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Maher Kurdi,1,2 Nasser Mulla,3 Yousef Katib,4 Taghreed Alsinani,5 Sahar Hakamy,2 Bassam MJ Addas,6 Husam Malibary,7 Taher F Halawa,8 Marwa S Farhan,9 Eyad Faizo,10 Saleh Baeesa6 1Department of Pathology, Faculty of Medicine, King Abdulaziz University, Rabigh, Saudi Arabia; 2Brain Tumour Unit, KFMRC, King Abdulaziz University, Jeddah, Saudi Arabia; 3Department of Internal Medicine, Faculty of Medicine, Taibah University, Medina, Saudi Arabia; 4Department of Radiology, Faculty of Medicine, Taibah University, Madinah, Saudi Arabia; 5Department of Surgery, King Fahad General Hospital, Jeddah, Saudi Arabia; 6Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; 7Department of Internal Medicine, Faculty of Medicine, King Abdul Aziz University, Jeddah, Saudi Arabia; 8Pediatric Hematology and Oncology Consultant, Faculty of Medicine, King Abdulaziz University, Rabigh, Saudi Arabia; 9Clinical Pathology Department, Cairo University, Cairo, Egypt; 10Division of Neurosurgery, Department of Surgery, Faculty of Medicine, Tabuk University, Tabuk, Saudi ArabiaCorrespondence: Maher Kurdi, Department of Pathology, Faculty of Medicine, King Abdulaziz University, Rabigh, Saudi Arabia, Tel +966 556655467, Email Ahkurdi@kau.edu.saPurpose: IDH1 and IDH2 are hotspot mutations commonly identified in WHO-grade 4 astrocytomas. Their association with TAMs has never been investigated. We aim to explore the crosstalk between the IDH1/2 mutation metabolic effect and TAMs in tumour microenvironment and how this relationship affects the tumour recurrence.Patients and Methods: The study included 20 samples of patients with WHO-grade 4 astrocytoma. The alteration hotspot in codon IDH1R132 and IDH2R172 was examined using direct sequencing. The protein expression of CD204 on TAM was detected through immunohistochemistry.Results: IDH1R132 and IDH2R172 were symmetrically identified as wildtype in 18/20 tumours (90%) and the remaining 2 tumours (10%) showed synonymous mutations on both codons. Tumours with IDH1/2-wildtype showed high expression of CD204+TAMs in 10 cases and low expression in 8 cases. Typical expression was seen equally in IDH1/2 mutant tumours. There was no significant association between IDH1/2 and CD204+TAM expression (p= 0.999). The association between the two groups was significantly observed among IDH-wildtype tumours (p=0.027). Highly expressed CD204 in IDH-wildtype tumours showed a median recurrence at 10 months compared to low CD204 expression, showed a median recurrence interval at 24 months.Conclusion: IDH1R132 or IDHR172 has the same impact on the classification and prognosis of WHO-grade 4 astrocytoma. There was no crosstalk between IDH1/2 metabolic effect and CD204+TAM. However, IDH-wildtype glioblastomas with dense CD204+TAM are associated with early recurrence. Because the sample size is small, a larger study is recommended to determine the impact of IDH1/2 on TAMs.Keywords: WHO-grade 4 astrocytoma, IDH1/2 mutation, TAM, CD204, recurrence

