Langerhans Cell Histiocytosis

Also known as Histiocytosis X, LCH

The name Langerhans cell histiocytosis has superseded Histiocytosis X as it indicates the origin of the cells rather than suggesting an unknown quantity. It is a group of idiopathic diseases involving proliferation of Langerhans cells from bone marrow and mature eosinophils. There is some debate as to whether it is truly a malignant or a reactive disorder. The disease has been reclassified in recent years.¹

Histiocytosis is divided into 3 different groups:

• Dendritic cell histiocytosis
• Erythrophagocytic macrophage disorders
• Malignant histiocytosis

Langerhans cell histiocytosis is part of the group of dendritic cell histiocytosis and is further divided into 3 different groups:

• Eosinophilic granuloma is an indolent variety. Lesions of bones and other organs are few and chronic.
• Hand-Schuller-Christian disease is multifocal and chronic. The classical presentation is as the triad of diabetes insipidus, proptosis, and lytic bone lesions.
  • There is also a congenital, self-healing form called Hashimoto-Pritzker disease that presents soon after birth.²
• Letterer-Siwe disease is an acute and fulminant disease of great malignancy with very poor prognosis.

It is a rare condition affecting between about 0.5 and 5 people per million per year. It tends to affect white races more often. Boys are affected about twice as often as girls.

• Letterer-Siwe disease occurs mostly in children under 2.
• The chronic multifocal form, including Hand-Schuller-Christian syndrome, occurs most often between 2 and 10 years.
• Localized eosinophilic granuloma tends to affect those between 5 and 15 years.
• LCH is uncommon in adults and rare in the elderly but has been reported.³

Presentation depends upon the extent of the disease. In multifocal disease presentation will depend upon the site and organ affected.

• Unifocal disease usually presents as a lytic lesion of bone that is found incidentally. It can affect any bone but the hands and feet are less commonly involved.
• Hand-Schuller-Christian syndrome occurs in 25% of patients with multifocal disease. It often presents with recurrent episodes of otitis media and mastoiditis due to erosion of the temporal and mastoid bones or with polyuria and polydypsia from diabetes insipidus.
• Letterer-Siwe disease presents with symptoms suggestive of a systemic infection or malignancy with widespread skin eruption, anaemia, hepatomegaly and splenomegaly. Patients with pulmonary involvement present with chest pain, haemoptysis, dyspnoea, failure to thrive, cystic changes, and pneumothorax. Neurological features include seizures, vertigo, headache, ataxia, and cognitive defects.
• The congenital form of LCH presents as skin lesions at birth or in the early postnatal period. There are cutaneous nodules and ulceration or possibly symptoms of organ involvement.
• In a study from America, 63% of children presented with problems of the head and neck and over 80% developed problems of the head and neck at some time.⁴

Physical findings are also variable and will depend upon the site and degree of involvement. Lesions may affect the liver (20%), the spleen (30%), and the lymph nodes (50%). Lungs and bones may be affected and there may be mucocutaneous lesions. Skin lesions are often the first sign.

Eosinophilic Granuloma

• It may present as a solitary lesion on the crown of the head. Other common sites include vertebrae, ribs, mandible, femur, ilium, and scapula. They are usually asymptomatic, but bone pain and a soft tissue mass may occur.
• If a lesion of the skull extends into the brain it can produce neurological signs.
• Proptosis can result from orbital masses, loose teeth from infiltration of the mandible and pituitary inadequacy from involvement of the sella turcica.
• Osteolytic lesions can cause fracture of long bones or vertebral collapse
• Skin disease presents with nodular or ulcerative lesions of the mouth, perineal, perivulvar or retroauricular regions.
• When adults are affected, pulmonary lesions may be the only feature.

Hand-Schuller-Christian Syndrome

See separate article Hand-Schuller-Christian Syndrome.

• Lesions will cause enlargement of the liver in 20%, spleen in 30% and lymph nodes in 50%.
• Osteolytic lesions of long bones cause pathological fractures.
• There may be signs in the chest.
• Around 30% have lesions of skin and mucous membranes. They are infiltrated nodules and ulcerated plaques, usually in the mouth, the axillae, and the anogenital region.

