Elsevier

The Lancet

Volume 398, Issue 10295, 10–16 July 2021, Pages 157-170
The Lancet

Seminar
Histiocytosis

https://doi.org/10.1016/S0140-6736(21)00311-1Get rights and content

Summary

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.

Introduction

Histiocytoses are a clinically heterogeneous group of rare disorders (appendix p 2) with onset at any age, which remain challenging to diagnose and treat. However, recent discoveries of oncogenic mutations in the mitogen-activated protein (MAP) kinase cell-signalling pathway have revolutionised clinical management. In the past, detection of phenotypic or ultrastructural markers specific to Langerhans cells (eg, CD1a, CD207, and Birbeck granules) defined the difference between Langerhans cell histiocytosis (LCH) and non-LCH.1 It is now known that a common molecular cause underlies most LCH and other non-LCH entities, notably Erdheim-Chester disease (ECD) and some cases of juvenile xanthogranuloma and Rosai-Dorfman-Destombes disease (RDD). Indeed, the majority of lesions that occur in histiocytoses harbour mutations in CSF1R, ALK, RET, NTRK, RAS, RAF, MAP2K, or other kinase genes, linking myeloid-specific growth factor receptor-binding to ERK activation.

Histiocytes can infiltrate virtually any tissue or organ, with a predilection for skin, bone, lung, lymph nodes, CNS, and heart (appendix p 12).2 Symptoms can reflect tumour mass and compression of adjacent organs, inflammation, tissue destruction, or progressive fibrosis, or a combination of these. Chronic inflammation can also cause constitutional symptoms (eg, fever, weight loss, lethargy). Most reviews have focused on one type of histiocytosis (childhood or adult LCH, ECD, or RDD);3, 4, 5, 6 however, disease overlap is not infrequent. Indeed, patients with ECD can also have LCH lesions, and both entities can be associated with RDD-like lesions.7, 8, 9 Furthermore, some presentations are not reflected in the current WHO classification.10 Finally, the histiocyte population within a single lesion is heterogeneous,11 and the histology and phenotype of some types of histiocytosis (eg, ECD and juvenile xanthogranuloma) can be indistinguishable.

Thus, the Histiocyte Society endorsed a revised classification in 2016,12 arranging the different histiocytoses into five main groups (L, R, C, M, and H) according to clinical, histological, and molecular characteristics. Since its publication, patients in groups R, C, and M have been found to share molecular alterations;13, 14, 15, 16 molecular alterations were previously considered a hallmark of group L. The different histiocytosis types can also share particular clinical or radiological features (eg, neurodegeneration in LCH and ECD). Thus, it is tempting to hypothesise that some historical histiocytosis types might only correspond to clusters of characteristics of a unique-but-heterogeneous disease. Therefore, an update of our current knowledge on all of these entities within a single review is warranted, while conserving the historical classification for better understanding and easier use in clinical practice.

Section snippets

MAP kinase pathway mutations

The presence of the BRAF mutation encoding the V600E (Val600Glu) variant in LCH was first reported in 2010.17 BRAF was already a known oncogenic driver in several human neoplasms.18 That finding from 2010 revolutionised understanding of histiocytoses and opened the way for targeted therapies. BRAF is a protein in the MAP kinase cell-signalling pathway, a cascade of successively activated cytoplasmic proteins. In normal cells, activation of a membrane tyrosine kinase receptor by its specific

Epidemiology

The annual incidence of LCH is five to nine cases per 1 000 000 people for children younger than 15 years.52 Most cases are sporadic, but variant SMAD6 has been associated with susceptibility to LCH.53

Clinical presentation

Presenting features of LCH are extremely variable. The most frequent are bone pain or fracture, skin papules, lymphadenopathy, palpable tumour, polyuria and polydipsia related to diabetes insipidus, and exophthalmia (table 1).

