ROMANIAN JOURNAL of MORPHOLOGY and EMBRYOLOGY

Vol. 65 No. 1, January-March 2024

1. Primitive neuroectodermal tumors of the ovary: a multidecade review of the scientific literature

Tiberiu-Augustin Georgescu, Antonia Carmen Georgescu, Andrei Dennis Voichitoiu, Dragos Cretoiu, Nicolae Suciu, Adriana-Irina Ciuvica

Primitive neuroectodermal tumor (PNET) is a general term used in scientific literature for a heterogeneous group of small round-cell malignant tumors primarily arising from neural crest cells. These are extremely aggressive neoplasms which usually occur within soft tissue or bone of young adults. Ovarian tumors composed of primitive neuroectodermal elements are extremely rare, with only few case reports in scientific literature. Due to being so exceedingly rare, PNETs are frequently misdiagnosed and there are no standard therapeutic guidelines. Young patients seem to have better prognoses and individualized strategy is recommended. Limited data suggests that various gene deletions as well as amplifications may be crucial factors for tumorigenesis and the aggressive behavior of PNET. In this paper, we performed a brief review of all cases of primary ovarian PNETs published in the scientific literature to date, in regard to their clinical, histopathological, and therapeutic aspects, with the aim to provide a more comprehensive understanding of this exceedingly rare pathology.

Corresponding author: Antonia Carmen Georgescu, Assistant Professor, MD, PhD; e-mail: antoniacarmen.georgescu@gmail.com

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2. Neurobiological mechanisms and therapeutic impact of electroconvulsive therapy (ECT)

Ana-Maria Cojocaru, Antonia Ioana Vasile, Simona Corina Trifu

Electroconvulsive therapy (ECT) is an efficient therapeutic resource for psycho-pharmacotherapeutic resistant forms of depression. ECT is a form of electrical brain stimulation involving the induction of a controlled seizure, clinically similar to an epileptic seizure, that is initiated in the prefrontal region of the brain and spreads to the cortex and subcortex, including the diencephalic structures. This is achieved by creating a transcranial electric field and synchronously depolarizing neuronal membranes. The mechanisms of action of ECT are not yet fully understood, but several hypotheses have been proposed to explain how it affects the brain: neurotransmitter changes, neuroplasticity, network connectivity, endocrine system regulation and changes in regional cerebral blood flow and regional metabolism.

Corresponding author: Antonia Ioana Vasile, MD; e-mail: antoniaioana97.vasile@gmail.com

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3. Immunoexpression of Ki67, P16 and Beta-catenin in precursor lesions of cutaneous squamous cell carcinoma

Alina Maria Vilcea, Loredana Elena Stoica, Bianca Catalina Andreiana, Cecil Sorin Mirea, Tiberiu Stefanita Tenea Cojan, Ioana Cristina Vilcea, Claudiu Margaritescu

Cutaneous squamous cell carcinoma (CSCC) is the second most common type of skin cancer, after basal cell carcinoma, representing about 10-20% of all malignant skin tumors. The mortality rates of CSCC approach those of renal and oropharyngeal carcinomas, as well as melanoma, with the increasing of the risk once metastases and perineural invasion occur. Both actinic keratosis (AK) and Bowens disease (BD) are direct precursors with the potential for progression to CSCC. In this study, we analyzed the expression of Ki67, P16 and Beta-catenin in the precursor lesions of CSCC in relation to histological prognostic parameters, respectively between them, with the aim of identifying possible correlations with a role in prognosis. Ki67 and P16 presented higher scores in advanced precancerous lesions, such as keratinocyte intraepithelial neoplasia (KIN) III and BD and low scores in seborrheic keratosis (SK). The immunoreactivity to the investigated markers confirms the multistage skin carcinogenesis, and their involvement starting from the initiation phase of the cancer process. The importance of the studied markers in the evolution and prognosis of precancerous lesions of CSCC is also supported by the linear correlations revealed between the immunoexpressions of P16, Ki67 and the membranous immunoexpression of Beta-catenin in AK.

