title: Discerning malignancy in adrenocortical tumors: are molecular markers useful?
abstract: OBJECTIVE
  Adrenocortical carcinoma (ACC) is a rare neoplasm with poor prognosis. Discerning ACCs from benign adenomas histologically may be difficult if invasion into surrounding tissues or metastases are missing.
  
  
  METHODS
  In order to establish molecular markers for malignancy, we analyzed seven normal adrenals, three massive macronodular ACTH-independent adrenocortical hyperplasias (MMAHs), 30 adrenocortical adenomas (ACAs) and ten ACCs.
  
  
  METHODS
  All tissues were studied for the presence of alterations in the p53 tumor suppressor gene using the PAb 1801 antibody, which detects mutant p53 protein and the pYNZ22 microsatellite marker to show loss of heterozygosity (LOH) at 17p, for expression of the proliferation-associated antigen Ki67 using the MIB1 antibody, for the rate of apoptotic tumor cells with the TdT-mediated dUTP biotin nick end labeling (TUNEL) method, and for LOH of 11q13 (menin gene locus) with the D11S956 microsatellite marker.
  
  
  RESULTS
  0/3 MMAH, 1/28 ACA and 3/10 ACC revealed immunopositive staining for p53. LOH for pYNZ22 was observed in 1/3 MMAH, 1/23 informative ACA and 6/6 informative ACC. The rate of apoptotic cells was significantly higher in ACC (P<0.0001 by ANOVA) than in ACA but there was some overlap between groups. The Ki67 index (% immunopositive cells) was 1.9+/-1.30% (mean+/-s.d.) in normal adrenals, 3.47+/-1.37% in MMAH, and 2.11+/-1.01% in ACA. ACC had the highest Ki67 index of 11.94+/-7.58% distinguishing all ACC from the ACA and MMAH studied with a cut-off level of 5%. LOH for 11q13 was detected in 2/3 MMAH, 5/26 ACA and 6/8 ACC.
  
  
  CONCLUSIONS
  We conclude that a Ki67 index above 5% is a sensitive and specific indicator of ACC and may be useful in the differentiation of adenomas from carcinomas.
authors.affiliation: Schwerpunkt Endokrinologie, Medizinische Universitätsklinik Würzburg, Würzburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Wachenfeld
authors.forename: F
authors.initials: F
authors.lastname: Beuschlein
authors.forename: O
authors.initials: O
authors.lastname: Zwermann
authors.forename: P
authors.initials: P
authors.lastname: Mora
authors.forename: M
authors.initials: M
authors.lastname: Fassnacht
authors.forename: B
authors.initials: B
authors.lastname: Allolio
authors.forename: M
authors.initials: M
authors.lastname: Reincke
mesh_terms: D000236:Adenoma / Q000175:diagnosis; D000293:Adolescent; D000302:Adrenal Cortex / Q000473:pathology; D000306:Adrenal Cortex Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D000328:Adult; D000368:Aged; D017209:Apoptosis; D002277:Carcinoma / Q000175:diagnosis; D002648:Child; D002675:Child, Preschool; D003937:Diagnosis, Differential; D015870:Gene Expression; D016158:Genes, p53 / Q000235:genetics; D005819:Genetic Markers; D006801:Humans; D006965:Hyperplasia; D007223:Infant; D019394:Ki-67 Antigen / Q000032:analysis; D019656:Loss of Heterozygosity; D008875:Middle Aged; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics; D011379:Prognosis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
chemical_list: D005819:Genetic Markers; D019394:Ki-67 Antigen; D016159:Tumor Suppressor Protein p53