Non-endometrioid Carcinomas Research Articles

Endometrial carcinoma in the Baby Boomer generation: Tumor characteristics and clinical outcome.

e15512 Background: Baby Boomers (BB) enterring retirement are representing a significant burden on medical resources. The unique lifestyle characteristics engendered by the BB may lead to different endometrial cancer characteristics that bear understanding. We sought to characterize surgically staged BB patients with endometrioid carcinoma and compare the results to pre-Boomers (PB) patients. Methods: After reviewing our database of 1,450 patients with endometrial cancer, we identified 595 patients with 2009 FIGO stage I-II uterine endometrioid carcinoma who were born between 1926 and 1964. Their medical records were reviewed in this IRB-approved study. Patients with non-endometrioid carcinoma and those received preoperative therapy or chemotherapy were excluded. Patients were defined as BB (born 1946-1964) or PB (born in 1926-1945). The two groups were compared regarding patient’s demographics, tumor characteristics and survival. Results: All patients were surgically staged with a minimum of two years follow-up.BB group included 234 patients (39%) and PB with 361 patients (61%).Median follow-up for the study cohort was 72 months. Baby boomers had higher BMI (p=0.027), younger age at diagnosis (p=0.002), lower tumor grade (p=0.002), earlier FIGO stage (p=0.023), higher number of lymph dissected (p=0.008), less lymphovascular space involvement (LVSI) (p=<0.034), and less frequent utilization of adjuvant therapy (p=<0.001). However, there was no statistically significant difference found between the BB and PB in regards to local control, disease-specific survival and overall survival. For the study cohort, FIGO stage and tumor grade were independent predictors of local control and disease-specific survival. As to be expected, there was a trend towards shorter overall survival for the PB patients (p=0.063). Conclusions: Athough tumor characteristics were more favorable in the baby boomers generation, local control and survival endpoints were not statistically different compared to pre boomers. As more baby boomers are diagnosed with endometrial carcinoma, further research is warranted to further elucidate the characteristic differences of endometrial carcinoma, if any, in this generation.

Clinical assessment of PTEN loss in endometrial carcinoma: immunohistochemistry outperforms gene sequencing

AbstractPTEN (phosphatase and tensin homolog) is a tumor suppressor that negatively regulates the PI3K–AKT signaling pathway, which is implicated in the pathogenesis of endometrial carcinoma. Sanger sequencing has been considered to be the gold standard for detection of PTEN sequence abnormalities. However, this approach fails to address the epigenetic mechanisms that contribute to functional PTEN loss. Using a study cohort of 154 endometrioid and non-endometrioid endometrial carcinomas, we performed full-length PTEN sequencing and PTEN immunohistochemistry on each tumor. PTEN sequence abnormalities were detected in a significantly lower proportion of cases (43%) than PTEN protein loss (64%, P=0.0004). Endometrioid tumors had a significantly higher proportion of PTEN sequence abnormalities and PTEN protein loss than non-endometrioid tumors. Within the latter group, PTEN sequence abnormalities and PTEN protein loss were most frequent in undifferentiated carcinomas, followed by mixed carcinomas; they were least frequent in carcinosarcomas. Overall, at least one PTEN sequence abnormality was detected in each exon, and the greatest number of sequence abnormalities was detected in exon 8. Pure-endometrioid tumors had a significantly higher frequency of sequence abnormalities in exon 7 than did the non-endometrioid tumors (P=0.0199). Importantly, no mutational hotspots were identified. While PTEN protein loss by immunohistochemistry was identified in 89% of cases with a PTEN sequence abnormality, PTEN protein loss was detected by immunohistochemistry in 44% of cases classified as PTEN wild type by sequencing. For the first time, we demonstrate that PTEN immunohistochemistry is able to identify the majority of cases with functional PTEN loss. However, PTEN immunohistochemistry also detects additional cases with PTEN protein loss that would otherwise be undetected by gene sequencing. Therefore, for clinical purposes, immunohistochemistry appears to be a preferable technique for identifying endometrial tumors with loss of PTEN function.

