Clonal proliferation of Langerhans cells in Langerhans cell histiocytosis
Abstract
X-chromosome-inactiavtion assays can be used to assess clonality. We used such an assay at the human androgen-receptor gene locus in three female patients with histologically proven Langerhans cell histiocytosis. All patients were heterozygous for this locus. Cells bearing the Langerhans cell phenotype were purified from involved tissue after fluorescence-activated cell sorting with monoclonal antibodies against the CD1a complex. After Hhaldigestion of DNA, these CD1a positive cells demonstrated a non-random X-chromosome-inactivation pattern, whereas CD1a negative cells in the same tissue showed a random pattern. Our data suggest that Langerhans cell histiocytosis represents a clonal proliferation of cells bearing the Langerhans cell phenotype.
References (7)
- Ms Birbeck et al.
An electron microscopic study of basal melanocytes and high-level clear cells (Langerhans cells) in vitiligo
J Invest Dermatol
(1961) - Writing Group of the Histiocyte Society
Histiocytosis syndromes in children
Lancet
(1987) - G. Stingl et al.
Immunological functions of Ia-bearing epidermal Langerhans cells
J Immunol
(1978)
Cited by (357)
Histiocytosis
2023, Ophthalmic Pathology: The Evolution of Modern ConceptsThe term histiocytosis refers to a collection of proliferative disorders of dendritic-macrophage-monocyte lineage. This historical review focuses on one member of the group ─ Langerhans cell histiocytosis. It took nearly two-thirds of a century to unite the seemingly disparate syndromes of Hand-Schüller-Christian disease, Letterer-Siwe disease, and eosinophilic granuloma into the single entity of Langerhans cell histiocytosis (LCH). The Langerhans cell was discovered in 1847 but its function took 130 years to figure out. The abnormal proliferation of Langerhans cells has fascinated scientists as the cells have morphologic features of benignancy yet can behave as if malignant. Using X-linked DNA probes, the cells were found to be clonally expanded proliferations. LHC pathogenesis is being scrutinized with evidence of somatic mutations in MAPK pathway genes. The eye and ocular adnexa are commonly involved in LCH. The photograph gallery includes examples of the pathology of LCH and Rosai-Dorfman disease.
Developmental and Inherited Liver Disease
2023, MacSween's Pathology of the Liver, Eighth EditionA section on the approach to diagnostic histological interpretation is the overture to this chapter on inherited and developmental disorders. This initial section is split chronologically into the early neonatal and infantile period and later childhood and adulthood, with the intention of reflecting clinical practice as closely and succinctly as possible. Disorders of the biliary tree, bile formation and secretion and hepatocyte metabolism are the core of this chapter, a merger of Chapters 3 and 4 of previous editions. Considerations on the pathogenetic and/or clinical overlap among developmental, genetic and metabolic disorders were the rationale behind this change. The complexity of hepatocyte metabolism is reflected into the myriad of related pathological conditions. Two short new paragraphs on disorders of manganese metabolism and DNA repair and nuclear envelope have been added. Recent technological advances, particularly in genomics in the last 5 years, have resulted in a plethora of new entities and changes in terminology, challenging the authors to balance detail and application to clinical practice. Tables and figures from the previous edition have been largely kept due to their quality and contemporary relevance, and updated where necessary. Liver involvement in immunodeficiency and miscellaneous disorders precede the final section on anatomical anomalies. Vascular anomalies are now included in the chapters on vascular disorders.
Socio-behavioral dysfunction in disorders of hypothalamic-pituitary involvement: The potential role of disease-induced oxytocin and vasopressin signaling deficits
2022, Neuroscience and Biobehavioral ReviewsDisorders involving hypothalamic and pituitary (HPIT) structures—including craniopharyngioma, Langerhans cell histiocytosis, and intracranial germ cell tumors—can disrupt brain and endocrine function. An area of emerging clinical concern in patients with these disorders is the co-occurring socio-behavioral dysfunction that persists after standard hormone replacement therapy. Although the two neuropeptides most implicated in mammalian social functioning (oxytocin and arginine vasopressin) are of hypothalamic origin, little is known about how disease-induced damage to HPIT structures may disrupt neuropeptide signaling and, in turn, impact patients’ socio-behavioral functioning. Here we provide a clinical primer on disorders of HPIT involvement and a review of neuropeptide signaling and socio-behavioral functioning in relevant animal models and patient populations. This collective evidence suggests that neuropeptide signaling disruptions contribute to socio-behavioral deficits experienced by patients with disorders of HPIT involvement. A better understanding of the biological underpinnings of patients’ socio-behavioral symptoms is now needed to enable the development of the first targeted pharmacological strategies by which to manage patients’ socio-behavioral dysfunction.
Primary Benign Tumors of the Spinal Canal
2022, World NeurosurgeryBenign tumors that grow in the spinal canal are heterogeneous neoplasms with low incidence; from these, meningiomas and nerve sheath tumors (neurofibromas and schwannomas) account for 60%–70% of all primary spinal tumors. Benign spinal canal tumors provoke nonspecific clinical manifestations, mostly related to the affected level of the spinal cord. These tumors present a challenge for the patient and healthcare professionals, for they are often difficult to diagnose and the high frequency of posttreatment complications. In this review, we describe the epidemiology, risk factors, clinical features, diagnosis, histopathology, molecular biology, and treatment of extramedullary benign meningiomas, osteoid osteomas, osteoblastomas, aneurysmal bone cysts, osteochondromas, neurofibromas, giant cell tumors of the bone, eosinophilic granulomas, hemangiomas, lipomas, and schwannomas located in the spine, as well as possible future targets that could lead to an improvement in their management.
Histiocytosis
2021, The LancetHistiocytoses 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.
Langerhans cell histiocytosis (LCH) is a myeloid neoplasia, driven by sporadic activating mutations in the MAPK pathway. The misguided myeloid dendritic cell (DC) model proposes that high-risk, multisystem, risk-organ–positive (MS-RO+) LCH results from driver mutation in a bone marrow (BM)-resident multipotent hematopoietic progenitor, while low-risk, MS-RO− and single-system LCH would result from driver mutation in a circulating or tissue-resident, DC-committed precursor. We have examined the CD34+c-Kit+Flt3+ myeloid progenitor population as potential mutation carrier in all LCH disease manifestations. This population contains oligopotent progenitors of monocytes (Mo's)/macrophages (MΦs), osteoclasts (OCs), and DCs. CD34+c-Kit+Flt3+ cells from BM of MS-RO+ LCH patients produced Langerhans cell (LC)-like cells in vitro. Both LC-like and DC offspring from this progenitor carried the BRAF mutation, confirming their common origin. In both high- and low-risk LCH patients, CD34+c-Kit+Flt3+ progenitor frequency in blood was higher than in healthy donors. In one MS-RO+ LCH patient, CD34+c-Kit+Flt3+ cell frequency in blood and its BRAF-mutated offspring reported response to chemotherapy. CD34+c-Kit+Flt3+ progenitors from blood of both high- and low-risk LCH patients gave rise to DCs and LC-like cells in vitro, but the driver mutation was not easily detectable, likely due to low frequency of mutated progenitors. Mutant BRAF alleles were found in Mo's /MΦs, DCs, LC-like cells, and/or OC-like cells in lesions and/or Mo and DCs in blood of multiple low-risk patients. We therefore hypothesize that in both high- and low-risk LCH, the driver mutation is present in a BM-resident myeloid progenitor that can be mobilized to the blood.