FIGURE 7.1 Endometrial endometrioid adenocarcinoma, FIGO grade 1, back-to-back glandular proliferation.

FIGURE 7.2 Extensive papillary pattern, diagnostic feature of adenocarcinoma.

Grading

The grading standard of endometrial endometrioid adenocarcinoma is the International Federation of Gynecology and Obstetrics (FIGO) system (9,10). In this system, grade 1 tumors contain up to 5% of a solid, nonmorular component (Fig. 7.4, e-Figs. 7.15 and 7.16); grade 2 tumors contain 6% to 50% of a solid, nonmorular component (Fig. 7.5, e-Figs. 7.17–7.21); and grade 3 tumors contain >50% of a solid, nonmorular component (Fig. 7.6, e-Figs. 7.22–7.27).

FIGURE 7.3 Fibroblastic/desmoplastic stroma infiltrated by irregular glands, diagnostic feature of adenocarcinoma.

FIGURE 7.4 Endometrial endometrioid adenocarcinoma, FIGO grade 1.

FIGURE 7.5 Endometrial endometrioid adenocarcinoma, FIGO grade 2.

FIGURE 7.6 Endometrial endometrioid adenocarcinoma, FIGO grade 3.

Although the FIGO grading system states that a tumor with a grade 1 architectural pattern but with marked cytologic atypia (i.e., grade 3 nuclear atypia) should be designated as a grade 2 tumor, this combination is exceedingly rare. In reality, and in our opinion, when detected, the diagnosis of serous carcinoma with a glandular pattern should be considered.

Variants

SQUAMOUS DIFFERENTIATION. Squamous differentiation in endometrioid adenocarcinoma can be seen in various forms: morular (rounded intraluminal masses) (Fig. 7.7, e-Figs. 7.28–7.30), nests with the appearance of squamous carcinoma (Fig. 7.8), sheets of squamous cells with clear cytoplasm due to abundant intracytoplasmic glycogen (Fig. 7.9, e-Figs. 7.31–7.33), sheets of spindled cells with minimal evidence of squamous differentiation such as eddies of immature squamous cells, and papillary areas associated with mucinous metaplasia and neutrophils (e-Fig. 7.34). The grading of tumors with squamous differentiation is based on the grade of the glandular component (11,12). Care should be taken to not mistake morular metaplasia for solid areas in an endometrioid adenocarcinoma as morules potentially can mimic solid architecture. In such cases, nuclear expression of CDX-2 typically highlights areas of morular metaplasia (13,14).

VILLOGLANDULAR. Villoglandular pattern in endometrioid adenocarcinoma is characterized by the presence of finger-like papillae lined by columnar cells, with bland nuclei that are vertically oriented in relation to the basement membrane of the epithelium (Fig. 7.10A and B). The presence of this histologic pattern in the myoinvasive component of an endometrial adenocarcinoma has been found to be associated with a higher incidence of vascular/lymphatic invasion and lymph node metastasis by some investigators (e-Figs. 7.35–7.37) (15).

FIGURE 7.7 Endometrioid adenocarcinoma with squamous differentiation, morule formation.

FIGURE 7.8 Endometrioid adenocarcinoma with squamous differentiation that resembles squamous carcinoma.

FIGURE 7.9 Endometrioid adenocarcinoma with squamous metaplasia rich in glycogen.

SECRETORY. The secretory variant of endometrial adenocarcinoma is composed of cells with glycogen vacuoles in the cytoplasm. The vacuoles can be supranuclear, subnuclear, or both (Fig. 7.11, e-Figs. 7.38 and 7.39). Secretory carcinoma and complex atypical secretory hyperplasia show an increased Ki-67 index when compared with non-neoplastic endometrium with secretory changes (mean Ki-67 index 45% vs. 5%) (16). This variant is rare, usually seen in postmenopausal patients (age range 35 to 76 years; mean 57 years), and has a good prognosis (17,18).

Other Changes

CILIATED CELL. In this type of change, the glands are lined predominantly by ciliated cells (Fig. 7.12A and B, e-Fig. 7.40). The behavior appears to be similar to typical endometrioid adenocarcinoma (3,19).

CLEAR CELL CHANGES. Endometrioid adenocarcinoma may have focal cytoplasmic clearing. The specific cause of this change is unknown, but in some cases, it can be related to the presence of intracytoplasmic lipids.

SARCOMATOID (SPINDLE CELL) FEATURES. In some endometrioid adenocarcinomas, the neoplastic cells can become focally spindled (Fig. 7.13, e-Fig. 7.41). Attention to the merging of the spindle cell areas with the regular areas of endometrioid adenocarcinoma and the use of keratin immunostaining (e-Fig. 7.42), which highlights many of the cells in the spindle cell component, will facilitate the distinction of this tumor from a malignant mixed Müllerian tumor.

