A. Classification

1. Childhood Histiocytosis Syndromes [1]
   1. Class I: Langerhan's Cell Histiocytosis
   2. Class II: Benign disorders not fitting Classes I or III
   3. Class III: Maligannt Histiocytic Diseases
2. Langerhan's Cell Histiocytosis
   1. Premaligmant disorder of dendritic Langerhans' Cells
   2. Incidence is 2-5 cases per million persons annually
   3. Formerly called Histiocytosis X or other syndromic names:
   4. Eosinophilic granuloma - confined to bone, usually in children; or to lung (usually adult)
   5. Hand-Schuller-Christian Syndrome - more systemic form, usually in children
   6. Letterer-Siwe Disease - multiple bone lesions, fulminant reticuloendothelial invovlement [2]
3. Class II Histiocytic Diseases
   1. Familial (congenital [5]) and virus-associated hemophagocytic syndromes (see below)
   2. Rosai-Dorfman Disease - sinus histiocytosis, pancarditis, uveitis, masive lymphadenopathy [9]
   3. Juvenile xanthogranuloma
   4. Reticulohistiocytoma
4. Simplified Classification of Histiocytosis [3]
   1. Single Organ versus Multisystem Involvement
   2. Single Organ: Lung, Bone, Skin, Pituitary, Lymph nodes
   3. Single Organ, uncommon: thyroid, liver, spleen, brain (including retro-orbital [4])
   4. Multisystem: multiorgan disease with or without lung involvement
   5. Other Multisystem: multiorgan histiocytic disorder
5. Traditional Classification of Histiocytosis

B. Pathogenesis

1. Langerhans cells are clonal and are derived from bone marrow [10]
   1. Usually found near B cells in lymph nodes and in skin
   2. Surface markers include Class II MHC, T6 antigen, and CD1a antigen
   3. May also have role in antigen presentation to T cells
   4. Express S100 protein and contain Birbeck granules
   5. Birbeck granules are five-layered, rod-shaped intracellular structures
   6. Birbeck granules and CD1a antigen expression is unique to histiocytosis
2. Cytokines
   1. Langerhans' cells produce TNFa, GM-CSF, IL-1, IL-6, IFNg
   2. Pulmonary Langerhans' cells also produce transforming growth factor ß (TGFß)
   3. TNFa and GM-CSF are trophic for Langerhans' cells
3. Vasculitis usually found along with granulomas
4. Clonal Proliferative Disorder
   1. Likely arises from immune dysregulation
   2. Clonal proliferative disorder derived from CD34+ hematopoietic stem cells
   3. Proved by PCR on female patients (using allelic X chromosome markers) [2]

C. Pulmonary Histiocytosis [3,6,8]

1. Usually age 20-40 years in smokers; male ~ female prevalence
2. Histiocytosis comprises ~5% of interstitial lung disease
   1. Lung may be involved in isolation (85%), or as part of systemic disease (15%)
   2. Diffuse, interstitial form usually seen with histiocytosis
   3. Upper lobes are usually involved (contrast with heart failure)
3. Risk Factors
   1. Strongly associated with smoking
   2. 80% of patients are current smokers, ~97% had history of smoking
   3. Cigarette smoke causes increases in numbers of Langerhans' cells in the lungs
   4. No known genetic risk factors
   5. Disease is most common in Caucasians
4. Symptoms at Presentation
   1. Cough (nonproductive) ~50%
   2. Dyspnea on Exertion ~35%
   3. Chest pain (usually pleuritic) ~20%
   4. Fever ~15%
   5. Weight loss ~10%
   6. Hemoptysis ~5%
5. Other Anomalies
   1. Abnormal A-a gradient >80%
   2. Airway obstruction (~60%) or restriction (~30%) on pulmonary function tests
   3. Lytic bone lesions ~4%
   4. Sclerotic bone lesions may also occur
6. Diagnosis
   1. Confirmed by presence of atypical histiocytes (actually Langerhans' cells) on tissue
   2. Usually associated with small airways
   3. Bronchoalveolar lavage, transbronchoscopic lung biopsy, or open lung biopsy required
   4. Reduction in carbon monoxide difusing capacity (DLCO) in >60% of patients
   5. Restrictive lung disease may occur in late stages of disease
   6. Diagnosis should be suspected in any patient with upper load disease, especially smokers
7. Chest Radiograph (CXR)
   1. Abnormal CXR is first indication in ~25% of presentations (asymptomatic)
   2. ~60% normal lung volumes, ~40% have increased volumes (probably due to smoking)
   3. Usually upper lobe disease, sparing of costophrenic angles
   4. Stellate nodules or irregular nodules with shaggy margins
   5. High resolution Computed Tomography (CT) scanning show nodular and cystic pattern
   6. Honeycombing common (more easily seen on CT)
   7. Hilar abnormalities ~25%
8. Diabetes Insipidus may occur due to granulomas of hypothalamus (or pituitary lesions)
9. Treatment requires smoking cessation, which leads to stabilization of disease
10. Survival in adults is less than general population
11. Reduction in lung function parameters is poorest prognostic indicator, particularly DLCO