Corresponding author: Bianca Catalina Andreiana, Assistant Professor, MD, PhD; e-mail: bianca_naidin@yahoo.com

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4. Cyclophosphamide stimulates endoplasmic reticulum stress and induces apoptotic cell death in human glioblastoma cell lines

Mustafa Oztatlici, Hulya Oztatlici, Suna Karadeniz Saygili, Ismail Kaya, Ilker Deniz Cingoz

Cyclophosphamide (CP) is an alkylating chemotherapeutic agent commonly used in cancer treatments. In this study, we aimed to investigate the effects of 4-Hydroperoxy cyclophosphamide (4-HC), which is active form of CP, on glucose-regulated protein 78 (GRP78), activating transcription factor 6 (ATF6), phospho-protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (p-PERK), phospho-inositol-requiring enzyme 1 alpha (p-IRE1alpha), eukaryotic translation initiation factor 2 alpha (eIF2alpha), and caspase-3 messenger ribonucleic acids (mRNAs) and proteins that play roles in the ER stress pathway and apoptosis in U87 and T98 human glioblastoma cell lines. U87 and T98 human glioblastoma cell lines were divided into control and 4-HC-treated groups. Cell viability assay was used to detect the half maximal inhibitory concentration (IC50) for 24 hours of 4-HC. Immunocytochemistry and quantitative polymerase chain reaction (qPCR) methods were used to evaluate the levels of proteins and their mRNAs. The IC50 values of U87 and T98 cells were calculated as 15.67+/-0.58 microM and 19.92+/-1 microM, respectively. The levels of GRP78, ATF6, p-PERK, p-IRE1alpha, eIF2alpha, and caspase-3 protein expressions in the 4-HC-treated group compared to that in the control group. These increased protein expressions also were correlated with the mRNA levels. The ER stress signal pathway could be active in 4-HC-induced cell death. Further studies of ER-related stress mechanisms in anticancer treatment would be important for effective therapeutic strategies.

Corresponding author: Mustafa Oztatlici, Assistant Professor, PhD; e-mail: mustafaoztatlici@gmail.com

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5. Epidemiological and histopathological aspects of ocular melanomas in Northeastern Romania

Claudia Florida Costea, Andrei Ionut Cucu, Gabriela Florenta Dumitrescu, Anca Sava, Gabriela Dimitriu, Tina Botoc, Mihaela Roxana Popescu, Catalin Mihai Buzduga, Ana Maria Dumitrescu, Alexandra Starica, Georgiana Macovei, Iulian Prutianu, Laurentiu Andrei Blaj, Daniela Maria Tanase, Dragos Viorel Scripcariu

Ocular melanoma is a rare but complex disease in current medical practice. Our retrospective study spans over a period of 28 years and analyzed uveal and conjunctival melanomas that were consecutively admitted, diagnosed, and treated in the 2nd Ophthalmology Clinic of Prof. Dr. Nicolae Oblu Emergency Clinical Hospital, Iasi, Romania. The patients were selected from the records of the Department of Pathology of our Hospital, being diagnosed by standard histopathological techniques. The aim of this study was to summarize the epidemiological and pathological aspects of uveal and conjunctival melanomas in Northeastern region of Romania. In our study, we did not notice a predilection of uveal and conjunctival melanoma to one particular gender. The most common histological subtypes of ocular melanomas were the heavily pigmented spindle cell subtype, followed by the epithelioid subtype. Our patients sought medical help in a timely manner, before the systemic invasion of the disease could develop.

