Mismatch repair (MMR)-deficient endometrial carcinomas (ECs) bearing Lynch syndrome (LS)-associated germline mutations or sporadic MLH1 promoter hypermethylation (MLH1hm) are highly immunogenic and ...may represent excellent candidates for therapies targeting the programmed cell death (PD)/programmed cell death ligand-1 (PD-L1) immune checkpoint pathway. This study evaluates PD-L1 expression in MMR-deficient ECs including LS-associated and MLH1hm cases, in comparison with MMR-intact tumors. Immunohistochemistry for PD-L1/CD274 was performed on 38 MMR-deficient and 29 MMR-intact ECs. Staining was scored in the tumor and the peritumoral immune compartment. The majority of MMR-deficient tumors were PD-L1 positive (53%) in at least a subset of tumor cells. LS-associated tumors were more likely to be PD-L1 positive relative to MLH1hm tumors (70% vs. 33%, P=0.05). Only 10% of MMR-intact ECs demonstrated any tumoral PD-L1 expression; this was significantly lower than was observed in MMR-deficient tumors (P=0.0005). When reviewed by histologic grade, PD-L1 expression remained highest in LS-associated ECs followed by MLH1hm and MMR-intact carcinomas, respectively. The MMR immunohistochemical pattern most uniformly associated with PD-L1 expression was MSH6 loss. Immune PD-L1 expression was seen in 100% of MMR-deficient and 66% of MMR-intact cases. This study represents the first to characterize differences in PD-L1 expression between LS-associated and MLH1hm endometrial cancers. It demonstrates that tumoral PD-L1 expression is more common in LS-associated endometrial cancers relative to MLH1hm and MMR-intact tumors, although sporadic cancers often show PD-L1 positive immune staining. These data suggest that MMR deficiency may be a better predictor of response to PD-1/PD-L1 inhibitor therapy than tumor grade in EC, and that potential benefit may vary based on the molecular mechanism of MMR defects.
Endometrial Hyperplasia Ring, Kari L; Mills, Anne M; Modesitt, Susan C
Obstetrics and gynecology (New York. 1953),
12/2022, Letnik:
140, Številka:
6
Journal Article
Recenzirano
The objectives of this Clinical Expert Series on endometrial hyperplasia are to review the etiology and risk factors, histologic classification and subtypes, malignant progression risks, prevention ...options, and to outline both surgical and nonsurgical treatment options. Abnormal uterine and postmenopausal bleeding remain the hallmark of endometrial pathology, and up to 10-20% of postmenopausal bleeding will be either hyperplasia or cancer; thus, immediate evaluation of any abnormal bleeding with either tissue procurement for pathology or imaging should be undertaken. Although anyone with a uterus may develop atypical hyperplasia, also known as endometrial intraepithelial neoplasia (EIN), genetic predispositions (eg, Lynch syndrome), obesity, chronic anovulation, and polycystic ovarian syndrome all markedly increase these risks, whereas use of oral contraceptive pills or progesterone-containing intrauterine devices will decrease the risk. An EIN diagnosis carries a high risk of concomitant endometrial cancer or eventual progression to cancer in the absence of treatment. The definitive and curative treatment for EIN remains hysterectomy; however, the obesity epidemic, the potential desire for fertility-sparing treatments, the recognition of varying rates of malignant transformation, medical comorbidities, and an aging population all may factor into decisions to employ nonsurgical treatment modalities.
Endometrial cancer is the most common gynecological malignancy in the developed world. It is the fifth most common cancer and accounts for 4.8% of all cancers in women. Long intergenic non-coding ...RNAs (lincRNAs), a subclass of long non-coding RNAs, are pervasively transcribed throughout the human genome.
LincRNA expression patterns in endometrial cancer compared to normal healthy tissue are poorly characterised. In this study, the lincRNA transcriptome of endometrial cancers and adjacent normal endometrium from the same patients was sequenced and compared with transcriptomes of other gynaecologic malignancies including ovarian and cervical cancers.
RNA was isolated from malignant and adjacent non-affected endometrial tissue from 6 patients with low grade and stage Type I endometrial cancer. Subsequently, Illumina paired-end RNA sequencing was performed, followed by bioinformatics analysis, to determine differential transcriptome expression patterns.
LINC00958 was upregulated in all three cancers, and four lincRNAs including LINC01480, LINC00645, LINC00891 and LINC00702 demonstrated exquisite specificity for malignant endometrium compared to normal endometrium while also distinguishing endometrial cancer from ovarian and cervical cancers. Furthermore, LINC01480 has features required to express a micropeptide.
The lincRNAs, characterised in this study, represent high priority genes to be tested for functional significance in the pathogenesis and/or progression of endometrial cancer. Furthermore, lincRNAs have potential to be released into the bloodstream and therefore the four lincRNAs identified here may represent biomarkers for early detection of endometrial cancer without biopsy.
