A Diagnostic Dilemma and Classification Conundrum: Atypical Histiocytic Neoplasm Presenting as a Calvarial Mass.

Histiocytic disorders are a wide range of disorders arising from abnormal proliferation and infiltration of dendritic cells. The Histiocyte Society has arranged the disorders into five main groups: L, C, M, R, and H. We present a case in which an elderly woman presented with a solitary osseous lesion in her skull in the right anterior calvarium. Biopsy and histological studies were strongly positive for cyclin D1; positive for CD68, S100, and ZBTB46; weakly positive for OCT2; and equivocal for ALK1 and CD163. Genomic studies also identified KRAS and GPS2 mutations. KRAS-positive genomic analysis favors a diagnosis of histiocytoma, while the solitary calvarium and spontaneous resolution with remission favor a diagnosis of Langerhans cell histiocytosis (LHC). Despite the strong clinical evidence favoring LCH, our patient's clinical and histologic features did not fit any of the five histiocytic categories and were classified as an atypical histiocytic disorder.

Enfermedad de Rosai-Dorfman cutánea, reporte de un caso / Cutaneous Rosai-Dorfman disease, a case report

RESUMEN La enfermedad de Rosai-Dorfman cutánea (ERDC) es una rara proliferación reactiva de histiocitos, que cursa con lesiones cutáneas sin compromiso generalizado. Las manifestaciones clínicas cutáneas son diversas y la variante clínica "tipo tumoración" es la forma más infrecuente. Se describe el caso de un paciente con ERDC que se presentó con esta forma inusual.

ABSTRACT Cutaneous Rosai-Dorfman disease (CRDD) is a rare reactive histiocytic proliferation, which presents with skin lesions without systemic involvement. The clinical cutaneous manifestations are diverse and the "tumor-like" clinical variant is the most infrequent. We describe the case of a patient with CRDD who presented with this unusual form.

Clinical and pathological evaluation of cladribine treatment response in a case series of patients with xanthoma disseminatum.

BACKGROUND: Xanthoma disseminatum (XD) is a rare form of non-Langerhans histiocytosis with extensive cutaneous involvement. There is a paucity of evidence-based recommendations for treatment decision-making. Previous case reports have established purine analogues, especially cladribine, as a hopeful first-line treatment option, but characterization of the clinical and pathological responses is lacking. OBJECTIVES: To characterize the clinical and pathological responses to cladribine monotherapy based on serial examinations in XD patients. MATERIALS & METHODS: We retrospectively studied the clinical, pathological and laboratory data in a cohort of five XD patients who received intravenous cladribine monotherapy with serial examinations in our hospital. Compared with baseline characteristics, changes in clinical features and pathological patterns were identified and analysed. We also conducted a literature review of reported cases of cladribine treatment in XD patients. RESULTS: Four male and one female patient were involved in the study. All patients demonstrated satisfactory clinical responses to cladribine monotherapy after 5 to 10 cycles. We observed a pathological shift in pattern from classic xanthogranuloma to transitional fibrohistiocytic infiltration during the treatment, and pathological responses heralded persistent clinical improvement. Other than afebrile neutropenia, no prominent adverse events were identified. Sustainable lesion clearance was achieved in all five patients during the follow-up period, ranging from 19 to 66 months. CONCLUSION: Cladribine monotherapy is an effective and well-tolerated therapeutic option for XD patients. Pathological transformation is a signature of the clinical response and possibly unveils the underlying histiocyte biology of diseases in the xanthogranuloma family.

Imaging features of juvenile xanthogranuloma.

