Background. Studies conducted by The Cancer Genome Atlas (TGCA) using molecular and immunohistochemical analyses have identified four molecular subtypes of endometrial carcinoma through the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE): POLE ultramutated, MSI hypermutated, Non-Specific Molecular Profile or Copy number Low, P53 abnormal or Copy number High. Purpose of the study. This study aims to retrospectively evaluate the prognostic risk of 153 patients followed from January 1, 2019, to December 31, 2022, at the Obstetrics and Gynecology unit of Ca’ Foncello Hospital in Treviso using the molecular stratification proposed by the ProMisE algorithm. The care plan included a preoperative diagnostic-anamnestic program, a staging and therapeutic surgical procedure, and subsequent follow-up monitoring. Special attention was given to collecting anamnestic elements, such as age and BMI, and anatomo-pathological factors, such as molecular classification, myometrial infiltration, lymphovascular invasion, and stage, to assess their potential prognostic role in disease progression. Material and methods. The study included only female patients aged ≥ 18 years with histologically confirmed malignant epithelial neoplasia of endometrial origin via biopsy. All biopsy samples were evaluated by expert gynecologic oncology pathologists. Data from patients with a follow-up of less than 12 months were considered in the statistical analysis concerning the anamnestic component, preoperative staging, surgical intervention, and histological diagnosis but not for status evaluation. Immunohistochemical analysis was employed to evaluate p53 and microsatellite instability (MSI). Molecular analysis searched for POLE gene mutations, microsatellite instability (if immunohistochemistry was ambiguous), and MLH1 promoter methylation in MSI cases. Statistical analysis was performed using Python programming language, Pandas library, chi-square test, Kaplan-Meier method for survival curves, log-rank test, and Cox regression for significance. Results. The data statistically conform to the evidence in the literature, demonstrating a percentage distribution of patients among molecular subgroups consistent with the Cancer Genome Atlas cohort and an overlap of survival curves with those obtained from the ProMisE study. The analysis of anamnestic and anatomo-pathological elements collected at the beginning of the study defined the peculiarities of each molecular subgroup. Univariate analysis identified p53 mutation, >50% myometrial infiltration, presence of vascular invasion, and stage IV as negative prognostic factors. Multivariate analysis identified age at diagnosis as the most impactful prognostic element. Conclusions. Molecular classification is an essential tool for correctly approaching endometrial carcinoma and provides the foundation for selecting targeted therapies. The importance of molecular classification is also evidenced by its integration into the FIGO 2023 classification. For instance, POLE-mutated patients are placed in stage IA (IAmPOLEmut), which involves a conservative approach, whereas patients with p53 mutation, regardless of all prognostic factors, are placed in stage II (IICmp53abn), which involves aggressive treatment. Immunotherapy represents the elective treatment for recurrent or advanced-stage MMRd mutated tumors at diagnosis. The validation of negative prognostic factors offers new insights for planning follow-up schedules tailored to the risk factors identified in each patient.
Presupposti dello studio. Gli studi condotti da Cancer Genome Atlas (TGCA) sulla base delle analisi molecolari e immunoistochimiche hanno permesso di distinguere quattro sottotipi molecolari di carcinoma endometriale tramite il Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE): POLE ultramuted, MSI hypermutated, Non Specific Molecular Profile o Copy number Low, P53 abnormal o Copy number High. Scopo dello studio. L’intento del presente studio è la valutazione retrospettiva del rischio prognostico di 153 pazienti seguite dal 1° gennaio 2019 al 31 dicembre 2022 presso l’unità operativa di Ostetricia e Ginecologia dell’ospedale Ca’ Foncello di Treviso utilizzando la stratificazione molecolare proposta dall’algoritmo ProMiSe. È stata posta particolare attenzione alla raccolta di elementi anamnestici, quali l’età e il BMI, e anatomo-patologici, quali la classificazione molecolare, l’infiltrazione miometriale, l’invasione linfovascolare e lo stadio, per la valutazione di un eventuale ruolo prognostico di tali fattori nell’evoluzione della malattia. Materiali e metodi. Sono state incluse nello studio solo pazienti donne di età ≥ 18 anni con diagnosi di neoplasia maligna epiteliale di origine endometriale confermata istologicamente tramite prelievo bioptico. Tutti i campioni bioptici sono stati valutati da anatomopatologi esperti in oncologia ginecologica. I dati delle pazienti con un follow-up inferiore a 12 mesi sono stati considerati nell’analisi statistica riguardante la componente anamnestica, la stadiazione preoperatoria, l’intervento chirurgico e la diagnosi istologica ma non per la valutazione dello status. L’analisi immunoistochimica è stata impiegata per la valutazione di p53 e dell’instabilità microsatellitare (MSI). L’analisi molecolare ha ricercato mutazioni del gene POLE, l’instabilità dei microsatelliti (se l’immunoistochimica risultava dubbia) e la presenza di metilazione del promotore di MLH1 nei casi risultati MSI. L’analisi statistica è stata