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The histiocytoses have been known by a variety of terms. Broadly speaking, they can be divided into Langerhans and non-Langerhans cell histiocytoses. Langerhans cell histiocytoses are all defined by the presence of a unique ultrastructural organelle, the Birbeck granule. This tennis racquet shaped cytoplasmic organelle has an unknown function. Currently, the preferred term is Langerhans cell histiocytosis.

Langerhans Cell Histiocytoses (LCH)

Histiocytosis X
Eosinophilic granuloma
Hand-Schuller-Christian Disease
Letterer-Siwe Disease
Hashimoto-Pritzker Disease (Congenital Self-Healing Langerhans Cell Histiocytosis)

Non-Langerhans Cell Histiocytoses

Benign Cephalic Histiocytosis
Crystal-Storing Histiocytosis
Erdheim-Chester disease

The International Lymphoma Study Group has identified the following classification scheme:

Macrophage/Histiocytic neoplasms Histiocytic sarcoma
Dendritic Cell Neoplasms Langerhans Cell Tumor
Langerhans Cell Sarcoma
Interdigitating Cell Tumor/Sarcoma
Follicular Dendritic Cell Tumor/Sarcoma
Histiocytic sarcoma
Langerhans cell tumor/sarcoma
Interdigitating cell tumor/sarcoma
Follicular dendritic cell tumor/sarcoma

Adapted from Pileri SA, Grogan TM, Harris NL, etal. Histopathology 2002;31:1-29.


Disease Associations  
Laboratory/Radiologic/Other Diagnostic Testing  
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
Electron Microscopy
Differential Diagnosis  
Commonly Used Terms  
Internet Links  

SYNONYMS Histiocytosis X
INCIDENCE Annual incidence of 4 to 5.4 per million for LCH
AGE RANGE-MEDIAN In general, Letterer-Siwe disease occurs in first 2 years
Hand-Schuller-Christian occurs in older children
Eosinophilic granuloma occurs in older children and adults

Langerhans cell histiocytosis presenting in the neonatal period: a retrospective case series.

Stein SL, Paller AS, Haut PR, Mancini AJ.

Department of Dermatology, Northwestern University Medical School, Chicago, IL 60614, USA.


Arch Pediatr Adolesc Med 2001 Jul;155(7):778-83 Abstract quote

OBJECTIVES: To describe the morphologic characteristics of skin lesions, extent of extracutaneous disease, and outcomes in patients with neonatal presentation of Langerhans cell histiocytosis (LCH), and to examine clinical predictors of disease prognosis.

DESIGN: Retrospective validation cohort study. Maximum duration of follow-up was 10 years.

SETTING: A tertiary care children's hospital in Chicago, Ill.

PATIENTS: Nineteen children with cutaneous findings in the first 4 weeks of life and subsequently diagnosed with LCH based on compatible tissue histologic analysis, confirmed by electron microscopy and/or immunohistochemical analysis.

MAIN OUTCOME MEASURE: Cutaneous lesion morphologic characteristics, extracutaneous manifestations, treatments, and outcomes were tabulated and compared.

RESULTS: The most common initial skin lesion was erythematous, often crusted, vesiculopustules. Skin lesion morphologic traits did not correlate with extent of extracutaneous disease. One third of patients had disease limited to the skin and/or mucous membranes. All of these patients are alive and well, and 1 has developed diabetes insipidus. Twelve of the 19 patients had multisystem disease, and 2 died of disease. The results of a multiorgan workup performed at the time of diagnosis were predictive of which patients in this cohort manifested multisystem disease. The overall incidence of diabetes insipidus was 21%.

CONCLUSIONS: Vesiculopustular lesions are common in congenital/neonatal LCH, but the morphologic characteristics of lesions are not helpful in predicting the extent of disease. A multiorgan evaluation at the time of diagnosis may be predictive of the probability of multisystem involvement with LCH.


Epidemiologic study of Langerhans cell histiocytosis in children.

Bhatia S, Nesbit ME Jr, Egeler RM, Buckley JD, Mertens A, Robison LL.

Department of Pediatrics, University of Minnesota, Minneapolis 55455, USA.

J Pediatr 1997 May;130(5):774-84 Abstract quote

OBJECTIVE: The etiology and pathogenesis of Langerhans cell histiocytosis (LCH) remain poorly understood. We conducted an exploratory epidemiologic study to investigate potential risk factors associated with LCH.

STUDY DESIGN: We used a case-control study design to obtain data from parents of children with LCH (n = 459) who were members of the Histiocytosis Association of America and Canada. The two control groups consisted of 683 community control subjects and 3719 children with childhood cancers treated at participating Children's Cancer Group institutions.

RESULTS: The median age at diagnosis of LCH was 1.8 years (range 0.1 to 14.6 years). Cases were categorized as multisystem LCH (MS-LCH) (n = 208) and single-system LCH (SS-LCH) (n = 198). Statistically significant associations included the following: infections in the neonatal period (MS-LCH, odds ratio (OR) = 2.2), solvent exposure (SS-LCH, OR = 54.9), childhood vaccinations (MS-LCH and SS-LCH, OR = 0.4), thyroid disease in the proband (MS-LCH and SS-LCH, OR = 21.6), and family history of thyroid disease (MS-LCH and SS-LCH, OR = 1.4). The association with thyroid disease in the proband was explained partially by the involvement of the pituitary, with the relative risk decreasing when patients with diabetes insipidus and thyroid involvement were excluded from analysis.

CONCLUSIONS: This large hypothesis-generating study provides directions for future investigations in well-designed population-based or hospital-based epidemiologic studies.

Langerhans cell histiocytosis associated with myelodysplastic syndrome in adults.

Billings SD, Hans CP, Schapiro BL, Martin RW 3rd, Fivenson D, Fruland JE, Moores WB, Cotton J.

Departments of Pathology and Dermatology, Indiana University School of Medicine, Indianapolis, IN.

J Cutan Pathol. 2006 Feb;33(2):171-4. Abstract quote  

Background: Myelodysplastic syndrome (MDS) is a group of bone marrow disorders associated with dyplasia of myeloid elements that may have cutaneous manifestations including infections, vasculitis, Sweet's syndrome, pyoderma gangrenosum, erythema elevatum diutinum, and leukemia cutis. These cutaneous manifestations are attributed to the underlying bone marrow defect. Langerhans cell histiocytosis (LCH) is primarily a pediatric disease, and rarely LCH has been described in association with pediatric MDS. We are aware of only a single case report of LCH associated with MDS in an adult.

Methods: We report two new cases of LCH in elderly patients with underlying MDS. The specimens were examined by routine microscopy as well as immunohistochemical stains for S100 protein and CD1a.

Results: Both patients were elderly men with established diagnoses of MDS. One presented with a solitary pruritic papule while the other had a 2-year history of erythematous papules involving the trunk and extremities. Histologic examination revealed intraepidermal and dermal collections of mononuclear cells with reniform nuclei. The cells were strongly positive for S100 and CD1a, confirming their identity as Langerhans cells.

Conclusion: Cutaneous LCH may be associated with underlying MDS in adults and should be considered in the differential diagnosis of cutaneous eruptions in patients with MDS.



Differentiation of Langerhans cells in Langerhans cell histiocytosis.

Geissmann F, Lepelletier Y, Fraitag S, Valladeau J, Bodemer C, Debre M, Leborgne M, Saeland S, Brousse N.

Institut Federatif de Recherche Necker-Enfants Malades (Service d'Anatomie Pathologique EA 219, Unite Mixte de Recherche 8603 CNRS/Universite Paris-V, Paris, France.

Blood 2001 Mar 1;97(5):1241-8 Abstract quote

Langerhans cell histiocytosis (LCH) consists of lesions composed of cells with a dendritic Langerhans cell (LC) phenotype. The clinical course of LCH ranges from spontaneous resolution to a chronic and sometimes lethal disease.

We studied 25 patients with various clinical forms of the disease. In bone and chronic lesions, LCH cells had immature phenotype and function. They coexpressed LC antigens CD1a and Langerin together with monocyte antigens CD68 and CD14. Class II antigens were intracellular and LCH cells almost never expressed CD83 or CD86 or dendritic cell (DC)-Lamp, despite their CD40 expression. Consistently, LCH cells sorted from bone lesions (eosinophilic granuloma) poorly stimulated allogeneic T-cell proliferation in vitro. Strikingly, however, in vitro treatment with CD40L induced the expression of membrane class II and CD86 and strongly increased LCH cell allostimulatory activity to a level similar to that of mature DCs. Numerous interleukin-10-positive (IL-10(+)), Langerin(-), and CD68(+) macrophages were found within bone and lymph node lesions. In patients with self-healing and/or isolated cutaneous disease, LCH cells had a more mature phenotype. LCH cells were frequently CD14(-) and CD86(+), and macrophages were rare or absent, as were IL-10-expressing cells.

We conclude that LCH cells in the bone and/or chronic forms of the disease accumulate within the tissues in an immature state and that most probably result from extrinsic signals and may be induced to differentiate toward mature DCs after CD40 triggering. Drugs that enhance the in vivo maturation of these immature DCs, or that induce their death, may be of therapeutic benefit.

Immunohistochemical detection of the apoptosis-related proteins FADD, FLICE, and FLIP in Langerhans cell histiocytosis.

Bank MI, Gudbrand C, Rengtved P, Carstensen H, Fadeel B, Henter JI, Petersen BL.

Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen O, Denmark.
J Pediatr Hematol Oncol. 2005 Jun;27(6):301-6. Abstract quote  

Langerhans cell histiocytosis (LCH) is characterized by an accumulation of dendritic Langerhans cells in granulomatous lesions in various organs. The etiology of LCH remains enigmatic. Fas/APO-1/CD95 belongs to the "death receptor" family of apoptosis regulators and has been implicated in the downregulation of immune responses.

The authors examined the expression of three proteins that are engaged in the Fas signaling cascade-FADD/Fas-associated death domain-containing protein, FLICE/FADD-like interleukin-1beta-converting enzyme (both pro-apoptotic), and FLIP/FLICE-inhibitory protein (anti-apoptotic)-in lesions from LCH patients. Immunohistochemistry was performed on paraffin-embedded tissue specimens from 43 children with LCH. The infiltrates were scored according to the amount of positive pathologic Langerhans cells (pLCs). In all investigated specimens, the majority of the pLCs expressed FADD, active FLICE, and FLIP. The clinical outcome of the disease could not be correlated to the expression of the investigated proteins. This study shows a high expression of the apoptosis-related proteins FADD, active FLICE, and FLIP in pLCs.

The authors previously showed that pLCs express Fas and Fas ligand. Taken together, these findings suggest that the Fas signaling pathway may be involved in the pathogenesis of LCH.

Genotypic analysis of pulmonary Langerhans cell histiocytosis.

Dacic S, Trusky C, Bakker A, Finkelstein SD, Yousem SA.

Department of Pathology, Division of Anatomic Pathology, University of Pittsburgh Medical Center, PA 15213, USA.

Hum Pathol. 2003 Dec;34(12):1345-9 Abstract quote.  

Reported studies show that the systemic form of Langerhans cell histiocytosis (LCH) is a clonal expansion of Langerhans cells (LC) associated with aberrant expression of several oncogenes or tumor-suppressor genes. LCH of the lung is a heterogenous group of lesions thought to be a reactive rather than neoplastic process. The histogenesis of the LCH of the lung is uncertain, and to date there are no studies investigating its underlying molecular abnormalities.

We performed comparative genotypic analysis by using allelic loss (LOH) of polymorphic microsatellite markers associated with tumor suppressor genes. Fourteen cases of formalin-fixed, paraffin-embedded LCH of the lung were studied. Microdissection of a total of 26 nodules from 14 patients and paired reference lung tissue was performed under stereomicroscopic visualization.

To evaluate allelic loss, we used a panel of 11 polymorphic microsatellite markers that were situated at or near tumor suppressor genes on chromosomes 1p, 1q, 3p, 5p, 9p, 17p, and 22q. The PCR products were analyzed by using capillary electrophoresis to identify germline heterozygous alleles and LOH. Allelic loss at 1 or more tumor suppressor gene loci was identified in 19 of 24 nodules. The total fractional allelic loss (FAL) ranged from 6% (1q) to 41% (22q), with a mean of 22%. The FAL in individual cases ranged from 0 (7 nodules) to 57% (1 nodule). Fifteen discordant allelic losses at 1 to 3 chromosomal loci were identified in 8 patients with multiple synchronous nodules.

Our results show that LOH of tumor suppressor genes is present in the LCH of the lung, and they indicate that the putative tumor suppressor genes situated on chromosomes 9p and 22q may play a role in the development of a subset of the LCH of the lung.

Detection of molecular cytogenetic aberrations in langerhans cell histiocytosis of bone.

Murakami I, Gogusev J, Fournet JC, Glorion C, Jaubert F.

Department of Pathology, INSERM U507, Pediatric Orthopedic Department, Hopital Necker-Enfants Malades, Paris, France

Hum Pathol 2002 May;33(5):555-60 Abstract quote

Langerhans cell histiocytosis (LCH) is a disorder of unknown etiology that gives rise to clonal expansion of Langerhans-like cells or their precursors. The molecular basis include aberrant expression of several adhesion molecules and elevated expression of p53, c-myc, and H-ras.

To identify new locations of LCH-related oncogenes or tumor-suppressor genes, we performed comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) analysis on a series of 7 bone LCH lesions. Recurrent abnormalities were found by the CGH in all cases representing losses of DNA sequences on chromosomes 1p, 5, 6, 7, 9, 16, 17, and 22q. Gain of DNA copy number was seen on chromosomes 2q, 4q, and 12. The CGH data were supplemented by LOH analysis by means of 85 polymorphic microsatellite markers distributed along chromosomes 1, 7, 9, and 22. The highest frequency of LOH was found on 1p region in 3 of 7 informative cases and on chromosome 7 in 4 cases. Allelic loss was also detected on chromosomes 9 in 2 of 7 informative cases and on 22q in 1 of 7 cases.

These results indicate that the deleted chromosomal segments may contain genes important in LCH initiation and progression.


