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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0b013e318234ab36
Review Articles

Strategies for Distinguishing Low-grade Endometrioid and Serous Carcinomas of Endometrium

Garg, Karuna MD; Soslow, Robert A. MD

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Author Information

Department of Pathology, Memorial Sloan Kettering Cancer Center, York Avenue, New York, NY

The authors have no funding or conflicts of interest to disclose.

Reprints: Karuna Garg, MD, Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (e-mail: gargk@mskcc.org).

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Abstract

Distinction between endometrioid and serous carcinomas of the endometrium has important prognostic and therapeutic implications. Misdiagnosing a serous carcinoma as endometrioid can have significant consequences for the patient and pathologist. Although many cases are straightforward and easy to classify, there are occasional problematic cases. This review focuses on strategies that help differentiate between low-grade endometrioid carcinoma and serous carcinoma of the endometrium. We will discuss clinical, morphologic, and immunohistochemical differences between the 2 entities and provide practical tips for practicing pathologists when confronted with this differential diagnosis.

Endometrial carcinomas are a heterogeneous group of tumors with variable morphology and clinical behavior. They are traditionally divided into types 1 and 2 as described by Bokhman (Fig. 1).1 Type 1 or endometrioid carcinomas are low-grade tumors that are associated with estrogen excess and pursue favorable clinical outcomes whereas type 2 tumors, serous carcinomas representing the prototype, are high-grade, aggressive tumors associated with poor clinical outcomes. Type 1 tumors are usually associated with microsatellite instability and mutations in PTEN, β-catenin, k-RAS, and PIK3CA.2–11 Type 2 endometrial tumors typically show Tp53 mutations and may show PIK3CA mutations.12–16 Recently, mutations in PPP2R1A have been implicated in serous carcinoma tumorigenesis.17

Figure 1
Figure 1
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Although this classification is useful, it is overly simplistic, and does not take into account tumors that may show both type 1 and type 2 features (Fig. 1). Most serous carcinomas arise de novo, but some may arise as a progression phenomenon from endometrioid carcinomas, resulting in tumors with mixed or overlapping endometrioid and serous features.18 The prognosis in these mixed tumors is dictated by the serous component, even when it constitutes as little as 10% or less of total tumor volume.18

Distinction between low-grade endometrioid and serous carcinomas of the endometrium is important for prognostic and therapeutic purposes (Table 1).

Table 1
Table 1
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Endometrial serous carcinomas frequently have extrauterine disease, particularly in the form of peritoneal dissemination in 40% to 60% of cases.19 In contrast, endometrioid carcinomas are typically confined to the uterus, less than 10% of patients have extrauterine disease and the rate of peritoneal metastases is less than 5%.19,20 Therefore, a diagnosis of serous carcinoma on endometrial biopsy or curettage results in more extensive ovarian cancer-type staging, with omentectomy. Failure to perform appropriate staging in such cases may result in understaging and therefore undertreatment of these patients.

Endometrial serous carcinomas typically show 3-year progression-free survival of 46% to 54% and 3-year disease-specific survival of 43% to 62%.21–24 In contrast, the 3 years progression-free survival and disease-specific survival for International Federation of Gynecology and Obstetrics (FIGO) grade 2 endometrioid carcinomas is 85%.25

Distinction between low-grade endometrioid and serous carcinomas in hysterectomy specimens determines need for (and type of) adjuvant therapy. Most endometrial serous carcinoma patients receive postoperative chemotherapy, whereas only selected endometrioid carcinomas may receive radiation therapy and/or chemotherapy.24

In most cases, distinction between low-grade endometrioid and serous carcinomas is straightforward. However, some endometrial tumors are difficult to classify, particularly those with mixed features.26,27 An accurate diagnosis can be particularly difficult on small endometrial biopsies.22,28 In one study, serous carcinomas were correctly diagnosed in only 76% of preoperative biopsies and half of the cases not diagnosed as uterine serous carcinoma were classified as low-grade (FIGO grade 1 to 2) endometrioid carcinomas.28 In our institution, one of the most common major discrepancies we encounter is cases of endometrial serous carcinoma that were diagnosed as complex atypical hyperplasia or FIGO grade 1 or 2 endometrioid carcinoma at another institution.

