Juvenile xanthogranuloma manifesting in the forehead: A case report.

A 3 -year-old boy presented with a forehead nodular mass, which was excised and confirmed histologically as Juvenile Xanthogranulomma (JXG). It affects children with a predilection for the head and neck region. A relatively rare, benign, histiocytic proliferative cutaneous disorder with a potential for malignancy. A prompt and wide resection is recommended.

Orbital necrobiotic xanthogranuloma with necrotizing scleritis and absent cutaneous manifestations.

Necrobiotic xanthogranuloma (NXG) is a rare systemic disease, that commonly manifests with orbital and ocular adnexal involvement, presenting with periocular yellow papules and plaques that may ulcerate. Periorbital skin lesions are a hallmark of the disease, and in their absence the diagnosis may be delayed, preventing prompt systemic evaluation and appropriate treatment of this condition. We report a unique case of a 58-year-old female patient with NXG that presented with severe bilateral necrotizing scleritis, left orbital mass and no cutaneous manifestations of NXG. This case highlights the importance of considering NXG, despite absence of skin lesions, when other ophthalmological manifestations are present. Recognition of NXG is crucial due to the high lifelong risk of developing hematological malignancy.

Clinical features and outcomes of 17 children with systemic juvenile xanthogranuloma (sJXG) including five complicated with hemophagocytic lymphohistiocytosis (HLH).

Juvenile xanthogranuloma (JXG) is primarily limited to the skin, and systemic JXG (sJXG) is rarely reported. Reports of sJXG patients with hemophagocytic lymphohistiocytosis (HLH) are particularly rare. Herein, we conducted a retrospective study of children diagnosed with sJXG in the Hematology Centre of Beijing Children's Hospital from Jan. 2016 to Dec. 2021. The clinical features, laboratory parameters, treatments and outcomes of 17 sJXG patients were investigated, including five complicated with HLH. All sJXG-HLH patients had intermittent fever, rash, hepatosplenomegaly, cytopenia and high levels of soluble CD25, but interferon-γ was almost normal. Patients with sJXG-HLH had a younger diagnosis age (P = 0.035) and were more likely to have skin, liver, and spleen involvement than those without HLH (P = 0.029, P = 0.003, P = 0.003, respectively). Corticosteroids and/or ruxolitinib could be used to control the hyperinflammatory status when HLH was diagnosed. The treatment of sJXG varied, including Langerhans cell histiocytosis (LCH)-based chemotherapy and targeted therapy. The overall response rate of sJXG for first-line and second-line chemotherapy was 50.0% (5/10) and 50% (4/8), respectively. Patients with BRAF V600E mutation showed a response to dabrafenib. There was no significant difference in the overall survival and progression-free survival between sJXG patients without and with HLH (P = 0.12 and P = 0.46, respectively). Therefore, LCH-based chemotherapy could serve as an effective treatment for sJXG patients, and dabrafenib, to some extent, showed efficacy in controlling sJXG in patients with BRAF V600E mutation. The prognosis of sJXG-HLH patients seemed to be comparable to patients without HLH.

Remission of necrobiotic xanthogranuloma after intravenous immunoglobulin interruption: A case report.

Necrobiotic xanthogranuloma is a rare non-Langerhans cell histiocytosis with the potential for multisystemic involvement. It's a challenging disease to treat and multiple treatments have been reported in the literature with variable results. We present the case of a 92-year-old woman with multiple orange-brown papules and plaques on her face progressing for several years. The biopsy showed dermal xanthogranulomatous infiltration with multinucleated giant cells and necrobiosis, and she was diagnosed with necrobiotic xanthogranuloma. A complete response was obtained with intravenous immunoglobulins and she remained in remission despite treatment discontinuation.

Spatial transcriptomics reveals organized and distinct immune activation in cutaneous granulomatous disorders.