Risk factors for diabetes insipidus in langerhans cell histiocytosis.

Grois N, Potschger U, Prosch H, Minkov M, Arico M, Braier J, Henter JI, Janka-Schaub G, Ladisch S, Ritter J, Steiner M, Unger E, Gadner H.

Children's Cancer Research Institute, Vienna, Austria.
Pediatr Blood Cancer. 2005 Jul 26; [Epub ahead of print] Abstract quote  

BACKGROUND: Diabetes insipidus (DI) is the most frequent central nervous system (CNS)-related permanent consequence in Langerhans cell histiocytosis (LCH), which mostly requires life-long hormone replacement therapy. In an attempt to define the population at risk for DI, 1,741 patients with LCH registered on the trials DALHX 83 and DALHX 90, LCH I and LCH II were studied.

RESULTS: Overall 212 of 1,741 patients (12%) was reported to have DI. In 102 of 1,741 patients (6%) DI was present at diagnosis of LCH. One thousand one hundred eighty three of 1,539 patients without DI at diagnosis had follow up information. One hundred ten of these (9%) later developed DI. The risk of developing DI was 20% at 15 years after diagnosis. Multisystem disease patients at diagnosis carried a 4.6-fold risk for DI compared to single system patients. Craniofacial lesions, in particular in the "ear," "eye," and oral region were associated with a significantly increased risk for DI (relative hazard rate, RHR 1.7), independent of the extent of disease. No influence of the duration of therapy could be determined, but the duration of initial disease activity (RHR 1.5) and the occurrence of reactivations (RHR 3.5) significantly increased the risk for DI.

CONCLUSIONS: Patients with multisystem disease and craniofacial involvement at diagnosis, in particular of the "ear," "eye," and the oral region carry a significantly increased risk to develop DI during their course. This risk is augmented when the disease remains active for a longer period or reactivates.

Diabetes insipidus in Langerhans cell histiocytosis: results from the DAL-HX 83 study.

Grois N, Flucher-Wolfram B, Heitger A, Mostbeck GH, Hofmann J, Gadner H.

St. Anna Children's Hospital, Vienna, Austria.

Med Pediatr Oncol 1995 Apr;24(4):248-56 Abstract quote

Diabetes insipidus (DI) in Langerhans cell histiocytosis (LCH) is a common complication of unclear etiology.

The incidence varies among different publications from 15% to 50%. In the prospective DAL-HX 83 study, 19 out of 199 patients (9.5%) registered with newly diagnosed LCH were diagnosed to have DI. All patients were stratified according to uniform criteria. One hundred and six patients with disseminated disease were treated with standardized polychemotherapy promptly after diagnosis. At the time of diagnosis of LCH, DI was already established in 8 out of 199 patients (4%). After diagnosis, DI occurred in only one out of the remaining 91 patients with localized disease (1%) and in 10 out of 100 remaining patients with disseminated disease (10%). In 8 patients, the onset of DI was associated with other signs of active LCH.

The cumulative risk to develop DI after a median observation time of 5 years 3 months was 11%. Retrospective analysis of clinical features revealed multisystem involvement, skull and orbital lesions, and in particular intracranial extension from osseous lesions to constitute risk factors for DI. Magnetic resonance imaging studies (MRI) were available in 12 patients and showed abnormalities of the pituitary region in 10 children.

In none of the patients with established DI was it reversed or ameliorated by any treatment. However, the rapid institution of systemic chemotherapy for disseminated disease seems to prevent the occurrence of DI and may be responsible for the low frequency of DI in the DAL-HX83 study.

Late manifestation of diabetes insipidus in "pure" cutaneous Langerhans cell histiocytosis.

Hoeger PH, Janka-Schaub G, Mensing H.

Department of Paediatrics, University of Hamburg, Germany.

Eur J Pediatr 1997 Jul;156(7):524-7 Abstract quote

We report a case of congenital Langerhans cell histiocytosis (LCH), presenting with a generalized varicelliform rash in an otherwise well newborn. No signs of organ involvement were found on repeated skeletal radiography, abdominal ultrasonography and laboratory studies. A diagnosis of "pure cutaneous" LCH was established. Skin manifestation was unusually severe and recurred during the first 20 months of life, but responded well to combination chemotherapy (methylprednisone, vinblastine) while the child continued to thrive. At the age of 2 years the patient presented with acute onset diabetes insipidus due to infiltration of the hypothalomo-pituitary stalk region. He died for reasons unknown at the age of 28 months.

CONCLUSION: "Pure cutaneous" LCH, frequently also referred to as congenital self-healing LCH, is a variable disorder which may be complicated by late organ involvement. Close follow up and thorough diagnostic evaluation is therefore mandatory.

CNS sequelae in Langerhans cell histiocytosis: progressive spinocerebellar degeneration as a late manifestation of the disease.

Cervera A, Madero L, Garcia Penas JJ, Diaz MA, Gutierrez-Solana LG, Benito A, Ruiz-Falco ML, Villa M.

Department of Pediatric Oncology, Hospital del Nino Jesus, Madrid, Spain.

Pediatr Hematol Oncol 1997 Nov-Dec;14(6):577-84 Abstract quote

Central nervous system involvement in Langerhans cell histiocytosis (LCH), formerly known as histiocytosis X, is manifested mainly by diabetes insipidus reflecting local infiltration of Langerhans cells into the posterior pituitary or hypothalamus.

We describe two patients with progressive spinocerebellar degeneration appearing 4 and 6 years after the initial diagnosis of LCH. No correlation was found between the clinical course of the disease or its treatment and the neurological impairment. An extensive search for metabolic, toxic, neoplastic, and hereditary etiologies for progressive cerebellar degeneration was negative.


Langerhans cell histiocytosis in a child while in remission for acute lymphocytic leukemia

Lenore R. Chiles, MD
Mary M. Christian, MD
Danny K. McCoy, MD
Hal K. Hawkins
Angela H. Yen, MD
Sharon S. Raimer, MD

Galveston, Texas

J Am Acad Dermatol 2001;45:S233-4 Abstract quote

The occurrence of Langerhans cell histiocytosis (LCH) and malignancy in the same patient is rare. When LCH occurs concomitantly with acute leukemia, distinct temporal patterns often exist; acute myelogenous leukemia (AML) typically succeeds LCH, whereas acute lymphocytic leukemia (ALL) usually precedes it.

We report a case of LCH developing in a child while in remission for ALL. Unique features of this case include the disseminated nature of the LCH and the death of the patient from LCH rather than ALL.


CD79a(+) T-cell lymphoblastic lymphoma with coexisting Langerhans cell histiocytosis.

Li S, Borowitz MJ.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.

Arch Pathol Lab Med 2001 Jul;125(7):958-60 Abstract quote

Although there is a close association between Langerhans cell histiocytosis and malignant neoplasms, simultaneous occurrence of lymphoblastic lymphoma and Langerhans cell histiocytosis in the same lymph node is an extremely rare finding.

Herein, we describe such a case in a 26-year-old woman who presented with progressive cervical lymphadenopathy.

The lymphoma cells have an immature T-cell phenotype (terminal deoxynucleotidyl transferase(+), HLA-DR(+), CD34(+), CD38(+), and CD7(+)) with expression of both CD3 and CD79a on immunohistochemical stain. The Langerhans cells are present focally with the characteristic morphologic features and immunophenotype (CD1a(+) and S100(+)). The significance of CD79a coexpression in T-cell lymphoblastic lymphoma and the association between lymphoblastic lymphoma and Langerhans cell histiocytosis are discussed.



Pituitary stalk thickening with diabetes insipidus preceding typical manifestations of Langerhans cell histiocytosis in children.

Schmitt S, Wichmann W, Martin E, Zachmann M, Schoenle EJ.

Department of Paediatrics, University of Zurich, Switzerland

Eur J Pediatr 1993 May;152(5):399-401 Abstract quote

In up to 25% of cases of children with central diabetes insipidus no organic cause can be documented.

We present three boys (age 2.2, 2.3 and 6 years at diagnosis) with acute onset central diabetes insipidus, in whom the only pathological finding using MRI was a thickened central part of the pituitary stalk (> 2.5 mm).

Recent reports demonstrate similar MRI findings in adults with Langerhans cell histiocytosis (LCH), sarcoidosis, or tuberculosis, and in children with proven LCH and diabetes insipidus. In those adults with LCH, the pituitary stalk lesion has been histologically verified as a sequela of LCH. In contrast, in two of our three patients pituitary stalk thickening preceded the typical peripheral lesions of LCH by several months, whereas in the third patient there is as yet no evidence of systemic disease.

We conclude that thickening of the central part of the pituitary stalk might represent the first manifestations of LCH clinically presenting with diabetes insipidus. MRI investigation of the pituitary stalk in children with unexplained central diabetes insipidus and accurate follow up in patients with thickening of the pituitary stalk in necessary to avoid missing other manifestations of a systemic disease.

The sonographic appearance of lesions of the spleen and pancreas in an infant with Langerhans' cell histiocytosis.

Muwakkit S, Gharagozloo A, Souid AK, Spirt BA.

Department of Pediatrics, SUNY Health Science Center, Syracuse 13210.

Pediatr Radiol 1994;24(3):222-3 Abstract quote

Langerhans' cell histiocytosis (LCH), the term now used to describe the group of diseases known as histiocytosis X, is a rare disorder of the bone marrow-derived histiocytes that may involve the skin, bone, bone marrow, liver, spleen, lungs, lymph nodes, and rarely the pancreas. Sonographically demonstrable lesions of the spleen and pancreas have not been reported.

We present a case of disseminated LCH in a 4-week-old infant to demonstrate the sonographic appearance of splenic and pancreatic lesions that occur with this disease.

Langerhans cell histiocytosis: presentation and evolution of radiologic findings with clinical correlation.

Meyer JS, Harty MP, Mahboubi S, Heyman S, Zimmerman RA, Womer RB, Dormans JP, D'Angio GJ.

Department of Radiology, Children's Hospital of Philadelphia, PA 19104, USA.

Radiographics 1995 Sep;15(5):1135-46 Abstract quote

Radiologic images and medical records of 42 children with Langerhans cell histiocytosis (LCH) (histiocytosis X) were reviewed to evaluate the presentation of the disease and the evolution of the radiologic findings.

There were 26 male and 16 female patients aged 3 months to 18 years. Twenty-two patients presented with localized disease; 20 presented with multifocal disease. Four patients developed diabetes insipidus. Two patients had organ dysfunction. The radiologic findings were largely due to destructive bone lesions; 83% of the patients had at least one affected bone. Isolated soft-tissue masses, interstitial lung disease, and central nervous system abnormalities were also seen. Of patients in whom results of appropriate follow-up were available, 91% showed improvement in their lesions, 43% developed new lesions, and 92% had good clinical outcomes.

LCH is usually a self-limited disease with a varied clinical and radiologic presentation. The prognosis is generally poor in children with organ dysfunction. In the absence of organ dysfunction, children with either localized or multifocal LCH have an excellent prognosis.

Pulmonary and mediastinal lesions in children with Langerhans cell histiocytosis.

Smets A, Mortele K, de Praeter G, Francois O, Benoit Y, Kunnen M.

Department of Radiology, University Hospital Gent, Gent, Belgium.

Pediatr Radiol 1997 Nov;27(11):873-6 Abstract quote

Langerhans cell histiocytosis (LCH) is an uncommon group of disorders affecting mainly children and young adults. In children, pulmonary involvement occurs mostly in the disseminated forms; isolated pulmonary lesions are unusual.

A retrospective study was undertaken on a group of 42 children diagnosed with LCH over a 19-year period. Eight children (19 %) had radiological evidence of pulmonary involvement. The lung lesions were either present at the time of diagnosis or, when appearing during the course of the disease, always coinciding with exacerbation or recurrence of the disease in other sites.

Lung involvement did not appear to be an unfavourable prognostic factor. However, the toxic effects of treatment on the lungs might lead to important pulmonary sequelae.

Langerhans cell histiocytosis: unusual skeletal manifestations observed in thirty-four cases.

Hindman BW, Thomas RD, Young LW, Yu L.

Loma Linda University Medical Center, CA 92354, USA.

Skeletal Radiol 1998 Apr;27(4):177-81 Abstract quote

OBJECTIVE: Unusual manifestations are occasionally encountered in Langerhans cell histiocytosis and may be a source of confusion. The objective of this study was to determine the frequency of occurrence of the unusual manifestations in our case material.

DESIGN AND PATIENTS: Thirty-four children, average age 4.4 years (range 3 months to 16 years) with 262 skeletal lesions of biopsy-proven Langerhans cell histiocytosis (LCH) were retrospectively reviewed to determine the frequency of occurrence of unusual manifestations defined either as an atypical location of a skeletal lesion or an atypical radiographic appearance of the lesion.

RESULTS: Twenty-four unusual lesions were found in this retrospective review. Among these were epiphyseal lesions, transphyseal lesions, extracranial 'button' sequestra, posterior vertebral arch lesions, dural extension of vertebral lesions, and fluid-fluid levels. The finding of fluid-fluid levels has not previously been described in the radiologic literature. Involvement of unusual sites included clavicles and small bones of the hands and feet.

CONCLUSIONS: Radiographic, computed tomographic, and magnetic resonance imaging of LCH yield a variety of unusual manifestations. Recognition of these varied appearances of LCH may prevent confusion of such appearances with other pathologic processes. When the unusual manifestation occurs as the initial finding of the disease, LCH should be included in the differential diagnosis.

The thymus in Langerhans' cell histiocytosis.

Junewick JJ, Fitzgerald NE.

DeVos Children's Hospital, Grand Rapids, MI 49503, USA.

Pediatr Radiol 1999 Dec;29(12):904-7 Abstract quote

OBJECTIVE: To determine the frequency of thymic involvement in Langerhans' cell histiocytosis and describe its imaging appearance before and after treatment.

MATERIALS AND METHODS: A retrospective review of the radiology and clinical records of all patients diagnosed with Langerhans' cell histiocytosis at DeVos Children's Hospital between 1992 and 1998.

