Langerhans' Cell Histiocytosis
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Langerhans cell histiocytosis (LCH) is an abnormal clonal proliferation of
Langerhans cell A Langerhans cell (LC) is a tissue-resident macrophage of the skin once thought to be a resident dendritic cell. These cells contain organelles called Birbeck granules. They are present in all layers of the epidermis and are most prominent in t ...
s, abnormal
cell Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a de ...
s deriving from
bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
and capable of migrating from skin to
lymph node A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...
s. Symptoms range from isolated bone lesions to multisystem disease. LCH is part of a group of syndromes called histiocytoses, which are characterized by an abnormal proliferation of
histiocyte A histiocyte is a vertebrate cell that is part of the mononuclear phagocyte system (also known as the reticuloendothelial system or lymphoreticular system). The mononuclear phagocytic system is part of the organism's immune system. The histiocy ...
s (an archaic term for activated
dendritic cell A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
s and
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s). These diseases are related to other forms of abnormal proliferation of
white blood cell White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
s, such as
leukemia Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...
s and
lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). The name typically refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlarged lymph node ...
s. The disease has gone by several names, including Hand–Schüller–Christian disease, Abt-Letterer-Siwe disease, Hashimoto-Pritzker disease (a very rare self-limiting variant seen at birth) and histiocytosis X, until it was renamed in 1985 by the Histiocyte Society.


Classification

The disease spectrum results from clonal accumulation and proliferation of cells resembling the epidermal
dendritic cell A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
s called
Langerhans cell A Langerhans cell (LC) is a tissue-resident macrophage of the skin once thought to be a resident dendritic cell. These cells contain organelles called Birbeck granules. They are present in all layers of the epidermis and are most prominent in t ...
s, sometimes called dendritic cell histiocytosis. These cells in combination with
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), an ...
s,
eosinophil Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along wi ...
s, and normal
histiocyte A histiocyte is a vertebrate cell that is part of the mononuclear phagocyte system (also known as the reticuloendothelial system or lymphoreticular system). The mononuclear phagocytic system is part of the organism's immune system. The histiocy ...
s form typical LCH lesions that can be found in almost any
organ Organ and organs may refer to: Biology * Organ (biology), a group of tissues organized to serve a common function * Organ system, a collection of organs that function together to carry out specific functions within the body. Musical instruments ...
. A similar set of diseases has been described in
canine histiocytic diseases Histiocytic diseases in dogs are a group of diseases in dogs which may involve the skin, and which can be difficult to differentiate from granulomatous, reactive inflammatory or lymphoproliferative diseases. The clinical presentation and behaviour ...
. LCH is clinically divided into three groups: unifocal, multifocal unisystem, and multifocal multisystem.


Unifocal

Unifocal LCH, also called ''
eosinophilic granuloma Humans Human eosinophilic granuloma is characterized by abnormal proliferation of Langerhans cells (LCs). LCs are antigen-presenting cells derived from dendritic cells. In humans, eosinophilic granulomas are considered to be benign tumors that occ ...
'' (an older term which is now known to be a
misnomer A misnomer is a name that is incorrectly or unsuitably applied. Misnomers often arise because something was named long before its correct nature was known, or because an earlier form of something has been replaced by a later form to which the nam ...
), is a disease characterized by an expanding proliferation of Langerhans cells in one organ, where they cause damage called lesions. It typically has no extraskeletal involvement, but rarely a lesion can be found in the skin, lungs, or stomach. It can appear as a single lesion in an organ, up to a large quantity of lesions in one organ. When multiple lesions are scattered throughout an organ, it can be called a multifocal unisystem variety. When found in the lungs, it should be distinguished from Pulmonary Langerhans cell hystiocytosis—a special category of disease most commonly seen in adult smokers. When found in the skin it is called cutaneous single system Langerhans cell LCH. This version can heal without therapy in some rare cases. This primary bone involvement helps to differentiate eosinophilic granuloma from other forms of Langerhans Cell Histiocytosis (Letterer-Siwe or Hand-Schüller-Christian variant).


