000 Pulmonary Langerhans Cell Histiocytosis

Smoking Induces the Accumulation of Langerhans Cells in the Lungs

Cell – Dendritic Cell

Langerhans Dendritic Macrophage
Ashley Davidoff MD
TheCommonVein.net

Langerhans Cells – Dendritic Cells

Pulmonary Langerhans cell histiocytosis.). (c) Irregular nuclear groove with abundant cytoplasm of Langerhans cells (Papanicolau stain, ×1000) (insert. CD1a).
Courtesy IMAGES IN CYTOPATHOLOGY Myunghee Kang et al Cytologic features of pulmonary langerhans cell histiocytosis in bronchial washing: A report of two cases

Langerhans Cell Histiocytosis
Langerhans Cell is a dendritic white cell with a wavy nucleus that creates granulomas and infiltrates the interstitium. It thus causes spiculated nodules that appear as spiculated nodules on CT
Ashley Davidoff
TheCommonVein.net

Smoking in Two Puff Harmony
From the series “People of Israel”
Ashley Davidoff MD
TheCommonVein.net

Membranous airways (respiratory bronchiole, alveolar ducts, alveolar sacs)
At the level of the membranous airways the effect is predominantly related to the loss of elasticity, and aberrant accumulation of smoking related macrophages.
The weakening and destruction results in emphysema and the abnormal accumulation of smoking related macrophages relates to DIP
Ashley Davidoff
TheCommonVein.net

The Bronchocentric Nodule

Image a shows a normal bronchiole. Smoking excites the Langerhans cell which in turn induces attracts early cellular interstitial infiltrates of surrounding the bronchiole (b) including lymphocytes, macrophages, eosinophils, plasma cells, and fibroblasts. The cellular infiltrate progresses in a peribronchial pattern with mass effect on the bronchiole which becomes narrowed (c) and eventually disappears, a nodules of varying size manifest in the bronchiole pathway, sometimes round but often spiculated as the inflammatory reaction extends into the interstitium (d) The wall of the bronchiole breaks down and the cellular infiltrate may undergo necrosis resulting in thick walled cavities, sometimes round in shape (e) and sometimes with bizarre shapes (f) Eventually the inflammation recedes and a thin walled cyst remains (g ,h)
Ashley Davidoff MD TheCommonVein.net

Langerhans Cells Attract Other Inflammatory cells and Surround the Bronchiole

Bronchocentric Langerhans Nodules
Proliferation of the Langerhans Cell induces other cells to join causing a significant reaction around the bronchus with the inflammatory reaction extending into the interstitium and accounting for the stellate appearance
Pulmonary Langerhans Cell Histiocytosis: An Update From the Pathologists’ Perspective
March 2016 Archives of Pathology & Laboratory Medicine 140(3):230-240
Authors: Anja C Roden Eunhee S Yi

Florid Early Phase
Bronchocentric Nodules = Inflammatory Changes Around the Bronchus

Smoking excites the Langerhans cell which in turn induces and attracts early cellular interstitial infiltrates which surround the bronchiole. The diagram shows a bronchiole surrounded by an acute cellular inflammatory response
Ashley Davidoff MD TheCommonVein.net lungs-0722

CT shows extensive disesae that appears to be centered around the bronchioles and small airways associated with centrilobular nodules, bronchiolectasis and thick walled cysts, more prominent in the upper lobes and mid lung fields but also involving the bases
Ashley Davidoff MD TheCommonVein.net 50F 001b

Tree in Bud and Peribronchial Nodules with a Hint of Central Cavitation ie Bronchocentricity

As the inflammatory response progresses it has mass effect on the bronchiole causing the bronchiole to become narrowed.
Ashley Davidoff MD TheCommonVein.net lungs-0723

CT shows extensive disease that appears to be centered around the bronchioles and small airways associated with centrilobular nodules, bronchiolectasis and thick walled cysts, more prominent in the upper lobes and mid lung fields but also involving the bases
Ashley Davidoff MD TheCommonVein.net 50F 001

The inflammatory response is often aggressive and may infiltrate the surrounding interstitium resulting in a spiculated appearance. As the inflammatory response progresses it has mass effect on the bronchiole causing the bronchiole to become narrowed.
Ashley Davidoff MD TheCommonVein.net lungs-0723b

