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Abstract
The purpose of our investigation was to correlate the extent and degree of organ involvement at presentation of Langerhans' cell histiocytosis (LCH) with subsequent disease course, survival, and late sequelae.
The medical records of 71 patients with a pathologic diagnosis of LCH, age 0 to 21 years, who presented between January 1, 1969 and June 30, 1994, were reviewed for organ involvement at diagnosis, treatment, disease course, and late sequelae. Supplementary data were obtained by mailed questionnaire.
The median follow-up time from diagnosis for all patients was 8.1 years. Involvement at diagnosis included nine patients with skin-only disease, 22 with monostotic disease, 12 with polyostotic disease, and 28 with multisystem presentation. Treatment was surgery only in 17 and chemotherapy and/or radiotherapy in 54 patients. Recurrences were seen in 35 patients, with the highest rate in the polyostotic group. Ten patients died: seven with the multisystem presentation, two with monostotic disease, and one with skin-only disease. Causes included progressive LCH (n = 6) and late sequelae of either treatment (n = 3) or disease (n = 1). Late sequelae were seen in 64% of 51 patients with more than 3 years of follow-up data. The most common were skeletal defects in 42%, dental problems in 30%, diabetes insipidus in 25%, growth failure in 20%, sex hormone deficiency in 16%, hypothyroidism in 14%, hearing loss in 16%, and other CNS dysfunction in 14%. The overall estimated survival rates at 5, 15, and 20 years are 88%, 88%, and 77%, with an estimated event-free survival rate of only 30% at 15 years.
Despite the favorable survival, more than half of LCH patients will have further dissemination of disease or late sequelae, including even some patients with single-system disease at diagnosis. Future treatment needs to be designed to prevent disease progression and late sequelae.
... Alguns estudos apontam uma breve relação entre genética (incluindo os genes BRAF ou MAP2K1) além de estilo de vida, e condições do sistema imunológico, podendo acometer todas as faixas etárias, mas sendo mais comum em criança (acometendo 0,5 para cada 100.000 crianças por ano). Embora possa ocorrer em qualquer idade, é mais comum na população pediátrica, especialmente em crianças de 0 a 15 anos (Lichtman, 2017;Willis et al., 1996). ...
... Além da inespecificidade etimológica, tem-se a sintomatologia é variada que a HCL possui, podendo ter apresentações cutâneas como nódulos, (Lichtman, 2017;Willis et al., 1996). ...
... Fisiologicamente, os histiócitos desempenham uma função fagocitária essencial, atuando como barreira de defesa no sistema imunológico inato (Lichtman, 2017). No entanto, na HCL, há Larah Cristina Pereira Siqueira, Taynara de Souza Natal, Gerson Hiroshi Yoshinari Junior _____________________________________________________________________________________ uma exacerbação patológica na produção dessas células, levando à fagocitose de tecidos saudáveis e comprometendo a função fisiológica normal dos órgãos afetados (Catolino et al., 2020 (Quattrino et al., 2007;Willis et al., 1996). ...
A Histiocitose de células de Langerhans é uma doença rara caracterizada pela proliferação anormal de células do sistema mononuclear fagocitário. Este estudo relata o caso de uma paciente feminina de 3 anos e 4 meses, com início dos sintomas aos 8 meses, apresentando lesão papulosa na região frontotemporal e irritabilidade ao ser mobilizada. O diagnóstico foi desafiador, inicialmente confundido com outras condições, em que para a obtenção de dados foi através da análise documental de exames e relatórios médicos da paciente em questão durante todo o processo laudatório da paciente alvo de estudo. A cintilografia óssea levantou a suspeita de Histiocitose, confirmada por biópsia imunohistoquímica. O tratamento incluiu Vimblastina, Purinethol e corticoides, resultando em melhora significativa. Este caso destaca a importância dos exames específicos, como cintilografia e biópsia, no diagnóstico precoce de lesões cutâneas em lactentes, especialmente quando associadas a sintomas inespecíficos, contribuindo para o manejo adequado desta condição rara.
... Diabetes insipidus (DI), orthopedic abnormalities, hearing loss, and neurological consequences were reported as most common CHC among LCH survivors [13,14]. However, no previous studies compared the prevalence of CHC to healthy peers [13][14][15][16][17][18][19][20][21][22]. Previous studies included only survivors of skeletal LCH [22], excluded survivors of single system unifocal LCH [14], and reported about survivors from single centers only [15,16,18,19,21] or only about survivors who received systemic therapy [14,17]. ...
... However, no previous studies compared the prevalence of CHC to healthy peers [13][14][15][16][17][18][19][20][21][22]. Previous studies included only survivors of skeletal LCH [22], excluded survivors of single system unifocal LCH [14], and reported about survivors from single centers only [15,16,18,19,21] or only about survivors who received systemic therapy [14,17]. Since a comprehensive, population-based description of CHC among LCH survivors is lacking, we describe the spectrum and prevalence of CHC among LCH survivors compared with siblings and describe factors associated with CHC in our study. ...
... Chow et al. reported 56% of 70 LCH survivors suffered from CHC in a single-center study of retrospectively reviewed medical records after a median follow-up time of 10 years [21]. Similarly, Willis et al. reported 64% of 51 LCH survivors with median time since diagnosis of 8 years with CHC in a single-center study [18]. Ceci et al. reported 48% of 90 LCH survivors with CHC in their prospective multicenter study of < 5-year LCH survivors [17]. ...
Purpose
Langerhans cell histiocytosis (LCH) is a rare disease characterized by dysregulated proliferation of myeloid marrow progenitors and subsequent organ infiltration. While LCH is associated with a favorable prognosis, some survivors may develop chronic health conditions (CHC) because of the disease. In this study, we aimed to assess the spectrum and prevalence of CHC among LCH survivors compared with siblings and identify factors associated with the development of CHC.
Methods
The Swiss Childhood Cancer Survivor Study sent questionnaires to all ≥ 5-year LCH survivors registered in the Swiss Childhood Cancer Registry and diagnosed between 1976 and 2015. Siblings also received similar questionnaires. We compared CHC prevalence between LCH survivors and siblings and used logistic regression to identify determinants of CHC.
Results
A total of 123 LCH survivors participated in the study, with a response rate of 69%. Median time since diagnosis was 13 years (interquartile range 9–20). Among LCH survivors, 59% had at least one CHC. Cardiovascular (13% vs. 6%), endocrine (15% vs. 2%), musculoskeletal (22% vs. 13%), and digestive (15% vs. 8%) CHC were more common among LCH survivors compared to siblings (all p < 0.05). Factors most strongly associated with the occurrence of CHC were multisystem LCH, multifocal bone involvement, and involvement of the pituitary gland.
Conclusions
More than half of long-term LCH survivors suffered from one or more CHC and were affected considerably more than siblings.
Implications for Cancer Survivors
LCH survivors in follow-up care should be screened especially for cardiovascular, endocrine, musculoskeletal, and digestive conditions.
... In very severe cases, even an allogeneic stem cell transplant can be indicated [3,[5][6][7][8][9][10][11][12]. Depending on the extent and location of lesions and therapy, affected children develop long-term sequelae in 16% to 75%, most commonly involving the endocrine system [4,6,10,[13][14][15][16][17][18]. ...
... Fractions of main molecular groups are indicated in boldface multisystemic LCH, disease recurrence (p = 0.001) and involvement of risk organs and pituitary gland were associated with a higher risk for long-term sequelae, in concordance with published data [13,15,17,18,43]. Of interest, especially given the fact that LCH is a clonal myeloid disorder, is the relative rarity of secondary neoplasms, especially hematopoietic cancer both in our study as well as in published studies, perhaps with the exception of patients treated with high-dose VP-16 [13,18,44]. ...
... Fractions of main molecular groups are indicated in boldface multisystemic LCH, disease recurrence (p = 0.001) and involvement of risk organs and pituitary gland were associated with a higher risk for long-term sequelae, in concordance with published data [13,15,17,18,43]. Of interest, especially given the fact that LCH is a clonal myeloid disorder, is the relative rarity of secondary neoplasms, especially hematopoietic cancer both in our study as well as in published studies, perhaps with the exception of patients treated with high-dose VP-16 [13,18,44]. The single case of skin cancer observed in our cohort can be linked to local radiation. ...
Langerhans cell histiocytosis (LCH) is a clonal histiocytic disorder with recurrent mutations of BRAF and MAP2K1, but data on the impact of genetic features on progression and long-term sequelae are sparse. Cases of pediatric LCH with long-term follow-up from our institution were analyzed for mutations in BRAFV600 and MAP2K1 exons 2 and 3 by immunostaining with mutation-specific VE1 antibody, as well as allele-specific PCR and sequencing, respectively. Clinical and follow-up data were obtained from our files and a questionnaire sent to all former patients. Sixteen of 37 (43%) evaluable cases showed BRAFV600E, one case a BRAFV600D and eleven (30%) a MAP2K1 mutation. Nine cases were unmutated for both genes. All cases with risk organ involvement showed either BRAFV600 or MAP2K1 mutation. Patients with BRAFV600 mutation excluding Hashimoto-Pritzker cases had a significantly higher risk for relapses (p = 0.02). Long-term sequelae were present in 19/46 (41%) patients (median follow-up 12.5 years, range 1.0 to 30.8) with a trend for higher rates in mutated cases (mutated = 9/17, 53% versus non-BRAFV600/MAP2K1 mutated = 2/7, 29%). In addition, 8/9 cases with skin involvement including all Hashimoto-Pritzker cases (n = 3) were positive for BRAFV600E. Infants below 2 years more frequently had BRAFV600 mutations (p = 0.013). Despite favorable prognosis, pediatric LCH shows a high frequency of relapses and long-term medical sequelae.
... ND-LCH is a potentially devastating, permanent consequence of LCH. Its real prevalence is still unclear, ranging between 1% and 25% in different cohorts [12][13][14][15][16][17]. Patients with "cranio-facial" lesions involving the orbital, temporal, sphenoid, ethmoid or mastoid bones, the paranasal sinuses, the anterior or middle cranial fossa and/or with DI, carry a higher risk of developing this serious complication [7][8][9][10][11][12][13][14][15][16][17][18].The pathogenic process might propagate from long-standing granulomatous lesions of the craniofacial bones to the intracranial space, and then stimulate a chemokine/cytokine tissue damage or initiate an autoimmune response to brain components [11]. ...
... Its real prevalence is still unclear, ranging between 1% and 25% in different cohorts [12][13][14][15][16][17]. Patients with "cranio-facial" lesions involving the orbital, temporal, sphenoid, ethmoid or mastoid bones, the paranasal sinuses, the anterior or middle cranial fossa and/or with DI, carry a higher risk of developing this serious complication [7][8][9][10][11][12][13][14][15][16][17][18].The pathogenic process might propagate from long-standing granulomatous lesions of the craniofacial bones to the intracranial space, and then stimulate a chemokine/cytokine tissue damage or initiate an autoimmune response to brain components [11]. ...