BACKGROUND: Juvenile xanthogranuloma is rare in children and there are limited data on its imaging features. OBJECTIVE: To analyze the computed tomography (CT) and magnetic resonance imaging (MRI) features of juvenile xanthogranuloma in children. MATERIALS AND METHODS: A retrospective review was performed of clinical and radiographic data of histologically confirmed juvenile xanthogranuloma between January 2009 and June 2020. RESULTS: Fourteen children (4 girls, 10 boys; age range: 1 day to 13 years, mean age: 73 months) were included in the study: 4/14 had CT only, 5/14 had MRI only and 5/14 had CT and MRI. Sites of extracutaneous juvenile xanthogranuloma involvement included subcutaneous soft tissue (8/14), liver (2/14), lungs (2/14), kidney (2/14), nose (2/14), pancreas (1/14), central nervous system (1/14) and greater omentum (1/14), mainly manifested as single or multiple nodules or masses in different organs. On CT, the lesions mainly manifested as an iso-hypo density mass with mild or marked enhancement. On MRI, the lesions mainly manifested as slightly hyperintense on T1 and slightly hypointense on T2, with decreased diffusivity and homogeneous enhancement. Juvenile xanthogranuloma was not included in the imaging differential diagnosis in any case. CONCLUSION: Juvenile xanthogranuloma mainly manifests as single or multiple nodules or masses in different organs. Slight hyperintensity on T1 and slight hypointensity on T2 with decreased diffusivity and homogeneous enhancement are relatively characteristic imaging findings of juvenile xanthogranuloma. Combined with its typical skin lesions and imaging features, radiologists should include juvenile xanthogranuloma in the differential diagnosis when confronted with similar cases.

A Rare Case of Combined Langerhans Cell Histiocytosis and Adult-Onset Xanthogranuloma: A Case Report.

Langerhans cell histiocytosis (LCH) and adult-onset xanthogranuloma (AXG) are rare disorders characterized by the accumulation of macrophage, dendritic cells, or monocyte-derived cells in various tissues of the body. Many researchers now consider LCH a form of malignancy, but this classification remains controversial. As per our knowledge, there are only 36 cases of AXG reported so far in the English literature. Here, we report a case of AXG and single-system LCH found in the oral cavity and cervical lymph nodes, respectively. In this article, we intend to define a clear understanding of some classic clinical, radiological, and histopathological findings of LCH and AXG, to differentiate them from oral malignancies. The primary goal of this article is to increase awareness regarding conditions that closely resemble malignancies and to save patients from the burden of extensive treatment under the presumption of malignant disorders. In the medical field, reporting of rare cases is highly encouraged; however, proper treatment for the patient depends on the accurate diagnosis that, in this case, was made postoperatively, which only added more physical and mental distress for the patient and their family.

A rare case of Erdheim-chester disease reported from Nepal.

Introduction: Erdheim-Chester Disease (ECD) is a rare non-Langerhans cell histiocytosis with a propensity to involve multiple organs. Case presentation: We report a case of a patient in mid-60s with occipital headache and ataxia. Following the radiological and immunohistochemical investigations and genomic studies, a diagnosis of ECD was made with two intracerebral lesions. Brain lesions were resected and the patient was discharged with the medication Vemurafenib. After 3 years of diagnosis and 13 years of initial presentation, patient passed away. Discussion: ECD frequently presents with Diabetes Insipidus as initial presentation, long bone osteosclerosis as the most common presentation, and has multi-system predisposition. ECD can be differentiated from Langerhans Cell Histiocytosis (LCH) with immunohistochemistry images of the biopsy specimens. Further, with genomic analysis of ECD, the neoplastic nature has been highlighted and targeted therapies like Vemurafenib and Cobimetinib are shown to be effective. Conclusion: Good clinical judgement and supporting investigations can aid in diagnosing rare entities like ECD even in resource-limited settings.

Rare case of acute renal failure secondary to Erdheim-Chester disease.

In this report we describe the clinical journey of a 62-year-old male that presented with acute kidney injury secondary to Erdheim-Chester disease, a non-Langerhans variant of histiocytosis rarely encountered by urological surgeons. ECD can uncommonly cause acute renal failure and management includes decompression of the collecting system. A multi-disciplinary approach is required to facilitate adequate investigation to determine the specific ECD subtype and most appropriate treatment options, particularly as the available targeted therapies have only recently been utilised.

