Langerhans cell histiocytosis

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Langerhans cell histiocytosis
Other names: Histiocytosis X[1]
Langerhans cell histiocytosis - very high mag.jpg
Micrograph showing a Langerhans cell histiocytosis with the characteristic reniform Langerhans cells accompanied by abundant eosinophils. H&E stain.
SpecialtyHematology
SymptomsLesions in various tissues, fever, weight loss, diabetes insipidus, tiredness[1]
TypesUnifocal, chronic multifocal, multifocal multisystem, Hashimoto-Pritzker disease[2]
Diagnostic methodTissue biopsy, medical imaging[2]
TreatmentNone, surgery, radiation therapy, chemotherapy[2]
PrognosisVariable[2]
Frequency1 to 2 per 100,000[3]

Langerhans cell histiocytosis (LCH) is an abnormal increase in Langerhans immune cells from the bone marrow, which than migrate to the skin and other organs.[4] They can form a type of tumor, known as a granuloma.[4][5] Symptoms may include lesions in various tissues such as skin or bone, fever, weight loss, diabetes insipidus, or tiredness.[1]

LCH is due to a mutation in the MAPKinase pathway.[1] It is part of a group of syndromes called histiocytoses, which are characterized by an increased number of histiocytes (an old term for dendritic cells).[1][4] Diagnosis is confirmed by medical imaging and biopsy.[2] Blood tests may show low red blood cells, and occasionally low white blood cells and low platelets.[1] Many consider it a form of cancer, but there is still some disagreement.[2][6]

Mild cases may simple resolve on their own without treatment.[2] Otherwise treatment options may include some combination of surgery, radiation therapy, or chemotherapy.[2] LCH affects about 1 to 2 people per 100,000.[3] Most cases start in childhood;[3] though adults may also be affected.[4] Males are more commonly affected than females.[1] Hispanic people are more commonly affected.[1]

Evidence of the disease has been found in mummy dating back to 900-790. B.C.[7] LCH was previously known as "histiocytosis X".[8] Subtype include chronic multifocal LCH, previously known as "Hand–Schüller–Christian disease", unifocal LCH, previously known as "eosinophilic granuloma", multifocal multisystem LCH, previously known as "Letterer-Siwe disease", and Hashimoto-Pritzker disease.[2][9]

Signs and symptoms

Langerhans cell histiocytosis[10]
A person with chronic multifocal Langerhans cell histiocytosis, a subtype of LCH.

LCH provokes a non-specific inflammatory response, which includes fever, lethargy, and weight loss.

Either one or several parts of the body can be involved, with clinical features depending on which organ is affected, resulting in an array of signs and symptoms from mild to life-threatening.[1]

  • Bone involvement can cause bone pain and swelling. The skull is most frequently affected, followed by long bones of arms and legs. Lytic bone lesions can lead to fractures.[6] Signs and symptoms due to bone damage reflect the type of bone affected, such as ear infections with temporal bone involvement, and spinal cord damage with vertebral damage.[1] Disease of the jaw may result in swollen and bleeding gums and teeth problems.[1]
  • Skin involvement may prevent with a dry scaly rash or bumps and ulcers.[1]
  • Liver and spleen involvement causes enlargement of these organs, in addition to low protein, edema, jaundice and large lymph glands.[1][4] Bleeding easily and anemia may be worse if the spleen enlarges.[1]
  • Lungs and gastrointestinal tract involvement may not always result in symptoms and be diagnosed incidentally because of lung nodules on radiographs.[15] Difficulty breathing and coughing blood can arise from lung involvement and bloody diarrhoea can result from lesions in the intestinal tract.[1]

Causes

LCH is due to mutations in the MAPKinase pathway.[1] It is part of a group of syndromes called histiocytoses, which are characterized by an abnormal proliferation of histiocytes (an archaic term for activated dendritic cells and macrophages), which were also termed Langerhans cells. These diseases are related to other forms of abnormal proliferation of white blood cells, such as leukemias and lymphomas.[1]

LCH is usually a sporadic and non-hereditary 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.[16]

Describing LCH as a cancer has caused some controversy.[6] Some sources such as the National Cancer Institute describe it as a type of cancer,[17] while other sources specifically state it is not a type of cancer.[18]

Pathophysiology

The pathogenesis of Langerhans cell histiocytosis (LCH) is a matter of debate. There are ongoing investigations to determine whether LCH is a reactive (non-cancerous) or neoplastic (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) in the lesional tissue, favorable prognosis and relatively good survival rate in patients without organ dysfunction or risk organ involvement.[19][20]

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.[21][22][23] 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.[24] 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%).[25] This study documented the first recurrent mutation in LCH samples. Two independent studies have confirmed this finding.[26][27] Presence of this activating mutation could support the notion to characterize LCH as myeloproliferative disorder.

Diagnosis

CT scan showing LCH infiltrating peri-orbital tissue (arrowed).
Micrograph showing Langerhans Cell Histiocytosis. H&E stain.

