During the reproductive years as the menstrual cycle is completed, the endometrium is shed during menstruation and this shedding continues into the proliferative phase of the next menstrual cycle. Benign endometrial glandular and stromal cells are normally shed during the first half of the cycle and are commonly found in cervical cytology samples (Fig. 6.1). Shed cells are most commonly arranged as three-dimensional groupings because after shedding the cell groupings have time to round up while they travel down the endocervical canal before being picked up by the sampling device. Dense three-dimensional groups of clumped endometrial stroma surrounded by degenerating endometrial glandular cells are most commonly seen from day 6 to day 10 (Fig. 6.2). The dense clusters along with single small histiocytes were termed “exodus” by George Papanicolaou and their counterpart on histologic sections of endometrial biopsies are very familiar to surgical pathologists [4] (Fig. 6.3). The shed endometrial glandular cells have uniform small nuclei with inapparent to slightly more abundant vacuolated cytoplasm (Fig. 6.4). The increase in vacuolated cytoplasm may be due to cellular degeneration. The nuclei most commonly have a coarse granular chromatin pattern, probably a degenerative phenomenon. In addition to these familiar biphasic cell groupings, clusters made up purely of either glandular or stromal cells are also commonly noted in menstrual specimens. Apoptotic debris is often identified in clusters of glandular cells indicative of cellular breakdown (Fig. 6.5). The stromal cells, whether associated with glandular cells or present as pure groups or as single cells, are very small, with groupings in which the nuclei are tightly packed together, and have scant cytoplasm (Fig. 6.6). In the liquid-based cytology preparations, one may encounter more abundant clear cytoplasm with vacuoles, as compared to conventional smears; the difference is thought to be secondary to more rapid fixation leading to better preservation of the degenerative changes in the cells (Fig. 6.7a, b). The nuclear sizes of the cells in the SurePath samples remain small and uniform, although occasional degenerated nuclei can become quite large and hyperchromatic, a feature that can sometimes lead to erroneous interpretations of atypia. Macrophages/histiocytes may also accompany the shed endometrium (Fig. 6.8).

According to the 2001 Bethesda System (TBS) for reporting cervical cytology, the presence of shed endometrial cells should not be reported in women under age 40, as this is a normal finding associated with menses. However, in women 40 and older, reporting becomes more important as benign endometrium in the cervical cytology specimen can be a marker of neoplasia, and this risk becomes greater starting at age 40 and increasing in each subsequent decade. The presence of benign-appearing endometrium in this age group is reported under the general categorization of “other” so that the clinician may correlate the finding with the patient’s menstrual history. Since this reporting terminology was initiated in 2001, numerous studies have documented that the risk of endometrial neoplasm in women over 40 who are still normally menstruating is very low [2, 3, 5–8]. After menopause, however, the cytologic identification of benign endometrial cells warrants follow-up [9]. Therefore, many laboratories now only report benign-appearing endometrial cells when the patient is known to be postmenopausal or no menstrual history is given. Using this local modification of the Bethesda System terminology at Massachusetts General Hospital has decreased the number of endometrial biopsies performed without a significant loss of sensitivity for endometrial neoplasia (unpublished personal observation).

Directly sampled, or abraded, endometrium is present in the cervical cytology specimen when the sampling device (endocervical brush or Cervex broom™) scrapes endometrial glands and stroma from the lower uterine segment (LUS) while obtaining the endocervical sample. This can occur from vigorous sampling, but is most commonly seen in women who have undergone a prior cone biopsy or loop electrosurgical excision procedure (LEEP). The LUS is more likely to be sampled due to the foreshortened endocervical canal [10, 11]. Similarly, in patients who have undergone a trachelectomy for carcinoma of the cervix (amputation of the cervix with anastomosis of the LUS to the vagina), follow-up surveillance by cytology will frequently produce abundant cells from the LUS [12].

With direct sampling, endometrial cells appear as they would in their native state, similar to what might be found on a fine needle aspiration specimen. When cells are retained in groups, the architecture is most commonly that of two-dimensionality as the groups have not had time to round up as in the shedding process described above. Intact endometrial glands are present as tubular structures with parallel sides (Fig. 6.9), or if the gland is disrupted and opened during sampling it will appear as flat honeycomb sheets of uniform cells (Fig. 6.10). Endometrial glandular cells are also present as strips of pseudostratified columnar cells when the sampling occurs in the proliferative phase, but can also show prominent single-layered vacuolated cells during the secretory phase. Cytoplasm tends to be more delicate and wispy than in shed endometrial epithelial cells. The glandular cell nuclei are uniform in size and are spaced uniformly. Mitoses and apoptotic debris may be identified during the proliferative phase (Fig. 6.11) although the LUS along with the basalis layer of the endometrium in the corpus is less responsive to the hormonal stimulation of the reproductive cycle. The presence of mitotic activity may mimic endocervical AIS, but the nuclei in LUS are smaller than those of the most common forms of AIS. In some cases, differentiation of LUS sampling from endocervical neoplasia may be difficult. Several clues favoring benign abraded endometrium include the presence of densely cellular stromal fragments which may have embedded blood vessels (Fig. 6.12) or even more revealing, intact glands (Fig. 6.13). The stromal cytoplasmic borders are ill defined and these cells have ovoid nuclei with nonaligned long axes giving the impression of a jumbled arrangement of cells. Stromal cells can often have small cytoplasmic tails that protrude from the margins of the groups and can mimic the “feathered” edges of neoplastic endocervical AIS. Stromal cells can also appear as isolated nuclei devoid of cytoplasm and sprinkled in the background of the slide (Fig. 6.14). Small epithelioid cells which are probably histiocytes may accompany the stromal cells and cell fragments. Abraded endometrial glands also will show attached stromal cells on the outside surfaces of the groups, a feature not appreciated in endocervical neoplastic lesions (Fig. 6.15).