FIGURE 7.10 Endometrioid adenocarcinoma, villoglandular pattern. Note the finger-like papillary formations (A) and the low-grade cytologic atypia with preservation of the polarity of the nuclei of the neoplastic cells (B).

FIGURE 7.11 Secretory carcinoma, note sub- and supranuclear vacuoles.

FIGURE 7.12 Ciliated cell carcinoma, a proliferation of glands lined by cells with cilia (A); higher magnification (B).

FIGURE 7.13 Sarcomatoid spindle cell features in endometrioid adenocarcinoma.

FIGURE 7.14 Endometrial adenocarcinoma, microglandular hyperplasia like.

MICROGLANDULAR PATTERN. A conspicuous microglandular hyperplasia–like pattern can be seen in adenocarcinomas arising in the endometrium of postmenopausal women. A history of exogenous hormone use (i.e., medroxyprogesterone acetate, estradiol, or a combination of both) is common in these cases (20). The microglandular hyperplasia–like pattern is characterized by a proliferation of small glands, although some of them can be large or cystic, lined by one or more layers of cuboidal, columnar, or flattened cells with a variable amount of amphophilic or mucin-rich cytoplasm (Fig. 7.14, e-Figs. 7.43–7.46). Solid foci can be seen. There is variability in the degree of atypia, from absent to moderate, and in the mitotic index from low (≤1 mitosis per 10 high-power fields [HPFs]) to frequent, including abnormal forms. Abundant mucinous intraluminal secretion and numerous neutrophils are always present. Lymphocytes and plasma cells also can be seen. Microglandular-like adenocarcinoma can occur in a pure form or mixed with typical endometrioid adenocarcinoma (20). Immunohistochemical studies show that this type of tumor stains variably with carcinoembryonic antigen (CEA), vimentin, Ki-67, and p63 (21–25). The only features that allow for definitive diagnosis of this type of tumor in an endometrial biopsy are continuity of the tumor with the endometrium or the presence of fragments of typical endometrial adenocarcinoma in the same specimen, usually demonstrating a transition between these two patterns. For cases in which a definitive diagnosis cannot be provided, a descriptive diagnosis such as “glandular proliferation with a microglandular-like pattern” should be provided, in addition to a recommendation to obtain additional tissue (i.e., fractional curettage) and/or clinical correlation (i.e., physical examination and imaging studies of the uterus) to facilitate a definitive diagnosis.

SMALL NONVILLOUS PAPILLAE. This pattern refers to the presence of small papillae within the glandular spaces of an otherwise typical endometrioid adenocarcinoma. These papillae may or may not be complex and are composed of neoplastic cells with eosinophilic cytoplasm and low nuclear grade (e-Figs. 7.47 and 7.48). The prognosis of tumors with this feature is similar to that of typical endometrioid adenocarcinomas (26).

SERTOLIFORM PATTERN. Rare cases of low-grade endometrioid adenocarcinoma have tubules or cords of columnar cells with apical and occasionally clear cytoplasm. This pattern can be focal or diffuse. Immunohistochemically, these neoplasms express keratin, epithelial membrane antigen (EMA), and vimentin. In addition, a rare case has been reported as inhibin positive (27). The behavior of these tumors is similar to that of typical endometrioid adenocarcinomas (28,29).

SEX CORD–LIKE FORMATION AND HYALINIZATION. This rare pattern in an endometrioid adenocarcinoma can be mistaken for a malignant mixed Müllerian tumor. It is characterized by cords or clusters of epithelioid and/or spindle cells that are admixed and often merge with typical endometrioid adenocarcinoma. Usually, these cords or clusters of cells are embedded in a hyalinized matrix that can appear as small spherules or resemble osteoid. Areas of squamous differentiation are common (Fig. 7.15A and B, e-Figs. 7.49–7.58). Immunohistochemically, the neoplastic cells in the areas with this pattern have variable expression of keratin and EMA, ranging from no staining to diffuse staining (e-Fig. 7.59); however, the expression is usually seen in <50% of the cells (30). In this pattern, there is less cytologic atypia and less mitotic activity than the ones seen in a malignant mixed Müllerian tumor. Due to the low stage and good posthysterectomy prognosis in the majority of patients in the large series of such tumors reported to date, endometrioid adenocarcinomas composed of this variant pattern are generally considered low grade (30).

