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. 2014 Oct 23;16(10):868-73.
doi: 10.1016/j.neo.2014.09.002. eCollection 2014 Oct.

Adrenal medullary hyperplasia is a precursor lesion for pheochromocytoma in MEN2 syndrome

Esther Korpershoek  1 , Bart-Jeroen Petri  2 , Edward Post  1 , Casper H J van Eijck  3 , Rogier A Oldenburg  4 , Eric J T Belt  3 , Wouter W de Herder  5 , Ronald R de Krijger  1 , Winand N M Dinjens  1
Affiliations

Adrenal medullary hyperplasia is a precursor lesion for pheochromocytoma in MEN2 syndrome

Esther Korpershoek et al. Neoplasia. .

Abstract

Adrenal medullary hyperplasias (AMHs) are adrenal medullary proliferations with a size < 1 cm, while larger lesions are considered as pheochromocytoma (PCC). This arbitrary distinction has been proposed decades ago, although the biological relationship between AMH and PCC has never been investigated. Both lesions are frequently diagnosed in multiple endocrine neoplasia type 2 (MEN2) patients in whom they are considered as two unrelated clinical entities. In this study, we investigated the molecular relationship between AMH and PCC in MEN2 patients. Molecular aberrations of 19 AMHs and 13 PCCs from 18 MEN2 patients were determined by rearranged during transfection (RET) proto-oncogene mutation analysis and loss of heterozygosity (LOH) analysis for chromosomal regions 1p13, 1p36, 3p, and 3q, genomic areas covering commonly altered regions in RET-related PCC. Identical molecular aberrations were found in all AMHs and PCCs, at similar frequencies. LOH was seen for chromosomes 1p13 in 8 of 18 (44%), 1p36 in 9 of 15 (60%), 3p12-13 in 12 of 18 (67%), and 3q23-24 in 10 of 16 (63%) of AMHs, and for chromosome 1p13 in 13 of 13 (100%), 1p36 in 7 of 11 (64%), 3p12-13 in 4 of 11 (36%), and 3q23-24 in 11 of 12 (92%) of PCCs. Our results indicate that AMHs are not hyperplasias and, in clinical practice, should be regarded as PCCs, which has an impact on diagnosis and treatment of MEN2 patients. We therefore propose to replace the term AMH by micro-PCC to indicate adrenal medullary proliferations of less than 1 cm.

Keywords: AMH, adrenal medullary hyperplasia; Adrenal medullary hyperplasia; LOH, loss of heterozygosity; MEN2; MEN2, multiple endocrine neoplasia type 2; PCC, pheochromocytoma; RET, rearranged during transfection proto-oncogene; loss; molecular alterations; pheochromocytoma.

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Figures

Figure 1
Figure 1
Left panel displays the LOH patterns of germ-line DNA (upper), PCC DNA (middle), and AMH DNA (lower) of case 14, for chromosome 3q24. Loss is indicated by the arrow. Note that the PCC and AMH show different LOH patterns. Right panel shows the sequences of a healthy control DNA (control) and the germ-line DNA, PCC DNA, and AMH DNA of case 9. Germ-line DNA displays the p.Cys634Arg, T>C mutation in an equal ratio, whereas both PCC DNAs show a higher signal of the mutation (C) compared to the wild-type signal (T), indicating amplification of the mutant allele.
Supplementary Figure 1.
Supplementary Figure 1.
Sub-macroscopic and microscopic examples of (A) AMH and (B) PCC.
See this image and copyright information in PMC

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