FIGURE 3.1 Reactive atypia, enlarged nuclei, a rare mitosis, and inflammation.
Endometriosis of the uterine cervix can occur in three forms: superficial, polypoid, and deep. The latter is usually associated with pelvic endometriosis and does not constitute a diagnostic challenge because the recognition of typical epithelial and stromal components tends to be straightforward. In contrast, the superficial and polypoid forms can represent a diagnostic challenge as the former can be mistaken for adenocarcinoma in situ or Kaposi sarcoma while the superficial or polypoid forms can be mistaken for sarcoma involving the cervix (i.e., endometrial stromal sarcoma and adenosarcoma). In addition, changes in the glandular component such as Arias-Stella reaction and metaplastic or hyperplastic changes can be mistaken for malignancy (3,4). Superficial endometriosis of the uterine cervix may be associated with previous cervical trauma (curettage, biopsy, cautery, abortion, or vaginal delivery) (5), while polypoid endometriosis has been associated with the use of hormonal therapy or soybean phytoestrogen (4,6). Superficial endometriosis is usually an incidental finding; however, it can produce macroscopic alterations such as friable areas, red patches, nodules, and blood-filled blebs, measuring up to 2 cm (5).
FIGURE 3.2 Atypical oxyphilic metaplasia, eosinophilic cytoplasm, enlarged nuclei, and a rare mitosis.
Microscopically, it can replace the surface epithelium (Fig. 3.3) or lie in the stroma underneath it. Less commonly, it extends into the middle third of the cervical wall where it can simulate perineural invasion (7). Polypoid endometriosis is characterized by an exophytic growth projecting into the cervical canal (Fig. 3.4) (6). Cervical endometriosis is composed of glands that are usually small or medium sized, round or oval, and occasionally cystic (e-Fig. 3.3). The lining epithelium is columnar, arranged in a single row, or pseudostratified (e-Figs. 3.4 and 3.5). The nuclei are round or elongated and have evenly distributed fine or dark chromatin (e-Fig. 3.6). The number of mitotic figures is variable, from none in the entire lesion up to three mitoses per gland (e-Fig. 3.7). Only rare apoptotic bodies and no abnormal mitoses are seen. Secretory and hyperplastic changes as well as Arias-Stella reaction can be present (3, 4,7).
FIGURE 3.3 Cervical endometriosis: hemorrhage and inflammation obscure the endometrial stroma.
FIGURE 3.4 Polypoid endometriosis.
The stromal component can be obscured by marked inflammation, hemorrhage, smooth muscle metaplasia, and/or fragmentation (e-Figs. 3.8–3.12). In these cases, the lesion can be mistaken for adenocarcinoma in situ. Awareness of this lesion, with special attention to the absence of irregularity in chromatin distribution and the identification of the stromal component (which may require additional levels), will allow for the correct diagnosis. In difficult cases, Bcl-2 immunostaining is a useful adjunct for diagnosis because this marker is diffusely positive in endometriosis and is negative or only focally positive in adenocarcinoma in situ. In addition, endometriosis is positive for PAX-2, in contrast to adenocarcinoma in situ which is negative for this marker. Other immunomarkers such as p16 and MIB1 are not useful because p16 can be diffusely positive in endometriosis and MIB1 staining in endometriosis can overlap with results obtained in cases of adenocarcinoma in situ (8,9). In cases in which only the stromal component is present (e-Figs. 3.13 and 3.14), it is necessary to exclude cervical involvement by endometrial stromal sarcoma and Kaposi sarcoma. The former is usually associated with symptoms such as vaginal bleeding, infiltrates the stroma in an irregular fashion, and shows vascular/lymphatic invasion. Additional levels to identify the glandular component or procurement of additional tissue may be necessary for a definitive diagnosis. Kaposi sarcoma of the uterine cervix is exceedingly rare, with only a few cases reported in immunodeficient patients (10). Features that characterize this tumor include spindle cells arranged in intersecting fascicles, slit-like spaces containing red blood cells, and intra- and extracellular eosinophilic globules. In addition, positive immunostaining for CD31, CD34, and LNA-1 (HHV8) will facilitate the correct diagnosis (10,11). When both the glandular and stromal components are present, adenosarcoma and endometrial stromal sarcoma with extensive endometrioid glandular differentiation may be entertained in the differential diagnosis. In our practice, we make the diagnosis of the former when two of the following features are present: (a) hypercellular cuffing of the glands by stroma, (b) presence of stromal atypia, and (c) a mitotic index of at least 2 mitoses per 10 high-power fields (HPFs) in the stromal cells. Endometrial stromal sarcoma with extensive endometrioid glandular differentiation is very rare and its diagnosis cannot be made on a biopsy material alone; however, it should be suspected in cases where repeated biopsies show a histologic picture consistent with endometriosis in the context of a large tumor, especially if multiple anatomical sites are involved (12).
