Structural and functional hepatic factors as prognostic indicators in children with Langerhans cell histiocytosis.

Background and aim: Langerhans cell histiocytosis (LCH) is a clonal myeloid neoplasm with variable outcomes; hepatic involvement is uniformly classified as high-risk. However, liver disease includes distinct structural and biochemical phenotypes with unclear prognostic significance. This study aimed to identify prognostic determinants in pediatric hepatic LCH, define phenotype-specific risk, and assess whether Z-score-standardized liver size independently predicts disease course and treatment response. Methods: This retrospective study included 453 children with LCH treated at Children's Cancer Hospital, Egypt, between 2007 and 2021. Patients received the LCH-III protocol before 2012 and the LCH-IV protocol thereafter. Liver involvement was evaluated using baseline biochemical tests and ultrasonography, and liver span Z-scores were calculated to standardize hepatomegaly. Results: Eighty patients had hepatic involvement: 27 presented with hepatomegaly and preserved liver function, while 53 had hepatic dysfunction. Hepatic dysfunction independently predicted initial treatment failure (OR 9.28; 95% CI, 2.21-64.3; p = 0.001) and was associated with markedly inferior 5-year overall survival (OS) (39.4% vs 92.6%) and event-free survival (EFS) (12.9% vs 70.4%) compared with those with hepatomegaly and preserved function (all p< 0.0001). In addition, hypoalbuminemia emerged as an adverse biochemical prognostic factor (HR 4.40; 95% CI, 1.52-12.7; p = 0.003). Multivariable analysis demonstrated that week 6 non-response was the only independent predictor of both OS (HR 3.17; 95% CI, 1.37-7.31; p = 0.007) and EFS (HR 9.26; 95% CI, 4.12-20.84; p< 0.001). Conversely, outcomes were not affected by the extent of hepatomegaly, suggesting that liver size alone does not confer prognostic significance in the absence of functional hepatic impairment. Conclusions: In pediatric LCH, hepatic dysfunction, rather than hepatomegaly, emerges as the true determinant of high-risk liver involvement. Lake of early response at week 6 independently predicts inferior outcomes. Children with preserved liver function demonstrate excellent outcomes irrespective of liver size. These findings suggest potential refinement of current risk definitions and support a shift toward function-based risk stratification, pending validation in larger, multicenter prospective studies.