Histiocytosis Workup

Updated: Feb 14, 2017
  • Author: Cameron K Tebbi, MD; Chief Editor: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP  more...
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Workup

Laboratory Studies

Laboratory investigations and diagnostic tests should partly be tailored to the extent of disease suspected on the basis of the patient's history and physical findings. For genetic studies of FHLH, please see etiology section.

Table 2 shows minimal frequencies of follow-up. Testing more frequent than that shown might be necessary.

Table 2. Laboratory and Imaging Studies in Patients With LCH (Open Table in a new window)

Type of Study Study Involvement With Monostotic Lesion
Laboratory Hemoglobin and/or hematocrit Monthly Every 6 mo None
Leukocyte count and differential cell count Monthly Every 6 mo None
Liver function tests* Monthly Every 6 mo None
Coagulation studies Monthly Every 6 mo None
Urine osmolality test after overnight water fast Every 6 mo Every 6 mo None
Radiography Chest, posteroanterior and lateral Monthly Every 6 mo None
Skeletal survey Every 6 mo None Once at 6 mo
* Measurements of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase.

Table 3 lists the indications for various laboratory evaluations, with the minimal frequencies of follow-up. Testing more frequent than that shown might be necessary.

Table 3. Indication for Laboratory Evaluations Based on Findings in LCH (Open Table in a new window)

Evaluation Indication Follow-Up Interval
Bone-marrow aspiration biopsy Anemia, leukopenia, or thrombocytopenia 6 mo
Pulmonary function tests Abnormal chest radiographic findings, tachypnea, intercostal retractions 6 mo
Lung biopsy after bronchoalveolar lavage, if available* Abnormal findings on pretreatment chest radiography to rule out infection None
Small-bowel series and biopsy Unexplained chronic diarrhea, failure to thrive, malabsorption None
Hepatic ERCP, angiography, or biopsy High liver enzyme levels and hypoproteinemia not caused by protein-losing enteropathy to rule out active LCH vs liver cirrhosis When all evidence of disease resolves but hepatic dysfunction persists
IV gadolinium-enhanced MRI of brain and hypothalamic-pituitary Visual, neurologic, hormonal abnormalities 6 mo
Panoramic radiography of the teeth, mandible, and maxilla; consultation with an oral surgeon Oral involvement 6 mo
PET scan Surveillance 6 mo
Endocrine investigation Growth failure, diabetes insipidus, hypothalamic syndromes, galactorrhea, precocious or delayed puberty; hypothalamic and/or pituitary abnormality on CT or MRI None
Consultation with an audiologist and an otolaryngologist Aural discharge, impaired hearing 6 mo
Note.—ERCP = endoscopic retrograde cholangiopancreatography; IV = intravenous.



* Diagnostic findings on bronchoalveolar lavage obviate lung biopsy.



Although high serum levels of interleukin-17 (ILITA), which is a T-cell–specific cytokine involved in chronic inflammation processes, have been found in LCH with correlation to the activity of the disease. However, this is not expressed by CD207 t-cells in LCH lesions. [213, 214]

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Imaging Studies

See the tables above for appropriate imaging studies when LCH is suspected.

Radiographic imaging of lytic lesions of the skull reveals a punched-out pattern without evidence of periosteal reaction or marginal sclerosis, shown below.

Radiograph of lytic lesions of the skull reveals a Radiograph of lytic lesions of the skull reveals a punched-out pattern without evidence of periosteal reaction or marginal sclerosis.

Radionuclide bone scanning with technetium-99m polyphosphate may reveal a localized increased uptake. This study is complementary to plain radiography.

