Ki-67 labeling index as an adjunct in the diagnosis of serous tubal intraepithelial carcinoma

Abstract

There is mounting evidence that serous tubal intraepithelial carcinoma (STIC) may be the immediate precursor of ovarian high-grade serous carcinoma (HGSC) but the criteria for its diagnosis are not well established as highlighted in a recent study showing that interobserver reproducibility, even among expert gynecologic pathologists, was moderate at best. Given the clinical significance of a diagnosis of STIC in a patient who has no other evidence of ovarian carcinoma, this is a serious issue that we felt needed to be addressed. Although it is not clear, at this time, whether such a patient should or should not be treated, the importance of an accurate and reproducible diagnosis of precursors of ovarian carcinoma cannot be underestimated. We hypothesized that an elevated Ki-67 labeling index may aid the diagnosis of STIC. Accordingly, we compared the Ki-67 index of STIC and HGSC to normal fallopian tube epithelium (FTE) in the same patients and to a control group of patients without carcinoma, matched for age. A total of 41 STICs were analyzed, of which 35 were associated with a concurrent HGSC. In FTE, immunoreactivity for Ki-67 was restricted to a few scattered cells (mean 2.0%). No statistically significant difference was found between patients with and without HGSC (P>0.05). However, both STICs and HGSC had significantly higher Ki-67 indices than normal FTE (P<0.0001). STICs uniformly had an elevated Ki-67 labeling index that ranged from 11.7% to 71.1% (average 35.6%). There was no correlation of the Ki-67 labeling index in the STICs and the associated HGSC, as the labeling index was lower in STIC in 18/35 (51.4%) whereas it was higher in 17/35 (48.6%) (P=0.86). In conclusion, the findings in this study indicate that compared with FTE, STICs have a significantly higher Ki-67 index similar to HGSC. Accordingly, the Ki-67 index can aid the diagnosis of intraepithelial tubal proliferations suspicious for STIC. Therefore, we propose that a Ki-67 index of 10% is a useful diagnostic tool to distinguish STICs from normal FTE.

Fig. 1

Ki-67 immunoreactivity in normal-appearing fallopian tube epithelium. The Ki-67-positive cells scatter in the tubal epithelium with a labeling index ranging widely from <1% in (A) and (B), whereas the index increases in (C) (approximately 6%) and (D) (approximately 10%).

Fig. 2

Ki-67 labeling index for all cases examined in this study. (A) In normal tubal epithelium, no correlation is found between the Ki-67 labeling index and patients' age (P = 0.66 and r² = 0.0042). (B) Comparison of the Ki-67 index among normal fallopian tube epithelium (FTE), concurrent serous tubal intraepithelial carcinoma (STIC), and high-grade serous carcinoma (HGSC). Connecting lines indicate the specimens from the same patients. The Ki-67 labeling index is significantly higher in STIC than that in normal fallopian tube epithelium (P<0.0001). However, there is no statistically significant difference in the Ki-67 labeling index between STIC and HGSC.

Fig. 3

Ki-67 immunoreactivity in a serous tubal intraepithelial carcinoma (STIC). (A) Hematoxylin and eosin-stained section shows a discrete STIC occupying approximately 40% of epithelium in the cross-section of a tube. (B) The Ki-67 immunoreactivity is confined largely to the STIC. (C and D) A higher magnification view demonstrating morphologic features of the STIC that contains highly atypical epithelial cells and has a very high Ki-67 labeling index, whereas the adjacent normal-appearing tubal epithelium has a low index. The squares in (A) and (B) show the magnified views in (C) and (D).

Fig. 4

Receiver operation curve analysis of the Ki-67 labeling index. (A) Ki-67 labeling index can distinguish a serous tubal intraepithelial carcinoma from a normal fallopian tube with high sensitivity and specificity and the area under the curve (AUC) is 0.999. (B) Ki-67 labeling index is not useful in distinguishing a serous tubal intraepithelial carcinoma from a high-grade serous carcinoma with an AUC of only 0.519.

Fig. 5

Ki-67 immunoreactivity in a serous tubal intraepithelial carcinoma. A tufted and multilayer serous tubal intraepithelial carcinoma shows that many Ki-67-positive cells are located in the basal-parabasal compartment. The lesion is also diffusely positive for p53.