Adrenocortical Adenoma and Carcinoma: Histopathological and Molecular Comparative Analysis

Abstract

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. Paraffinembedded 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. Wellestablished 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.KEY WORDS: Adenoma, Adrenal, Carcinoma, IHC, Tissue microarray. Mod Pathol 2003;16(8):742-751Adrenocortical carcinoma is a highly aggressive, rare endocrine malignancy. However, benign, clinically occult adrenal adenomas, adrenal "incidentalomas," are encountered frequently by abdominal imaging performed for unrelated indications. The unsuspected adrenal mass is detected in 2-4% of the general population and in Յ6% of abdominal computed tomography scans in patients aged 60 -70 years (1, 2). The size of the adrenal mass is considered to be the most reliable predictor of malignancy. As 8 -13.5% of resected adrenocortical carcinomas are Ͻ5 cm, size alone is an imperfect criterion for malignancy (3). In a study of metastasizing and nonmetastasizing adrenocortical tumors among 43 patients followed for a median of 11 years, Weiss (4) demonstrated the utility of nine histomorphologic criteria in predicting the biology of adrenocortical neoplasms. The histologic findings most predictive of malignancy were Ͼ5 mitoses per 50 high-power fields, atypical mitoses, and venous invasion. No single criterion could distinguish benign from malignant tumor biology; all but one of the benign adrenocortical tumors had two or fewer criteria. In a later study, Weiss et al. (5) modified the diagnostic criteria for benign and malig...

Comparative diagnostic and prognostic performances of the hematoxylin-eosin and phospho-histone H3 mitotic count and Ki-67 index in adrenocortical carcinoma

“…Moreover, it has been also successfully applied in different neoplasms of the breast, [22][23][24][25][26] meninges, [27][28][29] brain, 30 lung, 31 soft tissues, [32][33][34] esophagus, 35 female genital tract, 36,37 prostate, 38 and urothelium, 39 as well as in cytology material from pancreatic endocrine tumors 40 and urothelial carcinoma. 41 The Ki-67 index represents an alternative method for assessing the proliferative potential in adrenocortical tumors and has already been shown to differentiate adrenocortical adenoma from carcinoma, [42][43][44][45][46][47][48][49] and to predict tumor behavior. 42,50,51 However, the use of the Ki-67 index is not officially incorporated in the diagnostic work up of adrenocortical carcinoma, which still largely relies on histomorphological parameters.…”

Surgical management of large adrenal tumours: the University of Miami experience using liver transplantation techniques

“…Adrenal masses were associated with vena cava thrombus in five patients ( Slooten et al [12] and Stojadinovic et al [13]. The vena cava thrombus did not contain tumour extension.…”

“…The median (range) intraoperative blood loss, except in the patient who required CPB, was 500 (250-1500) mL (Table 1), and the median operative time was 320 (260-475min) min. The median tumour size was 11 (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) cm (Fig. 3).…”

“…At this juncture, ancillary biological or molecular markers are of little practical value for differential diagnosis between adrenocortical adenoma and carcinoma but tumours with MIB1 or Ki-67 labelling index of > 2.5 may be considered malignant. Well-established histopathological criteria and Ki-67 can specifically distinguish adrenocortical adenoma from carcinoma [13]. It sometimes is important for surgical pathologists to differentiate adrenocortical carcinoma from metastatic malignancies of other sites.…”

Extremely long survival in six patients despite recurrent and metastatic adrenal carcinoma.

“…A few prognostic factors have been investigated that might elucidate why some patients survive this long. Whereas the influence of gender, age and functionality of the tumour on prognosis is subject to debate (19)(20)(21) and the prognosis was influenced by tumour stage at diagnosis and the possibility to perform a complete resection (19,22). Recently, Assié et al discussed the prognostic parameters of metastatic adrenocortical carcinoma.…”