The frequency of p53, k‐ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma

Lax, Sigurd; Kendall, Brian; Tashiro, Hironori; Slebos, Robbert J.C.; Ellenson, Lora Hedrick

doi:10.1002/(sici)1097-0142(20000215)88:4<814::aid-cncr12>3.3.co;2-l

Cited by 55 publications

(78 citation statements)

References 15 publications

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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: Discussionmentioning

confidence: 40%

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: Discussionmentioning

confidence: 40%

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

et al. 2012

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“…12 The gene is also frequently mutated in ovarian mucinous neoplasms and endometrial mucinous carcinoma. 14 More recently, KRAS mutation was found in a high proportion of a small, highly selected cohort of complex, papillary mucinous lesions of the endometrium. 11 Similar to the latter, the current study also identifies a significant difference in the prevalence of KRAS mutation between simple and complex mucinous lesions (0% vs 55%).…”

Section: Discussionmentioning

confidence: 99%

“…12 KRAS is frequently mutated in ovarian mucinous neoplasms and endometrial mucinous carcinoma as well. 14 Prompted by the recent report of a high frequency of KRAS mutations found in a small cohort of endometrial papillary mucinous lesions, 11 we investigated various mucinous lesions for the presence of KRAS mutation in endometrial biopsy or curettage specimens in correlation with clinical progression.…”

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confidence: 99%

Frequent KRAS mutation in complex mucinous epithelial lesions of the endometrium

et al. 2014

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KRAS mutation correlates with mucinous differentiation in various human cancers, and recently, was found in a high proportion of a small cohort of papillary mucinous lesions of the endometrium. In this study, a large number of endometrial mucinous lesions were analyzed for the presence of KRAS mutation along with clinical progression. A total of 45 endometrial biopsy/curettage cases were included in the study and classified into the following categories: simple mucinous change (5 cases), complex mucinous change (33 cases) and mucinous adenocarcinoma (7 cases). Follow-up hysterectomy specimens were available in 14 of 33 patients (42%) with complex mucinous lesions, of which 9 cases (64%) showed atypical complex hyperplasia with an average interval of 21 weeks. None of the 5 cases of simple mucinous change showed KRAS mutation. KRAS mutation was observed in 18 of 33 patients with complex mucinous lesions (55%) and in 6 of 7 cases of mucinous adenocarcinoma (86%). Overall, KRAS mutation has a positive predictive value (PPV) of 88% (7/8 cases) for complex atypical hyperplasia or adenocarcinoma in the follow-up hysterectomy. In conclusion, the current data further emphasizes the architectural complexity as an important prognostic indicator for patients with mucinous endometrial lesions. The presence of KRAS mutation in both mucinous adenocarcinoma and complex mucinous changes indicates that KRAS mutational activation is implicated in the pathogenesis of a significant subset of endometrial mucinous carcinoma. With a high PPV, KRAS mutation analysis may offer an additional discriminatory power to refine risk stratification algorithm for patients with endometrial mucinous lesions.

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“…The proposed dualistic model of endometrial carcinoma pathogenesis, of which uterine endometrioid carcinoma (UEC) and uterine serous carcinoma (USC) are prototypic examples, is based on clinicopathologic differences between the two tumor subtypes 1 and supported by immunohistochemical and molecular genetic studies. [2][3][4] Type I tumors are thought to arise in the setting of estrogenic stimulation and are endometrioid in histology, while type II tumors are unrelated to estrogen exposure, arising in a background of atrophy and often serous in histology. The most common genetic alterations in UEC are PTEN mutations (30-50%) 5 and microsatellite instability (MI) (20%), [6][7][8] while in USC mutations of the p53 gene are found in approximately 90% of cases.…”

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confidence: 99%

“…The most common genetic alterations in UEC are PTEN mutations (30-50%) 5 and microsatellite instability (MI) (20%), [6][7][8] while in USC mutations of the p53 gene are found in approximately 90% of cases. 3,9,10 Recent immunohistochemical studies using p53, Ki67, estrogen and progesterone receptors performed on uterine clear cell carcinoma (UCC) have suggested differences in the molecular events that underlie the pathogenesis of this subtype. 11 To date, the molecular characteristics of UCC have not been studied and the pathogenetic pathway of this tumor type is unclear.…”

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confidence: 99%

Molecular characterization of uterine clear cell carcinoma

Logani

Isacson

et al. 2004

Modern Pathology

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Clinicopathological studies support a broad classification of endometrial carcinoma into two major types, designated as type I and type II, which correlate with their biological behavior. More recently, molecular studies have provided further insights into this classification scheme by elucidating the genetic events involved in the development and progression of endometrial carcinoma. Microsatellite instability and mutations in the PTEN gene have been widely associated with type I (endometrioid) endometrial carcinoma, while p53 mutations have been identified in the majority of type II endometrial carcinoma, of which uterine serous carcinoma is the prototype. Uterine clear cell carcinoma (UCC) is an uncommon variant of endometrial carcinoma, and clinicopathological studies have produced conflicting results regarding its biological behavior with 5-year survival ranging from 21 to 75%. The molecular characteristics of endometrioid and serous carcinoma have been studied extensively; however, there have been few molecular genetic studies of the clear cell subtype. In this study, we evaluated 16 UCCs (11 pure and 5 mixed) for mutations in the p53 gene, PTEN gene and for microsatellite instability. Although we found that these alterations were uncommon in pure clear cell carcinomas, all three were identified. In addition, two cases of mixed serous and clear cell carcinoma showed an identical mutation of the p53 gene in the histologically distinct components and one case of mixed clear cell and endometrioid carcinoma had identical mutations in the PTEN and p53 genes, and microsatellite instability in both components. Our data suggest that UCC represent a heterogeneous group of tumors that arise via different pathogenetic pathways. Additional molecular studies of pure clear cell carcinoma are required to further elucidate the genetic pathways involved in its development and progression. Keywords: uterine clear cell carcinoma; PTEN mutation; microsatellite instability; p53 mutation Clear cell carcinoma of the endometrium has been recognized as a distinct, but uncommon, histologic variant accounting for only 1-5% of all endometrial adenocarcinoma. The proposed dualistic model of endometrial carcinoma pathogenesis, of which uterine endometrioid carcinoma (UEC) and uterine serous carcinoma (USC) are prototypic examples, is based on clinicopathologic differences between the two tumor subtypes 1 and supported by immunohistochemical and molecular genetic studies. 2-4 Type I tumors are thought to arise in the setting of estrogenic stimulation and are endometrioid in histology, while type II tumors are unrelated to estrogen exposure, arising in a background of atrophy and often serous in histology. The most common genetic alterations in UEC are PTEN mutations (30-50%) 5 and microsatellite instability (MI) (20%), 6-8 while in USC mutations of the p53 gene are found in approximately 90% of cases. 3,9,10 Recent immunohistochemical studies using p53, Ki67, estrogen and progesterone receptors performed on uterine clear cell carcinoma ...

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The frequency of p53, k‐ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma

Cited by 55 publications

References 15 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

Frequent KRAS mutation in complex mucinous epithelial lesions of the endometrium

Molecular characterization of uterine clear cell carcinoma

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