10 Endometrial Carcinoma

Important Issues in Interpretation of The tumors are often associated with hyper- Biopsies ...... 209 plasia and atypical hyperplasia, conditions that Criteria for the Diagnosis of result from unopposed estrogenic stimulation Well-Differentiated Endometrial such as anovulatory cycles that normally occur Adenocarcinoma ...... 209 at the time of menopause or in younger women Benign Changes that Mimic with the Stein–Leventhal syndrome (polycystic Carcinoma ...... 214 ovarian disease). Unopposed exogenous estro- Malignant Neoplasms—Classification, gen use as hormone replacement therapy in Grading, and Staging of the Tumor ...... 216 older women also predisposes to endometrial Classification ...... 216 carcinoma that tends to be low-grade. In hys- Grading ...... 216 Clinically Important Histologic terectomy specimens these low-grade tumors Subtypes ...... 221 generally show minimal myometrial invasion, Staging ...... 236 although deep invasion can occur in some Endometrial Versus Endocervical cases.5;6 The prognosis is generally good, with a Carcinoma ...... 237 5-year survival of 80% or better.3 Metastatic Carcinoma ...... 238 Type II neoplasms represent another, very Clinical Queries and Reporting ...... 239 different, form of endometrial carcinoma. They are high-grade neoplasms that do not appear to be related to sustained estrogen stimulation.1;2;4 Endometrial adenocarcinoma is the most com- Tumors in this group account for 15% to 20% mon malignant tumor of the female genital of all endometrial carcinomas. The prototypical tract in the United States. This neoplasm rep- type II neoplasm is serous carcinoma, but other resents a biologically and morphologically histologic subtypes include clear cell carcino- diverse group of tumors, with differing patho- mas and other carcinomas that show high-grade genesis.1–4 These tumors have two basic clinico- nuclear features. They tend to occur in older pathologic forms, type I and type II. These two postmenopausal women, are not associated forms of endometrial carcinoma display differ- with atypical hyperplasia, and often occur in ent clinicopathologic, immunohistochemical, atrophic endometrium. Endometrial intra- and molecular biologic features suggesting two epithelial carcinoma (EIC), the putative pre- pathways of carcinogenesis. cursor lesion, is frequently associated with Type I carcinomas are generally well to mod- serous carcinoma (see Chapter 9). Serous erately differentiated and account for 80% to carcinoma usually invades the myometrium 85% of all endometrial carcinomas. The typical deeply, permeates lymphatic and vascular chan- patient is an obese, hypertensive, and diabetic nels, and not infrequently has spread beyond perimenopausal or postmenopausal woman. the uterus at the time of hysterectomy.

208 Important Issues in Interpretation of Biopsies 209

Although most endometrial carcinomas tend Important Issues in to be either type I or type II, there are cases that do not fall neatly into either category. For Interpretation of Biopsies instance, some endometrioid carcinomas are There are two major concerns in the evaluation very high grade. Also, some endometrioid car- of endometrial biopsies from the standpoint of cinomas can show foci of serous or clear cell a diagnosis of carcinoma. First, is the lesion carcinoma. benign or malignant? Second, if the biopsy con- Clinicopathologic studies over the past tains a malignant tumor, what is the grade, his- several years have shown the importance of tologic subtype, and is it a primary endometrial recognizing specific histologic subtypes and or an endocervical carcinoma? accurately grading carcinomas to help pre- dict outcome and direct treatment.7–26 Most endometrial tumors diagnosed on a biopsy Criteria for the Diagnosis of are subsequently treated by extrafascial total Well-Differentiated Endometrial abdominal hysterectomy and bilateral salp- Adenocarcinoma ingo-oophorectomy that allows precise surgical–pathologic staging.27 Nonetheless, Because a diagnosis of carcinoma will have an identification of more aggressive tumors is important impact on clinical management, it is important at the time of biopsy, as these necessary for the pathologist to be familiar with neoplasms have greater potential for metasta- the minimal histologic criteria for that diagno- tic spread, including involvement of the peri- sis. One of the most problematic areas is the dis- toneal surfaces. The aggressive neoplasms are tinction of atypical hyperplasia (see Chapter 9) high-grade carcinomas that merit surgical from well-differentiated adenocarcinoma.30–33 staging. The clinical relevance of the histologic Separation of these entities is based on identi- classification and grading of endometrial carci- fication of specific morphologic criteria that noma is reflected in the revised World Health establish the diagnosis of low-grade carcinoma. Organization (WHO) Histologic Classifica- Hyperplasia without atypia generally is not a tion28;28a and the International Federation of problem in the differential diagnosis, as these Gynecology and Obstetrics (FIGO) staging forms of hyperplasia do not have nuclear system.29 atypia. It is important, however, to accurately The morphologic diversity of endometrial separate carcinoma from other, benign changes carcinoma can lead to problems in the diagno- that mimic neoplasia, including tissue artifacts sis of carcinoma in biopsies and curettings. For and pregnancy-related changes. low-grade carcinoma, distinction from atypical Diagnosis of low-grade adenocarcinoma can hyperplasia and other benign lesions that be difficult at times,because these tumors do not mimic carcinoma is an important issue. Identi- always show clear-cut destructive stromal inva- fying and properly classifying aggressive, sion. Furthermore, invasion into myometrium clinically significant histologic subtypes of is rarely, if ever, demonstrated in biopsies. endometrial carcinoma is a second important Nonetheless, invasion is a logical criterion for area of biopsy interpretation. Another problem separating frank adenocarcinoma from atypical in biopsy interpretation is ascertaining whether hyperplasia or other lesions that mimic the tumor originates in the endometrium or the adenocarcinoma. endocervix. This chapter addresses the general For practical application, specific patterns of classification, staging, and grading of endome- stromal and epithelial alterations have been trial carcinoma, the differential diagnosis of defined that reflect “endometrial stromal inva- benign lesions versus low-grade carcinoma, and sion” and identify carcinoma.31;34 There are the classification of different types of carci- three separate features, any of which indicates noma once the diagnosis of carcinoma has been stromal invasion in low-grade glandular established. proliferations: 210 10. Endometrial Carcinoma

1. A confluent glandular pattern in which evident, a diagnosis of carcinoma should be individual glands, uninterrupted by stroma, made even if the diagnostic area does not merge and create a cribriform arrangement; occupy one-half of a low-power field. 2. An irregular infiltration of glands associated with an altered fibroblastic stroma (desmo- Confluent Gland Pattern plastic response); and This pattern reflects invasion by showing a 3. An extensive papillary pattern. complete absence of stroma between glands.At Although quantitative features have limited times a cribriform bridging pattern with true usefulness in endometrial biopsy diagnosis, “gland in gland” formation is present. With these specific and objective criteria for invasion cribriform growth, trabeculae of columnar cells also should be quantitatively significant. There- bridge the lumen, subdividing the lumen into fore, the glandular proliferation that fulfills smaller glandular spaces (Figs. 10.1 and 10.2). criteria for well-differentiated adenocarcinoma No stroma supports the bridging cells. A con- should be sufficiently extensive to involve at fluent gland pattern also is represented by large, least one half of a low-power (¥4) field, a dis- irregular glands that interconnect continuously tance of 2.0mm. This guideline helps mainly to throughout the field, exceeding the outline of avoid the problem of tangential sectioning or any acceptable non-neoplastic gland (Fig. 10.3). other artifacts in establishing the diagnosis of Confluent gland patterns should be identified in carcinoma. This general rule should not be too areas free of squamous differentiation, as squa- rigidly applied, particularly in scant specimens. mous morules may bridge gland lumens, but If the features of “stromal invasion” are clearly these do not reflect stromal invasion.

Figure 10.1. Adenocarcinoma, FIGO grade 1. The grade 1 with minimal pleomorphism, small nucleoli, neoplasm shows well-formed glands with a confluent and low mitotic rate. pattern. The stroma is desmoplastic. The nuclei are Figure 10.2. Adenocarcinoma, FIGO grade 1. Confluent gland pattern. Confluent glands with a cribriform bridging arrangement. There is no stromal support to the epithelium that bridges the glandular lumens.

Figure 10.3. Adenocarcinoma, FIGO grade 1. Confluent gland pattern. Large irregular and branching glands interconnect continuously throughout the field. 212 10. Endometrial Carcinoma

Altered Fibrous or Desmoplastic Stroma in establishing an unequivocal diagnosis of malignancy. With this change, atypical glands are dispersed in a reactive fibroblastic mesenchyme rather Extensive Papillary Pattern than in endometrial stromal cells (Fig. 10.4). These fibrous stromal cells are different from The extensive papillary growth pattern is char- normal endometrial stromal cells, being more acterized by delicate, elongate, branching spindle-shaped and having elongate nuclei. papillary fronds (Fig. 10.6). The fronds have The mesenchyme also contains collagen that thin, fibrous cores. These papillary structures compresses the stromal cells and gives an are much more elaborate and branching than eosinophilic appearance (Fig. 10.5). The fibrous the small papillary tufts that may occur in the change also leads to retraction and distortion of glands of atypical hyperplasia. Papillary tufts the normal architecture, resulting in a haphaz- also lack fibrovascular cores. The diffuse ard glandular pattern. Dense stroma in polyps, papillary pattern distinguishes this form of alteration of the stroma associated with marked adenocarcinoma from focal alterations, such as inflammation, the stroma of the atypical poly- papillary arrangements in eosinophilic syncytial poid adenomyoma, and stroma of the lower change (see Chapter 5) or hyperplastic papil- uterine segment all may mimic the desmoplas- lary proliferations in polyps (see Chapter 9).35 tic response of carcinoma. In these types of Serous papillary adenocarcinoma is readily sep- cases, in which desmoplasia is difficult to arated from this well-differentiated neoplasm evaluate, other features of carcinoma, such by its high-grade nuclear features and extensive as a confluent gland pattern, should be used papillary tufting (see later).

Figure 10.4. Adenocarcinoma, FIGO grade 1. Desmoplastic stroma. A fibroblastic mesenchyme encom- passes the neoplastic glands. Figure 10.5. Adenocarcinoma, FIGO grade 1. lasts and collagen. Squamous change is present in the Desmoplastic stroma. The stroma supporting the lower portion of the field. malignant glands is composed of elongated fibrob-

Figure 10.6. Adenocarcinoma, FIGO grade 1. Extensive papillary pattern. This low-grade adenocarcinoma with a villoglandular pattern forms multiple delicate papillae. 214 10. Endometrial Carcinoma