Endometrial carcinoma: molecular alterations involved in tumor development and progression

In the western world, endometrial carcinoma (EC) is the most common cancer of the female genital tract. The annual incidence has been estimated at 10-20 per 100,000 women. Two clinicopathological variants are recognized: the estrogen related (type I, endometrioid) and the non-estrogen related (type II, non-endometrioid).The clinicopathological differences are paralleled by specific genetic alterations, with type I showing microsatellite instability and mutations in phosphatase and tensin homologue deleted on chromosome 10, PIK3CA, K-RAS and CTNNB1 (β-catenin), and type II exhibiting TP53 mutations and chromosomal instability. Some non-endometrioid carcinomas probably arise from pre-existing endometrioid carcinomas as a result of tumor progression and, not surprisingly, some tumors exhibit combined or mixed features at the clinical, pathological and molecular levels. In EC, apoptosis resistance may have a role in tumor progression. Understanding pathogenesis at the molecular level is essential in identifying biomarkers for successful targeted therapies. In this review, the genetic changes of endometrial carcinogenesis are discussed in the light of the morphological features of the tumors and their precursors.

Pathologic Scoring of PTEN Immunohistochemistry in Endometrial Carcinoma is Highly Reproducible

Endometrial carcinomas show frequent PTEN-PI3K pathway abnormalities, and there are currently multiple trials focused on PI3K pathway inhibitors in patients with endometrial carcinoma. PTEN immunohistochemistry may help to select patients with potential for response to targeted therapy, making it important to develop and validate this stain in formalin-fixed, paraffin-embedded tissue. Immunohistochemistry for PTEN was performed and scored independently on 118 cases of endometrial carcinomas from 2 cancer centers using monoclonal DAKO 6H2.1 antibody. Cases were scored as positive, negative, or heterogeneous; reproducibility of PTEN staining and interpretation was assessed. Overall interobserver agreement was good (weighted κ=0.80), with 82% concordance, similar for nonendometrioid (81%) and endometrioid carcinomas (85%). Twenty-one of 118 cases showed discrepant results (17%) that resulted from differences in interpretation and not staining. Our study shows that evaluation of PTEN loss by immunohistochemistry is highly reproducible with the application of standard immunohistochemical techniques and simple scoring criteria.

The comparison of clinicopathological characteristics in primary malignant mixed műllerian tumour with epithelial endometrial carcinoma

We performed an age-matched case-control study to compare the clinical and pathology outcomes between histologically diagnosed primary malignant mixed műllerian tumour (MMMT) of the uterus and endometrial carcinoma. Thirty-two women were treated for primary MMMT at seven tertiary medical centres in Korea from 2000 to 2006. For each woman with MMMT, four women with endometrioid and two with non-endometrioid endometrial carcinoma were selected as age-matched controls for analysis. Medical records were retrospectively reviewed to obtain outcome data. The incidence of MMMT was 2.57% (32/1244). In comparison with women with endometrioid endometrial cancer, those with MMMT were characterised by large tumour size, higher incidence of adnexal involvement and lymph node metastases, leading to advanced disease stage. Despite the frequent use of adjuvant treatment, the 5-year survival rate of women with MMMT was significantly poorer than those with endometrioid endometrial cancer. However, women with MMMT were not significantly different from those with non-endometrioid endometrial cancer in terms of important pathologic variables, apart from larger tumour size. In addition, the 5-year survival rate of women MMMT was poorer than that those with non-endometrioid endometrial cancer, but the difference was not statistically significant. Malignant mixed műllerian tumour is characterised by a high incidence of lymph node metastases and advanced stage at diagnosis, leading to poorer overall survival than other subtypes of endometrial carcinoma. Clinical trials for MMMT are critical for improving treatment strategies.

