Impact of microsatellite instability (MSI) on survival in high grade endometrial carcinoma

Arabi, Haitham; Guan, Hui; Kumar, Sanjeev; Coté, Michele L.; Bandyopadhyay, Sudeshna; Bryant, Christopher S.; Shah, Jay P.; Abdul‐Karim, Fadi W.; Munkarah, Adnan; Ali-Fehmi, Rouba

doi:10.1016/j.ygyno.2009.02.004

Cited by 33 publications

(32 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2,32,33 Microsatellite instability is caused by an inability of the MMR system to cut out and replace the mismatching DNA strains due to methylation or mutation of its proteins (MLH1, MSH2 and MSH6). 34 Two previous studies showed that microsatellite instability was present in 5% 35 and 23.3% 21 of uterine carcinosarcomas. The latter study observed that microsatellite instability is mainly a feature of the epithelial component.…”

Section: Discussionmentioning

confidence: 98%

Molecular markers and clinical behavior of uterine carcinosarcomas: focus on the epithelial tumor component

et al. 2011

View full text Add to dashboard Cite

Carcinosarcomas (malignant mixed Mü llerian tumors) of the uterus are rare and aggressive malignancies consisting of an epithelial (carcinoma) and a mesenchymal (sarcoma) tumor component and are considered as metaplastic endometrial carcinomas. This study evaluated molecular characteristics and clinical behavior of uterine carcinosarcomas to improve treatment regimens in the future. Immunohistochemical expression of estrogen receptor-a and -b, progesterone receptor-A and -B, MLH1, MSH2, MSH6, PTEN (phosphatase and tensin homolog deleted on chromosome 10), p53, b-catenin and cyclin D1 was determined in 40 uterine carcinosarcomas. Immunostaining was compared between epithelial and mesenchymal tumor components. To determine the prognostic role of the epithelial component, clinicopathological data and survival were compared between patients with endometrioid and non-endometrioid epithelial tumor components. To determine prognosis of carcinosarcomas compared with high-risk endometrial carcinomas, clinicopathological characteristics and survival were compared between these patients. Hormone receptor expression occurred infrequently: estrogen receptor-a (8%) and -b (32%), progesterone receptor-A (0%) and -B (23%), next to b-catenin (4%) and cyclin D1 (7%). PTEN, MLH1, MSH2 and MSH6 mutations occurred in 39%, 33%, 22% and 21%, respectively (based on absent immunostaining). Overexpression of p53 was observed in 38%. Expression patterns of p53, MSH2 and MSH6 corresponded between epithelial and mesenchymal tumor components. In our cohort, the epithelial component caused the majority of metastases (72%) and vascular invasion (70%). Survival tended to be worse for patients with a non-endometrioid epithelial component compared with an endometrioid epithelial component (5-year survival: 26% and 55%, respectively). Survival was worse for patients with uterine carcinosarcomas compared with high-risk endometrial carcinomas (grade 3 endometrioid and non-endometrioid); 5-year survival rates: 42%, 77% and 57%, respectively. Our results support the monoclonal origin of uterine carcinosarcomas. The epithelial component determines prognosis by causing the majority of metastases and vascular invasion. To improve prognosis, treatment should focus on the epithelial tumor component of uterine carcinosarcomas. Modern Pathology (2011Pathology ( ) 24, 1368Pathology ( -1379 doi:10.1038/modpathol.2011; published online 13 May 2011Keywords: carcinogenesis; clinical behavior; epithelial component; immunohistochemistry; uterine carcinosarcomas Uterine carcinosarcomas (malignant mixed Mü llerian tumors) are rare malignancies of the female genital tract, accounting for 1-5% of uterine malignancies. 1,2 Microscopically, carcinosarcomas consist of two histological malignant components: an epithelial (carcinoma) and a mesenchymal (sarcoma) component. The epithelial component is usually a

show abstract

Section: Discussionmentioning

confidence: 98%

Molecular markers and clinical behavior of uterine carcinosarcomas: focus on the epithelial tumor component