FIGURE 7.15 Endometrioid carcinoma with hyalinization and sex cord–like pattern (A); higher magnification of the tumor showing cord formation (B).

OXYPHILIC (ONCOCYTIC) CHANGES. Occasionally, endometrioid adenocarcinomas are composed predominantly or entirely of cells with abundant oxyphilic cytoplasm (Fig. 7.16, e-Figs. 7.60 and 7.61). Some of these tumors can be rich in mitochondria (31). Although the reported cases have been grades 1 or 2, several of them have invaded the myometrium, or were stages II or III (31–33).

FIGURE 7.16 Endometrioid carcinoma with oxyphilic changes.

SEROUS CARCINOMA

Serous carcinoma accounts for 10% of all endometrial cancers (34). It is composed of moderately to markedly atypical cells arranged in papillary, glandular, or solid patterns. Typically, there is tufting with detachment of clusters of neoplastic cells within the luminal spaces. Mitoses tend to be numerous (Figs. 7.17 and 7.18, e-Figs. 7.62–7.78) (35). Hobnail cells, psammoma bodies, vacuolization of the cytoplasm (e-Figs. 7.79–7.81), abnormal mitotic figures, and tumor giant cells can be seen.

FIGURE 7.17 Serous carcinoma, papillary formation, and marked cytologic atypia.

FIGURE 7.18 Serous carcinoma, glandular pattern.

This tumor can be intermixed with other types of carcinoma such as endometrioid, clear cell, or neuroendocrine carcinoma, either large or small cell type (36–38). Serous carcinoma is usually associated with myometrial and/or vascular invasion (e-Figs. 7.82–7.84), but it is important to bear in mind that even in cases in which the tumor is confined to the endometrium or to an endometrial polyp, there is often associated extrauterine disease and/or increased risk of recurrence (34,39–43). Therefore, the use of terms such as “serous endometrial intraepithelial carcinoma,” “endometrial intraepithelial carcinoma,” “noninvasive serous carcinoma,” “minimal uterine serous carcinoma,” “endometrial carcinoma in situ,” “early uterine serous carcinoma,” or “uterine surface carcinoma” (1,40,41,44–48) is discouraged. Cases occurring in association with pelvic radiation (49), long-term tamoxifen treatment (43,44,50,51), BRCA1 mutation (52,53), breast cancer (54,55), paraneoplastic hypercalcemia (56), high levels of serum CEA (57), and cervical or axillary lymph node metastases at presentation (58) have been reported. Uterine serous carcinoma is usually found in postmenopausal patients. It is an aggressive neoplasm and the most important prognostic factor is its stage (43). Tumors confined to the endometrium have approximately an 80% survival rate (34).

Differential Diagnosis

ENDOMETRIOID ADENOCARCINOMA. As outlined below, endometrioid adenocarcinoma may have features that mimic those of serous carcinoma. In each of these patterns, the absence of discordant marked cytologic atypia relative to low-grade architectural features aids in the distinction of endometrioid from serous carcinoma.

ENDOMETRIOID ADENOCARCINOMA, VILLOGLANDULAR TYPE. In contrast to serous carcinoma, the villoglandular variant of endometrioid adenocarcinoma is characterized by finger-like papillae, with a smooth surface, lined by columnar epithelium with a bland appearance and basally oriented nuclei.

ENDOMETRIAL ADENOCARCINOMA, PAPILLARY TYPE OF INTERMEDIATE GRADE. This tumor has features that are intermediate between villoglandular adenocarcinoma and serous carcinoma. The papillae are lined by cells with nuclei that are mildly or moderately pleomorphic and disorganized, but not to the degree typically seen in uterine serous carcinoma (Fig. 7.19, e-Figs. 7.85–7.87). Foci of squamous differentiation and collections of neutrophils may be seen. In addition, this tumor tends to be associated with a microcystic elongated and fragmented (MELF) pattern of myometrial invasion (e-Figs. 7.88 and 7.89) and vascular/lymphatic invasion (e-Fig. 7.90) (personal observation). The behavior of this neoplasm also appears to be intermediate between villoglandular adenocarcinoma and serous carcinoma (59).

FIGURE 7.19 Endometrial adenocarcinoma, papillary type of intermediate grade.

ENDOMETRIAL ADENOCARCINOMA (ENDOMETRIOID TYPE AND FIGO GRADE 1) OR COMPLEX ENDOMETRIAL HYPERPLASIA. These processes are characterized by the presence of well-formed glands lined by cells without marked nuclear pleomorphism or loss of nuclear polarity (e-Figs. 7.91–7.93).

