Form Of Histiocytosis Research Articles

Letterer-Siwe disease presenting with gastrointestinal and cutaneous manifestations.

Histiocytosis is a set of distinct proliferative illnesses defined by the proliferation and infiltration of varied numbers of dendritic cells, macrophages, and monocytes in the afflicted tissues. The skin and other organs may be impacted by the inflammatory infiltration. It can occur at any age. The severity of the symptoms can range from mild to severe, depending on the degree and type of organ involvement. Although certain forms of histiocytosis can be fatal, others can be treated successfully without sequelae. Langerhans cell histiocytosis manifests itself clinically in both children and adults. A combination of clinical, histological, and radiological tests is required to achieve a diagnosis. A severe, multisystemic, acute form of Langerhans cell histiocytosis is called Letterer-Siewe illness, which usually affects infants in their first year of life. In this article, we provide a brief literature review and a case study of a 9-month-old girl who presented with recurring gastrointestinal problems as the first sign of Letterer-Siwe disease.

Phenotypic intrafamilial variability including H syndrome and Rosai\u2013Dorfman disease associated with the same c.1088G\u2009>\u2009A mutation in the SLC29A3 gene

BackgroundMutations in the SLC29A3 gene, which encodes the nucleoside transporter hENT3, have been implicated in syndromic forms of histiocytosis including H syndrome, pigmented hypertrichosis with insulin-dependent diabetes, Faisalabad histiocytosis and Familial Rosai–Dorfman disease (RDD). Herein, we report five new patients from a single family who present with phenotypes that associate features of H syndrome and Familial Rosai–Dorfman disease.MethodsWe investigated the clinical, biochemical, histopathological and molecular findings in five Tunisian family members' diagnosed with Familial RDD and/or H syndrome. The solute carrier family 29 (nucleoside transporters), member 3 (SLC29A3) gene was screened for molecular diagnosis using direct Sanger sequencing.ResultsGenetic analysis of all affected individuals revealed a previously reported missense mutation c.1088 G > A [p.Arg363Gln] in exon 6 of the SLC29A3 gene. Four affected members presented with clinical features consistent with the classical H syndrome phenotype. While their cousin’s features were in keeping with Familial Rosai–Dorfman disease diagnosis with a previously undescribed cutaneous RDD presenting as erythematous nodular plaques on the face. This report underlines the clinical variability of SLC29A3 disorders even with an identical mutation in the same family.ConclusionWe report a rare event of 5 Tunisian family members' found to be homozygous for SLC29A3 gene mutations but showing a different phenotype severity. Our study reveals that despite a single mutation, the clinical expression of the SLC29A3 disorders may be significantly heterogeneous suggesting a poor genotype–phenotype correlation for the disease.

