Stains & CD markers
ABCC2
Copyright: 2019-2023, PathologyOutlines.com, Inc.
PubMed Search: ABCC2[TI] pathology
ABCC2
Author: Rola Saleeb, M.D., Ph.D.
Editor-in-Chief: Debra L. Zynger, M.D.
Last author update: 23 July 2019
Last staff update: 26 May 2023 (update in progress)
Copyright: 2019-2023, PathologyOutlines.com, Inc.
PubMed Search: ABCC2[TI] pathology
Table of Contents
Definition / general | Essential features | Terminology | Pathophysiology | Clinical features | Interpretation | Uses by pathologists | Prognostic factors | Microscopic (histologic) description | Microscopic (histologic) images | Positive staining - normal | Positive staining - disease | Negative staining | Molecular / cytogenetics description | Board review style question #1 | Board review style answer #1Cite this page: Saleeb R. ABCC2. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsABCC2.html. Accessed June 10th, 2023.
Definition / general
- Adenosine triphosphate (ATP) binding cassette subfamily C member 2 (ABCC2) belongs to the C subfamily of the ABC transmembrane protein transporters
- It is located on chromosome 10 (Nat Rev Cancer 2010;10:147)
- ABCC transporters are involved in active drug transportation
- Contributes to chemotherapy resistance in some tumors by what is thought to be drug efflux mechanisms
- Also called multidrug resistant protein 2 (MRP2)
Essential features
- Diagnostically, ABCC2 is to be used together with morphology to subtype papillary renal cell carcinomas according to the proposed biological classification
- ABCC2 has prognostic significance in some tumors, particularly papillary renal cell carcinoma, as well as breast, colon, ovary and fallopian tube
- Might have predictive significance as has been implicated in chemotherapy resistance
Terminology
- Adenosine triphosphate (ATP) binding cassette subfamily C member 2 (ABCC2)
- Multidrug resistance associated protein 2 (MRP2)
- Canalicular multispecific organic anion transporter 1 (CMOAT1)
- Canalicular multidrug resistance protein (cMRP)
- ABC30
- Dubin-Johnson syndrome (DJS)
Pathophysiology
- ABC transporters have 7 subfamilies
- ABCC2 belongs to the C subfamily, also known as multidrug resistance protein family (Nat Rev Cancer 2010;10:147)
- They are involved in active drug transportation
- ABCC2 contributes to chemotherapy resistance through active ATP dependent efflux of drugs (Nat Rev Cancer 2010;10:147)
- Some studies indicate that they play a role in tumor biology beyond the efflux properties (Nat Rev Cancer 2010;10:147)
- Transporters are ATP dependent
- Cells enriched in ABC transporters are reported to be larger than average and hold numerous mitochondria to compensate for high energy demand needed for the transporter properties
- This could contribute to the oncocytic nature of some of the reported ABCC2 high tumors (Curr Cancer Drug Targets 2005;5:457)
- Renal drug transporters, including ABCC2, are upregulated downstream to the NRF2-ARE pathway that is enriched in papillary renal cell carcinoma type 2 (N Engl J Med 2016;374:135, Toxicol In Vitro 2015;29:884)
Clinical features
- Germline mutations in ABCC2 are associated with autosomal recessive Dubin-Johnson syndrome
- It is characterized by impaired secretion of conjugated bilirubin by hepatocytes
- Grossly, the liver is black in appearance
- Microscopically, there is accumulation of dark, coarsely granular pigment in the centrilobular zone
- Electron microscopy shows the pigment accumulating in lysosomes
- These patients are usually asymptomatic, with incidental detection of hyperbilirubinemia (Talaga: Dubin Johnson Syndrome, 2019)
Interpretation
- Cytoplasmic staining consistently observed in all reported tumors and normal tissue
- Additional nuclear staining reported in breast, ovary and fallopian tube
Uses by pathologists
- Papillary renal cell carcinoma subtyping: in the proposed combined morphological and molecular classification of papillary renal cell carcinoma, ABCC2 plays an important role in making the distinction between subtypes 1, 2, 3 and 4 (oncocytic low grade) (Am J Surg Pathol 2017;41:1618)
Prognostic factors
