FIGURE 10.1 Clusters of highly atypical cells floating between a fragment of cervical stroma and strip of benign endocervical epithelium.

1.Mesothelial cells and histiocytic aggregates: A variety of immunoperoxidase studies are used in the distinction of serous from mesothelial proliferations, including calretinin, cytokeratin 5/6, D2-40, and thrombomodulin as mesothelial markers and PAX-8, estrogen receptor, Ber-EP4, and MOC-31 as epithelial markers (Fig. 10.6, e-Fig. 10.13). A panel including multiple markers to distinguish mesothelial from epithelial cells is encouraged because none of these stains are free of overlap. WT-1 is of limited value as it is expressed in mesothelioma and many ovarian carcinomas (16). Histiocytes can be excluded by a negative CD68 stain.

2.Serous carcinoma arising in the endometrium: This differential diagnosis applies to cases with high-grade cytology since serous tumors with low-grade features only arise in the ovary or peritoneum. WT-1 is the most reliable marker to make the distinction of a serous carcinoma of endometrial origin from one arising in the upper genital tract. Essentially, less than 20% of the cases of uterine and cervical serous carcinomas show nuclear expression of WT-1 (usually weak or patchy, although a rare case can be diffuse). In contrast, strong nuclear staining for WT-1 is noted in 76% to 97% of serous carcinomas of the upper genital tract (15,17,18).

3.Adenocarcinoma of the uterine cervix: Rarely, primary adenocarcinomas of the uterine cervix can show marked cytologic atypia reminiscent to the one seen in serous carcinoma or can represent a bona fide example of serous carcinoma (see Chapter 3). Human papillomavirus (HPV) testing is required in order to distinguish these primary cervical tumors from an upper genital tract metastasis, as most cases of cervical adenocarcinoma are associated with high-risk HPV (19). It has to be kept in mind that diffuse expression of p16 is seen in serous carcinomas with high-grade features regardless of the site of origin (cervix, endometrium, or upper genital tract) (20,21). In addition, a low-grade serous carcinoma arising in the ovary or peritoneum with cervical involvement can display glandular and papillary areas that can mimic a cervical primary. Attention to the lack of conspicuous mitotic activity or apoptosis as usually seen in cervical primaries and the expression of WT-1 and estrogen receptor in the context of a negative p16 will allow for the correct diagnosis (e-Figs. 10.14 and 10.15) (13).

4.Metastatic micropapillary breast carcinoma: This tumor, characterized by small papillae of tumor cells, usually with an intermediate to high nuclear grade, lacking fibrovascular cores and floating within stromal lacunae could potentially be detected in a uterine sampling and be mistaken for an upper genital tract primary. However, this type of tumor tends to metastasize to lymph nodes and not to distant sites (22). PAX-8 is the immunomarker of choice to distinguish micropapillary breast carcinoma from an upper genital primary since nuclear staining is seen in over 95% of ovarian serous carcinomas (23–25). Attention has to be paid to the fact that WT-1, a marker typically expressed in serous carcinoma of the upper genital tract, can be expressed in a small percentage of breast carcinomas (23). Use of CA-125 is of limited value. Although >90% of ovarian carcinomas have membranous staining with this marker, it is not considered specific as 10% to 30% of breast carcinomas as well as some cholangiocarcinomas and pancreatic carcinomas stain with this marker (26,27).

FIGURE 10.2 Small cell clusters floating within endocervical mucus of an endocervical curettage specimen; cells are uniform and bland; patient was ultimately found to have an ovarian serous tumor of low malignant potential.

FIGURE 10.3 Fragment of high-grade serous carcinoma adjacent to benign endometrium.

FIGURE 10.4 High-grade serous carcinoma present within a cervical stromal lymphatic space.

FIGURE 10.5 Low-grade serous carcinoma involving the cervical stroma; note the adjacent uninvolved gland (arrow).

FIGURE 10.6 The cells in Figure 10.2 are negative for calretinin.

EXTRAGENITAL METASTASES

The most common primary sites of carcinoma metastatic to the uterus and cervix are the breast, colorectum, and stomach (3,4). However, pancreas, biliary tract, liver, lung, thyroid, and kidney can represent the primary site on an occasional case (28–38). The presence of histologic features not typically seen in uterine or cervical primaries such as numerous signet ring cells, a single-file cell arrangement, prominent dirty necrosis, nests of markedly eosinophilic cells, nests of clear cells associated with a distinct vascular pattern, or small and partially disrupted glands with clearing of the cytoplasm should raise the possibility of an extragenital origin and prompt the use of immunohistochemical markers to arrive at the correct diagnosis. The features of the more commonly encountered extragenital sources of metastases involving the uterus are discussed below.

