Langerhans Cell Histiocytosis Research Articles

Successful treatment of orbital Langerhans cell histiocytosis with stereotactic radiosurgery: A case report and literature review

Key Clinical MessageLangerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasm arising from the proliferation of pathologic Langerhans cells. LCH has a spectrum of presentations predominantly affecting male pediatric patients. As LCH is a relatively uncommon diagnosis, there is no standard of care for treatment of the disease and treatment is based largely on clinical judgment, lesion characteristics, and symptoms at presentation. Here we present a case of unifocal, isolated orbital LCH in a 19‐year‐old young man treated initially with surgical resection. Follow‐up imaging 2 months later demonstrated significant regrowth of the mass and no other sites of disease. The recurrent orbital disease was treated with stereotactic radiosurgery (SRS) to 7 Gy in one fraction. Near complete resolution of the mass was achieved with no recurrence after 1.5 years of follow‐up. SRS for treatment of orbital LCH is a novel treatment not previously described in the literature which may provide benefit in select cases.

Disseminated langerhans cell histiocytosis presenting as decompensated childhood cirrhosis

Childhood cirrhosis is a rare disease of multifactorial etiopathogenesis. One of the rare underlying causes is Langerhans cell histiocytosis (LCH). The multifocal multisystemic variant of LCH can rarely involve the hepatobiliary system. Indirect and direct forms of hepatobiliary involvement are known. Early diagnosis of underlying liver involvement in cases of LCH is crucial to prevent decompensation and ameliorate prognosis post-liver transplantation. This is a case of an 18-month-old male child who developed cutaneous lesions in the early infancy. He was brought to clinical attention due to progressively increasing abdominal girth. His laboratory, clinical and radiological examination suggested multisystem pathology, subsequently confirmed on biopsy as LCH with predominant involvement of hepatobiliary, pulmonary, and integumentary systems. Unfortunately, he succumbed within a week of diagnosis.

NEUROHISTIOCYTOSIS: TWO CASES OF A RARE DISEASE

Histiocytosis is a rare systemic disease, with heterogeneous and diverse clinical and radiological presentations. Diagnosis can therefore be intriguing. Several consensus recommendations have emerged in recent years, particularly with the advent of targeted therapies, changing the management and prognosis. The authors present two cases of neurohistiocytosis. The case of Langerhans cell histiocytosis was about an adolescent with polyuria-polydipsic syndrome in whom a cerebellar biopsy was inconclusive. The patient was lost to follow-up for one year and then returned with a multisystemic neurological, bone, and dermatological presentation. The diagnosis was confirmed based on skin biopsy results. The patients condition rapidly deteriorated after chemotherapy with vinblastine and corticosteroids, leading to his death. The case of Erdheim-Chester disease was about a 53-year-old man who presented with cerebellar syndrome. His biological and radiological workup showed neurological, endocrine (diabetes insipidus) renal (hairy kidney), and bone (fibrosis) involvement. The diagnosis was confirmed by femoral biopsy and the patient was treated with Cladribine with an excellent evolution with an 18-month follow-up. This manuscript aims to report our personal experience and underline the entitys heterogeneity, non-specificity, and repercussions.

Palatal manifestations of Langerhan cell histicytosis in pediatric age: a case report with review of literature

Langerhans cell histiocytosis (LCH) is characterised by multisystem disorder with various entities grouped together under same name. Oral cavity manifestations of this disease is yet to be explored. In oral cavity it can present with ulceration, swelling or osteolysis of underlying bone. Oral cavity involvement due to LCH might confuse the examining doctor resulting in misdiagnosis of such dreadful disease. So here we are reporting a case of LCH in a 4 years old female presented to us with ulceration over hard palate mucosa. Biopsy was taken from the ulcer site which was positive for LCH. On further examination and evaluation of the patient multisystem involvement was found with involvement of skull bone.

