CLONAL ANALYSIS OF HUMAN ADRENOCORTICAL CARCINOMAS AND SECRETING ADENOMAS

OBJECTIVES Adrenocortical tumours in man are characterized mainly on b iochemical, anatomical and histological grounds which establish their secretory pattern and, with some uncertainty, their benign or malignan t nature. To study further these tumours and eventually to shed some l ight on their pathogenesis, we determined their clonal composition. ME THODS Clonal composition was determined by X-chromosome inactivation a nalysis on tumour and leucocyte DNA using three markers: M27 beta, pho sphoglycero-kinase (PGK) and hypoxanthine- phosphoribosyl transferase (HPRT) with 88, 33 and 27% heterozygosity rates respectively. PATIENTS Clonal analysis was performed on 25 tumours from 19 heterozygous fema le patients: four had a carcinoma, 14 had a single secreting adenoma, and one had autonomous bilateral macronodular hyperplasia with Cushing 's syndrome (seven adenomas examined). RESULTS The malignant tumours h ad patterns indicative of monoclonality. The single adenomas displayed contrasting results with patterns indicative of monoclonality in eigh t cases, and patterns indicative of polyclonality in six cases; monocl onal adenomas were larger and had a higher prevalence of nuclear pleom orphism than the apparently polyclonal adenomas. In the patient with b ilateral macronodular hyperplasia, different clonal patterns were pres ent in different adenomas: whereas a clear monoclonal pattern was obse rved in the three adenomas of the right gland, in which the active X-a llele was not always the same, in two interpretable adenomas of the le ft gland, a moderately skewed pattern suggested a partial monoclonal c omponent. CONCLUSIONS These data show that adrenocortical carcinomas a re monoclonal and suggest that adenomas may arise from a single cell o r from more than one cell under the putative action of local growth fa ctors. In adenomas, which until now had appeared homogeneous, this gen etic heterogeneity may reflect different pathophysiological mechanisms or it may represent different stages of a common multistep process ex ceptionally occurring in a single patient with bilateral macronodular hyperplasia.