BACKGROUND: Noninfectious (inflammatory) cutaneous granulomatous disorders include cutaneous sarcoidosis (CS), granuloma annulare (GA), necrobiosis lipoidica (NL), and necrobiotic xanthogranuloma (NXG). These disorders share macrophage-predominant inflammation histologically, but the inflammatory architecture and the pattern of extracellular matrix alteration varies. The underlying molecular explanations for these differences remain unclear. OBJECTIVE: We sought to understand spatial gene expression characteristics in these disorders. METHODS: We performed spatial transcriptomics in cases of CS, GA, NL, and NXG to compare patterns of immune activation and other molecular features in a spatially resolved fashion. RESULTS: CS is characterized by a polarized, spatially organized type 1-predominant response with classical macrophage activation. GA is characterized by a mixed but spatially organized pattern of type 1 and type 2 polarization with both classical and alternative macrophage activation. NL showed concomitant activation of type 1, type 2, and type 3 immunity with a mixed pattern of macrophage activation. Activation of type 1 immunity was shared among, CS, GA, and NL and included upregulation of IL-32. NXG showed upregulation of CXCR4-CXCL12/14 chemokine signaling and exaggerated alternative macrophage polarization. Histologic alteration of extracellular matrix correlated with hypoxia and glycolysis programs and type 2 immune activation. CONCLUSIONS: Inflammatory cutaneous granulomatous disorders show distinct and spatially organized immune activation that correlate with hallmark histologic changes.

Presentation of Adult-onset Asthma and Periocular Xanthogranuloma with Intermediate Uveitis and Hodgkin's Lymphoma: A Case Report.

Purpose: To report a case of adult-onset asthma and periocular xanthogranuloma (AAPOX) in a patient with intermediate uveitis and a history of Hodgkin's lymphoma (HL). Case Report: A 51-year-old man with a past medical history of HL presented with blurred vision, asthma, and bilateral yellowish eyelid lesions. The eyelid lesions and asthma appeared 10 years after being diagnosed with HL. Physical examination was significant for multiple subcutaneous and firm eyelid masses in addition to the presence of pre-auricular and submandibular lymphadenopathies. Ophthalmic examination revealed bilateral intermediate uveitis and mild macular edema. Further systemic evaluations, including laboratory testing and imaging, were normal. Excisional biopsy of the eyelid lesions was performed and the histopathologic examination was consistent with the diagnosis of AAPOX. Conclusion: The presence of AAPOX in a patient with intermediate uveitis and history of HL suggests that immunological dysfunction may play a role in the pathogenesis of adult orbital xanthogranulomatous disease.

Histiocytosis and adult-onset orbital xanthogranuloma in 2023: a review of the literature and mini case series.

PURPOSE: Within the large umbrella of histiocytosis are a few similar yet heterogenous entities involving the orbit and periocular tissues with or without systemic infiltration, termed adult onset xanthogranuloma or orbital xanthogranuloma. Due to rarity of these conditions, different classifications in use, diverse clinical presentations and still unknown etiology, the aim of this paper was to provide an up-to-date literature review of the actual understanding of histiocytosis and its subgroups involving the orbit and periocular area, diagnostic strategies and therapeutic modalities. METHODS: We present a review of literature and small case series comprising four patients diagnosed and treated in the period from 2001 until 2023 in our hospital. Clinical files of 4 patients with adult-onset xanthogranulomatous disease of the orbit and ocular adnexa (AOXGD) were reviewed retrospectively. Clinical, laboratory, radiological, histopathological, and immunohistochemical findings were reexamined. RESULTS: Reviewing medical records of our patients with AOXGD, we found significant overlap between histiocytosis and different immune disorders. A broad workup should be considered in these patients as they can harbour severe immune disfunctions and hematologic disorders. Preferred treatment modality depends on a histopathologic type of AOXGD, clinical presentation and systemic involvement and should be conducted multidisciplinary. CONCLUSION: The diagnosis is often delayed because of its rarity and diverse clinical findings. Development of molecular genetic tests, detection of BRAF V600E mutation and different types of kinase mutations, mutations in transcriptional regulatory genes as well as tyrosine kinase receptors have shed a new light on the etiopathogenesis and potential targeted treatment of histiocytosis.

Advancements in the understanding and management of histiocytic neoplasms.

Histiocytic neoplasms are rare diseases involving macrophages, dendritic cells, and monocytes. They include Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), Rosai-Dorfman disease (RDD), juvenile xanthogranuloma (JXG), and histiocytic sarcoma. Histiocytic neoplasms are characterized by varied clinical courses and prognoses, necessitating a nuanced understanding of their classification, epidemiology, and clinical manifestations. Genetic studies have revealed somatic mutations, predominantly in the MAPK pathway, suggesting a clonal neoplastic nature. This review covers the current understanding of histiocytic neoplasms, molecular pathophysiology, with a particular focus on mutations in genes such as BRAF, MAP2K1, and the PI3K-AKT signaling pathways, and evolving treatment strategies, especially focusing on LCH, ECD, RDD, and JXG. The treatment landscape has evolved with advancements in targeted therapies. BRAF inhibitors, such as vemurafenib and dabrafenib, have shown efficacy, especially in high-risk LCH cases; however, challenges remain, including relapse post-treatment discontinuation, and adverse effects. MEK inhibitors have also demonstrated effectiveness, and cobimetinib has recently been approved for use in adults. Further research is required to determine the optimal treatment duration and strategies for managing therapy interruptions. Advancements in molecular genetics and targeted therapies have revolutionized the management of histiocytic neoplasms. However, ongoing research is crucial for optimizing patient outcomes.

