Fig. 1.1 Uterus at 18 weeks. Note the central epithelium-lined uterine canal surrounded by uterine mesenchyme Fig. 1.2 Uterus at 22 weeks. The endometrial lining shows surface undulations and gland-like invaginations. Even at term, the endometrial lining is often simple and is devoid of the complex glandular architec- ture that may be encountered in the adult endometrium Fig. 1.3 (a, b) Uterus at 18 weeks. Endometrial epithelium shows ciliation and abundant pseudostratification. The surrounding mesenchyme shows vague layering and increased cellularity. Smooth muscle differentiation is demonstrable in the uterine mesenchyme at this stage Fig. 1.4 Uterine mesenchyme at 23 weeks. A muscular layer is well developed. An outer layer (lower field) and inner layer are discernible. The endometrium epithelium is seen in the upper right field Fig. 1.5 Myometrium in the second trimester. There is more cellularity than in the adult myometrium, and there is significantly less fascicular arrangement of cells Fig. 1.6 Primary components of the uterus Fig. 1.7 The anterior surface of the uterus (left) can be distinguished from the posterior surface (right) based on the fact that the anterior surface has a larger area that is devoid of peritoneal lining than the posterior, in its lower component. Additionally, the stump of the round ligament is anteriorly directed Fig. 1.8 Uterine arteries. Thick-walled vessels of the outer myome- trium include the lateral perforating branches of the uterine artery, from which branch the arcuate artery and then the radial arteries. These arter- ies not infrequently show atherosclerosis and calcification Fig. 1.9 Uterine arteries. Comparing this specimen to Fig. 1.8 high- lights the fact the relative thickness and prominence of myometrial vessels may vary significantly between patients Fig. 1.10 Uterine arteries. Arteries at the endometrial basalis and at the myometrial/endometrial interface may also be prominent and notably clustered. These are basal branches of the radial arteries Fig. 1.11 Uterine arteries. Arterioles may occasionally be clustered in the endometrial functionalis; this is a clinically insignificant variation Fig. 1.12 Uterine arteries. Clustered arterioles in the functionalis at high magnification Fig. 1.13 The endometrium is composed of a functional layer (stratum functionalis) and a basal layer (stratum basalis). The functional layer is generally of greater volume than the basal layer, especially in cycling, premenopausal patients. The functional layer shows significantly greater sensitivity to endogenous and exogenous hormones than the basal layer Fig. 1.14 The stratum functionalis in the secretory phase can be classi- fied into a superficial compact layer (stratum compactum) and a deep spongy layer (stratum spongiosum), but in the early and mid parts of the secretory phase, as shown here, the stratum compactum is not apparent Fig. 1.15 The stratum compactum is the sub-surface epithelial zone that has the appearance of comprising mostly confluent predecidualization. The stratum spongiosum is the deeper zone of serrated glands. The stra- tum compactum/spongiosum layering is seen in the late secretory phase Fig. 1.16 The stratum basalis in a patient who has been treated with exogenous progestins. Even in this setting, the stratum basalis fre- quently shows less hormonal responsiveness than the stratum functio- nalis. In the second half of gestation, however, or after prolonged treatment with progestins, the stratum basalis may show alterations consistent with hormone responsiveness, including complete stroma precidualization/decidualization Fig. 1.17 Stratum basalis. The stroma typically appears more compact and cellular than the stratum functionalis with which it is associated. The stroma may also be spindled, especially near the myometrial/endo- metrial interface Fig. 1.18 Stratum basalis. Clusters of vessels are commonly present, representing the basal branches of the myometrial radial arteries Fig. 1.19 (a, b) Stratum basalis in a biopsy specimen. The stroma of the stratum basalis fragment is often distinct because of its increased stromal cellularity compared with the stratum functionalis fragments. The glands of the basalis are often simple or branched tubular glands lined with nonsecretory, pseudostratified cells with basophilic chromatin; mitotic figures are rare. The glands in the stratum basalis may show slight dilatation, which is most likely either a secretion retention or an atrophic phenomenon. Another feature that may be seen in the basalis is one or more lymphoid aggregates Fig. 1.20 (a, b) Stratum basalis in a biopsy specimen. The glands of the stratum basalis may display more dilatation than the glands of the stratum functionalis. This finding should not be mistaken for an anovulatory pattern (disordered proliferative endometrium). The concurrent presence of increased stromal spindling and cellularity are useful morphologic features that support the interpretation that the fragment that displayed such glands represents stratum basalis Fig. 1.21 (a, b) Surface epithelium overlying proliferative pattern endometrium. The surface epithelium is continuous with the underlying glands, but generally shows less cyclic variation. The epithelium is lined by cells that are columnar, variably pseudostratified, and frequently ciliated Fig. 1.22 (a, b) Surface epithelium overlying early secretory pattern endometrium. The surface epithelium shows less secretory change than the underlying glands. This dissonance is more appreciable in the early parts of the secretory phase Fig. 1.23 Surface epithelium overlying mid secretory pattern endometrium. The surface epithelium more closely resembles the underlying glands, with which it is contiguous Fig. 1.24 (a, b) The uterine isthmus (lower uterine segment) shows significantly reduced responsiveness to hormones, compared with the uterine corpus. Accordingly, the functional state of the lower