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Some studies reported that microsatellite instability is associated with a favorable prognosis, 31,32 whereas in other studies a significant worse prognosis was found. 33,34 Possible explanations for these discrepancies include cohort differences, lack of statistical power, and diversity of methodology. Further studies will be required to clarify the effects of POLE mutations and microsatellite instability on the biological behavior of endometrial tumor cells and the associated mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative

et al. 2015

View full text Add to dashboard Cite

This study aimed to investigate whether molecular analysis can be used to refine risk assessment, direct adjuvant therapy, and identify actionable alterations in high-risk endometrial cancer. TransPORTEC, an international consortium related to the PORTEC3 trial, was established for translational research in high-risk endometrial cancer. In this explorative study, routine molecular analyses were used to detect prognostic subgroups: p53 immunohistochemistry, microsatellite instability and POLE proofreading mutation. Furthermore, DNA was analyzed for hotspot mutations in 13 additional genes (BRAF, CDKNA2, CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, and PTEN) and protein expression of ER, PR, PTEN, and ARID1a was analyzed. Rates of distant metastasis, recurrence-free, and overall survival were calculated using the Kaplan-Meier method and log-rank test. In total, samples of 116 high-risk endometrial cancer patients were included: 86 endometrioid; 12 serous; and 18 clear cell. For endometrioid, serous, and clear cell cancers, 5-year recurrence-free survival rates were 68%, 27%, and 50% (P = 0.014) and distant metastasis rates 23%, 64%, and 50% (P = 0.001), respectively. Four prognostic subgroups were identified: (1) a group of p53-mutant tumors; (2) microsatellite instable tumors; (3) POLE proofreading-mutant tumors; and (4) a group with no specific molecular profile (NSMP). In group 3 (POLE-mutant; n = 14) and group 2 (microsatellite instable; n = 19) patients, no distant metastasis occurred, compared with 50% distant metastasis rate in group 1 (p53-mutant; n = 36) and 39% in group 4 (NSMP; Po 0.001). Five-year recurrence-free survival was 93% and 95% for group 3 (POLE-mutant) and group 2 (microsatellite instable) vs 42% (group 1, p53-mutant) and 52% (group 4, NSMP; Po 0.001). Targetable FBXW7 and FGFR2 mutations (6%), alterations in the PI3K-AKT pathway (60%) and hormone receptor positivity (45%) were frequently found. In conclusion, molecular analysis of high-risk endometrial cancer identifies four distinct prognostic subgroups, with potential therapeutic implications. High frequencies of targetable alterations were identified and may serve as targets for individualized treatment. Modern Pathology (2015) 28, 836-844; doi:10.1038/modpathol.2015 published online 27 February 2015 Risk classification of endometrial carcinomas is based upon a combination of clinical and histopathological factors and is used in guiding adjuvant therapy. High-risk factors are (combinations of) advanced age, high-grade, non-endometrioid histology, extensive lymphovascular space invasion, and

show abstract

“…Nuclear staining for ER, PR, p53, and MLH1 was considered positive when the extent of immunostaining was more than 10%, regardless of the intensity [20][21][22]. Immunostaining of Her2 was observed in the cell membrane, and scores of 0 or 1+ indicated negative results, whereas scores of 2+ and 3+ were regarded as positive results.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Clinicopathologic analysis of loss of AT-rich interactive domain 1A expression in endometrial cancer

et al. 2013

View full text Add to dashboard Cite

Impact of microsatellite instability (MSI) on survival in high grade endometrial carcinoma

Cited by 33 publications

References 36 publications

Molecular markers and clinical behavior of uterine carcinosarcomas: focus on the epithelial tumor component

Molecular markers and clinical behavior of uterine carcinosarcomas: focus on the epithelial tumor component

Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative

Clinicopathologic analysis of loss of AT-rich interactive domain 1A expression in endometrial cancer

Contact Info

Product

Resources

About