Histiocytosis Differential Diagnoses

  • Author: Cameron K Tebbi, MD; Chief Editor: Robert J Arceci, MD, PhD  more...
Updated: Jun 15, 2016

Diagnostic Considerations

Establishing a diagnosis of Langerhans cell histiocytosis (LCH) largely depends on a high degree of suspicion. With the widely varied presentations of histiocytosis disorders, the differential diagnosis can be broad. Clinical differential diagnoses range from seborrheic dermatitis and chronic otitis media to acute leukemias, lymphomas, myeloproliferative disorders, storage diseases, Rosai-Dorfman syndrome, and solid tumors.

Bone involvement

The differential diagnoses of bone lesions include malignant disorders (eg, metastatic neoplasms), neuroblastomas, primary sarcomas of the bone, and even leukemias. The lesions of Langerhans cell histiocytosis can involve any bone and may be singular or multicentric.[203, 204]

Other lesions that radiologically produce bone defects must be considered. These include congenital disorders, such as meningioma, hemangioma, neurofibromatosis, congenital or developmental defect (eg, lacunar skull), parietal foramina, parietal thinning, pacchionian depressions, primary cholesteatoma, arachnoid cyst, dermoid cyst, meningocele or encephalocele, arteriovenous malformation, fibrous dysplasia, cysts, sarcoidosis, hyperthyroidism, and radiation necrosis.

Because the initial signs and symptoms of patients with bone disease often include local pain and swelling,[203, 205] infections such as osteomyelitis and tuberculosis (TB) should be considered. Paget disease and calvarial doughnut, although rare, must also be included in the differential diagnosis of bone lesions.

Skin disorders

Skin lesions of Langerhans cell histiocytosis must be differentiated from other dermatologic disorders, such as diaper rash, seborrheic dermatitis, juvenile xanthogranulomas, xanthoma disseminatum, and various other skin eruptions.

Lymphatic disorders

In patients with localized disease (especially those in whom solitary nodes are present), malignant lymphoma, malignant histiocytosis, metastatic disorders, and leukemic infiltrates, and (uncommonly) Spitz nevus and mastocytosis must be considered. The differential diagnosis of enlarged lymph nodes also includes infectious disorders, granulomatous diseases, and lymphomas.

Otorrhea must be distinguished from infectious otitis media. Oral lesions should be differentiated from relatively common maxillofacial bone and soft tissue lesions.[206]

With multisystemic disease, Langerhans cell histiocytosis must be distinguished from familial hemophagocytic lymphohistiocytosis (FHLH) and viral-associated hemophagocytic syndrome.

Lung, liver,[76] and GI involvement are often, but not always, associated with systemic disease and must be differentiated from immune deficiency, leukemia, and metastatic solid tumors. Single-system disease has been reported in the eyes[207] and lungs[20, 208] in patients, including a newborn.[209] Serum KL-6 levels have been used as a marker and appeared to be correlated with pulmonary involvement in an infant with Langerhans cell histiocytosis.[210]

In patients with pituitary and hypothalamic lesions, other causes of diabetes insipidus, such as adenomas, craniopharyngioma, sellar chondromas, meningiomas, gangliocytomas, hypothalamic and optic gliomas, and germ-cell tumors, should be considered.

Involvement of hypothalamic-pituitary region and neurodegenerative changes in the cerebellum, basal ganglia, and pons are seen in Langerhans cell histiocytosis.[211] Intracerebral Langerhans cell histiocytosis is rare, but a case report describes involvement of temporal lobe.[212]

Genetic syndromes with chromosomal disorders, such as multiple endocrine neoplasia type 1 (MEN-1), familial acromegaly, McCune-Albright syndrome, and Carney syndrome, can also be associated with pituitary tumors.

Other histiocytosis disorders, such as sinus hyperplasia and sinus histiocytosis with sinus histiocytosis with massive lymphadenopathy (SHML), or Rosai-Dorfman disease, must be differentiated from viral, bacterial, acid-fast bacterial, and parasitic infections. These infections may produce signs, symptoms, and hematologic findings similar to those of SHML. When tests for rheumatoid factor and lupus erythematosus yield positive results, these disorders may need to be considered.

Differential Diagnoses

Contributor Information and Disclosures

Cameron K Tebbi, MD Professor of Pediatrics, Chief, Division of Pediatric Hematology-Oncology, University of South Florida Morsani College of Medicine; Director, Pediatric Hematology/Oncology, Tampa General Hospital and Tampa Region, Children's Medical Services, Department of Health, State of Florida

Cameron K Tebbi, MD is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, Histiocyte Society, International Society of Paediatric Oncology

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Gary D Crouch, MD Associate Professor, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Uniformed Services University of the Health Sciences

Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Hematology

Disclosure: Nothing to disclose.

