnosis of CCS could be ruled out. Because of the expression of S100 protein reactivity and pigment like particle deposition, melanoma also need to be considered. But there were no special abnormalities in skin of this patient and both the melanocytic markers of HMB45 and A103 were negative, these features were useful to rule out melanoma. MPNST should be entered in the differential diagnosis because of similar histological features (spindle and/or epithelioid cells) and S100 protein immunoreactivity. However, MPNST usually doesn’t show strong and diffuse immunoreactivity for S100 protein, and genetic study for EWSR1 may help to separate GNET from MPNST [9]. ES/PNET present the similar morphology and protein expression of Syn and CD56 in GNET, however, ES/PNET often shows expression of CD99 protein and genetic alterations of EWSR1-Fli1 gene fusion [10]. Finally, because of the location at the right ventricle of the present tumor, IS which is the most frequent primary cardiac sarcoma, must be excluded. IS often demonstrates MDM2 amplification and negative expression of S100 or SOX10 [4].
It has been widely accepted that GNET is a unique clinicopathological entity with an origin from a gastrointestinal tract. According to Chang’s study [9], GNET occurs typically arising in the small intestine with a predilection for the ileum (57.9%), followed by the stomach (15.8%), colon (10.5%), ileocecal junction (5.3%), lower esophagus (5.3%), and anal canal (5.3%). In addition, there were also five cases of GNET have been reported including parapharyngeal and tongue location [1,10−12]. Although GNET may occurs in any location in the gastrointestinal tract, it was almost exclusively occurred in gastroenteric trace, extra-gastrointestinal GNET has never been reported at present. In this study, we reported a case that share almost all the characteristics with GNET, which not occurred in the digestive tract but in the right atrium. As far as we know, this is the first reported case of extra-gastrointestinal GNET.
GNET is a highly malignant tumor and prone to local recurrence and metastasis [3, 9]. The treatment of GNET was dominated by surgical resection, and a small number of patients showed partial response to apatinib and anlotinib[9]. The patient in our case did not receive chemotherapy or radiotherapy, and presented with local recurrence for only one months after diagnosis and then died of the disease 20 months later, suggested that this tumor entity had a very poor prognosis in the extra-gastrointestinal. However, owing to the low incidence, the treatment of GNET still at the elementary step and no evidence-based guidelines, and need further research and exploration.