Perplexing Polyuria Caused by a Rare Disorder

Background: Central diabetes insipidus is an uncommon condition characterized by polyuria and polydipsia. In adults, central diabetes insipidus is most commonly caused by a primary brain tumor, followed by idiopathic causes, head trauma, and neurosurgery. The presence of diabetes insipidus is often discovered prior to the underlying culprit and detection may reveal further pituitary dysfunction. Herein an unusual cause of central diabetes insipidus is presented. Case: A 35-year-old male was seen in consultation for polyuria. He initially presented with fevers, cloudy urine, and excess urine output. He indicated frequent water consumption, craving cold water and feeling persistently dehydrated with poor energy levels. During hospitalization, the patient had up to 9 liters of urine output daily, with low urine osmolality and intermittent hypernatremia. As patients’ labs were consistent with central diabetes insipidus a brain MRI was completed and showed a thickened enhancing infundibulum and some fullness of the right pituitary without a focal lesion noted, concerning for autoimmune or inflammatory hypophysitis. Other pituitary axes were evaluated, and patient was noted to have a low morning total testosterone and low IGF-1. Concurrently, the patient was discovered to have multiple bone lesions on an MRI abdomen and pelvis, which prompted a bone scan showing diffuse uptake in osseous structures. A PET scan was then obtained demonstrating mandibular uptake as well as hypermetabolic activity in both adrenal glands, the right iliac bone, bilateral femurs and humeri. Biopsy of the mandibular lesion was performed, and the specimen revealed chronic xanthogranulomatous and lymphocytic inflammation consistent with a diagnosis of Erdheim-Chester disease. The patient was discharged on desmopressin and a biologic agent for treatment of Erdheim-Chester disease. Clinical Lesson: Erdheim-Chester disease is a rare non-Langerhans histiocytic multisystem disorder that often presents with skeletal, neurologic, endocrine, cutaneous, cardiac and renal abnormalities. There is a slight male predominance of the disorder and diagnosis occurs between the 5th and 7th decade of life. Erdheim-Chester disease is a form of histiocytosis with a histologic hallmark of xanthomatous infiltration of tissues by CD68-positive foamy histiocytes. This case reflects the diagnostic delay often associated with the condition. Early identification is essential to organize a multidisciplinary team to ensure accurate diagnosis and to initiate appropriate therapy. Presently interferon-alpha is the first line treatment, but other biologics are often used and provide promising outcomes. The presented case highlights many of the idiosyncrasies associated with this rare disorder and calls attention to the possibility of Erdheim-Chester disease when an initial cause of central diabetes insipidus is not obvious.

Erdheim-Chester disease-A histiocytic multisystem disease with unusual renal involvement

Erdheim-Chester disease (ECD) is nowadays classified as belonging to those neoplasms with origins in the myeloid dendritic cell lines. The clonal alterations maintain achronic inflammatory condition, which dominates the pathogenesis and clinical expression. Characteristic for ECD are many skeletal manifestations; however, the multisystem disease affects many other organs (including the respiratory tract, heart, retroperitoneum, eyes, central nervous system and endocrine system). The diagnosis is usually first made only after adisease duration of many years. This is due to the rarity of the disease and the very diffuse symptoms in addition to the heterogeneous organ manifestations. There are no uniform diagnostic criteria. The constellation of unclear polyserositis and ostealgia, possibly in association with neurological and endocrine deficiencies, should steer the suspicion towards an ECD. The diagnosis can be confirmed by an organ biopsy and the immunohistochemical examination enables the relatively certain differentiation from other forms of histiocytosis. The detection of activating oncological mutations in signal transduction pathways has opened up the possibility of targeted treatment with kinase inhibitors, such as vemurafenib for BRAF V600E mutations. Up to the discovery of activating mutations, interferon-alpha was used as the first line treatment; however, in view of the superiority of kinase inhibitors, the first line treatment with interferon-alpha currently appears to be questionable. The prognosis for untreated ECD is exceptionally poor and interferon-alpha leads to aclear improvement. Further progress is hoped for with the use of targeted treatments.

Bone Scintigraphy in the Examining of Treatment-Naive Pediatric Patients With Langerhans Cell Histiocytosis

