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.

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.
В статье представлен редкий случай некротической ксантогранулемы у пациента 46 лет, дебютировавшей с развития периорбитальных ксантелазм, прогрессирующей двусторонней сенсоневральной тугоухости и двусторонней вестибулопатии с последующим развитием множественной миеломы и амилоидоза. В течение нескольких лет пациент проходил стандартную реабилитацию по поводу хронической сенсоневральной тугоухости, слухопротезирован. Во время стационарного лечения по поводу обострения хронического бронхита выявлена моноклональная гаммапатия. В дальнейшем при тщательном обследовании и неоднократном взятии биопсийного материала верифицированы некротическая ксантогранулема, множественная миелома и AL-амилоидоз. В результате проведения таргетной иммунохимиотерапии удалось добиться улучшения слуховой функции и значительного восстановления вестибулоокулярного рефлекса с двух сторон.

A 55-year-old male patient presenting with 6 months of bilateral difficulty in eye opening was referred to the ophthalmology department. Upon examination, multiple yellowish tumor-like plaques and nodules were observed on the eyelids and chest of the patient, accompanied by keratitis and iridocyclitis. Histopathological examination of the skin lesions on the chest revealed dermal xanthomatous granulomas with progressive necrosis. Bone marrow biopsy showed mantle cell lymphoma. Based on the medical history, the diagnosis of progressive necrotizing xanthogranuloma with mantle cell lymphoma was confirmed. After 6 months of treatment with bendamustine combined with rituximab, there was partial alleviation of ocular symptoms in the patient.
1例主诉为双眼睁眼困难半年的55岁男性患者就诊眼科，查体发现患者双眼眼睑、胸部多发性黄瘤样斑块和结节，并伴有角膜炎和葡萄膜炎。胸部皮损组织病理学检查示真皮内黄色瘤性肉芽肿伴渐进性坏死。骨髓活检示套细胞淋巴瘤。结合病史，确诊为渐进性坏死性黄色肉芽肿伴套细胞淋巴瘤。患者全身应用苯达莫司汀联合利妥昔单抗治疗6个月后眼部症状有所缓解。.

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Necrobiotic xanthogranuloma is a rare disease that is part of the non-Langerhans cell histiocytoses. It is characterized by yellowish skin lesions, which are typically periorbitally localized. Extracutaneous manifestations of all organs are possible and can cause potentially life-threatening complications. The disease also belongs to the facultative paraneoplasias and is often associated with paraproteinemia. These aspects should be considered regarding further diagnostics. Due to the rarity of the disease, there are no standardized guidelines for therapy so far. The combination of prednisolone and chlorambucil as well as intravenous immunoglobulins seem to be effective therapeutic options. We present four cases from our clinic as well as the current results of the literature in this mini-review and would like to highlight the therapeutic challenge as well as the need for the development of guidelines.

Necrobiotic xanthogranuloma is a condition that was first identified in 1980 based on its characteristic histological identity, and it has been known since then as a dermatologic manifestation of an underlying systemic dysproteinemia. Intracranial manifestation is a rare presentation of this condition and has been reported only once in its more than 40 years of existence. Herein and to our knowledge, we report the second observation of an intracranial manifestation and, surprisingly, the first case without the expected dermatologic and systemic dysproteinemia associations. This case identifies an existing knowledge gap in our understanding of necrobiotic xanthogranuloma and emphasises the need for further research into understanding the presentation, comorbidities and management of this condition.

Granulomatous skin disorders comprise a large group of diseases that are typically characterized by granuloma formation both in the skin and in many other tissues. Cutaneous lesions are usually seen as erythematous papules and plaques that may occasionally be arranged in an annular, ringlike configuration. The etiopathogenesis is unclear in most cases, and granuloma formation may be associated with various systemic, infectious, and metabolic disorders, foreign bodies, environmental antigens, or malignancies. Treatment options are dependent on the etiology, extent, and severity of the lesions. This review includes the clinical, histopathologic, and dermatoscopy findings, differentials, and treatment options for noninfectious granulomatous annular skin disorders.

Necrobiotic xanthogranuloma (NXG) is a progressive non-Langerhans cell histiocytosis with a predilection for the periorbital area. NXG is most commonly associated with monoclonal gammopathy and ophthalmic complications. The authors present a 69-year-old man who was evaluated for a left upper eyelid nodule and plaques on the lower extremities, trunk, abdomen, and right upper extremity. Biopsy of the eyelid was supportive for NXG. Serum protein electrophoresis was positive for a monoclonal gammopathy, IgG light chain kappa. MRI showed preseptal involvement. The periocular nodules cleared with a high dose of prednisone; however, the other skin lesions persisted. Bone marrow biopsy showed kappa-restricted 6% plasma cells and he was treated with intravenous immunoglobulin. This case illustrates the importance of clinicopathologic correlations to render an NXG diagnosis.

