Marius Raica

Background/Objectives: Cutaneous melanoma spreads preferentially through the lymphatic system, and sentinel lymph node status is among the strongest prognostic factors. Whether tumour angiogenesis and lymphangiogenesis add prognostic information beyond conventional histopathology has been examined in many immunohistochemical studies, with heterogeneous results. We conducted a systematic review, reported according to PRISMA 2020 and not registered, of blood microvascular density (MVD), lymphatic vessel density (LVD) in the intratumoral and peritumoral compartments, proliferating (Ki-67-positive) lymphatic vessels and lymphatic invasion (LI) as prognostic markers in primary cutaneous melanoma. Methods: PubMed/MEDLINE was searched to 10 September 2026, supplemented by a Web of Science export and by citation tracking of the reference meta-analysis by Pastushenko et al. (2014). Twenty-one cutaneous study units (25 reports) and four ocular studies providing indirect evidence were included, and risk of bias was rated with the QUIPS tool. Results: In the reference meta-analysis, peritumoral LVD and LI, but not MVD or intratumoral LVD, were associated with metastasis. The newer cohorts confirmed this pattern and provided adjusted effect sizes: peritumoral LVD predicted disease-free (HR 2.14) and melanoma-specific survival (HR of 2.74; 95% CI 1.31 to 5.73), immunohistochemically detected LI predicted sentinel node metastasis (33% vs. 11% positive nodes) and overall survival, and a Ki-67-positive lymphatic endothelium predicted melanoma-specific mortality (adjusted HR of 2.03; 95% CI 1.33 to 3.10) in 264 patients. Blood MVD and blood endothelial proliferation were not prognostic. Heterogeneity of markers, counting methods and effect measures precluded re-pooling. Conclusions: Peritumoral LVD, LI and proliferating lymphatics are promising adjunct biomarkers for selecting patients for sentinel node biopsy, adjuvant therapy and closer follow-up, pending standardised, digital-pathology-based quantification.

Background: The tumor immune microenvironment, particularly the role of cytotoxic CD8+ T lymphocytes, is crucial in cancer progression but remains poorly understood in pituitary neuroendocrine tumors (PitNETs). The significance of CD8+ cell infiltration varies across PitNET subtypes, suggesting a complex interplay with tumor cell lineage. This study aimed to characterize the distribution of CD8+ tumor-infiltrating lymphocytes across different PitNET subtypes defined by the current WHO classification and to explore their association with clinicopathological features. Methods: We conducted a retrospective study on 40 surgically resected PitNETs. All cases were classified based on immunohistochemical expression of pituitary hormones and lineage-specific transcription factors (PIT-1, TPIT, SF-1). CD8+ lymphocyte density was quantified using immunohistochemistry and calculated as cells/mm². Exploratory statistical analysis was performed based on non-parametric tests to compare CD8+ cell density across tumor subtypes and with parameters like tumor size, invasiveness (Knosp grade), and proliferation index (Ki-67). Findings are to be treated as observational trends. Results: The highest density of CD8+ lymphocytes was observed in plurihormonal PIT-1-positive tumors [17.61 cells/mm² (IQR: 17.61–60.36)], followed by somatotroph [13.2 (6.6–15.72)] and mammosomatotroph [13.83 (0–21.38)] tumors. A difference in CD8+ density was found between PIT-1-positive and PIT-1-negative tumors (n1 = 34, n2 = 6, U = 49.5, p_exact = 0.050, r = 0.33); the medium effect size indicates a possible lineage-related trend. Another difference was observed between SF-1-positive and SF-1-negative tumors (p = 0.025), with SF-1 lineage tumors showing the lowest infiltration. No correlations were found between CD8+ density and tumor size, Knosp grade, or Ki-67 index. Conclusions: The distribution of intratumoral CD8+ T lymphocytes in PitNETs is highly heterogeneous and appears to be strongly dictated by the transcription factor-defined tumor lineage rather than by traditional clinicopathological markers of aggressiveness. PIT-1 lineage tumors harbor a more active immune microenvironment, while SF-1 lineage tumors are relatively ‘immune-poor’. These findings highlight the immunological diversity of PitNETs and support further investigation of the tumor immune landscape. Collaborative multi-institutional studies are required to validate these trends.