FGFR2 alterations in endometrial carcinoma

Fibroblast growth factor receptor 2 (FGFR2) is a tyrosine kinase receptor involved in many biological processes such as embryogenesis, adult tissue homeostasis and cell proliferation. Mutations in FGFR2 have been reported in up to 10–12% of endometrial carcinomas identical to those found in congenital craniofacial disorders. Inhibition of FGFR2 could be a new therapeutic target in endometrial carcinoma. FGFR2 immunostaining was assessed in three tissue microarrays: one constructed from paraffin-embedded blocks of 60 samples of normal endometrium in different phases of menstrual cycle, and two tissue microarrays containing endometrial carcinoma samples (95 and 62 cases). FGFR2 expression was correlated with stage, histological type and grade as well as with immunostaining of PTEN, RASSF1A, estrogen and progesterone receptors, KI67, Cyclin D1, STAT-3 and SPRY2. FGFR2 mutations were assessed by PCR and direct sequencing, with DNA obtained from 31 paraffin-embedded endometrial carcinoma samples. In normal endometrium, FGFR2 expression was higher in the secretory than in the proliferative phase (P=0.001), with an inverse correlation with Ki67 (P=0.00032), suggesting a tumor-suppressor role for FGFR2 in normal endometrium. Cytoplasmic expression of FGFR2 was higher in endometrial carcinoma when compared with the atrophic endometrium from the same patients (P=0.0283), but was lower in comparison with normal endometrium from women in the menstrual cycle. Interestingly, nuclear staining was observed in some cases, and it was less frequent in endometrial carcinoma when compared with the adjacent atrophic endometrium (P=0.0465). There were no statistical differences when comparing superficial and myoinvasive endometrial carcinoma samples. Endometrioid endometrial carcinomas showed higher expression of FGFR2 than nonendometrioid endometrial carcinomas (fold change 2.56; P=0.0015). Grade III endometrioid endometrial carcinomas showed decreased FGFR2 expression when compared with grade II endometrioid endometrial carcinomas (P=0.0055). No differences were found regarding pathological stage. Two missense mutations of FGFR2 gene were detected in exons 6 and 11 (S252W and N549K, respectively; 6.45%). Results support the hypothesis that FGFR2 has a dual role in the endometrium, by inhibiting cell proliferation in normal endometrium during the menstrual cycle, but acting as an oncogene in endometrial carcinoma.

Venous Thromboembolism in Uterine Cancer

To determine the incidence, time course, and risk factors associated with the development of venous thromboembolism (VTE) and the effect of VTE on survival in women with uterine cancer. Using the California Cancer Registry, the date, stage, and histology of all incident uterine cancer cases during 1993-1999 were identified. These cases were linked with the state's hospital discharge database, allowing identification of incident VTE events, after excluding cases with a previous history of VTE. Proportional hazards modeling was used to analyze the association of baseline risk factors with the development of VTE (<1 year), using major surgery as a time-dependent covariate. In a similar model for death (<2 years), VTE was included as a time-dependent covariate. Among 18,440 cases with uterine cancer, the 2-year cumulative incidence of VTE was 2.7%. The cumulative incidence varied from 1.5% among women with local stage disease to 10.5% among women with advanced disease. Among cases diagnosed with local disease, risk factors for the development of VTE within 1 year in localized disease included major surgery (hazard ratio [HR]=2.1, P<0.01), presence of long-term comorbidities (HR=2.9 for ≥3 comorbidities, P<0.0001), black race (HR=2.0, P<0.006), and sarcoma histology (HR=1.7, P<0.04). Among cases with regional disease, presence of comorbidities, black race, and sarcomas or nonendometrioid carcinomas were all associated with significantly higher risk of VTE. In advanced disease, the presence of any comorbidities and black race were the strongest predictors (HR=2.4 and 1.9, respectively). Women (aged<45 years) with advanced disease had a notably high 2-year incidence of 18%. Age did not predict VTE in localized and regional diseases. For all stages of cancer, development of VTE within 2 years was a significant predictor of decreased survival, and the magnitude of the risk was greatest among the cases diagnosed with localized disease (HR=6.1; confidence interval, 4.6-8.1). The incidence of VTE in women with uterine cancer was high, particularly in younger women with metastatic disease. The strong association between development of VTE and death suggests a close coupling between the biological aggressiveness of the cancer and the activation of thrombosis.