Intestinal metaplasia, the rarest form of metaplasia of the endocervical epithelium, is characterized by the presence of goblet cells, with or without accompanying neuroendocrine cells (Fig. 3.5). Because intestinal metaplasia is often associated with adenocarcinoma in situ and invasive adenocarcinoma, when it is identified, these entities should be ruled out through a complete gross and microscopic examination (13). The absence of nuclear atypia and mitotic activity allows the distinction of intestinal metaplasia from adenocarcinoma in situ.
BENIGN LESIONS THAT MIMIC INVASIVE ADENOCARCINOMA
Microglandular hyperplasia is a lesion mostly seen in women of reproductive age, although it can be found in up to 6% of postmenopausal women. It is commonly associated with pregnancy and oral contraceptive use; however, it can occur in patients without this history (14). Most cases are found incidentally, but gross abnormalities such as an erosion, polyp formation, or friable raised areas in the cervix can be seen. Microglandular hyperplasia can be focal or multifocal and can involve the surface epithelium and/or the endocervical glands. It is composed of closely packed glands of variable size and shape, with acute and chronic inflammation and little intervening stroma (Fig. 3.6). The epithelium lining the glands is columnar or cuboidal and mucin producing and contains supra- or subnuclear vacuoles (Fig. 3.7). The nuclei are usually uniform, but focal atypia or nuclear variability can be encountered (e-Fig. 3.15) (14). Reserve cell hyperplasia and squamous metaplasia may be present (e-Fig. 3.16). Mitotic figures are rare (14). Occasionally, microglandular hyperplasia has variable foci with a solid, trabecular, pseudoinfiltrative, or reticular pattern; hobnail or signet ring cells; mild to moderate nuclear atypia; or stromal myxoid changes or hyalinization (e-Figs. 3.17–3.19) (14). Immunohistochemically, microglandular hyperplasia is positive for p63 in the reserve/immature squamous cell component and is usually p16 negative; however, the latter may be strongly, but usually patchy, positive. Cases of microglandular hyperplasia with p16 expression do not co-localize MIB1 or cyclin E expression and are not associated with human papillomavirus (HPV) infection (14,15). The differential diagnosis of this lesion includes clear cell carcinoma and endometrial adenocarcinoma with a microglandular pattern. The former is usually associated with a cervical mass and has an infiltrative pattern. Additionally, it has a greater degree of cytologic atypia than that seen in microglandular hyperplasia. Endometrial adenocarcinoma with a microglandular pattern can represent a true diagnostic challenge that many times may not be solved upon review of a limited sampling. Features that favor endometrial adenocarcinoma with a microglandular pattern are a large amount of tissue in a biopsy (i.e., two or three blocks), a lack of subnuclear vacuoles, transition to other patterns of endometrial adenocarcinoma, connection with endometrial stroma, an association with foamy stromal cells, and the presence of complex endometrial hyperplasia or mucinous metaplasia in the background endometrium (14). In addition, a positive immunostain for vimentin in the cytoplasm of the cells favors endometrial adenocarcinoma with a microglandular pattern. However, a negative result is not helpful in a biopsy sample because the expression of vimentin in endometrial adenocarcinoma can be focal and rarely may be absent. Carcinoembryonic antigen (CEA) has been found to be negative in both microglandular hyperplasia and endometrial adenocarcinoma with a microglandular pattern (16).
FIGURE 3.5 Intestinal metaplasia with characteristic goblet cells.
FIGURE 3.6 Microglandular hyperplasia—glands of variable size and shape.
FIGURE 3.7 Microglandular hyperplasia—closely packed glands.