... Despite a relatively homogeneous MRI pattern, the clinical manifestations of ND-LCH are extremely heterogeneous, ranging from minimal or no neurological impairment, to a severe clinical picture including ataxia, spastic quadriparesis, intellectual disability and psychiatric symptoms [9,[12][13][14][15][16]. Although the likelihood of observing clinical manifestations appears to be related to the observation time [12], some patients unexpectedly remain asymptomatic for years despite exhibiting MRI abnormalities [9,[12][13][14][15][16][17]19]. ...
... The disease may occur in any organ of the body, but often particularly involves the skeleton (Fig. 1) of subadults and young adults (Papadopoulou et al., 2018). Macroscopically, the typical bone lesions for this group of diseases appear as circumscribed osteolytic defects, which can appear isolated but also as multiple lesions (Allen et al., 2018;Burkhardt, 1970;Jayram et al., 1998;Merglová et al., 2014;Krooks et al., 2018;Willis et al., 1996). Periosteal new bone formation is usually not observed (Burkhardt, 1970). ...
... Clinically, three basic forms can be distinguished which are heterogeneous, have a tumor-like character and can merge into each other (Adler, 2005;Burkhardt, 1970;Hefti and Jundt, 1995;Jaffe, 1972;Jayram et al., 1998;Leavey et al., 1991;Lichtenstein, 1953;Martinez-Perez et al., 1996;Ortner, 2003;Resnick and Niwayama, 1995;Schmidt et al., 1991;Willis et al., 1996): 1) Abt-Letterer-Siwe syndrome-the acute and most severe form of LCH usually occurring in the first three years of life and is often fatal; 2) Hand-Schüller-Christian disease-mostly affects infants and older children, adolescents and middle-aged adults, and is chronically progressive and often lethal; 3) Eosinophilic granuloma-a relatively benign variation of Hand--Schüller-Christian disease, in which defects in the bones (skull, vertebrae, ribs and diaphyses of long bones) lead to frequent spontaneous fractures. As a rule, children and young adults suffer from eosinophilic granuloma and approximately 70 % of all cases are male. ...
Objective
To outline the importance of accurate diagnosis in ancient rare diseases by presenting a possible case of Langerhans-cell histiocytosis.
Materials
Skeletal elements from a well-preserved skeleton of a nine to eleven-year-old, probably female child who lived around 300–400 AD Late Roman Neuburg / Donau (Germany).
Methods
Macroscopic, radiologic, light and scanning-electron microscopic and physical techniques were used.
Results
Resorptive defects, particularly in the cranium, but also in the left hip bone and the right femur, suggest the presence of Langerhans-cell histiocytosis macroscopically and radiologically. The presence of morphological changes along the edges of osteolytic lesions and in the diploic spaces appear to be post-mortem artifacts based on microscopic investigation and elemental analysis.
Conclusions
Re-evaluation of morphological structures and elemental constitution of lesions is critical to differential diagnosis. In the case examined here, the identification of post-mortem structures rules out the former diagnosis of Langerhans-cell histiocytosis. Re-evaluation of cases of rare diseases require applying a range of methods during the analysis, as every single case makes a difference in the numbers of this very small group of diseases.
Significance
This study emphasizes the importance of utilizing different analytical techniques to avoid false diagnoses.
Limitations
Not all morphological features can reliably be diagnosed using microscopic and elemental techniques.
Suggestions for Further Research
In the case of rare diseases that are difficult to diagnose, the widest possible spectrum of techniques should always be used, particularly microscopy.
... Studies on radiotherapy for LCH have demonstrated radiographic and symptomatic response in more than 90% of children and 70% of adults. [15][16][17][18] LCS-related bone pain generally resolves within 4 months with the long-term control well documented. [18][19][20] For such localized lesions, SRS would be preferred to conventional radiation techniques, including intensity-modulated radiation therapy, given its safety (precision and accuracy), efficacy, ease of delivery, and comfort. ...
... Thus, a child with a single noneCNS-risk skull lesion will have a low recurrence rate (4%e10%) after curettage. [10][11][12][13][14][15] However, single skull lesions of the orbit, mastoid, temporal, or sphenoid bones (CNS-risk) may be better served with a combination of vinblastine and prednisolone, [16][17][18][19] although bone marrow suppression remains a valid concern. 20 Cases with pure CNS involvement may present as white matter lesions, endocrine abnormalities, or neurodegenerative syndrome. ...
Background
A histiocytosis is a group of immunoproliferative disorders of clonal cells. The management protocols are still evolving, with chemotherapy as the mainstay of treatment.
Objective
This study aims to evaluate the feasibility, safety, efficacy, and complication profile of stereotactic radiosurgery for intracranial histiocytosis.
Methodology
Authors reviewed PubMed, SCOPUS, Web of Science, and Embase for “radiosurgery”, “histiocytosis” in the English/Japanese language following PRISMA guidelines. The patient profile, radiosurgical parameters(dose and isodose), target volume, mode of radiosurgery(Gamma knife, LINAC radiosurgery, etc.) were collected. Its use as primary or adjuvant therapy, clinical and radiological outcome was also evaluated.
Results
We identified 7 studies(9 patients);mean age of 41.9 years(24-57years). Six patients received Gamma knife radiosurgery(GKRS), while 3 received CyberKnife radiosurgery. The LCH variants were eosinophilic granuloma in 3 while four were not defined. 2 cases had Rosai Dorfman disease(RDD), two different yet pathogenetically related histiocytic disorders. Four patients harbored lesions in the pituitary stalk and posterior pituitary, two patients in the petrous region, one patient had a pontine lesion, while two patients had multiple lesions. The dose delivered ranged from 8-28Gy. 18 lesions(9 patients) were followed for 81.67patient-years:7(39%) disappeared, 8(44.4%) showed radiologic reduction, while 2(11%) remained stable. One lesion(5%) showed an increase in size needed surgical excision. There were no adverse effects.
Conclusion
The role of SRS needs to be further evaluated as the current cohort with only 9 cases (2 are RDD) is insufficient to make conclusions. It may be a viable alternative in localized disease, along with chemotherapy and targeted surgery.
... The involvement of other organs is considered as low risk-organ (RO − ) subgroup. During their life-time, nearly half of the MS-LCH patients develop permanent sequelae affecting their quality of life [13][14][15][16]. In these patients, diabetes insipidus (DI) is the most frequent complication [17][18][19]. ...
... In these patients, diabetes insipidus (DI) is the most frequent complication [17][18][19]. However, the most devastating sequela is the neurodegenerative LCH (ND-LCH): the patient develops ataxia, dysarthria and other cerebellar symptoms, as well as cognitive and psycho-social deficits [13,14,19]. ...
Objective: Langerhans cell histiocytosis (LCH) is a granulomatous inflammatory myeloid neoplasia associated with a cytokine storm in both serum and lesions. Increased levels of plasma interleukin-17A (IL-17A) in LCH patients have been reported, but this finding was not confirmed in all studies. Neurodegeneration is a devastating complication of LCH (ND-LCH). We aimed to revisit the issue of plasma IL-17A levels in LCH, by using a larger number of patients, and also to investigate the relationship between IL-17A and LCH sequelae, especially ND-LCH.
Methods: Plasma samples from 68 LCH patients and 127 controls were analyzed for IL-17A levels by two ELISAs with different anti-IL-17A capture antibodies: either polyclonal or neutralizing monoclonal antibodies in 17polyAb-ELISA or 17mAb-ELISA, respectively.
Results: Both ELISAs had a similar capacity to specifically detect recombinant or native human IL-17A, as well as plasma IL-17A from LCH patients. We confirmed the finding of higher levels of plasma IL-17A in LCH patients compared to controls (p < 0.0001). The association of IL-17A with LCH was independent of the ELISA used, and of gender, age, disease class activity, and pattern of tissue-organ involvement (single-system versus multi- system). ROC analyses (p < 0.0001) allow to discriminate LCH patients from the control group, supporting the notion that IL-17A may be a potential biomarker for LCH. More interestingly, high IL-17A levels were significantly associated with LCH patients having sequelae, with the highest plasma levels in patients with ND-LCH (p < 0.0001).
Conclusion: The association between high levels of IL-17A and LCH was confirmed. IL-17A may be associated with ND-LCH development. This might have therapeutic implications, offering a novel target for precision therapy of ND-LCH.
... 21 out of 35 (60%) were children. Median age at diagnosis was 8 (3)(4)(5)(6)(7)(8)(9)(10)(11) in children and 30 (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43) in adults; female to male ratio was 1/2 among children and 1/1.8 among adults. All patients were classified according to complete medical history, physical examination, laboratory tests (complete blood cell count, liver function tests, renal function tests) and bone survey (the classical bone survey was conducted for 12 patients, the others went through bone scan). ...
... Our results are in corcordance with the literature data reporting 73-96% local control and 60-93% complete response rates. 1,[8][9][10]17,[21][22][23][24][25][26][27] In general, RT is usually indicated as adjuvant therapy after large, marginal or incomplete resection, as palliative therapy for painfull or unstable bony lesions, relapsing or progressing lesions, also as first-line local therapy with curative intent in unresectable cases and in unresectable cases if surgery would result in functional compromise. 1,8,23,[28][29][30] The mechanism of action of RT is an unresolved issue, but suppression of inflammatory process by radiation and radiosensitivity of langerhans cells could be the main explanations. ...
