High-grade Endometrioid Adenocarcinoma Research Articles

It is not the time to abandon intraoperative frozen section in endometrioid adenocarcinoma: A large-scale, multi-center, and retrospective study.

Stage IB (deep myometrial invasion) high-grade endometrioid adenocarcinoma (EA), regardless of LVSI status, is classified into high-intermediate risk groups, requiring surgical lymph node staging. Intraoperative frozen section (IFS) is commonly used, but its adequacy and reliability vary between reports. Hence, we determined the utility of IFS in identification of high-risk factors, including deep myometrial invasion and high-grade. We retrospectively analyzed 9,985 cases operated with hysterectomy and diagnosed with FIGO stage I/II EA in postoperative paraffin section (PS) results at 30 Chinese hospitals from 2000 to 2019. We determined diagnostic performance of IFS and investigated whether the addition of IFS to preoperative biopsy and imaging could improve identification of high-risk factors. IFS and postoperative PS presented the highest concordance in assessing deep myometrial invasion (Kappa: 0.834), followed by intraoperative gross examination (IGE Kappa: 0.643), MRI (Kappa: 0.395), and CT (Kappa: 0.207). IFS and postoperative PS presented the highest concordance for high-grade EA (Kappa: 0.585) compared to diagnostic curettage (D&C 0.226) and hysteroscope (Hys 0.180). Sensitivity and specificity for detecting deep myometrial invasion were 86.21 and 97.20% for IFS versus 51.72 and 88.81% for MRI, 68.97 and 94.41% for IGE. These figures for detecting high-grade EA were 58.21 and 96.50% for IFS versus 16.42 and 98.83% for D&C, 13.43 and 98.64% for Hys. Parallel strategies, including MRI-IFS (Kappa: 0.626), D&C-IFS (Kappa: 0.595), and Hys-IFS (Kappa: 0.578) improved the diagnostic efficiencies of individual preoperative examinations. Based on the high sensitivity of IFS, parallel strategies improved the sensitivities of preoperative examinations to 89.66% (MRI), 64.18% (D&C), 62.69% (Hys), respectively, and these differences were statistically significant (p=0.000). IFS presented reasonable agreement rates predicting postoperative PS results, including deep myometrial invasion and high-grade. IFS helps identify high-intermediate risk patients in preoperative biopsy and MRI and guides intraoperative lymphadenectomy decisions in EA.

Differential Characteristics and Prognosis of PD-L1-Positive Endometrial Carcinomas: A Retrospective Chart Review.

Women with endometrial carcinomas that express PD-L1 may respond better to immunotherapy. Our aim was to investigate the differential characteristics of PD-L1–positive endometrial carcinomas and the prognostic significance of PD-L1. We performed a retrospective chart review of 231 women with endometrial carcinomas who were managed at King Hussein Cancer Center (2007–2016) and performed immunohistochemistry for MLH1, PMS2, MSH2, MSH6, p53, and PD-L1. Overall, 89 cases (38.5%) were MMR-deficient. PD-L1 was expressed in 49 cases (21.2%) and its expression was significantly associated with MLH1/PMS2 deficiency (p = 0.044) but not MSH2/MSH6 deficiency (p = 0.59). p53 was mutant in 106 cases (46.5%), and its mutation was significantly associated with MMR proficiency (p < 0.001) but not PD-L1 expression (p = 0.78). In women with endometrioid adenocarcinomas, PD-L1 expression was significantly associated with the Fédération Internationale de Gynécologie et d′Obstétrique (FIGO) grade (p = 0.008). Overall, PD-L1 expression did not significantly predict overall survival in unadjusted or adjusted analyses (p = 0.92 and 0.54, respectively). In conclusion, tumors with MLH1/PMS2 loss and high-grade endometrioid adenocarcinomas were more likely to express PD-L1 in tumor cells. Further research is required to investigate whether the presence of either characteristic signals a higher likelihood of a favorable response if immunotherapy is administered.

A "Null" Pattern of p16 Immunostaining in Endometrial Serous Carcinoma: An Under-recognized and Important Aberrant Staining Pattern.