Objective: To investigate the clinicopathological features of adult orbital xanthogranulomatous disease (AOXGD) with lacrimal gland reactive lymphoid hyperplasia. Methods: Retrospective case series study. The clinical and pathological data of AOXGD cases diagnosed and treated in Tianjin Eye Hospital from January 2002 to December 2021 was reviewed, and the clinical characteristics, radiologic findings and pathological characteristics of periocular and lacrimal gland lesions of 5 cases were retrospectively analyzed. The expression of IgG4 and IgG protein in periocular and lacrimal gland lesions was detected by immunohistochemical staining, and the role of IgG4 in AOXGD was preliminarily studied. Results: There were four females and one male with an average age of 53.8 years (39 to 77 years). Among the five AOXGD cases, there were three cases of adult-onset xanthogranuloma, one case of adult-onset asthma and periocular xanthogranuloma, and one case of necrobiotic xanthogranuloma. All cases involved both eyes. The swelling of eyelids was observed in five cases, and the yellow or pale yellow eyelid skin was found in two cases. Imaging examinations showed the tumor mainly involved the eyelids, subcutaneous tissues, anterior orbit and lacrimal gland. A large number of foam cells and typical Touton giant cells were found in the periorbital lesions, accompanied by different degrees of fibrosis. The fibrinoid necrosis was detected in one case of necrobiotic xanthogranuloma. The lacrimal gland lesions showed different types of reactive lymphoid hyperplasia, including IgG4-related disease in two cases, follicular lymphoid hyperplasia in two cases and focal lymphoid hyperplasia in one case. IgG4 levels of periorbital and lacrimal gland lesions were elevated in four cases. Asthma and elevated serum IgG4 were found in one case of adult-onset periocular xanthogranuloma. Three patients underwent surgical resection and adjuvant hormone or immunosuppressive therapy, and two patients underwent simple surgical resection. The patients were followed up for 1.5 to 10.0 years, one patient was lost, and four patients had no recurrence. Conclusions: AOXGD with lacrimal gland reactive lymphoid hyperplasia is a group of rare diseases. The periorbital lesions of that are characterized by proliferation of foamy histiocytes and Touton giant cells, and the lacrimal gland lesions of that manifest as IgG4-related disease in some cases.
目的： 分析成人眼眶黄色肉芽肿病（AOXGD）伴泪腺反应性淋巴组织增生的临床病理学特点。 方法： 回顾性病例系列研究。收集2002年1月至2021年12月于天津市眼科医院诊治的5例伴有泪腺肿大的AOXGD患者的临床病理资料，所有患者均同时切除眶周和泪腺病变。采用免疫组织化学染色方法检测眶周和泪腺病变中IgG4和IgG蛋白表达情况，分析患者临床表现、影像学和组织病理学特点，探讨IgG4在AOXGD疾病中的作用。 结果： 患者中女性4例，男性1例，年龄39~77岁，平均年龄53.8岁。成人黄色肉芽肿3例，成人眼周黄色肉芽肿合并哮喘型1例，坏死性黄色肉芽肿1例。5例均双眼发病，表现为眼睑肿胀，其中2例眼睑皮肤呈黄色或淡黄色。影像学检查显示病变主要位于眼睑及皮下组织、眶前部和泪腺。组织病理学特征为眶周病变中可见大量泡沫细胞和典型的Touton巨细胞，伴有不同程度的纤维化，1例坏死性黄色肉芽肿同时伴有明显的纤维素性坏死；泪腺病变表现为不同类型的反应性淋巴组织增生性病变，其中2例为IgG4相关性疾病（IgG4-RD），2例为滤泡状淋巴组织增生，1例为灶状淋巴组织增生。免疫组织化学染色显示，4例泪腺和眶周病变组织中IgG4阳性。1例成人眼周黄色肉芽肿合并哮喘型患者血清IgG4等免疫学指标异常。3例经手术切除病变组织后，辅助糖皮质激素或免疫抑制剂治疗，2例行单纯手术切除。随访1.5~10.0年，1例失访，其余4例均未复发。 结论： AOXGD伴泪腺反应性淋巴组织增生罕见，眶周病变以泡沫细胞和Touton巨细胞增生为主要特征，个别病例的泪腺病变表现为IgG4-RD。.