Molecular and Pathologic Aspects of Endometrial Carcinogenesis

Hecht, Jonathan L.; Mutter, George L.

doi:10.1200/jco.2006.06.7173

Cited by 477 publications

(360 citation statements)

References 83 publications

(6 reference statements)

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“…When KRAS mutations are associated with PTEN mutations, neoplastic glands frequently result in endometrioid glandular morphology, as seen in endometrial hyperplasias, endometrial intraepithelial neoplasia lesions, and endometrioid adenocarcinoma. [26][27][28] In our study, PTEN mutations were not observed in any cases, which may suggest that papillary mucinous metaplasia is not a direct precursor lesion of endometrioid adenocarcinoma. Nevertheless, papillary mucinous metaplasia may have some correlation with endometrioid adenocarcinoma, because one case of papillary mucinous metaplasia was associated endometrioid adenocarcinoma as separate lesion in the same patient and three patients had received tamoxifen treatment following breast cancer surgery.…”

Section: Discussioncontrasting

confidence: 42%

Papillary mucinous metaplasia of the endometrium as a possible precursor of endometrial mucinous adenocarcinoma

et al. 2012

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Mucinous adenocarcinoma is an uncommon type of endometrial adenocarcinoma for which precursor lesions have yet to be clarified. During a review of noncancerous endometrial lesions in postmenopausal women, we found that mucinous endometrial glands showed variable degrees of epithelial changes that ranged from the formation of simple tubular glands to the formation of complex glands with papillary tufts, and some of the glands with papillary tufts were architecturally similar to low-grade mucinous adenocarcinomas. Based on histological similarities, we have postulated that mucinous metaplasia could be a precursor lesion of mucinous adenocarcinoma. To explain the pathogenetic significance of endometrial mucinous metaplasia, we analyzed the immunohistochemical expression of ER, PR, MKI67, PTEN, b-catenin, P16 INK4A , TP53, and PAX2 in 21 endometrial mucinous metaplasias, screened for KRAS (n ¼ 16) and PTEN (n ¼ 14) mutations, and compared expression patterns between samples with simple mucinous glands, those with complex glands having intraglandular papillary tufts, and endometrioid adenocarcinomas. Compared with the surrounding flat mucinous epithelium and simple mucinous metaplasia, the intraglandular papillary tufts associated with papillary mucinous metaplasia were characterized by selectively decreased expression of PAX2 (P ¼ 0.029) and PR (Po0.001), and overexpression of P16 INK4A (P ¼ 0.014). There were no significant differences in the levels of expression of ER, PTEN, b-catenin, TP53, and MKI67 between the two groups. In contrast with endometrioid adenocarcinomas, rates of MKI67 proliferation were very low in both groups. Mutations in KRAS were identified in 89% of cases with papillary mucinous metaplasia, in contrast to 14% in simple mucinous metaplasia (P ¼ 0.001). No PTEN mutations were observed in either of the two groups. In conclusions, immunohistochemical and molecular genetic profiling suggest that papillary mucinous metaplasia is a possible precancerous lesion in a subset of endometrial carcinomas. Modern Pathology (2012Pathology ( ) 25, 1496Pathology ( -1507 doi:10.1038/modpathol.2012; published online 6 July 2012Keywords: endometrium; mucinous; mucinous metaplasia; papillary metaplasia; PAX2; P16 INK4A ; senescence Endometrial carcinoma is classified into two major groups, types I and II, according to clinicopathological features and molecular pathogenetic mechanisms. Most type I tumors are characterized by an endometrioid histology and are frequently associated with PTEN mutations, whereas type II tumors show a serous histology and are frequently associated with the altered expression of TP53 tumor-suppressor genes. Endometrial hyperplasia and endometrial intraepithelial carcinoma are thought to be precursor lesions of type I and II endometrial carcinomas, respectively. However, this simplified classification and their precursor lesions cannot explain the pathogenesis of all endometrial carcinomas.Mucinous adenocarcinoma, an uncommon type of endometrial adenocarcinoma comprising o10% of endometr...

