George S Stoyanov

Cell biology of glioblastoma multiforme: from basic science to diagnosis and treatment

First described in the 1800s, glioblastoma multiforme (GBM), a class IV neoplasm with astrocytic differentiation, as per the revised 2016 World Health Organization classification of tumors of the central nervous system (CNS) is the most common malignant tumor of the CNS. GBM has an extremely wide set of alterations, both genetic and epigenetic, which yield a great number of mutation subgroups, some of which have an established role in independent patient survival and treatment response. All of those components not only represent a closed cycle but are also relevant to the tumor biological behavior and resistance to treatment as they form the pathobiological behavior and clinical course. The presence of different triggering mutations on the background of the presence of key mutations in the GBM stem cells (GBMsc) further separates GBM as primary arising de novo from neural stem cell precursors developing into GBMsc and secondary, by means of aggregated mutations. Some of the change in cellular biology in GBM can be observed via light microscope as they form the cellular and tissue hallmarks of the condition. Changes in genetic information, resulting in alteration, suppression and expression of genes compared to their physiological levels in healthy astrocytes lead to not only cellular, but also extracellular matrix reorganization. These changes result in a multiform number of micromorphological and purely immunological/biochemical forms. Therefore, in the twenty-first century the term multiforme, previously outcast from nomenclatures, has gained new popularity on the background of genotypic diversity in this neoplastic entry.

On the Concepts and History of Glioblastoma Multiforme - Morphology, Genetics and Epigenetics

Abstract Glioblastoma multiforme (GBM) is a grade IV WHO malignant tumor with astrocytic differentiation. As one of the most common clinically diagnosed central nervous system (CNS) oncological entries, there have been a wide variety of historical reports of the description and evolution of ideas regarding these tumors. The first recorded reports of gliomas were given in British scientific reports, by Berns in 1800 and in 1804 by Abernety, with the first comprehensive histomorphological description being given in 1865 by Rudolf Virchow. In 1926 Percival Bailey and Harvey Cushing gave the base for the modern classification of gliomas. Between 1934 and 1941 the most prolific researcher in glioma research was Hans-Joachim Scherer, who postulated some of the clinico-morphological aspects of GBM. With the introduction of molecular and genetic tests the true multifomity of GBM has been established, with different genotypes bearing the same histomorphological and IHC picture, as well as some of the aspects of gliomagenesis. For a GBM to develop, a specific trigger mutation needs to occur in a GBM stem cell – primary GBM, or a slow aggregation of individual mutations, without a distinct trigger mutation – secondary GBM. Knowledge of GBM has been closely related to general medical knowledge of the CNS since these malignancies were first described more than 200 years ago. Several great leaps have been made in that time, in the footsteps of both CNS and advancements in general medical knowledge.

The Human Vomeronasal (Jacobson’s) Organ: A Short Review of Current Conceptions, With an English Translation of Potiquet’s Original Text

The vomeronasal organ (VNO) is a structure located in the anteroinferior portion of the nasal septum and is part of the accessory olfactory system. The VNO, together with its associated structures, has been shown to play a role in the formation of social and sexual behavior in animals, thanks to its pheromone receptor cells and the stimulating effect on the secretion of gonadotropin-releasing hormone. The VNO was first described as a structure by the Dutch botanist and anatomist Frederik Ruysch in 1703 while dissecting a young male cadaver. This finding, however, is widely contradicted due to no elaborate descriptions being made by the Ruysch. The description of the VNO is more widely attributed to the Danish surgeon Ludwig Jacobson, with whom the VNO has been synonymized, as in 1803 he described the structure in a variety of mammals. Whilst Jacobson extensively studied prior reports of the VNO, he publicly denied its existence in humans. Following these discoveries and some contradictory statements in 1891, M. Potiquet published one of the more influential reviews on the topic. To this day, despite the first report of the organs existence being made in a human and many articles stating its presence and supporting its function, the presence of a VNO in humans is still widely debated upon.