A childhood secondary headache case associated with Langerhans cell histiocytosis

Neurological involvement is very rare in patients with a diagnosis of Langerhans Cell Histiocytosis (LCH). During the course of the disease, headache can also be seen in addition to systemic effects. A 6 years old girl was admitted to the hospital with only a headache without any systemic symptoms and was diagnosed with LCH. Magnetic resonance imaging showed a solid mass extending from the sphenoid bone corpus to the left great wing of the sphenoid, left orbital apex, left posterior ethmoid cells, left cavernous sinus, and dural space. The correct decision for neuroimaging in patients with headaches is very important in terms of mortality and morbidity. We wanted to share our patient’s case who was diagnosed with LCH by presenting only with headache without any other systemic finding, to remind that LCH may be a secondary cause of headache.

Neurological Manifestations of Histiocytic Disorders.

Histiocytic disorders, including Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH), and Rosai-Dorfman disease (RDD), are rare neoplasms that may present with a spectrum of neurologic involvement. Diagnostic delay is common due to heterogeneity in presentation and challenging pathology. Recent advances in the treatment of these diseases targeted towards mutations in the MAP kinase pathway have led to an improved prognosis in these patients with neurologic involvement. It is critical for clinicians to have a high index of suspicion to allow for early targeted treatment and optimize neurologic outcomes. A systematic approach to diagnosis is presented in this article to allow for accurate diagnosis of these rare diseases.

Treatment of Langerhans Cell Histiocytosis and Histiocytic Disorders: A Focus on MAPK Pathway Inhibitors.

Histiocytic disorders are rare diseases defined by the clonal accumulation of a macrophage or dendritic cell origin. These disorders include Langerhans cell histiocytosis, Erdheim-Chester disease, juvenile xanthogranuloma, malignant histiocytoses, and Rosai-Dorfman-Destombes disease. These histiocytic disorders are a diverse group of disorders with different presentations, management, and prognosis. This review focuses on these histiocytic disorders and the role of pathological ERK signaling due to somatic mutations in the mitogen--activated protein kinase (MAPK)pathway. Over the last decade, there has been growing awareness of the MAPK pathway being a key driver in many histiocytic disorders, which has led to successful treatment with targeted therapies, in particular, BRAF inhibitors and MEK inhibitors.

Comparison of neuroimaging features of histiocytic neoplasms with central nervous system involvement: a retrospective study of 121 adult patients

ObjectivesTo compare neuroimaging characteristics of three types of histiocytoses, namely Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman disease (RDD), with central nervous system (CNS) involvement.MethodsA total of 121 adult patients with histiocytoses (77 LCH, 37 ECD, and 7 RDD) and CNS involvement were retrospectively included. Histiocytoses were diagnosed based on histopathological findings combined with suggestive clinical and imaging features. Brain and dedicated pituitary MRIs were systematically analyzed for tumorous, vascular, degenerative lesions, sinus, and orbital involvement and for hypothalamic pituitary axis involvement.ResultsEndocrine disorders, including diabetes insipidus and central hypogonadism, were more common in LCH patients than in ECD and RDD patients (p < 0.001). In LCH, tumorous lesions were mostly solitary (85.7%), located in the hypothalamic pituitary region (92.9%), and without peritumoral edema (92.9%), while in ECD and RDD, tumorous lesions were often multiple (ECD: 81.3%, RDD: 85.7%), their distribution was more widespread with meninges mostly involved (ECD: 75%, RDD: 71.4%), and they most likely presented with peritumoral edema (ECD: 50%, RDD: 57.1%; all p ≤ 0.020). Vascular involvement was an exclusive imaging characteristic of ECD (17.2%), which was not observed in LCH or RDD; this was also associated with a higher risk of death (p = 0.013, hazard ratio = 11.09).ConclusionThe typical characteristic of adult CNS-LCH was endocrine disorders with radiological findings limited to the hypothalamic pituitary axis. The pattern of multiple tumorous lesions with predominant involvement of meninges was the main manifestation of CNS-ECD and CNS-RDD, while vascular involvement was pathognomonic for ECD and associated with poor prognosis.Clinical relevance statementInvolvement of the hypothalamic-pituitary axis is the typical imaging characteristic of Langerhans cell histiocytosis. Multiple tumorous lesions, predominantly involving but not limited to meninges, occur in most Erdheim-Chester disease and Rosai-Dorfman disease patients. Vascular involvement occurs only in Erdheim-Chester disease patients.Key Points• The different distribution patterns of brain tumorous lesions can help differentiate among LCH, ECD, and RDD.• Vascular involvement was an exclusive imaging finding of ECD and was associated with high mortality.• Some cases with atypical imaging manifestations were reported to further expand the knowledge on these diseases.

