Endometrial Clear Cell Carcinoma Research Articles

Double heterozygosity for BRCA1 and hMLH1 gene mutations in a 46-year-old woman with five primary tumors

Germline mutations in BRCA1 and BRCA2 genes predispose to hereditary breast cancer, whereas carriers of mutations in any of the mismatch repair genes (MMR; hMLH1, hMSH2, hMSH6, hPMS2) are highly susceptible to Lynch syndrome. In the present study, we describe a woman affected by unilateral breast cancer at the age of 35years. After 4years, during the follow-up she developed synchronous (and asymptomatic) endometrial cancer, ovarian carcinoma and renal clear cell carcinoma. After 7years (at age 46), the patient developed an infiltrating carcinoma of the contralateral breast and died in a few months of metastatic disease. Initial investigations led to the detection of a constitutional mutation in the BRCA1 gene. The extended genealogical tree disclosed a suspected history of colorectal carcinoma in the maternal branch. Endometrial cancer of the proband was investigated for microsatellite instability (MSI) and immunohistochemical expression of MLH1, MSH2 and MSH6 proteins. An high MSI status and lack of expression of MLH1 protein were detected. hMLH1 gene sequencing revealed the presence of a constitutional mutation, which was also found in the mother of the proband. Loss of the wild-type hMLH1 allele was detected in both breast tumors, thus suggesting that the MMR defect contributed to the development of the breast cancer.

Expression of the oncofetal protein IGF2BP3 in endometrial clear cell carcinoma: assessment of frequency and significance

Insulin-like growth factor-II messenger RNA-binding protein 3 (IGF2BP3 or IMP3) is a biomarker whose expression has been found to be a negative prognostic factor in several neoplasms including ovarian clear cell carcinoma (CCC). In this study, we analyzed the frequency and clinicopathologic significance of IMP3 expression, as assessed by immunohistochemistry and as scored using a modified H-score system, in a cohort of 50 endometrial CCCs. Cases with scores of 0 to 100, 101 to 200, and 201 to 300 were classified as negative/mildly positive (n = 17), moderately positive (n = 20), and strongly positive (n = 13), respectively. A distinctive pattern of increased staining at the myoinvasive front (relative to the main tumor) was evident in 46% of the cases with evaluable foci of myometrial invasion. Moderate/strong IMP3 staining was associated with a tumor architectural pattern that has been reported to be of poor prognostic significance: at least 10% of the tumor composed of solid architecture or individual infiltrating tumor cells (P = .01). Increasing levels of IMP3 expression showed a trend toward decreasing relapse-free survival (RFS; median survival, 75.6, 81.3, and 48.4 months for the negative/mildly, moderately, and strongly positive groups, respectively [P = .09]). However, IMP3 expression was not significantly associated with reduced overall survival or RFS in a multivariate analytic model. The finding in a subset of our cases of increased IMP3 expression at the tumoral myoinvasive front is consistent with a role for IMP3 in invasiveness, as is the trend toward reduced RFS in cases expressing IMP3 at high levels. These preliminary findings suggest that IMP3 expression may be involved in the pathogenesis of CCC and is worthy of further exploration.

Diagnostic Utility of Hepatocyte Nuclear Factor 1-Beta Immunoreactivity in Endometrial Carcinomas