Nav1.7/SCN9A is a voltage gated sodium ion channel (VGSC), expressed by nociceptive neurons. Its role in pain mechanism was well- established but its involvement in the carcinogenic pathways is still under investigation. We aimed to explore the expression of Nav1.7/ SCN9A receptors in intracranial meningiomas and compare it with urothelial, prostate, and ovarian cancers. Methods: Ten paraffin embedded tissue samples of brain meningioma and 5 cases each of bladder, prostate and ovarian carcinomas were utilized. Immunohistochemistry (IHC) was performed using anti-SCN9A antibody. Cases were scored based on the intensity of expression and number of positive tumour cells. A score of (+3) indicated highest intensity, (+2) as moderate and (+1) as weak intensity. Similarly, 50-100% expression in cells was labelled as (+3), moderate, 30-50% as (+2) and 10-20% as weak or (+1) expression, and (0) as negative. Results: Nine cases of meningioma were in grade I and single case was grade III. The nine grade I meningioma were negative for SCN9/Nav1.7 expression while the single grade III case was positive. Tumour cells in urothelial, prostate, and ovarian carcinomas were all strongly positive for SCN9/Nav1.7, having intensity expression as (+3). Conclusions: This study suggests an emerging role of Nav1.7/SCN9A receptor expression in urothelial, prostate, and ovarian cancers as well as grade III meningiomas compared to grade I meningioma. This clarifies that Nav1.7/SCN9A has a possible role in carcinogenesis of most body tumours. Key Words: Nav1.7, sodium channels, Ion channels, Channelopathy, meningioma, carcinoma

Dermatomyositis (DM) is an immune-mediated inflammatory disease characterized by pathognomic lesions in skin and skeletal muscle including lymphocytic infiltrates. It rarely presents with ectopic lymphoid structures, as other autoimmune and chronic inflammatory diseases. We describe a case of a 47-year-old male, who presented clinically with proximal muscle weakness, skin rash and elevated creatin kinase (CK) levels. The muscle biopsy revealed inflammatory myopathy, with perifascicular pathology, and scattered ectopic lymphoid follicles-like structures harboring reactive B-cells. Clonality analysis of B-cells using polymerase chain reaction ruled out malignant lymphoma. The patient responded favorably to steroid therapy, and his muscle weakness improved. In conclusion, the clinical and histopathologic features of DM can be atypical, and the presence of lymphoid follicles, although rare, is not inevitably linked to an unfavorable prognosis.

Maher Kurdi,1 Nadeem Shafique Butt,2 Saleh Baeesa,3 Abudukadeer Kuerban,4 Yazid Maghrabi,5 Anas Bardeesi,5 Rothaina Saeedi,3 Badrah S Alghamdi,6 Ahmed I Lary,7 Fawaz Mohamed,1 Sahar Hakamy8 1Department of Pathology, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 2Department of Family and Community Medicine, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 3Division of Neurosurgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 4Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 5Department of Neuroscience, King Faisal Specialist Hospital and Research Center, Jeddah, Kingdom of Saudi Arabia; 6Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 7Section of Neurosurgery, Department of Surgery, King Abdulaziz Medical City, Jeddah, Kingdom of Saudi Arabia; 8Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Kingdom of Saudi ArabiaCorrespondence: Maher KurdiDepartment of Pathology, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah, Kingdom of Saudi ArabiaTel +966 556655467Email Ahkurdi@kau.edu.saPurpose: Wilms tumor 1 (WT1) gene has recently shown a role in gliomagenesis, making it a potential immunotherapy target in glioblastomas. We aimed to investigate the most sensitive method to detect WT1 expression in glioblastoma and explore the relationship between WT1 expression, IDH1 mutation and recurrence interval.Patients and Methods: Clinical data were collected from 44 patients with glioblastomas, treated with adjuvant therapies. WT1 expression was assessed in all cases using immunohistochemistry (IHC), while its gene expression was assessed in 13 clustered samples using polymerase chain reaction (qPCR). IDH1 mutation was assessed using IHC. The sensitivity between IHC and RT-qPCR was examined. Kaplan–Meier curves were used to compare the recurrence-free interval (RFI) between IDH1 and WT1 expression groups.Results: IDH1wildtype was found in 26 cases (59.1%) and the remaining 18 cases (40.9%) were IDH1mutant. Through IHC, WT1 was overexpressed in 32 cases (72.7%), partially expressed in 9 cases (20.5%) and not expressed in only 3 cases. For the 13 cases tested by qPCR, 6 cases showed WT1 upregulation and 7 cases showed WT1 downregulation. There was no significant difference in WT1 expression among cases with different RNA concentrations regardless the testing method (p-value > 0.05). However, the difference between IHC and qPCR was significant. IDH1mutant cases with WT1 overexpression showed significant difference in RFI (p-value =0.048).Conclusion: Parallel testing for WT1 expression using IHC and qPCR is not reliable. However, IHC provides more accurate results. Moreover, IDH1mutant glioblastomas with WT1 overexpression are associated with late RFI particularly if temozolomide with additional chemotherapies are used.Keywords: glioblastoma, IDH1 mutation, WT1 expression, chemotherapies, PCR sensitivity

