Histiocyte is an Outdated Term Used to Describe Large White Blood Cells Which are Resident in Tissues: various cells may be classified as histiocytes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-Schüller-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)
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
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
Sclerosing Cholangitis (see Sclerosing Cholangitis, [[Sclerosing Cholangitis]]): may be progressive (even when other LCH disease manifestations respond to therapy), eventually requiring liver transplant
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: 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
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]])
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
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
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
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
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
Intravenous Immunoglobulin (IVIG) and Prednisone with/without Vinblastine or Methotrexate (see Intravenous Immunoglobulin, [[Intravenous Immunoglobulin]], Prednisone, [[Prednisone]], Vinblastine, [[Vinblastine]], and Methotrexate, [[Methotrexate]]): case reports
Disease Which Resembles Both Erdheim-Chester Disease and Langerhans Cell Histiocytosis
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]
