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.

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.

BACKGROUND: Rosai-Dorfman disease (RDD) is a form of non-Langerhans cell histiocytosis in which the activated histiocytes of the lymph nodes and other organs begin to accumulate following excessive production. Bilateral, massive, and painless lymphadenopathy are classic presentations. Systemic RDD is already known to be a rare condition, but isolated cutaneous RDD is extremely rare. We presented a rare and unusual presentations of a disease.
METHODS: A 35-year-old Thai female with a 6-month history of a small acne-like lesion that rapidly progressed to 5 cm tumor-like lesions on the face within 3 months. Tissue histology showed a dense dermal infiltration of histiocytes with emperipolesis phenomenon. Immunohistochemistry was positive for S100 protein and CD68 and negative for CD1a. Oral prednisolone (50 mg/day) was initiated with a favorable outcome at the one-month follow-up. However, prednisolone yielded a partial response at 2-month follow-up, leading to application of another modality.
CONCLUSIONS: Although cutaneous Rosai-Dorfman disease is considered benign and well medical responded disease, patients with atypical presentation and rapid growing lesion may necessitate aggressive multimodal treatment.

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).
CONCLUSIONS: 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.

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.

Rosai-Dorfman disease (RDD) is a rare non-Langerhans cell histiocytosis characterized by an accumulation of activated histiocytes within the affected tissues. It is a heterogeneous disease that includes the classical (nodal) and extra-nodal variants. The cutaneous form of the disease without the characteristic lymphadenopathy is rare and is often misdiagnosed as other dermatologic diseases. Misdiagnosis as lymphoproliferative and infectious diseases such as lymphoma and tuberculosis have been reported in the literature. Herein, we report a case of facial cutaneous RDD with successful surgical treatment. In addition, we provide dermoscopic findings and literature review as dermoscopy can be a useful adjuvant tool in the diagnosis of cutaneous RDD.

Tissue eosinophilia is seldom reported in B-cell lymphoma. It poses diagnostic challenges and frequently leads to the consideration of other diagnoses, particularly T-cell lymphomas. The scarce literature underscores the need for in-depth studies to enhance awareness and understanding of this phenomenon. We investigated 54 cases of B-cell lymphoma with notable tissue eosinophils, analyzing clinical information, hematoxylin and eosin staining, immunohistochemistry, and PCR-based clonality analysis. Nodal marginal zone lymphoma (NMZL) emerged as the most prevalent type (n=26), followed by B-cell lymphoma, not otherwise specified (n=13), diffuse large B-cell lymphoma (n=10), follicular lymphoma (n=2), chronic lymphocytic leukemia/small lymphocytic lymphoma (n=1), extranodal marginal zone lymphoma (n=1), and primary cutaneous marginal zone lymphoma (n=1). Shared features across different lymphoma types, best exemplified by NMZL, included plasmacytic differentiation (57.7%), increased vascularity (84.6%) with a tendency for perivascular distribution of neoplastic cells, and a tumor microenvironment abundant in T cells and histiocytes; some cases showed increased PD-1-positive cells. These features often raise consideration of angioimmunoblastic T-cell lymphoma. Along with clonality analysis, features supporting the diagnosis of B-cell lymphoma included cytological atypia in B cells rather than T cells, and the lack of follicular dendritic cell meshwork expansion. In addition, diffuse large B-cell lymphoma frequently exhibited interfollicular distribution and monocytoid appearance, indicating the possibility of transformed NMZL. Collectively, tissue eosinophilia can occur in diverse B-cell lymphomas but is most prevalent in tumors with a postgerminal stage of differentiation.

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.