The ability to distinguish endometrial serous carcinoma (SC) from high-grade endometrioid adenocarcinoma is of great importance given their differences in prognosis and management. In practice, this distinction typically relies upon the use of a focused immunohistochemical panel including p53, p16, and mismatch repair proteins. The expression of p16 is characteristically strong and diffuse in SCs, and weak and/or patchy in many high-grade endometrioid adenocarcinomas. Here, we report a subset of SCs that are entirely negative for p16 immunostaining, a pattern we refer to as "p16 null." This pattern was identified in 2 of 63 cases of SC diagnosed at our institution-1 with histologically classic features and 1 with ambiguous high-grade histologic features. These tumors otherwise showed a SC signature by immunohistochemical and demonstrated an SC pattern of genetic mutations. No mutation in the gene for p16, cyclin-dependent kinase inhibitor 2A (CDKN2A), was identified in either case. However, molecular correlates for the absent p16 expression were present, including homozygous deletion of CDKN2A in one case and hemizygous deletion of CDKN2A with promotor hypermethylation of the remaining allele in the other case. To our knowledge, this constitutes the first report conclusively demonstrating the existence of a small subset of SCs that are completely negative by p16 immunohistochemistry, and the molecular lesions responsible for this pattern. In the context of an otherwise clinically and histologically classic example of SC, we endorse this "null" p16 staining pattern as an alternative aberrant staining pattern that should not deter one from committing to this diagnosis.

Aberrant Diffuse Intense CD10 Expression In P16 Positive Undifferentiated Endometrial Carcinoma: A Diagnostic Dilemma

Abstract Introduction/Objective High-grade endometrial neoplasms frequently pose a diagnostic challenge on purely histologic evaluation due to their ambiguous morphologic features. High grade endometrioid adenocarcinoma, serous carcinoma, undifferentiated carcinoma, and a minority of sarcoma cases can present with a solid growth pattern. Methods We present a 59-year-old patient who underwent a hysterectomy and bilateral salpingo-oophorectomy for a biopsy proven FIGO grade 2 endometrial carcinoma. Results Grossly, the entire endometrial cavity was involved by a hemorrhagic tumor. Microscopic examination showed the entire specimen to be replaced by predominantly non-cohesive diffuse sheets of mitotically active, pleomorphic cells without any glandular, papillary, serous or clear cell features.The differential diagnosis included undifferentiated carcinoma, serous carcinoma, carcinosarcoma, stromal sarcoma and other tumors including high- grade lymphoma. By immunohistochemistry, the tumor cells showed variable positivity for CK7, EMA, CK19, CK18, CK8, AE1/AE3, pan-keratin, CAM5.2, CD56, synaptophysin, p53, cyclinD1 and with a high Ki-67 proliferation index of 80%. The tumor was diffusely/intensely positive for CD10 and P16 while being negative for ER, PR, PAX8, HPV, mesenchymal and lymphoid markers. While diffuse/intense CD10 positivity and ER/PR negativity raised a concern for stromal sarcoma component, the above phenotype confirmed an aggressive/high grade carcinoma. Diffuse/intense p53 and p16 expression raised a consideration of serous carcinoma, but morphology and absence of PAX-8 failed to support this diagnosis. Undifferentiated carcinoma of the endometrium is a high-grade carcinoma which has been recognized as a distinct entity with diffuse p16 and p53 positivity in the absence of PAX-8 and hormone receptors. Positive vimentin, along with a negative HPV, confirmed the endometrial rather than cervical origin of this neoplasm. Conclusion By reporting this case, we draw attention to the previously unreported diffuse intense CD10 expression in undifferentiated carcinoma of endometrium to avoid misdiagnosis with considerations that include stromal sarcoma.

External Beam, Brachytherapy, or Chemotherapy? Defining Adjuvant Therapy for Early-Stage and High- and High-Intermediate-Risk Endometrial Cancer.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 54-year-old postmenopausal female with a history of stroke and carotid endarterectomy presented with 3 weeks of vaginal bleeding with passage of clots. Gynecologic exam revealed a 3-cm barrel-shaped cervix with friability at the os and no appreciable parametrial involvement. Cervical biopsy showed high-grade endometrioid adenocarcinoma. Pelvic magnetic resonance imaging demonstrated a 9.9-cm × 4.5-cm × 6.2-cm mass extending from the uterus to the cervix with greater than 50% myometrial invasion (MMI; Fig 1 ). Total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy revealed International Federation of Gynecology and Obstetrics (FIGO) stage II endometrial cancer: a 12-cm grade 3 endometrioid adenocarcinoma with 80% MMI and lymphovascular invasion (LVI) involving the outer half of the cervical stroma ( Fig 1 ), and without pelvic lymph node involvement.