uterine segment endometrium should not be used as an indicator for the functional state of the entire endometrium. The glands are typically lined by weakly proliferative columnar glands with prominent ciliation. The stroma is more spindled, more collagenous, and generally less cellular than the endometrial stroma in the upper uterine corpus Fig. 1.25 Endometrial epithelium. Proliferative-type glands are lined by cells with fusiform nuclei, variably dense chromatin, and inconspic- uous nucleoli. During the proliferative phase, mitotic figures are easily identifiable in such glands in the stratum functionalis, and the nuclei appear to be pseudostratified Fig. 1.26 Endometrial epithelium. Proliferative-type glands frequently show ciliation. Ciliated cells are commonly identified in the surface epithelium and underlying endometrial glands, especially towards the cornu and the cervix. Ciliated cells become more prominent in conditions associated with estrogen excess Fig. 1.27 Endometrial epithelium. Clear cells (such as the one at the 9 o'clock position) are characterized by round nuclei and clear cyto- plasm; they often have a cytoplasm diameter that appears to be signifi- cantly wider than adjacent non-clear cells. These cells are significantly less common than ciliated cells, but are almost invariably identified in association with the latter and are thought to be their precursors. Clear cells also show a more specific association with conditions of estrogen excess than ciliated cells Fig. 1.28 Endometrial epithelium. Secretory cells vary in appearance depending on the day of the menstrual cycle, as described in detail in subsequent sections Fig. 1.29 Endometrial stroma. The endometrial stroma in the prolif- erative phase comprises round to fusiform cells with scant cytoplasm, dense chromatin, and inconspicuous nucleoli. Mitotic activity is promi- nent during the proliferative phase Fig. 1.30 Endometrial stroma. At various points during the cycle, the endometrial stroma shows prominent interstitial edema, giving the cells a "dispersed" appearance Fig. 1.31 Endometrial stroma. Later in the menstrual cycle, the endometrial stroma shows increased eosinophilic cytoplasm, poorly defined cell membranes, nuclei with more vesicular chromatin, and variably discernible nucleoli. These changes define stroma "pseudodecidualization" or "predecidualization" [10]. Similar changes associated with pregnancy are termed "decidualization" Fig. 1.32 (a, b) Endometrial lymphocytes. Aggregates of lymphocytes are a common (and essentially normal) finding in the endometrium. They are more commonly identified in the stratum basalis than in the stratum functionalis Fig. 1.33 Endometrial foam cells show abundant vacuolated cyto- plasm and oval or bean-shaped nuclei. They are associated with condi- tions of estrogen excess, such as endometrioid carcinomas and hyperplasias, but they are nonspecific and may be seen in other conditions, such as xanthogranulomatous endometritis. Various authors think them to be of either histiocytic origin or stromal origin Fig. 1.34 Stromal granulocytes (also known as granular/granulated lymphocytes, K cells, large granular lymphocytes, endometrial granu locytes, or decidual granulated lymphocytes) are present in large popu- lations during the last days of the menstrual cycle. Stromal granulocytes display eosinophilic cytoplasmic granules; small, somewhat lobulated hyperchromatic nuclei; and a CD3-CD56brightCD16- phenotype. This phenotype distinguishes them from the natural killer (NK) cells of the peripheral blood, wherein CD56 expression is dim. These cells should not be mistaken for neutrophils Fig. 1.35 Neutrophils are commonly present when the menstrual phase is well developed, typically around day 2 of the cycle Fig. 1.36 Early proliferative phase (Cycle days 4-7). The early prolif- erative phase is characterized by short, straight glands devoid of any significant tortuosity Fig. 1.37 Early proliferative phase (Cycle days 4-7). The stroma is loose and forms a significant component of the sample Fig. 1.38 Early proliferative phase (Cycle days 4-7). Glands show nuclear pseudostratification, with round to oval nuclei and dense chromatin. There is brisk mitotic activity in both stroma and glands Fig. 1.39 (a, b) Mid proliferative phase (Cycle days 8-10). Glands begin to show early tortuosity, accompanied by stromal edema Fig. 1.40 Mid proliferative phase (Cycle days 8-10). Glands show nuclear pseudostratification with round to oval nuclei and dense chromatin. The mitotic activity and nuclear characteristics of the proliferative phase glands are generally similar in different points of the proliferative phase Fig. 1.41 (a–c) Late proliferative phase (Cycle days 11-14). Glands are overtly tortuous. Stroma is cellular and dense, although edematous areas may be seen. Glands show nuclear pseudostratification with round to oval nuclei and dense chromatin. Brisk mitotic activity is present in glands and stroma Fig. 1.42 (a, b) The interval phase pattern is the morphologic correlate to the 48-hour period between ovulation and definitive morphologic evidence of ovulation on day 17. The glands show proliferative-type nuclear features, mitotic figures, and scattered glands with subnuclear vacuolization. This pattern does not allow for a definitive conclusion that ovulation has taken place Fig. 1.43 Early secretory phase: menstrual cycle day 17 (post- ovulatory day 3): Tortuous glands lined by columnar cells. Mild pseu- dostratification is still present, but the uniform subnuclear vacuolization pushes the nuclei to the center of the cell, aligned in a "piano-keys" pattern. Subnuclear cytoplasmic vacuolization is seen in the majority of glands. Mitotic figures are scant. Stroma is loose and edematous. The day 17 pattern is the first unequivocal morphologic evidence that ovula- tion has taken place Fig. 1.44 Early secretory phase: menstrual cycle day 17 (post- ovulatory day 3). By