Lobular Endocervical Glandular Hyperplasia
Lobular endocervical glandular hyperplasia is an uncommon glandular proliferation seen in women of reproductive age. Most patients are asymptomatic, but presenting symptoms can include cervical discharge, abdominal discomfort, or a cervical mass (17,18). Some cases are seen in the context of Peutz-Jeghers syndrome (18). Macroscopically, the cervix is unremarkable in most cases, but can have a polypoid mass or numerous cysts. Microscopically, there is a distinct lobular proliferation of round glands of variable size, small to cystic, lined by a single layer of columnar mucin-producing cells with bland, basally located nuclei (Figs. 3.8 and 3.9, e-Fig. 3.20). In some cases, the cytoplasm is eosinophilic and granular, which is indicative of gastric-type differentiation (14). The glands may have an undulating contour (e-Figs. 3.21 and 3.22) and are often centered around a larger gland. Atypia consisting of nuclear enlargement with vesicular chromatin and prominent nucleoli can be identified (e-Figs. 3.23 and 3.24). Mitotic activity of up to 2 mitoses per 10 HPFs can be seen. The surrounding stroma may be cellular or contain inflammatory cells. The proliferation is usually well demarcated and confined to the inner half of the cervical wall, although occasionally it can extend to the outer half (14,17). Immunohistochemically, this lesion stains for MUC6 and/or HIK 1083 and can show scattered chromogranin A and/or synaptophysin-positive cells. It shows no expression of estrogen receptor (ER), progesterone receptor (PR), or CEA. This immunohistochemical profile has prompted the designation “complex gastric/pyloric metaplasia” by some investigators (18). Although an atypical variant of lobular endocervical glandular hyperplasia containing at least four of the following features: (a) nuclear enlargement, (b) irregular nuclear contour, (c) distinct nucleoli, (d) coarse chromatin texture, (e) loss of polarity, (f) occasional mitotic figures, (g) apoptotic bodies and/or nuclear debris in the lumen, and (h) infolding of the epithelium or papillary formations with a delicate fibrovascular stroma has been described in association with minimal deviation or gastric-type adenocarcinomas (18), it seems that some of these cases may instead represent a form of adenocarcinoma in situ (18). The major differential diagnosis of lobular endocervical glandular hyperplasia is minimal deviation adenocarcinoma. The distinction between these two requires the recognition of the lobular arrangement of glands in the former, which contrasts with the haphazard arrangement of glands with variable size and shape in the latter. In addition, minimal deviation adenocarcinoma extends deep into the cervical wall and shows, at least focally, desmoplasia and cytologic atypia. Moreover, this tumor may show vascular/lymphatic invasion and/or perineural invasion (14). Although there are immunohistochemical differences between lobular endocervical glandular hyperplasia and minimal deviation adenocarcinoma, including diffuse expression of p53 (not in all cases) and CEA cytoplasmic expression (which can be just focal) as well as loss of nuclear PAX-2 expression in the latter and a wild-type pattern of p53 expression, just apical expression of CEA, and intact PAX-2 nuclear expression in the former (18), recognition of the morphologic features listed above is of paramount importance to make a correct diagnosis. Such a task is only possible with an adequate amount of tissue (i.e., cone specimen).
FIGURE 3.8 Lobular endocervical glandular hyperplasia, vague lobular pattern.
FIGURE 3.9 Lobular endocervical glandular hyperplasia, well-defined border.
Diffuse Laminar Endocervical Glandular Hyperplasia
Diffuse laminar endocervical glandular hyperplasia is an uncommon lesion that is detected mainly in reproductive-aged patients as an incidental finding; however, it can be associated with a watery or mucoid discharge (19,20). It is characterized by a proliferation of round or abnormally shaped, small- or medium-sized glands, confined to the inner third of the cervical wall, and clearly demarcated from the underlying cervical stroma (Fig. 3.10, e-Fig. 3.25). The glands are lined by mucin-producing columnar cells, which rarely may have a mitotic figure (e-Figs. 3.26 and 3.27). Reactive changes such as nuclear enlargement, chromatin clearing, and nucleoli can be seen in the presence of inflammation. The latter, either acute or chronic, is commonly present within the stroma (19). The superficial location of this lesion, the sharp demarcation, and the absence of focal atypia and desmoplasia allow differentiation of this process from minimal deviation adenocarcinoma.
FIGURE 3.10 Diffuse laminar hyperplasia, well-defined border.