Originally, another pattern, squamous a minimum, the histologic criteria for well- masses, in which sheets of bland squamous cells differentiated carcinoma described previously form irregular coalescent nests throughout the or if the lesion shows unequivocal features of stroma, was proposed as a criterion for inva- malignancy with cytologic features of grade 2 sion.31 This pattern is rare by itself, however, or 3 carcinoma. Detached epithelial fragments, and not useful for recognizing carcinoma in especially when they lack significant nuclear most cases. When this pattern is present, other atypia, should not be diagnosed as carcinoma. areas usually show confluent gland patterns or These epithelial changes may occur in carci- an altered (desmoplastic) stroma. noma, however, and equivocal cases require Applying these criteria for invasion to estab- processing of additional tissue. Cytoplasmic lish the diagnosis of well-differentiated adeno- change is discussed in greater detail in carcinoma yields a clinically significant Chapter 9. diagnosis of carcinoma, when present. One study found that in curettage specimens with Atypical Polypoid Adenomyoma well-differentiated adenocarcinoma, defined by The atypical polypoid adenomyoma can be at least one of these features of invasion, sub- confused with carcinoma of the endometrium sequent hysterectomy specimens showed resid- because the lesion shows atypical glands, ual adenocarcinoma in one half of the cases.31 usually with squamous morules, in smooth Frequently the residual carcinoma was well dif- muscle that can be confused with carcinoma ferentiated but in about one third of cases the invading the myometrium (see Chapter 8).48–50 tumor was grade 2 or 3, and in one quarter of Myometrial invasion is rarely seen in biopsy the cases with tumor, the myometrium was and curettage specimens, however. Further- deeply invaded. In another study that used the more, the orderly pattern of the smooth muscle same criteria to assess “stromal invasion,” 16% of the atypical polypoid adenomyoma contrasts of patients without stromal invasion in with the desmoplasia typically associated with endometrial samples had myometrial invasion neoplasia. In those rare cases in which the dif- in the hysterectomy specimens whereas 62.5% ferential diagnosis includes the atypical poly- of patients with invasion in the biopsy had poid adenomyoma and adenocarcinoma, it is myometrial invasion.36 These studies show the important to note that a confluent or cribriform utility of these criteria for determining the pres- pattern does not occur in the atypical polypoid ence of well-differentiated adenocarcinoma. adenomyoma. Immunohistochemical stains for desmin can help to demonstrate the smooth Benign Changes that Mimic muscle in the atypical adenomyoma and distin- Carcinoma guish it from the fibroblastic desmoplasia of carcinoma. Epithelial Cytoplasmic Change Pregnancy and the Arias-Stella Reaction Benign cytoplasmic changes and metaplasia can be confused with endometrial carcinoma In pregnancy, crowded secretory glands, includ- (see Chapter 9).34;37–42 This differential diagno- ing those that display the Arias-Stella reaction, sis is most likely to occur in the presence of may resemble carcinoma, especially clear cell prominent squamous or eosinophilic cell carcinoma. For a premenopausal patient, the change, especially in specimens with consider- possibility of non-neoplastic lesions, such able tissue fragmentation. These cytoplasmic as the Arias-Stella reaction, is much more changes can occur in a variety of conditions, likely than carcinoma. Thus, the clinical history including polyps, hyperplasia, inflammation and often clarifies the diagnosis in questionable nonspecific glandular and stromal breakdown, cases. as well as in carcinoma.34;39–41;43–47 Consequently, Several microscopic features also help in the carcinoma should be diagnosed only when recognition of the Arias-Stella reaction (see there is a glandular proliferation that fulfills, at Chapter 3). This lesion tends to be multifocal, Important Issues in Interpretation of Biopsies 215 admixed with secretory glands, and does not Stromal artifacts also can mimic adeno- form a discrete lesion. Usually decidua is carcinoma, especially when they develop a present, too. In addition, this change lacks the signet-ring cell morphology.51 Aggregates of features of invasion, such as confluent glands, signet-ring cells in the stroma can be seen in an extensively papillary pattern, or altered cases with extensive stromal decidual change, stroma. The nuclei in the Arias-Stella reaction especially following progestin hormone generally appear to be degenerated, with therapy.51 Rarely, stromal histiocytes may also smudged chromatin, and mitotic figures almost have a signet-ring appearance. In these cases never are present. Other pregnancy-related the apparent signet-ring cells lack nuclear cytologic changes, such as vacuolated cytoplasm atypia. In addition, these signet-ring cells are and optically clear nuclei, also may be found in negative for broad-spectrum keratin immuno- the epithelial cells when the Arias-Stella reac- stains and are mucin negative by histochemical tion is present. In addition, Ki-67 immuno- stains. staining is useful in the differential diagnosis, Fragmentation and artifacts also occur in as the Arias-Stella reaction has a very low pro- curettage specimens containing adenocarci- liferative index. noma. When this occurs, the diagnosis of carci- noma still can be made if the epithelial cells Tissue Artifacts, Contaminants, demonstrate high nuclear grade. Those areas where glands are attached to surrounding mes- and Necrosis enchymal tissue and are free of the changes of Tissue artifacts can yield worrisome patterns breakdown and bleeding demonstrate the true that may mimic carcinoma. For example, the relationship of the glands to each other. To reli- artifactual crowding and distortion of glands ably identify malignancy in equivocal cases, that occur during biopsy can result in glands however, it is best to evaluate the features that becoming closely apposed (see Chapter 2). establish the diagnosis of well-differentiated Likewise, breakdown and bleeding distort the adenocarcinoma in clearly intact areas. normal architecture and present a variety of Actual tumor necrosis rarely, if ever, occurs cytologic alterations, including eosinophilic in well-differentiated tumors. This form of syncytial change (see earlier). Cervical contam- necrosis is often seen in high-grade tumors, but inants, especially endocervical squamous meta- in these cases the histologic and nuclear fea- plasia, prominent detached fragments of tures readily identify the lesion as carcinoma. endocervical epithelium, or microglandular The presence of tumor cell necrosis in what hyperplasia, may become mixed with endome- appears to be a low-grade carcinoma is a red trial tissue in curetting specimens and yield a flag that the tumor is, in fact, a high-grade complex pattern that can mimic carcinoma at carcinoma and therefore further sampling is first glance.These tissue artifacts usually are not warranted. Much of the “necrosis” that is a major problem in the differential diagnosis, commonly encountered in biopsy material is as they are generally focal and admixed unique to the endometrium and actually with normal endometrium. In menstrual reflects breakdown rather than necrotic tumor. endometrium, in which there is more diffuse The necrosis associated with bleeding and and extensive breakdown, the possibility of breakdown is apparent in low-grade carcinoma mistaking the pattern for adenocarcinoma is but often occurs in benign conditions, too, greater. In such cases it is important to attempt regardless of cause. Because tissue breakdown to identify secretory glandular changes and and necrosis are so ubiquitous in endometrial intact endometrium that is not undergoing tissue, the finding of this pattern of necrosis is breakdown. Furthermore, the clinical history, not helpful in establishing the diagnosis of including the patient’s age and menstrual neoplasia. Another pattern of necrosis can status, can be very helpful in recognizing a men- be seen in the center of nests of squamous strual pattern that may not be obvious at first change (morules). Central necrosis in areas of inspection. squamous change can occur in benign lesions, 216 10. Endometrial Carcinoma including any form of hyperplasia, polyps, and otherwise specified (NOS)” pattern referred to the atypical polypoid adenomyoma. Conse- as “endometrioid” carcinoma. More than one quently, the necrosis associated with squamous half of all endometrial carcinomas have this change has no significance and does not indi- pattern.3;10;11;42 The term “endometrioid” pro- cate malignancy. vides a specific designation for this neoplastic pattern, clearly separating it from the other histologic types of endometrial carcinoma. Malignant Neoplasms— Because “endometrioid carcinoma” is more Classification, Grading, and widely applied to primary ovarian cancer, however, this terminology for primary uterine Staging of the Tumor neoplasia is potentially confusing to clinicians. Practically, ordinary adenocarcinoma with this Once the diagnosis of carcinoma is established, pattern is frequently classified as endometrial it is important that the tumor be properly carcinoma and graded in the microscopic classified in order to identify aggressive forms diagnosis. of carcinoma (Table 10.1). Also, because the From 20% to 30% of endometrial carcino- biopsy or curettage is generally a blind proce- mas show an “endometrioid” pattern with squa- dure with no direct visualization of the neo- mous differentiation.18 Previously, these tumors plasm, it is important to ascertain whether or with squamous differentiation were separated not the carcinoma is primarily in the into two categories: “adenoacanthoma” endometrium or whether it arises in the cervix. denoted tumors that had cytologically benign- Finally, especially if the tumor displays an appearing squamous epithelium (squamous unusual pattern, the possibility of a metastasis metaplasia), and “adenosquamous carcinoma” from another site should be considered. denoted tumors that had a cytologically malig- nant squamous component. More recently, Classification studies have shown that endometrioid carcino- mas with or without squamous epithelium The current WHO histologic classification rec- behave in the same fashion when stratified ognizes several distinct types of carcinoma that according to the grade of the glandular compo- are important to identify in biopsies (Table nent.18;19;53 Accordingly, these tumors are best 10.1).52 Many examples of endometrial adeno- classified as adenocarcinomas with squamous carcinoma have the “typical,” “usual,” or “not differentiation and graded. The terms “adenoa- canthoma” and “adenosquamous carcinoma” are no longer used for endometrial carcinoma. Table 10.1. World Health Organization (WHO) classification of endometrial adenocarcinoma. The other histologic types of endometrial carcinoma are relatively infrequent. Serous and Endometrioid adenocarcinoma, NOS mucinous tumors both account for 10% to 15% Variants Villoglandular of endometrial primary tumors in most series, Ciliated cell and clear cell adenocarcinoma occurs in no Secretory more than 5% of all cases.3 Adenocarcinoma, NOS, with squamous differentiation Mucinous adenocarcinoma Serous adenocarcinoma Grading Clear cell adenocarcinoma Squamous carcinoma In addition to identifying specific histologic Undifferentiated carcinoma subtypes in biopsies, the histologic grade pro- Mixed carcinomaa vides useful prognostic information and assists Metastatic carcinoma in planning treatment. Low-grade tumors NOS, Not otherwise specified. usually are confined to the corpus at the time a Tumor with greater than 10% of a second cell type. of diagnosis, and the overall survival is very Malignant Neoplasms—Classification, Grading, and Staging of the Tumor 217

Figure 10.7. Adenocarcinoma, FIGO grade 2. Although glandular differentiation is readily apparent, a sub- stantial amount (approximately 20%) of the tumor has a solid growth pattern. good. High-grade tumors, in contrast, are more example, determination of more than 5% solid aggressive and have a poor prognosis. This growth that determines grade 2 instead of grade latter group is more likely to spread beyond the 1 tumor is an estimate and is subject to indi- corpus and involve the endocervix or extrauter- vidual variation. In addition, significant varia- ine sites at the time of diagnosis. tion in architectural grade can be seen within The traditional grading of endometrial ade- a tumor. Well-formed glands (grade 1 tumor) nocarcinoma standardized by FIGO uses a may be adjacent to solid masses of grade 3 car- three-grade system based on architectural fea- cinoma. Not surprisingly, the heterogeneity of tures. Tumors are grade 1 when most (95%) of tumor grade can result in discordance between the tumor forms glands (Figs. 10.1 to 10.4), curettage and hysterectomy specimens. grade 2 when 6–50% of the tumor exhibits solid Although architectural grading generally growth (Fig. 10.7), and grade 3 when more than correlates with prognosis, studies suggest the 50% of the tumor has a solid growth pattern grading system can be improved by incorporat- (Fig. 10.8). Solid growth in this grading system ing nuclear grading.54–57 Consequently, FIGO consists of areas with glandular components and WHO Histopathologic Classification modi- but limited gland formation. It is important to fied the standard architectural grading system to avoid areas of squamous change in making this include nuclear grade.27;29 Like architectural assessment. grading,nuclear grading is somewhat subjective. Like all morphologic grading systems, this Nuclei with small,relatively uniform,oval nuclei grading scheme is somewhat subjective, espe- and low mitotic activity are grade 1 (Fig. 10.9). cially at the cut points between grades. For Nuclei with features between grade 1 and grade Figure 10.8. Adenocarcinoma, FIGO grade 3. A few residual glands are present, but more than 50% of the tumor shows a solid growth pattern with sheets and nests of malignant epithelial cells.

Figure 10.9. Nuclear grade 1. Nuclei are round to oval with small nucleoli. The mitotic rate is low. Malignant Neoplasms—Classification, Grading, and Staging of the Tumor 219

3 are grade 2 (Fig. 10.10). Highly pleomorphic upgrade architectural grade. In fact, this com- nuclei with irregular outlines, macronucleoli, bination should be regarded as a red flag for the and numerous, often abnormal mitotic figures diagnosis of serous carcinoma (see later). are grade 3 (Fig. 10.11 and Table 10.2).9;58 Other histologic features that influence the FIGO recommends that “notable” nuclear grade according to the FIGO system are: atypia, inappropriate for the architectural 1. Nuclear grading takes precedence in serous, grade, raises an architectural grade 1 or grade clear cell, and squamous cell carcinoma. 2 tumor by 1 (i.e., grade 1 becomes grade 2, and 2. Adenocarcinomas with squamous differenti- grade 2 becomes grade 3). Notable nuclear ation are graded according to the nuclear atypia was not defined, but one study found grade of the glandular component. that for clinical significance, nuclear atypia should be grade 3.54 For example, a tumor with Although these guidelines provide a reason- grade 1 architecture but grade 2 nuclei would able baseline for grading endometrial carci- be given a final FIGO grade of 1, whereas an noma, they require further evaluation. For architectural grade 1 tumor with grade 3 nuclei example, serous carcinoma, by definition, has a should be given a final FIGO grade of 2. It high nuclear grade, so the concept of “prece- should be noted that the combination of grade dence” of nuclear grading for serous carcinoma 1 architecture and grade 3 nuclei is quite has no relevance, in our opinion. uncommon in endometrioid carcinoma, and The grade of the tumor from the biopsy spec- therefore it is unusual for nuclear atypia to imen agrees with the grade in the hysterectomy

Figure 10.10. Nuclear grade 2. In contrast to grade not as abnormal as grade 3 nuclei. Mitoses are 1, these nuclei are more pleomorphic and have readily identified. coarser chromatin and larger nucleoli, but they are 220 10. Endometrial Carcinoma

Figure 10.11. Nuclear grade 3. Nuclei are markedly enlarged and highly /pleomorphic. Although glands are well formed in this field, this tumor had overall features of serous carcinoma.