late day 17, subnuclear cytoplasmic vacuolization is still prominent, but early supranuclear vacuolization is discernible Fig. 1.45 Early secretory phase: menstrual cycle day 18 (post- ovulatory day 4): Tortuous glands lined by columnar cells. Subnuclear cytoplasmic vacuolization is still present, but supranuclear vacuoliza- tion is now prominent Fig. 1.46 (a, b) Early secretory phase: menstrual cycle day 18 (post- ovulatory day 4): Tortuous glands lined by columnar cells. Subnuclear cytoplasmic vacuolization is still present, but supranuclear vacuoliza- tion is now more prominent than subnuclear vacuolization. Mitotic fig- ures are notably scant. Mild pseudostratification may be present. Nuclei are more round than oval. There is stroma edema Fig. 1.46 (continued) Fig. 1.47 Mid secretory phase: menstrual cycle day 19 (post-ovulatory day 5). Glands no longer show cytoplasmic vacuolization and are pre- dominantly lined by columnar cells with no significant nuclear pseu- dostratification. Mitotic figures are absent. Scattered glands display intraluminal secretions. Stroma is edematous Fig. 1.48 (a, b) Mid secretory phase: menstrual cycle day 20 (post- ovulatory day 6). Glands are similar to day 19, except with more promi- nent intraluminal secretions. Glands with intraluminal secretions constitute the majority of glands on day 20 Fig. 1.49 Mid secretory phase: menstrual cycle day 21 (post-ovulatory day 7). Glands are irregular and are without serrations. There is increasing stromal edema Fig. 1.50 (a, b) Mid secretory phase:; menstrual cycle day 22 (post- ovulatory day 8). Glands are irregular but are devoid of overt serration. There is maximal stromal edema, resulting in stromal cells that appear to be devoid of cytoplasm. Scattered spiral arterioles may be seen, but they are neither prominent nor clustered. The spiral arterioles do not display any peri-arteriolar stromal predecidualization Fig. 1.51 (a, b) Mid secretory phase: menstrual cycle days 23 and 24 (post-ovulatory days 9 and 10). Predecidua surrounds spiral arterioles, which are mostly clustered. The peri-arteriolar predecidualization starts on day 23 and becomes more prominent in day 24. For both days, pre- decidualization is not diffuse and is absent from the superficial subepi- thelial zone. Non-predecidualized stroma show edema. Stromal mitotic figures may be seen. Glands are irregular, and may show variable lumi- nal secretions. On day 24, secretory exhaustion begins. (See Fig. 1.56) Fig. 1.52 (a, b) Mid secretory phase: menstrual cycle day 25 (post- ovulatory day 11). Small predecidualized zones are present throughout the stroma, including in the zone below the surface epithelium. Diffuse areas of coalesced predecidualization are absent. Non-predecidualized stroma show some edema. Stromal mitotic figures may be seen. Glands are irregular, and may show variable luminal secretions Fig. 1.53 Late secretory phase: menstrual cycle day 26 (post- ovulatory 12). Stromal predecidualization is diffuse. There is an abundance of granulated lymphocytes. Glands show secretory exhaustion Fig. 1.54 (a, b) Late secretory phase: menstrual cycle day 27 (post- ovulatory day 13). Stromal predecidualization is diffuse. There is an abundance of granulated lymphocytes. Glands show prominent serration. Focal necrosis of stroma may be seen. The stratification between the compactum and spongiosum layers of the functionalis has become very prominent Fig. 1.55 Late secretory phase: menstrual cycle day 27 (post- ovulatory day 13). The compactum spongiosum shows confluent glands. Constituent cells are tall and columnar Fig. 1.56 (a-c) Various iterations of glands with secretory exhaustion. These glands are seen on menstrual cycle days 24-27, but become more diffuse after day 26. Secretory exhaustion is variably characterized by tortuous glands with intraluminal serration or sawtooth pattern, “fluffy" luminal borders, some vacuolization, and (to various extents) luminal secretions Fig. 1.57 (a, b) Menstrual phase endometrium. The first day of clini- cal menstruation denotes the first day of the menstrual cycle. Key fea- tures include marked fragmentation of endometrial glands; glands with secretory exhaustion or a vaguely secretory appearance; absence of any mitotic figures; an abundance of red blood cells, neutrophils, and other inflammatory cells, (including plasma cells and histiocytes); and promi- nent stromal breakdown. If the biopsy is obtained at the beginning of the menstrual phase or late on day 28, residual predecidua may be prominent; if obtained later in the menstrual phase, fragments of proliferative endometrium may be seen Fig. 1.58 (a, b) Menstrual phase endometrium. Prominent stromal breakdown is a key feature of menstrual pattern endometrium, and is characterized by nodules of condensed stromal cells with associated syncytial regenerative cells (the so-called blue balls). The stromal condensates may display apoptotic bodies and scattered plasma cells Fig. 1.59 Weakly proliferative endometrium. "Weakly proliferative endometrium" is a term that is used to describe endometrium with a predominance of non-tortuous glands that are lined by non-stratified or mildly pseudostratified columnar cells but which are devoid of mitotic figures. The lesser pseudostratification, as well as the absence of abun- dant mitotic figures, distinguishes weakly proliferative endometrium from proliferative-pattern endometrium. Weakly proliferative endome- trium does not denote a specific functional state but is better conceptu- alized as a morphologic pattern. This pattern may be seen in the perimenopausal years, or in postmenopausal years if there is a source of at least low-level estrogenic stimulation (e.g., from endogenous sources such as obesity or from exogenous sources such as hormone replacement therapy) Fig. 1.60 Endometrium after menopause. (a, b) This atrophic endo- metrium shows foci with complete glandular absence and only a resid- ual