Which Malignancies Are Most Linked With Langerhans Cell Histiocytosis?

New data show the types of malignancies, such as leukemias and myeloproliferative disorders, that are most common in children with Langerhans cell histiocytosis (LCH).

A new report is helping quantify the type and timing of associated malignancies (AMs) in patients with Langerhans cell histiocytosis (LCH).

The study, published in European Journal of Cancer, shows significant differences between pediatric and adult patients.

The authors said scientists’ understanding of LCH has changed significantly in recent years. Typically seen in children and young adults, LCH involves proliferating CD1a+ and langerin-positive cells, which interact with multiple other cell types, such as lymphocytes and eosinophils. Sometimes, the disease results in self-healing lesions, they said. Other times, the disease can be life threatening.

More recently, investigators identified BRAF V600E as a recurrent mutation in about half of patients, leading investigators to reclassify the disease as an inflammatory myeloid neoplasm, instead of a reactive disorder.

“Lately, additional MAP kinase pathway–activating as well as somatic-activating ARAF mutations have been demonstrated, further shedding light on LCH pathogenesis,” the authors said.

However, even as the collective understanding of LCH has increased, questions remain about its association with other malignancies. The authors said the frequency of other malignancies in patients with LCH is greater than would be expected by chance alone, but there has been little genetic analysis looking at such malignancies in LCH.

To fill the research gap, the investigators used questionnaire responses from a Histiocyte Society database launched in 1991, which regularly tracked instances of malignancies in patients with LCH. Data were also taken from published reports. Cases were then grouped by age at LCH diagnosis, as well as type and timing of AMs.

The investigators identified 285 LCH-associated malignancies in 270 patients. In patients with multiple AMs, only the first was considered for the analysis.

Most of the cases occurred in people older than 18 years (57%). In those adults, solid tumors were most common (39.6%), followed closely by lymphoma (36.4%) and leukemias and myeloproliferative disorders (24.0%).

In children, the results were somewhat different. Fifty percent of the cases were leukemias and myeloproliferative disorders, followed by solid tumors (37.1%) and lymphoma (12.9%).

A plurality of adults (44.8%) received their AM diagnosis concurrent with LCH, whereas in children, the AM diagnosis typically followed the LCH diagnosis (59.5%). The investigators said T-lineage acute lymphoblastic leukemia (T-ALL), promyelocytic acute myeloid leukemia, and retinoblastoma were overrepresented in children.

“Notably, in our data set, pediatric ALL mostly occurred prior to LCH,” they said. “While ALL is the single most prevalent neoplasm in children in general, in our data set, T-ALL was considerably overrepresented among ALL cases.”

In adults, thyroid carcinoma was overrepresented in the LCH group, the authors added.

“Thyroid carcinomas can carry BRAF mutations, and mutations in the MAP kinase pathway have been recognized as the predominant pathogenic mechanism in pediatric low-grade gliomas,” the investigators noted.

They added that they have already set up a prospective registry which will include blood and tissue sampling.

“Prospective thorough genetic analysis is warranted and will hopefully shed light on the association of LCH and second neoplasms,” they concluded.


Bagnasco F, Zimmerman SY, Egeler RM, et al. Langerhans cell histiocytosis and associated malignancies: a retrospective analysis of 270 patients. Eur J Cancer. 2022;172:138-145. doi:10.1016/j.ejca.2022.03.036

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