in fewer than 60% of cases, with both apparent clinician a reasonable expectation of the degree under grading and over grading of biopsies, as of malignancy to be expected in the hysterec- compared to the hysterectomy specimens.59–63 tomy specimen. Furthermore, in occasional Over-grading may be caused by heterogeneity cases, biopsy or curettage will remove all or of the tumor, with the surface component most of the carcinoma, so there can be insuffi- removed at biopsy showing the higher grade. cient tumor in the hysterectomy for further Under grading in biopsy specimens is most evaluation. often due to limited sample size. Thus, the The utility of nuclear grade in the assessment biopsy gives a general assessment of the of endometrial carcinoma has been examined degree of differentiation of a tumor. Treatment in several reports.9;11;16;54;64;65 In general, a corre- decisions are generally based on the grade of lation between nuclear and architectural grade the tumors in the hysterectomy specimen. has been found,9;10;16;58;64 although some reports Nonetheless, grading of the biopsy gives the found interobserver reproducibility for nuclear grading was not as good as for architectural grading.54;66 Nuclear grading in hysterectomy Table 10.2. Nuclear grading. specimens can identify a small subset of nuclear Grade 1. Oval/elongated nuclei, fine chromatin, small grade 3 tumors that have a poorer prognosis nucleoli, few mitoses but do not show grade 3 architectural patterns. Grade 2. (Features between grades 1 and 3) Some studies suggest that nuclear grading is not Grade 3. Enlarged/pleomorphic nuclei, coarse chromatin, an independent index of prognostic utility com- prominent nucleoli, many mitoses pared to the FIGO architectural grade.65 The Malignant Neoplasms—Classification, Grading, and Staging of the Tumor 221 method of nuclear grading has not been with FIGO grade 3 was another reproducible uniform throughout the studies, however, and method of defining tumors with a significant often has failed to incorporate all cytologic fea- difference in prognosis.67a tures in determining the final nuclear grade. For example, one study considered a tumor to have Clinically Important high-grade nuclei if it showed “large nucleoli” Histologic Subtypes and “coarsely clumped chromatin,” but not Typical (Endometrioid) Carcinoma necessarily nuclear pleomorphism.65 In our opinion, however, nuclear grading should con- This type of adenocarcinoma typically shows a sider all features, including pleomorphism, glandular pattern with prominent cribriform mitotic activity, and abnormal mitotic figures bridging, but not infrequently it may display (Table 10.2). Also, the current schemes for a papillary pattern that has been referred to nuclear grading are relatively subjective, and in as “villoglandular” (Figs.10.6 and 10.12).3;42;68;69 our experience endometrioid carcinoma with Glands may contain a small amount of mucin grade 3 nuclei are almost always solid and or necrotic debris (Fig. 10.13). The cells lining would have been graded as 3 based on archi- the glands have a moderate amount of tecture alone. For apparent large discrepancies eosinophilic to amphophilic cytoplasm (Figs. with high nuclear grade and apparent grade 1 10.9 and 10.12),3;37 and the cell membrane at the architecture, it is important to make sure that luminal border of the glands often is ill defined. one is not dealing with a serous or clear cell car- In the papillary tumors, the cells are columnar cinoma. Further study will be needed to deter- and perpendicular to the fibrovascular core. mine the ultimate role of nuclear grading in the Nuclei are oval and relatively bland (see later, assessment of endometrial carcinoma. Serous Carcinoma, for further discussion of Recently, several investigators have pro- papillary patterns). posed a two-grade or binary grading system in Other variants of endometrioid carcinoma place of the FIGO three-grade system.66;67 One include ciliated carcinoma and secretory carci- analysis used a system with 20% or more solid noma.3;37;42 Ciliated carcinoma is an extremely tumor to separate high-grade from low-grade rare neoplasm in which the invasive glands tumors.67 This two-tiered system found im- are lined by cells with cilia along the luminal proved interobserver agreement and better border.3;70;71 Its significance lies in the recogni- prediction of uterine histology at hysterectomy. tion that cilia do not always indicate a benign In another study utilizing a binary grading lesion. system, tumors that displayed two or more of In the secretory variant of endometrial ade- the following features: (1) >50% solid growth nocarcinoma, the neoplastic glands are lined (glandular or squamous), (2) tumor cell necro- by cells with vacuolated cytoplasm (Fig. sis, or (3) an infiltrating as opposed to an expan- 10.14).3;8;12;72 Cytoplasmic vacuolization is a sile pattern of invasion were classified as high feature also seen in many clear cell carcinomas grade.66 This binary grading was useful in (see later, Clear Cell Carcinoma), but it is separating tumors into prognostic groups. In important to separate the low-grade secretory particular it identified a subset of patients carcinoma from clear cell carcinoma, which is with low-grade endometrioid carcinomas with generally a high-grade neoplasm. In secretory metastatic disease who had a relatively better carcinoma, clear vacuoles fill the subnuclear or prognosis that was comparable to that of high- supranuclear cytoplasm, and the cells resemble grade carcinomas confined to the uterus. This those seen in normal early secretory phase. The grading system was evaluated only on hys- nuclei usually show minimal atypia, although terectomy specimens, and, therefore, its utility the glands fulfill the criteria for invasion. These in biopsy material needs further testing. rare tumors have an excellent prognosis. Secre- Another study suggested that reducing the tory carcinoma can occur in premenopausal or FIGO grading system to a two-tiered system by postmenopausal patients and are not necessar- combining FIGO grades 1 and 2 in comparison ily related to progestin treatment. Figure 10.12. Adenocarcinoma.Typical (endometri- fied nuclei. This well-differentiated, FIGO grade 1 oid) pattern. Classic “endometrioid” pattern with the tumor also shows villoglandular papillary features. glands lined by cells with pale cytoplasm and strati-

Figure 10.13. Adenocarcinoma.Typical (endometri- mucoid contents within the glandular lumens do not oid) pattern, FIGO grade 1. The glandular cells have affect the classification of the carcinoma. a moderate amount of eosinophilic cytoplasm. The Malignant Neoplasms—Classification, Grading, and Staging of the Tumor 223

Figure 10.14. Secretory carcinoma, FIGO grade 1. bling secretory phase endometrium. The secretory This variant shows neoplastic glandular cells with changes are accompanied by low-grade nuclei. extensive cytoplasmic vacuoles, superficially resem-

Foam cells often are present in the stroma of serous or clear cell carcinoma. At least 10% of endometrioid carcinoma or its variants, espe- the tumor should have squamous features for it cially when they are low grade.37;73 The presence to qualify as adenocarcinoma with squamous of foam cells by themselves does not influence differentiation. Typically, the squamous epithe- the diagnosis or the classification of endome- lium is intimately admixed with glands (Fig. trial carcinoma as foam cells can occur in a 10.15). variety of benign conditions in which there is In the low-grade neoplasms, the squamous abnormal glandular and stromal breakdown changes often include so-called morules, (see Chapter 5).74 Some endometrial carcino- rounded masses of bland squamous cells largely mas show a marked neutrophilic infiltrate. Poly- filling the lumens of the malignant glands (Fig. morphonuclear leukocytes can be intimately 10.16). These squamous cells are incompletely admixed with the tumor, and the tumor cells differentiated and have eosinophilic cytoplasm can show apparent phagocytosis of neutrophils. and indistinct cell borders. The nuclei are The neutrophilic response has no known effect uniform, bland, and lack prominent nucleoli; on the prognosis. they do not palisade. Mitotic figures are infre- quent. The squamous cells can show intercellu- Adenocarcinoma with Squamous lar bridges, but this finding is infrequent. Often Differentiation these squamous nests are nonkeratinizing, but keratinization can, at times, be present. Squamous differentiation commonly occurs in When the squamous component appears tumors with a typical (endometrioid) glandular malignant, it is usually associated with a neo- pattern.3 It is rarely, if ever, associated with plasm that is grade 2 or 3. Portions of the tumor Figure 10.15. Adenocarcinoma with squamous differentiation. Multiple foci of squamous change are inter- spersed in this well–differentiated (FIGO grade 1) adenocarcinoma.

Figure 10.16. Adenocarcinoma with squamous dif- of the glandular and the squamous element is the ferentiation. Central nests of squamous epithelium same (grade 1). in FIGO grade 1 adenocarcinoma.The nuclear grade Malignant Neoplasms—Classification, Grading, and Staging of the Tumor 225 may show squamous carcinoma without glan- squamous change, because it occurs in adeno- dular differentiation. Tumors with a cytologi- carcinoma, is malignant, regardless of its histol- cally malignant squamous component often are ogy. When these tumors are stratified by grade composed of nests of spindle-shaped cells that and depth of myometrial invasion, the presence obliterate gland lumens (Fig. 10.17). Kera- of squamous epithelium does not alter the tinization and squamous pearl formation are prognosis when compared to endometrioid frequently apparent. Abundant keratin forma- carcinoma lacking squamous epithelium.18;19;53 tion may even incite a foreign body response. Accordingly, it is the grade of the glandular Mitotic activity often is brisk in the squamous component that has prognostic significance. For component. these reasons, the term “adenocarcinoma with At times a clear distinction between cytolog- squamous differentiation” is preferred. These ically benign and malignant squamous epithe- tumors should be graded 1, 2, or 3 based on the lium is not possible. The squamous component architectural and nuclear features of the glan- may show mild degrees of atypia and scattered dular component. mitotic figures (Fig. 10.18). In these cases the cytologic features exceed the “benign” appear- Mucinous Carcinoma ance required for a diagnosis of adenoacan- thoma but do not have all the characteristics Mucinous carcinoma of the endometrium has a of malignancy required for a diagnosis of glandular architecture resembling endometri- adenosquamous carcinoma. Furthermore, this oid carcinoma but is composed of cells con-

Figure 10.17. Adenocarcinoma with squamous dif- nent is cytologically malignant, with multiple mitoses ferentiation. Poorly differentiated, FIGO grade 3 and no keratinization.The spindle pattern should not adenocarcinoma shows nests of spindle–shaped be mistaken for a sarcomatous component. squamous cells filling glands. The squamous compo- 226 10. Endometrial Carcinoma

Figure 10.18. Adenocarcinoma with squamous dif- (compare to Figs. 10.16 and 10.17). The glandular ferentiation. In this tumor the squamous cell nuclei component showed features of moderately differen- are intermediate between grade 1 and grade 3 tiated (FIGO grade 2) adenocarcinoma.

taining abundant intracytoplasmic mucin (Fig. results in basal alignment of the nuclei with 10.19).3;13;14;37;75 It is cytoplasmic mucin, not minimal nuclear stratification, but usually the extracellular and luminal that establishes the tumor merges with a more typical endometri- diagnosis of endometrial mucinous carcinoma. oid pattern. Foam cells are often present, and a Furthermore, the presence of cytoplasmic neutrophilic infiltrate may be seen. mucin should be extensive, involving greater The morphologic features of low-grade muci- than 50% of the cells, for a tumor to be classi- nous carcinoma overlap with the patterns of fied as mucinous carcinoma, as some mucin so-called secretory carcinoma; both types of production is present in most endometrial car- tumors have abundant pale cytoplasm and cinomas.14;76 Special stains for epithelial mucin, basal nuclei with minimal stratification. In such as mucicarmine or the periodic acid–Schiff mucinous carcinoma the cells contain cytoplas- (PAS) with diastase digestion, can be helpful to mic mucin, whereas in secretory carcinoma the demonstrate the mucin. Up to 9% of all stage cytoplasmic vacuoles contain glycogen.The dis- 1 endometrial carcinomas are of the mucinous tinction is largely academic, however, because type according to these criteria.14 tumor grade rather than cytoplasmic differenti- Mucinous carcinomas tend to be well to mod- ation determines prognosis. These neoplasms erately differentiated, and they frequently have show no difference in behavior from a papillary or villous architecture. Portions of endometrioid tumors of similar grade.14 these carcinomas often appear extremely well Because the cell population of mucinous differentiated, because the mucinous cytoplasm carcinoma resembles endocervical epithelium, Malignant Neoplasms—Classification, Grading, and Staging of the Tumor 227 with basal nuclei and abundant supranuclear endometrioid adenocarcinoma, which facili- cytoplasm that contains mucin, the differential tates the diagnosis. In addition, the criteria diagnosis often includes endocervical adeno- outlined in a later section for distinguish- carcinoma. This differential is discussed in ing endometrial and endocervical primary greater detail below. tumors also help in the recognition of these carcinomas. Endocervical-Like Endometrial Carcinoma Serous Carcinoma Occasional well-differentiated mucinous Serous carcinoma is recognized by its marked endometrial carcinomas have patterns that nuclear atypia and its resemblance to ovarian mimic cervical microglandular hyperplasia.77;78 serous carcinoma.20;23;68;79–8

Figure 10.19. Mucinous carcinoma. In this FIGO basal portion of the cells, resulting in a resemblance grade 1 tumor, the glandular cells have abundant to endocervical epithelium. cytoplasmic mucin. Nuclei are oriented along the Figure 10.20. Adenocarcinoma with endocervical- sia of the cervix. This is the confluent, cribriform like pattern. This FIGO grade 1 adenocarcinoma is pattern of adenocarcinoma, however. Neutrophils composed of anastomosing small glands that have a are present in the epithelium and the extracellular superficial resemblance to microglandular hyperpla- mucin. Inset: The nuclei are low grade.