Hepatocyte nuclear factor 1-beta (HNF1β) has recently emerged as a relatively sensitive and specific marker for ovarian clear cell carcinoma. The purpose of this study is to assess the diagnostic utility of this marker for endometrial clear cell carcinoma. Immunohistochemical analysis was performed on 75 endometrial tissues using a goat polyclonal antibody raised against a peptide mapping at the C-terminus of human HNF1β protein. The 75 cases included 15 clear cell carcinomas, 20 endometrioid carcinomas, 15 endometrial serous carcinomas/uterine papillary serous carcinomas, 20 cases of normal endometrium, 2 cases of clear cell metaplasia, and 3 cases of Arias Stella reaction. Staining interpretations were based on a semiquantitative scoring system, a 0 to 12+ continuous numerical scale that was derived by multiplying the extent of staining (0 to 4+ scale) by the intensity of staining (0 to 3+ scale) for each case. HNF1β expression was found to be present in a wide spectrum of tissues. Twenty-seven (54%) of the 50 carcinomas displayed at least focal nuclear HNF1β expression, including 11 (73%) of 15, 9 (60%) of 15, and 7 (35%) of 20 clear cell, serous, and endometrioid carcinomas, respectively. The average nuclear staining scores for clear cell carcinomas, endometrioid carcinomas, and serous carcinomas were 5.2, 1.4, and 4.1, respectively. Clear cell carcinomas and endometrioid carcinomas displayed statistically significant differences regarding their nuclear staining scores (P = 0.0027), but clear cell carcinomas and endometrial serous carcinomas did not (P = 0.45). The calculated sensitivity of any nuclear HNF1β expression in classifying a carcinoma as being of the clear cell histotype was 73%, whereas the specificity was 54%. Nineteen of 20 normal endometrium samples displayed at least focal nuclear expression of HNF1β, and this expression was often diffuse. The 5 cases of benign histologic mimics of clear cell carcinomas (Arias Stella reaction and clear cell metaplasia) displayed some degree of HNF1β immunoreactivity, with an average nuclear staining score of 7.3. We conclude that although HNF1β is frequently expressed in clear cell carcinomas, it should be used with caution as a diagnostic marker because of its lack of specificity. It neither distinguishes endometrial serous carcinomas from clear cell carcinomas nor clear cell carcinomas from its benign mimics. The greatest diagnostic utility of HNF1β expression may be in a supportive evidentiary role favoring clear cell carcinoma when the principal differential diagnostic consideration is endometrioid carcinoma.

Clear cell carcinomas of the mullerian system: does the pathogenesis vary depending on their nuclear grade and their association with endometriosis? An immunohistochemical analysis.

Clear cell carcinomas (CCC) of the mullerian system are considered high grade tumors, but morphologically, the cells of CCC show both low and high grade features. The aims of the current study were to categorize CCC into low and high nuclear grade types, correlate their association with endometriosis, and then observe possible variations in pathogenesis based on their expression of p53 and Ki-67. We studied 41 pure mullerian CCCs and designated each as either a high (HNG) or low (LNG) nuclear grade tumor. Morphologically, 17 (41%) CCCs were LNG and 24 (59%) were HNG. Nine (38%) HNG and 2 (12%) LNG tumors showed positive immunostaining with p53. Endometriosis was associated with 8 (47%) LNG tumors and 8 (33%) HNG CCCs. Of the 11 cases with p53 alteration, 4 (1 LNG and 3 HNG) were associated with endometriosis. Conclusions: HNG CCCs, irrespective of their association with endometriosis, have alterations of p53. In general, LNG ovarian and endometrial CCCs, irrespective of their association with endometriosis/adenomyosis, are less likely to show p53 alteration. It appears that mullerian CCCs may have variable pathogenesis depending on their nuclear grade and association with endometriosis. A larger study is needed to validate these findings.

Clear cell and papillary serous endometrial carcinomas: survival in a series of 128 cases

Clear cell (CC) and papillary serous carcinoma (PS) are histotypes at high risk of recurrence. We analyse patients' survival in a retrospective series of 128 CC and PS endometrial cancer cases. All women with a histologically confirmed CC and PS endometrial cancer who underwent primary surgery in five institutions in Lombardy, Italy, were eligible for this study. A total of 77 (60.2 %) were PS endometrial cancer cases, 45 (35.2 %) CC cases and 6 (4.6 %) cases had mixed CC and PS histotype. 54 (42 %) cases were diagnosed at stage I, 10 (8 %) at stage II, 47 (37 %) at stage III and 17 (13 %) at stage IV. Recurrence was observed in 49 cases (38.3 %). The median time at recurrence was 12 months (interquartile range 7-18). The rate of recurrence was 20.3 % in cases at stage I-lI and 56.2 % in cases at stage III-IV (p < 0.0001). With regard to the site of recurrence 24 recurrences were in and 52 outside the pelvis. Finally, the rate of recurrence was 32.6 % (14 cases) in CC cases, 43.1 % (31 cases) in PS cases and 66.7 % (4 cases) in cases with mixed histotype. The 5-year progression-free survival was 59.5 % (67.4 % for CC cases, 55.1 % for PS and mixed cases). In this study including CC and PS endometrial cancers, the 5-year survival from surgery was 72.7 % and the 5-year progression-free survival was 59.5 %.

