Beta-catenin

Immunohistochemical expression

Beta-catenin binds to the cytoplasmic domain of E-cadherin, so forming a component of cell-cell adhesion. The b-catenin-cadherin complex recruits a-catenin, which in turn binds the actin of the cytoskeleton. These interactions permit the formation of intercellular adherens junctions2. Secondly, it acts as a component of the Wnt signal transduction pathway. This pathway regulates cell proliferation and differentiation2. The level of free b-catenin is controlled by a complex that facilitates its breakdown. The complex includes the adenomatous polyposis coli protein and glycogen synthetase kinase3b. Wnt inactivates glycogen synthetase kinase3b, allowing b-catenin to accumulate in both cytoplasm and nucleus. Within the nucleus, b-catenin activates the TCF/LEF transcription factors, which in turn act on genes including c-Myc, tcf-1 and cyclin D12. Mutant CTNNB1 (encoded on chromosome 3p21) can lead to stabilisation of b-catenin in the cytoplasm and translocation to the nucleus. Normal cells therefore show membrane staining for b-catenin, while cytoplasmic and/or nuclear staining is abnormal.

Beta-catenin expression is regulated by the adenomatous polyposis coli (APC) gene9,10. Dysregulation of b-catenin occurs in Gardners syndrome, where it leads to both familial adenomatous polyposis and fibromatosis2. Expression of beta-catenin is increased in aggressive fibromatosis9. Dysregulation also occurs in synovial sarcoma, osteosarcoma, liposarcoma and malignant fibrous histiocytoma2.

High levels nuclear expression is seen in a restricted range of mesenchymal tumours. (Cytoplasmic staining is seen in many mesenchymal tumours.)

Other studies have not differentiated between nuclear and cytoplasmic staining8.

There is nuclear accumulation of beta-catenin in sessile serrated colonic adenomas after BRAF activation and in association with the development of dysplasia:

Diagnostic utility

• Positive in some uterine high grade endometrioid carcinomas but not uterine serous carcinomas.

•   As a member of a panel to differentiated primary ovarian endometrioid/mucinous carcinoma of the ovary from metastatic colorectal carcinoma.

• Differential diagnosis of mesenchymal tumours: high level nuclear positivity is largely confined to desmoid-type fibromatosis, solitary fibrous tumour, synovial sarcoma and endometrial stromal sarcoma and carcinosarcomas. Low level nuclear positivity is seen with a low frequency in a wide variety of tumours.

References

1 Darvishian, F., A. J. Hummer, et al. (2004). "Serous endometrial cancers that mimic endometrioid adenocarcinomas: a clinicopathologic and immunohistochemical study of a group of problematic cases." Am J Surg Pathol 28(12): 1568-78.

2 Ng TL, Gown AM, Barry TS, et al. Nuclear beta-catenin in mesenchymal tumors. Mod Pathol 2005; 18:68-74 (study used tissue microarrays)

3 Saito T, Oda Y, Kawaguchi K, et al. Possible association between higher beta-catenin mRNA expression and mutated beta-catenin in sporadic desmoid tumors: real-time semiquantitative assay by TaqMan polymerase chain reaction. Lab Invest 2002; 82:97-103

4 Montgomery E, Torbenson MS, Kaushal M, Fisher C,Abraham SC Beta-catenin immunohistochemistry separates mesenteric fibromatosis from gastrointestinal stromal tumor and sclerosing mesenteritis. Am J Surg Pathol 2002; 26:1296-301

5 Abraham SC, Reynolds C, Lee JH, et al. Fibromatosis of the breast and mutations involving the APC/beta-catenin pathway. Hum Pathol 2002; 33:39-46

6 Sakamoto A, Oda Y, Adachi T, et al. Beta-catenin accumulation and gene mutation in exon 3 in dedifferentiated liposarcoma and malignant fibrous histiocytoma. Arch Pathol Lab Med 2002; 126:1071-8

7 Haydon RC, Deyrup A, Ishikawa A, et al. Cytoplasmic and/or nuclear accumulation of the beta-catenin protein is a frequent event in human osteosarcoma. Int J Cancer 2002; 102:338-42

8 Kuhnen C, Herter P, Muller O, et al. Beta-catenin in soft tissue sarcomas: expression is related to proliferative activity in high-grade sarcomas. Mod Pathol 2000; 13:1005-13

9 Alman BA, Li C, Pajerski ME, et al. Increased beta-catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors). Am J Pathol 1997; 151:329-34

10 Li C, Bapat B,Alman BA Adenomatous polyposis coli gene mutation alters proliferation through its beta-catenin-regulatory function in aggressive fibromatosis (desmoid tumor). Am J Pathol 1998; 153:709-14

11 Kuhnen C, Herter P, Monse H, et al. APC and beta-catenin in alveolar soft part sarcoma (ASPS)--immunohistochemical and molecular genetic analysis. Pathol Res Pract 2000; 196:299-304

12 Bhattacharya B, Dilworth HP, Iacobuzio-Donahue C, et al. Nuclear beta-catenin expression distinguishes deep fibromatosis from other benign and malignant fibroblastic and myofibroblastic lesions. Am J Surg Pathol 2005; 29:653-9

13 Yachida S, Mudali S, Martin SA, Montgomery EA, Iacobuzio-Donahue CA. Beta-catenin nuclear labeling is a common feature of sessile serrated adenomas and correlates with early neoplastic progression after BRAF activation. Am J Surg Pathol. 2009 Dec;33(12):1823-32.

This page last revised 2.4.2105.

©SMUHT/PW Bishop