p53 in endometrial cancer and its putative precursors: Evidence for diverse pathways of tumorigenesis

Sherman, Mark E.; Bur, Martin; Kurman, Robert J.

doi:10.1016/0046-8177(95)90204-x

Cited by 321 publications

(201 citation statements)

References 30 publications

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“…Cytologically, the cells show marked nuclear membrane irregularities, chromatin that varies from vesicular to smudgy, mitoses including abnormal forms, and apoptotic bodies. EIC may be found in the absence of invasive serous carcinoma, and like the latter, EIC demonstrates strong, diffuse immunostaining for p53 protein and Ki-67 and p53 gene mutations (1,21,22). Noninvasive lesions resembling EIC, termed "intraepithelial carcinoma," may be identified in approximately 25% of serous carcinoma patients in the endocervix, fallopian tube, and peritoneum and on the surface of the ovary (Fig.…”

Section: Evidence From Precursor Studies Supporting the Existence Of mentioning

confidence: 96%

“…Features favoring EIC include patient age over 60 years, a background of atrophic endometrium, and strong, diffuse p53 and Ki-67 immunostaining (1,18,21). Eosinophilic metaplasia with atypia may pose an especially challenging differential diagnosis, but metaplastic lesions are usually more focal and the cells show degenerative, smudgy chromatin lacking well-preserved nuclear features of malignancy.…”

Section: Evidence From Precursor Studies Supporting the Existence Of mentioning

confidence: 99%

“…The goal of this review is to propose a dualistic model of endometrial carcinogenesis that incorporates two pathways that differ in regard to epidemiologic risk factors, histopathologic lesions, and molecular events (1). The "classic" pathway is proposed as a mechanism by which indolent tumors develop from hyperplastic precursors in an estrogen-rich milieu.…”

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confidence: 99%

“…Type 2 tumors are unrelated to these features, behave aggressively, and lack the progesterone responsiveness of type 1 tumors. Building on these clinical observations, it has been suggested that the majority of type 1 tumors correspond to the endometrioid type of endometrial carcinoma, whereas type 2 tumors probably include most serous carcinomas and some other aggressive types (1). Although the correspondence between specific histopathologic tumor types and risk factors is imperfect, this generalization has been used to propose a dualistic model of endometrial carcinogenesis that may prove useful in planning future etiologic studies and, ultimately, in clinical practice.…”

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confidence: 99%

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Theories of Endometrial Carcinogenesis: A Multidisciplinary Approach

2000

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Historical observations have suggested that endometrial carcinomas vary in histopathologic appearance and clinical features. More recent, systematic studies have provided epidemiologic, clinicopathologic, and molecular support for these observations. Specifically, studies suggest that the most common type of endometrial carcinoma, endometrioid adenocarcinoma, develops from endometrial hyperplasia in the setting of excess estrogen exposure and usually pursues an indolent clinical course. In contrast, a minority of endometrial carcinomas, best represented by serous carcinoma, do not seem to be related to estrogenic risk factors or elevated serum hormone levels, and these tumors seem to develop from atrophic rather than hyperplastic epithelium. We have proposed that serous carcinomas develop from "endometrial intraepithelial carcinoma," a lesion representing malignant transformation of the endometrial surface epithelium. Whereas endometrioid carcinoma and endometrial hyperplasia are associated with microsatellite instability and ras and PTEN mutations, serous carcinoma and endometrial intraepithelial carcinoma are associated with p53 mutations and abnormal accumulation of p53 protein. Based on these data regarding the pathogenesis of endometrioid and serous carcinoma, we have proposed a dualistic model of endometrial carcinogenesis incorporating a "classic" estrogen-driven pathway and an "alternative" pathway seemingly unrelated to hormones. It is hoped that further studies may permit the extension and modification of this model and that these advances will lead to improved diagnosis, management, and prevention.

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Section: Evidence From Precursor Studies Supporting the Existence Of mentioning

confidence: 96%

Section: Evidence From Precursor Studies Supporting the Existence Of mentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Theories of Endometrial Carcinogenesis: A Multidisciplinary Approach

2000

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“…These tumors, now generally referred to as Type 1 endometrial carcinomas, tend to occur in nulliparous, obese, hypertensive, and/or diabetic women, frequently with ovarian hormone-producing lesions, or in women who have received exogenous estrogens, and are generally low grade and low stage, slowly progressive, and associated with a favorable prognosis. Type 2 endometrial carcinomas, on the other hand, occur in women who are not constitutionally predisposed in any known way, and usually occur on a background of nonhyperplastic, often atrophic endometrium, and these carcinomas tend to be high grade, frequently of nonendometrioid type, often present at a high clinical stage, and have a highly unfavorable prognosis (1,3,(43)(44)(45)(46)(47). These clinical and pathologic differences, as well as their implications for the pathogenesis of the two different types of carcinoma, are discussed by Sherman (1) in much greater detail.…”

