Heterogeneous distribution of K-ras-mutated epithelia in mucinous ovarian tumors with special reference to histopathology

Mandai, Masaki; Konishi, Ikuo; Kuroda, Hisao; Komatsu, Takayuki; Yamamoto, Shinichi; Nanbu, Kanako; Matsushita, K; Fukumoto, Manabu; Yamabe, Hirohiko; Mori, Takahide

doi:10.1016/s0046-8177(98)90387-2

Cited by 74 publications

(49 citation statements)

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“…2,12 This hypothesis is also supported by the results of recent investigations of the genetic alterations occuring in ovarian mucinous tumors. [13][14][15] An increasing frequency of codon 12/13 K-ras mutations in benign, borderline tumors, and carcinomas has been reported, supporting that K-ras mutational activation is an early event in mucinous ovarian tumorigenesis ( Figure 6). [13][14][15] Using microdissection, we have detected the same K-ras mutation in separate areas exhibiting different histological grades within the same neoplasm in 15 mucinous tumors.…”

Section: Somatic Geneticsmentioning

confidence: 93%

Ovarian carcinomas, including secondary tumors: diagnostically challenging areas

Prat

2005

Mod Pathol

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The differential diagnosis of ovarian carcinomas, including secondary tumors, remains a challenging task. Mucinous carcinomas of the ovary are rare and can be easily confused with metastatic mucinous carcinomas that may present clinically as a primary ovarian tumor. Most of these originate in the gastrointestinal tract and pancreas. International Federation of Gynecology and Obstetrics (FIGO) stage is the single most important prognostic factor, and stage I carcinomas have an excellent prognosis; FIGO stage is largely related to the histologic features of the ovarian tumors. Infiltrative stromal invasion proved to be biologically more aggressive than expansile invasion. Metastatic colon cancer is frequent and often simulates ovarian endometrioid adenocarcinoma. Although immunostains for cytokeratins 7 and 20 can be helpful in the differential diagnosis, they should always be interpreted in the light of all clinical information. Occasionally, endometrioid carcinomas may exhibit a microglandular pattern simulating sex cord-stromal tumors. However, typical endometrioid glands, squamous differentiation, or an adenofibroma component are each present in 75% of these tumors whereas immunostains for calretinin and alpha-inhibin are negative. Endometrioid carcinoma of the ovary is associated in 15-20% of the cases with carcinoma of the endometrium. Most of these tumors have a favorable outcome and they most likely represent independent primary carcinomas arising as a result of a Mü llerian field effect. Although the criteria for distinguishing metastatic from independent primary carcinomas rely mainly upon conventional clinicopathologic findings, loss of heterozygosity and gene mutation analyses can be helpful. Transitional cell carcinomas are distinguished from undifferentiated carcinomas by the presence of thick, undulating papillae with smooth luminal borders, microspaces, and tumor cells with distinctive 'urothelial' appearance. Krukenberg tumors are metastatic adenocarcinomas traditionally perceived as composed of mucin-filled signet-ring cells associated with a striking proliferation of the ovarian stroma but many variations on this pattern occur.

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Section: Somatic Geneticsmentioning

confidence: 93%

Ovarian carcinomas, including secondary tumors: diagnostically challenging areas

Prat

2005

Mod Pathol

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“…Most studies have shown a high and increasing frequency of KRAS mutations in mucinous cystadenomas, borderline tumors and carcinomas, ranging from 33 to 86%. 47,70,72,75,87,88 Several groups 75,87,88 have noted similar KRAS mutation patterns in benign, borderline and malignant mucinous areas within the same neoplasm, which suggests that KRAS mutation is an early event in mucinous tumorigenesis. It has also been noted that the rate of TP53 mutations is lower in mucinous borderline tumors than mucinous carcinomas (13 vs 40%).…”