svolta utilizzando il linguaggio di programmazione Python, la libreria Pandas, il test del chi-quadrato, il metodo Kaplan-Meier per le curve di sopravvivenza, il test del log rank e la regressione di Cox per la ricerca di significatività. Risultati. I dati risultano statisticamente conformi alle evidenze presenti in letteratura poiché dimostrano una distribuzione percentuale delle pazienti tra i sottogruppi molecolari omogenea alla coorte studiata dal Cancer Genome Atlas e una sovrapposizione delle curve di sopravvivenza con quelle ottenute dallo studio ProMise. L’analisi univariata ha permesso di definire la mutazione p53, l’infiltrazione miometriale >50%, la presenza di invasione vascolare e lo stadio IV come fattori prognostici negativi. L’analisi multivariata ha identificato come elemento prognostico maggiormente impattante l’età alla diagnosi. Conclusioni. La classificazione molecolare è uno strumento indispensabile per approcciare correttamente il carcinoma endometriale e fornisce le basi per la scelta di terapie mirate. L’importanza della classificazione molecolare è testimoniata anche dall’integrazione della stessa nella classificazione FIGO 2023. Infatti, le pazienti POLE mutate vengono inserite nello stadio IA (IAmPOLEmut) che prevede un approccio conservativo, invece, le pazienti con mutazione di p53, indipendentemente da tutti i fattori prognostici, vengono inserite nello stadio II (IICmp53abn) che prevede un trattamento aggressivo. L’immunoterapia rappresenta il trattamento elettivo per i tumori MMRd mutati recidivanti o in stadi avanzati. La validazione dei fattori prognostici negativi offre nuovi spunti per pianificare il follow-up con cadenze personalizzate a seconda degli elementi di rischio riscontrati in ogni paziente.
Introduzione dell'analisi genetica e immunoistochimica nel carcinoma endometriale: studio retrospettivo su 150 pazienti.
ARTUSO, SOFIA
2023/2024
Abstract
Background. Studies conducted by The Cancer Genome Atlas (TGCA) using molecular and immunohistochemical analyses have identified four molecular subtypes of endometrial carcinoma through the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE): POLE ultramutated, MSI hypermutated, Non-Specific Molecular Profile or Copy number Low, P53 abnormal or Copy number High. Purpose of the study. This study aims to retrospectively evaluate the prognostic risk of 153 patients followed from January 1, 2019, to December 31, 2022, at the Obstetrics and Gynecology unit of Ca’ Foncello Hospital in Treviso using the molecular stratification proposed by the ProMisE algorithm. The care plan included a preoperative diagnostic-anamnestic program, a staging and therapeutic surgical procedure, and subsequent follow-up monitoring. Special attention was given to collecting anamnestic elements, such as age and BMI, and anatomo-pathological factors, such as molecular classification, myometrial infiltration, lymphovascular invasion, and stage, to assess their potential prognostic role in disease progression. Material and methods. The study included only female patients aged ≥ 18 years with histologically confirmed malignant epithelial neoplasia of endometrial origin via biopsy. All biopsy samples were evaluated by expert gynecologic oncology pathologists. Data from patients with a follow-up of less than 12 months were considered in the statistical analysis concerning the anamnestic component, preoperative staging, surgical intervention, and histological diagnosis but not for status evaluation. Immunohistochemical analysis was employed to evaluate p53 and microsatellite instability (MSI). Molecular analysis searched for POLE gene mutations, microsatellite instability (if immunohistochemistry was ambiguous), and MLH1 promoter methylation in MSI cases. Statistical analysis was performed using Python programming language, Pandas library, chi-square test, Kaplan-Meier method for survival curves, log-rank test, and Cox regression for significance. Results. The data statistically conform to the evidence in the literature, demonstrating a percentage distribution of patients among molecular subgroups consistent with the Cancer Genome Atlas cohort and an overlap of survival curves with those obtained from the ProMisE study. The analysis of anamnestic and anatomo-pathological elements collected at the beginning of the study defined the peculiarities of each molecular subgroup. Univariate analysis identified p53 mutation, >50% myometrial infiltration, presence of vascular invasion, and stage IV as negative prognostic factors. Multivariate analysis identified age at diagnosis as the most impactful prognostic element. Conclusions. Molecular classification is an essential tool for correctly approaching endometrial carcinoma and provides the foundation for selecting targeted therapies. The importance of molecular classification is also evidenced by its integration into the FIGO 2023 classification. For instance, POLE-mutated patients are placed in stage IA (IAmPOLEmut), which involves a conservative approach, whereas patients with p53 mutation, regardless of all prognostic factors, are placed in stage II (IICmp53abn), which involves aggressive treatment. Immunotherapy represents the elective treatment for recurrent or advanced-stage MMRd mutated tumors at diagnosis. The validation of negative prognostic factors offers new insights for planning follow-up schedules tailored to the risk factors identified in each patient.| File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12608/66524