Tumor-associated macrophages (TAMs) are principal immune cells in glioma microenvironment which support tumor growth and proliferation. Our aim in this study was to assess the relationship between CD204-expressed TAMs and OThe expression of CD204There were 10 cases (22.2%) with isocitrate dehydrogenase (Grade 4 astrocytomas with diffusely expressed CD204

Background: Neurotrophic tyrosine receptor kinase (NTRK) fusion has been detected in rare types of CNS tumours, which can promote tumorigenesis. The efficacy of Trk inhibitor became a significant therapeutic interest. Our aim was to investigate whether Pan-Trk immunohistochemistry (IHC) is a reliable and efficient marker for detecting NTRK-fusion in different brain tumours.Methods: This study included 23 patients diagnosed with different types of CNS tumours. Testing for Pan-Trk IHC with monoclonal Ab (EPR17341) has been performed on all FFPE tissues. Parallelly, NTRK-rearrangements were tested using both DNA and RNA-based next-generation sequencing (NGS) assay using TruSight Onco500 platform.Results: The cohort included eight pilocytic astrocytomas, one oligodendroglioma, six IDHwildtype glioblastomas, four IDHmutant grade four astrocytomas, and one sample of each (astroblastoma, central neurocytoma, medulloblastoma, and liponeurocytoma). The mean age was 35 years; seven cases were in the paediatric age group, and 16 were adult. Pan-Trk expression was detected in 11 (47.8%) tumours, and 12 (52.1%) tumours showed no Pan-Trk expression. Nine Cases (82%) with different Pan-Trk expressions did not reveal NTRK-rearrangement. The other two positively expressed cases (liponeurocytoma and glioblastoma) were found to have NTRK2-fusions (SLC O 5A1-NTRK2, AGBL4-NTRK2, BEND5-NTRK2). All the 12 cases (100%) with no Pan-Trk expression have shown no NTRK-fusions. There was no statistically significant association between Pan-Trk expression and NTRK-fusion (p = 0.217). The detection of NTRK- fusions using NGS had high specificity over NTRK-fusion detection by using Pan-Trk IHC.Conclusion: Pan-Trk IHC is not a suitable tissue-efficient biomarker to screen for NTRK-fusions in CNS tumours, however RNA-based NGS sequencing should be used as an alternative method.

Background: TIMP3 is a multifunctional proteolytic enzyme belonging to TIMPs family and acts as a potent inhibitor of matrix metalloproteinases (MMPs). TIMP3 possesses a tumor suppresive function by directly promoting tumor cell apoptosis, preventing angiogenesis and extracellular matrix remodelling. The lower expression of TIMP3 was associated with poor prognosis and overall survival in various cancer types. The aim of this study was to evaluate the association of TIMP3 protein expression with ovarian cancer (OC) clinicopathological features and survival outcomes. Patients and Methods: One hundred forty four of OC FFPE samples were collected from King Abdulaziz University Hospital, Saudi Arabia and constructed in tissue microarray (TMA) slides. Automated Ventana immunostainer platform was used to evaluate TIMP3 protein expression patterns. Results: The study showed that TIMP3 exhibits cytoplasmic localisation. This TIMP3 protein expres- sion was not associated with age, tumor size and the involvement of lymph nodes (p > 0.05). However, it was significantly correlated with tumor stage (p < 0.05) and borderline significant with endpoint status (p = 0.07). Interestingly, the Kaplan-Meier analysis of disease specific survival (DSS) outcomes showed a significant association (p = 0.02, log rank) between OC patients with higher TIMP3 expression compared to those with lower expression. In fact, OC patients with high TIMP3 expression had longer survivals. Multivariate Cox’s regression analysis suggests that low TIMP3 protein expression pattern is an independent poor survival marker (p = 0.025). Conclusion: Cytoplasmic TIMP3 protein expression could be used as a good prognosticator to stratify poorly prognostic OC patients in order to personlaize their disease management.

