Lynch Syndrome-associated Genomic Variants.

BACKGROUND AND AIMS: Lynch Syndrome, a hereditary disorder characterized by germline mutations in mismatch repair (MMR) genes, is a major contributor to colorectal cancers. It has also been identified in endometrial cancer. Despite the established role of MMR deficiency in tumorigenesis, the specific genomic alterations driving Lynch syndrome-associated endometrial cancer, and their overlap with colorectal cancer, remain incompletely understood. This study aims to fill this gap by performing a detailed comparative analysis of germline and somatic mutations in endometrial cancer within the context of Lynch syndrome. METHODS: We conducted whole exome sequencing on matched germline and somatic DNA from 13 patients diagnosed with Lynch syndrome-associated endometrial cancer. High-depth sequencing was performed, followed by rigorous bioinformatics analysis to identify and annotate variants, focusing on their potential pathogenicity and relevance to both endometrial and colorectal cancer. RESULTS: Our analysis revealed 1,118 germline and 14,051 somatic variants, with 493 variants common to both. Recurrent pathogenic mutations in MLH1, MSH2, and MSH6 were confirmed, highlighting their critical role in Lynch syndrome. Notably, frequent somatic mutations in the PIK3CA and PTEN genes were identified, implicating the PI3K/AKT/mTOR pathway as a key oncogenic driver in these cancers. Additionally, novel somatic mutations in genes related to the extracellular matrix such as FBN1 and SPARC were uncovered, suggesting a possible unique role in endometrial tumor progression. CONCLUSIONS: This study provides new insights into the molecular basis of Lynch syndrome-associated endometrial cancer, emphasizing the overlap in oncogenic pathways with colorectal cancer. The discovery of shared and unique genetic mutations highlights the importance of developing combined treatment strategies and suggests that targeting these specific mutations could improve therapy for patients with Lynch syndrome-associated cancers.

Somatic and germline mutations in endometrial cancer.

Endometrial cancer is a complex disease influenced by both somatic and germline mutations. While individual mutations in genes such as PTEN, PIK3CA, and members of the DNA mismatch repair (MMR) system have been extensively studied, comprehensive analyses comparing somatic and germline mutations within the same cohort are limited. This study compares these mutations using whole exome sequencing (WES) data from tumor and blood samples in patients with endometrial cancer. Thirteen female patients with histologically confirmed endometrial cancer were selected. Tumor tissues and matched blood samples were collected and subjected to WES at the CeGaT laboratory, followed by bioinformatics analysis and annotation using the Geneyx platform. WES revealed significant somatic and germline DNA mutations, with key pathogenic variants identified in genes such as PTEN, PIK3CA, TP53, MLH1, and MSH2. Comparative analysis showed distinct and overlapping mutation profiles, highlighting the importance of integrating somatic and germline data in endometrial cancer research.

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

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.

A Novel Algorithm for Evaluating Bone Metastatic Potential of Breast Cancer through Morphometry and Computational Mathematics.

Bone metastases represent about 70% of breast cancer metastases and are associated with worse prognosis as the tumor cells acquire more aggressive features. The selection and investigation of patients with a high risk of developing bone metastasis would have a significant impact on patients' management and survival. The patients were selected from the database of Carol Davila Clinical Nephrology Hospital of Bucharest. Their tumor specimens were pathologically processed, and a representative area was selected. This area was scanned using an Olympus VS200 slide scanner and further analyzed using QuPath software v0.4.4. A representative group of approximately 60-100 tumor cells was selected from each section, for which the following parameters were analyzed: nuclear area, nuclear perimeter, long axis and cell surface. Starting from these measurements, the following were calculated: the mean nuclear area and mean nuclear volume, the nucleus to cytoplasm ratio, the length of the two axes, the long axis to short axis ratio, the acyclicity and anellipticity grade and the mean internuclear distance. The tumor cells belonging to patients known to have bone metastasis seemed to have a lower nuclear area (<55 µm2, p = 0.0035), smaller long axis (<9 µm, p = 0.0015), smaller values for the small axis (<7 µm, p = 0.0008), smaller mean nuclear volume (<200 µm3, p = 0.0146) and lower mean internuclear distance (<10.5 µm, p = 0.0007) but a higher nucleus to cytoplasm ratio (>1.1, p = 0.0418), higher axis ratio (>1.2, p = 0.088), higher acyclicity grade (>1.145, p = 0.0857) and higher anellipticity grade (>1.14, p = 0.1362). These parameters can be used for the evaluation of risk category of developing bone metastases. These results can be useful for the evaluation of bone metastatic potential of breast cancer and for the selection of high-risk patients whose molecular profiles would require further investigations and evaluation.

