OBJECTIVE: 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.
METHODS: 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.
CONCLUSIONS: 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.

BACKGROUND: Tenosynovial giant cell tumor (TGCT) is a monoarticular fibrohistiocytic benign or locally aggressive soft tissue tumor that originates from the synovium of joints, bursae, and tendon sheaths. It has an inflammatory neoplastic nature, with a clinical presentation ranging from pain, swelling, stiffness, and limited range of movement to joint instability and blockage. Its uncommon incidence leads to a poorly understood pathogenesis. Localized forms of TGCT (LTGCT) can cause significant morbidity, interfere with daily patient activities, and decrease the patient\'s quality of life in challenging cases. This study aimed to investigate the immunohistochemical expression of PPARγ (peroxisome proliferator-activated receptor gamma) and P53 in LTGCT to understand the disease better and offer potential therapeutic targets.
METHODS: The study is cross-sectional, in which 27 LTGCT cases were collected from the Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt. Solitary and multiple LTGCT cases retrieved between January 2018 and December 2022 were included, and immunohistochemically stained with anti-PPARγ and P53 antibodies. The TGCT samples were excluded if they were insufficient for sectioning, processing, and interpretation, over-fixed, had process artifacts, or were of the diffuse TGCT type. Scoring of stain expression was performed by ImageJ (National Institutes of Health, Bethesda, MD) analysis using the threshold method and was expressed in percent area/high power field. Clinicopathological correlations were analyzed.
RESULTS: All the 27 collected LTGCT cases were located in the small joints of patients\' hands. Cases with solitary LGTCTs constituted 55.6% (n = 15), while 44.4% (n = 12) had multiple LTGCTs related to one affected site/case (e.g., multiple tumors in one finger). PPARγ was expressed in the cytoplasm of mononuclear and multinucleated tumor cells and foamy histiocytes, while P53 expression was mainly in mononuclear cells\' nuclei. PPARγ significantly correlated with P53 expression (r = 0.9 and P = 0.000). PPARγ (r = 0.4 and P = 0.02) and P53 (r = 0.5 and P = 0.01) were positively correlated with tumor size. Only P53 expression was positively correlated with tumor multiplicity (r = 0.4 and P = 0.03). Using the receiver operating characteristic curve test, the P53 cutoff score detecting the multiplicity of TGCTs was ≥20.5%, with a 75% sensitivity and 80% specificity.
CONCLUSIONS: PPARγ and P53 have a significant role in LTGCT growth, while P53 plays a role in tumor multiplicity. They can be possible targets in LTGCTs unfit for excision.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma with sparse tumor B-cells and a favorable prognosis. Variant growth patterns of NLPHL, however, often show advanced stage, progression to T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) and a worse prognosis. We studied the tumor microenvironment (TME) of NLPHL and THRLBCL using highplex imaging and spatial profiling at the single cell level. Our findings show distinct differences in TME composition and spatial configuration that differ among typical and variant NLPHL and THRLBCL. Typical NLPHL show abundant helper T-cell subsets, while THRLBCL show abundant cytotoxic T-cells and macrophages. Tumor B-cell size and content is lowest in typical NLPHL, followed by variant NLPHL, and highest in THRLBCL, whereas an opposite trend characterized TME B-cells. CD4/CD8 double-positive T-cells are seen in all NLPHL but not in the majority of THRLBCL and are spatially distant from LP-cells and TFH-rosettes. The differences in macrophage/monocyte content in distinguishing NLPHL pattern E from THRLBCL is further corroborated in independent cohorts of cases. Our results validate the current approach to classification and in addition provide novel insights that could be leveraged to refine clinical management for patients with this spectrum of lymphomas.

Neurologic Rosai-Dorfman disease (RDD) is a rare type of non-Langerhans cell histiocytosis that affects the central nervous system. Most neurologic RDDs grow like meningiomas, have clear boundaries, and can be completely resected. However, a few RDDs are invasive and aggressive, and no effective treatment options are available because the molecular mechanisms involved remain unknown. Here, we report a case of deadly and glucocorticoid-resistant neurologic RDD and explore its possible pathogenic mechanisms via single-cell RNA sequencing. First, we identified two distinct but evolutionarily related histiocyte subpopulations (the C1Q+ and SPP1+ histiocytes) that accumulated in the biopsy sample. The expression of genes in the KRAS signaling pathway was upregulated, indicating gain-of-function of KRAS mutations. The C1Q+ and SPP1+ histiocytes were highly differentiated and arrested in the G1 phase, excluding the idea that RDD is a lympho-histio-proliferative disorder. Second, although C1Q+ histiocytes were the primary RDD cell type, SPP1+ histiocytes highly expressed several severe inflammation-related and invasive factors, such as WNT5A, IL-6, and MMP12, suggesting that SPP1+ histiocytes plays a central role in driving the progression of this disease. Third, oligodendrocytes were found to be the prominent cell type that initiates RDD via MIF and may resist glucocorticoid treatment via the MDK and PTN signaling pathways. In summary, in this case, we report a rare presentation of neurologic RDD and provided new insight into the pathogenic mechanisms of progressive neurologic RDD. This study will also offer evidence for developing precision therapies targeting this complex disease.

