Langerhans Cell Histiocytosis (LCH)

Definition of Histiocyte (see Histiocytic Disorders, [[Histiocytic Disorders]])

  • Histiocyte is an Outdated Term Used to Describe Large White Blood Cells Which are Resident in Tissues: various cells may be classified as histiocytes
    • Dermal/Interstitial Dendritic Cells
    • Langerhans Cells: specialized dendritic cells normally found in the dermis/mucosa, reticuloendothelial system, lung, and pleura
      • Langerhans cells can also be found in cigarette smoking normal patients
      • Langerhans cells can also be found in other pulmonary disorders, such as idiopathic pulmonary fibrosis (see Idiopathic Pulmonary Fibrosis, [[Idiopathic Pulmonary Fibrosis]])
    • Monocytes/Macrophages

Definitions/Terminology

  • Historical Terms Which are No Longer Used for Langerhans Cell Histiocytosis
    • Diffuse Reticuloendotheliosis
    • Hand-SchĂĽller-Christian Disease
    • Histiocytosis-X
    • Letterer-Siwe Disease
  • Eosinophilic Granuloma: term used to describe the pathology of a single lesion (especially an isolated lytic bone lesion)

Epidemiology

  • Incidence: most commonly diagnosed in children 1-3 y/o
    • Adults: 1-2 cases per million
    • Children: 3-5 cases per million
  • Sex: male predominance has been described in most case series
  • Race: incidence is higher in whites of northern European descent than in blacks
  • Familial Cases: have been reported (but genetics are poorly-defined)

Risk Factors

  • Tobacco (see Tobacco, [[Tobacco]])
    • Pulmonary Langerhans Cell Histiocytosis: almost universally associated with cigarette smoking in adults
    • Extrapulmonary Langerhans Cell Histiocytosis: not associated with cigarette smoking in adults
  • Solvent Exposure in Parents [MEDLINE]: possible risk factor in pediatric cases
  • Perinatal Infections [MEDLINE]: possible risk factor in pediatric cases
  • Family History of Thyroid Disease [MEDLINE]
  • Presence of Other Histiocytic Disorders (Erdheim-Chester Disease, Rosai Dorfman Disease)

Physiology

  • Morphology and Immunophenotype of the Abnormal Cells in Langerhans Cell Histiocytosis are Similar to that of Langerhans Cells: however, gene expression array studies demonstrate that the skin Langerhans cell is not the origin for cells in Langerhans Cell Histiocytosis
    • Langerhans Cell Histiocytosis Originates From a Myeloid Dendritic Cell Which Expresses the Same Antigens (CD1a, CD207) as the Skin Langerhans Cell
    • Non-Langerhans Histicoytoses Originate From Dendritic Cells Which Ultimately Produce the Monocyte/Macrophage Lineage

Diagnosis

Skeletal Survey

  • Required to Identify Bone Lesions

Tissue Biopsy

  • BRAF V600E Mutation: present in the pathological dendritic cell population in 65% of LCH cases

Clinical Subtypes of Langerhans Cell Histiocytosis

Single Organ System Langerhans Cell Histiocytosis

  • Age: any age
  • Clinical
    • Absence of Systemic Symptoms (Fever, Weight Loss)
    • Unifocal/Multi-Focal Involvement of Specific Organs
      • Bone
      • Central Nervous System
      • Lungs
      • Lymph Nodes (Excluding Lymph Nodes Which Drain from Another LCH Lesion)
      • Skin
      • Thymus: uncommon site of involvement
      • Thyroid: uncommon site of involvement

Multi-Organ System Langerhans Cell Histiocytosis

  • Clinical
    • Presence of Systemic Symptoms (Fever, Weight Loss)
    • Involvement of At Least Two Organ Systems
      • Central Nervous System: involvement of sphenoid/orbital/ethmoid/temporal bones carries an increased risk of central nervous system involvement
      • Hematopoeitic System: considered a “risk organ” -> involvement carries a worse prognosis
      • Liver: considered a “risk organ” -> involvement carries a worse prognosis
      • Lung: although previously considered a “risk organ”, lung involvement probably has lesser impact on prognosis than other organ systems
      • Spleen: considered a “risk organ” -> involvement carries a worse prognosis