Figure 10.21. Serous carcinoma. Arborizing papillae with multiple papillary tufts are a frequent character- istic of this tumor. Many of the papillae appear as free-floating clusters of cells. Malignant Neoplasms—Classification, Grading, and Staging of the Tumor 229

Table 10.3. Histologic features of serous carcinoma. aggressive neoplasms. Serous carcinoma was Complex, coarse papillae originally considered a predominantly papillary Irregular, gaping glands neoplasm, but studies now show that it is mor- Papillary tufting phologically diverse.80 In some cases the papil- High nuclear/cytoplasmic ratio lae are long and slender instead of short and Marked nuclear pleomorphism coarse. The tumor may even be primarily com- Numerous and abnormal mitoses Macronucleoli posed of glands with lumens (Fig. 10.11). In the Clear cell componenta myoinvasive component of the tumor the Psammoma bodiesa glands have a gaping appearance (Fig. 10.23). a Psammoma bodies are present in up to one Nonspecific features found occasionally in serous 68 carcinoma. third of cases. It is the combination of a low-grade archi- tecture (papillary or glandular pattern) and composed of dense papillary aggregates of high-grade nuclear atypia that identifies serous tumor cells. In contrast to low-grade papillary carcinoma.83 The nuclei are hyperchromatic carcinoma, the papillary fronds usually are and pleomorphic with macronucleoli and many coarse, with thick fibrotic cores lined by highly mitoses (Figs. 10.11 and 10.24). Abnormal epithelial atypical cells (Fig. 10.22). Because of mitotic figures are frequent. Some nuclei are the papillary growth, serous carcinoma can lobulated with deep clefts, and, not infre- appear deceptively well differentiated in the quently, the chromatin appears smudged. The endometrium, although these are high-grade, cells of serous carcinoma tend to be rounded

Figure 10.22. Serous carcinoma. In this field the tumor forms multiple coarse papillae. 230 10. Endometrial Carcinoma

Figure 10.23. Serous carcinoma. This tumor shows gaping glands and papillae with papillary tufts. There is marked nuclear pleomorphism, and the high nuclear grade is a constant feature of serous carcinoma.

Figure 10.24. Serous carcinoma. At high magnification the cells show nuclear grade 3 changes. The nuclei are large, with macronucleoli, a high nuclear/cytoplasmic ratio, and numerous mitoses with abnormal forms. Malignant Neoplasms—Classification, Grading, and Staging of the Tumor 231 and often have abundant granular, eosinophilic it is the high nuclear grade that is most useful cytoplasm. Areas displaying the features of for identifying this neoplasm. An occasional serous carcinoma but containing clear cells, that tumor may show intermediate features between is, clear cell carcinoma, are seen in up to one low-grade villoglandular and serous carcinoma third of cases (see later, Clear Cell Carcinoma). with papillary architecture showing somewhat Because these tumors always contain high- coarser papillae and grade 2 nuclei (Fig. 10.26). grade nuclei, nuclear grading as recommended If a tumor with increased architectural and cyto- by FIGO is not relevant. The diagnosis of logic atypia does not fulfill all the criteria of serous carcinoma itself establishes the presence serous carcinoma, however, it should be classi- of a highly malignant carcinoma. fied as a grade 2 endometrioid carcinoma. To Several other histologic subtypes of endome- avoid confusion between these papillary tumors trial carcinoma, including low-grade endometri- with different cytologic features and prognosis, oid tumors, also may show papillary growth, we recommend not using the term “papillary” so-called villoglandular pattern.3;15;37;58;68;84 The as a diagnostic term for any type of endometrial papillary endometrioid tumors have low- to carcinoma. moderate-grade nuclei (see earlier, Grading) Immunohistochemical analysis can assist in and often grow in long, slender branching pap- the recognition of serous carcinoma and dis- illary fronds (Figs. 10.12, 10.25, and 10.26). The tinction from endometrioid carcinoma. Serous lining cells are columnar and do not form pap- carcinomas usually show diffuse, intense reac- illary tufts. In contrast, the papillae in serous tivity for p53 protein which correlates with p53 carcinoma tend to be small and coarse, although gene mutations which are found in more than

Figure 10.25. Well-differentiated villoglandular seen in serous carcinoma. Nuclei are round to oval adenocarcinoma. The nuclei lining the papillae have and exhibit minimal pleomorphism. Also present is grade 1 features, in contrast to the high nuclear grade stromal desmoplasia. 232 10. Endometrial Carcinoma

Figure 10.26. Moderately differentiated adenocar- Inset: The nuclei show considerable atypia but do cinoma with papillary features. Typical (“endometri- not have features of serous carcinoma, indicating a oid”) adenocarcinoma shows a papillary pattern. FIGO grade 2 carcinoma.

90% of serous carcinomas (Fig. 10.27).85–88 ting specimens only with no residual serous In addition, they have a high proliferation carcinoma in the subsequent hysterectomy.100 index reflected in diffuse reactivity for Ki-67 Serous carcinoma with invasion of less than protein in the nuclei.89 Generally, serous carci- 1.0cm has been termed “minimal uterine serous noma lacks estrogen and progesterone recep- carcinoma (MUSC.)101 Even with no or minimal tors.89–91 Low-grade endometrioid carcinomas, myometrial invasion, serous carcinoma can dis- in contrast, have relatively low prolifera- seminate widely.11;15;68;79;80;84;96;101–106;106a tion indices, do not express p53, and show Patients with serous carcinoma often either strong reactivity for estrogen and progesterone have peritoneal spread at the time of hysterec- receptors.90–92 tomy or relapse with peritoneal carcinomatosis, Serous carcinoma is a highly malignant form so in this regard they behave like their ovarian of endometrial carcinoma that usually occurs in counterparts. Occasional cases also appear to older women, with a median age in the seventh be multifocal, with associated ovarian serous decade.15;68;82;84;93;94 Rare cases are seen in carcinoma at the time of diagnosis. Because of younger women, however.95–97 These tumors their aggressive behavior, even when superficial often invade the myometrium deeply and per- or confined to a polyp, mixed tumors with both meate lymph-vascular spaces.Not uncommonly, endometrioid and serous patterns in which at serous carcinoma is minimally invasive and may least 25% of the tumor contains a serous even be confined to an endometrial polyp.98;99 component should be classified as serous Serous carcinoma also can be limited to curet- carcinoma. Malignant Neoplasms—Classification, Grading, and Staging of the Tumor 233

Figure 10.27. Serous carcinoma, p53 immunohistochemistry. Diffuse, strong reactivity for p53 protein is a characteristic of most serous carcinomas.

Clear Cell Carcinoma cinoma, and, as mentioned earlier, this tumor pattern may be admixed with serous carci- In clear cell carcinoma, the majority of the cells noma.68 The similarity with serous carcinoma have clear, vacuolated cytoplasm because of the is reflected in the high nuclear grade of presence of glycogen.3;8;12;21;22;25;37 This tumor can many clear cell tumors (Fig. 10.28). Especially have a variety of growth patterns, including in the papillary and solid patterns, the nuclei tubular, cystic, papillary, and solid (Figs. 10.28 generally are pleomorphic with marked and 10.29). The stroma and papillary cores of atypia, although the hyalinized stroma of clear clear cell carcinoma typically have hyalinized cell carcinoma is a distinguishing feature. stroma. In some cases the clear cytoplasm is Macronucleoli and abnormal mitotic figures inconspicuous and the nuclei bulge into the usually are present. Occasionally, these tumors, gland lumens, forming so-called hobnail cells like serous carcinoma, contain psammoma (Fig. 10.29). Clear cell carcinoma also occurs in bodies. Clear cell carcinoma is another aggres- the ovary, cervix, and vagina. In the ovary or sive variant of endometrial cancer.8;12;107 Like cervix, clear cell tumors in older women have serous carcinoma, it tends to occur in older patterns similar to those found in the patients and has a high relapse rate.25;107;108 endometrium, but in the vagina and cervix of Although clinically similar to serous carci- women exposed to in utero diethylstilbstrol noma, high-grade clear cell carcinoma less fre- (DES), the tubulocystic pattern predominates. quently demonstrates the diffuse strong reac- Many examples of clear cell carcinoma tivity for p53 protein that is seen in serous appear to be closely related to serous car- carcinoma.89 Figure 10.28. Clear cell carcinoma. Papillary pat- marked enlargement, irregular outlines, smudged tern in which the cells have clear, vacuolated cyto- chromatin, and prominent nucleoli. plasm. Inset:The nuclei are high grade (grade 3) with

Figure 10.29. Clear cell carcinoma. Tubular pattern lumens (arrows). The hyalinized stroma is an occa- in which clear cytoplasm is less conspicuous, and the sional feature of clear cell carcinoma. nuclei bulge, hobnail fashion, into the glandular Malignant Neoplasms—Classification, Grading, and Staging of the Tumor 235

Clear cell carcinoma should be differentiated nucleoli.117 These neoplasms may show neu- from secretory carcinoma or endometrioid car- roendocrine differentiation.118–121 Some tumors cinoma with clear cell/secretory change. In con- with a small cell component are admixed with trast to the high nuclear grade of clear cell typical adenocarcinoma.117 The large-cell carcinoma, other carcinomas with clear or pale variant is composed of sheets of large epithelial cytoplasm lack high nuclear grade and do not cells that have a moderate amount of cytoplasm show the consistent growth patterns of clear and large vesicular nuclei with prominent cell carcinoma including papillary growth with nucleoli. hyalinized stroma cores, hobnail cells, and tubu- Rarely, carcinomas show unusual patterns of locystic arrangements. Some of these carcino- differentiation, such as osteoclastic-type giant mas with lower grade nuclei tend to be solid, cells or trophoblast.69;122 Choriocarcinoma of the containing cells with clear cytoplasm that may endometrium may be found in postmenopausal represent squamous differentiation. If an women, usually resulting from dedifferentiation endometrial carcinoma with clear cells does not of a poorly differentiated carcinoma.122–127 Other show the typical growth patterns with high rare histologic types include glassy cell carci- nuclear grade, it should be classified as an noma,128;129 oxyphilic variant of endometrioid endometrioid tumor with secretory change. carcinoma,130 signet-ring cell carcinoma,131 A rare case of apparent secretory carcinoma lymphoepithelioma-like carcinoma,132 and giant may show foci with high-grade nuclei, suggest- cell carcinoma.133 Most of these are high- ing that clear cell carcinoma may be present, so grade malignancies that occur in older patients. it is important to thoroughly sample any low- Other rare tumors include primary yolk sac grade tumor with clear cytoplasm to determine tumor,134;135 a-fetoprotein–secreting hepatoid if grade 3 nuclei and a more aggressive neo- adenocarcinoma associated with endometrioid plasm may be present. carcinoma,136 and endometrioid carcinoma associated with Ewing sarcoma/peripheral primitive neuroectodermal tumor.137–141 Wilms Rare Histologic Patterns tumor also may rarely occur as a primary uterine Primary squamous carcinoma of the endo- neoplasm.142;143 metrium does occur, but is rare.109–112 To diag- On occasion an endometrial neoplasm is nose this entity, it is necessary to exclude a difficult to classify. Small tissue samples or primary cervical carcinoma (see later, Endome- extensive necrosis may limit the histologic trial Versus Endocervical Carcinoma). Primary evaluation. Immunohistochemistry has little verrucous squamous cell carcinoma also has utility for subclassification of primary endome- been reported to arise in the endometrium.113 trial carcinomas, although keratin reactivity can Recently, there have been several reports help determine whether or not a malignant of transitional cell carcinomas of the endome- tumor is a carcinoma. The one exception is the trium that are usually admixed with other pat- strong immunoreactivity for p53 that is often terns of endometrial carcinoma.114;115 seen in serous carcinoma. Undifferentiated carcinomas show no evi- dence of glandular or squamous differentia- Mixed Mesodermal Tumors tion.116 They account for fewer than 2% of primary endometrial carcinomas. Some undif- The distinction between a malignant mesoder- ferentiated carcinomas have features resem- mal mixed tumor (MMMT) or carcinosarcoma bling small cell carcinoma of the lung, whereas and high-grade carcinoma may at times be dif- others are composed of large cells that range ficult. In MMMT the epithelial element usually from polygonal to spindle in shape. Undifferen- has features of high-grade endometrial adeno- tiated carcinoma often has a solid growth carcinoma, often serous or clear cell carcinoma, pattern with extensive necrosis. With the small although endometrioid patterns, including car- cell pattern, the neoplastic cells have scant cyto- cinoma with squamous differentiation, may be plasm and hyperchromatic nuclei with indistinct found. Clinicopathologic, immunohistochemi- 236 10. Endometrial Carcinoma