Corresponding author: Andrei Ionut Cucu, MD, PhD; e-mail: andreiucucu@yahoo.com; Catalin Mihai Buzduga, Professor, MD, PhD; e-mail: buzdugacatalin@yahoo.com

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6. MMP1, MMP9, MMP11 and MMP13 in melanoma and its metastasis - key points in understanding the mechanisms and celerity of tumor dissemination

Bogdan Stelian Mastalier Manolescu, Angela Madalina Lazar, George Sorin Tiplica, Sabina Andrada Zurac, Adrian Rebosapca, Bogdan Andreescu, Cristiana Gabriela Popp

Background: Matrix metalloproteinase (MMP)1, MMP9, MMP11, and MMP13 are overexpressed in malignant melanoma (MM), being associated with tumor invasive phase, metastases, and more aggressive neoplastic phenotypes. Aim: The main objective of the current study was to correlate the expression of the MMPs with the evolution of MM toward distant metastasis. Patients, Materials and Methods: We designed a retrospective cohort study, including 13 patients with metastatic MM. Data concerning age, sex, localization of the primary lesion and metastasis, and histological and immunohistochemical features (intensity of expression and percent of positive cells for MMPs) were statistically processed. Results: The time between the diagnosis of primitive melanoma and the diagnosis of metastasis ranged between 0 and 73 months, with a mean value of 18.3 months. The metastases rich in MMP1- and MMP9-positive cells occurred earlier than the metastases with low levels of positive cells. The mean period until metastasis was shorter for the MMP1-expressing tumors than the ones without MMP1 expression. MMP13 expression in the tumor and its metastasis was significantly linked with the time until the metastasis occurrence. Conclusions: This study emphasizes the roles of MMP1, MMP9, and MMP13 in the process of metastasis in melanoma and the opportunity to use them as therapeutic targets and surveillance molecules.

Corresponding author: Angela Madalina Lazar, Assistant Professor, MD, PhD; e-mail: angelalazar.2008@yahoo.com

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7. Ultrastructural changes of lung tissue under conditions of experimental obesity and smoking

Yuliia Kuzyk, Olena Mazur, Yuryj Bisyarin

Obesity can cause respiratory disorders inflicted by adipose tissue accumulation and the numerous cytokines adipocytes produce. Smoking is, first of all, associated with a wide range of lung diseases characterized by diffuse changes in the lung tissue and a decrease in the respiratory volume of the lungs. The study aimed to investigate the ultrastructural changes in the lungs of sexually mature male rats under conditions of experimental obesity and smoking. The total sample of experimental animals consisted of 120 rats, divided into four groups: the control group (n=30) - conditionally healthy rats fed on a standard diet; a group of rats subjected to isolated exposure to tobacco smoke (n=30); a group of experimentally obese rats (n=30) and a group of experimentally obese rats simultaneously exposed to tobacco smoke (n=30) - feeding using a high-fat diet with exposure to a chamber with tobacco smoke. The revealed ultrastructural features of the lungs in the group of rats with experimental obesity and the group of rats with experimental obesity that were simultaneously exposed to tobacco smoke did not differ qualitatively, which indicates that pathological changes in the ultrastructure of the lung tissue developed regardless of the presence or absence of a direct damaging effect on the lung tissue of passive smoking.

Corresponding author: Yuliia Kuzyk, Professor, MD, PhD; e-mail: juliakuzyk21@gmail.com

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8. Endothelial cell proliferation and vascular patterns in urothelial carcinoma

Tiberiu Gabriel Adelmann, Amalia Raluca Ceausu, Nela Pusa Gaje, Marius Raica

Introduction: The bladder cancer has some characteristics: the sixth most incident neoplasm in the United States, the majority of diagnosed cases in those 55 years of age and older, four times more common in man than women, a reduced five-year survival rate in case of metastatic disease. Despite the beneficial effects of the combination therapy and immunotherapy, the low response rate and drug resistance were reported. The main goal of this work was evaluation of the endothelial cell proliferation from urothelial carcinomas. Patients, Materials and Methods: Fifty-two cases of T2-T4 infiltrative bladder tumors, aged between 46 and 78 years, were investigated. Morphological, simple and cluster of differentiation 31 (CD31)/Ki67, CD31/smooth muscle actin (SMA) double immunostaining were performed. Results: In all the analyzed infiltrative bladder tumors, three types of vessels were noticed: immature, intermediate and mature. In the central part of the tumor area, the following distribution of vessel types was noticed: immature (62.25%), intermediate (35.1%), and mature vessels (2.65%). In the peripheral tumor area, the intermediate vessels increase numerically, up to 54% and the mature ones, up to 18.6%. The peritumoral area was characterized by the absence of immature vessels and the presence of intermediate and mature ones only. It was found the presence of endothelial cell nuclei stained for Ki67 only for immature and intermediate vessels, and never for mature ones. Conclusions: The vascular patterns may contribute to a better stratification of the patient subgroups and antiangiogenic treatment algorithms.