Fibular hemimelia.

Fibular hemimelia is defined as a partial or complete absence of the fibula. Alongside fibular deformities, there is a wide spectrum of anomalies, foot deformities, and absent rays. A literature review showed only a handful of cases of prenatal diagnosis of fibular hemimelia. It is a rare disorder that might be isolated or associated with visceral anomalies.

A Systematic Approach of the Intrauterine Morphogenesis of the Human Palpebral Apparatus.

The human eyelid embodies a vast diversity of functions. Acting as a protective shield for the ocular apparatus and as a light regulator in the sight process, eyelids stand a fascinating - yet omitted - role in facial aesthetics, serving as a racial trait by which humankind succeeded to manifest heterogeneity as a species. These assumptions are precisely forecasted right from in-utero life through intricate processes of growth and cell differentiation. In the Department of Anatomy of "Carol Davila" University of Medicine and Pharmacy, we performed morphological assessments on 41 embryos and fetuses with gestational ages ranging from 6 to 29 weeks. This study aims to illustrate the morphogenesis of eyelids in human embryos and fetuses and highlight macroscopic features which could potentially have significant clinical implications in ophthalmic pathology.

Pituitary adenoma apoplexy in pregnancy: Case report and literature review.

Gestational pituitary apoplexy is an extremely rare condition. It is characterised by an unexpected headache, vomiting, nausea, and visual disturbances. Pituitary apoplexy in pregnancy and postpartum is a challenging diagnosis with symptoms overlapping multiple conditions. There is a limited number of articles presenting cases or case series of gestational pituitary apoplexy. This is a potentially life-threatening emergency which requires a high index of suspicion for its diagnosis. This article presents a case of postpartum pituitary apoplexy and outlines the current stage of clinical, imagistic diagnosis and management options. A 26-year-old primipara was submitted to a Caesarean section, with no perioperative incidents. Forty-eight hours later she reported the apparition of frontal and temporal throbbing headaches, nausea, photophobia, and she was diagnosed with a pituitary tumor measuring 33x10.5x15.5 mm. Although initially conservative treatment was proposed, the clinical outcome was not favourable, thus the patient was submitted to endoscopic transsphenoidal resection. The histopathological studies demonstrated the presence of a pituitary macroadenoma. At the 2-year follow-up, the patient is free of disease. Although it represents an extremely rare condition, gestational pituitary apoplexy should be suspected whenever headache and neurological disorders such as nausea and photophobia are reported during the postpartum period.

Success rate of methotrexate in the conservative treatment of tubal ectopic pregnancies.

An ectopic pregnancy (EP) involves the implantation of the gestational sac outside the uterine cavity. In the event of diagnosing an EP, the current medical approach is to avoid surgery and to preserve fertility whenever possible; therefore, methotrexate (MTX)-based therapy has become prominent in recent years. MTX, a drug usually used to treat severe forms of autoimmune diseases and several types of cancer, has proven its utility in the conservative treatment of EPs. The success rate of MTX correlates with lower values of ß subunit of human chorionic gonadotropin hormone (ß-hCG) serum levels, especially below 2,000 mUI/ml, side effects being insignificant. In the present study, the results obtained concerning the success rate of MTX in the conservative treatment of EPs were obtained at the Department of Obstetrics and Gynecology of the Bucharest University Emergency Hospital from January 2014 to December 2020. The aim of the present study was to highlight the necessity for revising current guidelines for ectopic pregnancy medical treatment in order to manage this pathology optimally and to select carefully the proper treatment, whether medical, surgical or expectant management, so that morbidity is reduced to a minimum.

Polycythemia vera in pregnancy represents a challenge for a multidisciplinary collaboration: A case report and literature review.