Table 10.4. International Federation of Gynecology and Obstetrics (FIGO) staging of corpus cancer. Stage Description

Ia G123 Tumor limited to endometrium Ib G123 Invasion of less than half of the myometrium Ic G123 Invasion of more than half of the myometrium IIa G123 Endocervical glandular involvement only IIb G123 Cervical stromal invasion IIIa G123 Tumor invades serosa and/or adenexae and/or positive peritoneal cytology IIIb G123 Vaginal metastases IIIc G123 Metastases to pelvic and/or paraaortic lymph nodes IVa G123 Tumor invasion of bladder and/or bowel mucosa IVb Distant metastases including intraabdominal and/or inguinal lymph node

G, Grade. cal, and molecular genetic studies now indicate ment of the cervix, and peritoneal cytology that MMMT represents a variant of carcinoma (Table 10.4).27 (sarcomatoid carcinoma), yet it is important to Endometrial carcinoma confined to the identify a sarcomatous component because corpus is stage I, and about three quarters of all MMMT is even more aggressive than other primary endometrial carcinomas are stage I. high-grade carcinomas. In such cases, ascertain- Based on the presence and amount of myome- ing the presence of a malignant stromal com- trial invasion, carcinomas are subdivided into ponent, a feature discussed in the next chapter, IA when tumor is limited to the endometrium, becomes important. Often, the sarcomatous IB when tumor invades less than one half the component is readily identified, especially myometrium, and IC when tumor invades more when heterologous elements, such as cartilage than one half the myometrium. With cervical or rhabdomyoblasts, are present. In many cases, invasion the tumor is stage II. Stage II is subdi- however, the malignant stroma is composed vided into IIA when there is only endocervical only of spindle cells, identified as malignant by glandular involvement, and IIB when there is their cellularity,nuclear atypia, and high mitotic cervical stromal invasion by endometrial carci- activity. Typically, the sarcomatous component noma.As this assessment is based on the micro- is intimately associated with, yet distinct from, scopic findings in the hysterectomy specimen, the carcinomatous component. In these cases, fractional dilation and curettage, with curettage keratin immunohistochemical stains can be specimens of the endometrium and endocervix helpful for distinguishing the carcinomatous submitted separately to differentiate stage I from the sarcomatous component, as the sarco- and stage II, is no longer necessary. In fact, matous elements are negative or only focally the office-based endometrial biopsy often positive for keratin. establishes the diagnosis and the patient is spared further endometrial evaluation prior to Staging hysterectomy. Although staging is based on surgical–patho- In 1988 FIGO revised its staging system from logic analysis of the hysterectomy specimen, one that was strictly based on clinical evalua- accurate histologic evaluation of biopsies is tion to one based on combined surgical and important, as grade and histologic findings histopathologic findings.29 Staging of endome- influence the planning for surgery and whether trial carcinoma (corpus cancer) now employs a surgical staging and lymph node sampling is variety of histologic risk factors, including necessary. Furthermore, with a high-grade neo- grade, depth of myometrial invasion, involve- plasm, a gynecologist should request the assis- Malignant Neoplasms—Classification, Grading, and Staging of the Tumor 237 tance of a gynecologic oncologist in order that not show the prominent nests of morular appropriate staging and therapy are performed. growth with squamous differentiation confined to gland lumens that are very frequent in Endometrial Versus Endocervical endometrial adenocarcinoma. Carcinoma Added evidence in favor of an endometrial primary carcinoma is the presence of associated At times it is difficult to determine whether car- hyperplasia. Stromal foam cells also would cinoma in an endometrial biopsy involves the suggest a primary tumor of the endometrium. endometrium, the endocervix, or both sites. On the other hand, the presence of cervical Assigning a primary site is important, because intraepithelial neoplasia or endocervical ade- endometrial carcinoma confined to the corpus nocarcinoma in situ, as well as transitions to is managed differently from endocervical carci- normal endocervical epithelium, supports the noma. The usual therapy for endometrial diagnosis of cervical carcinoma. In addition, in carcinoma is extrafascial total abdominal hys- a fractional curettage, if more tumor is present terectomy and bilateral salpingo-oophorec- in the endometrial fraction, it is more likely that tomy. In contrast, surgical management of the neoplasm is arising in the endometrium. invasive endocervical carcinoma is a radical Conversely, if the endocervical fraction con- hysterectomy and pelvic lymph node dissec- tains the bulk of the tumor, the primary tumor tion, an operation with potential for greater is most likely in the endocervix. morbidity. Immunohistochemical and in situ hybridiza- If the tumor in the endometrial biopsy has tion studies can help to distinguish endometrial the typical endometrioid pattern and the clini- from endocervical primary tumors. Recent cal information, such as older age and uterine studies indicate that estrogen and especially enlargement, is consistent with an endometrial progesterone receptor protein is reactive in cancer, there is little question regarding the endometrioid type carcinoma, while cervical primary site. In contrast, if the tumor has a adenocarcinoma is not.144–147 In addition, detec- pattern that is more commonly found in the tion of human papilloma virus (HPV) by in situ cervix, such as mucinous carcinoma, or carci- hybridization is seen in endocervical but not noma with extensive squamous differentiation, endometrial carcinomas.144 The combination of then determination of the primary site is more hormone receptor and HPV in situ analysis difficult. appears to be very useful in this differential Squamous differentiation can be prominent diagnosis. Preliminary data suggest that strong in primary endometrial carcinoma and diffuse expression of p16, which occurs in close adenosquamous carcinoma is a well-recognized to 100% of cervical squamous and adenocarci- variant of endocervical carcinoma. Conse- nomas, is either absent or only patchy in quently, when curettage specimens show a endometrioid carcinoma.148;149 mixture of glandular and squamous compo- Other immunohistochemical stains have nents, the differential diagnosis often includes been applied although the results suggest that endometrial and endocervical primary sites. these are less specific for differentiating these Adenocarcinoma with a squamous component two primary sites. For instance, vimentin fre- at each site has different histologic features. In quently stains endometrial carcinomas whereas endometrial carcinoma, the squamous element cervical adenocarcinomas are nega- often is intimately associated with glands, tive.150;145;146;151 Conversely, carcinoembryonic appearing to arise in and differentiate from antigen (CEA) often is present in endocervical the glands. The glandular element typically carcinomas but is less common in endometrial predominates in endometrial carcinomas. In primary tumors.146;151–154 The majority of endo- contrast, in endocervical adenosquamous cervical carcinomas show abundant, diffuse carcinoma, the squamous element usually pre- intracellular CEA reactivity, whereas only dominates and glandular differentiation is about half of endometrial carcinomas contain subtle. Furthermore, the cervical neoplasms do CEA, and this reactivity is usually focal and at 238 10. Endometrial Carcinoma the luminal surface. This immunostaining primary ovarian epithelial carcinoma.158;159 In pattern for CEA is not useful for endometrial particular, serous and endometrioid carcinomas mucinous carcinoma from endocervical adeno- are common in the ovary, and these tumors are carcinoma as both of these tumor types tend to histologically identical to their endometrial be CEA positive. Differential cytokeratin stain- counterparts. Despite these difficulties, the ing for cytokeratin 7 and cytokeratin 20 is not question of ovarian metastasis versus an useful in distinguishing between these primary endometrial primary site in a biopsy or curet- sites.151 Histochemical stains for mucin have ting is infrequent. This differential diagnosis little value in determining the primary site, is most likely to occur when the biopsy shows however, because endometrial adenocarcinoma a serous carcinoma, usually with psammoma often shows at least focal cytoplasmic mucin bodies. In such cases it may be impossible to and some endocervical adenocarcinomas show exclude an ovarian primary site, but metastatic little cytoplasmic mucin. tumor presenting in biopsies is extremely infre- If the morphologic features do not clearly quent compared to a primary endometrial establish the primary site, clinical information serous carcinoma. Furthermore, cases with often resolves the problem. The presence or involvement of the endometrium and ovary absence of gross tumor involving the cervix is often appear to represent synchronous primary important information. If tumor clinically tumors rather than metastases. Metastatic involves the cervix, then the issue of primary lesions should be considered, however, when site is largely irrelevant. The tumor can be the amount of tumor is relatively scant and is managed as a cervical neoplasm.27 If the tumor admixed with more abundant fragments of is occult, information on age and menopausal benign, nonhyperplastic endometrium. Also, status can be helpful. Endometrial carcinoma clinical history of an adnexal mass should alert usually occurs in older patients with an average the pathologist to the possibility of primary age of 55 to 60 years. Endometrial carcinoma ovarian neoplasia. is unusual before the menopause unless the Metastatic carcinoma from other sites, patient has a predisposing condition, such as although rare, can be problematic. Occasion- the Stein–Leventhal syndrome. Endocervical ally, colon carcinoma may involve the adenocarcinoma, in contrast, has a much wider endometrium and closely simulate a uterine age range, with many tumors occurring in primary tumor, having an “endometrioid” premenopausal women. The average age is pattern (Fig. 10.30). In such cases a history of a between 45 and 55 years. known extrauterine primary tumor or a mass lesion in the bowel can be essential for estab- Metastatic Carcinoma lishing the correct diagnosis. Colon adenocarci- noma may have a so-called garland-like The most common extrauterine carcinomas arrangement of glands surrounding areas of that metastasize to or extend into the “dirty” necrosis composed of cellular debris endometrium arise in the ovary, breast, or gas- that helps in recognizing the tumor. The glands trointestinal tract, especially the colon.155–157 of metastatic colon carcinoma have a sharp Metastases from other primary sites are rare, luminal border. Endometrial carcinoma, on the but on occasion a tumor from the stomach, pan- other hand, typically does not show much creas, or other visceral site metastasizes to the necrosis in glandular lumens, and the cells have endometrium. It is very unusual for tumors an ill-defined, fuzzy luminal border in routine from these sites to present with abnormal sections. Mucin stains have little utility in deter- vaginal bleeding and to be diagnosed first in an mining the primary site, as endometrial carci- endometrial biopsy. noma can have abundant cytoplasmic mucin. Separating metastatic ovarian carcinoma Immunohistochemical stains for CEA may be from an endometrial primary tumor can be helpful in establishing whether the tumor is especially difficult, as virtually all patterns of metastatic from the gastrointestinal tract or is primary endometrial carcinoma can occur in the primary tumor in the endometrium. In Clinical Queries and Reporting 239

Figure 10.30. Metastatic colon carcinoma. Irregular glands in markedly desmoplastic stroma suggests a glands with sharply delimited luminal borders are metastasis from a gastrointestinal primary.Also, the haphazardly distributed in a reactive, fibroblastic small nests of malignant cells (arrow) are not stroma. This pattern can closely mimic an endome- typical of endometrial carcinoma. trial primary, but the haphazard distribution of the

general, colon primary tumors are diffusely epithelial origin of the cells. Also, an immunos- positive for CEA while endometrial carcino- tain for gross cystic disease fluid protein-15 mas are not. Also, endometrial carcinomas would help identify the primary site of a breast usually are positive for cytokeratin 7 and nega- metastasis. Differential immunostaining for tive for cytokeratin 20,151 while metastatic colon cytokeratins 7 and 20 has no utility in the adenocarcinoma usually is strongly positive for differential diagnosis of endometrial versus cytokeratin 20 and negative for cytokeratin 7.160 breast carcinoma.161 Metastatic breast carcinoma, although rare, can be especially difficult to diagnose. These tumors typically infiltrate in solid sheets or Clinical Queries and Reporting small groups in a linear pattern, often sparing glands and diffusely invading the stroma (Fig. It is important to establish the diagnosis of 10.31). The neoplastic cells may resemble atypical hyperplasia versus well-differentiated stromal cells or inflammatory cells, lacking adenocarcinoma whenever possible. A biopsy the organoid arrangements seen in most car- diagnosis of atypical hyperplasia may be cinomas. In such cases, immunohistochemical managed medically with progestin therapy with stains for keratin and histochemical stains periodic resampling of the endometrium. This for mucin are useful for demonstrating the conservative management is possible because 240 10. Endometrial Carcinoma

Figure 10.31. Metastatic breast carcinoma. A solid matory cells, and special stains for mucin and keratin sheet of cells representing metastatic breast carci- may be needed to establish the diagnosis. The resid- noma infiltrates the endometrium. The pattern could ual glands show progestin effect with glandular be mistaken for an aggregate of stromal or inflam- atrophy secondary to therapy for breast carcinoma.