Erdheim Chester Disease (ECD) is a rare histiocytic disorder marked by infiltration of organs with CD68+ histiocytes. ECD stems from mutations of BRAF and MAP2K1 in hematopoietic stem and progenitor cells (HSPCs), which further differentiate into monocytes and histiocytes. Histopathology reveals lipid-containing histiocytes, which test positive for CD68 and CD133 in immunohistochemistry. Signs and symptoms vary and depend on the organ/s of manifestation. Definitive radiological results associated with ECD include hairy kidney, coated aorta, and cardiac pseudotumor. Treatment options primarily include anti-cytokine therapy and inhibitors of BRAF and MEK signaling.

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The majority of patients with Parkinson disease (PD) experience a loss in their sense of smell and accumulate insoluble α-synuclein aggregates in their olfactory bulbs (OB). Subjects affected by a SARS-CoV-2-linked illness (COVID-19) also frequently experience hyposmia. We previously postulated that microglial activation as well as α-synuclein and tau misprocessing can occur during host responses following microbial encounters. Using semiquantitative measurements of immunohistochemical signals, we examined OB and olfactory tract specimens collected serially at autopsies between 2020 and 2023. Deceased subjects comprised 50 adults, which included COVID19 + patients (n = 22), individuals with Lewy body disease (e.g., PD; dementia with Lewy bodies (n = 6)), Alzheimer disease (AD; n = 3), and other neurodegenerative disorders (e.g., progressive supranuclear palsy (n = 2); multisystem atrophy (n = 1)). Further, we included neurologically healthy controls (n = 9), and added subjects with an inflammation-rich brain disorder as neurological controls (NCO; n = 7). When probing for microglial and histiocytic reactivity in the anterior olfactory nuclei (AON) by anti-CD68 immunostaining, scores were consistently elevated in NCO and AD cases. In contrast, microglial signals on average were not significantly altered in COVID19 + patients relative to healthy controls, although anti-CD68 reactivity in their OB and tracts declined with progression in age. Mild-to-moderate increases in phospho-α-synuclein and phospho-tau signals were detected in the AON of tauopathy- and synucleinopathy-afflicted brains, respectively, consistent with mixed pathology, as described by others. Lastly, when both sides were available for comparison in our case series, we saw no asymmetry in the degree of pathology of the left versus right OB and tracts. We concluded from our autopsy series that after a fatal course of COVID-19, microscopic changes in the rostral, intracranial portion of the olfactory circuitry -when present- reflected neurodegenerative processes seen elsewhere in the brain. In general, microglial reactivity correlated best with the degree of Alzheimer\'s-linked tauopathy and declined with progression of age in COVID19 + patients.

Histiocytic neoplasms are diverse clonal haematopoietic disorders, and clinical disease is mediated by tumorous infiltration as well as uncontrolled systemic inflammation. Individual subtypes include Langerhans cell histiocytosis (LCH), Rosai-Dorfman-Destombes disease (RDD) and Erdheim-Chester disease (ECD), and these have been characterized with respect to clinical phenotypes, driver mutations and treatment paradigms. Less is known about patients with mixed histiocytic neoplasms (MXH), that is two or more coexisting disorders. This international collaboration examined patients with biopsy-proven MXH with respect to component disease subtypes, oncogenic driver mutations and responses to conventional (chemotherapeutic or immunosuppressive) versus targeted (BRAF or MEK inhibitor) therapies. Twenty-seven patients were studied with ECD/LCH (19/27), ECD/RDD (6/27), RDD/LCH (1/27) and ECD/RDD/LCH (1/27). Mutations previously undescribed in MXH were identified, including KRAS, MAP2K2, MAPK3, non-V600-BRAF, RAF1 and a BICD2-BRAF fusion. A repeated-measure generalized estimating equation demonstrated that targeted treatment was statistically significantly (1) more likely to result in a complete response (CR), partial response (PR) or stable disease (SD) (odds ratio [OR]: 17.34, 95% CI: 2.19-137.00, p = 0.007), and (2) less likely to result in progression (OR: 0.08, 95% CI: 0.03-0.23, p < 0.0001). Histiocytic neoplasms represent an entity with underappreciated clinical and molecular diversity, poor responsiveness to conventional therapy and exquisite sensitivity to targeted therapy.