Polycythemia vera (PV) is a rare chronic myeloproliferative neoplasm which represents an additional thrombotic factor in pregnancy. PV may be difficult to diagnose, particularly as its incidence is extremely uncommon among young women. The main diagnostic method involves a bone marrow biopsy, and high hemoglobin and platelet counts are usually indicative of the condition, after excluding other more frequent pathologies. PV is associated with a high risk of thrombosis, particularly in pregnancy, and requires anti-platelet treatment. At present, only a limited number of PV cases in pregnancy have been reported in the literature, at least to the best of our knowledge, with the largest case series being a retrospective study that included 25 pregnancies in 15 women. The present study describes the case of a patient diagnosed with JAK2-positive PV and also discusses this rare condition with particular focus on the following: i) The management of PV in pregnancy along with the additional pathologies in this specific case; and ii) the particularities of the pregnancy course. By identifying women suffering from PV superimposed by other possible procoagulant factors and applying the latest standard in healthcare, fetal and maternal prognosis may be significantly improved.

Ultrasound Pitfalls in a Complex Fetal Cardiac Malformation-Case Report of a New Arteriovenous Central Communication.

Cardiac and cardiovascular malformations are of real interest in terms of definition, epidemiology, and means of early diagnosis by imaging. Although ultrasound examination reaches exceptional performance nowadays, unusual pathologies are still exposed to the risk of either incorrect acquired image or misinterpretation by the specialist in a routine scan. Herein, we present a case of a 20-week-old fetus (from an apparently low-risk pregnancy) with complex cardiac and vascular abnormalities, including an arteriovenous malformation along with ventricular septal defect, ductal coarctation of the aorta, aneurysm of a brachiocephalic vein, and dilation of the entire neck and upper mediastinum venous system, and the limitations that were encountered in the process of diagnosis and management of the case.

Emerging Therapeutic Concepts and Latest Diagnostic Advancements Regarding Neuroendocrine Tumors of the Gynecologic Tract.

Neuroendocrine neoplasms (NENs) are particularly rare in all sites of the gynecological tract and include a variety of neoplasms with variable prognosis, dependent on histologic subtype and site of origin. Following the expert consensus proposal of the International Agency for Research on Cancer (IARC), the approach in the latest World Health Organization (WHO) Classification System of the Female Genital Tumours is to use the same terminology for NENs at all body sites. The main concept of this novel classification framework is to align it to all other body sites and make a clear distinction between well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The previous WHO Classification System of the Female Genital Tumours featured more or less the same principle, but used the terms 'low-grade neuroendocrine tumor' and 'high-grade neuroendocrine carcinoma'. Regardless of the terminology used, each of these two main categories include two distinct morphological subtypes: NETs are represented by typical and atypical carcinoid and NEC are represented by small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC). High-grade NECs, especially small cell neuroendocrine carcinoma tends to be more frequent in the uterine cervix, followed by the endometrium, while low-grade NETs usually occur in the ovary. NENs of the vulva, vagina and fallopian tube are exceptionally rare, with scattered case reports in the scientific literature.

Prenatal Diagnosis and Outcome of Tracheal Agenesis as Part of Congenital High Airway Obstruction Syndrome. Case Presentation and Literature Review.

Tracheal atresia is an extremely rare condition whereby a partial or total obstruction of the trachea is seen. It is almost always lethal, with just a handful of cases that ended with a good outcome. In this study we report on a 15-week male fetus, diagnosed with hyperechogenic lungs, midline heart position and inverted diaphragm. Sonographic findings suggest congenital High Airway Obstruction Syndrome (CHAOS) An ultrasound scan and fetal MRI were not able to point out the exact obstruction level. In spite of extensive counselling, the parents opted to carry on with the pregnancy. Fetal demise was noted on a scan at 19 weeks gestation. After the elective termination of pregnancy, a post-mortem examination showed partial tracheal atresia with no other anomalies. Despite technological progress in CHAOS syndrome, a precise diagnosis and accurate prognosis remain elusive.

A novel histopathological grading system for ganglioglioma.