surface epithelium. The endometrium after menopause may range from proliferative to weakly proliferative to inactive or atrophic Fig. 1.61 (a, b) Endometrium after menopause. An advanced form of atrophy (called "cystic atrophy") is characterized by cystic glands that are lined by flat cells with very minimally discernible cytoplasm. Some weakly proliferative endometrium may be concurrently present (b, lower field). Atrophy may also be associated with some stromal fibrosis Fig. 1.62 Endometrium after menopause. Atrophic endometrium in biopsies or curettages is characterized by detached fragments of atrophic epithelium. The sample is typically of small volume Fig. 1.63 (a, b) Endometrial biopsy artifact: Telescoping. This effect is brought about by the biopsy itself, which causes an intussusception of the bottom half of the gland, and making it appear as if there is a gland within a larger gland Fig. 1.64 Endometrial biopsy artifact. In this uncommon artifact of unknown cause, a small cluster of glands appear "pasted" onto each other, with each constituent gland modulating the shape of the other "attached" glands Fig. 1.65 Endometrial biopsy artifact: Artifactual crowding due to stromal "breaks." In this artifact, there are areas of stromal "degeneration" that are probably associated with the biopsy itself. The net effect is for stroma to collapse onto each other, giving a false crowded appearance Fig. 2.1 Papillary syncytial metaplasia. (a-d) This retrogressive change is frequently associated with stromal breakdown. It is typically a surface process that may also involve underlying glands, comprising a syncytial mass of cells with poorly defined cell membranes and typically bland, pyknotic, or degenerated nuclei. When associated with breakdown, the syncytial cells appear to partially envelop the stromal condensates with which they are associated Fig. 2.2 Papillary syncytial metaplasia with a more overtly papillary appearance Fig. 2.3 Papillary syncytial metaplasia with pyknotic nuclei. The nuclei are hyperchromatic and irregular. There are no mitotic figures Fig. 2.4 Papillary syncytial metaplasia, showing the typical level of pleomorphism. There is only a slight variability in nuclear size and shape Fig. 2.5 Papillary syncytial metaplasia. Rare cases display nuclear enlargement, but other features identify it as papillary syncytial metaplasia Fig. 2.6 Papillary syncytial metaplasia, showing typical infiltration by neutrophils Fig. 2.7 (a, b) Florid papillary syncytial metaplasia. Some cases are overtly florid and may show complicated branching, but it remains a surface process without significant anaplasia or mitotic figures Fig. 2.7 (continued) Fig. 2.8 Papillary syncytial metaplasia: This papillary syncytial metaplasia is in direct morphologic continuity with background endometrial epithe- lium, highlighting the fact that it is a direct derivative of the epithelium Fig. 2.9 Papillary syncytial metaplasia. Apoptotic bodies may be identified, but mitotic figures are distinctly rare Fig. 2.10 (a, b) A florid iteration of papillary syncytial metaplasia may be associated with infarcted endometrial polyps [12]. The foci may display moderate atypia, which is thought to be a reactive change. Mitotic figures are absent or inconspicuous Fig. 2.11 Papillary syncytial metaplasia shows a very low proliferative index (lower right field) Fig. 2.12 Papillary syncytial metaplasia is diffusely positive for p16 (lower right field) Fig. 2.13 Papillary syncytial metaplasia shows increased staining for p53 relative to background epithelium, but is still p53-wild type (lower right field) Fig. 2.14 (a, b) Icthyosis uteri. In conventional squamous metaplasia, the endometrial surface is replaced to various extents by mature, squa- mous, well-differentiated squamous epithelium. When the entire surface of the endometrium is replaced by squamous epithelium, the condition is referred to as icthyosis uteri. Conventional squamous meta- plasia has been associated with conditions where there is irritation of the uterine surface, including cervical canal obstruction, foreign bodies, chronic endometritis, or pyometra. Squamous change also has been associated with vitamin A deficiency, embolization of uterine leiomyomata, and hormonal therapy [3]. Conventional squamous metaplasia is immunoreactive for epithelial membrane antigen (EMA), CK5/6, and p63, and is mostly negative for CD10, SATB2, CDX2, estrogen receptor (ER), progesterone receptor (PR), synaptophysin, and chromo- granin. B-catenin shows mostly membranous expression without significant nuclear expression [3]. Conventional squamous metaplasia and squamous morular change (also known as "squamous morular metaplasia," "morular metaplasia." or "morular change," seen in Figs. 2.15, 2.16, 2.17, 2.18, 2.19, 2.20, 2.21, and 2.22 below) are two distinct and different processes, although both may coexist in approximately 20% of cases [3]. Both conventional squamous metaplasia and squamous morular change may be associated with endometrial hyperplasias and endometrioid carcinoma Fig. 2.15 Morular change describes the presence of squamous mor- ules, which are nodular aggregates of uniform, oval or spindle-shaped cells with bland nuclei and eosinophilic cytoplasm. They are function- ally inactive (low proliferative index and lack of estrogen and progesterone receptor expression) and arise directly from endometrial epithelium, eventually abridging the epithelium on both sides of the gland [5, 6] Fig. 2.16 Squamous morules arise directly from endometrial epithelium Fig. 2.17 (a-d) Squamous morules are frequently associated with benign hyperplasia, atypical hyperplasia/endometrioid intraepithelial neoplasia, and endometrioid adenocarcinoma. When associated with these entities, they share the same PTEN mutation, suggestive of a shared lineage [6]. Squamous morules are also strongly associated with atypical polypoid adenomyoma Fig. 2.18 (a-c) Squamous morules may