ROMANIAN JOURNAL of MORPHOLOGY and EMBRYOLOGY

Vol. 66 No. 3, July-September 2025

1. Multimodal spectrum of approach in poorly differentiated thyroid carcinoma (an updated analysis)

Mihai Costachescu, Nina Ionovici, Dana Cristina Terzea, Florina Vasilescu, Lucian-George Eftimie, Alexandra-Ioana Trandafir, Ana-Maria Gheorghe, Oana-Claudia Sima, Claudiu Nistor, Mara Carsote

Thyroid malignancy represents the most common type of endocrine cancer, with an increasing incidence all over the world, including an increasing rate of detection among younger adults, 90% to 95% of all cases being non-medullary types. Poorly differentiated thyroid cancer, accounting 1% to 5% of all thyroid malignancies, is a less understood neoplasm compared to the other more frequent and better described thyroid cancers, associating various histological patterns that might bring pitfalls of diagnosis in everyday practice. We aimed to provide an updated analysis in the field of poorly differentiated thyroid carcinoma, based on a multimodal approach, including emergent biomarkers. The current data offers a robust framework for elucidating the biology of poorly differenced thyroid malignancy and further on, it provides the basis for a multilayered therapeutic approach. Emergent biomarkers might be detected from cytological analysis based on fine-needle aspiration or blood assays as cell-free deoxyribonucleic acid (cfDNA), but the most important remains the identification of the molecular and genetic constellation in terms of analyzing RAS, telomerase reverse transcriptase (TERT), B-Raf proto-oncogene, serine/threonine kinase (BRAF), tumor protein p53 (TP53), phosphatase and tensin homolog (PTEN), copy number alterations (CNA) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) profile, which serve as prognostic markers and pointers of anti-cancer medical therapy. Overall, despite recent advances in multimodal management, the prognostic remains severe. The issue is ongoing, and we expect a massive expansion within the following years, across a guideline-based, as well as a personalized decision.

Corresponding author: Nina Ionovici, Associate Professor, MD, PhD; e-mail: nina.ionovici@umfcv.ro

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2. Delayed onset of HPV-associated uterine malignancies: seven pathogenetic factors in contrast to cervical cancer

Anda Lorena Dijmarescu, Ioana-Victoria Camen, Maria Magdalena Manolea, Mirela Radu, Liliana Anghelina, Ana-Maria Boldea, Alexandra-Daniela Rotaru-Zavaleanu, Mircea-Sebastian Serbanescu

Human papillomavirus (HPV) is a well-established etiological agent for cervical cancer, yet its contribution to endometrial malignancies remains underrecognized and mechanistically distinct. This paper synthesizes current evidence to explain the delayed onset of HPV-associated endometrial tumors compared with cervical cancer, organizing the discussion into seven pathogenetic factors. Anatomical distance and the barrier function of the cervical canal and mucus reduce direct viral access to the endometrium. Cyclical shedding of the functional layer imposes a reset that hinders long-term viral persistence, in contrast to the relatively stable cervical epithelium. Prolonged viral latency in the endometrium, combined with a lower frequency of reactivation, further extends the carcinogenic timeline. We highlight the necessity of additional, non-HPV-driven genetic alterations, particularly involving phosphatase and tensin homolog (PTEN), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and mismatch repair (MMR) defects, on which HPV oncoproteins E6/E7 may act as late-stage accelerants rather than primary initiators. Hormonal factors, especially prolonged unopposed estrogen exposure and progesterone-driven immune tolerance, modulate both tissue susceptibility and viral persistence. The endometrial immune microenvironment, adapted for reproductive tolerance, provides cyclical windows of reduced antiviral surveillance that HPV can exploit, while co-infections and microbial dysbiosis facilitate viral ascent, chronic inflammation, and genomic instability. These concepts are illustrated by a case of a woman with prior HPV-induced cervical squamous cell carcinoma who, a decade later, developed a vulvar condyloma and an endometrial stromal sarcoma with a mesenchymal immunophenotype [desmin, cluster of differentiation 10 (CD10), and caldesmon positivity]. The case underscores the possibility of long-latency, field effects, and divergent histological outcomes following HPV exposure. We also discuss emerging data suggesting that endometriosis and other ectopic endometrial proliferations may act as viral reservoirs. Overall, HPV appears to function as a co-factor within a multifactorial pathogenetic network, contributing to a subset of endometrial malignancies after a protracted, decades-long carcinogenic course.

Corresponding author: Ana-Maria Boldea, MD, PhD Student; e-mail: icalugaruanamaria11@yahoo.ro; Ioana-Victoria Camen, MD, PhD; e-mail: ci_victoria0701@yahoo.com

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3. Brain histopathological changes caused by SARS-CoV-2 infection

Roberta Andreea Cercel, Florin Ionut Buibas, Mircea-Sebastian Serbanescu, Daniel Pirici, George Popescu, Nina Ionovici, Marian Valentin Zorila, Ionut Tanase, Laurentiu Mogoanta, Maria Magdalena Manolea