many lesions are reversible. A biopsy diagnosis fills the minimal criteria for well-differentiated of well-differentiated adenocarcinoma, in adenocarcinoma before establishing a diagno- contrast, clearly establishes the presence of sis of malignancy. If the glands are atypical but malignancy. do not clearly show features of “stromal inva- Although the criteria for distinguishing atyp- sion” as defined earlier, then the lesion is best ical hyperplasia from well-differentiated ade- classified as atypical hyperplasia.These patients nocarcinoma are well defined, the diagnosis can be managed conservatively and re- should also be placed in the appropriate clini- biopsied, with one study showing a 90% regres- cal context in equivocal cases. For example, in sion rate.162 In older postmenopausal women, younger, premenopausal patients, a conserva- atypical glands should be viewed even more tive approach is appropriate when the biopsy suspiciously for the possibility of underlying shows an atypical lesion that may represent carcinoma, and criteria for the histologic diag- well-differentiated adenocarcinoma. Studies nosis of carcinoma can be applied more liber- show that these lesions, even if they fulfill cri- ally. Most of these patients are best treated by teria for adenocarcinoma, are indolent and a total abdominal hysterectomy and bilateral reversible in up to 75% of cases with progestin salpingo-oophorectomy if they are candidates therapy.162 Thus, in the premenopausal patient for surgery. younger than 40 years of age, it is especially Once the diagnosis of endometrial adenocar- important to be certain that a lesion at least ful- cinoma is made, the gynecologist often needs References 241 information on several other aspects of the References tumor. Whenever possible, the FIGO grade of endometrial carcinoma in biopsies should be (1) Smith M, McCartney AJ. Occult, high-risk given. For instance, low-grade adenocarcinoma endometrial cancer. Gynecol Oncol 1985; frequently is confined to the endometrium or is 22:154–161. only superficially invasive of the myometrium; (2) Bokhman JV. Two pathogenetic types of extrauterine spread is unlikely. Conversely, endometrial carcinoma. Gynecol Oncol 1983; high-grade carcinoma, including aggressive his- 15:10. tologic subtypes of serous and clear cell carci- (3) Ronnett BM, Zaino RJ, Ellenson LH, noma, has greater potential for extrauterine Kurman RJ. Endometrial carcinoma. In: spread at the time of hysterectomy. If grading Kurman RJ, ed. Blaustein’s pathology of the female genital tract. 5th ed. New York: is not possible owing to limited sampling, or to Springer-Verlag; 2002: 501–559. necrosis or other distortion of the tissue, this (4) Sherman ME. Theories of endometrial car- should be noted. cinogenesis: A multidisciplinary approach. Classifying the tumor according to histologic Mod Pathol 2000; 13:295–308. subtype also is important. When the tumor has (5) Longacre TA, Hendrickson MR. Diffusely an endometrioid, villoglandular, secretory, or infiltrative endometrial adenocarcinoma: an mucinous pattern, the type of tumor has little adenoma malignum pattern of myoinvasion. clinical significance by itself once the tumor has Am J Surg Pathol 1999; 23:69–78. been assigned the appropriate histologic grade. (6) Landry D, Mai KT, Senterman MK, Perkins Squamous differentiation, too, has little clinical DG, Yazdi HM, Veinot JP, et al. Endometri- significance once the tumor is graded but may oid adenocarcinoma of the uterus with a minimal deviation invasive pattern. be relevant to note for histologic correlation Histopathology 2003; 42:77–82. with any subsequent metastases or recurrences. (7) Alberhasky RC, Connelly PJ,Christopherson On the other hand, serous and high-grade clear WM. Carcinoma of the endometrium. IV. cell carcinomas are aggressive tumors that are Mixed adenosquamous carcinoma.Am J Clin important to identify. The diagnosis of these Pathol 1982; 77:655–664. tumors indicates that there is an increased risk (8) Christopherson WM, Alberhasky RC, for deep myometrial invasion and metastases. Connelly PJ. Carcinoma of the endometrium. Mixed carcinomas have at least 10% of a I. A clinicopathologic study of clear cell car- second cell type. An example would be a cinoma and secretory carcinoma. Cancer mixture of endometrioid and serous patterns. If 1982; 49:1511–1523. 25% or more of such tumor is composed of (9) Christopherson WM, Connelly PJ, Alberhasky RC. Carcinoma of the endome- serous carcinoma, then it should be classified as trium. V. An analysis of prognosticators in such because these mixed neoplasms behave patients with favorable subtypes and stage I the same as pure serous carcinoma. Otherwise disease. Cancer 1983; 51:1705–1709. it can be termed a “mixed carcinoma,” with a (10) Connelly PJ,Alberhasky RC, Christopherson note describing the different types of carci- WM. Carcinoma of the endometrium. III. noma present. Analysis of 865 cases of adenocarcinoma The amount of tumor in the specimen and and adenoacanthoma. Obstet Gynecol 1982; associated lesions such as hyperplasia or polyps 59:569–575. are potentially useful data. For example, a (11) Hendrickson M, Ross J, Eifel PJ, Cox RJ, small amount of tumor may alert the clinician Martinez A, Kempson R. Adenocarcinoma to difficulties in accurate grading. The pres- of the endometrium: An analysis of 256 cases with carcinoma limited to the uterine corpus. ence of associated hyperplasia suggests I. Pathology review and analysis of prognos- estrogenic effects that may influence the tic variables. Gynecol Oncol 1982; 13:373– method of therapy. Should the pattern suggest 392. a metastatic process, the report should clearly (12) Kurman RJ, Scully RE. Clear cell carcinoma indicate this and suggest the primary sites, if of the endometrium. An analysis of 21 cases. possible. Cancer 1976; 37:872–882. 242 10. Endometrial Carcinoma

(13) Melhem MF, Tobon H. Mucinous adenocar- copathologic study of 20 cases. Int J Gynecol cinoma of the endometrium:A clinico-patho- Pathol 1991; 10:67–78. logical review of 18 cases. Int J Gynecol (26) Kadar N, Malfetano JH, Homesley HD. Pathol 1987; 6:347–355. Determinants of survival of surgically staged (14) Ross JC, Eifel PJ, Cox RS, Kempson RL, patients with endometrial carcinoma histo- Hendrickson MR. Primary mucinous adeno- logically confined to the uterus: Implications carcinoma of the endometrium. A clinico- for therapy. Obstet Gynecol 1992; 80: pathologic and histochemical study. Am J 655–659. Surg Pathol 1983; 7:715–729. (27) DiSaia PJ, Creasman WT. Clinical gyneco- (15) Chen JL, Trost DC, Wilkinson EJ. Endome- logic oncology, 6th ed. St. Louis: Mosby-Year trial papillary adenocarcinomas: Two clinico- Book, 2002. pathological types. Int J Gynecol Pathol (28) Scully RE, Bonfiglio TA, Kurman RE, 1985; 4:279–288. Silverberg SG, Wilkinson EJ. Histological (16) Mittal KR, Schwartz PE, Barwick KW.Archi- typing of female genital tract tumours. New tectural (FIGO) grading, nuclear grading, York: Springer-Verlag; 1994. and other prognostic indicators in stage I (28a) Silverberg SG, Kurman RJ, Nogales F,Mutter endometrial adenocarcinoma with identifica- GL, Kubik-Nuch RA, Tavassoli FA. Tumours tion of high-risk and low-risk groups. Cancer of the uterine corpus. Epithelial tumours and 1988; 61:538–545. related lesions. In: World Health Organiza- (17) Wilson TO, Podratz KC, Gaffey TA, Malka- tion Classification of tumours. Pathology and sian GD, O’Brien PC, Naessens JM. Evalua- genetics of tumours of the breast and female tion of unfavorable histologic subtypes in genital organs. Tavassoli FA, Devilee P, eds. endometrial adenocarcinoma. Am J Obstet Lyon: IARC Press; 2003: 221–232. Gynecol 1990; 162:418–426. (29) Benedet JL, Bender H, Jones H, III, Ngan (18) Zaino RJ, Kurman R, Herbold D, Gliedman HY, Pecorelli S. FIGO staging classifications J, Bundy BN, Voet R, et al. The significance and clinical practice guidelines in the man- of squamous differentiation in endometrial agement of gynecologic cancers. FIGO carcinoma—Data from a Gynecologic Committee on Gynecologic Oncology. Int J Oncology Group study. Cancer 1991; Gynaecol Obstet 2000; 70:209–262. 68:2293–2302. (30) Hendrickson MR, Ross JC, Kempson RL. (19) Abeler VM, Kjorstad KE. Endometrial ade- Toward the development of morphologic cri- nocarcinoma with squamous cell differentia- teria for well-differentiated adenocarcinoma tion. Cancer 1992; 69:488–495. of the endometrium. Am J Surg Pathol 1983; (20) Abeler VM, Kjorstad KE. Serous papillary 7:819–838. carcinoma of the endometrium: A (31) Kurman RJ, Norris HJ. Evaluation of criteria histopathological study of 22 cases. Gynecol for distinguishing atypical endometrial hyper- Oncol 1990; 39:266–271. plasia from well-differentiated carcinoma. (21) Abeler VM, Kjorstad KE. Clear cell carci- Cancer 1982; 49:2547–2557. noma of the endometrium: A histopatholog- (32) Norris HJ, Tavassoli FA, Kurman RJ. ical and clinical study of 97 cases. Gynecol Endometrial hyperplasia and carcinoma. Oncol 1991; 40:207–217. Diagnostic considerations. Am J Surg Pathol (22) Webb GA, Lagios MD. Clear cell carcinoma 1983; 7:839–847. of the endometrium. Am J Obstet Gynecol (33) Kraus FT. High-risk and premalignant 1987; 156:1486–1491. lesions of the endometrium. Am J Surg (23) Dunton CJ, Balsara G, McFarland M, Pathol 1985; 9(Suppl):31–40. Hernandez E. Uterine papillary serous carci- (34) Ronnett BM, Kurman RJ. Precursor lesions noma. A review. Obstet Gynecol Survey of endometrial carcinoma. In: Kurman R, ed. 1991; 46:97–102. Blaustein’s pathology of the female genital (24) Fanning J, Evans MC, Peters AJ, Samuel M, tract. 5th ed. New York: Springer-Verlag, Harmon ER, Bates JS. Endometrial adeno- 2002: 467–500. carcinoma histologic subtypes: Clinical and (35) Lehman MB, Hart WR. Simple and complex pathologic profile. Gynecol Oncol 1989; hyperplastic papillary proliferations of the 32:288–291. endometrium: A clinicopathologic study of (25) Kanbour–Shakir A, Tobon H. Primary clear nine cases of apparently localized papillary cell carcinoma of the endometrium. A clini- lesions with fibrovascular stromal cores and References 243

