Langerhans Cell Histiocytosis Workup

Updated: Nov 06, 2017
  • Author: Christopher R Shea, MD; Chief Editor: William D James, MD  more...
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Workup

Laboratory Studies

Blood testing

Recommended baseline diagnostic evaluations for Langerhans cell histiocytosis (LCH) include CBC count with differential, reticulocyte count, erythrocyte sedimentation rate, direct and indirect Coombs test, and immunoglobulin levels. [43] In case of anemia, leukopenia, or thrombocytopenia, a bone marrow aspirate is indicated. Coagulation studies may be indicated.

Liver function tests

These can include tests measuring total protein, albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase values. If liver function test results are abnormal, a liver biopsy should be considered to differentiate LCH from cirrhosis.

Urinalysis

Urine specific gravity and osmolality are measured after overnight water deprivation to screen for diabetes insipidus.

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Imaging Studies

Chest radiography (posteroanterior and lateral)

Langerhans cell histiocytosis (LCH) can present as a micronodular and interstitial infiltrate in the mid zone and base of the lungs, with sparing of the costophrenic angles. Older lesions show a honeycomb appearance.

High-resolution CT scanning may be required if lung involvement is suspected based on radiography findings of pulmonary infiltrates or a cystic appearance. [18]

Patients with radiographically demonstrated pulmonary involvement, in whom chemotherapy is being considered, require a biopsy of the lung preceded by bronchoalveolar lavage (BAL) to exclude opportunistic infections. If the BAL findings are diagnostic, the biopsy of the lung can be obviated.

Skeletal radiograph survey

Unifocal LCH presents as a single osteolytic lesion, usually affecting long or flat bones (in children, the calvaria and femurs; in adults, the ribs).

Multifocal LCH shows osteolytic lesions involving the calvaria, sella turcica, mandible, vertebrae, and/or long bones of the upper extremities.

Note the image below.

On a plain skull radiograph, lesions are typically On a plain skull radiograph, lesions are typically lytic, with sharp borders and a punched out appearance.

Although radionuclide bone scanning is suggested for establishing the extent of osseous involvement, the latter is not as sensitive as the skeletal radiograph survey in most patients.

MRI of the head and spine is also useful to identify craniofacial or vertebral bone lesions.

CT scanning or MRI

CT scanning or MRI of the hypothalamic-pituitary region may reveal abnormalities of these organs. In particular, magnetic resonance spectroscopy may be valuable in the early detection and evaluation of the neurodegenerative component. [44]

Fluorodeoxyglucose positron-emission tomography scanning

Fluorodeoxyglucose (FDG) positron-emission tomography (PET) scanning may also be used when evaluating patients for LCH. In one study, FDG-PET scanning found 35% more sites of active disease than radiography, CT scanning, MRI, and bone scanning and was particularly effective at identifying bony lesions. FDG-PET scanning has therefore been suggested as a superior alternative to bone scanning in the early evaluation of patients with LCH. [45] Notably, FDG-PET scanning has poor sensitivity for spinal lesions. FDG-PET scanning is able to identify LCH in tissues, including lymph nodes, spleen, and lung.

FDG-PET scanning may also be useful in measuring response to treatment, particularly in patients with only bony involvement who may not require periodic CT scanning or MRI evaluation. [45, 46]

Also see Imaging in Eosinophilic Granuloma of the Skeleton.

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Other Tests

Other testing in Langerhans cell histiocytosis (LCH) patients may involve the following:

  • Pulmonary function testing may help identify otherwise asymptomatic pulmonary involvement. [18]
  • A small bowel series and biopsy are indicated in cases of unexplained diarrhea, failure to thrive, and malabsorption. [25]
  • Hormonal studies of the hypothalamic-pituitary axis may reveal abnormalities.
  • Visual and neurologic testing may be required.
  • Consultation with an otolaryngologist for auditory testing may also be considered as needed. [4, 47]
  • The results of a small Swedish study evaluating LCH patients with known neurodegeneration on MRI suggest that serial monitoring of cerebrospinal fluid biomarkers (including neurofilament light chain [NF-L], Tau, and glial fibrillary acidic protein [GFAp]) may help evaluate disease onset, severity, and response to therapy in patients with neural involvement. [48] However, more robust studies must be performed to evaluate this claim before such tests become common practice.
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Procedures

A biopsy of the skin is extremely helpful in establishing the diagnosis.