Clinical Manifestations

General Features

  • Asymptomatic: many cases
  • Distribution of Organ Involvement: Langerhans cell histiocytosis is limited to one organ in 55% of cases (remainder have multi-system involvement)
    • Pediatric Cases: acute disseminated multisystem Langerhans cell histiocytosis is most commonly diagnosed in children <3 y/o
    • Adult Cases: more indolent single-organ Langerhans cell histiocytosis is more common in older children and adults
  • Time Course of Disease: variable (but disease may be presently for years before a diagnosis is made)

Dermatologic Manifestations

  • General Comments: dermatologic involvement occurs in 40% of cases
  • Brown-Purple Papules (Congenital Self-Healing Reticulohistiocytosis, Hashimoto-Pritzker Disease) (see Papular-Nodular Skin Lesions, [[Papular-Nodular Skin Lesions]]): most common dermatologic manifestation
    • Epidemiology: occurs in infants
    • Clinical: involves any part of body
  • Eczematous Rash
    • Epidemiology: may occur in children and adults
    • Clinical: resembles a Candidal skin infection
      • Sites of Involvement: groin, abdomen, back, chest
      • Lesion Size: pinhead to dime-size lesions
      • Ulcerative Lesions: may occur behind the ears, on the scalp, on genitalia, or in the perianal region
  • Pustular/Papular-Nodular Skin Lesions (see Papular-Nodular Skin Lesions, [[Papular-Nodular Skin Lesions]]): may occur less commonly
  • Petechiae (see Petechiae, [[Petechiae]]): may occur less commonly
  • Purpuric Skin Lesions (see Purpura, [[Purpura]]): may occur less commonly
  • Vesicular Skin Lesions (see Vesicular-Bullous Skin Lesions, [[Vesicular-Bullous Skin Lesions]]): may occur less commonly

Endocrinologic Manifestations

Diabetes Insipidus (see Diabetes Insipidus, [[Diabetes Insipidus]])

  • Epidemiology: most common endocrine abnormality in LCH
    • May occur early in the course
    • In patients with known LCH, 25% develop DI within 10 years of the diagnosis
  • Physiology: due to posterior pituitary involvement
  • Diagnosis
    • Brain MRI (see Brain Magnetic Resonance Imaging, [[Brain Magnetic Resonance Imaging]]): loss of the posterior bright spot of the pituitary gland is suggestive of pituitary involvement in LCH
  • Clinical
    • Nocturia
    • Polydipsia
    • Polyuria

Panhypopituitarism (see Panhypopituitarism, [[Panhypopituitarism]])

  • Epidemiology: may occur

Other Endocrine Abnormalities

  • Growth Failure: due to growth hormone deficiency
  • Hypogonadism (see Hypogonadism, [[Hypogonadism]])
  • Impaired Glucose Tolerance/Diabetes Mellitus (see Diabetes Mellitus, [[Diabetes Mellitus]])
  • Thyromegaly (see Thyromegaly, [[Thyromegaly]])

Gastrointestinal Manifestations

  • General Comments: hepatic involvement occurs in 16% of cases
  • Diarrhea/Malbasorption (see Diarrhea, [[Diarrhea]]): occurs in 2% of cases
    • Diagnosis: endoscopic biopsies may be necessary (although lesions may be intermittent, making the diagnosis difficult)
  • Hepatomegaly with/without Hepatic Dysfunction (see Hepatomegaly, [[Hepatomegaly]])
    • Clinical
      • Ascites
      • Coagulation Factor Deficiencies
      • Elevated Liver Function Tests (LFT’s)
  • Hepatic Mass (see Hepatic Mass, [[Hepatic Mass]])
    • Clinical: tumor-like or cystic
  • Sclerosing Cholangitis (see Sclerosing Cholangitis, [[Sclerosing Cholangitis]]): may be progressive (even when other LCH disease manifestations respond to therapy), eventually requiring liver transplant
  • Weight Loss (see Weight Loss, [[Weight Loss]])

