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Histological classifications of endometrial mucinous lesions: simple mucinous changes (a), complex mucinous changes with variable degrees of papillation (b and c, H&E × 10) and mild-to-moderate cytological atypia (d, H&E × 20) and mucinous adenocarcinoma (e, H&E × 10 and f, H&E × 20).
Source publication
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...
Contexts in source publication
Context 1
... to previous studies emphasizing the importance of structural complexity and cytological atypia in mucinous changes, 3,11 the cases were classified into the following categories: simple mucinous change, complex mucinous change and mucinous adenocarcinoma. Simple mucinous change was defined by the presence of linear or pseudo- stratified epithelial lining with minimal architec- tural complexity (mild epithelial tufting was permitted) and no or minimal cytological atypia ( Figure 1a). Complex mucinous changes included the presence of mucinous epithelium or glands with epithelial papillation, stratification, presence of microglandular or cribriforming configuration (Figures 1b and c). ...
Context 2
... mucinous change was defined by the presence of linear or pseudo- stratified epithelial lining with minimal architec- tural complexity (mild epithelial tufting was permitted) and no or minimal cytological atypia ( Figure 1a). Complex mucinous changes included the presence of mucinous epithelium or glands with epithelial papillation, stratification, presence of microglandular or cribriforming configuration (Figures 1b and c). Focal mild-to-moderate cytolo- gical atypia was allowed including variably en- larged nuclei, pseudostratification and presence of prominent nucleoli (Figure 1d). ...
Context 3
... mucinous changes included the presence of mucinous epithelium or glands with epithelial papillation, stratification, presence of microglandular or cribriforming configuration (Figures 1b and c). Focal mild-to-moderate cytolo- gical atypia was allowed including variably en- larged nuclei, pseudostratification and presence of prominent nucleoli (Figure 1d). Rare cases with moderate cytological atypia in an otherwise simple mucinous lesion were classified into the complex mucinous category. ...
Context 4
... However, cases with significant suspicion for carcinoma-due to the presence of more complex architectural changes (extensive papillation or cribriforming) and/or severe cytologi- cal atypia-were excluded from the complex muci- nous category and classified as adenocarcinoma in this study. Mucinous adenocarcinoma was qualified by the presence of intracytoplasmic mucin produc- tion in at least 50% of tumor cells within a type I endometrial carcinoma (Figures 1d and f). The patients' demographics and additional follow-up specimens (whenever available) were reviewed. ...
Citations
... PMP consists of irregular or complex mucinous glands displaying distinctive intraluminal papillary tufts and the absence of nuclear atypia. PMP is recognized as a potential precancerous lesion for endometrial carcinoma with mucinous differentiation as it frequently harbors KRAS mutations [99][100][101][102]. A significant proportion of APAs and PMPs exhibited one or more marker aberrancies [47]. ...
Simple Summary
Endometrial carcinoma is a common type of cancer in women, ranking as the most frequent gynecological cancer and the fourth most common overall. Its occurrence has been rising steadily, becoming a serious health concern. Detecting its immediate precursors, known as precancers, is crucial for saving lives. In recent years, research into the genetic makeup of endometrial carcinoma and its precancers has progressed, especially focusing on the most common subtype called endometrioid. New biomarkers have been discovered that could help in identifying precancers, potentially improving diagnosis and treatment. This review summarizes these recent discoveries and their significance in diagnosing precancers of endometrial carcinoma.
Abstract
Endometrial carcinoma stands as the most prevalent gynecological cancer and the fourth most common cancer affecting women. The incidence of endometrial cancer has been steadily increasing over the past decade, posing a significant threat to public health. The early detection of its precancers remains a critical and evolving concern to reduce mortality associated with endometrial carcinoma. In the last decade, our understanding of endometrial carcinoma and its precancers has advanced through systematic investigations into the molecular genetics of endometrial carcinoma and its precancers. In this review, we focus on advances in precancers associated with the endometrioid subtype, by far the most common histologic variant of endometrial adenocarcinoma. Recent investigations have led to the identification of new biomarkers, and the proposed incorporation of these biomarkers or biomarker panels into the diagnostic framework of endometrial carcinoma precancers. Here, we review these recent advances and their relevance to the histopathologic diagnosis of endometrial carcinoma precancers.
... Hot-spot KRAS variants seem to represent a common driver for tumours with mucinous phenotype across anatomical sites, suggesting that mucinous tumors arising in the seminal vesicles may also harbor mutations in RAS GTPases. [8][9][10] Our results confirm this hypothesis, as both low-grade mucinous neoplasms harboured hot-spot gain-of-function KRAS variants. In both tumours, KRAS variants represented the only genomic alteration, consistent with their low-grade phenotype (although copy-number analysis was limited by the low cellularity). ...
