Pathology Outlines

Stains & CD markers
WT1

Authors: Urooba Nadeem, M.D., Aliya N. Husain, M.D.

Editor-in-Chief: Debra L. Zynger, M.D.

Minor changes: 18 June 2021

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PubMed Search: WT1[TI] pathology review

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Table of Contents

Cite this page: Nadeem U, Husain A. WT1. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainswt1.html. Accessed July 28th, 2021.

Definition / general

WT1 gene encodes for Wilms tumor protein located on chromosome 11p13
Expressed / mutated in several different tumors

Essential features

Interpretation is based on staining pattern and antibody used
- Staining patterns: nuclear and cytoplasmic
- Antibodies: against N and C terminal
Expressed in a broad spectrum of tumors, including malignant mesothelioma, ovarian epithelial tumors and sex cord stromal tumors, astrocytoma, glioblastoma, benign and malignant vascular tumors and desmoplastic malignant melanoma
Expression linked to poor prognosis of several tumors, including acute myeloid leukemia, pancreatic and colorectal cancers and astrocytoma and a better prognosis in high grade serous carcinoma of the ovary
Vaccination and immunotherapy directed against WT1 is in trials

Pathophysiology

Transcription factor essential for normal development of the urogenital system
Both tumor suppressing and tumorigenic role in several neoplasias, including breast, acute myeloid leukemia (AML) and mesothelioma
Affects genes of the Wnt / β-catenin pathway and p53 tumor suppressor pathway

Clinical features

WT1 mutations in Denys-Drash syndrome, diffuse mesangial sclerosis kidney, Fraiser syndrome, Wilms tumor in 15% of cases, congenital nephrotic syndrome, cytogenetically normal acute myeloid leukemia and prostate cancer (Adv Pediatr 2012;59:247)
Chromosomal translocation (11;22)(p13;q12) EWSR1-WT1 gene fusion in desmoplastic round blue cell tumor
Mutated in 1.45% of all carcinomas

Interpretation

Can be exclusively nuclear or cytoplasmic according to the antibodies used (anti-C or N terminus WT1 antibody)
Interpretation has to be based on the tissue being stained and the context

Uses by pathologists

Nuclear stain against N terminus (disregard any cytoplasmic staining in these tumors) to differentiate:
- Malignant mesothelioma (WT1+) from non small cell lung carcinomas (WT1-) (Arch Pathol Lab Med 2018;142:89)
- Wilms tumor (WT1+ in blastemal and epithelial components) from mesoblastic nephroma, clear cell sarcoma, renal cell carcinoma and peripheral neuroectodermal tumor and angiomyolipoma (WT1-) (Indian J Med Res 2016;143:S59)
- Adenomatoid tumor (WT1+) from signet ring cell carcinoma and lymphangioma (WT1-) (Arch Pathol Lab Med 2015;139:39, Int J Gynecol Pathol 2004;23:123)
- Metanephric adenoma (WT1+) from solid variant of papillary renal cell carcinoma (WT1-) (Histopathology 2013;62:941, Mod Pathol 2015;28:1236)
- Fallopian tube and ovarian serous carcinoma (WT1+) from endometrioid, mucinous and clear cell adenocarcinoma (WT1-) (Int J Gynecol Pathol 2004;23:110)
- Transitional cell carcinoma of the ovary (WT1+) from malignant Brenner tumor (WT1-) (Int J Gynecol Pathol 2012;31:499)
- CIC-DUX4 sarcoma (WT1+) from BCOR-CCNB3 and Ewing sarcoma (WT1-) (Virchows Arch 2017;470:373)
- Desmoplastic melanoma (WT1+) from scar, fibromatosis and dermatofibroma (WT1-) (J Cutan Pathol 2016;43:313)
- Pleural endometriosis (WT1+) from biphasic pulmonary blastoma and lung adenocarcinoma (WT1-)
Cytoplasmic stain against N terminus to differentiate:
- Benign and malignant vascular tumors (WT1+) from vascular malformations (WT1-) (J Am Acad Dermatol 2010;63:1052)
- Mammary myofibroblastoma, epithelioid type (WT1+) from lobular breast lobular carcinoma (WT1-) (Acta Histochem 2014;116:905)
- Young type fibromatosis, e.g. congenital / infantile fibrosarcoma, fibrous hamartoma of infancy, myofibroma / myofibromatosis and lipofibromatosis (WT1+) from adult type fibromatosis e.g. nodular fasciitis and desmoid type (WT1) (Acta Histochem 2014;116:1134)
Nuclear stain against C terminus to differentiate:
- Desmoplastic round blue cell tumor (WT1+) from Ewing sarcoma / primitive neuroectodermal tumors, neuroblastomas or rhabdoid tumors of the kidney (WT1) (Am J Surg Pathol 2000;24:830)

