Xanthoma Disseminatum Research Articles

7418 Xanthoma Disseminatum - A Rare cause of Diabetes Insipidus

Abstract Disclosure: P. Balasubramanian: None. J. Cohen: None. Z. Corbin: None. G. Panse: None. S.E. Inzucchi: None. Background: Xanthoma disseminatum is a rare non-Langerhans cell-derived benign histiocytosis of unknown etiology, characterized by mucocutaneous xanthomatosis. Systemic involvement occurs in a subset of patients, the most common manifestation being central diabetes insipidus in the setting of hypothalamic-pituitary- infundibulum infiltration, occurring in about 30-50% of the patients. We present the case of a man with biopsy proven cutaneous xanthoma disseminatum who developed central diabetes insipidus due to pituitary stalk involvement. Case Presentation: A 69-year-old male presented with a 2-year history of symmetrically distributed, erythematous to hyperpigmented macules and papules in the axillae and inguinal folds. He did not have any mucosal lesions. Skin biopsy revealed histiocytic infiltrate consistent with non-Langerhans cell histiocytosis, likely xanthoma disseminatum. He developed symptoms of polyuria and nocturia around the same time of the eruption, resulting in a large daily fluid intake of 100-120 ounces/day for several months. Laboratory evaluation revealed normal electrolytes. After an overnight water deprivation test, serum osmolality was 299mOsm/kg, serum sodium was 144mmol/L and urine osmolality was 280mOsm/kg, consistent with partial central diabetes insipidus. MRI pituitary with and without IV contrast showed thickening and hyperenhancement of the pituitary stalk. Anterior pituitary function was intact except for mild hypogonadotropic hypogonadism. He was started on DDAVP with good response and resolution of symptoms. Conclusion: Xanthoma disseminatum is characterized by extensive mucocutaneous xanthomatosis with occasional systemic involvement. The natural history of xanthoma disseminatum is usually benign, indolent, and slowly progressive with spontaneous regression described in a few cases. Hypothalamic and pituitary involvement may cause hyperprolactinemia, central diabetes insipidus, and variable degrees of hypopituitarism. Diabetes insipidus is often mild and sometimes transient. Occasionally, central diabetes insipidus can precede the skin lesions. Prognosis is generally good. Central nervous system involvement outside the hypothalamus/pituitary carries a poor prognosis. Presentation: 6/2/2024

54116 A Systematic Review of Clinical Features and Treatment Outcomes of Xanthoma Disseminatum

54116 A Systematic Review of Clinical Features and Treatment Outcomes of Xanthoma Disseminatum

A case of non-Langerhans histiocytosis effectively treated with Cobimetinib: A rare case report

non-Langerhans histiocytosis is a group of very rare, clinically heterogeneous diseases, characterized by the proliferation of histiocytes in the connective tissue, it preferentially affects middle-aged men, their classification is difficult, it is based on clinical, histological, immune criteria histochemical and evolutionary. We report the case of a 58-year-old man with an HIV infection under treatment. The patient initially presented with skin lesions, the skin biopsy was in favor of xanthoma disseminatum, and then the patient presented with bone pain and respiratory symptoms. , the extension assessment and the biopsies confirm the diagnosis of Erdheim-Chester disease with bone, cardiac, aortic and pulmonary involvement and diffuse skin involvement « disseminated xanthoma », the patient was put on Cobimetinib 20 mg / day which resulted in an excellent clinical and radiological response with no reported toxicity. Cobimetinib is effective and well tolerated in cases of Erdheim-Chester disease; therefore, it could be considered as a good therapeutic option as a monotherapy for patients without BRAF mutation.

Disseminated Xanthogranuloma with BRAF Gene Fusion and Profound Response to MEK Inhibitor Therapy