Are Uterine Grade 3 Endometrioid Adenocarcinoma and Carcinosarcoma Really Clinically Similar?

The aim of this study was to compare the clinical characteristics and outcomes of the cases with uterine high-grade endometrioid adenocarcinoma (HGEAC) and uterine carcinosarcoma (UCS). A total of 141 patients were included in this study. Of them, 61 cases had uterine HGEAC (group 1) and 80 had UCS (group 2). Both groups were compared in terms of clinical and pathological characteristics including age, stage, initial symptom, surgical approach, myometrial invasion, lymphovascular space invasion (LVSI), lymph node invasion, adjuvant therapy, and survival. The Kaplan–Meier and Cox proportional hazards models were used to compare the outcomes and prognostic factors. There were no statistically significant differences between the groups with regard to age, nulliparity, menopausal status, and the main initial symptom. Both groups were similar in terms of stage, depth of myometrial invasion, and lymph node metastasis. Lymphadenectomy was performed in 74% and 91% of the cases in group 1 and group 2, respectively (p < 0.001). LVSI was found to be more frequent in group 1 (p = 0.032); however, in group 2, positive cytology was more common (p = 0.008). Chemotherapy was the main adjuvant therapy for UCS, while radiotherapy was the main adjuvant therapy for HGEAC. There was no difference between the groups in terms of disease-free survival (DFS); however, overall survival (OS) was found to be longer in group 1 (p = 0.029). Histopathologic type and LVSI were determined as independent predictive factors for OS. UCSs are clinically more aggressive than HGEAC and should be considered as a separate group of tumors.

Can the apparent diffusion coefficient differentiate the grade of endometrioid adenocarcinoma and the histological subtype of endometrial cancer?

Background Diffusion-weighted imaging (DWI) provides useful information for the identification of benign and malignant uterine lesions. However, the use of the apparent diffusion coefficient (ADC) for histopathological grading of endometrial cancer is controversial. Purpose To explore the use of ADC values in differentiating the preoperative tumor grading of endometrioid adenocarcinomas and investigate the relationship between the ADC values of endometrial cancer and the histological tumor subtype. Material and Methods We retrospectively evaluated 98 patients with endometrial cancers, including both endometrioid adenocarcinomas (n = 80) and non-endometrioid adenocarcinomas (n = 18). All patients underwent DWI procedures and ADC values were calculated. The Kruskal-Wallis test and the independent samples Mann-Whitney U test were used to compare differences in the ADC values between different tumor grades and different histological subtypes. Results The mean ADC values (ADCmean) for high-grade endometrioid adenocarcinomas were significantly lower than the values for low-grade tumors (0.800 versus 0.962 × 10-3 mm2/s) ( P = 0.002). However, no significant differences in ADCmean and minimum ADC values (ADCmin) were found between tumor grades (G1, G2, and G3) of endometrial cancer. Compared with endometrioid adenocarcinomas, the adenocarcinoma with squamous differentiation showed lower ADC values (mean/minimum = 0.863/0.636 versus 0.962/0.689 × 10-3 mm2/s), but the differences were not significant ( Pmean = 0.074, Pmin = 0.441). Moreover, ADCmean for carcinosarcomas was significantly higher than the value for G3 non-carcinosarcoma endometrial cancers (1.047 versus 0.823 × 10-3 mm2/s) ( P = 0.001). Conclusion The ADCmean was useful for identifying high-grade and low-grade endometrioid adenocarcinomas. Additionally, squamous differentiation may decrease ADCmean and ADCmin of endometrioid adenocarcinoma, and carcinosarcomas showed relatively high ADCmean.

Abstract LB-273: Comprehensive sequencing analyses of uterine and ovarian carcinosarcoma