Background and Objectives: Angiogenesis plays an important role in many types of cancers, including melanoma. Mast cells are among the most important cellular partners involved in the angiogenic process. The purpose of the present study is to establish the interrelations between microvessels and mast cell density, and to describe the prognostic role of mast cells in malignant melanoma. Materials and Methods: A total of 92 cases of melanoma were evaluated. Hematoxylin–eosin staining and CD34/mast cell tryptase double immunostaining were performed. Results: Of the cases, 28 were classified as T1 (30.43%), 31 as T2 (33.69%), 21 as T3 (22.82%), and 12 as T4 (13.04%). Mast cells were mainly located in the infiltrate area in cases with inflammatory infiltrate. Few mast cells were observed in the absence of infiltrate. A granular type was observed in intratumoral areas with an isolated and perivascular distribution of mast cells. A significant correlation was found between intratumoral MVD and intratumoral MCD (mast cell density) in T1 and T4 melanoma cases (p = 0.0001 and p = 0.0029, respectively). In T2 cases, significant correlations were found between intratumoral and peritumoral MVD and G (p = 0.0169, p = 0.0003), between intratumoral MCD and MVD (p = 0.0041), and between peritumoral MVD and the number of peritumoral mast cells (p = 0.0011). T3 cases showed a significant correlation between the density of intratumoral mast cells and peritumoral ones (p = 0.001); between the MVD and mast cell density of the intratumoral area (p = 0.0001); between the intratumoral MVD and peritumoral mast cell density (p = 0.0001); between the MVD and mast cell density of the peritumoral area (p = 0.0325); and between the peritumoral MVD and intratumoral mast cell density (p = 0.0458). Conclusions: Both intratumoral and peritumoral mast cells were found to participate in melanoma progression, and they showed greater involvement in the early phases of angiogenesis in malignant melanoma.

Current histological staining methods for intestinal tissue analysis face limitations in simultaneously visualizing multiple tissue components, often requiring multiple sequential stains that increase processing time and tissue consumption. This proof-of-concept study aimed to define and develop a pentachromatic staining method for enhanced visualization of gastrointestinal tissue architecture. We developed the Pentachroma O-H method, an original protocol using readily available histological reagents (Alcian Blue pH 2.5, Weigert’s resorcin–fuchsin, Mayer’s hematoxylin, and Van Gieson’s solution) applied in an optimized sequence. The protocol was tested on healthy human ileum tissue obtained from surgical specimens as proof of concept. Thirty serial sections were stained with Pentachroma O-H and compared to adjacent sections stained with conventional hematoxylin–eosin (H&E) to document the emerging morphological characteristics of this original stain. Pentachroma O-H achieved distinct five-color differentiation in approximately 45 min: acidic mucins appeared turquoise–blue, collagen fibers red, elastic fibers black–purple, smooth muscle and erythrocyte cytoplasm yellow, and nuclei blue–black. The method clearly delineated intestinal architecture, including mucosal goblet cells, muscularis mucosae, connective tissue vasculature (parietal smooth muscle and elastic laminae), fibers, and cellular components, as well as lymphoid tissue aggregates and infiltrates, with improved contrast compared to H&E. All tissue components were simultaneously visualized in single sections with excellent morphological preservation. This first description of Pentachroma O-H demonstrates its capability to provide comprehensive ileum tissue visualization equivalent to multiple traditional special stains in a single, efficient protocol, offering significant potential advantages for gastrointestinal pathology assessment and warranting future validation studies across diverse tissue types and pathological conditions.