Samuel Thomas von Sömmerring’s Contributions on the Cranial Nerves and Vomeronasal Organ

Samuel Thomas von Sömmerring (January 28th, 1755, Thorn, then Royal Prussia, now Torun Poland – March 2nd, 1830, Frankfurt am Main, then a free city, now Germany) was one of the most respected Germanic scientists of his time. Whilst working on his philosophy doctorate (Ph.D.) thesis, when he was only 23 years old (circa 1778), Sömmerring proposed a new classification for the arrangement of the cranial nerves, based on the order in which they become visible on the surface of the brain. Amongst his many other anatomical studies worthy of notice, in 1809 Sömmerring began studying the human olfactory system. During this period, he published a detailed text with sketches, being the first to describe in detail the human vomeronasal organ (VNO), working in parallel with Jacobsen, whose name has been synonymous with the VNO, despite denying its existence in man. Nonetheless, Sömmerrings contributions are numerous. Some of his other works include the description of the structure of the female skeleton and how it differs from the male and the first description of the Pterodactyl in 1812, with which he has been epitomized in modern times and denoted due to his erroneous concepts on it. Even though he studied a wide range of subjects from medical to political, most of his work has been overlooked or forgotten but it is important to understand the range of his contributions.

The Final Diagnosis: Colorectal Carcinoma, In the Context of Attenuated Familial Adenomatous Polyposis, Mimicking Pulmonary Carcinoma

Pulmonary carcinoma is one of the most common malignant conditions worldwide. The current case presents a patient with lung lesions clinically and radiologically diagnosed as lung cancer, which was not biopsied due to patient’s refusal. The patient was a heavy smoker and prior to the lung lesions, he was diagnosed with chronic obstructive pulmonary disease. Following recurrent hospitalizations, the patient died and he was referred for an autopsy. The autopsy established six lesions in the lung, one in the liver, one in the cerebrum and multiple polyps of the colon, two of which were with a visible invasive growth. The histological sections revealed that the lung, liver, and cerebral lesions were composed of the atypical gland with excessive mucus production. The colorectal specimens revealed benign polyps and colorectal adenocarcinoma. The diagnosis of advanced colorectal adenocarcinoma with multiple metastases in the context of attenuated familial adenomatous polyposis (AFAP) was established due to the combined histological findings, the age of the patient, and the number of benign polyps in the colon.

Histopathological Findings in an Unclassifiable Case of Empty Nose Syndrome with Long-term Follow-up

One of the major components of the functional process in the nasal cavity is taken up by the respiratory epithelium covering the posterior two-thirds of the nasal cavity. Disruption in the cytoarchitectonics and subcellular changes in this epithelium results in a number of functional changes in the nasal cavity. One of the rare and usually iatrogenic disturbances of this type is described in 1996, although noticed and discussed significantly earlier, by Kern and Stenkvist empty nose syndrome (ENS) or secondary atrophic rhinitis. The clinical hallmarks of ENS are described as paradoxical feeling for nasal obstruction in the presence of actually widened nasal airways. This phenomenon is attributed to the efferent neuronal signal dissociation accompanying the changes in the nasal mucosa. Herein we report the findings in a 50-year-old male. The patient presented with chronic right-sided headache, foul discharge and complaints of a stuffed nose in 2011. Endoscopy and computed tomography (CT) showed complete destruction of the hard plane, nasal septum, and right maxillary septum, leading to a formation of a huge neocavity. Due to the past medical history and the severity of the case biopsy specimens were obtained under general anesthesia. The sections showed severe but unspecific changes of the nasal epithelium with areas of minimal remaining preserved respiratory epithelium. Based on the clinical data and endoscopic, CT and histomorphologic data, despite the case is not applicable to the current classification of ENS, the diagnosis of ENS was accepted based on the combined extensive but unspecific findings. A seven-year follow-up period included multiple hospital admissions for monitoring of the condition and extensive sinus lavage. No advancement was noticed.

Psoas Minor Muscle: A Cadaveric Morphometric Study

Introduction The psoas muscle group is part of the posterior abdominal wall and is comprised of long muscles – major, minor, and tertius. Out of those, only the psoas major muscle is an obligatory muscle present in all individuals. The psoas minor muscle (PMM) originates as vertical fascicles inserted in the bodies of the last thoracic and first lumbar vertebrae and inserting into the iliopectineal eminence. The muscle provide flexion of the lumbar spine in a limited fashion. The aim of the study was to establish the frequency of the muscle in the Bulgarian population. Materials and methods This study was carried out in the Department of Anatomy and Cell Biology, Medical University, Varna, Bulgaria, by Dr. Paraskev Stoyanov in November 2017, on a total of 10 cadavers. The length, width, and circumference of the muscles were measured. The collected data were interpreted in a descriptive manner. Results The PMM was present in six out of ten cadavers (60%). Out of those six cadavers, the muscle was bilateral in three, unilateral on the left side in one, and unilateral on the right side in two cadavers. The average length of the muscle was 19.66 cm (range:14.4 cm - 21.7 cm), average width was 1.73 cm (range: 1.0 cm - 3.2 cm ) and average circumference was 3.48 cm (range: 1.7 cm - maximum 5.6 cm). The male to female ratio of cadavers with a PMM was 1:1. Conclusion The frequency of the muscles variations considering its presence in the Bulgarian population (60%) is higher when compared to its presence in the Indian population (36.67%), virtually identical to the Brazilian population (59%), and lower than that reported in the US (65.6%). The morphometric analyses of the different populations showed a shorter psoas minor in the Bulgarian population.