It can be particularly challenging in some cases to distinguish serous and endometrioid carcinoma in the setting of carcinosarcoma (malignant mixed Mullerian tumor) with unsampled or inapparent mesenchymal components and in patients with Lynch syndrome. The adenocarcinoma component of a carcinosarcoma is most often serous and sometimes endometrioid.29 In many cases, however, it shows overlapping features and is difficult to classify, particularly when seen in biopsy specimens where it may be unassociated with the mesenchymal component.29 We sometimes raise the possibility of carcinosarcoma in a biopsy or curettage composed of a high-grade, gland-forming tumor which we are unable to subclassify.

Patients with Lynch syndrome are at increased risk for endometrial and colon cancer, among others. Early recognition of the syndrome gives the patient and her family members an opportunity to undergo genetic counseling, screening, and appropriate surveillance measures. Like colorectal carcinoma, it appears that tumor morphology may be helpful in detection of these patients.30 Young women with Lynch syndrome are at increased risk for nonendometrioid tumors such as serous, clear cell, and carcinosarcomas.31,32 We have noticed that tumors that arise in this setting can sometimes show ambiguous morphology. Examples include gland-forming tumors that have intracellular mucin (feature of endometrioid differentiation) but very high-grade nuclei (feature of serous differentiation), or tumors with overlapping serous and clear cell or endometrioid and clear cell features. Patients with Lynch syndrome are at particular risk for lower uterine segment tumors, which can often show morphological and immunohistochemical overlap between endometrioid and endocervical carcinomas.33

Studies relating to interobserver diagnostic agreement in classification of endometrial carcinomas have shown variable results.26,27 In our study, there was good interobserver agreement between 2 gynecologic pathologists, but the agreement rates fell substantially when general surgical pathologists were included in the study.27 In another study involving high-grade endometrial carcinomas, diagnostic agreement between experienced gynecologic pathologists was poor, including some cases where there was no agreement between low-grade endometrioid and serous carcinomas.34 Therefore, this distinction can be problematic even for experienced gynecologic pathologists.

Although this review focuses on distinction between low-grade endometrioid and serous carcinomas, it is worth noting that accurate separation of FIGO grade 3 endometrioid carcinomas and serous carcinomas with solid growth can be extremely difficult. Although both are high-grade tumors, there are differences in patterns of tumor dissemination and clinical outcomes between the 2 tumor types.19,35

When confronted with an endometrial tumor with a differential diagnosis of serous carcinoma versus low-grade endometrioid carcinoma, application of the following clinical, morphologic, and immunohistochemical criteria should be helpful.

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CLINICAL FEATURES

Patients with serous and endometrioid carcinomas show clinical differences (Table 2). Endometrial serous carcinomas typically occur in older patients (>60 y age) with low body mass index.18 In contrast, low-grade endometrioid carcinoma is a disease of overweight or obese young patients.1,36

Table 2
Table 2
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Patients with breast carcinoma are prone to serous carcinoma.37,38 This may, in part, be related to tamoxifen therapy, although patients on tamoxifen can develop both uterine endometrioid and serous carcinomas. It seems that this relationship may be temporal, with a propensity for low-grade endometrioid carcinomas during therapy or early on after therapy and serous carcinomas long after cessation of tamoxifen use.37,39

Serous carcinomas may be seen in relatively younger patients in some situations including those with history of breast carcinoma,38 including patients with exposure to tamoxifen for breast cancer,39 history of pelvic radiation for cervical/rectal cancer18,40 and in patients with Lynch syndrome.31,32