Introduction: Histiocytosis is a heterogeneous group of rare diseases of unknown etiology. LCH is characterized by an abnormal proliferation of histiocytes (activated dendric cells and macrophages). Langerhans cell histiocytosis (LCH) is the most common form of histiocytosis, it is a potentially fatal diseases. Early detection of LCH plays an important role in its prognosis and outcome. However, the role of advanced methods of nuclear medicine in diagnosis of LCH is still to be researched. We have long-term experience in observing pediatric patients with LCH. Taking into the account the difficulty of diagnostic task for bone scintigraphy in identifying lytic bone destruction, we stated the following objective of the study.Purpose: Retrospective and prospective analysis of bone scintigraphy examinations of treatment-naive pediatric patients with LCH and calculate the diagnostic efficacy of bone scintigraphy. Material and methods: We analyzed 60 examinations of treatment-naive pediatric patients with proven case of LCH (2014-2019). The scanning was performed using whole body mode, 3 hours after intravenous injection of bone-seeking radiopharmaceutical 99mTc-MDP on Symbia E, T2 (Siemens, Germany). The median age was 5.6 years.Results: During examination we visualized 88 lesions with pathological level of accumulation of radiopharmaceutical in 60 patients. 84 with high level of accumulation (>120 %); 3 with slightly increased level of accumulation (100–120 %) and 1 with lower than normal level of accumulation (<100 %). The median level of accumulation of radiopharmaceutical was 268 %. Max level of accumulation was 1422 % (patient with subtotal involvement of femoral bone). Min — 60 % (patient with lytic destruction in orbital bone). During X-Ray we found out 97 pathological focuses of bone lytic destruction. In 3 patients with polyostotic form we found extra focuses on scintigraphy, which were confirmed with following examination and X-Ray. 8 lesions were not found on scintigraphy in 8 patients.Сonclusions: We evaluated diagnostic accuracy of bone scintigraphy with 99mTc-MDP in treatment-naïve pediatric patients with proven case of LCH. Sensitivity, specificity, NPV and PPV — 91.6, 50.0, 11.1, 98.6 %, respectively.

Relevance of Bone Scintigraphy in the Diagnostic Algorithm for Examining Treatment-Naive Pediatric Patients with Langerhans Cell Histiocytosis: a Retrospective Cohort Study

Background. Histiocytosis is a heterogeneous group of rare diseases of unknown etiology. Langerhans cell histiocytosis (LCH) is characterized by an abnormal proliferation of histiocytes (activated dendric cells and macrophages). LCH is the most common form of histiocytosis, it is a potentially fatal diseases. Early detection of LCH plays an important role in its prognosis and outcome. However, the role of advanced methods of nuclear medicine in diagnosis of LCH is still to be researched. We have long-term experience in observing pediatric patients with LCH. Taking into the account the difficulty of diagnostic task for bone scintigraphy in identifying lytic bone destruction, we stated the following objective of the study. Objective. Our aim was to perform retrospective analysis of bone scintigraphy examinations of treatment-naive pediatric patients with LCH and calculate the diagnostic efficacy of bone scintigraphy. Methods. We retrospectively analyzed 55 examinations of treatment-naive pediatric patients (the median age was 5.9 years) with proven case of LCH (2014–2018). Results. During examination we visualized 82 lesions with pathological level of accumulation of radiopharmaceutical in 55 patients. 78 with high level of accumulation (>120%); 3 with slightly increased level of accumulation (100–120%) and 1 with lower than normal level of accumulation (<100%). The median level of accumulation of radiopharmaceutical was 276%: max. level of accumulation was 1422% (patient with subtotal involvement of femoral bone), min. — 60% (patient with lytic destruction in orbital bone). During X-Ray we found out 91 pathological focuses of bone lytic destruction. In 3 patients with polyostotic form we found extra focuses on scintigraphy, which were confirmed with following examination and X-Ray. 8 lesions were not found on scintigraphy in 8 patients. Сonclusion. Bone scintigraphy with 99mTc-MDP in treatment-naïve pediatric patients with proven case of LCH showed sensitivity — 91.0%, specificity — 50.0%, NPV — 11.1%, and PPV — 98.8%.

Clinical and positron emission tomography responses to long-term high-dose interferon-\u03b1 treatment among patients with Erdheim\u2013Chester disease