In some cases, morphologic features overlap and the distinction of endometrioid from serous carcinoma is not possible on hematoxylin and eosin examination alone. In such cases, an immunohistochemical panel including p53, p16, estrogen receptor, and progesterone receptor may be useful. Endometrioid adenocarcinoma typically has patchy, variable intensity expression of p53 (nuclear) and p16 (nuclear + cytoplasmic), while serous carcinoma has either strong expression or total absence of the former and shows diffuse and strong expression of the latter (e-Figs. 7.94–7.96). It should be kept in mind that serous carcinoma usually retains the expression of both estrogen and progesterone receptors or just loses the expression of progesterone receptor (60,61).

CLEAR CELL CARCINOMA. The papillae of clear cell carcinoma usually are lined by a single row of neoplastic cells. In addition, they may have a hyalinized stromal core. Although focal clearing of the cytoplasm has been reported in an otherwise typical serous carcinoma of the endometrium (37), this is an infrequent finding.

EOSINOPHILIC SYNCYTIAL CHANGES (PAPILLARY SYNCYTIAL METAPLASIA). Generally regarded as a degenerative or regressive process and frequently associated with endometrial breakdown, worrisome features such as architectural complexity and/or nuclear enlargement with prominent nucleoli may be seen in a small percentage of cases (62). Atypia, when present, is usually focal with minimal nuclear pleomorphism, absent or minimal mitotic activity, and an associated inflammatory infiltrate (62). Definitive diagnosis should be based on morphologic features as overlap in the staining patterns of syncytial change and serous carcinoma with respect to estrogen receptor, p53, and p16 has been reported (63).

CLEAR CELL CARCINOMA

Clear cell carcinoma accounts for approximately 5% of all endometrial carcinomas (64). It is composed of clear or hobnail cells arranged in papillary, tubulocystic, or solid patterns. In some cases, the cells are eosinophilic (oncocytic) rather than clear. The clear or eosinophilic cells are polygonal, cuboidal, or flattened (Figs. 7.20–7.22, e-Figs. 7.97–7.115). The degree of nuclear atypia is variable, with most of the cells having marked atypia, while in some areas minimal or no atypia is detected. The nuclei are usually eccentric and the mitotic activity is quite variable, ranging from 0 mitosis per 10 HPFs to >10 mitoses per 10 HPFs (65,66). The stroma can be densely hyalinized, either in the stalk of the papillary structures or interspersed throughout the tumor. Epithelial hyaline bodies, eosinophilic granular or homogeneous intraluminal material, and psammoma bodies can be seen (65,67).

Immunohistochemically, clear cell carcinoma is usually, but not always, negative for progesterone receptor and has a high Ki-67 proliferation index and variable expression of p53 and estrogen receptor (68,69). Although most tumors are stage I, once myometrial invasion is detected there is a higher incidence of extrauterine disease as compared to grade 3 endometrioid adenocarcinomas (64,70,71). The prognosis depends on the stage of disease, with low-stage cases (FIGO stages 1 and 2) having a much better prognosis than advanced-stage cases. In addition, the prognosis of low-stage clear cell carcinoma is better than serous carcinoma of the endometrium of similar stage (66,72).

FIGURE 7.20 Clear cell carcinoma, papillary pattern.

FIGURE 7.21 Clear cell carcinoma, tubulocystic pattern.

FIGURE 7.22 Clear cell carcinoma, solid pattern.

Differential Diagnosis

SEROUS CARCINOMA. See previous discussion.

ENDOMETRIOID ADENOCARCINOMA. Endometrioid adenocarcinoma may show the features listed below which can mimic those of clear cell carcinoma.

ENDOMETRIOID CARCINOMA WITH SECRETORY CHANGES. These are characterized by columnar cells with sub- and supranuclear glycogen vacuoles and no nuclear atypia.

ENDOMETRIOID CARCINOMA WITH AREAS OF SQUAMOUS METAPLASIA RICH IN GLYCOGEN. These cases have overt squamous differentiation or typical endometrioid carcinoma in the vicinity of the area in question.

ENDOMETRIOID CARCINOMA WITH CLEAR CELL CHANGES. These can be secondary to lipids or hydropic changes. They do not show significant cytologic atypia. Hepatocyte nuclear factor-1β (HNF-1β), p504s, and Napsin A represent a group of immunohistochemical markers proposed as useful to distinguish endometrioid from clear cell carcinoma (73–75). Each of these markers appears to preferentially stain clear cell carcinoma over endometrioid carcinoma, with Napsin A demonstrating the highest sensitivity and specificity (74). Because none of these markers is perfect, a panel including HNF-1β, p504s, Napsin A, and estrogen receptor may help in difficult cases. Attention has to be paid to the fact that the experience with these new markers is limited and the results obtained with the use of these immunomarkers can be less than optimal on a given case.