Background
Carcinomas of the seminal vesicle are exceedingly rare, with a limited number of cases described in the literature. Reported cases span a relatively wide morphological spectrum, and their genomic features remain unexplored.
Design
In this study, we interrogated five primary epithelial neoplasms of the seminal vesicle using a targeted DNA sequencing platform (OncoPanel, 447 genes).
Results
The tumours included one adenocarcinoma with intestinal phenotype presenting after external beam radiation (for prostatic adenocarcinoma), one carcinoma with Müllerian‐type clear cell phenotype, two mucinous tumours resembling low‐grade mucinous neoplasms of the appendix (LAMN) and one mucinous cystadenoma. The post‐radiation mucinous adenocarcinoma had genomic findings consistent with bi‐allelic inactivation of TP53 , as well as multiple copy‐number changes with regional and chromosomal arm‐level copy‐number losses. The Müllerian‐type clear cell carcinoma exhibited a complex copy‐number profile with numerous regional and arm‐level copy‐number changes, as well as focal amplification events, including copy‐number gain of 8q and amplification of a region within 20q13. Both low‐grade mucinous tumours resembling LAMN harboured hot‐spot gain‐of‐function KRAS variants (p.G12V and p.G13D) as the only genomic alteration. No genomic alterations were detected inthe lesion diagnosed as mucinous cystadenoma.
Conclusion
Our results suggest that primary low‐grade mucinous neoplasms of the seminal vesicle may represent a distinct entity equivalent to appendiceal counterparts, driven by gain‐of‐function variants of RAS GTPases. The remaining tumours showed genomic features that closely resembled those of neoplasms with comparable phenotypes and/or biological characteristics arising in other sites, suggesting that they could be managed similarly, with special considerations related to their anatomical location.
... There was a trend for those harboring KRASmut-Clin to have a lower CR rate, but without a significant difference. According to previous studies, KRAS mutation might be an unfavorable prognostic factor in endometrial cancer cases, predicting not only endometrial tumorigenesis and development [33,34], but also progressive biological behaviors of invasive proliferation [35] and metastasis [36]. Our analyses also showed that the patients harboring PIK3CAmut-Clin had a lower BMI and were less likely to develop insulin resistance. ...
Objective:
This study aimed to investigate the impact of molecular classification and PTEN, KRAS and PIK3CA gene mutation on the outcome of fertility-preserving treatment in the patients with endometrioid endometrial cancer (EEC) and endometrial atypical hyperplasia (EAH).
Methods:
This is a single-center retrospective study. A total of 135 patients with EEC and EAH receiving fertility-preserving treatment and molecular classification were reviewed. The distribution of the four types of molecular classification was described. The impact of non-specific molecular profile (NSMP), mismatch repair-deficiency (MMRd), and PTEN, KRAS and PIK3CA gene mutation on the outcome of fertility-preserving treatment was analyzed.
Results:
Of the patients analyzed, 86.7% (117/136) were classified as having NSMP; 14 (10.4%), MMRd; 1 (0.7%), POLEmut EAH; and 3 (2.2%), p53abn EEC. The patients having NSMP and MMRd achieved similar 16-, 32-, and 48-week complete response rates. The patients harboring tier I and tier II PTEN mutations (PTENmut-Clin) achieved lower cumulative 32-week CR rates than those with PTEN-others (without PTENmut-Clin) (22/47, 46.8% vs. 50/74, 67.6%; p=0.023; odds ratio=0.422; 95% confidence interval [CI]=0.199-0.896). Insulin-resistance (hazard ratio [HR]=0.435; 95% CI=0.269-0.702; p=0.001) and PTENmut-Clin (HR=0.535; 95% CI=0.324-0.885; p=0.015) were independent negative predictors for lower 32-week CR rates.
Conclusion:
PTENmut-Clin is an independent risk factor for unfavorable fertility-preserving treatment outcomes in the patients with EEC and EAH. The patients with MMRd receiving fertility-preserving treatment achieved outcomes similar to those of the patients with NSMP. The molecular profiles might guide fertility-preserving treatment in the prognosis and clinical decisions.
... Although none of our cases showed mucinous differentiation, KRAS mutations are also prevalent in mucinous carcinoma of the endometrium (71.4-86%) and complex papillary mucinous lesions of the endometrium. 59 A few studies suggest that pure mucinous, endometrioid carcinoma is frequently associated with poor prognostic factors, including deep myometrial invasion and lymph node metastasis. 60,61 We provide additional evidence that KRAS mutations are associated with DM in patients with low-grade EEC as well as in MLC. ...