Hematologic Manifestations

  • Bone Marrow Infiltration
    • Epidemiology: occurs in 34% of cases
      • Most cases occur in young children with diffuse liver/spleen/lymph node/skin involvement
    • Physiology: anti-CD1a Langerhans cell histiocytosis cells may be found in the bone marrow of patients with multi-focal bone disease with normal cell counts, as well as in patients with single organ disease
    • Clinical: cytopenias are variably present
  • Lymphadenopathy (see Lymphadenopathy, [[Lymphadenopathy]])
    • Epidemiology: occurs in 20% of cases
    • Clinical: cervical lymph nodes are the most commonly involved
      • Nodes are soft and matted
  • Splenomegaly (see Splenomegaly, [[Splenomegaly]]): splenic involvement occurs in 13% of cases
    • Clinical
      • Hypersplenism: may result in cytopenias
      • Massive Splenomegaly: may result in respiratory compromise
  • Thymic Enlargement (see Thymic Mass, [[Thymic Mass]])

Neurologic Manifestations

General Comments

  • Central Nervous System Involvement: occurs in 6% of cases at the time of diagnosis

Mass Lesions in Brain Parenchyma/Choroid Plexus

  • Epidemiology: occurs in 1% of cases
  • Clinical: hydrocephalus may occur (see Hydrocephalus, [[Hydrocephalus]])

Neurodegenerative Symptoms

  • Diagnosis
    • Brain MRI (see Magnetic Resonance Imaging, [[Magnetic Resonance Imaging]]): bilateral symmetric lesions in the dentate nucleus of the cerebellum or basal ganglia
  • Clinical
    • Ataxia (see Ataxia, [[Ataxia]])
    • Cognitive Dysfunction

Posterior Pituitary Involvement with Diabetes Insipidus (see Diabetes Insipidus, [[Diabetes Insipidus]])

  • Clinical: see above
    • Patients with Hypothalamic-Pituitary Involvement: these patients are at high-risk for later development of neurodegenerative/neuropsychological deficits

Orbital Lesions with Proptosis (see Proptosis, [[Proptosis]])

  • Physiology: soft-tissue mass in orbital region

Otolaryngologic Manifestations

  • General Comments: oral mucosal involvement occurs in 13% of cases
  • Gingival Hypertrophy/Gingivitis (see Gingival Hypertrophy, [[Gingival Hypertrophy]])
  • Oral Mass (see Oral Mass, [[Oral Mass]])
  • Loose Teeth
  • Mucosal Ulcers (see Mucocutaneous Ulcers, [[Mucocutaneous Ulcers]])

Pulmonary Manifestations

General Comments

  • Pulmonary Involvement: occurs in 10% of cases
  • Age: pulmonary involvement is more common in adults than children
    • Peak Age of Onset for Pulmonary Involvement: 20-40 y/o
  • Gender: M = F (although women tend to present at an older age)
  • Race: Caucasians are affected more commonly than patients of African/Asian descent
  • Relationship Between Tobacco Exposure and Pulmonary Langerhans Cell Histiocytosis (see Tobacco, [[Tobacco]]): there is a near universal association of cigarette smoking with pulmonary Langerhans cell histiocytosis, suggesting a likely causative role
    • Note: smoking is NOT associated with extrapulmonary Langerhans cell histiocytosis
  • Duration of Illness: usually <1 year prior to diagnosis
  • Asymptomatic: pulmonary involvement may be asymptomatic in 20% of cases

Chest Wall Mass

  • Clinical: mass may impinge on lung

Hilar/Mediastinal Lymphadenopathy (see Mediastinal Mass, [[Mediastinal Mass]])

  • Epidemiology: this presentation is considered rare -> if found, it should prompt consideration of malignancy as an etiology
  • Clinical: this presentation may mimic lymphoma
    • Mediastinal adenopathy may result in airway compression

Increased Risk of Specific Neoplasms

  • General Comments: tobacco exposure may additionally play a role in the development of some of these neoplasms
    • Malignancy May Precede, Follow, or Occur Concomitantly with the Diagnosis of Pulmonary Langerhans Cell Histiocytosis
  • Bronchogenic Carcinoma (see Lung Cancer, [[Lung Cancer]]): occurs in 5% of cases
  • Hodgkin’s Disease (see Hodgkin’s Disease, [[Hodgkins Disease]])
  • Non-Hodgkin’s Lymphoma (see Lymphoma, [[Lymphoma]])
  • Pulmonary Carcinoid Tumor (see Bronchial Carcinoid, [[Bronchial Carcinoid]])
  • Mediastinal Ganglioneuroma

