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.

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。.

Erdheim-Chester disease (ECD) is a rare histiocytosis characterized by the foamy CD68+CD1a- histiocytes infiltrating multiple organs and tissues. ECD might be asymptomatic or present with variable manifestations. The diagnosis of ECD requires characteristic radiological findings and pathological features. Herein, we described a 52-year-old female patient who was admitted to our hospital for recurrent pericardial effusion for two months. She has a medical history of papillary thyroid carcinoma (PTC) and underwent a total thyroidectomy two years before admission. The radiological findings suggested a potential diagnosis of ECD. Cytological analysis of the effusion cytology specimen revealed CD68+CD1a- histiocytes, confirming the ECD diagnosis. The BRAF V600E mutation was identified in the histiocytes, prompting the administration of vemurafenib, a BRAF inhibitor. After two months of standard-dose vemurafenib treatment, the disease was well controlled with pericardial effusion regression.

As the soil of life, the composition and shaping process of the immune microenvironment of the uterus is worth exploring. Macrophages, indispensable constituents of the innate immune system, are essential mediators of inflammation and tissue remodeling as well. Recent insights into the heterogeneity of macrophage subpopulations have renewed interest in their functional diversity in both physiological and pathological settings. Macrophages display remarkable plasticity and switch from one phenotype to another. Intrinsic plasticity enables tissue macrophages to perform a variety of functions in response to changing tissue contexts, such as cancer and pregnancy. The remarkable diversity and plasticity make macrophages particularly intriguing cells given their dichotomous role in either attacking or protecting tumors and semi-allogeneic fetuses, which of both are characterized functionally by immunomodulation and neovascularization. Here, we reviewed and compared novel perspectives on macrophage biology of these two settings, including origin, phenotype, differentiation, and essential roles in corresponding microenvironments, as informed by recent studies on the heterogeneity of macrophage identity and function, as well as their mechanisms that might offer opportunities for new therapeutic strategies on malignancy and pregnancy complications.

UNASSIGNED: Immunohistochemically, histiocytosis differentiating into Langerhans cells is typically characterized by the expression of CD1a, S100, and varying degrees of Langerin. However, CD1a-positive but S100-negative histiocytosis is extremely rare in clinical practice. We present a case of a 9-year-old boy with multiple erythematous to brown dome-shaped nodules. Histopathologic examination revealed dermal infiltrates of histiocytic cells, exhibiting a distinctive immunohistochemical profile of CD68+, S100-, CD1a+, and Langerin-. This exceptional case may contribute to our understanding of the etiology and differentiation processes of histiocytic proliferative disorders.

Rosai-Dorfman disease (RDD) is currently considered a group of neoplastic diseases of unknown etiology, with monoclonal proliferation of histiocytes, showing unique histopathologic features and varying clinical presentation. Primary thymic RDD is an extremely rare extranodal form of this disorder. In this study, we describe the case of an otherwise healthy 64-year-old Chinese man who presented with an isolated, asymptomatic soft tissue density lesion in the anterior mediastinum detected by computed tomography. Histology of the surgical specimen revealed infiltration of thymic tissue by sheets of large histiocytes with mixed lymphocytes and plasma cells, and background fibrosis. Immunohistochemical staining of the histiocytes was positive for S100, CD68, CD163, OCT2 and cyclin D1, but negative for CD1a and BrafV600E expression, thus supporting a diagnosis of RDD. Primary thymic RDD is extremely rare and may be a diagnostic challenge when presenting as mediastinal lesion.

OBJECTIVE: The authors investigated the expression of IgG4 and IgG in cutaneous Rosai-Dorfman Disease (CRDD) to further improve the understanding of this disease.
METHODS: The authors retrospectively reviewed the clinicopathological features of 23 CRDD patients. The authors diagnosed CRDD by the presence of emperipolesis and immunohistochemical (IHC) staining of histiocytes consisting of S-100(+)/CD68(+)/CD1a(-) cells. The expressions of IgG and IgG4 in cutaneous specimens were assessed by IHC (EnVision) and quantitatively calculated by a medical image analysis system.
RESULTS: All 23 patients, including 14 males and 9 females, were confirmed to have CRDD. Their ages ranged from 17 to 68 years (mean 47.91 ± 14.16). The most frequently affected skin regions were the face, followed by the trunk, ears, neck, limbs, and genitals. In 16 of these cases, the disease presented as a single lesion. IHC staining of sections showed that IgG was positive (≥ 10 cells/High-Power Field [HPF]) in 22 cases, while IgG4 was positive (≥ 10 cells/HPF) in 18 cases. Moreover, the IgG4/IgG proportion ranged from 1.7% to 85.7% (mean 29.50 ± 24.67%, median 18.4%) in the 18 cases.
CONCLUSIONS: In the majority of studies, as well as in the current study, the design. RDD is a rare disease, so the sample size is small. In the next studies to come, the authors will expand the sample for multi-center verification and in-depth study.
CONCLUSIONS: The positive rates of IgG4 and IgG and the IgG4/IgG ratio assessed through IHC staining may be important in understanding the pathogenesis of CRDD.

