Langerhans Cell Histiocytosis

 

• Histiocytic disorders are a group of diseases derived from macrophages and dendritic cells, which are important antigen presenting cells and mediators of host immune responses
• Dendritic cell disorders consists of:

1. Langerhans cell histiocytosis (LCH) – Incidence 4 to 4.5 per million
2. Erdheim-Chester disease (ECD)
3. Juvenile xanthogranuloma (JXG)

• Macrophage related disorders include:

1. Rosai-Dorfman disease (RDD)
2. Hemophagocytic lymphohistiocytosis (HLH)

Langerhans Cell Histiocytosis:

• LCH is the most common dendritic cell disorder
• Caused by abnormal monoclonal proliferation and accumulation of pathological Langerhans cells in tissues.
• These histiocytes can infiltrate any organ, therefore the clinical presentation and prognosis are highly variable.
• Unique intracytoplasmic organelles, known as Birbeck granules which appear racquet shaped in electron microscopy helps to differentiate LCH from other disorders.

Types:

• According to number and types of organs involved, LCH is classified into:
• Single system LCH – which involves only one organ or system, particularly bone. It can be:

1. Unifocal/localized seen in approx. 70% of cases, usually present between 5 and 15 years of age
2. Multifocal (chronic recurring form) seen in approx. 20% of cases, presents between 1 and 5 years of age

• Multisystem LCH – which affects  ≥ 2 organs or systems, seen in 10% of cases, usually diagnosed in first 2 years of life

                   Multisystem LCH is subdivided into low-risk and high-risk groups; high-risk group shows involvement of organs such as liver, spleen, lung, hematopoetic system and CNS, leading to less favorable prognosis.

Investigations:

• Conventional imaging modalities included radiographs, skeletal surveys, bone scan, CT, MRI and ultrasound
• Advantages of PET/CT:

1. Identifies metabolically active histiocytes along with anatomical localization in a single study
2. Has the potential to detect new lesions that are difficult to diagnose clinically by physical examination and conventional imaging
3. Helps in monitoring response to therapy.

• Disadvantages:

1. Less useful in evaluating lung disease due to variable FDG uptake depending on morphological pattern
2. Evaluating intracerebral LCH lesions like the pituitary stalk is difficult due to adjacent cerebral cortical uptake.

Bone lesions:

• Bone lesions occur in approx. 80% of patients
• Predilection for flat bones – skull is m/c involved, followed by mandible, ribs, pelvis and spine.
• Skull lesions may be asymptomatic or present with focal pain and scalp swelling.

• Well-defined lytic punched out appearance of skull lesions is due to asymmetric destruction of inner and outer cortices, which results in characteristic beveled edge
• When temporal bone is affected, classic location is mastoid and patients present with swelling, dizziness, vertigo and otorrhea
• Unlike other osseous lesions in LCH, calvarial disease lacks periosteal reaction
• Skull lesions may grow in size and coalesce, creating a map-like appearance referred to as geographic skull.
• Vertebral body is the m/c affected part of the spine in LCH
• Early lesions appear lytic and as disease progresses it can result in symmetric uniform collapse of the vertebral body termed vertebra plana
• May result in pain and substantial neurological deficits
• RT is Rx of choice for vertebral lesions at risk for collapse
• Spinal fusion or bracing may be required in pts with neurological symptoms.
• Long bone involvement is more common in children than in adults
• May be asymptomatic or present with focal pain and swelling and are at risk for pathological fractures
• Femur, humerus and tibia are most commonly involved long bones and lesions typically occur in diaphysis or metaphysis
• Early lesions appear lytic, expansile and aggressive
• Less aggressive lesions show cortical thickening and a smooth periosteal reaction
• Bone scan typically shows increased tracer uptake; however, false negatives are common, particularly with older lesions. Bone scan may also remain positive for a long period for fully treated lesions
• As lesions become chronic, they may resolve or appear sclerotic from periosteal new bone formation.
• Whereas long bone lesions are more frequently encountered in children, isolated flat bone involvement (most commonly rib or mandibular lesions) is more frequent in adults
• Severe mandibular lesions may destroy the alveolar ridge, resulting in a radiographic appearance of “floating teeth” – patients may present with gingival bleeding and facial swelling

Treatment of Bone lesions:

• Rx of a single skull lesion  includes curettage, curettage with intralesional steroid injection or radiotherapy
• Chemotherapy and oral systemic steroids may be used to Rx multiple skull lesions or to prevent CNS extension if the mastoid, temporal or orbital bones are involved.

Liver, Spleen and Lymph node involvement:

• Liver is involved in approx. 15% of cases, findings include hepatomegaly, focal solid or cystic lesions and hepatic dysfunction
• A potential complication is sclerosing cholangitis, which is progressive and may eventually require liver transplantation.

• Spleen is involved less frequently than liver. Splenomegaly can lead to cytopenias secondary to hypersplenism
• Lymph nodes are involved in approx. 20% of cases and most commonly in neck, manifesting as hard or soft matted groups of nodes with lymphedema

• Rx includes chemotherapy and steroids.

CNS Involvement:

• CNS is involved in approx. 16% of cases
• If facial bones or anterior and middle cranial fossa are affected, incidence of CNS involvement is higher, affecting up to 25% of patients
• m/c clinical manifestation is diabetes insipidus, secondary to infiltration of posterior pituitary gland
• Growth hormone deficiency has been recognized as occurring later in life in pts with LCH
• Pts may also present with ataxia and cognitive dysfunction from neurodegeneration, when lesions occur in cerebellum and basal ganglia
• Rx includes chemotherapy with or without steroids in cases of active disease with diabetes insipidus. Retinoic acid and intravenous immunoglobulins may be added if there are neurodegenerative symptoms.

Lung Involvement:

• Lung involvement occurs in approx. 10% of cases
• More common in adults and is almost always associated with smoking
• Pts usually present with shortness of breath and non-productive cough and sometimes with fever or weight loss
• In CT, LCH is characterized by  centrilobular micronodules with a predominantly bilateral symmetrical upper-to-mid-lung distribution, costophrenic angles are usually spared
• As disease progresses, cysts develop and can eventually become the predominant finding
• Cysts vary in size, usually less than 1 cm. A confluence of cysts may result in a bullous formation, which predisposes to spontaneous pneumothorax
• PET/CT – Nodular disease appears more likely to yield a positive PET/CT, while cystic disease does not exhibit FDG uptake. Also, size of lesion could be related to metabolic behavior due to resolution power and partial volume effect.

• Rx includes smoking cessation as well as chemotherapy and steroids in persistent or progressive cases.

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