Langerhans'-cell histiocytosis in adults

Guided by a long-term retrospective observation, the clinical course and treatment of Langerhans'-cell histiocytosis (LCH) in adult patients are represented. The series included 19 patients meeting the histopathologic criteria of presumptive LCH who were followed for 1.5–20 years (average 7.7 years). Most frequently, skeletal lesions (16 patients), diffuse interstitial lung infiltrates (seven patients), and pituitary gland involvement with diabetes insipidus (four patients) were present. Bone lesions of the skull and axial skeleton were associated with an infiltration of adjacent soft tissues in 10 of 16 patients. Liver, lymph node, and bone marrow involvement appeared sporadically. LCH was divided into localized or multifocal form. Localized disease took a benign course with remission of bone (n = 4) or lymph node lesions (n - 2). Also, in isolated pulmonary LCH (n = 2), spontaneous transition to inactive disease occurred. With the exception of isolated bone lesions (n = 27), which remained asymptomatic or showed a remission to treatment, multifocal LCH had a more aggressive course. Osseous lesions with adjacent soft tissue infiltration (n = 20) showed a relapse rate in excess of 80% independent of the treatment applied. Pulmonary involvement led to a more marked functional impairment compared to the isolated form, and systemic treatment yielded no convincing effect. In three patients with liver or bone marrow involvement, LCH showed a persistent, serious disease activity. One patient died of transition into acute monomyelocytic leukemia 18 months after diagnosis without preceding chemotherapy. In adults, LCH seems to be limited to a few organ systems. Multifocal LCH represents the more aggressive form with unfavorable prognosis in patients with bone lesions spreading into the adjacent soft tissue and liver or bone marrow involvement. © 1997 Wiley-Liss, Inc.     

Langerhans cell histiocytosis manifesting as recurrent simultaneous bilateral spontaneous pneumothorax in early infancy

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by infiltration of either single or multiple organs by a distinct cell type that is S-100 and CD1a positive and contains ultrastructural Birbeck granules on electron microscopy. Historically, LCH included four main clinical forms: Letter-Siwe disease, Hand-Schuller-Christian disease, eosinophilic granuloma (together grouped as histiocytosis) and Hashimoto-Pritzker disease. The writing group of the Histiocytotic Society in 1987 proposed the uniform term of 'Langerhans cell histiocytosis' to encompass all the aforementioned eponymous forms. Lung involvement occurs in up to half of all children with multisystem disease and usually parallels overall disease activity. Spontaneous pneumothorax (SP) occurs in approximately 10% of children with pulmonary disease and may be a fatal complication. Patients with pulmonary LCH are likely predisposed to the development of pneumothorax based on destructive changes in the lung parenchyma. Here, we report a case of multisystem LCH in which the patient presented at 2 months of age because of simultaneous bilateral pneumothorax.     

Need for a cooperative study: Pulmonary Langerhans cell histiocytosis and its management in adults

BACKGROUND: Pulmonary involvement with Langerhans cell histiocytosis (LCH, formerly known as histiocytosis-X) presents as an interstitial process in children and adults either with or without symptoms. In contrast to other manifestations of LCH, most patients with pulmonary disease are adults. PROCEDURES: We reviewed the literature on pulmonary LCH to determine what were the clinical presentations, prognostic variables, and treatment options for this disease. RESULTS: Although there are spontaneous remissions, a large number of patients have progressive pulmonary deficiency and experience significant morbidity if not mortality from the disease. The efficacy of steroid versus chemotherapy in halting the process remains controversial, even if smoking is taken into consideration. CONCLUSIONS: A multicenter study of therapy for pulmonary LCH is the obvious answer to this dilemma. We propose that interested centers organize via the Histiocyte Society to plan and execute such a trial.     

A phase II trial using thalidomide for Langerhans cell histiocytosis

BACKGROUND: Few new drugs for treatment of Langerhans cell histiocytosis (LCH) have been studied. Tumor necrosis factor-alpha (TNF-alpha) is a prime therapeutic target since it appears to be present in elevated amounts in LCH lesions. Thalidomide inhibits TNF-alpha production by affecting the gene promoter as well as other anti-cytokine effects. PROCEDURES: A Phase II trial of thalidomide for treatment of LCH patients who had failed primary and at least one secondary regimen was conducted. Sixteen patients were enrolled: nine males and seven females ranging in age from 19 months to 45 years. Six patients were high risk (HR) because of spleen, liver, lung, or bone marrow involvement. The low risk (LR) patients included six with bone/skin LCH, one with multiple bone, one with skin/bone/pituitary, one with skin/bone/brain, and one with skin only disease involvement. Fifteen patients remained on treatment from 3 weeks to over 1 year. RESULTS: Among the LR patients there were four complete responses, three partial responses, and two with no response to thalidomide. No HR patient responded to thalidomide and all died of pulmonary, liver, or bone marrow failure. Thalidomide may have played a role in the pulmonary failure. Other toxicities that required stopping therapy included neutropenia, peripheral neuropathy, and fatigue. CONCLUSIONS: Thalidomide is an effective therapy for some LR patients with LCH, but showed no significant responses in HR patients. Dose-limiting toxicities may reduce its efficacy in LR patients. Additional trials with improved anti-TNF therapies would appear warranted.     

