Large Adrenal Cortical Adenomas with Extensive Myelolipomatous Metaplasia: Upregulation of Jak-Stat Pathway and Solitary Fibrous Type Stromal Reaction
Emma Garratt, Alfredo Blanes, Salvador J Diaz-Cano. Barts and The London Hospitals, London, United Kingdom; University of Malaga School of Medicine, Malaga, Spain; King's College Hospital, London, United Kingdom
Background: The presence of extensive myelolipomatous metaplasia (MLM) is rare in adrenocortical neoplasms, and the biological reasons are unknown. We investigate the cell survival and proliferation pathways and the stromal reaction in these neoplasms.
Design: We selected adrenocortical adenomas (ACA, 82; 8 with extensive/multifocal MLM), ACTH-independent nodular hyperplasias with no dominant nodules (ACNH, 23), and carcinomas (ACC, 22) (WHO criteria) to analyze cell survival-proliferation pathways (MKI67, ERK1, AKT1, CASP3, BCL2, CCND1, FN1, JUN, MMP7, MYC, BMP1, BMP7, TERT, IGF2), and stromal-inflammatory reaction types (CDH11, SDC1, SPARC, MMP11, CSF1, CD68, CD163, FCGR2, CXCL9, IL4, IL4R, IRF1, MMP10) in a low-density selective cDNA array. Total RNA was extracted, cleaned from normal and neoplastic tissues (RNeasy columns), first-strand cDNA synthesized using T7-(dT24)-oligomer and used as template for cRNA synthesis. The cRNA was fragmented, Cy3-/Cy5-labeled, and hybridized to arrays noncompetitively, cross-validating the results (expression factor>2, significance<0.01). Variables were studied regarding MLM presence and histological diagnosis. Significant variables were then tested on tissue sections by in-situ techniques.
Results: Multifocal and extensive MLM was only observed in ACA: ACA+MLM were significantly bigger (7.9±1.5cm, 142.6±9.9g) than the remaining ACA, and they showed bone metaplasia and positive PET scan in 7/8 cases. ACA with MLM showed significant upregulation (expression factor>2, p<0.01) for AKT1, BMP1, TERT, CCND1, CD68, CD163, and IL4/IL4R (when compared with ACC), and for CASP3, FN1, CXCL9, IL4, BMP1, CD68, MMP11 (when compared with ACNH and conventional ACA). Remaining genes showed no significant differences.
Conclusions: ACA with MLM is worth recognizing because it is frequently be confused preoperatively with ACC due to its bigger size and positive PET scan. Biologically, this pattern is related with the tumor upregulation of Jak-Stat pathway (CXCL9, IL4, IL4R), downregulation of PI3k/AKT pathway (AKT1, CCND1, CASP3) and solitary fibrous type stromal reaction (CD68, CD163) from BMP1 producing ACA.
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 50, Tuesday Afternoon