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), affected over 775 million people in 232 countries and regions between 2020 and 2024, causing over seven million deaths and becoming the largest pandemic of the 21st century. Initially considered a respiratory virus with various clinical forms (from asymptomatic to severe clinical forms with severe respiratory failure), it was later shown that the disease also affects other organs and systems, including the nervous system. Therefore, in this study, we aimed at highlighting the histopathological lesions present in the central nervous system (CNS) in patients who died from SARS-CoV-2 infection. For microscopic study, 65 brain fragments were collected from 36 patients infected with SARS-CoV-2, clinically, imaging, and biologically diagnosed with COVID-19 [by real-time reverse transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2]. The patients died under suspicious circumstances from a forensic medicine perspective during 2020 and required autopsy at the Institute of Forensic Medicine, Craiova or the Mina Minovici National Institute of Forensic Medicine, Bucharest, Romania to determine the main causes of death. The most common brain lesions were ischemic, with the aspect of neurons with intensely eosinophilic cytoplasm (red neurons), condensed, pyknotic, hyperchromic nuclei, perineuronal edema, giving the cerebral cortex a spongy appearance, fragmentation of unmyelinated extensions in the neuropil, collapse of blood vessels, and perivascular edema. Multiple vascular thromboses were identified, predominantly in small vessels (capillaries, arterioles, venules) or destruction of endothelial cells (ECs) with increased blood-brain barrier (BBB) permeability, perivascular edema, and collapse of blood vessels or areas of intracranial hemorrhage. The anti-spike antibody showed that the SARS-CoV-2 infected large neurons (pyramidal cells in the cerebral cortex and Purkinje cells in the cerebellar hemispheres), ECs, pericytes, and even smooth muscle cells in the structure of arterioles, metarterioles, and venules.

Corresponding author: George Popescu, MD, PhD; e-mail: george_popescu39@yahoo.com; Maria Magdalena Manolea, Associate Professor, MD, PhD; e-mail: magdalena.manolea@umfcv.ro

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4. Immunoprofile of some transmembrane adhesion molecules in oral squamous cell carcinoma

Ionut-Octavian Ilie, Ionut-Andrei Muraru, Mircea Sorin Ciolofan, Daniela Dumitrescu, Maria-Cristina Munteanu, Marius Matei, Eugeniu Cazacu, Claudiu Margaritescu

Cancer of oral cavity is an increasingly public health concern, ranking as the seventh most frequent cancer in Europe and it is the eleventh deadliest cancer. Oral squamous cell carcinoma (OSCC) has one of the lowest 5-year survival rates, about 50% of these patients will die within five years. Tumors arising in this area often exhibit highly aggressive characteristics, with a strong tendency toward local infiltration and distant spread, leading many patients to be diagnosed with advanced locoregional disease. Thus, it becomes necessary to identify new biomarkers with significant impact on the diagnosis and prognosis of OSCC, to improve clinical management and the quality of life of these patients. Studies in recent decades have investigated the involvement of adhesion molecules in OSCC initiation, tumorigenesis, progression and dissemination. Based on these considerations, this study sought to evaluate the immunoreactivity of three transmembrane adhesion molecules (desmoglein-3, claudin-4, and claudin-7) in primary OSCC and their lymph node (LN) metastases, as well as to assess their potential prognostic significance. To achieve this, we analyzed 39 OSCC samples from diverse anatomical regions and their associated locoregional LN metastases using enzymatic immunohistochemistry, applying integrated optical density (IOD) for quantitative assessment. Our results highlighted a progressive decrease of membranous staining pattern followed by a progressive increase in cytoplasmic and nuclear reactivity for all three investigated markers as these lesions progress from low-grade to high-grade one. The highest cytoplasmic and nuclear reactivity was noticed in poorly differentiated forms, mainly at the periphery of tumor proliferation and at the invasion front. A similar reactivity to that from primary tumors was also noticed in metastatic LN proliferations. So, we concluded that these three biomarkers are involved in OSCC progression and dissemination and their investigation may have prognostic and therapeutic utility.

Corresponding author: Mircea Sorin Ciolofan, Associate Professor, MD, PhD; e-mail: sorin.ciolofan@yahoo.com; Daniela Dumitrescu, Assistant Professor, MD, PhD; e-mail: daniela.dumitrescu@gmail.com

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5. Assessment of the clinical and morphological characteristics of visceral melanoma metastases and primary extracutaneous melanomas

Bianca Roxana Nataras, Alis Liliana Carmen Dema, Aura Jurescu, Octavia Cornelia Vita, Sorina Maria Taban, Ioana Hurmuz, Diana Nadina Szilagyi, Daciana Grujic, Valentin Tudor Popa, Sorin Dema

Aim: This study aimed to assess the clinical and morphological characteristics of patients with visceral melanoma metastases and primary extracutaneous melanomas. Patients, Materials and Methods: We performed a retrospective study on patients with visceral melanoma metastases and primary extracutaneous melanomas, diagnosed in two pathology departments. Results: We identified 50 cases of visceral metastases and eight cases of primary extracutaneous melanomas. A percentage of 56% of the distant metastases involved the brain, 28% were localized in the digestive tract (stomach, small bowel, colon, liver, cystic duct), 16% involved the lung, spleen, adrenal gland, peritoneum, urinary bladder and bone. In 34% of the cases, the metastases were diagnosed prior to the primary melanoma. A percentage of 62.5% of primary extracutaneous melanomas were ocular melanomas, 25% were anal mucosa melanomas and one case (12.5%) involved the penile glans. Statistical analysis showed that distant melanoma metastases were more frequently diagnosed in the seventh decade (p<0.0001), and a higher percentage of patients lived in urban areas (p=0.001). The majority of the primary cutaneous melanomas associated with brain metastases were located on the trunk (p=0.0565). The brain metastases were more frequently diagnosed in males (64%; p=0.0604). Conclusions: The brain is the most frequent organ involved by distant melanoma metastases, followed by the digestive tract. It is important to be aware of the least common metastatic locations such as cystic duct, urinary bladder, adrenal gland, spleen and peritoneum, in order to avoid misdiagnosis.

