Metachronous Squamous Cell Carcinomas of the Uterine Cervix and Lung: True Metachrony or Metastasis.

Human papillomaviruses (HPV) are a big group of infection agents with oncogenic potential, especially regarding squamous epithelium. Some high-risk variants are key in the development of squamous cell carcinomas (SCC) across multiple systems, the most affected of which is the female reproductive system, but also parts of the gastrointestinal tract, head, and neck SCC, and cutaneous and pulmonary (bronchogenic) SCCs. In cases where a patient develops two SCCs in different systems, often the main question is whether these tumors are synchronous, metachronous, or if one of the tumors is a metastasis from the other, with HPV testing and stereotype identification often being of aid in differentiating between these. Herein, we report the case of a female patient in her 50s, initially diagnosed with SCC of the uterine cervix. The patient remained stable for three calendar years after completing preoperative radiotherapy, surgical resection, and postoperative chemo-radiotherapy. At that point, she developed respiratory symptoms, and radiography suggested a pulmonary malignancy. After undergoing surgical resection of the pulmonary lesion, histological specimens were initially interpreted to be a metachronous pulmonary SCC. Immunohistochemical testing proved that both the cervical and pulmonary lesions were HPV-associated, with further testing proving that both lesions were associated with high-risk HPV (genotype 16). Based on the clinical history and aggregated data, the pulmonary lesion was interpreted as a metastatic and not a metachronous one, and the patient is currently undergoing treatment for metastatic disease.

Cauda Equina Neuroendocrine Tumor: A Histopathological Case Report.

Cauda equina neuroendocrine tumors (CENET) are rare neoplastic processes that develop in the cauda equina or filum terminale region of the spinal cord, which in previous incarnations of the World Health Organization (WHO) classification of the central nervous system (CNS) tumors were designated as paragangliomas. The change of terminology was carried out due to the rarity of the condition, its specific place of origin, the non-specific clinical and imaging characteristics with which the tumors present, and differences in biological properties (secretion and progression) as well as some minor differences in immunohistochemical protein expression patterns. Herein, we present a case of a male patient in his sixties who presented to us for a histopathological consultation of a previously excised tumor, which was grossly well-demarcated and connected to a nerve root in the cauda equina region. The tumor presented with histomorphological features of a sharply demarcated, non-infiltrative tumor growing in a nested to pseudopapillary pattern with a highly vascularized, intersecting stroma. Tumor cells were mildly atypical ovoid ones, with eosinophilic cytoplasm, central hyperchromatic nuclei, some with nucleoli, and salt and pepper chromatin. Intersecting stroma was rich in reticulin fibers, and the cell did not express epithelial membrane antigen, excluding the diagnosis of ependymoma as well as glial markers, excluding glial origin. Pan-cytokeratin was focally positive, neuroendocrine markers were diffusely positive, and the proliferative index was low. As such, the diagnosis of CENET, WHO CNS grade 1 was established, and the patient was referred back to the institution at which the surgery was performed for follow-up and further management.

Spindle Cell Renal Neoplasms: A Pathological Case Report on Primary Renal Leiomyosarcoma and Sarcomatoid Renal Cell Carcinoma.

Renal oncopathology in adults, as a field of pathology, is dominated by a single entity - clear cell renal cell carcinoma (RCC) with other entries, such as urothelial carcinoma of the renal pelvis, angiosarcoma, and others being extremely rare. Herein, we report two histopathological cases with differential diagnoses of spindle cell renal neoplasms. The first patient, a 42-year-old male, presented with new-onset right-sided abdominal flank pain, and imaging showed a 12 cm renal tumor. Histopathology showed a spindle cell neoplasm, with significant mitotic activity and giant cell, with immunohistochemistry being positive for caldesmon and vimentin, focally for smooth muscle actin (SMA). No reaction was noted for pan-cytokeratin (CK AE1/AE3), epithelial membrane antigen (EMA), cytokeratin (CK) 7, cluster of differentiation (CD) 117, soluble 100 protein (S100), human melanoma black (HMB) 45, Melan A, CD10, and desmin. Due to peculiar histomorphology and the immunophenotype, the tumor was interpreted as primary renal leiomyosarcoma. Due to continuous outpatient consultations, treatment initiation was delayed, and three months later, the patient had already developed an 87 mm local recurrence and liver metastasis. The second patient, a 53-year-old male, presented to our institution for consultation of an already excised renal tumor, diagnosed as an incidental finding on a prophylactic abdominal ultrasound. The tumor presented for consultation histologically grew as intertwining bundles of spindle cells with polymorphic hyperchromic nuclei with prominent nucleoli and had extensive areas with necrosis. Immunohistochemically, the tumor diffusely expressed CK AE1/AE3 and caldesmon and had a patchy reaction for EMA and CD10. The SMA, desmin, CD117, and CK7 reactions were negative; hence, the tumor was interpreted as a spindle cell variety (sub-type) of clear RCC.