Does the Loss of ARID1A (BAF-250a) Expression in Endometrial Clear Cell Carcinomas Have Any Clinicopathologic Significance? A Pilot Assessment

SWI/SNF chromatin-modification complexes use the energy of ATP hydrolysis to remodel nucleosomes and to affect transcription and several cellular processes. Accordingly, their loss of function has been associated with malignant transformation. ARID1A (the expression of whose product, BAF250a, a key complex component, is lost when mutated) has recently been identified as a tumor suppressor gene that is mutated in 46-57% of ovarian clear cell carcinoma (CCC). The purposes of this study are to assess the frequency of loss of BAF250a expression in endometrial CCC and whether this loss has any discernable clinicopathologic implications. 34 endometrial carcinomas with a CCC component (including 22 pure CCC, 8 mixed carcinomas with a 10% CCC component, and 4 carcinosarcomas with a CCC epithelial component), were evaluated by immunohistochemistry using a monoclonal antibody directed against the human BAF250a protein. 5 (22.7%) of the 22 pure CCC were entirely BAF250a negative, whereas the remainder showed diffuse immunoreactivity. None of 4 carcinosarcomas and only 1 (12.5%) of the 8 mixed carcinomas were BAF250a negative. There was no discernable relationship between BAF250a immunoreactivity status and tumor architectural patterns (solid, papillary or tubulocystic areas) or cell type (flat, hobnail or polygonal). Of the 22 patients with pure CCC, 14, 2, 3, and 3 were International Federation of Gynecology and Obstetrics stages 1, II, III and IV respectively. Interestingly, all 5 BAF250a negative cases were late stage [stages III or IV] as compared with 1 of 17 BAF250a positive cases (p=0.0002). Thus, 83% (5/6) of all late stage cases were BAF250a [-], as compared with 0 (0%) of the 16 early stage (I or II) cases (p=.0002). BAF250a negative and positive cases did not show any statistically significant difference regarding patient age and frequency of lymphovascular invasion or myometrial invasion. As may be anticipated from the concentration of late stage cases in the BAF250a negative group, patient outcomes were worsened in that group on univariate analysis. In conclusion, we found in this pilot assessment that 22.7% of endometrial CCC displays complete loss of BAF250a expression. There was a disproportionate concentration of BAF250a negative cases in the late stage group, with the attendant possibility of an associated worsened prognosis for those CCC patients whose tumors are BAF250a negative. These preliminary findings suggest the need for larger analyses to evaluate the prognostic significance, if any, of the loss of BAF250a expression in this rare histotype of endometrial cancer.

Expression of Tissue Factor and Heparanase in Endometrial Clear Cell Carcinoma

Earlier reports have indicated that patients with endometrial clear cell carcinoma (CCC) may have an increased risk for thromboembolic events. Tissue factor is a 47-Kd transmembrane glycoprotein that plays a critical role in platelet activation, fibrinogenesis, blood clot formation, and as such, general hemostasis. The mammalian heparanase is an endo-β-glucuronidase that can cleave heparan sulfate at specific molecular sites, resulting in structural modification of the extracellular matrix barrier, facilitating cancer cell invasion, and eventual metastasis. Recent reports indicate that heparanase may also induce tissue factor expression. The purpose of this study is to assess the clinicopathologic significance of tissue factor and heparanase expression, especially as they relate to the risk of thromboembolic events, in endometrial CCC and selected other endometrial cancers. Eighty-four endometrial carcinomas, including 17 CCC, 20 endometrial serous carcinomas, 15 grade 1 endometrial endometrioid carcinomas (EEC), 15 grade 2 EEC, 10 grade 3 EEC, and 7 mixed endometrial carcinomas with at least a 10% clear cell component (mixed CCC) were evaluated for the immunophenotypic expression of heparanase and tissue factor, and their associated frequency of thromboembolic events. Seven of the 84 patients experienced 8 thromboembolic events during the follow-up period. By multivariate analysis, the pure CCC histotype [odds ratio 5.2; 95% confidence interval (CI): 2.4523-13.6754; P=0.026] was significantly associated with an elevated risk for thromboembolic events. Tissue factor expression was present in 12 (14.28%) of the 84 endometrial carcinomas, including in 7 (41.17%) of 17 pure CCC, 2 (10%) of 20 endometrial serous carcinomas, 1 (14.3%) of 7 mixed CCC, 2 (13.3%) of 15 grade 1 EEC, and in 0% of grade 2 and 3 EEC. Tissue factor expression was significantly more likely to be seen in pure CCC than in all other cancers as a group (P=0.0018) and in all other high-grade endometrial cancers (P=0.007). By multivariate analysis, tissue factor expression was significantly associated with the risk of thromboembolic events [odds ratio 4.8 (95% CI: 1.9196-11.93), P=0.013]. Tissue factor expression was not associated with patient outcome or any other clinicopathologic parameter. Heparanase expression was present in 57 (67.8%) of the 84 endometrial carcinomas, and was significantly associated with the endometrioid histotype, but not outcome or the risk of thromboembolic events. For the overall group of all cancers, there was no significant correlation between heparanase and tissue factor expression (Spearman rank correlation, r=0.311, P=0.4). In summary, patients with endometrial CCC have an increased risk of developing thromboembolic events compared with patients with the other histotypes. This increased risk may be related, at least partially, to an increased rate of tissue factor expression in endometrial CCC.