Corresponding author: Valentin Tudor Popa, MD, PhD Student; e-mail: popa.valentin@umft.ro

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6. Development and assessment of a histopathological stability score for atheroma plaques

Daniela Cristina Pavel Mironescu, Costel Vasile Siserman, Mihaela Laura Vica, Bogdan-Alexandru Gheban, Ioana-Andreea Gheban-Rosca, Alexandra Maria Sonfalean, Denisa Stefania Jurje, Denisa Lucian, Andrei Laurentiu Marusca, Horea-Vladi Matei

Background: Vulnerable atherosclerotic plaques are central to the onset of acute coronary events and abrupt cardiac fatalities. Although significant strides have been made in understanding cardiovascular (CV) diseases, the field continues to require reliable, quantifiable approaches to assess plaque instability. Objective: The purpose of this study was to develop and confirm a novel tissue-based scoring system for evaluating the stability of atherosclerotic plaques, based on an in-depth examination of cases involving sudden cardiac death (SCD). Materials and Methods: We conducted a retrospective analysis of coronary artery specimens from 1189 instances of SCD, which were autopsied at the Institute of Forensic Medicine, Cluj-Napoca, Romania, from 2014 to 2018. The microscopic evaluation focused on key markers of plaque vulnerability, including the thickness of the fibrous cap, the extent of the necrotic core, the degree of inflammatory activity, the presence of bleeding within the plaque, and the nature of calcified deposits. These features were scored separately and integrated into an overall vulnerability metric. The score s consistency and accuracy were tested against expert pathologist evaluations and evidence of plaque rupture or clot formation. Results: Macroscopic examination revealed diffuse cardiosclerosis in 94.9%, myocardial infarctions (26.4% healed, 13.62% acute), and myocardial hypertrophy in 7.82%. Microscopic analysis of atherosclerotic plaques showed high vulnerability with hemorrhage (76.0%), necrotic core (92.6%), cholesterol crystals (61.6%), plaque erosion (42.7%), and rupture (15.3%), despite a median fibrous cap thickness of 149.1 micrometers and 76.6% of plaques classified as moderately stable by histopathological stability score (HSS). Conclusions: This extensive validation establishes the new histopathology-based stability score as a trustworthy, repeatable, and efficient method for assessing atherosclerotic plaque vulnerability. Its use could standardize diagnoses in forensic pathology and support future studies on CV risk assessment.

Corresponding author: Mihaela Laura Vica, Associate Professor, MD, PhD; e-mail: mvica@umfcluj.ro

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7. Immunohistochemical quantification of inflammation associated with gastric adenocarcinomas

Roxana-Andreea Pisica-Ilinca, Oana-Iulia Cretu, Bianca Catalina Andreiana, Anne-Marie Badiu, Claudiu Margaritescu, Raluca-Niculina Ciurea, Mirela Marinela Florescu, Anda Elena Crisan, Razvan Grigoras Capitanescu, Alex Emilian Stepan

Tumor heterogeneity and the multitude of mechanisms involved in the progression of gastric adenocarcinomas (GACs) are reflected in the incidence and mortality rates, which continue to be a problem in oncological pathology. The way in which immune inflammatory elements intervene in the modeling of the tumor environment and influence gastric carcinogenesis is insufficiently known. The study investigated the intratumoral and peritumoral distribution and density of T- and B-lymphocytes and macrophages in 54 cases of GAC in relation to the histological prognostic parameters of the tumors. Discohesive, mixed and tubular adenocarcinomas presented the highest value of cluster of differentiation (CD)45RO reactions in the tumor compartments. In the case of GAC with associated histological aggressiveness parameters, we found higher values of CD20 and CD68 reactions at the intratumoral level, and of CD45RO peritumorally, which suggests different immune immunophenotypes not only in relation to the tumor type, grade and stage, but also to the two compartments. These observations may be useful for establishing criteria for approaching and interfering with immune mechanisms in gastric carcinogenesis, which may improve patient prognosis.