Langerhans cell histiocytosis in a premature baby presenting with skin-isolated disease: case report and literature review

Langerhans cell histiocytosis (LCH) in premature babies is extremely rare as is a vesicular skin rash, while gastrointestinal involvement is associated with a poor outcome. We report a case of LCH in a premature baby presented with isolated vesiculo-papulo-macular skin lesions and insidiously developed gastrointestinal symptoms, haematological and severe pulmonary involvement. We also reviewed a few cases of LCH in premature babies in the English language medical literature. LCH in preterm babies appears to be a severe systemic disease, usually lethal in-utero or post delivery. CONCLUSION: Careful observation should be applied to newborns with skin-only Langerhans cell histiocytosis in order to identify in time progression to potentially fatal systemic disease.     

Langerhans cell histiocytosis with involvement of nails and lungs in an adolescent

Skin and/or pulmonary involvement occur frequently in Langerhans cell histiocytosis (LCH) whereas nail involvement is rare. Herein, we present a case of LCH with initial nail disease and subsequent lung involvement causing recurrent pneumothoraces. Systemic chemotherapy was applied and intrapleural bleomycine and thoracoscopic pleurodesis with talc were performed. Although prognosis is not satisfactory in LCH with recurrent pneumothorax and nail involvement, the patient is under follow-up with no evidence of skin lesions, nail involvement, and pneumothorax for the last 10 months.     

An infant with self‐healing cutaneous Langerhans cell histiocytosis followed by isolated thymic relapse

Thymic involvement with Langerhans cell histiocytosis (LCH) typically occurs in children as part of multi‐system (M‐S) LCH. Patients who develop skin‐only LCH during infancy may either follow a self‐healing course with spontaneous regression or may progress to M‐S involvement. We describe a male infant who developed isolated thymic LCH after spontaneous complete regression of isolated cutaneous lesions. His erythrocyte sedimentation rate and C‐reactive protein increased temporarily during the skin‐only stage of LCH, and increased again considerably during the thymic relapse. Even for patients with skin‐only LCH, these laboratory data might indicate possible relapse or late progression of the disease. Pediatr Blood Cancer 2009;53:229–231. © 2009 Wiley‐Liss, Inc.     

Whole-body MRI of Langerhans cell histiocytosis: comparison with radiography and bone scintigraphy

Background In Langerhans cell histiocytosis (LCH) evaluation of the extent of disease is one of the major predictors of patient outcome. Historically this is undertaken using plain radiography and bone scintigraphy. Recently, whole-body (WB) MRI has been reported to be useful in detecting skeletal and extraskeletal metastases in both adults and children. Objective To evaluate the usefulness of WB MRI in patients with LCH in comparison with plain radiography and bone scintigraphy. Materials and methods In nine children (1–7 years of age; mean 3.3 years) who had a pathological diagnosis of LCH and had either plain radiography or bone scintigraphy for comparison, 43 WB MR examinations were performed. Skeletal and extraskeletal lesions of the disease on WB MRI were compared with those on plain radiography and bone scintigraphy. Results LCH showed unifocal single-system involvement in one patient, multifocal single-system involvement in three, and multifocal multisystem disease in five. WB MRI identified additional skeletal lesions in three (38%) of eight patients, compared with plain radiography, and in two (25%) of eight, compared with bone scintigraphy. WB MRI detected extraskeletal lesions of the disease in five (56%) of the nine patients exclusively, except for one patient whose lung lesions were also detected on plain radiography. In two patients, treatment was changed according to WB MRI findings. Conclusion WB MRI is a useful initial and follow-up diagnostic method to assess the extent of LCH because WB MRI not only identifies more skeletal lesions of the disease than do plain radiography and bone scintigraphy, but also detects extraskeletal lesions of the disease.     

