Molecular Signature of Endometrial Cancer with Coexistent Adenomyosis: A Multicentric Exploratory Analysis
by
, , , , , , ,
Diego Raimondo
1,
Antonio Raffone
2,3,*,
Agnese Virgilio
1,2
,
Stefano Ferla
1,2,
Manuela Maletta
1,2,
Daniele Neola
3,
Antonio Travaglino
4,
Roberto Paradisi
2,*,
Alicia Hernández
5,6,
Emanuela Spagnolo
5,
Virginia García-Pineda
6,
Jacopo Lenzi
7,
Maurizio Guida
3,
Paolo Casadio
1,2,† and 
Renato Seracchioli
1,2,† 1
Division of Gynecology and Human Reproduction Physiopathology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
2
Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
3
Gynecology and Obstetrics Unit, Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, 80138 Naples, Italy
4
Unit of Pathology, Department of Medicine and Technological Innovation, University of Insubria, 21100 Varese, Italy
5
Department of Gynecology, La Paz University Hospital, Hospital Universitario La Paz, Paseo de la Castellana, 261, 28046 Madrid, Spain
6
Department of Gynecologic Oncology, La Paz University Hospital, Hospital Universitario La Paz, Paseo de la Castellana, 261, 28046 Madrid, Spain
7
Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2023, 15(21), 5208; https://doi.org/10.3390/cancers15215208
Submission received: 22 August 2023
/
Revised: 21 October 2023
/
Accepted: 23 October 2023
/
Published: 30 October 2023
(This article belongs to the Special Issue Therapy for Human Endometrioid - Endometrial Carcinoma and Endometriosis)
Abstract
:Simple Summary
The impact of the molecular signature on the favorable prognosis of endometrial cancer patients with coexistent adenomyosis is undefined. We aimed to compare the prevalence of molecular groups at poor and intermediate prognosis (p53-abn and MMR-d groups) between endometrial cancer patients with and without coexistent adenomyosis through a multicentric, observational, retrospective, cohort study. We included 147 endometrial cancer patients (38 in the adenomyosis group and 109 in the no adenomyosis group) and we found no significant difference in the prevalence of p53-abn (p = 1.000) and MMR-d (p = 0.2880) signatures between the two groups. Therefore, the molecular signature does not appear to explain the better prognosis associated with coexistent adenomyosis in endometrial cancer patients. Further investigation of the topic requires future larger studies.
Abstract
Adenomyosis has been associated with better survival outcomes in women with endometrial cancer. However, although the endometrial cancer patients’ risk stratification has been revolutionized by molecular findings, the impact of the molecular signature on the favorable prognosis of endometrial cancer patients with coexistent adenomyosis is unknown. The aim of our study was to compare the prevalence of molecular groups at poor and intermediate prognosis between endometrial cancer patients with and without coexistent adenomyosis. A multicentric, observational, retrospective, cohort study was performed to assess the differences in the prevalence of p53-abnormal expression (p53-abn) and mismatch repair protein-deficient expression (MMR-d) signatures between endometrial cancer patients with and without coexistent adenomyosis. A total of 147 endometrial cancer patients were included in the study: 38 in the adenomyosis group and 109 in the no adenomyosis group. A total of 37 patients showed the MMR-d signature (12 in the adenomyosis group and 25 in the no adenomyosis group), while 12 showed the p53-abn signature (3 in the adenomyosis group and 9 in the no adenomyosis group). No significant difference was found in the prevalence of p53-abn (p = 1.000) and MMR-d (p = 0.2880) signatures between endometrial cancer patients with and without coexistent adenomyosis. In conclusion, the molecular signature does not appear to explain the better prognosis associated with coexistent adenomyosis in endometrial cancer patients. Further investigation of these findings is necessary through future larger studies.
1. Introduction
Endometrial cancer is the most frequent gynecological neoplasm in Western countries [1,2,3,4,5,6,7,8]. The risk stratification of endometrial cancer patients had been mainly based on post-surgical pathological prognostic factors prior to the introduction of the Cancer Genome Atlas (TCGA) Research Network molecular classification [9] and the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) [1,2,4,10,11]. According to the ProMisE, endometrial cancer patients are classified into four molecular groups with different prognosis [1,2,4,10,11]: ultramutated group, characterized by mutations in the exonuclease domain of Polymerase-ε (POLEmt) and good prognosis; hypermutated group, characterized by mismatch repair (MMR) protein-deficient immunohistochemical (IHC) expression (MMR-d) and intermediate prognosis; copy-number high group, characterized by abnormal p53 IHC expression (p53-abn) and the worst prognosis; and copy-number low group, characterized by good to intermediate prognosis and lack of specific molecular profile (NSMP) [1,2,4,10,11]. Nowadays, the integration of ProMisE groups with conventional pathological prognostic factors is recommended by the international guidelines [1,2,4,10,11] in order to further tailor the risk stratification and adjuvant treatment of endometrial cancer patients.