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Section: Discussioncontrasting

confidence: 42%

Papillary mucinous metaplasia of the endometrium as a possible precursor of endometrial mucinous adenocarcinoma

et al. 2012

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“…3 Among the molecular methods available, here we have implemented the currently most accepted analyses concerning genetics alterations frequently encountered in single endometrial and ovarian cancers (microsatellite instability, b-catenin expression, and CTNNB1 mutations). 19,20 It is striking that microsatellite instability analysis alone was informative only in two (18%) cases in our sample set. It was confirmatory in one case and helped define diagnosis in the unclassified S2 case.…”

Section: Discussionmentioning

confidence: 89%

Mitochondrial DNA genotyping efficiently reveals clonality of synchronous endometrial and ovarian cancers

et al. 2014

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Simultaneous independent primary tumors of the female genital tract occur in 1-2% of gynecological cancer patients, 50-70% of which are synchronous tumors of the endometrium and ovary. Recognition of synchrony upon multiple tumors is crucial for correct prognosis, therapeutic choice, and patient management. Current guidelines for determining synchrony, based on surgical and histopathological findings, are often ambiguous and may require further molecular analyses. However, because of the uniqueness of each tumor and of its intrinsic heterogeneity, these analyses may sometimes be inconclusive. A role for mitochondrial DNA genotyping was previously demonstrated in the diagnosis of synchronous endometrial and ovarian carcinoma. We have analyzed 11 sample pairs of simultaneously revealed endometrial and ovarian cancers and have thereby applied conventional histopathological criteria, current molecular analyses (microsatellite instability, b-catenin immunohistochemical staining/CTNNB1 mutation screening), and mitochondrial DNA sequencing to distinguish separate independent tumors from metastases, comparing the performance and the informative potential of such methods. We have demonstrated that in ambiguous interpretations where histopathological criteria and canonical molecular methods fail to be conclusive, mitochondrial DNA analysis may act as a needle of balance and allow to formulate a diagnosis in 45.5% of our cases. Additional advantages of mitochondrial DNA genotyping, besides the high level of information we demonstrated here, are the easy implementation and the need for small amounts of starting material. Our results show that mitochondrial DNA genotyping may provide a substantial contribution to indisputably recognize the metastatic nature of simultaneously detected endometrial and ovarian cancers and may change the final staging and clinical management of these patients. Modern Pathology (2014) 27, 1412-1420; doi:10.1038/modpathol.2014.39; published online 14 March 2014 Keywords: gynecological cancer; mitochondrial DNA mutations; synchronous tumors About 1-2% of women with gynecological cancers are found to have simultaneous independent primary malignancies. Synchronous tumors in the ovary and endometrium are the commonest combination (50-70%) among all synchronous female genital tract malignancies. Only a subset of these can be accurately categorized by standard histological examination. Criteria for synchrony diagnosis were first documented in 1985 1 and subsequently detailed in 1998. 2 Unfortunately, a relevant fraction of cases remains which may not be classified with confidence, either because of widespread involvement, in which case the distinction is of academic rather than practical or prognostic significance, or, more importantly, because of overlapping or

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“…[12][13][14]22,23 Abnormalities of b-catenin have also been shown in a significant proportion of endometrial neoplasms. 3,5 Mutations have been recorded in 13-31% cases and appear more common in lowgrade endometrioid adenocarcinomas, [31][32][33][34][35][36] whereas an abnormal immunolocalization in the form of reduced membrane staining with diffuse cytoplasmic and/or nuclear staining has been recorded in 25-76% cases. [34][35][36][37][38][39] Most b-catenin mutations lead to decreased protein degradation and are associated with altered (usually nuclear) immunoreactivity.…”