In addition, immunoperoxidase stain expression patterns as related to the primary site are summarized in Table 10.1.

BREAST

Lobular carcinoma, the most common subtype of breast carcinoma metastasizing to the uterus (39), should be considered when dealing with a carcinoma composed of monotonous cells, arranged in solid or single-file patterns or as single cells infiltrating the stroma with preservation of the endometrial or endocervical glands (Fig. 10.7, e-Figs. 10.16–10.19). In addition, some cases can show signet-ring cells that are also the hallmark of signet-ring cell carcinoma arising in the breast (40,41). Of interest, ductal carcinomas metastatic to the endometrium or cervix may lose their typical features (42). As mentioned earlier, micropapillary breast carcinoma (Figs. 10.8 and 10.9, e-Figs. 10.20 and 10.21) can be potentially encountered and this type of case can be mistaken for a metastasis not only from the upper genital tract but also from the lung or bladder (43). Immunohistochemical stains used to establish a breast origin for a given carcinoma include gross cystic disease fluid protein-15 (GCDFP-15), mammaglobin, and GATA-3. The staining pattern of GCDFP-15 is often only focal, and the protein has reportedly been identified in up to 55% of breast carcinomas overall (26,44,45). In contrast, mammaglobin is more sensitive, with expression reported in up to 88% of breast carcinomas, preferentially in lobular carcinoma. However, mammaglobin is less specific than GCDFP-15, with expression reported in ovarian, endometrial, and lung carcinomas (44–48). A newer marker, GATA-3, appears to have more specificity for breast carcinoma in the correct clinical setting. Over 90% of ductal and lobular carcinomas will have nuclear staining for GATA-3 (49,50). Additionally, less common breast carcinomas such as triple-negative tumors and metaplastic carcinoma may have nuclear expression of GATA-3 (49). As with mammaglobin, GATA-3 is also not entirely specific as it is expressed in the majority of bladder transitional carcinomas as well as in a minority of pancreaticobiliary, ovarian serous carcinoma, and endometrioid carcinomas (50). Because no single marker is perfect, GATA-3 plus one other breast marker should help confirm the diagnosis. Markers to exclude other entities in the differential diagnosis should be included to serve as additional confirmation.

FIGURE 10.7 Carcinoma cells in small clusters infiltrate the endometrial stroma in a patient with a history of lobular carcinoma.

FIGURE 10.8 Papillary clusters of atypical cells are present within the endometrial stroma adjacent to a benign endometrial gland. Morphology simulates high-grade serous carcinoma.

FIGURE 10.9 Immunoperoxidase studies performed on the case referenced in Figure 10.8. A: Positive GATA-3 immunoperoxidase stain (nuclear expression); B: PAX-8 immunoperoxidase stain lacks nuclear staining (negative result).

COLON/RECTUM

Colorectal adenocarcinoma can involve the endometrium or cervix by direct extension from the primary, but may also be a hematogenous metastasis. Because colorectal adenocarcinoma shares histologic features with endometrioid adenocarcinoma (51) and intestinal-type endocervical adenocarcinomas (52,53), the absence of pertinent history could lead to a missed diagnosis. On histologic grounds, the admixture of normal endometrium, absence of preneoplastic or preinvasive changes such as hyperplasia/adenocarcinoma in situ, and the presence of disrupted glands, dirty necrosis, and marked cytologic atypia in the context of a predominant glandular pattern should raise the possibility of metastatic colorectal carcinoma (Figs. 10.10 and 10.11, e-Figs. 10.22–10.24) (4). Diagnostic immunohistochemistry can confirm the diagnosis (51) as colon cancer is usually strongly positive for cytokeratin 20 and CDX-2 with absent to rarely minimal expression of cytokeratin 7 (e-Figs. 10.25–10.28) (54). Endometrial carcinoma usually has the opposite immunohistochemical profile. The immunohistochemical profile of endocervical adenocarcinoma with intestinal differentiation more closely resembles the profile of a lower gastrointestinal primary (53). Diffuse nuclear expression of CDX-2 may be of limited utility in the identification of a colorectal primary because this marker may also be expressed in endometrioid adenocarcinoma and mucinous endocervical adenocarcinoma (e-Figs. 10.29 and 10.30) (53,55,56). Carcinoembryonic antigen (CEA) is also expressed in both colorectal and endocervical adenocarcinoma (53). Due to the potential for gastrointestinal marker staining in uterine carcinomas with mucinous differentiation (53