MRI sometimes helps in identifying lesions that cannot be detected with other modalities. For example, in one study, 28% of children with Langerhans cell histiocytosis had MRI findings suggestive of neurodegenerative disease. [83]

Neurologic findings may not always be correlated with the MRI results and may lag behind findings on MRI. [83, 104, 215]

CT and MRI can show the detailed anatomic pattern of involvement and can help in staging the disease. [216]

Positron emission tomography (PET) with 18F-fluoro-deoxyglucose (FDG) may be an effective tool for evaluating LCH and may provide additional information regarding the activity of the lesions. [187] In a retroactive study of F-18 FDG PET/MRI scan in 16 children with LCH, PET scanning produced less false-positive results in the follow-up of patients undergoing chemotherapy compared with MRI. However, the MRI had a higher sensitivity for primary staging. [217]

In neurodegenerative LCH, F-18 FDGPET may be a useful tool for an early diagnosis before neuroradiologic abnormalities appear. [218]

With pulmonary involvement, CT scanning is the best modality to reveal cysts and micronodular infiltrates.

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Other Tests

When pulmonary involvement occurs, pulmonary function may be abnormal. [120] {Re121} Diffuse cystic changes, nodular infiltrate, pleural effusion, and pneumothorax are known to occur.

Pulmonary function tests may reveal restrictive lung disease with decreased pulmonary volume and are critical components of follow-up in patients with pulmonary involvement. [120, 121]

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Procedures

Biopsy is needed to establish the diagnosis of Langerhans cell histiocytosis.

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Histologic Findings

Regardless of the clinical severity, the histopathology of Langerhans cell histiocytosis is generally uniform. To some extent, the location and age of the lesion may influence the histopathology of the disease. [219, 220] Early in the course of the disease, lesions tend to be cellular and contain aggregates of pathologic Langerhans cells (PLCs), intermediate cells, interdigitating cells, macrophages, T cells, and giant histiocytes. Mitotic figures number 0-23 per 10 high-power fields. [221]

Multinucleated giant cells are common, and some may exhibit phagocytosis. Lesions may also include eosinophils, necrotic cells, and Langerhans cell histiocytosis cells. With time, the cellularity and number of Langerhans cell histiocytosis cells are reduced, and macrophages and fibrosis become eminent. The infiltrates tend to destroy epithelial cells. Table 5 shows the phenotypes and cell-marker characteristics of Langerhans cell histiocytosis.

LCH is characterized by accumulation and proliferation of histiocytic cells displaying the phenotype of the pathological Langerhans cell, positive for CD207(+). [222]

Table 4. Cell Markers and Phenotypes of Histiocytic and Related Disorders (Open Table in a new window)

Cell Marker LCH SHML Follicular Dendritic Tumor Histiocytic Sarcoma Acute Monocytic Leukemia Anaplastic Large-Cell Lymphoma
CD1a + - - - - -
CD4 + + - + + +
CD21 - +/- + - - -
CD25 - + - + + ++
CD30 - - - - - ++
CD35 - + + - - -
CD45 - + - +/- + +/-
CD68 - + - + + +/-
ALK-1 - - - - - +
S-100 + + - +/1 - -
Lysozyme - + - + + -

 

Table 5 shows specialized stains for diagnosing these disorders, and Table 7 shows labeling pattern of histiocytes and dendritic cells.

Table 5. Stains for Diagnosing Histiocytosis (Open Table in a new window)

Type of Test Stain Mononuclear Phagocytic System Langerhans Cells Interdigitating Dendritic Cells Dendritic Reticulum Cells
Frozen-section enzyme histochemistry Nonspecific esterase - - - -
Acid phosphatase + - - -
ATPase - + + -
Lambda-mannosidase - + - -
5' nucleotidase - - - +
Immunohistochemistry CD14 (Leu M3/MY4) + + + +
CD11 C (Leu M5) + + + +
CD68 (EBM 11) + - - -
CD1a - + + -
Paraffin-section immunohistochemistry HLA-DR + + + +
CD68 + - - -
Mac 387 + - - -
Lysozyme + - - -
Alpha-antitrypsin + - - -
S-100 - + + -
Peanut agglutinin Diffuse Halo and dot Halo and dot -
Note.—ATPase = adenosine triphosphatase; HLA = human leukocyte antigen.

Table 6. Labeling Pattern of Histiocytes and Dendritic Cells (Open Table in a new window)

Marker Histiocytes Langerhans Cells Interdigitating Cells Follicular Dendritic Cells
CD1a 0 S 0 0
S-100 protein 0 S S W
HLA-DR S S S W
CD45 S W W 0
Alpha-naphthyl acetate esterase S W W W
ATPase W S S S
Fascin 0 0 S S
R4/23 0 0 0 S
Note.—0 = no staining; S = strong and constant; W = weak or inconstant.