Imaging Phenotypes and Evolution of Hepatic Langerhans Cell Histiocytosis on CT/MRI: A Retrospective Study of Clinical Cases and Literature Review.

(1) Background: pathological changes in hepatic Langerhans cell histiocytosis (LCH) have been observed; however, corresponding imaging findings can appear vague to physicians and radiologists. The present study aimed to comprehensively illustrate the imaging findings of hepatic LCH and to investigate the evolution of LCH-associated lesions. (2) Methods: LCH patients with liver involvement treated at our institution were retrospectively reviewed along with prior studies in PubMed. Initial and follow-up computed tomography (CT) and magnetic resonance imaging (MRI) were systematically reviewed, and three imaging phenotypes were created based on the lesion distribution pattern. Clinical features and prognoses were compared among the three phenotypes. Liver fibrosis was evaluated visually on T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC) values of the fibrotic areas were measured. Descriptive statistics and a comparative analysis were used to analyze the data. (3) Results: based on the lesion distribution pattern on CT/MRI scans, patients with liver involvement were categorized as the disseminated lesion phenotype, scattered lesion phenotype, and central periportal lesion phenotype. Patients with scattered lesion phenotype were typically adults, and only a few of them had hepatomegaly (npresent = 1, 1/6, 16.7%) and liver biochemical abnormalities (npresent = 2, 2/6, 33.3%); patients with central periportal lesion phenotype were typically young children, and hepatomegaly and biochemical abnormalities were more apparent in these patients than those with another phenotype; and those with the disseminated lesion phenotype were found in all age groups, and the lesions evolved rapidly on medical imaging. Follow-up MRI scans show more details and can better document the evolution of lesions than CT. T2-hypointense fibrotic changes, including the periportal halo sign (npresent = 2, 2/9, 22.2%), patchy liver parenchyma changes (npresent = 6, 6/9, 66.7%), and giant hepatic nodules close to the central portal vein (npresent = 1, 1/9, 11.1%), were found, while fibrotic changes were not observed in patients with the scattered lesion phenotype. The mean ADC value for the area of liver fibrosis in each patient was lower than the optimal cutoff for significant fibrosis (METAVIR Fibrosis Stage ≥ 2) in a previous study that assessed liver fibrosis in chronic viral hepatitis. (4) Conclusions: The infiltrative lesions and liver fibrosis of hepatic LCH can be well characterized on MRI scans with DWI. The evolution of these lesions was well demonstrated on follow-up MRI scans.

Lineage switching of the cellular distribution of BRAFV600E in multisystem Langerhans cell histiocytosis.

