Literature
Clinical Pearls & Morning Reports
Published August 29, 2018
Is Langerhans-cell histiocytosis primarily a neoplastic disorder or an immunodysregulatory disorder?
In the case of Langerhans-cell histiocytosis (LCH), granulomatous lesions comprising langerin-positive (CD207+) histiocytes and an inflammatory infiltrate can arise in virtually any organ system but have a particular affinity for bone, skin, the lungs, and the pituitary. LCH has a widely variable clinical presentation, ranging from single indolent lesions to explosive multisystem disease. Read the latest NEJM Review Article here.
Clinical Pearls
Q: What subset of patients is most at risk of death from LCH?
A: Children with liver, spleen, or bone marrow involvement are at highest risk for death from LCH and are therefore classified as having high-risk LCH. Although clinical outcomes have steadily improved over the past several decades, standard-of-care chemotherapy (vinblastine, prednisone, and mercaptopurine) fails to cure more than 50% of children with high-risk disease, and the majority of patients have long-term consequences, including a devastating neurodegenerative syndrome that can arise years after a patient is presumed to be cured.
Q: What mutation characterizes the majority of LCH lesions?
A: Improved genomic technology heralded a breakthrough in LCH biology. Badalian-Very and colleagues identified the BRAF V600E mutation in a remarkable 57% of LCH lesions, a finding that was subsequently verified in other series and attributed to the pathogenic LCH cell. BRAF is a central kinase of the RAS–RAF–MEK signal-transduction pathway that is involved in numerous cell functions. The BRAF V600E mutation renders the mitogen-activated protein kinase (MAPK) pathway constitutively active. In addition to BRAF V600E, other activating mutations in BRAF, including in-frame deletions, fusions, and duplications, have been reported in LCH lesions.
Morning Report Questions
Q: Is LCH primarily a neoplastic disorder or an immunodysregulatory disorder?
A: The benign histologic appearance of the CD207+ cell, the accompanying inflammatory infiltrate, and the characteristic local and systemic cytokine storm support an inflammatory origin of LCH, whereas clonality, somatic activating gene mutations in the MAPK pathway, and shared mutations with hematopoietic precursors favor reclassification of LCH as a myeloid neoplastic disorder. The authors of this review article believe that the presence of activating somatic MAPK mutations in resilient myeloid precursor cells provides the basis for defining LCH as a myeloid neoplastic disorder.
Q: What therapies are available or are being studied for LCH?
A: Despite advances in unraveling the pathogenetic mechanisms of LCH, the current standard of frontline care for multifocal LCH remains empirically derived chemotherapy. Overall outcomes have improved in LCH clinical trials over the past decades, though progression-free survival among high-risk patients remains at less than 50%. The potential for prolonged chemotherapy (12 months vs. 24 months) to improve progression-free survival for patients with high-risk LCH is currently being tested in the LCH-IV trial of frontline therapy conducted by the Histiocyte Society. A paucity of data exist to guide therapy after frontline treatment has failed. Nucleoside analogues may be a reasonable class of drug for LCH, though optimal dosing remains to be defined. Early trials involving adults with LCH or the related Erdheim–Chester disease showed promising responses to MAPK-pathway inhibition. Similarly, early case reports and series support a potential benefit of MEK inhibition. The potential for MAPK-targeted therapy to cure LCH is not known.