ArticlePDF Available

Langerhans cell histiocytosis: A multisystem disorder

Authors:
A Munir
A Munir
A Munir
  • This person is not on ResearchGate, or hasn't claimed this research yet.
Nicola Leech at The Newcastle upon Tyne Hospitals NHS Foundation Trust
Nicola Leech
Kevin P Windebank at Newcastle University
Kevin P Windebank
J McLelland
J McLelland
J McLelland
  • This person is not on ResearchGate, or hasn't claimed this research yet.
Show all 8 authorsHide
Download full-text PDF
Read full-text
Download citation

Abstract and Figures

Langerhans cell histiocytosis can involve single or multiple organ/tissue systems and may go undiagnosed for years until it enters the clinician's differential diagnosis framework. We report on a young patient who initially presented with diabetes insipidus and subsequently with pyrexia of unknown origin. She progressed from single system Langerhans cell histiocytosis to multisystem involvement and remains in long-term remission following chemotherapy.
Figures - uploaded by Richard Quinton
Author content
All figure content in this area was uploaded by Richard Quinton
Content may be subject to copyright.
Content uploaded by Richard Quinton
Author content
All content in this area was uploaded by Richard Quinton
Content may be subject to copyright.
311
clinical
Langerhans cell histiocytosis: a multisystem
disorder
ABSTRACT Langerhans cell histiocytosis can involve single or multiple organ/tissue
systems and may go undiagnosed for years until it enters the clinician’s differential
diagnosis framework. We report on a young patient who initially presented with
diabetes insipidus and subsequently with pyrexia of unknown origin. She progressed
from single system Langerhans cell histiocytosis to multisystem involvement and
remains in long-term remission following chemotherapy.
KeywoRdS Langerhans cell histiocytosis, diabetes insipidus
deClARATion of inTeReSTS No conflicts of interest declared.
1A Munir, 2N Leech, 3KP Windebank, 4J McLelland, 5GL Jones, 6D Mitra, 7A Jenkins, 8R Quinton
1Specialty Registrar Diabetes and Endocrinology; 2Consultant Diabetologist; 3Consultant Paediatric and Adolescent Oncology; 4Consultant
Dermatologist; 5Consultant Haematologist; 6Consultant Radiologist; 7Consultant Neurosurgeon; 8Consultant Endocrinologist, Royal Victoria
Infirmary, Newcastle upon Tyne, UK
Correspondence to A Munir
Royal Victoria Infirmary,
Queen Victoria Road,
Newcastle upon Tyne
NE1 4LP, UK
tel. +44 (0)776 723 5182
e-mail atif113_2000@yahoo.co.uk
Cases of the quarter
A high index of suspicion is required to consider
Langerhans cell histiocytosis (LCH) as a possible unifying
differential diagnosis in patients presenting with
multisystem manifestations, which can lead to early
diagnosis and hence better treatment outcomes. In this
report we outline an index case to highlight the difficulties
in diagnosis and recognition. Patients should be managed
in centres with appropriate expertise and enrolled in
ongoing clinical trials to provide more insight into the
natural history of the disease and treatment outcomes.
CASe RepoRT
A 24-year-old woman with type 1 diabetes mellitus
presented with new-onset diabetes insipidus and was
started on desmopressin. Anterior pituitary function was
normal, but a magnetic resonance imaging (MRI) scan
demonstrated pituitary stalk thickening. Although
hypothalamic LCH was among the differential diagnoses
at this point, the history of recurrent pneumothoraces
(which would have enabled a near-definitive clinical
diagnosis of multisystem LCH) was not appreciated. She
subsequently failed to attend for planned endocrine
treatment and imaging follow-up, presenting 18 months
later with weight gain, amenorrhoea, confusion, memory
impairment, pyrexia of unknown origin and deranged
liver function tests. There was also a history of vulval
irritation, for which she had been self-medicating with
antifungals, along with rapidly evolving pruritic, non-
genital skin lesions.
Endocrine evaluation confirmed panhypopituitarism and
severe vitamin D deficiency. Abdominal imaging revealed
multiple focal deposits in her liver that appeared
infective or neoplastic, but on liver biopsy appearances
were more consistent with cholangitis and immuno-
histochemistry was inconclusive. A repeat pituitary MRI
scan showed an inflammatory hypothalamic mass (that
subsequently showed hyperintense uptake on F18
fluorodeoxyglucose positron emission tomography/
computed tomography [18-FDG PET-CT]) with a normal
appearing pituitary gland. A stereotactic biopsy of this
mass showed S100 proteins and cluster of differentiation
(CD1a) immunopositive cells, establishing a diagnosis of
LCH. Further investigations were arranged to determine
if this was the unifying diagnosis for her other systemic
manifestations and to evaluate the extent of the disease.