Adenomyosis is a disease defined by the presence of ectopic endometrium within the myometrium [12,13]. It has been reported in up to one in four patients with EC [12], representing a factor associated with better survival outcomes [14]. Several hypotheses have been made to explain such a difference in prognosis between endometrial cancer patients with and without coexistent adenomyosis. In particular, differences in the prevalence of pathological, clinical and/or molecular prognostic factors between women with and without coexistent adenomyosis have been supposed. In detail, while clinical factors (with the exception for nulliparity) have shown no significant differences between endometrial cancer patients with and without adenomyosis, conventional pathological prognostic factors have been shown to be less frequently unfavorable in endometrial cancer patients with adenomyosis compared to endometrial cancer patients without adenomyosis [8,14]. However, to our knowledge, data about molecular prognostic factors (i.e., molecular groups) in endometrial cancer patients with coexistent adenomyosis have never been reported; thus, the impact of the molecular signature on the reported favorable prognosis of endometrial cancer patients with coexistent adenomyosis is unknown.
The aim of this study was to compare the prevalence of molecular groups at poor and intermediate prognosis (i.e., p53-abn and MMR-d groups) between endometrial cancer patients with and without coexistent adenomyosis.
2. Materials and Methods
2.1. Study Protocol
Following an a priori defined study protocol, this study was designed as a multicentric, observational, retrospective, cohort study.
The STrengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement and checklist [15] were used to report this study.
2.2. Selection Criteria
Medical records and electronic clinical databases were consulted for all consecutive patients who underwent surgical staging for endometrial cancer and IHC evaluation for MMR protein and p53 expression on final surgical specimens, at two tertiary level referral centers for gynecological cancers (S. Orsola Hospital, University of Bologna, Bologna, Italy; and Department of Gynecologic Oncology, La Paz University Hospital, Hospital Universitario La Paz, Madrid, Spain) from September 2020 to September 2022. The exclusion criteria were the absence of IHC assessment on final surgical specimens and incomplete surgical staging.
The endometrial cancer patients were divided into two groups based on the presence of adenomyosis on final surgical specimens, assessed by experienced gynecological pathologists: patients with coexistent adenomyosis (adenomyosis group) and patients without coexistent adenomyosis (no adenomyosis group). Adenomyosis was diagnosed based on the presence of ectopic endometrium (seen at least 2.5 mm or more than one microscopic field at 10× magnification from the endomyometrial junction), circumferentially surrounded by a bundle of hypertrophic smooth muscle cells [16,17].
2.3. Study Endpoints
The study endpoints were the differences in the prevalence of molecular signatures at poor and intermediate prognosis (i.e., p53-abn and MMR-d) between endometrial cancer patients of the adenomyosis group and those of the no adenomyosis group.
Immunohistochemical analysis was performed as per routine clinical practice. In fact, IHC was found as a highly accurate surrogate of gene sequencing in detecting TP53 mutations and microsatellite instability [18,19]. In particular, MMR protein IHC expression was categorized as “proficient” (MMR-p) in the case of positive nuclear expression of 2 MMR proteins (MSH6 and PMS2), and “deficient” (MMR-d) in the case of loss of nuclear expression of the MSH6 and PMS2 proteins in at least 10% of the tumoral area, in the presence of an internal positive control (stromal cells and lymphocytes) [19]. Regarding p53 IHC expression, it was categorized as “normal” (p53-wt) in the case of nuclear expression in <70–80% of tumor cells with heterogeneous intensity, and “abnormal” (p53-abn) in the case of (i) strong nuclear expression in ≥70–80% of tumor cells (with or without cytoplasmic expression) and (ii) complete loss of nuclear expression in the presence of an internal positive control (stromal cells and lymphocytes) [19]. According to ProMisE [18], endometrial cancers with both MMR-d and p53-abn signatures were classified as MMR-d cases. On the other hand, endometrial cancer patients with either the MMR-d or p53-abn signature were screened for the presence of mutations in the exonuclease domain of POLE through sequencing [18,20]; in fact, cases with both MMR-d and POLE-mt, and cases with both p53-mt and POLE-mt signatures were considered as POLE-mt and, therefore, not included in our study population. Indeed, as our centers restrict POLE testing to only those patients in whom this would alter adjuvant therapy recommendations in order to restrict sequencing costs, the POLE signature was not available for all endometrial cancer patients. Thus, a retrospective calculation of the prevalence of the POLE signature (and subsequently of the NSMP signature) was not feasible. Based on these considerations, during the elaboration of the study protocol, we a priori decided to only assess p53-abn and MMR-d signatures.
