J. Mol. Pathol., Volume 5, Issue 4 (December 2024) – 7 articles

Background/Objectives: Colorectal cancer (CRC) is the third leading cause of cancer death globally, with rising incidence. The immunohistochemistry (IHC) for mismatch repair (MMR) proteins is the first technique used in routine practice to evaluate an MMR status. Microsatellite instability (MSI) may be tested in case of doubt during IHC staining. This study introduces a novel high-resolution melt (HRM) protocol for MSI detection and compares it with traditional fragment length analysis (FLA) via capillary electrophoresis. Methods: A total of 100 formalin-fixed and paraffin-embedded CRC specimens were analyzed using two distinct protocols: one based on FLA (TrueMark MSI Assay kit) and another one based on HRM (AmoyDx^® Microsatellite Instability Detection Kit). Results: Overall, 68 (68.0%) of the cases were MSS, and 32 (32.0%) were MSI-H. HRM analysis was first successfully carried out in all the cases. A perfect concordance in MSI evaluation between HRM and FLA was observed. HRM showed slightly shorter hands-on time and turnaround time. Conclusions: We provided evidence of the validity of this new HRM approach in determining the MSI status of colorectal carcinomas. Full article

Periodontal disease remains a significant global health concern, characterized by complex host–pathogen interactions leading to tissue destruction. This review explored the role of pattern recognition receptors (PRRs) in the pathogenesis of periodontal disease, synthesizing current knowledge on their molecular mechanisms and potential as therapeutic targets. We examined the diverse family of PRRs, focusing on toll-like receptors (TLRs) and NOD-like receptors (NLRs), elucidating their activation by periodontal pathogens and subsequent downstream signaling cascades. This review highlights the intricate interplay between PRR-mediated pathways, including NF-κB and MAPK signaling, and their impact on inflammatory responses and bone metabolism in periodontal tissues. We discussed the emerging concept of PRR crosstalk and its implications for periodontal homeostasis and disease progression. Furthermore, this review addressed the potential of PRR-targeted therapies, exploring both challenges and opportunities in translating molecular insights into clinical applications. By providing an overview of PRRs in periodontal health and disease, this review aims to stimulate future research directions and inform the development of novel diagnostic and therapeutic strategies in periodontology. Full article

Birt–Hogg–Dubé syndrome (BHDS) is an autosomal dominant disease characterized by skin, lung, and renal manifestations. This syndrome is caused by a germline mutation in the FLCN gene, which leads to disruption in multiple downstream pathways. Renal cell carcinomas are one of the serious clinical manifestations of the disease, which usually presents as bilateral and multiple tumors. Morphologically, most of these tumors are classified as hybrid oncocytic tumors. Recent advances in molecular techniques have shed light on the pathogenesis of these renal tumors. In this review, we evaluate and summarize the current knowledge of BHDS, pathologic changes, and its molecular basis with the focus on the renal hybrid oncocytic tumor (HOT), their pathogenesis, and molecular underpinning. Full article

The rising global incidence of uterine cancer has been linked to the escalating prevalence of obesity. Obesity results in insulin resistance which alters the IGF system, thereby driving cancer progression via increased cell proliferation and the inhibition of apoptosis, although the precise mechanisms remain unclear. In a previous study, we compared the levels of IGF1 and IGF2 between fifty endometrial cancer patients (study group) and fifty age-matched non-cancer patients with benign gynaecological conditions (control group), identifying a correlation with menopause. Building on these data, we now report that IGF levels in pre-menopausal women were significantly lower in the study group compared to the control group, a pattern not observed in post-menopausal women. We undertook the receiver operating characteristic (ROC) curve analysis for calculating the potential of IGF1 and IGF2 to effectively distinguish pre-menopausal women with endometrial cancer from those without it. For pre-menopausal women, the area under ROC curve values were 0.966 for IGF1 and 0.955 for IGF2, both with significant p-values, indicating that IGF1 and IGF2 levels have the potential to be diagnostic biomarkers for distinguishing pre-menopausal women with endometrial cancer from those without it. In summary, our findings emphasise the importance of considering menopausal status in the context of IGF level assessments and suggest that IGF1 and IGF2 could play a crucial role in the early diagnosis of endometrial cancer in pre-menopausal women. Full article

