Publication: La endometriosis atípica como lesión histológica premaligna en el cáncer de ovario asociado a endometriosis : propuesta de manejo clínico
Authors
Sánchez Gómez, Rocío
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Escuela Internacional de Doctorado
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Machado Linde, Francisco ; Marín Sánchez, Pilar
Publisher
Universidad de Murcia
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DOI
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info:eu-repo/semantics/doctoralThesis
Description
Abstract
La presente tesis doctoral tiene como objetivo principal evaluar el papel de la endometriosis atípica (EA) como lesión histológica premaligna dentro del continuum biológico que conduce al cáncer de ovario asociado a endometriosis (COAE). Se plantea la hipótesis de que la EA no constituye únicamente un hallazgo histológico incidental, sino un marcador de riesgo oncológico con implicaciones clínicas relevantes.
De forma específica, los objetivos incluyen:
1. Determinar la prevalencia de la endometriosis atípica en una amplia cohorte de pacientes con endometriosis y cáncer de ovario.
2. Analizar las características clínicas, ecográficas, anatomopatológicas e inmunohistoquímicas de la EA y su relación con el desarrollo de COAE.
3. Comparar el comportamiento clínico, estadio al diagnóstico, supervivencia y recidiva del COAE frente al cáncer de ovario no asociado a endometriosis.
4. Identificar factores predictores independientes de malignización mediante análisis multivariante.
5. Proponer un modelo estructurado de manejo clínico y seguimiento de la EA basado en la estratificación del riesgo.
Metodología
Se diseñó un estudio observacional analítico que integra dos cohortes diferenciadas. La Serie 1 incluyó una cohorte amplia de pacientes intervenidas quirúrgicamente por endometriosis, cáncer de ovario o ambas entidades, permitiendo analizar la prevalencia de EA, su asociación con COAE y su impacto pronóstico. La Serie 2 correspondió a una cohorte específica de pacientes con diagnóstico histológico de EA, con y sin cáncer asociado, seguidas de forma prospectiva para evaluar su evolución clínica.
Se recogieron de forma sistemática variables epidemiológicas, reproductivas, clínicas, ecográficas y quirúrgicas. La evaluación preoperatoria de la masa anexial se realizó mediante ecografía transvaginal estructurada, aplicando el sistema GI-RADS, y se analizaron marcadores tumorales séricos, fundamentalmente CA-125 y HE4.
El estudio anatomopatológico incluyó la revisión histológica detallada de las lesiones endometriósicas, diferenciando entre atipia citológica y arquitectural, así como el análisis inmunohistoquímico de marcadores clave implicados en la carcinogénesis asociada a endometriosis: ARID1A/BAF250a, PTEN, Ki-67 y COX-2. El procesamiento estadístico incorporó análisis descriptivos, comparativos y modelos multivariantes de regresión logística para identificar predictores independientes de COAE, además de análisis de supervivencia y recidiva.
Resultados y conclusiones
La prevalencia global de endometriosis atípica fue del 10,45%, aumentando de forma significativa hasta el 40,74% en los casos de COAE, lo que refuerza su consideración como lesión de riesgo. Las pacientes con COAE mostraron un perfil clínico intermedio entre la endometriosis benigna y el cáncer de ovario no asociado, con diagnóstico a edades más tempranas y mayor proporción de estadios iniciales, lo que se tradujo en un mejor pronóstico global.
Desde el punto de vista ecográfico y bioquímico, el GI-RADS >3, el tamaño tumoral y el marcador HE4 demostraron utilidad en la sospecha preoperatoria de malignidad en este contexto. En el análisis inmunohistoquímico, la pérdida de expresión de ARID1A/BAF250a y el incremento del índice proliferativo Ki-67 se asociaron de manera consistente con la progresión neoplásica. Por el contrario, PTEN mostró un patrón más heterogéneo, compatible con un papel temprano y no exclusivo en la secuencia de transformación maligna.
El análisis multivariante identificó la menopausia, el GI-RADS >3 y la presencia de endometriosis atípica como predictores independientes de COAE, permitiendo definir umbrales clínicos útiles para el triaje y la confirmación diagnóstica.
En conjunto, los resultados de esta tesis apoyan de forma sólida la consideración de la endometriosis atípica como marcador de riesgo oncológico, con implicaciones clínicas directas. Se propone un algoritmo de manejo postquirúrgico y seguimiento individualizado, que integra variables clínicas, radiológicas e histopatológicas, orientado a optimizar la detección precoz del COAE y a mejorar la toma de decisiones clínicas en pacientes con EA.