display varying degrees of central necrosis. This finding has no clinically significant implications Fig. 2.19 Isolated squamous morules may occasionally be identified without any cytoarchitectural abnormalities in the associated glands. In one study of 31 cases, follow-up showed 7.4% regression, 16.1% per- sistence, and 6.5% cancer rates, with an interval to cancer of approximately 98 months [6] Fig. 2.20 Isolated squamous morules. In these cases, the squamous morules themselves are functionally inert and as such are not intrinsically worrisome. The concern is for an occult glandular lesion that may not have been sampled. Our approach in these cases is to get at least one round of levels/recuts into the block; if no lesion emerges, we report the finding with a comment suggesting follow-up sampling. In this case, the focus of glandular crowding (right field) was not apparent on the initial sections, wherein only apparently isolated squamous morules were initially found Fig. 2.21 (a, b) Florid squamous morules without any cytoarchitec- tural abnormalities in the associated glands. The approach for these cases is similar to the approach for isolated squamous morules. The clinical concern for the pathologist is uncertainty regarding whether an underlying clinically significant lesion is being obstructed by the florid squamous morules. If no underlying lesion is identified after recuts into the block, our approach is to report the finding and suggest follow-up sampling Fig. 2.22 Squamous morular metaplasia is immunoreactive for CDX2, SATB2, and CD10, with mosaic staining for p16, nuclear and cytoplas- mic expression of B-catenin, and occasional expression of synaptophysin and chromogranin. Morules show no diffuse expression of p63,EMA, CK5/6, ER, or PR [3, 10] Fig. 2.23 (a, b) Hobnail metaplasia can be attributed in most cases to one or more conditions: a recent endometrial curettage, chronic inflammation, Arias-Stella reaction, an intrauterine device, ischemia within a polyp or endometrium, or radiation. It may also be an idiopathic find- ing. Hobnail metaplasia appears on the surface of the endometrium or constituent glands as a non-stratified layer of cells with high nuclear/ cytoplasmic ratios and hyperchromatic nuclei, whose nuclei protrude into the glandular lumina Fig. 2.24 (a, b) Hobnail metaplasia in an isolated fragment in an endo- metrial curettage. This case highlights the potential for significant hyperchromasia and some nuclear enlargement in hobnail metaplasia. The differential diagnosis is an endometrial serous or clear cell carcinoma. These foci are not mass-forming, lack mitotic activity, and are devoid of the known architectural patterns of those carcinomas Fig. 2.25 Hobnail metaplasia associated with an infarcted polyp Fig. 2.26 Reactive active and other reparative changes, including hobnail metaplasia post-curettage Fig. 2.27 Hobnail change at the superficial part of a myometrium- invasive endometrial carcinoma, likely a reaction to the prior curettage Fig. 2.28 (a-d) Ciliated (tubal) metaplasia. The surface epithelium and most endometrial glands are lined by variably pseudostratified ciliated cells with oval to round monomorphic nuclei, eosinophilic cyto- plasm, and surface cilia. A second population of cells with clear cytoplasm (clear cells) are thought to be the precursor of ciliated cells .The term ciliated (tubal) metaplasia should not be applied to the ciliated change of normal endometrium. True ciliated (tubal) metaplasia has a prominently dual cellular population, including the ciliated and clear cells. Extensive tubal metaplasias are highly associated with con- ditions of estrogen excess but in themselves are not diagnostic of it Fig. 2.29 Normal surface epithelium. The normal surface endometrial epithelium and most glands are lined by ciliated cells. The second population of clear cells are less predominant in the absence of true tubal metaplasia Fig. 2.30 Ciliated (tubal) metaplasia shows immunoreactivity for p16 [8]. They are also p53-wild type and show a low Ki67 proliferative index Fig. 2.31 (a-d) The spectrum of atypical changes that may be encoun- tered in ciliated (tubal) metaplasia includes nuclear enlargement (b) nuclear pleomorphism (b), and hyperchromasia (a, c, d). These are degenerative changes that show staining patterns for p53 and Ki67 that are similar to the patterns seen in tubal metaplasia without such changes. These changes do not increase the risk of follow-up hyperplasia or malignancy [7] Fig. 2.31 (continued) Fig. 2.32 (a, b) Focus of hyperplasia with ciliated (tubal) change. Ciliated (tubal) change is not infrequently identified in endometrial hyperplasias or endometrioid carcinomas. When assessing the malignant potential of a given focus with tubal change, the complexity of the glandular architecture is the primary determinant. In essence, the emphasis in diagnostic assessment should be placed entirely on the architecture, and the tubal change should be ignored Fig. 2.33 Eosinophilic metaplasia, also known as oncocytic metaplasia, describes the phenomenon whereby endometrial glands or surface epithelium are lined by non-ciliated cells with abundant eosinophilic to granular cytoplasm, and round (usually uniform) nuclei (a, b). Variations include nucleolomegaly, nuclear enlargement, hyperchromasia (c), and notably granular cytoplasm. An association with mucinous metaplasia has been postulated Fig. 2.34 Eosinophilic change may be associated with endometrial hyperplasias and endometrioid carcinomas. In this case, the focus with eosinophilic change (right field) and the focus without (left field) are different areas of the same hyperplasia, and the eosinophilic change is devoid of any intrinsic significance. When assessing the malignant potential of a given focus with eosinophilic change, the glandular architecture is the primary determinant Fig. 2.35 (a, b) Mucinous metaplasia is a characterized by a replace- ment of native