Carbonic anhydrase IX

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Stains & CD markers
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

Cite this page: Baniak N. Carbonic anhydrase IX. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainscarbonicanhydraseix.html. Accessed December 27th, 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

B. Clear cell papillary renal cell carcinoma

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Reference: Carbonic anhydrase IX

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

B. Clear cell renal cell carcinoma

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Reference: Carbonic anhydrase IX

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