Langerhans cell histiocytosis (LCH) is a rare disorder. Uncontrolled clonal proliferation of langerhans cells leads to a diversity of clinical manifestations. Low dose Radiotherapy (RT) is used mainly for osseous manifestations as a sole treatment or in combination with surgery/chemotherapy/steroids. Altough the mechanism of action of RT is an unresolved issue, it's usually used in adjuvant/palliative settings, also as first-line local therapy with curative intent in unresectable or resectable cases in case surgery would result in functional compromise. This study is conducted to review indications, dose-fractionation schedules, clinical characteristics and outcomes of LCH patients received local RT mainly for osseous lesions. The medical records of biopsy proven all LCH patients referred to our center and treated with RT between 2000-2016 were evaluated retrospectively. Disease-free survival (DFS), local control and side effects were defined as study end-points. There was 35 patients, 21 of them were children. At presentation 65.7% had single system-single bone, 20% had single system-multiple bone, 15% had multisystem disease.Soft tissue extension were detected in 16 children, 4 adults (p= 0.013).Mean radiation dose was 10.8 Gy. Median follow-up from the date of biopsy was 105 months (range= 8-204) in children and 88 (range:31-245) in adults (log rank p:0.029).Complete response rate was 97%. 11 children and 1 adult experienced relapse (p= 0.05), median interval for relapse was 9months in children, 19months in adults. The most common relapse pattern was as single system-multiple bone (58.3%). Local control was 97.1%. Median disease free survival was 85 months. Low dose local RT seems to be effective and safe in multidisciplinary management of LCH. ÖZET Langerhan Hücreli Histiositozis: Düşük Doz Radyoterapi ile Mükemmel Lokal Kontrol Langerhans hücreli histiositozis (LCH), langerhans hücrelerine benzer dentritik hücrelerin çeşitli organlarda birikimi ve kontrolsüz klonal çoğalması ile karakterize, nadir görülen bir hastalıktır. Düşük doz radyoterapi (RT) ağrılı ve stabil olmayan kemik lezyonları ve kemik dışı yumuşak doku lezyonlarının tedavisinde tek başına ve/veya cerrahi, kemoterapi, steroidlerle birlikte kullanılmaktadır. Etki mekanizması halen net olarak anlaşılmamıştır. RT genelde adjuvant ve palyatif endikasyonlarda, ayrıca rezeke edilemeyen veya cerrahinin fonksiy-onel hasar yaratabileceği rezektable olgularda küratif amaçlı olarak kullanılmaktadır. Bu çalışmada, çoğunlukla kemik lezyonlarına yönelik lokal RT uygulanan LCH tanılı olgularda klinik özellikler, RT endikasyonları, doz-fraksiyonizasyon şemaları ve tedavi sonuçlarının araştırılması amaçlanmıştır. 2000-2016 tarihlerinde kliniğimizde RT uygulanan biopsi ile kanıtlanmış tüm LCH tanılı olguların tedavi ve izlem kayıtları geriye dönük olarak değerlendirilmiştir. Hastalıksız sağkalım, lokal kontrol ve geç yan etki çalışmanın sonlanım noktaları olarak belirlenmiştir. 35 olgu saptanmıştır. Ortanca yaşı 12 (6-27), 21 olgu (%60) pediatrik yaş grubundadır. Olguların %65.7'sinde tek sistem-tek kemik tutulumu, %20'sinde tek sistem-çoklu kemik tutulumu, %15'inde çoklu sistem tutulumu saptanmıştır. Pediatrik yaş grubundaki olguların 16'sında ve erişkinlerin 4'ünde kemik lezyonlarına yumuşak doku uzanımının eşlik ettiği tespit edilmiştir (p= 0.013). Ortanca RT dozu10,8 Gy'dir. Patolojik tanı tarihinden itibaren olan ortanca izlem süresi pediatrik olgularda 105 (18-195), erişkinlerde 88 (31-245) aydır. Tam yanıt oranı %97'dir. İzlemde 11 pediatrik, 1 erişkin olguda yineleme saptanmıştır (p= 0.05), yineleme için geçen ortanca süre pediatrik olgularda 9ay, erişkin olguda 19aydır.Ortanca hastalıksız sağkalım 85 ay (52-117) olarak tespit edilmiştir. En sık yineleme paterni tek sistem-çoklu kemik tutulumu olarak izlenmiştir.Lokal control %97.1'dir. Ortanca hastalıksız sağkalım 85 aydır. LCH'de düşük dozda RT multidisipliner tedavinin bir parçası olarak, etkin lokal kontrol sağlayabilen, güvenilir bir tedavi seçeneğidir.
... Langerhans cell histiocytosis (LCH) is a rare heterogeneous histiocytic disorder, and the dominant sites of involvement are bone and adjacent soft tissue, liver, spleen and bone marrow [1,2,15]. The central nervous system (CNS) may also be involved [2,21]. In patients The aetiology of the histiocytic lesions is largely unknown [1,2]. ...
... The treatments for LCH involving the CNS, such as conservative treatment, surgical intervention, chemotherapy and radiotherapy, were dependent on the lesion location, size, number and symptoms, and high-dose corticosteroid therapy was also used to control the inflammatory process. Additionally, CyberKnife radiosurgery was performed in some patients [2,21,[28][29][30]. However, the treatment of HPLCH patients is controversial because localized radiotherapy and chemotherapy were associated with tumour regression and stabilization but did not appear to prevent the evolution or deterioration of LCH-associated endocrine deficiency [3][4][5][6][7]30]. ...
Background
Isolated hypothalamic-pituitary Langerhans cell histiocytosis (HPLCH) is very rare. We investigated the clinicopathological characteristics, endocrine function changes, BRAFV600E mutations and treatments of isolated HPLCH. Methods
We identified seven patients with isolated HPLCH by reviewing the clinical and pathological files in our hospital from 2007 to 2015. The clinical characteristics of the seven patients were retrospectively reviewed, especially the endocrine function changes. Immunostaining and mutation profiling of BRAFV600E were performed. ResultsThe seven HPLCH patients included three men and four women, aged 9–47 years. All patients presented with symptoms of central diabetes insipidus (CDI), and four displayed anterior pituitary hypofunction as well. Magnetic resonance imaging showed hypothalamic-pituitary axis involvement in all patients. There was no evidence for the involvement of other organs in all seven patients. Langerhans cell histiocytosis was confirmed by neuroendoscopic procedures, and immunohistochemical staining showed that all cases (7/7) were positive for CD68, CD1a, Langerin, and S-100. The BRAFV600E mutation was detected in three of the six cases (3/6). Six patients had follow-up information; all received desmopressin acetate and high-dose corticosteroid therapy, and two patients received radiotherapy. Conclusions
Our study indicated that all patients with isolated HPLCH had CDI as the earliest symptom, and more than half of the patients had anterior pituitary deficiencies. The BRAFV600E mutation is a common genetic change in HPLCH patients. Treatment of HPLCH patients is difficult, and the progressive loss of endocrine function is irreversible in most cases.
... Despite a relatively homogeneous MRI pattern, the clinical picture of ND-LCH is very heterogeneous, ranging from mild to severe neurological impairment, including tremor, abnormal osteotendinous reflexes, spasticity, gait disturbance up to severe ataxia, cognitive and psychiatric symptoms (3,4,(15)(16)(17)(18). Not all patients with imaging findings suggestive of ND-LCH develop clinical symptoms, even many years after the initial diagnosis (3).Despite all efforts made over the last 20 years to better understand epidemiology, risk factors and pathogenesis of ND-LCH, an effective treatment is still lacking. ...
Aims
Early detection and treatment of neurodegenerative Langerhans cell histiocytosis (ND-LCH) have been suggested to prevent neurodegenerative progression. The aim of the study is to validate a standardized multidisciplinary diagnostic work-up to monitor the intravenous immunoglobulins (IVIG) treatment response and the natural course of the disease in untreated patients.
Methods
Patients with abnormal somatosensory evoked potentials (SEPs) received monthly 0.5 g/kg IVIG. The diagnostic protocol included structural 3T MRI, neurological examination, brainstem auditory evoked potentials (BAEPs) and SEPs.
Results
Twenty-two patients were followed for 5.2 years (median) from the first MRI evidence of ND-LCH. Eleven patients received IVIG for 1.7 years (median). At treatment start neurological examination was abnormal in 10 patients, of whom two had severe clinical impairment and four had abnormal BAEPs. At last follow-up, 1/11 remained stable and 7/11 improved, while worsening of neurological or neurophysiological findings, or both, occurred in 3/11. Risk factors for worsening were a severe clinical or MRI ND-LCH at treatment initiation and prolonged exposure to LCH. Of the 11 untreated patients, none improved and three worsened.
Conclusions
Using a standardized diagnostic protocol, we demonstrated that IVIG treatment can lead to clinical stabilization or improvement in all pauci-symptomatic patients with an MRI grading of less than 4.
... Treatment depends on the extent of the disease and may involve surgery, chemotherapy, or radiation therapy [20][21][22]. Prognosis is generally favorable, although long-term follow-up is necessary due to the risk of disease recurrence [23][24][25][26]. ...
Purpose
Langerhans cell histiocytosis (LCH) is a rare condition arising from the monoclonal expansion of myeloid precursor cells, which results in granulomatous lesions that characteristically express CD1a/CD207. We report a case of LCH in a 3-year-old male involving the sphenoid bone with extension into the sellar/suprasellar region.
Case report
A 3-year-old male presented with progressively worsening headaches and associated night sweats, neck stiffness, and fatigue over the previous 4 weeks. Magnetic resonance imaging (MRI) revealed a 2.4-cm lytic lesion within the basisphenoid, exerting mass effect upon the pituitary gland. A biopsy was performed to determine the etiology of the lesion. Postoperatively, the patient developed an intralesional hematoma with visual complications requiring emergent surgical resection via endoscopic endonasal approach. Final pathology confirmed LCH. The patient had improvement in his vision long term.
Conclusions
LCH extending into the sella is a rare but important diagnosis to consider in pediatric patients presenting with lesions in this region. We presented a case of a pediatric patient presenting with LCH of the sphenoid bone extending into the sella, with subsequent apoplexy and vision loss. Review of the literature showed varying treatment options for these patients, including purely surgical and non-surgical treatments. Early intervention may be necessary to avoid potentially devastating neurologic sequelae.
... However, it has a heterogeneous spectrum of phenotypic expression with clinical outcomes ranging from spontaneous remission to rapidly progressive and potentially fatal disease [3][4][5] . Later stage sequelae may also include skeletal disfigurement and/or neurodegeneration [6] . Clinical prognoses and courses of treat- ment vary with age as well as the extent and severity of disease [7] . ...
LCH Dural lesions Pediatric case MRI FDG avid CNS a b s t r a c t We report a case of multisystem Langerhans cell histiocytosis in a pediatric patient with central nervous system involvement, highlighting F-18(FDG) uptake characteristics of dural sites of disease. We also highlight the advantages of functional data offered by FDG-PET as a useful follow-up tool to assess viability and, therefore, treatment response of previously known central nervous system lesions. The utility of recognizing characteristic patterns of FDG uptake in dural disease is also applicable in cases of diagnostic uncertainty, such as when evaluating isolated dural lesions or when distinguishing between Langerhans cell histiocytosis and similar appearing lesions such as meningiomas. Published by Elsevier Inc. on behalf of University of Washington. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
... However, lesions of the vertebrae and femoral neck with a risk of pathologic fracture should be considered for RT. The rate of response to RT for LCH is over 90 percent for children and 70 percent for adults [11][12][13][14]. For severely unstable bone lesions neurosurgical intervention or bracing may be necessary besides RT and diagnostic biopsy. ...
... 7 Despite a relatively homogeneous MRI pattern, the clinical picture of ND-LCH is very heterogeneous, ranging from mild to severe neurological impairment, including tremor, abnormal osteotendinous re exes, spasticity, gait disturbance up to severe ataxia, cognitive and psychiatric symptoms. 3,4,15,16,17,18 Not all patients with imaging ndings suggestive of ND-LCH develop clinical symptoms, even many years after the initial diagnosis. 3 Despite all efforts made over the last 20 years to better understand epidemiology, risk factors and pathogenesis of ND-LCH, an effective treatment is still lacking. ...
Background: Early detection and treatment of neurodegenerative Langerhans cell histiocytosis (ND-LCH) have been suggested to prevent neurodegenerative progression. The aim of the study is to validate a standardized multidisciplinary diagnostic work-up to monitor the intravenous immunoglobulins (IVIG) treatment response and the natural course of the disease in untreated patients.
Methods: Patients with abnormal somatosensory evoked potentials (SEPs) received monthly 0.5 g/kg IVIG. The diagnostic protocol included structural 3T MRI, neurological examination, brainstem auditory evoked potentials (BAEPs) and SEPs.