Lymphadenectomy as a prognostic marker in uterine non-endometrioid carcinoma

A pelvic lymphadenectomy with or without para-aortic lymphadenectomy is performed during surgery for endometrial cancer at least in high-risk patients for recurrence or progression. The question of whether pelvic and/or para-aortic lymphadenectomy improves survival rates of high-risk patients with uterine non-endometrioid carcinoma is still unclear. Therefore, the aim of this study was to evaluate the outcome of patients with uterine non-endometrioid cancer, with regard to the performance of a lymphadenectomy in a well-characterized cohort population. The prognostic value of a performed lymphadenectomy was examined in 55 patients with a histological diagnosis of a uterine non-endometrioid carcinoma. A performed lymphadenectomy was analyzed with respect to the surgical and pathological stage and characteristics. Of the 55 patients with an uterine non-endometrioid carcinoma, 38 (69.1%) and 2 (3.6%) patients were diagnosed in FIGO stage I and II, respectively, while 14 (25.5%) patients had FIGO stage III and 1 patient (1.8%) presented with metastatic disease (FIGO IV). 16 patients (29.1%) demonstrated a myometrial invasion of more than 50%, while a cervical and ovarian involvement could be observed in 7 (12.7%) and 9 (16.4%) cases, respectively. Pelvic and/or para-aortic lymph node sampling was performed for 42 patients (76.4%) while 7 patients (12.7%) demonstrated lymph node metastasis. Univariate survival analysis demonstrated no differences in progression-free survival, cause-specific survival or overall survival for a performed lymphadenectomy. Regression analysis led to a model containing only the FIGO surgical stage as an independent term that was predictive of progression-free survival, cause-specific survival and overall survival. Although a performed lymphadenectomy did not have any positive benefit in the survival of patients with uterine non-endometrioid carcinomas in this study, it might provide important prognostic information with a subsequent adjuvant treatment. However, these results remain to be confirmed in further larger and prospective studies.

Abstract LB-15: Overexpression of Pak1 and Pak4 contributes to endometrial carcinogenesis

Abstract Introduction: Endometrial cancer is the most common gynaecological cancer worldwide and its incidence in Asia is rising. It can be classified into two major types: the estrogen dependent type I endometrioid carcinoma that comprises about 80% of endometrial cancers and the type II non-endometroid carcinoma, which is estrogen-independent, including serous carcinoma and clear cell carcinoma. p21-activated kinases (Paks) are major effectors of the small Rho GTPases Rac1 and Cdc42 that play important roles in cell morphology, cytoskeletal reorganization, apoptosis, survival and angiogenesis. This study investigated the expression patterns, clinical significance, functional roles and putative downstream targets of Pak1 and Pak4 in endometrial cancer. Methods and Results: Immunohistochemical study of Pak1, Pak4 and p-Pak4 Ser474 (the activated form) was performed on 10 normal atrophic endometrium, 16 hyperplastic endometrium without atypia, 17 atypical complex hyperplasia and 67 endometrial carcinomas. Pak1 was expressed in cytoplasm whereas Pak4 and p-Pak4 were expressed in both cytoplasm and nucleus. Significantly higher Pak1, Pak4 and p-Pak4 expression was detected in hyperplastic endometrium and endometrial carcinomas than normal atrophic endometrium. Moreover, endometrioid carcinomas showed significantly higher Pak1 expression than non-endometrioid carcinomas. In endometrial carcinomas, expression of Pak4 was found to be correlated with proliferation markers, MCM7 and Ki67. By quantitative real-time polymerase chain reaction, significantly higher Pak1 and Pak4 mRNA expression was observed in endometrial cancer samples when compared with the corresponding non-tumor counterparts. Up-regulation of Pak1 and Pak4 mRNA and protein expression was also found in cancer cell lines compared with normal endometrial cells. Knockdown of Pak1 by siRNA in RL-95–2, an endometrial cancer cell line with relatively high Pak1 expression, inhibited cell proliferation along with down-regulation of estrogen receptor alpha mRNA and protein expression. Conclusion: This is the first report revealing the expression of Pak1 and Pak4 in normal atrophic, hyperplastic endometrium and endometrial carcinomas, suggesting Pak1 and Pak4 to be useful markers in detection of endometrial carcinoma in postmenopausal women and potential therapeutic targets in endometrial cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-15. doi:10.1158/1538-7445.AM2011-LB-15