Other collected data for each included patient were the following: age at diagnosis, body mass index (BMI), tumor histotype and grade, depth of myometrial invasion, lymphovascular space invasion (LVSI), International Federation of Gynecology and Obstetrics (FIGO) staging, lymph node involvement, adjuvant treatment, disease recurrence, and any deaths during follow-up for causes independent of or dependent on endometrial cancer.
2.4. Statistical Analysis
Continuous data were described as mean ± standard deviation (SD) or median (interquartile range), as appropriate. Categorical variables were presented as numbers and percentages. Student’s t-test or Mann–Whitney U-test and χ2 or Fisher’s exact test were used for continuous and categorical data, respectively, as appropriate. A value of p < 0.05 was considered significant for all tests. Statistical analysis was carried out using the SPSS software version 24.0 (IBM Corp., Armonk, NY, USA).
Post hoc Analysis
Based on the sample size of 38 and 109 patients with and without adenomyosis and the observed prevalence of the MMR-d signature of about 32% and 23% in the two groups, respectively, which gives an odds ratio of 1.55, we obtained a retrospective power for a two-sample proportions test of only 21%.
2.5. Ethical Statement
The Institutional Review Board of the IRCCS Azienda Ospedaliero-Universitaria di Bologna (CE-AVEC 389/2021/Oss/AOUBo) approved this study which was conducted in accordance with the Helsinki Declaration. An informed consent form was signed by all patients for the use of their anonymized data for research purposes.
3. Results
During the study period, 220 women underwent surgical staging for endometrial cancer. Seventy-three patients were excluded since they did not meet the selection criteria. Finally, 147 endometrial cancer patients were included in the study: 38 (25.8%) in the adenomyosis group and 109 (74.1%) in the no adenomyosis group.
Median age (range) at surgery was 62 (38–84) years in the adenomyosis group and 64 (28–92) years in the no adenomyosis group. Most of the endometrial cancer showed an early FIGO stage (89.5% in the adenomyosis group and 82.6% in the no adenomyosis group), low grade (78.9% in both groups) and endometrioid histotype (89.5% in the adenomyosis group and 84.4% in the no adenomyosis group).
No statistically significant difference between adenomyosis and no adenomyosis group was found in terms of age, BMI, FIGO stage, histotype, tumor grade, LVSI, sentinel lymph node involvement and adjuvant treatment.
Regarding survival outcomes, five (3.4%) recurrences (two in the adenomyosis group and three in the no adenomyosis group) were observed during the follow-up (median follow-up time: 18 months) (Table 1). In particular, in the no adenomyosis group, two patients with advanced FIGO stage and high-grade endometrioid endometrial cancer experienced recurrence after 6 and 17 months, while another patient with low-grade early-stage endometrioid endometrial cancer showed recurrence 18 months after surgery. On the other hand, in the adenomyosis group, two recurrences occurred at 12 months and 24 months after surgery for early-stage low-grade endometrial cancer. Moreover, one death due to endometrial cancer was reported in the adenomyosis group: a 61-year-old woman developed local recurrence and distant metastasis and died 24 months after surgery and brachytherapy for IB FIGO stage, low-grade endometrioid endometrial cancer which showed the MMR-d signature.
Concerning the study endpoints, 37 (25.2%) patients showed the MMR-d signature (12 in the adenomyosis group and 25 in the no adenomyosis group), while 12 (8.2%) showed the p53-abn signature (3 in the adenomyosis group and 9 in the no adenomyosis group). No significant difference was found in the prevalence of p53-abn (p = 1.000) and MMR-d (p = 0.2880) signatures between endometrial cancer patients with and without coexistent adenomyosis (Table 2).
4. Discussion
4.1. Main Findings and Interpretations
This study showed no significant difference in the prevalence of p53-abn and MMR-d signatures between endometrial cancer patients with and without coexistent adenomyosis. This would indicate that the molecular signature is not among the prognostic factors underlying the better prognosis reported for endometrial cancer patients with coexistent adenomyosis.
In a recent systematic review and meta-analysis assessing 5573 endometrial cancer patients, adenomyosis has shown to be a common finding at histological examination of hysterectomy specimens, with a pooled prevalence of 22.6% (95% Confidence Interval (CI) 12.7–37.1%) [12]. Given such a high prevalence in women with endometrial cancer, several cohort studies have investigated the impact of adenomyosis on prognosis. A meta-analysis by An et al. including fourteen retrospective observational studies concluded that endometrial cancer patients with adenomyosis showed a significant increase in overall survival rate, indicating that coexistent adenomyosis might be associated with favorable endometrial cancer characteristics and considered a potential protective factor for the prognosis of endometrial cancer [21]. These results were confirmed in our recent meta-analysis which analyzed a population of 2505 women with endometrial cancer (553 with and 1952 without adenomyosis) and showed that endometrial cancer patients with adenomyosis had a halved risk of death and recurrence compared to endometrial cancer patients without adenomyosis [14]. In particular, compared to endometrial cancer patients without adenomyosis, endometrial cancer patients with coexistent adenomyosis showed a pooled hazard ratio (HR) of 0.533 (CI 95%, 0.329–0.864) for overall survival (OS) at univariate analysis, 0.536 (CI 95%, 0.334–0.859) for disease-free survival (DFS) at univariate analysis, and 0.875 (CI 95%, 0.331–2.315) for DFS at multivariate analysis [14].