Multifocal unisystem

Seen mostly in children, multifocal unisystem LCH is characterized by fever, bone lesions and diffuse eruptions, usually on the scalp and in the ear canals. 50% of cases involve the
pituitary stalk The pituitary stalk, also known as the infundibular stalk, infundibulum, or Fenderson's funnel, is the connection between the hypothalamus and the posterior pituitary, the posterior lobe of the pituitary gland. The floor of the third ventricle is ...
, often leading to
diabetes insipidus Diabetes insipidus (DI) is a condition characterized by large amounts of dilute urine and increased thirst. The amount of urine produced can be nearly 20 liters per day. Reduction of fluid has little effect on the concentration of the urine. ...
. The triad of diabetes insipidus,
exophthalmos Exophthalmos (also called exophthalmus, exophthalmia, proptosis, or exorbitism) is a bulging of the eye anteriorly out of the orbit. Exophthalmos can be either bilateral (as is often seen in Graves' disease) or unilateral (as is often seen in ...
, and lytic bone lesions is known as the ''
Hand-Schüller-Christian triad Chronic multifocal Langerhans cell histiocytosis, previously known as Hand–Schüller–Christian disease, is a type of Langerhans cell histiocytosis (LCH), which can affect multiple organs. The condition is traditionally associated with a combina ...
''. Peak onset is 2–10 years of age.


Multifocal multisystem

Multifocal multisystem LCH, also called '' Letterer-Siwe disease'', is an often rapidly progressing disease in which Langerhans cells proliferate in many tissues. It is mostly seen in children under age 2, and the prognosis is poor: even with aggressive chemotherapy, the five-year survival is only 50%.


Pulmonary Langerhans cell histiocytosis (PLCH)

Pulmonary Langerhans cell histiocytosis (PLCH) is a unique form of LCH in that it occurs almost exclusively in cigarette smokers. It is now considered a form of smoking-related
interstitial lung disease Interstitial lung disease (ILD), or diffuse parenchymal lung disease (DPLD), is a group of respiratory diseases affecting the interstitium (the tissue) and space around the alveoli (air sacs) of the lungs. It concerns alveolar epithelium, pulm ...
. PLCH develops when an abundance of monoclonal CD1a-positive Langerhans (immature histiocytes) proliferate the bronchioles and alveolar interstitium, and this flood of histiocytes recruits
granulocyte Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear, that i ...
s like eosinophils and
neutrophil Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...
s and
agranulocyte In immunology, agranulocytes (also known as nongranulocytes or mononuclear leukocytes) are one of the two types of leukocytes (white blood cells), the other type being granulocytes. Agranular cells are noted by the absence of granules in the ...
s like lymphocytes further destroying bronchioles and the interstitial alveolar space that can cause damage to the lungs. It is hypothesized that bronchiolar destruction in PLCH is first attributed to the special state of Langerhans cells that induce cytotoxic T-cell responses, and this is further supported by research that has shown an abundance of T-cells in early PLCH lesions that are CD4+ and present early activation markers. Some affected people recover completely after they stop smoking, but others develop long-term complications such as
pulmonary fibrosis Pulmonary fibrosis is a condition in which the lungs become scarred over time. Symptoms include shortness of breath, a dry cough, feeling tired, weight loss, and nail clubbing. Complications may include pulmonary hypertension, respiratory ...
and
pulmonary hypertension Pulmonary hypertension (PH or PHTN) is a condition of increased blood pressure in the pulmonary artery, arteries of the lungs. Symptoms include dypsnea, shortness of breath, Syncope (medicine), fainting, tiredness, chest pain, pedal edema, swell ...
.


Signs and symptoms

LCH provokes a non-specific
inflammatory response Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
, which includes fever,
lethargy Lethargy is a state of tiredness, sleepiness, weariness, fatigue, sluggishness, or lack of energy. It can be accompanied by depression, decreased motivation, or apathy. Lethargy can be a normal response to inadequate sleep, overexertion, overw ...
, and weight loss. Organ involvement can also cause more specific symptoms. * Bone: The most-frequently seen symptom in both unifocal and multifocal disease is painful bone swelling. The skull is most frequently affected, followed by the long bones of the upper extremities and flat bones. Infiltration in hands and feet is unusual. Osteolytic lesions can lead to pathological fractures. * Skin: Commonly seen are a rash which varies from scaly erythematous lesions to red papules pronounced in
intertriginous In medicine, an intertriginous area is where two skin areas may touch or rub together. Examples of intertriginous areas are the axilla of the arm, the anogenital region, skin folds of the breasts and between digits. Intertriginous areas are know ...
areas. Up to 80% of LCH patients have extensive eruptions on the scalp. * Bone marrow: Pancytopenia with superadded infection usually implies a poor prognosis. Anemia can be due to a number of factors and does not necessarily imply bone marrow infiltration. * Lymph node: Enlargement of the liver in 20%, spleen in 30% and lymph nodes in 50% of Histiocytosis cases. *
Endocrine The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypotha ...
glands: Hypothalamic pituitary axis commonly involved.
Central Diabetes insipidus Central diabetes insipidus, recently renamed arginine vasopressin deficiency (AVP-D), is a form of diabetes insipidus that is due to a lack of vasopressin (ADH) production in the brain. Vasopressin acts to increase the blood volume, volume of bl ...
can be the first manifestation of LCH.
Anterior pituitary The anterior pituitary (also called the adenohypophysis or pars anterior) is a major Organ (anatomy), organ of the endocrine system. The anterior pituitary is the glandular, Anatomical terms of location#Usage in human anatomy, anterior lobe that t ...
hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...
deficiency is usually permanent. * Lungs: some patients are asymptomatic, diagnosed incidentally because of lung nodules on radiographs; others experience chronic cough and shortness of breath. * Less frequently
gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...
,
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
, and
oral cavity A mouth also referred to as the oral is the body orifice through which many animals ingest food and vocalize. The body cavity immediately behind the mouth opening, known as the oral cavity (or in Latin), is also the first part of the alime ...
.


