Stains & CD markers
Carbonic anhydrase IX
Copyright: 2003-2024, PathologyOutlines.com, Inc.
PubMed Search: stains carbonic anhydrase ix [TI]
Carbonic anhydrase IX
Author: Nick Baniak, M.D.
Editorial Board Member: Maria Tretiakova, M.D., Ph.D.
Editor-in-Chief: Debra L. Zynger, M.D.
Last author update: 23 March 2021
Last staff update: 18 June 2021
Copyright: 2003-2024, PathologyOutlines.com, Inc.
PubMed Search: stains carbonic anhydrase ix [TI]
Table of Contents
Definition / general | Essential features | Terminology | Pathophysiology | Clinical features | Interpretation | Uses by pathologists | Prognostic factors | Microscopic (histologic) images | Virtual slides | Positive staining - normal | Positive staining - disease | Negative staining | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Baniak N. Carbonic anhydrase IX. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainscarbonicanhydraseix.html. Accessed April 18th, 2024.
Definition / general
- Member of zinc metalloenzyme family, which accelerates the rate of conversion between carbon dioxide (CO2) and bicarbonate (HCO3) (Am J Clin Pathol 2014;141:219)
- Transmembrane protein that is regulated by hypoxia (Cancer Res 2000;60:7075, SpringerLink: Carbonic Anhydrase - Mechanism, Regulation, Links to Disease, and Industrial Applications [Accessed 17 February 2021])
- Roles in cell proliferation and migration, cell adhesion, tumorigenesis and pH control (Cancer Res 2004;64:6160, Oncogene 2010;29:6509)
Essential features
- Carbonic anhydrase IX (CAIX / CA9) is a transmembrane protein (membranous expression) (Am J Clin Pathol 2014;141:219)
- Primarily used in differentiating kidney tumors but not specific to renal primary tumors
- Diffusely positive in clear cell renal cell carcinoma (box-like) and clear cell papillary renal cell carcinoma (cup-like) (Histopathology 2020;77:659)
- Strong membranous staining in mesothelioma, mesothelial lesions and mesothelium (Virchows Arch 2012;460:89, Am J Clin Pathol 2014;142:82)
- Upregulated in hypoxic environments, including around necrosis (Cancer Res 2000;60:7075)
Terminology
- Carbonic anhydrase IX / CA9 (NCBI: CA9 Carbonic Anhydrase 9 [Accessed 11 December 2020])
- MN / G250 (NCBI: CA9 Carbonic Anhydrase 9 [Accessed 11 December 2020])
Pathophysiology
- CAIX is under control of the hypoxia inducible factor 1 (HIF1) and is predominantly located in chronically hypoxic tumor regions (Semin Cancer Biol 2015;31:52, Cancer Res 2000;60:7075)
- CAIX protein is attached to the plasma membrane with a single transmembrane domain (Br J Cancer 2020;122:157)
- CAIX catalyzes the reversible hydration of CO2 at the plasma membrane (Br J Cancer 2020;122:157)
- By facilitating CO2 excretion, CAIX maintains a more intracellular alkaline pH and more acidic extracellular space, facilitating invasion (J Biol Chem 2008;283:20473, J Biol Chem 2009;284:20299, Oncotarget 2012;3:84)
- CAIX also drives cell migration and invasion by both catalytic and noncatalytic mechanisms (J Biol Chem 2012;287:3392, Front Physiol 2013;4:271, Cancer Res 2009;69:358)
- CAIX expression also promotes cell cancer cell migration by competing with E-cadherin for binding to β catenin, inactivation of Rho kinase and induction of epithelial - mesenchymal transition (Exp Cell Res 2003;290:332, J Cell Sci 2011;124:1077)
Clinical features
- CAIX is overexpressed in hypoxia; hypoxia inducible factor is controlled by the VHL gene (Nature 1999;399:271)
Interpretation
- Membranous staining (box-like or cup-like [negative luminal border])
- Disregard cytoplasmic staining
Uses by pathologists
- Primarily used in differentiating renal cell carcinoma (RCC) subtypes
- Clear cell RCC (diffuse) versus papillary RCC (focal, very often < 50%) (Histopathology 2020;77:659, Am J Clin Pathol 2014;141:219)
- Clear cell RCC (diffuse, box-like) versus clear cell papillary RCC (diffuse, cup-like) (Histopathology 2020;77:659)
- Clear cell RCC (diffuse) versus chromophobe RCC (negative) (Histopathology 2020;77:659, Am J Clin Pathol 2014;141:219)
- Clear cell RCC (diffuse) versus Xp11 translocation RCC (negative or focal) (Histopathology 2020;77:659, Am J Surg Pathol 2010;34:1295)
- Supports clear cell RCC subtype in metastatic tumor consistent with RCC primary
- Potential in discriminating select meningioma subtypes (negative in clear cell versus positive in microcystic and angiomatous (J Neuropathol Exp Neurol 2019;78:1081)
Prognostic factors
- Prognostic role under investigation in multiple organ systems
- May be associated with worse outcome in clear cell renal cell carcinoma and papillary renal cell carcinoma (Urol Oncol 2018;36:531.e19, Eur J Surg Oncol 2020;46:209)
- Expression may be a negative prognostic marker in:
- Hepatocellular carcinoma (Int J Oncol 2017;51:1179)
- Breast carcinoma; may also be associated with better treatment response in breast carcinoma (Histol Histopathol 2011;26:1279, Cancer Res 2011;71:3364, BMC Cancer 2019;19:1173)
- Gastric adenocarcinoma (J Environ Pathol Toxicol Oncol 2016;35:207)
- Pancreatic ductal adenocarcinoma (Pathol Oncol Res 2018;24:899)
- Oral squamous cell carcinoma (Int J Mol Sci 2019;20:375, Oncotarget 2017;8:83088, Oral Oncol 2012;48:615)
Microscopic (histologic) images
Contributed by Nick Baniak, M.D.