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Histologic Findings

The histologic picture unifies the varied presentations of Langerhans cell histiocytosis (LCH), which are influenced by the location and age of the lesions. Although lesions typically appear granulomatous, with a reactive background of macrophages, eosinophils, multinucleated giant cells, and T-cells, the key to diagnosis is to identify the pathologic Langerhans cells. [49, 41] The latter cell resembles the normal Langerhans cell of the skin, except that it is not dendritic.

It consists of a large, ovoid, mononuclear cell that is 15-25 µm in diameter, with a folded nucleus, a discrete nucleolus, and a moderate amount of slightly eosinophilic homogeneous cytoplasm. When the indentation of the nucleus affects its center, it acquires a reniform pattern; however, if it is peripheral, the nucleus has a coffee-bean shape.

Special studies are useful for definitive identification of normal and pathologic Langerhans cells. The Birbeck granule is their distinctive ultrastructural hallmark. It consists of an intracytoplasmic membranous body that is 33 nm wide and 190-360 nm long, possessing a short, rodlike shape with a dotted line down the midline of the space between the membranes (resembling a zipper) and a terminal expansion in the form of a vesicle, giving a racquet appearance. Although these granules are resistant to destruction by formalin fixation and paraffin embedding, the sensitivity of detection in such specimens is slightly decreased. Birbeck granules are rarely detected in lesions of the liver, the gastrointestinal tract, and the spleen. Langerhans cells also contain laminated substructures of lysosomes, tuboreticular structures, and trilaminar membranous loops. Note the image below.

Electron microscopy. Tennis racquet form of Birbec Electron microscopy. Tennis racquet form of Birbeck granules with a small terminal expansion.

Ultrastructural methods and enzyme histochemical studies (alpha-D-mannosidase and adenosine triphosphatase [ATPase]) have largely been replaced by immunohistochemical techniques. S-100 protein is strongly expressed in a cytoplasmic pattern, while peanut agglutinin (PNA) has a characteristic cell surface and paranuclear dot expression. LCH cells are positive for major histocompatibility (MHC) class II and CD1a. Expression of langerin (CD207), a Langerhans cell–restricted protein that induces the formation of Birbeck granules and is constitutively associated with them, is a highly specific marker of Langerhans cells. [50] The pathologic Langerhans cell expresses phenotypic markers of an activated normal Langerhans cell in its early stages. Fine-needle aspiration combined with immunohistochemistry of the cell preparation plays an important role in documenting organ involvement by LCH.

Note the images below.

High-power views. Marked epidermotropism is noted High-power views. Marked epidermotropism is noted (left). The lesional cells are large, with abundant pink cytoplasm and reniform nuclei. An admixture of inflammatory cells, including occasional eosinophils, is present (right).
High-power views. Diffuse immunoreactivity for S-1 High-power views. Diffuse immunoreactivity for S-100 protein (right). Langerhans cells and lymphocytes (left, hematoxylin and eosin).
Widespread positivity for CD1a. Note the presence Widespread positivity for CD1a. Note the presence of epidermotropism (right). Langerhans cells and lymphocytes are present in the epidermis and the papillary dermis (left, hematoxylin and eosin).

The Writing Group of the Histiocyte Society (1987) has proposed 3 levels of certainty in the diagnosis of LCH, based on clinical features, histopathology, and immunohistochemical techniques. A presumptive diagnosis is based on a typical clinical presentation and light microscopic findings. A designated diagnosis includes light microscopy in combination with positive S-100 and PNA staining studies. To make a definitive diagnosis, identification of Birbeck granules and CD1a antigens is required.

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Staging

The Histiocyte Society stratifies patients with Langerhans cell histiocytosis (LCH) into single-system LCH (SS-LCH) or multisystem LCH (MS-LCH).

SS-LCH includes involvement of one of the following systems (either unifocal or multifocal involvement):

  • Bone
  • Skin
  • Lymph Node
  • Lungs
  • Central nervous system
  • Other (eg, thyroid, thymus)

MS-LCH is defined as involvement of 2 or more organs or organ systems, irrespective of involvement of "risk organs." The following organ systems are classified as risk organs, and their involvement indicates a worse prognosis [41] :

  • Spleen
  • Liver
  • Hematopoietic system
  • Lung
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