•RNA-Seq analysis was performed on cancerous and normal endometrial tissue from six obese patients.•Annotated and unannotated lincRNAs were differentially expressed in malignant endometrium compared to matched control.•Four lincRNAs were differentially expressed in endometrial cancer, but not ovarian or cervical cancer.•Differentially expressed lincRNAs may have functional roles in cancer pathogenesis or serve as biomarkers.
Mismatch repair-deficient endometrial carcinomas are optimal candidates for immunotherapy given their high neoantigen loads, robust lymphoid infiltrates, and frequent PD-L1 expression. However, ...co-opting the PD-1/PD-L1 pathway is just one mechanism that tumors can utilize to evade host immunity. Another immune modulatory molecule that has been demonstrated in endometrial carcinoma is indoleamine 2,3-dioxygenase (IDO). We herein evaluate IDO expression in 60 endometrial carcinomas and assess results in relation to PD-L1 and mismatch repair status. IDO immunohistochemistry was performed on 60 endometrial carcinomas (20 Lynch syndrome (LS)-associated, 20 MLH1 promoter hypermethylated, and 20 mismatch repair-intact). Eight-five percent of endometrial carcinomas showed IDO tumor staining in >1% of cells. Twenty-five percent were positive in >25% of tumor cells and only 7% exceeded 50% staining. Mismatch repair-deficient cancers were more likely than mismatch repair-intact cancers to be >25% IDO-positive (35% vs. 5% p = 0.024). Differences were amplified when Lynch syndrome-associated cases were evaluated in isolation (50% Lynch syndrome-associated vs. 10% mismatch repair-intact and MLH1-hypermethylated, p = 0.001). Of the four cases showing >50% staining, three were Lynch syndrome-associated and one was MLH1-hypermethylated; no mismatch repair-intact cases had >50% staining. Forty-three percent of IDO-positive tumors were also positive for PD-L1, whereas only two cases showed tumoral PD-L1 in the absence of IDO. In summary, IDO expression is prevalent in endometrial carcinomas and diffuse staining is significantly more common in mismatch repair-deficient cancers, particularly Lynch syndrome-associated cases. Given that the majority of PD-L1 positive cancers also express IDO, synergistic combination therapy with anti-IDO and anti-PD1/PD-L1 may be relevant in this tumor type. Furthermore, anti-IDO therapy may be an option for a small subset of mismatch repair-intact cancers.
Expanded testing for Lynch syndrome (LS) is increasingly recommended for patients with endometrial carcinomas, and immunohistochemistry (IHC) for tumor loss of mismatch-repair (MMR) protein ...expression is the most common primary screen. This has led to the recognition of MMR-IHC–deficient cases without identifiable mutations on directed germline sequencing. The clinical implications of such “Lynch-like” (LL) cancers are unclear. We here report the clinicopathologic features of putative familial endometrial carcinoma identified on universal MMR-IHC screening with attention to cases with discordant IHC and germline results. The files of the University of Virginia Pathology Department were retrospectively searched for all MMR-deficient endometrial carcinomas identified on screening. Cases were categorized as likely sporadic (MLH1/PMS2 loss, evidence of MLH1 promoter hypermethylation) or putative LS (PLS) (loss of MSH2/MSH6, MSH6, or PMS2). PLS cases were further subdivided into LS and LL groups on the basis of the presence or absence of a confirmatory mutation by germline testing, and the clinicopathologic features of these cases were compared. A deficiency of ≥1 MMR protein was observed in 31.4% (66/210) of endometrial carcinomas, including 26 PLS cases, 15 of which had germline testing. Directed germline sequencing confirmed LS in 46.7% (7/15); the remaining cases were classified as LL. High-grade and/or biphasic morphology was seen in 42.9% (3/7) of LS and 62.5% (5/8) of LL cases; the remaining cases showed low-grade, conventional endometrioid morphology. High level microsatellite instability was observed in 71.4% (5/7) of LL cases. The majority of cases from both groups (LS85.7% 6/7; LL87.5% 7/8) were low-stage (T1a/T1b). Endometrial carcinoma was the presenting malignancy in 85.7% (6/7) of LS patients and 87.5% (7/8) of LL patients. Family history was suggestive of LS in 28.5% (2/7) of LS patients and 12.5% (1/8) of LL patients. Screening algorithms based on age and cancer history would have failed to identify LS patients in 57.1% (4/7) of cases. Although universal MMR-IHC identifies endometrial carcinoma patients with LS who would have been missed using targeted screening algorithms, it also identifies cancers with discordant IHC and germline results for which the somatic versus germline origin of the MMR defect is unclear. Further study of this LL group is required before drawing definitive conclusions about their familial cancer risk.