A biopsy of her skin rash also showed abundant
histiocytes that also stained positive for CD1a and S100
and a high-resolution chest CT scan revealed multiple
cysts and nodules bilaterally, typical of LCH, although
bone marrow examination did not show any involvement.
With a proven diagnosis of multisystem LCH and
initiation of appropriate endocrine replacement therapy,
the focus shifted to disease-specific therapy. Although
neurocognitive assessment was influenced by a strong
element of anxiety, there was a definite defect of short-
term memory and information-retention. We were
concerned that caudal spread of the neuroinflammatory
process towards the mamillary bodies might result in an
irreversible Korsakoff-like syndrome that could prove
damaging to her prospects of independent living,
particularly in the context of poorly-controlled type 1
diabetes. However, her insulin requirements indicated
significant obesity-related insulin resistance, making us
reluctant to initiate conventional therapy with high-dose
steroids, with the risk of inducing major destabilisation
of glycaemic control.
There were no published guidelines at the time of
diagnosis and her treatment decisions were taken in
view of the evidence available. She failed to respond to a
J R Coll Physicians Edinb 2012; 42:311–3
doi:10.4997/JRCPE.2012.406
© 2012 Royal College of Physicians of Edinburgh
312
clinical
therapeutic trial of the protein kinase inhibitor imatinib,
but experienced significant clinical and radiologic
improvement over the course of eight cycles of the
antimetabolite agent cladribine. Systemic symptoms,
including pyrexia, resolved and neurocognitive function
improved, with subsequent MRI scans showing major
reduction in the size of the inflammatory hypothalamic
mass after just two cycles of cladribine, which reached a
plateau with subsequent courses. However, her skin
lesions remained problematic, but fortunately responded
to periodic pamidronate infusions and, overall, her
disease remains in remission. A recent 18-FDG PET CT
scan did not show any abnormal uptake.
diSCuSSion
Histiocytosis encompasses a group of diverse idiopathic
disorders which have a common primary trigger:
accumulation of monocytes, macrophages and dendritic
cells in the affected tissues. Viral infections, cellular and
immune dysfunction, neoplastic mechanisms, genetic
factors and their combinations have been implicated in
aetiology and pathogenesis. Estimated prevalence is
one to two cases of LCH per million population. It can
affect all age groups, ranging from neonates to adults and
can be local or systemic.1–7 Patients may be asymptomatic.
Presenting symptoms or signs from published studies in
order of decreasing frequency are: skin rash, dyspnoea,
polydipsia and polyuria, bone pain, lymphadenopathy,
weight loss, fever, gingival hypertrophy, ataxia and
memory problems.
Dermatological manifestations include brown to purplish
papules. Cystic or nodular lesions within the lung can
lead to the destruction of parenchymal tissue, so a
spontaneous pneumothorax is often the first sign of
LCH. Endocrine manifestations include diabetes insipidus,
anterior hypopituitarism and a goitre. About 80% of
patients presenting with diabetes insipidus develop a
permanent deficiency of anterior pituitary hormones.8,9
Primary sites of bone involvement in order of frequency
include the jaw, skull, vertebrae, pelvis, extremities and
ribs. Central nervous system (CNS) involvement results
in inflammation, followed by neurodegeneration. Splenic
involvement can cause splenomegaly. Hepatic mani-
festations include hepatomegaly and tumour-like or
cystic lesions which can be accompanied by elevated
liver enzymes, hypoalbuminaemia or clotting factor
deficiencies. Sclerosing cholangitis is a recognised
serious complication, with liver biopsy showing
lymphocytic infiltration of the biliary tree, though classic
immunopositive histiocytes are rarely found.10,11 Bone
marrow involvement is uncommon in adults, but can be
associated with anaemia or leukopenia.
The length of time from the first symptom(s) to diagnosis
can be very long. Diabetes insipidus is frequently the
initial symptom, sometimes starting in childhood.
Langerhans cell histiocytosis may remain unrecognised
until other systemic symptoms occur later in life. Except
for pulmonary LCH, which can be diagnosed on high
resolution computed tomography (HRCT) imaging
characteristics alone, the diagnosis is based on histological
and immunophenotypic examination of lesional tissue
(biopsy of CNS tissue or skin lesion, or bone marrow
exam), with core features being the morphologic
identification of the characteristic LCH cells. Positive
staining with CD1a and/or langerin (CD207) is required
for definitive diagnosis.12 A PET scan is considered to be
the most sensitive functional test to detect LCH lesions
and can be used to evaluate response to therapy.
