Histiocytosis

Abstract

Histiocytoses constitute a heterogeneous group of rare disorders, characterised by infiltration of almost any organ by myeloid cells with diverse macrophage or dendritic cell phenotypes. Histiocytoses can start at any age. Diagnosis is based on histology in combination with appropriate clinical and radiological findings. The low incidence and broad spectrum of clinical manifestations often leads to diagnostic delay, especially for adults. In most cases, biopsy specimens infiltrated by histiocytes have somatic mutations in genes activating the MAP kinase cell-signalling pathway. These mutations might also be present in blood cells and haematopoietic progenitors of patients with multisystem disease. A comprehensive range of investigations and molecular typing are essential to accurately predict prognosis, which can vary from spontaneous resolution to life-threatening disseminated disease. Targeted therapies with BRAF or MEK inhibitors have revolutionised salvage treatment. However, the type and duration of treatment are still debated, and the prevention of neurological sequelae remains a crucial issue.

Figure 1:

Proteins of the MAP kinase cell-signalling pathway involved by activating mutations, and inhibitors already reported to benefit patients with histiocytoses

Figure 2:. Langerhans cell histiocytosis

(A) Young child with disseminated Langerhans cell histiocytosis (LCH) skin lesions. (B) Chest CT scan showing multiple cysts. (C) X-rays showing LCH involvement of the skull. (D) X-rays showing LCH involvement of the mandible, as revealed by so-called floating teeth. (E) MRI showing a femoral lesion revealed by a fracture. (F) CT scan showing the spinal column. (G, H) MRI showing degenerative neuro-LCH on axial T2 spin echo-weighted images, which reveal symmetrical hyperintensities within the cerebellar corpus medullare (arrows).

Figure 3:. Erdheim-Chester disease

(A) Chest CT scan showing lung and pleural involvement of Erdheim-Chester disease (ECD). (B) Coronal, post-gadolinium, T1-weighted MRI showing bilateral ECD infiltration of the orbits (predominantly in the right eye). (C) Chest CT scan showing a so-called coated aorta in a patient with ECD. Xanthelasma in a patient with ECD (D) before treatment and (H) after 3 years of interferon alfa-2a. ¹⁸F-fluorodeoxyglucose PET scans showing (E) pretreatment metabolite uptake in the long bones that was (I) decreased after 12 months of cobimetinib. MRI-documented response of (F) a CNS tumour to (J) 12 months of vemurafenib (red arrows). CT scans showing (G) perirenal lesions and (K) their regression after 3 years of cobimetinib (red arrows).

Figure 4:. Group C cutaneous histiocytosis

(A) An infant with multiple benign cephalic histiocytosis lesions. Adults with (B) multicentric reticulohistiocytosis, (C) generalised eruptive histiocytosis, (D) xanthoma disseminatum, and (E) mucinous progressive histiocytosis.

Figure 5:. Histology of some histiocytoses

Histology of formalin-fixed biopsy specimens with infiltration by: LCH (A, B, C); RDD (D, E, F, G); ECD (H, I); or malignant histiocytosis (J, K, L). Original magnifications were ×40 (D, H), ×100 (A), and ×400 (B, E, I, J) for haematoxylin and eosin staining; and ×100 (C, G) and ×200 (F, K, L) for immunohistochemistry. Green scale bar is 500 μm. Red scale bar is 100 μm. LCH=Langerhans cell histiocytosis. RDD=Rosai-Dorfman-Destombes disease. ECD=Erdheim-Chester disease. VE1-BRAF=clone specific to BRAF^V600E.