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by symmetrical joint inflammation, cartilage degradation, and bone erosion. This review explores the multifaceted aspects of RA pathogenesis, focusing on the dynamic interplay between innate and adaptive immune responses, genetic predisposition, and environmental triggers. The development of RA involves genetic susceptibility and trigger events such as infections, trauma, smoking, obesity, and microbiome alterations, fostering autoimmune reactions and tissue/organ destruction. The innate immune response, including toll-like receptor activation and synovial fibroblasts’ roles, contributes to the acceleration of inflammatory processes in joint tissues. Monocytes and macrophages organize and sustain chronic joint inflammation, leading to tissue damage and bone resorption, while highlighting the significance of CD14 and CD16 subsets in RA pathogenesis. In the adaptive immune response, aberrant activation and proliferation of CD4+ T cells and the role of regulatory T cells in maintaining immune tolerance are discussed. Target cytokines like TNF-α, IL-6, IL-1, IL-17, and BAFF, as well as chemokines such as CCL2, CXCL10, CCL5, and CXCL12, have emerged as critical components in managing chronic inflammation and joint damage in RA. This comprehensive overview provides insights into the pathophysiology of RA and potential therapeutic avenues, emphasizing the importance of understanding these complex immunological and genetic mechanisms for developing more effective treatment strategies. Full article

The extracellular matrix is an organized three-dimensional network of protein-based molecules and other macromolecules that provide structural and biochemical support to tissues. Depending on its biochemical and structural properties, the extracellular matrix influences cell adhesion and signal transduction and, in general, can influence cell differentiation and proliferation through specific mechanisms of chemical and mechanical sensing. The development of body tissues during ontogenesis is accompanied by changes not only in cells but also in the composition and properties of the extracellular matrix. Similarly, tumor development in carcinogenesis is accompanied by a continuous change in the properties of the extracellular matrix of tumor cells, called ‘oncomatrix’, as the tumor matures, from the development of the primary focus to the stage of metastasis. In this paper, the characteristics of the composition and properties of the extracellular matrix of tumor tissues are considered, as well as changes to the composition and properties of the matrix during the evolution of the tumor and metastasis. The extracellular matrix patterns of tumor tissues can be used as biomarkers of oncological diseases as well as potential targets for promising anti-tumor therapies. Full article

Aggressive B-cell lymphoma encompasses Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and, as per the 2016 WHO classification, high-grade B-cell lymphoma (HGBL) not otherwise specified (NOS) and HGBL double/triple hit (DH/TH). However, the diagnostic distinction of HGBL from BL and DLBCL is difficult by means of histology/immunostaining in a substantial number of patients. This study aimed to improve subtyping by the identification of molecular features of aggressive B-cell lymphomas, with a specific focus on HGBL. To this end, we performed a comprehensive gene expression and mutational pattern analysis as well as the detection of B-cell clonality of 34 cases diagnosed with BL (n = 4), DLBCL (n = 16), HGBL DH (n = 8), and HGBL NOS (n = 6). Three distinct molecular subgroups were identified based on gene expression, primarily influenced by MYC expression/translocation and cell proliferation. In HGBL, compared to BL, there was an upregulation of PRKAR2B and TERT. HGBL DH exhibited elevated expression of GAMT and SMIM14, while HGBL NOS showed increased expression of MIR155HG and LZTS1. Our gene mutation analysis revealed MYC, ARID1A, BCL2, KMT2D, and PIM1 as the most affected genes in B-cell lymphoma, with BCL2 and CREBBP predominant in HGBL DH, and MYC and PIM1 in HGBL NOS. Clonality analysis of immunoglobulin heavy and light chain rearrangements did not show distinguishable V- or J-usage between the diagnostic subgroups. Full article