Assessment of the Risk on Endometrial Cancer in Hyperplasia, by Means of Morphological and Morphometrical Features

“…Some cases of endometrial hyperplasia, especially atypical hyperplasia, are considered to be precursors of endometrial endometrioid adenocarcinoma. (44,45) In our present study, the DAX-1 LI in hyperplasia was significantly higher than that in normal endometrium during the proliferative phase or in endometrial carcinoma. Endometrial hyperplasia was in general believed to be caused by continuous estrogenic stimulation such as ovulatory dysfunction, which results in abnormal cell proliferation with altered patterns of expression for several genes.…”

Section: Discussionsupporting

confidence: 44%

Orphan nuclear receptor DAX‐1 in human endometrium and its disorders

Saito¹,

Itō²,

Suzuki³

et al. 2005

Cancer Science

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DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1) is a recently characterized member of the orphan nuclear receptor family. DAX-1 functions as a global negative regulator of steroid hormone production. It inhibits adrenal 4 binding protein (Ad4BP)/steroidogenic factor-1 (SF-1) pathway-dependent P450arom expression in cultured human endometriotic stromal cells and acts as a corepressor for estrogen receptors (ER). In this study we first examined the localization of DAX-1 in 46 normal cycling endometria, 36 cases of endometrial hyperplasia and 103 cases of endometrial carcinoma by using immunohistochemistry to elucidate the possible involvement of DAX-1 and its correlation to the status of Ad4BP/SF-1, a universal transcription factor of steroidogenesis. We then evaluated DAX-1 mRNA expression, using quantitative reverse transcription-polymerase chain reaction for DAX-1 in 33 cases of endometrial carcinoma for further characterization. We subsequently correlated these findings with various clinicopathological parameters of the cases. Ad4BP/SF-1 immunoreactivity was not detected in any human endometria examined. A significant inverse correlation was detected between the status of DAX-1 immunoreactivity and histological grade (P = 0.0003) in endometrial carcinoma. The labeling index (LI) values of DAX-1 in normal endometrium during the secretory phase (P < 0.0001) and hyperplasia (P < 0.0001) were significantly higher than that of carcinoma. No significant correlations were detected between DAX-1 immunoreactivity and amounts of aromatase mRNA. There was a statistically significant positive correlation between DAX-1 and ERα α α α (P = 0.006) and ERβ β β β LI (P < 0.001). These findings suggest that DAX-1 may inhibit the proliferation and progression of endometrial carcinoma through inhibition of estrogenic actions, possibly by interacting with ER present in carcinoma cells, rather than regulating in situ steroidogenesis. (Cancer Sci 2005; 96: 645-652) E ndometrial carcinoma is one of the most common pelvic malignancies among women worldwide, and its incidence has recently increased.(1,2) In situ estrogen metabolism, including synthesis and degradation, has been recently recognized as a very important factor in the development and progression of various human estrogen-dependent neoplasms, including endometrial carcinoma, especially the endometrioid type. (3,4) In endometrial carcinoma, in situ 17β-estradiol (E2) availability has been reported to be closely associated with the pathogenesis and development of endometrial proliferative disorders including endometrial hyperplasia and carcinoma, especially the endometrioid type.(5) DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1) is a recently characterized member of the orphan nuclear receptor family.(6,7) DAX-1 is expressed in the adrenal cortex, ovary, Leydig cells and other endocrine cells such as testicular Sertoli cells, pituitary gonadotropes, vent...

