A Study of Gata3 and Phox2b Expression in Tumors of the Autonomic Nervous System

Abstract

Autonomic neurons and chromaffin cells, which constitute the autonomic nervous system, are derived from a common progenitor from the neural crest, and its development is controlled by a network of transcription factors, including the master regulator, Phox2b, and its downstream, Gata3. Anti-Phox2b and anti-Gata3 antibodies were applied to a total of 77 autonomic nervous system tumors, including 35 paragangliomas, 21 pheochromocytomas, 9 neuroblastomas, 4 ganglioneuroblastomas, and 8 ganglioneuromas, as well as their potential morphologic mimics, including tumors of the small round cell tumor group, neuroendocrine carcinomas of lung and gastrointestinal tract (carcinoid tumors/neuroendocrine tumors, large cell neuroendocrine carcinomas, and small cell carcinomas), Merkel cell carcinomas, benign and malignant tumors of thyroid, parathyroid, and adrenal cortex, and malignant melanomas. A variety of nonendocrine/neuroendocrine carcinomas were also studied. Gata3 expression was seen in 89% of paragangliomas, 95% of pheochromocytomas, and all neuroblastomas, ganglioneuroblastomas, and ganglioneuromas, as well as in all parathyroid tumors, a majority of urothelial and mammary carcinomas, and a subset of squamous cell carcinomas, but all other tumors were negative. Phox2b expression was seen in all neuroblastomas, ganglioneuroblastomas, and ganglioneuromas and in 40% of paragangliomas, but pheochromocytomas and all other tumors were negative. Gata3 is a highly reliable marker for paragangliomas, pheochromocytomas, and neuroblastic tumors to distinguish from their simulators. This is an additional utility for this marker, which is used for the diagnosis of urothelial and mammary carcinomas. Phox2b is also highly specific, but its low sensitivity to paragangliomas and pheochromocytomas would limit the utility only to neuroblastic tumors.

Comparison of metastatic neuroendocrine neoplasms to the breast and primary invasive mammary carcinomas with neuroendocrine differentiation

“…In this setting, a panel of site-specific lineage markers (TTF-1 for pulmonary origin, CDX2 for gastrointestinal tract origin, PAX8/PAX6 for gastropancreatic and duodenal origin, and ER/PR, mammaglobin, GCDFP-15 and GATA3 for mammary origin) may be helpful in distinguishing metastatic neuroendocrine neoplasms (particularly well-differentiated neuroendocrine tumors) from invasive mammary carcinomas with neuroendocrine differentiation. [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52] In this study, CDX2 was positive in all examined metastatic neuroendocrine neoplasms of small bowel origin, TTF-1 was positive in 70% of examined metastatic neuroendocrine neoplasms of lung origin, and ER and GATA3 were positive in 91 and 100% of invasive mammary carcinomas with neuroendocrine differentiation, respectively. Similarly, in the study by Perry et al 9 (which with the exception of one high-grade neuroendocrine carcinoma consisted entirely of well-differentiated neuroendocrine tumors), all metastatic neuroendocrine neoplasms from the gastrointestinal tract expressed CDX2 and 60% of tumors originating from the lung expressed TTF-1.…”

“…GATA3 expression is well recognized in breast carcinomas and urothelial carcinomas and more recently has also been described in a variety of other tumors, including (but not limited to) certain renal epithelial tumors, cutaneous squamous cell carcinomas, certain skin adnexal and salivary gland tumors, mesotheliomas, and autonomic nervous system tumors such as paragangliomas, pheochromocytomas, and neuroblastic tumors (neuroblastomas, ganglioneuroblastomas, and ganglioneuromas), but its expression in extramammary epithelial neuroendocrine tumors has not been described. 47,[50][51][52] Hence, GATA3 positivity in a breast tumor with neuroendocrine morphology would argue against a metastatic neuroendocrine neoplasm and in favor of a primary invasive mammary carcinoma with neuroendocrine differentiation.…”

Differential Expression Patterns of GATA3 in Uterine Mesonephric and Nonmesonephric Lesions

“…It has also been shown to be a regulator of and to be required in nephric (Wolffian) duct morphogenesis and guidance of the mesonephric duct (17). GATA3 has proven to be a useful immunohistochemical marker in the diagnosis of breast and urothelial carcinomas, and has been described in autonomic nervous system tumors (18,19). During the preparation of this manuscript, a study with a large cohort of different types of human neoplasms reported that GATA3 is expressed in basal cell and squamous cell carcinomas as well as adnexal tumors of the skin, trophoblastic lesions, and some germ cell tumors including choriocarcinoma and yolk sac tumors, and approximately half of chromophobe renal cell; carcinomas and mesotheliomas among other tumors with focal expression; however, it was not studied in mesonephric lesions (20).…”

GATA3 Is a Sensitive and Specific Marker of Benign and Malignant Mesonephric Lesions in the Lower Female Genital Tract

“…[9][10][11][12][13][14][15] Relatively small studies looking at GATA3 expression in other tumor types revealed frequent positivity in paragangliomas, salivary gland tumors, ovarian Brenner tumors, and signet ring cell adenocarcinomas of the urinary bladder. 16,17 Less common expression has been documented in renal cell carcinomas, endometrial adenocarcinomas, and squamous cell carcinomas from the head/neck, lung, and cervix. [18][19][20][21] In a recent comprehensive analysis of GATA3 expression in human tumors, the spectrum of neoplasms commonly positive for GATA3 was expanded to include not only those previously mentioned, but also a subset of cutaneous basal cell carcinomas and other skin adnexal tumors, yolk sac tumor, choriocarcinoma, mesothelioma, pancreatic ductal adenocarcinoma, chromophobe renal cell carcinoma, oncocytoma, and the epithelial component of synovial sarcoma.…”