Corresponding author: Amalia Raluca Ceausu, Associate Professor, MD, PhD; e-mail: ra.ceausu@umft.ro

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9. Effects of quercetin on gentamicin-induced experimental testicular injury in rats

Ayse Firuze Biyik, Esin Yulug, Engin Yenilmez, Abdulkadir Kutlu, Ahmet Alver, Seniz Erdem

The purpose of this study was to investigate the effects of gentamicin (GEN) on the testis and whether quercetin (QUE) has any protective effect. Twenty-four adult male Sprague-Dawley rats were divided into equal four groups: control (0.9% saline solution), GEN (80 mg/kg GEN), QUE (50 mg/kg QUE) and GEN+QUE (80 mg/kg GEN + 50 mg/kg QUE). Histopathological (HP) evaluation of testis was performed, epididymal sperm parameters were analyzed and oxidative status was evaluated. The use of QUE improved the HP findings, such as decrease in the germinal epithelial thickness in the testicular tissue of the GEN group, decrease in the Johnsens tubular biopsy score (JTBS), increase in the rate of immature cell shedding tubules, and the apoptotic index (AI). In the GEN group, sperm count, and abnormal morphology increased compared to the control group; the viability and motility decreased according to the sperm analysis results. In the GEN+QUE group, QUE was found to improve sperm viability and morphology. In the GEN group, tissue malondialdehyde (MDA) levels increased while superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) levels decreased. Compared with the GEN+QUE group, it was found that the tissue MDA level decreased, while the levels of SOD, CAT and GPx increased. The results demonstrate that GEN impairs testicular structure and function, and QUE treatment can prevent this adverse effect.

Corresponding author: Ayse Firuze Biyik, MD; e-mail: aysfrz@gmail.com

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10. The role of fine-needle aspiration biopsy in the diagnosis of malignant tumors

Marius Rus, Mircea Ioachim Popescu, Ioana Adriana Ardelean, Felicia Liana Andronie-Cioara, Mihaela Gabriela Bontea, Razvan Marius Vicas, Iulia Denisa Bogdan

Cytopathology and histopathology play a key role in the process of diagnosing oncological diseases and premalignant conditions. Fine-needle aspiration (FNA) is one of the techniques used for obtaining biopsy of a wide variety of body tissues, causing patients minimal discomfort. Therefore, it is often considered to be the best strategy for investigating and diagnosing some precancerous or potential malignant lesions. Being successful as a means of confirming the clinical suspicion of metastatic recurrence in the cases of an already known cancer, the interest has further focused on the preliminary diagnosis of various types of benign or malignant tumors. In cases of inoperable tumors, this technique is useful for formulating the final diagnosis. FNA biopsy proved its effectiveness as a highly accurate, cost-effective, and safe technique, with potential high diagnostic yield. Immunohistochemistry, used as an additional tool to classical histopathological examination, remains a very practical and reliable technique that promises good results especially in determining the site of origin within metastatic disease.