Corresponding author: Anda Elena Crisan, Lecturer, MD, PhD; e-mail: anda_crisan2005@yahoo.com; Razvan Grigoras Capitanescu, Lecturer, MD, PhD; e-mail: razvancapitanescu@gmail.com

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8. Pituitary neuroendocrine tumors in patients with prior extrapituitary cancer - clinical and immunohistochemical insights into a complex association. Evidence from a retrospective series

Ana-Marina Radulescu, Dragos Viorel Scripcariu, Ana-Maria Dumitrescu, Daniel Ilie Rotariu, Veronica Scripcaru, Lucian Eva, Marius Gabriel Dabija, Corina Ciupilan, Anca Sava, Gabriela Florenta Dumitrescu, Cristinel Ionel Stan

Pituitary neuroendocrine tumors (PitNETs), as the old pituitary adenomas are now defined, represent almost 15% of all intracranial neoplasms. Their particularity consists in considerable morphological and functional heterogeneity. Although mostly benign, PitNETs may coexist with systemic malignancies. The aim of this research was to identify possible associations between PitNETs and prior extrapituitary cancers in a series of patients in order to identify common mechanisms between pituitary and systemic pathology because such associations, although rare, are clinicopathologically significant, raising issues of differential diagnosis and therapeutic strategy. We realized a retrospective descriptive study on six patients diagnosed with PitNETs and a documented history of extrapituitary malignancy, surgically treated at Prof. Dr. Nicolae Oblu Emergency Clinical Hospital, Iasi, Romania, between January 2023 and June 2025. Clinical, imaging, and pathological data were collected. Immunohistochemical profile included synaptophysin, cytokeratins, transcription factors [pituitary-specific transcription factor-1 (Pit1), T-box transcription factor 19 (Tpit; Tbx19), steroidogenic factor-1 (SF-1), and pituitary GATA-binding protein 3 (GATA3)], hormonal markers [growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH)], as well as proliferative indices [p53 and Ki67 labeling index (LI)]. The study group comprised four women and two men (mean age 52.7 years). The most frequently associated malignancies were breast carcinoma (BC) and renal cell carcinoma (RCC) (33.3% each), followed by thyroid carcinoma (TC) and hepatocellular carcinoma (HCC) (16.6% each). PitNET subtypes included somatotroph (50%), lactotroph (16.6%), gonadotroph (16.6%), and plurihormonal (16.6%) variants, predominantly microadenomas (83.3%). The mean interval between the two diagnoses was 1632 days (approx. 4.6 years). GH and PRL immunopositivity predominate in cases with BC, RCC, and TC. Proliferative indices were low (Ki67 <4%), except for one lactotroph PitNET (Ki67 LI: 15%, p53: 20%) associated with HCC. This study highlights a potential bidirectional link between pituitary and systemic tumorigenesis mediated by hormonal and proliferative signaling pathways. The predominance of GH/PRL-secreting PitNETs in patients with prior systemic malignancies supports the hypothesis of endocrine and molecular crosstalk through the GH/insulin-like growth factor-1 (IGF-1) axis. Although causality cannot be established, these findings underscore the need for oncological surveillance and endocrine monitoring in patients with PitNETs, especially in those with a previous malignancy.

Corresponding author: Dragos Viorel Scripcariu, MD, PhD; e-mail: dscripcariu@gmail.com; Ana-Maria Dumitrescu, MD, PhD; e-mail: anna.dumitrescu91@gmail.com

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9. Testicular cancer in adolescents: clinicopathological and immunohistochemical aspects

Cristina Elena Singer, Razvan Cosmin Pana, Mihaela Popescu, Jaqueline Abdul-Razzak, Iulian Alin Silviu Popescu, Alex Emilian Stepan, Ileana Octavia Petrescu, Elena Savu, Simina Gaman, Liviu Vasile, Cristina Popescu, Ana Maria Petrescu

Testicular germ cell malignancies have a low prevalence among pediatric neoplasia, presenting a bimodal distribution, the two peaks being around the age of five years and postpuberty. Early identification of these types of solid tumors is extremely important, since the prognosis has improved significantly in recent decades through the multimodal diagnostic and therapeutic approach. Our study refers to two cases of testicular neoplasm diagnosed in the postpubertal period. The two adolescents were diagnosed in the Department of Oncopediatrics, in a short interval (February and March 2023). The diagnostic process was based on biological dosing, histopathological (HP) and immunohistochemical examination of orchiectomy specimens and imaging evaluations (computed tomography and magnetic resonance imaging). Following the investigations described, non-seminomatous germ cell tumors were identified in both cases. In the first patient, the tumor was classified in stage IB, while the second patient presented with advanced stage disease, presenting pulmonary, hepatic and ganglia metastases, being classified in stage IIIC. In both patients, chemotherapy was initiated according to current therapeutic protocols. Testicular tumors are a rare pathology with a specific clinical-biological and HP picture that require a multimodal approach (pediatric oncologist, pediatric surgeon, pathologist, radiologist), and for which the prognosis differs depending on the diagnosis stage and the detected histological type.