Results: Twenty-two patients were enrolled and followed for 5.2 years (median) from the first MRI evidence of ND-LCH. Eleven patients were treated with IVIG for 1.7 years (median). At treatment initiation neurological examination was abnormal in 10 patients, of whom two had severe clinical impairment and four had abnormal BAEPs. At last follow-up, 1/11 remained stable and 7/11 improved, while worsening of neurological or neurophysiological findings, or both, occurred in 3/11. Risk factors for worsening were a severe clinical or MRI ND-LCH at treatment initiation and prolonged exposure to LCH. Of the 11 untreated patients, none improved and three worsened.
Conclusions: Using a standardized diagnostic protocol, we demonstrated that IVIG treatment can lead to clinical stabilization or improvement in all pauci-symptomatic patients with an MRI grading of less than 4.
... Однако до 50% больных ГКЛ после окончания программной терапии развивают различные формы так называемых «перманентных осложнений», снижающих качество жизни и представляющих серьезную угрозу здоровью [90]. К наиболее частым «перманентным осложнениям» при ГКЛ относят ортопедические нарушения (> 40% всех случаев осложнений [91,92]), различные формы неврологических и эндокринных дефицитов [93]. Центральный несахарный диабет, по разным данным, развивается с частотой 15-50% [94]. ...
Relevant information on Langerhans cell histiocytosis development and course in children is presented. The current concepts of disease pathogenesis, principles of its severity evaluation, patients stratification into risk groups, as well as of clinical course features are described. Modern approaches to the disease treatment via targeted therapy are summarized and analyzed.
... Radiotherapy (RT) is a highly effective treatment for LCH bone lesions. LCH has been reported to be more than 70% effective in adults in the treatment of bone involvement and pain (19). Two patients with bone relapse were treated with RT and their pain decreased and also received remission. ...
Aim: Langerhans cell histiocytosis (LCH) is a proliferative disease caused by abnormal proliferation of histiocytes in the bone marrow dendritic cell structure. LCH is very rare in adults and its incidence is 1-2 cases per million. Therefore, there is still no clear management plan in adults. It was aimed to evaluate the very rare adult LCH patients. Materials and Methods: Ten LCH patients who were followed up at Erciyes University Hematology Department between January 2010 and January 2020 were included. Results: Eight (80%) of them were male and 2 (20%) were female. The median age of the patients was 34.5 ± 8.4 (23-52) years. Although the most common involvement at the time of diagnosis was bone in 7 patients (70%) and lung in 3 patients (30%); pituitary, tympanic membrane, liver and brain involvement were also observed. Three (30%) patients had single system involvement and 7 (70%) had multisystem. Four (40%) patients had relapsed and all had multisystemic involvement. The BRAF V600E mutation could be performed in 3 patients. It was negative in two patients and positive in 1 patient. All patients still have remission. Conclusion: Unlike children, LCH has a better course in adults. The most important approach is to determine single or multisystem involvement. In our patients with single system involvement, we obtained response with corticosteroid and surgery alone. We have observed that vinblastin plus metilprednizolon treatment is a good option for multisystemic involvement. In relapsed patients, we obtained a significant response with clofarabine.
... Otic capsule involvement is reported in 20%-29% of cases, resulting in sensineuronal hearing loss in 75% of these cases. 7,19,[27][28][29] After treatment, there may be bone re-mineralization and re-constitution of the labyrinth, 30 but the sensineuronal hearing loss usually persists, 7,28,31 except for extremely rare cases. 32,33 However, there are reports of successful cochlear implantation to restore hearing ability. ...
A 4‐year‐old girl was admitted to hospital with disturbance of balance. After being questioned, parents remembered an otitis with effusion 3 months earlier. CT‐scans revealed destruction of both temporal bones. Initial biopsy showed granulomatous, necrotic inflammation, which led to comprehensive differential diagnoses. A second tissue sample confirmed Langerhans cell histiocytosis.
... This is particularly relevant since the consensus is to now consider LCH a neoplastic process. 2 Although overall 5-year survival is generally positive in LCH, [16][17][18] long-term morbidity of disease recurrence is significant, especially in multisystem disease. [19][20][21] Optimal treatment regimens for LCH differ according to the involved site and may include surgery, steroids, radiation, and/or chemotherapy. ...
Objectives
Retrospectively analyze head and neck Langerhans Cell Histiocytosis at a rural tertiary referral center and compare results with previously published data.
Methods
Electronic health record review was performed from 2003 to 2019. Patients with biopsy proven LCH with primary head and neck involvement were included. Demographics, presentation, imaging characteristics, treatment modality, delay in diagnosis (DD, ≥60 days), and outcomes were analyzed and reported.
Results
Twenty-four patients were included. The most common presenting symptoms were otorrhea (n = 6) and scalp pain or swelling (n = 6). All patients had bony involvement. The most common site was facial or skull lesions (n = 20). Most skull lesions (75%) demonstrated CNS risk. Six patients were treated with primary surgery, 15 with primary chemotherapy, and 3 with surgery plus adjuvant chemotherapy. Nine patients experienced relapse of disease with median time to documented relapse of 11.4 months; all were treated with salvage chemotherapy to achieve complete remission (median follow-up: 72 months). Patients most likely to relapse were those with multisystem disease (5/7, 71.4%), temporal bone lesions (4/7, 57.1%), and DD (7/12, 58.3%). Of the 9 total patients who experienced relapse, 78% had a delay in diagnosis.
Conclusions
LCH is a complex disease process in which diagnosis can be delayed if not considered in the differential. Within the head and neck, the skull, including isolated temporal bone involvement, is the most common site of involvement. Treatment modality does not appear to have an influence on relapse rates. Relapse was more likely to occur in the first year after treatment and close monitoring is required.
... In this case, there were no significant adverse events other than hair loss during the treatment course and we were able to do cladribine safely and obtain a long progression-free relapse period. In the past, however, adverse events associated with radiotherapy have been shown to be highly prevalent especially in children (11). Currently, CT-based treatment planning is the standard for radiotherapy, and the accuracy of radiotherapy has been improved by the combination of technological advances such as image-guided radiotherapy and particle therapy, and reduced adverse events (12,13). ...
Background:
Langerhans cell histiocytosis (LCH) is a rare disease, especially in adults. It is often associated with non-fatal bone and skin lesions and has relatively good radiosensitivity. In contrast, brain and lymph node metastases from LCH lesions are considered to be less sensitive to radiotherapy.
Case report:
At our institution, 30 Gy radiotherapy was used to treat bone lesions with dural invasion in a patient with adult-onset LCH. The patient was treated with chemotherapy and radiotherapy for 21 years since the initial diagnosis. After radiotherapy, the tumor shrank rapidly, and a complete response was achieved 1 year after treatment. The patient survived without local recurrence.
Conclusion:
Here, we report the details of this case, along with a review of the literature. We suggest that even with invasion of the tissues around the bone lesions in LCH, local recurrence can be prevented by middle radiation doses.
... While he had a history of pituitary dysfunction, this appeared unrelated to his subsequent diagnosis of LCH. Skin-only LCH is less common than single-system bone disease but however has been described to occur in approximately 13% of patients [12]. ...
Langerhans cell histiocytosis (LCH) is a rare disease, afflicting approximately 4.6 and 1-2 per 1 million children and adults, respectively. While LCH can involve numerous organ systems such as the lung or bone, it is uncommon for the disease to be limited to the skin. Radiotherapy has an established role for osseous lesions. However, the efficacy and dose for nonosseous manifestations of the disease are not well described. In the current case report, we detail a 49-year-old adult male with skin-limited LCH requiring palliative radiotherapy (RT) to numerous sites for pain control. The patient was initially diagnosed and treated with single agent cytarabine for approximately 6 months. Despite treatment, he had little symptomatic response of his cutaneous lesions. We delivered a single dose of 8 Gray (Gy) to 3 separate skin lesions, including the bilateral groin, right popliteal region, and right axillary lesion, which resulted in pain reduction and partial response at four-month follow-up. Subsequently, we decided to treat the left axillary untreated lesion to a higher dose of 24 Gy in 12 fractions. At four-month follow-up, the left axilla RT resulted in complete clinical response and improved pain control compared to the right axilla. Following RT treatments, the patient was found to have a BRAF mutation, and vemurafenib was initiated. Further follow-up with positron emissions tomography demonstrated complete metabolic response in numerous disease areas, including both axillae. Based on this case report’s findings, a higher radiotherapy dose may be more effective for treating cutaneous LCH.
... Compared to other CNS-related PC, it occurs early in the disease process [34,61]. The proportion of patients with CDI varied in different cohorts from 11% [62] up to 35% [12,35,38,59,63]. In some cases, DI is an inaugural manifestation of LCH [34,61], posing considerable diagnostic challenge [61,64,65]. ...
Langerhans cell histiocytosis (LCH) is a rare disease with a wide range of clinical presentations and variable outcome. The prognosis of this potentially fatal disease has dramatically improved over the last years. However, about 50% of the survivors experience disease reactivations and suffer from permanent consequences (PC) affecting their quality of life. Some PC can be the inaugural manifestation of the underlying disease (e.g., central diabetes insipidus); others (e.g., neurodegeneration) may develop up to decades after diagnosis of LCH. Particularly prone to PC are patients with young age at first disease manifestation and those with multisystem LCH (≥ two organ systems involved). Single-system LCH predominantly affects the skeleton, and therefore, the PC in those patients constitute a variety of permanent defects of the affected bones or of the adjacent tissues and organs (e.g., facial asymmetry, proptosis, deafness, loss of vision, dental abnormalities). In patients with multisystem LCH, the most common PC are endocrinopathies (mostly due to the involvement of the hypothalamic-pituitary axis), neurocognitive and behavioral deficits (pontocerebellar syndrome), and much less frequently PC due to permanent damage of the lungs or liver. Treatment-related late effects are rare in LCH.
... CRL included vertebral lesions with a intraspinal soft tissue component, and lesions in temporal, mastoid, sphenoid, zygomatic, ethmoid, maxilla bones, the orbit, paranasal sinuses, or cranial fossa. RO included liver, spleen, and the hematopoietic system [22][23][24][25][26] . Two radiologists (H.M.Y. and J.R.K.) performed risk stratifications for three separate sessions according to the findings of each whole-body imaging modality (skeletal survey, bone scan, and WB-MRI) in each patient. ...
Accurate risk stratification according to the extent of Langerhans cell histiocytosis (LCH) determined on whole-body evaluation is important for determining the treatment plans and prognosis in patients with LCH. This study aimed to compare the lesion detectability and the accuracy of risk stratification of skeletal survey, bone scan, and whole-body magnetic resonance imaging (WB-MRI) in patients with LCH. Patients with newly-diagnosed LCH who underwent all three imaging modalities were retrospectively included (n = 46). The sensitivity and mean number of false-positives per patient for LCH lesions, and the accuracy of risk stratification of each modality were assessed. WB-MRI had significantly higher sensitivity (99.0%; 95% confidence interval, 93.2–99.9%) than skeletal survey (56.6%; p < 0.0001) and bone scan (38.4%; p < 0.0001) for LCH lesions, and there were no significant differences in the number of false-positives per patient (p > 0.017). WB-MRI tended to have higher accuracy for the risk stratification than skeletal survey and bone scan (concordance rate of 0.98, 0.91, and 0.83, respectively), although the differences were not significant (overall p-value 0.066). In conclusion, WB-MRI had higher detectability for LCH lesions than skeletal survey and bone scan, while the three whole-body imaging modalities had comparable accuracy in the initial risk stratification of LCH.