The reported better prognosis of endometrial cancer with coexistent adenomyosis has been explained by different hypotheses. For example, adenomyosis has been linked to a specific profile of cytokines that includes higher levels of anti-tumoral cytokines and lower levels of oncogenic cytokines and growth factors; the local microenvironment could be impacted by this profile and tumor progression and invasiveness could be limited [21,22,23]. Moreover, the thickened endometrial stroma observed in the adenomyotic uterus following repeated inflammations might result in a block of endometrial cancer invasion in the myometrium [21,22,23]. Yet, a better prognosis might be subsequent to an early endometrial cancer diagnosis provided by adenomyosis-related symptoms (e.g., dysmenorrhea and abnormal uterine bleeding) [14]. However, these mechanisms have never been proved in large clinical studies. Furthermore, although the impact of adenomyosis on the risk of death from any cause in endometrial cancer patients was not evaluable at multivariate analysis in our recent meta-analysis [14], the risk of endometrial cancer recurrence in women with coexistent adenomyosis did not decrease significantly at multivariate analysis, suggesting that this association might be not independent. In other words, the association found at univariate analysis might be related to other prognostic factors that could be related to the coexistence of adenomyosis in endometrial cancer patients. Hence, it is necessary to investigate possible differences in clinical, histological and molecular prognostic factors between endometrial women with and without coexistent adenomyosis [14].
While comparisons of molecular prognostic factors between endometrial cancer patients with or without associated adenomyosis were not suitable when conducting a systematic review and meta-analysis of the literature because of the lack of individual eligible studies, differences in clinical and histological prognostic factors were evaluable by analyzing previous studies.
In particular, for clinical factors, in another systematic review and meta-analysis, we included eight studies with 5681 patients in the qualitative analysis, and seven studies with 4366 patients in the quantitative analysis. Specifically, the pooled mean difference in mean ± SD between endometrial cancer patients with and without adenomyosis was −1.19 (95% CI: −3.18 to 0.80; p = 0.24) for age, and 0.23 (95% CI: −0.62 to 1.07; p = 0.60) for BMI. When compared to endometrial cancer patients without adenomyosis, endometrial cancer patients with adenomyosis showed a pooled odds ratio (OR) of 1.53 (95% CI: 0.92 to 2.54; p = 0.10) for premenopausal status, and of 0.60 (95% CI: 0.41 to 0.87; p = 0.007) for nulliparity [8]. In conclusion, we found that there are no significant differences in clinical characteristics between endometrial cancer patients with and without adenomyosis in terms of age, BMI and premenopausal status, with the exception of nulliparity [8]. Therefore, clinical features seem not to underlie the better endometrial cancer prognosis of patients with adenomyosis compared to patients without adenomyosis.
On the other hand, in another systematic review and meta-analysis investigating the possible impact of histological prognostic factors on the better endometrial cancer prognosis in women with coexistent adenomyosis, we found that the prevalence of unfavorable histological prognostic factors significantly differed between endometrial cancer patients with and without coexistent adenomyosis [7]. In particular, a significantly decreased risk for FIGO grade 3, FIGO stages II-IV, LVSI and deep myometrial infiltration was found in endometrial cancer patients with adenomyosis compared to endometrial cancer patients without adenomyosis. In particular, when compared to endometrial cancer without adenomyosis, endometrial cancer with a adenomyosis showed a pooled relative risk of 0.77 (95% CI: 0.59, −1.00; p = 0.05) for the non-endometrioid histotype; 0.55 (95% CI: 0.42−0.71; p = 0.000001) for FIGO grade 3; 0.60 (95% CI: 0.42–0.85; p = 0.005) for FIGO stage II–IV; 0.75 (95% CI: 0.62–0.92; p = 0.004) for LVSI; and 0.65 (95% CI: 0.51–0.84; p = 0.001) for deep myometrial invasion [7].