Langerhans cells express CD1a antigen, HLA-DR, and a subunit S-100 protein. See the image below.

Photomicrograph shows sample of Langerhans cell hi Photomicrograph shows sample of Langerhans cell histiocytosis (LCH) that immunocytochemically stains positive for S-100 protein.

Upon morphologic evaluation, cells are 12 µm in diameter with moderately abundant cytoplasm and a medium-sized folded, indented, or lobulated nucleus that has vesicular chromatin with 1-3 nucleoli and an elongated central groove producing a coffee-bean appearance. [223, 224, 225]

The histopathology of the Langerhans cell histiocytosis does not appear to be prognostic of the outcome of the disease. [221] The aggregation of Langerhans cells is observed in various disorders, such as lymphomas (eg, Hodgkin disease), lung cancer, and thyroid cancer. However, these disorders are secondary and resolve with control of the primary disorder. [6, 226]

In LCH, the cytoplasm and, rarely, the nucleus contain the characteristic structures termed Birbeck granules.

These trilaminar organelles are 190-360 nm long and approximately 33 nm wide, with a central striated line. These are derived from cytoplasmic membrane and are involved in receptor (T6)-mediated and non–receptor-mediated endocytosis. An electron microscopic finding of racquet-shaped granules in the cells can be helpful in confirming the pathologic diagnosis.

Relatively nonspecific findings include cytoplasmic, trilaminar, membranous loops and laminated substructures of lysosomes. [227] Langerin is a type II transmembrane C-type lectin associated with formation of Birbeck granules. This can be used as a selective marker for Langerhans cells and cells involved in Langerhans cell histiocytosis. Langerin expression is present in most cases of Langerhans cell histiocytosis. [228] Immunohistochemical determination of Langerin and CD1a may be used to separate Langerhans cell histiocytosis from other histiocyte proliferations. (However, a study by Lommatzsch et al suggested that in pulmonary LCH, CD80 is a more sensitive and specific marker of the disease than CD1a, with the expression of CD80 being low on myeloid dendritic cells in the bronchoalveolar lavage fluid of these patients. [229] )

Birbeck granules are the products of internalization of complexes originating from cell-membrane antigens and corresponding antibodies. CD1a antigen can be detected in paraffin-embedded tissues to provide for reliable diagnostic testing. [230, 231] ATPase peanut lectin and alpha-D-mannoside can be positive in the dendritic reticulum. An electron microscopic finding of racquet-shaped granules in the cells can be helpful to confirm the pathologic diagnosis. [129, 227, 232] Enzyme histochemistry and immunocytochemistry can also aid in the diagnosis of histiocytosis. [46]

The organs and tissues most commonly involved are the bones, skin, lymph nodes, [125] bone marrow, lungs, [121] brain, [233] hypothalamic-pituitary axis, spleen, liver, GI tract, and orbits. [105] Multisystemic involvement is common. [234] Bones can be involved in isolation or as a part of multisystemic disease. The skull or large bones are often involved. Bone lesions may contain an accumulation of eosinophils, multinucleated giant histiocytes, necrosis, and hemorrhage. The term eosinophilic granuloma was previously used to describe single bone lesions of Langerhans cell histiocytosis.

Cutaneous involvement can also be singular or can be a part of generalized involvement. [115, 117, 118, 235] A spontaneously regressing nodular form of cutaneous Langerhans cell histiocytosis is reported in infants; it involves deep dermis with a nodular aggregate of histiocyte and is called congenital self-healing reticulohistiocytosis. [9, 116, 119, 236] In general, skin lesions have a pattern of diffuse or multifocal nodular aggregation of PLCs deep in the papillary dermis; destruction of epidermal-dermal interface; and infiltration of histiocytes, T-cell lymphocytes, and eosinophils. The lymph nodes and thymus can be involved as a primary site or as a part of multiorgan and systemic involvement. The most common sites are the cervical, inguinal, axillary mediastinal, and retroperitoneal areas. [123, 237]

Five histologic motifs have been recognized. These include sinusoidal, limited sinusoidal, epithelioid granulomatous, partial effacement, and total effacement. However, the prognostic significance of these appearances is not proven. The cellular composition includes Langerhans cells, macrophages, multinucleated giant histiocytes, T lymphocytes, and eosinophils. [223, 224] Histologic involvement may have different appearances in lesions from separate sites. In some instances, lymph nodes are massive and cause airway obstructions.