Nonendometrioid endometrial carcinomas

Clinicopathologic studies support a classification of endometrial carcinoma into two main categories (type I and type II). Type I cancers consist of endometrioid and mucinous carcinomas, with the former being the most common, whereas serous and clear cell carcinomas are the so-called "prototype" of type II cancers. Nonendometrioid carcinomas account for approximately 10% of endometrial carcinomas and differ from endometrioid carcinomas in terms of patient demographics, morphologic features, and biological behavior. Molecular studies have provided further insights into the differing alterations involved in the development and progression of these tumors. This review summarizes the characteristic clinical, morphologic, immunophenotypic, and molecular features of the various subtypes of nonendometrioid carcinomas and also highlights relevant conditions (both nonneoplastic and neoplastic) that should be considered in the differential diagnosis of these tumors.

Inhibin-alpha, -betaA and -betaB subunits in uterine non-endometrioid carcinomas: Prognostic significance and clinical implications

Inhibins, dimeric peptide hormones composed of an alpha-subunit and one of two possible beta-subunits (betaA or betaB), exhibit substantial roles in human reproduction and in endocrine-responsive tumours. However, the prognostic significance and clinical implications of the inhibin-alpha, -betaA and -betaB subunits in uterine non-endometrioid cancers are still quite unclear. A series of 41 uterine non-endometrioid carcinomas were immunohistochemically analysed with monoclonal antibodies against inhibin-subunits. The staining reactions were correlated with several clinicopathological characteristics and clinical outcome. The inhibin-alpha subunit showed a significant association with age although the loss of this subunit did not affect the survival of patients with non-endometrioid carcinomas and did not constitute an independent prognostic parameter. The inhibin-betaA expression was not associated with any of the analysed clinicopathological parameters and did not affect patients’ survival. In contrast, a low betaB-subunit demonstrated a significant better cause-specific survival. Moreover, inhibin-βB did constitute an independent prognostic parameter in uterine non-endometrioid cancer patients. In contrast to inhibin-alpha and -betaA subunits, the inhibin-betaB subunit seems to have a substantial role in the carcinogenesis and pathology of uterine non-endometrioid carcinomas and might be used as a marker to identify high-risk patients and may aid in the selection of patients for a more aggressive adjuvant therapy.

Does high-grade endometrioid carcinoma (grade 3 FIGO) belong to type I or type II endometrial cancer? A clinical–pathological and immunohistochemical study

This study was aimed at determining whether high-grade endometrioid carcinomas (grade 3 International Federation of Gynecology and Obstetrics) might overlap, at least partially, non-endometrioid carcinomas (type II). To this end, a panel of clinical-pathological and immunohistochemical parameters was evaluated in three different populations: low-grade endometrioid carcinomas (LGECs; n = 57), high-grade endometrioid carcinomas (HGECs; n = 26), and non-endometrioid carcinomas (NECs; n = 30). Besides morphological appearance, HGECs appeared similar to LGECs in p53 immunostaining profile; features different from LGECs included a higher local aggressiveness, a higher invasion of lymph-vascular spaces, a lower expression of ERalpha and PR, and a higher proliferative index. HGECs were similar to NECs for local aggressiveness, invasion rate of lymph-vascular spaces, lymph node metastasis incidence, and proliferative index. HGECs, however, showed a lower rate of extra-nodal metastases, a lower incidence of p53 overexpression, and a higher positivity for ERalpha and PR. In conclusion, results from this study show that HGECs exhibit overlapping morphological and immunohistochemical features of both type I and type II endometrial carcinomas. Further research is needed to clarify the clinical value of this observation.