glands or surface epithelium by cells with mucin- containing cytoplasm. The mucinous change should be discernible at the morphologic level. Mucinous metaplasia most commonly resembles endocervical epithelium but may occasionally display an intestinal mucinous or gastric-type mucinous phenotype. Nuclei are bland and mitotic figures are rare to absent. Mucinous metaplasias may be associated with endometrial polyps, papillary syncytial metaplasias, or other- wise unremarkable endometrium Fig. 2.36 (a-c) Mucinous metaplasia may show some focal tufting or minor papillary change. In defining the upper limit of what is allowable for mucinous metaplasia, the key points are simplicity and localization. Mucinous metaplasia do not display complex branching papillae and are limited in extent. The changes illustrated here are within the morphologic spectrum for mucinous metaplasia Fig. 2.37 (a-c) Clear cell metaplasia. Clear cell change is most com- monly associated with pregnancy or exogenous use of progestins, but it occasionally may be present without an identifiable underlying cause. Clear cell metaplasia displays cytoplasmic clarity, with bland nuclear features, and is devoid of mitotic figures. The cells may be columnar in configuration (secretory-like) or round/epithelioid. Unlike the principal differential diagnostic consideration, clear cell carcinoma, clear cell metaplasia is typically a focal finding that lacks cytologic atypia and does not form masses. Clear cell metaplasia is also devoid of the architectural patterns of clear cell carcinoma Fig. 2.38 Clear cell change associated with radiation to the pelvis. The changes are diffuse within the endometrium and may be associated with some nuclear atypia. There are no other abnormalities Fig. 2.39 (a, b) Synovial-like metaplasia is a recently described endo- metrial alteration that is associated with the levonorgestrel-releasing intrauterine system [13]. This alteration is thought to be a stromal reaction to the foreign body-associated endometrial surface erosion. Typically a focal finding, synovial-like metaplasia is characterized by a palisade of cells that are oriented perpendicular to the endometrial sur- face. Occasional multinucleate cells may be present, but overt granulomatous inflammation is absent. Constituent cells express to varying degrees vimentin and CD68, whereas smooth muscle antibody (SMA), PAX8, cytokeratin, ER, PR, and CD10 expression are largely absent [13] Fig. 2.40 Endometrial polyp, showing differences in the cellularity and collagenization of the polyp (central field) compared with the background endometrium (right field). In general, the stroma of endometrial polyps is more collagenized and less cellular than background endometrium Fig. 2.41 Endometrial polyp. The glands of endometrial polyps may be modestly crowded. The crowded areas do not show cytologic demar- cation from the background polyp epithelium, and exist in a polypoid fragment with fibrous stroma and thick-walled vessels, features that help identify it as a polyp. The glands are ectatic and irregularly shaped, and may also be cystic. The lining of these glandular units may be atrophic, weakly proliferative, secretory, or proliferative; most often they are weakly proliferative to atrophic. Overall, we refrain from diagnosing the "simple" iteration of the old diagnostic category "simple hyper- plasia without atypia" in polyps. Note the thick-walled vessels at the center of the polyp in (a), shown at higher magnification in (b). These vessels are mostly thick-walled and are diagnostically useful in a sampling specimen Fig. 2.42 (a, b) Endometrial polyps occasionally show stromal cellu- larity that is comparable to proliferative-type endometrium. In these cases, stromal mitotic figures may be present Fig. 2.43 (a, b) Endometrial polyp with paucity of glands. Some endometrial polyps display such paucity of glands as to raise the possibility of an endometrial stromal neoplasm. Diagnostically useful features include classic areas of an endometrial polyp (not shown), the presence of thick-walled vessels, the presence of residual glands typi- cally at the surface area or periphery of the polyp, and foci of uniform collagenization Fig. 2.44 Endometrial polyp. This case highlights the distinct collagenization that may be seen in some polyps Fig. 2.45 Mixed endometrial/endocervical polyp. Polyps of this kind show both endocervical and endometrial type glands, and are frequently located in the lower uterine segment. They may protrude through the cervical os Fig. 2.46 (a, b) Endometrial polyp with myomatous stroma. Some conventional endometrial polyps have distinctive "lobules" of smooth muscle, which may or may not entrap glands. These may be conceptual- ized as iterations of lesions that some authors classify as "adenomyomatous polyps" or just "adenomyoma" [21], but in endometrial polyp with myomatous stroma, most of the polyp is a conventional endometrial polyp. The glands are also devoid of periglandular endometrial stroma. We prefer to classify these cases as endometrial polyps with myomatous stroma Fig. 2.47 Endometrial polyp with myomatous stroma. (a) In some polyps, the myomatous stroma takes on a distinctive perivascular, pseudo- rosetted arrangement. (b) Diffuse expression of desmin in constituent cells Fig. 2.48 (a, b) Endometrial polyp, functional. The lining of glandular units in endometrial polyps may be atrophic, weakly proliferative, secretory, or proliferative; most often they are weakly proliferative to atrophic. When the endometrial glands are secretory, such polyps have been traditionally referred to as "functional," but the level of secretory maturation in such endometrial polyps may differ from the background, and does not provide any information on the functional state of the background endometrium. Other features of endometrial polyps, including the polypoid configuration, thick-walled vessels, and altered stroma, are diagnostically