Suppuration resembling infection has been reported. [124] The bone marrow may be normal or heavily involved. Bone marrow lesions may be focal with pathologic infiltration of Langerhans cells or may contain neutrophils, eosinophils, lymphocytes, multinucleated cells, fibrosis, and (in rare cases) eosinophilic accumulation. Pulmonary involvement is more common in adults than in children (especially adults with a history of smoking), but it occurs in 20-40% of all patients. [120, 121] Small cysts can coalesce and rupture into the pleural cavity, leading to pneumothorax. [122]

CNS involvement, including pituitary involvement, is often part of systemic disease. [238, 239, 240] The CNS is rarely a primary site of Langerhans cell histiocytosis involvement. [233, 241, 242, 243, 244, 245, 246, 247] The most common site of CNS involvement in patients with Langerhans cell histiocytosis is the hypothalamic-pituitary axis, which results in diabetes insipidus in 10-50% of patients. [248] Histiocytosis can be associated with cerebellar white matter abnormalities. [246] Pathologic changes in the cerebellum, basal ganglia, and pons have been reported. [211]

Local involvement of the temporal lobe has also been observed and represents a neurodegenerative disorder that is thought to be similar to a paraneoplastic syndrome. [246] The neurodegenerative changes may occur well before, during, or long after diagnosis of histiocytosis. Manifestation may include cerebellar and pyramidal dysfunction, hormonal abnormalities, ataxia, spasticity, and cognitive problems. [246, 212] MRI abnormalities in cerebellar white matter, brain stem, basal ganglia and cerebral white matter are found. [165, 246]

Involvement of the anterior pituitary is relatively uncommon. However, it can result in growth-hormone deficiency or, in rare cases, panhypopituitarism. [112] Cerebellar dysfunction with in coordination and white matter changes has been reported. [90] Langerhans cell histiocytosis may affect the spleen and liver. Primary involvement of the liver is uncommon. [249] Involvement of the liver is often part of multiorgan disease. Even when PLCs are not present, sclerosing cholangitis can be observed. [249] Liver infiltration may result in tissue damage and increased enzyme levels, jaundice, coagulation disorders, and hypoalbuminemia.

Involvement of the GI tract is probably more common than is clinically recognized. [250] Lesions in the stomach, small bowel, colon, and rectum have been reported. [250, 251, 252, 253] The usual pathology of GI involvement with Langerhans cell histiocytosis includes infiltration of lamina propria and submucosa with glandular, mucosal, and, possibly, villus atrophy. Diarrhea and GI bleeding can be the presenting features of the disease. Involvement of the pancreas is rare. [254]

Langerhans cell histiocytosis rarely involves the intraocular structures. Isolated eye disease has been reported. [207] Lytic lesions of the orbit and resulting soft-tissue extension may cause proptosis. Ptosis and optic atrophy rarely occur. Patients with ear involvement often present with chronic otorrhea, lesions of the external auditory meatus, middle-ear involvement, and mastoid involvement. Although rare, involvement of the genital tract has been reported. [255, 256, 257]

In patients with Langerhans cell histiocytosis and hematopoietic involvement, Langerhans cell infiltration is often not evident; however, other abnormalities are common. These include abnormal M:E ratio; hyperplasia and dysplasia of megakaryocytes, including mononucleated and bilobed micromegakaryocytes and paratrabecular and grouped megakaryocytes; existence of neutrophil remnants in megakaryocytes (emperipolesis); increased numbers of macrophages; hemophagocytosis; and myelofibrosis. [258]

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