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The lymphoreticular system and bone marrow
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Classical HL (CHL) accounts for 94% of all HLs, and is characterized by the presence of typical Reed–Sternberg cells and their mononuclear variants, collectively termed ‘Hodgkin/Reed–Sternberg cells’ (HRS cells). As cells similar to HRS cells can sometimes be seen in other conditions, it is important that there is also a mixed inflammatory background consisting of small lymphocytes, histiocytes, plasma cells, eosinophils, and neutrophils (Figure 9.3). The Reed–Sternberg cells each have multiple nuclei (mostly two muclei are seen), each with a large eosinophilic nucleolus (Figure 9.4); the cytoplasm is abundant. Mononuclear and pleomorphic variants are common. The HRS cells have a particular phenotype that can easily be established by immunocytochemistry on paraffin sections. They are positive for CD30 and CD15, and negative for the standard B-and T-cell antigens (see Figure 9.10). The expression of Pax5, a transcription factor initiating B-cell development, is proof of the B-cell origin of these cells and helps in difficult cases to make the distinction between HL and certain T-cell lymphomas. Surprisingly, HRS cells are also negative for CD45, the common leukocyte antigen that is expressed on all lymphocytes. Although the pathologist is usually fairly certain of the diagnosis based on the H&E morphology, it is good practice to perform immunophenotyping to support this impression. If the immunocytochemical profile does not fit, an alternative diagnosis should be considered, because there are many mimics of HL.
Monocyte and lymphocyte membrane markers: Ontogeny and clinical significance
Published in Gabriel Virella, Medical Immunology, 2019
Scott Sugden, Damien Montamat-Sicotte, Karen K. Yam, Joseph Murphy, Bader Yassine Diab, Virginia Litwin
B lymphopoiesis requires three transcription factors, E proteins (E2A and EBF), and Pax5. E2A and EBF act in concert to drive the differentiation of common lymphocyte precursors toward the B-lineage pathway by activating B cell–restricted gene expression and μIgH chain gene rearrangements. Commitment to the B cell lineage is orchestrated by Pax5, which simultaneously represses the transcription of B cell lineage-inappropriate and activates the expression of B cell lineage-specific genes. Terminal differentiation of B cells to memory cells and plasma cells depends on the transcriptional repressor Blimp-1.
Classical Hodgkin Lymphoma
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
NS HL is the most common subtype of classical HL. It is characterized by a thickened lymph node capsule and prominent bands of collagen springing from the capsule, dividing the lymph node into variably sized nodules (Figure 24.6). Even early faint collagenous bands, which are birefringent under polarized light, qualify for categorization as NS HL. The neoplastic cells occur in variable proportions. They have multiple or multilobated nuclei with prominent macronucleoli. In formalin-fixed tissue, R–S cells often display contraction of the cytoplasm creating “empty” space around large tumor cells, hence the term lacunar cells. The syncytial variant of NS HL contains increased numbers of neoplastic cells that form sheets and large clusters (Figure 24.7). The R–S cells, including lacunar and all other variants, have classic phenotype (CD30+, CD15+/−, CD20−/+, CD19−, CD45−, EBV/EBER−/+, PAX5+, EMA−, and MUM1). The expression of PAX5 is dimmer than in benign small B cells. CD15 is positive in the majority of cases, but occasionally may be focal and dim. CD20 is positive in ~20% and EBV (EBER) with similar frequency. Although NS HL is a well-defined category, it is still very heterogeneous in its histologic appearance and survival. It is suggested that the grading of NS HL based on eosinophilia, lymphocyte depletion, and atypia of the Hodgkin/R–S cells may indicate a prognosis in intermediate and advanced stages of HL. Mostly intrasinusoidal involvement of the lymph node by HL, mimicking anaplastic lymphoma, may be occasionally seen (Figure 24.7).