RESULTS: Of the 14 patients diagnosed with Langerhans' cell histiocytosis, 7 demonstrated multisystem involvement. The thymus was involved in 5 of 7 patients. The thymus was enlarged in 5; thymic contours were nodular/lobulated in 2; cystic changes were noted in 4; and dystrophic vascular-appearing calcifications were seen in 1. In all cases, findings regressed or resolved following chemotherapy.

CONCLUSION: The thymus is commonly involved in Langerhans' cell histiocytosis, especially in multisystem disease. Radiologically, the thymus is enlarged and may be smooth or lobulated/nodular in contour, possibly containing cysts and calcifications.




Langerhans cell histiocytosis presenting in the neonatal period: a retrospective case series.

Stein SL, Paller AS, Haut PR, Mancini AJ.

Department of Dermatology, Northwestern University Medical School, Chicago, IL 60614, USA.

Arch Pediatr Adolesc Med 2001 Jul;155(7):778-83 Abstract quote

OBJECTIVES: To describe the morphologic characteristics of skin lesions, extent of extracutaneous disease, and outcomes in patients with neonatal presentation of Langerhans cell histiocytosis (LCH), and to examine clinical predictors of disease prognosis.

DESIGN: Retrospective validation cohort study. Maximum duration of follow-up was 10 years.

SETTING: A tertiary care children's hospital in Chicago, Ill.

PATIENTS: Nineteen children with cutaneous findings in the first 4 weeks of life and subsequently diagnosed with LCH based on compatible tissue histologic analysis, confirmed by electron microscopy and/or immunohistochemical analysis.

MAIN OUTCOME MEASURE: Cutaneous lesion morphologic characteristics, extracutaneous manifestations, treatments, and outcomes were tabulated and compared.

RESULTS: The most common initial skin lesion was erythematous, often crusted, vesiculopustules. Skin lesion morphologic traits did not correlate with extent of extracutaneous disease. One third of patients had disease limited to the skin and/or mucous membranes. All of these patients are alive and well, and 1 has developed diabetes insipidus. Twelve of the 19 patients had multisystem disease, and 2 died of disease. The results of a multiorgan workup performed at the time of diagnosis were predictive of which patients in this cohort manifested multisystem disease. The overall incidence of diabetes insipidus was 21%.

CONCLUSIONS: Vesiculopustular lesions are common in congenital/neonatal LCH, but the morphologic characteristics of lesions are not helpful in predicting the extent of disease. A multiorgan evaluation at the time of diagnosis may be predictive of the probability of multisystem involvement with LCH.

Letterer-Siwe syndrome
Fatal, multisystemic, life-threatening lymphoproliferative disorders
Christian disease
Classic triad of exopthalmos, diabetes insipidus, and bone destruction
Eosinophilic Granuloma
Solitary bone lesion

Langerhans' cell histiocytosis (histiocytosis X) of bone. A clinicopathologic analysis of 263 pediatric and adult cases.

Kilpatrick SE, Wenger DE, Gilchrist GS, Shives TC, Wollan PC, Unni KK.

Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA.

Cancer 1995 Dec 15;76(12):2471-84 Abstract quote

BACKGROUND. Langerhans' cell histiocytosis (LCH) of bone is a disorder of histiocytic proliferation with variable and often unpredictable behavior.

METHOD. The authors evaluated the clinical and pathologic features of 263 patients (172 children, 91 adults) with biopsy-proven LCH examined during an 80-year period at the Mayo Clinic. Only patients with bone involvement pathologically and/or radiographically were included in the study. Clinical follow-up was available for 245 patients and ranged from 3 months to 50 years (mean, 12 years; median, 10 years). Chi-square tests were used to determine associations between age, gender, extent of osseous involvement, visceral disease, and pathologic features. Survival analyses were performed by univariate and multivariate Cox regression methods.

RESULTS. Age at presentation ranged from 2 months to 71 years with a clear predominance in children. The most common presenting complaint was pain, often worse at night. The skull was the most frequent osseous site in children and adults. Diabetes insipidus was documented in 40 patients. Forty-four children developed skeletal recurrence and/or new bone lesions, 19 of whom had diabetes insipidus. Fourteen children and 3 adults died either directly or indirectly from LCH. One adult patient developed systemic amyloidosis. All but two of these pediatric patients were 3 years of age or younger at presentation. All children with hepatosplenomegaly (7 patients) and/or thrombocytopenia (9 patients) died. Nine of the 14 children who died presented initially with three or more bone lesions.

CONCLUSIONS. The clinical behavior of LCH of bone is often unpredictable; however, young age at diagnosis, hepatosplenomegaly, thrombocytopenia, and polyostotic (> or = 3 bones involved) disease are associated with a poor prognosis (P < 0.005). Recrudescence in children, but not in adults, strongly correlates with the presence of diabetes insipidus (P < 0.0005).

Congenital self-healing reticulohistiocytosis (Hashimoto-Pritzker disease): ten-year experience at Dallas Children's Medical Center.

Department of Pathology, Children's Medical Center Dallas, Texas, USA.


J Am Acad Dermatol. 2007 Feb;56(2):290-4. Abstract quote

The real incidence of congenital self-healing reticulohistiocytosis (CSHR) may be underreported because of its high rate of spontaneous resolution and lack of clinical recognition. Currently, there are no criteria other than clinical that can reliably distinguish CSHR from cutaneous involvement by disseminated Langerhans cell histiocytosis (LCH).

In this study we investigate the role of E-cadherin, Ki-67, and phosphorylated histone H3 (PHH3) immunohistochemical stains in distinguishing CSHR from disseminated LCH.

We found that no significant difference was seen in the histologic features and the expression of E-cadherin, Ki-67, and PHH3 between the two groups; thus supporting the theory that CSHR and LCH represent different ends of a spectrum of the same condition.
Hashimoto-Pritzker Disease
(Congenital Self-Healing Langerhans Cell Histiocytosis/

Arch Dermatol 1973;107:263

Clinical appearance resembling TORCH infection in neonates
Papules, plaques, and occasionally vesicles in an otherwise healthy child
Varies from isolated lesions in 25% of cases to widely disseminated lesions
Typically involute within weeks to months and are not associated with internal involvement

Congenital "self-healing" Langerhans cell histiocytosis: the need for long-term follow-up.

Longaker MA, Frieden IJ, LeBoit PE, Sherertz EF.

Department of Dermatology, University of California, San Francisco 94143-0316.

J Am Acad Dermatol 1994 Nov;31(5 Pt 2):910-6 Abstract quote

Congenital self-healing Langerhans cell histiocytosis (CSHLCH) is a rare disorder initially seen at birth or in the newborn period with spontaneously involuting skin lesions. In contrast to other forms of Langerhans cell histiocytosis in infancy, such as Letterer-Siwe disease, the prognosis of CSHLCH is generally good.

We describe four children with widespread CSHLCH at birth. In all patients a congenital infection was initially suspected. All patients, except one who had transient lower extremity edema and pulmonary symptoms, had an uncomplicated neonatal course, and in all patients skin lesions resolved spontaneously. Two patients showed no further evidence of disease, but one had a cutaneous relapse at age 3 months, and in another a bony relapse that required systemic therapy developed at 6 months of age.

CSHLCH is usually a benign, self-limited condition, but careful evaluation for systemic disease must be performed. Long-term follow-up for evidence of relapse or progression of disease is essential.

Unusual variants of non-Langerhans cell histiocytoses.

Institute of Dermatological Sciences, University of Milan-Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy.


J Am Acad Dermatol. 2007 Dec;57(6):1031-45 Abstract quote

Histiocytic syndromes represent a large, heterogeneous group of diseases resulting from proliferation of histiocytes. In addition to the classic variants, the subset of non-Langerhans cell histiocytoses comprises rare entities that have more recently been described. These last include both forms that affect only the skin or the skin and mucous membranes, and usually show a benign clinical behavior, and forms involving also internal organs, which may follow an aggressive course.

The goal of this review is to outline the clinical, histologic, and ultrastructural features and the course, prognosis, and management of these unusual histiocytic syndromes.
Solitary Langerhans cell histiocytosis of the
sternum in a 6-year-old girl: how should it be treated?

Wilson GJ,
Versluys AB
, Bax KN.

Department of Pediatric
Surgery, Wilhelmina
Children's Hospital,
University Medical
Centre, 3508 AB
Utrecht, The Netherlands.
J Pediatr Surg. 2005 Jul;40(7):e13-5. Abstract quote  

We report a 6-year-old girl with Langerhans cell histiocytosis (LCH) of the sternum successfully managed with intralesional methylprednisolone. Sternal LCH is a rare condition with only 8 cases published to date.

Management has included partial sternectomy, radiotherapy, and chemotherapy. Recent literature regarding the solitary osseous focus of LCH supports conservative management with excellent outcome after intralesional steroid administration and reports of spontaneous resolution of disease.

We advocate that conservative management should also be applied to LCH of the sternum.

Langerhans cell
histiocytosis involving epiphysis of a long bone.

Caballes RL, Caballes RA Jr, McKeon JJ.
Ann Diagn Pathol. 2004 Apr;8(2):91-5 Abstract quote.  

Eosinophilic granulomas of long tubular bones, a form of Langerhans cell histiocytosis, occurs in metaphyses and diaphyses with equal frequency. Epiphyseal location is unusual, with only 13 cases previously reported in the literature.

The present case involves the epiphysis of the upper end of the left femur in a 12-year-old boy with pain and limp in the affected area. Radiographic findings were an oval, radiolucent rarefaction with nonsclerotic border, measuring approximately 3.5 x 3.0 cm.

Microscopic examination identified aggregates of histiocytes, multinucleated giant cells, scattered eosinophils, and few plasma cells and lymphocytes. Ultrastructural studies demonstrated Birbeck granules within cytoplasm of histiocytes diagnostic of Langerhans cell histiocytosis.

Whether Langerhans cell histiocytosis is a neoplastic disorder or a reactive process remains controversial. The true nature of the Langerhans cell, the proliferating cells and hallmark of this disease, is likewise under scrutiny.

Langerhans cell histiocytosis of the female genital tract.

Axiotis CA, Merino MJ, Duray PH.

Warren Grant Magnuson Clinical Center, Bethesda, Maryland.

Cancer 1991 Mar 15;67(6):1650-60 Abstract quote

Langerhans cell histiocytosis (LCH) of the female genital tract is rare.

Four new cases are reported, and there is a review of the 38 cases in the literature. This disease may involve the vulva, vagina, cervix, endometrium, and ovary.

Four distinct patient groups, segregated on the basis of initial presentation and subsequent anatomic extent of disease, were categorized as follows: (1) "pure" genital LCH, (2) genital LCH with subsequent multi-organ involvement, (3) oral or cutaneous LCH with subsequent genital and multi-organ involvement, and (4) diabetes insipidus with subsequent genital and multi-organ disease. Although involvement of the genital tract can occur at any age, it is most common in young adulthood. Clinically, LCH may mimic either primary neoplasia or various inflammatory lesions; the major pathologic differential diagnosis is venereal and other inflammatory diseases. The pure genital form may have a distinct nosologic position in the spectrum of LCH similar to the "pure," self-limited cutaneous histiocytosis seen in infants. There is no correlation between histologic findings and the outcome of the genital lesions. There is also no correlation between clinical presentation and/or the extent of involvement and outcome of genital lesions; complete regression, partial improvement, persistent lesions, and recurrences were seen in all four groups of patients. The treatment of genital LCH is not well defined and is highly individualized.

Therapy has included surgery, radiation, topical corticosteroids, topical nitrogen mustard, systemic chemotherapy, and combination therapy; mixed results were obtained with all treatment modalities. Although no modality has been shown to yield a superior outcome, complete surgical excision is advocated as initial therapy.

Cutaneous Langerhans cell histiocytosis of the genitalia in the elderly: a report of three cases.

Meehan SA, Smoller BR.

Department of Pathology, Stanford University School of Medicine, California, USA.

J Cutan Pathol 1998 Aug;25(7):370-4 Abstract quote

Langerhans cell histiocytosis (LCH) is a disease with a broad spectrum of clinical presentations. All of the variants have in common the proliferation of cells which are morphologically, biochemically, and immunophenotypically indistinguishable from Langerhans cells.

A retrospective study of three elderly patients revealed the unique presentation of cutaneous Langerhans cell histiocytosis limited to the genitalia.

These cases produced a diagnostic challenge because of their unusual clinical presentation and their morphological similarity to certain other entities, including extramammary Paget's disease and malignant melanoma, which may also show S-100-positive atypical cells. All three cases showed infiltrates of histiocytic-appearing cells with folded nuclei and moderate amounts of cytoplasm which involved the epidermis, dermis, or both. Immunoperoxidase studies using antibody to S-100, CD1a and CD68 in each case showed positive staining.


Digestive tract involvement in Langerhans cell histiocytosis. The French Langerhans Cell Histiocytosis Study Group.

Geissmann F, Thomas C, Emile JF, Micheau M, Canioni D, Cerf-Bensussan N, Lazarovits AI, Brousse N.

Unite d'Immunologie et d'Hematologie, Hopital Necker-Enfants Malades, Universite Rene Descartes, Paris, France.

J Pediatr 1996 Dec;129(6):836-45 Abstract quote

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disease with a wide clinical spectrum. Although little is known of gastrointestinal involvement in LCH, it may be a major clinical problem. We investigated clinical, pathologic, and immunohistochemical features of digestive tract LCH involvement in children.

PATIENTS: Selection criteria consisted of the presence of LCH with digestive symptoms, and histologic confirmation of gastrointestinal involvement. Seven children (2%) met the criteria among 348 cases of LCH in a French national retrospective survey from 1983 to 1993. Two children whose LCH was diagnosed in 1994 were also selected.

RESULTS: Nine children with LCH and digestive tract involvement were studied. Clinical features at presentation included skin (9/9) and mucosal (4/9) involvement, failure to thrive (5/9), diarrhea (7/9), bloody stools (4/7), vomiting (4/9), and hypoalbuminemia (8/9). Five of the nine children died; factors associated with a poor prognosis included young age, organ dysfunction (stage 4), and need for parenteral nutrition. Unlike control biopsy specimens, LCH cells of children with digestive tract involvement disclosed expression of the mucosal homing receptor integrin alpha 4 beta 7 on frozen skin and digestive tract biopsy specimens.