Pituitary neuroendocrine tumors (PitNETs) represent a complex pathology based on numerous incompletely elucidated molecular mechanisms. Beyond tumor cells, analyzing the tumor microenvironment may help identify novel prognostic markers and therapies. A key component of this environment is the folliculo-stellate (FS) cell. We examined FS cells in 77 PitNETs obtained by transsphenoidal surgery, using glial fibrillary acidic protein (GFAP) as an immunohistochemical marker. Immunohistochemistry for anterior pituitary hormones and transcription factors was performed to accurately classify the tumors. Our study included 19 somatotroph, 16 mammosomatotroph, 5 plurihormonal PIT-1 positive, 7 corticotroph, 14 gonadotroph, 11 unusual plurihormonal, and 5 null cell PitNETs. FS cells were observed in 55 of the cases, distributed isolated, in small groups or diffuse networks. A considerable number of tumors immunopositive for more than one hormone (including associations between GH/PRL, but also unusual combinations like GH/ACTH) also contained FS cells (p < 0.01), suggesting their involvement in tumor lineages differentiation. In 27 tumors, GFAP-positive cells clustered in highly vascularized areas. Additionally, in 11 of these cases a direct interaction between endothelial cells and FS cells was noted, sustaining their potential role in tumor angiogenesis. Given their complexity, FS cells may be crucial for understanding tumorigenesis mechanisms.

Odontogenesis, the development of teeth, is a complex, multistage process that unfolds from early embryogenesis through tooth eruption and maturation. It serves as a classical model of organogenesis due to the intricate reciprocal interactions between cranial neural crest-derived mesenchyme and oral epithelium. This narrative review synthesizes current scientific knowledge on human tooth development, tracing the journey from the embryological origins in the first branchial arch to the formation of a fully functional tooth and its supporting structures. Key morphogenetic stages—bud, cap, bell, apposition, and root formation—are described in detail, highlighting the cellular events and histological features characterizing each stage. We discuss the molecular and cellular regulatory networks that orchestrate odontogenesis, including the conserved signaling pathways (Wnt, BMP, FGF, SHH, EDA) and transcription factors (e.g., PAX9, MSX1/2, PITX2) that drive tissue patterning and cell differentiation. The coordinated development of supporting periodontal tissues (cementum, periodontal ligament, alveolar bone, gingiva) is also examined as an integral part of tooth organogenesis. Finally, developmental anomalies (such as variations in tooth number, size, and form) and the fate of residual embryonic epithelial cells are reviewed to underscore the clinical significance of developmental processes. Understanding the normal course of odontogenesis provides crucial insight into congenital dental disorders and lays a foundation for advances in regenerative dental medicine.

Background/Objectives: The main mechanism of the formation of granulation tissue is the progression of an infection from the tooth to the periapical bone. At this level, the immune system tries to localize and annihilate the microorganism’s injury. Ki-67 is a protein directly associated with the cell proliferation rate, while CD34 is a biomarker involved in angiogenesis, and studies suggest that they both have a positive correlation with the intensity of the local inflammatory infiltrate. This study will determine the immunoexpression of CD34 and Ki-67 in periapical granulomas and assess their impact on the growth and development of this tissue, as well as consider their roles in the proliferative process and aggressiveness of evolution. Methods: In the present study, 35 periapical granulomas obtained after a tooth extraction were included. The specimens were analyzed via histopathology and immunohistochemistry. Results: A positive reaction for the Ki-67 antibody was observed in 32 (86.5%) of the 35 periapical granuloma cases included in our study. We identified the overexpression of Ki-67 and CD34 and further calculated the Ki-67 index to evaluate and correlate the proliferation potential and angiogenesis with regard to the presence of an inflammatory infiltrate. Conclusions: These findings suggest that the persistence of an inflammatory environment directly influences Ki-67 and CD34 expression, sustaining the proliferative capacity of cells and abnormal angiogenesis. This study is the first to evaluate the presence of the CD34+ and Ki-67+ proliferating vessels in periapical granulomas.