OBJECTIVE:To examine implementing an enhanced recovery after surgery (ERAS) protocol for women undergoing major gynecologic surgery at an academic institution and compare surgical outcomes before and ...after implementation.
METHODS:Two ERAS protocols were developeda full pathway using regional anesthesia for open procedures and a light pathway without regional anesthesia for vaginal and minimally invasive procedures. Enhanced recovery after surgery pathways included extensive preoperative counseling, carbohydrate loading and oral fluids before surgery, multimodal analgesia with avoidance of intravenous opioids, intraoperative goal-directed fluid resuscitation, and immediate postoperative feeding and ambulation. A before-and-after study design was used to compare clinical outcomes, costs, and patient satisfaction. Complications and risk-adjusted length of stay were drawn from the American College of Surgeons’ National Surgical Quality Improvement Program database.
RESULTS:On the ERAS full protocol, 136 patients were compared with 211 historical controls and the median length of stay was reduced (2.0 compared with 3.0 days; P=.007) despite an increase in National Surgical Quality Improvement Program-predicted length of stay (2.5 compared with 2.0 days; P=.009). Reductions were seen in median intraoperative morphine equivalents (0.3 compared with 12.7 mg; P<.001), intraoperative (285 compared with 1,250 mL; P<.001) and total intravenous fluids (−917.5 compared with 1,410 mL; P<.001), immediate postoperative pain scores (3.7 compared with 5.0; P<.001), and total complications (21.3% compared with 40.2%; P=.004). On the ERAS light protocol, 249 patients were compared with 324 historical controls and demonstrated decreased intraoperative and postoperative morphine equivalents (0.0 compared with 13.0 mg; P<.001 and 15.0 compared with 23.6 mg; P<.001) and decreased intraoperative and overall net intravenous fluids (P<.001). Patient satisfaction scores showed a marked and significant improvement on focus questions regarding pain control, nurses keeping patients informed, and staff teamwork; 30-day total hospital costs were significantly decreased in both ERAS groups.
CONCLUSION:Implementation of ERAS protocols in gynecologic surgery was associated with a substantial decrease in intravenous fluids and morphine administration coupled with reduction in length of stay for open procedures combined with improved patient satisfaction and decreased hospital costs.
Circular RNAs (circRNAs) are a naturally occurring family of non-coding RNA that may regulate gene expression in mammals. circRNAs are more stable than messenger RNAs due to their resistance to RNA ...exonuclease. A growing body of evidence has shown that the expression of circRNAs is regulated during development in a tissue-specific manner. CircRNAs have been implicated in a number of cancers; however, their role in endometrial cancer (EC) is completely unknown. Here, we report the circular transcriptome specific for EC as determined by RNA sequencing. We found that the overall abundance of circRNAs is lower in EC than in normal endometrium. Further, there are numerous 'hotspot' genes from which circRNAs are transcribed that may account for alterations in circRNA expression between the normal and malignant endometrium. Most importantly, we have also identified circRNAs that are differentially expressed between malignant and normal endometrial tissue. The functional significance of these circRNAs in cancer remains to be determined, but they may serve as potential biomarkers for the diagnosis of EC or monitoring of EC progression.
Abstract Objective To evaluate the association between body mass index (BMI) and mortality in women with endometrial cancer. Methods A systematic review was performed utilizing a Medline search with ...Mesh keywords ‘endometrial neoplasms’ and (‘body mass index’ or ‘obesity’) and (‘survival analysis’ or ‘mortality’ or ‘survivor’ or ‘survival’) for studies published prior to June 2013. Inclusion criteria included studies that assessed associations between BMI and survival in endometrial cancer patients. Two investigators independently reviewed the title and abstract and full-text of articles for inclusion or exclusion decision; discordant decisions were adjudicated by a third reviewer. A random-effects model was constructed that was comparable to the standard random-effects models used in the meta-analysis of odds ratios. The model was fitted using SAS PROC NLMIXED. Results 1451 studies were identified and reviewed in duplicate, 18 met inclusion criteria. A random-effects meta-analysis demonstrated significantly higher odds of mortality with increasing BMI in endometrial cancer patients. Specifically the odds ratios were 1.01, 1.17, 1.26, and 1.66 for BMI categories of 25–29.9, 30–34.9, 35–39.9, and 40 +, respectively. The odds ratio for all-cause mortality in endometrial cancer patients with a BMI ≥ 40 compared to those with a BMI < 25 was 1.66 (CI: 1.10–2.51, p = 0.02). A single dose–response model indicated that a 10% increase in BMI resulted in a 9.2% increase in the odds of all-cause mortality (p = 0.007). Conclusion Increased BMI is significantly associated with increased all-cause mortality in women with endometrial cancer, with the highest risk for those with a BMI ≥ 40.
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