epithelial metaplasia.Am J Surg Pathol 2001; (49) Mazur MT.Atypical polypoid adenomyomas 25:1347–1354. of the endometrium. Am J Surg Pathol 1981; (36) King A, Seraj IM, Wagner RJ. Stromal inva- 5:473–482. sion in endometrial carcinoma. Am J Obstet (50) Young RH, Treger T, Scully RE. Atypical Gynecol 1984; 149:10–14. polypoid adenomyoma of the uterus. A (37) Silverberg SG, Kurman RJ. Tumors of the report of 27 cases. Am J Clin Pathol 1986; uterine corpus and gestational trophoblastic 86:139–145. disease. Atlas of tumor pathology, 3rd series, (51) Iezzoni JC, Mills SE. Nonneoplastic endome- Fascicle 3. Washington, DC: Armed Forces trial signet-ring cells. Vacuolated decidual Institute of Pathology, 1992. cells and stromal histiocytes mimicking (38) Winkler B, Alvarez S, Richart RM, Crum adenocarcinoma. Am J Clin Pathol 2001; CP. Pitfalls in the diagnosis of endometrial 115:249–255. neoplasia. Obstet Gynecol 1984; 64:185– (52) Scully RE, Poulson H, Sobin LH. Interna- 194. tional Histological Classification and Typing (39) Crum CP, Richart RM, Fenoglio CM. Ade- of Female Genital Tract Tumours. Berlin: noacanthosis of the endometrium. A clinico- Springer-Verlag; 1994. pathologic study in premenopausal women. (53) Demopoulos RI, Dubin N, Noumoff J, et al. Am J Surg Pathol 1981; 5:15. Prognostic significance of squamous differ- (40) Hendrickson MR, Kempson RL. Endome- entiation in stage I endometrial adenocarci- trial epithelial metaplasias: Proliferations noma. Obstet Gynecol 1986; 68:245–250. frequently misdiagnosed as adenocarcinoma. (54) Zaino RJ, Kurman RJ, Diana KL, Morrow Report of 89 cases and proposed classifica- CP. The utility of the revised International tion. Am J Surg Pathol 1980; 4:525–542. Federation of Gynecology and Obstetrics (41) Blaustein A. Morular metaplasia misdiag- histologic grading of endometrial adenocar- nosed as adenoacanthoma in young women cinoma using a defined nuclear grading with polycystic ovarian disease. Am J Surg system. A Gynecologic Oncology Group Pathol 1982; 6:223. study. Cancer 1995; 75:81–86. (42) Clement PB, Young RH. Endometrioid car- (55) Nordstrom B, Strang P, Lindgren A, cinoma of the uterine corpus: A review of its Bergstrom R, Tribukait B. Endometrial car- pathology with emphasis on recent advances cinoma: the prognostic impact of papillary and problematic aspects. Adv Anat Pathol serous carcinoma (UPSC) in relation to 2002; 9:145–184. nuclear grade, DNA ploidy and p53 expres- (43) Andersen WA, Taylor PT, Fechner RE, sion. Anticancer Res 1996; 16:899–904. Pinkerton JAV. Endometrial metaplasia (56) Ayhan A, Taskiran C, Yuce K, Kucukali T. associated with endometrial carcinoma. Am The prognostic value of nuclear grading and J Obstet Gynecol 1987; 157:597–604. the revised FIGO grading of endometrial (44) Clement PB. Pathology of the uterine corpus. adenocarcinoma. Int J Gynecol Pathol 2003; Hum Pathol 1991; 22:776–791. 22:71–74. (45) Zaman SS, Mazur MT. Endometrial papillary (57) Alkushi A, Lim P, Coldman A, Huntsman D, syncytial change. A nonspecific alteration Miller D, Gilks B. Assessment of a novel associated with active breakdown. Am J Clin grading system for endometrial carcinoma. Pathol 1993; 99:741–745. Mod Pathol 2003; 16:180A. (46) Kaku T, Tsukamoto N, Tsuruchi N, Sugihara (58) Christopherson WM, Alberhasky RC, K, Kamura T, Nakano H. Endometrial meta- Connelly PJ. Carcinoma of the endometrium: plasia associated with endometrial carci- II. Papillary adenocarcinoma: A clinical noma. Obstet Gynecol 1992; 80:812–816. pathologic study of 46 cases. Am J Clin (47) Rorat E,Wallach RC. Papillary metaplasia of Pathol 1982; 77:534–540. the endometrium: Clinical and histopatho- (59) Daniel AG, Peters WA,III.Accuracy of office logic considerations. Obstet Gynecol 1984; and operating room curettage in the grading 64:90S–92S. of endometrial carcinoma. Obstet Gynecol (48) Sherman ME, Mazur MT, Kurman RJ. 1988; 71:612–614. Benign diseases of the endometrium. In: (60) Cowles TA, Magrina JF, Masterson BJ, Kurman RJ, ed. Blaustein’s pathology of Capen CV. Comparison of clinical and surgi- the female genital tract. 5th ed. New York: cal staging in patients with endometrial car- Springer-Verlag; 2002: 421–466. cinoma. Obstet Gynecol 1985; 66:413–416. 244 10. Endometrial Carcinoma

(61) Piver MS, Lele SB, Barlow JJ, Blumenson L. uterine corpus and cervix. New York: Paraaortic lymph node evaluation in stage I Churchill Livingstone; 1993: 181–264. endometrial cancer. Obstet Gynecol 1982; (70) Hendrickson MR, Kempson RL. Ciliated 59:97–100. carcinoma–a variant of endometrial adeno- (62) Larson DM, Johnson KK, Broste SK, carcinoma. A report of 10 cases. Int J Krawisz BR, Kresl JJ. Comparison of D&C Gynecol Pathol 1983; 2:1–12. and office endometrial biopsy in predicting (71) Gould PR, Li L, Henderson DW, Barter RA, final histopathologic grade in endometrial Papadimitriou JM. Cilia and ciliogenesis in cancer. Obstet Gynecol 1995; 86:38–42. endometrial adenocarcinomas. Arch Pathol (63) Obermair A, Geramou M, Gucer F, Denison Lab Med 1986; 110:326–330. U, Graf AH, Kapshammer E, et al. Endome- (72) Tobon H, Watkins GJ. Secretory adenocarci- trial cancer: Accuracy of the finding of a well noma of the endometrium. Int J Gynecol differentiated tumor at dilatation and curet- Pathol 1985; 4:328–335. tage compared to the findings at subsequent (73) Dawagne MP, Silverberg SG. Foam cells in hysterectomy. Int J Gynecol Cancer 1999; endometrial carcinoma. Gynecol Oncol 1982; 9:383–386. 13:67–75. (64) Nielsen AL, Thomsen HK, Nyholm HCJ. (74) Silver SA, Sherman ME. Morphologic and Evaluation of the reproducibility of the immunophenotypic characterization of foam revised 1988 International Federation of cells in endometrial lesions. Int J Gynecol Gynecology and Obstetrics grading system of Pathol 1998; 17:140–145. endometrial cancers with special emphasis (75) Tiltman AJ. Mucinous carcinoma of the on nuclear grading. Cancer 1991; 68:2303– endometrium. Obstet Gynecol 1980; 55: 2309. 244–247. (65) Zaino RJ, Silverberg SG, Norris HJ, Bundy (76) Czernobilsky B, Katz Z, Lancet M, Gaton E. BN, Morrow CP, Okagaki T. The prognostic Endocervical type epithelium in endometrial value of nuclear versus architectural grading carcinoma: A report of 10 cases with empha- in endometrial adenocarcinoma. A Gyneco- sis on histochemical methods for differen- logic Oncology Group study. Int J Gynecol tial diagnosis. Am J Surg Pathol 1980; 4: Pathol 1994; 13:29–36. 481–489. (66) Lax SF, Kurman RJ, Pizer ES, Wu L, Ronnett (77) Young RH, Scully RE. Uterine carcinomas BM. A binary architectural grading system simulating microglandular hyperplasia. A for uterine endometrial endometrioid carci- report of six cases. Am J Surg Pathol 1992; noma has superior reproducibility compared 16:1092–1097. with FIGO grading and identifies subsets (78) Zaloudek C, Hayashi GM, Ryan IP, Powell of advance-stage tumors with favorable and CB, Miller TR. Microglandular adenocarci- unfavorable prognosis. Am J Surg Pathol noma of the endometrium: A form of muci- 2000; 24:1201–1208. nous adenocarcinoma that may be confused (67) Taylor RR, Zeller J, Lieberman RW, with microglandular hyperplasia of the O’Connor DM. An analysis of two versus cervix. Int J Gynecol Pathol 1997; 16:52–59. three grades for endometrial carcinoma. (79) Lee KR, Belinson JL. Recurrence in nonin- Gynecol Oncol 1999; 74:3–6. vasive endometrial carcinoma. Relationship (67a) Scholten AN, Smit VTHBM, Beerman H, van to uterine papillary serous carcinoma. Am J Putten WLJ, Creutzberg CL. Prognostic Surg Pathol 1991; 15:965–973. significance and interobserver variablility of (80) Sherman ME, Bitterman P, Rosenshein NB, histologic grading systems form endometrial Delgado G, Kurman RJ. Uterine serous carcinoma. Cancer 2004; 100:764–772. carcinoma—a morphologically diverse neo- (68) Hendrickson M, Ross J, Eifel P, Martinez A, plasm with unifying clinicopathologic Kempson R. Uterine papillary serous carci- features. Am J Surg Pathol 1992; 16:600–610. noma. A highly malignant form of endome- (81) Lee KR, Belinson JL. Papillary serous ade- trial adenocarcinoma. Am J Surg Pathol nocarcinoma of the endometrium: A clinico- 1982; 6:93–108. pathologic study of 19 cases. Gynecol Oncol (69) Clement PB, Scully RE. Endometrial hyper- 1992; 46:51–54. plasia and carcinoma. In: Clement PB,Young (82) Carcangiu ML, Chambers JT. Uterine papil- RH, ed. Tumors and tumorlike lesions of the lary serous carcinoma—A study on 108 References 245

cases with emphasis on the prognostic sig- in uterine endometrioid carcinoma and nificance of associated endometrioid carci- endometrioid carcinoma with squamous, noma, absence of invasion, and concomitant mucinous, secretory, and ciliated cell differ- ovarian carcinoma. Gynecol Oncol 1992; 47: entiation. Hum Pathol 1998; 29:924–931. 298–305. (93) Chambers JT, Merino M, Kohorn EI, et al. (83) Demopoulos RI, Genega E, Vamvakas E, Uterine papillary serous carcinoma. Obstet Carlson E, Mittal K. Papillary carcinoma of Gynecol 1987; 69:109. the endometrium: Morphometric predictors (94) Jeffrey JF, Krepart GV, Lotocki RJ. Papillary of survival. Int J Gynecol Pathol 1996; 15: serous adenocarcinoma of the endometrium. 110–118. Obstet Gynecol 1986; 67:670. (84) Sutton GP, Brill L, Michael H, et al. Malig- (95) Woolas RP, Williams K, McCartney AJ. nant papillary lesions of the endometrium. Uterine papillary serous carcinoma in a 32- Gynecol Oncol 1987; 27:294–304. year-old with Turner’s syndrome. Gynecol (85) Lax SF, Kendall B, Tashiro H, Slebos RJ, Oncol 1994; 52:395–401. Hedrick L.The frequency of p53, K-ras muta- (96) Cirisano FD, Jr, Robboy SJ, Dodge RK, tions, and microsatellite instability differs in Bentley RC,Krigman HR,Synan IS,et al.Epi- uterine endometrioid and serous carcinoma: demiologic and surgicopathologic findings of evidence of distinct molecular genetic path- papillary serous and clear cell endometrial ways. Cancer 2000; 88:814–824. cancers when compared to endometrioid car- (86) Sherman ME, Bur ME, Kurman RJ. p53 in cinoma. Gynecol Oncol 1999; 74:385–394. endometrial cancer and its putative precur- (97) Evans-Metcalf ER, Brooks SE, Reale FR, sors: Evidence for diverse pathways of Baker SP. Profile of women 45 years of age tumorigenesis. Hum Pathol 1995; 26: and younger with endometrial cancer. Obstet 1268–1274. Gynecol 1998; 91:349–354. (87) Tashiro H, Isacson C, Levine R, Kurman RJ, (98) Silva EG, Jenkins R. Serous carcinoma in Cho KR, Hedrick L. p53 gene mutations are endometrial polyps. Mod Pathol 1990; common in uterine serous carcinoma and 3:120–128. occur early in their pathogenesis. Am J (99) McCluggage WG, Sumathi VP,McManus DT. Pathol 1997; 150:177–185. Uterine serous carcinoma and endometrial (88) Kovalev S, Marchenko ND, Gugliotta BG, intraepithelial carcinoma arising in endome- Chalas E, Chumas J, Moll UM. Loss of p53 trial polyps: Report of 5 cases, including 2 function in uterine papillary serous carci- associated with tamoxifen therapy. Hum noma. Hum Pathol 1998; 29(6):613–619. Pathol 2003; 34:939–943. (89) Lax SF, Pizer ES, Ronnett BM, Kurman RJ. (100) Aquino-Parsons C, Lim P, Wong F, Milden- Clear cell carcinoma of the endometrium berger M. Papillary serous and clear cell car- is characterized by a distinctive profile of cinoma limited to endometrial curettings in p53, Ki-67, estrogen, and progesterone FIGO stage 1a and 1b endometrial adeno- receptor expression. Hum Pathol 1998; 29: carcinoma: treatment implications. Gynecol 551–558. Oncol 1998; 71:83–86. (90) Carcangiu ML, Chambers JT, Voynick IM, (101) Wheeler DT, Bell KA, Kurman RJ, Sherman Pirro M, Schwartz PE. Immunohistochemical ME. Minimal uterine serous carcinoma: evaluation of estrogen and progesterone Diagnosis and clinicopathologic correlation. receptor content in 183 patients with Am J Surg Pathol 2000; 24:797–806. endometrial carcinoma. Part I: Clinical and (102) Carcangiu ML, Tan LK, Chambers JT. Stage histologic correlations. Am J Clin Pathol IA uterine serous carcinoma: A study of 13 1990; 94(3):247–254. cases. Am J Surg Pathol 1997; 21:1507–1514. (91) Kounelis S, Kapranos N, Kouri E, Coppola D, (103) Baergen RN,Warren CD, Isacson C, Ellenson Papadaki H, Jones MW. Immunohistochemi- LH. Early uterine serous carcinoma: Clonal cal profile of endometrial adenocarcinoma:A origin of extrauterine disease. Int J Gynecol study of 61 cases and review of the literature. Pathol 2001; 20(3):214–219. Mod Pathol 2000; 13:379–388. (104) Gehrig PA, Groben PA, Fowler WC, Jr, (92) Lax SF, Pizer ES, Ronnett BM, Kurman RJ. Walton LA, Van Le L. Noninvasive papillary Comparison of estrogen and progesterone serous carcinoma of the endometrium. receptor, Ki-67, and p53 immunoreactivity Obstet Gynecol 2001; 97:153–157. 246 10. Endometrial Carcinoma