CONCLUSION: Cutaneous, mucosal, and digestive tract involvement in LCH is a clinicopathologic entity. The prognosis and treatment of LCH depend on the extent of the disease; therefore the treatment of these disseminated forms should not be delayed. Thus children with cutaneous LCH and digestive symptoms should undergo digestive tract biopsies. Studies of homing receptors may contribute to our understanding of the mechanisms of dissemination in LCH.

Colon involvement in Langerhans' cell histiocytosis.

Nanduri VR, Kelly K, Malone M, Milla P, Pritchard J.

Department of Haematology and Oncology, Great Ormond Street Hospital for Children, London, United Kingdom.

J Pediatr Gastroenterol Nutr 1999 Oct;29(4):462-6 Abstract quote

BACKGROUND: Langerhans' cell histiocytosis (LCH), a granulomatous disorder of unknown cause, most often affects the bony skeleton and skin. Obvious gut involvement is uncommon, and colon involvement has been cited in only a small number of case reports, probably because most patients who have LCH with diarrhoea and/or failure to thrive are not investigated by colonoscopy and biopsy. The current study was conducted to determine the incidence of symptomatic colon involvement among patients with multisystem LCH treated at a single institution.

METHOD: A retrospective review of cases in hospital records and the literature.

RESULTS: Of the 275 children with LCH in the database, 5 were identified as having biopsy-confirmed colonic involvement. Another 14 cases were identified by a literature review.

CONCLUSION: Colonic involvement in patients with multisystem LCH is probably more common than currently recognised. In addition to the other investigations recommended by the Writing Group of the Histiocyte Society, it is recommended that patients with any symptoms suggestive of gut involvement undergo colonoscopy and biopsy of the colonic mucosa.


Langerhans cell histiocytosis of the thyroid: a report of two cases and review of the literature.

Behrens RJ, Levi AW, Westra WH, Dutta D, Cooper DS.

National Cancer Institute, Bethesda, Maryland, USA.

Thyroid 2001 Jul;11(7):697-705 Abstract quote

Langerhans cell histiocytosis (LCH) is a monoclonal disease of histiocytes that can involve many or very few organ systems. It is a relatively benign disorder with a 3% mortality in adults. LCH rarely involves the thyroid gland. We report two cases, both presenting in males with a goiter. Both patients were treated with subtotal thyroidectomy. The first patient also received radiotherapy to his thyroid bed and scalp.

We summarize the prior reported cases of LCH involving the thyroid and review the current treatment modalities used for LCH.

Langerhans Cell Histiocytosis Involving the Thyroid and Parathyroid Glands

Mod Pathol 2001;14:111-115

Case report
Document histologically, for the first time, concurrent involvement of the thyroid and parathyroid glands by LCH. A young Chinese woman with a history of diabetes insipidus and hypogonadism underwent a total thyroidectomy for enlarged thyroid gland secondary to LCH causing airway obstruction. Microscopic examination of the excised specimen disclosed CD1a- and S-100–positive LCH cells involving the thyroid and parathyroid glands.

In a patient with LCH affecting the thyroid gland, parathyroid gland disease should be suspected when the serum calcium levels are depressed in association with an inappropriate serum parathyroid hormone level, such as a normal parathyroid hormone level in this case.


Pulmonary Langerhans' Cell Histiocytosis Molecular Analysis of Clonality

Samuel A. Yousem, etal.

Am J Surg Pathol 2001;25:630-636 Abstract quote

Pulmonary Langerhans' cell histiocytosis (LCH) is a form of Langerhans' cell disease that primarily affects smokers in the third to fifth decade. Extrapulmonary manifestations are rare. Its clinical course is typically characterized by stabilization or regression of bilateral micronodular infiltrates seen on chest radiographs; progression to honeycomb fibrosis is rare.

Because the clinical course of pulmonary LCH is distinct from systemic multiorgan LCH, currently thought to be a clonal proliferative disorder, we examined the X-linked polymorphic human androgen receptor assay (HUMARA) locus to assess clonality in female patients with one or more discrete LCH cell nodules in open lung biopsies. Langerhans' cells (LCH cells) were excised from formalin-fixed, paraffin-embedded tissue by microdissection to assure a relatively pure cellular population, and studies for differential methylation patterns at the HUMARA locus were performed.

Twenty-four nodules in 13 patients were evaluated. Seven (29%) were clonal and 17 (71%) were nonclonal. Of six cases with multiple discrete nodules, three (50%) showed a nonclonal LCH cell population. In one biopsy with five nodules, two nodules were clonal with one allele inactivated, one nodule was clonal with the other allele inactivated, and two nodules were nonclonal.

In contrast to systemic LCH, pulmonary LCH appears to be primarily a reactive process in which nonlethal, nonmalignant clonal evolution of LCH cells may arise in the setting of nonclonal LCH cell hyperplasia. Cigarette smoking may be the stimulus for pulmonary LCH in contrast to other forms of LCH.

Lymph node involvement by Langerhans cell histiocytosis: a clinicopathologic and immunohistochemical study of 20 cases.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.


Hum Pathol. 2007 Oct;38(10):1463-9. Abstract quote

Twenty cases of Langerhans cell histiocytosis (LCH) involving lymph nodes with no other sites of disease are presented. The patients were 12 men and 8 women between 3 months and 68 years of age. Seven patients were younger than 11 years; the other 13 patients were older than 16 years. Clinically, all patients presented with lymphadenopathy and underwent excisional biopsy; clinical and imaging studies did not reveal abnormalities in other organs. Cervical lymph nodes were most commonly involved; other lymph nodes involved included axillary, inguinal, and supraclavicular.

Histologically, LCH in lymph nodes had 3 main architectural patterns: (1) preserved nodal architecture with subtle involvement, (2) subtotal effacement of nodal architecture, and (3) total effacement of nodal architecture. There was a gradient of involvement by LCH from focal sinus involvement to diffuse sinus involvement and from focal paracortical involvement to diffuse paracortical involvement. In some cases, focal involvement was initially unrecognized because of the subtle nature of the changes in the lymph node, posing difficulties for diagnosis. Langerhans cells in the involved areas showed strong positivity by immunohistochemical studies for S100 protein and CD1a in all 11 cases assessed.

In conclusion, LCH can initially manifest clinically with involvement limited to lymph nodes. Recognition of the different patterns of LCH, particularly cases with subtle involvement, is important for recognizing this disease and separating LCH from other more common causes of lymphadenopathy.
Langerhans cell histiocytosis presenting as blueberry muffin baby.

Shaffer MP, Walling HW, Stone MS.

Department of Dermatology, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.
J Am Acad Dermatol. 2005 Aug;53(2 Suppl 1):S143-6. Abstract quote  

Blueberry muffin baby is a descriptive term for purpuric lesions reflective of extramedullary hematopoeisis. The clinical lesions most commonly result from intrauterine infections, such as rubella and cytomegalovirus, and less commonly with malignancy and hematologic disorders. Langerhans cell histiocytosis is a clonal proliferation of dendritic histiocytes in the skin. This has very rarely been associated with a blueberry muffin presentation.

We report the case of a newborn with typical lesions of cutaneous hematopoiesis and lytic bone lesions related to Langerhans cell histiocytosis. At birth, approximately 40 2 mm to 5 mm purpuric, nonblanching macules were scattered on the trunk, extremities, and soles of our patient. Laboratory studies were unremarkable and cultures were negative. Skin biopsy showed a dermal proliferation of histiocytes staining positive for S100 and Cd1a. Pediatric bone surveys, chest radiographs, and computed tomography scans of the head were normal.

Six months later, the skin lesions had resolved, but radiographs revealed lytic bone lesions of the right tibia, right ilium, and left pubic ramus, consistent with skeletal Langerhans cell histiocytosis.
Adult onset folliculocentric langerhans cell histiocytosis confined to the scalp.

Hancox JG, James AP, Madden C, Wallace CA, McMichael AJ.

*Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Am J Dermatopathol. 2004 Apr;26(2):123-6. Abstract quote  

Langerhans cell histiocytosis (LCH) is a pleomorphic disease entity characterized by local or disseminated atypical Langerhans cells found most commonly in bone, lungs, mucocutaneous structures, and endocrine organs. Cutaneous disease occurs in approximately one quarter of all cases. Cutaneous findings include soft-tissue swelling, eczematous changes, a seborrheic dermatitis-like appearance, and ulceration.

We report a rare case of LCH confined to the scalp with folliculocentric infiltrates. This 32-year-old male patient presented with follicularly based erythema, scale, and pustules unresponsive to topicals and oral antibiotics. The patient's lesions mimicked lichen planopilaris and folliculitis decalvans during the disease process.

On hematoxylin and eosin stain, scalp biopsy showed a perivascular interstitial patchy lichenoid mononuclear cell infiltrate that focally abutted follicular infundibula. Prominent mononuclear cells having reniform nuclei were present, and immunoperoxidase stains for CD1a confirmed Langerhans cell differentiation. Serological and imaging workup failed to display systemic involvement.

Langerhans cell histiocytosis presenting as a varicelliform eruption over the entire skin.

Johno M, Oishi M, Kohmaru M, Yoshimura K, Ono T.

Department of Dermatology, Kumamoto University School of Medicine, Japan.

J Dermatol 1994 Mar;21(3):197-204 Abstract quote

A boy with skin eruptions resembling varicella and specific for Langerhans cell histiocytosis (LCH) is reported. At his initial visit when he was four months old, vesiculopustular lesions were present over the entire body; these had first appeared on the third day post partus.

Histopathological, immunohistochemical, and electron microscopical examination confirmed the Langerhans cell phenotype and Birbeck granules in the responsible cells. He also had hydronephrosis, recurrent fever, and cutaneous bacterial infections. His parents refused further medical treatment and he died of diarrhea with cachexia about two years later.

LCH may present diagnostic difficulties by manifesting as a skin eruption which resembles varicella.

Langerhans cell histiocytosis presenting as a thyroid gland mass.

Elliott DD, Sellin R, Egger JF, Medeiros LJ.

Division of Pathology and Laboratory Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
Ann Diagn Pathol. 2005 Oct;9(5):267-74. Abstract quote  

We report 2 cases of Langerhans cell histiocytosis (LCH) presenting as a thyroid mass. The first case is a 45-year-old woman with a 13-year history of diabetes insipidus who presented with an enlarging thyroid mass with substernal extension. The second case is a 29-year-old man who presented with an enlarging thyroid mass and skin lesions.

Histologic evaluation of the thyroid gland in both cases revealed extensive involvement by LCH, confirmed by immunohistochemical analysis showing Langerhans cells that were positive for CD1a and S-100 protein. Langerhans cell histiocytosis can rarely involve the thyroid gland in adults, and we have identified 30 cases reported in literature. Most patients had evidence of LCH involving other anatomic sites, as was true in these 2 cases, and the diagnosis was initially established by examination of other sites in a subset of patients.

Affected patients frequently have diabetes insipidus, as was true in case 1. Thyroid gland involvement as the initial presentation of LCH is a rare phenomenon that can result in misdiagnosis.



Lancet, 1987; I: 208–9

Under the recommendation of the Writing Group of the Histiocyte Society, a definitive diagnosis of LCH can only be rendered when either there is demonstration of Birbeck granules on electron-microscopic study or there is the demonstration of CD1a expression with appropriate histological settings


Infiltrated by sheets and islands of histiocyte-like cells containing vesicular nuclei with an indented, notched, grooved or "coffee bean"-shaped appearance, one or two nucleoli, and abundant lightly eosinophilic to eosinophilic cytoplasm

Some binucleated and occasional multinucleated cells may be present

Eosinophils present in variable numbers
Accompanying lymphocytes that formed fairly dense aggregates


Langerhans cell (eosinophilic) granulomatosis. A clinicopathologic study encompassing 50 years.

Lieberman PH, Jones CR, Steinman RM, Erlandson RA, Smith J, Gee T, Huvos A, Garin-Chesa P, Filippa DA, Urmacher C, Gangi MD, Sperber M.

Department of Pathology, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

Am J Surg Pathol 1996 May;20(5):519-52 Abstract quote

We summarize our experience with 238 cases of Langerhans cell granulomatosis (LCG), 198 of whom were followed for a median period of 10.5 years.

Our patients did well unless overtreated, and no deaths were attributed to the disorder itself. The disease may appear in unifocal or multifocal form, and treatment is based on this fact. Virtually all patients recovered completely except for occasional residual orthopedic problems or residual diabetes insipidus. Several of the patients underwent subsequent pregnancies without difficulty. The granulomas primarily occur in bone, but lung, skin, and lymph nodal involvement is not uncommon. Involvement of thyroid, thymus, and other sites is rare.

The hallmark of the disease is the accumulation of Langerhans cells (LCs). We review the pathology of LCG by histology, electron microscopy, and immunolabeling. LCs originally were identified in squamous epithelium, but these cells are part of the widespread system of dendritic cells. The latter cells, which arise from CD34+ progenitors, are specialized and efficient antigen-presenting cells for T-cell-mediated immunity. In LCG, however, the major associated cells are not T cells, but mature eosinophils: hence the original name eosinophilic granuloma. Confusion about terminology has been based upon the scanty and rather crude pathology reports in the original literature. The term histiocytosis X was meant to cover a spectrum of three diseases--eosinophilic granuloma, Hand-Schuller-Christian disease (HSC), and Letterer-Siwe disease (LS)--but HSC and LS have no basis in pathology and hence the terms are meaningless. The term HSC has become a synonym for multifocal eosinophilic granuloma (LCG). The term LS has been used in reporting a number of benign, malignant, or unknown conditions.

We prefer the term LCG to avoid confusion with the term histiocytosis X because there is evidence that the LC is not a member of the mononuclear phagocyte system and hence not a tissue macrophage, and because the use of the term "histiocyte" has become a convenience in much of the literature when reporting incompletely understood diseases.