Background: Histiocytic neoplasms represent a diverse group of clonal hematopoietic disorders, varying in severity from xanthogranuloma to multisystemic Erdheim-Chester Disease (ECD). Both Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (nLCH) are characterized by activating mutations in the MAPK pathway, primarily involving BRAF point mutations. In this report, we present a compelling case of disseminated xanthogranuloma with a unique BRAF fusion, which exhibited a remarkable therapeutic response to MEK inhibition. This finding adds to our understanding of the molecular heterogeneity within histiocytic neoplasms and highlights the potential significance of targeted therapies in managing these rare but clinically significant disorders Clinical Observation: In this clinical observation, we present the case of a 71-year-old female who sought medical attention due to a 3-year history of progressive cutaneous lesions, accompanied by hoarseness and blurry vision. A biopsy of a lesion revealed characteristic features consistent with xanthogranuloma. Further examination through direct laryngoscopy unveiled lesions on the vocal cords and tracheal masses, which exhibited identical histologic findings as the skin biopsies. A comprehensive analysis involving massively parallel DNA sequencing revealed the presence of a GAB2-BRAF fusion, along with a tumor mutational burden of 1 mutation/megabase (Mb). Immunohistochemical testing of the endobronchial biopsy demonstrated a combined positive score of 10% for PDL-1 expression, suggesting the potential for immune checkpoint blockade. Given the implicated role of MAPK pathway activation due to the identified fusion, a therapeutic approach utilizing the MEK inhibitor Trametinib was initiated. Encouragingly, the patient exhibited a favorable response with a reduction in tumor burden, near-resolution of hoarseness, and improved vision. However, this treatment was accompanied by MEK inhibitor-associated cardiotoxicity, leading to the discontinuation of Trametinib. Regrettably, following the cessation of Trametinib, the patient's lesions rapidly progressed, and her disease worsened beyond the pre-treatment state. Taking into account the 10% PDL-1 positivity, immunotherapy with Pembrolizumab was commenced, resulting in partial improvement. Nonetheless, the patient developed immunotherapy-related cardiotoxicity. In light of the continued disease progression off therapy, the MEK inhibitor Cobimetinib was introduced. The patient responded rapidly to this therapeutic intervention; however, during a one-week break in Cobimetinib treatment, the disease worsened back to the baseline. Consequently, Cobimetinib was discontinued, and a continuously dosed MEK inhibitor, Binimetinib, was cautiously administered at a lower dose to mitigate the risk of cardiotoxicity. As of the time of this report, the patient remains on Binimetinib, achieving complete clinical remission, and there is no evidence of further cardiotoxicity. This clinical observation underscores the challenges and complexities in managing advanced xanthogranuloma with unique molecular alterations and highlights the importance of closely monitoring and tailoring therapies to optimize patient outcomes. Conclusion: To our knowledge, this is the first clinical trial documenting MEK inhibition for a patient with xanthoma disseminatum harboring a BRAF fusion. Seeking to target downstream of BRAF, MEK inhibition demonstrated a dramatic response, with rapid relapse upon cessation, supporting a central oncogenic role for BRAF fusion. Further studies should explore alterations in the RAS-BRAF-ERK pathway in nLCH and consider clinical trials with MEK inhibitors. Our clinical experience suggests continuous MEK inhibitor exposure may be necessary for effective disease control. These findings advance our understanding of therapeutic options in histiocytic neoplasms, paving the way for more precise and impactful treatments.

Atypical Human Papillomavirus Infection with Secondary Tinea in a Middle-Aged Caucasian Male

We present a case of an atypical diffuse cutaneous eruption due to HPV infection and Tinea in a 51-year-old male patient with a past medical history of mild cytopenia, vasectomy and difficult socio-economic situation. Differential diagnosis at initial visit included Epidermodysplasia Verruciformis vs Pityriasis Rubra Pilaris vs Secondary Syphilis vs Xanthoma Disseminatum vs atypical presentation of Tinea vs less likely other. Through clinical examination, repeat biopsy, tissue culture and extensive HPV testing, it was revealed that the patient had multiple HPV infections type FA52, 96, 16 and 13, with a possible secondary Tinea infection. The patient was treated with antifungal medications first. Topical Cidofovir was recommended but not covered by insurance. The skin eruption improved gradually highlighting the importance of additional samples, tissue culture and extensive HPV testing in such atypical cases. Our case describes the importance of multidisciplinary care to help patients with proper diagnostics and treatment regimens.

P87 Therapeutic outcomes in xanthoma disseminatum with cladribine: a long-term experience of six patients from a tertiary care institute