Juvenile and adult xanthogranuloma: A 30-year single-center experience and review of the disorder and its relationship to other histiocytoses.

BACKGROUND: Juvenile xanthogranuloma (JXG) is the most common type of non-Langerhans cell histiocytosis whose cell of origin, etiology and pathogenesis are not fully understood. We aimed to provide an update on histopathologic and immunophenotypic profile of this well-characterized entity whose relationship to the other histiocytoses has received renewed attention in light of recent molecular genetic studies. MATERIALS AND METHODS: A retrospective review of all the cases with the pathologic diagnosis of "xanthogranuloma" was performed on our archives from 1989 to 2019. RESULTS: A total of 525 patients with 547 lesions diagnosed as JXG were identified with the median age of 4.5 years, a male predominance (M:F ratio 1.3:1) and a predilection for the head and neck region (40.8%). Cutaneous lesions comprised 76.8% cases and another 15.7% presented within soft tissues. The most common non-soft tissue, extracutaneous lesions included the brain (2.6%), and lungs (1.8%). Three basic histopathologic patterns were identified: early classic (EJXG) (14.2%), classic (CJXG) (45.3%), and transitional JXG (TJXG) (40.5%). Multinucleated giant cells, either Touton or non-Touton, were most frequently present in CJXG followed by TJXG. Mitosis was rare (<1/10 high-power field) among different patterns. There was an association among the patterns and lymphocytic infiltrates (P = 0.036), and presence of Touton or non-Touton giant cells (P < 0.001 for both) but not for mitotic count (P = 0.105) or eosinophilic infiltrates (P = 0.465). Additionally, there was a correlation between age groups and presence of non-Touton giant cells (P = 0.012) but not for Touton cells (P = 0.127). We have demonstrated that immunophenotypic expression of the lesion was not associated with age at diagnosis nor morphologic pattern: factor XIIIa 192/204 (94.1%), CD11c 75/77 (97.4%), CD4 82/84 (97.6%), CD68 200/201 (99.5%), CD163 15/15 (100%), CD1a 1/110 (0.9%), S-100 48/152 (31.6%), CD31 15/21 (71.4%), and vimentin 104/105 (99.0%). CONCLUSION: We have documented in a substantial series of cases of JXG that there is a correlation between one of the three basic histopathologic patterns with age at diagnosis, but with a consistent immunophenotype among the three patterns. Considering sensitivity and specificity rates, we suggest that a combination of CD11c, CD4, CD1a and either CD163 (preferred) or CD68 stains provides more specific diagnostic yield in the differentiation of JXG from other histiocytic disorders. JXG is also discussed in terms of its relationship and distinction from other similar histiocytic disorders in the context of MAPK/ERK pathway mutations.

Progressive nodular histiocytosis in a 9-year-old boy treated with cobimetinib.

Progressive nodular histiocytosis is a rare variant of non-Langerhans cell histiocytosis that affects the skin and mucous membranes and displays a progressive clinical course and poor response to treatment. We describe a case of severe progressive nodular histiocytosis harboring a KRAS p.G12S mutation in a 9-year-old boy, refractory to chemotherapy, who was successfully treated with the MEK inhibitor cobimetinib. This is the first report of the use of MEK inhibition for this histiocytosis subtype in a pediatric patient.

Urologic Manifestations and Hydronephrosis as Initial Presentation of Erdheim-Chester Disease: A Rare Form of Non-Langerhans Histiocytosis.