Diagnosis is confirmed histologically by tissue biopsy. Hematoxylin-eosin stain of biopsy slide will show features of Langerhans Cell e.g. distinct cell margin, pink granular cytoplasm. Presence of Birbeck granules on electron microscopy and immuno-cytochemical features e. g. CD1 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.[citation needed]

Imaging may be evident in chest X-rays with micronodular and reticular changes of the lungs with cyst formation in advanced cases. MRI 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, MRI shows a hyperintense T1 signal in the globus pallidus.[28]

Assessment of endocrine function and bonemarrow biopsy are also performed when indicated.[citation needed]

Classification

Alternative names
Histiocytosis X

Histiocytosis X syndrome

Subordinate terms

Histiocytosis X, unspecified
Langerhans cell granulomatosis
Langerhans cell histiocytosis, Hashimoto-Pritzker type
Langerhans cell histiocytosis of lung
Unifocal Langerhans cell histiocytosis (clinical)

  • Eosinophilic granulomatosis (obsolete)[1]

Disseminated Langerhans cell histiocytosis (clinical)

  • Hand-Schüller-Christian disease (obsolete)[35]
  • Letterer-Siwe disease (obsolete)[1]

The disease spectrum results from clonal accumulation and proliferation of cells resembling the epidermal dendritic cells called Langerhans cells, sometimes called dendritic cell histiocytosis. These cells in combination with lymphocytes, eosinophils, and normal histiocytes form typical LCH lesions that can be found in almost any organ.[36] A similar set of diseases has been described in canine histiocytic diseases.

LCH is clinically divided into three groups: unifocal, multifocal unisystem, and multifocal multisystem.[37]

Unifocal

Unifocal LCH, also called eosinophilic granuloma (an older term which is now known to be a misnomer), 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.[38] When found in the skin it is called cutaneous single system Langerhans cell LCH. This version can heal without therapy in some rare cases.[39] This primary bone involvement helps to differentiate eosinophilic granuloma from other forms of Langerhans Cell Histiocytosis (Letterer-Siwe or Hand-Schüller-Christian variant).[40]

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, often leading to diabetes insipidus. The triad of diabetes insipidus, exophthalmos, and lytic bone lesions is known as the chronic multifocal Langerhans cell histiocytosis. Peak onset is 2–10 years of age.[citation needed]

Multifocal multisystem

Multifocal multisystem LCH, also called Letterer-Siwe disease, is an often rapidly progressing disease in which Langerhans Cell 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%.[41]

Lungs

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. PLCH develops when an abundance of monoclonal CD1a-positive Langerhans (immature histiocytes) proliferate the bronchioles and alveolar interstitium, and this flood of histiocytes recruits granulocytes like eosinophils and neutrophils and agranulocytes like lymphocytes further destroying bronchioles and the interstitial alveolar space that can cause damage to the lungs.[42] 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. [43]Some affected people recover completely after they stop smoking, but others develop long-term complications such as pulmonary fibrosis and pulmonary hypertension.[44] PLCH patients, families, and caregivers are encouraged to join the NIH Rare Lung Diseases Consortium Contact Registry. This is a privacy protected site that provides up-to-date information for individuals interested in the latest scientific news, trials, and treatments related to rare lung diseases.[citation needed]

Treatment

Guidelines for management of patients up to 18 years with Langerhans cell histiocytosis have been suggested.[45][46][47][48] 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 for diabetes insipidus which can be applied as nasal drop. Chemotherapeutic agents such as alkylating agents, antimetabolites, vinca alkaloids either singly or in combination can lead to complete remission in diffuse disease.[citation needed]

Prognosis

Excellent for single-focus disease. With multi-focal disease 60% have a chronic course, 30% achieve remission and mortality is up to 10%.[49]

Epidemiology

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;[50] and in adults even rarer, in about 1 in 560,000.[51] It has been reported in elderly but is vanishingly rare.[52] It is most prevalent in Caucasians, and affects males twice as often as females.[53] In other populations the rates in males is slightly more than in females.[54]

History

MRI and CT scan findings in a mummy have revealed evidence of the disease dating back to 900-790. B.C.[7]

The subtype chronic multifocal Langerhans cell histiocytosis was previously known as Hand–Schüller–Christian disease, and was named for the American pediatrician Alfred Hand Jr.,[9] the Austrian neuroradiologist Arthur Schüller,[9][55] and the American pathologist Henry Asbury Christian,[9][56] who described it in 1893,[9][57] 1915[9][58] and 1919, respectively.[9][59] Shortly afterwards, Letterer in 1924 and Siwe in 1933 described a fatal condition in children who presented with large livers and spleens, large lymph nodes and bone damage. In 1940, Louis Litchtenstein and Henry L. Jaffe described a self-limiting disease characterised by "isolated bone lesions".[60] A common feature of all these conditions was revealed to be the histological findings of large numbers of histiocytes in the tissue biopsies, leading Litchtenstein to propose that the three described conditions were part of a spectrum of a disease he named "Histiocytosis X", where "X" denoted the unknown cause at the time.[60] In 1973, Christian Nezelof recognised the abnormal cell as a 'Langerhans-like' cell, however it took another ten years for the term 'Langerhans cell histiocytosis' to be internationally recognised. In 1987, the Histiocyte Society published their classification of the histiocyte disorders together with criteria for diagnosis and clinical assessment of Langerhans cell histiocytosis.[61]

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.[62]

Society and culture

In the 10th episode of season 3 of House entitled "Merry Little Christmas", the primary patient is a girl with dwarfism who has a variety of symptoms, who is ultimately diagnosed with Langerhans cell histiocytosis.[63]Also in the 5th episode, season 1 of "The Good Doctor", Dr. Murphy tries to diagnose Langerhans cell histiocytosis in a boy with a previously diagnosed osteosarcoma.[citation needed]In an episode of Mystery Diagnosis, "The Woman Who Saw Pink", Brooke Rohrer has experiencing symptoms of abdominal pain, was diagnosed with Langerhans cell histiocytosis.[citation needed]

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