D. Treatment [3]

1. Smoking cessation is required in all patients, particularly with lung disease
2. Glucocorticoids
   1. Clear benefit for pneumonitis, particularly with progressive disease
   2. Eosinophilic pneumonia typically is exquisitely sensitive to glucocorticoids
   3. Disseminated histiocytosis requires chemotherapeutic agents
   4. Pulse methylprednisolone 1gm IV qd x 3 followed by oral prednisone
3. Chemotherapeutic Agents
   1. Used for disease which progresses on glucocorticoids and smoking cessation
   2. Alkylating agents such as cyclophosphamide are commonly used
   3. Methotrexate, etoposide (VP-16), cladribine (CDA) are also active
4. Radiation very effective for isolated bone histiocytomas
5. Lung transplantation for progressive disease

E. Hemophagocytic Lymphohistiocytosis [11]

1. Three Types
   1. Infection - viral (EBV, CMV, parvovirus, others), fungal, parasitic, ? septic
   2. Familial (hereditary)
   3. Associated with rheumatoid arthritis
2. Symptoms
   1. Thrombocytopenia
   2. Splenomegaly or Hepatosplenomegaly
   3. Pancytopenia
   4. Infiltration of histiocytes beyond bone marrow including CNS
3. Familial Hemophagocytic Lymphohistiocytosis
   1. Inherited autosomal recessive disorder
   2. Impaired natural killer and cytotoxic T cell activities
   3. Type 1 due to mutations at chromosome 9q21.3-22 (~10% of cases)
   4. Type 2 due to mutations in perforin gene at chromosome 10q21-22 (~30% of cases)
   5. Unclear genetic causes in remaining cases
   6. Demonstration of impaired perforin mediated natural killer cell activity for diagnosis
   7. Most infants present at age 2-6 months
   8. Allogeneic bone marrow transplantation is only currently effective treatment

F. Lipogranulomatosis [7]

1. Non-Langerhans' Cell Histiocytosis
2. Usually occurs in adults >40 years of age
3. Erdheim-Chester Disease is most common form (lipoid granulomatosis)
   1. Develops in middle aged adults
   2. Both sclerotic and lytic lesions of bone
   3. Diaphyseal sclerosis
   4. Symmetric appendiculal without axial skeletal involvement
   5. Mandible may be involved, however (skull rarely)
   6. Pathologic fractures ucnommon
4. Laboratory
   1. Elevated erythrocyte sedimentation rate (ESR)
   2. Thrombocytosis (may be acute reactant)
   3. Anemia
   4. Diagnosis by needle biopsy of lesions showing
5. Prognosis is poor with >50% mortality within 3 years

G. Hand-Schuller-Christian Syndrome

1. Multifocal eosinophilic granuloma
2. Mainly in male children, young adults
3. Granulomas involving posterior pituitary lead to diabetes insipidus
4. Lesions in orbit can lead to exophthalmos

References

1. Leonidas JC, Guelfguat M, Valderrama E. 2003. Lancet. 361(9365):1293
2. Usmani GN, Westra SJ, Younes S. 2003. NEJM. 348(17):1692
3. Vassallo R, Ryu JH, Colby TV, et al. 2000. NEJM. 342(26):1969
4. Hurwitz CA and Faquin WC. 2002. NEJM. 346(7):513 (Case Record)
5. Lerner LH and Bailey EM. 1996. NEJM. 334(23):1591
6. Vassallo R, Ryu JH, Schroeder DR, et al. 2002. NEJM. 346(7):484
7. Rosier RN and Rosenberg AE. 2000. NEJM. 342(12):875 (Case Record)
8. Rajagopal J and Mark EJ. 2002. NEJM. 347(16):1262 (Case Record)
9. Sakai Y, Atsumi T, Itoh T, Koike T. 2003. Lancet. 361(9360):834 (Case Report)
10. Willman CL, Busque L, Griffith BB, et al. 1994. NEJM. 331(3):154
11. Lipton JM, Westra S, Haverty CE, et al. 2004. NEJM. 351(11):1120 (Case Record)