Aim and objectives: Melanoma is one of the most complex skin cancers based on its numerous somatic mutations and chromosomal instability. Besides the traditional causative factors, such as ultraviolet radiation, or genetic factors, recent studies showed that melanoma highly depends on its adjacent microenvironment. A malignant tumor, like melanoma, is composed of oncogenic cells, regular cells (melanocytes, macrophages, mast cells, keratinocytes, and others), the supporting stroma, which includes fibroblasts, endothelial cells, immune cells, soluble molecules, and the extracellular matrix (ECM). This article aims to present the tumor microenvironment's main functions in the development or progression of melanoma. Material and methods: we have studied some of the most recent 30 articles based on the role of the microenvironment in melanoma. Results: After analyzing the most recent articles regarding melanoma’s tumor microenvironment (TME) and its impact, we have found that the cells that comprise the TME can affect melanoma’s onset or progression. TME’s cells actively interact with each other and have many functions, from tumor-suppressing roles to the initiation or progression of melanoma. Conclusions: Understanding the complex interplay between tumor cells, and systemic mediators of disease progression is critical for the rational development of effective melanoma treatments. Each cell involved in the TME can play an important role either in the onset or advancement of melanoma with the help of certain mutagenic factors.

Angiogenesis, primarily mediated by vascular endothelial growth factor (VEGF), is a fundamental step in the progression and metastasis of head and neck squamous cell carcinoma (HNSCC). Traditional anti-angiogenic therapies that target the VEGF pathway have shown promise but are often associated with significant side effects and variable efficacy due to the complexity of the angiogenic signaling pathway. This review highlights the potential of a specific VEGF splice form, VEGF165b, as an innovative therapeutic target for HNSCC. VEGF165b, unlike standard VEGF, is a natural inhibitor that binds to VEGF receptors without triggering pro-angiogenic signaling. Its distinct molecular structure and behavior suggest ways to modulate angiogenesis. This concept is particularly relevant when studying HNSCC, as introducing VEGF165b’s anti-angiogenic properties offers a novel approach to understanding and potentially influencing the disease’s dynamics. The review synthesizes experimental evidence suggesting the efficacy of VEGF165b in inhibiting tumor-induced angiogenesis and provides insight into a novel therapeutic strategy that could better manage HNSCC by selectively targeting aberrant vascular growth. This approach not only provides a potential pathway for more targeted and effective treatment options but also opens the door to a new paradigm in anti-angiogenic therapy with the possibility of reduced systemic toxicity. Our investigation is reshaping the future of HNSCC treatment by setting the stage for future research on VEGF splice variants as a tool for personalized medicine.

This pictorial essay aims to navigate through the complexities and challenges of renal transplantation (RT), by weaving together visual imagery with clinical insights within a comprehensive illustrative surgical guide. Herein, we provide a detailed visual exploration of the intricate anatomy and surgical processes necessary for both renal graft retrieval from the donor and also for an adequate implantation in the recipient. Regarding graft retrieval, after reviewing the relevant retroperitoneal surgical anatomy, and donor nephrectomy techniques, graft preservation and optimal backbench graft dissection principles were meticulously analyzed. Thereafter, the recipient surgical strategy for graft implantation was addressed, focusing on preoperative preparations, the site of implantation selection, exposure, operative bed dissection, graft revascularization, and urinary tract reconstruction. Careful donor and recipient selection, meticulous surgical execution, and rigorous postoperative management clearly hold a pivotal role in optimizing patient outcomes. Fostering a deeper understanding of the surgical nuances and clinical management practices that contribute to successful results post-RT, we hope to provide a useful practical tool for clinicians about to embark on the treacherous road of RT surgery. Innovative technologies and surgical practices that have already significantly improved the safety and effectiveness of RT stand testament to the importance of further scientific inquiry, conceptual developments, and clinical integration. Moving forward, it is essential that the medical community continues to refine these strategies and advocate for equitable access to transplantation, ensuring that advancements in the field translate into real-world benefits for all patients grappling with ESRD. The collaborative efforts of multidisciplinary teams are essential in addressing the complex clinical challenges associated with RT, with the ultimate goal of improving patient survival, enhancing graft longevity, and reducing healthcare disparities.