Endocervical Gland Hyperplasia, Not Otherwise Specified
The number of endocervical glands can be increased without any of the specific patterns mentioned earlier (Fig. 3.11, e-Figs. 3.28 and 3.29). The distinction from minimal deviation adenocarcinoma is based on the criteria mentioned previously for the various types of endocervical hyperplasia and on those following the description of minimal deviation adenocarcinoma.
Deep Glands in the Uterine Cervix
Occasionally, a few endocervical glands can be identified deep in the cervical wall (Fig. 3.12); however, rarely, the glands may be numerous. These cases are always an incidental finding. Microscopically, the deep glands show limited variability in size and shape and a columnar, cuboidal, or flattened epithelium with no atypia or mitotic activity. Nucleoli are occasionally noted. The glands do not express CEA. These deeply located glands are distinguished from minimal deviation adenocarcinoma by the lack of cytologic atypia and desmoplastic response, which are present focally in the latter, and by a greater uniformity of glandular size and shape than that seen in minimal deviation adenocarcinoma (21).
FIGURE 3.11 Endocervical hyperplasia, not otherwise specified.
FIGURE 3.12 Glands are present at the deep margin of a section from a cold knife cone.
Deep Nabothian Cysts
Nabothian cysts are dilated endocervical glands, which account for their usual superficial location. In most cases, they are an incidental finding, but they can extend deep into the cervical wall and are associated with macroscopic abnormalities such as cervical enlargement or mass formation. On sectioning, the cervical tissue demonstrates numerous cysts extending from the mucosa into the deep stroma, approaching the outer surface of the cervix in some cases. Microscopically, the cysts are more or less round but can have a slightly irregular contour (Fig. 3.13, e-Fig. 3.30). They are filled with mucin and are lined by a single layer of columnar to flattened endocervical-type epithelium with basally located bland nuclei (e-Figs. 3.31 and 3.32). There is no mitotic activity and the stroma is normal (22). The differential diagnosis of deep nabothian cysts includes minimal deviation adenocarcinoma and microcystic adenocarcinoma. In biopsies or loop electrocautery excision procedure (LEEP) specimens, the distinction between deep nabothian cysts and these types of adenocarcinoma may not be possible because the features that allow for definitive diagnosis of malignancy (i.e., definitive cytologic atypia, conspicuous mitotic activity, marked variation in the size and shape of the glands, and stromal response) can be focal in these carcinomas and may not be present in a limited sample.
FIGURE 3.13 Deep nabothian cysts extend to the deep margin of a section from a cold knife cone.
Changes Associated with Mucin Extravasation in the Cervical Stroma
The stroma in the vicinity of ruptured endocervical glands can have reactive changes, including edema, inflammatory cells, histiocytic aggregates, and foreign body giant cells, as a response to mucin extravasation. On a rare occasion, the ruptured glands are not identifiable; instead, there is a conspicuous amount of mucin dissecting the cervical stroma and, in some cases, within vascular spaces (Fig. 3.14, e-Figs. 3.33 and 3.34). This change can raise concern about a primary or metastatic mucinous adenocarcinoma (13).
Endocervicosis is a lesion that has been reported in premenopausal patients who presented with either pelvic pain or dysmenorrhea. Grossly, a nodular mass in the anterior cervix, ranging from 1.5 to 2.5 cm, was detected in these cases. Microscopically, there is a proliferation of glands lined by bland epithelium within the outer third of the cervical wall and paracervical soft tissue. The glands tend to be of medium size, although they can also be either small or dilated. The epithelium is columnar, cuboidal, or flattened, and mitotic figures are rare or absent. The following features allow distinction from minimal deviation adenocarcinoma: very deep location without connection to the more superficial endocervical glands, bland epithelium throughout the lesion, lack of desmoplastic response, and absence of conspicuous mitotic activity (23).
FIGURE 3.14 Mucin within vascular spaces of an endocervical polyp.
There are three types of hyperplasia that arise from mesonephric remnants: lobular, diffuse, and ductal (24). Lobular is the most common; its distinction from mesonephric remnants is arbitrary and based on lobules that are larger, more loosely organized, and more irregularly shaped in cases of hyperplasia (24). Lobular mesonephric hyperplasia is found in patients with a mean age of 35 years. In general, it is an incidental finding, although it can produce nodularity or induration of the cervix. It ranges in size from 4 to 22 mm and retains, for the most part, a lobular architecture that can be lost focally and extend deep into the cervical wall (Fig. 3.15, e-Figs. 3.35–3.37). The cuboidal or columnar lining epithelium can form small tufts, and rare mitotic figures can be seen.