Clear cell RCC
Clear cell papillary RCC
Papillary RCC
Negative renal parenchyma
Virtual slides
Images hosted on other servers:
Clear cell papillary RCC
Positive staining - normal
- Liver bile ducts (Am J Clin Pathol 2014;141:219)
- Gastric (body and antrum) (Am J Clin Pathol 2014;141:219)
- Duodenum (Am J Clin Pathol 2014;141:219)
- Mesothelium (Virchows Arch 2012;460:89)
Positive staining - disease
- Clear cell renal cell carcinoma (> 90%, diffuse, box-like) (Histopathology 2020;77:659)
- Clear cell papillary renal cell carcinoma (100%, diffuse, cup-like) (Histopathology 2020;77:659)
- Papillary renal cell carcinoma (30 - 82%, focal only) (Histopathology 2020;77:659, Am J Clin Pathol 2014;141:219, Histopathology 2011;59:1229)
- Malignant mesothelioma (100%, diffuse, box-like) (Virchows Arch 2012;460:89)
- Adenomatoid tumor (100%, diffuse, box-like) (Virchows Arch 2012;460:89)
- Endolymphatic sac tumors (100%) (Head Neck Pathol 2019;13:355)
- Epididymal papillary cystadenoma (100%) (Urology 2018;112:172)
- Clear cell adenocarcinoma of the urothelial tract (Histopathology 2011;59:1229)
- Pancreatic serous cystadenoma (100%) (Pancreatology 2009;9:182)
- Intrahepatic cholangiocarcinoma (90%) (Am J Clin Pathol 2014;141:219)
- Other tumors may be positive but staining is less diffuse and often concentrated in areas of necrosis:
- Urothelial carcinoma (35 - 100%) (Am J Clin Pathol 2014;141:219, Histopathology 2011;59:1229)
- Endocervical adenocarcinoma (> 60%) (Am J Clin Pathol 2014;141:219)
- Pancreatic adenocarcinoma (> 50%) (Am J Clin Pathol 2014;141:219)
- Squamous cell carcinoma (> 50%) (Am J Clin Pathol 2014;141:219)
- Gastric adenocarcinoma (42 - 57%) (J Environ Pathol Toxicol Oncol 2016;35:207, Am J Clin Pathol 2014;141:219)
- Colonic adenocarcinoma (> 50%) (Am J Clin Pathol 2014;141:219)
- Endometrial endometrioid adenocarcinoma (> 50%) (Am J Clin Pathol 2014;141:219)
Negative staining
- Chromophobe renal cell carcinoma (Histopathology 2020;77:659, Am J Clin Pathol 2014;141:219)
- Oncocytoma (Histopathology 2020;77:659, Am J Clin Pathol 2014;141:219)
- Translocation renal cell carcinoma (5 - 37%) (Am J Surg Pathol 2020;44:1450, Histopathology 2020;77:659, Am J Surg Pathol 2010;34:1295)
- Hepatocellular carcinoma (15%) (Am J Clin Pathol 2014;141:219)
- Seminoma (0 - 7%) (Histopathology 2011;59:1229, Am J Clin Pathol 2014;141:219)
- Yolk sac tumor (Histopathology 2011;59:1229)
- Choriocarcinoma (Histopathology 2011;59:1229)
- Leydig cell tumor (Histopathology 2011;59:1229)
- Pheochromocytoma (Histopathology 2011;59:1229)
- Adrenal cortical adenoma (Histopathology 2011;59:1229)
- Breast invasive carcinoma of no special type (ductal) (0 - 15%, higher with increasing grade) (Am J Clin Pathol 2014;141:219)
- Prostate adenocarcinoma (Histopathology 2011;59:1229, Am J Clin Pathol 2014;141:219)
- Thyroid papillary carcinoma (Am J Clin Pathol 2014;141:219)
- Renal cortex tubules and glomeruli
Board review style question #1
A 68 year old man was found to have a 2.5 cm cystic kidney mass. The mass was positive for CK7 while negative for CD10 and AMACR. CAIX showed the staining pattern in the picture above. What is the diagnosis?
- Clear cell renal cell carcinoma
- Clear cell papillary renal cell carcinoma
- Multilocular cystic renal neoplasm of low malignant potential
- Papillary renal cell carcinoma
Board review style answer #1
Board review style question #2
Which of the following kidney tumors is most often diffusely positive for CAIX (shown in the images above)?
- Chromophobe renal cell carcinoma
- Clear cell renal cell carcinoma
- Oncocytoma
- Papillary renal cell carcinoma
Board review style answer #2
