Immunophenotypic features of MELF pattern invasion in endometrial adenocarcinoma: evidence for epithelial–mesenchymal transition

Stewart, Colin J.R.; Little, Leonie

doi:10.1111/j.1365-2559.2009.03327.x

Cited by 67 publications

(72 citation statements)

References 42 publications

(55 reference statements)

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“…These findings illustrate the importance of considering microanatomical variation in staining and lend further support to the hypothesis that MELF pattern invasion represents an active rather than a degenerative process during the progression of endometrial carcinoma. 19,20 Expression of cyclin D1 in MELF areas would also be consistent with epithelial-mesenchymal transition as cyclin D1 is characteristically upregulated during this process in other types of carcinoma. [12][13][14]22,23 Abnormalities of b-catenin have also been shown in a significant proportion of endometrial neoplasms.…”

Section: Endometrial Carcinoma Invasionmentioning

confidence: 82%

“…[12][13][14]22,23 Earlier, we have noted that areas of MELF-type invasion are strongly positive for CK7 and show reduced E-cadherin and hormone receptor expression. 20 These findings sometimes differed from those of the predominant conventional tumor areas, illustrating the importance of correlating the immunophenotypic findings with tumor distribution and morphology. In this study, we have further investigated the importance of microanatomical relationships in endometrial adenocarcinoma by comparing the expression of cell-cycle-related proteins within specific tumor areas, particularly in foci showing MELF pattern invasion.…”

Section: Discussionmentioning

confidence: 99%

“…We have noted earlier that CK7 is strongly expressed in areas of MELF pattern invasion within endometrial adenocarcinoma and therefore could be used as a reference for comparing the additional immunohistological preparations. 20 The staining patterns were assessed separately in the predominant areas of conventional myoinvasive adenocarcinoma and at the advancing tumor margin, especially in the areas exhibiting MELF-type features. In those sections that included several MELF foci, the predominant pattern was recorded although in practice staining was fairly uniform in these areas.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…11,17 We have noted earlier that endometrial carcinomas exhibiting a distinctive pattern of invasion comprising microcystic, elongated and fragmented ('MELF') glands 18 show specific pathological associations and morphological changes, some of which are suggestive of epithelial-mesenchymal transition. 19,20 Therefore, in this study, we have further explored the cellular alterations at the invasive margin of endometrial adenocarcinoma by comparing the expression of the cell-cycle-related proteins, cyclin D1, b-catenin and p16, between conventional tumor areas and foci exhibiting MELF pattern invasion. 19 and there were three subsequently identified tumors.…”

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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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Section: Endometrial Carcinoma Invasionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Immunohistochemistrymentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…16 Further studies are required to determine the significance of focal cyclin D1 expression in cervical adenocarcinoma but the present findings further illustrate the importance of considering microanatomical variations in staining patterns, even if these are restricted to a minority of cells, as they may be relevant to tumor progression. 33,34 Disclosure/conflict of interest…”

Section: Discussionmentioning

confidence: 99%

Cyclin D1 immunoreactivity in normal endocervix and diagnostic value in reactive and neoplastic endocervical lesions

Little

Stewart

2010

Modern Pathology

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It may be difficult to distinguish reactive glandular lesions from adenocarcinoma in situ of the uterine cervix, and although several immunohistochemical markers have established value in this diagnostic setting, none is completely reliable. We have noted that neoplastic endocervical lesions often show loss of nuclear cyclin D1 expression in contrast to benign glandular cells. Therefore, we investigated cyclin D1 staining in a series of 64 cervical biopsy specimens including examples of normal and reactive endocervical epithelium, adenocarcinoma in situ, stratified mucin-producing intraepithelial lesions, and invasive adenocarcinoma. Thirteen specimens also included a component of high-grade cervical squamous intraepithelial neoplasia. Normal endocervical epithelium usually expressed cyclin D1, although staining was typically focal, and there was increased immunoreactivity in reactive and metaplastic glandular cells including tubo-endometrioid metaplasia. In contrast, most cases of adenocarcinoma in situ were completely negative and, therefore, cyclin D1 staining distinguished benign from neoplastic epithelial cells. Although focal cyclin D1 expression was observed in 5/19 cases of adenocarcinoma in situ, the staining was associated with more marked cytological atypia precluding confusion with a reactive process. The invasive adenocarcinomas were mainly negative for cyclin D1. However, focal staining was observed in 10/19 cases and was mainly restricted to cells at the deep tumor margin, or to small infiltrative glands and detached cell clusters within the stroma. In conclusion, cyclin D1 can be included within an immunohistochemical panel to aid in the distinction between reactive cervical glandular lesions and adenocarcinoma in situ. The localized distribution of staining within invasive lesions suggests that cyclin D1 up-regulation has a specific role during the progression of some endocervical adenocarcinomas.

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Nicotinamide N‐methyltransferase is related to MELF pattern invasion in endometrioid carcinoma

et al. 2021

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Grade 1 (G1) endometrioid carcinoma (EC) is relatively a good prognosis. However, in a minority of cases, G1 shows an aggressive histological pattern known as the microcystic, elongated, and fragmented (MELF) pattern. We previously reported that EC with high expression levels of S100A4 and serum deprivation‐response protein (SDPR) was related to MELF pattern invasion. However, the molecular features of the invasive front area of the MELF pattern have not been investigated. In this study, we searched for genes preferentially expressed in the invasive front area of EC with the MELF pattern using laser microdissection and RNA sequencing, and showed that nicotinamide N‐methyltransferase (NNMT) is related to MELF pattern invasiveness. Immunohistochemical analyses confirmed high NNMT expression in the invasive front area of the MELF pattern. Moreover, NNMT promoted migration, invasion, colony formation, epithelial–mesenchymal transition (EMT), and chemoresistance using EC cell lines. We speculate that depletion of NNMT promotes histone methylation and leads to tumor suppression because NNMT consumes S‐adenosyl methionine (SAM), which is an essential methylation cofactor. NNMT knockout cells showed enhanced expression of H3K9me2. RNA sequencing using NNMT knockout cell lines suggested that methylation of H3K9 leads to repression of the transcription of various oncogenic genes. Our findings demonstrate the possibility that NNMT inhibitors, which are expected to be used for the treatment of metabolic disorders, would be effective for the treatment of aggressive EC. This is the first report of gene analyses focusing on the morphological changes associated with MELF pattern invasion of EC.

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Immunophenotypic features of MELF pattern invasion in endometrial adenocarcinoma: evidence for epithelial–mesenchymal transition

Cited by 67 publications

References 42 publications

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

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

Cyclin D1 immunoreactivity in normal endocervix and diagnostic value in reactive and neoplastic endocervical lesions

Nicotinamide N‐methyltransferase is related to MELF pattern invasion in endometrioid carcinoma

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