Langerhans' Cell Histiocytosis

Synonyms: histiocytosis X, eosinophilic granuloma, Hand-Schüller-Christian disease, Letterer-Siwe disease

Langerhans' cell histiocytosis (LCH) is one of the 'histiocytosis syndromes', as defined by the Histiocyte Society. LCH is an abnormal proliferation and dissemination of histiocytes. It is named after the appearance of the cells, which resemble the normal dentritic cells first noted by Langerhans.

LCH may affect one or many organs. The clinical presentation and severity are varied. It was formerly considered as a disease of childhood, but is now recognised as often presenting in adulthood.

Previous classifications of LCH include the following diseases and terms, which are now included under the 'umbrella' of LCH:

• Histiocytosis X
• Eosinophilic granuloma
• Letterer-Siwe disease
• Hand-Schüller-Christian disease
• Hashimoto-Pritzker syndrome
• Other terms including self-healing histiocytosis, pure cutaneous histiocytosis, Langerhans' cell granulomatosis, Type II histiocytosis, and the generic term 'nonlipid reticuloendotheliosis'.

Present classification of LCH focuses on the number of lesions and the systems involved; for example, dividing LCH into:¹

• Osseous LCH
• Single-system non-osseous LCH - further classified according to organ system, e.g. mucocutaneous, pulmonary, lymphatic, etc.
• Multisystem LCH

There is also a risk-stratification system based on degree of organ involvement and number of organs involved.³

LCH is rare, with an estimated incidence is 4-5.4 per million population.⁴

• This is largely unknown. It may be disorder of immune regulation.²
• Cigarette smoking appears to have a role in causing or potentiating the pulmonary form of LCH.⁵

Overview

• There is a wide spectrum of clinical presentation, from a single bony lesion, to multiple bony, skin and visceral lesions.
• Common presentations in one study were bony lesions, respiratory symptoms, malaise, abnormal chest X-ray or diabetes insipidus (DI).¹
• Average age at presentation (in one study) was 24 years.¹

Clinical features of LCH (listed by organ system)

Bony lesions - osseous LCH:¹

• Well-localised bone pain is a common presenting symptom, with pain during both activity and rest.
  • Bone pain usually correlates with a radiologically evident lesion.
• There may be tender swelling of the soft tissue overlying the bone.
• Common sites for bone LCH are skull, proximal femur and ribs.
• Involvement of other organs is common (40% in one study).¹
• Rarely, bone lesions may cause pathological fractures.

Skull and brain involvement may cause:⁴

• Endocrine disorders involving the hypothalamic-pituitary axis (see below).
• Neurological features, including cerebellar disorders and raised intracranial pressure.
• Ocular and periorbital disease, including proptosis and uveitis.
• Gum and dental disease.
• ENT disease, e.g. otitis media, sinusitis.
• Skull lesions, which may be visible/palpable.

Lungs - pulmonary LCH:⁵

• Non-productive cough and dyspnoea.
• Abnormal chest X-ray.¹
• Spontaneous pneumothorax.¹
• Haemoptysis (rarely).
• Chest pain (rarely).

Endocrine - thalamic axis LCH:

• DI is relatively common - presenting with polyuria and polydipsia.^1,4
• Other types of hypopituitarism can also occur, e.g. growth hormone deficiency.⁴

Skin and mucous membranes - mucocutaneous LCH:⁴

• Skin rashes- may be macular, papular, nodular or petechial.
  • Skin rashes in neonates may regress spontaneously.⁶
• Scalp lesions may be scaly.
• Mucosal ulceration and bleeding can occur.
• Vesiculopustular lesions are common in congenital LCH.⁶

Lymphadenopathy:

• This is fairly common.
• There are usually no symptoms unless the enlarged nodes damage or obstruct nearby organs

Systemic symptoms:¹

• Weight loss, fever, night sweats and anorexia

Hepatosplenomegaly and gastrointestinal (GI):

• Hepatosplenomegaly is uncommon; it may reflect a later stage or more aggressive form of LCH.¹
• GI features are uncommon; may involve infiltration of GI tract leading to ulceration and GI bleeding.⁷

Other presentations:

• LCH can involve other organs; e.g, scrotal mass was a rare presentation in one study.¹

These will depend on the clinical presentation, but usually requires:

• Full examination, height and weight.
• Blood tests: FBC, clotting studies, U&E, LFT, urine osmolality.
• Plain X-ray - for bone pain or suspected bone lesions.
• Skeletal survey.
• CT/MRI scans.
• Endoscopy if GI involvement suspected.
• Biopsy of lesions - may show:
  • Multinucleated Langerhans' cells, histiocytes and eosinophils
  • Birbeck's granules on electron microscopy
  • Antigens for CD1a glycoprotein and S100 cytoplasmic protein (diagnostic)
• For suspected pulmonary involvement, investigations are:⁵
  • Plain chest X-ray - may show upper lobe infiltrates
  • Lung function tests - may show impaired diffusing capacity
  • CT scan - may show typical changes of pulmonary LCH
  • Bronchoscopy or surgical lung biopsy
• Bone marrow biopsy is sometimes required for staging.⁶

The definitive diagnosis is made on the biopsy features (above).

General points:

• Treatment may be local or systemic, depending on the number and location of LCH lesions.
• Because LCH is rare, there are relatively few clinical trials and less experience available to inform treatment.
• Treatment may involve surgical excision, radiotherapy, chemotherapy, or combinations of these.
• The prognosis and treatment protocol depend on the number of organs involved, which organ systems are involved and the degree of organ dysfunction.
• Recommendations and protocols are available from the Histiocyte Society.⁸

The following is an overview of current possible treatments, according to organs involved.

