Langerhans cell histiocytosis LCH is a rare multi-organ disease due to accumulation of Langerhans cells in various tissues. The lesional Langerhans cells have been shown to be clonal. However, the neoplastic nature of the disease is not fully proved. It is not a malignant condition by itself. What to be alert for in the history LCH is mostly found in children younger than 15 years old.

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Langerhans cell histiocytosis LCH is a rare multi-organ disease due to accumulation of Langerhans cells in various tissues. The lesional Langerhans cells have been shown to be clonal. However, the neoplastic nature of the disease is not fully proved. It is not a malignant condition by itself. What to be alert for in the history LCH is mostly found in children younger than 15 years old.

According to the clinical presentation and the various internal organs involved, different names have been used in the past to describe this disease. All these conditions represent a spectrum of presentations of a single entity.

There are some intermediate forms. Moreover, some children with self-regressing diseases in early infancy have shown later recurrence of LCH with a more chronic evolution. The use of the descriptive term Langerhans cell histiocytosis should therefore be preferred to all previously cited names recommendation of the Histiocyte Society. Multisystem LCH is defined as an involvement of 2 or more organs or organ systems, irrespective of involvement of risk organ.

One should be alert for a history of polyuria and polydipsia, suspect for pituitary involvement leading to diabetes insipidus through post-pituitary or sella turcica infiltration, and anti-diuretic hormone ADH insufficiency. One should also be alert for a history of recurrent episodes of otitis media and mastoiditis, suspect for bone involvement around the middle ear. Characteristic findings on physical examination The typical presentation consists in diffuse skin disease, predominantly involving the head and neck region, the trunk and the proximal limbs.

Monolesional or paucilesional forms have been described and seem to portend a better prognosis self-regression. There are several forms of LCH: -Eosinophilic granuloma was used to describe a chronic unifocal LCH classically presenting as a solitary bone lesion in young adults, with no cutaneous involvement.

Cutaneous involvement was considered frequent in this form. Figure 1. One of them is necrotic This child had self-regressive Langerhans cell histiocytosis. LCH also occurs in bone, skin, lymph node, lungs, central nervous system, other eg, thyroid, thymus , spleen, liver, hematopoietic system, lungs. The papules can have a yellow to erythematous color.

Seborrhoeic-keratosis like presentation on the scalp of an infant. Figure 3. Most of the organs can be involved. Expected results of diagnostic studies Diagnosis is presumptive in front of typical histopathologic findings on skin biopsy: skin dermal infiltrate of cells with folded or reniform nucleus and eosinophilic cytoplasm, suggestive of Langerhans cells Figure 4,Figure 5. Additional features are represented by eosinophils, variable admixture of small lymphocytes and histiocytes, multinucleated cells, epidermal ulceration, epidermotropism of Langerhans cells, calcinosis rare.

Figure 4. At high power magnification, one can recognize Langerhans cells, with eosinophilic cytoplasm and reniform nucleus. There is exocytosis of Langerhans cells in the epidermis. Except for S protein, these markers are rarely used nowadays. Definitive diagnosis requires typical histopathologic findings and at least one of the following criteria: expression of CD1a immunohistochemistry Figure 6 or presence of Birbeck granules with electron microscopy.

The Birbeck granule is a distinctive ultrastructural intracytoplasmic membranous body that is 33nm wide and to nm long, possessing a short, rodlike shape with a dotted line down the midline of the space between the membrane resembling a zipper and a terminal expansion in the form of a vesicle, giving a racquet appearance.

Nowadays, electron microscopy is hardly ever performed. CD1a expression by cells with a compatible cytology is easily demonstrated on formalin-fixed paraffin embedded tissue. Figure 6. The cells strongly express CD1a immunohistochemical staining, X Another specific marker of the Langerhans cells is CD, or Langerin.

Langerin is a Langerhans-cell restricted protein that induces the formation of Birbeck granules and is constitutively associated with them. Although the expression of CD does not yet appear in the diagnostic criteria of the Histiocyte Society.

Identification of CD via immunohistochemistry may be formally used in the future to diagnose the disease. There is no specific serologic test. No genetic test is required. Imaging studies should comprise complete skeletal radiograph survey and chest radiography, which are mandatory. Other imaging studies will depend on the clinical and biologic findings. Chest computed tomography CT will be performed in case of suspected lung involvement; brain and pituitary magnetic resonance imaging MRI in case of neurologic signs or signs of diabetes insipidus; ear CT scan in case of suspected ENT involvement; cholangio-MRI in case of suspected liver involvement.

However, these techniques seem promising, as they can detect involvement of many organs by the disease with a good sensitivity. Their use in the initial evaluation and in the follow-up of LCH patients will surely be further precised in the next few years. Diagnosis confirmation To make a precise diagnosis, correlation of clinical features, histopathology and immunohistochemichal studies is essential.

