Immunohistochemical Expression of Wilms’ Tumor 1 Protein in Human Tissues: From Ontogenesis to Neoplastic Tissues

Abstract

The human Wilms’ tumor gene (WT1) was originally isolated in a Wilms’ tumor of the kidney as a tumor suppressor gene. Numerous isoforms of WT1, by combination of alternative translational start sites, alternative RNA splicing and RNA editing, have been well documented. During human ontogenesis, according to the antibodies used, anti-C or N-terminus WT1 protein, nuclear expression can be frequently obtained in numerous tissues, including metanephric and mesonephric glomeruli, and mesothelial and sub-mesothelial cells, while cytoplasmic staining is usually found in developing smooth and skeletal cells, myocardium, glial cells, neuroblasts, adrenal cortical cells and the endothelial cells of blood vessels. WT1 has been originally described as a tumor suppressor gene in renal Wilms’ tumor, but more recent studies emphasized its potential oncogenic role in several neoplasia with a variable immunostaining pattern that can be exclusively nuclear, cytoplasmic or both, according to the antibodies used (anti-C or N-terminus WT1 protein). With the present review we focus on the immunohistochemical expression of WT1 in some tumors, emphasizing its potential diagnostic role and usefulness in differential diagnosis. In addition, we analyze the WT1 protein expression profile in human embryonal/fetal tissues in order to suggest a possible role in the development of organs and tissues and to establish whether expression in some tumors replicates that observed during the development of tissues from which these tumors arise.

WT1 Clone 6F-H2 Cytoplasmic Expression Differentiates Astrocytic Tumors from Astrogliosis and Associates with Tumor Grade, Histopathology, IDH1 Status, Apoptotic and Proliferative Indices: A Tissue Microarray Study

“…This cellular localization had been described in preceding reports (Hashiba et al, 2007;Schittenhelm et al, 2008;Bassam et al, 2014;Rauscher et al, 2014;Kusum and Ramita;Lee et al, 2019). In fact, WT1 is a nuclear/cytoplasmic shuttling protein that transports with polysomes, and a substantial part of WT1 protein localizes in the cytoplasm (Salvatorelli et al, 2020). Our finding, conform with the datum that WT1 is involved in RNA metabolism beside its role as a transcription factor, additionally, overexpression of WT1 isoforms lacking a nuclear localization signal was proposed (Bassam et al, 2014;Lee et al, 2019).…”

“…Using IHC antibodies against C-terminal, WT1 expression was thought to be exclusively nuclear. Upon the development of antibodies against N-terminal (clone WT6F-H2), it became logical to detect WT1 in the cytoplasm, or concurrently in the nucleus and cytoplasm (Salvatorelli et al, 2020). Among our samples, WT1 was detected in the cytoplasm, astrocytic processes and fibrillary tumor matrix with infrequently, concomitant nuclear expression.…”

“…This study elucidates the role of WT1 as a diagnostic and prognostic marker in neuropathology, particularly for astrocytic tumors. WT1 is zinc finger transcription factor defined as a tumor suppressor gene but also have an oncogenic role that culminates diverse effects on cellular growth, differentiation, migration, invasion, proliferation and apoptosis and confers angiogenic, metastatic and drug resistance abilities to human cancers (Bourne et al, 2010;Clark et al, 2010;Qi et al, 2015;Kijima et al, 2016;Ramsawhook et al, 2018;Salvatorelli et al, 2020).…”

Wilms’ Tumor 1 (WT1): A Novel Immunomarker of Dermatofibrosarcoma Protuberans—An Immunohistochemical Study on a Series of 114 Cases of Bland-Looking Mesenchymal Spindle Cell Lesions of the Dermis/Subcutaneous Tissues

“…Interestingly, WT1 cytoplasmic immunostaining has also been documented in endothelial cells of most benign and malignant vascular tumors [ 35 , 36 ] in juvenile-type fibromatoses, infantile/congential fibrosarcomas, rhabdomyosarcomas, some neuroblastic tumors, some benign and malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors (GIST), leiomyosarcomas, epithelioid cell myofibroblastomas of the breast, and in rhabdomyosarcoma [ 37 , 38 , 39 ], a tumor composed of malignant mesenchymal cells showing morphological, immunohistochemical, and ultrastructural features of skeletal muscle differentiation. These findings seem to support the hypothesis that not only nuclear but also WT1 cytoplasmic expression in some tumors recapitulates that observed during normal development [ 33 , 34 ]. Based on these findings obtained in both developmental and neoplastic tissues, it has been suggested that WT1 is a reliable marker of both endothelial and skeletal muscle differentiation [ 33 , 34 ].…”

“…However, there is increasing evidence that the latter staining truly reflects the presence of the protein within the cytoplasm, suggesting its complex regulator activity in transcriptional/translational processes [ 30 , 31 , 32 ]. Recently, we showed that WT1 is also diffusely expressed in the cytoplasm of human fetal endothelial and skeletal muscle cells, as well as in developing sympathetic neuroblasts [ 33 , 34 ]. Interestingly, WT1 cytoplasmic immunostaining has also been documented in endothelial cells of most benign and malignant vascular tumors [ 35 , 36 ] in juvenile-type fibromatoses, infantile/congential fibrosarcomas, rhabdomyosarcomas, some neuroblastic tumors, some benign and malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors (GIST), leiomyosarcomas, epithelioid cell myofibroblastomas of the breast, and in rhabdomyosarcoma [ 37 , 38 , 39 ], a tumor composed of malignant mesenchymal cells showing morphological, immunohistochemical, and ultrastructural features of skeletal muscle differentiation.…”