Clinical classification is based on the extent of
involvement (Table 1). Optimal treatment has not been
established. Single-system disease may warrant
monitoring or local therapy.13 Significant disease variation
and spontaneous regression in up to 20% of patients
complicates comparisons of current therapies. Several
agents including chemotherapy have been effective in
treatment. According to Histiocytosis Society guidance
(2009) a combination of prednisolone and vinblastine
has been proven to be effective and is therefore the
standard initial therapy for all patients who should
receive systemic therapy (Table 2).14–16 Long-term survival
Single-system LCH
(one organ/system involved, uni- or multifocal)
• Bone: unifocal (single bone) or multifocal (>1 bone)
• Skin
• Lymph node (not the draining lymph node of another
LCH lesion)
• Lungs
• Hypothalamic-pituitary/central nervous system
• Other (e.g. thyroid, thymus)
Multisystem LCH
(two or more organs/systems involved)
• With or without involvement of ‘risk organs’
(haematopoietic, liver, spleen, lung)
TABLE 1 Clinical classification of Langerhans cell histiocytosis
• Single-system LCH with ‘central nervous system risk’
lesions (craniofacial lesions)
• Single-system LCH with multifocal bone lesions
• Single-system LCH with ‘special site’ lesions
(odontoid peg or vertebral lesions with soft tissue
extension)
• Multisystem LCH with/without involvement of ‘risk
organs’ (haematopoietic, liver, spleen, lung)
TABLE 2 Indications for systemic therapy in Langerhans cell
histiocytosis
J R Coll Physicians Edinb 2012; 42:311–3
© 2012 RCPE
A Munir, N Leech, KP Windebank, J McLelland, GL Jones, D Mitra, A Jenkins, R Quinton
313
clinical
is best for those without the involvement of high risk
organs (haematopoietic, liver, spleen, lung) and who
respond to standard initial therapy.
Evidence to date is insufficient to support an optimal
course of treatment for patients with progressive
multisystem LCH who fail to respond to standard
therapy. Results for patients treated with a combined
regimen of 2-chlorodeoxyadenosine (2-CdA, cladribin,
leustatin) and cytarabine (ara-C), as well as stem cell
transplantation after undergoing a reduced intensity
conditioning regimen are promising.17,18 All patients
should be enrolled in clinical trials organised by the
Histiocyte Society and should have long-term follow-up
with a multi-disciplinary team with knowledge of LCH.
ConCluSion
Langerhans cell histiocytosis in adults has many (but not
all) of the characteristics of neoplasia and can be
considered an ‘orphan disease’ as patients may present
with single-system involvement to any specialty and may
remain undiagnosed. Even when accurately diagnosed, no
organised treatment protocols are in place to define
optimal treatment. Diagnosis is easier when advanced
multisystem involvement is observed, but a high index of
suspicion is required to establish a diagnosis of LCH when
the disease is focal. A thorough workup is essential to
determine the extent of the disease and possible
complications. Patients need long-term follow-up for early
detection of recurrence and consideration of treatment.
RefeRenCeS
1 Kannourakis G, Abbas A. The role of cytokines in the pathogenesis
of Langerhans cell histiocytosis. Br J Cancer Suppl 1994; 23:S37–40.
2 Egeler RM, Favara BE, Van Meurs M et al. Differential in situ
cytokine profiles of Langerhans-like cells and T cells in Langerhans
cell histiocytosis: abundant expression of cytokines relevant to
disease and treatment. Blood 1999; 94:4195–201.
3 Ornvold K, Carstensen H, Larsen JK et al. Flow cytometric DNA
analysis of lesions from 18 children with langerhans cell
histiocytosis (histiocytosis x). Am J Pathol 1990; 136:1301–7.
4 Halton J, Whitton A, Wiernikowski J et al. Disseminated Langerhans
cell histiocytosis in identical twins unresponsive to recombinant
human alpha-interferon and total body irradiation. Am J Pediatr
Hematol Oncol 1992; 14:269–72. http://dx.doi.org/10.1097/00043426-
199208000-00016
5 de Graaf JH, Tamminga RY, Kamps WA et al. Expression of cellular
adhesion molecules in Langerhans cell histiocytosis and normal
Langerhans cells. Am J Pathol 1995; 147:1161–71.
6 Baumgartner I, von Hochstetter A, Baumert B et al. Langerhans
cell histiocytosis in adults. Med Pediatr Oncol 1997; 28:9–14. http://
dx.doi.org/10.1002/(SICI)1096-911X(199701)28:1<9::AID-
MPO3>3.0.CO;2-P
7 Malpas JS. Langerhans cell histiocytosis in adults. Hematol Oncol Clin
North Am 1998; 12:259–68. http://dx.doi.org/10.1016/S0889-
8588(05)70509-8
8 García Gallo MS, Martínez MP, Abalovich MS et al. Endocrine
manifestations of Langerhans cell histiocytosis diagnosed in adults.
Pituitary 2010; 13:298–303. http://dx.doi.org/10.1007/s11102-010-
0233-8
9 Kaltsas GA, Powles TB, Evanson J et al. Hypothalamo-pituitary
abnormalities in adult patients with langerhans cell histiocytosis:
clinical, endocrinological, and radiological features and response to
treatment. J Clin Endocrinol Metab 2000; 85:1370–6. http://dx.doi.
org/10.1210/jc.85.4.1370
10 Kaplan KJ, Goodman ZD, Ishak KG. Liver involvement in
Langerhans’ cell histiocytosis: a study of nine cases. Mod Pathol
1999; 12:370–8.