Most children with high-risk Langerhans cell histiocytosis (LCH) have BRAFV600E mutation. BRAFV600E alleles are detectable in myeloid mononuclear cells at diagnosis but it is not known if the cellular distribution of mutation evolves over time. Here, the profiles of 16 patients with high-risk disease were analyzed. Two received conventional salvage chemotherapy, 4 patients on inhibitors were tracked at intervals of 3 to 6 years, and 10 patients, also given inhibitors, were analyzed more than 2 years after diagnosis. In contrast to the patients responding to salvage chemotherapy who completely cleared BRAFV600E within 6 months, children who received inhibitors maintained high BRAFV600E alleles in their blood. At diagnosis, mutation was detected predominantly in monocytes and myeloid dendritic cells. With time, mutation switched to the T-cell compartment, which accounted for most of the mutational burden in peripheral blood mononuclear cells, more than 2 years from diagnosis (median, 85.4%; range, 44.5%-100%). The highest level of mutation occurred in naïve CD4+ T cells (median, 51.2%; range, 3.8%-93.5%). This study reveals an unexpected lineage switch of BRAFV600E mutation in high-risk LCH, which may influence monitoring strategies for the potential withdrawal of inhibitor treatment and has new implications for the pathogenesis of neurodegeneration, which occurred in 4 patients.

A case of langerhans cell histiocytosis with cholangitis

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How I Diagnose Rosai-Dorfman Disease.

Rosai-Dorfman disease (RDD) is one of 3 major types of histiocytosis, along with Erdheim-Chester disease and Langerhans cell histiocytosis. While historically, RDD was considered a benign self-limited condition, current data show MAPK/ERK pathway mutations in 30% to 50% of cases, indicative of a clonal process. Rosai-Dorfman disease was incorporated as a histiocytic neoplasm in the fifth edition of the World Health Organization classification of hematopoietic tumors and the International Consensus Classification. We discuss the diagnosis of RDD using 2 illustrative cases, interpretative challenges, and a diagnostic algorithm. Rosai-Dorfman disease involves nodal and extranodal sites, including skin, sinuses, salivary gland, orbit, central nervous system, kidney, and bone. In a subset, RDD can coexist with other neoplasms (lymphomas, other histiocytosis) or autoimmune disease. Morphologically, RDD histiocytes are characterized by enlarged round to oval nuclei, distinct nucleoli, and voluminous cytoplasm with engulfment of inflammatory cells (emperipolesis). By immunohistochemistry, they express CD68, CD163 (majority), S100, OCT2, and cyclin D1. Appropriate use of ancillary studies is important to support the diagnosis of RDD while excluding other histiocytic neoplasms and reactive histiocytic proliferations. Management of RDD is dependent on the extent of organ involvement and clinical symptoms. In patients who require therapy, next-generation sequencing is recommended to identify MAPK/ERK pathway mutations for targeted therapy.

Incidental Detection of Ilium Langerhans Cell Histiocytosis on 99mTc-DTPA Renal Dynamic Scintigraphy.

We report the case of a 24-year-old man who underwent 99mTc-DTPA scintigraphy for the evaluation the renal function. This scan incidentally showed an abnormal uptake of 99mTc-DTPA in the left lower abdominal region. SPECT/CT fusion images showed osteolytic bone destruction in the left ilium associated with soft tissue mass and elevated DTPA uptake. Biopsy pathology of the ilium lesion demonstrated Langerhans cell histiocytosis.

Langerhans Cell Histiocytosis in Children and Adults: Similarities and Differences

Langerhans cell histiocytosis is an uncommon hematological condition affecting children and adults. It is distinguished by neoplastic infiltration of myeloid dendritic cells and an inflammatory response. Any organ can become dysfunctional as a result of tissue destruction and fibrosis. In almost all cases, activating mutations in the MAPK signal transduction pathway have been found. The earlier these mutations appear during myeloid differentiation, the more severe the disease. The skeleton, skin, and pituitary gland are most typically afflicted in children, but the liver, spleen, and hematopoietic system may also be involved, associated with a worse outcome. In adults, manifestations are most commonly observed in the skeleton, lungs, skin, and in the pituitary region. The course of the disease might range from spontaneous remission to persistent relapse. A histological examination is required to get a definitive diagnosis. In youngsters, where therapeutic surgery and radiation are mostly obsolete, medical therapy is the treatment of choice. Chemotherapy is used when special risk lesions are involved or when children have multifocal skeletal involvement and multisystem disease. In adults, however, local treatments are sufficient in unifocal lesions, and supportive therapy with bisphosphonate is suitable for multifocal bone involvement. Systemic therapy is administered only in patients with multisystem disease and treatment-refractory or quickly reoccurring disease activity. Aside from cytostatics, targeted inhibitors of gene mutations are now accessible for this purpose. While most patients survive, chronic recurrent episodes and late sequelae are the main issues.