Comparison of mTOR and HIF pathway alterations in the clear cell carcinoma variant of kidney, ovary and endometrium

Objective: The inhibitors of mTOR and HIF pathway molecules have been approved to treat advanced clear cell renal cell carcinoma (RCC). Ovarian clear cell carcinoma (OCC) and endometrial clear cell carcinoma (ECC) exhibit similar morphology and have been reported to share overlapping gene expression profiles with clear cell RCC. Our objective was to study the expression of HIF and mTOR pathway markers in OCC and ECC, and to compare the patterns with those present in clear cell RCC as a rationale for investigating potentially similar treatment approaches for OCC and ECC.

Should All Patients with Serous and Clear Cell Endometrial Carcinoma Receive Adjuvant Chemotherapy?

Uterine papillary serous carcinoma (UPSC) and uterine clear cell carcinoma (UCCC) represent two rare subtypes that have an increased risk of recurrence and worse overall survival compared with the more common endometrioid endometrial cancers. Meaningful data in the form of prospective randomized trials is lacking for both advanced and early-stage UPSC and UCCC. Data extrapolated from prospective trials in advanced endometrioid endometrial cancer and retrospective trials on early-stage UPSC suggest that adjuvant platinum and taxane-based chemotherapy may provide a survival benefit for these patients. Future trials specifically examining UPSC and UCCC are needed to elucidate the optimal treatment regimen for these patients. Given the current data, the option of chemotherapy should be considered in treatment-planning discussions for all patients with UPSC and UCCC.

Up‐regulation of L1CAM is linked to loss of hormone receptors and E‐cadherin in aggressive subtypes of endometrial carcinomas

Endometrial carcinomas (ECs) are classified into type 1 (less aggressive) and type 2 (aggressive) tumours that differ in genetic alterations. So far, reliable immunohistochemical markers that can identify patients with high risk for recurrence are rare. We have defined the expression of L1 cell adhesion molecule (L1CAM), a biomarker previously identified for EC, and compared its expression to oestrogen receptor (ER)/progesterone receptor (PR) and E-cadherin. We found that L1CAM was absent in normal endometrium and the vast majority of endometrioid ECs (type 1) but was strongly expressed in serous and clear-cell ECs, considered as type 2. 78/272 cases were identified as L1CAM-positive endometrioid ECs that were correlated with a poor prognosis. Strikingly, we observed an inverse relationship between L1CAM and ER/PR/E-cadherin expression in all ECs. In mixed ECs, composed of endometrioid (L1CAM(-) ER/PR(+) E-cadherin(+)) and clear-cell/serous (L1CAM(+) ER/PR(-) E-cadherin(-)), both phenotypes were co-expressed. In some of these cases L1CAM was up-regulated at the leading edge of the tumour, where ER/PR and E-cadherin expression were selectively lost. In EC cell lines treated with the epithelial-mesenchymal transition (EMT) inducer TGFbeta1, L1CAM and vimentin were strongly up-regulated, while E-cadherin expression was reduced. The treatment also resulted in an increased expression of the EMT transcription factor Slug and an enhanced cell invasion. Depletion of Slug by siRNA knockdown prevented both L1CAM up-regulation and enhanced cell invasion. According to our analysis, we suggest that L1CAM is a novel marker for EMT in ECs and that L1CAM-typing could identify endometrioid ECs that have type 2-like features and are at high risk for recurrence.

Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: A Gynecologic Oncology Group study

Purpose This study evaluated efficacy of single-agent trastuzumab against advanced or recurrent HER2-positive endometrial carcinoma (EC), and explored predictors for HER2 amplification. Patients and methods Eligible patients had measurable stage III, IV, or recurrent EC. There was no limit on prior therapy although total prior doxorubicin dose was limited to 320 mg/m 2. Tumors were required to have HER2 overexpression (2+ or 3+ immunohistochemical staining) or HER2 amplification (FISH HER2/CEP 17 ratio > 2.0). Trastuzumab was administered intravenously at a dose of 4 mg/kg in week 1, then 2 mg/kg weekly until disease progression. The primary endpoint was tumor response. Results Of the 286 tumors centrally screened by LabCorp, 33 (11.5%) were HER2-amplified. Three of 8 clear (38%) cell carcinomas and 7 of 25 serous carcinomas (28%) screened exhibited HER2 amplification compared with 7% (2/29) of endometrioid adenocarcinomas. HER2 overexpression was correlated with HER2 amplification ( r = 0.459; p < 0.0001). Thirty-four women were enrolled; 1 was excluded (refused treatment); and 18 had tumors with known HER2 amplification. No major tumor responses were observed. Twelve women experienced stable disease, 18 had increasing disease, and 3 were indeterminate for tumor response. Neither HER2 overexpression nor HER2 amplification appeared to be associated with progression-free survival or overall survival. Conclusion Trastuzumab as a single agent did not demonstrate activity against endometrial carcinomas with HER2 overexpression or HER2 amplification, although full planned accrual of women with HER2 amplified tumors was not achieved due to slow recruitment. Serous and clear cell endometrial carcinomas appear to be more likely to demonstrate HER2 amplification.

Wilms' tumor gene 1 (WT1) in endometrial carcinoma

Objective Wilms' tumor gene (WT1), located on chromosome 11, encodes a transcription factor that contributes to the carcinogenesis of uterine sarcomas. To expand the knowledge on the biological role of WT1 in other uterine cancers, we focused on its detection in endometrial carcinoma. Methods In total, 36 paraffin-embedded tumors were available for WT1 immunohistochemical (IHC) analysis including endometrial endometrioid carcinoma ( n = 24), serous carcinoma ( n = 9) and clear cell carcinoma ( n = 3). Three slides from different sites of the tumor were analysed. Of these tumors, 32 snap frozen tissue samples were available for RT-PCR (endometrioid carcinoma (23), serous carcinoma (7) and clear cell carcinoma (2)). To compare, WT1 expression was also evaluated by IHC in benign endometrium (12) and benign endometrial polyps (5). Results WT1 positivity was noticed in tumor cells and endothelial cells, lining the intratumoral blood vessels. Overall, 72% (26/36) of tumors stained positive for WT1. RT-PCR results showed WT1 positivity in 75% (24/32) of samples. Comparing the staining patterns of the 3 different bioptic sites, tumor heterogeneity was demonstrated in the majority (72%) of samples. Conclusion Although WT1 is expressed in a majority of endometrial carcinomas, a heterogeneous staining pattern is observed. This information is important for WT1-directed immunotherapy.

