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Stains & CD markers
Claudins

Author: Nat Pernick, M.D.

Last author update: 1 July 2013

Last staff update: 24 June 2021

Copyright: 2003-2024, PathologyOutlines.com, Inc.

PubMed Search: claudins

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Cite this page: Pernick N. Claudins. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsclaudins.html. Accessed April 20th, 2024.

Claudins - general

Multigene family of integral membrane proteins active in tight junction formation and function
Claudins were first named in 1998 by Japanese researchers Mikio Furuse and Shoichiro Tsukita at Kyoto University, based on the Latin claudere ("to close"), suggesting the barrier role of these proteins (J Cell Biol 1998 Jun 29;141:1539)
Most claudin genes appear decreased in cancer, while CLDN3, CLDN4 and CLDN7 are elevated in several malignancies (BMC Cancer 2006;6:186)
Pathophysiology:
- Tight junctions (zonula occludens) form continuous barrier to fluids across epithelium and endothelium; regulate paracellular permeability and maintain cell polarity by blocking movement of transmembrane proteins between apical and basolateral cell surfaces (Annu Rev Cell Dev Biol 2006;22:207)
- Tight junctions are composed of claudin and occludin proteins, which join the junctions to the cytoskeleton
- Claudin family has > 20 integral membrane proteins, expressed in tissue specific pattern that may determine strength and properties of epithelial barrier; usually cells from a specific organ express multiple claudin proteins
Positive staining - normal: epithelial and endothelial cells

Claudin1

Tight junction-associated protein first identified in 1998 (J Cell Biol 1998;141:1539)
Also called CLDN1, Senescence-associated Epithelial Membrane Protein 1 (SEMP1)
Has role in cell entry of Hepatitis C virus and Dengue virus (Nature 2007;446:801, Biochem Biophys Res Commun 2010;391:952)
Defects cause ichthyosis-sclerosing cholangitis neonatal syndrome (OMIM #607626)
Interpretation: particulate staining along cell membrane (Am J Surg Pathol 2002;26:1620)
Uses by pathologists:
- Diagnosis of meningioma (with EMA) and to distinguish from hemangiopericytoma (Hum Pathol 2004;35:1413, Am J Clin Pathol 2006;125:203)
- Marker for perineurium / diagnosis of perineurioma but does not distinguish from low grade fibromyxoid sarcoma (Am J Surg Pathol 2008;32:1088, Arch Pathol Lab Med 2007;131:625)
- Sensitive marker for ovarian adenocarcinoma in effusions (Am J Clin Pathol 2007;127:928)
- Low levels associated with:
  - Poor survival in stage II colon carcinoma (Mod Pathol 2005;18:511)
  - Recurrence in prostatic adenocarcinoma (Hum Pathol 2007;38:564)
- Marker for epithelial differentiation (Mod Pathol 2005;18:1403, Mod Pathol 2004;17:141)
Positive staining - normal: brain, heart, kidney (strong), liver (strong), lung, spleen and testis; also normal perineurium and endothelial cells
Positive staining - disease:
- Gastric adenocarcinoma (intestinal: 74%, diffuse: 46%) (Hum Pathol 2005;36:886)
- Hepatoblastoma, fetal component (Hum Pathol 2006;37:555)
- Low grade fibromyxoid sarcoma (100%) (Hum Pathol 2009;40:1586)
- Meningioma (53%) (Am J Clin Pathol 2006;125:203)
- Perineuriomas:
  - Intestinal (40 - 93%) (Am J Surg Pathol 2005;29:859, Am J Surg Pathol 2008;32:1088)
  - Soft tissue (29%, Am J Surg Pathol 2005;29:845)
- Pulmonary squamous cell carcinoma (Mod Pathol 2007;20:947)
References: OMIM #603718

Claudin4

[Pending]

