Adrenal medullary hyperplasia is a precursor lesion for pheochromocytoma in MEN2 syndrome.
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.
Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Esther
E
Korpershoek
Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands ; Department of Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Bart-Jeroen
BJ
Petri
Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Edward
E
Post
Department of Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Casper H J
CH
van Eijck
Department of Clinical Genetics, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Rogier A
RA
Oldenburg
Department of Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Eric J T
EJ
Belt
Department of Internal Medicine, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Wouter W
WW
de Herder
Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Ronald R
RR
de Krijger
Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Winand N M
WN
Dinjens
D000310:Adrenal Gland Neoplasms / Q000209:etiology*; D000313:Adrenal Medulla / Q000473:pathology*; D002878:Chromosomes, Human, Pair 1; D002893:Chromosomes, Human, Pair 3; D004252:DNA Mutational Analysis; D006801:Humans; D006965:Hyperplasia; D019656:Loss of Heterozygosity; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics* / Q000473:pathology*; D010673:Pheochromocytoma / Q000209:etiology*; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
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