BackgroundErdheim–Chester disease (ECD) is a rare multi-systemic form of histiocytosis. Treatment with BRAF inhibitors has markedly improved outcomes of ECD; however, this targeted therapy is expensive (estimated annual cost is $50,000). Since estimated annual cost of interferon-α (IFN-α) is only approximately $1600 in China, we retrospectively evaluated the long-term therapeutic efficacy of IFN-α and the value of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) as an assessment method among 32 ECD patients who received high dose IFN-α therapy at Peking Union Medical College Hospital.ResultsThe median age at diagnosis was 48 years (range, 6–66 years). The median duration of treatment was 18.5 months (range, 1–51 months). The overall clinical response rates were 80.0%, including 33.3% complete response, 36.7% partial response and 10.0% stable disease. Thirty-one patients underwent a total of 81 scans by FDG-PET. Seventeen patients had serial FDG-PET results, nine patients had experienced a partial metabolic response at the last follow-up. The median reduction of ratios between the most active target lesion standardized uptake value (SUV) and liver SUV from baseline to last FDG-PET scan was 61.4% (range, 8.8–86.6%). Eight of thirteen patients who experienced continuous clinical improvement during follow-up had at least one target lesion SUV increased by FDG-PET which decreased in subsequent scans without changing treatment strategy. The estimated 3-year progression-free survival (PFS) and overall survival (OS) were 64.1 and 84.5%, respectively. Central nervous system (CNS) involvement was the only predictor for poor PFS and OS.ConclusionsHigh-dose IFN-α treatment is a cost-effective option, especially for patients without CNS involvement. Single target lesion SUV elevation according to FDG-PET do not accurately demonstrate disease progression, but serial FDG-PET imaging effectively discriminate treatment response.

Histiocytic diseases in childhood and adolescence

Histiocytic diseases are generally rare with a variable clinical course and variable morphology which often have a peak frequency of occurrence in childhood and adolescence. Histiocytoses are subdivided into Langerhans cell histiocytosis and the so-called non-Langerhans cell histiocytosis, such as juvenile xanthogranuloma, Erdheim-Chester disease and Rosai-Dorfman disease. The most common forms of histiocytosis in childhood are Langerhans cell histiocytosis and juvenile xanthogranuloma. In contrast, forms of histiocytosis which occur more frequently in adulthood, such as Erdheim-Chester disease and Rosai-Dorfman disease are rare in childhood. Some forms of histiocytosis harbor BRAFv600E mutations. In Langerhans cell histiocytosis they have been found in 50-55 % of the cases examined and in Erdheim-Chester disease in up to 100 % of cases. In the remaining forms of histiocytosis (especially juvenile xanthogranuloma and Rosai-Dorfman disease) BRAF mutations could not be detected. A prognostic relevance could not be shown so far; however, in individual cases a mutation analysis of BRAF could provide help in the differential diagnostic considerations or the option of a therapy approach with BRAF inhibitors.

Rosai-dorfman disease with cervical lymphadenopathy and orbital involvement: a case report

Rosai-Dorfman disease (RDD), which is also called as sinus histiocytosis with massive lymphadenopathy (SHML), is a rare histiocytic disorder which occurs due to the over-production of non Langerhans sinus histiocytes. It is a nonmalignant disorder that most frequently affects children and young adults and typically presents with fever, night sweats, nonpainful cervical lymphadenopathy, leukocytosis and an elevated ESR. Extranodal involvement may also occur, thus a variety of organs in the body can be affected. Although some viral etiology has been implicated, the disease generally is considered to have an unknown cause. RDD can often be misdiagnosed as lymphoma, leukemia or tuberculosis, so it is imperative to distinguish it from these conditions as well as other forms of histiocytosis because of difference in the modes of treatment. Diagnosis of Rosai-Dorfman disease is based on biopsy of affected tissue. Biopsy showing the presence of emperipolesis, or the engulfment of lymphocytes and other immune cells by histiocytes that express S-100 antigen is diagnostic of Rosai-Dorfman disease. Once diagnosed, further workup including imaging studies are undertaken in order to determine the extent of the disease. In majority of cases, the disease resolves on its own however, treatments including corticosteroids, chemotherapy, surgical treatment or radiotherapy are carried out in severe or persistent disease or when organ function is at stake (e.g. breathing obstruction, kidney failure, visual problems). The case we report is that of a 16 year old girl who presented with a 6 month history of gradual onset drooping of left upper eyelid with mild proptosis of the left eye alongwith mild drooping of right upper eyelid, low grade fever, night sweats and cervical lymphadenopathy. Blood workup showed increased ESR, CT scan of orbits showed superior orbital masses and diagnostic biopsy revealed Rosai-Dorfman disease.