Role of GATA3 in Early-Stage Urothelial Bladder Carcinoma Local Recurrence.

Background One of the most characteristic features of non-invasive urothelial carcinoma (UC) is its high recurrence rate. Guanine-adenine-thymine-adenine nucleotide sequence-binding protein 3 (GATA3), as a transcription factor, correlates with urothelial differentiation and has been reported with poor prognosis in high-grade UC and recurrence in breast malignancies. As such, we set out to study the specifics of GATA3 in non-invasive UC, emphasizing on prediction for recurrence. Methods The cohort comprised 163 patients, with a follow-up period of five years, including 109 pTa cases and 54 pT1 cases. Immunohistochemical expression of GATA3 was assessed using a histo score (H-score). Kaplan-Meier test was conducted for the time to recurrence, according to the level of expression of GATA3 and the indicators studied. Receiver operating characteristic (ROC) curve analysis was done to determine the role of accuracy and specificity of predictability of the indicators. Results Recurrence within the follow-up period was noted in 41.72% of cases. No recurrence relationship was established for age and gender. GATA3 expression showed a varying H-score. Using ROC curve analysis, a cut-off value of 155 divided UC expression levels into low and high, with a sensitivity of 72.7% and specificity of 78.7% (area under the curve=0.800, 95% confidence interval: 0.696-0.904, p<0.001), further showing an association between high levels of nuclear expression and risk of local recurrence (p<0.0001). Conclusion Herein we have described the sensitivity of high GATA3 expression in non-invasive UC of the urinary bladder and its relation to local recurrence, independent of gender, age, tumor differentiation, and stage.

Transcription Factor Zbtb20 as a Regulator of Malignancy and Its Practical Applications.

Zbtb20 (zinc finger and BTB domain-containing protein 20) is a transcription factor with a zinc finger DNA binding domain and a BTB domain responsible for protein-protein interaction. Recently, this TF has received attention because new data showed its pivotal involvement in normal neural development and its regulatory effects on proliferation and differentiation in different tissues. Zbtb20 was shown to increase proliferation and migration and confer resistance to apoptosis in the contexts of many malignant tumors like hepatocellular carcinoma, non-small-cell lung carcinoma, gastric adenocarcinoma, glioblastoma multiforme, breast cancer, and acute myeloid leukemia. The involvement of Zbtb20 in tumor biology is best studied in hepatocellular carcinoma, where it is a promising candidate as an immunohistochemical tumor marker or may be used in patient screening. Here we review the current data connecting Zbtb20 with malignant tumors.

Global Healthcare Systems: Perspectives on Pathology Practices in Bulgaria.

Healthcare in Bulgaria is a universal and free right as per legislation. However, due to limited government funding from a singular state-run insurance fund and the inequities in the distribution of limited healthcare professionals, access to quality healthcare is difficult for most citizens. Pathology is one of the most severely affected specialties as it is not only regarded as one of the most difficult ones due to its aspects and difficulties in obtaining it but also due to the lack of funding. The healthcare fund does not reimburse immunohistochemistry or genetic tests; however, hospital reimbursement relies on pathological diagnosis in most cases, prompting peer and institutional pressure towards adapting the diagnosis. A relatively good aspect of all of these is the low cost of immunohistochemistry if the patient chooses to pay for such, albeit when compared to the mean monthly salary within the country, the cost is still high. Lack of funding is not only limited to biopsy diagnosis, with research funding being minimal at best, while autopsy practice receives no funding whatsoever.