A subset of endometrial endometrioid carcinomas (EECs) with low-grade histology recur with poor outcomes. Published evidence suggests that poor outcomes may be associated with loss of expression of ER-alpha (ER-α) as well as with β-Catenin-1 (CTNNB1) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. This study reports on institutional experience with the incidence of recurrence in low-grade EEC and their association with CTNNB1 and KRAS mutations as well as estrogen/progesterone receptor (ER/PR) expression. Forty-eight (8.5%) out of 568 cases of low-grade EEC with biopsy-proven recurrence were identified; and were analyzed by immunohistochemistry for ER, PR, p53, MMR protein, and mutation analysis for exon 3 of the CTNNB1 and exon 2 of KRAS in relation to recurrence type, local or distant metastasis/recurrence. Twenty-three patients (4%) developed local, and 25 patients (4.4%) developed distant metastases/recurrence. Decreased expression or loss of ER/PR was found in 17/44 (38.6%) patients with recurrence. Eighty-four percent of patients with low-grade EEC and local recurrence had CTNNB1 mutations. Seventy-three percent of patients with distant metastasis/recurrence had KRAS mutations. The association of these mutations with the type of recurrence was statistically significant for both. Five cases with the morphology of low-grade EEC were reclassified as mesonephric-like carcinoma and were universally characterized by distant metastasis/recurrence, loss of ER/PR expression, large tumor size, absence of CTNNB1 mutations, and the presence of KRAS mutations. In low-grade EEC, CTNNB1 and KRAS mutations are associated with local recurrence and distant metastasis/recurrence, respectively, suggesting that these 2 different progression types may be conditioned by tumor genotype. ER/PR immunohistochemistry may be helpful in identifying poor performers in low-grade EEC. Furthermore, identification of the decreased expression or loss of ER/PR in tumors with low-grade histology should prompt consideration of mesonephric-like carcinoma, which is a more aggressive tumor than the low-grade EEC. KRAS mutations were associated with distant metastasis/recurrence in tumors with and without mesonephric-like phenotype.
... However, in our study, the frequencies of KRAS mutations were similar among three groups but were significantly correlated with the presence of mucinous metaplasia. Since KRAS mutation occurred in endometrial cancer was related to the mucinous metaplasia [12,[14][15][16], and Liu et al. also found that the incidence of KRAS mutation was higher in the PPE lesions with mucinous metaplasia; it was possible that the presence of KRAS mutation in PPE was determined by the mucinous differentiation [11] rather than the classification of PPE. ...
Papillary proliferation of the endometrium (PPE) is subdivided based on the complexity of the papillae and the proliferation of lesions, and the complex group is considered to have an increased risk of concurrent/subsequent endometrial neoplasia. However, the current subdivision criteria fail to prove the equivalence of the quantity of simple papillae and structural complexity. In this study, we divided PPE of 207 cases from 2014 to 2022 into 3 groups according to structural complexity and proliferation degrees: Group 1 equaled to the simple PPE with a simple papillary structure and typical localized proliferation; group 2 had the simple structure similar to group 1 but occupy over 50% of the endometrial polyp or > 2 lesions in the surface of nonpolypoid endometrium; group 3 had the truly complex branching papillae despite of its proportion. Group 3 was implicated with significantly more concurrent endometrial neoplasia (EAH and carcinoma) compared with groups 1 and 2 (P < 0.01), while no difference was found between groups 1 and 2. In 128 cases with no concurrent endometrial abnormalities in the initial biopsy or curettage specimens, 4 cases presented endometrial neoplasia (3 carcinoma and 1 atypical hyperplasia) in the subsequent specimens, all of which presented PPE of group 3 but not group 1 or 2 in the prior tissues (P < 0.01). The immunochemistry of 83 cases showed similar expressions of ER, PTEN, ARID1A, PTEN, p16, β-catenin, and p53 between PPE and the surrounding normal endometrium. Nearly 100% of PPE cases lost expressions of PR. A total of 2/83 cases showing PAX2 expression were all in the group 3 and correlated with endometrial neoplasia (2/17, 11.76%, P < 0.05). 76/83 (91.57%) of PPE lesions had KRAS mutations, and the distributions of which were similar among 3 groups. The frequency of mucinous metaplasia was significantly higher in the PPE lesions with KRAS mutations (72/74, 97.30%, P < 0.01). Group 3 showed higher frequency of single KRAS mutations compared with the combination of groups 1 and 2 (P < 0.01). Finally, the concordance of KRAS mutation profiles between PPE and endometrial neoplasia was significantly higher in group 3 than either group 1 or 2 (P < 0.01), while no difference was found between group 1 and 2. Thus, a new 2-tier subdivision system only emphasizing the complexity of papillae is recommended, which might precisely predict the risk of endometrial neoplasia and neoplasia-related molecular characteristics.