The Oncofetal Protein IMP3

Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is an oncofetal protein highly expressed in fetal tissue and malignant tumors but rarely found in adult benign tissues. The aim of this study is to determine the expression of IMP3 in benign endometrium, endometrial cancer, and its precursor lesions, trying to see whether IMP3 has any diagnostic usage. Two hundred ninety-eight endometrial samples were examined for IMP3 expression by immunohistochemistry. These included benign endometrium (n=68), atypical hyperplasia or endometrial intraepithelial neoplasia (n=35), endometrial glandular dysplasia (n=21), endometrial intraepithelial carcinoma (n=18), endometrioid carcinoma (n=70), mucinous carcinoma (n=8), serous carcinoma (n=51), clear cell carcinoma (n=12), and other malignancies (n=15). Maturational patterns in the 68 benign endometrial samples included atrophic (n=12), proliferative (n=18), secretory (n=14), menstrual (n=8), and gestational (n=16). Most of the carcinomas were histologically pure; where mixed, the second component constituted <10% of the total tumor volume. The extent and intensity of IMP3 expression was semiquantitatively determined and scored for all samples. A renal cell carcinoma with known IMP3 expression was used as positive control for each immunohistochemistry run. Among the malignant cases, IMP3 expression was predominantly found in endometrial serous carcinoma and its putative precursor lesions, with 3 (14%) of 21 endometrial glandular dysplasia, 16 (89%) of 18 serous endometrial intraepithelial carcinoma, and 48 (94%) of 51 serous carcinomas (P<0.001). In contrast, the frequency of IMP3 expression was significantly lesser in nonserous malignancies with 0 (0%) of 35, 5 (7%) of 70, 0 (0%) of 8, 3 (25%) of 12, and 5 (33%) of 15 positive expression rates in atypical hyperplasia or endometrial intraepithelial neoplasia, endometrioid, mucinous, clear cell carcinomas, and other malignancies, respectively. The IMP3 staining was universally cytoplasmic, with diffuse staining of strong intensity in serous carcinomas, whereas staining was typically patchy and of moderate or weak intensity in nonserous malignancies. Among the benign endometrial samples, decidualized endometrial stroma showed 100% positivity for IMP3. The remaining samples were negative, with the exception of a few weakly proliferative glands in 3 (5%) of 68 cases that showed focal weak immunoreactivity of IMP3. The trophoblasts in the first trimester chorionic villi were also diffusely positive, which was consistent with previously reported findings. We conclude that expression of IMP3, a newly identified cytoplasmic marker, is closely associated with type II endometrial cancer. It seems that IMP3 expression is associated with an aggressive histologic phenotype among endometrial neoplastic lesions. Strong and diffuse IMP3 expression is highly sensitive for endometrial serous and clear cell carcinomas including their putative precursor lesions. Therefore, IMP3 may be a useful diagnostic marker in the assessment of endometrial cancers and their precursor lesions, particularly when the amount of available tissue material is limited and a concern of type II cancer arises. High frequency of IMP3 expression is present in decidualized endometrial stroma of gestational endometrium and chorionic villi in early pregnancy. Although the significance of the latter finding remains unclear, the differential diagnosis between decidual changes and endometrial serous carcinoma is rarely problematic.

Endometrial glandular dysplasia and endometrial intraepithelial neoplasia

In recent decades, progress has been made in defining endometrial precancers. Endometrial intraepithelial neoplasia has been widely accepted as a precancer of type I endometrial cancer, while endometrial glandular dysplasia is a newly described entity as a probable precancer of type II cancer. As endometrial intraepithelial neoplasia has been discussed more extensively in the literature, we focus more on the recent development of endometrial glandular dysplasia in this review. Serous endometrial intraepithelial carcinoma was previously considered as a putative precancer for endometrial serous carcinoma or uterine papillary serous carcinoma. It is now considered as an early form of endometrial serous carcinoma, however. Endometrial glandular dysplasia was found to be a better candidate for precancer for both endometrial serous and clear cell carcinomas, which meets almost all recently defined criteria for precancer. Biomarkers of p53 and IMP3 are helpful for the early detection of endometrial glandular dysplasia as well as type II endometrial cancers. Two types of endometrial cancers are derived from two different precancers. Type I endometrioid carcinoma develops from endometrial intraepithelial neoplasia, while type II derives most probably from endometrial glandular dysplasia. Recognition and correct detection of endometrial glandular dysplasia may deepen our understanding and improve prevention and clinical management for type II endometrial cancer.

Endometrial Glandular Dysplasia (EmGD): morphologically and biologically distinctive putative precursor lesions of Type II endometrial cancers.