A Comparative Review of Demographics, Incidence, and Epidemiology of Histologically Confirmed Intracranial Tumors in Brazil and Bulgaria

Intracranial tumors (ICTs) attract numerous scientific teams and tremendous financial resources worldwide. These lesions of the central nervous system (CNS) can be both benign and malignant in biological behavior as well as local or metastatic in origin. We compared data from two studies on primary and metastatic ICTs from Brazil and Bulgaria, based on histopathologically confirmed ICTs from tertiary health centers. Primary ICTs significantly outweigh the frequency of metastatic ICTs. Primary ICTs represent 86.45% in Brazil and 69.17% in Bulgaria, with around 60% of their totals being malignant. There is a statistical dominance of tumors from the neuroepithelial origin, with the most common entry being glioblastoma multiforme. The second-most common primary ICT group comprises tumors of meningeal origin. Metastatic ICTs show great variance; 13.55% in Brazil and 31.38% in Bulgaria of all ICT cases being attributed to them. However, metastatic ICTs are even a more diverse group than neuroepithelial tumors, with the majority of this group comprising metastatic colorectal adenocarcinoma (almost exclusively in males), metastatic breast adenocarcinoma in females, metastatic pulmonary carcinomas (primarily from the non-small cell group with a male predominance), and metastatic melanoma with an even gender ratio.

The Diagnostic Dilemma of Epithelial Marker Expression in Glioblastoma

To the Editor, Glioblastoma Multiforme (GBM) is a hot topic for research as the intimacies of this type of malignancy seem to be a long way from being truly understood. Diagnostically however, despite decades of research and many attempts at standardizing the histopathological diagnostic process, GBM remains an entry to be diagnosed by experienced neuropathologists. A key point in the pathological diagnostic process is the immunohistochemical (IHC) phenotypisation of tumor samples. While some glial specific IHC markers such as glial fibrillary acidic protein (GFAP) give a constant positive reaction, and are used as a diagnostic medium in GBM, there is a wide panel of IHC markers that give positive IHC reactions with GBM tissue samples. Some of these such as Vimentin are very unspecific and are mainly used as a positive control for IHC reactions, but can also be used in some instances to distinguish between epithelial and non-epithelial tumors. Some IHC markers, such as cytokeratin (CK) AE1/AE3 and epithelial membrane antigen (EMA) are highly specific to epithelial cells, but can very often give positive IHC reaction with GBM tumor tissue, producing a diagnostic dilemma (Figs. 1 and 2) [1–5]. Terada (2015) reported positive IHC expression of several types of keratin antibodies, especially for the CKAE1/AE3 antibody, confirming the findings reported by other similar studies [1–3]. Terada also stated that this positivity is due to the production of keratin proteins from GBM cells, but this statement is not supported by anything more than IHC investigations [1]. However, IHC is not the most specific immunology based test and a phenotypically positive tissue sample on IHC may not truly express the antigens tested due to conformational mimicry between the antibody and a similar epitope in another antigen. Such is the case with keratins and perhaps also with other epithelial markers, such as EMA, in GBM [2–5]. Whilst many authors and practicing pathologists believe that IHC is a full proof testing method and that a high number of GBM cases express some type of keratin molecules, especially the epitheloid and giant-cell GBM subtypes. This is not entirely true, as demonstrated by Kriho et al. in 1997 in a comparative study of keratin expression in GBM [2]. She concluded that the AE3 fraction of the CKAE1/AE3 antibody cocktail is the one that reacts with an antigen in GBM cells, however in immunoblot and electrophoresis test a protein with the characteristics of keratin filaments was not detected [2]. Therefore, Kriho suggested that these IHC false positive results are caused by a three-dimensional conformational mimicry with another intermediate cytoskeletal protein such as the dysmorphic GFAP produced by the neoplastic astrocytes [2]. Although the result of Kriho et al. have not been recreated since, the specifics of a Western immunoblot test highly outweigh those of IHC and are used in explaining the GBM-CK AE1/AE3 phenomena by a number of authors [2–4]. Some * George Stoyanov georgi.geesh@gmail.com