Abstract Carcinosarcoma (CS) of the uterus or the ovary, known as malignant mixed Muellerian tumor, is a biphasic neoplasm composed of malignant epithelial (carcinoma) and mesenchymal (sarcoma) elements. CS is a rare disease (two per 100,000 women) and exhibits poor prognosis (5-year survival rates: uterus and ovary; 31 and 7.5 %, respectively). Treatment regimen for CS follows to that for endometrioid adenocarcinoma (EC) since CS has been considered as an aggressive form of high-grade EC. However, CS has a significantly worse prognosis than EC. Identification of a molecular target and/or a molecular mechanism in tumorigenesis from a large cohort study may improve unfavorable outcomes. Toward this aim, we perform targeted resequencing analysis with a panel of 596 genes, which were previously implicated as critical not only for uterine, ovarian or sarcomatus oncogenesis but also for molecular targets in therapeutics. Through analyses of 109 cases of uterine and ovarian CS, consensus clustering with deregulated pattern of CS genome identified four genomic subtypes that correlate with genetic or epigenetic alterations, histopathology and patient outcomes. Moreover, potentially actionable alterations were found in a substantial number of genes (including PIK3CA, MTOR, KRAS and CCNE1). This study would provide deep insights into the development of novel diagnostic and personalized treatment for CS patients. Citation Format: Seiichi Mori, Osamu Gotoh, Yuko Sugiyama, Kazuyoshi Kato, Tetsuo Noda. Comprehensive sequencing analyses of uterine and ovarian carcinosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-273. doi:10.1158/1538-7445.AM2017-LB-273

Abstract 145: Comprehensive sequencing analyses of uterine and ovarian carcinosarcoma

Abstract Carcinosarcoma (CS) of the uterus or the ovary, known as malignant mixed Muellerian tumor, is a biphasic neoplasm composed of malignant epithelial (carcinoma) and mesenchymal (sarcoma) elements. CS is a rare disease (two per 100,000 women) and exhibits poor prognosis (5-year survival rates: uterus and ovary; 31 and 7.5%, respectively). Treatment regimen for CS follows to that for endometrioid adenocarcinoma (EC) since CS has been considered as an aggressive form of high-grade EC. However, CS has a significantly worse prognosis than EC. Identification of a molecular target and/or a molecular mechanism in tumorigenesis from a large cohort study may improve unfavorable outcomes. Toward this aim, we perform targeted resequencing analysis with a panel of 596 genes, which were previously implicated as critical not only for uterine, ovarian or sarcomatus oncogenesis but also for molecular targets in therapeutics. Through analyses of 84 cases of uterine and ovarian CS, consensus clustering with deregulated pattern of CS genome identified four genomic subtypes that correlate with genetic or epigenetic alterations, histopathology and patient outcomes. Moreover, potentially actionable alterations were found in a substantial number of genes (including PIK3CA, MTOR, KRAS and CCNE1). This study would provide deep insights into the development of novel diagnostic and personalized treatment for CS patients. Citation Format: Seiichi Mori, Osamu Gotoh, Yuko Sugiyama, Kazuyoshi Kato, Yutaka Takazawa, Tetsuo Noda. Comprehensive sequencing analyses of uterine and ovarian carcinosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 145.

Abstract 70: Targeted sequencing analyses of uterine and ovarian carcinosarcoma

Abstract Carcinosarcoma (CS) of the uterus or the ovary, known as malignant mixed Muellerian tumor, is a biphasic neoplasm composed of malignant epithelial (carcinoma) and mesenchymal (sarcoma) elements. CS is a rare disease (two per 100,000 women) and exhibits unfavorable outcomes (5-year survival rates: uterus and ovary; 31 and 7.5%, respectively). CS has been considered as an aggressive form of high-grade endometrioid adenocarcinoma (EC), therefore, the treatment regimen for CS follows to that for EC. Nevertheless, the fact that CS shows substantially poorer prognosis than EC implies a need to identify therapeutic targets for CS. Toward this aim, we have been performing targeted resequencing with a panel of 521 genes (including 30 introns), which were previously implicated as critical not only for uterine, ovarian or sarcomatus oncogenesis but also for molecular targets in therapeutics and the panel covers 2.161 Mbp with 38,105 probes on Agilent's SureSelect. Genomic DNA was extracted from matched tumor and normal pairs derived from more than 70 cases of uterine and ovarian CS patients and then used to construct pooled libraries, which were subsequently subjected to sequencing analysis with an Illumina HiSeq sequencer. Consensus clustering with genomic changes such as mutational spectrum and number of somatic SNVs revealed several subtypes that correlate with histopathology and patient outcomes. Moreover, potentially actionable mutations or copy number aberrations were identified in a number of genes including PIK3CA, MTOR, KRAS and CCNE1. This study would provide deep insights into the development of novel diagnostic and personalized treatment for CS patients. Citation Format: Seiichi Mori, Osamu Gotoh, Sayuri Amino, Megumi Nakai, Yutaka Takazawa, Yuko Sugiyama, Tetsuo Noda. Targeted sequencing analyses of uterine and ovarian carcinosarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 70. doi:10.1158/1538-7445.AM2015-70