Corresponding author: Marius Rus, Associate Professor, MD, PhD; e-mail: rusmariusr@yahoo.com

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11. Magnetic resonance imaging combined with histological evaluation of repair process using the microfracture technique in an association of osteocartilaginous and meniscal surgically induced lesions of the knee. In vivo experiment on a rabbit model

Jenel Marian Patrascu Jr, Sorin Florescu, Silviu Brad, Bogdan Corneliu Andor, Iosif Ilia, Stefan Iulian Stanciugelu, Romeo Teodor Cristina

The present research study aimed to assess magnetic resonance imaging (MRI) changes and histological findings in the therapeutic effects of microfractures in the treatment of complex animal knee lesions resulting from osteochondral and meniscal defects resulting from non-total meniscectomies. The anterior cruciate ligament lesions are also proven to facilitate the development of osteoarthritis in the knee and worsen the prognosis. Surgery was performed on the right knee joint of 22 male rabbits in order to partially remove the anterior horn of the internal meniscus and to induce an osteochondral defect at the level of the internal femoral condyle. The induced lesion complex was aimed to simulate a clinical situation that occurs frequently in orthopedic practice when young adults undergo partial meniscectomy and at the time of surgery, an osteochondral defect is diagnosed. Rabbits were separated into two study groups: the control (C1) group and the microfractures (MF2) group. After the induced cartilage defect and partial meniscectomy, both groups were followed-up for six months using detailed MRI. Also, anatomical specimens were histologically analyzed to show modifications and signs of healing process, along with complications, in the study group. The results showed that the microfracture group had better results concerning articular surface defect healing in comparison to the control group. Our results suggest that microfractures do improve results concerning surface contact healing and serial MRI studies can be useful in observing the remodeling process in dynamics.

Corresponding author: Bogdan Corneliu Andor, Associate Professor, MD, PhD; e-mail: andormed@yahoo.com, andor.bogdan@umft.ro

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12. The importance of combined HPV and CINtec PLUS genotyping testing for p16 in women with cervical squamous cell carcinoma

Toader Septimiu Voidazan, Mihaela Alexandra Budianu, Ovidiu Simion Cotoi, Sabin Gligore Turdean

Introduction: Immunohistochemistry (IHC) for p16INK4A (p16) is a reliable surrogate test for the presence of a high-risk, potentially transformative human papillomavirus (HPV) infection in precursor and malignant lesions of the cervix. The purpose of this study was to evaluate changes in cervical cells caused by persistent HPV infection, by IHC (p16 protein) by comparison with HPV genotyping. Patients, Materials and Methods: The study included female patients aged between 26 and 57 years who presented to a public hospital, with complaints related to the genital area, namely vaginal bleeding and dyspareunia. After selecting the patients, samples were subjected to cytological testing and IHC for p16 and for the determination of HPV types. Results: The relationship between HPV status and p16 status was statistically significant (p=0.0001), of the 41 patients, 53.7% were HPV positive, respectively 56.1% were p16 positive, the agreement relationship between the two indicators was very high (weighted kappa: 0.951). The clinical performance of CINtec PLUS triage for p16 shows a high positive predictive value (PPV) and a high negative predictive value (NPV) of 95.7% and 100%, respectively, as regards HPV. Conclusions: The p16 marker (CINtec PLUS) can be used as a prognostic biomarker and provides clinical usefulness through increased sensitivity (Se) and specificity (Sp) in the triage of women at risk of developing precancerous lesions, compared to cytology that is based on morphology, but has a rather low Se and high Sp, while HPV testing is very sensitive but slightly more specific.

Corresponding author: Mihaela Alexandra Budianu, University Assistant, MD, PhD Student; e-mail: mihaela.budianu@umfst.ro

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13. Pulmonary Epstein-Barr virus-associated smooth muscle tumor after kidney transplantation: two case reports with review of differential diagnosis

Xiao-yu Fu, Xia Gao, Chun-lei Zhao, Xing-feng Qi, Xiao-juan Ouyang, Ling-hua Zhu, Dong Wang, Li-juan Qu, Xian-zong Ye

Pulmonary nodules are a common complication in solid organ transplant recipients, and may have various underlying causes, with Epstein-Barr virus-associated smooth muscle tumor (EBV-SMT) being one of them. Given the rarity of this entity, we describe the diagnosis and therapeutic interventions for post-transplant EBV-SMT in two individuals. Both cases involved female patients who were diagnosed with multiple pulmonary nodules 60 months and 116 months, respectively, after receiving living-related kidney transplantation. Pathological examination revealed a spindle cell tumor, with immunophenotype and EBV in situ hybridization supporting the diagnosis of EBV-SMT. After diagnosis, these two patients underwent intervention by decreasing their intake of immunosuppressants. As of the latest follow-up, the patients lesion size remained stable, and their overall condition was favorable. We also reviewed literature about the morphological and molecular pathological features of EBV-SMT and highlighted the diagnosis and differential diagnosis of pulmonary spindle cell lesions especially in the setting of immunosuppression.

