Histiocytosis X

ALSO KNOWN AS: Langerhans cell histiocytosis, eosinophilic granuloma, pulmonary histiocytosis X (PHX), eosinophilic granulomatosis, pulmonary Langerhans cell histiocytosis X (PLCH), Langerhans cell granulomatosis

RELATED CONDITIONS: Non-Langerhans cell histiocytosis, T-cell lymphoma (malignant histiocytosis syndrome)

DEFINITION: Histiocytosis X, usually called Langerhans cell granulomatosis (LCG) or Langerhans cell histiocytosis (LCH), is characterized by granulomatous lesions containing Langerhans cells. Histiocytosis X is a group of diseases that exhibit an increase in histiocytes. Variants of the condition may be localized or systemic. Once considered cancerous, these diseases are now classified as autoimmune diseases.

Histiocytes are cells critical to the immune response and arise from the mononuclear phagocytic system in the bone marrow. These precursor cells can potentially transform into macrophages or Langerhans cell lineages. Langerhans cells engulf antigens such as foreign microbes and alert the immune system to their presence.

Histiocytosis X now includes Letterer-Siwe disease and Hand-Schüller-Christian disease. These conditions, seen in children, were once considered separate diseases. When children are afflicted, the disease erupts in many organs. In adults, the condition affects primarily the lung and, more rarely, the bones (about 4 to 20 percent of cases) and, even less likely, the skin.

Risk factors: Risk factors include smoking and possibly genetic factors, but the exact etiology is unknown.

Etiology and the disease process: The defining pathology is an accumulation of Langerhans cells in epithelial cells lining the lung tissue. These lung-tissue cells first undergo an increase in their numbers (hyperplasia) following some chronic insult, such as persistent smoking, and then begin an uncontrolled immune response. The result and hallmark of this disease are discrete granulomatous lesions scattered through the upper and middle portions of the lung. In the early stages, these lesions comprise Langerhans cells surrounded by eosinophils, lymphocytes, macrophages, and plasma cells.

Granulomatous lesions are similar in the pediatric version of the disease but scattered throughout the viscera, skin, and bones. Although the disease process in children includes the classic lung pathology, it also results in skin and bone lesions and, typically, an enlarged liver and spleen. There are also severe dental consequences, such as inflamed gums, tooth loss, and mandibular hyperplasia.

Incidence: The condition afflicts 1 to 2 individuals out of every 100,000, and more than 60 percent of cases are diagnosed by age two. Langerhans cell granulomatosis represents approximately 1 percent of all interstitial lung disease. Most adult patients are between twenty and forty years old and have a history of smoking, while the childhood disease is most prevalent between ages one and three. Most cases of the disease occur before age seventeen.

Symptoms: Adults may first complain of a persistent cough, lethargy, and labored breathing. Less frequently, there is an associated weight loss, fever, and a vague feeling of illness, but surprisingly, about 25 percent of cases are symptom-free. The classic finding is pneumothorax, a collection of air in the pleural cavity, which may eventually cause the lung to collapse. This occurs in as many as 10 to 20 percent of cases. Typical symptoms may include cough, chest pain, fever, weight loss, bone pain, and skin rash.

In young children, symptoms may vary with the severity of organ compromise. In the form called Letterer-Siwe disease, there is a generalized involvement of the viscera with potentially fatal consequences. Skin lesions range from small papules to hemorrhagic nodules. Oral symptoms include ulcerations, bruising, gum inflammation, and tooth loss. Fetid breath odor is a conspicuous result. Other symptoms reflect organ and tissue damage in the liver, spleen, and bones. Typical symptoms may include weight loss, fever, abdominal pain, jaundice, dermatitis, mental deficits, short stature, abdominal pain, ear drainage, and enlarged lymph nodes.

Another childhood variation, Hand-Schüller-Christian disease, manifests itself in three waysdiabetes insipidus, lytic bone lesions, and a bulging of the eyes called proptosis. This condition also results in a dental pathology similar to Letterer-Siwe disease.

Screening and diagnosis: In the adult form of the disease, the symptoms are nonspecific and reflect interstitial lung disease, which may be common to other conditions. Chest imaging, including high-resolution computed tomography (CT) scans, is useful in revealing nodules, and pulmonary function tests may uncover obstructive irregularities. The results of bronchoalveolar lavage and smoking history are useful indicators, but they are not definitive. Only a lung tissue biopsy will confirm the diagnosis.

In children, bone radiographs, tissue and bone marrow biopsy, and general laboratory work are instructive, but biopsies containing clusters of Langerhans cells are required for a diagnosis.

Treatment and therapy: The cardinal treatment is smoking cessation in adults. Corticosteroid therapy is case-dependent and is used only in patients with notable lung function deficits. In the childhood form of the disease, there has been notable success using immune-signaling molecules such as interleukins, and research is investigating their potential in the adult form of the disease. Other treatment options are palliative, such as infection control, supplemental oxygen, and bronchodilator therapy. Asymptomatic patients having only mild impairment are treated conservatively.

Prognosis, prevention, and outcomes: With treatment, the prognosis is excellent, and without treatment, the five-year survival rate is 70 percent. Smoking cessation may halt the progression of the disease and initiate its reversal. For the very young and older adults, the prognosis is poor. This is also the case for those who have been treated with corticosteroids over an extended period, in patients suffering from multiorgan involvement, and when there are many cysts revealed radiographically. When the disease involves only the lungs and smoking is stopped, 50 percent of patients will improve, while 50 percent will suffer permanent pulmonary function loss. The outcome in children ranges from poor to excellent, depending on the extent of the disease.

Bibliography

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