... The likelihood of finding adenocarcinoma on subsequent hysterectomy is partly related to the degree of architectural complexity. Nevertheless, this can be challenging in actual practice [18]. The presence of MGH-like glands in an endometrial sampling in peri-or postmenopausal women, regardless of the degree of complexity, should be mentioned and discussed. ...
... Some studies have suggested that endometrial mucinous metaplasia strongly correlates with concurrent and subsequent carcinoma [9][10][11]. In previous studies, papillary mucinous metaplasia was a possible precancerous lesion of mucinous adenocarcinoma with frequent KRAS mutations [12,13]. Recently, we encountered a case of overt mucinous adenocarcinoma of the endometrium in a 35-year-old woman with concurrent papillary mucinous metaplasia. ...
Mucinous adenocarcinoma of the endometrium is heterogeneous, consisting of endometrioid adenocarcinoma composed of >50% mucinous cells, low-grade mucinous adenocarcinoma, microglandular adenocarcinoma, and gastric (gastrointestinal)-type adenocarcinoma. Previous studies have reported that papillary mucinous metaplasia is a possible precancerous lesion of mucinous adenocarcinoma with frequent KRAS mutations. Recently, we encountered a case of pure mucinous adenocarcinoma of the endometrium with concurrent papillary mucinous metaplasia in a 35-year-old woman. She underwent 6-month hormonal therapy for atypical endometrial hyperplasia. A follow-up biopsy led to a diagnosis of mucinous adenocarcinoma; therefore, total hysterectomy was performed. The tumor showed abundant intracytoplasmic mucin and mild-to-moderate cytologic atypia with papillary architecture. KRAS mutation analysis revealed a point mutation from GGT to GTT in codon 12. Although papillary mucinous metaplasia showed an overexpression of p16INK4, especially in the intragrandular papillary tufts, and a low MKi67 labeling index, overt mucinous adenocarcinoma with a loss of P16INK4a expression showed a high proliferating index of MKI67. The mass presented with stage ІA disease. During follow-up, the patient was stable and showed no recurrence. Considering the histologic similarity and incidence of KRAS mutations between papillary mucinous metaplasia and mucinous adenocarcinoma, papillary mucinous metaplasia may be a precancerous lesion for a subset of mucinous adenocarcinoma of the endometrium.
... These features have prompted researchers to assess whether some EMRCs may represent premalignant lesions. It has been suggested that the premalignant potential of EMRCs lies in architectural complexity, such as glandular crowding and papillation [6][7][8][9][10][11]; on the other hand, "simple" EMRCs have been regarded as benign reactive changes [3,4,[12][13][14][15]. However, to the best of our knowledge, no study assessed whether simple EMRCs associated with endometrial carcinoma may represent premalignant lesions. ...
The aim of this study was to assess the relationship between endometrial metaplastic/reactive changes (EMRCs) and endometrial neoplastic lesions. Twenty cases of “simple” (without architecture complexity) EMRCs coexistent with endometrial malignant/premalignant lesions, twenty cases of neoplasia-unassociated EMRCs, and eight cases of complex metaplastic lesions were assessed by immunohistochemistry. EMRCs coexisted with endometrioid carcinoma (n = 12), atypical endometrial hyperplasia (n = 3), serous carcinoma (n = 2), and clear cell carcinoma (n = 3). Neoplasia-associated EMRCs showed a mean Ki67 labeling index of 12.6% (range 0–30%); with nuclear atypia in 16/20 (80%) cases; diffuse p16 expression in 15/20 (75%) cases; and heterogeneous ER, PR, and vimentin expression. Compared to the associated neoplasia, EMRCs showed a lower Ki67 expression (p < 0.001) and higher p16 expression (p < 0.001). No EMRC case showed mitotic activity, PTEN loss, MMR deficiency, nuclear β-catenin, p53-mutant pattern, Napsin A, or AMACR expression. No significant differences were found between neoplasia-associated and neoplasia-unassociated EMRCs. Complex metaplastic lesions showed a lower Ki67 expression than EMRCs (p = 0.044) and PTEN loss in 5/8 cases, even in the absence of nuclear atypia. In conclusion, neoplasia-associated simple EMRCs may show evident atypia and a worrisome immunophenotype, but no data support their involvement in endometrial carcinogenesis. Architectural complexity appears as a crucial factor to identify precancerous lesions.