Gangliogliomas are central nervous system tumors located in the temporal lobe of young patients, frequently associated with epilepsy. In this paper, we propose a grading system based solely on histopathological criteria. We reevaluated all cases of ganglioglioma, atypical ganglioglioma, and anaplastic ganglioglioma diagnosed between 2011 and 2020 in the Pathology Department of the Emergency Clinical Hospital Bagdasar-Arseni, based on the type of glial mitoses, the number of neuronal and glial mitoses, presence of necrosis, microvascular proliferation, eosinophilic granular bodies, hypercellularity, presence and disposition of inflammatory infiltrate and atypical pleomorphism. Based on the proposed grading system, a score of 0-4 corresponded to a benign ganglioglioma, 5-9 to an atypical ganglioglioma, and 10-18 to an anaplastic ganglioglioma. The survival rates were 90% for benign ganglioglioma, 71.43% for atypical ganglioglioma, and 62.54% for anaplastic ganglioglioma. One case of benign ganglioglioma underwent a malignant transformation into anaplastic ganglioglioma, and recurrences were noticed in 28.57% of atypical ganglioglioma cases and 30.7% of all anaplastic gangliogliomas. The presence of rare glial mitoses and hypercellularity was correlated with mortality in cases of atypical ganglioglioma. We believe this histopathological scoring system could be used as a three-tier system to identify atypical ganglioglioma cases that are bound to have an aggressive course of evolution and require close follow-up. The other option would be to convert it to a two-tier grading system that can separate low-grade gangliogliomas from high-grade ones. The latter category can encompass both atypical and anaplastic ganglioglioma due to the high mortality of both entities.

Glycogen-rich clear cell carcinoma of the breast with solid papillary pattern: Two cases with heterogeneous clinicopathological features.

Invasive breast cancer is a heterogeneous disease, both in its histopathological classification and clinical course. Glycogen-rich clear cell carcinoma of the breast is an extremely rare subtype of invasive breast carcinoma, accounting for up to 3% of all breast carcinomas. The tumor is composed of polygonal cells with abundant clear cytoplasm containing glycogen and has a very controversial prognosis. Solid papillary pattern is an uncommon morphological variant of breast carcinoma which is associated with indolent behavior in the absence of an invasive component. To date, there are only three cases of glycogen-rich clear cell carcinoma with solid papillary pattern reported in the English literature. In this article, we present two cases of glycogen-rich clear cell carcinoma of the breast, encountered in our daily clinical practice over a period of 5 years (2015-2020) and perform a brief review of currently published literature. Unlike most cases of glycogen-rich clear cell carcinoma documented to date, follow-up of our case featuring solid papillary pattern revealed extremely favorable clinical outcome, suggesting a better prognosis for tumors with this morphology.

Breast cancer mortality gaps in Romanian women compared to the EU after 10 years of accession: Is breast cancer screening a priority for action in Romania? (Review of the Statistics).

Breast cancer remains the most common cause of morbidity and mortality by cancer in females worldwide, even though it is largely preventable through population screening. Despite notable progress in the last years in the EU, breast cancer screening programs still maintain wide variations among countries and socio-economic groups. This statistical review aimed to investigate the breast cancer-related health gaps in Romanian women compared to the average EU female population after 10 years of accession (2007-2016). We evaluated breast cancer-related deaths, age-standardized mortality rates and contribution of breast cancer to life expectancy. Trends and percentage changes were compared between Romania and EU-27 for breast cancer, all cancer and all causes of mortality. We found a higher increase of breast cancer deaths in Romania, an increasing trend of mortality (opposite to EU) and a contribution to life expectancy at birth that increased gradually from 0.45 to 0 48 years. All these health gaps compared to EU are aggravated by the fact that no population screening for breast cancer is organized in the country. The opportunities for organizing such a program are consistent, but they should be increased in the future, in order to control the health gap between Romania and EU.

Novel Perspectives Regarding CD34 Immunoexpression Patterns in Gangliogliomas.