Section: Endometrial Hyperplasia and Carcinoma (Sg Silverberg) 319mentioning

confidence: 99%

Problems in the Differential Diagnosis of Endometrial Hyperplasia and Carcinoma

Silverberg

2000

Modern Pathology

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The differential diagnosis of endometrial hyperplasia and well-differentiated endometrioid adenocarcinoma is complicated not only by the resemblance of these lesions to each other, but also by their tendency to be overdiagnosed (particularly hyperplasia) on the background of polyps, endometritis, artifacts, and even normally cycling endometrium. Atypical hyperplasia may also be overdiagnosed when epithelial metaplastic changes occur in simple or complex hyperplasia without atypia. Lowgrade adenocarcinomas are best recognized by architectural evidence of stromal invasion, usually in the form of stromal disappearance, desmoplasia, necrosis, or combinations of these findings between adjacent glands. Endometrioid adenocarcinomas are usually Type 1 cancers associated with manifestations of endogenous or exogenous hyperestrogenic stimulation and a favorable prognosis. Subtypes include adenocarcinomas with squamous differentiation and secretory, ciliated cell and villoglandular variants. Rules and pitfalls in the grading of endometrioid adenocarcinomas and the estimation and reporting of myometrial invasion are presented.KEY WORDS: Differential diagnosis, Endometrial carcinoma, Endometrial hyperplasia, Grading, Myoinvasion. Mod Pathol 2000;13(3):309 -327The purpose of this article is to review the relationships between hyperplasia and adenocarcinoma of the endometrium, with an emphasis on the differential diagnostic problems both between these two lesions and between them and other entities that enter into the differential diagnostic picture. However, differential diagnosis is not the only relationship between endometrial hyperplasia and carcinoma. During the course of this review, we briefly consider the questions of the progression of endometrial hyperplasia (and specifically its atypical variant) to carcinoma, as well as the prognostic effect of the presence of endometrial hyperplasia in cases of endometrial carcinoma, and the biologic significance of carcinoma that arises in the presence or absence of hyperplasia. The last of these topics, however, is considered in much greater detail in the article by Sherman (1) in this issue.There are four possible approaches to making the differential diagnosis between atypical endometrial hyperplasia and well-differentiated endometrioid adenocarcinoma of the endometrium. These approaches may be summarized briefly as follows:(1) adenocarcinoma in situ, (2) endometrial intraepithelial neoplasia (EIN), (3) nonhistologic techniques, and (4) so-called "routine" light microscopy.The oldest of these approaches is the first, in which it is assumed that there must be an entity, conveniently named adenocarcinoma in situ, that is intermediate between the most severe atypical hyperplasia and the earliest focal change recognizable as invasive adenocarcinoma. Probably the most effective rebuttal of this concept for diagnostic purposes was made by Professor Harold Fox, who stated, "A true adenocarcinoma in situ of the endometrium is one in which the glands have undergone neoplastic change bu...

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Molecular genetic evidence for the conversion hypothesis of the origin of malignant mixed Müllerian tumours

et al. 1997

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The origin of malignant mixed Müllerian tumours (MMMTs) has long been debated, due to the indefinite relationship between epithelial and mesenchymal malignant cells. In order to obtain insight into the clonal relationship between the two components of these tumours, molecular genetic changes were investigated at the level of loss of heterozygosity (LOH) in both cells types. LOH was studied in a series of six cases with 74 polymorphic microsatellite markers mapping to 19 different chromosomes. The epithelial and the mesenchymal neoplastic cells were separately microdissected from formalin‐fixed, paraffin‐embedded tissue, prior to DNA isolation. LOH was observed for 35 different markers mapping to chromosomes 3, 6, 8, 11, 15, 16, 17, 18, 21, and X. The most frequently involved chromosomes were 17p, 17q, 11q, 15q, and 21q. LOH was observed in five out of six cases and identical alleles were lost in the epithelial and in the mesenchymal cells. No genetic differences were observed between the two cell types for any of the informative markers. Immunohistochemistry (IHC) and TP53 mutation analysis revealed involvement of TP53 in all cases. Mutations were identified in five MMMTs. In four tumours, of which three had a missense mutation, strong nuclear staining for p53 was observed. In the remaining two cases, the mutation resulted in a stop codon, with no nuclear staining for p53 by IHC. The results support a monoclonal origin of MMMTs, with the absence of genetic changes uniquely associated with either of the phenotypes. The latter finding is compatible with current opinion that these neoplasms should be considered as metaplastic carcinomas and supports the conversion hypothesis. © 1997 John Wiley & Sons, Ltd.

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p53 in endometrial cancer and its putative precursors: Evidence for diverse pathways of tumorigenesis

Cited by 321 publications

References 30 publications

Theories of Endometrial Carcinogenesis: A Multidisciplinary Approach

Theories of Endometrial Carcinogenesis: A Multidisciplinary Approach

Problems in the Differential Diagnosis of Endometrial Hyperplasia and Carcinoma

Molecular genetic evidence for the conversion hypothesis of the origin of malignant mixed Müllerian tumours

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