Since pooled comparisons in the prevalence of the different molecular signatures between endometrial cancer patients with and without coexistent adenomyosis were not suitable due to the lack of previous studies on the topic in the literature, we carried out the present study with this aim. In particular, we assessed our study population and we found no significant difference in the prevalence of molecular groups at poor and intermediate prognosis between the adenomyosis and no adenomyosis groups of endometrial cancer patients.
Thus, conventional histological prognostic factors rather than clinical and molecular ones might explain the better survival outcomes of endometrial cancer patients with coexisting adenomyosis. Such a finding seems to be in line with the results of recent studies demonstrating that conventional histological prognostic factors retain a prognostic value independent of the molecular signature. In fact, although TCGA/ProMisE molecular groups have shown the potential to reduce past under- and overtreatment of EC patients [18,24], some studies reported that histotype, deep myometrial invasion and LVSI retain a prognostic value independent of the molecular signature [1,25,26]. In particular, non-endometrioid EC has shown a worse prognosis in each TCGA/ProMisE group [25], deep myometrial invasion has been shown to independently affect the risk of recurrence [1], and LVSI has been shown to independently increase the risk of death from any cause, death due to EC and recurrent or progressive disease by 1.5–2 times [26].
4.2. Strengths and Limitations of This Study and Future Perspectives
To the best of our knowledge, this study may be the first to investigate the impact of the molecular signature on the prognosis of endometrial cancer patients with coexistent adenomyosis.
However, despite their novelty, some limitations might impact our findings. Indeed, the retrospective design and the relatively small sample size are some of the drawbacks of this study. Yet, a major limitation might consist in the lack of information about the prevalence of the NSMP and POLE-mt signatures in the study population. In fact, our centers restrict POLE testing to only those patients in whom this would alter adjuvant therapy recommendations in order to restrict sequencing costs. In other words, as the POLE signature was not available for all endometrial cancer patients in our centers, a retrospective calculation of the prevalence of the POLE signature (and subsequently of the NSMP signature) was not feasible. In order to assess the prevalence of the NSMP and POLE-mt signatures, future prospective studies assessing mutations in the exonuclease domain of Polymerase-ε on all endometrial cancers samples are necessary.
In the near future, we hope that an increasingly tailored risk assessment based on an integration of clinical, histological and molecular prognostic factors will direct the preoperative, surgical and postoperative management of endometrial cancer patients.
4.3. Conclusions
The prevalence of p53-abn and MMR-d signatures does not differ between endometrial cancer patients with and without coexistent adenomyosis. Therefore, the molecular signature might not explain the better prognosis associated with coexistent adenomyosis in endometrial cancer patients.
In order to confirm these findings and further investigate the topic, larger prospective studies, also performing gene sequencing for the detection of POLE mutations on all samples, are necessary.
Author Contributions
Conceptualization, D.R. and P.C.; methodology, R.P.; software, D.N.; validation, A.R., A.H. and E.S.; formal analysis, S.F.; investigation, V.G.-P.; resources, S.F.; data curation, D.N. and J.L.; writing—original draft preparation, A.V. and S.F.; writing—review and editing, M.M. and A.R.; visualization, M.G. and A.T.; supervision, R.S. and P.C.; project administration, D.R. and R.P. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of the IRCCS Azienda Ospedaliero-Universitaria di Bologna (CE-AVEC389/2021/Oss/AOUBo).
Informed Consent Statement
All patients signed an informed consent for the use of their anonymized data for research purposes.
Data Availability Statement
The data that support the findings of this study are available from the corresponding authors (A.R. and R.P.) upon reasonable request.
Conflicts of Interest
The authors declare no conflict of interest.
