Langerhans cell histiocytosis: NACHO update on progress, chaos, and opportunity on the path to rational cures

Abstract

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by lesions with CD1a-positive/Langerin (CD207)-positive histiocytes and inflammatory infiltrate that can cause local tissue damage and systemic inflammation. Clinical presentations range from single lesions with minimal impact to life-threatening disseminated disease. Therapy for systemic LCH has been established through serial trials empirically testing different chemotherapy agents and durations of therapy. However, fewer than 50% of patients who have disseminated disease are cured with the current standard-of-care vinblastine/prednisone/(mercaptopurine), and treatment failure is associated with long-term morbidity, including the risk of LCH-associated neurodegeneration. Historically, the nature of LCH-whether a reactive condition versus a neoplastic/malignant condition-was uncertain. Over the past 15 years, seminal discoveries have broadly defined LCH pathogenesis; specifically, activating mitogen-activated protein kinase pathway mutations (most frequently, BRAFV600E) in myeloid precursors drive lesion formation. LCH therefore is a clonal neoplastic disorder, although secondary inflammatory features contribute to the disease. These paradigm-changing insights offer a promise of rational cures for patients based on individual mutations, clonal reservoirs, and extent of disease. However, the pace of clinical trial development behind lags the kinetics of translational discovery. In this review, the authors discuss the current understanding of LCH biology, clinical characteristics, therapeutic strategies, and opportunities to improve outcomes for every patient through coordinated agent prioritization and clinical trial efforts.

Keywords: Langerhans cell histiocytosis; clinical trials; mitogen‐activated protein kinase (MAPK) pathway; myeloid neoplasia.

Figure 1.. LCH Histology.

LCH lesions are characterized by “histiocytes” with reniform nuclei and surrounding inflammatory infiltrate. (A) H&E (80x), (B) CD1a immunohistochemistry (80x), (C) Electron microscopy demonstrating Birbeck granule, which is now replaced with Langerin (CD207) stain (not shown). LCH can be challenging to differentiate from reactive Langerhans cells/dendritic cells in skin and lymph nodes (LN). Skin with reactive CD1a+ dendritic cell hyperplasia in the dermis with perivascular histiocytes that are CD1a+ with spindled dendritic shape (D-E) are low to negative Langerin/CD207 staining (F) (10x). By comparison, (G-I) shows a case of skin with superficial dermal infiltrate of LCH with epidermotropism and surface ulceration. The CD1a (H) and Langerin (I) stains highlight the clustering of plump lesional histiocytes in the papillary dermis (10x). Activated DC drain into LN to present antigen to lymphocytes as demonstrated by hyperplasia of reactive dendritic/Langerhans cells in the paracortex ((J) H&E, (K) CD1a, (L) Langerin, 13x digital images). By comparison, nodal LCH is characterized by sinus expansion of LCH with variable spill over into the paracortex ((M) H&E, (N) CD1a, (O) Langerin, 10x). (Images courtesy of Jennifer Picarsic, MD, Cincinnati Children’s Hospital, Cincinnati, OH).

Figure 2.. LCH Pathogenic Mechanisms.

(A) Diagram of the MAPK signaling pathway. When growth factors/mitogens bind to receptor tyrosine kinases (RTKs), RTKs activate guanine exchange factors to exchange GDP for GTP on Ras, which activates Ras. Normally, GTP bound Ras is required for the downstream activation and homodimerization of Rafs (BRAF or ARAF) and further signaling components of MAPK. The BRAFV600E allows BRAF to function as a monomer independent of Ras activation, which leads to constitutive activation of MAPK signaling pathway. (B) Studies in patients with LCH have shown that acquisition of allelic MAPK-activating allelic variants in myeloid precursors leads to HR LCH due to pathological myeloid cells having access to the circulation, supported by the finding that HR-patients (but never LR-patients) harbor circulating mutation bearing myeloid cells. Circulating CD11a⁺ myeloid cells also contribute the LCH-ND. This risk-stratification can be modeled using genetic knock-in models where expression of BRAFV600E can be enforced in hematopoietic stem cells (Scl^Cre BRAFV600Elox-stop-lox; BRAFV600E^scl or Map17^Cre BRAFV600Elox-stop-lox; BRAFV600E^Map17) or the entire DC lineage (CD11c^Cre BRAFV600Elox-stop-lox; BRAFV600E^CD11c), which lead to lethal LCH-like disease. In comparison, enforced expression of BRAFV600E in tissue limited DCs (CD207^Cre BRAFV600Elox-stop-lox; BRAFV600^CD207) form lesions, but do not die from LCH-related causes. (C) Enforced expression of BRAFV600E in mouse models have found that enhanced myeloid differentiation, so called “myeloid skewing”; activation and exhaustion of T cells, tissue entrenchment by decreased CCR7 expression, and resistance to apoptosis promote the accumulation of pathological DCs in nearly any organ. The latter is part of the BRAFV600E-induced SASP, which is central to LCH pathophysiology.

Figure 3.. Clinical Features of LCH.

Positron-emission tomographic (PET) images show a single bone lesion involving the humerus (Panel A, arrow); low-risk lesions involving the orbit, lymph nodes, bone (multifocal lesion), and thymus (Panel B); and high-risk lesions involving the liver, spleen, and bone marrow (Panel C). Other classic presentations include a lytic bone lesion (Panel D, arrow), cystic lung lesions (Panel E), and various skin lesions (Panels F through I). Examples of LCH lesions involving the skull and brain include multifocal skull lesions (Panel J, arrow), an orbital lesion (Panel K, arrow), a pituitary lesion (Panel L, arrow), and LCH-associated neurodegeneration (Panel M, arrow). (Figure from Allen CE et al. N Engl J Med 2018;379:856–868).