The second most common type of mesonephric hyperplasia is diffuse. This occurs in patients with a mean age of 47 years and is also an incidental finding in most cases; however, it can produce irregularity in the shape of the cervix or hypertrophy and erosion. This lesion ranges from 13 to 25 mm in greatest dimension, extends deep into the cervical wall, can involve the lower uterine segment, and is not restricted to the lateral cervical walls. It is characterized by a diffuse proliferation of mesonephric tubules with or without accompanying ducts (Fig. 3.16, e-Figs. 3.38–3.40). There may be a rare mitotic figure, but there is no cytologic atypia.
FIGURE 3.15 Mesonephric hyperplasia, lobular type.
The least common form of mesonephric hyperplasia, the ductal type, is characterized by a prominent duct with papillary tufting and a minimal proliferation of tubules (Fig. 3.17) (24,25).
FIGURE 3.16 Mesonephric hyperplasia, diffuse type.
FIGURE 3.17 Mesonephric hyperplasia, ductal type.
Immunohistochemically, mesonephric hyperplasia is typically positive for EMA, calretinin, PAX-2, Bcl-2, androgen receptor, and CD10 (luminal pattern), while p16 may be focally positive (14).
These hyperplastic lesions must be distinguished from mesonephric adenocarcinoma. The latter is associated with symptoms and produces a cervical mass. In addition, nuclear atypia, conspicuous mitotic activity, vascular/lymphatic invasion, and the presence of other patterns of mesonephric adenocarcinoma, such as solid or ductal, will facilitate the correct diagnosis. Ki-67 immunostaining has been reported to be helpful in establishing the correct diagnosis, as approximately 15% of the neoplastic cells are positive for Ki-67 in cases of mesonephric adenocarcinoma and it is expressed by only 1% to 2% of the cells in mesonephric hyperplasia (26). In addition, GATA-3 has been reported to be strongly and diffusely positive in mesonephric hyperplasia and patchy in mesonephric carcinoma (14).
BENIGN LESIONS MIMICKING EITHER ADENOCARCINOMA IN SITU OR INVASIVE ADENOCARCINOMA
Tubal, Endometrioid, and Tuboendometrioid Metaplasia
Tubal, endometrioid, and tuboendometrioid metaplasia are metaplastic processes initially associated with cone biopsies (27); however, in many cases, this association is nonexistent and they are now considered to be idiopathic (28). Tubal metaplasia is defined as the replacement of the endocervical epithelium with ciliated, secretory, and intercalated (peg) cells typically seen in fallopian tube epithelium. This is usually an incidental finding, although on rare occasions, it can produce macroscopic alterations, such as “spongy mucoid material” or an endocervical polyp (28). Tubal metaplasia may be seen in the surface epithelium, superficial glands, and deep glands. In general, it is confined to the inner third of the cervical wall, although it can reach the outer third in some instances (28,29). The glands are typically small or medium sized and are variable in size and shape, including branching (e-Figs. 3.41–3.43). The cells are bland or have mild atypia (Fig. 3.18). The mitotic index is low. The adjacent stroma can be hypercellular, sometimes markedly so, edematous, myxoid, or focally calcified (e-Figs. 3.44 and 3.45) (28). A rare variant, extensively involving the four quadrants of the cervix, has been described in patients with in utero exposure to diethylstilbestrol (30). In these cases, the glands not only show the changes noted earlier, but they are also increased in number and have marked variation in size and shape.
Endometrioid metaplasia is the replacement of the endocervical epithelium by a columnar epithelium with or without pseudostratification and low mitotic activity (Fig. 3.19, e-Figs. 3.46 and 3.47) (31). In some cases, there is a mixture of tubal and endometrioid metaplasia and the term tuboendometrioid metaplasia is used (e-Fig 3.48) (28).