11 Haas S, Theuerkauf I, Kühnen A et al. [Langerhans’ cell histiocytosis
of the liver. Differential diagnosis of a rare chronic destructive
sclerosing cholangitis.] Pathologe 2003; 24:119–23. German.
12 Lau SK, Chu PG, Weiss LM. Immunohistochemical expression of
langerin in Langerhans cell histiocytosis and non-Langerhans cell
histiocytic disorders. Am J Surg Pathol 2008; 32:615–9. http://dx.doi.
org/10.1097/PAS.0b013e31815b212b
13 Broadbent V, Gadner H. Current therapy for Langerhans cell
histiocytosis. Hematol Oncol Clin North Am 1998; 12:327–38. http://
dx.doi.org/10.1016/S0889-8588(05)70513-X
14 Gadner H, Heitger A, Grois N et al. Treatment strategy for
disseminated Langerhans cell histiocytosis. DAL HX-83 Study
Group. Med Pediatr Oncol 1994; 23:72–80. http://dx.doi.org/10.1002/
mpo.2950230203
15 Gadner H, Grois N, Potschger U et al. Improved outcome in
multisystem Langerhans cell histiocytosis is associated with
therapy intensification. Blood 2008; 111:2556–62. http://dx.doi.
org/10.1182/blood-2007-08-106211
16 McClain KL. Drug therapy for the treatment of Langerhans cell
histiocytosis. Expert Opin Pharmacother 2005; 6:2435–41. http://
dx.doi.org/10.1517/14656566.6.14.2435
17 Bernard F, Thomas C, Bertrand Y et al. Multi-centre pilot study of
2-chlorodeoxyadenosine and cytosine arabinoside combined
chemotherapy in refractory Langerhans cell histiocytosis with
haematological dysfunction. Eur J Cancer 2005; 41:2682–9. http://
dx.doi.org/10.1016/j.ejca.2005.02.007
18 Steiner M, Matthes-Martin S, Attarbaschi A et al. Improved
outcome of treatment-resistant high-risk Langerhans cell
histiocytosis after allogeneic stem cell transplantation with
reduced-intensity conditioning. Bone Marrow Transplant 2005;
36:215–25. http://dx.doi.org/10.1038/sj.bmt.1705015
J R Coll Physicians Edinb 2012; 42:311–3
© 2012 RCPE
Langerhans cell histiocytosis: a multisystem disorder
... The Histiocyte Society classifies LCH based on the number of organ systems involved and whether or not disease activity is unifocal or multifocal in each organ system [ Table 1]. [5] They also classify disease based on the involvement of high-risk organs. ...
Multifocal, Multisystem Presentation of Adult-Onset Langerhans Cell Histiocytosis on 18F-Fluorodeoxyglucose Positron-Emission Tomography-Computed Tomography: A Rare Case Report
Article
Full-text available
  • Mar 2022
Langerhans cell histiocytosis (LCH), also known as histiocytosis X, is a rare systemic disorder arising from clonal proliferation of immature CD207-positive (langerin) myeloid dendritic cells (histiocytes) in the skin and visceral organs with a tendency to involve single or multiple organ systems with variable clinical course and prognosis. The incidence of LCH is very less in adult and occurs almost exclusively in children. Genital, perianal, and lung lesions are considered to be rare manifestations of adult LCH. We describe a case of 31-year-old, nonsmoker female who presented in February 2020 with itching and burning sensation in perianal and vulvar regions accompanied with multiple nonhealing ulcers and papillomatous lesions. These lesions gradually increased in size with no response to antibiotics and topical steroids. She was advised positron-emission tomography- computed tomography (PET-CT) scan for further evaluation. After PET-CT scan, her provisional diagnosis of multisystem, multifocal Langerhans cell histiocytosis with high-risk organ involvement was made. Both vulvar and perianal lesions were biopsied which was suggestive of Letterer-Siwe variant of LCH. The prognosis of this variant is very poor even with aggressive chemotherapy and 5-year survival rate of only 50%. Hence, it requires careful consideration during diagnosis and management.