Modified Banff Criteria in Assessing SARS-CoV-2-Associated Renal Pathology: An Autopsy Study.

Introduction SARS-CoV-2 is an epitheliotropic viral agent with epithelial tropism. Although the clinical significance and severity of affection is the most pronounced in the respiratory system, other organs and systems are also infected and, hence affected, such as the central nervous system, gastrointestinal tract, cardiovascular, and urinary systems. Herein, we set out to evaluate the presence and degree of morphological changes within the renal parenchyma and its relation to disease outcome. Materials and methods A retrospective non-clinical approach was utilized for the means of the study. All patients with real-time reverse transcriptase-polymerase chain reaction proven infection, subject to an autopsy performed in a period of two calendar years, were included in the study. Kidney tissue histopathology samples were analyzed using a modified Banff criteria system for acute onset and chronic changes. The results were compared for statistical significance with overall patient survival from symptom onset to death. Furthermore, SARS-CoV-2 viral presence was evaluated in renal structures by means of immunohistochemistry. Results A total of 40 patients were included in the study. Immunohistochemistry showed viral presence within a myriad of renal structured - endothelial cells, tubular cells, and podocytes. Modified Banff criteria showed significant acute changes within the parenchyma, including endotheliitis, glomerulitis, mesangial matrix expansion, tubulitis, capillaritis, arteritis, thrombosis (including thrombotic microangiopathy in four patients), and hemorrhages. Individual cases also presented with signs of rhabdomyolysis - myoglobulin casts. Signs of chronic injury were also present in most patients. However, when calculated as scores, neither acute nor chronic changes showed a correlation with time from symptom onset to death. Conclusion The results of the present study show both viral presence and a myriad of induced changes in the contents of SARS-CoV-2 infection within the renal parenchyma. The lack of correlation with the degree of changes, when compared to survival, is an encouraging fact that the changes are unlikely to play a role in direct tanatogenesis while having the potential to manifest as chronic kidney disease in the future.

Extracranial Glioblastoma Metastasis: A Neuropathological Case Report.

Glioblastoma (GBM) is a central nervous system (CNS) high-grade glioma with a dismal patient prognosis. Classical concepts surrounding GBM development and progression indicate its ability to produce metastasis within the CNS, one of the few primary tumors with such capabilities. While classical concepts state that no primary CNS tumor produces extracranial metastasis, there have been multiple reports of such occurrences over the previous two decades. Here, we report a case of a male in his forties who presented to our institution with complaints of progressive headache and a history of right temporal craniotomy one month prior with a histologically verified GBM performed at another institution. Neuroradiology confirmed a residual tumor in the areas of the previous craniotomy, and gross total excision confirmed the diagnosis of GBM, although based on the presence of connective tissue amidst the tumor stroma, gliosarcoma could not be ruled out. The patient initiated treatment, and his condition remained stable for four calendar years until he again presented to our institution with a rapidly growing tumor mass in the right lateral neck region. Excision of the neck mass showed histopathological features of a tumor comprised of atypical cells with pronounced polymorphism, some with spindle cell morphology and a tendency for fascicular growth and focal palisade necrosis. Immunohistochemistry with a broad set of markers disproved epithelial, mesenchymal, melanocytic, and lymphoid genesis, with some markers of glial genesis present; hence, metastatic GBM was established. The patient reinitiated treatment and is currently stable. The steadily increasing amount of similar reported cases, together with the steady, albeit small, increase in GBM patient survival and improvement of neurooncological healthcare distribution and follow-up, challenge the classical concepts of GBM and other primary CNS tumors being unable to produce metastasis and swaying this perception towards the biological capabilities of these tumors to produce metastasis, while such rarely develop due to the short patient survival.

Intestinal-Type Adenocarcinoma of the Urinary Bladder With Coexisting Cystitis Cystica et Glandularis and Intestinal Metaplasia: A Histopathological Case Report.

