Elsevier

Human Pathology

Volume 32, Issue 6, June 2001, Pages 569-577
Human Pathology

Molecular Pathology Premalignancy
Molecular pathology of endometrial hyperplasia and carcinoma*,**

Presented in part at the Arthur Purdy Stout Society of Surgical Pathologists meeting, March 2001, Atlanta, GA.
https://doi.org/10.1053/hupa.2001.25929Get rights and content

Abstract

Four different genetic abnormalities may occur in endometrioid adenocarcinomas of the endometrium (mircosatellite instability and mutations in the PTEN, k-RAS and β-catenin genes), whereas nonendometrioid carcinomas of the endometrium often have p53 mutations and loss of heterozygosity on several chromosomes. Occasionally, a nonendometrioid carcinoma may develop as a result of dedifferentiation of a preexisting endometrioid carcinoma; in such a case, the tumor exhibits overlapping clinical, morphologic, immunohistochemical, and molecular features of the 2 types. The insaturation of microsatellite instability in endometrial carcinogenesis seems to occur late in the transition from complex hyperplasia to carcinoma, and it is preceded by progressive inactivation of MLH-1 by promoter hypermethylation. Moreover, the endometrioid adenocarcinomas that exhibit microsatellite instability show a stepwise progressive accumulation of secondary mutations in oncogenes and tumor suppressor genes that contain short-tandem repeats in their coding sequences. Mutations in the PTEN and k-RAS genes are also frequent in endometrioid adenocarcinomas of the endometrium, particularly in the tumors that exhibit microsatellite instability, whereas β-catenin mutations do not seem to be associated with such a phenomenon. HUM PATHOL 32:569-577. Copyright © 2001 by W.B. Saunders Company

Section snippets

Two types of endometrial carcinomas

Bockman first described the 2 main clinicopathologic types of EC.1 Type I tumors are low-grade and estrogen-related EEC that usually develop in pre- and perimenopausal women and coexist with or are preceded by complex and atypical endometrial hyperplasia. In contrast, type II tumors are nonendometrioid carcinomas (NEEC)—mainly papillary serous and clear cell carcinomas—largely occurring in older women; they are aggressive tumors, unrelated to estrogen stimulation, occasionally arising in

Molecular genetic alterations of endometrioid carcinomas of the endometrium

Four main molecular genetic alterations have been described in EEC: MI, which occurs in 25% to 30% of the cases3, 4, 5, 6, 7, 8; PTEN mutations in 37% to 61%9, 10, 11, 12, 13, 14, 15, 16, 17; k-RAS mutations in 10% to 30%18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28; and β-catenin mutations with nuclear protein accumulation in 25% to 38% of the cases.29, 30, 31, 32, 33 Although MI, PTEN, or k-RAS mutations may coexist in many cases, these molecular abnormalities are not usually associated with

Microsatellite Instability

Microsatellite DNA sequences are short-tandem repeats distributed throughout the genome. The most common dinucleotide sequence in eukaryotes is the (CA)n repeat, and there are 50,000 to 100,000 (CA)n repeats in the entire human genome. The genes responsible for MI encode proteins involved in DNA mismatch repair (hMSH-2, hMLH-1, hPMS1, or hPMS2). Mutations of these genes alter the ability of the cells to repair errors produced during DNA replication. Therefore, cells with mutated mismatch repair

Molecular consequences of MI in endometrioid carcinomas

The instauration of MI (the so-called mutator phenotype) in one cell has important molecular implications. The MI-associated mismatch repair deficiency leads to the accumulation of myriads of mutations in coding and noncoding DNA sequences. Short-tandem repeats, like microsatellites, are particularly susceptible to mismatch repair alterations, but they are predominantly located in noncoding DNA sequences; and the presence of subtle mutations (insertions or deletions) do not have consequences in

MI is secondary to DNA-altered methylation

As previously mentioned, MI was initially noted in colon cancers from patients with the HNPCC syndrome (but also in some cases of sporadic colon cancer). In these patients, germline and somatic mutations in the MSH-2 and MLH-1 genes have been detected in chromosomes 2p and 3p. Nevertheless, the frequency of mismatch repair gene mutations in sporadic colonic, gastric, or endometrial carcinomas with MI is very low,56, 57 which suggests that other mechanisms of gene inactivation must be involved.

PTEN

The tumor suppressor gene termed PTEN (phosphatase and tensin homologue deleted from chromosome 10), also called MMAC1 (mutated in multiple advanced cancers), is located on chromosome 10q23.3. It is reasonable to think that the genes encoding phosphatases, such as PTEN, act as tumor suppressor genes because their proteins may counteract the effect of the proteins encoded by the protein kinase group of protooncogenes.

LOH at chromosome 10q23 occurs in 40% of ECs.69, 70, 71 Somatic PTEN mutations

k-RAS

k-RAS mutations have been identified in 40% to 50% of colon carcinomas, but in approximately 10% to 30% of ECs.18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 Although some investigators have failed to show a correlation between k-RAS mutations and stage, grade, depth of invasion, age, or clinical outcome in EC,75 others have described associations between k-RAS mutations and the presence of coexistent endometrial hyperplasia,23 lymph node metastases, and clinical outcome in postmenopausal patients

β-catenin

The β-catenin gene (CTNNB1) maps to 3p21. β-Catenin seems to be important in the functional activities of both APC and E-cadherin.77, 78, 79 Beta-catenin is a component of the E-cadherin-catenin unit, essential for cell differentiation and maintenance of normal tissue architecture. β-Catenin also plays an important role in signal transduction. Increased cytoplasmic and nuclear levels of β-catenin produce transcriptional activation through the LEF/Tcf pathway.80 The APC protein downregulates

Summary

In this review, we have discussed the molecular abnormalities involved in EC, particularly in EEC. Although different molecular pathways have been described for EEC and de novo NEEC, we have provided evidence indicating that NEEC may also result from dedifferentiation of preexisting EEC. Such a hypothesis would explain the occurrence of tumors showing overlapping clinical, morphologic, and molecular features.

We may hypothesize that altered methylation might be an initial alteration in the

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    *

    Supported by grants FISS 99/1145, FISS 01/1656, and Fundación Cientifica de la Asociación Española Contra el Cáncer.

    **

    Address correspondence and reprint requests to Dr. Jaime Prat, Department of Pathology, Hospital de la Santa Creu i Sant Pau, Avda Sant Antoni Ma Claret 167, 08025 Barcelona, Spain.

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