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Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignant disease and is considered the fourth leading cause of death among cancer patients in the United States. Mutations in the BRCA gene, which is a DNA repair gene, increase the risk of PDAC, and among all patients with PDAC, about 8%-10% have a BRCA2 mutation. The finding of gene mutations is associated with a better response to platinum-based chemotherapy. Here, we present a case of a 59-year-old male with a BRCA2 gene mutation who was diagnosed with locally advanced pancreatic cancer and had achieved a complete pathological response to the FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin) regimen and Whipple procedure. We also present our literature findings on response types in BRCA2 PDAC patients, as well as consensus on the use of different therapies. The use of platinum-based chemotherapy with BRCA2 is highly recommended as the first-line treatment. Most PDAC patients remain untested for BRCA2 mutation even though their genetic status influences the selection of drug regimens. Thus, we recommend genetic testing for everyone with PDAC., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Asiri et al.)

Background Kikuchi-Fujimoto disease (KFD) - also known as necrotizing histiocytic lymphadenitis - is a benign histiocytic lymphadenitis known for its low incidence and misdiagnosis that occurs mostly in young Asian females more than males. This disease resolves spontaneously in a few months with a low risk of relapse (one in 30 patients) after resolution. Objectives The aim of this study is to share King Abdulaziz Medical City's (KAMC's) experience with KFD by determining its clinicopathological characteristics. Materials and methods In this study, we reviewed histopathological slides and pathological reports of all lymphadenopathy cases (683 cases) in the period between January 2008 and December 2018. Results Forty-four cases of KFD were found and their clinicopathological characteristics were recorded. There is a slight female predominance (59% females versus 41% males) with a wide age range from 10 months to 97 years (mean = 28.8). The majority of the cases (63.6%) are seen in young adults (between 21 and 40 years). Association with autoimmune diseases was shown by 20.5% of cases while viral infection association was shown by few cases. Most cases showed remission (59%) and no deaths were reported upon follow-up. Histopathologically, the majority of cases have proliferative type followed by the necrotic type and few cases showed xanthomatous type. Conclusions Our study has the largest number of KFD cases in this region. It is obvious that KFD has clinical, radiological, and pathological features that overlap with malignancy, especially lymphoma. Knowing this disease and careful diagnostic approach can help avoid misdiagnosis., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, AlShieban et al.)

Background: Mucormycosis is a life-threatening fungal infection with variable epidemiology between countries. Limited data are available locally; we aim to describe the clinical spectrum and outcome of mucormycosis in Saudi Arabia., Methods: A retrospective multi-center study including all patients with clinical and pathological evidence of mucormycosis in 3 tertiary care centers in Saudi Arabia from January 2009 to December 2019., Results: Thirty-three patients were identified during the study period. The mean age was 42 years. People with diabetes accounted for 48% of the patient population. The most common site of infection was cutaneous (27%), followed by isolated sinusitis (21%) and pulmonary and rhino-orbital-cerebral mucormycosis (each 18%). The most common isolated species were Rhizopus (50%) and Mucor (15%). Most patients received medical therapy with amphotericin B (79%), and more than half were treated surgically. The 1-year mortality rate reached 48%, with higher mortality observed in disseminated and rhino-orbital-cerebral infections than in other sites., Conclusion: Our study addressed the epidemiology of mucormycosis in Saudi Arabia and showed comparable patterns of clinical and mycological aspects to worldwide reports. Further studies are needed to evaluate mucormycosis risk factors and prognosis based on the species, site of infection and therapy type., Competing Interests: The authors have no conflict of interest to disclose., (© 2022 The Author(s).)