View
Paediatric Supraorbital Mass: A Case of Langerhans Cell Histiocytosis
Article
  • Jun 2022
This is a case of 2-year-old boy who presented with painless right supraorbital swelling for 2 weeks. He had history of left humerus fracture and multiple scalp swelling. Examination revealed a hard, non-tender mass over right upper eye lid with downward placement of eye globe and limitation of extraocular muscle movement upon upward gaze. Systemic examination was unremarkable. MRI brain and orbit showed avid enhancing mass arising from right orbital roof. Histopathological examination of left humerus trucut biopsy revealed focal aggregation of histiocytes with scattered eosinophils. The diagnosis of LCH was further confirmed by positive CD1a and S100 protein staining on immunohistochemical studies. He was referred to oncology department for initiation of chemotherapy. Significant improvement was seen after the first cycle of chemotherapy. Keywords: Langerhans cell histiocytosis, supraorbital swelling
View
A review of systemic infiltrative diseases and associated endocrine diseases
Article
  • Sep 2021
Systemic infiltrative diseases are relatively rare conditions consisting of cell infiltration or substance deposition in multiple organs and systems, including endocrine glands. This article reviews endocrine changes in the main four diseases at epidemiological level: sarcoidosis, Langerhans cell histiocytosis, hereditary hemochromatosis, and systemic amyloidosis. Recommendations to endocrinologists for hormone work-up and management of patients with each of these conditions are provided.
View
Revisión sobre enfermedades infiltrativas sistémicas y patología endocrinológica asociada
Article
  • Nov 2020
Resumen Las enfermedades infiltrativas sistémicas son un grupo de enfermedades relativamente raras que consisten en la infiltración de células o depósito de sustancias en múltiples órganos y sistemas, entre los que se encuentran las glándulas endocrinas. En este artículo se revisan las alteraciones endocrinológicas de las cuatro más importantes a nivel epidemiológico, como son la sarcoidosis, la histiocitosis de células de Langerhans, la hemocromatosis hereditaria y la amiloidosis sistémica. En cada una de ellas se aportarán recomendaciones al endocrinólogo para el estudio hormonal de estos pacientes.
View
Cutaneous Neonatal Langerhans cell Histiocytosis: A Systematic Review of Case Reports
Article
Full-text available
  • Jan 2019
Abstract Background: Cutaneous langerhans cell histiocytosis (LCH) is a rare disorder characterized by proliferation of cells with phenotypical characteristics of Langerhans cells. Although some cases spontaneously resolve, no consistent variables have been identified that predict which cases will manifest with systemic disease later in childhood. Methods: A systematic review (Pubmed, Embase, Cochrane database and all published abstracts from 1946-2018) was undertaken to collate all reported cases of cutaneous LCH in the international literature. This study was registered with PROSPERO (CRD42016051952). Descriptive statistics and correlation analyses were undertaken. Bias was analyzed according to GRADE criteria. Results: A total of 83 articles encompassing 128 cases of cutaneous LCH were identified. Multiple lesions were weakly associated with an increased length of survival (R=0.304 (p<0.05)), Worse prognosis was associated with internal organ involvement with a statistically significant chi squared statistic (χ2 =14.96, 2DF p<0.001) and an elevated odds ratio ((OR)= 12.30 95% CI=2.67-56.74). Vesicular lesions (OR=10.8 95% CI=2.83-41.26), but not ulceration (OR=0.53 95% CI 0.12-2.05) were associated with greater risk of mortality. Conclusions: Congenital and neonatal LCH most commonly presents as multiple lesions in multiple anatomical sites at birth. Significant differences, including the associations of mortality with lesion morphology and number were seen in this neonatal cohort compared to overall pediatric LCH. These findings require validation in a large prospective cohort
View
Tumors of the Langerhans Cell System
Chapter
  • Oct 2017
Langerhans cell histiocytosis (LCH) is a rare proliferative disorder of bone marrow-derived antigen-presenting cells that home to diverse organs and tissues, predominantly the skin. LCH is a rare disease that mainly manifests in the pediatric age group, with several in part overlapping phenotypes. Clinically and morphologically, LCH is divided into unifocal LCH, single-system LCH, multifocal LCH, multiorgan/disseminated LCH, Langerhans cell sarcoma, and Langerhans tumors. All forms and variants are characterized by a progressive and monoclonal proliferation of medium-sized, CD1a-reactive, and langerin-/CD207-reactive cells that often contain Birbeck granules. Langerhans cell infiltrates are regularly accompanied by infiltrates of eosinophils, lymphoid cells, and macrophages. Lesions with a high density of eosinophils were previously termed eosinophilic granuloma. Hepatobiliary involvement in LCH presents with a characteristic spectrum of lesions that include a disseminated form, focal forms (microscopic and macroscopic), and a form associated with bile ducts (LCH cholangiopathy). A small subset of Langerhans cell proliferations present as tumorous lesions or Langerhans cell sarcoma. In addition to LCH, there are a group of so-called self-healing Langerhans cell and related disorders that can involve the hepatobiliary tract.