Corresponding author: Jaqueline Abdul-Razzak, MD, PhD Student; e-mail: jaquelineabdulrazzak90@gmail.com; Simina Gaman, DMD, PhD; e-mail: simina.gaman@umfcv.ro

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10. An exploratory study on the impact of endocrine and infectious comorbidities on reproductive outcomes after Palmer-type neosalpingostomy

Laurentiu Augustus Barbu, Nicolae Dragos Margaritescu, Liliana Cercelaru, Tiberiu Stefanita Tenea-Cojan, Ioana Alexia Tenea-Cojan, Valentina Caluianu, Gabriel Florin Razvan Mogos, Stelian Stefanita Mogoanta, Liviu Vasile

Background: Hydrosalpinx remains a major cause of female infertility, with Palmer-type neosalpingostomy representing a fertility-preserving alternative to salpingectomy in selected patients. While disease severity is a well-established prognostic factor, the contribution of endocrine and infectious comorbidities to reproductive outcomes after tubal reconstruction remains poorly characterized. Patients, Materials and Methods: This retrospective cohort study included 160 women with hydrosalpinx who underwent Palmer-type neosalpingostomy between January 2018 and December 2024 at Independenta VitaPlus Hospital, Craiova, Romania. Endocrine and infectious comorbidities were systematically assessed preoperatively, including polycystic ovary syndrome (PCOS), thyroid dysfunction, obesity, diabetes, pelvic inflammatory disease (PID), and urinary tract infections (UTI). Pregnancy outcomes were evaluated over a 24-month follow-up period. Statistical analysis included Kaplan-Meier survival estimates and multivariate logistic regression to identify independent predictors of clinical pregnancy. Results: PCOS (30.6%), PID (28.2%), and UTI (18.1%) were the most common comorbidities. Hydrosalpinx severity was the only independent predictor of clinical pregnancy [odds ratio (OR) 0.38, p<0.001]. Although endocrine and infectious comorbidities did not reach statistical significance in multivariate models, Kaplan-Meier analysis revealed observable prolongation in time-to-pregnancy for patients with PID, PCOS, or obesity. Increasing infectious burden (>=2 pathogens) was associated with higher pelvic adhesion rates and reduced conception probabilities. Conclusions: Hydrosalpinx severity remains the main determinant of reproductive prognosis after Palmer-type neosalpingostomy. However, endocrine and infectious comorbidities exert clinically relevant negative effects, supporting a comorbidity-informed approach to patient selection and preoperative optimization. Prospective, multicenter studies with in vitro fertilization (IVF) comparison arms are warranted to refine prognostic models and optimize fertility counseling and treatment strategies.

Corresponding author: Gabriel Florin Razvan Mogos, Lecturer, MD, PhD; e-mail: gabriel.mogos@umfcv.ro; Nicolae Dragos Margaritescu, Lecturer, MD, PhD; e-mail: dmargaritescu@yahoo.com

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11. Supernumerary molars prevalence in a Romanian population sample and their potential value in forensic investigation

Oana Cella Andrei, Daniela Ioana Tarlungeanu, Magdalena Natalia Dina, Mirela Ileana Dinescu, Adriana Bisoc, Livia Alice Tanasescu, Ruxandra Margarit

Aim: The aim of this study was to evaluate the prevalence of supernumerary molars in a Romanian population sample, using 1015 panoramic radiographs from a dental radiographs database, in order to assess the potential value of their presence in forensic identification. Patients, Materials and Methods: 1015 panoramic X-rays of patients aged between 18 and 90 years were examined. A detailed description was made of the supernumerary molars that were found, in order to assess their forensic value; only one case had a cone-beam computed tomography (CBCT) investigation available, that was also analyzed to compare the quantity and quality of the information in CBCT vs. panoramic radiograph. Data were analyzed using Microsoft Excel, analysis of variance (ANOVA) method and Pearson s chi-squared test, with a level of significance set at p<0.05. Results: Only three supernumerary molars were found in our study group, all unilateral, all in the maxilla, two on the left side and one on the right side. The prevalence was 0.3%, with a ratio of 2:1 female vs. male cases; p=0.00123 for males, p=0.00015 for females (p<0.05). Conclusions: In a group of 1015 panoramic dental radiographs, only three supernumerary molars were identified; when such a rare tooth is found in a forensic investigation, it can aid in the positive identification when antemortem dental radiographic or CBCT records are available. Although CBCT had proved superior in terms of details, panoramic radiographs, the routine method of investigation, offered sufficient information, which confirms their value in identifying a person or in confirming a previous identification.

Corresponding author: Adriana Bisoc, Lecturer, DMD, PhD; e-mail: adry_bis@yahoo.com; Livia Alice Tanasescu, Lecturer, DMD, PhD; e-mail: tanasescualice@gmail.com

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12. The influence of diabetes mellitus on blood vessels amounts and immune status in case of breast cancer

Ecaterina Foca, Dumitru Brinza, Ecaterina Carpenco, Valeriu David, Lilian Saptefrati, Veaceslav Fulga

Background: Breast cancer (BC) remains one of the most prevalent malignancies worldwide, and its progression can be influenced by systemic conditions such as type 2 diabetes mellitus (T2DM). Both diseases share common mechanisms of metabolic dysregulation, chronic inflammation, and vascular dysfunction that may reshape the tumor microenvironment (TME). Aim: To conduct a comparative evaluation of the vascular and immune components of the BC microenvironment in patients with and without T2DM, as well as in normal mammary tissue, with particular emphasis on cluster of differentiation (CD)34+ microvessel density (MVD), T-cell subsets (CD3+, CD4+, CD8+), and their association with hormonal receptor status and proliferative index (Ki67). Materials and Methods: Immunohistochemical analysis was performed on 58 invasive ductal carcinomas (29 T2DM-associated, 29 non-diabetic) and 10 normal breast samples. Quantification of immune and vascular markers was correlated with clinical and morphological parameters using Spearman s test and Welch statistics (p<=0.05). Results: T2DM-associated BCs demonstrated significantly increased intratumoral MVD (p=0.03) and decreased intratumoral CD3+, CD4+, and CD8+ lymphocytes compared with non-diabetic tumors, indicating an immune-excluded phenotype. Blood glucose correlated positively with CD34+ vessel content and inversely with Ki67 expression (rs=-0.29, p=0.05). Peritumoral CD8+ cells were positively associated with estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status, suggesting hormonal modulation of immune infiltration. Conclusions: T2DM promotes vascular proliferation and suppresses intratumoral immune activity in BC, creating an angiogenic yet immunosuppressed microenvironment. These findings highlight the impact of metabolic imbalance on tumor biology and underscore the need for integrating metabolic control and immunomodulatory strategies in the management of diabetic BC patients.