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TUMOR MORPHOLOGY

Evaluation of background endometrium can be very useful in separating endometrioid and serous carcinomas. Endometrioid carcinoma typically occurs in a background of complex atypical hyperplasia. Serous carcinoma, in contrast, usually arises in a background of atrophic endometrium and endometrial polyp.18,41–43 Mixed endometrioid and serous carcinomas, however, may occur in any of the above settings, but frequently show adjacent endometrial hyperplasia.18

The presence of endometrial intraepithelial carcinoma, is a useful clue to the diagnosis of serous carcinoma.43 Endometrial intraepithelial carcinoma is defined as a replacement of the endometrial surface epithelium by frankly malignant cells that cytologically resemble serous carcinoma cells (Fig. 2A). Recently, it has been proposed that endometrial serous carcinoma may show similar precursor lesions as those identified in the fallopian tube, that is, p53 signature lesion, that evolves to endometrial glandular dysplasia followed by intraepithelial serous carcinoma.44–47 The low-power architecture is not specific, because both serous and endometrioid carcinomas can be predominantly or entirely gland-forming, and both tumor types may show papillary/micropapillary architecture and foci with solid growth (Fig. 2B and C).48 In fact, serous carcinoma can sometimes simulate complex atypical hyperplasia on low power. Psammoma bodies, although rare, may also be observed in both tumor types.49

Figure 2
Figure 2
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The presence of squamous and/or mucinous metaplasia is often seen in endometrioid but not serous carcinomas (except in cases of mixed endometrioid and serous tumors), but intraluminal mucin can sometimes be present in uterine serous carcinomas. Serous carcinomas often show cell budding and detachment, and frequently display serration or slit-like spaces (Fig. 2D and E); none of these features is specific, but they are seen less often in endometrioid tumors. The cells in endometrioid carcinoma are often columnar, whereas polyhedral cells constitute most serous carcinomas. The most helpful clue to a diagnosis of serous carcinoma is the presence of diffuse high nuclear grade that is high nuclear to cytoplasmic ratio, nuclear pleomorphism, and prominent eosinophilic nucleoli. These nuclear features can sometimes be present focally in endometrioid carcinomas, but not diffusely. When one is dealing with a tumor that shows low-grade architecture (glandular) with diffuse high-grade nuclei, the presence of this architectural-cytologic dyssynchrony should immediately raise suspicion for a serous carcinoma (Fig. 2F).27 Serous carcinomas also show more brisk mitotic activity, including atypical mitoses, when compared with endometrioid tumors.

Unfortunately, occasional serous carcinomas that appear confined to endometrial polyps fail to show diffuse, easily appreciated nuclear atypia at low-power and intermediate-power magnification, which emphasizes the importance of recognizing the typical background in which serous carcinoma develops. Recognition of background atrophy, including an atrophic endometrial polyp, should encourage high-power examination of nuclear features (Fig. 3A and B).

Figure 3
Figure 3
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The pattern of myometrial invasion can be helpful in some cases. Typically, the so-called microcystic elongated and fragmented pattern of myometrial invasion is seen with endometrioid carcinomas (Fig. 4A).50 When a tumor displays the so-called gaping gland pattern of invasion (individual glands with dilated lumina present within myometrium without associated stromal response), it may be suggestive of serous differentiation, although this invasive pattern is not frequently seen (Fig. 4B).27

Figure 4
Figure 4
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Morphologic differences between serous and low-grade endometrioid carcinomas are outlined in Table 3.