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“…The endometrial intraepithelial neoplasia (EIN) diagnostic schema 3,4 is the end product of combined molecular, 5,6 objective histomorphometric, 7 and clinical outcome studies [8][9][10][11] specifically intended to redefine the histopathologic appearance of highrisk endometrial lesions. Premalignant lesions arise as clonal outgrowths of somatically mutated cells that present histologically as an expanding discrete focus of crowded glands with a distinctly different cytology than the background endometrium.…”

mentioning

confidence: 99%

“…This morphometric group of patients has a 45-fold elevated risk of future endometrial carcinoma compared to those with a Dscore41. [7][8][9][10]12 Key elements of the D-score that correspond to heightened risk of cancer outcome include a lesion size exceeding 1 mm in maximum dimension and a surface area of glands that exceeds that of stroma.…”

mentioning

confidence: 99%

Prediction of endometrial carcinoma by subjective endometrial intraepithelial neoplasia diagnosis

Hecht

Ince

Baak³

et al. 2005

Modern Pathology

130

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Endometrial intraepithelial neoplasia (also known as 'EIN') is a precursor to endometrioid endometrial adenocarcinoma characterized by monoclonal growth of mutated cells, a distinctive histopathologic appearance, and 45-fold elevated cancer risk. We have applied diagnostic criteria for EIN to 97 successive endometrial biopsies classified as hyperplastic according to World Health Organization criteria and correlated results with computer-assisted morphometry (D-score) and clinical cancer outcomes. Three pathologists separately reviewed all cases for presence or absence of EIN using published criteria (gland area4stromal area, cytologic change in focus of altered architecture, lesion size 41 mm, and exclusion of cancer and mimics). Discordant cases were resolved by a consensus review at a multiheaded scope. Clinical outcomes were obtained in 84 patients from patient visit and pathology records. Diagnoses of presence or absence of EIN were unanimous among all three pathologists in 75% of cases, and intraobserver-reproducibility was very good (kappa 0.73-0.90). Cases rediagnosed as EIN encompassed hyperplasias previously diagnosed as atypical (n ¼ 18) or nonatypical (eight complex, two simple). Eight follow-up cancers were scattered between hyperplasia types (5/21 atypical, 3/63 nonatypical), but all classified as EIN (8/25) and D-score r1 (8/38). Subjective application of criteria for diagnosis of EIN correlates well with objective morphometry and successfully segregates patients into high and low cancer risk subgroups with better reproducibility than atypical hyperplasia diagnosis. Keywords: EIN; endometrial hyperplasia; histomorphometry; precancer; pathology; prognosis Diagnosis and therapeutic ablation of premalignant lesions of the endometrium is central to endometrial cancer prevention. Accurate diagnosis of precursors to endometrioid endometrial cancer (Type I), 1,2 which may precede cancer by several years, presents a major challenge to pathologists. The World Health Organization (WHO) endometrial hyperplasia schema captures many precancers in the atypical hyperplasia subgroup, but is a poorly reproducible system. This report examines clinical performance of the alternative EIN diagnostic schema as practiced subjectively at our institution (BWH) since 2002.The endometrial intraepithelial neoplasia (EIN) diagnostic schema 3,4 is the end product of combined molecular, 5,6 objective histomorphometric, 7 and clinical outcome studies 8-11 specifically intended to redefine the histopathologic appearance of highrisk endometrial lesions. Premalignant lesions arise as clonal outgrowths of somatically mutated cells that present histologically as an expanding discrete focus of crowded glands with a distinctly different cytology than the background endometrium. The EIN schema more precisely defines 'atypia' and gland crowding than previous criteria for hyperplasia. The absolute cytology of EIN lesions varies greatly between patients, and in a number of cases lacks prominent nucleoli or nuclear rounding, definitions of '...

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Assessment of the Risk on Endometrial Cancer in Hyperplasia, by Means of Morphological and Morphometrical Features

Cited by 79 publications

References 5 publications

Computerised morphometrical analysis in endometrial hyperplasia for the prediction of cancer development. A long term retrospective study from northern Norway

Computerised morphometrical analysis in endometrial hyperplasia for the prediction of cancer development. A long term retrospective study from northern Norway

Orphan nuclear receptor DAX‐1 in human endometrium and its disorders

Prediction of endometrial carcinoma by subjective endometrial intraepithelial neoplasia diagnosis

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