Universal Endometrial Cancer Tumor Typing: How Much Has Immunohistochemistry, Microsatellite Instability, and MLH1 Methylation Improved the Diagnosis of Lynch Syndrome Across the Population?

Kahn, Richard L.; Gordhandas, Sushmita; Maddy, Brandon Paul; Nelson, Becky Baltich; Askin, Gülce; Christos, Paul J.; Caputo, Thomas A.; Chapman‐Davis, Eloise; Holcomb, Kevin; Frey, M.K.

doi:10.1097/ogx.0000000000000736

Cited by 9 publications

(15 citation statements)

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“…MLH1 and PMS2 were mutated in 19.5% and 8.8% of the cases. The frequency of each germline mutation obtained in this study mirrors the findings of other metaanalytic studies (13).…”

Section: Discussionsupporting

confidence: 87%

“…The frequency of methylation in tumours with loss of expression of MLH1 was 86.74% (628 patients). Kahn et al obtained similar findings with a frequency of MLH1 loss of 20% and an MLH1 methylation rate of 86% (13). MLH1 methylation appears to have a significant correlation with an MSI-H status.…”

Section: Discussionmentioning

confidence: 61%

“…A smaller proportion was obtained in a recent meta-analysis which found that family history-based triaging identifies only 56% of endometrial cancers with LS (13). Kahn et al found that family history-dependent screening of endometrial cancers can miss approximately 43% of LS endometrial cancers (13). This is because most LS gynecologic cancer patients with unknown germline mutation status are likely to be probands.…”

Section: Discussionmentioning

confidence: 99%

“…This is the first study to examine the frequency of LS-associated clinicopathologic and molecular characteristics in gynecologic cancers with mutationconfirmed LS. Previous studies have predominantly described these characteristics in MMR deficient and sporadic cancers (13,21). This study also used the individual sample sizes of the included studies to derive the proportions of LS gynecologic cancers exhibiting the clinicopathologic features of interest, which increased the accuracy of the findings.…”

Section: Discussionmentioning

confidence: 99%

“…However, MSI has low sensitivity in MSH2 and MSH6 mutations, with a sensitivity of 55% and 77% in MSH2 and MSH6, versus 90% in MLH1/PMS2 (12). MMR IHC deficiency and MSI-H are present in 28% and 31% of endometrial malignancies, respectively (13). However, LS gynaecological cancers have MMR expression patterns and MSI similarities with sporadic gynaecological malignancies, making molecular criteria insufficient in triaging potential LS cancers (14).…”

Section: Introductionmentioning

confidence: 99%

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Screening and identification of Lynch syndrome: a systematic review of the frequency of Lynch syndrome-associated clinicopathologic and molecular characteristics in Lynch syndrome gynecologic cancers

Yang¹,

Liu²,

Yang³

et al. 2021

Transl Cancer Res TCR

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Background: This study aimed to investigate the frequency of Lynch syndrome-associated clinicopathologic and molecular characteristics in Lynch syndrome gynecologic cancers.Methods: A systematic literature search was conducted in the literature databases (Medline, CINAHL, EMBASE, Google Scholar, Cochrane Library, and Clinicaltrials.gov) to identify the studies describing clinicopathologic characteristics, MMR protein immunohistochemistry and/or MSI, MLH1 methylation, and genetic testing in Lynch syndrome gynecologic cancer patients.Results: A total of 24 of the evaluated studies that met the inclusion criteria were identified. A clinicopathological examination confirmed 242 endometrial cancer, 17 clear cells endometrial cancer, 35 serous endometrial cancer, 30 mixed and 21 other endometrial cancer. Thus, a total of 345 endometrial cancer was confirmed from the screening of 1,317 gynaecological cancer. However, the morphological analysis demonstrated 236 patients with endometrial cancer associated with Lynch syndrome. The frequency of confirmed LS with endometrial cancer was 68.40%. At diagnosis, the median age was 49.94±4.34 years, and the average BMI was 26.07±3.77 kg/m 2 . Endometrioid histology and stage I disease were the most frequent at 70.97% and 71.19% histological type and FIGO stage, respectively. Similarly, morphological and histological analysis demonstrated a higher degree of grade I cancer (47.28) and lymphovascular invasion (56.52%), respectively.Discussion: Lynch syndrome-associated clinicopathologic and molecular characteristics occur significantly in Lynch syndrome gynecologic cancers and may improve risk stratification and triaging of gynecologic cancers for genetic testing.

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“…MLH1 and PMS2 were mutated in 19.5% and 8.8% of the cases. The frequency of each germline mutation obtained in this study mirrors the findings of other metaanalytic studies (13).…”

Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Screening and identification of Lynch syndrome: a systematic review of the frequency of Lynch syndrome-associated clinicopathologic and molecular characteristics in Lynch syndrome gynecologic cancers

Yang¹,

Liu²,

Yang³

et al. 2021

Transl Cancer Res TCR

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Endometrial cancer in Lynch syndrome

Zhao

Chen

Zang

et al. 2021

Intl Journal of Cancer

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Lynch syndrome (LS) is an autosomal dominant inherited disease caused by germline pathogenic variants (PVs) in mismatch repair (MMR) genes. LS‐associated endometrial cancer (LS‐EC) is the most common extraintestinal sentinel cancer caused by germline PVs in MMR genes, including MLH1, MSH2, MSH6 and PMS2. The clinicopathologic features of LS‐EC include early age of onset, lower body mass index (BMI), endometrioid carcinoma and lower uterine segment involvement. There has been significant progress in screening, diagnosis, surveillance, prevention and treatment of LS‐EC. Many studies support universal screening for LS among patients with EC. Screening mainly involves a combination of traditional clinical criteria and molecular techniques, including MMR‐immunohistochemistry (MMR‐IHC), microsatellite instability (MSI) testing, MLH1 promoter methylation testing and gene sequencing. The effectiveness of endometrial biopsy and transvaginal ultrasound (TVS) for clinical monitoring of asymptomatic women with LS are uncertain yet. Preventive strategies include hysterectomy and bilateral salpingo‐oophorectomy (BSO) as well as chemoprophylaxis using exogenous progestin or aspirin. Recent research has revealed the benefits of immunotherapy for LS‐EC. The NCCN guidelines recommend pembrolizumab and nivolumab for treating patients with advanced or recurrent microsatellite instability‐high (MSI‐H)/mismatch repair‐deficient (dMMR) EC.

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Implementing universal upfront multi-gene panel testing in endometrial cancer: From cost to practical considerations

Levine

Barrington

Hampel

et al. 2022

Gynecologic Oncology

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Universal Endometrial Cancer Tumor Typing: How Much Has Immunohistochemistry, Microsatellite Instability, and MLH1 Methylation Improved the Diagnosis of Lynch Syndrome Across the Population?

Cited by 9 publications

References 0 publications

Screening and identification of Lynch syndrome: a systematic review of the frequency of Lynch syndrome-associated clinicopathologic and molecular characteristics in Lynch syndrome gynecologic cancers

Screening and identification of Lynch syndrome: a systematic review of the frequency of Lynch syndrome-associated clinicopathologic and molecular characteristics in Lynch syndrome gynecologic cancers

Endometrial cancer in Lynch syndrome

Implementing universal upfront multi-gene panel testing in endometrial cancer: From cost to practical considerations

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