Stellate Appearance Because of Infiltration of the Inflammatory Process into the Interstitium

It may become a Solid Nodule as It Obliterates the Lumen

As the inflammatory response progresses it has mass effect on the and may eventually occlude the bronchiole becoming a nodule.
Ashley Davidoff MD TheCommonVein.net lungs-0724b

The inflammatory response is often aggressive and may infiltrate the surrounding interstitium resulting in a spiculated appearance
Ashley Davidoff MD TheCommonVein.net lungs-0724

Figure 9. Nodular infiltrates with a stellate border extending into the surrounding interstitium in a patient with PLCH. (Courtesy of Professor A. Pesci, University of Parma.)

Spiculated Nodule of Langerhans Cell Histiocytosis
TheCommonVein.net

Wall Starting to Break Down Creating a Thick Walled Cyst

The wall of the bronchiole breaks down and the cellular infiltrate may undergo necrosis resulting in thick -walled cavities, sometimes round in shape.
Ashley Davidoff MD TheCommonVein.net lungs-0725

Sometimes with Bizarre Shapes

The wall of the bronchiole breaks down and the cellular infiltrate may undergo necrosis resulting in thick -walled cavities, sometimes bizarre in shape.
Ashley Davidoff MD TheCommonVein.net lungs-0726

Thick Walled Cysts = Thick Walled Dilated Small Airways

CT AXIAL VIEW – APEX SHOWS MOST SEVERE DISEASE
LANGERHANS HISTIOCYTOSIS
53-year-old female with nicotine dependence presents with dyspnea and cough
CXR (PA and Lateral) shows bilateral and extensive reticular nodular changes slightly more prominent in the upper lung zones
CT scan from 16 months prior showed multiple relatively thick-walled cysts predominantly in the upper lobes. The cysts are round and air filled large and are between 5mm-8mm
CT scan 9 months later shows improvement in the thickened walls of the cysts but maintenance of diffuse cystic changes predominantly in the upper lobes
A CT scan done 2 years later shows no significant change in the diffuse bilateral cystic changes, dominant in the upper lobes and consistent with Langerhans histiocytosis
Ashley Davidoff MD

With Time Inflammation Settles and There is Thinning of the Walls of the Cysts

As the inflammatory response subsides, thin-walled cavities evolve.
Ashley Davidoff MD TheCommonVein.net lungs-0728b -hi res

As the inflammatory response subsides, thin-walled cavities evolve, sometimes bizarre in shape.
Ashley Davidoff MD TheCommonVein.net lungs-0728b

Pulmonary Langerhans Cell Histiocytosis
Thin Walled Bizarre Shaped Upper Lobe Cysts
Ashley Davidoff MD TheCommonVein.net

CT scans show multiple thin walled cysts among a left upper lobe nodule and a thick walled cyst in the left apex
Ashley Davidoff MD TheCommonVein.net adeno ca 007

In a Nutshell

Unknown Etiology
- Strong association with smoking
- Isolated to lungs
- can affect multiple organs
- 20-40 years
- M.F =1:1
- Can present with PTX (10-25% spontaneous)
Location
- - smokers therefore
    - upper mid lung involvement-
      - lower lobe sparing
      - costophrenic sparing
      - can affect bone
  - nodules
    - irregular margins
    - random
    - decrease as disease progresses
  - cysts
    - thin walls
    - rounded
    - irregular bizarre
    - progress s disease progresses
- ambivalent nature
  - Can get very sick needing lung transplant
    - steroid
    - cytotoxic drugs
    - lung transplant
  - Can resolve spontaneously
  - Stop smoking can resolve

Definition

- Pulmonary Langerhans cell histiocytosis (PLCH)
  - (previously called eosinophilic granuloma of the lung, pulmonary Langerhans cell granulomatosis, and pulmonary histiocytosis X,
  - is
    - a cystic interstitial lung disease
  - Cause and predisposing factors
    - almost exclusively in cigarette smokers.
    - Caucasian young adults (20-40 years of age).
  - Structures involved
    - small airways terminal bronchioles and
    - infiltration into the interstitium
    - no to
      - lymph nodes
      - pleura
  - Pathophysiology –
    - Langerhans (immature histiocytes – myeloid dendritic cells)
    - proliferate in the bronchioles and alveolar interstitium, forming granulomas
    - leading to destruction of bronchioles and the interstitial alveolar space
    - granulomas can cavitate
    - cysts with thick walls progressing to
    - cysts with thin wills which can become confluent
    - Cell – Dendritic Cell
      Langerhans Dendritic Macrophage
      Ashley Davidoff MD
      TheCommonVein.net
      