Letterer-Siwe Disease

• Skin lesions are often the presenting feature. 80% have extensive eruptions on the scalp, face, trunk, buttocks and groin with possibly secondary infection.
• Fever, anaemia and thrombocytopenia are common.
• Pulmonary infiltration may occur.
• Hepatosplenomegaly is typical.

Congenital Self Healing

• Congenital self-healing histiocytosis presents at birth or soon after with firm, red-brown, painless, papules about 1 to 10 mm in diameter or vesicles and crusts.
• They involve the scalp, face, and to a lesser extent, the trunk and the extremities.
• Ulceration may occur.

• FBC with differential white count, reticulocyte count, ESR, direct and indirect Coombs test and immunoglobulin levels. Coagulation studies.
• If there is anaemia, leukopenia, or thrombocytopenia, bone marrow aspiration is required.
• Thrombocytopenia and raised ESR are good indicators of disease activity.⁵
• If there are abnormal LFTs, liver biopsy may be required to differentiate from causes of cirrhosis.
• If diabetes insipidus is suspected, urine osmolarity is required after overnight depletion. It may not be present at presentation but develop over the years to affect up to a quarter.⁶
• CXR may show micronodular and interstitial infiltrate in the mid zone and base of the lung, with sparing of the costophrenic angles. Older lesions show a honeycomb appearance.
• Skeletal survey may show isolated or multiple lytic lesions.
• MRI scan or CT scan of the hypothalamic-pituitary region.
• Hormonal studies of the hypothalamic-pituitary axis. There may well be partial or complete hypopituitarism, especially growth hormone.⁷
• Biopsy of skin lesions

Management and also prognosis will depend upon the extent of the disease. There may be a single bone involved or several. There may be single or multiple lymph node involvement.

Single System Disease

• Single bone lesions need curettage or excision. Painful sites may require intralesional injection of steroid. Large lesions may merit radiotherapy.
• Multiple bone lesions are best treated with indomethacin or a short course of systemic steroids. It is uncertain if indomethacin has a specific action on the disease or simply acts as an analgesic.⁸
• Skin lesions are usually treated with moderate to potent steroid creams but severe cases may need topical nitrogen mustard (20% solution). Psoralen plus ultraviolet A (PUVA) is sometimes used.⁹
• Single lymph nodes can be excised but multiple nodes require a course of steroids.

Multi-system Disease

• Chemotherapy is required for multisystem disease or single system disease that does not respond to the above treatment. Methotrexate, prednisolone, and vinblastine are used, usually in quite moderate doses.
• In difficult cases a combination of cyclosporin A, antithymocyte globulin and prednisolone may be used.
• Bone marrow transplantation represents the ultimate step if a suitable donor can be found.
• A specific problem such as diabetes insipidus requires desmopressin.

• Between 30 and 50% of patients with LCD suffer complications.
• The commonest are orthopaedic disabilities, hearing impairment, diabetes insipidus, and neuropsychological defects.
• Less common are chronic pulmonary dysfunction, liver cirrhosis, and growth retardation.

This depends upon the type and extent of disease as well as response to treatment. Dysfunction of organs has a poor prognosis.

• For a single focus of disease prognosis is excellent. If no additional lesions present after a year it is unlikely that more will arise. There is usually full recovery from solitary lymph node involvement or isolated skin disease.
• With multi-focal disease 60% have a chronic course, 30% achieve remission and 10% die.
• Letterer-Siwe disease has a mortality of 50% and this is worse in the very young.
• The congenital form of histiocytosis tends to resolve spontaneously within weeks to months.
• A study of 60 children who had survived LCH was reported in 1980. In those whose disease involved soft tissue and bone 50% had severe disabilities. Treatment may have improved since then but such figures are cause for concern.¹⁰
• A review from 1999 concluded that patients with isolated bone lesions have the best prognosis compared with involvement of other systems. 20% of patients with multisystem involvement have a progressive disease course despite treatment. The identification of prognostic indicators to facilitate appropriate treatment and long term follow-up surveillance is recommended.¹¹

Paul Langerhans was born in Berlin in 1847. He graduated MD in 1869 and worked as a pathological anatomist. He also described the Islets of Langerhans that produce insulin. In 1874 pulmonary tuberculosis interrupted his career and the next year he moved to Madeira for a milder climate to ease his disease. He died there in 1888.¹²