Histological evidence of MAPK pathway activation across subtypes of adult orbital xanthogranulomatous disease irrespective of the detection of oncogenic mutations.

Adult orbital xanthogranulomatous disease (AOXGD) is a spectrum of histiocytoses with four subtypes. Mitogen-activated protein kinase (MAPK) pathway mutations have been detected in various histiocytic neoplasms, little is known about this in AOXGD. Targeted regions of cancer- and histiocytosis-related genes were analyzed and immunohistochemical staining of phosphorylated ERK (pERK), cyclin D1 and PU.1 was performed in 28 AOXGD and 10 control xanthelasma biopsies to assess MAPK pathway activation. Mutations were detected in 7/28 (25%) patients. Positive staining for pERK and/or cyclin D1 was found across all subtypes in 17/27 (63%) patients of whom 12/17 (71%) did not harbour a mutation. Xanthelasma tissue stained negative for pERK and cyclin D1. Relapse occurred in 5/7 (71%) patients with a MAPK pathway mutation compared to 8/21 (38%) patients in whom no mutation could be detected. Molecular analysis and evaluation for systemic disease is warranted to identify patients at risk of recurrent xanthomatous disease.

Orbital histiocytosis; From A to Z.

PURPOSE: Histiocytosis is one of the most challenging diseases in medical practice. Because of the broad spectrum of clinical manifestations, systemic involvements, unknown etiology, and complex management, different types of histiocytosis are still a big question mark for us. Orbital histiocytosis is characterized by the abnormal proliferation of histiocytes in orbital tissues. It could affect the orbit, eyelid, conjunctiva, and uveal tract. Orbital histiocytosis can cause limited eye movement, proptosis, decreased visual acuity, and epiphora. In this study, we review the novel findings regarding the pathophysiology, diagnosis, and treatment of different types of histiocytosis, focusing on their orbital manifestations. METHOD: This review was performed based on a search of the PubMed, Scopus, and Embase databases or relevant published papers regarding orbital histiocytosis on October 9th, 2023. No time restriction was proposed, and articles were excluded if they were not referenced in English. RESULTS: 391 articles were screened, most of them being case reports. The pathophysiology of histiocytosis is still unclear. However, different mutations are found to be prevalent in most of the patients. The diagnostic path can be different based on various factors such as age, lesion site, type of histiocytosis, and the stage of the disease. Some modalities, such as corticosteroids and surgery, are used widely for treatment. On the other hand, based on some specific etiological factors for each type, alternative treatments have been proposed. CONCLUSION: Significant progress has been made in the detection of somatic molecular changes. Many case studies describe various disease patterns influencing the biological perspectives on different types of histiocytosis. It is necessary to continue investigating and clustering data from a broad range of patients with histiocytosis in children and adults to define the best ways to diagnose and treat these patients.

Analysis of the characteristics of reflectance confocal microscopy images of xanthogranuloma and xanthoma.