Claudin5

Endothelial tight junction protein
- Encoded by CLDN5 gene (Wikipedia)
- Present in dermal capillaries and other vessels (but not postcapillary venules)
- Also in umbilical and coronary arteries (but not veins), some epithelium (Arterioscler Thromb Vasc Biol 2013;33:489)
Regulated by ubiquitin-proteasome pathway (J Cell Biochem 2012;113:2415)
Clinical features:
- Poor prognostic factor in breast and pancreatic adenocarcinoma (J Exp Clin Cancer Res 2012;31:43, Tumour Biol 2014;35:3803)
- Downregulation causes various vascular leakage syndromes:
  - Anthrax related pleural effusion and hemorrhage may be due to claudin5 downregulation by anthrax lethal toxin (PLoS One 2013;8:e62576)
  - Edema in nasal polyps may be due to decreased claudin5 expression in vascular endothelium (Cell Tissue Res 2013;352:647)
  - Ascities in ovarian cancer may be due to claudin5 downregulation by VEGF (Gynecol Oncol 2012;127:210)
- Blood brain barrier disrupted by HIV1 via changes in claudin5 expression (Methods Mol Biol 2011;762:355)
Uses by pathologists: strong membranous expression of claudin5 and claudin7 differentiates pancreatic solid papillary neoplasm from pancreatoblastoma, acinar cell and endocrine tumors (Am J Surg Pathol 2009;33:768, Zhonghua Bing Li Xue Za Zhi 2013;42:372)
Positive staining - normal:
- CNS: tight junctions of endothelial cells forming blood-brain barrier (World J Gastroenterol 2012;18:2132, J Cereb Blood Flow Metab 2012;32:860)
- Endothelial cells (tight junctions) and some epithelial cells
- Pancreas: acinar, endothelial, ductal tight junctions (World J Gastroenterol 2012;18:2132, Dev Dyn 2012;241:583)
Positive staining - disease:
- Angiosarcoma and hemangioendothelioma; biphasic synovial sarcoma (Am J Surg Pathol 2011;35:1848)
- Pancreatic solid papillary neoplasm: intense membranous claudin 5 expression (Am J Surg Pathol 2009;33:768)
- Many carcinomas (weaker expression than in angiosarcoma)

Claudin7

Has full length form (211 amino acids) and C-terminal truncated form (158 amino acids)
Also known as CLDN7
Important in aspirin-induced gastric barrier loss (Am J Physiol Cell Physiol 2008;295:C800)
Interpretation: membranous expression
Uses by pathologists:
- High expression may be poor prognostic factor in nasopharyngeal carcinoma, ovarian carcinoma (expression in serous effusions) (Hum Pathol 2010;41:944, Hum Pathol 2008;39:747)
- Membranous claudin7 and negative claudin8 may differentiate chromophobe renal cell carcinoma from onococytoma (Hum Pathol 2009;40:206)
Positive staining - normal: kidney (distal nephron epithelium), lung and prostate (J Membr Biol 2003;194:187)
Positive staining - disease:
- Ovarian adenocarcinoma (Am J Clin Pathol 2007;127:928, Int J Gynecol Cancer 2008;18:1262)
- Pancreatic solid papillary neoplasm (Am J Surg Pathol 2009;33:768)
- Renal cell carcinoma, chromophobe type (67%, Arch Pathol Lab Med 2007;131:1541)
- Synovial sarcoma, biphasic (J Biol Chem 2006;281:38941)
References: NCBI Entrez Gene

Claudin18

Claudins are large family of tight junction proteins with 4 transmembrane domains
Claudins function to produce a seal between cells, with critical role in maintaining cell polarity
Claudin18, first described in 2001 (Mol Cell Biol 2001;21:7380) is highly conserved member, specific for gastric and lung tissue (Gene 2011;481:83)
Also called CLDN18
Clinical features: expression may contribute to greater acid resistance of Barrett's esophagus (Am J Physiol Gastrointest Liver Physiol 2007;293:G1106)
Interpretation: membranous staining
Positive staining - disease:
- Bile duct: biliary intraepithelial neoplasia (78%), extrahepatic bile duct carcinoma (90%), intrahepatic (100%) and extrahepatic (89%) intraductal papillary neoplasm of bile duct (100%), intrahepatic cholangiocarcinoma (43%) (Virchows Arch 2011;459:73)
- Pancreas: PanIN, intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, infiltrating ductal adenocarcinoma (Am J Surg Pathol 2008;32:188, J Histochem Cytochem 2011;59:942)
- Signet ring cell adenocarcinoma (gastric 86%, colorectal 38%, not breast or lung) (Am J Surg Pathol 2008;32:1182)
- Urachal adenocarcinoma (Am J Surg Pathol 2011;35:787)
Negative staining: nonneoplastic pancreas; urachal remnants and benign disorders (Am J Surg Pathol 2011;35:787)