A novel hysteroscopic pattern of microvascular architecture in uterine endometrioid adenocarcinoma: Initial clinical experience

Abstract Objective To establish a specific hysteroscopic pattern–the “glomerular pattern”–to diagnose high-grade endometrial cancer and evaluate the accuracy rate of the pattern, based on final histology. Materials and methods From 2008 to 2011, 30 patients for whom pathology indicated endometrial cancer, based on the office hysteroscopy study, were included in the study. We reviewed the hysteroscopic pictures to determine the specific hysteroscopic pattern in high-grade endometrial cancer. Results Thirty patients who had endometrial cancer under hysteroscopy were included to the study. The study population had a mean age of 49.9 years. All patients had abnormal uterine bleeding. Office hysteroscopy was completed in all patients without anesthesia. The findings of the office hysteroscopy suggested endometrial cancer in 30 patients. Fifteen patients had the specific hysteroscopic pattern, called the “glomerular pattern.” All 15 patients had grade 2 or grade 3 disease. Among patients who had a glomerular pattern, 53.3% (8/15) of patients had grade 2 endometrioid adenocarcinoma and 46.7% (7/15) patients had grade 3 endometrioid adenocarcinoma. Among the nonglomerular pattern group patients, 66.7% (10/15) patients had grade 1 endometrioid adenocarcinoma, 26.7% (4/15) patients had grade 2 endometrioid adenocarcinoma and 6.7% (1/15) patients had grade 3 endometrioid adenocarcinoma. Conclusion Our conclusion is that patients with the glomerular pattern have a high percentage of moderate or high-grade endometrioid adenocarcinoma. The glomerular sign may provide information on preoperative pathohistology and decrease the possibility of histology upgrade after hysterectomy. However, large series, prospective, and comparison studies are still needed.

Malignant Mixed Mullerian Tumor with an Endometrioid Adenocarcinoma with a Component of Giant Cell Carcinoma: A Case Report and Literature Review

A 70 year old female underwent a hysterectomy due to a diagnosis of high grade endometrioid adenocarcinoma. Pathological examination revealed a Malignant Mixed Mullerian Tumor (MMMT) along with a conventional endometrioid adenocarcinoma with a component of giant cell carcinoma. Giant cell carcinoma of the endometrium is a rare tumor consisting of sheets of discohesive appearing cells with numerous anaplastic looking giant cells. Only 13 cases of giant cell carcinoma have been described and the majority present as a component of endometrioid carcinoma. The giant cells are often positive for keratin markers and are negative for CD68 and HCG which can help distinguish them from other tumors with multinucleate giant cells. Malignant Mixed Mullerian Tumors (MMMT) were once thought to originate from two separate neoplasms that underwent collision. But recently studies have found that these malignancies appear to arise from a malignant epithelial type cell that undergoes Epithelial to Mesenchymal Transition (EMT). Studies suggest that mutations in AKT2 and p53 result in increased levels of SLUG and ZEB, which represses E-cadherin. It is the loss of e-cadherin that is believed to be a central player in EMT. It is widely believed that tumors frequently display intra-tumoral heterogeneity that can result in neoplasms with striking variations in their characteristics. This case can make a nice example of how tumors can develop strikingly different characteristics.

Expression Levels of Adiponectin Receptors are Decreased in Human Endometrial Adenocarcinoma Tissues

Adiponectin is a cytokine secreted by adipocytes, whose plasma levels are decreased in obesity. Adiponectin has insulin-sensitizing, antiatherogenic, and antidiabetogenic effects. It has been shown that adiponectin may also exert antineoplastic activity through suppression of tumor proliferation and neoangiogenesis and through induction of apoptosis. Recently, low adiponectin serum concentration has been found in obesity-related malignancies, including endometrial cancer. In addition, the expression of adiponectin receptors (AdipoR1 and AdipoR2) has been documented in several human cancer tissues, but the expression has previously not been assessed in human endometrial cancer tissues. In this study, we analyzed the immunohistochemical expression of AdipoR1 and AdipoR2 in a series of surgically resected human endometrioid adenocarcinoma tissues from a total of 141 cases. Decreased AdipoR1 or AdipoR2 expression was significantly associated with histological higher grade (P=0.0026 and 0.0004, respectively). Decreased expression of AdipoR1 was associated with myometrial invasion and lymph node metastasis of endometrioid adenocarcinoma (P=0.0039 and P=0.0069, respectively). AdipoR1 and AdipoR2 immunoexpression was significantly associated with the expression of the progesterone receptor, although it was not significantly correlated with the expression of the estrogen receptor, Ki-67 or p53. Our present study raises the possibility that decreased expression of adiponectin receptors is implicated in the development, invasion, and metastasis of human endometrioid adenocarcinoma. Our findings, moreover, indicate that adiponectin receptors could be considered as therapeutic targets for endometrioid adenocarcinoma. In adiponectin receptor-positive endometrioid adenocarcinoma, we think adiponectin-based anticancer therapy is useful; however, in histological high-grade endometrioid adenocarcinoma, in which the expression levels of adiponectin receptors are relatively low, adiponectin therapy supported by adiponectin receptor induction is needed.

