Langerhans cell histiocytosis (LCH)

Idiopathic non-malignant disease characterized by idiopathic infiltration and accumulation of abnormal histiocytes (i.e. the Langerhans cells) within various tissues (bone marrow, skin, central nervous system, lung, liver, spleen, lymph nodes) causing focal or systemic effects.

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History:

The first descriptions of what we now recognize as LCH appeared in the early 1900s as case reports and case series. Hand–Schüller–Christian disease was described as eosinophilic granulomatous lytic bone lesions, diabetes insipidus, and exophthalmos in young children. Letterer–Siwe disease was described in infants with aggressive and generally fatal systemic disease, including skin, liver, spleen, and bone marrow infiltration by reticuloendothelial cells. In the mid-1900s, Farber and Lichtenstein noted that biopsy specimens from cases of fatal Letterer–Siwe disease and specimens from cases of clinically mild eosinophilic granuloma were indistinguishable, and the two pathologists hypothesized that these conditions represent manifestations of a common disorder. Lichtenstein proposed a common diagnosis, histiocytosis X, with the X indicating an uncertain cell of origin. Two decades later, with the advent of electron microscopy, Nezelof and colleagues identified a unique intracellular organelle, the Birbeck granule, in histiocytosis X lesions. At this point, Birbeck granules were thought to be exclusive to epidermal Langerhans cells, skin-restricted cells of the mononuclear phagocyte system. Histiocytosis X was renamed Langerhans-cell histiocytosis, reflecting the concept that LCH cells represented dysfunctional epidermal Langerhans cells. Over the next decades, reviews debated whether LCH was a disorder of transformed Langerhans cells or of normal Langerhans cells rendered pathologic by inappropriate stimuli.

Langerhans cells are named after Paul Langerhans, a bright, young medical student who worked with the new technique of gold colloid staining in the mid-19th century. In 1868, Langerhans described an epidermal cell population, accounting for approximately 1% of epidermal cells, with characteristic dendrites that he described as extracutaneous nerves. We now know that epidermal Langerhans cells are not nerves but dendritic cells, a heterogeneous group of hematopoietic cells enriched in interface tissues and lymphoid organs. In the 1970s, Steinman and Cohn distinguished dendritic cells from macrophages on the basis of specific morphologic features of dendritic cells and their superior capacity to present antigens to and activate antigen-specific T cells. Epidermal Langerhans cells are unique among dendritic cells in that they arise not from myeloid progenitor cells in bone marrow but rather from yolk-sac progenitors and fetal liver–derived monocytes that populate the skin before birth and are maintained locally under steady-state conditions.

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Classification

Histiocytosis society classification:

Classification system for histiocytic disorders according to cellular pattern

• Dendritic cell pattern:
  • Langerhann cell histiocytosis (LCH)
  • Xanthogranuloma
• Macrophage pattern:
  • Familial reactive hemophagocytic lymphohistiocytosis
  • Sinsusal histiocytosis with lymphadenopathy (Rosai-Dorfman disease)
• Malignant disorders:
  • Monocytic leukemia
  • Malignancy related to dendritic cells
  • Malignancy located/related to macrophages
  • Disseminated (Malignant histiocytosis)

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Etiology

• Smoking (typically affects young male smokers)

Langerhans cells are dendritic antigen-presenting cells. The abnormal cells in LCH have abnormal proliferation and lower antigen-presenting capability. LCH lesion also contains inflammatory cells and cytokines such as T lymphocytes, eosinophils, neutrophils, and macrophages. It is thought that the combination or interaction of these cells accounts for the continued proliferation of the abnormal Langerhans cells.

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Presentation

Symptoms depend on organ involvement at the time of presentation.

Rash (M/C presentation):

Resemble seborrheic dermatitis

• Ranges from a single lesion to widespread involvement.
• Characteristics include scaly papules/nodules/plaques, petechiae, bloody crusting, or firmly indurated nodules.

Skeletal involvement (78% cases):

• Single/multiple osseous lesions (skull, hip/pelvis, femur, or ribs)
• Bone pain

Other features:

• Pulmonary symptoms (20% cases)
• Lymphadenopathy (30% cases)
• Hepatosplenomegaly
• Exophthalmos (bilateral infiltration of the retro-orbital area)

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Complications

Diabetes insipidus:

Langerhans cell histiocytosis also has a predilection for infiltration of the pituitary and causing diabetes insipidus

• Polyuria, polydipsia, dilute urine, and hypernatremia.

Orthopedic complications:

• Vertebral collapse
• Spinal compression
• Pathological fractures
• Chronic draining ears
• Early eruption of teeth

Other complications:

• Growth failure
• Delayed puberty
• Hearing loss
• Secondary cancers
• Neurologic/cerebellar effects
• Liver disease
• Spontaneous pneumothorax
• Pulmonary fibrosis

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Diagnosis

Lab investigations:

• Complete blood count
• LFT
• Coagulation studies
• Skeletal survey
• Urine specific gravity

Fluorodeoxyglucose (FDG) PET scanning:

For assessing the hypothalamic-pituitary area and monitoring disease during treatment.

• Bilateral nodules/cysts in upper lobe

Radiographic findings:

• Skull radiography:
  • Solitary/multiple punched out lytic lesions without sclerotic rim
  • Hole within a hole sign: Double contour or bevelled edge appearance (due to asymmetric involvement of inner & outer table)
  • Button sequestra: Represents residual bone
  • Geographic skull
• Mandibular findings:
  • Irregular radiolucent areas, mostly involving superficial alveolar bone
  • Floating tooth: Loss of lamina dura
• Spinal features:
  • Vertebra plana (thoracic spine): LCH is the M/C cause of vertebra plana in children
• Long bone features:
  • Permeature and aggressive appearing lesions occur
  • Mainly involves diaphysis or meta diaphysis
  • Endosteal scalloping: Periosteal reaction (healing phase), cortical thinning, intracortical tunneling and associated soft tissue mass

Bone marrow biopsy:

To exclude infiltration

• Birbeck granules: Tennis racquet shaped granules
• Immunohistochemistry: CD1a, CD 207 (langerin +), S-100

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Management

Treatment varies greatly depending on the involved organs.

Observation:

If the disease is isolated or skin lesions at infancy (resolve spontaneously)

Chemotherapy and radiation:

Used for more systemic involved cases

• Prednisone + vinblastine regimen
• Other regimens: Vincristine, cytosine arabinoside, prednisone, cladribine, or pamidronate

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