Table 3
Table 3
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IMMUNOHISTOCHEMISTRY

p53

The majority of serous carcinomas show Tp53 mutations and immunohistochemistry (IHC) has been shown to be an effective means for their detection.51,52 Most Tp53 mutations in uterine serous carcinomas are missense, resulting in an altered p53 protein with a prolonged half life.53 Although variable amounts and staining intensity (from any staining to 50%) for p53 have been interpreted as evidence of p53 overexpression in the published literature,54–57 the presence of strong nuclear staining in more than 75% of tumor cells has been shown, more specifically, to correlate with the presence of Tp53 mutations.15 However, nonsense and frameshift Tp53 mutations can occasionally manifest as complete absence of p53 due to a protein product that is undetectable by IHC.15,16 Therefore, abnormal staining for p53 can be manifested in 2 forms: as strong and diffuse staining in more than 75% of tumor cells or as an absolute lack of p53 staining (p53 null) (Figs. 5A and B). Most endometrioid carcinomas show weak and patchy p53 staining (Fig. 5C) and amongst endometrioid carcinomas, p53 overexpression has been reported in a minority of FIGO grade 3 tumors, but only extremely rarely, if at all, in FIGO grade 1 and 2 carcinomas.58–60 Mixed endometrial carcinomas with serous and endometrioid components can show 2 patterns of p53 staining: strong and diffuse staining throughout tumor-like serous carcinoma or geographic overexpression (ie, overexpression confined to the serous component and not seen in the endometrioid portion).

Figure 5
Figure 5
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The data regarding the prognostic significance of p53 overexpression in endometrial carcinomas, however, is controversial. Some studies have shown p53 status to be independently predictive of clinical outcome,54,56,57,61–63 whereas in other studies p53 failed to retain prognostic significance on multivariate analysis.64,65 In our study, the presence of abnormal p53 staining in a set of morphologically ambiguous (difficult to classify) endometrial tumors correlated with adverse clinical outcomes.27 This suggests that the presence of p53 overexpression in an endometrial carcinoma, if not diagnostic of serous carcinoma, at least suggests the potential for aggressive behavior, and should be reported. Some pathologists find that p53 staining is unreliable and report the presence of p53 overexpression in normal tissue or low-grade tumors that should not have p53 mutations. We have also seen submitted cases with these staining patterns, but we have not encountered these issues in our practice.

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p16

Some studies suggest that p16 may be a good discriminator between serous and endometrioid carcinomas.66–69 The presence of diffuse moderate-to-strong p16 expression (nuclear and cytoplasmic) is a good indicator of serous differentiation (Fig. 5D). In contrast, endometrioid carcinomas show less diffuse and less intense staining for p16.69 We performed p16 stains on our set of morphologically ambiguous endometrial carcinomas and correlated these with p53 immunophenotype. We found that approximately half of the tumors that showed p53 overexpression did not display strong and diffuse p16 staining (unpublished data). This discrepancy between p16 and p53 staining may be attributable to the nature of the tumors, that is, these tumors did not display overt serous morphology. Given the small number of cases, firm conclusions cannot be drawn from these data, but it raises the possibility that p16 may not be that helpful in cases that are morphologically ambiguous.

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Imp2

Recently, Imp2 (insulin-like growth factor 2 messenger ribonucleic acid-binding protein 2) has been shown to be a sensitive and specific marker to differentiate between uterine endometrioid and serous carcinomas. In a recent study, all endometrioid adenocarcinomas showed loss of Imp2 in at least 25% of tumor cells. In contrast, there was no loss of Imp2 expression in serous carcinomas.70

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Imp3

The presence of strong and diffuse Imp3 (insulin-like growth factor 2 messenger ribonucleic acid-binding protein 3) staining was seen in endometrial serous carcinomas and patchy focal staining was seen in occasional low-grade endometrioid carcinomas.71

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MIB-1

Although there is no defined proliferation index cutoff that separates endometrioid and serous carcinomas, serous carcinomas tend to show high MIB-1 staining compared with endometrioid carcinomas. Some studies have found that a high proliferation index in endometrial carcinomas independently correlates with worse prognosis.57,72 Others have found that increased Ki-67 staining can be of prognostic significance in low-grade endometrioid carcinomas but not in serous carcinomas.73 We use MIB-1 in endometrial cancers that are p53 null; if such tumors show a very high proliferative rate, we favor a diagnosis of serous carcinoma in the appropriate clinical and morphologic context.