BACKGROUND: Both xanthogranuloma and xanthoma clinically manifest as yellowish skin lesions. Historically, the gold standard for diagnosis was skin histopathological examination. Currently, the advent of reflectance confocal microscopy (RCM) offers additional diagnostic support for these diseases by revealing their microscopic features, thereby enhancing the theoretical foundation for diagnosis. OBJECTIVE: This study aimed to elucidate the distinctive characteristics of RCM images in xanthogranuloma and xanthoma, assess their diagnostic value, and investigate the relationship between RCM and histopathological features, ultimately boosting diagnostic accuracy. METHODS: RCM and histopathological examinations were conducted on 13 patients with xanthogranuloma and 12 with xanthoma, recruited from our Dermatology Clinic between August 2022 and November 2023. The study involved analyzing RCM image features and correlating them with histopathological findings. RESULTS: The RCM images of 13 xanthogranuloma and 12 xanthoma cases showed similar features. Xanthogranuloma predominantly exhibited epidermal atrophy and thinning in 6 cases (46.15%). Additionally, in 69.23% of cases, scattered small mononuclear inflammatory cells were infiltrated in the superficial and middle dermis layers. Medium to high refractive cells, predominantly vacuolated and resembling foam, were observed in 61.54% of cases. All cases demonstrated high refractive cells with distinct target-shaped, disc-shaped, horseshoe-like, and flower-ring structures. Concordance rates with histopathological examinations were 69.23, 92.31, 92.31, and 100%, respectively. Regarding xanthoma, epidermal atrophy and thinning occurred in two cases (16.67%), and mononuclear inflammatory cell infiltration was observed in 25% of cases. High refractive cells with the previously mentioned shapes were present in 100% of cases, though only 16.67% displayed these characteristics exclusively. The concordance rates were 66.67, 91.67, 100, and 91.67%, respectively. CONCLUSION: RCM imaging of xanthogranuloma and xanthoma presents distinctive, highly consistent features with their histopathology, offering valuable insights for clinicians in diagnosing and differentiating these conditions.

Congenital isolated juvenile xanthogranuloma of the sole - a unique case report in a newborn.

Juvenile xanthogranuloma (JXG) is a rare, benign non-Langerhans cell histiocytosis that primarily affects the skin, with infrequent extracutaneous manifestations. Lesions typically emerge during early childhood and often resolve spontaneously, obviating the need for treatment. This paper details the case of a child diagnosed with a solitary JXG on the sole, necessitating surgical excision due to its functional impairment, specifically a delay in walking and weight bearing.

[Bilateral vestibulopathy and sensorineural hearing loss in necrobiotic xanthogranuloma, multiple myeloma and amiloidosis]. / Dvustoronnyaya vestibulopatiya i sensonevral'naya tugoukhost' u patsienta s nekroticheskoi ksantogranulemoi, mnozhestvennoi mielomoi i amiloidozom.

This article describes a rare case of necrotic xanthogranuloma in a 46-year-old patient who presented with the development of periorbital xanthelasms, progressive bilateral sensorineural hearing loss and bilateral vestibulopathy, followed by multiple myeloma and amyloidosis. For several years, the patient underwent standard rehabilitation for chronic sensorineural hearing loss and was fitted with a hearing aid. During hospitalisation for exacerbation of chronic bronchitis, monoclonal gammopathy was identified, and later, after careful examination and repeated biopsies, necrotic xanthogranuloma, multiple myeloma and AL-amyloidosis were confirmed. Targeted immunochemotherapy resulted in improvement of hearing and significant recovery of the vestibuloocular reflex bilaterally.

A Pelvic Hernia Through Two Defects in the Pouch of Douglas in a Patient With Peritoneal Xanogranuloma: A Report of a Very Rare Case.

Pelvic internal hernias, including pouch of Douglas hernias, are a very rare cause of small bowel obstruction. They pose a challenge in diagnosis due to their rarity and lack of specific radiological features. The definitive diagnosis is usually reached intraoperatively. The treatment consists of reduction with or without resection of the herniated bowel and primary repair of the defect. Mesh placement has been reported but is still arguable, as no musculofacial defect is involved. Here, we present a case of a 28-year-old female patient, a nulliparous with multiple medical conditions including familial Mediterranean fever (FMF) and an extremely rare tumor, peritoneal xanthogranuloma. She had a history of laparoscopic left ovarian cystectomy, and complained of abdominal pain and distention for three days prior to admission. Her symptoms were associated with constipation and recurrent vomiting and she was admitted as a suspected case of small bowel obstruction. CT scan suggested the possible diagnosis of a pelvic hernia, yet the definitive diagnosis was reached intraoperatively after noticing the presence of two defects on the left side of the pouch of Douglas. A primary repair of the defects was performed after reduction of the viable herniated bowel. The patient was discharged on the third postoperative day with uneventful course of recovery.

Juvenile xanthogranuloma manifesting with LCH-associated neurodegenerative disease-like radiological findings.