View
Tumors of the Langerhans Cell System
Chapter
  • Feb 2016
Langerhans cell histiocytosis (LCH) is a rare proliferative disorder of bone marrow-derived antigen-presenting cells that home to diverse organs and tissues, predominantly the skin. LCH is a rare disease that mainly manifests in the pediatric age group, with several in part overlapping phenotypes. Clinically and morphologically, LCH is divided into unifocal LCH, single-system LCH, multifocal LCH, multiorgan/disseminated LCH, Langerhans cell sarcoma, and Langerhans tumors. All forms and variants are characterized by a progressive and monoclonal proliferation of medium-sized, CD1a-reactive, and langerin-/CD207-reactive cells that often contain Birbeck granules. Langerhans cell infiltrates are regularly accompanied by infiltrates of eosinophils, lymphoid cells, and macrophages. Lesions with a high density of eosinophils were previously termed eosinophilic granuloma. Hepatobiliary involvement in LCH presents with a characteristic spectrum of lesions that include a disseminated form, focal forms (microscopic and macroscopic), and a form associated with bile ducts (LCH cholangiopathy). A small subset of Langerhans cell proliferations present as tumorous lesions or Langerhans cell sarcoma. In addition to LCH, there are a group of so-called self-healing Langerhans cell and related disorders that can involve the hepatobiliary tract.
View
Hand–Schüler–Christian disease presenting with recurrent, bilateral, symmetrical mandibular lesions in an 8-year-old boy: Report of a case
Article
  • Aug 2015
  • Spec Care Dent
Hand-Schüller-Christian disease (HSC) is the unisystem multifocal form of Langerhans Cell Histiocytosis (LCH) and is primarily seen in infants and children. An 8-year-old boy was referred for acute mandibular pain. His medical history included otic LCH and diabetes insipidus at age of 11 months. Intraorally, a pressure sensitive swelling, and radiographically, extensive bone loss were revealed on the area of lower second primary molars. The primary molars were extracted and histological examination confirmed the final diagnosis of HSC. The patient was treated with chemotherapy and the lesions decreased considerably. Two years later, a new swelling was recorded in the same area bilaterally. Biopsy confirmed recurrent HSC disease and the patient entered an alternative chemotherapy protocol. Six months later, improvement of the lesions was revealed. Dentists can contribute to a timely and valid identification of HSC disease by correctly differentially diagnosing lesions of head and neck. © 2015 Special Care Dentistry Association and Wiley Periodicals, Inc.
View
Flow cytometric DNA analysis of lesions from 18 children with Langerhans cell histiocytosis (histiocytosis X)
Article
Full-text available
  • Jul 1990
The DNA content in 26 formalin-fixed, paraffin-embedded histologic specimens from 18 children with Langerhans cell histiocytosis (LCH) was analyzed by flow cytometry. In two cases, the propidium iodide fluorescence histograms showed small (5 and 3% of the analyzed nuclei) but significant aneuploid subpopulations with DNA indices of approximately 1.5. This was confirmed by analysis of unfixed, frozen material in one patient. Both patients had disseminated disease without organ dysfunction and were treated with prednisone. Currently, they are without signs of disease activity after 1 and 10 years. DNA histograms were normal from a patient who died from disseminated disease and from two patients with disseminated disease who experienced several relapses and various chemotherapeutical regimens. The histograms were also normal in lesions from four patients with unifocal bone involvement. Our results show that DNA aneuploidy occurs in LCH lesions in the pediatric age group. Further investigation is necessary to reveal whether DNA aneuploidy is restricted to disseminated LCH or its presence has any value in predicting the course and outcome of the disease.
View
Expression of cellular adhesion molecules in Langerhans cell histiocytosis and normal Langerhans cells
Article
Full-text available
  • Nov 1995
Langerhans cell histiocytosis (LCH) is characterized by lesions with an accumulation and/or proliferation of Langerhans cells (LCs). Little is known of the etiology and pathogenesis of LCH. Although the relation between the LCH cell and normal LCs is currently uncertain, the localizations of the LCH cells is considered aberrant when compared with normal LCs. Cellular adhesion molecules (CAMs) are known to play an important role in a variety of cell functions such as migration, antigen presentation, and activation. Aberrant migration of LCs may play a role in the pathogenesis of LCH. We investigated CAMs in 27 tissue specimens of 20 patients with LCH retrieved from our files during the last 15 years. LCH cells showed strong expression of CAMs such as CD54, CD58, and the beta 1-integrin alpha 4 that are upregulated during activation of normal LCs. In contrast, CAMs not found on normal LCs could be demonstrated in a number of cases on LCH cells like CD2, CD11a, and CD11b. Also CD62L, normally expressed only by epidermal LCs, could be detected on LCH cells. The integrins alpha 5 and alpha 6, not or only weakly found on epidermal LCs and highly expressed by activated LCs, could not be demonstrated on LCH cells. Our data suggest abnormal expression of CAMs on LCH cells that may contribute to abnormal migration of LCs in LCH. The aberrant phenotype of LCH cells has characteristics of both epidermal LCs and activated LCs and may be indicative of an arrested state of activation and/or differentiation of LCs.