Abstract Xanthoma disseminatum is a rare, non-Langerhans-cell histiocytosis with systemic involvement that has limited treatment options and response. Cladribine has been previously reported in few case reports and a single case series to induce long-term remission of cutaneous lesions. The aim was to study the treatment outcomes in a long-term follow-up of patients with xanthoma disseminatum, treated with cladribine. This was an ambispective case series of six patients diagnosed with xanthoma disseminatum on the basis of clinical and histopathological features. All patients were treated with monthly cycles of cladribine (2-chlorodeoxyadenosine) 0.14 mg kg−1 daily for 5 days a month, ranging from two to eight cycles. The follow-up period ranged from 2 months to 4.75 years. There were four males and two females in our series, with mean (SD) age of 25.3 (13.1) years (range 9–48). Disease duration at presentation ranged from 1.5 to 8 years. All patients presented with skin-coloured to yellowish-brown papules in a periorbital, perioral and flexural distribution. Four of six (67%) patients had mucosal involvement. All but one patient had associated diabetes insipidus. Half the patients had bone involvement, and two showed extensive infiltrates in the brain causing neurological symptoms. Patients receiving at least three cycles (n = 5) reported a mean improvement of 72% in cutaneous lesions at the end of the follow-up period, allowing for the avoidance of tracheostomy in a patient with laryngeal involvement. Imaging (magnetic resonance imaging of the brain, positron emission computed tomography) repeated in four patients after 3–6 cycles showed evidence of significant improvement in extracutaneous disease. Adverse effects were noted in four (67%) patients, including transient leukopenia in three, post-infusion fever in one and proximal renal tubular acidosis in one. All side-effects were resolved after the cessation of therapy and/or with supportive treatment; no serious infections were reported. Cladribine is a purine analogue that has an antiproliferative effect on histiocytes and lymphocytes, as well as an immunomodulatory action. It has emerged as an effective therapeutic modality for patients with xanthoma disseminatum that necessitates further evaluation for dosage and safety.

Eruptive papules on axillary folds of an adolescent.

Eruptive papules on axillary folds of an adolescent.

Blinding Xanthoma Disseminatum

A 26-year-old female presented with gradual painless blindness of the right eye. Clinical and histological data suggested Xanthoma disseminatum (XD), a rare, benign non-familial mucocutaneous normolipemic,non-Langerhans cell histiocytosis. She has the typical triadof cutaneous xanthoma, mucosal xanthoma, and diabetes insipidus.1-3 Ocular lesions included progressive conjunctival and corneal yellow deposits which caused blindness in her right eye and are about to blind the seeing eye (Figure 1a &b).

Cladribine for the treatment with five male cases with xanthoma disseminatum

探讨播散性黄色瘤的临床特征、辅助检查表现、克拉屈滨治疗效果及中远期预后情况。2016年12月至2020年12月，共纳入5例患者，均为男性，平均年龄27岁，其中1例单纯累及皮肤，3例同时累及呼吸道黏膜，另有1例同时累及巩膜和垂体。自发病至确诊的平均时间为5.4年，诊断方法为临床表现结合病理组织学检查。治疗方法均为克拉屈滨单药化疗。5例患者治疗后均有缓解，2例随访1年后进展，1例予克拉屈滨巩固治疗后缓解，1例拟返院继续治疗。播散性黄色瘤为一类罕见非朗格汉斯细胞组织细胞增生症，以皮肤黏膜受累为常见表现，亦可累及其他器官，特征性免疫标志为CD68（+），CD1a（-）及S-100（-）。目前缺乏标准治疗，克拉屈滨治疗可取得相对满意疗效，但长期疗效仍有待于进一步观察。.

The Importance of Clinicopathological Correlation: A Case of Xanthoma Disseminatum

Xanthoma disseminatum (XD) is a rare disease that presents with pruritic papules, classically involving the extensor surfaces and mucosal areas. We present a case of XD that was misdiagnosed as eruptive xanthomas and eventually self-resolved. Self-resolving XD may be within a spectrum of adult-onset juvenile xanthogranuloma. However, as there may be systemic consequences of XD, it is critical to ensure these patients obtain a complete evaluation and close follow-up.

