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Histiocytosis Follow-up

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

Further Outpatient Care

Long-term follow-up care by a multidisciplinary team with knowledge of Langerhans cell histiocytosis (LCH) is critical for all patients, not just those with extensive multisystem disease or those treated with systemic chemotherapy.[304]

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Inpatient & Outpatient Medications

See the Medication section.

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Complications

Patients with Langerhans cell histiocytosis, especially those with multisystemic disease or multifocal skeletal involvement with a relapsing course, have a significant risk of developing adverse late sequelae from their disease or therapy.

  • Some estimate that more than one half of patients have at least 1 clinically significant late effect. Therefore, long-term follow-up is of utmost importance.
  • In a study of a subset of 40 patients followed up for a median of 16 years, 51% had pronounced late sequelae. [305] Those with multisystemic involvement had the greatest risk of late effects. They had 19% rate of CNS sequelae.
  • Some of the most important late effects involve the CNS and include diabetes insipidus and other deficiencies of hypothalamic-pituitary axis. These effects lead to stunted growth and failure to achieve sexual maturity.
  • Other late effects include orthopedic problems (particularly of the vertebral column), dental issues surrounding the loss of teeth and jawbone mass, hearing loss due to mastoid and inner-ear involvement (for which patients require cochlear implantation), [306] and scarring of involved areas of skin.
  • In patients who develop pulmonary or hepatic fibrosis, progression of disease may result in a need for organ transplantation.
  • Patients with Langerhans cell histiocytosis may have a lifelong susceptibility to pulmonary disease associated with cigarette smoking.
  • Pulmonary involvement of the young child may be extensive and characterized by micronodular involvement and cystic formation. However, adequate treatment can resolve the disease and normalize lung findings and function.

Neurocognitive and psychological problems are more frequently recognized likely because of intensified patient follow-up.

  • Patients with neurodegenerative CNS involvement often present with ataxia and decreased coordination.
  • Pathologic examination of biopsy material usually reveals gliosis, some neuronal cell death, and, sometimes, areas of active Langerhans cell histiocytosis. Although the condition of neurodegenerative involvement of the CNS can remain stable for years, clinical progression may occur in the absence of MRI findings. No definitive treatment has been developed for this manifestation of Langerhans cell histiocytosis. Radiation therapy does not appear to provide any benefits.
  • Neuropsychological sequelae of Langerhans cell histiocytosis can be substantial. In one study of 10 children with Langerhans cell histiocytosis (aged 5-17 y), 3 scored one standard deviation or more below the reference range on perceptual tasks, and 4 of 10 children had deficiency in performance on perceptual tasks. Decreases in attention, speed of performance, verbal working memory, and visual recall were noted. [307]

Proliferation of Kupffer cells may accompany the initial hepatic involvement with Langerhans cell histiocytosis and subsequently develop into sclerosing cholangitis. This, in turn, may lead to fibrosis and liver failure. Lung and liver transplantation have been successful in patients who develop organ failure due to progressive fibrosis.

Secondary malignancies are reported in patients with Langerhans cell histiocytosis. Malignancies include secondary leukemias (usually acute myelogenous leukemias) caused by exposures to alkylating agents and, in recent reports, to etoposide. Other cancers include thyroid carcinoma, lymphomas, and CNS tumors.

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Prognosis

The location of the lesions and the extent of the disease substantially affect the course of the disease and the patient’s prognosis.

  • Involvement of risk organs (hemopoietic system, liver, spleen, and lungs) at diagnosis and failure of response to the initial therapy are poor prognostic signs. Reactivation of risk organs is relatively rare. In one study, this reactivation occurred in 2% of patients. [308] Involvement of the risk organs at reactivation had relatively low impact on survival.
  • The degree of organ involvement is correlated with the patient’s prognosis.
  • Although Langerhans cell histiocytosis involvement of the spine causes lesions and, sometimes, asymmetric collapse, it is not usually associated with long-term sequelae and deformity. Therefore, aggressive surgical management of this involvement is generally not indicated.
  • Rapidity of the response to chemotherapy may also have prognostic value.
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Patient Education

Known genetic factors, when applicable, must be explained to the patients and their families.

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Contributor Information and Disclosures
Author

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

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, International Society of Paediatric Oncology, Histiocyte Society

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.

Acknowledgements

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



Pakistan



FHLH2 PRF



(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
FHLH3 UNC13D



(17 gr 25)



MUNC 13-4 20-30%



Worldwide, Turks, Kurds, US, Europe



>18 deep intronic mutations and large inversion Vesicle forming
FHLH4 STX 11



(6 gr 24)



Syntaxin-11 10-20%



Worldwide, Central Europe, Turkey, Saudi Arabia



Variable Vesicle transport and fusion
FHLH5 STXBP2



(19p)



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



Worldwide



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



Worldwide



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
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.
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