Corresponding author: Ecaterina Carpenco, Assistant Professor, PhD; e-mail: ecaterina.carpenco@usmf.md

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13. Leveraging artificial intelligence for cardiovascular risk: a primary care perspective

Christiana Raluca Danciulescu, Mircea Sorin Ciolofan, Constantin Renato Ivanescu, Dragos Ovidiu Alexandru

Background/Objectives: Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide. Primary care physicians, particularly family doctors, play a pivotal role in early detection and prevention. This study investigates the potential of artificial intelligence (AI)-based temporal deep learning (DL) models to support cardiovascular risk (CVR) stratification in primary care. Materials and Methods: We implemented temporal DL architectures, namely Long Short-Term Memory (LSTM) network and Gated Recurrent Unit (GRU), on a clinically realistic synthetic patient cohort. The dataset included demographic and clinical variables such as age, sex, body mass index (BMI), blood pressure (BP), and established risk factors (smoking, diabetes, and hypertension). Models were trained on sequential data to predict CVR categories (low, moderate, and very high) along with their corresponding probabilities. Model outputs were statistically benchmarked and subsequently aligned with actionable clinical recommendations. Results: Both LSTM and GRU models demonstrated the ability to forecast CVR across multiple time horizons. Predictions were successfully translated into clinically interpretable recommendations supporting tailored follow-up intervals and targeted interventions. Conclusions: Integration of AI-driven CVR forecasting into routine family medicine practice can enhance early intervention strategies, optimize patient management, and improve resource allocation. This approach highlights the potential of temporal DL to strengthen preventive care outcomes in primary care settings.

Corresponding author: Mircea Sorin Ciolofan, Associate Professor, MD, PhD; e-mail: sorin.ciolofan@yahoo.com

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14. Small bowel GISTs: clinicopathological patterns and the role of inflammatory markers

Nicolae Dragos Margaritescu, Daniela Marinescu, Tiberiu Stefanita Tenea-Cojan, Liviu Vasile, Liliana Cercelaru, Gabriel Florin Razvan Mogos, Stelian Stefanita Mogoanta, Laurentiu Augustus Barbu

Background: Small bowel gastrointestinal stromal tumors (GISTs) are less common but more aggressive than gastric GISTs, and the prognostic relevance of inflammation-nutrition markers in this subgroup remains unclear. This study evaluated clinical, pathological, and inflammatory-nutritional profiles in patients with small bowel GISTs. Patients, Materials and Methods: We retrospectively analyzed 16 cases of small bowel GIST and assessed clinical features, tumor morphology, immunohistochemistry, and laboratory indices [neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), prognostic nutritional index (PNI), red cell distribution width (RDW)]. Statistical correlations were examined using Spearman and Mann-Whitney tests. Results: Most tumors were large, frequently necrotic, and predominantly spindle-cell type; cluster of differentiation 117 (CD117) and discovered on GIST1 (DOG1) were positive in 93.8% of cases. Patients commonly presented with anemia, elevated inflammatory markers, and reduced PNI. Tumor size moderately correlated with NLR (rho=0.53). A strong inverse correlation was observed between PLR and PNI (rho=-0.686), and PNI was significantly lower in necrotic tumors (p=0.0498). No other significant associations emerged. Conclusions: Although inflammatory markers showed limited overall correlations, the PLR-PNI relationship and reduced PNI in necrotic tumors suggest that inflammation and nutritional decline may reflect tumor aggressiveness in small bowel GISTs. Larger studies are needed to confirm these findings.

Corresponding author: Liviu Vasile, Lecturer, MD, PhD; e-mail: vliviu777@yahoo.com; Gabriel Florin Razvan Mogos, Lecturer, MD, PhD; e-mail: gabriel.mogos@umfcv.ro

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15. Prognostic factors of oral squamous cell carcinoma: a five-year retrospective study in Cluj-Napoca, Romania

Madalina-Anca Moldovan, Cristina Maria Neghina, Bogdan Andrei Bumbu, Alexandru Iosif Precup, Razvan Marius Vicas, Dragos Alexandru Termure, Calin Rares Roman, Cristian Niky Cumpata