Cutaneous manifestations of hemophagocytic lymphohistiocytosis.

Morrell DS, Pepping MA, Scott JP, Esterly NB, Drolet BA.

University of North Carolina, Department of Dermatology, 3100 Thurston-Bowles CB#7287, Chapel Hill, NC 27514.

Arch Dermatol 2002 Sep;138(9):1208-12 Abstract quote

BACKGROUND: Hemophagocytic lymphohistiocytosis is a rare, rapidly progressive, and potentially fatal disorder of activated histiocytes. The initial clinical presentation commonly includes fever, hepatosplenomegaly, and pancytopenia. Skin eruptions are described in up to 65% of patients. Information regarding the morphological features, configuration, and distribution of these eruptions is lacking and is typically reported as nonspecific and "maculopapular." The aim of this report is to better delineate the cutaneous manifestations of the disorder to assist in differentiating the process from other systemic diseases.

OBSERVATION: A case report of a neonate with hemophagocytic lymphohistiocytosis with generalized purpuric macules is described. The clinical features of 5 other patients with hemophagocytic lymphohistiocytosis at Children's Hospital of Wisconsin, Milwaukee, are summarized. Clinical images of 1 additional neonatal patient with hemophagocytic lymphohistiocytosis are presented as well. These observations demonstrate the varied cutaneous manifestations of hemophagocytic lymphohistiocytosis: erythroderma, generalized purpuric macules and papules, and morbilliform eruptions.

CONCLUSION: Awareness of cutaneous involvement can assist in the initial diagnosis of hemophagocytic lymphohistiocytosis and potentially signify recurrences.

Indeterminate cell histiocytosis: fact or fiction?

Ratzinger G, Burgdorf WH, Metze D, Zelger BG, Zelger B.

Clinical Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria.

J Cutan Pathol. 2005 Sep;32(8):552-60. Abstract quote  

Indeterminate cell histiocytosis is a rare disorder, in which the predominant cells have the characteristics of both Langerhans cells and macrophages.

We, in this study, describe 18 patients and compare them with those previously published. Most patients were adults with either solitary or multiple red-brown papules or nodules. While most lesions were confined to the skin, both conjunctival and bony involvement was seen.

Histologically, the lesions showed patterns resembling those described for xanthogranulomas, with predominantly oncocytic (nine patients), spindled (five patients), scalloped (two patients) or vacuolated (two patients) macrophages. The accompanying infiltrate was mainly lymphocytic, although eosinophils and occasionally plasma cells were seen. All lesions were positive for macrophage markers, such as KP1 (CD68) and Ki-M1p, as well as for S-100 protein and showed variable reactivity for CD1a. No Birbeck granules were seen ultrastructurally in one patient. Some patients shared features with sinus histiocytosis with massive lymphadenopathy.

It is unclear whether this disorder is a separate entity or represents various macrophage disorders identified at various time points in the inflammatory response.

Indeterminate cell histiocytosis.

Rodriguez-Jurado R, Vidaurri-De La Cruz H, Duran-Mckinster C, Ruiz-Maldonado R.

Departments of Pathology (Dr Rodriguez-Jurado) and Dermatology (Drs Vidaurri-de la Cruz, Duran-Mckinster, and Ruiz-Maldonado), National Institute of Pediatrics of Mexico, Mexico City, Mexico.

Arch Pathol Lab Med 2003 Jun;127(6):748-51 Abstract quote

Indeterminate cell histiocytosis is a rare disorder involving altered homing mechanisms of the cutaneous histiocytic/dendritic system. It has been described predominantly in adults, with less than a dozen cases in children.

A 13-year-old adolescent girl presented with a 4-year history of asymptomatic erythematous nodules and plaques, measuring from 1 to 5 cm in diameter, that were located mainly on the trunk and proximal portions of her limbs. A skin biopsy showed dermal diffuse infiltration of histiocytic cells. Most of the histiocytic cells were strongly positive for S100 protein. No Birbeck granules were found.

Treatment with topical steroid was ineffective. After 6 months of pure coal tar and 5% 5-fluorouracil cream, an almost total clearing of lesions was observed. An accurate diagnosis of this condition is mandatory in order to avoid unnecessary treatments. Conservative management is also discussed.

Cutaneous indeterminate cell histiocytosis: a new spindle cell variant resembling dendritic cell sarcoma

Arlene Sylvia Rosenberg1 and Michael B. Morgan2

1 Departments of Pathology, University of South Florida, Tampa, Florida, USA, 2 James A. Haley Veterans Administration Hospital, Tampa, Florida, USA

Journal of Cutaneous Pathology 2001;28 (10), 531-537 Abstract quote

Background: Cutaneous indeterminate cell histiocytosis is a rare neoplastic disorder. Its varied histological presentation and rarity have limited efforts to determine its pathogenic relationship with other histiocytic lesions and possibly, its recognition.

Methods: We report on an unusual histologic pattern of indeterminate cell histiocytosis that resembled follicular dendritic sarcoma. A battery of immunohistochemical stains and electron microscopy were performed to elucidate the phenotype of the “histiocytic” cells. Based on a review of the literature, reported cases of indeterminate cell histiocytosis are presented and the diagnostic differential of spindle-cell lesions is discussed.

Results: Spindling histiocytes were positive for S-100 and CD1a. The monocytic/macrophage marker, CD68, and the dendritic cell marker, CD21, were negative. Electron microscopy failed to reveal Birbeck granules.

Conclusions: Relatively few reports of indeterminate cell histiocytosis exist, some of which include discussion of potential overlaps with the non-X histiocytoses. Although the presence of prominent spindling in our case expanded the differential to include non-histiocytic disorders, the identified histiocytes unequivocally fulfilled the criteria of S-100 and CD1a positivity without demonstrable Birbeck granules.

Indeterminate cell histiocytosis: a rare histiocytic disorder.

Manente L, Cotellessa C, Schmitt I, Peris K, Torlone G, Muda AO, Romano MC, Chementi S.

Department of Dermatology, University of L'Aquila, Italy.
Am J Dermatopathol. 1997 Jun;19(3):276-83. Abstract quote  

A 64-year-old woman, otherwise healthy, presented with multiple reddish-brown, slightly yellowish papules on the face and neck, which had developed 3 years earlier. The lesions were painless and nonpruritic and varied in diameter from 1 to 5 mm.

Histological and immunohistochemical examination of cutaneous biopsies revealed a diffuse dermal infiltrate composed mainly of histiocytes which expressed both Langerhans cell as well as monocytic/macrophages cell marker characteristics. Electron microscopic studies revealed no Birbeck granules within the cytoplasm of the neoplastic cells, leading to a diagnosis of indeterminate cell histiocytosis.

Indeterminate cell histiocytosis is a very rare disease characterized by the proliferation of indeterminate histiocytes which morphologically and immunophenotypically resemble Langerhans cells but lack Birbeck granules.

Indeterminate cell histiocytosis--a clinicopathological entity with features of both X- and non-X histiocytosis.

Sidoroff A, Zelger B, Steiner H, Smith N.

Department of Dermatology, University of Innsbruck, Austria.

Br J Dermatol 1996 Mar;134(3):525-32 Abstract quote

An otherwise healthy 50-year-old woman presented with a 6-month history of having developed more than 100 generalized, non-confluent, reddish-brown, partially yellow-coloured papules.

A non-epidemotropic, monomorphous infiltrate of vacuolated mononuclear, and occasionally multinuclear, histiocytes, positive for factor XIIIa and macrophage markers HAM56 and KiM1p, was consistent with the clinical impression of generalized eruptive histiocytomas. However, the additional reactivity for S100 protein, in the absence of features of histiocytosis X, suggested a diagnosis of indeterminate cell histiocytosis (ICH).

Further immunohistochemical studies, performed on snap-frozen material, characterized the lesions as being diffusely positive with LN3 (HLA-DR), Leu4 (CD3) and Leu3 (CD4), the infiltrate in the upper dermis as reactive for OKT6 (CD1) and IOT6c (CD1c), and the infiltrate in the lower dermis as reactive for a variety of macrophage markers. Ultrastructural studies showed various non-specific features of histocytic disorders, but no Birbeck granules. Our findings confirm those of previous reports suggesting that ICH is a distinct histiocytic entity, characterized by immunophenotypic features of both X- and non-X histiocytoses. Generalized eruptive histiocytoma seems to be an early indeterminate stage of various non-X histiocytic syndromes including ICH, multicentric reticulohistiocytosis, xanthogranuloma and xanthoma disseminatum.

The distribution pattern of the various X/non-X histiocytic markers suggests dermal arrest of antigen-presenting cells during their physiological trafficking from the skin to the lymph nodes.

Two sporadic cases of adult-onset progressive mucinous histiocytosis.

Young A, Olivere J, Yoo S, Martins C, Barrett T.

Department of Dermatology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.

J Cutan Pathol. 2006 Feb;33(2):166-70. Abstract quote  

Progressive mucinous histiocytosis is a rare, benign, non-Langerhans' cell histiocytosis limited to the skin. Ten cases - all women - in four families and one sporadic case have been described in the literature. The disorder usually begins in childhood and progresses slowly.

We report two sporadic cases of adult-onset progressive mucinous histiocytosis in unrelated African-American women, aged 48 and 55 years, respectively, who developed red-brown and flesh-coloured, asymptomatic papules on the face, the arms and the legs without truncal, mucosal or visceral involvement. The lesions showed no spontaneous regression. Both patients lacked associated systemic symptoms, including polyuria, polydipsia or seizures. There was no underlying hyperlipidaemia, paraproteinaemia or lymphoproliferative disease. No family history of similar lesions could be identified. Light microscopy revealed dermal proliferation of spindle-shaped histiocytes with abundant mucin deposition. Electron microscopy demonstrated a high number of myelin figures or zebra bodies in the cytoplasm of histiocytes.

On immunohistochemistry, positive staining with macrophage markers - CD68, HAM56 and lysozyme - and factor XIIIa, a transglutaminase present in dermal dendrocytes, and negative staining with Langerhans' cell markers - CD1a and S100 - and CD34, a marker present in dermal dendritic cells derived from uncommitted mesenchymal cells, were observed. .
Hereditary progressive mucinous histiocytosis.

Schroder K, Hettmannsperger U, Schmuth M, Orfanos CE, Goerdt S.

Hautklinik und Poliklinik, Universitatsklinikum Benjamin Franklin, Freie Universitat Berlin, Germany.

J Am Acad Dermatol. 1996 Aug;35(2 Pt 2):298-303. Abstract quote  

We describe hereditary progressive mucinous histiocytosis, a rare autosomal dominant non-Langerhans cell histiocytosis, in a mother and daughter.

Both had similar, progressive eruptions of skin-colored to red-brown papules on the nose, hands, forearms, and thighs. Light microscopy showed small collections of epithelioid histiocytes and telangiectatic vessels in the upper dermis of early lesions. In the mid dermis of early and well-developed lesions, nodular aggregates of tightly packed spindle-shaped cells were seen. Moderate to extensive mucin production was demonstrated in epithelioid histiocytes and spindle-shaped cells. Electron microscopy of spindle-shaped cells revealed many dendritic histiocytes with abundant lysosomal storage organelles such as myelin bodies and zebra bodies.

Immunohistochemistry showed expression of macrophage antigens (CD68; MS-1 high-molecular-weight protein) in epithelioid histiocytes and in some of the spindle-shaped cells. The histologic and immunohistochemical features of hereditary progressive mucinous histiocytosis most closely resemble solitary histiocytoma/cellular-type dermatofibroma.
Histiocytic sarcoma with secondary involvement of the skin and expression of CD1a: evidence of indeterminate cell differentiation?

Frater JL, Kling CW, Obadiah JM, Gardner LJ, Grosso LE, Resh B, Hurley MY.

Department of Pathology, Saint Louis University School of Medicine, St Louis, MO, USA.

J Cutan Pathol. 2006 Jun;33(6):437-42. Abstract quote  

Background: Histiocytic sarcoma is an exceedingly rare malignant neoplasm composed of cells with a monocyte/macrophage phenotype. In the current nosology of histiocytic neoplasms, histiocytic sarcoma is separate from indeterminate cell histiocytosis, a generally benign disorder characterized by proliferation of a CD1a(+) and S-100(+) population of cells lacking Birbeck granules usually limited to the skin.

Methods: We present a case of histiocytic sarcoma in a 64-year-old man presenting as a peritonsillar mass and secondarily involving the skin.

Results: The malignant cells in the extracutaneous foci of disease expressed macrophage-associated antigens including S-100 but were CD1a(-). The malignant cells in the skin coexpressed CD1a and S-100 but lacked ultrastructural features of Langerhans cells, findings indicative of indeterminate cells.

Conclusions: We discuss the clinical and histopathologic differential diagnosis in association with prior reported cases of histiocytic sarcoma, particularly in cases involving the skin and cases expressing the Langerhans cell-associated antigen CD1a.
Langerhans Cell Sarcoma.

Ferringer T, Banks PM, Metcalf JS.

From the *Dermatopathology Fellow, Medical University of South Carolina, Charleston, SC; daggerDepartment of Pathology, Carolinas Medical Center, Charlotte, NC; and double daggerProfessor of Pathology and Dermatology, Medical University of South Carolina, Charleston, SC, USA.

Am J Dermatopathol. 2006 Feb;28(1):36-39. Abstract quote  

Proliferations of Langerhans cells can be histologically divided into cytologically benign Langerhans cell proliferations, which include the clinical syndromes of Langerhans cell histiocytosis, and cytologically malignant Langerhans cell sarcoma.

We report a Langerhans cell sarcoma in a 33-year-old male that arose on the posterior thigh with subsequent regional lymph node involvement. Conventional microscopic, immunohistochemical, and ultrastructural analysis confirmed Langerhans cell differentiation.

Aberrant CD31 expression, similar to that described previously in Langerhans cell histiocytosis, was prominent in this tumor, possibly enhancing its migratory capabilities.



Special stains  

Strong and diffuse positive stain for CD1a and S-100 positivity are characteristic

Aberrant expression of macrophage marker CD68 occurs only in a substantial minority of cases of LCH

Langerhans' cell histiocytosis (histiocytosis X): immunophenotype and growth fraction.