Pathophysiology

The pathogenesis of Langerhans cell histiocytosis (LCH) is a matter of debate. There are ongoing investigations to determine whether LCH is a neoplastic (cancerous) or reactive (non-cancerous) process. Arguments supporting the reactive nature of LCH include the occurrence of spontaneous remissions, the extensive secretion of multiple cytokines by dendritic cells and bystander-cells (a phenomenon known as
cytokine storm A cytokine storm, also called hypercytokinemia, is a pathological reaction in humans and other animals in which the innate immune system causes an uncontrolled and excessive release of pro-inflammatory signaling molecules called cytokines. Cytok ...
) in the lesional tissue, favorable prognosis and relatively good survival rate in patients without organ dysfunction or risk organ involvement. On the other hand, the infiltration of organs by monoclonal population of pathologic cells, and the successful treatment of subset of disseminated disease using chemotherapeutic regimens are all consistent with a neoplastic process. In addition, a demonstration, using X chromosome–linked DNA probes, of LCH as a monoclonal proliferation provided additional support for the neoplastic origin of this disease. While clonality is an important attribute of cancer, its presence does not prove that a proliferative process is neoplastic. Recurrent cytogenetic or genomic abnormalities would also be required to demonstrate convincingly that LCH is a malignancy. An activating somatic mutation of a proto-oncogene in the Raf family, the BRAF gene, was detected in 35 of 61 (57%) LCH biopsy samples with mutations being more common in patients younger than 10 years (76%) than in patients aged 10 years and older (44%). This study documented the first recurrent mutation in LCH samples. Two independent studies have confirmed this finding. Presence of this activating mutation could support the notion to characterize LCH as myeloproliferative disorder.


Diagnosis

Diagnosis is confirmed
histologically Histology, also known as microscopic anatomy or microanatomy, is the branch of biology that studies the microscopic anatomy of biological tissue (biology), tissues. Histology is the microscopic counterpart to gross anatomy, which looks at large ...
by tissue
biopsy A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, an interventional radiologist, or an interventional cardiology, interventional cardiologist. The process involves the extraction of sampling (medicine), sample ...
. Hematoxylin-eosin stain of biopsy slide will show features of Langerhans Cell e.g. distinct cell margin, pink granular
cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...
. Presence of Birbeck granules on
electron microscopy An electron microscope is a microscope that uses a beam of electrons as a source of illumination. It uses electron optics that are analogous to the glass lenses of an optical light microscope to control the electron beam, for instance focusing i ...
and immuno-cytochemical features e. g.
CD1 CD1 (cluster of differentiation 1) is a family of glycoproteins expressed on the surface of various human antigen-presenting cells. CD1 glycoproteins are structurally related to the class I MHC molecules, however, in contrast to MHC class ...
positivity are more specific. Initially routine blood tests e.g. full blood count, liver function test, U&Es, bone profile are done to determine disease extent and rule out other causes. Electron microscopy ''or'' immunohistochemistry (only one of the two is required) may be used to definitively diagnose Langerhans cell histiocytosis, in the presence of other pathologic and histologic qualities of the disease. Imaging may be evident in
chest X-ray A chest radiograph, chest X-ray (CXR), or chest film is a Projectional radiography, projection radiograph of the chest used to diagnose conditions affecting the chest, its contents, and nearby structures. Chest radiographs are the most common fi ...
s with micronodular and reticular changes of the lungs with cyst formation in advanced cases.
MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...
and High-resolution CT may show small, cavitated nodules with thin-walled cysts. MRI scan of the brain can show three groups of lesions such as tumourous/granulomatous lesions, nontumourous/granulomatous lesions, and atrophy. Tumourous lesions are usually found in the hypothalamic-pituitary axis with space-occupying lesions with or without calcifications. In non-tumourous lesions, there is a symmetrical hyperintense T2 signal with hypointense or hyperintense T1 signal extending from grey matter into the white matter. In the
basal ganglia The basal ganglia (BG) or basal nuclei are a group of subcortical Nucleus (neuroanatomy), nuclei found in the brains of vertebrates. In humans and other primates, differences exist, primarily in the division of the globus pallidus into externa ...
, MRI shows a hyperintense T1 signal in the
globus pallidus The globus pallidus (GP), also known as paleostriatum or dorsal pallidum, is a major component of the Cerebral cortex, subcortical basal ganglia in the brain. It consists of two adjacent segments, one external (or lateral), known in rodents simpl ...
. Assessment of
endocrine The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypotha ...
function and bone marrow biopsy are also performed when indicated. * S-100 protein is expressed in a cytoplasmic pattern *
peanut agglutinin Peanut agglutinin (PNA) is plant lectin protein derived from the fruits of '' Arachis hypogaea''. Peanut agglutinin may also be referred to as ''Arachis hypogaea'' lectin. Lectins recognise and bind particular sugar sequences in carbohydrates; pean ...
(PNA) is expressed on the cell surface and perinuclearly * major histocompatibility (MHC) class II is expressed (because histiocytes are macrophages) *
CD1a CD1a (Cluster of Differentiation 1a) is a human protein encoded by the gene. This gene encodes a member of the CD1 family of transmembrane glycoproteins, which are structurally related to the major histocompatibility complex The major histo ...
* langerin ( CD207), a Langerhans Cell–restricted protein that induces the formation of Birbeck granules and is constitutively associated with them, is a highly specific marker.