Objective: Intraoperative frozen section (IOFS) diagnosis of brain tumors plays an important role in assessing the adequacy of the sample and determining the treatment plan. The aim of this study was to investigate the diagnostic accuracy between IOFS and permanent sections. Material and Method: The authors reviewed the histopathological results of 383 brain tumors, including IOFS and permanent histological diagnosis. The cases were classified into three diagnostic compatibilities (i) Perfect fit; the diagnosis of IOFS was identical to the permanent diagnosis, (ii) Partial compatibility; IOFS diagnosis was not incorrect but was too broad to be considered full compatibility, (iii) Conflict; IOFS diagnosis is completely different from the permanent diagnosis. The permanent diagnosis was used as a primary criterion and was compared to IOFS diagnosis and recurrence rate using different statistical methods. Results: 84% of the patients underwent craniotomy and tumor resection, while 15% only underwent tumor biopsy. Approximately, 53.8 % of the cases revealed perfect matching in the diagnosis between IOFSs and permanent sections, while 16.2% of the cases revealed complete mismatching in the diagnosis between the sections. The remaining 30% of the cases showed partial compatibility in the diagnosis between the two diagnostic methods. There was no significant difference in recurrence rate among all cases of different diagnostic compatibility (p=0.54). Conclusion: There is a diagnostic discrepancy between IOFSs and permanent sections. However, cases that revealed no consensus in the diagnoses showed no negative effect on the patient outcome. Further studies should be conducted to explore the reasons of this conflict in the two diagnostic methods.

Purpose Wilms tumor 1 (WT1) gene has recently shown a role in gliomagenesis, making it a potential immunotherapy target in glioblastomas. We aimed to investigate the most sensitive method to detect WT1 expression in glioblastoma and explore the relationship between WT1 expression, IDH1 mutation and recurrence interval. Patients and Methods Clinical data were collected from 44 patients with glioblastomas, treated with adjuvant therapies. WT1 expression was assessed in all cases using immunohistochemistry (IHC), while its gene expression was assessed in 13 clustered samples using polymerase chain reaction (qPCR). IDH1 mutation was assessed using IHC. The sensitivity between IHC and RT-qPCR was examined. Kaplan–Meier curves were used to compare the recurrence-free interval (RFI) between IDH1 and WT1 expression groups. Results IDH1wildtype was found in 26 cases (59.1%) and the remaining 18 cases (40.9%) were IDH1mutant. Through IHC, WT1 was overexpressed in 32 cases (72.7%), partially expressed in 9 cases (20.5%) and not expressed in only 3 cases. For the 13 cases tested by qPCR, 6 cases showed WT1 upregulation and 7 cases showed WT1 downregulation. There was no significant difference in WT1 expression among cases with different RNA concentrations regardless the testing method (p-value >0.05). However, the difference between IHC and qPCR was significant. IDH1mutant cases with WT1 overexpression showed significant difference in RFI (p-value =0.048). Conclusion Parallel testing for WT1 expression using IHC and qPCR is not reliable. However, IHC provides more accurate results. Moreover, IDH1mutant glioblastomas with WT1 overexpression are associated with late RFI particularly if temozolomide with additional chemotherapies are used.

Materials and methods Archival FFPE tumor samples were analyzed using immunohistochemistry (IHC) for monoclonal antiFGF19 (W12) antibody in 193 patients with BC. IHC analysis was done using the automatic system (BenchMark XT; Ventana Medical Systems, Inc. Tucson, AZ, USA). Patients were diagnosed and treated at the Departments of Pathology, Surgery and Oncology, King Abdulaziz University Hospital, Saudi Arabia and the National Oncology Institute, Sabratha, Libya during years 2000-2008.