Gangliogliomas are extremely rare central nervous tumors composed of an admixture of glial and neuroepithelial elements. Gangliogliomas mainly affect the temporal lobe and occur in the pediatric population. There are several controversies in the scientific literature regarding these tumors, which debuted with the exclusion of grade II gangliogliomas in the 2006 edition of the current World Health Organization (WHO) classification. The upcoming edition due in the last months of 2021 is not expected to include changes regarding the current classification of glio-neuronal tumors. This vision has led to a number of articles that have pushed for the reintroduction of this category. However, these articles support the reintroduction of this degree in terms of prognosis and evolution, without providing clear criteria for the inclusion of certain gangliogliomas in this category. On the other hand, there are uncertainties about the relationship of gangliogliomas with focal cortical dysplasia. The coexistence of the two entities, as well as their succession are occasionally encountered in practice and have led to numerous studies that have tried to clarify the relationship between them. The most common and most accessible element in routine practice is the immunoreactivity for CD34. Both entities express this marker, and dual lesions express the highest percentage of immunoreactivity for CD34. In this article, we study the expression of CD34 on a series of cases including both grade I gangliogliomas and anaplastic gangliogliomas diagnosed between 2011 and 2020 in a Neuropathology Unit in Bucharest Romania.

Diabetes, pregnancy and spina bifida.

Spina bifida is a disorder characterized by failure of the neural tube to form during embryological development. The early signs in the head and spine may be detected on ultrasound from 11 weeks of gestation. Diabetes is a well-known teratogen factor that increases the chances of birth defects, such as neural tube defects. We report a 12 weeks case of spina bifida in type 1 diabetes.

VACTERL association in a fetus with multiple congenital malformations - Case report.

VACTERL represents an acronym for a broad spectrum of congenital anomalies such as vertebral anomalies, anorectal anomalies (anal atresia), cardiac anomalies, tracheoesophageal fistula or atresia, renal anomalies, and limb anomalies. We present the case of a male fetus with multiple anomalies consistent with VACTERL association such as scoliosis, imperforate anus, common truncus arteriosus, tracheoesophageal fistula associated with inferior esophagus atresia, polycystic kidneys, with short right ureter, lower limb hypoplasia micrognathia, hygroma, duodenal atresia, and cloacal malformation, with an aberrant omphalomesenteric duct. The presented case highlights the crucial importance of pathologists specialized in the dissection and confirmation of fetal abnormalities as an essential part of the multidisciplinary team that establishes the management of complicated pregnancies with this type of pathology.

Prenatal Ultrasound Diagnosis of Double Aortic Arch versus Right Aortic Arch Variant in Vascular Ring Formation - Case Report and Review of the Literature.

Double aortic arch represents a congenital vascular malformation that is characterized by the development of a complete vascular ring around the esophagus and trachea due to an anomaly in the development of branchial arteries. We present the case of a 31-year-old gravida that was referred for fetal ultrasound anomalies screening at 22 weeks and six days of gestation. Routine ultrasound scanning of the fetus revealed a structural aortic arch anomaly consistent with a double aortic arch, with no other cardiac and diextracardiac congenital structural malformations. Knowledge of embryology and imaging spectrum of aortic arch anomalies that are able to form vascular rings around the trachea and esophagus are essential for an accurate antenatal diagnosis and therefore, for a correct clinical management.

Practical aspects regarding the histopathological grading and anaplastic transformation of gangliogliomas - a literature review.

Ganglioglioma represents a benign central nervous tumor, occurring predominantly in the pediatric population and affecting the temporal lobe. It is also renowned for its epileptogenic potential. However, to date, there are numerous uncertain features about this tumor, especially about its grading system. In the former World Health Organization (WHO) Classification of central nervous tumors system, gangliogliomas could have been attributed one out of three grades: grade I (benign), grade II (atypical), and grade III (anaplastic). The new classification systems have renounced to atypical ganglioglioma nomenclature, due to the lack of histopathological criteria for this entity. Another controversial aspect of grade I ganglioglioma is its potential to transform into a malignant tumor, namely, most frequently an anaplastic ganglioglioma. Based on our knowledge, there are no literature reviews to date focusing on anaplastic transformation potential. The present paper encompasses all anaplastic transformation of gangliogliomas and has analyzed the time frame between the two events, the age of the patients and its relationship to the complete or subtotal resection and administration of radiotherapy. Thirty-three cases of malignant transformation of ganglioglioma have been reported so far in the literature, with 54.54% of them undergoing progression to anaplastic ganglioglioma and 21.21% to anaplastic ganglioglioma. Median age was 26 years, and the cases were evenly distributed between the two genres. Only 27.27% of all evaluated cases had been administrated adjuvant radiotherapy, and only 44% of the latter have had an incomplete tumoral resection.