... Diabetes insipidus (DI), the most frequent hormonal abnormality, occurs in 15-50% patients with HPR LCH [4,7,9,10]. Pituitary dysfunction occurs in only 5-20% of patients, almost always accompanied by DI [9,11,12]. Herein, we present a patient with localised hypothalamic-pituitary LCH who had dominant tumour mass effects and pituitary dysfunction without DI and her 7-year follow-up. Procedures, data collection, and presentation were approved by the hospital ethics committee (decision no.: 37232/1). ...
Introduction:
Langerhans cell histiocytosis (LCH) localised in the hypothalamic-pituitary region (HPR) is very rare, especially in adults. Diabetes insipidus (DI) is considered to be a hallmark of HPR LCH, while anterior pituitary abnormalities are usually seen as consequences of surgery, radiotherapy or chemotherapy.
Case description:
We present a patient with localised HPR LCH with dominant anterior pituitary dysfunction and tumour mass effects but without DI. Seven years after surgery and local radiotherapy, she is stable. Control MRI shows no residual tumour growth and thorough physical examination is still without any signs of disease spread.
Conclusions:
Anterior pituitary deficiency can appear without DI and not only as a consequence of LCH treatment. All patients with LCH should be screened for this endocrine abnormality so that appropriate substitution therapy may be provided.
... This variability in distribution and extent of involvement best explains the long list of clinical designations under the LCH umbrella. 352 The cutaneous lesions, much like the overall clinical spectrum of LCH, are variable in appearance: cutaneous involvement is most common in multisystem disease in infants and children. In multisystem disease, the skin lesions are erythematous and maculopapular or nodular with ulceration at times. ...
This article focuses on cutaneous hematopoietic neoplasms that are more likely to be encountered in the pediatric age-group and includes both lymphoproliferative and histiocytic disorders. The cutaneous hematologic disorders in children have a different epidemiologic profile to what is seen during adulthood. Although mycosis fungoides is the most frequent form of cutaneous lymphoma in adults, it is very rare in children. Because lymphoblastic leukemias and lymphomas are more frequent in the pediatric setting, cutaneous leukemic infiltrates are relatively common in this age-group. Similarly, histiocytic disorders are more common in children, particularly Langerhans cell histiocytosis and juvenile xanthogranuloma. Notably, the histiocytic disorders have undergone significant modifications on their nomenclature in the basis of the molecular characteristics that are present in them. A summary of the most frequent cutaneous hematopoietic disorders in children will be discussed further in this review.
... Symptoms that are recognized timely and accurately are of vital importance in reaching a definitive diagnosis and thereby conducting an effective treatment. Early diagnosis and effective treatment of LCH have been documented to not only prevent the progression of disease but also avoid further complications including orthopaedic disabilities, hearing impairment, diabetes insipidus, skin scarring, and neuropsychological defects, chronic pulmonary dysfunction, liver cirrhosis, secondary malignancies such as acute lymphoblastic leukemia or solid tumors, and growth retardation [18][19][20][21][22][23]. ...
Background
Langerhans cell histiocytosis (LCH) is a rare disorder of the reticuloendothelial system with unknown etiology. This report aims to present a case of LCH with diffuse involvement of the oral cavity and to raise awareness of the distinguishing features of this diagnostically challenging entity.
Case Report
A 26-year-old male patient presented with complaints of teeth mobility, intense pain, and difficulty in chewing. Intraoral and radiological examinations revealed generalized gingival hyperplasia and severe teeth mobility with widespread alveolar bone loss. Periodontal therapy was performed with no significant improvement. An incisional biopsy revealed Langerhans cells and positive reaction to S-100 and CD1, and the patient was diagnosed with LCH. The patient underwent systemic chemotherapy with vinca alkaloids and corticosteroids. Regression of gingival lesions, as well as significant decrease in mobility of the remaining teeth and severity of pain, was achieved during 12 months of follow-up.
Conclusion
The rarity and variable system involvement of LCH necessitate a multidisciplinary approach be carried out for accurate diagnosis, effective treatment, and an uneventful follow-up. Awareness of oral manifestations of LCH may aid clinicians greatly in reducing morbidity and mortality associated with this debilitating condition.
... The replication control cohort was drawn from 2 authorizedaccess data sets obtained from the NIH, National Center for Biotechnology Information Database of Genotypes and Phenotypes (dbGaP). 17 Specifically, subjects from the Genotype-Tissue Expression and Genetic Architecture of Smoking and Smoking Cessation studies were used as non-LCH controls because the prevalence of adult survivors of LCH is ,4 in 1 000 000. 18 Quality-controlled genotype data for this locus was abstracted from dbGaP for 1645 controls. Germ line DNA BLOOD, 16 NOVEMBER 2017 x VOLUME 130, NUMBER 20 2229 For personal use only. ...
... The replication control cohort was drawn from 2 authorizedaccess data sets obtained from the NIH, National Center for Biotechnology Information Database of Genotypes and Phenotypes (dbGaP). 17 Specifically, subjects from the Genotype-Tissue Expression and Genetic Architecture of Smoking and Smoking Cessation studies were used as non-LCH controls because the prevalence of adult survivors of LCH is ,4 in 1 000 000. 18 Quality-controlled genotype data for this locus was abstracted from dbGaP for 1645 controls. Germ line DNA BLOOD, 16 NOVEMBER 2017 x VOLUME 130, NUMBER 20 2229 For personal use only. ...
... Although non-lethal, a number of permanent consequences including DI, sclerosing cholangitis, pulmonary failure, neurodegeneration, reduced linear growth, other endocrine dysfunctions and bone deformities, may represent quite a heavy burden for the quality of life of patients cured of LCH (The French LCH Study Group, 1996;Willis et al, 1996;Haupt et al, 2004;Nanduri et al, 2006). DI is rare in children but not in those with multisystem LCH, in which it may reach a 12-20% prevalence (Maghnie et al, 2000;Grois et al, 2006;Minkov et al, 2008). ...
Langerhans cell histiocytosis (LCH) is a rare disease, affecting subjects of any age, with extremely variable clinical manifestations. Although most patients with LCH have localized disease, requiring local or even no therapy, those patients with disseminated, 'multi-system' disease require specific therapy because they may be at risk for morbidity or even mortality. The current standard of care has developed empirically, based mainly on the experience of treating children with leukaemia and other haemo-proliferative disorders. At the time of writing, the combined use of vinblastine and prednisone remains the standard of care for children with multi-system LCH. The combination of cytarabine and cladribine is the current standard for second-line therapy of refractory cases with vital organ dysfunction. Recent advances in the knowledge of the pathogenesis of LCH may support a change in treatment strategy. Evidence of mutations that aberrantly activate RAF/MEK/ERK signalling in over two thirds of patients with LCH may direct a target therapy strategy. Vemurafenib, a small molecule widely used in the treatment of melanoma, is the main candidate for testing in prospective trials for patients with evidence of BRAF(V) (600E) mutation on lesional tissue. Additional molecules, including the recently approved trametinib, could follow. Identification of mutations in other genes in the remaining multisystem LCH cases could contribute to define a scenario in which target therapy becomes the main therapeutic choice in this intriguing disorder. However, because the long-term risks and benefits of these agents in children are unknown, and other effective treatments exist for many LCH patients, the optimal indications for administering a tyrosine kinase inhibitor to children is an open question.
Background: Langerhans cell histiocytosis (LCH) is characterized by dysregulated proliferation of LCH cells and subsequent organ infiltration. Clinical manifestations vary and range from a single system unifocal bone disease to multisystem LCH with risk organ involvement. The prognosis is in majority of cases favourable, but some LCH survivors experience chronic health conditions resulting from this disease. Since a comprehensive, population-based description of chronic health conditions among LCH survivors is lacking, we evaluated the spectrum and prevalence of chronic health conditions among LCH survivors compared with siblings of childhood cancer survivors and identified factors associated with chronic health conditions.
Results: In total, 123 LCH survivors participated (response rate 69%). Median time since diagnosis was 13 years (interquartile range 9–20) and median age at study was 20 years (interquartile range 15-26). LCH survivors were more often male (63%). We also included 866 siblings of childhood cancer survivors as a healthy comparison group.
Fifty-nine percent of LCH survivors had at least one chronic health condition while only 48% of siblings had one or more chronic health conditions (p=0.02). Cardiovascular (13% vs. 6%), endocrine (15% vs. 1%), musculoskeletal (22% vs. 12%), and digestive (15% vs. 8%) chronic health conditions were more common among LCH survivors than siblings. Among survivors of single system unifocal bone LCH, only musculoskeletal (23% vs. 12%) CHC were more prevalent compared with siblings. Among survivors of all other LCH forms, neurological (40% vs. 23%), endocrine (24% vs. 1%), musculoskeletal (21% vs. 12%), digestive (21% vs. 8%), and cardiovascular (18% vs. 6%) chronic health conditions were more prevalent compared with siblings (all p<0.05).
Factors most strongly associated with occurrence of chronic health conditions were multisystem LCH, multifocal bone involvement, and involvement of pituitary gland.
Conclusions: We showed more than half of long-term LCH survivors suffered from at least one chronic health condition and were affected considerably more than siblings. Clinicians in paediatric cancer survivorship programs should be vigilant regarding musculoskeletal, endocrine, digestive, and cardiovascular chronic health conditions in multisystem LCH, multifocal bone disease survivors, and those with pituitary gland involvement.
This article presents the international dataset of cases in which the association of Langerhans cell Histiocytosis (LCH) with other malignancies (AM) was documented occurring at any age before, concurrently or after LCH. These data are mostly derived from previously published manuscripts or from completed case report forms (CRFs) by Histiocyte Society (HS) members or colleagues. In particular, for each case of LCH-AM, the database reports all the available data about clinical and biologic characteristics of the two tumors, as well about treatment and status at follow-up. The AM were categorized as: i) leukemias [acute lymphoblastic or myeloid leukemia (ALL and AML, respectively), other leukemias] and myeloproliferative disorders; ii) lymphomas [Hodgkin lymphoma (HL) and non-Hodgkin lymphomas (NHL)] and iii) solid tumors.
A total of 270 LCH-AM cases were documented, of which 116 (43%) occurred among children. After stratification by age at LCH diagnosis, using 18 years as cut-off between children and adults, we here provide details on the clinical characteristics in terms of LCH system involvement and affected organs, as well on the temporal relationship between the LCH and AM diagnoses, including details on the AM malignancy types. In 19 cases the LCH and the corresponding AM occurred in a different age group.