Background and Objective: The survival of patients with oral squamous cell carcinoma (OSCC) is influenced not only by tumor characteristics but also by treatment strategies, follow-up, and patient-related factors. This study aimed to determine the overall five-year survival rate in a Romanian cohort and evaluate the impact of key prognostic factors. Patients, Materials and Methods: Seventy-two patients diagnosed with OSCC and treated surgically at the Department of Oral and Maxillofacial Surgery, Emergency County Clinical Hospital, Cluj-Napoca, Romania, between January 2016 and December 2019 were retrospectively analyzed. Prognostic factors included tumor stage, primary site, histological parameters, lymph node involvement, treatment modalities, and demographic variables. Results: Patients were stratified into four groups: five-year survivors (n=26), disease-specific mortality (n=21), mortality from non-oncological causes (n=5), and lost to follow-up (n=20). Overall, 36.1% of patients achieved five-year recurrence-free survival, corresponding to 50% among those with complete follow-up. Survivors were more often diagnosed at early or intermediate stages, had fewer tongue tumors, better differentiation, clear surgical margins, and consistent adjuvant therapy. Notably, 27.8% of patients were lost to follow-up despite favorable pathological features, suggesting systemic gaps in long-term surveillance. Conclusions: The five-year survival rate of 50% reflects both aggressive tumor biology and systemic barriers to care. Clinical stage remains the strongest prognostic factor, but tumor site and histological features, including perineural and lymphatic invasion, significantly influence outcomes even in early disease. Improved long-term survival requires earlier diagnosis, refined prognostic assessment, and multimodal therapy tailored to tumor behavior, alongside better patient follow-up strategies.

Corresponding author: Bogdan Andrei Bumbu, Assistant Professor, DDS, PhD; e-mail: bogdanbumbu@uoradea.ro

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16. Severe myelomeningocele in the fourth pregnancy of a 29-year-old woman: a case report

Liliana Anghelina, Mircea-Sebastian Serbanescu, Cristian Gheonea, Adelina-Maria Anghelina, Mirela Anisoara Siminel, Ancuta-Ramona Camen, Anda Lorena Dijmarescu

Neural tube defects represent a heterogeneous and complex group of congenital abnormalities affecting the central nervous system. These defects occur during embryogenesis as a result of the failure of the neural tube to close completely. A highly clinically significant form is myelomeningocele, often referred to as open spina bifida or spina bifida aperta. Delayed diagnosis presents considerable challenges, and folate deficiency is an important risk factor. This case reports a severe myelomeningocele located in the lumbosacral region of a female neonate, identified at 28-29 weeks gestation during the only prenatal consultation of a 29-year-old woman who had three previous normal pregnancies and did not take folic acid (FA) supplementation. The delayed diagnosis contributed to the progression of degenerative and traumatic lesions in the neural tissue, leading to the development of Chiari malformation type II and hydrocephalus. These conditions had a profound impact on brain development, significantly increasing the severity of the case. Primary prevention through the periconceptional use of FA supplements has been shown in extensive research to significantly reduce the probability of neural tube defects, including myelomeningocele. For this reason, FA fortification programs as a public health measure have been implemented in many countries.

Corresponding author: Mircea-Sebastian Serbanescu, Associate Professor, MD, PhD; e-mail: mircea_serbanescu@yahoo.com

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17. Columnar cell variant of papillary thyroid carcinoma in an adolescent: a comprehensive histopathological, immunohistochemical, and molecular analysis

Gizem Issin, Fatih Demir, Diren Vuslat Cagatay, Ismail Yilmaz

The columnar cell variant (CCV) of papillary thyroid carcinoma (PTC) is a rare histological subtype with distinct morphological and immunohistochemical (IHC) features, which can present diagnostic challenges. We report a case of a 13-year-old girl diagnosed with CCV of PTC (CCV-PTC) following a total thyroidectomy for a solitary thyroid nodule. Histopathological (HP) examination revealed aggressive features, including vascular invasion and extrathyroidal extension. However, no metastases or recurrences were observed during six years of follow-up. This case report provides a comprehensive analysis of a rare CCV-PTC in an adolescent, focusing on its HP, IHC, and molecular characteristics. It also discusses diagnostic pitfalls and differential diagnoses that should be considered.

Corresponding author: Gizem Issin, Associate Professor, MD, PhD; e-mail: gizemissin@gmail.com

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18. Traumatic thoracic extradural cyst - surgical management and literature review

George Popescu, Marius-Cristian Zaharia, Denisa Soci, Carla-Maria Andrasi, Angela Neacsu, Radu-Mircea Gorgan, Ana Catalina Tantu, Georgeta Ionescu

Extradural arachnoid cysts (EACs) are rare, fluid-filled lesions located outside the dura mater, predominantly found in the thoracic spine. While many remain asymptomatic, their progressive enlargement may lead to significant neurological deficits due to spinal cord compression. This case report describes a 43-year-old patient presenting with incomplete paraplegia (Frankel grade C) due to a thoracic EAC at the T5-T6 level. Surgical management involved laminectomy, complete cyst excision, and dural defect repair, leading to neurological improvement. The discussion reviews current diagnostic and therapeutic approaches, emphasizing the importance of early intervention to optimize patient outcomes.

