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

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.

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.

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.

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.