ELSEVIER
IMMUNOHISTOCHEMICAL ASSESSMENT OF Ki-67 IN THE DIFFERENTIAL DIAGNOSIS OF ADRENOCORTICAL TUMORS
MASSIMO TERZOLO, ADRIANA BOCCUZZI, SILVIA BOVIO, SUSANNA CAPPIA, PAOLO DE GIULI, ANNA ALÌ, PIERO PACCOTTI, FRANCESCO PORPIGLIA, DARIO FONTANA, AND ALBERTO ANGELI
ABSTRACT
Objectives. To evaluate the utility of Ki-67 immunohistochemical analysis in the differential diagnosis between benign and malignant adrenocortical neoplasms.
Methods. Tissue specimens were obtained from 37 patients referred to our institute from 1990 to 1999. The indications for adrenalectomy were adrenal-dependent Cushing syndrome (n = 9), hyperandrogenism (n = 1), mineralocorticoid excess (n = 8), and nonfunctioning adrenal masses (n = 19). The histologic diagnosis was cortical adenoma in 26 of 37 patients and cortical carcinoma in the remainder. Normal adrenal glands were obtained from subjects who underwent radical nephrectomy because of initial renal carcinoma. Immunohistochemical analysis was performed using the monoclonal antibody anti-Ki-67 (clone MIB-1). The Ki-67 labeling index was expressed as the number of positive cells per 1000 cells.
Results. The average Ki-67 expression was 2.0 (SD) in normal adrenal glands, 11.3 + 60.3 and 90 ± 60.3 ± 16.0 ± 16.0 ± 1.2 ± 23.6, P <0.001) and between cor- tisol-producing adenomas and aldosterone-pro- ducing adenomas (28%o ± 23.6 ± 2.6%o, P <0.001) (Fig. 3). A statistically significant inverse correlation (r -0.74, P = 0.009) was ob- served between the Ki-67 LI and the survival of patients affected by adrenal carcinoma who were followed up for 12 to 93 months (median 48) after surgery. No correlation was found between the Ki-67 LI and the serum or urinary cortisol levels in patients affected by Cushing syndrome, although a significant positive correlation (r = 0.41, P = 0.003) was recorded between the Ki-67 LI and the dehydroepiandrosterone sulfate (DHEAS) levels in the overall series.
Ki-67 ( and 90%% (Fig. 1). The present find- ings validate the use of Ki-67 as a simple, reliable, and repeatable method in the differential diagnosis of adrenocortical tumors.
Furthermore, we observed a significant inverse relationship between the Ki-67 LI and the overall survival of patients affected by adrenocortical car- cinoma. Patients with a higher level of the Ki-67 LI had a reduced life expectancy compared with those with lower Ki-67 LI values. These findings suggest that this immunohistochemical marker may aid in identifying patients with a worse prognosis. The observation of very high values of the Ki-67 LI could prompt adjuvant therapy after radical sur- gery. Although the effectiveness of the adjuvant mitotane therapy has not been proved in random- ized, controlled studies, a very recent report on the efficacy of low-dose mitotane as adjuvant treat- ment in a small series has been published.13
The observation of a positive correlation be- tween the Ki-67 LI values and DHEAS levels is
interesting, because DHEAS is a classic, although imperfect, biochemical marker of malignancy.14,15
The KI-67 LI values were higher in cortisol-pro- ducing adrenal adenomas than in aldosterone-pro- ducing adenomas and nonfunctioning adenomas (Fig. 3). Since the tumor sizes were comparable overall, these data suggest that cortisol-secreting adenomas have a faster cell cycle. This unexpected finding is shared by pituitary adrenocorticotropin- secreting microadenomas, which have higher Ki-67 values than other adenomas, although they are smaller. 16
CONCLUSIONS
Our results suggest that the immunohistochem- ical analysis of Ki-67 should be used routinely in the pathologic assessment of an adrenal mass. This technique is reliable and cost effective and has widespread availability to be used in clinical prac- tice and not only for research purposes.
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