A 45-year-old female patient was found to have a nodule in the right lower lobe on physical examination. Chest CT showed the nodule was lobulated measuring 24 mm×23 mm, with obvious enhancement and adjacent pleural traction. As the PET-CT showed increased 18F-FDG uptake suggesting malignancy, the wedge resection of the right lower lobe was performed. Grossly, the mass was adjacent to the pleural area with indistinct boundary. On cut sections, the lesion was solid and tough, with a greyish-pink colour. Microscopically, the lesion had an ill-defined margin, and was composed of spindle and polygonoid histiocytes with rich eosinophilic cytoplasm similar to rhabdoid muscle cells. The cytoplasm of histiocytes was filled with diamond-shaped or club-shaped crystals. Immunohistochemistry (IHC) showed the histiocytes were positive for CD68, κ, λ, IgG, IgM and IgA. The patient had been followed up for 41 months and had shown neither recurrences nor new diseases. CSH is a rare non-neoplastic histiocytic proliferative disease. Pulmonary CSH should be differentiated from multiple diseases. Accurate pathological diagnosis depends on its morphology and immunophenotype. This disease is often related to potential lymphoproliferative or plasma cell disorder. After diagnosis, a systemic examination is required and long-term follow-up is recommended.
本文报道1例发生于肺的结晶体贮积性组织细胞增生症（crystal-storing histiocytosis，CSH）。患者体检发现肺部肿物，胸部CT示右肺下叶结节影，边缘毛糙，分叶状，增强后见明显强化，邻近胸膜受牵拉。PET-CT示代谢稍高，考虑恶性病变。行右肺下叶楔形切除术。根据病理形态及免疫组织化学（immunohistochemistry，IHC）诊断为CSH。患者术后随访41个月，未提示病灶复发，未提示其他新发疾病。CSH是一种罕见的非肿瘤性组织细胞增生性疾病，以嗜酸性晶体物质在组织细胞胞质内聚集为特征。该疾病往往与淋巴细胞增生性疾病或浆细胞性疾病相关，诊断后需进行全身检查，并建议长期随诊。.

Anaplastic lymphoma kinase (ALK)-positive histiocytosis, a novel rare histiocytic proliferation, was first described in 2008; it occurs in early infancy with liver and hematopoietic involvement. The spectrum was subsequently broadened to include localized diseases in older children and young adults. However, its full clinicopathological features and molecular lineage have not been fully elucidated.
Here, we report four cases of multisystem ALK-positive histiocytosis without hematopoietic involvement. Clinically, three patients were adults aged between 32 and 51 years. Two patients\', whose main manifestations were intracranial mass and numerous micronodules in the thoracoabdominal cavity organs and skin papules respectively, had a partial response to ALK inhibitors after surgery. One patient presented with mediastinal neoplasm without surgical treatment, and progressive disease occurred after two years of ALK inhibitor therapy. The fourth patient was a 17-month-old male with a large intracranial mass and presented with a poor response to ALK inhibitor and chemoradiotherapy; he died eight months after surgery. Pathologically, the histiocytes were large, with abundant eosinophilic cytoplasm, and mixed with variable numbers of foamy cells and Touton giant cells. Interstitial fibrosis was also observed. Histiocytes were positive for macrophage markers (CD68 and CD163) and ALK. KIF5B-ALK fusions were detected in two cases, EML4-ALK in one, and both DCTN1-ALK and VRK2-ALK fusions were detected in one case.
We observed that ALK inhibitors present robust and durable responses in adult patients but a poor response in young children with central nervous system involvement. There is no consensus on the optimal treatment regimen and long-term prognosis requires further observation. Moreover, every unusual histiocytic proliferative lesion, especially unresectable and multisystem involvement, should be routinely tested for ALK immunohistochemical staining to identify this rare disease.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis (LCH) that results in multiorgan disease involving the skin, bones, lungs, and kidneys. Female reproductive system manifestation of ECD was rare. Herein, we report a case of ECD involving the left ovary and fallopian tube. A 69-year-old woman presented with abdominal pain for 20 days. Magnetic resonance imaging revealed a solid and cystic mass on the left pelvic cavity. Histological examination revealed ovarian and fallopian tube infiltration by abundant histiocytes, with single small nuclei and foamy cytoplasm, reactive small lymphocytes, and plasma cells. Based on histopathological and immunohistochemical findings of positivity for CD68, CD163, and BRAF V600E and negativity for CD1α and S100, the molecular finding of BRAF V600E mutation, the patient was diagnosed with ECD. Positron emission tomography examination did not reveal any other lesions. The patient recovered well 12 months after surgery without any treatment. ECD involving the left fallopian tube and ovary was rare and needed to be differentiated from LCH, Rosai-Dorfman disease (RDD), juvenile xanthogranuloma (JXG), IgG4+-related disease (IgG4+RD), and metastatic signet ring cell carcinoma.