Erdheim-Chester disease (ECD) is a rare non-Langerhans histiocytosis that is classified as a malignancy of myeloid progenitor cells, with only 1,000 confirmed cases in the literature so far. It often manifests as a multi-system disorder with an initial presentation predominantly in the long bones, central nervous system (CNS), and retroperitoneal space, sometimes causing urologic symptoms as a result. ECD often presents indolently and in a spectrum of different ways, making it challenging to identify and treat. We report a case of a 63-year-old female with ECD that first presented with abdominal pain and acute renal injury due to ECD-related retroperitoneal fibrosis. We also explore the literature at large around ECD, its diagnosis, pathophysiology, and advances in treatments.

Symmetrical Facial Giant Plaque-Type Juvenile Xanthogranuloma: Case Report and Review of the Literature.

Juvenile xanthogranuloma (JXG) is the most common type of non-Langerhans cell histiocytosis. JXG is a rare benign tumor, which may be present at birth or develop later. The classical form of JXG is characterized by a red-yellowish benign papule or nodule with predilection sites on the head, neck, and trunk, although lesions can appear on extremities or extracutaneous sites. In most cases there is only one lesion, whereas numerous papules or nodules may occur. Special forms of JXG such as mixed, giant, subcutaneous, eruptive, clustered, and plaque-like have been reported and associations between JXG and systemic diseases have been made. Diagnosis mainly relies on the clinical appearance, and histology usually can confirm the disease. Here we present a very rare case of symmetrical giant facial plaque-type juvenile xanthogranuloma (SGFP-JXG) and compare it with classical JXG, variations of JXG, and discuss the differential diagnosis. A 4-year-old Caucasian female presented with plaque-like lesions composed of yellowish confluent papules on both the cheeks. The histological evaluation revealed a histiocytic lesion with a formation of Touton giant cells and immunohistochemistry results confirmed the diagnosis of the SGFP-JXG. In comparison to classical JXG, the onset of SGFP-JXG sometimes occurs later and the spontaneous resolution period may be prolonged. No associated diseases and no systemic involvements were observed. Histopathology is required to differentiate this form of JXG from other histiocytosis. To the best of our knowledge, only four cases of SGFP-JXG have been reported in the literature so far.

Malignant behaviour of primary intracranial Rosai Dorfman disease: A rare presentation of a benign disease.

BACKGROUND AND PURPOSE: The Rosai Dorfman disease (RDD) is a rare and usually benign lymphoproliferative disorder of unknown aetiology, typically characterized by head and neck lymphadenopathies. However, it may occasionally present with primary extra-nodal involvement including the central nervous system. We firstly described the potential malignant behaviour and fatal evolution of primary intracranial RDD. ILLUSTRATIVE CASE: A 69-year-old woman sought clinical attention for recurrent episodes of headache, fever and malaise associated with bilateral proptosis and left lower limb paresis. The brain MRI revealed bilateral retro-bulbar and fronto-parieto-occipital subdural lesions. The body CT did not show extracranial lesions. A right fronto-parietal craniotomy was performed and a subtotal resection was achieved. The histopathological diagnosis was consistent with RDD. Despite the patient was commenced on high-dose corticosteroids, she developed a worsening respiratory distress syndrome and a rapid systemic disease progression with liver and kidney failure. Given the poor general status, adjuvant medical and radiation therapies were not deemed safe and feasible and the patient died of multi-organ failure a month later. CONCLUSIONS: We documented an exceptional case of primary intracranial RDD with malignant behaviour characterized by rapid systemic disease progression and poor prognosis. Although RDD with intracranial location has usually a benign and self-limiting course with good response to adjuvant treatments, it hides a malignant potential that may lead patients to death.

Imaging features of neonatal systemic juvenile xanthogranuloma: a case report and review of the literature.