Tumor Mutational Burden in Histiocytic Neoplasms

▪BackgroundHistiocytic disorders are rare hematologic neoplasms characterized by their high clinical heterogeneity. Evidence of constitutive activation of the mitogen-activated protein kinase (MAPK) pathway in a number of these disorders has led to the increasing use of BRAF- and MEK-inhibitors as a therapeutic strategy. Response to these therapies is not universal and additional effective treatment options are required. Immune checkpoint inhibitors have proven effective for a wide array of malignancies. Tumor mutational burden (TMB), the total number of somatic pathogenic variants per coding region in a tumor genome, is a clinical biomarker associated with response to immunotherapy. We have previously reported preliminary findings of low TMB in a small cohort of patients with histiocytic neoplasms (Goyal G et al. Blood 2019). In this study, our aim was to confirm the findings in a larger clinical cohort using next generation sequencing studies.MethodsA retrospective review of adult patients consecutively seen at Mayo Clinic from 2017 to April 2021 and diagnosis of a histiocytic neoplasm was performed. Electronic records were queried for demographic and laboratory data of all patients who consented to undergo tumor-tissue next-generation sequencing with the Tempus-xT ® or xO ® assay (Chicago, IL), throughout the course of their evaluation. TMB was reported as the number of nonsynonymous mutations per coding area of a tumor genome. TMB across groups was compared via an independent-samples T-test or via analysis of variance and post hoc subgroup testing via Turkey's Test as required.ResultsSeventy-three patients were included in the study. Individual diagnoses included: Erdheim-Chester disease (ECD) in 31.5% (n=23), including 3 patients with overlap features of ECD and other histiocytoses; Rosai Dorfman disease (RDD) in 28.8% (n=21); Langerhans cell histiocytosis in 21.9% (n=16), histiocytic sarcoma (HS) in 5.5% (n=4), and other histiocytic neoplasms in 12.3% (n=10) including adult xanthogranuloma, xanthoma disseminatum, undifferentiated histiocytoses, and one case of Langerhans cell sarcoma.Median tumor percentage on analyzed samples was 30% (range 10%-90%) and was ≤20% in 29 samples. TMB was <1.0 mutations per megabase (mpMb) in 42.5% (n=31) and >5.0 mpMb in only 6 cases. Median TMB was 1.58 (range 0 - 5.26) for ECD, 1.08 (range 0 - 6.3) for LCH, 0.2 (range 0 - 5.8) for RDD, 3.19 (range 1.67 - 6.8) for HS, and 1.6 (range 0 - 7.5) for other histiocytic neoplasms (Figure 1). No clear association between increasing TMB and number of systems with histiocytic infiltration was observed (Figure 2). A significant increase in TMB was observed among the 5 cases of sarcoma as compared to the rest of the cohort (p=0.014). When not considering sarcomas, no differences were observed in TMB between patients with ECD, LCH, RDD or other histiocytoses (F=0.775; p=0.512).ConclusionIn this large cohort of histiocytic disorders, TMB was low compared to that historically seen in other neoplasms though this is likely influenced by tumor purity ≤20% in 29 cases. Only 6 tumors had TMB reports with mpMb above the threshold thought to be associated with an increased likelihood of response to PD-1/PDL1-targeted therapies (>5 mpMb). Our results suggest a low likelihood of response among histiocytic disorders using immune checkpoint inhibitors. Further exploration among malignant histiocytoses (HS and Langerhans cell sarcoma) is warranted given our findings of higher TMB compared with other histiocytic neoplasms. [Display omitted] DisclosuresBennani: Kymera: Other: Advisory Board; Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board.

Periocular Necrobiotic Xanthogranuloma Response to Cladribine.

A 42-year-old woman presented to the Ophthalmology department with bilateral large nodular lesions around her eyes for the past 2 years (panel A). On examination, yellow to skin colored, ill as well as well-defined multiple papules and nodules were noted around the periorbital area, forehead, and neck. Many papules had coalesced to form large plaques. Blood investigations including electrophoresis were performed to rule out paraproteinemia. A biopsy from the periocular lesion revealed necrobiotic granulomatous inflammation, atypical giant cells, cholesterol clefts, plasma cells, and minimal fibrosis. A diagnosis of xanthogranuloma necrobiotica was made. Intralesional steroids were injected, and the patient was started on oral steroids. However, there was no response. Eventually, 4 cycles of intravenous cladribine were administered with routine monitoring of liver function, kidney function, and other blood parameters. A marked reduction in the size of the lesions were noted. (Panel B) There was no obvious systemic adverse reaction of the drug and the lesions did not flare up once the chemotherapy was halted. Necrobiotic xanthogranuloma is a rare, chronic and gradually progressive disease characterized by yellowish plaque lesions typically involving the periorbital area and unlike other orbital xanthogranulomas, having a high propensity to ulcerative and fibrose. The clinical condition principally involves the skin and subcutaneous tissue and is known to be associated with characteristic dermatopathologic findings, monoclonal gammopathy, and less commonly malignant tumors. Medical management including chemotherapy with alkylating agents and antimetabolites as well as administration of intralesional, topical and systemic steroids has yielded varied results. Although multiple other modes of treatment have also been advocated in the management of xanthogranuloma necrobiotica ranging from, radiation therapy, plasmapheresis, surgical excision, or a combination of them, there still remains a dispute regarding the definite management. In the recent times, cladribine has shown encouraging results in the management of xanthoma disseminatum, with that knowledge in background the authors used the drug in the management of xanthogranuloma necrobiotica.FIG.: A, Clinical picture of the patient at presentation showing bilateral huge periocular nodular lesions. B, Clinical picture of the patient after 4 cycles of Cladribine showing reduction in size of the lesions.

Xanthoma Disseminatum Presenting as Liver Failure in an Adult: A Case Report

Xanthoma disseminatum (XD) is a rare, primarily cutaneous non-Langerhans cell histiocytosis...