P16INK4a Expression in Undifferentiated Carcinoma of the Uterus Does Not Exclude Its Endometrial Origin

Undifferentiated carcinoma of the endometrium is a rare neoplasm, which, when involving the cervix, raises a question about its origin. Diffuse p16 positivity of uterine cancers is usually interpreted as a surrogate marker for high-risk human papilloma virus and favors cervical origin. In this study, we investigated the expression of cytokeratin 7 (CK7), monoclonal carcinoembryonic antigen (mCEA), estrogen receptor (ER), vimentin, and p16 in 28 cases of undifferentiated endometrial carcinoma, 20 high-grade endometrioid adenocarcinomas, and 50 cervical adenocarcinomas. Staining was considered positive when it was cytoplasmic for CK7, mCEA, and vimentin, nuclear for ER, and both nuclear and cytoplasmic for p16. Percentages of cells staining were recorded as follows: negative (0%-5%), 1+ (6%-25%), 2+ (26%-50%), 3+ (51%-75%), and 4+ (>75%). P16 was considered positive if it stained more than 75% of the tumor cells. Diffuse/strongly positive staining for p16 was seen in 40/50 (80%) cases of cervical adenocarcinoma and 14/28 (50%) cases of undifferentiated endometrial carcinoma. In high-grade endometrioid adenocarcinoma, staining was mainly patchy. CK7, mCEA, ER, progesterone receptor, and vimentin staining in undifferentiated endometrial carcinoma was as follows: 10/28 (36%), 4/28 (14%), 21/28 (75%), 23/28 (82%), and 26/28 (93%), respectively; for high-grade endometrioid carcinoma: 20/20 (100%), 1/20 (5%), 17/20 (85%), 18/20 (90%), and 19/20 (95%); for endocervical adenocarcinoma: 50/50 (100%), 45/50 (90%), 9/50 (18%), 8/50 (16%), and 6/50 (12%), respectively. Our data indicate that p16 may play a role in the tumorigenesis of a subset of undifferentiated endometrial carcinoma. In the setting of p16 positivity, undifferentiated endometrial carcinomas are more likely to be ER, progesterone receptor, and vimentin positive and mCEA negative when compared with endocervical adenocarcinomas. Distinction between undifferentiated endometrial carcinoma and endocervical adenocarcinoma, both of which can share diffuse p16 expression, should rely on detection of human papilloma virus in the latter.

Functional and Clinicopathological Analysis of Loss of MKK4 Expression in Endometrial Cancer

Objective: In the current study, we investigated the mechanism relating downregulation of mitogen-activated protein kinase kinase-4 (MKK4) expression to the development of endometrial cancer. Methods: MKK4 expression in endometrial cancer was assessed by immunohistochemistry using 87 paraffin-embedded tissue specimens, and clinical data was collected via a retrospective chart review. MKK4 gene knockdown using silencing RNA and an MKK4 gene transfection system was used to assess MKK4 function in tissue samples of endometrial cancer. Results: Lower expression of MKK4 immunointensity was observed in 63.2% (55/87) of the analyzed tumors. High-grade endometrioid adenocarcinoma (G2 and G3) (p = 0.024), postmenopausal status (p = 0.018), and patient age (≧60) (p = 0.012) were significantly correlated with lower MKK4 expression. Patients with lower MKK4 expression in endometrial cancer tissues tended to have a shorter overall survival (p = 0.197). Using cell growth and anchorage-independent assays, we determined that both the growth and colony-forming ability of MKK4-transfected HEC1B cells, a line with a low endogenous expression of MKK4, were significantly reduced compared to control vector-transfected cells. Overexpression of the MKK4 gene in HEC1B cells resulted in reduced cell migration activity in a simulated wound healing assay. To confirm that MKK4 expression is related to tumor suppressor function, we used 2 independent but complementary approaches. MKK4 gene knockdown in JHEM1 cells, which overexpressed MKK4, increased proliferation activity. Additionally, the engineered expression of MKK4 in Ishikawa cells, a line with low endogenous MKK4 expression, produced a phenotype similar to that of HEC1B. Similar results were produced in tumor xenografts in nude mice. Conclusion: These results indicate that MKK4 acts as a tumor suppressor, and reduced expression of MKK4 may contribute to the development of endometrial cancer.