      Langerhans Cells – Dendritic Cells
      
      Pulmonary Langerhans cell histiocytosis.). (c) Irregular nuclear groove with abundant cytoplasm of Langerhans cells (Papanicolau stain, ×1000) (insert. CD1a).
      Courtesy IMAGES IN CYTOPATHOLOGY Myunghee Kang et al Cytologic features of pulmonary langerhans cell histiocytosis in bronchial washing: A report of two cases
      
      Figure 9. Nodular infiltrates with a stellate border extending into the surrounding interstitium in a patient with PLCH. (Courtesy of Professor A. Pesci, University of Parma.)
      
      Note
      spiculated cell
      can cause spiculated nodules (?due to interstitial infiltration?
      - Histiocytosis
        
        fibrous – granuloma
        
        small airway
        
        interstitial infiltrate
  - Result
    - 25% can be asymptomatic and resolve spontaneously
    - Clinical
      - Sx
        
        fever, fatigue, night sweats, anorexia, weight loss) and hemoptysis
        
        10% of cases, PLCH presents with
        
        spontaneous pneumothorax, which can be bilateral or recurrent
        
        Extra pulm manifestations
        
        bone lesions (skull, ribs, and pelvis)
        
        pituitary involvement producing diabetes insipidus,
        
        skin lesions
      - Imaging
      - Spiculated Nodule of Langerhans Cell Histiocytosis
        TheCommonVein.net
        
        Langerhans Cell Histiocytosis
        Langerhans Cell is a dendritic white cell with a wavy nucleus that creates granulomas and infiltrates the interstitium. It thus causes spiculated nodules that appear as spiculated nodules on CT
        Ashley Davidoff
        TheCommonVein.net
        
        nodular or reticulonodular opacities
        
        middle and upper lung zones
        
        sparing of the
        
        bases
        
        costophrenic angles
        
        nodules
        
        cavitating nodules
        
        thick walled cysts
        
        thin walled bizarre shaped cysts
        
        preservation of lung volume
        
        Hilar or mediastinal adenopathy is rare
        
        Pleural thickening or effusion is rare
        
        Honeycombing in advanced disease
        
        FDG-PET scan
        
        early in the course of disease (nodular phase)
        
        may show increased uptake in the lungs
        
        PFT
        
        reduction in DLCO.
        
        total lung capacity and expiratory flow rates are well-preserved
        
        Restrictive, obstructive, and mixed patterns have
        been described
      - BAL
      - Bx
        
        transbronchial
        
        surgical
      - Path
        
        Early
        
        cellular interstitial infiltrates of
        
        Langerhans’ cells,
        
        Staining with antibodies against CD1a antigen on the cell surface
        
        lymphocytes,
        
        macrophages,
        eosinophils, plasma cells, and fibroblasts
        
        Mid stages
        
        infiltrates enlarge to form nodules centered on small airways (peribronchial)
        
        often stellate in configuration

- - - - Spiculated Nodule of Langerhans Cell Histiocytosis
        
        TheCommonVein.net
        
        Spiculated Nodule of Langerhans Cell Histiocytosis in a background of Centrilobular Emphysema
        TheCommonVein.net
        
        Next Phase
        
        Nodules Become Cysts
        
        Cavitation within nodules due to
        
        either an
        
        airway remnant or
        
        cavitation due to an enlarging
        inflammatory infiltrate
        
        Figure 2. Pulmonary Langerhans cell histiocytosis. Multiple nodules and cysts seen on computed tomography (CT) imaging ( A ) with histology showing cellular nodules ( B ), some with central cavities ( B , *) containing diagnostic Langerhans cell aggregates highlighted by positive immunohistochemical staining for CD1a ( C , brown stain ) typical of the early cellular stage of the disease. Coronal CT image from another patient showing multiple bizarre-shaped cysts in an upper-zone–predominant distribution, with sparing of the costophrenic angles representative of later-stage disease ( D ). Histologic features typical of later disease stages include cystic spaces ( E ) associated with paucicellular stellate fibrosis ( E , arrow ). Accumulations of smoking-related pigmented macrophages ( F , arrowhead ) are frequently seen in the surrounding parenchyma. Original magnifications: 2 3 ( E ); 4 3 ( B ); 40 3 ( C ); 100 3 ( F ).
        Gupta et al Diffuse Cystic Lung Disease: Part I American Journal of Respiratory and Critical Care Medicine 191(12) April 2015
        
