Langerhans Cell Histiocytosis

Langerhans cell histiocytosis

Langerhans Cell Histiocytosis (LCH) is a rare disease involving clonal proliferation of langerhans cells, abnormal cells deriving from bone marrow and capable of migrating from skin to lymph nodes. Clinically, its manifestations range from isolated bone lesions to multisystemic disease.

The disease is part of a group of clinical syndromes called histiocytoses, which are characterized by an abnormal proliferation of histiocytes (an archaic term for dendritic cells and macrophages). These diseases are related to other forms of abnormal proliferation of white blood cells, such as leukemias and lymphomas.

Langerhans Cell Histiocytosis used to be called histiocytosis X, until it was renamed in 1985 by the Histiocyte society.^[1]

Pathophysiology

The disease spectrum results from clonal accumulation and proliferation of cells resembling the epidermal dendritic cells called Langerhans' cells, hence sometimes called dendritic cell histiocytosis. These cells in combination with lymphocytes, eosinophils and normal histiocytes form typical LCH lesion that can be found in almost any organ^[2].

There are three types of histiocytoses^[3]: malignant (true histiocytic lymphomas), "reactive" (benign histiocytoses), Langerhans Cell Histiocytosis.

"Reactive" in this context indicates that the abnormality may be due to a physiological reaction to infection. For example leukocytosis (proliferation of white blood cells) is a normal reaction to infection, and "histiocytes" are developmentally related to white blood cells (see article hematopoiesis).

Langerhans Cell Histiocytoses are traditionally divided into three groups:^[3]

• Unifocal (aka "Eosinophilic granuloma"): a slowly progressing disease, characterized by an expanding proliferation of Langerhans cells in various bones, skin, lungs or stomach.
• Multifocal unisystem: characterized by fever and diffuse eruptions, usually on the scalp and in the ear canals, as well as bone lesions. Mostly seen in children. In 50% of cases the stalk of the pituitary gland is involved, leading to diabetes insipidus. The triad of diabetes insipidus, proptosis, and lytic bone lesions is known as Hand-Schuller-Christian triad.
• Multifocal multisystem (Letterer-Siwe disease): a rapidly progressing disease where 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 5-year survival is only 50%.

Pulmonary Langerhans cell histiocytosis (PLCH) is a smoking-related interstitial lung disease. It was once considered a benign condition in adults, but long term complications like pulmonary hypertension are becoming increasingly recognized.

 Prevalence

LCH usually affects children of between 1 and 15 years old and peak incidence is between age 5 and 10. Among children under the age of 10, yearly incidence is thought to be 1 in 200,000^[4]; and in adults even more rare, in about 1 in 560,000.^[5] It has been reported in elderly but is vanishingly rare^[6]. It is most prevalent in Caucasians, and affects males twice as often as females.

LCH is usually sporadic and non-hereditary condition but familial clustering has been noted in limited number of cases. Hashimoto-Pritzker disease, a variant of Hand-Schüller-Christian disease, is a congenital self-healing form^[7].

Clinical Features

Features can be non-specific from generalized inflammatory response e.g. fever, lethargy, weight loss or can be due to specific organ involvement.

Organs involved:

• Bone: Most frequent in both unifocal and disseminated disease presenting as painful swelling. Skull, long bone of upper extremity, flat bones are affected in descending order. Infiltration in hands and feet is unusual. Osteolytic lesions can lead to pathological fractures.
• Skin: Commonly present as rash which varies between scaly erythematous lesions to red papules pronounced in intertriginous areas. Up to 80% of LS would have extensive eruptions on the scalp.
• Bone marrow : Pancytopenia with super added infection usually implies poor prognosis. Anemia can be due to number of factors and not necessarily implies bone marrow infiltration.
• Lymph node: Enlargement of the liver in 20%, spleen in 30% and lymph nodes in 50% of HSC.^[8]
• Endocrine glands: Hypothalamic pituitary axis commonly involved. Diabetes insipidus most common. Anterior pituitary hormone deficiency is usually permanent.
• Lungs: Less frequently GIT, CNS.

 Diagnosis

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. Radiology will show osteolytic bone lesions and damage to the lung. Latter may be evident in CXR with micronodular and interstitial infiltrate in the mid and lower zone of lung, with sparing of the Costophrenic angle or honeycomb appearance in older lesions. MRI and CT may show infiltration in sella turcica. Assessment of endocrine function and bonemarrow biopsy are also performed when indicated.

 Treatment

Treatment is guided by extent of disease. Solitary bone lesion may be amenable through excision or limited radiation. However systemic disease 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 diabates 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.

 Prognosis

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

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