A patient with known Langerhans cell histiocytosis presents with polyuria and polydipsia

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

A rare cause of solitary rib lytic lesion in adult – A case report

Langerhans cell histiocytosis (LCH) is characterized by the proliferation of Langerhans cells, which can occur in single or multiple organ systems. The most common sites of involvement include skeletal system, central nervous system, lungs, skin, and lymph nodes. LCH involving the rib is one of the rarest site among adults. Herein, we report a case of a 40-year-old man with solitary LCH in posterior aspect of 4th rib.

Resolution of blood eosinophilia and limited mouth opening after short-term follow-up in a pediatric Langerhans cell histiocytosis case.

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia that often affects children, presenting a broad clinical spectrum. Here, we report a 13-year-old male Salvadorian patient who was referred presenting a nodular swelling at the mandibular angle region, mildly symptomatic, few weeks ago, which relevantly was associated with limited mouth opening. Intraoral examination was unremarkable. Imaginological exams revealed an osteolytic lesion affecting the vestibular cortex at the right mandibular angle. The blood test results were normal, except for eosinophilia (21%; absolute eosinophil count 4 × 109/L). After an incisional biopsy, microscopical and immunohistochemical analyses were consistent with LCH diagnosis, which corresponded to a single system-single site category. After a few weeks, the mandibular movements were re-established, and complete resolution of blood eosinophilia was observed. LCH with blood eosinophilia is rarely reported. To our knowledge, 3 cases have been previously published.

Thyroid fine needle aspiration for the diagnosis of Langerhans Cell Histiocytosis of the suprasellar region

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Focal bone tumors of mesenchymal origin

This paper will review the main features of focal lesions with a benign characteristic involving bone and with a mesenchymal origin. It includes bone cyst, fibrous dysplasia, osteofibrosus dysplasia, intraosseous lipoma, Langerhans cell histiocytosis and desmoplastic fibroma of bone; the latter according the WHO Classification of tumors of bone belong respectively to hematopoietic and fibrogenic lesions of bone. However, we included they in this paper for the overall benign nature of these lesions and the possible differential diagnosis.

Expression and Clinical Correlation of PD-1/PD-L1 and VE1(BRAFp.V600E) in Pediatric Langerhans Cell Histiocytosis.

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm with a wide spectrum of clinical presentations. Programmed Cell Death-1 (PD-1) receptor and its ligand (PD-L1) are overexpressed in LCH, but their clinical significance is unknown. We performed a clinical correlation study of PD-1/PD-L1 and VE1(BRAFp.V600E) expression in 131 children with LCH. A total of 111 samples were tested for PD-1/PD-L1 and 109 for VE1(BRAFp.V600E) mutant protein by immunohistochemistry. PD-1, PD-L1 and VE1(BRAFp.V600E) positivity was observed in 40.5%, 31.53% and 55%, respectively. PD-1/ PD-L1 expression showed no significant effect on the rate of disease reactivations, early response to therapy or late sequelae. The 5-year EFS was not statistically different between patients with PD-1 positive compared to those with PD-1 negative tumours (47.7% vs.58.8%, p=0.17). Similar 5-year EFS rates were also seen in those who were PD-L1 positive compared to PD-L1 negative cases (50.5% vs.55.5%, p=0.61). VE1(BRAFp.V600E) positivity was associated with a significantly higher frequency of risk-organ involvement (p=0.0053), but no significant effect on early response to therapy or rates of reactivations or late sequelae. Our study showed no significant correlation between VE1(BRAFp.V600E) expression, PD-1 and PD-L1 and clinical outcome in pediatric LCH.