Adenocarcinomas of the urinary bladder are exceedingly rare and present in various morphological forms. Virtually all of these are identical to glandular malignant neoplasia native to topographically neighboring organs, where the incidence of adenocarcinoma is also much more common, such as the large intestine. Cases of glandular malignancies of the urinary bladder, therefore, require not only a detailed histopathological evaluation and interpretation but also a detailed clinical and radiological one. These should be performed with the goal of proving the origin of the tumor as one arising from the urinary bladder and not an entry originating from another organ and invading or producing metastasis to it. A controversial etiopathogenic link to urinary bladder adenocarcinoma is that of cystitis cystica et glandularis, which often coexists with the condition. Herein, we present a case report of non-muscle-invasive urinary bladder adenocarcinoma in a previously healthy male patient in his forties with a known history of cystitis cystica et glandularis. The patient presented with gross hematuria, and based on his known urological condition, a cystoscopy with biopsy was performed, showing submucosal proliferation of atypical glands. The detailed clinical and radiological evaluation showed no evidence of malignancy at other sites. As the malignancy was non-muscle-invasive, an intravesical dose of the Bacillus Calmette-Guérin vaccine was administered. The patient was followed up with cystoscopy, and a biopsy showed no evidence of residual malignancy, with cystitis cystica et glandularis persisting. A year following the diagnosis, the patient is still actively monitored, and no recurrence is noted.

Bullous Henoch-Schönlein Purpura and Associated Nephritis: A Pathological Case Report.

Henoch-Schönlein purpura (HSP) is the most common vasculitis in childhood, presenting with purpura, predominantly of the lower extremities and occasionally with renal involvement as well. Although associated with childhood, HSP, although rarely, can also develop in adults as well. Here we present a patient in his sixties, presenting with a myriad of rash units on his lower extremities, including bullous ones, and a constellation of chronic kidney failure. Skin and renal biopsy specimens revealed morphological changes and immune depositions representative of HSP. Despite treatment, the patient's kidney failure slowly progressed, and he expired eight months after his presentation due to associated complications. Although rare, the bullous form of HSP can be viewed as a more aggressive form of the disease, as seen by the presentation constellation and rapid progression in our case.

Fibroblast Growth Factor-2 and the Invasive Potential in Urothelial Malignancies of the Bladder.

Introduction Urothelial carcinomas represent a distinct group of malignancies with a high recurrence potential. Multiple studies have established a set of interactions between the tumor cells of urothelial neoplasms and the extracellular matrix regarding invasion and tumor progression. In the present study, we evaluated the expression of fibroblast growth factor-2 (FGF2) in early-stage urothelial carcinomas of the urinary bladder (pTa and pT1) regarding the invasive potential of these tumors. Materials and methods A retrospective non-clinical approach was utilized for the study. Tumor tissue sections used for the initial diagnosis were stained by immunohistochemical means with an anti-FGF2 antibody and the expression within the extracellular matrix was evaluated using a histo-score (h-score). Statistical parameters regarding tumor invasion, FGF2 expression pattern and levels, patient demographic characteristics, and disease recurrence were analyzed for significance. Results A total of 163 cases were analyzed, with an h-score of 110 determined as the optimal cut-off value for invasive potential regarding FGF2 expression, with a sensitivity of 75.4% and a specificity of 78.9%. No statistical correlation was established between the demographic profile of the patients and the occurrence of disease recurrence. Conclusion Based on our results, the study of tumor-extracellular matrix interactions in regards to FGF2 expression is a promising field, at least in urothelial malignancies of the urinary bladder, in regards to tumor invasive potential, while it remains unestablished how these interactions affect metastatic potential.

Not All Monstrous Cells Indicate Glioblastoma: A Neuropathological Case Report of Pleomorphic Xanthoastrocytoma Misdiagnoses As Giant Cell Glioblastoma.