Juvenile xanthogranuloma (JXG) is the most common non-Langerhans cell histiocytic disorder in children. This report describes the case of a 28-day-old boy that presented with multiple subcutaneous nodular lesions on the trunk and extremities, and multiple red nodular lesions on the scrotum. Magnetic resonance imaging (MRI) of the brain showed a well-demarcated extra-axial dura-based mass that appeared isointense or slightly hyperintense on T1-weighted images, hypointense on T2-weighted images and had intense enhancement on gadolinium-enhanced T1-weighted images. Computed tomography (CT) or MRI scans of the chest and abdomen revealed multiple scattered nodular or patchy lesions of varying sizes in the lungs, liver and left kidney. Histological analysis of a subcutaneous mass suggested JXG. The patient was diagnosed with neonatal systemic JXG with involvement of the central nervous system, lungs, liver, kidneys, subcutaneous soft tissue and skin. CT and MRI after 3 months of treatment with methylprednisolone sodium succinate demonstrated that the lesions were obviously diminished. This report discusses the imaging findings in this current case of multi-organ JXG and reviews the imaging literature on this condition to improve awareness of the lesions in order to help radiologists establish an accurate differential diagnosis when confronted with similar cases.

Bone mineral density and bone microarchitecture in a cohort of patients with Erdheim-Chester Disease.

BACKGROUND: Erdheim-Chester Disease (ECD) is a rare type of non-Langerhans histiocytosis. Skeletal structures are affected in over 95% ECD patients. Due to the lack of proper imaging assessment tools, the alteration of bone microarchitecture in ECD has not been well studied. High-resolution peripheral quantitative computed tomography (HR-pQCT) is a newly developed assessment of bone mineral density and bone microarchitecture. METHODS: We performed a cross-sectional study with 13 patients diagnosed with ECD in Peking Union Medical College Hospital between October 2018 and June 2019. The diagnosis of ECD was based on typical pathological findings in the context of appropriate clinical and radiological manifestations. Bone geometry, volumetric bone mineral density and bone microarchitecture of those ECD patients were assessed using HR-pQCT at the non-dominant distal radius and distal tibia. Those HR-pQCT parameters were then compared to an ongoing population-based database of HR-pQCT for Mainland Chinese. RESULTS: As a result, remarkable heterogeneity of osteosclerosis in the HR-pQCT images was found in ECD patients, ranging from apparent normal structure, scattered thickening of trabecula, to homogenous consolidation. In terms of quantitative measurements, total volumetric BMD (383.50 mg/cm3, 1.352 times of normal mean, p = 0.023) of the tibia differed significantly in ECD patients, due to the increased trabecular volumetric BMD (291 mg/cm3, 2.058 times of normal mean, p = 0.003). The increased trabecular volumetric BMD of tibia was associated with remarkably increased number of trabecula (1.7/mm, 1.455 times of normal mean, p = 0.002) and increased thickness of trabecula (0.37 mm, 1.466 times of normal mean, p = 0.003). These differences could be due to the existence of dense bone interposed in the trabecula. CONCLUSION: This study is the first to assess the volumetric bone mineral density and bone microstructure with HR-pQCT in a cohort of ECD patients and indicated that the application of HR-pQCT may help to reveal the nature of bone lesions in the disease.

Isolated intraocular histiocytosis-A rarely reported entity masquerading clinically as uveitis.

An immunocompetent, 25-year-old gentleman with bilateral chronic uveitis presented to various uveitis clinics at different points of time with documented typical clinical features of Toxoplasma Chorioretinitis (Headlight in fog appearance), Behcet's Disease (Hypopyon with peripheral retinal vasculitis), and Presumed Ocular Tuberculosis (Granulomatous Intermediate Uveitis with positive Interferon-gamma release assay) and had been treated with anti-toxoplasma drugs, oral prednisolone, and immunomodulation with oral Mycophenolate/oral Azathioprine to no avail. After cytological examination of vitreous aspirate, he was found to have non-Langerhans cell Histiocytosis which responded to chemotherapy with Vinblastine and Cyclophosphamide.

Manifestations of Pediatric Extranodal Rosai Dorfman Disease in the head and neck.