Hage C, Willman CL, Favara BE, Isaacson PG.

Department of Histopathology, University College London Medical School, UK.

Hum Pathol 1993 Aug;24(8):840-5 Abstract quote

The immunophenotype and proliferation fraction have been investigated in 26 cases of Langerhans' cell histiocytosis (LCH).

In all cases LCH cells were positive for S-100 protein, CD1a, or both. In most cases LCH cells expressed the macrophage-associated marker CD68 and in two cases they contained lysozyme. Expression of both cytoplasmic CD2 and CD3 was observed in cryostat sections. An unexpected finding was the presence of placental alkaline phosphatase in LCH cells. Langerhans' cells in normal skin were negative for both CD2 and CD3, but a proportion contained placental alkaline phosphatase. In four cases of Rosai-Dorfman disease the histiocytic cells, which share certain immunophenotypic properties with Langerhans' cells, also were positive for placental alkaline phosphatase. A significant proportion of LCH cells stained positively with the antibody to proliferating cell nuclear antigen and also with the proliferation marker Ki-S1. A good correlation between the percentage of Ki-67-positive and proliferating cell nuclear antigen- and Ki-S1-positive cells, respectively, was observed.

Thus, in comparison with their putative precursors, LCH cells have an aberrant phenotype and are proliferating locally. This might suggest that LCH is a neoplastic rather than a reactive process.

Differential Expression of Markers in Extensive and Restricted Langerhans Cell Histiocytosis (LCH).

Kohalmi F, Strausz J, Egervary M, Szekeres G, Timar J.

Semmelweis University of Medicine, 1st Institute of Pathology and Experimental Cancer Research, Budapest, Hungary.

Pathol Oncol Res 1996;2(3):184-187 Abstract quote

Langerhans cell histiocytosis (LCH) represents a poorly defined pathologic entity characterized by diverse clinical appearence and falling into two major categories namely a restricted and an extensive disease. Since the outcome and the course of the disease is variable, we postulated that this might be reflected by the phenotype of the Langerhans cells.

We have selected 11 adult restricted cases and 10 extensive childhood cases and compared the phenotype of LCH cells by immunohistochemistry on paraffin sections. Morphometric analysis indicated a significantly higher expression of histiocytic (CD68, S-100, lysozyme) markers in the adult restricted cases compared to the extensive form of the disease. Both groups were equally positive for LCH marker CD1a and negative for T cell marker CD4. On the other hand, HLA-DR expression was significantly higher in LCH cells of the extensive childhood cases suggesting higher activation.

These data suggest that LCH cells have a different phenotype in the extensive childhood and restricted adult LCH where the latter is characterized by a more differentiated histiocytic phenotype.


CD101 expression by Langerhans cell histiocytosis cells.

Bouloc A, Boulland ML, Geissmann F, Fraitag S, Andry P, Teillac D, Bensussan A, Revuz J, Boumsell L, Wechsler J, Bagot M.

Department of Dermatology; INSERM U448; Department of Pathology, Hopital Henri-Mondor, Creteil, France.

Histopathology 2000 Mar;36(3):229-32 Abstract quote

AIMS: Our objective was to study the expression of a recently identified cell surface molecule, CD101 and in Langerhans cell histiocytosis (LCH) patients as CD101 has been shown to be present on dendritic cells. We wanted to determine if CD101 expression could be helpful for the diagnosis of LCH in conjunction with other markers (CD1a, S100 protein), and could be predictive of the evolution and dissemination of the disease. METHODS AND

RESULTS: The expression of CD101 was studied by immunohistochemical technique in 11 cases of Langerhans cell histiocytosis on frozen sections. The expression of CD101 was positive in nine cases, high in six cases and low in three cases. There was no expression in the other two cases. No correlation with the evolution, the localization or the dissemination of the disease could be evidenced.

CONCLUSIONS: CD101 is a new phenotypic marker that might be useful in combination with other markers for the diagnosis of LCH. However, as the anti-CD101 antibody works only in frozen sections, its value is limited compared to anti-CD1a antibody.


Langerhans cell histiocytosis immunohistochemical expression of fascin, a dendritic cell marker.

Pinkus GS, Lones MA, Matsumura F, Yamashiro S, Said JW, Pinkus JL.

Department of Pathology, Brigham & Women's Hospital, Boston, MA 02115, USA.

Am J Clin Pathol 2002 Sep;118(3):335-43 Abstract quote

Langerhans cell histiocytosis (LCH) is a clonal disorder believed to be derivedfrom cells of the dendritic system. Fascin, a 55-kd actin-bundling protein, represents a highly selective marker for dendritic cells of lymphoid tissues and peripheral blood and is involved in the formation of dendritic processes in maturing epidermal Langerhans cells.

Since lesional cells of LCH may represent Langerhans cells arrested at an early stage of activation, immunohistochemical expression offascin in epidermal Langerhans cells and in the lesional cells of 34 cases of LCH was evaluated in paraffin sections using an immunoalkaline phosphatase technique. Though epidermal Langerhans cells were nonreactive for fascin, lesional cells in all LCH cases exhibited immunoreactivity for fascin, CD1a, and S-100 protein.

Variation in staining intensity was observed in some cases, possibly reflecting differences in cell maturation or activation. Involved tissues included bone, soft tissue, lymph node, thyroid, orbit, and extradural cranial tissue. Immunoreactivity of lesional cells of LCH for fascin supports their derivation from cells of the dendritic system and represents another alteration in the phenotype of Langerhans cells that is associated with maturation, migration, culture, or clonal expansion.

Electron microscopy (EM) Characteristic Birbeck granule

Electron microscopy in histiocytosis X.

Mierau GW, Favara BE, Brenman JM.

Ultrastruct Pathol 1982 Apr-Jun;3(2):137-42 Abstract quote

In an ultrastructural study of 24 cases of histiocytosis X, we were able to demonstrate Langerhans cell granules in all of 18 cases from which tissues had been submitted primarily for electron microscopy and in 4 of 6 cases from which only tissue retrieved from paraffin blocks was available for examination. In a subsequent correlative study we were able to demonstrate Langerhans cell granules in deparaffinized material from 11 of 14 cases (79%) in which they were known to exist.

The incidence of histiocytes displaying Langerhans cell granules (in a single plane of section) fell from a median of 48% in samples processed primarily for electron microscopy to 14% in those retrieved from paraffin blocks.

Our data suggest that electron microscopy, even when applied to the study of suboptimally preserved material, is a highly sensitive technique for confirming a diagnosis of histiocytosis X.

Histiocytosis-X: clonal culture, histocytochemistry, electron microscopy.

Selvaggi S, Greco MA, Wolman SR, Harlow P.

Am J Pediatr Hematol Oncol 1983 Winter;5(4):333-6 Abstract quote

Pathologic interpretation of an osteolytic lesion from the skull of a 13-month-old boy was amplified by histocytochemistry of cells grown in a methylcellulose clonal culture system.

Electron microscopy demonstrated the presence of X granules in the cytoplasm of malignant histiocytes, confirming a diagnosis of histiocytosis-X. Freshly fixed tissue containing histiocytosis-X cells and granulocytes showed histiocytosis-X cells that were positive for alpha-naphthyl acetate esterase (non-specific esterase) and negative with naphthol AS-D chloracetate as the esterase substrate (specific esterase). Clonal cell aggregates, harvested after 6 days' growth in culture, showed histiocytosis-X cells that were positive for both the nonspecific and specific esterases. Differences in staining reactions for the histiocytosis-X cells may be explained on the basis of immaturity of the histiocytosis-X cells growing in culture.

This interpretation would support their origin from monocytes, monocytic precursors, or a still less differentiated myelomonocytic precursor cell. Furthermore, gel systems of clonally cultured cells appear to provide a useful tool for the growth and analysis of histiocytosis-X cells.

Immunohistochemical and ultrastructural study of histiocytosis X and non-X histiocytoses.

Fartasch M, Vigneswaran N, Diepgen TL, Hornstein OP.

Department of Dermatology, University of Erlangen, F.R.G.

J Am Acad Dermatol 1990 Nov;23(5 Pt 1):885-92 Abstract quote

The diagnostic reliability of ultrastructural and immunohistochemical examinations on routinely processed biopsy specimens of cutaneous histiocytic proliferations (histiocytosis X, n = 7; juvenile xanthogranuloma, n = 4; necrobiotic xanthogranuloma, n = 2; traumatic granuloma of the tongue, n = 1) was evaluated. S-100 protein, peanut agglutinin, and the antibody Mac-387 were used as markers for histiocytes.

The frequency of Birbeck granule-containing cells in seven histiocytosis X lesions did not correspond with the number of S-100+ or peanut agglutinin+ cells. All neoplastic histiocytosis X cells were positive for S-100 protein and peanut agglutinin but were negative for Mac-387. Histiocytes of juvenile xanthogranuloma, necrobiotic xanthogranuloma, and traumatic granuloma were strongly positive for Mac-387 but were negative for S-100 protein and peanut agglutinin, except for the peanut agglutinin-reactive Touton giant cells. Mac-387 reliably differentiates histiocytic proliferations of the monocyte/macrophage system from those of the dendritic cell system.

For the diagnosis of histiocytosis X, both S-100 protein and peanut agglutinin positivity in histiocytes is as reliable as ultrastructural demonstration of Birbeck granules.


Lesions resembling Langerhans cell histiocytosis in association with other lymphoproliferative disorders: a reactive or neoplastic phenomenon?

Christie LJ, Evans AT, Bray SE, Smith ME, Kernohan NM, Levison DA, Goodlad JR.

Department of Pathology, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. l

Hum Pathol. 2006 Jan;37(1):32-9. Epub 2005 Nov 22. Abstract quote  

Langerhans cell histiocytosis (LCH) has been described in association with a variety of neoplasms preceding, after, or synchronous with the other tumor. In some cases, a neoplasm may arise as a complication of therapy for LCH, and in others, the association may be coincidental. Synchronous occurrence has been reported most commonly in association with malignant lymphoma in which discrete proliferations of Langerhans cells (LCs) histologically indistinguishable from LCH are seen. In most cases, these LCs are closely related to or intermingling with the primary pathology. The nature of LCs in this context remains elusive with debate as to whether they represent a true clonal neoplasm or an exaggerated reactive phenomenon. The lack of evidence for LCH progression or disease elsewhere strongly supports the latter.

We have encountered 5 examples of LCH-like proliferations occurring in the context of other lymphoproliferative disorders. These include 2 cases of mycosis fungoides and 1 of cutaneous B-cell pseudolymphoma, associations that to our knowledge have not been described before. Two patients were female, and the clonality of the LC proliferation was assessed using laser capture microdissection and the human androgen receptor. The results showed that the LCs forming discrete nodules in a case of cutaneous B-cell pseudolymphoma and a case of Hodgkin's lymphoma were polyclonal.

This suggests that, at least in a proportion of cases, the aggregates of LCs occasionally identified within other lymphoproliferative lesions represent a reactive proliferation rather than a potentially aggressive second neoplasm.
Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases.

Pileri SA, Grogan TM, Harris NL, Banks P, Campo E, Chan JK, Favera RD, Delsol G, De Wolf-Peeters C, Falini B, Gascoyne RD, Gaulard P, Gatter KC, Isaacson PG, Jaffe ES, Kluin P, Knowles DM, Mason DY, Mori S, Muller-Hermelink HK, Piris MA, Ralfkiaer E, Stein H, Su IJ, Warnke RA, Weiss LM.

Service of Pathologic Anatomy and Hematopathology, Institute of Haematology and Clinical Oncology L.e A. Seragnoli, Bologna University, Italy.
Histopathology. 2002 Jul;41(1):1-29. Abstract quote  

Neoplasms of histiocytes and dendritic cells are rare, and their phenotypic and biological definition is incomplete.

Seeking to identify antigens detectable in paraffin-embedded sections that might allow a more complete, rational immunophenotypic classification of histiocytic/dendritic cell neoplasms, the International Lymphoma Study Group (ILSG) stained 61 tumours of suspected histiocytic/dendritic cell type with a panel of 15 antibodies including those reactive with histiocytes (CD68, lysozyme (LYS)), Langerhans cells (CD1a), follicular dendritic cells (FDC: CD21, CD35) and S100 protein.

This analysis revealed that 57 cases (93%) fit into four major immunophenotypic groups (one histiocytic and three dendritic cell types) utilizing six markers: CD68, LYS, CD1a, S100, CD21, and CD35. The four (7%) unclassified cases were further classifiable into the above four groups using additional morphological and ultrastructural features. The four groups then included: (i) histiocytic sarcoma (n=18) with the following phenotype: CD68 (100%), LYS (94%), CD1a (0%), S100 (33%), CD21/35 (0%). The median age was 46 years. Presentation was predominantly extranodal (72%) with high mortality (58% dead of disease (DOD)). Three had systemic involvement consistent with 'malignant histiocytosis'; (ii) Langerhans cell tumour (LCT) (n=26) which expressed: CD68 (96%), LYS (42%), CD1a (100%), S100 (100%), CD21/35 (0%). There were two morphological variants: cytologically typical (n=17) designated LCT; and cytologically malignant (n=9) designated Langerhans cell sarcoma (LCS). The LCS were often not easily recognized morphologically as LC-derived, but were diagnosed based on CD1a staining. LCT and LCS differed in median age (33 versus 41 years), male:female ratio (3.7:1 versus 1:2), and death rate (31% versus 50% DOD). Four LCT patients had systemic involvement typical of Letterer-Siwe disease; (iii) follicular dendritic cell tumour/sarcoma (FDCT) (n=13) which expressed: CD68 (54%), LYS (8%), CD1a (0%), S100 (16%), FDC markers CD21/35 (100%), EMA (40%). These patients were adults (median age 65 years) with predominantly localized nodal disease (75%) and low mortality (9% DOD); (iv) interdigitating dendritic cell tumour/sarcoma (IDCT) (n=4) which expressed: CD68 (50%), LYS (25%), CD1a (0%), S100 (100%), CD21/35 (0%). The patients were adults (median 71 years) with localized nodal disease (75%) without mortality (0% DOD).