IMP3 Distinguishes Uterine Serous Carcinoma From Endometrial Endometrioid Adenocarcinoma

Differentiating uterine serous carcinoma (USC) from endometrioid adenocarcinoma (EAC) could be problematic, especially in high-grade EACs and tumors exhibiting architectural variations. To address this issue, we evaluated 103 endometrial carcinoma cases using 4 immunomarkers, beta-catenin, IMP3, PTEN, and p53. Cases included 31 USCs, 57 EACs, and 15 mixed EAC-USCs. Of 31 USCs and 57 EACs, 8 and 9, respectively, were considered diagnostically difficult and challenging. beta-catenin was more frequently expressed in EAC (P = .001); p53, PTEN, and IMP3 were more frequently found in USC (P < .001 for each). IMP3 was the best independent predictive marker for USCs. The best marker combination for predicting USCs was PTEN+/IMP3+ (exact odds ratio, 163.87; 95% confidence interval, 19.62 to infinity; P < .001). IMP3 was consistently negative in all 9 challenging EAC cases and consistently positive in all 8 challenging USC cases. None of the markers or their combinations demonstrated any value in making the diagnosis of serous component in mixed EAC-USC tumors. IMP3 immunoexpression and the IMP3+/PTEN+ pattern are the best independent and combination markers, respectively, to predict USCs. We strongly recommend using them in difficult and challenging cases.

Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis

The status of p53 and the phosphatidylinositol 3-kinase–AKT (PI3K–AKT) signaling pathway was investigated in 132 endometrial carcinomas, including endometrioid endometrial carcinomas, non-endometrioid endometrial carcinomas, and mixed endometrioid adenocarcinomas-non-endometrioid adenocarcinomas. Results were compared with the clinicopathologic parameters associated with prognosis, patients' follow-up, and other genetic alterations found frequently in these tumors. Molecular genetic differences between low-grade and high-grade endometrioid adenocarcinomas were encountered; ie, PIK3CA mutations were detected in 26 and 34% of cases, respectively. We found p53 alterations in only 17% of high-grade endometrioid adenocarcinomas. In contrast, non-endometrioid adenocarcinomas had a higher frequency of p53 alterations (54%), PIK3CA mRNA overexpression (45%), and exon 20 PIK3CA mutations (21%). In the mixed endometrioid adenocarcinomas-non-endometrioid adenocarcinomas, the most frequent alterations were p53 (50%) and PIK3CA (44%) mutations, followed by PTEN mutations (38%). In some cases, p53 and PIK3CA alterations coexisted, but they rarely coexisted with the PTEN mutations. Our findings suggest that the PIK3CA mutations are frequent events in endometrial carcinomas of any histological type. However, location of the PIK3CA mutations, either in exon 9 or exon 20, varies significantly according to the histologic grade and type of carcinoma. Carcinomas with exon 20 PIK3CA mutations or PIK3CA mRNA overexpression were often high-grade carcinomas associated with myometrial invasion; in contrast, tumors that carried exon 9 mutations were more likely to be low-grade carcinomas. The Kaplan–Meier analysis suggested that p53 alterations (strong immunoexpression or mutations) conferred a worse prognosis (P=0.000). Although alterations in the PI3K–AKT signaling pathway alone did not influence overall survival, patients with deregulated PI3K–AKT pathway (PIK3CA and/or PTEN alterations) and p53 alterations had shorter survival (P=0.000) than patients with only p53 alterations. Such a relationship was lost when we considered exon 9 PIK3CA mutations. Our results contribute to further characterize the molecular genetic model for endometrial carcinogenesis.