Interstitial Lung Disease (see Interstitial Lung Disease, [[Interstitial Lung Disease]])

  • Physiology
    • Nonspecific Increase in IgG in Bronchoalveolar Lavage (BAL) Fluid
    • Immune Complexes in the Circulation and Bound to Tissue
    • Abnormalities in T-cell Function
  • Diagnostic
    • Arterial Blood Gas (ABG) (see Arterial Blood Gas, [[Arterial Blood Gas]]): hypoxemia may be present in more advanced disease
    • Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests, [[Pulmonary Function Tests]])
      • Normal: may be seen with earlier nodular disease
      • Restriction with Decreased DLCO: most common with earlier nodular disease
      • Obstruction (Which May Be Bronchodilator-Responsive) and Hyperinflation: most common in those with more advanced cystic disease
        • Increased RV/TLC ratio has been shown to correlate with cyst formation
    • Exercise Testing (see Exercise Testing, [[Exercise Testing]]): limitation in activity and exercise intolerance out of proportion to PFT abnormalities
      • Markedly Decreased Exercise Capacity: decreased work achieved or oxygen utilization (VO2) at maximal exercise
      • Decreased Oxygen Pulse at Maximal Exercise and at Anaerobic Threshold
      • Maximal Ventilatory Response is Excessive (But Not Limiting) for the Maximal Level of Work
    • High-Resolution CT (HRCT) Scan (see High-Resolution Chest Computed Tomography, [[High-Resolution Chest Computed Tomography]]): specific features may aid in the diagnosis (serial HCRT suggests the following progression: nodules -> cavitating nodules -> cystic lesions)
      • Upper Zone Cysts/Honeycombing: most cysts are <1 cm in diameter (however, large cysts may occur as disease progresses) with barely perceptible to few mm wall thickness
      • Sparing of the Costophrenic Angles
      • Mid-Upper Lung Zone-Predominant Ill-Defined/Stellate Nodules (2-10 mm)
      • Interstitial Thickening
      • Reticular/Nodular Opacities: with mid-upper zone predominance
      • Preservation of Lung Volumes: although both hyperinflation and decreased lung volumes may occur
    • Fluorodeoxyglucose-Positron Emission Tomography Scan (FDG-PET) (see Fluorodeoxyglucose-Positron Emission Tomography, [[Fluorodeoxyglucose-Positron Emission Tomography]]): may demonstrate increased uptake (especially early in the course of disease)
      • PET-Positive Scan in LCH: more likely to occur with nodular disease, suggesting earlier-stage disease
      • PET-Negative Scan in LCH: more likely to occur with cystic disease and fewer nodules, suggesting more advanced disease
    • Bronchoscopy (see Bronchoscopy, [[Bronchoscopy]])
      • Bronchoalveolar Lavage (BAL): increased (>5%) CD1a-positive cells strongly suggest the diagnosis (however, CD1a-positive cells <5% does not exclude the diagnosis)
        • Note: lower percentages of Langerhans cells can also be seen in current smokers, patients with other interstitial lung disorders, and bronchioloalveolar carcinoma
      • Transbronchial Biopsy (TBB): may be useful to demonstrate increased numbers of CD1a-positive cells -> may be diagnostic in some cases
    • Open Lung Biopsy: may be required
      • Langerhans Cell: characterized by pale staining cytoplasm, large nucleus and nucleoli, positive immunohistochemical staining for S100 protein, positive staining for CD1a (OKT-6) on the cell surface, positive staining for MT-1 (electron microscopy: classic pentalaminar cytoplasmic inclusions or Birbeck granules, aka X-bodies)
      • Langerhans cells are typically found in clusters and significantly outnumber those found in other lung diseases (however, there are no quantitative guidelines for the diagnosis of pulmonary Langerhans cell histiocytosis)
      • Mid-Upper Zone Predominance: in contrast to the typical lower lung zone predominance of idiopathic pulmonary fibrosis
      • “Stellate Lesions”: lesions frequently extend widely into the parenchyma of the lung surrounding the bronchovascular structures
      • Early Inflammatory Lesions Surround the Smaller Bronchioles (and Sometimes Pulmonary Arterioles/Venules): contain eosinophils, lymphocytes, and neutrophils (however, since eosinophils are not a prominent pathologic component and lesions are often devoid of eosinophils, the term “eosinophilic granuloma” is really a misnomer)
      • Pseudo-Desquamative Interstitial Pneumonia (May Also Be Seen): accumulation of alveolar macrophages in the pulmonary parenchyma in between the typical lesions containing Langerhans cells
      • Respiratory (“Smokers”) Bronchiolitis (May Also Be Seen): pigmented macrophages filling the lumen of bronchioles and the surrounding alveolar spaces
      • Intraluminal Fibrosis (May Also Be Seen): mural incorporation, alveolar obliteration, and intraluminal buds (this finding suggests that intraluminal fibrosis is a mechanism for alveolar collapse with progression to interstitial fibrosis and further lung remodeling)
      • Interstitial Fibrosis/Small Cyst Formation: occur in advanced disease
        • Lesser numbers of Langerhans cells may be seen in later stage cases with more advanced fibrosis
  • Clinical
    • Cough: 56-70% of cases
    • Dyspnea: 40-87% of cases
    • Fatigue: 30% of cases
    • Fever: 15% of cases
    • Hemoptysis: occurs in 13% of cases
    • Pleuritic Chest Pain: 10-21% of cases
    • Weight Loss: 20-30% of cases
    • Absence of Crackles/Digital Clubbing: usually