The data set is available for future studies in view of new insights of the genetic or environmental determinants of LCH and/or of treatment related subsequent neoplasms.
Langerhans' cell histiocytosis (LCH), a chronic granulomatous disorder, can involve one or more organs/tissues including bone, skin, lungs, liver, spleen, bone marrow, pituitary gland and brain. Long term sequelae involving these organs have been reported, but their true prevalence is unknown. In order to assess long term outcome in survivors of multisystem LCH, we performed a cross-sectional study of 40 patients, all of whom were more than 5 years from treatment. Most of the patients had had involvement of bone and/or skin, with other organs being affected less often. They had received a wide range of treatments, including surgery, steroids, radiotherapy and chemotherapy. The study involved clinical examination, MRI scan of brain, endocrine function tests, neuropsychometry, respiratory function tests and audiometry. Most patients had one or more long term sequelae. Half of the patients had endocrine abnormalities, ranging from isolated diabetes insipidus to panhypopituitarism. Brain involvement, including cerebellar involvement, was the most worrying problem, occurring in 10 patients, with severe abnormalities in seven. New findings include the presence of significant learning deficit in 20% of patients, psychological and behavioural abnormalities in 11 patients (27.5%), and an acquired abnormality of the skull base, basilar invagination, in 8 patients (20%). A specific morbidity score was devised and provided an objective measure of outcome. Using this scale only 10 patients (25%) had no sequelae. Eleven (27.5%) had mild impairment which required no specific treatment, 9 (22.5%) had moderate disability, including diabetes insipidus, growth hormone insufficiency and moderate hearing loss, while 10 (25%) had severe disabilities such as panhypopituitarism, learning difficulty, motor deficit and psychological abnormalities resulting in significant handicap and inability to lead an independent adult life. We assessed the Health-Related Quality of Life and found that this correlated with the Morbidity score. Both these measures can easily be applied to any patient with LCH and can be incorporated into long term follow up studies. In conclusion, long term sequelae are more common in survivors of multisystem LCH than previously recognised and cause significant long term morbidity. An important implication of the work presented in this thesis is that carefully planned regular long-term follow up is essential for all patients 'cured' of LCH to ensure that sequelae are recognised early and the appropriate interventions made to improve the patients' "quality of life".
Langerhans cell histiocytosis (LCH) is a rare proliferative disorder, more frequent in children, characterized by an abnormal accumulation of Langerhans cells admixed with eosinophils, lymphocytes, neutrophils, and macrophages. The clinical presentation is variable and depends on whether a single or multiple organs are affected. Skin lesions are common in LCH (40% of cases) and represent a frequent form of presentation (in up to 80% of cases). Cutaneous manifestations of LCH are highly variable, frequently presenting as crusted papules or scaly seborrheic-like lesions localized in the scalp. We report the first case of a localized acral sclerosing LCH, a new form of LCH. This case highlights the broad and surprising form of presentation of LCH which may be overlooked and can significantly delay its diagnosis. The development of systemic disease may occur months to years after the initial skin presentation. Prompt diagnosis and treatment may prevent progression to systemic disease, as documented in some cases.
Langerhans cell histiocytosis (LCH) occurs as a clonal disease with enigmatic immune responses. LCH patients occasionally present with fever, although the significance remains elusive. We investigated the predicting factors for developing intractable disease of refractory and/or reactivated LCH. In total, 40 pediatric LCH patients managed in Kyushu University from 1998 to 2014 were enrolled. The medical records were analyzed retrospectively. Sixteen patients suffered from multisystem (MS) LCH involving risk organs (ROs) (n=4) or not (n=12). In total, 24 patients had single-system LCH affecting bone (multi n=8, single n=13), skin (n=2), or lymph node lesions (n=1). Eight patients had the intractable disease of 7 MS or 1 multibone LCH. Two patients died from MS LCH with or without RO involvement. Ten patients showed persistent fever (>38°C) at onset. Intractable cases had fever, RO and skin involvement, leukocytosis, coagulopathy, microcytic anemia, higher levels of soluble interleukin-2 receptor and C-reactive protein, more frequently at diagnosis. Multivariate analysis indicated that fever and skin lesions at diagnosis were independently associated with the intractability (odds ratio: fever, 35.5; 95% confidence interval, 3.0-1229.1; skin lesions, 24.6; 95% confidence interval, 1.9-868.7). Initial fever and skin involvement might predict the development of intractable and fatal-risk LCH even without the RO involvement.
The term permanent consequences is often used to describe the portfolio of possible late complications occurring in patients with LCH. Consequences may be already evident at the moment of LCH diagnosis or become manifest even more than 10 years after the end of therapy. They may be due either to the site of the original disease or to age at treatment and type and doses of treatments received. Since the bony skeleton is the most common site of involvement of LCH, the commonest sequelae tend to be orthopaedic and include pathological fractures, malformation, scoliosis and vertebra plana. Diabetes insipidus is the most reported endocrine abnormality, and patients with multisystem disease and involvement of the craniofacial bones are those at higher risk. Other abnormalities may affect anterior pituitary with growth hormone deficit being the most frequent. Neurological problems such as cerebellar ataxia, psychological problems and learning difficulties can occur, with impact on school performance and quality of life. Hearing loss and pulmonary problems are other common possible late complications. Possible other side effects should also be carefully monitored in patients treated with novel targeted therapies involving BRAF/MAPK pathways. LCH may be associated with other malignancies occurring either before, concurrently or after LCH diagnosis. In general ALL usually precedes LCH, while AnLL and solid tumours develop after LCH. Long-term and patient-oriented follow-up in children with LCH is recommended.
Langerhans cell histiocytosis (LCH) can affect virtually any organ of the human body, including the central nervous system (CNS). Based on correlation of clinical, imaging, and pathology findings, two patterns of CNS-LCH have been identified: granulomatous (“tumorous”) and non-granulomatous “neurodegenerative” (ND)-CNS-LCH. Granulomatous CNS-LCH can manifest with polyuria and polydipsia, seizures, increased intracranial pressure, or other signs, depending on location. The typical location on MRI is extra-axial (hypothalamic-pituitary region, meninges, pineal gland, choroid plexus), and pathology in a proliferative phase reveals CD1a/langerin+ histiocytes. ND-CNS-LCH manifests insidiously with cerebellar and bulbar symptoms. MRI typically reveals parenchymal signal alterations in the cerebellum, pons, basal ganglia, and supratentorial white matter consistent with neuronal loss and demyelination. Biopsies of such lesions are rare. In the few published cases biopsied, variable pathologies are described with perivascular inflammatory changes, variable neuronal loss, demyelination, and gliosis, but are nondiagnostic for CD1a+/CD207+ LCH cells. Granulomatous LCH can be responsive to chemotherapy agents such as vinblastine, cytarabine, or cladribine, while the optimal treatment of ND-CNS-LCH is yet to be defined.
Purpose
Langerhans cell histiocytosis (LCH) is a rare malignant disease characterized by histiocytic proliferation. We intended to characterize the efficacy and safety of radiation therapy (RT) in a contemporary cohort and to explore if there are sites at higher risk for local recurrence.
Materials/Methods
Between 1995 and 2015, we identified 39 consecutive LCH patients who were treated primarily with radiation therapy. Patients were staged by single/multisystem involvement (SS/MS) and established risk organ criteria. In 46 irradiated lesions, clinical and radiologic responses were evaluated at multiple time points after radiotherapy. Patient demographics, treatment, and local failure were compared by site of lesion.
Results
Median age at RT was 35 years (range 1.5 – 67). Twelve patients had multisystem involvement, and of those, 5 patients had disease in organs considered to be high-risk. The following sites were irradiated: bone (31), brain (6), skin (3), lymph node (3), thyroid (2), and nasopharynx (1). Median dose was 11.4 Gy (7.5 – 50.4). At a median follow-up of 45 months (6 – 199), local recurrence or progression was noted in 5 of 46 (11%) lesions. There were no local failures of the 31 bone lesions evaluated, while the 3-year freedom from local failure in the 15 non-bone lesions was 63% (95% CI 32 – 83%; p = 0.0008). Local failures occurred in 2 of 3 skin lesions, in 2 of 6 brain lesions, and 1 of 3 lymph node lesions. Deaths were recorded in 5 of 39 (13%) patients, all of whom were adults with multisystem disease.
Conclusion
Radiotherapy is a safe and effective measure for providing local control of LCH involving the bone. While bone lesions are well controlled with low doses of radiation, disease in other tissues such as the skin and brain may require higher doses of radiation or additional treatment modalities.
Rheumatische Erkrankungen können verschiedene anatomische Strukturen der Atemwege und der Lunge betreffen. Am bekanntesten ist die Pleuritis bei Morbus Still, der systemischen Form der juvenilen idiopathischen Arthritis. Rheumatische Krankheiten können aber auch das Lungengewebe als interstitielle Pneumonitis mit der möglichen Folge einer Lungenfibrose betreffen. Obstruktive Ventilationsstörungen finden sich als Folge einer subglottischen Stenose oder Bronchusstenose bei der Wegener-Granulomatose. Bei der Dermatomyositis kann es durch die Schwäche der Atemmuskulatur bis zur respiratorischen Insuffizienz kommen. Eine mangelnde Dehnbarkeit der Thoraxwand kann bei der Sklerodermie zu einer restriktiven Ventilationsstörung führen.
Rheumatische Erkrankungen können verschiedene anatomische Strukturen der Atemwege und der Lunge betreffen. Am bekanntesten ist die Pleuritis bei Morbus Still, der systemischen Form der juvenilen chronischen Arthritis, oder als Symptom des Lupus erythematodes. Rheumatische Krankheiten können aber auch das Lungengewebe als interstitielle Pneumonitis mit der möglichen Folge einer Lungenfibrose betreffen. Obstruktive Ventilationsstörungen finden sich als Folge einer subglottischen Stenose oder Bronchusstenose bei der Wegener-Granulomatose. Bei der Dermatomyositis kann es durch die Schwäche der Atemmuskulatur bis zur respiratorischen Insuffizienz kommen. Eine mangelnde Dehnbarkeit der Thoraxwand kann bei der Sklerodermie zu einer restriktiven Ventilationsstörung führen.
Langerhans cell histiocytosis is characterized by the clonal proliferation of histiocytes, a type of white blood cell, in various organs of the body. There is a large range of presentations, from isolated lesions, most often of bone, to widespread, multisystem disease. Disease that appears to be isolated may be more widespread either at diagnosis or in the future, so broad workup and vigilant surveillance is required. Patients with involvement of only one organ system can often be cured with surgical resection or curettage alone, whereas patients with involvement of high-risk bony sites, risk organs, or widespread disease require chemotherapy and have variable outcomes.
Histiocytic tumors are a heterogeneous group of tumors and tumorlike masses commonly associated with histologically identical extracranial lesions.