Pleomorphic xanthoastrocytoma (PXA) is a rare central nervous system malignant neoplasm with a relatively favorable prognosis. As PXA histologically presents with large, multinucleated neoplastic cells, its principal differential diagnosis is giant cell glioblastoma (GCGBM). While there is a significant overlap between the two histologically and the neuropathological diagnosis can be challenging, as well as having some overlap neuroradiologically, the patient prognosis differs significantly, with PXA having a more favorable one. Herein we present a case report of a male patient in his thirties diagnosed with GCGBM and presenting again six years later with thickening of the wall of the porencephalic cyst suggestive of disease recurrence. Histopathology revealed neoplastic spindle, small lymphocyte-like, large epithelioid-like, some with foamy cytoplasm, and scattered large multinucleated cells with bizarre nuclei. For the most part, the tumor had a distinct border to the surrounding brain parenchyma, except for a single zone of invasion. As per the depicted morphology, with a lack of pathognomic features of GCGBM, the diagnosis of PXA was defined, and the oncologic committee reevaluated the patient with treatment reinitiation. Based on the close morphological profile of these neoplasias, it is likely that in the case of limited material, multiple PXA cases are diagnosed as GCGBM, resulting in misdiagnosed long survivors.

Effects of Melatonin Supplementation on the Aortic Wall in a Diet-Induced Obesity Rat Model.

Background Cardiovascular disease (CVD) is still the leading cause of death globally. Alterations in the arterial wall architecture predict CVD morbidity and mortality and are associated with other CVD risk factors. Aortic wall thickness is closely linked to short- and long-term CVD morbidity and mortality, even without pronounced atherosclerotic changes. Obesity increases the risk of a broad spectrum of pathologies with vascular manifestation, which are often pathogenically associated with chronic oxidative stress and inflammatory response. Hence, as an antioxidant and anti-inflammatory agent, the pineal gland hormone melatonin is expected to have vasoprotective effects. This study evaluated the effects of melatonin supplementation on aortic wall thickness by assessing the cross-sectional associations of abdominal obesity with aortic intima-media thickness in a diet-induced obesity rat model. Methodology The model comprised of male Wistar rats that were on a high-fructose diet (HFD) (20% glucose-fructose corn syrup) for 12 weeks; the rats were divided into four groups (n = 8): control, HFD, HFD and melatonin supplementation (per os - 4 mg/kg/24h), and control and melatonin supplementation. All rats received a standard rodent diet and tap water. Zoometric measurements and the Lee index were calculated. Morphometric analysis of the abdominal aorta was performed by staining with hematoxylin-eosin and measuring the thickness of the abdominal aortic wall. For this, we used the Aperio Image Scope software. To evaluate the functional properties of the abdominal aorta, the modified Kernogan's index (KI) was employed. Results The results showed significantly elevated body weight (Lee index), KI, and wall thickness of the aorta abdominalis with morphometric changes in the vessel wall in HFD rats compared to the control group. Melatonin supplementation prevented these changes. Conclusions The administration of HFD to Wistar rats led to pathomorphological and morphometric changes in their abdominal aorta, which constitute the main diagnostic criteria of endothelial dysfunction. Melatonin supplementation regressed vascular wall remodeling and restored its functional capacity.

Posterior Fossa Dysembryoplastic Neuroepithelial Tumor: A Neuropathological Report.

Dysembryoplastic neuroepithelial tumors (DNTs) are rare neoplastic entries of the central nervous system. Conventionally DNTs are with cortical location and predominantly occur in the temporal lobe associated with epilepsy. Subtentorial DNTs are rare entries. Herein we report a case of a two-year-old female with a DNT located in the cerebellum. The patient presented clinically with new onset gait instability, headaches and strabismus. Neuroradiology revealed a heterogenous, predominantly cystic lesion in the cerebellar vermis and left cerebellar hemisphere, which was interpreted as possible medulloblastoma based on the patient profile. Frozen section neuropathology was more suggestive of a low-grade glial tumor, with conventional histology and immunohistochemistry showing an admixture of glial and neuronal cells - a complex variety of DNT. Due to the histological appearance, differential diagnosis was required with other neuroglial tumors native to the posterior fossa, such as Lhermitte-Duclos disease. There have been several such published case reports, which, although of older patients, present with similar symptoms and neuropathological findings. The complexity of the neuropathological finding in posterior fossa DNTs can lead to future separation of this entry from conventional DNT, as was seen in the past with septum pellucidum DNT, now referred to as myxoid glioneuronal tumor.