In conclusion, definitive immunophenotypic classification of histiocytic and accessory cell neoplasms into four categories was possible in 93% of the cases using six antigens detected in paraffin-embedded sections. Exceptional cases (7%) were resolvable when added morphological and ultrastructural features were considered. We propose a classification combining immunophenotype and morphology with five categories, including Langerhans cell sarcoma. This simplified scheme is practical for everyday diagnostic use and should provide a framework for additional investigation of these unusual neoplasms.

Interferon-gamma receptor deficiency mimicking Langerhans' cell histiocytosis.

Edgar JD, Smyth AE, Pritchard J, Lammas D, Jouanguy E, Hague R, Novelli V, Dempsey S, Sweeney L, Taggart AJ, O'hara D, Casanova JL, Kumararatne DS.

Regional Immunology Service, The Royal Hospitals, Belfast, N Ireland.

J Pediatr 2001 Oct;139(4):600-3 Abstract quote

Two patients who were initially given a diagnosis of Langerhans' cell histiocytosis on the basis of the clinical, radiologic, and biopsy findings had mycobacterial infection subsequently identified.

The correct diagnosis of dominant partial interferon-gamma receptor deficiency was established.

Prominent Langerhans' cell migration in the arthropod bite reactions simulating Langerhans' cell histiocytosis.

Department of Pathology, College of Medicine, Yonsei University, Seoul, Korea.


J Cutan Pathol. 2007 Dec;34(12):899-902. Abstract quote

Background: Epidermal Langerhans' cells (LCs) play pivotal roles in cutaneous immune responses. An encounter with antigens or other stimuli causes the mobilization and migration of LCs. Therefore, some dermatoses, which originated from antigenic stimuli or trauma, can show LC migration. Recently, we experienced several cases of anthropod bites that showed marked inflammatory infiltrates with eosinophils and CD1a-positive LCs. It was difficult to differentiate these cases from Langerhans' cell histiocytosis (LCH).

Methods: The degree and pattern of LC infiltration in the skin of arthropod bite reaction was evaluated. The characteristics of CD1a immunohistochemical expression in the arthropod bite reactions were compared with those of LCH.

Results: A few arthropod bite cases (approximately 36%) showed extensive CD1a-positive LCs in the dermis, especially in the perivascular area. In addition, the CD1a expression patterns of LCs in the arthropod bite reactions were dendritic, whereas that of tumor cells in LCH were distinctly membranous and cytoplasmic.

Conclusion: Some arthropod bite reactions can show marked CD1a-positive LCs in the dermis, especially in the perivascular area. The dendritic CD1a immunohistochemical staining pattern in arthropod bite reactions is useful in helping to differentiate from LCH.
Evaluation of Langerhans' cells in normal and eczematous dermatitis skin by CD1a protein immunohistochemistry: preliminary findings.

Department of Pathology, Faculty of Medicine, Assuit University Hospitals, Assuit University, Assuit, Egypt.

J Cutan Pathol. 2008 Jun;35(6):554-8. Abstract quote

BACKGROUND: Langerhans' cells (CD1a positive, bone marrow-derived cells), are the antigen presenting cells of the skin. Our knowledge about the status of these cells in eczematous dermatitis is incomplete.

AIM: This study tests the hypothesis that 'the development of eczematous dermatitis is associated with alterations of Langerhans' cells'.

MATERIALS AND METHODS: Biopsy specimens from patients with eczematous dermatitis and normal skin (20 cases, each) were studied. Langerhans' cells were stained for CD1a using imunoperoxidase-staining methods and mouse monoclonal antibodies. RESULTS: In normal skin, CD1a+ Langerhans' cells were seen in suprabasal position. In eczematous dermatitis skin, CD1a positive cells were seen scattered in the acanthotic epidermis. Compared with normal skin, the mean values of the Langerhans' cells were statistically significantly higher in eczematous dermatitis [epidermal Langerhans' cells: 1.20 (standard error of mean, SEM, 0.13) vs. 2.50 (SEM, 0.16); and dermal Langerhans' cells: 1.30 (SEM, 0.15) vs. 2.7 (SEM, 0.15); for normal and eczematous skin, respectively; p < 0.05].

CONCLUSIONS: The higher Langerhans' cell counts in eczematous dermatitis suggest a possible link between antigen presenting capabilities of these cells, and development of these lesions.


Treatment and outcome of vertebral Langerhans cell histiocytosis at the Children's Hospital of Eastern Ontario.

Brown CW, Jarvis JG, Letts M, Carpenter B.

Division of Orthopaedic Surgery, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ont.
Can J Surg. 2005 Jun;48(3):230-6. Abstract quote  

BACKGROUND: We wished to evaluate the treatment methods for vertebral Langerhans cell histiocytosis (LCH) (a rare reticuloendothelial disorder) at a tertiary care pediatric centre and compare treatment and outcomes with those reported in the recent literature.

METHODS: A total of 55 charts were retrieved between 1980 and 2003 for children with LCH. Only those children who were under 18 years of age, had a diagnosis of LCH, histiocytosis X or eosinophilic granuloma and had documented vertebral involvement were included. The data collected were compared with data in the literature with respect to epidemiologic features, symptoms, investigations and procedures done, treatment, outcome and follow-up.

RESULTS: Of the 8 children who met the inclusion criteria for vertebral LCH, the most common presenting complaint was back or neck pain. The thoracic vertebrae were most commonly affected followed equally by cervical and lumbar spines. Most children underwent a complete diagnostic work-up. A single solitary lesion was found in only 1 child. Biopsies were attempted in all cases with 6 positive results. Treatment varied depending on the severity of the presenting complaint; however, none of the tumours was completely resected. Follow-up averaged 3.4 years, and only 1 child has had a recurrence.

CONCLUSION: A multidisciplinary investigation is recommended for children with suspected vertebral LCH. Treatment depends on the severity of the disease.

Langerhans cell histiocytosis--a 31 year review.

Leavey P, Varughese M, Breatnach F, O'Meara A.

Department of Oncology, Our Lady's Hospital for Sick Children, Crumlin, Dublin.

Ir J Med Sci 1991 Sep;160(9):271-4 Abstract quote

Forty-one patients with Langerhans Cell Histiocytosis (LCH) were treated over a thirty-one year period in our institution.

These children were classified according to the number of systems involved: twenty-two had unisystem disease while nineteen had multisystem disease. A histological diagnosis was reached in 82% of cases, the remainder being diagnosed on both radiological and clinical grounds. 68% of those with multisystem disease had a rash at diagnosis whilst 64% had a persistent ear discharge. The diagnosis was established accidentally in 25% of those with unisystem disease. The mortality rate was 21% and was confined to those who were under two years of age at diagnosis, all of whom had multisystem disease. Morbidity was 20% and was restricted to patients with multisystem disease. Only one patient died within the last 10 years; there were no therapy related deaths. Treatment related morbidity was seen in only three children. In keeping with other series, our review has identified the following adverse prognostic factors a) age under 2 years at presentation, b) multisystem disease and c) major organ dysfunction.

In view of the natural history of the disease, it is suggested that chemotherapy only be used in those patients who have major organ dysfunction or progressive disease and that radiotherapy is rarely indicated.

Lack of expression of E-cadherin is associated with dissemination of Langerhans' cell histiocytosis and poor outcome.

Geissmann F, Emile JF, Andry P, Thomas C, Fraitag S, De Prost Y, Brousse N.

Service d' Anatomie et de Cytologie Pathologiques, Hopital Necker-Enfants Malades, Universite Rene Descartes-Paris V, France.

J Pathol 1997 Mar;181(3):301-4 Abstract quote

Langerhans' cell histiocytosis (LCH) often occurs in children as a cutaneous disease. The course of the disease is characterized by either spontaneous resolution or multivisceral dissemination with poor prognosis. The pathogenesis of LCH is not known.

Since E-cadherin mediates homophilic adhesion of normal Langerhans' cells to keratinocytes and is also a ligand of the alpha E beta 7 intraepithelial lymphocyte integrin, this study was undertaken to investigate whether its expression on LCH cells correlates with the clinical behaviour of the disease. Clinical records of 14 children with LCH, all of whom had cutaneous involvement, were retrospectively analysed. The expression of E-cadherin was studied by in situ immunohistochemistry on 22 frozen biopsy samples with two specific monoclonal antibodies. LCH cells of the seven children with only skin involvement were positive for E-cadherin. By contrast, LCH cells of the seven children who further developed extensive LCH disclosed a negative or low expression of E-cadherin.

This study shows that dissemination and poor prognosis are associated with lack of E-cadherin expression on LCH cells. Aggressive clinical evolution of LCH may therefore be related to the loss of functions mediated by E-cadherin.

A multicentre retrospective survey of Langerhans' cell histiocytosis: 348 cases observed between 1983 and 1993.

The French Langerhans' Cell Histiocytosis Study Group.

Arch Dis Child 1996 Jul;75(1):17-24 Abstract quote

A multicentre retrospective survey of Langerhans' cell histiocytosis: 348 cases observed between 1983 and 1993. The French Langerhans' Cell Histiocytosis Study Group. In a retrospective study involving 32 haematology/oncology departments in France, 348 cases of Langerhans' cell histiocytosis diagnosed between 1983 and 1993 were collated. The percentage of males was 56.4%. Median age at diagnosis was 30.2 months. The median follow up was 35.5 months. Initially, 108 patients (31%) had isolated unifocal or bifocal bone involvement, 67 (19%) had isolated multifocal bone involvement, 136 (39%) had soft tissue involvement without organ dysfunction, and 37 (11%) had organ dysfunction. Two thirds of the sites of involvement diagnosed throughout the course of the disease were present at diagnosis, while the remaining one third appeared during a relapse. Treatment was tailored to the individual patient and was extremely varied, hampering any comparison of regimens. Vinblastine with or without steroids was the most common regimen when systemic chemotherapy was used for the first episode (246/348). Twenty four of the 216 patients received VP 16 as first line treatment. Two patients with progressive multiorgan relapse, despite the use of several drugs, underwent bone marrow transplantation and are alive and disease free 60 and 22 months later. Altogether 21.9% of patients had sequelae, including diabetes insipidus in 17.5% of cases. The overall survival rate is 91.7% (confidence interval 90.7 to 95%) three years after diagnosis. In the univariate analysis, age less than 1 year, ear, nose, and throat, cutaneous, lymph node, liver, spleen, lung, marrow and intestinal involvement, male sex, progressive episodes, the absence of response, and partial responses, were associated with a poor vital prognosis. In a multivariate analysis of prognostic factors, poor early outcome emerged as the most important parameter, closely linked to other poor outcome features such as young age and organ dysfunction. It identified a small number of patients with a poor initial response to treatment, for whom intensive treatment should be assessed in a phase II trial.

Langerhans cell histiocytosis: retrospective evaluation of 123 patients at a single institution.

Braier J, Chantada G, Rosso D, Bernaldez P, Amaral D, Latella A, Balancini B, Masautis A, Goldberg J.

Hematology/Oncology Department, Hospital JP Garrahan, Buenos Aires, Argentina.

Pediatr Hematol Oncol 1999 Sep-Oct;16(5):377-85 Abstract quote

The aim of this study was to retrospectively evaluate clinical characteristics at diagnosis and outcome of patients with Langerhans cell histiocytosis (LCH).

From October 1987 to March 1996, 133 patients with confirmed LCH were admitted to Hospital JP Garrahan in Buenos Aires (123 evaluable). Median age was 5 years (range 15 days to 18 years). Initial organ involvement included bone 114 patients, ear 34, skin 30, liver 18, lung 14, lymph nodes 14, spleen 12, diabetes insipidus 9, and bone marrow 2. Nineteen patients had organ dysfunction, pulmonary 14, hematological 14, and hepatic 12.

Two groups were defined: Group A included patients with single system disease (uni- or multifocal) and group B multisystem (with or without organ dysfunction). In group A (n = 82), 24 patients were treated with chemotherapy (prednisone and vinblastine), 21 with surgery, 15 received radiotherapy, and 22 were only observed. Patients of group B (n = 41) were treated with chemotherapy consisting of prednisone and vinblastine, DALHX 83, or LCH1-based chemotherapy. At a median follow-up of 3 years (range 1 month-8 5/12 years) 93% of patients of group A and 39% of group B survive free of reactivation. In group B, 22% had a reactivation and 39% died of progressive disease. Sequelae were detected in 35 patients (28%), which included diabetes insipidus in 17, hearing loss in 13, bony sequelae in 11, sclerosing cholangitis in 6, and lung fibrosis with bullae in 6. Two patients had a subsequent malignant disease. A total of 17 (14%) patients died and 16 of them belonged to the group B: 13 died of progressive disease, 2 due to sclerosing cholangitis (with sepsis in one case and encephalitis in the other one), 1 with progressive disease and associated myelofibrosis, and 1 patient of group A with active disease and brain stem tumor. Patients who had organ dysfunction had a reactivation free survival of 32%. All these patients survived with sequelae.

Logistic regression analysis showed that organ dysfunction and hematological involvement had significant predictive values in relation to death. Patients of group A had an excellent survival rate, whereas in those of group B a high mortality was found, especially in the subgroup of patients with organ dysfunction. Lahey's criteria should be revised. Sequelae were also more common in this group.

Langerhans cell histiocytosis: diagnosis, natural history, management, and outcome.

Howarth DM, Gilchrist GS, Mullan BP, Wiseman GA, Edmonson JH, Schomberg PJ.

Department of Nuclear Medicine, Mayo Clinic Rochester, Minnesota, USA.

Cancer 1999 May 15;85(10):2278-90 Abstract quote

BACKGROUND: The objective of this descriptive analysis of a large cohort of patients with Langerhans cell histiocytosis (LCH) was to add to the understanding of the natural history, management, and outcome of this disease.