Skin lesions are usually multiple (figure 2A) and polymorphic:

Epidemiology and risk

The annual incidence of LCH for patients older than 18 years is at least 0·07 per 1 000 000; this figure is probably an underestimation arising from the involvement of a wide range of medical specialties.65 In the French Registry of Histiocytoses, patients older than 15 years account for over 25% of LCH entries. Smoking is a major risk factor for pulmonary LCH in young adults.66

Clinical presentation

The pattern of organ involvement in adults is very similar to that in children, but multisystem disease can have a

Epidemiology and clinical presentation

The median age at diagnosis of ECD is 55 years, with a male:female ratio of 2·4:1.75 Symptoms of ECD can include fatigue, weight loss, fever, lower limb pain, polyuria, and polydipsia (table 1). Normolipaemic relapsing xanthelasma (figure 3D) is typical of ECD,76 and can precede other symptoms by several years. As in LCH, orbital infiltration (figure 3B) can cause exophthalmos. Serosal involvement is frequent and can cause effusions; effusions can be abundant and can even result in cardiac

Epidemiology and risk

The prevalence of RDD is five per 1 000 000.3 Mean age at diagnosis is 20·6 years. Most cases are sporadic, although some are inherited. Patients harbouring the SLC29A3 germline mutation, responsible for H syndrome, often have RDD lesions.99 Germline mutation of TNFRSF, coding for FAS and responsible for autoimmune lymphoproliferative syndrome type 1, confers an increased risk of developing RDD.100

Clinical presentation

Cervical lymph node enlargement is the classic manifestation of RDD (table 1); however, as for

Cutaneous and mucosal histiocytoses

Group C non-Langerhans cell histiocytoses include a wide variety of entities, with localised skin or mucosa lesions infiltrated by mononuclear and multinuclear CD1a histiocytes.12

Malignant histiocytosis

For completeness, we mention malignant histiocytoses, which are extremely rare conditions. The histological diagnosis is difficult, and more than half of around 100 cases seen in the French Histiocytosis Referral Centre were revised to undifferentiated malignant tumours rich in reactive macrophages (Emile JF, unpublished). When associated with another haematological neoplasm, the disorder should be classified as secondary malignant histiocytosis.12 The prognosis is usually poor, but transient

Laboratory investigations

Biopsies should be considered mandatory to exclude differential diagnoses and confirm histiocyte tissue infiltration. Histology, immunolabelling (figure 5A–L), and molecular testing should be done on samples fixed in buffered formalin for 12–72 h. When possible, a specimen other than bone is preferred, because molecular testing on decalcified bone can be difficult. Some reactive lesions (eg, scabies and dermatopathic lymphadenitis) rich in CD1a+ histiocytes can sometimes be mistaken for LCH.

Ontogeny and classification

Until recently, histiocytoses were considered idiopathic inflammatory diseases. The discovery of clonal oncogenic mutations in most patients with LCH or ECD showed that these conditions are rooted in neoplasia.48 For the 10% of patients with ECD who have concomitant myeloid malignancy (eg, myelodysplastic syndrome or a myeloproliferative neoplasm or an overlap syndrome of the two),83 their histiocytes, blood monocytes, and blood progenitor cells harbour the same mutation, and some of these

Conclusion

The last decade has seen significant progress made in the field of histiocytoses. Many advances have resulted from the discovery of somatic clonal molecular alterations in tissue samples. Active research networks dedicated to these rare diseases have accelerated that progress. Further analyses and clustering of clinical, imaging, histological, and molecular characteristics of large series of children and adults with histiocytosis will help better define homogeneous or overlapping entities, and

Search strategy and selection criteria

We searched PubMed and Embase for relevant articles on histiocytosis. For PubMed, the key search terms included: “histiocytos*”, “Erdheim Chester”, “Rosai Dorfman”, “sarcoma” AND (“dendritic” OR “Langerhans” OR “histiocyt*”) OR (“LCH” AND “Langerhans*”) OR (“Histiocytosis”). We reviewed articles published between Jan 1, 2010, and Jan 14, 2021. For Embase, the key search terms included: “histiocytosis”, “sinus histiocytosis”. We reviewed articles published between Jan 1, 2010, and Jan 14, 2021.

Declaration of interests

OA-W reports personal fees from Envisagenics, Pfizer Boulder, AIChemy, Janssen, Merck, H3 Biomedicine, Prelude Therapeutics, and Foundation Medicine, and grants from LOXO Oncology, during the conduct of the study. FC-A and JH are investigators (FC-A being the principal investigator) of an academic study on the efficacy of cobimetinib for treating histiocytoses (COBRAH, NCT 04007848). AI reports grants, research support, and travel funding from Carthera; grants from Transgene, Sanofi, Air

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