Pulmonary Hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]])

  • Epidemiology: severe pulmonary hypertension is a common feature in patients with end-stage pulmonary Langerhans cell histiocytosis
  • Physiology: in some patients, pulmonary hypertension is probably related to chronic hypoxemia and/or abnormal pulmonary mechanics
    • However, in others, especially those patients with more severe elevation of pulmonary artery pressures, pulmonary hypertension is unrelated to parenchyma lung disease
  • Diagnostic
    • Lung Biopsy: severe diffuse pulmonary vasculopathy (medial hypertrophy and intimal fibrosis) involving predominantly intralobular pulmonary veins and, to a lesser extent, muscular pulmonary arteries
  • Prognosis: the development of pulmonary hypertension is strongly associated with increased mortality, suggesting that severe pulmonary hypertension is not limited to patients with end-stage pulmonary disease

Spontaneous Pneumothorax (see Pneumothorax, [[Pneumothorax]])

  • Epidemiology: occurs in 14% of cases
  • Clinical
    • Pleuritic Chest Pain
    • Recurrent Spontaneous Pneumothorax: occurs in 15-20% of cases

Rheumatologic Manifestations

General Comments

  • Bone Involvement: occurs in 77% of cases

Osteolytic Bone Lesions (see Bone Metastases, [[Bone Metastases]])

  • Epidemiology: occur in most cases
  • Diagnosis
    • X-Ray: lytic, “punched-out” lesion, sometimes with an accompanying soft tissue mass
  • Most Common Bony Sites of Involvement
    • Pediatric Cases
      • Skull (40% of cases)
      • Femur
      • Humerus
      • Ribs
      • Vertebrae
    • Adult Cases
      • Jaw (30% of cases)
      • Skull (21% of cases)
      • Extremities (17% of cases)
      • Pelvis (13% of cases)
      • Vertebrae (13% of cases): may result in neurologic compromise or asymmetric vertebral body collapse
      • Ribs (6% of cases)
  • Clinical
    • May Be Asymptomatic: some cases
    • Localized Pain with Raised, Soft, Tender Area
    • Neurologic Deficits: may occur with spinal or skull lesions

Other Manifestations

  • Fever (see Fever, [[Fever]])

Treatment

Single Organ System Disease Treatment Options

Single Bone Lesions in Central Nervous System Risk Area (Orbit/Mastoid/Temporal/Sphenoid Bones)