- Papillary renal cell carcinoma subtypes show different prognosis: on univariate and multivariate analysis, types 1 and 4 showed indolent behavior with significantly better outcome than types 2 and 3 (Am J Surg Pathol 2017;41:1618, Eur Urol Focus 2018;4:740)
- Prognostic and predictive marker for other tumors
- ABCC2 immunohistochemistry is reported as having prognostic value and potential predictive value (associated with chemotherapy resistance) in colon carcinoma, ovarian carcinoma, fallopian tube carcinoma and breast carcinoma (Gynecol Oncol 2006;100:239, Clin Cancer Res 2000;6:2401, Clin Cancer Res 2006;12:7149, Pathol Oncol Res 2012;18:331, Arch Gynecol Obstet 2013;287:563)
- Possible predictive value in metastatic papillary renal cell carcinoma type 2 (Mol Oncol 2018;12:1673)
Microscopic (histologic) description
- Papillary renal cell carcinoma subtypes (Am J Surg Pathol 2017;41:1618):
- Type 1 shows complete absence of ABCC2 staining
- Type 2 exhibits strong diffuse staining equal to or stronger than the background renal tubules
- Type 3 shows patchy staining weaker than the normal renal tubules
- Type 4 (oncocytic low grade type) has a distinct morphology with reverse polarity nuclear pattern and shows a strong diffuse ABCC2 staining pattern; however, unlike type 2, they harbor GATA3+ nuclear staining (Am J Surg Pathol 2019 May 22 [Epub ahead of print])
- Type 3 can be difficult to distinguish from type 1 on morphology alone without ABCC2 immunohistochemistry ancillary testing
Microscopic (histologic) images
Contributed by Rola Saleeb, M.D., Ph.D.
Papillary renal cell carcinoma type 1
Papillary renal cell carcinoma type 2
Papillary renal cell carcinoma type 3
Papillary renal cell carcinoma type 4
Positive staining - normal
- Renal tubules (cytoplasmic)
- Liver bile canaliculi (bile canaliculi expression)
- Cerebral cortex (cytoplasmic)
- Squamous epithelium (cytoplasmic)
- Pancreatic acini (cytoplasmic)
- Normal fallopian tube epithelium (cytoplasmic)
Positive staining - disease
- Papillary renal cell carcinoma subtypes 2, 3 and 4 (cytoplasmic)
- Colon adenocarcinoma (cytoplasmic)
- Ovarian cancer (cytoplasmic and nuclear)
- Breast carcinoma (cytoplasmic and nuclear)
- Fallopian tube carcinoma (cytoplasmic and nuclear)
Negative staining
Molecular / cytogenetics description
- Molecular analysis of papillary renal cell carcinoma showed statistically significant very high ABCC2 gene expression by RNA sequencing platform in papillary renal cell carcinoma type 2 in comparison with type 1
- Data was based on The Cancer Genome Atlas papillary cohort (Eur Urol Focus 2018;4:740)
- Studies on colon cancer, breast carcinoma, fallopian tube carcinoma and ovarian carcinoma showed correlation between ABCC2 gene expression by polymerase chain reaction and clinical outcomes, as well as chemotherapy resistance (Gynecol Oncol 2006;100:239, Clin Cancer Res 2000;6:2401, Clin Cancer Res 2006;12:7149, Pathol Oncol Res 2012;18:331, Arch Gynecol Obstet 2013;287:563)
Board review style question #1
A 56 year old man has an incidentally discovered renal mass, 4 cm in size. He was treated with partial nephrectomy. Microscopic examination shows a papillary renal cell carcinoma. You run an immunopanel including ABCC2 stain. Which pattern of staining reflects indolent tumor behavior?
- Complete absence of ABCC2 staining in both the tumor and the surrounding kidney
- Complete absence of ABCC2 staining in the tumor with preserved staining in renal tubules
- Strong diffuse staining equal to or stronger than the surrounding renal tubules
- Weak patchy staining, slightly weaker than the surrounding renal tubules
Board review style answer #1
B. Complete absence of ABCC2 staining in the tumor with preserved staining in renal tubules. Papillary renal cell carcinoma type 1 shows complete absence of ABCC2 staining, while type 3 shows patchy weak staining and type 2 shows strong diffuse staining. Type 1 tumors with low ABCC2 levels by both mRNA and immunohistochemistry analysis have been shown in multiple studies to have excellent outcomes.
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Reference: ABCC2
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