Section: Molecular Genetic Datamentioning

confidence: 98%

Origins and molecular pathology of ovarian cancer

2005

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Epithelial ovarian cancer comprises the majority of malignant ovarian tumors in adult women. These neoplasms are classified into distinct morphologic categories based on the appearance of the epithelium into tumors of serous, mucinous, endometrioid, clear cell, transitional, squamous, mixed and undifferentiated type. Current data indicate that each of these histologic subtypes is associated with distinct morphologic and molecular genetic alterations: high-grade serous and possibly endometrioid carcinomas most probably arise from surface epithelial inclusion glands with TP53 mutations and dysfunction of BRCA1 and/or BRCA2; low-grade serous carcinomas probably arise in a stepwise fashion in an adenoma-borderline tumor-carcinoma sequence from typical to micropapillary borderline tumors to low-grade invasive serous carcinoma via activation of the RAS-RAF signaling pathway secondary to mutations in KRAS and BRAF; mucinous carcinomas arise via an adenoma-borderline tumor-carcinoma sequence with mutations in KRAS; low-grade endometrioid carcinomas arise from endometriosis via mutations in CTNNB1 (the gene encoding b-catenin) and PTEN. Although the morphologic data strongly support an origin of clear cell carcinoma from endometriosis, there is limited data on the genetic alterations in these uncommon tumors. Thus it is likely that most low-grade, relatively indolent ovarian carcinomas of serous, mucinous and endometrioid type arise from pre-existing cystadenomas or endometriosis whereas most high-grade serous carcinomas arise without an easily identifiable precursor lesion. Modern Pathology (2005) 18, S19-S32. doi:10.1038/modpathol.3800306Keywords: ovarian cancer; ovarian borderline tumors; histogenesis; molecular pathology Epithelial ovarian cancer comprises the majority of malignant ovarian tumors in adult women. These neoplasms are classified into distinct morphologic categories based on the appearance of the epithelium into tumors of serous, mucinous, endometrioid, clear cell, transitional, squamous, mixed and undifferentiated type. 1,2 Two types of ovarian surface epithelial lesions have been described as possible precursors of these carcinomas: lesions that appear in situ in surface epithelium or surface epithelial inclusion glands (SEIG); and preexisting benign epithelial ovarian tumors and endometriosis. The morphologic and genetic data implicating each as a precursor lesion of the major histologic subtypes of ovarian carcinoma are discussed. Surface epithelium and surface epithelial inclusion glands as precursor lesions Morphologic DataTwo types of morphologic data are available regarding the malignant potential of ovarian surface epithelium and inclusion glands, alterations in these structures and studies on microscopic ovarian carcinoma.Surface epithelium and surface epithelial inclusion glands Despite the widespread acceptance of the origin of surface epithelial cancers from the ovarian surface epithelium and its inclusion glands, only rarely have putative precursor lesions been described at these sites. Two...

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“…For example, p53 mutations have been found in 37% of stage I and II tumours and 58% of stage III and IV tumours (Shelling et al, 1995) and the K-ras oncogene is activated in a proportion of these tumours, particularly those of mucinous histology (Mandai et al, 1998). There are also a number of tumour suppressor genes (e.g.…”

mentioning

confidence: 99%

“…Despite this progress, the molecular changes associated with the development and progression of this disease remain unclear. There is increasing evidence for heterogeneity in the pathway to malignancy with respect to histologic sub-types (Mandai et al, 1998;Obata et al, 1998;Wright et al, 1999) but there is no established model for ovarian tumorigenesis.…”

mentioning

confidence: 99%

Decreased expression of the Id3 gene at 1p36.1 in ovarian adenocarcinomas

et al. 2001

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SummaryThe molecular events that drive the initiation and progression of ovarian adenocarcinoma are not well defined. We have investigated changes in gene expression in ovarian cancer cell lines compared to an immortalized human ovarian surface epithelial cell line (HOSE) using a cDNA array. We identified 17 genes that were under-expressed and 10 genes that were over-expressed in the cell lines compared to the HOSE cells. One of the genes under-expressed in the ovarian cancer cell lines, Id3, a transcriptional inactivator, was selected for further investigation. Id3 mRNA was expressed at reduced levels in 6 out of 9 ovarian cancer cell lines compared to the HOSE cells while at the protein level, all 7 ovarian cancer cell lines examined expressed the Id3 protein at greatly reduced levels. Expression of Id3 mRNA was also examined in primary ovarian tumours and was found in only 12/38 (32%) cases. A search was conducted for mutations of Id3 in primary ovarian cancers using single stranded conformation polymorphism (SSCP) analysis. Only one nucleotide substitution, present also in the corresponding constitutional DNA, was found in 94 ovarian tumours. Furthermore no association was found between LOH at 1p36 and lack of expression of Id3. These data suggest that Id3 is not the target of LOH at 1p36.

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Heterogeneous distribution of K-ras-mutated epithelia in mucinous ovarian tumors with special reference to histopathology

Cited by 74 publications

References 14 publications

Ovarian carcinomas, including secondary tumors: diagnostically challenging areas

Ovarian carcinomas, including secondary tumors: diagnostically challenging areas

Origins and molecular pathology of ovarian cancer

Decreased expression of the Id3 gene at 1p36.1 in ovarian adenocarcinomas

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