• 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
• Recent publications show that ATP transporters contribute to cancer aggressiveness beyond the drug efflux effect (Cancer Biol Med 2020;17:253)
  • Also called multidrug resistant protein 2 (MRP2)

• 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, PASD positive, 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 (StatPearls: Dubin Johnson Syndrome [Accessed 25 July 2023])

• Papillary renal cell carcinoma can be prognostically stratified using monoclonal knock out validated ABCC2 IHC (Am J Surg Pathol 2017;41:1618, Eur Urol Focus 2018;4:740, Hum Pathol 2022;120:57, USCAP 2023 Abstracts: Genitourinary Pathology (Including Renal Tumors) [Accessed 25 July 2023])
  • Negative and cytoplasmic staining showing favorable survival outcomes
  • Brush border expression associated with poor prognosis
• Prognostic and predictive marker for other tumors
  • ABCC2 immunohistochemistry is reported to have prognostic value and potential predictive value (associated with chemotherapy resistance) in colon carcinoma, pancreatic 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, Sci Rep 2019;9:19782)
• Possible predictive value in metastatic papillary renal cell carcinoma (Mol Oncol 2018;12:1673)

Contributed by Rola Saleeb, M.D., Ph.D.

• Renal tubules (weak blush cytoplasmic and brush border; monoclonal antibody) (Hum Pathol 2022;120:57)
• Liver bile canaliculi (bile canaliculi expression, brush border expression; monoclonal antibody) (J Tissue Eng Regen Med 2018;12:2287)
• Endocrine pancreas - membranous (Histopathology 2002;41:65)
• Small intestine / colon (Histopathology 2002;41:65)

• Papillary renal cell carcinoma (weak blush cytoplasmic and brush border) (Hum Pathol 2022;120:57)
• Colon adenocarcinoma (cytoplasmic) (Clin Cancer Res 2000;6:2401)
• Pancreatic adenocarcinoma - brush border (Sci Rep 2019;9:19782)
• Ovarian cancer (cytoplasmic and nuclear) (Gynecol Oncol 2006;100:239, Clin Cancer Res 2006;12:7149)
• Breast carcinoma (cytoplasmic and nuclear) (Pathol Oncol Res 2012;18:331)
• Fallopian tube carcinoma (cytoplasmic and nuclear) (Arch Gynecol Obstet 2013;287:563)

• Papillary renal cell carcinoma (low risk group) (Hum Pathol 2022;120:57)
• Glomeruli (Hum Pathol 2022;120:57)
• Brain (J Pharmacol Exp Ther 2004;311:449)
• Lymph nodes (Histopathology 2002;41:65)
• Endocrine pancreas (Histopathology 2002;41:65)

• Molecular analysis of papillary renal cell carcinoma showed statistically significant very high ABCC2 gene expression by RNA sequencing platform in papillary renal cell carcinoma formerly classified as type 2
  • Data was based on The Cancer Genome Atlas papillary cohort (Eur Urol Focus 2018;4:740)
• ABCC2 RNA transcripts can be quantitatively assessed by ISH (USCAP 2023 Abstracts: Genitourinary Pathology (Including Renal Tumors) [Accessed 25 July 2023])
  • Negative: complete absence of RNA signals
  • Cytoplasmic blush: focal cytoplasmic RNA ISH signals
  • Brush border < 50%: scattered punctate RNA ISH signals
  • Brush border ≥ 50%: dense, numerous RNA ISH signals
• 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)

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 (PRCC). An immunopanel including ABCC2 IHC stain is ordered. Which pattern of staining may predict a poor clinical outcome?

1. Brush border staining in ≥ 50% of the PRCC cells
2. Complete absence of ABCC2 staining in the tumor with preserved staining in renal tubules
3. Concurrent ABCC2 and GATA3 expression in PRCC cells
4. Weak patchy cytoplasmic ABCC2 staining in the PRCC cells

A. Brush border staining in ≥ 50% of the PRCC cells. Brush border ABCC2 staining in the tumor is shown to be a poor prognostic feature in papillary renal cell carcinoma ≤ 4 cm in size. Brush border pattern also correlates with higher ABCC2 RNA transcript by ISH. Answers B and D are incorrect because completely negative or cytoplasmic expression shows a relatively better prognosis. Answer C is incorrect because GATA3 positive papillary renal cell carcinoma is known as the entity of papillary renal neoplasm of reverse polarity which is quite indolent.

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Reference: ABCC2