Body weight changes and duration of estrogen exposure modulate the evolution of hepatocellular adenomas after contraception discontinuation

Abstract

Background and Aims: The natural history of hepatocellular adenomas (HCAs) remains to be better described, especially in nonresected patients. We aim to identify the predictive factors of HCA evolution after estrogen‐based contraception discontinuation. Approach and Results: We retrospectively included patients with a histological diagnosis of HCA from three centers. Clinical, radiological, and pathological data were collected to identify predictive factors of radiological evolution per Response Evaluation Criteria in Solid Tumors, version 1.1, and occurrence of complications (bleeding, malignant transformation). We built a score using variables that modulate estrogen levels: body mass index and duration of estrogen‐based contraception. An external cohort was used to validate this score. 183 patients were included in the cohort, including 161 women (89%) using estrogen‐based contraception for a median of 12 years. Thirty percent of patients had at least one HNF1A‐inactivated HCA, 45.5% at least one inflammatory HCA, and 11% at least one HCA with activation of β‐catenin (bHCA). Twenty‐one symptomatic bleedings (11%) and eleven malignant transformations (6%) occurred. Ages < 37 years old (p = 0.004) and HCA > 5 cm at imaging were independently associated with symptomatic bleeding (p = 0.003), whereas a bHCA was associated with malignant transformation (p < 0.001). After a median follow‐up of 5 years, radiological regression was observed in 31%, stabilization in 47%, and progression in 22% of patients. Weight loss was associated with regression (p < 0.0001) and weight gain with progression (p = 0.02). The estrogen exposure score predicted radiological regression (odds ratio, 2.33; confidence interval 95%, 1.29–4.19; p = 0.005) with a linear relationship between the rate of estrogen exposure and the probability of regression. This result was confirmed in an external cohort of 72 female patients (p = 0.003). Conclusion Weight variation is strongly associated with radiological evolution after oral contraception discontinuation. A score of estrogen exposure, easily assessable in clinical practice at diagnosis, predicts regression of HCA.

Now you see it, now you don't: Estrogen exposure and obesity effects on HCA development and regression

“…Additionally, obesity has been shown to promote HCC development through inflammatory pathways,2,7 although the current study had too few HCC events to evaluate this association 6. No patients in the current study had the sonic hedgehog HCA subtype, which, along with inflammatory HCA subtype, is associated with obesity 1,6. Whether weight loss differentially influences HCA regression by genotype–phenotype classification subtypes remains unclear.…”

“…In summary, in this relatively large multicenter analysis, Demory et al highlight the role of estrogen exposure and weight changes in HCA evolution, [6] which should be considered in algorithms for HCA management. Patients who are obese and have longer duration of CHC exposure ≥ 12 months at baseline are more likely to develop tumor regression, presumably through weight loss and CHC cessation.…”

“…Finally, this study used the RECIST 1.1 criteria to characterize HCA evolution. [6] HCA literature use varying criteria to describe HCA evolution. [4,10] The RECIST criteria were developed to objectively assess changes in tumor burden by anatomical measurements of tumor size with guidelines regarding measurable versus nonmeasurable tumors, number of lesions, lymph nodes, and types of lesions.…”

“…This estrogen exposure score was developed to predict HCA regression among patients who have been treated with intervention or with conservative management using BMI and duration of CHC exposure 6. Overall, the authors found that the same risk factors for HCA development (BMI and CHC exposure) were associated with HCA regression if addressed.…”

“…A second clinically helpful tool for HCA prognosis was a 4-point estrogen exposure score including duration of CHC use and BMI at diagnosis, which was validated in an external cohort of 72 female patients (Figure 1). [6] For example, a patient with ≥ 12 years of CHC exposure with a BMI ≥ 30 kg/m 2 would have an estrogen exposure score of 4, whereas a patient with no CHC exposure with normal BMI < 25 kg/m 2 would have a score of 0. Increasing estrogen exposure at baseline was associated with greater probability of tumor regression, with 0% regression in patients with a score of 0, to 70% with regression in patients with a score of 4.…”