In this article, the authors briefly review the historical evolution of the various putative precursor lesions for Type II endometrial cancers, with an emphasis on the newly defined "Endometrial Glandular Dysplasia (EmGD)". The evidentiary basis for delineating serous EmGD as the most probable precursor lesions to endometrial serous carcinoma is reviewed in detail. An argument is advanced for the discontinuation of the term serous "endometrial intraepithelial carcinoma (EIC)" as a descriptor for a supposedly intraepithelial, precancerous lesion. Preliminary evidence is also presented that suggests that there is a morphologically recognizable "clear cell EmGD" that probably represents a precancerous lesion to endometrial clear cell carcinomas.

Precursors of Endometrial Clear Cell Carcinoma

The recognition of morphologically identifiable lesions which may confer an increased risk for subsequent development of an invasive malignancy offers an opportunity to investigate and better understand the molecular-genetic etiopathogenesis of the well-developed tumor, and potentially, to administer a therapeutic intervention before its development. In contrast to uterine endometrioid and serous carcinomas, very little is known about the potential precursor lesions of endometrial clear cell carcinoma (ECCC). In our routine practice, we have noted the presence of a spectrum of atypical glandular changes in the endometria adjacent to ECCC or endometrial carcinomas with a clear cell component, which on the basis of current criteria, would not qualify for any specific designation. We hypothesize that these lesions represent the earliest morphologically recognizable precursor lesions of ECCC and systematically characterize their clinicopathologic features herein. Thirty archived cases of pure ECCC (n=14) or mixed endometrial carcinomas with a >10% clear cell component (n=16) were retrieved and the "normal" endometria adjacent to the malignancies were evaluated in detail. Thirty-eight benign uteri and 30 uteri with classic endometrial endometrioid carcinoma (EEC) served as controls. All cases were reviewed in a blinded fashion. Putative precursor lesions (PPL) were searched for and identified microscopically. The lesions were typically isolated glands or surface epithelium (within an otherwise normal endometrial region) that displayed cytoplasmic clarity and/or eosinophilia with varying degrees of nuclear atypia. Twenty-seven (90%) of the 30 cases had at least 1 PPL. In contrast, PPL were identified neither in the benign uteri nor in endometrioid carcinoma control groups (P<0.001). A total of 67 foci of PPL were identified in the 27 cases with an average of 2.5 foci per case. The immunohistochemical expression of p53, mib-1, estrogen receptor (ERs), and progesterone receptor in the benign endometria, ECCC, and the PPL were evaluated on all 27 cases. The mean p53 scores for the benign endometria, PPL, and ECCC were 0, 4.5, and 6.2, respectively. Parallel values for mib-1 were 15%, 45%, and 63%. ER/progesterone receptor indices for benign endometria, PPL, and carcinoma were 90/80, 21.52/4.61, and 11/4, respectively. The PPL described herein have a morphologic and immunophenotypic profile which seems to be distinct from both the benign endometria in which they reside and the adjacent areas of ECCC. The high frequency of association of these lesions with ECCC, their frequent occurrence as isolated lesions within otherwise "benign-appearing" endometria, and their continuous spectrum of nuclear atypia from minimum (grade 1, cytologic atypia falls short of ECCC cells) to maximum (grade 3, cytologically identical to ECCC cells), argues in favor of our hypothesis that these may represent precursor lesions of ECCC. Further studies are required to conclusively define the nature of these lesions. However, such studies can only be performed if diagnostic surgical pathologists recognize, highlight, and segregate these lesions for further analysis.

Uterine malignant mixed mullerian tumors should not be included in studies of endometrial carcinoma