References
- Raffone, A.; Travaglino, A.; Raimondo, D.; Neola, D.; Renzulli, F.; Santoro, A.; Insabato, L.; Casadio, P.; Zannoni, G.F.; Zullo, F.; et al. Prognostic Value of Myometrial Invasion and TCGA Groups of Endometrial Carcinoma. Gynecol. Oncol. 2021, 162, 401–406. [Google Scholar] [CrossRef] [PubMed]
- Raffone, A.; Travaglino, A.; Santoro, A.; Esposito, I.; Angelico, G.; Spadola, S.; Zannoni, G.F. Accuracy of One-Step Nucleic Acid Amplification in Detecting Lymph Node Metastases in Endometrial Cancer. Pathol. Oncol. Res. 2020, 26, 2049–2056. [Google Scholar] [CrossRef] [PubMed]
- Raffone, A.; Troisi, J.; Boccia, D.; Travaglino, A.; Capuano, G.; Insabato, L.; Mollo, A.; Guida, M.; Zullo, F. Metabolomics in Endometrial Cancer Diagnosis: A Systematic Review. Acta Obstet. Gynecol. Scand. 2020, 99, 1135–1146. [Google Scholar] [CrossRef] [PubMed]
- Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer Statistics, 2015. CA Cancer J. Clin. 2015, 65, 5–29. [Google Scholar] [CrossRef]
- Talhouk, A.; McConechy, M.K.; Leung, S.; Li-Chang, H.H.; Kwon, J.S.; Melnyk, N.; Yang, W.; Senz, J.; Boyd, N.; Karnezis, A.N.; et al. A Clinically Applicable Molecular-Based Classification for Endometrial Cancers. Br. J. Cancer 2015, 113, 299–310. [Google Scholar] [CrossRef]
- World Health Organization. GLOBOCAN 2018: Estimated Cancerincidence, Mortality and Prevalence Worldwide in 2018, Corpus Uteri; WHO: Geneva, Switzerland, 2018. [Google Scholar]
- Raffone, A.; Travaglino, A.; Raimondo, D.; Maletta, M.; Salucci, P.; Santoro, A.; Zullo, F.; Zannoni, G.F.; Casadio, P.; Seracchioli, R.; et al. Histological Prognostic Factors of Endometrial Cancer in Patients with Adenomyosis: A Systematic Review and Meta-Analysis. Pathobiology 2022, 89, 127–134. [Google Scholar] [CrossRef]
- Casadio, P.; Raffone, A.; Maletta, M.; Travaglino, A.; Raimondo, D.; Raimondo, I.; Santoro, A.; Paradisi, R.; Zannoni, G.F.; Mollo, A.; et al. Clinical Characteristics of Patients with Endometrial Cancer and Adenomyosis. Cancers 2021, 13, 4918. [Google Scholar] [CrossRef]
- Levine, D.A. Integrated Genomic Characterization of Endometrial Carcinoma. Nature 2013, 497, 67–73. [Google Scholar] [CrossRef]
- Talhouk, A.; McConechy, M.K.; Leung, S.; Yang, W.; Lum, A.; Senz, J.; Boyd, N.; Pike, J.; Anglesio, M.; Kwon, J.S.; et al. Confirmation of ProMisE: A Simple, Genomics-based Clinical Classifier for Endometrial Cancer. Cancer 2017, 123, 802–813. [Google Scholar] [CrossRef]
- Hoang, L.N.; McConechy, M.K.; Köbel, M.; Han, G.; Rouzbahman, M.; Davidson, B.; Irving, J.; Ali, R.H.; Leung, S.; McAlpine, J.N.; et al. Histotype-Genotype Correlation in 36 High-Grade Endometrial Carcinomas. Am. J. Surg. Pathol. 2013, 37, 1421–1432. [Google Scholar] [CrossRef]
- Raffone, A.; Seracchioli, R.; Raimondo, D.; Maletta, M.; Travaglino, A.; Raimondo, I.; Giaquinto, I.; Orsini, B.; Insabato, L.; Pellicano, M.; et al. Prevalence of Adenomyosis in Endometrial Cancer Patients: A Systematic Review and Meta-Analysis. Arch. Gynecol. Obstet. 2021, 303, 47–53. [Google Scholar] [CrossRef] [PubMed]
- Struble, J.; Reid, S.; Bedaiwy, M.A. Adenomyosis: A Clinical Review of a Challenging Gynecologic Condition. J. Minim. Invasive Gynecol. 2016, 23, 164–185. [Google Scholar] [CrossRef] [PubMed]
- Raimondo, D.; Raffone, A.; Travaglino, A.; Maletta, M.; Casadio, P.; Ambrosio, M.; Chiara Aru, A.; Santoro, A.; Franco Zannoni, G.; Insabato, L.; et al. Impact of Adenomyosis on the Prognosis of Patients with Endometrial Cancer. Int. J. Gynecol. Obstet. 2022, 157, 265–270. [Google Scholar] [CrossRef]
- Cuschieri, S. The STROBE Guidelines. Saudi J. Anaesth. 2019, 13, 31. [Google Scholar] [CrossRef] [PubMed]