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PTEN

PTEN mutations are frequent in endometrioid adenocarcinomas.8 By IHC, loss of PTEN staining is detected in 30% to 50% of sporadic endometrial cancers74–77 through both genetic and epigenetic mechanisms. Many of these molecular alterations seem to be an early event in endometrial carcinogenesis, as they are frequently seen in endometrial hyperplasia. PTEN staining is typically retained in uterine serous carcinomas.68,78,79 However, the PTEN antibody can be difficult to work with,80 and rare uterine serous carcinomas show loss of PTEN expression. This may be related to other mutations in the PI3K pathway or it is possible that these serous carcinomas developed from endometrioid carcinomas.

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CTNNB1

CTNNB1 mutations have been reported in 10% to 15% of endometrioid carcinomas.7,81 By IHC, the presence of nuclear β-catenin staining can be helpful for a diagnosis of endometrioid carcinoma.6,81,82

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Estrogen and Progesterone Receptors

Uterine serous carcinomas are more often ER/PR negative compared with low-grade endometrioid carcinomas that usually show diffuse ER/PR staining.83 However, in our experience, endometrial serous carcinomas can frequently show ER expression, while staining for PR is observed less often.78

Immunohistochemical staining patterns of serous and endometrioid carcinomas are listed in Table 4. Some studies suggest that using combinations of immunohistochemical stains are most helpful. We often use a combination of p53, p16, and occasionally MIB-1 in difficult cases.

Table 4
Table 4
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STRATEGIES FOR RESOLVING DIFFICULT CASES

Endometrial serous carcinomas were first described as tumors that showed prominent papillary architecture and low-grade endometrioid carcinomas were supposed to be predominantly glandular tumors. However, our knowledge of the spectrum of morphologic features that can be seen in both tumor types has evolved, and it is now well known that serous carcinomas can be entirely gland-forming and endometrioid carcinomas can have papillary growth. Therefore, when one approaches a gland-forming endometrial tumor, the differential diagnosis must include serous carcinoma. This distinction is extremely important, as discussed above. In cases where the morphologic features still remain ambiguous, immunohistochemical stains may be helpful. Although IHC is generally useful, there may be occasional cases where stains cannot be performed or are inconclusive. In such cases, obtaining an expert opinion or consensus diagnosis may be prudent. Application of an alternative grading scheme in tumors where the cell type is not clear may also provide useful information for clinical management.

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Consensus Diagnosis

In difficult cases, it may be helpful to obtain a second opinion, preferably from a pathologist with training/experience in gynecologic pathology. In our study, a consensus morphologic diagnosis of serous carcinoma between 2 gynecologic pathologists was predictive of p53 overexpression and adverse clinical outcomes.27 However, this correlation was lost when general surgical pathologists were included in the study.

In the study by Lomo et al,26 when endometrial carcinomas were divided into type 1 versus 2, the reviewers achieved very good-to-excellent reproducibility and p53-staining pattern prediction was made with good concordance. Many of the indeterminate cases (those with lack of consensus diagnosis) showed diffuse p53 staining, suggesting that p53 IHC may be particularly helpful in cases where diagnostic agreement cannot be reached.