Defining the extent of cables loss in endometrial cancer subtypes and its effectiveness as an inhibitor of cell proliferation in malignant endometrial cells in vitro and in vivo

Loss of Cables expression is associated with a high incidence of endometrial hyperplasia and endometrial adenocarcinoma in humans. The Cables mutant mouse develops endometrial hyperplasia and following exposure to chronic estrogen develops early endometrial adenocarcinoma. The objectives of the current study were to determine if: 1) loss of Cables expression occurred in high grade endometrioid adenocarcinoma, uterine serous and clear cell carcinoma as observed in endometrial hyperplasia and low grade endometrial adenocarcinoma; 2) overexpression of Cables inhibited cell proliferation in endometrial cancer (EC) cells in vitro and in vivo; and 3) progesterone could regulate the expression of Cables mRNA. Hyperplastic endometrium and low and high grade endometrioid adenocarcinoma showed loss of Cables expression when compared to benign control secretory endometrium. Loss of Cables expression in serous and clear cell tumors was similar to that observed in endometrioid adenocarcinomas with greater than 80% showing loss of protein expression. Treatment of EC lines with progesterone increased cables expression in low-grade EC whereas it had no effect on cables expression in cells derived from high-grade EC. The progesterone-induced increase in cables was abrogated in the presence of a progesterone receptor (PR) antagonist, suggesting the PR mediates the increase. Cables overexpression inhibited cell proliferation of well differentiated EC cells and had no effect on the poorly differentiated EC cells. The capacity to form tumors was dramatically reduced in the Cables overexpressing cell lines compared to those cells containing the control vector. Collectively these results suggest that Cables is an important regulator of cell proliferation and loss of Cables expression contributes to the development of all types of EC.

Distinctive p53 and mdm2 immunohistochemical expression profiles suggest different pathogenetic pathways in poorly differentiated endometrial carcinoma.

Endometrial serous carcinoma (ESC) and FIGO (International Federation of Gynecology and Obstetrics) grade 3 endometrioid adenocarcinoma (EC) are high-grade endometrial tumors that have different clinical and morphologic attributes. Alteration of p53 tumor suppressor protein function has been implicated in the pathogenesis of both tumors, although the mechanisms may differ. We sought to investigate this difference by comparing immunohistochemical expression of p53 and mdm2. p53 immunoreactivity often correlates with gene mutation, whereas increased mdm2 expression is linked to complex formation with wild-type p53 resulting in its inactivation. Twenty cases of ESC and 21 cases of EC were evaluated and an immunoreactivity score (IRS) was assigned using both the percentage of cells stained and the intensity of staining. The overall IRSs were significantly different in ESCs versus ECs for both p53 and mdm2 (p < 0.001 and p < 0.01, respectively). Strong mean immunoreactivity for p53 was detected in 15 (75%) ESCs as compared to only weak mean immunoreactivity in 17 (81%) ECs. Conversely, for mdm2 expression, 17 (81%) ECs had moderate mean immunoreactivity whereas 9 (45%) ESCs showed only weak mean immunoreactivity. mdm2 expression more closely correlated with p53 expression in ECs than in ESCs. In ECs, mdm2 was detected in 16 of 17 (94%) p53-positive tumors but in only 1 of 3 (33%) p53-negative tumors (p < 0.025). In ESCs, mdm2 was detected in 9 of 15 (60%) p53-positive tumors but in none of the 5 p53-negative tumors (p < 0.10). Overall, our results demonstrate an inverse relationship between the expression of p53 and mdm2 in ESC versus high-grade EC. Specifically, strong p53 immunoreactivity is associated with weak mdm2 expression-in ESC and weak p53 expression is associated with moderate mdm2 expression in EC. These results suggest different pathogenetic pathways resulting in loss of normal p53 function in these two tumors: by p53 gene mutation (strong p53 overexpression) in ESCs, or by mdm2 complex formation and inactivation of p53 in high-grade ECs.

Uterine neoplasms in patients treated with tamoxifen.

Since 1985, when Killackey originally described three cases of endometrial carcinoma in patients receiving tamoxifen, there have been several reports confirming or denying the relationship between tamoxifen and endometrial carcinoma. Our study of 15 patients treated for breast carcinoma with tamoxifen found that papillary serous carcinoma was the most common tumor in this group of patients. Several other retrospective studies reported a high incidence of high-grade endometrioid adenocarcinoma or high-risk variants of endometrial carcinoma in patients receiving tamoxifen.