- Bergeron, C.; Amant, F.; Ferenczy, A. Pathology and Physiopathology of Adenomyosis. Best Pract. Res. Clin. Obstet. Gynaecol. 2006, 20, 511–521. [Google Scholar] [CrossRef]
- Chapron, C.; Vannuccini, S.; Santulli, P.; Abrão, M.S.; Carmona, F.; Fraser, I.S.; Gordts, S.; Guo, S.-W.; Just, P.-A.; Noël, J.-C.; et al. Diagnosing Adenomyosis: An Integrated Clinical and Imaging Approach. Hum. Reprod. Update 2020, 26, 392–411. [Google Scholar] [CrossRef]
- Kommoss, S.; McConechy, M.K.; Kommoss, F.; Leung, S.; Bunz, A.; Magrill, J.; Britton, H.; Kommoss, F.; Grevenkamp, F.; Karnezis, A.; et al. Final Validation of the ProMisE Molecular Classifier for Endometrial Carcinoma in a Large Population-Based Case Series. Ann. Oncol. 2018, 29, 1180–1188. [Google Scholar] [CrossRef]
- Raffone, A.; Travaglino, A.; Cerbone, M.; Gencarelli, A.; Mollo, A.; Insabato, L.; Zullo, F. Diagnostic Accuracy of Immunohistochemistry for Mismatch Repair Proteins as Surrogate of Microsatellite Instability Molecular Testing in Endometrial Cancer. Pathol. Oncol. Res. 2020, 26, 1417–1427. [Google Scholar] [CrossRef]
- Raffone, A.; Travaglino, A.; Gabrielli, O.; Micheli, M.; Zuccalà, V.; Bitonti, G.; Camastra, C.; Gargiulo, V.; Insabato, L.; Zullo, F. Clinical Features of ProMisE Groups Identify Different Phenotypes of Patients with Endometrial Cancer. Arch. Gynecol. Obstet. 2021, 303, 1393–1400. [Google Scholar] [CrossRef]
- An, M.; Duan, H.; Zhang, Y. Prognostic Significance of Co-existent Adenomyosis on Outcomes and Tumor Characteristics of Endometrial Cancer: A Meta-analysis. J. Obstet. Gynaecol. Res. 2020, 46, 1851–1863. [Google Scholar] [CrossRef]
- Sanci, M.; Erkilinç, S.; Taylan, E.; Gülseren, V.; Erkilinç, G.; Karadeniz, T.; Bağci, M.; Temel, O.; Solmaz, U.; Gökçü, M. The Effect of Adenomyosis in Myometrial Invasion and Overall Survival in Endometrial Cancer. Int. J. Gynecol. Cancer 2018, 28, 145–151. [Google Scholar] [CrossRef] [PubMed]
- Matsuo, K.; Cahoon, S.S.; Gualtieri, M.; Scannell, C.A.; Jung, C.E.; Takano, T.; Paulson, R.J.; Muderspach, L.I.; Roman, L.D. Significance of Adenomyosis on Tumor Progression and Survival Outcome of Endometrial Cancer. Ann. Surg. Oncol. 2014, 21, 4246–4255. [Google Scholar] [CrossRef] [PubMed]
- Arciuolo, D.; Travaglino, A.; Raffone, A.; Raimondo, D.; Santoro, A.; Russo, D.; Varricchio, S.; Casadio, P.; Inzani, F.; Seracchioli, R.; et al. TCGA Molecular Prognostic Groups of Endometrial Carcinoma: Current Knowledge and Future Perspectives. Int. J. Mol. Sci. 2022, 23, 11684. [Google Scholar] [CrossRef] [PubMed]
- Travaglino, A.; Raffone, A.; Stradella, C.; Esposito, R.; Moretta, P.; Gallo, C.; Orlandi, G.; Insabato, L.; Zullo, F. Impact of Endometrial Carcinoma Histotype on the Prognostic Value of the TCGA Molecular Subgroups. Arch. Gynecol. Obstet. 2020, 301, 1355–1363. [Google Scholar] [CrossRef]
- Raffone, A.; Travaglino, A.; Raimondo, D.; Neola, D.; Maletta, M.; Santoro, A.; Insabato, L.; Casadio, P.; Fanfani, F.; Zannoni, G.F.; et al. Lymphovascular Space Invasion in Endometrial Carcinoma: A Prognostic Factor Independent from Molecular Signature. Gynecol. Oncol. 2022, 165, 192–197. [Google Scholar] [CrossRef]
- Concin, N.; Matias-Guiu, X.; Vergote, I.; Cibula, D.; Mirza, M.R.; Marnitz, S.; Ledermann, J.; Bosse, T.; Chargari, C.; Fagotti, A.; et al. ESGO/ESTRO/ESP Guidelines for the Management of Patients with Endometrial Carcinoma. Int. J. Gynecol. Cancer 2021, 31, 12–39. [Google Scholar] [CrossRef]
- Berek, J.S.; Matias-Guiu, X.; Creutzberg, C.; Fotopoulou, C.; Gaffney, D.; Kehoe, S.; Lindemann, K.; Mutch, D.; Concin, N. FIGO Staging of Endometrial Cancer: 2023. Int. J. Gynecol. Obstet. 2023, 162, 383–394. [Google Scholar] [CrossRef]
Table 1.