View
The role of cytokines in the pathogenesis of Langerhans cell Histiocytosis
Article
Full-text available
  • Oct 1994
  • Br J Canc Suppl
Langerhans cell histiocytosis (LCH) is characterised by an accumulation of cells ('LCH cells') with the same phenotypic features as normal Langerhans cells found in skin and other organs. The pathogenesis of LCH is unknown but there is increasing evidence to implicate the involvement of lymphokines and proinflammatory cytokines in the tissue damage seen in this disorder. Apart from histiocytes, the lesions contain giant cells, macrophages, neutrophils, eosinophils, lymphocytes, plasma cells and occasional mast cells that are the hallmark of an inflammatory process. The role of cytokines in the recruitment of haemopoietic cells within inflammatory lesions has only recently been recognised. In this article, we review the possible role of cytokines in the pathogenesis of LCH, and provide an overview of the methods currently used to detect and quantitate them. An appreciation of the type, distribution and amount of different cytokines released within lesions can provide clues to the possible aetiology of LCH. Using immunoassays, in situ hybridisation and RT-PCR, increased amounts of IL-1, IL-3, IL-4, IL-8, GM-CSF, TNF alpha, TGF beta and LIF have been demonstrated in LCH lesions. Lymphocytes constitutively produce GM-CSF and IL-3 and, to a lesser degree, IL-1, IL-4 and LIF whilst histiocytes produce TNF alpha, IL-1 beta and GM-CSF.
View
Treatment strategy for Langerhans cell Histiocytosis. DAL HX-83 Study Group
Article
  • Jan 1994
  • Med Pediatr Oncol
Treatment of Langerhans cell histiocytosis (LCH) remains problematic. To test the hypothesis that rapid initiation and longterm continuation of chemotherapy can improve survival and reduce recurrence and late consequences of disseminated LCH, we have completed a prospective clinical trial (DAL HX-83). One hundred six newly diagnosed patients were stratified into three risk groups (A: multifocal bone disease [n = 28]; B: soft tissue involvement without organ dysfunction [n = 57]; C: organ dysfunction [n = 21]). All patients received an identical initial 6-week treatment (etoposide [VP-16], prednisone, and vinblastine), and continuation treatment for 1 year, slightly adapted according to stratification at diagnosis. It included oral 6-mercaptopurine and eight pulses of vinblastine and prednisone for all patients, plus VP-16 in group B and VP-16 and methotrexate in group C. Eighty-nine percent and 91% of patients in groups A and B and 67% of the most severely affected group C, achieved complete resolution of disease. The speed of resolution was rapid (median 4 months) and independent of disease severity. The frequency of recurrence after initial resolution was low (12%, 23%, and 42% in groups A, B, and C); overall fully 77% of patients have remained free of recurrence. Permanent consequences developed after diagnosis in 20% of the patients. Diabetes insipidus after initiation of treatment occurred in only 10% of patients. Mortality (9%) was limited to patients of groups B (two patients) and C (eight patients). Finally, among the 106 patients treated by DAL HX-83 none have developed a malignancy (median follow-up 6 years, 9 months). The shorter duration of active disease, low rate of recurrence and permanent consequences, and improved survival among patients with poor prognosis support the strategy of rapid initiation of a predefined prolonged treatment upon the diagnosis of disseminated LCH. © 1994 Wiley-Liss, Inc.
View
Endocrine manifestations of Langerhans cell histiocytosis diagnosed in adults
Article
  • Dec 2010
  • PITUITARY
Langerhans cell histiocytosis (LCH) is a rare granulomatous disease of unknown etiology. We retrospectively reviewed data from four patients (3 males and 1 female), mean age 33.5 years old (range: 21-40), with histopathological diagnosis of LCH. All of them presented with symptoms suggestive of endocrine involvement. The main complaint was goiter in two patients and polyuria and polydipsia in three. Before the LCH diagnosis, two patients had unevaluated symptoms of diabetes insipidus (DI) and hypogonadism. The mean time from symptoms onset to diagnosis was 6.25 years (range: 2-13). Histopathological diagnosis was established by total thyroidectomy (TT) biopsy in two patients, skin lesion biopsy in one, and pituitary stalk biopsy in the other. In the two-first patients, surgery was indicated after the fine-needle aspiration biopsy (FNAB) showed a false positive result of differentiated thyroid carcinoma and immunohistochemistry was used for diagnosis confirmation. Three cases were treated with chemotherapy; one of them had already received radiation therapy on the hypothalamic-pituitary region, developing post-radiation hypopituitarism.
View
Disseminated Langerhans Cell Histiocytosis in Identical Twins Unresponsive to Recombinant Human α-Interferon and Total Body Irradiation
Article
  • Sep 1992
  • J Pediatr Hematol Oncol
Monozygotic twin boys presented at 1 year of age with seborrheic skin rash, otorrhea, and hepatosplenomegaly. Skin biopsy confirmed Langerhans cell histiocytosis. Treatment with conventional antineoplastic drugs and with calf thymus extract was ineffective. The disease remained refractory to recombinant human alpha-interferon and to low-dose total body irradiation, and the children died between 3 and 3 1/2 years of age.