Role of Cytokeratin 20 as a Predictive and Prognostic Marker in Urothelial Neoplasms.

Introduction Several clinical peculiarities mark urothelial carcinomas and their biological behavior. Key in these are its relatively indolent course before manifestation and its high recurrence rate. So far, no biomarker has been identified as a predictor for these factors. The current study aims to evaluate the role of cytokeratin 20 (CK20) in non-invasive urothelial carcinomas (pTa and pT1) of the urinary bladder and its diagnostic and predictive role in tumor staging and recurrence. Materials and methods The study utilizes a retrospective, non-clinical approach via immunohistochemical marking of the paraffin-embedded tumor tissues for the initial diagnosis. Expression patterns were compared with tumor grade and stage, as well as the incidence of recurrence within a five-year follow-up period. Results A strong statistical correlation was established between expression and tumor grade, with high-grade tumors showing weak to moderate expression of CK20 while low-grade tumors showed an intensive expression pattern. No correlation was noted between the expression pattern, patient age and gender, tumor stage, and the likelihood of local recurrence. Conclusion While CK 20 is a reliable diagnostic marker when used together with other markers, its expression pattern in our study correlated only with bladder urothelial carcinoma grade.

Modified Silver Impregnation Method for Basal Membranes in Renal Biopsies.

Silver impregnation methods are essential in biopsy interpretation in nephropathology with regard to visualizing the basal lamina and its associated changes. The most widely used methods, mainly Jones methenamine impregnation, are time-consuming in their protocols and require multiple microscopy control points. In this report, we propose an alternative, modified method for silver impregnation with methenamine solution with a significantly shorter protocol time and good staining quality, allowing for proper interpretation of basal lamina changes in the glomeruli and blood vessels. Furthermore, unlike some other modified techniques, our proposed protocol does not include microwaving of the solutions but rather a thermostat is used, thereby reducing fire hazards. Implementing the protocol in our everyday practice has reduced sample processing time while not negatively impacting biopsy interpretation.

The Rapid Development of Glioblastoma: A Report of Two Cases.

Diffuse astrocytic gliomas and their most common and aggressive representation, glioblastoma (GBM), which as per the 2021 World Health Organization (WHO) guidelines is an isocitrate dehydrogenase (IDH) wildtype without alteration in histone 3 and has glomeruloid vascular proliferation, tumor necrosis, telomerase reverse transcriptase (TERT) promoter mutation, epidermal growth factor receptor (EGFR) gene amplification, or +7/-10 chromosome copy-number changes, are fast-growing tumors with a dismal patient prognosis. Herein, we present cases of a 63-year-old male who, despite no evidence of tumor growth, developed a 6-cm tumor, histologically verified as GBM, WHO CNS grade 4, within eight months, and a 74-year-old female in whom a 1.5-cm tumor grew to 43 mm within 28 days, once again histologically confirmed as GBM, WHO CNS grade 4. Other studies using previous WHO guidelines and including up to 106 cases have shown that these tumors have a daily growth rate of 1.4% and can double their size in a period varying from two weeks to 49.6 days. These growth rates further underline the need for extensive surgical resection as disease progression is rapid, with studies reporting that resection of more than 85% of the tumor volume determined on neuroradiology improves survival compared to biopsy or limited resection and resection of more than 98% of the tumor volume statistically improves patient survival.

Light Chain Deposition Disease: A Morphological Case Report.

Light chain deposition disease (LCDD) is a rare condition associated with the overproduction and deposition of monoclonal light chain immunoglobulins. The kidneys are universally affected in LCDD, with the development of renal failure with nephrotic syndrome, microscopic hematuria, and proteinuria. Most cases are associated with a plasma cell neoplasm (multiple myeloma or plasmacytoma) or other lymphoproliferative disorders, with a reasonable number of cases also being idiopathic. Other organs can be affected in rare cases, without producing significant symptoms, predominantly the liver and heart. In this report, we discuss a case of a 72-year-old female presenting with the aforementioned symptoms. Percutaneous ultrasound-guided kidney biopsy revealed nodular sclerosis with periodic acid-Schiff stain (PAS)-positive, Congo red-negative, silver impregnation weakly-positive, and Masson's trichrome-positive (red reaction) deposits with ribbon-like changes together with light chain deposits in the tubular basement membranes. As LCDD was diagnosed, the patient was subjected to further tests, with multiple myeloma of the thoracic vertebrae also being diagnosed. The patient was started on myeloma treatment; however, she subsequently developed a severe lower limb infection that required amputation, after which she developed sepsis and expired.