Corresponding author: Li-juan Qu, Chief Physician, MMed; e-mail: qljuan6516@sina.com; Xian-zong Ye, Associate Chief Physician, MD, PhD; e-mail: yexianzong@126.com

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14. Chronic sclerosing sialadenitis of the bilateral submandibular glands in childhood - a diagnostic dilemma

Octavian Marius Dinca, Alexandru Bucur, Sabina Andrada Zurac, Tiberiu Nita, Gheorghita Jugulete, George Cristian Vladan, Lavinia Cristina Padurariu

Chronic sclerosing sialadenitis (CSS), currently included in the group of immunoglobulin G4 (IgG4)-related diseases, is an under-recognized inflammatory lesion that afflicts mostly the submandibular gland of 40-60 years adults. To our knowledge, only one case of CSS located in the submandibular gland has been reported in childhood to date. We present a case of CSS in a 5-year-old male child. He presented with bilateral submandibular swellings that clinically resembled discrete lumps, suspected to be tumors. The completely resected tumors composed predominantly of dense lymphoplasmacytic inflammatory infiltrate rich in IgG4-positive cells [77-90 IgG(+) cells per high-power field; IgG4(+)/IgG(+) cells ratio of 42.77%]. We discuss the peculiarities of this case, and we also review the literature on CSS.

Corresponding author: Alexandru Bucur, Professor, MD, PhD; e-mail: alexandru.bucur@umfcd.ro; George Cristian Vladan, Associate Professor, MD, PhD; e-mail: cristi.vladan@umfcd.ro

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15. The influence of sepsis on erythrocytes morphology: case report and literature review

Cristian Mircea Nicolescu, Silviu Daniel Moldovan

This paper highlights a clinical case of sepsis caused by soft tissue infection. Peripheral blood smear, plasma value of inflammatory biomarkers and the white blood cells count were performed. Significant morphological changes were revealed through peripheral blood smear test two days after patient admission. Patient developed septic shock after the third day in intensive care unit (ICU). Laboratory results showed major morphological changes (erythrocytes deformity, abnormal neutrophils); these were correlated with elevated plasma value of interleukin-6 and procalcitonin.

Corresponding author: Cristian Mircea Nicolescu, Lecturer, MD, PhD; e-mail: cristian_ans@yahoo.com

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16. Fetal acrania diagnosed at 17 weeks of gestation by 2D/3D ultrasound: a case report and literature review

Bogdan Ioan Stefanescu, Tiberiu Ioan Mihalache, Georgiana Bianca Constantin, George Tocu, Miruna Maria Stefanescu, Roxana Elena Bogdan Goroftei

Acrania is a fetal malformation characterized by complete or partial absence of the calvaria above the orbits and supraciliary ridge. No exact mechanism is demonstrated for this anomaly but disturbances in mesenchymal migration during the fourth week of development are the most documented. The key sonographic features of acrania are absent calvaria and dorsally bulging brain (Mickey Mouse head). Due to the normal process of ossification of cranial bones, the diagnosis can be established only after 11 weeks of gestation. Early detection is extremely important. The prognosis is extremely poor so elective termination of pregnancy is the treatment of choice. In this paper, we discuss the things we know about pathogeny and ultrasonographic features of fetal cranial malformations based on a case diagnosed late during gestation.

Corresponding author: George Tocu, Assistant Professor, MD, PhD; e-mail: george_tocu@yahoo.com

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