Prognostic factors

Acute myeloid leukemias: WT1+ have mutations in exon 7 and 9 of WT1 genes, have a worse prognosis and are resistant to chemotherapy
Diffuse astrocytic tumors: WT1+ tumors have a higher WHO tumor grade, no IDH1 mutations and a poor outcome
Colorectal and pancreatic ductal adenocarcinoma: WT1+ have a poorer prognosis
High grade ovarian serous carcinomas: WT1+ have a better prognosis, especially when the tumor cells also express estrogen receptor (Gynecol Oncol 2016;140:494)

Microscopic (histologic) images

Contributed by Urooba Nadeem, M.D., Aliya N. Husain, M.D. and Jeffrey Schulte, M.D.

Pleura: malignant mesothelioma (H&E and WT1)

Omental mass: serous carcinoma (H&E and WT1)

Lymph node: metastatic Wilms (H&E and WT1)

Brain tumor: glioblastoma (H&E and WT1)

Skeletal muscle cytoplasmic, WT1

Positive staining - normal

Nuclear
- Glomerular podocytes (Curr Biol 2001;11:1805)
- Sertoli cells of the testis (Mech Dev 1993;40:85)
- Surface epithelium and granulosa cells of the ovary (Am J Surg Pathol 2008;32:884)
- Myometrium and endometrial stromal cells of the uterus (Genes Dev 1991;5:1345)
- Mesothelium (Cancer Cytopathol 2014;122:586)
- CD34 positive hematopoietic stem cells (Br J Haematol 2002;116:409)
Cytoplasmic
- Skeletal muscle (Acta Histochem 2013;115:70)
- Endothelial cells (Acta Histochem 2013;115:70)
- Cardiac muscle cells (Acta Histochem 2013;115:70)
- Adrenal gland (Mol Pathol 1997;50:138)
- Plasma cells (Cancer Cytopathol 2014;122:586)

Positive staining - disease

Nuclear N terminus
- Epithelioid mesothelioma (93%) (Am J Surg Pathol 2003;27:1031)
- Adenomatoid tumor and well differentiated papillary mesothelioma (Arch Pathol Lab Med 2015;139:39, Mod Pathol 2019;32:88)
- Wilms tumor: strong in blastemal and epithelial component and absent in the epithelial and stromal elements (Appl Sci 2020;10:40)
- Metanephric adenoma (Mod Pathol 2015;28:1236)
- Fallopian tube and ovarian serous carcinoma (Int J Gynecol Pathol 2004;23:110)
- Transitional cell carcinoma of the ovary (67%) (Int J Gynecol Pathol 2012;31:499)
- Ovarian Sertoli cell tumor (Am J Surg Pathol 2007;31:1378)
- Sex cord stromal tumors (78 - 100%) (Am J Surg Pathol 2009;33:354)
- Adult granulosa cell tumor (65 - 88%) (Am J Surg Pathol 2009;33:354)
- Small cell carcinoma of the ovary, hypercalcemic type (Rare Dis 2014;2:e967148)
- CIC-DUX4 sarcoma (Virchows Arch 2017;470:373)
- Pleural endometriosis (Suster: Diagnostic Pathology - Thoracic, 2nd Edition, 2017)
- Cutaneous Müllerian cyst (Case Rep Med 2016;2016:2487820)
- Breast adenocarcinoma mucinous (64%) and mixed mucinous (10%) (Mod Pathol 2008;21:1217)
Cytoplasmic N terminus
- Vascular tumors, both benign and malignant (100%) (J Am Acad Dermatol 2010;63:1052)
- Rhabdomyosarcoma, all histologic variants (100%) (Mod Pathol 2002;15:1080)
- Malignant peripheral nerve sheath tumor (71%) (World J Surg Oncol 2014;12:214)
- Mammary myofibroblastoma, epithelioid type only (Acta Histochem 2014;116:905)
- Endometrial sarcomas: leiomyosarcoma (76%), carcinosarcoma (44%), endometrial stromal sarcoma (47%), undifferentiated sarcoma (57%) (Eur J Cancer 2007;43:1630)
- Congenital / infantile fibrosarcoma (Am J Surg Pathol 1994;18:14)
- Fibrous hamartoma of infancy, myofibroma / myofibromatosis and lipofibromatosis (Acta Histochem 2015;117:367)
- Brain astrocytoma / glioblastoma (Neuropathol Appl Neurobiol 2009;35:69)
- Pancreatic ductal adenocarcinomas (75%) (Cancer Sci 2004;95:583)
- Colorectal adenocarcinomas (89%) (Cancer Sci 2003;94:712)
- Desmoplastic melanoma (71%) and nondesmoplastic melanoma (47%) (Am J Dermatopathol 2014;36:238)
- Compound / intradermal nevi (68.3%), congenital nevi (9.1%), Spitz nevi (62.5%), atypical nevi (30.4%) (J Cutan Pathol 2010;37:542)
Nuclear C terminus
- Desmoplastic round blue cell tumor (90%)

