Langerhans cell histiocytosis in adults: Advances in pathophysiology and treatment

Abstract

Langerhans cell histiocytosis (LCH) is a rare systemic disorder characterized by the accumulation of CD1a+/Langerin+ LCH cells and wide-ranging organ involvement. Langerhans cell histiocytosis was formerly referred to as histiocytosis X, until it was renamed in 1987. Langerhans cell histiocytosis β was named for its morphological similarity to skin Langerhans cells. Studies have shown that LCH cells originate from myeloid dendritic cells rather than skin Langerhans cells. There has been significant debate regarding whether LCH should be defined as an immune disorder or a neoplasm. A breakthrough in understanding the pathogenesis of LCH occurred in 2010 when a gain-of-function mutation in BRAF (V600E) was identified in more than half of LCH patient samples. Studies have since reported that 100% of LCH cases show ERK phosphorylation, indicating that LCH is likely to be a clonally expanding myeloid neoplasm. Langerhans cell histiocytosis is now defined as an inflammatory myeloid neoplasm in the revised 2016 Histiocyte Society classification. Randomized trials and novel approaches have led to improved outcomes for pediatric patients, but no well-defined treatments for adult patients have been developed to date. Although LCH is not fatal in all cases, delayed diagnosis or treatment can result in serious impairment of organ function and decreased quality of life. This study summarizes recent advances in the pathophysiology and treatment of adult LCH, to raise awareness of this "orphan disease".

Keywords: Langerhans cell; adult; histiocytosis; mitogen-activated protein kinase; proto-oncogene protein BRAF.

Figure 1

Schematic representation of BRAF structure and the location of reported mutations in Langerhans cell histiocytosis (LCH). AS, activation segment; CR, conserved region; CRD, cystine‐rich domain; RBD, RAS binding domain

Figure 2

Diagram of the MAPK and PI3K pathways. The reported mutations in Langerhans cell histiocytosis (LCH) are indicated in red. The dotted arrow represents an effect that has not been fully evaluated. PIP1, phosphatidylinositol 3‐phosphate; PIP3, phosphatidylinositol‐3,4,5‐triphosphate; PTEN, phosphatase and tensin homolog deleted on chromosome 10; RTK receptor tyrosine kinase

Figure 3

Treatment algorithm for adult Langerhans cell histiocytosis (LCH). Diagnosis of LCH is based on histological and immunophenotypic examination. The primary indicators are characteristic LCH cells and positivity for CD1a and/or Langerin (CD207) cells. Confirmation of cytoplasmic Birbeck granules by electron microscopy is no longer necessary. Complete patient history, including smoking history, must be determined, and specific physical examinations should be carried out, including neurological evaluation of central nervous system (CNS) and peripheral nerves. *In certain situations, such as involvement in vertebra or tissues near sensory organs, systemic therapy is recommended. **Involvement in craniofacial bones, eyes, ears, and oral cavity. MS, multisystem; PLCH, pulmonary LCH; SS, single system