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) gene^9,10. 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.)

			Nuclear staining.
			low level positivity	high level positivity
	adipocytic tumours	hibernoma	0/12
		lipoblastomatosis	0/32
		liposarcoma	2/34 (positivity in 1/13 well differentiated and 1/14 dedifferentiated liposarcomas)2	0/342, 0/30 (18 well differentiated and 12 dedifferentiated)6
	fibroblastic/myofibroblastic tumours	scar	0/912
		fasciitis	2/62	0/62
			0/11 (nodular fasciitis)12
		inflammatory myofibroblastic tumour	0/32
		benign fibroma	0/12
		elastofibroma	0/12
		desmoplastic fibromatosis	0/22
		desmoid-type fibromatosis	2/172, 3/20 (chest wall, mesentry and smallintestine)12	12/172 , 12/12 (>50% of nuclear positive)3, 6/69, 17/20 (neck, submandibular, groin, mesentry x 3, sternum, abdominal wall x 6, hip, leg, scapular, shoulder)12
		breast fibromatosis	5/335	22/335
		mesenteric fibromatosis		9/10 (>50% of nuclear positive)4
		sclerosing mediastinitis	0/54
		myofibroma	0/1212
		solitary fibrous tumour	4/152	6/152
		haemangiopericytoma	2/52	0/52
		dermatofibrosarcoma protuberans	1/92	0/92
		low-grade fibromyxoid sarcoma	2/62	0/62
			0/1012
		myxofibrosarcoma	0/22, 0/1 (myxohyaline tumour/myxoinflammatory fibroblastic sarcoma)12
		myofibrosarcoma	0/312
		sclerosing epithelioid fibrosarcoma	0/212
		fibrosarcoma	0/32	1/32
			0/3 (two cases low grade, third arising from DFSP)12
	fibrohistiocytic and histiocytic tumours	eosinophilic granuloma	0/12
		Rosai-Dorfmann lesion	0/12
		Tenosynovial giant cell tumour	0/92
		Fibroxanthoma	1/22	0/22
		Atypical fibroxanthoma	0/22
		Malignant fibrous histiocytoma	0/462	0/462, 0/30 (cut off set at 50% of nuclei staining)6
	muscle tumours	uterine leiomyoma	0/82
		extra-uterine soft tissue leiomyosarcoma	1/412	0/412
			0/1012
		rhabdomyoma	0/12
		rhabdomyosarcoma	2/132	0/132
		gastrointestinal stromal tumour	0/372 , 0/114
		endometrial stromal sarcoma	2/102	4/102
	vascular/perivascular tumours	glomus tumour	0/82
		haemangioma	0/22
		lymphangioma	0/32
		Kaposi sarcoma	0/22
		epithelioid haemangioendothelioma	1/32	0/32
		infantile haemangioendothelioma	0/22
		angiosarcoma	2/142	0/142
	peripheral nerve sheath tumours	neurofibroma	0/22
		Schwannoma	0/32
		granular cell tumour	0/92
		paraganglioma	1/12	0/12
		ganglioneuroma	0/12
		neuroblastoma	0/12
		MPNST	0/192
		Ewing's sarcoma	1/142	0/142
	uncertain differentiation	intramuscular myxoma	0/82
		angiomyxoma	0/12
		desmoplastic small round cell tumour	1/22	0/22
		synovial sarcoma	13/582	16/582
		epithelioid sarcoma	0/22
		alveolar soft part sarcoma	0/22, 0/4 (there was membranous and cytoplasmic positivity)11
		clear cell sarcoma	1/32	1/32
		extraskeletal myxoid chondrosarcoma	0/42
	bone tumours	enchondroma	0/122
		osteochondroma	0/42
chondroblastoma		0/42
chondromyxoid fibroma		0/42
chondrosarcoma		3/55 (1/42 low grade, 1/5 high grade, 1/4 dedifferentiated, 0/1 juxtacortical, 0/3 mesenchymal)2	0/552
osteosarcoma		0/192, 3/47 (see personal communication in reference 2)7
epithelial tumours	adenocarcinoma, soft tissue	1/12	0/12
	carcinosarcomas	3/72	3/72

Other studies have not differentiated between nuclear and cytopalsmic staining⁸.

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

This page last revised 17.7.2005.

©SMUHT/PW Bishop