Most of all, children must not be treated with chemotherapy without histopathologic confirmation of the diagnosis. The clinical differential diagnosis of cutaneous LCH includes the following entities: -Localized or diffuse seborrheic dermatitis Leiner-Moussous disease : scaly erythematous rash on the seborrheic regions of the face and on the scalp -Diaper dermatitis: erythematous scaly diaper area often with papulovesicular or bullous lesions, fissures, and erosions -Atopic dermatitis: Lesions affect the creases, with erythema and exudation.

They localize to the cheeks, the forehead and scalp, and the extensors of the lower legs, sparing the diaper area. Who is at Risk for Developing this Disease? Langerhans cell histiocytosis is a rare disease. The estimated annual incidence ranges from 0. Approximately new cases per year are reported in the United States. In France, estimated annual incidence is 4.

LCH can be found in any race. The prevalence of LCH seems to be higher among whites than in persons of other races, but no definitive comparative epidemiologic data are available. LCH affects patients from the neonatal period to adulthood. It appears far more common in children younger than 15 years than in adults. Median age at diagnosis in children is 3. Incidence in infants reaches The frequency of LCH is greater in males than in females, with a male-to-female ratio varying between 1.

No LCH risk factor is known for children. However, no clear explanation has been provided regarding these cases although it raises the question of possible genetic factors or infectious triggers. Pulmonary LCH is more common during the third and fourth decades of life. Smoking is a risk factor in these forms. What is the Cause of the Disease? The epidermal Langerhans cell has been presumed to be the cell of origin of the disease. However, other cellular populations have been identified that possess phenotypic characteristics similar to intraepidermal Langerhans cells ie, Langerin and Birbeck granules.

Other potential cellular origins for LCH now include dermal Langerin plus dendritic cells, lymphoid-tissue resident Langerin plus dendritic cells.

A debate still exists regarding the neoplastic or reactive nature of the disease. Arguments supporting the reactive process are the occurrence of spontaneous remissions, the extensive elaboration of multiple cytokines by the LCH cells and by the T cells in the LCH lesions, and the good survival rate in the patients without organ dysfunction. Furthermore, no genetic abnormalities have been found in LCH via analysis of ploidy, karyotype, single-nucleotide polymorphism arrays, and array-based comparative genomic hybridization.

However, studies on multifocal diseases did not confirm this finding. Clonality is not sufficient to prove the neoplastic nature of the disease. The disease seems to be due to accumulation rather than proliferation of the LCH cells. Local immunomodulation and creation of a permissive immunosurveillance system should be responsible for the local accumulation of LCH cells semimature Langerhans cells. It has been shown that there is a local expansion of polyclonal regulatory T-cells in the lesions, which may in turn inhibit the immune system in part via the elaboration of Interleukin and prevent it from effectively clearing the LCH cells and from resolving the lesion.

E-cadherin expression by LCH cells in the skin may be associated with single-system cutaneous disease. Down-regulation of E-cadherin in LCH cells may be associated with dissemination. To date, no molecular or immunohistochemical criteria is able to predict self-regression of the lesions in infants with cutaneous LCH.

Systemic Implications and Complications Many organ systems may be involved by LCH cell infiltration, leading to various organ dysfunction. Baseline clinical and biological evaluations should orientate the specific imaging studies and other tests to consider, according to suspected organ involvement.

The most common are orthopedic disabilities, hearing impairment, diabetes insipidus, skin scarring, and neuropsychological defects. Less common sequelae include chronic growth retardation, pulmonary dysfunction, liver cirrhosis, loose teeth, proptosis, and secondary malignancies due to chemotherapeutic treatments. Pituitary gland: Sella turcica infiltration and pituitary involvement are frequent.

They may lead to diabetes insipidus through ADH deficiency. Other hormonal deficiencies may be found, especially growth hormone deficiency. Work-up for diabetes insipidus with urine gravity and osmolality after overnight water deprivation is mandatory.

Additional hormonal studies may be done in case of specific signs or presence of diabetes insipidus. Hormone deficiencies represent definitive sequelae and require substitutive treatment.

Patients with multisystem disease, craniofacial involvement, long-standing disease, or reactivation may be at increased risk of developing diabetes insipidus. Central nervous system CNS : Neurologic involvement may consist in tumoral infiltration or in a neurodegenerative component.

Neurologic involvement may produce seizures, vertigo, headache, ataxia, and cognitive defects. Magnetic resonance spectroscopy may be valuable in the early detection of the neurodegenerative component. Middle ear involvement leads to recurring otitis media and to secondary hearing loss. It should be managed by an otolaryngologist for auditory testing and a middle ear CT scan.

Lungs: Chest radiography is mandatory.


Hashimoto-Pritzker syndrome

Langerhans Cell Histiocytosis, Hashimoto-Pritzker Type Langerhans Cell Histiocytosis of lung Langerhans Cell Histiocytosis, disseminated clinical Langerhans Cell Histiocytosis, unifocal clinical 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. LCH is clinically divided into three groups: unifocal, multifocal unisystem, and multifocal multisystem. 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.


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