Abstract 1472: Bcl-3 as a carcinogenic factor in non-endometrioid endometrial carcinoma

Abstract Objectives : The aim of the study was to evaluate the Bcl-3 expression in normal endometrium, endometrial hyperplasia, and endometrial cancer. Methods : Retrospectively collected paraffin blocks from 30 cases of normal endometrium, 16 of endometrial hyperplasia, 24 of endometrioid endometrial cancer, and 12 of non-endometrioid endometrial cancer were analyzed. Expression of Bcl-3 was assessed by immunohistochemistry. The staining pattern was correlated with clinicopathological variables. Results : While none was positive in normal endometrium and endometrial hyperplasia and only 2 cases (8.3%) were positive for Bcl-3 in endometrioid endometrial cancer, 5 cases (41.7%) was positive in non-endometrioid endometrial cancer. Positive expression of Bcl-3 significantly correlated with non-endometrioid endometrial carcinoma (p=0.017), advanced stage (p=0.030), and high grade (p=0.001). Moreover, Bcl-3 positivity was associated with aggressive parameters including ovarian invasion (p=0.004), peritoneal cytology (p=0.029), lymphovascular space invasion (p=0.002), and lymph node metastases (p=0.029). In contrast, there was no significant correlation between expression of Bcl-3 and myometrial invasion or cervical invasion. In addition, Bcl-3 expression was not related to recurrence of disease. Conclusion : Bcl-3 is strongly expressed in non-endometrioid endometrial cancer, but less frequently in endometrioid endometrial cancer and hyperplasia. It is suggested that Bcl-3 is related with the carcinogenesis of non-endometrioid endometrial cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1472.

The novel estrogen-induced gene EIG121 regulates autophagy and promotes cell survival under stress.

We previously identified a novel estrogen-induced gene, EIG121, as being differentially regulated in endometrioid and nonendometrioid endometrial carcinoma. The function of EIG121 was unknown. Using a tetracycline-inducible system, we found that overexpression of EIG121, but not of LacZ, caused a profound suppression of cell growth. Subcellular fractionation and immunofluroscent labeling indicated that EIG121 was a transmembrane protein localized in the plasma membrane-late endosome–lysosome compartments. Deletion of the putative transmembrane domain abolished the membrane association. In cells overexpressing EIG121, cytoplasmic vacuoles accumulated after EIG121 induction, and the autophagosome marker LC3 translocated into punctuate, dot-like structures. Electron microscopy revealed that in cells overexpressing EIG121, autophagosomes were markedly increased. Overexpression of EIG121 also increased the cells containing acidic vesicles and induced lysosomal degradation of long-lived proteins. In MCF-7 cells, both EIG121 and LC3 were rapidly degraded by a lysosomal mechanism after starvation. Knockdown of EIG121 blocked starvation-induced LC3 degradation. By itself, knockdown of EIG121 did not affect cell survival. When combined with starvation or cytotoxic agents, EIG121 knockdown greatly increased apoptosis. Our results suggest that EIG121 is associated with the endosome–lysosome compartments and may have an important role in autophagy. Under unfavorable conditions such as starvation and exposure to cytotoxic agents, EIG121 may protect cells from cell death by upregulating the autophagy pathway.