Congenital aggressive variant of Langerhans cells histiocytosis with CD56+/E‐Cadherin− phenotype

In children <2 years of age, cutaneous involvement is the most frequent presentation of Langerhans cell histiocytosis (LCH). Cutaneous LCH can be localized or associated with dissemination and organ dysfunction. The clinical course is variable, ranging from spontaneous regression to a fatal outcome. We describe a female newborn presenting with congenital cutaneous lesions who rapidly developed pulmonary infiltrates and multiple osteolytic lesions. Skin biopsy showed a dermal infiltrate of medium to large cells morphologically and phenotypically consistent with LCH. The clinical course was rapidly fatal in spite of chemotherapy. No strict correlation between morphology and prognosis has been documented in LCH, but, in our case, distinct morphological and immunohistochemical features (CD56 expression and no E‐Cadherin expression) may have contributed to an aggressive clinical course. Pediatr Blood Cancer 2009;53:1107–1110. © 2009 Wiley‐Liss, Inc.     

Long term follow up of topical mustine treatment for cutaneous langerhans cell histiocytosis.

BACKGROUND AND OBJECTIVES: Skin lesions in Langerhans cell histiocytosis (LCH) are often painful and difficult to treat. Topical application of nitrogen mustard (0.02% mechlorethamine hydrochloride, mustine), an alkylating cytostatic agent, has been shown to be effective. There is, however, concern about potentially harmful long term side effects. STUDY DESIGN: In a retrospective study 20 children with LCH (average extent of initial skin involvement: 16.4% body surface) were followed up for an average of 8.3 years after completion of topical mustine therapy. They had received a total of 34 courses (mean duration 14.2 weeks) of topical mustine. Disease status on follow up was assessed according to the Histiocyte Society classification. RESULTS: After mustine was introduced, 16 patients were able to discontinue systemic steroids and/or chemotherapy. Topical mustine was well tolerated in 18 patients, but two developed irritant dermatitis. On follow up, the disease was inactive in 10 patients. Among the children with active disease, six had mild skin disease and four had progressive disease, two of them with skin lesions unresponsive to mustine treatment. Scars confined to areas of formerly active skin disease were found in six patients. There was no evidence of premalignant or malignant skin disease in the treated areas. CONCLUSION: Topical mustine is an effective and safe treatment for skin disease in most children with LCH. Residual scarring was probably a result of the disease itself rather than to mustine. Although no evidence of skin cancer was found in this study, continued long term follow up is advisable.     

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

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.     

Neuropsychologic deficits in children with Langerhans cell histiocytosis.

BACKGROUND: Manifestations of Langerhans cell histiocytosis (LCH) in children range from only a rash, to bony lesions accompanied by pain, to major organ disease. When the central nervous system (CNS) is affected, the LCH patient may exhibit signs and symptoms of hypothalamic and pituitary dysfunction (most often resulting in diabetes insipidus or other endocrinopathies) or more global neurologic and neuropsychologic sequelae. Surprisingly, researchers have only recently begun to examine the neuropsychologic manifestations of the disease, but early findings suggest that they may, in fact, be significant in a small percentage of children with LCH. PROCEDURE: We evaluated two CNS-positive patients with LCH and long-term intermittent treatments, using extensive neuropsychologic assessments, including intellectual functioning, memory, visual-motor functioning, attention and concentration, sensory and motor performance, and gross academic achievement. Objective measures of behavior were obtained through parental report. Neuroradiologic imaging was obtained concurrently with the neuropsychologic evaluations. RESULTS: The neuropsychologic assessments indicated significant deficits in a number of the measured areas of functioning. Global cognitive deficiencies in full-scale IQ were identified, as were deficits in memory, attention/concentration, and perceptual-organizational capabilities. Similarities were noted in the patterns of deficits obtained with both patients, despite differences in the pathophysiology of their disease. Behavioral functioning in both children had suffered, presumably in relation to the neuropsychologic deficits. There were radiologic findings of gross cerebellar white matter damage in one patient, in addition to focal (e.g., hypothalamic) lesions in the other. CONCLUSIONS: LCH has an adverse impact on cognitive functions in some children with evidence of CNS involvement, and further study into the etiology, incidence, and means of remedial intervention is needed.     