useful in identifying them as polyps Fig. 2.49 (a, b) Endometrial polyp with atypical (bizarre) stromal cells. These cells may show hyperchromasia of the "smudged" chromatin variety, nuclear enlargement, and no mitotic figures [22]. The atypical cells may be focal or multifocal, and rarely, may be distributed in a band-like fashion beneath the surface epithelium. Full architectural features of adenosarcoma are absent, including intraglandular stromal papillation, robust and diffuse periepithelial stromal condensation, and stromal mitotic figures Fig. 2.50 Endometrial polyp associated with tamoxifen use. The pathologic features of these polyps are not distinctive enough to be diagnosable based on their morphologic features alone. Such polyps tend to be larger than controls and to display notably fibrous stroma [18, 19], with no to very scant residual periglandular stromal cells. They have also been described as showing glands that are oriented along the long axis of the polyp, with glandular dilatation and frequent metaplastic changes, but the diagnostic specificity of these features has not been assessed in a large cohort Fig. 2.51 (a-c) Endometrial polyp with some focal features that over- lap with müllerian adenosarcoma, including intraglandular polypoid projections or focal phyllodes-like architecture, alterations in the peri- glandular stromal zones, mild stromal atypia, mildly increased stromal mitoses, and rigid cysts. Unlike müllerian adenosarcoma, these endo- metrial polyps are small (<3 cm) and show the aforementioned changes very focally and in poorly developed forms [23]. Müllerian adenosarcoma is discussed in more detail in Chap. 4 Fig. 2.52 Endometrial polyps may occasionally show confluent zones of infarction, which may be seen as active, hemorrhagic, or prior necrosis (diffuse hyalinization). The residual viable glands within these zones frequently show reactive changes, including hobnail, papillary syncytial, clear cell, and eosinophilic metaplasia, and moderate nuclear atypia [12]. These areas are devoid of significant mitotic figures. This image highlights necrosis in the upper field and glands with papillary syncytial metaplasia in the lower right field Fig. 2.53 Adenomyosis. Adenomyosis is a pathologic condition in which endometrial glands and/or stroma are present in the myometrium beyond a defined distance (arbitrarily set at 2.5 mm) from the endometrial/myometrial interface [24] Fig. 2.54 (a, b) Adenomyosis. In their most common iteration, each adenomyotic focus is composed of proliferative or weakly proliferative glands surrounded by endometrial stroma and myometrium. The glands may display the full spectrum of functional, metaplastic, or neoplastic alterations that may be encountered in the overlying endometrium Fig. 2.55 Adenomyosis. Some of the constituent glands of adenomyosis may be cystic or may display intraglandular papillary-like alterations. These changes should not be mistaken for adenosarcoma. This change was focal in an otherwise typical case of adenomyosis Fig. 2.56 (a, b) Adenomyosis involving vascular spaces may be seen in 12.4% of cases [25]. This finding has no clinical significance. Occasionally, glands may be seen in these intravascular foci, which has prompted the proposed diagnostic term intravascular adenomyomatosis [27] Fig. 2.57 Adenomyosis with sparse glands. Adenomyosis foci may be devoid of discernible glands [26]. The differential diagnosis is low- grade endometrial stromal sarcoma. The adenomyosis foci may be dis- tinguished from the sarcoma because they are incidental, microscopic, non-mass-forming lesions that are frequently arranged in a distinctive concentric zonal pattern, with pale centers surrounded by more cellular peripheries and hypertrophic smooth muscle Fig. 2.58 Adenomyosis with sparse stroma. Adenomyosis foci may comprise only glands. The stroma may be thin (and made more obvious by CD10 immunohistochemistry) or may be absent (presumably the result of muscle metaplasia) Fig. 2.59 (a, b) Subserosal adenomyosis. In subserosal adenomyosis, adenomyotic glands and stroma are found just beneath the uterine serosa, clearly embedded within myometrial fibers [28]. Subserosal adenomyosis is typically an incidental finding; the uterus is not enlarged and adenomyosis foci are absent elsewhere in the uterus. In one study, 11.7% cases of adenomyosis had a subserosal component [28]. We apply the term only when the subserosal foci are the only evidence of adenomyosis in the uterus. Subserosal adenomyosis may represent a manifestation of pelvic endometriosis, but additional studies are needed Fig. 2.60 Adenomyoma. Adenomyomas may be submucosal, mural, or subserosal [21]. They are composed of glands lined by cytologically bland endometrial-type epithelium bounded by endometrial stroma and a dominant smooth muscle component. The epithelium may show vari- ous metaplasias and usually has <5 mitotic figures (MF) per 10 high- power fields (HPF) Fig. 2.61 (a, b) Chronic endometritis. The key diagnostic feature in chronic endometritis is the presence of plasma cells. These plasma cells are most easily discernible in the stroma adjacent to epithelial cells Other cells that may be encountered to varying degrees include lymphocytes, eosinophils, neutrophils, and macrophages (including hemosiderin-laden macrophages) Fig. 2.62 Chronic endometritis. Edema is frequently present in the superficial stroma Fig. 2.63 Chronic endometritis. Other cases show an increase in stro- mal cellularity. Note the hemosiderin-laden macrophages, another feature that may be seen especially when there is concurrent sinusoidal thrombin and breakdown Fig. 2.64 (a, b) Chronic endometritis. A common feature is a fibroblastic alteration of the stroma, with increased spindling Fig. 2.65 (a, b) Chronic endometritis. Intraepithelial neutrophils, including intraluminal microabscesses, may be encountered in chronic endometritis Fig. 2.66 Chronic endometritis. Plasma