Clinical significance of benign endometrial cells found in papanicolaou tests of Turkish women aged 40 years and older

Abstract

Background:

Spontaneously exfoliated benign-appearing endometrial cells (BEC) on a Papanicolaou smear might indicate endometrial pathology in postmenopausal women, necessitating further investigation. A cut-off age of 40 years was included in the Bethesda System 2001 based on studies of clinical significance of endometrial cells in Pap smears in Western countries.

Aims:

The purpose of this study was to determine the significance of age subgroup for women with a cytological diagnosis of BEC, regardless of menopausal status, in a retrospective cohort of Turkish women.

Materials and Methods:

Between October 2006 and November 2011, 41 patients with a BEC diagnosis and 64 patients with a cytological diagnosis of normal smear (NS) were enrolled; regardless of menopausal status, these women were 40 years and older and for whom follow-up endometrial biopsies had been performed.

Results:

On subsequent histopathologic evaluation, no malignant lesion was detected in women aged 40-50 years compared to three endometrioid-type adenocarcinomas in women older than 50 years with cytological diagnosis of BEC. There was a significant difference between women older than 50 years with cytologic diagnosis of BEC and NS in relation to premalignant lesions on histopathologic evaluation; however, this was not the case for women aged 40-50 years.

Conclusions:

According to our study, reporting BEC for women aged between 40 and 50 years has minor clinical significance but is significant for women older than 50 years, regardless of menopausal status. Larger sample size would be appropriate to confirm the results of the current study.

Introduction

The goal of cervical cytology is to detect cervical pre-cancer/cancer; it is not a screening method for endometrial abnormalities. However, when benign-appearing endometrial cells (BEC) are seen, they must be noted. Several studies have suggested that spontaneously exfoliated BEC on a Papanicolaou (Pap) smear might indicate endometrial pathology in postmenopausal women, necessitating further investigation.[1,2,3,4,5,6] The 1991 Bethesda System (TBS) recommended that the presence of BEC in postmenopausal women, which may be a harbinger of endometrial carcinoma or its precursors, should be reported in Pap test reports.[7] However, menopausal status often is not documented in test requisition forms. If clinical information is provided, it may be incorrect. A cut-off age of 40 years rather than menopausal status was included in the TBS 2001 based on studies of the clinical significance of endometrial cells in Pap smears in Western countries.[8] Reporting a cytological diagnosis of BEC in all women aged 40 years and older may create the potential for unnecessary clinical intervention because there is no recommended approach for managing women with BEC. Setting an appropriate cut-off age of 40 years is an example of the question of sensitivity versus specificity of reporting BEC.

Using a retrospective cohort of Turkish women in Istanbul, this study aimed to determine the significance of reporting BEC between age subgroups for women, regardless of menopausal status, and to make a case for increasing the cut-off age to 50 years.

Materials and Methods

Between October 2006 and November 2011, 41 patients with a cytological diagnosis of BEC and 64 patients with a cytological diagnosis of normal smear (NS) were enrolled at the Umraniye Education and Research Hospital, Istanbul; regardless of menopausal status, the women were 40 years and older and for whom follow-up endometrial biopsies had been performed (within 12 months). A diagnosis of BEC was made based on the presence of three-dimensional clusters of endometrial cells with small, round nuclei, inconspicuous nucleoli and scant cytoplasm with indistinct cell borders.[7] The specimens consisted of conventional smears obtained with a cytobrush, fixed in alcohol and Pap-stained. Follow-up histology included endometrial biopsy or hysterectomy specimens.

The Fisher's exact test was used to assess the association between categorical variables. P < 0.05 (two-sided test) was considered significant. All statistical analyses were carried out using Number Cruncher Statistical System 2007 and Power Analysis and Sample Size 2008 Statistical Software (Utah, USA).

Results

On subsequent histopathologic evaluation (HE), no malignant lesion was detected in women aged 40-50 years compared to three endometrioid-type adenocarcinomas in women older than 50 years with cytological diagnosis of BEC (P = 0.232). The difference was insignificant, probably because of the small sample size. In women older than 50 years, 3 of 13 patients with cytologic diagnosis of BEC had malignancy on HE, whereas 0 of 30 patients with NS did (P = 0.064). The difference was marginally significant, probably because of the small sample size. The results are summarized in Table 1.

Table 1.

Histological correlation (benign endometrial lesions×malignant lesion) of cytologic diagnosis of normal smear and benign-appearing endometrial cells according to age subgroup

On HE, eight of the 41 women with cytologic diagnosis of BEC and one of the 64 patients with NS had premalignant lesions (P = 0.001). The difference was highly significant. In women aged 40-50 years, premalignant lesions were detected on HE in 3 of 20 patients with cytologic diagnosis of BEC and in 1 of 34 patients with NS (P = 0.138). The difference was insignificant. However, in patients who were older than 50 years, premalignant lesions were detected on HE in 5 of 21 women with cytologic diagnosis of BEC and in 0 of 30 women with NS (P = 0.001). There was a highly significant difference between women older than 50 years with cytologic diagnosis of BEC and NS regarding premalignant lesions on HE. The results are summarized in Table 2. Premalignant lesions were endometrial simple/complex hyperplasia with or without atypia, and non-neoplastic lesions were endometrial polyp, inactive endometrium, dissociating endometrium, nonspecific chronic endometritis and secretory endometrium.

Table 2.

Histological correlation (benign endometrial lesions×premalignant lesion) of cytologic diagnosis of normal smear and benign-appearing endometrial cells according to age subgroup

Discussion

In Turkey, the mean and median age at which menopause begins is 44.38-47.8 and 51 years, respectively.[9,10,11] The cut-off age of 40 years for cytological diagnosis of BEC for Turkish women appears young, but the age of 50 years comes 2-6 years after the onset of menopause in Turkey. The current study revealed that the reporting of BEC for Turkish women aged between 40 and 50 years has minor clinical significance, but is significant for women older than 50 years regardless of menopausal status. No malignant lesions were detected on HE in women aged 40-50 years, compared to three endometrioid-type adenocarcinomas in women older than 50 years with cytological diagnosis of BEC. Similar results were detected with regard to premalignant lesions. For premalignant lesions, HE revealed a significant difference between women older than 50 years with cytologic diagnosis of BEC and NS; however, this was not the case for women aged 40-50 years. Therefore, it appears that the withdrawal of the cut-off age of 50 years in reporting cytological diagnosis of BEC would reduce unnecessary anxiety and interventions without diminishing safety in Turkish women.

Menopausal status was a significant independent parameter in determining the clinical significance of the cytological diagnosis of BEC.[5] Fadare's[12] review of the medical literature of the last half century concluded that increasing age is an independent predictor of endometrial pathology. In the study of Browne et al.,[13] all cancers were noted in women older than 45 years. Two studies showed that cytological diagnosis of BEC in premenopausal women aged over 40 years alone is clinically insignificant.[14,15] The studies detected significant endometrial pathology in 14 of 121 (11.6%) postmenopausal patients compared to 7 of 300 (2.3%) in the control group (postmenopausal women without BEC on cytology), and in no premenopausal patients aged 40 years and older.

The current study revealed that reporting of BEC for Turkish women aged between 40 and 50 years has minor clinical significance but is significant for women older than 50 years, regardless of menopausal status. The results of the current study led to the emergence of the idea that it may be more appropriate for each community to determine its own cut-off age for reporting BEC, considering the particular menopause profile of that country. Larger sample size would be appropriate to analyse this idea.