Corresponding author: Marius-Cristian Zaharia, MD; e-mail: zahariamarius16@gmail.com; Ana Catalina Tantu, MD; e-mail: catalina.tantu8@gmail.com

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19. Renal clear cell carcinoma with bilateral parotid and orbital metastases - case report

Marius Octavian Pricop, Horatiu Constantin Urechescu, Flavia Zara, Adrian Camen, Serban Talpos-Niculescu, Cristiana Cuzic, Alisia Pricop, Raluca Maria Closca

Metastatic involvement of the oral and maxillofacial region is an uncommon clinical event. These secondary lesions may develop in several anatomical locations, most frequently within the parotid glands or orbital structures. While many primary tumors that spread to these regions arise from neighboring sites such as the scalp, face, oral cavity, or pharynx, distant subclavicular malignancies can also give rise to metastases in these areas. Among such tumors, renal cell carcinoma (RCC) is the third most frequent source of metastasis to the oral and maxillofacial region. Nevertheless, reports of RCC spreading to the parotid or orbital regions remain exceptionally rare. We present a distinctive clinical case of a 54-year-old man with clear cell RCC that, during its progression, produced simultaneous metastases to both parotid glands and to the orbital region - a combination that, to our knowledge, has not been previously documented in the medical literature.

Corresponding author: Horatiu Constantin Urechescu, Lecturer, DMD, PhD; e-mail: urechescu.horatiu@umft.ro

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20. Localized gingival enlargements: clinical, histopathological and surgical evaluation in five cases

Bilge Cansu Uzun Saylan, Ayca Muhterem, Sulen Sarioglu

Background: Localized gingival enlargements (GEs) are frequently encountered reactive lesions with various etiologies, including chronic irritation, trauma, systemic conditions, hormonal influences, and medication use. Despite their benign nature, these lesions can significantly affect oral function and aesthetics and may occasionally mimic neoplastic processes. This case series aims to present the clinical and histopathological (HP) features of five patients with localized GEs, describe different surgical approaches including scalpel and diode laser excision, and report short-term clinical outcomes. Case presentations: Five patients with gingival overgrowths of varying etiology were evaluated. All underwent thorough periodontal debridement and oral hygiene instruction prior to surgical intervention. HP evaluation followed surgical excision. Patients were monitored for recurrence for at least three months. Lesions included inflammatory epithelial hyperplasia, cavernous hemangioma, and squamous cell papilloma. One case revealed immunoglobulin G4 (IgG4)-positive plasma cells and was referred to Rheumatology Department. A suspected vascular lesion was successfully managed with laser excision to minimize bleeding. One patient exhibited recurrence of a papillomatous lesion, prompting referral to infectious disease. No major complications occurred during the follow-up period. Conclusions: Localized GEs can present diverse HP profiles. Biopsy remains essential for definitive diagnosis, especially when clinical features are ambiguous. Laser surgery proved beneficial in vascular lesions by reducing intraoperative bleeding and enhancing patient comfort. Identifying and managing underlying systemic or local factors is crucial to prevent recurrence.

Corresponding author: Ayca Muhterem, DDS; e-mail: ayca.muhterem@deu.edu.tr

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21. The pineal gland as the hegemonikon of the microcosm: anatomical and philosophical interpretations in Descartes works

Marius Dumitrescu, Ana-Maria Dumitrescu, Elena Sapte, Veronica Scripcaru, Raluca Ozana Chistol, Lucian Eva, Corina Ciupilan, Dragos Andrei Chiran

The pineal gland, a small, unpaired structure located at the center of the brain, was first identified as a distinct organ by Galen of Pergamon, yet its function remained obscure until the early modern period, when philosophers and physicians alike try to understand its function. This paper examines Rene Descartes interpretation of the pineal gland in the treatise Le Monde and within the intellectual context of the heliocentric revolution. As research investigation methods we used social-historical documentation and hermeneutic analysis on Descartes Le Monde and L Homme in relation to the scientific thought of the 17th century, i.e., Harvey s anatomical achievements, and Copernicus, Kepler s, and Galileo s astronomical discoveries. In L Homme, a chapter of his treatise Le Monde, Descartes analyzed the complex role of the pineal gland not only in a philosophical manner, but also from a medical point of view. The French thinker gave up the analogy between the gland located in the middle of the brain and the pinecone and preferred the analogy with the Sun which in ancient Greek mythology was called Helios, whose role in the cosmic system was considered to be a Hegemonikon. Thus, Descartes named the pineal gland as gland H. Inspired by Copernicus and Kepler s heliocentric theory and by William Harvey s conception about blood circulation, Descartes has built an analogy between the Sun (Helios), heart, and gland H. As Sun (Helios) ruled the planets in its system, and heart pumped the blood into circulatory system, so gland H (pineal gland) could direct animal spirits through the nerves. Metaphors and analogy method allowed the French philosopher to establish an objective scientific presentation about pineal gland, emphasizing the macrocosm-microcosm analogy and the conceptual shift of the vital center from the heart to the brain.

Corresponding author: Ana-Maria Dumitrescu, University Assistant, MD, PhD; e-mail: anna.dumitrescu91@gmail.com

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22. Letter to the Editor: Comments on Comprehensive insights into Pindborg tumor: etiology, advanced diagnostic approaches, and evidence-based management strategies - review of literature by Cumpata et al.

Manas Bajpai

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Corresponding author: Manas Bajpai, Professor, MDS; e-mail: dr.manasbajpai@gmail.com

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