Loss of PRKAR1A Expression in Carney Complex-Associated Versus Nonsyndromic Cardiac Myxomas: Immunohistochemical and Molecular Analysis of 112 Cases
Brandon T Larsen, Mathieu C Castonguay, Nifize S Kip, Benjamin R Kipp, Joseph J Maleszewski. Mayo Clinic, Rochester, MN
Background: Cardiac myxoma usually presents in a sporadic, nonsyndromic fashion as a solitary mass, but occasionally occurs as part of the Carney complex (CNC). Two-thirds of CNC-associated myxomas exhibit mutations in PRKAR1A, the gene encoding the cAMP-dependent protein kinase type Iα regulatory subunit. PRKAR1A mutations occur in both familial and nonfamilial forms of CNC, but whether these mutations occur in nonsyndromic cardiac myxomas is unknown.
Design: All cardiac myxomas (1993-2011) were retrieved from our institutional pathology files, and clinical and pathologic findings were reviewed. Immunohistochemistry was performed with an antibody directed against PRKAR1A protein, and staining of myxoma cells was graded semiquantitatively. Bi-directional Sanger sequencing was also performed to test for the presence of mutations in all coding regions and intron/exon boundaries of the PRKAR1A gene.
Results: Among 112 patients, 9 patients with CNC were identified (mean age 28 yrs, range 12-45, 7 female). In these patients, cardiac myxomas originated in diverse locations (left atrium 52%, right atrium, right ventricle, and left ventricle each 16%) and were multiple in 5 cases. Additional features of CNC included family history of cardiac myxomas (5 cases), Cushing syndrome (3), ephelides (3), cutaneous myxomas (2), blue nevi (1), and calcifying testicular tumors (1). Mutational analysis has been completed in 2 CNC cases, confirming PRKAR1A mutations in each (G891A and R228X). The remaining 103 patients (mean age 62 yrs, range 18-92, 65 female) presented with a solitary cardiac myxoma (left atrium 87%, right atrium 11%, right ventricle 2%), without other features of CNC. From all patients, 118 cardiac myxomas were available for review. Immunostaining for PRKAR1A was absent in all CNC-associated cardiac myxomas, consistent with loss of PRKAR1A expression. Unexpectedly, PRKAR1A staining was also absent in 30% of nonsyndromic myxomas and diminished (<50% of myxoma cells positive) in an additional 2% of cases, but was preserved in cardiomyocytes, indicating that PRKAR1A is selectively lost in many nonsyndromic tumors. Complete mutational analysis of the non-CNC cohort is ongoing.
Conclusions: Loss of PRKAR1A expression occurs not only in CNC-associated cardiac myxomas, but also in nearly one-third of sporadic nonsyndromic tumors. PRKAR1A mutations and/or alterations in its protein product may play a role in nonsyndromic cardiac myxomagenesis.
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 46, Monday Morning