Diagnostic Utility of GATA3 and ISL1 in Differentiating Neuroblastoma From Other Pediatric Malignant Small Round Blue Cell Tumors

Abstract

Accurate diagnosis of neuroblastoma may be challenging, especially with limited or inadequate specimen and at the metastatic sites due to overlapping imaging, histopathologic, and immunohistochemical (immunohistochemistry [IHC]; infidelity among various lineage-associated transcription factors eg FLI1, transducin-like enhancer 1, etc) features. GATA3 and ISL1 have recently been described as markers of neuroblastic differentiation. This study aims at determining the diagnostic utility of GATA3 and ISL1 in differentiating neuroblastoma from other pediatric malignant small round blue cell tumors. We evaluated GATA3 and ISL1 expression in 74 pediatric small round blue cell tumors that included 23 NMYC-amplified neuroblastomas, 11 EWSR1-rearranged round cell sarcomas, 7 SYT::SSX1-rearranged synovial sarcomas, 5 embryonal rhabdomyosarcomas, 10 Wilms tumors (nephroblastomas), 7 lymphoblastic lymphoma, 7 medulloblastoma, and 4 desmoplastic small round cell tumor. All 23 neuroblastomas (moderate to strong staining in >50% of the tumor cells), 5 T-lymphoblastic lymphomas (moderate to strong staining in 40%-90% of the tumor cells), and 2 desmoplastic small round cell tumors (weak to moderate staining in 20%-30% of the tumor cells) expressed GATA3, while other tumors were negative. ISL1 immunoreactivity was observed in 22 (96%) neuroblastomas (strong staining in in >50% of the tumor cells, n = 17; moderate to strong staining in 26%-50% of the tumor cells, n = 5), 3 embryonal rhabdomyosarcoma (moderate to strong staining in 30%-85% of the tumor cells), 1 synovial sarcoma (weak staining in 20% of the tumor cells), and 7 medulloblastoma (strong staining in 60%-90% of the tumor cells). Other tumors were negative. Overall, GATA3 showed 86% specificity, 100% sensitivity, and 90% accuracy for neuroblastoma, with a positive predictive value (PPV) and negative predictive value (NPV) of 77% and 100%, respectively. ISLI showed 72% specificity, 96% sensitivity, and 81% accuracy for neuroblastoma, with a PPV and NPV of 67% and 97%, respectively. After the exclusion of T-lymphoblastic lymphoma and desmoplastic small round cell tumors, GATA3 had 100% specificity, sensitivity, accuracy, and PPV and NPV for neuroblastoma. Similarly, in pediatric small round blue cell tumors, ISL1 had 100% specificity, sensitivity, accuracy, PPV, and NPV for neuroblastoma, after embryonal rhabdomyosarcoma, synovial sarcoma, and medulloblastoma were excluded. Conclusions GATA3 and ISL1 may be valuable in the diagnostic work-up of neuroblastoma and may reliably be used to support the neuroblastic lineage of pediatric small round blue cell tumors. Furthermore, dual positivity helps in challenging scenarios, when there is equivocal imaging, overlapping IHC features, limited specimen, and the lack of facility for a molecular work up.

Analyses of combined Merkel cell carcinomas with neuroblastic components suggests that loss of T antigen expression in Merkel cell carcinoma may result in cell cycle arrest and neuroblastic transdifferentiation

“…Importantly, the classical MCC component stained positive for MCPyV LT, while no expression of LT or Keratin 20 was observed in the neuroblastic components, which were further characterized by strong and diffuse expression of synaptophysin, neurofilament and CD56 in a fibrillar pattern. Interestingly, in addition to the advanced age of the patients, a further finding atypical for neuroblastic tumors was lack of the well established neuroblastic markers PHOX2B and GATA3 [46,47]. In contrast, GFAP, a marker for glial tumors [48,49], stained focally in the neuroblastic component, which also exhibited focal cytokeratin (AE1/AE3) staining.…”

Neurogenic tumours of the posterior mediastinum and differential diagnosis considerations

“…32 Lymphoblastic lymphoma is readily distinguished from neuroblastoma and other SBRCTs by an appropriate immunohistochemistry panel, although care must be taken with CD99, which is positive in ES/PNET and GATA-3, which will mark both neuroblastoma and T-cell lymphoblastic lymphoma. 28 Poorly differentiated SyS, which appears to be more common in the mediastinum than elsewhere in the body, 4 will not stain for the highly specific markers for neuroblastoma, such as PHOX2B. Conversely, recently highly specific immunohistochemical markers associated with the specific t(X;18) SSX-SS18 molecular translocation in SyS were reported, which may be a useful adjunct tool to distinguish SyS and neuroblastoma (Figure 5A,B).…”

“…26,27 Recently, GATA-3 was shown the be a promising marker for distinguishing neuroblastoma and ES/ PNET, although care should be taken to exclude other SBRCTs, as T-cell lymphoblastic lymphoma similar to neuroblastoma was shown to stain for GATA-3 and otherwise shows an overlapping immunoprofile, with ES/PNET sharing expression of CD99. 28,29 A highly specific marker for neuroblastoma is PHOX2B, which in large series failed to stain in other SBRCTs, including ES/PNET. 15,30 Molecular identification of EWSR1 gene aberrations may be useful in difficult cases, confirming the diagnosis of ES/PNET.…”

“…In equivocal cases, specific immunohistochemical markers may be applied; however, PHOX2B has also been reported to be positive in paraganglioma. 28,50 Alveolar rhabdomyosarcoma may show a nested growth pattern but lacks sustentacular cells and will stain for desmin and myogenin. Moreover, alveolar rhabdomyosarcoma has not been reported in the posterior mediastinum.…”

GATA3: Everyday Marker Supporting Neuroblastoma, but Pitfall With Rhabdoid Tumors

“…We read with great interest the article entitled “Diagnostic utility of GATA3 and ISL1 in differentiating neuroblastoma from other pediatric malignant small round blue cell tumors.” published by Mohanty et al 1 recently in this journal. Having previously studied this marker in neuroblastoma, 2 we were pleased to see a more extensive panel of entities in the differential tested with GATA3, including EWSR1 -rearranged tumors, synovial sarcomas, rhabdomyosarcomas, Wilms tumors, lymphoblastic lymphomas, medulloblastomas, and desmoplastic small round cell tumors.…”