Negative staining

GU:
- Renal cell carcinoma, including papillary type (Arch Pathol Lab Med 2018;142:89, Mod Pathol 2015;28:1236)
- Congenital mesonephric tumor (Indian J Med Res 2016;143:S59)
Gynecologic:
- Normal endometrium and cervical epithelium (Int J Gynecol Pathol 2000;19:158)
- Endometrioid adenocarcinoma (Int J Gynecol Pathol 2004;23:110)
- Mucinous and clear cell carcinomas of ovary (Arch Pathol Lab Med 2005;129:85)
Lung:
- Non small cell lung carcinoma (Arch Pathol Lab Med 2018;142:89)
Pleura:
- Sarcomatoid mesothelioma (33.3%) (Am J Cancer Res 2011;1:14)
Soft tissue:
- Lymphangioma (Indian Dermatol Online J 2017;8:282)
- Vascular malformations (J Am Acad Dermatol 2010;63:1052)
- Desmoid type fibromatosis (20%) (Acta Histochem 2014;116:1134)
- Nodular fasciitis (Acta Histochem 2014;116:1134)
- Ewing sarcoma (Virchows Arch 2017;470:373)
- Scar, fibromatoses, dermatofibroma (J Cutan Pathol 2016;43:313)

Molecular / cytogenetics description

Desmoplastic small round cell tumor translocation in EWS1 and WT1 genes t(11;22)(p13;q12) (Med Pediatr Oncol 1996;27:434)

Sample pathology report

Example:
- This pleural tumor is immunoreactive for WT1, suggestive of an mesothelial versus a lung origin.

Additional references

Mod Pathol 2015;28:1043

Board review style question #1

WT1-, calretinin-, cytokeretain AE1 / AE3+, TTF1+, BAP1 lost
WT1+, calretinin+, cytokeretain AE1 / AE3+, TTF1-, BAP1 lost
WT1+, calretinin+, cytokeratin AE1 / AE3+, TTF1+, BAP1 lost
WT1-, calretinin-, cytokeratin AE1 / AE3-, TTF1-, BAP1 retained

Board review style answer #1

B. WT1+, calretinin+, cytokeretain AE1 / AE3+, TTF1-, BAP1 lost. The diagnosis is malignant mesothelioma. The best panel to separate malignant mesothelioma from an adenocarcinoma should include at least 2 mesothelial markers and 2 carcinoma markers. The most specific mesothelial markers are WT1 and calretinin. WT1 staining is nuclear in malignant mesothelioma. Cytokeratin is positive in both mesotheliomas and carcinomas; however, it is important to rule out malignancies from other cell lineages, e.g. melanoma and vascular tumors. BAP1 is mutated / lost in 55 - 66% of malignant mesotheliomas and this can be demonstrated by IHC.

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Reference: WT1