Endometrial polyp is a common benign disease of the uterus. The overall incidence where cancer arises in the endometrial polyp has been reported as only a few percent, while postmenopausal women with EMP are at an increased risk of malignancy, compared to premenopausal women [10, 13–15]. As risk factors for development of the malignancy in EMP, hypertension, obesity, and unopposed estrogen therapy have been indicated in addition to postmenopausal status . There are unique or specific pathological and clinical features for EIC as a putative precursor of uterine body serous adenocarcinoma, as follows [1, 4, 5, 7, 16–20]: close association with an EMP; multicentric occurrence in the inactive or resting thin endometrium, lacking alteration in the architecture in the endometrium lacking an intervening phase of endometrial hyperplasia; extrauterine invasive extent, irrespective of an absence of stromal invasion of the uterus; and controversial outcome, whether taking a favorable or unfavorable clinical course. Development of EIC associated with an EMP may also be explained in part by Tamoxifen administration following breast cancer treatment [6, 17]. However, little has been documented about the endometrial cytological features of minimal serous adenocarcinoma of the uterine body including EIC, mainly due to the fact that the disease is not frequently encountered in the routine practice. To the best of our knowledge, there is a case report cytologically referring to serous adenocarcinoma of the uterine body associated with an EMP , but here the patient already showed peritoneal dissemination at the initial presentation. In another report, serous adenocarcinomas of the uterine body were clinico-cytologically reviewed but they were all at advanced stages . The latter report mentions that cytologically diagnostic findings of uterine body serous adenocarcinoma would be based on the following features: papillary cluster as well as tubular cluster, arborescent structure, frequent exfoliation, psammoma body, eccentric enlarged nuclei, coarsely granular chromatin, numerous nucleoli, and diameter of greater than G1 endometrioid adenocarcinoma . In our review, 5 patients were purely non-invasive as they were composed of only EIC existing in an EMP, with few or no necroinflammatory changes. The background was found to be characteristically watery or mucous (Figure 1) in a way of simulating the immigration of extrauterine carcinoma cells via the fallopian tubes . Many clusters were arranged in micropapillary architecture without fine vascular stroma, and others were occasionally tubular. An abrupt transition between the EIC cells and atrophic endometrial cells was noted by front formation (Figure 2). Conspicuous nucleoli were found in 3 patients (Figure 3). Even though it seems difficult to reach a definite diagnosis, these findings may serve as a diagnostic indicator for the uterine body serous adenocarcinoma, whether being at an early stage or an advanced stage.
Differential diagnoses for atypical epithelial sheets in the normal-appearing endometrial background include variable interpretations as follows: EIC, endometrial glandular dysplasia, endometrial intraepithelial neoplasia, hyperplastic polyp, and metastatic carcinoma [9, 23]. In addition to these, isolated atypical glands with morphological and immunohistochemical features of a typical endometrial hyperplasia or type I endometrial adenocarcinoma may be encountered in grossly normal postmenopausal endometrium of asymptomatic patients . Especially in the postmenopausal state, thin and smooth endometrium with atrophy is composed of hypocellular and flattened glands lined by cells with reduced or absent mitosis and sparse fibrous stroma . It is supposed that the abrupt transition of the atrophic endometrial cells to atypical cells may indicate EIC in postmenopausal women.
Overexpression of p53 is closely linked to the rapid growth of uterine body serous adenocarcinoma . In EIC, too, frequent p53 mutation is reported to be associated with LOH of 17p . Thus, immunohistochemistry for p53 is also adjunctively available in the diagnosis of uterine body serous adenocarcinoma, irrespective of whether it is at an early stage or advanced stage , in the discrimination between uterine body serous adenocarcinoma and benign morphologic mimics . Negativity of ER and PgR staining is more reasonable with the diagnosis of serous adenocarcinoma including EIC.
In summary, EMP arising in postmenopausal women is at a high risk of giving birth to the tumorigenetic background for endometrial carcinomas such as endometrioid adenocarcinoma and serous adenocarcinoma including EIC. Endometrial cytology may become a helpful diagnostic approach for serous adenocarcinoma, whether it is at early or advanced stage, from the viewpoint of the distinctive cytological features. Above all, it should be noted that some EIC behaves in a more aggressive fashion regardless of whether or not it lacks apparent stroma invasion and extrauterine extent.