Heterogeneity in a mouse model of histiocytosis: transformation of Langerin+ dendritic cells, macrophages, and precursors

Neoplastic diseases of macrophages (M phi) and dendritic cells (DC), collectively called histiocytoses, are relatively rare. The etiology of most forms of histiocytosis is poorly understood, and the development of animal models is crucial for further research in this field. Previously, an animal model for malignant histiocytosis (MH), involving transformed histiocytic cells, has been generated by infecting mice with malignant histiocytosis sarcoma virus (MHSV). However, increased insight into the heterogeneity of M phi and DC, and the associated reappraisal of human proliferative diseases involving these cells inspired us to re-evaluate the mouse model. We analyzed spleen, bone marrow, and lymph nodes of susceptible mice at various time points after infection. From day 11 onwards, a heterogeneous population of cells, consisting of CD8 alpha(+) Langerin(+) DC, ER-MP58(+) CD11b(+) myeloid precursor cells, CD169(+) metallophilic M phi, and CD71(hi) erythroblasts, was affected by viral transformation. In different mice, these subsets expanded at different rates in different organs, causing a variable disease profile in terminal stages. Cell lines, which were generated from MHSV-transformed tumors, showed a DC-like morphology and phenotype, and appeared to be arrested in different stages of maturation. Upon injection into healthy mice, different preferential homing patterns were observed for the various cell lines, and the cells acquired distinct phenotypes depending on the organ of homing. This indicates that these transformed cells adapt to their microenvironment by switching between precursor, DC/Langerhans cell, and M phi phenotypes. Our results demonstrate that the MHSV model represents a heterogeneous neoplastic disease with characteristics of M phi/DC sarcomas.

Cytologic evaluation of benign and malignant hemophagocytic disorders in canine bone marrow.

Canine hemophagocytic disorders were studied to better understand the cytologic features that differentiate benign and malignant disease. Of 286 canine clinical bone marrow reports evaluated retrospectively, 13 (4.5%) noted at least 3% hemophagocytic macrophages. Macrophages comprised between 6% and 44% of nucleated bone marrow cells. Clinical diagnoses for dogs with hemophagocytic disorders included malignant histiocytosis (n = 2), myelodysplastic syndromes (n = 4), round cell neoplasia (n = 2), immune-mediated disorders (n = 2), and idiopathic hemophagocytic syndrome (n = 3). Differentiation of benign and malignant forms of histiocytosis was problematic. Two dogs with a diagnosis of hemophagocytic syndrome had macrophages with atypical features similar to those described for malignant histiocytosis. Furthermore, only 2 of 11 dogs with presumably benign hemophagocytic disorders had exclusively mature macrophages in bone marrow. Other dogs had variable numbers of large reticular-type cells characterized by lacy chromatin, anisocytosis, anisokaryosis, and prominent and/or multiple nucleoli. On the basis of these results, cytomorphologic evaluation of bone marrow alone may not be adequate to consistently differentiate benign and malignant forms of hemophagocytic disorders.

Erdheim-Chester disease: a bilateral orbital mass as an indication of systemic disease

A case of bilateral orbital mass and xanthelasma of the eyelids is presented. Histology confirmed it to be a form of histiocytosis, possibly an Erdheim-Chester disease. This was further confirmed by the presence of a retroperitoneal mass and hydronephrosis, which resolved with treatment. A review of the literature on and pathological features of this rare fatal disease is presented.

A case of histiocytic medullary reticulosis complicated with x-ray-irradiated oral cancer

We report the case of a patient in whom oral squamous cell carcinoma and a fatal reactive form of histiocytosis were simultaneously manifested. Our conclusions indicate that such a hematophagocytic syndrome may occur in the setting of oral squamous cell carcinoma as previously described in other malignancies.