Pituitary adenomas comprise 10-15% of all primary brain tumors and benign tumors usually of slow growth (1). The goal of management is to improve visual and other neurological deficits and to remove as much of the tumor as possible (2). Complete removal of tumors is infrequent because of the large size and invasive nature of these tumors. It has been estimated that approximately 50% of patients have tumor remnants after surgery (3). Some authors advocate adjunctive radiotherapy in the early postoperative period to prevent tumor recurrence (4, 5). Others prefer individualized treatment recommending additional therapy only after demonstration of unequivocal tumor recurrence or residual symptomatic disease (6, 7). Ki-67 antigen, which may be detected in all stages of the cell cycle except G0, represents a marker associated with tumor proliferation, invasiveness, and ultimately prognosis (8-10). However, it is still controversial whether Ki-67 is related to the aggressive behavior in pituitary adenomas (11). To assess the relationship between Ki-67 and recurrences, we used MIB-1 monoclonal antibody to detected the Ki-67 antigen in formalin-fixed, paraffin-embedded tissues (11, 12).

Most of the pituitary microadenomas are excised completely, but it is difficult to totally remove invasive pituitary macroadenomas (13). Although most of the pituitary adenomas grow slowly, some show aggressive or invasive growth (10, 13). Until now, no routine markers have been available to identify the aggressive behavior of pituitary adenoma. Recently, however, several cell cycle specific nuclear antigens have been recognized, using various immunohistochemical methods, which has aided reliable evaluation of tumor growth characteristics. Among these, Ki-67, a nuclear antigen readily identified by the monoclonal antibody MIB-1 (14), is typically expressed in proliferating cells during the G1, S, G2, and M phases of the cell cycle (15, 16). It has been found to be useful in assessing several brain tumors, providing information about cell proliferation and thus long-term prognosis (17, 18). Ki-67 antigen detectable at all stages of the cell cycle except G0 is considered a useful proliferation marker (12). The MIB-1 antibody permits detection of the Ki-67 antigen in formalin-fixed, paraffin-embedded tissues. In the studies by Knosp et al. (15), Zhao et al. (11) and Mastronardi et al. (17), the mean positive reaction to Ki-67 was 1.1%, 1.4%, and 2.64%, respectively. Generally the Ki-67 labeling index in pituitary adenomas is relatively low compared with other brain tumors (12). With respect to the patient gender and age, Yonezawa et al. (19) reported a significantly higher MIB-1 in nonfunctioning adenomas of patients younger than 30 yr than in patients older than 40 yr. Similarly, Jaffrain-Rea et al. (20) reported a significantly higher index in patients younger than 30 than in older patients. However, Mastronardi et al. (17) compared different age groups (<25, between 25 and 50, >50 yr) and found no significant difference in the Ki-67 index. In the present study, there was no significant difference in the Ki-67 index among the different age groups analyzed. Others reported no significant differences in the Ki-67 index regarding patients gender or tumor diameter (10, 21). In prolactinomas, Delgrange et al. (22) found that the indices were likely to be higher in males than in females, though such difference was not statistically significant. Landolt et al. (10) examined the proliferative activity of 31 pituitary adenomas and reported higher Ki-67 values for acromegalic patients. In the present series, there was no significant relationship between the proliferation and hormonal states of the adenomas (15). Mindermann and Wilson (23) analyzed the gender-specific incidence of different types of pituitary adenomas according to clinical phenotypes and found that prolactinomas occurred predominantly in females, while hormonally inactive adenomas and GH-secreting adenomas occurred mainly in males. In the present study, clinically GH-secreting adenomas were predominant in females (1:1.6), while nonfunctioning adenomas were predominant in males (1.2:1). Functioning pituitary tumors tend to be more common among younger adults, whereas nonfunctioning adenomas become more prominent with increasing age (24). The tumor size, expressed as the maximal diameter measured on preoperative MR image scans, did not correlate with the Ki-67 labeling index (7, 21). Hardy (25) classified them into five type: A) tumor bulging into the chiasmatic cistern; B) tumor reaching the anterior third ventricle; C) huge suprasellar extension filling the entire third ventricle; D) parasellar extension into the temporal, frontal, or posterior fossa; and E) lateral expansion towards the cavernous sinus. Lath et al. (26) reported a higher Ki-67 labeling index in Hardy's classification type E than tumors without extrasellar extension. The Ki-67 labeling index of the other Hardy's classification was not different among the other types. Pituitary adenoma frequently invade surrounding structures such as the cavernous sinus, sphenoid sinus, and even the brain (11). Invasive adenomas are not considered to be malignant; their biological behavior lies between non-infiltrative adenomas and pituitary carcinomas (27). The reported frequency of invasive pituitary adenomas varied greatly from 10% to 85%, a reflection of differenct criteria for the definition of invasiveness. Scheithauer et al. (27) reported a frequency of 35%. Tumor size did not correlate with the growth fraction in pituitary adenomas (28), whereas invasiveness correlated in most studies (2). Indeed, Gandour-Edwards et al. (29) did not observe any difference in the Ki-67 labeling indexes between 10 patients with pituitary adenomas involving the sphenoid sinus, and 10 patients with noninvasive tumors. By contrast, Thapar et al. (30) reported significantly higher Ki-67 labeling indexes of 3% or higher to distinguish noninvasive from invasive adenomas. Pituitary adenomas may be associated with a suprasellar extension, as well outlined by coronal and sagittal MR images. Tumor invasion leads to neurological complications and also compromises complete tumor excision and normalization of hormone levels (1). Residual tumor usually continues to grow, becoming evident as a recurrence with further invasion of surrounding structures requiring repeat surgery (12). Invasion of the cavernous sinus occurs in 6 to 10% of all pituitary adenomas (1). Kawamoto et al. (31) reported that adenomas with invasion of the cavernous sinus had a significantly greater volume than those without invasion, although they showed no significant difference in the cell proliferation indexes assessed. Landolt et al. (10) demonstrated a significantly higher Ki-67 labeling index in invasive pituitary adenomas (mean 1.15%) than in non-invasive adenomas (mean 0.06%). In our study, the Ki-67 labeling index in the recurrent group was higher than in the non-recurrent group. The recurrence rate of pituitary adenoma has been reported to be as high as 10% to 35% despite their slow growth and benign nature (32). Incomplete removal of the tumor was one of the most important causes of recurrence. Ekramullah et al. (13) and Shibuya et al. (21) reported that they observed higher Ki-67 labeling index values in recurrent adenomas.

In conclusion, the careful clinical, hormonal, and MR image follow-up is necessary to identify the predicted recurrence of the tumor as early as possible. The Ki-67 labeling index does not seem to provide independent information to identify tumor recurrences. Although studies on the Ki-67 labeling index from long-term follow-up series are limited, the index does appear to provide valuable prognostic information. The high Ki-67 labeling index might suggest the need for careful clinical and radiological follow-up, as a useful marker to determine the characteristics and recurrence of pituitary adenomas, and therefore on appropriate therapeutic strategy.