METHODS: Three hundred fourteen Mayo Clinic patients with histologically proven LCH were categorized into those patients with multisystem disease and those patients with single system disease. Clinical features, treatment, and outcome were determined from the case history notes and tumor registry correspondence. Treatment included chemotherapy, radiotherapy, and surgical excision. The end points were disease free survival, active disease, or death. The median time of follow-up was 4 years (range, 1 month to 47.5 years).

RESULTS: The age of the patients ranged from 2 months to 83 years. Of the 314 patients, there were 28 deaths. Multisystemic LCH was found in 96 patients, 25 of whom had continuing active disease after treatment. Isolated bone LCH lesions were observed in 114 of the 314 patients, 111 of whom (97%) achieved disease free survival after treatment. The most common sites of osseous LCH were the skull and proximal femur. Of the 87 patients with isolated pulmonary involvement, only 3 were nonsmokers. After treatment with corticosteroids (+/- cyclophosphamide or busulphan), 74 patients achieved disease free survival, but 10 patients died. Pituitary-thalamic axis LCH, characterized by diabetes insipidus, was found in 44 patients. After treatment, 30 of these patients had disease free survival, but all required long term hormone replacement with desmopressin acetate. Lymph node involvement was found in 21 patients, and mucocutaneous involvement was found in 77 patients.

CONCLUSIONS: Patients with isolated bone LCH lesions have the best prognosis compared with patients with LCH involvement of other systems. By contrast, 20% of patients with multisystem involvement have a progressive disease course despite treatment. The identification of prognostic indicators to facilitate appropriate treatment and long term follow-up surveillance is recommended.

Permanent disabilities in childhood survivors of Langerhans cell histiocytosis.

Kusumakumary P, James FV.

Department of Pediatric Oncology, Regional Cancer Centre, Trivandrum, India.

Pediatr Hematol Oncol 2000 Jul-Aug;17(5):375-81 Abstract quote

This study evaluates the permanent disabilities in children treated for Langerhans cell histiocytosis (LCH).

From January 1983 to December 1993, 50 patients with newly diagnosed biopsy proven LCH were seen at the Regional Cancer Centre, Trivandrum, India. Disease pattern, treatment, survival, and disabilities of the patients were studied. Patients with localized disease had surgery, irradiation, or steroids. Patients with disseminated disease had combination chemotherapy. Follow-up ranged from 36 to 156 months (median follow-up 85 months). Twelve of the 41 surviving patients (29.2%) had one or more disabilities. Growth retardation was seen in 8 patients, diabetes insipidus in 7, loss of teeth in 6, and mandibular defect, chronic aural discharge, partial hearing loss, facial palsy, and proptosis in 2 each. In short, a significant proportion of survivors of LCH had sequelae, which affected their quality of life.

More intensive chemotherapy at the beginning might be helpful in reducing the disabilities.


Successful treatment of multisystem Langerhans cell histiocytosis (histiocytosis X) with etoposide.

Yu LC, Shenoy S, Ward K, Warrier RP.

Department of Pediatrics, LSU Medical Center, New Orleans 70112-2822.

Am J Pediatr Hematol Oncol 1994 Aug;16(3):275-7 Abstract quote

PURPOSE: Langerhans cell histiocytosis (LCH) in its disseminated form usually occurs in the very young, and has a fulminant, rapidly progressive, and fatal course despite different forms of therapy.

PATIENTS AND METHODS: We treated two patients, who had failed on vinblastine treatment, with i.v. etoposide (VP-16) at a dose of 150 mg/kg/day for 3 days. Patient I, 8 months of age, presented with failure to thrive and huge bilateral granulomatous lesions of the external auditory canal with erosion and extensive destruction of the petrous pyramids and mastoid area. Patient II, 20 months of age, presented with widespread purpuric skin rash, hepatosplenomegaly, and bone marrow involvement.

RESULTS: Both patients sustained complete remission (CR) following three to six courses of VP-16 and continued to be in unmaintained CR for > 48 months from diagnosis. No major toxicity was noted.

CONCLUSIONS: Etoposide (VP-16), an epipodophyllotoxin known for its usefulness in the treatment of malignancies of the monocyte/macrophage lineage, appears to be an effective treatment for the severe multisystem (disseminated) LCH of childhood and should be strongly considered as front-line therapy for this subgroup of patients with poor prognostic factors.

Treatment of multisystem Langerhans cell histiocytosis. Results of the DAL-HX 83 and DAL-HX 90 studies. DAL-HX Study Group.

Minkov M, Grois N, Heitger A, Potschger U, Westermeier T, Gadner H.

St. Anna Children's Hospital, Vienna, Austria.

Klin Padiatr 2000 Jul-Aug;212(4):139-44 Abstract quote

BACKGROUND: The prognosis of children with multisystem Langerhans cell histiocytosis (LCH) has improved with the application of chemotherapy. However, treatment strategies used varied from conservative approach with treatment only during disease exacerbation to intensive chemotherapy starting immediately after diagnosis. No single drug or regimen has been proven to be superior to the others. Thus, optimal treatment of multisystem LCH remains still an unsolved problem.

PATIENTS: Three hundred and twenty-four patients enrolled in the DAL-HX 83 and DAL-HX 90 studies were retrospectively re-evaluated by using the current definition for disease extent. Sixty-three patients fulfilling the criteria for multisystem LCH (involvement of > or = 2 organ systems) were object of the present study. These were 33 males and 30 females, median age at diagnosis 11.5 months (range, birth-13 years 2 months). The median observation time was 7 years 6 months (4 years-11 years 8 months).

METHODS: All patients had morphologically confirmed diagnosis, which was additionally verified through demonstration of CD1a antigen, presence of Birbeck granules or central pathologic review. Uniform evaluation including a complete medical history and physical examination, laboratory tests (complete blood count, liver function tests, coagulation profile) and radiographic survey (skeletal survey and/or radionuclide bone scan) was performed in all patients. Additional investigations (bone marrow tap, CT, MRI etc.) were performed upon specific indications. The 63 patients with multisystem LCH were evaluated with respect to response to therapy, clinical course, outcome and development of permanent disabilities. The results of the DAL-HX studies were compared with the results of the first randomized international clinical trial on multisystem LCH (LCH-I).

RESULTS: Response to 6 weeks of initial therapy showed a clear discrimination between responders and non-responders, with only 6% of the patients having intermediate response. When correlated to survival response to initial therapy appears to be a powerful prognosticator in multisystem LCH. There were some typical patterns of clinical course. Complete disease resolution at some point of the clinical course was documented in 50 (79%) patients. Thirty-five of them remained disease free, while 15 experienced one or more episodes of disease reactivation. Chronic reactivating course without complete disease resolution was observed in one patient. Deteriorating disease with fatal outcome was shown in 12 (19%) patients. The overall survival after 5 years of observation was 81%. One or more disease-related permanent disabilities were documented in 24 patients, in 4 of them these were shown at diagnosis and in 20 patients these developed after therapy had been commenced. Despite more intensive chemotherapy, the overall survival in DAL-HX 83/90 cohort was comparable with that in LCH-I studies. However, LCH-I compares unfavorably to DAL-HX 83/90 in some very important aspects. With respect to reactivation rate, reactivation free interval and development of permanent disabilities better results were achieved with the more intensive initial and prolonged continuation therapy concept of the DAL-HX studies. Even after extended analysis it remains unclear whether the superiority of the DAL-HX studies has to be attributed to the administration of continuous steroids, to the combination of vinblastine and etoposide, or to the prolonged continuation therapy including mercaptopurine. Answers to these questions are expected from the ongoing international clinical trial LCH-II.

Etoposide as the basic and interferon-alpha as the maintenance therapy for Langerhans cell histiocytosis: a RTC.

Culic S, Jakobson A, Culic V, Kuzmic I, Scukanec-Spoljar M, Primorac D.

Department of Pediatrics, Pediatric Hemato-Oncology, Clinical Hospital Split, Split, Croatia.

Pediatr Hematol Oncol 2001 Jun;18(4):291-4 Abstract quote

The treatment of patients who suffer from a disseminated form of Langerhans cell histiocytosis (LCH) is still controversial. So far, few larger randomized studies have been performed.

The authors present 3 patients with a disseminated form of LCH--4 months, 9 months, and 2 years old, respectively. The lesional Langerhans cells in each patient showed positive immunohistochemical reaction to S-100 protein and the presence of Birbeck granules was confirmed by electron microscopy. All the patients were treated with etoposide (VP-16), 200 mg/m2 for 3 consecutive days, with 15 cycles at intervals of 3 weeks between each cycle, followed by maintenance therapy with IFN-alpha. All 3 patients reached complete stabile remission. The patients were young, at high risk, with multiple-organ involvement of LCH, and two of them had obvious signs of organ dysfunction at presentation, suggesting a poor prognosis. All remain disease-free several years after therapy.

The results suggest that INF-alpha may prevent recurrences in high-risk patients.

A randomized trial of treatment for multisystem Langerhans' cell histiocytosis.

Gadner H, Grois N, Arico M, Broadbent V, Ceci A, Jakobson A, Komp D, Michaelis J, Nicholson S, Potschger U, Pritchard J, Ladisch S;

The Histiocyte Society. St Anna Children's Hospital, Vienna, Austria.

J Pediatr 2001 May;138(5):728-34 Abstract quote

OBJECTIVE: To compare 2 active agents, vinblastine and etoposide, in the treatment of multisystem Langerhans' cell histiocytosis (LCH) in an international randomized study.

STUDY DESIGN: One hundred forty-three untreated patients were randomly assigned to receive 24 weeks of vinblastine (6 mg/m(2), given intravenously every week) or etoposide (150 mg/m(2)/d, given intravenously for 3 days every 3 weeks), and a single initial dose of corticosteroids.

RESULTS: Vinblastine and etoposide were equivalent (P > or = .2) in all respects: response at week 6 (57% and 49%); response at the last evaluation (58% and 69%); toxicity (47% and 58%); and probability of survival (76% and 80%), of disease reactivation (61% and 55%), and of developing permanent consequences (39% and 51%) including diabetes insipidus (22% and 23%). LCH reactivations were usually mild, as was toxicity. All children > or = 2 years old without risk organ involvement (liver, lungs, hematopoietic system, or spleen) survived. With such involvement, lack of rapid (within 6 weeks) response was identified as a new prognostic indicator, predicting a high (66%) mortality rate.

CONCLUSIONS: Vinblastine and etoposide, with one dose of corticosteroids, are equally effective treatments for multisystem LCH, but patients who do not respond within 6 weeks are at increased risk for treatment failure and may require different therapy.


Radiation therapy in soft-tissue lesions in histiocytosis X (Langerhans' cell histiocytosis).

Gramatovici R, D'Angio GJ.

Newfoundland Cancer Clinic, Health Sciences Centre, St. John's, Canada.

Med Pediatr Oncol 1988;16(4):259-62 Abstract quote

Langerhans' cell histiocytosis (LCH) (previously histiocytosis X) is an infrequent disease with protean clinical manifestations and an unpredictable course. The role of radiotherapy in the soft tissue complications of LCH was evaluated in this retrospective study of 40 patients seen in two major Philadelphia institutions between 1970 and 1984.

The patients were divided into two groups according to the extent of disease: unifocal versus multifocal. There was a higher rate of complete response in the unifocal form (4 of 12 patients), but this was associated with a high rate of spontaneous remissions (6 out of 12 patients). Multifocal LCH has a more aggressive course, and the major organs involved (lung, liver, and spleen) did not respond to radiotherapy. Eight patients had diabetes insipidus, and none of them responded to radiotherapy or chemotherapy.

Autopsies were performed in two patients with diabetes insipidus who died of disease. There were no pathologic changes in the pituitary gland or stalk, hypothalamus, or supraoptic nuclei.


Improved outcome of treatment-resistant high-risk Langerhans cell histiocytosis after allogeneic stem cell transplantation with reduced-intensity conditioning.

Steiner M, Matthes-Martin S, Attarbaschi A, Minkov M, Grois N, Unger E, Holter W, Vormoor J, Wawer A, Ouachee M, Woessmann W, Gadner H.

1St Anna Children's Hospital, Vienna, Austria.
Bone Marrow Transplant. 2005 Aug;36(3):215-25. Abstract quote  

Summary:Children with multisystem Langerhans cell histiocytosis (LCH) and risk organ involvement who fail to respond to conventional chemotherapy have an extremely poor prognosis. Myeloablative stem cell transplantation (SCT) as a possible salvage approach for these patients has been associated with a high risk of transplant-related mortality. Therefore, allogeneic stem cell transplantation following a reduced-intensity conditioning regimen (RIC-SCT) has recently been performed as an alternative salvage approach.

We report on the experience with allogeneic RIC-SCT in nine pediatric high-risk LCH patients. Conditioning regimen included fludarabine in all patients, melphalan in eight patients, total lymphoid irradiation in six patients, total body irradiation in two, antithymocyte globulin in five, and Campath in four patients. RIC-SCT was well tolerated with regard to common procedure-related complications. Two patients died 50 and 69 days after RIC-SCT, respectively. Seven out of the nine patients survived and showed no signs of disease activity (including one with nonengraftment and full autologous hematopoietic recovery) after median follow-up of 390 days post-SCT.

Based on this observation, we conclude that RIC-SCT is a feasible procedure with low transplant-related morbidity and mortality and a promising new salvage approach for high-risk LCH patients with resistant risk organ involvement.

Liver transplantation in Langerhans' cell histiocytosis (histiocytosis X).

Concepcion W, Esquivel CO, Terry A, Nakazato P, Garcia-Kennedy R, Houssin D, Cox KL.

Division of Transplantation, Pacific Presbyterian Medical Center, San Francisco, CA 94115.

Semin Oncol 1991 Feb;18(1):24-8 Abstract quote

Two children with biopsy-proven LCH underwent successful hepatic transplantation for end-stage liver disease. These patients were thought not to have active LCH disease at the time of transplantation, although one had developed a new osteolytic lesion a few months before the operation and the other had suspicious osteolytic lesions at the time of transplantation. The histologic examination of the excised liver showed features consistent with primary sclerosing cholangitis.

The two patients had an excellent recovery with no evidence of progression of LCH or recurrence of the underlying disease in the hepatic allograft at 1 and 3 years after organ transplantation.

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