Ein 2 Jahre altes Mädchen kommt wegen einer seit über 12 Monaten bestehenden ulzerierenden Windeldermatitis und rezidivierenden Mittelohrentzündungen mit Otorrhö zur Aufnahme. Die Untersuchung ergibt normale Laborwerte bis auf eine erhöhte BSG (48/83 mm/h) und eine geringe Hepatomegalie. Ein Schä delcomputertomogramm zeigt osteolytische Veränderungen im Os temporale, die Hautbiopsie bestätigt eine Langerhans-Zell-Histiozytose. Nach 6-monatiger Chemotherapie (Prednisolon und Vinblastin) bilden sich alle Symptome bis auf eine geringe persistierende Verschattung im Mastoid rasch zurück.
9 Monate nach Therapieende entwickelt das Kind einen Diabetes insipidus, nach 6 Monaten kommt es zu einer Gingivaschwellung und Lockerung von Zähnen sowie zur Rötung und Schuppung der Kopfhaut. Das Computertomogramm zeigt multiple Kieferosteolysen und bestätigt die Reaktivierung. Eine erneute Chemotherapie führt zu einem neuerlichen Response, die Zähne bleiben alle erhalten. Ein Kontroll-MRT nach 1 Jahr zeigt einen normalen Hypophysenstiel einen fehlenden »bright spot«, eine kleine Hypophyse und pathologische Signale im Zerebellum und den Basalganglien. Das mittlerweile 6 Jahre alte Mädchen besucht die Schule und ist neurologisch unauffä llig. Es hat jedoch einen Wachstums- und Schilddrüsenhormonmangel entwickelt und zeigt Konzentrations- und Merkstörungen.
Les histiocytoses regroupent l’ensemble des proliférations de cellules d’origine histiocytaire. Les histiocytes appartiennent àdeux grandes classes: — le système phagocytaire mononucléé monocytes circulants/macrophages tissulaires : monocytes circulants, macrophages des cavités (plèvre, péritoine), cellules de Kupffer du foie, ostéoclastes et cellules microgliales. Sa fonction principale est la phagocytose et l’apprêtement antigénique («antigen processing» — la famille des cellules dendritiques/cellules de Langerhans ou cellules présentatrices d’antigènes : cellules de Langerhans et dendritiques dermiques de la peau et des muqueuses, cellules dendritiques de la rate et des ganglions lymphatiques. Sa fonction principale est la présentation d’antigène aux lymphocytes.
Langerhans cell histiocytosis (LCH) is a rare semimalignant disease involving uncontrolled clonal proliferation of Langerhans cells, i.e. abnormal cells deriving from bone marrow and capable of migrating from skin to lymphnodes. LCH can involve one or more body systems or tissues, leading to different clinical manifestations. The disease is part of a group of clinical syndromes called histiocytoses characterized by pathologic proliferation of histiocytes (a former term for dendritic cells and macrophages). These diseases are related to other forms of abnormal proliferation of white blood cells, such as leukemias and lymphomas.
PURPOSEPatient records were reviewed to identify cases of secondary acute myeloid leukemia (AML) with clinical and cytogenetic features characteristic of classic epipodophyllotoxin-related AML in patients whose prior treatment for cancer did not include these agents.PATIENTS AND METHODS
Four cases of secondary AML with chromosomal abnormalities involving bands 11q23 and 21q22, in the absence of prior treatment with etoposide or teniposide, were identified among patients treated at St Jude Children's Research Hospital between January 1980 and April 1992.RESULTSThe four identified patients were initially treated for rhabdomyosarcoma, non-Hodgkin's lymphoma (n = 2), and Hodgkins' disease. Prior chemotherapy included relatively low cumulative doses of doxorubicin (median, 150 mg/m2; range, 120 to 375 mg/m2) and cyclophosphamide (median, 3,100 mg/m2; range, 2,250 to 11,400 mg/m2). All four patients had received radiation therapy: 59.4 Gy to the right middle ear for rhabdomyosarcoma; 15 Gy and 12 Gy to the abdom...
REPORT OF A CASE
CASE 1
A 59-year-old woman treated for diabetes insipidus by desmopressin (Minirin) for 8 years was seen with large granulomatous ulcerations and infiltrated papules of the perianal region that were present for 3 years (Figure 1 ). A few papular lesions were seen in the submammary region. Histopathologic examination of a skin biopsy specimen taken from the perianal lesions disclosed a thick dermal infiltrate with lymphocytes, eosinophils, and large histiocytes (Figure 2). Immunohistopathologic study showed that the histiocytes stained positive for S100 and CD la. Electron microscopy confirmed the diagnosis of Langerhans cell histiocytosis, showing 20% of the cells in the infiltrate contained Birbeck's granules (Figure 3). The patient's clinical examination showed negative findings, and no pulmonary involvement was seen on a chest roentgenogram and a thoracic computed tomographic scan. The bone marrow biopsy specimen showed normal findings. Endocrine tests revealed deficiences in corticotropin, gondatropin, and somatotropin
Sixty-four patients with biopsy-proven Langerhans' cell histiocytosis (LCH, formerly designated as histiocytosis X) were managed at the Children's Hospital of Philadelphia from 1970 through 1984. Their median age was 3 yr (range, 0.1–22 yr). Thirty-three patients had localized lesions affecting a bone (27) or soft-tissue region (6). Twenty-two patients had multifocal disease affecting bones (17) or soft, nonosseöüs tissues (5). None of these patients had evidence of dysfunction of liver or lungs, and none had abnormal peripheral blood cell counts. The remaining nine patients had multifocal LCH plus dysfunction of liver or lungs (6) or abnormal blood counts (3). Treatment consisted primarily of surgical excision for patients with localized lesions and of drug therapy with or without irradiation and surgery for those with multifocal disease. Recurrence was infrequent (7%) in those with localized LCH, and all survived. Recurrence was frequent (74%) in those with multifocal LCH but without organ dysfunction or abnormal blood counts, but 21 of the 22 survived. By contrast, only three of the nine patients with organ dysfunction or abnormal blood counts survived. Thus organ dysfunction and abnormal blood counts at diagnosis emerged as the major adverse prognostic factors in children with LCH.
In lifetesting, medical follow-up, and other fields the observation of the time of occurrence of the event of interest (called a death) may be prevented for some of the items of the sample by the previous occurrence of some other event (called a loss). Losses may be either accidental or controlled, the latter resulting from a decision to terminate certain observations. In either case it is usually assumed in this paper that the lifetime (age at death) is independent of the potential loss time; in practice this assumption deserves careful scrutiny. Despite the resulting incompleteness of the data, it is desired to estimate the proportion P(t) of items in the population whose lifetimes would exceed t (in the absence of such losses), without making any assumption about the form of the function P(t). The observation for each item of a suitable initial event, marking the beginning of its lifetime, is presupposed.
For random samples of size N the product-limit (PL) estimate can be defined as follows: List and label the N observed lifetimes (whether to death or loss) in order of increasing magnitude, so that one has Then , where r assumes those values for which and for which measures the time to death. This estimate is the distribution, unrestricted as to form, which maximizes the likelihood of the observations.
Other estimates that are discussed are the actuarial estimates (which are also products, but with the number of factors usually reduced by grouping); and reduced-sample (RS) estimates, which require that losses not be accidental, so that the limits of observation (potential loss times) are known even for those items whose deaths are observed. When no losses occur at ages less than t the estimate of P(t) in all cases reduces to the usual binomial estimate, namely, the observed proportion of survivors.
The records of 70 patients presenting to this hospital since 1961 with histiocytosis X confirmed by biopsy examination have been reviewed. The patients were subdivided into three groups: group A, those under 2 years of age at diagnosis; group B, those between 2 and 5 years; and group C, those over 5 years. All eight patients who died (11% overall mortality) were under 2 years of age at diagnosis. Involvement of lung, liver, and bone marrow were confirmed as poor prognostic features. The presence of bone disease and absence of skin rash were identified as favourable features.
• Despite an extensive literature, histiocytosis X is still a poorly understood disease and the origin remains unknown. To study the impact of recent therapeutic and diagnostic advances on this disease, 28 cases of histiocytosis X treated at Childrens Hospital of Los Angeles, Calif, from 1976 through 1987 were reviewed. A classification system was developed that accurately described the clinical outcome in our patients. Type patients (n=7) had monostotic disease, and type 2 patients (n=15) had multiple tissue sites other than the viscera. The latter type was further divided into types 2A and 2B, depending on whether lesions were solely osseous (type 2A [n=8]) or if soft-tissue sites were involved (type 2B [n=7]). Type 3 patients (n=6) had disseminated disease at the time of presentation, as defined by visceral involvement other than the liver. Type 1 patients were usually treated by surgical curettage alone and had an excellent prognosis. Type 2A patients required either surgery or radiation for symptomatic lesions. Type 2B patients were treated similarly. In addition, Type 2B patients received chemotherapy, a practice that is intensively debated in the literature. All the Type 2 patients survived with varying morbidity. Type 3 patients were all treated with chemotherapy but none of them survived. The majority of patients with histiocytosis X had otolaryngologic manifestations ranging from bony lesions to infectious complications. To conclude, the term histiocytosis X should be maintained to describe a spectrum of diseases. A simple classification system with three divisions gives reliable prognostic and therapeutic guidelines.
(Arch Otolaryngol Head Neck Surg. 1992;118:945-948)
Langerhans cell histiocytosis (LCH) embraces disorders characterized by the presence of marrow-derived abnormal Langerhans cells. A small number of patients with multisystem disease, vital organ dysfunction and rapid disease progression are considered to have a poor prognosis despite various treatments. Antiproliferative and immunosuppressive therapy, in combination with marrow transplantation, could be the appropriate treatment for these poor-prognostic patients. Four patients with progressive LCH were treated with high dose chemotherapy and fractionated total body irradiation followed by either an allogeneic (n = 2) or autologous (n = 2) marrow graft. Two of them are alive and have been disease free for almost 2 and 4 years after marrow grafting, respectively. One of the two survivors is the recipient of an allogeneic and the other of an autologous marrow graft. Two patients died, one of intrapulmonary hemorrhage 14 days after transplantation with active disease at autopsy, and the other of relapse of the original disease 355 days after marrow grafting. For patients with multisystem progressive LCH, allogeneic and autologous marrow transplantation may offer an opportunity for long-term remission and disease-free survival.
This report describes a case of multi-focal histiocytosis X of bone in two adjacent vertebrae that caused a spinal cord compression. This case was treated radically with combined surgery and postoperative radiotherapy (RT).