Positive expression of PAX7 indicates poor prognosis of pediatric and adolescent AML patients
Published in Expert Review of Hematology, 2020
Tianyou Yan, Duolan Naren, Yuping Gong
PAX7 is a member of the paired box (PAX) family of transcription factors. Members of this gene family typically contain a paired box domain, an octapeptide, and a paired-type homeodomain. These genes play critical roles during fetal development and cancer growth. Furthermore, PAX7 was well studied in postnatal skeletal muscle development. In mouse skeletal muscles, PAX7 was expressed in proliferating myoblasts and was downregulated after myogenic differentiation [10]. Consistently, during differentiation of goat skeletal muscles, PAX7 expression in satellite cells was significantly downregulated [11]. PAX3 and PAX7 are co-expressed in the dermomyotome during mouse embryonic development [12]. Their expression gives rise to myogenic progenitor cells, which are necessary for myogenic development. Unlike its partner, PAX7 is predominantly required for adult myogenesis and specifies the adult stem cell population in muscles [10,13,14]. Moreover, the expression of PAX genes is also essential for growth and survival of certain cancers [15–17]. Studies showed that PAX5 expression occurs in various types of malignant tumors, including hematological malignancies, B-cell non-Hodgkin lymphoma, and Hodgkin lymphoma [17]. However, PAX7 expression is a unique feature of rhabdomyosarcoma and Ewing sarcoma [18]. In fact, PAX7 expression was present in 86% of rhabdomyosarcoma cases, and its expression was significantly increased in Ewing sarcoma compared to other soft tissue tumors, demonstrating the utility of immunohistochemical analysis of PAX7 expression as a diagnostic marker of Ewing sarcoma and rhabdomyosarcoma [18,19].
FOXO1 and PAX5 Rearrangement in Alveolar Rhabdomyosarcoma in Saudi Pediatric Patients
Published in Fetal and Pediatric Pathology, 2023
There are many ways for PAX5 to be abnormally expressed that are not related to gene rearrangement and PAX5 expression by immunohistochemistry has been previously described. However, PAX5 rearrangement was considered invalid in defining the molecular profile of ARMS [17]. The transcription factor PAX5 is frequently detected in inflammation, cancers, and other diseases by controlling B-cell development and impeding PI3K-AKT signaling [16,29,30]. Because PAX5 facilitates differentiating mature B cells, it promotes humoral immunity. Recently, PAX5 is considered a tumoral suppressor oncogene in gastric cancer [31] and pancreatic cancers [32].
Identification of latent core genes and pathways associated with myelodysplastic syndromes based on integrated bioinformatics analysis
Published in Hematology, 2020
According to the PPI network data, we selected twelve DEGs as core genes with degrees no less than 10. Our study found that the twelve core genes were more greatly downregulated in the MDS cases than in the normal samples, and the analysis of cellular biology processes revealed that these genes were mainly enriched in immune process, leukocyte activation, and response to stimulus. Among these core genes, PAX5 and RAG1 showed higher node degrees with 17 and 15. PAX5, which forms transcriptional regulators and fulfills an instructive role in the early B cell stage, has been shown to be correlated with B cell commitment, development, and leukemogenesis [29,30]. In addition, conditional loss of PAX5 allows mature B cells from peripheral lymphoid organs to dedifferentiate back to early uncommitted progenitors homing to the bone marrow [31]. On the other hand, PAX5 also functions as a tumor suppressor in human B cell malignancies [32]. In the present study, the PPI network showed that PAX5 could directly interact with RAG1/2, FOXO1 and EBF1, indicating a dispensable role of PAX5 in tumor maintenance. RAG1/2, the recombination activating gene protein complex, regulates cell cycle progression through phosphorylation of RAG2 mediated by the complex called cyclin A – cyclin-dependent kinase 2 (CDK2) [33,34]. In addition, conditional deletion of RAG1 in MDS mouse models has also increased the incidence of transformation into AML [35]. Hence, it may be regarded as a valuable biomarker for the diagnosis, treatment and prognosis of MDS. FOXO1, a key RAG1/2 transcription factor, was found to regulate RAG expression by IL7R signaling and pre-B cell signaling [36–38]. Gross et al. [39] have reported that FOXO1 belongs to major transcription factors related to the stress response pathway. We observed that the dysregulation of FOXO1 was significantly associated with TGFβ, IL2/STAT5, Notch signaling and apoptosis pathways, which were abnormal signaling resulting in impaired hematopoiesis, promotion of bone marrow fibrosis, and driving of osteoblastic lineage cell remodeling in the bone marrow niche [40]. Moreover, it has been reported in a human liver cancer cell line that FOXO1 was identified as a core molecule interacting with other genes for the processes of positive transcriptional regulation and inhibitory regulation of programed cell death [41]. Thus, FOXO1 might function as a latent tumor biomarker in the prognosis prediction for MDS.