Expression of mitochondrial transcription factor A in endometrial carcinomas: clinicopathologic correlations and prognostic significance

Mitochondrial transcription factor A (mtTFA) is necessary for both transcription and maintenance of mitochondrial DNA. This study was conducted to elucidate the clinicopathologic and prognostic significance of mtTFA in patients with endometrial carcinoma. This study investigated the relationship between the immunohistochemical expression of mtTFA and various clinicopathological variables in 276 endometrial carcinomas, including 245 endometrioid adenocarcinomas and 31 nonendometrioid carcinomas (21 serous carcinomas and 10 clear cell adenocarcinomas). Both uni- and multivariate regression analyses were performed. The mtTFA labeling index of endometrioid adenocarcinomas ranged from 0% to 98%, with a median value of 32%, which was selected as the cut-off point for mtTFA expression. The mtTFA expression in endometrioid adenocarcinomas was significantly associated with the surgical stage, myometrial invasion, lymphovascular space invasion, cervical invasion, and lymph node metastasis. In contrast, no correlation between clinicopathologic variables and mtTFA expression was found in nonendometrioid carcinomas. Correlation analysis between mtTFA and p53 expression by using the Pearson test showed significant correlation in endometrioid adenocarcinomas (P = 0.007), but no significant correlation in nonendometrioid carcinomas (P = 0.947). A univariate survival analysis showed that the 10-year overall survival rate of the patients with mtTFA-positive endometrioid adenocarcinoma was significantly worse than that of patients with mtTFA-negative endometrioid adenocarcinoma (80.8% vs. 93.8%, P = 0.012). However, the multivariate analysis revealed that mtTFA expression in endometrioid adenocarcinomas was no independent prognostic factor. The positive mtTFA expression is a useful maker for progression of the tumors and the poor prognosis of the patients in endometrioid adenocarcinomas.

Genetics of Endometrial Cancers

Endometrial cancers exhibit a different mechanism of tumorigenesis and progression depending on histopathological and clinical types. The most frequently altered gene in estrogen-dependent endometrioid endometrial carcinoma tumors is PTEN. Microsatellite instability is another important genetic event in this type of tumor. In contrast, p53 mutations or Her2/neu overexpression are more frequent in non-endometrioid tumors. On the other hand, it is possible that the clear cell type may arise from a unique pathway which appears similar to the ovarian clear cell carcinoma. K-ras mutations are detected in approximately 15%–30% of endometrioid carcinomas, are unrelated to the existence of endometrial hyperplasia. A β-catenin mutation was detected in about 20% of endometrioid carcinomas, but is rare in serous carcinoma. Telomere shortening is another important type of genomic instability observed in endometrial cancer. Only non-endometrioid endometrial carcinoma tumors were significantly associated with critical telomere shortening in the adjacent morphologically normal epithelium. Lynch syndrome, which is an autosomal dominantly inherited disorder of cancer susceptibility and is characterized by a MSH2/MSH6 protein complex deficiency, is associated with the development of non-endometrioid carcinomas.

Molecular clustering of endometrial carcinoma based on estrogen-induced gene expression

Identification of biomarkers potentially provides prognostic information that can help guide clinical decision-making. Given the relationship between estrogen exposure and endometrial cancer, especially low grade endometrioid carcinoma, we hypothesized that high expression of genes induced by estrogen would identify low risk endometrioid endometrial cancers. cDNA microarray and qRT- PCR verification were used to identify six genes that are highly induced by estrogen in the endometrium. These estrogen-induced biomarkers were quantified in 72 endometrial carcinomas by qRT-PCR. Unsupervised cluster analysis was performed, with expression data correlated to tumor characteristics. Time to recurrence by cluster was analyzed using the Kaplan-Meier method. A receiver operating characteristic (ROC) curve was generated to determine the potential clinical utility of the biomarker panel to predict prognosis. Expression of all genes was higher in endometrioid carcinomas compared to non-endometrioid carcinomas. Unsupervised cluster analysis revealed two distinct groups based on gene expression. The high expression cluster was characterized by lower age, higher BMI, and low grade endometrioid histology. The low expression cluster had a recurrence rate 4.35 times higher than the high expression cluster. ROC analysis allowed for the prediction of stage and grade with a false negative rate of 4.8% based on level of gene expression in endometrioid tumors. We have therefore identified a panel of estrogen-induced genes that have potential utility in predicting endometrial cancer stage and recurrence risk. This proof-of-concept study demonstrates that biomarker analysis may play a role in clinical decision making for the therapy of women with endometrial cancer.