Hypothalamic-pituitary radiation therapy has been the standard treatment for the diabetes insipidus of Langerhans cell histiocytosis. The goal of this study was to assess the role of radiation therapy in Langerhans cell histiocytosis-associated diabetes insipidus and to compare the results with nonirradiated controls. Forty-seven patients with pathologically confirmed Langerhans cell histiocytosis were diagnosed with diabetes insipidus between 1950 and 1989 and were treated at the Mayo Clinic. These patients were divided into two groups on the basis of treatment for the diabetes insipidus: The first group (radiation group) included 30 patients (28 of whom were evaluable for response) who received hypothalamic-pituitary radiation therapy, and the second group (control group) included 17 patients who did not. A partial response to treatment was defined as a reduction in vasopressin dosage or improvement in computed tomography (CT) or magnetic resonance imaging (MRI). A complete response was defined as no further need for vasopressin therapy or normalization of CT or MRI. End points analyzed included treatment response, patient characteristics, morbidity, dose-response relationship, and survival. Patient characteristics of the two groups were similar except for age and lung involvement, both of which were significantly less in the radiation group. Thirty-six percent of patients (10 of 28) in the radiation group responded to hypothalamic-pituitary radiation therapy (22% complete response and 14% partial response), whereas none in the control group responded. Five of the six complete responders were irradiated within 14 days of the diagnosis of diabetes insipidus. The mean dose used in the responding and nonresponding patients was 11.2 and 10 Gy, respectively. Three of five patients (60%) treated with more than 15 Gy responded compared to seven of 23 (30%) treated with less than 15 Gy. Eight of the 10 responders (80%), compared to 16 of 35 nonresponders (46%), were female. Only one in 20 patients with concomitant lung histiocytosis responded. Complications of therapy may include insufficiency in other hypothalamic-pituitary axes in the treated patients. Actuarial survivals at 5, 10, 20, and 40 years for the entire group were 80%, 78%, 75%, and 65%, respectively, with a median follow-up in living patients of 14.7 years.
In Langerhans' cell histiocytosis, the prognostic significance of pulmonary disease is controversial. The clinical and radiological features and lung function tests of Langerhans' cell histiocytosis patients presenting to a single tertiary referral center between 1981 and 1987 were reviewed. Age at diagnosis ranged from 2 weeks to 16 years (median 1.7 years) and the male-female ratio was 2.4:1. No child presented with lung involvement alone. In 18 (40%) of 45 patients with multisystem disease there was clinical and/or radiological evidence of lung pathology. Another 6 children (13%) with normal chest roentgenograms had abnormal lung function tests, suggesting subclinical ("occult") involvement. Those with overt lung disease tended to present at a younger than average age (median 0.6 years). The most common functional disturbance was reduced lung or respiratory compliance with reduced lung volumes. Patients with and without lung involvement showed a similar pattern of involvement of other organs, with skin and bone most commonly affected. Of the 45 children with multisystem disease, 38 (84%) survived 2 to 7 years after diagnosis; there was a similar proportion of deaths in children with and without lung involvement. It is concluded that lung involvement occurs in nearly half of young children with multisystem Langerhans' cell histiocytosis but does not adversely affect outcome.
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.
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.
Three cases of juvenile chronic myeloid leukemia (JCML) are reported. The patients were aged 3-4.5 years and presented with generalized lymphadenopathy, hepatosplenomegaly, anemia, thrombocytopenia, elevated white blood cell count with monocytosis, and high fetal hemoglobin level. Philadelphia chromosome was absent in two cases studied. The bone marrow showed myeloid hyperplasia with increased monocytoid cells and blasts. Biopsy or postmortem material available in two cases revealed malignant infiltration of lymph nodes, liver, spleen, lungs, intestines, and skin. The neoplastic cells ranged from cells with irregular nuclei possessing nuclear grooves to large blastic cells with round to lobulated nuclei and prominent nucleoli. They showed weak staining for acid phosphatase and nonspecific esterase and exhibited the immunophenotype EBM11+KiM1+KiM6+KiM8+CD4+HLADR+ S-100 protein+. The neoplastic cells of JCML therefore share features of dendritic cells and mononuclear phagocytes. The authors' findings show that JCML is a unique histiocytic malignancy in which S-100 protein is a useful marker.
Histiocytosis X is a complex and poorly understood entity. Nevertheless, it would appear as if certain themes are found recurrently throughout the literature dealing with this disease and a review of them serves as a useful summary. 1. Problems with Nomenclature. To name or categorize a disease based on end-organ pathology is generally not clinically useful, but this is what we have done with histiocytosis X. It has caused substantial confusion among physicians and patients alike concerning diagnosis, prognosis, and treatment. Further attempts at improving the nosology of this disease will not be useful unless those new names also reflect scientific advances in our understanding of etiology, pathogenesis, and therapy. 2. Identification of the Langerhans' Cell as the Consistent Pathognomonic Cell in the Lesions of Histiocytosis X. Although the Langerhans' cell was identified more than a century ago, it has only recently been recognized as the cell that proliferates in this disease. Nevertheless, several important questions remain regarding the relationship of the Langerhans' cell to histiocytosis. Foremost among these questions is whether the Langerhans' cell is a truly normal Langerhans' cell, responding appropriately to immune system signals, or if it is an abnormal variant, possibly even neoplastic. 3. Recognition that Immune System Dysfunction Is a Critical Part of Histiocytosis X. The immune system is the focus of most recent clinical research. Results of these studies are obviously important with regard to both the biology and management of this disease. 4. Histiocytosis X Is an Extremely Heterogeneous Clinical Disorder. As mentioned before, the term histiocytosis X was originally intended by Lichtenstein to describe a pathologic, and not clinical, entity. It is rare to find two patients with this disease who are exactly alike. To make matters even more confusing, the disease includes both infants with disseminated fatal disease as well as middle-aged adults with solitary bony lesions. 5. The Disease Requires Improved Therapy, but it Is a Difficult Setting in which to Perform Clinical Studies. Improved therapy is required in patients with this disease, especially those with the disseminated form. But it will be difficult to develop improved therapy until definitive answers are provided to some of the basic questions of etiology and pathogenesis. Unfortunately, these clinical studies are not readily available because of the rare occurrence of this disease and its extreme clinical heterogeneity.(ABSTRACT TRUNCATED AT 400 WORDS)
This article has no abstract; the first 100 words appear below.
Nearly a century has passed since Alfred Hand reported a case of "polyuria and tuberculosis,"¹ later considered to be the first case of the Hand-Schül1er–Christian syndrome. Although early investigators considered this syndrome pathologically distinct from Letterer–Siwe disease, the later recognition of eosinophilic granuloma of bone as part of the same spectrum led Lichtenstein to propose the pathologically inclusive term "histiocytosis X" for the varying clinical manifestations.² Modern pathological techniques have revealed the identity of the offending cell, and we can now call this disorder by its proper name, Langerhans cell histiocytosis.³ The Langerhans cell is a dendritic cell derived from . . .
Diane M. Komp, M.D.
Yale University School of Medicine New Haven, CT 06510
Histiocytoses represent a large, puzzling group of rare skin diseases. The purpose of this review is to schematically outline the clinical, histologic, and ultrastructural features of the most important histiocytic syndromes and to provide the pertinent differential diagnoses. For convenience, we have followed the criterion suggested by Winkelmann, distinguishing these conditions into X and non-X. Among the non-X histiocytoses the self-healing forms have been treated first; the progressive forms follow.
The term histiocyte refers to cells of either the macrophage or Langerhans cell lineages. The histiocytic disorders are characterized by the proliferation of cells of these lineages. With recent advances in knowledge of the developmental biology of histiocytic cells, it is now possible to formulate a reasonable catalogue of histiocytic diseases based on ultra-structural and phenotypic markers of cellular origins and molecular or chromosomal markers of malignancy. The catalogue includes the following groups of diseases. Nonmalignant reactive macrophage disorders include (1) macrophage storage diseases, (2) several benign proliferative macrophage disorders that predominantly involve skin and bone, and (3) several hemophagocytic syndromes that vary from indolent and benign to fulminant and fatal. In some of the latter disorders, viruses have been identified as the inciting stimulus. The malignant macrophage disorders include (1) acute monocytic leukemia and (2) chronic myelomonocytic leukemia. A rare disorder that gave rise to a permanent cell line with an anomaly of chromosomal segment 5q35 may also be an example of a histiocytic malignancy. The existence of a separate category of true histiocytic lymphoma of macrophage type is uncertain. Reactive Langerhans cell disorders include (1) congenital self-healing histiocytosis, (2) the many variants of eosinophilic granuloma, and (3) a related disorder designated as relapsing Langerhans cell histiocytosis that is characterized by a relapsing course and infiltration of bone and soft tissues by Langerhans cells. Presumptively neoplastic diseases of Langerhans and dendritic cells include (1) progressive Langerhans cell histiocytosis, a disease with prominent involvement of blood and BM as well as skin and viscera; (2) Langerhans cell lymphoma, and (3) dendritic cell lymphoma. However, clonality as a marker of malignancy has not been proven in these disorders.
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.
The lesions of Langerhans'-cell histiocytosis (histiocytosis X), a proliferative histiocytic disorder of unknown cause, contain histiocytes similar in phenotype to dendritic Langerhans' cells. The disease ranges in severity from a fatal leukemia-like disorder to an isolated lytic lesion of bone. Intermediate forms of the disease are usually characterized by multiorgan involvement, diabetes insipidus, and a chronic course.
To determine whether Langerhans' histiocytosis is a polyclonal reactive disease or a clonal disorder, we used X-linked polymorphic DNA probes (HUMARA, PGK, M27 beta[DXS255], and HPRT) to assess clonality in lesional tissues and control leukocytes from 10 female patients with various forms of the disease. Lymphoid clonality was also assessed by analysis of rearrangements at immunoglobulin and T-cell-receptor gene loci.
The HUMARA assay detected clonal cells in the lesions of 9 of the 10 patients: 3 patients had acute disseminated disease, 3 had unifocal disease, and 3 had intermediate forms. The percentage of clonal cells closely approximated the percentage of CD1a-positive histiocytes in each lesion. Clonality was also confirmed in two of nine cases with the PGK or M27 beta probe. Extreme constitutional lyonization precluded assessment of clonality in the 10th case. Lymphoid clonality was ruled out in all cases.
The detection of clonal histiocytes in all forms of Langerhans'-cell histiocytosis indicates that this disease is probably a clonal neoplastic disorder with highly variable biologic behavior. Thus, genetic mutations that promote clonal expansion of Langerhans' cells or their precursors may now be identified.
Fifty-two pediatric patients with Langerhans cell histiocytosis (LCH) were diagnosed at the Emma Kinderziekenhuis (EKZ) in Amsterdam over a 20-year period. Eight patients with multiorgan involvement with organ dysfunction and ten patients with multi-organ involvement without organ dysfunction received chemotherapy containing cytosine-arabinoside, vincristine, and prednisolone as part of their treatment. Five of the 8 patients (63%) with organ dysfunction and eight of the 10 (80%) without the organ dysfunction who needed chemotherapy because of the deteriorating of symptoms despite conventional therapy are presently in complete clinical remission. Two of those with organ dysfunction have died. Four of the total 18 patients developed diabetes insipidus either as an initial symptom or during the course of the disease. These results in both groups compare satisfactorily with other chemotherapeutic regimens, and since this combination is only mildly toxic, it has been well tolerated. Therefore we would recommend wider experience using this regimen in patients with widespread LCH with organ dysfunction as well as in patients with disseminated LCH in which chemotherapy proved to be necessary.
The first case of secondary leukemia (FAB M3 microgranular variant) after single-agent chemotherapy with etoposide is described. The peculiar morphology and the absence of previously described cytogenetic abnormalities make this case of interest and emphasize the need for further study of epipodophyllotoxin-related leukemia.
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