Single Bone Lesions in Non-Central Nervous System Risk Area (Frontal/Occipital/Parietal Bones) or Other Bone

  • Curettage of Bone Lesion

Bone Lesions in Axial/Appendicular Skeleton

  • Intralesional Corticosteroid Injection (see Corticosteroids, [[Corticosteroids]]): steroids may help control pain and increase mobility

Spine/Femoral Bone Lesions

  • Surgical Stabilization with Radiation Therapy: as these lesions may produce bone pain, fractures/vertebral collapse, and/or spinal cord compression

Solitary Lymph Node Involvement

  • Surgical Excision, Followed by Observation

Isolated Skin Involvement

  • Methotrexate (PO) with/without Mercaptopurine (see Methotrexate, [[Methotrexate]] and Mercaptopurine, [[Mercaptopurine]])
  • Topical Corticosteroids (see Corticosteroids, [[Corticosteroids]]): has been used in small case series
  • Topical Nitrogen Mustard (Mechlorethamine) (see Mechlorethamine, [[Mechlorethamine]]): has been used in small case series
  • Thalidomide (see Thalidomide, [[Thalidomide]]): has been used in small case series

Pulmonary Langerhans Cell Histiocytosis Treatment Options

  • Smoking Cessation (see Tobacco, [[Tobacco]])
    • Continuation of Smoking: most patients demonstrate gradual disease progression
    • Smoking Cessation regression of disease may occur
  • Corticosteroids (see Corticosteroids, [[Corticosteroids]]): corticosteroids are probably only useful in patients with nodular disease
  • Cladribine (see Cladribine, [[Cladribine]]): case reports
  • Radiation Therapy: useful for bone lesions, but not for pulmonary lesions
  • Lung and Heart-Lung Transplant (see Lung Transplant, [[Lung Transplant]]): may be considered for advanced lung disease
    • Disease May Recur in the Transplanted Lung: unclear if this affects survival though
  • Specific Treatment of Langerhans Cell Histiocytosis-Associated Pulmonary Hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]])

Multi-Organ System Disease Treatment Options

Induction Chemotherapy

Maintenance Chemotherapy

  • Prednisolone + Vinblastine (see see Prednisolone, [[Prednisolone]] + Vinblastine, [[Vinblastine]]):
  • Mercaptopurine (see Mercaptopurine, [[Mercaptopurine]]): may be added for risk organ involvement

Multi-Focal Bone Disease Treatment Options

  • Cladribine (see Cladribine, [[Cladribine]]): preferred treatment

Central Nervous System Disease Treatment Options

Central Nervous System Mass Lesions

  • Cladribine (see Cladribine, [[Cladribine]])
  • Resection with/without Radiation Therapy: case reports

Neurodegenerative Disease

Disease Which Resembles Both Erdheim-Chester Disease and Langerhans Cell Histiocytosis


Prognosis

  • Pulmonary Langerhans Cell Histiocytosis: 5-year survival is >75%
    • Pulmonary hypertension is independently associated with decreased survival

References

  • Epidemiologic study of Langerhans cell histiocytosis in children. J Pediatr. 1997 May;130(5):774-84 [MEDLINE]
  • The epidemiology of Langerhans cell histiocytosis. Hematol Oncol Clin North Am. 1998;12(2):379 [MEDLINE]
  • Severe pulmonary hypertension in histiocytosis X. Am J Respir Crit Care Med 2000;161:216-23 [MEDLINE]
  • Lung transplantation for pulmonary Langerhans’ cell histiocytosis: a multicenter analysis. Transplantation 2006;81:746-50 [MEDLINE]
  • Severe pulmonary hypertension in histiocytosis X: long-term improvement with bosentan. Eur Respir J. 2010 Jul;36(1):202-4. doi: 10.1183/09031936.00004810 [MEDLINE]
  • Dramatic and sustained responsiveness of pulmonary Langerhans cell histiocytosis-associated pulmonary hypertension to vasodilator therapy. Respir Med Case Rep. 2014 Nov 22;14:13-5. doi: 10.1016/j.rmcr.2014.11.005. eCollection 2015 [MEDLINE]