cells may be concentrated at the periphery of lymphoid follicles; the latter are also on average more extensive in chronic endometritis than in control patients Fig. 2.67 Chronic endometritis. A vague, predecidua-like alteration may be seen in the stroma Fig. 2.68 Chronic endometritis. Micropolyps, which may be seen hystereoscopically, have been associated with chronic endometritis. This requires further study Fig. 2.69 (a, b) Chronic endometritis. Synedecan-1 (CD138) immunohistochemistry highlights plasma cells, as well as normal endometrial epithelium. CD138 increases the sensitivity of plasma cell detection in endometrial samplings Fig. 2.70 CD138-positive cell in an otherwise histologically unremarkable endometrium. The cell that corresponded to this focus could not be identified on routine hematoxylin and eosin (H&E)-stained sections. CD138 should be performed only when there are other clinicopathologic findings that raise the possibility of chronic endometritis. The clinicopathologic significance of plasma cells that are detected by CD138 immunohistochemistry in the absence of such changes is unclear Fig. 2.71 Cervix with inflammation. Inflamed pieces of cervix may be seen in an endometrial sample. An erroneous diagnosis of chronic endometritis may be rendered if enough attention is not paid to the asso- ciated epithelium Fig. 2.72 Focal necrotizing endometritis is a disease of postmenopausal women, who typically present with bleeding. It is characterized by scattered, nonconfluent, patchy inflammation around endometrial glands and lumen, with partial necrosis of the epithelium. The inflammation comprises lymphocytes and neutrophils, with rare macrophages. Plasma cells are absent [31] Fig. 2.73 Plasma cells are an expected finding associated with stromal and glandular breakdown, and as such are not indicative of chronic endometritis Fig. 2.74 (a, b) Xanthogranulomatous endometritis describes infiltra- tion of the endometrium by a population of histiocytes with abundant foamy to eosinophilic cytoplasm. Other inflammatory cells are typi- cally admixed. They are associated with obstruction/stenosis of the cer- vical canal, pyometra, neoadjuvant therapy for cancers, or prior sampling. Patients may present with abnormal bleeding in the absence of the aforementioned risk factors. Xanthogranulomatous endometritis is distinguished from malakoplakia by the absence of Michaelis- Gutmann bodies and from nodular histiocytic aggregates by the nodular configuration of the latter, as well as their constituent histiocytes with notably eosinophilic cytoplasm. Foamy histiocytes may also be associated with endometrial hyperplasia and carcinoma, and these conditions should be excluded if foamy histiocytes are encountered Fig. 2.75 (a, b) Nodular histiocytic aggregates that are seen in the endometrial samples of mostly postmenopausal women who present with bleeding. A nonremote history of prior endometrial sampling may be present. The lesions, which range in size from 1 to 15 mm, are composed of monomorphic polygonal or round cells with abundant pink eosinophilic cytoplasm with a vaguely nodular arrangement [35] Fig. 2.76 Nodular histiocytic aggregates. Constituent cells are diffusely immunoreactive for CD68 Fig. 2.77 Actinomycosis. Endometrial actinomycosis refers to infec- tion or colonization of the endometrium by Actinomyces spp., most frequently Actinomyces israelii [36-38]. Actinomyces israelii is a branching, anaerobic or microaerophilic bacterium that is seen in approximately 1.6-11.6% of intrauterine device (IUD) users, but which is very rarely seen in the non-IUD setting [36-38]. Chiesa-Vottero [38] identified Actinomyces endometritis in 0.02% of consecutive biopsies over a 10-year period. This infection, which is most frequently associ- ated with long-standing progestin-laden IUDs, may occasionally lead to active endometritis, and a small subset of patients develop tubo-ovarian abscesses, which may be life-threatening. Actinomyces is characterized by radiating filaments of Gram-positive, Fite-negative and Silver- positive bacteria ("sulfur granules") with a dense central eosinophilic core. There is typically a background of suppurative inflammation Fig. 2.77 (continued) Fig. 2.78 (a, b) Pseudoactinomycotic radiate granules. These distinc- tive structures may be identified in isolation, in association with IUDs, and/or in association with IUDs and actinomycosis [39, 40]. In our experience, pseudoactinomycotic radiate granules are more common in IUD users than actinomycosis. They contain neutral glycoproteins, lipid, and calcium with no microorganisms. On H&E, they are composed of refractile granules with laminated club-like peripheral projec- tions and no central dense core. They are typically negative for Gram, Silver, and Fite histochemical stains Fig. 2.79 (a, b) Pseudoactinomycotic radiate granules and actinomycosis. Both of these processes may coexist, as is exemplified in this case. A Silver histochemical stain selectively highlights the Actinomyces spp Fig. 2.80 (a-d) Endometrial calcifications. Calcifications, which may be psammomatous or nonspecific, may occasionally be identified in endometrial biopsies [42, 43]. In one study by Fausett et al. [43], assess- ing a small group of patients, the most significant uterine pathology that was found to be potentially associated with calcifications was endome- trial polyps. In another study of ultrasonography-detected calcifica- tions, 55% of cases had a histologically confirmed calcification [42] that study, Truskinovsky et al. reported the extent of microcalcifications to be positively correlated with endometrial polyps, postmenopausal state, hormone replacement therapy, and atrophic endometrium. We have also identified calcifications in the setting of IUD use, but in our experience, in most cases in which a calcification is present in a biopsy, there is no significant pathologic change in the background endometrium
