eMedicine Specialties > Dermatology > Malignant Neoplasms

Langerhans Cell Histiocytosis: Differential Diagnoses & Workup

Author: Christopher R Shea, MD, Professor and Chief, Section of Dermatology, Department of Medicine, University of Chicago
Coauthor(s): Markus D Boos, PhD, Medical Scientist Training Program, Pritzker School of Medicine, University of Chicago
Contributor Information and Disclosures

Updated: Aug 26, 2009

Differential Diagnoses

Acrodermatitis Enteropathica
Incontinentia Pigmenti
Acropustulosis of Infancy
Mastocytosis
Eosinophilic Pustular Folliculitis
Seborrheic Dermatitis
Erythema Toxicum Neonatorum
Wiskott-Aldrich Syndrome

Other Problems to Be Considered

Rosai-Dorfman disease
Xanthoma disseminatum
Neonatal pustular melanosis
Congenital candidiasis
Perinatal listeriosis
Perinatal herpes simplex
Neonatal varicella
Leukemia
Lymphoma
Myeloma
Malignant melanoma19

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.20
    • In case of anemia, leukopenia, or thrombocytopenia, a bone marrow aspirate is indicated.
    • Coagulation studies may be indicated.
  • Liver function tests (including total protein, albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase): If liver function test results are abnormal, a liver biopsy should be considered to differentiate Langerhans cell histiocytosis from cirrhosis.
  • Urinalysis: Urine specific gravity and osmolality are measured after overnight water deprivation to screen for diabetes insipidus.

Imaging Studies

  • Chest radiography (posteroanterior and lateral)
    • Langerhans cell histiocytosis 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.11
    • 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 Langerhans cell histiocytosis presents as a single osteolytic lesion, usually affecting long or flat bones (in children, the calvaria and the femur; in adults, the ribs).
    • Multifocal Langerhans cell histiocytosis show osteolytic lesions involving the calvaria, the sella turcica, the mandible, the vertebrae, and/or the long bones of the upper extremities.
    • 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.
    • 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.21
    • MRI of the head and spine is also useful to identify craniofacial or vertebral bone lesions.
  • Fluorodeoxyglucose (FDG) positron-emission tomography (PET) scanning may also be used when evaluating patients for Langerhans cell histiocytosis.
    • 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 Langerhans cell histiocytosis.22 Notably, FDG-PET scanning has poor sensitivity for spinal lesions.
    • FDG-PET scanning is able to identify Langerhans cell histiocytosis 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.22
  • Also see Eosinophilic Granuloma, Skeletal.


On a plain skull radiograph, lesions are typicall...

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

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On a plain skull radiograph, lesions are typicall...

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

Other Tests

  • Pulmonary function testing may help identify otherwise asymptomatic pulmonary involvement.11
  • A small bowel series and biopsy are indicated in cases of unexplained diarrhea, failure to thrive, and malabsorption.
  • 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.23

Procedures

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

Histologic Findings

The histologic picture unifies the varied presentations of Langerhans cell histiocytosis, which are influenced by location and age of the lesion. 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 (LCs).24,25 The latter cell resembles the normal LC 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 LCs. 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. LCs also contain laminated substructures of lysosomes, tuboreticular structures, and trilaminar membranous loops.

Electron microscopy. Tennis racquet form of Birbe...

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

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Electron microscopy. Tennis racquet form of Birbe...

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. Langerhans cell histiocytosis cells are positive for major histocompatibility (MHC) class II and CD1a. Expression of langerin (CD207), a LC-restricted protein that induces the formation of Birbeck granules and is constitutively associated with them, is a highly specific marker of LCs.26 The pathologic LC expresses phenotypic markers of an activated normal LC in its early stages. Fine-needle aspiration combined with immunohistochemistry of the cell preparation plays an important role in documenting organ involvement by Langerhans cell histiocytosis.

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).

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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-...

High-power views. Diffuse immunoreactivity for S-100 protein (right). Langerhans cells and lymphocytes (left, hematoxylin and eosin).

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High-power views. Diffuse immunoreactivity for S-...

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).

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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 Langerhans cell histiocytosis, 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.

Staging

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

  • SS-Langerhans cell histiocytosis 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-Langerhans cell histiocytosis is defined as involvement of 2 or more organs or organ systems, irrespective of involvement of "risk organs." Typically, their involvement indicates a worse prognosis.
    • Spleen
    • Liver
    • Lung

More on Langerhans Cell Histiocytosis

Overview: Langerhans Cell Histiocytosis
Differential Diagnoses & Workup: Langerhans Cell Histiocytosis
Treatment & Medication: Langerhans Cell Histiocytosis
Follow-up: Langerhans Cell Histiocytosis
Multimedia: Langerhans Cell Histiocytosis
References
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  79. Willman CL, McClain KL. An update on clonality, cytokines, and viral etiology in Langerhans cell histiocytosis. Hematol Oncol Clin North Am. Apr 1998;12(2):407-16. [Medline].

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Further Reading

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Keywords

Langerhans cell histiocytosis, LCH, histiocytosis X, Langerhans cell granulomatosis, type II histiocytosis, nonlipid reticuloendotheliosis, Langerhans cells, LCs

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Contributor Information and Disclosures

Author

Christopher R Shea, MD, Professor and Chief, Section of Dermatology, Department of Medicine, University of Chicago
Christopher R Shea, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Society of Dermatopathology, Arthur Purdy Stout Society, Association of Professors of Dermatology, Chicago Dermatological Society, Dermatology Foundation, Illinois Dermatological Society, International Society of Dermatopathology, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Coauthor(s)

Markus D Boos, PhD, Medical Scientist Training Program, Pritzker School of Medicine, University of Chicago
Disclosure: Nothing to disclose.

Medical Editor

Bernice R Krafchik, MBChB, FRCPC, Professor Emeritus, Department of Pediatrics, Section of Dermatology, University of Toronto
Bernice R Krafchik, MBChB, FRCPC is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, Canadian Medical Association, College of Physicians and Surgeons of Ontario, Royal College of Physicians and Surgeons of Canada, and Society for Pediatric Dermatology
Disclosure: Nothing to disclose.

Pharmacy Editor

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey Meffert, MD, Assistant Clinical Professor of Dermatology, University of Texas Health Science Center-San Antonio
Jeffrey Meffert, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Association of Military Dermatologists, and Texas Dermatological Society
Disclosure: Nothing to disclose.

CME Editor

Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania
Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology
Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds None; Genentech Consulting fee Consulting; Centocor Consulting fee Consulting; Centocor Grant/research funds None; Covance Consulting fee Consulting; Shire  Consulting

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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