The Role of Preoperative Neutrophil, Platelet, and Monocyte to Lymphocyte Ratios as Independent Prognostic Factors for Patient Survival in WHO 2021 Glioblastoma: A Single-Center Retrospective Study.

Introductions Immuno-oncology is a rapidly developing field wherein tumor-immune system interactions can be harnessed for diagnostics. Herein, we set out to establish the role of the immune system response, as measured by preoperative neutrophil, platelet, and monocyte to lymphocyte ratios (NLR, PLR, and MLR) as prognostic markers for patient survival based on the newly defined criteria for glioblastoma (GBM). Materials and methods The study included patients diagnosed with GBM at a four-year interval. Exclusion criteria were patients subject to reoperation in the time period; tumors in more than one system; a history of hematological and autoimmune diseases; and cases with infectious or other inflammatory conditions. Data regarding patient demographics and preoperative blood counts were pulled from patient records and compared to postoperative survival. Results A total of 22 patients fit the established criteria, with a male to female ratio of 2.14:1, a mean age of 66.23 years, and a mean survival of 255.72 days (8.04 months, range 24-801 days). Eight patients had an elevation of NLR and five of PLR, with no statistical correlation to survival. Six patients had an increase in MLR with a statistically significant (p=0.0044) shorter postoperative survival. Synergic increases in NLR and PLR did not show significance, while synergic increases with MLR showed no added benefit. Conclusion Preoperative MLR, but not NLR or PLR, is a promising independent biomarker for patient survival in GBM. It is suggested that elevations in these ratios directly correlate to tumor biological potential.

Diaph3 underlines tumor cell heterogeneity in glioblastoma with implications for treatment modalities resistance.

INTRODUCTION: Glioblastoma (GBM) is the most aggressive central nervous system (CNS) tumor with astrocytic differentiation. The growth pattern of GBM mimics that of the precursor cell migration during the fetal development of the brain. Diaphanous homolog (Diaph3) has been established to play a role in both CNS maturation and cancer progression as it is required both for cell migration and division. Furthermore, Diaph3 has been shown to play a role in malignant disease progression through hyperactivation of the EGFR/MEK/ERK in loss of expression and its overexpression correlating to hyperactivity of the mTOR pathway, both of which are with a well-established role in GBM. Herein, we aimed at establishing the diagnostic role of Diaph3 immunohistochemistry expression patterns in GBM and their possible implications for molecular response to different therapies. MATERIALS AND METHODS: The study utilized a retrospective nonclinical approach. Results of Diaph3 immunohistochemical expression were compared to healthy controls and reactive gliosis and statistically analyzed for correlation with neuroradiological tumor parameters and patient survival. RESULTS: Healthy controls showed individual weakly positive cells, while reactive gliosis controls showed a strong expression in astrocytic projections. GBM samples showed a heterogeneous positive reaction to Diaph3, mean number of positive cells 62.66%, median 61.5, range 12-96%. Areas of migrating cells showed a strong diffuse cytoplasmic reaction. Cells located in the tumor core and those in areas of submeningeal aggregation had no antibody expression. Statistical analysis revealed no correlation with tumor size or patient survival. CONCLUSION: The different expression pattern of Diaph3 in healthy controls, reactive gliosis and GBM shows promise as a clinical differentiating marker. Despite Diaph3 expression not correlating with survival and tumor size in GBM, there is an accumulating body of evidence that Diaph3 correlates with mTOR activity and can thus be used as a predictor for response to rapamycin and taxanes, clinical studies of which have shown promising, if mixed results in GBM.