View
Treatment strategy for disseminated Langerhans cell histiocytosis. DAL HX-83 Study Group
Article
  • Feb 1994
Treatment of Langerhans cell histiocytosis (LCH) remains problematic. To test the hypothesis that rapid initiation and long-term continuation of chemotherapy can improve survival and reduce recurrence and late consequences of disseminated LCH, we have completed a prospective clinical trial (DAL HX-83). One hundred six newly diagnosed patients were stratified into three risk groups (A: multifocal bone disease [n = 28]; B: soft tissue involvement without organ dysfunction [n = 57]; C: organ dysfunction [n = 21]). All patients received an identical initial 6-week treatment (etoposide [VP-16], prednisone, and vinblastine), and continuation treatment for 1 year, slightly adapted according to stratification at diagnosis. It included oral 6-mercaptopurine and eight pulses of vinblastine and prednisone for all patients, plus VP-16 in group B and VP-16 and methotrexate in group C. Eighty-nine percent and 91% of patients in groups A and B and 67% of the most severely affected group C, achieved complete resolution of disease. The speed of resolution was rapid (median 4 months) and independent of disease severity. The frequency of recurrence after initial resolution was low (12%, 23%, and 42% in groups A, B and C); overall fully 77% of patients have remained free of recurrence. Permanent consequences developed after diagnosis in 20% of the patients. Diabetes insipidus after initiation of treatment occurred in only 10% of patients. Mortality (9%) was limited to patients of groups B (two patients) and C (eight patients). Finally, among the 106 patients treated by DAL HX-83 none have developed a malignancy (median follow-up 6 years, 9 months). The shorter duration of active disease, low rate of recurrence and permanent consequences, and improved survival among patients with poor prognosis support the strategy of rapid initiation of a predefined prolonged treatment upon the diagnosis of disseminated LCH.
View
Langerhans'-cell histiocytosis in adults
Article
  • Jan 1997
Guided by a long-term retrospective observation, the clinical course and treatment of Langerhans'-cell histiocytosis (LCH) in adult patients are represented. The series included 19 patients meeting the histopathologic criteria of presumptive LCH who were followed for 1.5-20 years (average 7.7 years). Most frequently, skeletal lesions (16 patients), diffuse interstitial lung infiltrates (seven patients), and pituitary gland involvement with diabetes insipidus (four patients) were present. Bone lesions of the skull and axial skeleton were associated with an infiltration of adjacent soft tissues in 10 of 16 patients. Liver, lymph node, and bone marrow involvement appeared sporadically. LCH was divided into localized or multifocal form. Localized disease took a benign course with remission of bone (n = 4) or lymph node lesions (n = 2). Also, in isolated pulmonary LCH (n = 2), spontaneous transition to inactive disease occurred. With the exception of isolated bone lesions (n = 27), which remained asymptomatic or showed a remission to treatment, multifocal LCH had a more aggressive course. Osseous lesions with adjacent soft tissue infiltration (n = 20) showed a relapse rate in excess of 80% independent of the treatment applied. Pulmonary involvement led to a more marked functional impairment compared to the isolated form, and systemic treatment yielded no convincing effect. In three patients with liver or bone marrow involvement, LCH showed a persistent, serious disease activity. One patient died of transition into acute monomyelocytic leukemia 18 months after diagnosis without preceding chemotherapy. In adults, LCH seems to be limited to a few organ systems. Multifocal LCH represents the more aggressive form with unfavorable prognosis in patients with bone lesions spreading into the adjacent soft tissue and liver or bone marrow involvement.
View
Current therapy of Langerhans cell histiocytosis
Article
  • May 1998
  • HEMATOL ONCOL CLIN N
The changing concept of the pathogenesis of Langerhans cell histiocytosis over the past 50 years has been mirrored by evolving treatment regimens. The publications by the Histiocyte Society in the 1980s of diagnostic, clinical, and laboratory criteria allowed international collaboration in treatment trials. These, in turn, have allowed stratification of risk groups and the evolution of a salvage therapy protocol for the poorest risk patients. Experimental therapies now being evaluated may be the treatment strategies for the next decade.
View
Langerhans cell histiocytosis in adults
Article
  • May 1998
  • HEMATOL ONCOL CLIN N
Langerhans cell histiocytosis in the adult is rare, but it is important to recognize its occurrence, as it must be differentiated from lymphoma, myeloma, and a variety of skin conditions and endocrinopathies. It has been reported in patients up to the ninth decade of life, and occurs equally in men and women. Local disease has a good prognosis, but associated diseases--particularly malignancy--may be the cause of death in some adults. The optimal treatment is not known. Coordinated investigation of the epidemiology and therapy of this disease is needed.
View