MELF pattern invasion in endometrial carcinoma: association with low grade, myoinvasive endometrioid tumours, focal mucinous differentiation and vascular invasion

To investigate the frequency of microcystic, elongated and fragmented (MELF) pattern invasion in endometrial carcinoma and its association with other pathological findings. The histology slides from 170 consecutively accessioned endometrial malignancies were reviewed to identify cases showing MELF type invasion. Histological subtype, tumour grade, presence of squamous and mucinous differentiation, and frequency of lymphovascular space invasion (LVSI) were compared in MELF positive and negative cases. Additional stains for cytokeratin and stromal mucin were performed in the MELF positive tumours and immunohistochemistry to demonstrate vascular endothelium was performed in 12 selected cases. There were 133 endometrioid adenocarcinomas (EEC) and 37 non-endometrioid carcinomas. MELF type invasion was identified in 27 cases (15.9%) all of which were FIGO grade 1 or 2 myoinvasive adenocarcinomas of endometrioid type. The histochemical and immunohistochemical stains were useful in demonstrating the relatively subtle invasive foci in some tumours. MELF positive cases more frequently showed focal mucinous differentiation and LVSI. MELF type invasion appears restricted to low grade, myoinvasive carcinomas of endometrioid type and is more common in tumours exhibiting focal mucinous differentiation. These associations suggest that MELF changes represent a specific tumour-stromal interaction rather than a degenerative process. Tumours exhibiting MELF pattern invasion should be carefully examined for LVSI. Ancillary techniques, in particular cytokeratin immunohistochemistry, are useful in diagnostic assessment.

Lynch Syndrome—Related Endometrial Carcinomas Show a High Frequency of Nonendometrioid Types and of High FIGO Grade Endometrioid Types

Although endometrial cancer (EC) represents the second most common cancer after colonic cancer in patients with Lynch syndrome (LS), the pathologic features and behavior of LS-related EC are not well recognized. ECs from 23 patients (mean age 46.2 years) with MSH2 (16), MLH1 (6), and MLH1/MSH2 (1) constitutional mutations were evaluated for histologic type, FIGO grade, FIGO stage, association with tumors in other sites, and survival. For every LS-associated tumor, 2 same-age cases from patients with no family history of LS-associated cancer were evaluated (sporadic group). In LS-associated EC there were 13 (56.5%) endometrioid (eec) and 10 (43.5%) nonendometrioid carcinomas (neec), and among the sporadic tumors there were 44 (95.7%) eec and 2 (4.3%) neec (P = .001). The eec in women with germline LS mutation had a significantly higher FIGO grade (P = .0378) and more frequent vascular invasion than the controls. The mean survival of the entire group of 23 patients with LS-related EC was 17.326 (14.066 to 20.585). Mean survival according to FIGO stage was significant (P = .010). Difference in mean survival according to age of the patient at the time of the diagnosis (patients >46 years vs <46 years) was not significant. The mean survival of the mutated patients with eec was 20.462 (17.564 to 23.359) and was not significantly different from that of the mutated patients with neec, which was 14.240 (9.119 to 19.361). Log-rank analysis showed that histology did not affect the survival. However, the hazard ratio of neec patients, although not significant, resulted higher. Mean survival of patients with a neec tumor combined with an endometrioid component (14.375 [8.084 to 20.666]) was not different from that of patients with pure neec cancers (14.250 [7.885 to 20.615]). When compared with the control population, LS-related ECs show a wider variety of histologic types; a higher frequency of neec types despite the younger age of the patients, and a higher frequency of high grades among the eec.

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.