Crystal-storing histiocytosis (CSH) is a rare condition in which crystals accumulate in the cytoplasm of histiocytes and is usually associated with a lymphoplasmacytic neoplasm. Cutaneous CSH is extraordinarily rare and limited to case reports in the literature. We report two cases of this disease with cutaneous involvement. Case 1 was a 65-year-old male with a 4-month history of a pruritic eruption that started as a solitary pink to skin-colored indurated plaque on the anterior neck before progressing to involve the whole neck, chest wall, and face. Case 2 was a 54-year-old woman with a history of unspecified \"lymphoma\" who presented with a soft nodule on the forearm. Biopsies from both cases had similar findings and showed a proliferation of epithelioid cells with pink cytoplasm and intracellular crystalline structures infiltrating the dermis and subcutaneous fat. In the first case, the cells were positive for CD43, CD45, CD68, and IgG kappa, and in the second case, the crystals were positive for IgG lambda. Based on these findings, the patients were diagnosed with cutaneous CSH. We highlight this rare diagnosis and the importance of investigating an underlying lymphoplasmacytic neoplasm.

Objective: To investigate the clinicopathological features of Erdheim-Chester disease (ECD) initially diagnosed at extraskeletal locations. Methods: Clinical and pathological data of four cases of ECD diagnosed initially in extraskeletal locations were collected at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, from January 2013 to June 2023. BRAF V600E gene was detected by reverse transcription polymerase chain reaction (RT-PCR). Pertinent literatures were reviewed. Results: Four ECD patients included two males and two females ranging in ages from 2 years 11 months to 69 years. The lesions located in the lung (two cases), central nervous system (one case), and the testicle (one case) were collected in the study. One patient had occasional fever at night, one had nausea and vomiting, and two were asymptomatic. Radiologically, the two pulmonary ECD showed diffuse ground-glass nodules in both lungs, and the lesions in central nervous system and testicle both showed solid masses. Microscopically, there were infiltration of foamy histiocyte-like cells and multinucleated giant cells in a fibrotic background, accompanied by varying amounts of lymphocytes and plasma cells. The infiltration of tumor cells in pulmonary ECD was mainly seen in the subpleural area, interlobular septa, and perivascular and peribronchiolar areas. The fibrosis was more pronounced in the pleura and interlobular septa, and less pronounced in the alveolar septa. Immunohistochemical staining showed that all tumor cells expressed CD68, CD163 and F􀃼a; one case showed S-100 expression; three cases were positive for BRAF V600E; all were negative for CD1α and Langerin. RT-PCR in all four cases showed BRAF V600E gene mutation. Conclusions: Extraskeletal ECD is often rare and occult, and could be easily misdiagnosed, requiring biopsy confirmation. The radiologic findings of pulmonary ECD is significantly different from other types of ECD, and the histopathological features of pronounced infiltration in the subpleura area, interlobular septa, perivascular and peribronchiolar areas can be helpful in the differential diagnosis from other pulmonary diseases. Detection of BRAF V600E gene mutation by RT-PCR and its expression by immunohistochemical staining are also helpful in the diagnosis.
目的： 探讨以骨外为首发部位的Erdheim-Chester病（Erdheim-Chester disease，ECD）的临床病理学特征。 方法： 收集华中科技大学同济医学院附属协和医院病理科2013年1月至2023年6月诊断的ECD，分析4例以骨外为首发部位的ECD的临床及病理资料，采用逆转录聚合酶链反应（RT-PCR）法检测BRAF V600E基因，并复习相关文献。 结果： 4例ECD患者，男女各2例，年龄2岁11个月至69岁，病变分别位于肺（2例）、中枢神经系统（1例）及睾丸（1例）。1例偶发夜间发热，1例有恶心、呕吐，其余2例无明显临床症状。2例肺ECD表现为双肺弥漫分布的磨玻璃结节影，中枢神经系统及睾丸的病例表现为实性占位。镜下均见纤维化背景中泡沫样组织细胞浸润，伴数量不等的多核巨细胞、小淋巴细胞及浆细胞浸润，其中肺ECD的肿瘤细胞浸润主要出现在胸膜下、小叶间隔、血管周和细支气管周围，纤维化在胸膜和小叶间隔更为明显，在肺泡间隔中不明显。免疫组织化学染色肿瘤细胞均表达CD68、CD163及F􀃼a，不表达CD1α及Langerin，仅1例表达S-100蛋白，3例BRAF V600E阳性。RT-PCR法检测4例均具有BRAF V600E基因突变。 结论： 以骨外为首发部位的ECD罕见且起病隐匿，临床上容易误诊，需通过活检予以明确诊断。肺ECD与其他脏器ECD的影像学改变显著不同，其胸膜下、小叶间隔、血管周和细支气管周围浸润的组织学特点也有助于与其他肺疾病进行鉴别。使用免疫组织化学染色或RT-PCR技术检测BRAF V600E基因突变状态有助于诊断，且2种检测方法有较好的一致性。.