        Initially Thick Walled
        
        Pulmonary Langerhans Cell Histiocytosis
        (A) High resolution computed tomographic scan of the lung of a patient with pulmonary LCH showing the association of nodules (some of which are cavitary) and parenchymal cysts. (B) An advanced stage of the disease showing the presence of numerous cysts of various size, some of which are confluent.
        Tazi, A et al Adult pulmonary Langerhans’ Cell Histiocytosis
        BMJ – Thorax Volume 55, Issue 5
        
        Nodules Becoming Cysts
        
        Figure 9. Nodular infiltrates with a stellate border extending into the surrounding interstitium in a patient with PLCH. (Courtesy of Professor A. Pesci, University of Parma.)
        
        Cavitation
        
        Cyst Formation Initially Thick Walled
        
        Then Thin Walled Cysts
        
        CT UPPER LUNG ZONE PROMINENCE OF SMALL THIN WALLED CYSTS
        LANGERHANS HISTIOCYTOSIS
        28 -year-old male with only minimal reported nicotine dependence presents with dyspnea and cough
        CXR (PA and Lateral) shows no acute cardiopulmonary disease with mild interstitial prominence
        CT scan showed multiple small cysts predominantly in the upper lobes. The cysts are round and air filled large and are between 5mm-8mm
        These findings are consistent with Langerhans histiocytosis though the relatively minor smoking history was inconsistent with the diagnosis and thus the person was subjected to multicentric wedge biopsies.
        Pathology revealed numerous stellate nodules which suggested “burnout pulmonary Langerhans cell histiocytosis though immunostains including Langerin, CD1a and S100 were negative thus failing to confirm the diagnosis Other findings of histiocytic aggregates raised the possibility of an inhalational hypersensitivity pneumonitis.
        Ashley Davidoff MD
        
        Next Phase
        
        Cavitation within nodules due to
        
        either an airway remnant or
        
        de novo cavitation due to an enlarging
        inflammatory infiltrate
        
        Figure 2. Pulmonary Langerhans cell histiocytosis. Multiple nodules and cysts seen on computed tomography (CT) imaging ( A ) with histology showing cellular nodules ( B ), some with central cavities ( B , *) containing diagnostic Langerhans cell aggregates highlighted by positive immunohistochemical staining for CD1a ( C , brown stain ) typical of the early cellular stage of the disease. Coronal CT image from another patient showing multiple bizarre-shaped cysts in an upper-zone–predominant distribution, with sparing of the costophrenic angles representative of later-stage disease ( D ). Histologic features typical of later disease stages include cystic spaces ( E ) associated with paucicellular stellate fibrosis ( E , arrow ). Accumulations of smoking-related pigmented macrophages ( F , arrowhead ) are frequently seen in the surrounding parenchyma. Original magnifications: 2 3 ( E ); 4 3 ( B ); 40 3 ( C ); 100 3 ( F ).
        Gupta et al Diffuse Cystic Lung Disease: Part I American Journal of Respiratory and Critical Care Medicine 191(12) April 2015
        
        Costophrenic Sparing
        
        Costophrenic Sparing
        Ashley Davidoff MD TheCommonVein.net
        
        Costophrenic Sparing
        Ashley Davidoff MD TheCommonVein.net
        
        Costophrenic Sparing
        Ashley Davidoff MD TheCommonVein.net
        
        Sclerotic Bone Disease
        
        Sclerotic Bone Disease possibly related to Pulmonary Langerhans Cell Histiocytosis but may just be a benign bone island
        Ashley Davidoff MD TheCommonVein.net
        
        End-stage
        
        prominent fibrotic scars and Langerhans cells absent