(105) Soslow RA, Pirog E, Isacson C. Endometrial (116) Abeler VM, Kjorstad KE, Nesland JM. intraepithelial carcinoma with associated Undifferentiated carcinoma of the peritoneal carcinomatosis. Am J Surg Pathol endometrium. A histopathologic and clinical 2000; 24:726–732. study of 31 cases. Cancer 1991; 68:98–105. (106) Chan JK, Loizzi V, Youssef M, Osann K, (117) Huntsman DG, Clement PB, Gilks CB, Scully Rutgers J, Vasilev SA, et al. Significance of RE. Small-cell carcinoma of the endo- comprehensive surgical staging in noninva- metrium. A clinicopathological study of sive papillary serous carcinoma of the sixteen cases.Am J Surg Pathol 1994; 18:364– endometrium. Gynecol Oncol 2003; 90: 375. 181–185. (118) Olson N, Twiggs L, Sibley R. Small-cell carci- (106a) Slomovitz BM, Burke TW, Eifel PJ, noma of the endometrium: Light microscopic Ramondetta LM, Silva EG, Jhingran A, et al. and ultrastructural study of a case. Cancer Uterine papillary serous carcinoma (UPSC): 1982; 50:760–765. A single institution review of 129 cases. (119) Paz RA, Frigerio B, Sundblad AS, Eusebi V. Gynecol Oncol 2003; 91:463–469. Small-cell (oat cell) carcinoma of the (107) Sakuragi N, Hareyama H,Todo Y,Yamada H, endometrium. Arch Pathol Lab Med 1985; Yamamoto R, Fujino T, et al. Prognostic sig- 109:270–272. nificance of serous and clear cell adenocarci- (120) Manivel C, Wick MR, Sibley TK. Neuro- noma in surgically staged endometrial endocrine differentiation in mullerian neo- carcinoma.Acta Obstet Gynecol Scand 2000; plasms. An immunohistochemical study of a 79:311–316. “pure” endometrial small-cell carcinoma and (108) Abeler VM, Vergote IB, Kjorstad KE, a mixed mullerian tumor containing small- Trope CG. Clear cell carcinoma of the cell carcinoma. Am J Clin Pathol 1986; 86: endometrium. Prognosis and metastatic 438–443. pattern. Cancer 1996; 78:1740–1747. (121) Meydanli MM, Erguvan R, Altinok MT, (109) Simon A, Kopolovic J,Beyth Y.Primary squa- Ataoglu O, Kafkasli A. Rare case of neu- mous cell carcinoma of the endometrium. roendocrine small cell carcinoma of the Gynecol Oncol 1988; 31:454–461. endometrium with paraneoplastic membra- (110) Melin JR,Wanner L, Schulz DM, Cassell EE. nous glomerulonephritis. Tumori 2003; 89: Primary squamous cell carcinoma of the 213–217. endometrium. Obstet Gynecol 1979; (122) Pesce C, Merino MJ, Chambers JT, Nogales 53:115–119. F. Endometrial carcinoma with trophoblastic (111) Goodman A, Zukerberg LR, Rice LW, Fuller differentiation.An aggressive form of uterine AF, Young RH, Scully RE. Squamous cell cancer. Cancer 1991; 68:1799–1802. carcinoma of the endometrium: A report of (123) Deligdisch L, Kase NG, Bleiweiss IJ. eight cases and a review of the literature. Endometrial cancer in elderly women: A his- Gynecol Oncol 1996; 61:54–60. tologic and steroid receptor study. Gerontol- (112) Houissa-Vuong S, Catanzano-Laroudie M, ogy 2000; 46:17–21. Baviera E, Balaton A, Galet B, Gedeon I, (124) Kalir T, Seijo L, Deligdisch L, Cohen C. et al. Primary squamous cell carcinoma of the Endometrial adenocarcinoma with chorio- endometrium: Case history, pathologic find- carcinomatous differentiation in an elderly ings, and discussion. Diagn Cytopathol 2002; virginal woman. Int J Gynecol Pathol 1995; 27:291–293. 14:266–269. (113) Ryder DE. Verrucous carcinoma of the (125) Savage J, Subby W, Okagaki T. Adenocarci- endometrium—a unique neoplasm with long noma of the endometrium with trophoblastic survival. Obstet Gynecol 1982; 59:78S–80S. differentiation and metastases as choriocar- (114) Spiegel GW, Austin RM, Gelven PL. Transi- cinoma: A case report. Gynecol Oncol 1987; tional cell carcinoma of the endometrium. 26:257–262. Gynecol Oncol 1996; 60:325–330. (126) Tunc M, Simsek T, Trak B, Uner M. (115) Lininger RA, Ashfaq R, Albores-Saavedra J, Endometrium adenocarcinoma with chorio- Tavassoli FA. Transitional cell carcinoma of carcinomatous differentiation: A case report. the endometrium and endometrial carci- Eur J Gynaecol Oncol 1998; 19:489–491. noma with transitional cell differentiation. (127) Black K, Sykes P, Ostor AG. Trophoblastic Cancer 1997; 79:1933–1943. differentiation in an endometrial carcinoma. References 247

Aust N Z J Obstet Gynaecol 1998; 38: endometrioid carcinomas associated with 472–473. Ewing sarcoma/peripheral primitive neuro- (128) Arends J, Willebrand D, Gans HJD, Swaen ectodermal tumor. Int J Gynecol Pathol GJV, Bosman FT. Adenocarcinoma of the 2000; 19:127–132. endometrium with glassy cell features— (140) Sorensen JB, Schultze HR, Madsen EL, Immunohistochemical observations.Histopa- Holund B. Primitive neuroectodermal thology 1984; 8:873–879. tumor (PNET) of the uterine cavity. Eur J (129) Christopherson WM, Alberhasky RC, Obstet Gynecol Reprod Biol 1998; 76:181– Connelly PJ. Glassy cell carcinoma of the 184. endometrium. Hum Pathol 1982; 13:418–421. (141) Fraggetta F, Magro G, Vasquez E. Primitive (130) Pitman MB, Young RH, Clement PB, neuroectodermal tumour of the uterus with Dickersin GR, Scully RE. Endometrioid focal cartilaginous differentiation. Histo- carcinoma of the ovary and endometrium, pathology 1997; 30:483–485. oxyphilic cell type: A report of nine cases. Int (142) Bittencourt AL, Britto JF, Fonseca LEJ. J Gynecol Pathol 1994; 13:290–301. Wilms’ tumor of the uterus: The first report (131) Mooney EE, Robboy SJ, Hammond CB, of the literature. Cancer 1981; 47:2496–2499. Berchuck A, Bentley RC. Signet-ring cell (143) Muc RS, Grayson W, Grobbelaar JJ. Adult carcinoma of the endometrium: A primary extrarenal Wilms tumor occurring in the tumor masquerading as a metastasis. Int J uterus. Arch Pathol Lab Med 2001; 125: Gynecol Pathol 1997; 16:169–172. 1081–1083. (132) Vargas MP,Merino MJ. Lymphoepithelioma- (144) Staebler A, Sherman ME, Zaino RJ, Ronnett like carcinoma: An unusual variant of BM. Hormone receptor immunohistochem- endometrial cancer.A report of two cases. Int istry and human papillomavirus in situ J Gynecol Pathol 1998; 17:272–276. hybridization are useful for distinguishing (133) Jones MA, Young RH, Scully RE. Endome- endocervical and endometrial adenocarcino- trial adenocarcinoma with a component of mas. Am J Surg Pathol 2002; 26(8):998–1006. giant cell carcinoma. Int J Gynecol Pathol (145) Kamoi S, AlJuboury MI, Akin MR, Silver- 1991; 10:260–270. berg SG. Immunohistochemical staining in (134) Joseph MG, Fellows FG, Hearn SA. Primary the distinction between primary endometrial endodermal sinus tumor of the and endocervical adenocarcinomas: Another endometrium. A clinicopathologic, immuno- viewpoint. Int J Gynecol Pathol 2002; 21: cytochemical, and ultrastructural study. 217–223. Cancer 1990; 63:297–302. (146) McCluggage WG, Sumathi VP,McBride HA, (135) Ohta M, Sakakibara K, Mizuno K, Kano T, Patterson A. A panel of immunohistochemi- Matsuzawa K, Tomoda Y, et al. Successful cal stains, including carcinoembryonic treatment of primary endodermal sinus antigen, vimentin, and estrogen receptor, aids tumor of the endometrium. Gynecol Oncol the distinction between primary endometrial 1988; 31:357–364. and endocervical adenocarcinomas. Int J (136) Hoshida Y, Nagakawa T, Mano S, Taguchi K, Gynecol Pathol 2002; 21:11–15. Aozasa K. Hepatoid adenocarcinoma of the (147) Zhang X, Lin Z, Lee ES, Kim I. Immuno- endometrium associated with alpha–fetopro- histochemical profiles of endometrial and tein production. Int J Gynecol Pathol 1996; endocervical adenocarcinomas. Mod Pathol 15:266–269. 16[217A]. 2003. (137) Daya D, Lukka H, Clement PB. Primitive (148) Ansari-Lari MA, Staebler A, Ronnett BM. neuroectodermal tumors of the uterus—A Distinction of endocervical and endometrial report of four cases. Hum Pathol 1992; 23: adenocarcinomas: p16 expression correlated 1120–1129. with human papillomavirus (HPV) DNA (138) Hendrickson MR, Scheithauer BW.Primitive detection by in situ hybridization (ISH). Mod neuroectodermal tumor of the endometrium: Pathol 2003; 16:180A. Report of two cases, one with electron micro- (149) McCluggage WG, Jenkins D. p16 immunore- scopic observations. Int J Gynecol Pathol activity may assist in the distinction between 1986; 5:249–259. endometrial and endocervical adenocarci- (139) Sinkre P, Albores-Saavedra J, Miller DS, noma. Int J Gynecol Pathol 2003; 22:231– Copeland LJ, Hameed A. Endometrial 235. 248 10. Endometrial Carcinoma

(150) Dabbs DJ, Geisinger KR, Norris HT. Inter- clinicopathologic study of 63 cases. Cancer mediate filaments in endometrial and endo- 1982; 50:2163–2169. cervical carcinomas. The diagnostic utility of (157) Mazur MT, Hsueh S, Gersell DJ. Metastases vimentin patterns. Am J Surg Pathol 1986; to the female genital tract. Analysis of 325 10:568–576. cases. Cancer 1984; 53:1978–1984. (151) Castrillon DH, Lee KR, Nucci MR. Distinc- (158) Ulbright TM, Roth LM. Metastatic and inde- tion between endometrial and endocervical pendent cancers of the endometrium and adenocarcinoma: An immunohistochemical ovary: A clinicopathologic study of 34 cases. study. Int J Gynecol Pathol 2002; 21:4–10. Hum Pathol 1985; 16:28–34. (152) Cohen C, Shulman G, Budgeon LR. Endo- (159) Eifel P, Hendrickson M, Ross J, Ballon S, cervical and endometrial adenocarcinoma: Martinez A, Kempson RL. Simultaneous pre- An immunoperoxidase and histochemical sentation of carcinoma involving the ovary study. Am J Surg Pathol 1982; 6:151–157. and uterine corpus. Cancer 1982; 50:163– (153) Tamimi HK, Gown AM, Kimdeobald J, Figge 170. DC, Greer BE, Cain JM. The utility of (160) Gown AM. Immunohistochemical determi- immunocytochemistry in invasive adenocar- nation of primary sites of carcinomas. J His- cinoma of the cervix. Am J Obstet Gynecol totechnol 1999; 22:209–215. 1992; 166:1655–1662. (161) Agoff SN, Grieco VS, Garcia R, Gown AM. (154) Maes G, Fleuren GJ, Bara J, Nap M. The Immunohistochemical distinction of distribution of mucins, carcinoembryonic endometrial stromal sarcoma and cellular antigen, and mucus-associated antigens in leiomyoma. Appl Immunohistochem Mol endocervical and endometrial adenocarcino- Morphol 2001; 9:164–169. mas. Int J Gynecol Pathol 1988; 7:112–122. (162) Randall TC, Kurman RJ. Progestin treatment (155) Kumar A, Schneider V. Metastases to the of atypical hyperplasia and well–differenti- uterus from extrapelvic primary tumors. Int J ated carcinoma of the endometrium in Gynecol Pathol 1983; 2:134–140. women under age 40. Obstet Gynecol 1997; (156) Kumar NB, Hart WR. Metastases to the 90:434–440. uterine corpus from extagenital cances. A