... In EC, the incidence of KRAS mutation is increasing globally ( Table 1), which was reported to be approximately 15.0% in the past (37,(61)(62)(63). Ahmed et al. (64) found the presence of KRAS mutation in both complex mucinous changes and mucinous adenocarcinoma, indicating that KRAS mutational activation was implicated in the pathogenesis of a significant subset of endometrial mucinous carcinoma. Xiong et al. (65) noticed that the KRAS status in the neoplastic lesion presented on the surface of the endometrium was different from that in the benign metaplastic areas, while Van der Putten et al. (66) found that KRAS mutation appeared both in the hyperplastic lesions and the adjacent benign endometrial tissues. ...
... Other studies (46,62) also supported that KRAS mutation occurred in the early stages of type I EC (endometrioid) before clonal expansion, which is similar to the role of KRAS mutation in colorectal cancer (67,68). Endometrial atypical hyperplasia (EAH) is now believed to be the precancerous lesion of EEC, in which KRAS was also a highly mutated gene (63,64,69). Contrarily, some studies found no KRAS mutation in endometrial atypical hyperplasia (70,71), probably due to the small sample size. ...
... It has been reported that KRAS mutation is associated with obesity (73, 74), a high-risk factor for the development of EEC (75), and decreased expression of estrogen receptor (76), suggesting a potential crosstalk between KRAS-mediated signaling pathway and the estrogen receptor activated signaling pathway. Recently, Ahmed et al. (64) demonstrated that KRAS mutation had a positive predictive value of 88% for complex atypical hyperplasia (the precancerous lesion of EEC) or adenocarcinoma. The KRAS mutation testing may be valuable for predicting the therapeutic effect of conservative treatment in EC, and the patients carrying specific mutations of KRAS may profit from the targeted therapy. ...
The annually increasing incidence of endometrial cancer in younger women has created a growing demand for fertility preservation. However, the diverse therapeutic efficacy among patients under the same histological subtype and the same tumor grade suggests the potential interference of the innate molecular characteristics. The molecular classification has now been applied in clinical practice and might help to stratify the endometrial cancer patients and individualize the therapy, but the candidates for the fertility-spared treatment are most likely to be subdivided in the subgroup lacking the specific signature. KRAS mutation has been linked to the malignant transition of the endometrium, while its role in molecular classification and fertility preservation is vague. Here, we mainly review the advance of molecular classification and the role of KRAS in endometrial cancer, as well as their correlation with fertility-preservation treatment.
... There is also a positive relationship between the KRAS gene and estrogen receptors (ER) (39), MSI-positive and a molecular assessment of the depth of myometrial invasion of EC, which are generally thought to occur early in the EC pathway (40,41). KRAS mutations are present in 6-16% of endometrial hyperplasia specimens, 88% complex atypical hyperplasia and 10-30% type I estrogen-related EC (37,40,42). An increase in KRAS expression has been associated with a poor outcome in 3% of the primary and 18% of metastatic lesions, and an aggressive phenotype (43). ...
Background:
We demonstrated that drinking hydrogen-rich water (HRW) inhibits endometrial tumor growth in our previous work. This research is to identify differentially expressed proteins (DEPs) between HRW and purified water groups in a xenograft mouse model of endometrial cancer (EC).
Methods:
Samples were analyzed using tandem mass tags (TMTs) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). DEPs were identified using bioinformatics to determine potential molecular functions and immunohistochemical (IHC) staining.
Results:
In total, 11 DEPs were identified in the HRW group relative to the control. The up-regulated proteins included Gatad1, Ttyh3, Nek4, Dyrk2, and Gimap1, while the down-regulated proteins included SP1, Msl1, Plekha7, Dtwd2, MSRA, and KRAS. Gene Ontology (GO) annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were associated with the binding region, biological regulation, endocrine resistance, estrogen signaling, choline metabolism in cancer and human cytomegalovirus infection. Furthermore, network analysis indicated that KRAS and MSRA interact with YWHAE. KRAS, YWHAE and SP1 were strongly expressed, while MSRA was weak expressed in atypical hyperplasia and EC tissue as well as in HRW group in xenograft tumor tissue.
Conclusions:
KRAS, YWHAE, SP1 and MSRA might be regarded as focused biomarkers to assess the prognosis of EC.