Xanthoma disseminatum in dark-skinned people: diagnostic delay and difficulties in treatment in a patient who had a fatal outcome in sub-Saharan Africa

Medical image Xanthoma disseminatum is a proliferative non-Langerhans histiocytosis first described by Montgomery in 1938. We here report the case of a 8-year-old Senegalese boy having skin type VI who died. In 2015 this boy presented with slowly progressive dermatosis, which had occurred at the age of 7 years. Dermatological examination showed diffuse xanthomatous orange papules and nodules on the trunk, axillary and inguinal folds, scrotum, neck and face. Extradermatological examination was normal. Histopathological examination of a skin biopsy showed dermal infiltrate composed of histiocytes and multinucleated giant Touton cells. The diagnosis of non-Langerhans histiocytosis was retained, subject to immunohistochemical analyses which were not availabe. Immunohistochemical analyses were too expensive in the absence of health insurance (our patient was from a low socio-economic background). Tests measuring the amount of lipids were normal. At the age of 11 years, diabetes insipidus and systemic involvement of mediastino-pulmonary and abdominal and pelvic organs supported the diagnosis of xanthoma disseminatum. Mediastino-pulmonary disease was complicated by pneumonitis with dyspnoea which didn´t regress on prednisone treatment (1mg/kg/day). The patient underwent surgical resection of a massive mediastinal mass that compressed the organs. Five months later (in 2019), the patient died due to respiratory distress. The difficulty of diagnosing non-Langerhans histiocytosis in our context is largely related to the inaccessibility of immunohistochemistry. Indeed, if CD68 positive and CD1a negative labeling cells had been early detected, fairly early diagnosis would be made. Thus, we could have offered treatments to improve the quality of child´s life.

The histopathologic characteristics of Xanthoma Disseminatum does not increase the risk of intubation or extubation

The histopathologic characteristics of Xanthoma Disseminatum does not increase the risk of intubation or extubation

Non-Langerhans cell histiocytosis with peripheral joint destruction and mediastinal lymph node invasion: The continuous feature spectrum of clinical multicentric reticulohistiocytosis and microscopical xanthoma disseminatum

The non-Langerhans cell histiocytoses (non-LCH) are rare and benign histiocytic disorders. We present a 61-year-old female with progressive skin-colored nodules on the face and extremities. The skin biopsy showed dermal infiltration of foamy histiocytes. Further imaging study showed erosive arthritis and lymphadenopathy. The microscopical feature of anterior mediastinal lymph node was similar to that in the skin. Thus, the diagnosis is non-LCH with joints and lymph nodes involvement. This patient presented both the clinical manifestations of multicentric reticulohistiocytosis (MRH) and histologic findings of xanthoma disseminatum (XD), indicating the plausible association and the shared disease spectrum of MRH and XD.

A Rare Case of Persistent Xanthoma Disseminatum without Any Systemic Involvement.

A Rare Case of Persistent Xanthoma Disseminatum without Any Systemic Involvement.

Diabetes insipidus as first clinical manifestation of Xanthoma Disseminatum: a case report

Diabetes insipidus as first clinical manifestation of Xanthoma Disseminatum: a case report

Osteoarticular lesion in xanthoma disseminatum treated with total hip arthroplasty: a case report

IntroductionXanthoma disseminatum is a very rare disease classified as a benign non-Langerhans cell histiocytosis, which is rarely associated with osteoarticular lesions. There is only a report of tumor abrasion during treatment of osteoarticular lesions of this disease, artificial joint replacement has not been reported. We describe a patient in whom bilateral total joint replacement was performed for disseminated xanthoma lesions of the hip joints.Case presentationA 34-year-old Japanese woman had a chief complaint of bilateral coxalgia. She had been diagnosed as having disseminated xanthoma. Radiographs showed numerous 5-mm radiolucent bands that resembled worm-eaten tracks in the lower part of the femoral heads adjacent to the joint surface. In addition, short tau inversion recovery imaging scans showed high-intensity areas from the femoral head to the neck in both femurs, suggesting bone marrow edema. Total hip arthroplasty was performed for hip arthrosis on both hip joints caused by disseminated xanthoma. Deflection of the implants was a concern from the early stages postoperatively, but both the imaging and clinical findings have been satisfactory for 4 years of follow-up.ConclusionsA very unusual hip joint lesion of xanthoma disseminatum was replaced with a total artificial joint replacement, and the course over 4 years was good. Our patient’s course will continue to be followed carefully.

Airway management of a patient with severe airway obstruction caused by xanthoma disseminatum

Airway management of a patient with severe airway obstruction caused by xanthoma disseminatum