The main objective of this doctoral thesis is to evaluate the role of atypical endometriosis (AE) as a premalignant histological lesion within the biological continuum leading to endometriosis-associated ovarian cancer (EAOC). The central hypothesis is that AE does not merely represent an incidental histological finding, but rather a clinically relevant marker of oncologic risk. Specifically, the aims of this study are: 1. To determine the prevalence of atypical endometriosis in a large cohort of patients with endometriosis and ovarian cancer. 2. To analyze the clinical, ultrasound, histopathological, and immunohistochemical characteristics of AE and its relationship with the development of EAOC. 3. To compare clinical behavior, stage at diagnosis, survival, and recurrence between EAOC and ovarian cancer not associated with endometriosis. 4. To identify independent predictors of malignant transformation through multivariate analysis. 5. To propose a structured clinical management and follow-up model for AE based on risk stratification. Methodology An observational analytical study design was employed, integrating two distinct cohorts. Series 1 consisted of a large cohort of patients who underwent surgery for endometriosis, ovarian cancer, or both, allowing evaluation of AE prevalence, its association with EAOC, and its prognostic impact. Series 2 included a specific cohort of patients with histologically confirmed AE, with and without associated ovarian cancer, who were prospectively followed to assess clinical outcomes. Epidemiological, reproductive, clinical, ultrasound, and surgical variables were systematically collected. Preoperative evaluation of adnexal masses was performed using structured transvaginal ultrasound, applying the GI-RADS classification system, and serum tumor markers were analyzed, mainly CA-125 and HE4. Histopathological assessment included detailed review of endometriotic lesions, distinguishing between cytologic atypia and architectural atypia, as well as immunohistochemical analysis of key markers involved in endometriosis-associated carcinogenesis: ARID1A/BAF250a, PTEN, Ki-67, and COX-2. Statistical analysis comprised descriptive and comparative analyses, as well as multivariate logistic regression models to identify independent predictors of EAOC, together with survival and recurrence analyses. Results and Conclusions The overall prevalence of atypical endometriosis was 10.45%, increasing significantly to 40.74% in cases of EAOC, supporting its consideration as a lesion associated with increased oncologic risk. Patients with EAOC exhibited a clinical profile intermediate between benign endometriosis and ovarian cancer not associated with endometriosis, characterized by earlier age at diagnosis and a higher proportion of early-stage disease, which translated into a more favorable prognosis. From an ultrasound and biochemical perspective, GI-RADS >3, tumor size, and the serum marker HE4 proved useful for preoperative suspicion of malignancy in this setting. At the molecular level, loss of ARID1A/BAF250a expression and an increased Ki-67 proliferative index were consistently associated with neoplastic progression. In contrast, PTEN showed a more heterogeneous pattern, compatible with an early and context-dependent role rather than a specific marker of malignant transformation. Multivariate analysis identified menopausal status, GI-RADS >3, and the presence of atypical endometriosis as independent predictors of EAOC, enabling the definition of clinically meaningful thresholds for diagnostic triage and confirmation. Overall, the findings of this thesis strongly support considering atypical endometriosis as a marker of oncologic risk with direct clinical implications. A postoperative management and individualized follow-up algorithm is proposed, integrating clinical, radiological, and histopathological variables, with the aim of optimizing early detection and clinical management of endometriosis-associated ovarian cancer.
The main objective of this doctoral thesis is to evaluate the role of atypical endometriosis (AE) as a premalignant histological lesion within the biological continuum leading to endometriosis-associated ovarian cancer (EAOC). The central hypothesis is that AE does not merely represent an incidental histological finding, but rather a clinically relevant marker of oncologic risk. Specifically, the aims of this study are: 1. To determine the prevalence of atypical endometriosis in a large cohort of patients with endometriosis and ovarian cancer. 2. To analyze the clinical, ultrasound, histopathological, and immunohistochemical characteristics of AE and its relationship with the development of EAOC. 3. To compare clinical behavior, stage at diagnosis, survival, and recurrence between EAOC and ovarian cancer not associated with endometriosis. 4. To identify independent predictors of malignant transformation through multivariate analysis. 5. To propose a structured clinical management and follow-up model for AE based on risk stratification. Methodology An observational analytical study design was employed, integrating two distinct cohorts. Series 1 consisted of a large cohort of patients who underwent surgery for endometriosis, ovarian cancer, or both, allowing evaluation of AE prevalence, its association with EAOC, and its prognostic impact. Series 2 included a specific cohort of patients with histologically confirmed AE, with and without associated ovarian cancer, who were prospectively followed to assess clinical outcomes. Epidemiological, reproductive, clinical, ultrasound, and surgical variables were systematically collected. Preoperative evaluation of adnexal masses was performed using structured transvaginal ultrasound, applying the GI-RADS classification system, and serum tumor markers were analyzed, mainly CA-125 and HE4. Histopathological assessment included detailed review of endometriotic lesions, distinguishing between cytologic atypia and architectural atypia, as well as immunohistochemical analysis of key markers involved in endometriosis-associated carcinogenesis: ARID1A/BAF250a, PTEN, Ki-67, and COX-2. Statistical analysis comprised descriptive and comparative analyses, as well as multivariate logistic regression models to identify independent predictors of EAOC, together with survival and recurrence analyses. Results and Conclusions The overall prevalence of atypical endometriosis was 10.45%, increasing significantly to 40.74% in cases of EAOC, supporting its consideration as a lesion associated with increased oncologic risk. Patients with EAOC exhibited a clinical profile intermediate between benign endometriosis and ovarian cancer not associated with endometriosis, characterized by earlier age at diagnosis and a higher proportion of early-stage disease, which translated into a more favorable prognosis. From an ultrasound and biochemical perspective, GI-RADS >3, tumor size, and the serum marker HE4 proved useful for preoperative suspicion of malignancy in this setting. At the molecular level, loss of ARID1A/BAF250a expression and an increased Ki-67 proliferative index were consistently associated with neoplastic progression. In contrast, PTEN showed a more heterogeneous pattern, compatible with an early and context-dependent role rather than a specific marker of malignant transformation. Multivariate analysis identified menopausal status, GI-RADS >3, and the presence of atypical endometriosis as independent predictors of EAOC, enabling the definition of clinically meaningful thresholds for diagnostic triage and confirmation. Overall, the findings of this thesis strongly support considering atypical endometriosis as a marker of oncologic risk with direct clinical implications. A postoperative management and individualized follow-up algorithm is proposed, integrating clinical, radiological, and histopathological variables, with the aim of optimizing early detection and clinical management of endometriosis-associated ovarian cancer.
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