Detection of Langerhans cell histiocytosis lesions with somatostatin analogue scintigraphy--a preliminary report

BACKGROUND: Langerhans cell histiocytosis (LCH) is a disease where granulomatous lesions occur in various organs of the body. The etiology and pathogenesis remain unknown. Inflammatory destructive activity give rise to a wide range of clinical symptoms, including fractures, skin lesions, pulmonary fibrosis, endocrinopathies, and central nervous system deterioration. Since disease activity may ultimately lead to fibrosis and organ damage, it is important to have diagnostic tools to detect disease activity early. PROCEDURE: The present study was undertaken in order to evaluate whether somatostatin analogue scintigraphy ((111)In-pentetreotide or OctreoScan could be used in detecting LCH granulomas and to compare this method with the radiologic methods used today in LCH diagnosis and follow-up. The somatostatin analogue octreotide used here binds to the cell membrane of activated lymphocytes expressing somatostatin receptors. RESULTS: In five out of six children studied, LCH lesions detected by other means were also detected with (111)In-pentetreotide. It can be speculated that the lesion in the remaining patient was not active at the time of investigation. In addition, in two of the patients signs of disease activity not previously known were revealed. CONCLUSION: (111)In-pentetreotide can be used to detect active LCH lesions. Since the biologically active somatostatin analogue decreases inflammatory activity, this may also be of therapeutic value in selected patients with LCH. More studies are needed to evaluate the diagnostic and potential therapeutic usefulness of this radionuclide.     

"Primary" pulmonary Langerhans cell histiocytosis in a two-year-old child: case report and literature review

Langerhans cell histiocytosis (LCH) can involve multiple organs. "Primary" or isolated pulmonary LCH is a well-described entity in young adults but is exceedingly rare in children younger than 15 years of age. The authors report a new case in a 2-year-old girl and review other reported cases in the pediatric population. The patient had had respiratory symptoms since early infancy suggestive of hyperactive airway disease. At 2 years of age, she had severe pulmonary insufficiency with remarkable cystic changes noted on chest imaging studies. Biopsy of a pulmonary lesion confirmed the diagnosis of LCH. She had no other organ involvement. Pulmonary histiocytosis, though rare, should be considered in any child with chronic respiratory disease such as bronchial asthma, especially when the response to anti-asthma treatment is poor and/or there are cystic changes on the chest x-ray.     

Elevated serum levels of the decoy receptor osteoprotegerin in children with Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is characterized by an accumulation of dendritic Langerhans cells in granulomatous lesions in the bone, skin, and other sites in the body. The pathogenesis of the disease remains unknown. We measured serum levels of the decoy receptor osteoprotegerin (OPG), an important regulator of bone metabolism as well as immune responses, in 18 children with single system (SS) or multi-system (MS) forms of LCH and 20 pediatric controls. OPG levels were significantly increased in LCH patients at diagnosis when compared with controls, and pretreatment levels of OPG were elevated in MS compared with SS patients. Moreover, OPG levels in LCH patients were elevated in patients with involvement of risk organs (liver, lungs, hematopoietic system, or spleen) when compared with patients without risk organ involvement, indicative of an association between OPG values and disease severity. We also observed a positive correlation between serum levels of OPG and tumor necrosis factor (TNF)-alpha, a pro-inflammatory cytokine, at the time of onset of disease. These findings show, for the first time, that serum OPG levels are elevated in LCH patients, and suggest that OPG may play a role in the pathogenesis of this enigmatic disease.     

p53 expression in biopsies from children with Langerhans cell histiocytosis

PURPOSE: Langerhans cell histiocytosis (LCH) is a rare pediatric and adult disease causing skin rashes, osteolytic bone lesions, tumorous growth in various organs, and in some patients, organ dysfunction. The cause of the disease is obscure, and it is not yet understood why some patients develop single-system lesions only without relapse, whereas others develop fatal multiorgan disease. The expression of p53 tumor suppressor gene product detected immunohistochemically can be used as a guideline to alterations in DNA repair control and apoptosis. The authors have chosen to analyze p53 expression in biopsies from children with LCH and correlate it with clinical manifestation and outcome in a broad range of organs. PATIENTS AND METHODS: The study was performed on 50 specimens from 32 children (19 boys and 13 girls), median age 3 1/4 years, range 5 months to 12 1/3 years with a definite diagnosis of LCH based on CD1a positivity. The slides were stained with p53 antibody and semiquantitatively evaluated using a grading system from 1 to 5 as an estimate for 0% to 20%, 20% to 40%, 40% to 60%, 60% to 80%, and 80% to 100% p53-positive for pathologic Langerhans cells (pLC), respectively. RESULTS: The p53 protein was expressed in various degrees in pLC in all lesions. The degree of p53 expression could not be correlated to either clinical manifestation or outcome. CONCLUSIONS: An increased expression of p53 in pLC indicates an altered DNA repair control with or without abnormal control of apoptosis.     