In another study related to interobserver reproducibility in the diagnosis of high-grade endometrial carcinomas, there were significant major diagnostic disagreements between experienced gynecologic pathologists in subtyping of high-grade endometrial carcinoma. Although this study was not designed to look at the reproducibility of diagnosis of low versus high-grade endometrial carcinoma, even this distinction proved to be challenging.34

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Application of Alternate Grading Schemes

FIGO grading is very helpful for prognostication of uterine endometrioid carcinomas.25 However, application of FIGO grading can be inaccurate in nonendometrioid tumors. If misclassified, a glandular serous carcinoma (architecture grade 1 and nuclear grade 3) would be graded as FIGO grade 2 endometrioid carcinoma, which could have profound consequences for the pathologist, treating clinician and patient. Therefore, when dealing with an endometrial tumor in which the tumor type is obscure, it may be best to avoid using FIGO grading and instead utilize an alternate grading scheme such as the binary scheme proposed by Alkushi et al.84 This grading system takes into account tumor architecture, nuclear grade and mitotic index. A tumor is classified as high grade if it shows the presence of at least two criteria of three, that is predominantly papillary or solid growth pattern, mitotic index >5/10 high-power fields or severe nuclear atypia. Low-grade tumors show no more than one of these criteria. This grading system was found to be an independent predictor of patient outcome when adjusted for stage, patient age, and, most importantly, tumor cell type. Application of this binary grading system may be particularly useful when additional studies such as IHC cannot be performed or are inconclusive. We use this grading scheme most often in difficult endometrial biopsies submitted from another institution where immunohistochemical stains cannot be performed. A diagnosis of high-grade endometrial carcinoma in such cases results in staging procedures similar to those undertaken for serous carcinoma.

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Suggested Algorithm

Distinction between low-grade endometrioid and serous carcinoma is important at the time of endometrial biopsy and at hysterectomy. However, the implications are slightly different in both settings. The following is a brief outline of our approach to problematic cases (Fig. 6).

Figure 6
Figure 6
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Endometrial Biopsy/curettage

In an endometrial biopsy or curettage, if the possibility of serous carcinoma is considered or cannot be excluded, this must be conveyed in the pathology report. The surgeon should understand that patients with this diagnosis should receive appropriate serous carcinoma-type staging procedure.

Difficult cases in this setting may be approached as follows:

1. Obtain an expert opinion or consensus diagnosis.

2. Immunohistochemical stains (IHC) may be helpful.

3. If IHC not available or inconclusive, consider using Gilks’ binary grading system.

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Hysterectomy

In a hysterectomy specimen, every effort should be made to confirm the presence or absence of a serous component, as this dictates patient therapy and prognosis.

Difficult cases in this setting may be approached as follows:

1. Consider patient factors (age, body mass index, history of breast cancer, tamoxifen, or radiation).

2. Assess tumor morphology including background endometrium.

3. Tumor dissemination pattern: serous carcinoma has a predilection for peritoneal metastasis.

4. Immunohistochemical studies as discussed.

5. Consider expert or consensus diagnosis.

6. Tumor morphology in metastatic sites. Sometimes an ambiguous tumor may show overt serous or endometrioid features when it metastasizes.

7. IHC either for histologic subtype assignment and/or prognostication and adjuvant treatment planning.

8. If histologic subtype is still uncertain, use Gilks’ binary grading scheme.

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SUMMARY

Some endometrial carcinomas can be morphologically ambiguous and show overlapping features of endometrioid and serous carcinoma. When a practicing pathologist is confronted with such a diagnostically challenging case, consideration of patient features, tumor histology, and IHC may be valuable in reaching a definitive diagnosis. It is important to remember that serous and low-grade endometrioid carcinomas can show similar growth patterns (glandular, papillary, micropapillary, solid). The presence of diffuse significant nuclear atypia should be a clue to a diagnosis of serous carcinoma. Immunohistochemical stains, including p53 and p16, can be very helpful in this distinction. Other options for resolving such cases include obtaining an expert opinion or consensus diagnosis. Finally, when the tumor type remains unclear, application of Gilks’ binary grading system may provide more useful prognostic information compared with FIGO grading. Use of these features should resolve the majority of problematic cases, although a handful of elusive cases that defy all criteria remain.

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Keywords:

endometrium; serous carcinomas; endometrioid carcinomas; morphologically ambiguous carcinomas

© 2012 Lippincott Williams & Wilkins, Inc.

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