Here, we describe two patients with juvenile xanthogranuloma (JXG) manifesting with Langerhans cell histiocytosis (LCH)-associated neurodegenerative disease (ND)-like radiological findings. One patient showed typical radiological abnormalities at onset, which worsened with progressing central nervous system symptoms 7 years after LCH-oriented chemotherapy. Another showed spontaneous regression of clinical symptoms, with a transient radiological change 1 year after salvage chemotherapy for recurrence of JXG. These data regarding JXG-associated ND will facilitate future investigation of the disease, as well as development of therapeutic interventions.

Congenital Juvenile Xanthogranuloma in the Perioral Region: A Case Image.

Juvenile xanthogranuloma (JXG) is the most common form of non-Langerhans cell histiocytosis in childhood. It often presents with cutaneous involvement and exhibits a predilection for the head and neck region. This article illustrates a case of congenital JXG in a 5-month-old boy, characterized by a solitary, well-circumscribed nodule above the left upper lip. Histopathologically, the lesion exhibited histiocytes with eosinophilic cytoplasm and Touton giant cells. Immunohistochemistry revealed histiocytes positive for CD68 and Factor XIIIa, while negative for S-100 protein. Clinicians should become familiar with the broad clinical spectrum of cutaneous JXG, particularly its congenital presentation, in order to ensure timely and accurate management.

Clinicopathological study of ophthalmic cutaneous and mucocutaneous non-langerhans cell histiocytic lesions.

BACKGROUND: The "C group" of the histiocytic disorders is characterized by non-Langerhans-cell histiocytic lesions in the skin, mucosal surfaces, or both, out of which Juvenile xanthogranuloma (JXG) is the most common typically affecting the skin. The eye is the most common extra-cutaneous site of JXG., we aim at providing our clinical and histopathological experience with this group of diseases including the adult-onset xanthogranuloma (AXG). METHODS: This is a retrospective cohort study of all patients with the tissue diagnosis of ocular and periocular cutaneous and mucocutaneous non-LCH disorders who presented to us over a period of 25 years (January 1993 to December 2018). RESULTS: Twenty patients were diagnosed as "Group C" disease with an age range of 2 months-60.9 years. Eleven patients were females (55%) and nine were males (45%). The involvement was mostly unilateral in 80.9%. All cases fell into the xanthogranuloma family with 11 JXG patients, 8 AXG patients of skin and ocular surface, and one patient with solitary reticulohistiocytoma (SRH). The clinical site of involvement in JXG was primarily in the eyelid in 5 patients (45%), ocular surface lesions in 2 (18%), iris in 2 (18%), choroidal and bilateral orbital lesions in 1 patient each (9%). The group of AXG, presented equally with eyelid lesions in 4/8 and ocular surface lesions in 4/8. The non-Langerhans' histiocytic infiltrate showed supportive immunohistochemical staining properties (reactive to CD68 marker and negative to S-100 and langerin markers). CONCLUSION: Among the rare histiocytic disorders, xanthogranulomatosis is the commonest and has wide clinical manifestations. Accurate diagnosis needs to be supported by typical histopathological findings. JXG was the commonest in our study with relatively older mean age at presentation and frequent eyelid rather than iris involvement. AXG is often confused with xanthelasma when involving the eyelids with corneal limbal involvement is relatively frequent.

Adult Onset Orbital Xanthogranuloma, a Variant of Adult Orbital Xanthogranulomatous Disease: An Infrequent Entity.

Adult orbital xanthogranulomatous diseases (AOXGD) present clinically with symmetrical swellings around the eyes and are collectively considered within the broader group of non-Langerhans cell histiocytosis. A 45-year-old female presented with asymptomatic progressive, skin-colored, thick raised lesions around the eyes of 1 year duration. On dermatological examination, large indurated, lobulated, skin-colored thick plaques were seen bilaterally over infraorbital areas, along with a few hard, discrete nodules over the left infraorbital area. Histopathology showed pan-dermal infiltration with foamy histiocytes, non-lipidized histiocytes, a few multinucleate giant cells, lymphocytes, and a few plasma cells, with immunohistochemistry showing CD68 and S100 positivity. Laboratory and imaging studies did not show any abnormality. Based on the above findings and the absence of internal organ involvement, the patient was diagnosed with adult-onset orbital xanthogranuloma (AOX). The patient was treated with three monthly sessions of intralesional corticosteroid injections, along with methotrexate 12.5 mg per week for 8 weeks, resulting in a moderate reduction in the size of the plaques. The patient is under regular follow-up. The present case highlights the rare case of AOX and the importance of prompt recognition and evaluation in view of its potential hematological and systemic associations.