Alexander Stojadinovic M.D.³, Murray F Brennan M.D.¹, Axel Hoos M.D., Ph.D.^1,2,

Atilla Omeroglu M.D.², Denis H Y Leung Ph.D.⁴, Maria E Dudas², Aviram Nissan M.D.¹,

Carlos Cordon-Cardo M.D.² and Ronald A Ghossein M.D.²

1.                    ¹Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York

2.                    ²Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York

3.                    ³Department of Surgery, Walter Reed Army Medical Center, Washington, D.C.

4.                    ⁴School of Economics and Social Sciences, Singapore Management University, Singapore

Correspondence: Alexander Stojadinovic, M.D., Walter Reed Army Medical Center, General Surgery Service, 6900 Georgia Avenue, N.W., Washington, D.C. 20307; fax: 202-782-1234; e-mail: ta.stojadinovic@verizon.net.

Accepted 1 May 2003.

We compared histomorphological features and molecular expression profiles of adrenocortical adenomas (ACAd) and carcinomas (ACCa). A critical histopathological review (mean, 11 slides per patient) was conducted of 37 ACAd and 67 ACCa. Paraffin-embedded tissue cores of ACAd (n = 33) and ACCa (n = 38) were arrayed in triplicate on tissue microarrays. Expression profiles of p53, mdm-2, p21, Bcl-2, cyclin D1, p27, and Ki-67 were investigated by immunohistochemistry and correlated with histopathology and patient outcome using standard statistical methodology. Median follow-up period was 5 years. Tumor necrosis, atypical mitoses, and >1 mitosis per 50 high-power fields were factors that were highly specific for ACCa (P < .001). Number (0 to 4) of unfavorable markers [Ki-67 (+), p21 (+), p27 (+), mdm-2(-)] expressed was significantly associated with mitotic activity and morphologic index (i.e., number of adverse morphologic features) and highly predictive of malignancy (P < .001). Ki-67 overexpression occurred in 0 ACAd and 36% ACCa (P < .001) and was significantly associated with mitotic rate and unfavorable morphologic index (P < .001). Tumor necrosis, atypical mitoses, >5 mitoses per 50 high-power fields, sinusoidal invasion, histologic index of >5, and presence of more than two unfavorable molecular markers were associated significantly with metastasis in ACCa. Well-established histopathologic criteria and Ki-67 can specifically distinguish ACCAd from ACCa. Tumor cell proliferation (Ki-67) correlates with mitotic activity and morphologic index. Tumor morphology is a better predictor of metastatic risk in ACCa than current immunohistochemistry-detected cell cycle regulatory and proliferation–associated proteins.

Keywords:

Adenoma, Adrenal, Carcinoma, IHC, Tissue microarray

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