Chief Editor

Robert J Arceci, MD, PhD Director, Children’s Center for Cancer and Blood Disorders, Department of Hematology/Oncology, Co-Director of the Ron Matricaria Institute of Molecular Medicine, Phoenix Children’s Hospital; Editor-in-Chief, Pediatric Blood and Cancer; Professor, Department of Child Health, University of Arizona College of Medicine

Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, American Association for Cancer Research, American Pediatric Society, American Society of Hematology, American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.


Gary R Jones, MD Associate Medical Director, Clinical Development, Berlex Laboratories

Gary R Jones, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, and Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Thomas W Loew, MD Clinical Professor of Pediatrics, Division Director of Pediatric Hematology/Oncology, University of Missouri Children's Hospital

Thomas W Loew, MD is a member of the following medical societies: American Academy of Pediatrics, American Academy of Pediatrics, American College of Physician Executives, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and Children's Oncology Group

Disclosure: Genzyme Grant/research funds Independent contractor; Genzyme Honoraria Speaking and teaching; Amicus Grant/research funds Independent contractor; Purdue Pharmaceuticals Grant/research funds Independent contractor

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Erosion of the gingiva that creates the appearance of premature eruption of the teeth in a young child.
Clinically detectable skull lesions in a child with advanced Langerhans cell histiocytosis (LCH).
Cutaneous Langerhans cell histiocytosis (LCH) in a child. Skin infiltrates are seen on the face, and the chest has maculoerythematous, petechial, and xanthomatous appearance.
Severe scalp disease in a patient with scaly erythematous patches. Patches of alopecia are present. The lesions were not pruritic.
Photomicrograph shows sample of Langerhans cell histiocytosis (LCH) that immunocytochemically stains positive for S-100 protein.
Photomicrograph of Langerhans cell histiocytosis (LCH) stained with hematoxylin and eosin. The characteristic Langerhans cells have reniform or convoluted nuclei and abundant cytoplasm.
Transmission electron micrograph shows a diagnostic rod-shaped Langerhans Birbeck granule.
Transmission electron photomicrograph shows Langerhans cells characterized by convoluted nuclear contours and abundant cytoplasm.
Radiograph of lytic lesions of the skull reveals a punched-out pattern without evidence of periosteal reaction or marginal sclerosis.
Three-dimensional reconstructive view of skull lesions in a child with Langerhans cell histiocytosis.
Genetic defect/syndrome Genetic Defect Protein Frequency % FHL cases (location) Mutation Type Function
FHLH1 Unknown (9 gr 21.3-22) Rare



(10 gr 21-22)

Perforin 20-40%

Often in blacks, Turks, Japanese

>50 deletions, non-sense and missense mutations; heterozygosity for C272T, A91V substitution Pore-forming protein

(17 gr 25)

MUNC 13-4 20-30%

Worldwide, Turks, Kurds, US, Europe

>18 deep intronic mutations and large inversion Vesicle forming

(6 gr 24)

Syntaxin-11 10-20%

Worldwide, Central Europe, Turkey, Saudi Arabia

Variable Vesicle transport and fusion


MUNC 18-2 5-20%

Worldwide ,Italy, UK, Kuwait, Pakistan, North America

Multiple motatronin MUNC 18-2, impaired binding to syntaxin-11 Vesicle transport and fusion SNARE complex assembly and disassembly
Immune deficiency and albinism
Chédiak-Higashi syndrome LYST LYST Rare


Size function of lytic granules
Griscelli syndrome type II Rab 27A Rab 27A Rare

Northern Europe

Vesicle docking, granule movement
Hermansky-Pudlak syndrome Type II AP3B1 Rare


Vesicle biogenesis, protein sorting
Primary Immune Deficiencies
X-linked lymphoproliferative disease Type I SH2D1A SAP Worldwide Signal transduction, activation of lymphocytes
X-linked lymphoproliferative disease Type II BIRC4 XIAP Worldwide Inhibition of apoptosis
ITK deficiency ITK ITK Worldwide T-cell kinase
Table 2. Laboratory and Imaging Studies in Patients With LCH
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. Indication for Laboratory Evaluations Based on Findings in LCH
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.

Table 4. Cell Markers and Phenotypes of Histiocytic and Related Disorders
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. Stains for Diagnosing Histiocytosis
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
Marker Histiocytes Langerhans Cells Interdigitating Cells Follicular Dendritic Cells
CD1a 0 S 0 0
S-100 protein 0 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.
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