Langerhans cell histiocytosis in children born 1982–2005 after in vitro fertilization

Aim: In a recent Swedish study, comparing data from the Swedish Cancer Register with the Medical Birth Register including data on IVF, an increased risk of Langerhans cell histiocytosis (LCH) was found in children born 1982–2005 after IVF. Here, we aimed to verify the LCH diagnoses and examine whether any special forms of the disease were overrepresented in this population. Methods: Medical records for all children with LCH conceived by IVF were acquired and the diagnosis confirmed or discarded. Disease characteristics were compared with data from children diagnosed with LCH 1992–2001 in the Stockholm County. Results: We verified LCH in seven children born after IVF, all born prior to 2002. These children did not have milder disease forms. The odds ratio (OR) to develop LCH for the whole group born after IVF was 3.2 [95% confidence interval (CI), 1.4–7.3] and for children born before 2002, 5.2 [95% CI, 2.3–11.9], compared with children in Stockholm County 1992–2001. Conclusion: LCH was overrepresented in children born after IVF prior to 2002. Affected children did not have milder disease forms. These findings may be valuable to understand LCH aetiology. Additional studies on a putative correlation between IVF and LCH in the offspring are encouraged.     

Pulmonary Langerhans cell histiocytosis: a variable disease in childhood

BACKGROUND: Pulmonary Langerhans cell histiocytosis (PLCH) is rare in childhood but occurs most commonly in children with multisystem (MS) LCH. In adults, by contrast, the lung is the most common and usually the sole organ affected. This retrospective study describes the clinical manifestation, course, and outcome of PLCH in children consecutively diagnosed at two Canadian institutions. PROCEDURE: The medical records of children (<18 years of age) consecutively diagnosed with LCH at the two institutions, were examined to ascertain the demographic details, pathological diagnosis, and organs involved. Further clinical details including, the clinical manifestation, details of therapy, course of lung disease, and clinical outcome were extracted for patients with PLCH. Initial and follow-up lung radiographs and CT scans were re-reviewed. RESULTS: Of the 178 patients with LCH, 40 (22.5%) presented with MS disease. Thirteen (7.3%) had PLCH, seven at initial diagnosis, and six at the time of disease progression. The median age was 10.1 months and mean was 11.9 months at diagnosis of PLCH. Lung involvement was always in the context of MS LCH, and half of the patients had no respiratory symptoms. Disease-free survival was around 70%, with a mean follow-up duration of 7 years. Of the four patients who died, three had other risk-organ involvement. Five of the nine surviving patients have had complete radiological resolution of PLCH. CONCLUSION: PLCH is seen in less than 10% of childhood LCH, but more than 30% of MS LCH. About half of children with PLCH may be asymptomatic, and the prognosis appears to depend on the presence or absence of other risk-organ involvement. The MS PLCH found in children appears to be a different disease from the single system (SS) PLCH seen in adults.     

Digestive Tract Involvement with Exudative Enteropathy in Langerhans Cell Histiocytosis

Protein-losing enteropathy was observed in two children with Langerhans' cell histiocytosis (LCH). One patient was an infant with congenital cutaneous lesions; the second child had sigmoid and lymph node infiltration. Electron microscopy and immunohistochemistry confirmed, in both, infiltration of duodenum, skin, and liver by LCH. Gastrointestinal involvement by LCH seldom produces prominent clinical manifestations but indicates widespread multisystem disease. Immunohistochemual and/or ultrastructural features allow definitive diagnosis from mucosal biopsy specimens. Review of the literature of gastrointestinal infiltration by LCH emphasizes its poor prognosis, especially when associated with organ dysfunction.     

Severe isolated pulmonary Langerhans cell histiocytosis in a 6-year-old girl

Langerhans cell histiocytosis (LCH) usually affects different organs or bones. Isolated pulmonary disease is rare in childhood. We report about a 6-year-old girl with progressive pulmonary insufficiency, onset of clubbing at 4 years of age and honeycombing lung infiltrations on X-ray films. The radiological suspicion of primary pulmonary LCH was confirmed by the presence of CD1a positive cells in the bronchoalveolar lavage fluid. Other organs were not involved. The girl was treated according to the LCH-III International Study Protocol with a good response. Follow-up showed no reactivation of LCH but a reduced vital capacity and signs of interstitial pulmonary involvement on a CT scan. CONCLUSION: Langerhans cell histiocytosis should be considered in the aetiology of cystic lung diseases. Early responders to treatment have a high likelihood of becoming free of disease. However, pulmonary fibrosis is an important mechanism of lung remodelling in pulmonary Langerhans cell histiocytosis and the long-term prognosis is unclear.