OBJECTIVES: To systematically evaluate the clinico-diagnostic profile and management outcomes of otorhinolaryngologic manifestations of Extranodal Rosai-Dorfman Disease (ENRDD) in the pediatric population. METHODS: The search terms Rosai Dorfman Disease and Sinus Histiocytosis were used to query PubMed, Ovid/Medline, and Scopus databases from inception through September 30, 2018. Studies were systematically reviewed in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. All reports of ENRDD involving at least one otorhinolaryngologic subsite in children less than 18 years were eligible for inclusion. RESULTS: A total of 31 studies met inclusion criteria resulting in identification of 31 ENRDD cases with a mean age of 11.5 years. Of the 31 patients, 23 were male (74.2%) and 7 were female (22.6%). Extranodal lesions were limited to otorhinolaryngologic subsites in 24 patients (77.4%), while 7 patients (22.5%) were found to have extranodal lesions simultaneously involving otorhinolaryngologic and nonotorhinolaryngologic sites. The nasal vault was the most common otorhinolaryngologic site involved (n = 13, 41.9%), followed by the paranasal sinuses (n = 10, 32.3%). The most common non-otorhinolaryngologic site that was concurrently involved was the orbit (n = 4, 57.1%). Concurrent cervical lymphadenopathy was present in 19 patients (61.2%). While not documented for 2 cases, emperipolesis on histopathology was confirmed in 29 patients (93.5%). Single therapy with surgical excision was the most common modality of treatment (n = 15, 53.6%) and yielded highest remission rates (80%). In 11 instances (34.36%), ENRDD was misdiagnosed. CONCLUSION: Pediatric ENRDD is a rare disease entity that maintains a high misdiagnosis potential. The most common otorhinolaryngologic location for extranodal manifestation is the sinonasal compartment. Surgical excision remains the most common treatment modality yielding lowest persistence and/or recurrence rates.

Case of Erdheim-Chester presenting with xanthelasma-like eruption and osteolytic bone lesions: A case report.

Erdheim-Chester disease is a rare multisystemic non-Langerhans cell histiocytosis presenting 95% with skeletal lesions. Erdheim-Chester disease is due to mutations in the RAS-MEK-ERK pathway where 50% are due to BRAF-V600E mutations. Typical histopathological, clinical, and radiologic features are necessary for the diagnosis of Erdheim-Chester disease. Prognosis depends on the extent of the systemic involvement, and central nervous system involvement has a poorer outcome. We present a 30-year-old Moroccan woman with diabetes insipidus, bone marrow, and asymmetrical axial osteolytic bone lesions. Biopsies were consistent with Erdheim-Chester disease. Despite no treatment, the patient has demonstrated clinical improvement.

Periorbital Necrobiotic Xanthogranuloma Successfully Treated with Intravenous Immunoglobulin.

BACKGROUND: Necrobiotic xanthogranuloma (NXG) is a rare non-Langerhans histiocytosis with cutaneous manifestations, most commonly of the periorbital skin, and is often associated with hematologic disorders such as monoclonal gammopathy. Treatment of NXG is notoriously difficult, and fraught with recurrence and progression. CASE PRESENTATION: The authors describe a case of NXG with periorbital involvement in a patient with a complex autoimmune and hematologic medical history. The biopsy of this rare lesion prompted subsequent evaluation for an underlying disorder, which led to the diagnosis of multiple myeloma. Her NXG lesions demonstrated remarkable clinical improvement after treatment with intravenous immunoglobulin (IVIG). CONCLUSIONS: This case demonstrates the ophthalmologist's critical role in the diagnosis and management of NXG, as early detection cannot only prevent ophthalmic consequences such as ocular perforation and blindness, but also prompt further investigation that may reveal an underlying disorder or systemic involvement, including hematologic malignancy as in this case. NXG has been effectively treated with IVIG in a handful of reported cases. To the author's knowledge, this is the third case of periorbital NXG successfully treated with IVIG, and the first in the ophthalmic literature.