Characteristics of the study population.
| Characteristic | All (n = 147) | Adenomyosis | p-Value | |
|---|---|---|---|---|
| Yes (n = 38) | No (n = 109) | |||
| Age, years | 64 (28–92) | 62 (38–84) | 64 (28–92) | 0.6729 |
| BMI | 0.6303 | |||
| <25 kg/m2 | 41 (27.9) | 8 (21.1) | 33 (30.2) | |
| 25–30 kg/m2 | 46 (31.3) | 14 (36.8) | 32 (29.4) | |
| 30–35 kg/m2 | 30 (20.4) | 7 (18.4) | 23 (21.1) | |
| >35 kg/m2 | 30 (20.4) | 9 (23.7) | 21 (19.3) | |
| FIGO stage | 0.4384 | |||
| I–II | 124 (84.3) | 34 (89.5) | 90 (82.6) | |
| III–IV | 23 (15.6) | 4 (10.5) | 19 (17.4) | |
| Histotype | 0.5931 | |||
| Endometrioid | 126 (85.7) | 34 (89.5) | 92 (84.4) | |
| Not endometrioid | 21 (14.3) | 4 (10.5) | 17 (15.6) | |
| Tumor grade | 1.0000 | |||
| G1–G2 | 116 (78.9) | 30 (78.9) | 86 (78.9) | |
| G3 | 31 (21.1) | 8 (21.1) | 23 (21.1) | |
| Lymphovascular Invasion | 0.5598 | |||
| Negative | 87 (59.2) | 25 (65.8) | 62 (56.9) | |
| Focal | 36 (24.5) | 7 (18.4) | 29 (26.6) | |
| Diffuse | 24 (16.3) | 6 (15.8) | 18 (16.5) | |
| Sentinel Lymph Node | 0.9326 | |||
| Negative | 123 (83.7) | 32 (84.2) | 91 (83.5) | |
| Positive | 14 (9.5) | 4 (10.5) | 10 (9.2) | |
| Missing | 10 (6.8) | 2 (5.3) | 8 (7.3) | |
| Pelvic Lymphadenectomy | 0.4185 | |||
| Yes | 32 (21.8) | 6 (15.8) | 26 (23.8) | |
| No | 115 (78.2) | 32 (84.2) | 83 (76.2) | |
| Paraortic Lymphadenectomy | 0.6984 | |||
| Yes | 15 (10.2) | 5 (13.2) | 10 (9.2) | |
| No | 132 (89.8) | 33 (86.8) | 99 (90.8) | |
| Adjuvant Therapy | 0.0505 | |||
| Yes | 67 (45.6) | 23 (60.5) | 44 (40.4) | |
| No | 80 (54.4) | 15 (39.5) | 65 (59.6) | |
| Recurrence | 5 (3.4) | 2 (5.2) | 3 (2.7) | - |
| Death from any cause | 0 | 0 | 0 | - |
| Death due to tumor | 1 (0.6) | 1 (2.6) | 0 | - |
Values are given as numbers (% or range) unless otherwise noted. BMI: Body Mass Index; FIGO: International Federation of Gynecology and Obstetrics.
Table 2.
Molecular signatures at poor and intermediate prognosis in the study population.
| Molecular Signature | All (n = 147) | Adenomyosis | p-Value | |
|---|---|---|---|---|
| Yes (n = 38) | No (n = 109) | |||
| MMR-d | 37 (25.2) | 12 (31.6) | 25 (22.9) | 0.2880 |
| p53-abn | 12 (8.2) | 3 (7.9) | 9 (8.3) | 1.0000 |
Values are given as numbers (% or range) unless otherwise noted. MMR-d: mismatch repair deficient expression; p53-abn: p53 abnormal expression.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Raimondo, D.; Raffone, A.; Virgilio, A.; Ferla, S.; Maletta, M.; Neola, D.; Travaglino, A.; Paradisi, R.; Hernández, A.; Spagnolo, E.; et al. Molecular Signature of Endometrial Cancer with Coexistent Adenomyosis: A Multicentric Exploratory Analysis. Cancers 2023, 15, 5208. https://doi.org/10.3390/cancers15215208
AMA Style
Raimondo D, Raffone A, Virgilio A, Ferla S, Maletta M, Neola D, Travaglino A, Paradisi R, Hernández A, Spagnolo E, et al. Molecular Signature of Endometrial Cancer with Coexistent Adenomyosis: A Multicentric Exploratory Analysis. Cancers. 2023; 15(21):5208. https://doi.org/10.3390/cancers15215208
Chicago/Turabian StyleRaimondo, Diego, Antonio Raffone, Agnese Virgilio, Stefano Ferla, Manuela Maletta, Daniele Neola, Antonio Travaglino, Roberto Paradisi, Alicia Hernández, Emanuela Spagnolo, and et al. 2023. "Molecular Signature of Endometrial Cancer with Coexistent Adenomyosis: A Multicentric Exploratory Analysis" Cancers 15, no. 21: 5208. https://doi.org/10.3390/cancers15215208
Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.