Limited cutaneous disease:

• No treatment (it may remit)
• Topical steroids
• Topical nitrogen mustard
• PUVA therapy

Localised bone lesions:

• Surgical curettage is the usual treatment (for accessible sites)
• Other treatments for bone lesions include:⁴
• Radiotherapy
• Intralesional steroids
• Bisphosphonates
• Early chemotherapy (vinblastine and prednisolone) for bony lesions at crucial anatomical sites

Lymphadenopathy:⁴

• Surgical excision of single nodes with LCH
• Regional node involvement may respond to a course of systemic steroids
• Chemotherapy for nodes resistant to treatment

Pulmonary LCH:⁵

• Smoking cessation - an essential part of treatment which can stabilise symptoms in most patients. This may be the only treatment required.
• Corticosteroids are the main treatment (after smoking cessation).
• Chemotherapy may be used for progressive disease not responding to steroids, but this is a last resort because its efficacy is uncertain. Drugs which have been used in this context are vinblastine, methotrexate, cyclophosphamide, etoposide and cladribine.
• Lung transplantation can be considered for advanced disease.

Multiorgan disease:

• Some experts have used a conservative approach, with no treatment or prednisolone initially.⁹
• However, other sources suggest that multi-agent chemotherapy may be more effective long-term.
• Drugs used include prednisolone, vinblastine, methotrexate and 6-mercaptopurine.⁴
• Currently trials are in progress to evaluate optimal chemotherapy regimes.⁴
• Stem cell transplantation may be used in patients with a poor prognosis whose LCH has not responded to convention treatment.⁴

Follow-up

Lifelong follow-up is required because of the possibility of late recurrence or late complications (see below).^1,6

Complications of LCH may occur at any time from presentation or many years later. Complications can arise even in patients without multi-organ involvement. It is estimated that about 50% of LCH patients have late complications of the disease or its treatment.¹⁰ Complications include:

• DI (relatively common) - treated with desmopressin
• Late relapse or progression to systemic involvement
• Hypothalamic-pituitary dysfunction
• Cognitive dysfunction
• Cerebellar involvement
• There may be an increased risk of other neoplasms⁵

• Prognosis depends on the extent and nature of of organ involvement, and is very variable.
• The majority of cases have a good prognosis. In one study, 90% of LCH patients achieved disease-free survival after treatment.¹
• Patients with single bone lesions have the best prognosis.¹
• A small minority of patients have a rapidly progressive disease course with higher mortality.¹
• For patients requiring chemotherapy, the response after six weeks' treatment is a major prognostic factor.¹⁰
• Pulmonary LCH has a variable course. Most patients have a good prognosis: symptoms may be mild, and stabilisation or spontaneous improvement is possible. Some patients have progressive pulmonary LCH leading to progressive respiratory impairment.⁵
• Neonates with LCH limited to the skin and mucous membranes seem to have a good prognosis.⁶

1. Howarth DM, Gilchrist GS, Mullan BP, et al; Langerhans cell histiocytosis: diagnosis, natural history, management, and outcome. Cancer. 1999 May 15;85(10):2278-90. [abstract]
2. Leonidas JC, Guelfguat M, Valderrama E; Langerhans' cell histiocytosis. Lancet. 2003 Apr 12;361(9365):1293-5.
3. Satter EK, High WA. Langerhans Cell Histiocytosis: A case report and summary of the current recommendations of the Histiocyte Society. Dermatol Online J. 2008 Mar 15;14(3):3
4. Tebbi CK, Arceci RJ, Loew TW. Histiocytosis. emedicine, updated July 2009.
5. Vassallo R, Ryu JH; Pulmonary Langerhans' cell histiocytosis. Clin Chest Med. 2004 Sep;25(3):561-71, vii. [abstract]
6. Stein SL, Paller AS, Haut PR, et al; Langerhans cell histiocytosis presenting in the neonatal period: a retrospective Arch Pediatr Adolesc Med. 2001 Jul;155(7):778-83. [abstract]
7. Hait E, Liang M, Degar B, et al; Gastrointestinal tract involvement in Langerhans cell histiocytosis: case report Pediatrics. 2006 Nov;118(5):e1593-9. Epub 2006 Oct 9. [abstract]
8. The Histiocyte Society. An international group of physicians and scientists researching histiocyte disorders.
9. McLelland J, Broadbent V, Yeomans E, et al; Langerhans cell histiocytosis: the case for conservative treatment. Arch Dis Child. 1990 Mar;65(3):301-3. [abstract]
10. McClain KL, Natkunam Y, Swerdlow SH; Atypical cellular disorders. Hematology Am Soc Hematol Educ Program. 2004:283-96. [abstract]

• The Histiocytosis Research Trust. A UK charity promoting information and research for histiocyte disorders.
• Histiocytosis Association of America. Information and support for those with histiocyte disorders.
• Broadbent V, Gadner H, Komp DM, et al; Histiocytosis syndromes in children: II. Approach to the clinical and laboratory Med Pediatr Oncol. 1989;17(6):492-5. [abstract]
• Satter EK, High WA; Langerhans cell histiocytosis: a review of the current recommendations of the Pediatr Dermatol. 2008 May-Jun;25(3):291-5. [abstract]
• Favara BE, Feller AC, Pauli M, et al; Contemporary classification of histiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Med Pediatr Oncol. 1997 Sep;29(3):157-66. [abstract]
• Alston RD, Tatevossian RG, McNally RJ, et al; Incidence and survival of childhood Langerhans cell histiocytosis in Northwest Pediatr Blood Cancer. 2007 May;48(5):555-60. [abstract]