These three metaplastic processes must be differentiated from adenocarcinoma, either in situ or invasive. Findings such as irregular chromatin distribution, hyperchromasia, and conspicuous mitotic activity are in keeping with the diagnosis of adenocarcinoma in situ. Of note is the tubal variant of adenocarcinoma in situ, in which apical cilia are seen in addition to the other features of usual adenocarcinoma in situ (32). Cytologic atypia and a desmoplastic stromal response, at least focally, are detected in cases of invasive adenocarcinoma. In difficult cases, immunoperoxidase studies can be helpful. Ki-67 is expressed by scattered nuclei in tuboendometrioid metaplasia (proliferation index <10%) and many nuclei in adenocarcinoma in situ (usually a proliferation index >30%), although overlap can exist. Some cases of adenocarcinoma in situ have a proliferation index <10%, and occasional benign lesions (i.e., tubal metaplasia during the proliferative phase of the menstrual cycle or endocervical epithelium after a recent biopsy) have a proliferation index >30% (9,33,34). p16 is expressed only by scattered ciliated cells and reserve cells of the normal endocervix and by scattered cells of tubal and tuboendometrioid metaplasia, while it is diffusely expressed in adenocarcinoma in situ (8,35,36). Bcl-2 is diffusely positive in tuboendometrioid metaplasia (e-Fig 3.49) and is absent or focally positive in adenocarcinoma in situ; however, it can be expressed by invasive adenocarcinoma. p53 can be focally positive in tuboendometrioid metaplasia and in adenocarcinoma in situ, while it may be diffusely expressed in invasive adenocarcinoma. CEA is positive in 63% to 67% of cases of adenocarcinoma in situ, while it is expressed by up to 39% of cases of tuboendometrioid metaplasia (8,9,37–39).
FIGURE 3.19 Endometrioid metaplasia.
These benign glandular proliferations are very common. They are mostly found in multigravid women older than 30 years and are divided into two types, A and B (40). Both are multifocal and tend to be incidental findings; however, type B may be extensive and produce cysts that can be detected on gross examination, even producing distortion of the endocervical mucosa and underlying wall (cystic variant) (41). Type A tunnel clusters are characterized by a well-circumscribed, sometimes pseudoinfiltrative, proliferation of oval, round, or angulated glands lined by cells that are either cuboidal with amphophilic cytoplasm or mucin-producing columnar (Fig. 3.20). The former cells have enlarged nuclei with vesicular chromatin and conspicuous nucleoli (e-Fig. 3.50). Nuclear hyperchromasia, if present, is of the degenerative type (e-Fig. 3.51). Mitoses are absent or rare. The stroma is usually unremarkable, although it can be cellular, edematous, or inflamed. Extravasated mucin is sometimes seen (40). Type A tunnel clusters tend to be associated with type B. This association has prompted the hypothesis that the latter evolve from the former due to obstruction (42). Type A tunnel clusters may contain gastric mucin (i.e., gastric metaplasia) (18).
Type B tunnel clusters are composed of dilated glands arranged in lobules (Fig. 3.21). The lining epithelium is cuboidal or flattened and is not mitotically active (e-Figs. 3.52 and 3.53). In the cystic variant, the process can deeply penetrate the wall, even through it. The regular chromatin distribution and inconspicuous mitotic activity allow distinction between type A tunnel clusters and adenocarcinoma in situ. The absence of symptoms, as well as the absence of at least a focal infiltrative pattern and cytologic atypia, allows distinction between type B tunnel clusters and minimal deviation adenocarcinoma. CEA is negative in tunnel clusters and may be only focally positive in minimal deviation adenocarcinoma; therefore, CEA immunostaining may not be helpful in this differential diagnosis, especially on biopsy (41,43).
FIGURE 3.20 Tunnel cluster, type A.
FIGURE 3.21 Tunnel cluster, type B.
Arias-Stella reaction in the endocervix is usually associated with pregnancy, with a reported incidence ranging from 9% to 38% in utero of pregnancy (44,45). However, on rare occasions, it can occur in patients taking oral contraceptives or with no documented history of hormone exposure (46). It can involve endocervical polyps or be detected incidentally in a biopsy or LEEP specimen obtained for cervical dysplasia. The Arias-Stella reaction can involve superficial and/or deep glands and be either focal or extensive (45,46). The latter can result in a confluent appearance (e-Fig. 3.54). The epithelial changes that characterize this process consist of cellular enlargement, eosinophilia or vacuolization of the cytoplasm, a hobnail appearance, and nuclear irregularity with occasional hyperchromasia (Fig. 3.22, e-Fig. 3.55). In some cases, there is marked epithelial proliferation producing papillary tufting, or a solid and cribriform pattern (e-Figs. 3.56–3.59). Rare mitotic figures, intranuclear pseudoinclusions, and focal decidual changes in the stroma can be seen (46