Section: Endometrial Carcinoma Invasionmentioning

confidence: 99%

“…1,2 The pathogenesis of uterine endometrioid adenocarcinoma has been subject to intense investigation in recent years, and several common molecular abnormalities have been identified, including inactivation of the tumor suppressor gene PTEN, mutations of the k-ras oncogene and microsatellite instability. [3][4][5][6] Additional changes that occur in a significant proportion of cases include dysregulation of the Wnt and retinoblastoma (Rb) signaling pathways. These are complex and interconnected pathways, each of which includes multiple positive and negative regulatory factors that influence cellular proliferation and differentiation.…”

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confidence: 99%

Expression of cell cycle regulatory proteins in endometrial adenocarcinoma: variations in conventional tumor areas and in microcystic, elongated and fragmented glands

et al. 2009

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Endometrial adenocarcinomas may show a distinctive pattern of invasion characterized by the presence of microcystic, elongated and fragmented glands, often most evident along the advancing tumor margin. Earlier, we have shown that these changes appear restricted to low-grade endometrioid carcinomas, many of which show focal mucinous differentiation and lymphovascular space invasion. However, the molecular alterations associated with this morphological alteration are not known. In this study, we have examined immunoreactivity for the cell cycle regulatory proteins cyclin D1, p16 and b-catenin in 22 endometrial carcinomas, specifically comparing the results in conventional tumor areas and in foci in which the glands exhibited microcystic, elongated and fragmented appearances. The conventional neoplastic glands exhibited cyclin D1 and p16 expression in most cases, with 450% tumor cells positive in 8 cases and 11 tumors, respectively. Membranous expression of b-catenin was usually preserved, with variable cytoplasmic and nuclear staining. Cyclin D1 and b-catenin predominantly stained cells at the peripheral or basal aspect of the conventional glands, whereas p16 was more uniformly expressed centrally. Tumor foci composed of microcystic, fragmented and elongated glands showed strong expression of cyclin D1 and p16, sometimes in contrast to unstained contiguous or adjacent conventional neoplastic elements, and there was also loss or fragmentation of membranous b-catenin staining. Intravascular tumor cells also expressed cyclin D1 and p16 and therefore the immunostains often highlighted subtle foci of lymphovascular invasion. The heterogenous expression of cell cycle regulatory proteins within endometrial adenocarcinoma illustrates the importance of assessing microanatomical variations in immunoreactivity, particularly at the advancing margin of tumors. The upregulation of cyclin D1 and p16, together with loss of membranous b-catenin expression in microcystic, fragmented and elongated glands, is similar to epithelial-mesenchymal transitions observed in other malignancies and suggests that this pattern of invasion represents an active rather than a degenerative cellular process. Modern Pathology (2009) 22, 725-733; doi:10.1038/modpathol.2009 published online 6 March 2009 Keywords: endometrial; carcinoma; invasion; MELF; epithelial-mesenchymal transition; immunohistochemistry Endometrial carcinomas can be divided into two major groups on the basis of clinicopathological, immunohistological and molecular features. 1,2 The more common (type 1) subgroup accounts for 80-85% of cases and mainly comprises endometrioid adenocarcinomas of low-to-intermediate grade. These tumors typically occur in perimenopausal and younger postmenopausal patients, often arise in hyperestrogenic states and are associated with atypical endometrial hyperplasia/endometrial intraepithelial neoplasia. Frequently, type 1 carcinomas are confined to the uterine corpus at the time of diagnosis (stage 1), and the prognosis in such patients is generally ...

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Molecular and Pathologic Aspects of Endometrial Carcinogenesis

Cited by 477 publications

References 83 publications

Papillary mucinous metaplasia of the endometrium as a possible precursor of endometrial mucinous adenocarcinoma

Papillary mucinous metaplasia of the endometrium as a possible precursor of endometrial mucinous adenocarcinoma

Mitochondrial DNA genotyping efficiently reveals clonality of synchronous endometrial and ovarian cancers

Expression of cell cycle regulatory proteins in endometrial adenocarcinoma: variations in conventional tumor areas and in microcystic, elongated and fragmented glands

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