Benign Cellular Changes

CLEAR CELL METAPLASIA. This type of metaplasia is usually associated with progestin effect. This change tends to be focal and there is no cytologic atypia.

REACTIVE ATYPIA INCLUDING HOBNAIL METAPLASIA. This feature is usually focal and can be seen in response to inflammation, progestin therapy, infarction of a polyp, recent curettage, or an intrauterine device.

ARIAS-STELLA REACTION. The Arias-Stella reaction is usually associated with pregnancy, although it can occur in nonpregnant or older patients. Attention to the following features will facilitate the recognition of this reaction: the patient’s young age, clinical history of pregnancy or progestin treatment, areas of decidualization of the stroma, and paucity of mitoses. In difficult cases, an immunopanel consisting of Ki-67 and p53 has been proposed as a useful tool because most cases of Arias-Stella reaction are negative for these two markers, while the reverse tends to be true for clear cell carcinoma (76).

UNDIFFERENTIATED CARCINOMA

Although undifferentiated carcinoma has been considered to be rare and its definition by the WHO is vague (i.e., an epithelial tumor with no differentiation) (1), in our experience, this neoplasm is usually intermixed with endometrioid adenocarcinoma and has specific histologic features that allow for its recognition (77). Undifferentiated carcinoma of the endometrium is characterized by a proliferation of medium-sized, monotonous epithelial cells, usually arranged in a solid pattern. However, focal trabeculae or cord formation, rhabdoid-like cells, and pleomorphism of the tumor cells can be present. Areas of necrosis are commonly seen (Fig. 7.23A and B, e-Figs. 7.116–7.121). Immunohistochemical studies show that the neoplastic cells are usually only focally positive for pan-keratin cocktail (only 5% to 10% of the tumor cells), although on rare occasions, the expression is diffuse (>75% of the tumor cells). The expression of pan-keratin is very heterogeneous in these neoplasms. Therefore, in many cases, it may be necessary to test additional blocks for keratin expression in order to obtain a positive result. Undifferentiated carcinoma of the endometrium also expresses EMA, usually focally (in 10% to 20% of the cells) and less frequently diffusely (in >75% of the cells) (77). It can also express keratin 18 (78) and appears to be negative for PAX-8 (79). Neuroendocrine markers such as synaptophysin and chromogranin can be expressed focally (≤10% of the cells). Approximately one-half of the cases show high microsatellite instability (MSI) with MLH1 promoter methylation and loss of expression of MLH1 and PMS2 (78).

FIGURE 7.23 Undifferentiated carcinoma, nests of tumor cells and necrosis (A); higher magnification shows the monotonous appearance of the tumor cells (B).

Differential Diagnosis

ENDOMETRIOID CARCINOMA. A frequent problem is to mistake a mixed carcinoma of the endometrium, composed of a grade 1 or 2 endometrioid adenocarcinoma and undifferentiated carcinoma, for an endometrioid adenocarcinoma of a higher grade (i.e., FIGO grade 2 or 3) because of the solid appearance of the undifferentiated component. In these cases, the correct diagnosis is facilitated by attention to the histologic features listed previously and by the use of keratin and EMA immunostains, which stain the solid component of an endometrioid carcinoma diffusely, rather than focally as is typical in undifferentiated carcinoma of the endometrium. PAX-8 and estrogen receptor immunoperoxidase studies may play a role in the distinction of FIGO grade 3 endometrioid adenocarcinoma from undifferentiated carcinoma. The former typically has stronger expression of these markers relative to undifferentiated carcinoma (79,80).

HIGH-GRADE SARCOMA. Uterine high-grade sarcomas are rarely composed exclusively of epithelioid cells, except for epithelioid leiomyosarcoma. In these cases, the use of desmin, caldesmon, and smooth muscle actin facilitates the recognition of the smooth muscle differentiation of this neoplasm.

MALIGNANT MIXED MÜLLERIAN TUMOR. The solid pattern characteristic of undifferentiated carcinoma, when associated with an endometrioid adenocarcinoma, can be mistaken for the sarcomatous component of a malignant mixed Müllerian tumor. Attention to the typical histologic features of undifferentiated carcinoma will prompt consideration of this neoplasm.

NEUROENDOCRINE CARCINOMA. As up to 40% of undifferentiated endometrial carcinomas will have expression of one or more neuroendocrine markers, the distinction between undifferentiated and neuroendocrine carcinoma can be difficult (81