Treatment

Guidelines for management of patients up to 18 years with Langerhans cell histiocytosis have been suggested. Treatment is guided by extent of disease. Solitary bone lesion may be amenable through excision or limited radiation, dosage of 5-10 Gy for children, 24-30 Gy for adults. However systemic diseases often require chemotherapy. Use of systemic steroid is common, singly or adjunct to chemotherapy. Local steroid cream is applied to skin lesions. Endocrine deficiency often require lifelong supplement e.g.
desmopressin Desmopressin, sold under the trade name DDAVP among others, is a medication used to treat diabetes insipidus, bedwetting, hemophilia A, von Willebrand disease, and high blood urea levels. In hemophilia A and von Willebrand disease, it should ...
for diabetes insipidus which can be applied as nasal drop.
Chemotherapeutic Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) in a standard regimen. Chemotherapy may be given with a curat ...
agents such as
alkylating agents Alkylation is a chemical reaction that entails transfer of an alkyl group. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effectin ...
, antimetabolites,
vinca alkaloids ''Vinca'' alkaloids are a set of anti-mitotic and anti-microtubule alkaloid agents originally derived from the periwinkle plant '' Catharanthus roseus'' (basionym ''Vinca rosea'') and other ''vinca'' plants. They block beta-tubulin polymeriza ...
either singly or in combination can lead to complete remission in diffuse disease.


Prognosis

There is a general excellent prognosis for the disease as those with localized disease have a long life span. With multi-focal disease 60% have a chronic course, 30% achieve remission and mortality is up to 10%. A full recovery can be expected for people who seek treatment and do not have more lesions at 12 and 24 months. However, 50% of children under 2 with disseminated Langerhans cell histiocytosis die of the disease. The prognosis rate decreases for patients who experience lung involvement. Whereas patients with skin and a solitary lymph node involvement generally have a good prognosis.Tillotson CV, Anjum F, Patel BC. Langerhans Cell Histiocytosis. pdated 2022 Jul 18 In: StatPearls nternet Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430885/ Although there is a general good prognosis for Langerhans cell histiocytosis, approximately 50% of patients with the disease are prone to various complications such as musculoskeletal disability, skin scarring and diabetes insipidus.


Prevalence

LCH usually affects children between 1 and 15 years old, with a peak incidence between 5 and 10 years of age. Among children under the age of 10, yearly incidence is thought to be 1 in 200,000; and in adults even rarer, in about 1 in 560,000. It has been reported in elderly but is vanishingly rare. It is most prevalent in Caucasians, and affects males twice as often as females. In other populations too the prevalence in males is slightly more than in females. LCH is usually a sporadic and non-
hereditary Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic inform ...
condition but familial clustering has been noted in limited number of cases. Hashimoto-Pritzker disease is a congenital self-healing variant of Hand-Schüller-Christian disease.


Nomenclature

Langerhans cell histiocytosis is occasionally misspelled as "Langerhan" or "Langerhan's" cell histiocytosis, even in authoritative textbooks. The name, however, originates back to its discoverer, Paul Langerhans.


References


External links

{{Histiocytosis Histiocytosis Monocyte- and macrophage-related cutaneous conditions Rare diseases