Objective Uterine mixed malignant mullerian tumors (MMMT) have traditionally been excluded from clinical trials of endometrial cancer because of a belief that they are more correctly included in the sarcoma category. Recently, investigators have suggested that uterine MMMTs are actually dedifferentiated epithelial tumors and should be treated as such. The current study was undertaken to compare outcomes, stage for stage, of uterine MMMT with poor prognosis endometrial adenocarcinomas. Methods Cases of MMMT from 1996 to 2004 were identified from the Tumor Registry after IRB consent was obtained. Retrospective chart review was performed. Cases were matched by age, stage, performance status, and surgical procedure to controls consisting of grade 3 endometrioid, papillary serous, and clear cell endometrial carcinomas from the same time period. Overall survival was compared using the Log-Rank test. Results 68 patients with MMMT were identified. 23 were excluded due to incomplete records. Patients with MMMT ranged in age from 51 to 95 years (mean 75.3 years). Approximately half of the patients (53%) had stage III or IV disease. Of the controls, 31 (69%) had grade 3 endometrioid, 11 (24%) papillary serous, and 3 (7%) clear cell carcinoma. Median overall survival for all patients with MMMT was significantly shorter than for controls, 18 months (range 0.5–72) versus 36 months (range 0.5–123) ( P = 0.02). Patients with early stage disease (stage I or II) had shorter median survival than controls, 26 months (range 3–7) vs. 95 months (range 4–123) ( P = 0.003). There was no difference in median survival when comparing advanced disease (stage III or IV) to matched controls, 15 months (range 0.5–70) vs. 19 months (range 0.5–100) ( P = NS). Conclusions Patients with uterine MMMT have a poorer prognosis than those patients with high grade epithelial tumors, especially for those with early stage disease. Given the discrepancy in survival, these patients should not be included in studies of endometrial carcinoma. Further investigations are necessary to identify factors to improve survival of these patients.

Skeletal carcinomatosis in endometrial clear cell carcinoma at initial presentation: a case report

Bone metastasis is frequently seen in different solid tissue malignancies. However, it is a very rare entity in endometrial cancers and most of the previous reports were localized to a single bone. To the best of our knowledge, this is the first report of a case with disseminated bone metastasis from endometrial clear cell carcinoma. A 69-year-old, multiparous woman presented with the complaint of postmenopausal bleeding. Diagnostic workup revealed endometrial clear cell carcinoma. After comprehensive surgical staging, the patient was found to be at FIGO stage IIIC. Three weeks after the operation, an intractable back pain developed. Direct graphics of the lumbosacral region were suspicious of metastasis, and further evaluation of the patient revealed metastasis in multiple bones including calvarium, thoracolumbal vertebrae, pelvic bones, costae, collum of the right femur, and trochanter major of the left femur. Bone metastasis in endometrial clear cell carcinoma may be seen at initial presentation and may involve multiple bones. Whole-body scanning with scintigraphic evaluation is a reasonable approach to evaluate the extension of the bone involvement. Further studies are needed to elucidate the true incidence and management of bone metastasis in endometrial clear cell carcinoma.

Skeletal carcinomatosis in endometrial clear cell carcinoma at initial presentation: a case report

Skeletal carcinomatosis in endometrial clear cell carcinoma at initial presentation: a case report

Adjuvant whole abdominal irradiation in clinical stages I and II papillary serous or clear cell carcinoma of the endometrium: A phase II study of the Gynecologic Oncology Group

Objectives. To evaluate outcome in patients with clinical stage I/II papillary serous (PS) or clear cell (CC) endometrial carcinoma treated with whole abdominal radiotherapy. Methods. After total abdominal hysterectomy with bilateral salpingo-oophorectomy, pelvic/para-aortic lymph node sampling, and peritoneal washings, eligible patients received radiotherapy (RT) to the abdomen (3000 cGy at 150 cGy/day) with a pelvic boost (1980 cGy at 180 cGy/day). Results. Among 21 PS patients (median age: 68 years), one refused therapy, and another received a non-protocol vaginal boost. In total, eight patients died of disease (DOD) between 9.6 and 35.2 months. Five others died due to protocol treatment (1), toxicity from subsequent chemotherapy (1), intercurrent disease (1), and unknown cause (2). Five-year progression-free survival (PFS) was 38%. Among treated patients who DOD, sites of recurrence included lung (2), lung/vagina (1), abdomen/pelvis (1), vagina (1), and abdomen (2). Among 13 CC patients (median age: 63 years), one received pelvic RT only and died with intercurrent disease. Five others died due to DOD (3), intercurrent disease (1), and unknown cause (1). Five-year PFS was 54%. Among patients who DOD, sites of recurrence included lung (1), vagina (1), and unknown (1). Grade 3/4 toxicities for both histologic groups included gastrointestinal (three grade 4; three grade 3), hematologic (one grade 4), and cutaneous (one grade 3). Conclusions. Over half of the treatment failures were within the radiation field. Systemic chemotherapy, radiosensitizing chemotherapy, or sequential radiation and chemotherapy should be considered in future adjuvant trials for these patients.