Background: Hodgkin lymphoma (HL) is lymphoid neoplasm usually affecting lymphatic system; it accounts 3.6% of cancers in Saudi Arabia. Modern treatment protocols had shown particular success rates in overall-survival (OS) and event-free-survival (EFS). In our study, we reviewed the medical records of 80 pediatric and young adolescent patients diagnosed HL from January 2006 to July 2020, treated at tertiary care hospital in Riyadh, Saudi Arabia. Demographic, clinical, and pathological data were explored. First line therapy was ABVD, COG, COPP, R-CHOP, or radiotherapy alone in 53/80 (66.4%), 24/80 (30%), 1/80 (1.2%), 1/80 (1.2%), or 1/80 (1.2%) patients; respectively. Response assessment was done by CT + / - PET scan after first 2 cycles then every 2 cycle and end of therapy. Another assessment was done if any clinical suspicion of recurrence., Results: Median age 11 (range 3-16) years. Males to females 1.3:1. Seventy-two out of eighty (90%) patients showed first complete remission (CR1) and maintained remission for median 40 (range 7-136) months. Eight out of eighty (10%) patients showed refractory disease. Nineteen patients received salvage therapy (ICE or ESHAP/brentuximab vedotin or gemcitabine/brentuximab vedotin), 14/19 (73.7%) had 2nd complete remission (CR2) for median time 24 (ranged 9-78) months, while 5/19 (26.3%) did not show any response. Five-year OS and EFS were 95% and 75%. Two patients had 2ry malignant neoplasms, one had AML and died, the other had malignant fibrous histocytoma and still alive. None of our patients had fertility problem. Also, they did not experience chronic pulmonary or cardiotoxicity. Classic Hodgkin's lymphoma: nodular sclerosis subtype was more prominent (55%) than mixed cellularity subtype (22.5%), which is similar to several European and US studies, lymphocyte rich (11.25%) and lymphocyte depleted (0%), while nodular lymphocyte predominant Hodgkin's lymphoma (11.25%)., Conclusions: Our study provided unique descriptive study of childhood HL, in Saudi Arabia, with valuable insight into the long-term outcome and late toxicity. Our results are comparable to other studies in the Middle East and European countries., (© 2021. The Author(s).)

Biomarker discovery would be an important tool in advancing and utilizing the concept of precision and personalized medicine in the clinic. Discovery of novel variants in local population provides confident targets for developing biomarkers for personalized medicine. We identified the need to generate high-quality sequencing data from local colorectal cancer patients and understand the pattern of occurrence of variants. In this report, we used archived samples from Saudi Arabia and used the AmpliSeq comprehensive cancer panel to identify novel somatic variants. We report a comprehensive analysis of next-generation sequencing results with a coverage of >300X. We identified 466 novel variants which were previously unreported in COSMIC and ICGC databases. We analyzed the genes associated with these variants in terms of their frequency of occurrence, probable pathogenicity, and clinicopathological features. Among pathogenic somatic variants, 174 were identified for the first time in the large intestine. APC, RET, and EGFR genes were most frequently mutated. A higher number of variants were identified in the left colon. Occurrence of variants in ERBB2 was significantly correlated with those of EGFR and ATR genes. Network analyses of the identified genes provide functional perspective of the identified genes and suggest affected pathways and probable biomarker candidates. This report lays the ground work for biomarker discovery and identification of driver gene mutations in local population.

The prognostic impact of CD20 expression and rituximab therapy in classical Hodgkin lymphoma (cHL) is unclear. Among 310 patients, CD20 was expressed in 66 (22%) cases. The 3-year PFS was 75.1% for CD20 + and 70% for CD20 - ( p  = 0.36). The 3-year PFS was 84.7% for the rituximab group and 67.8% for the no rituximab group ( p  = 0.23). Only constitutional symptoms and positive interim PET/CT were significantly associated with worse outcome, HR 3.2 (1.14-9.01; p  = 0.028) and 4.3 (2.27-8.1; p < 0.0001), respectively. Neither CD20 expression nor rituximab use significantly impacted outcome., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s). Published by Elsevier Ltd.)

Infectious mononucleosis (IM) is a syndrome caused by the Epstein-Barr virus. IM typically presents with fever, pharyngitis and lymphadenopathy. Rarely, it can cause acute appendicitis. We report the case of a 19-year-old female presenting with a chief complaint of colicky, non-radiating abdominal pain for 2 days. Abdominal examination revealed rebound tenderness in right iliac fossa tenderness and splenomegaly. The diagnosis of acute appendicitis was confirmed by computed tomography. She underwent laparoscopic appendectomy and mesenteric lymph node biopsy. She was later diagnosed with IM based on laboratory findings and histopathology results. She received a course of intravenous acyclovir and was discharged. This shows that IM may present with acute appendicitis as the initial presentation and may not be accompanied by any other significant symptoms of IM., (Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author(s) 2021.)

Plasmablastic lymphoma (PBL) is a rare subtype of non-Hodgkin's lymphoma that is associated with acquired immunodeficiency syndrome (AIDS), characterized by its association with Epstein-Barr virus (EBV), aggressive nature, and plasmacytic/plasmablastic differentiation. PBL remains a therapeutic and diagnostic challenge. Diagnosis of PBL by fine-needle aspiration cytology (FNAC) is reported infrequently. We herein describe the cytodiagnosis of a rare case of HIV-negative PBL in a 58-year-old man without EBV infection presented by parotid swelling. The current case study highlights the cytomorphologic features that may help to distinguish PBL from other mimics. However, although the cytomorphologic features may suggest PBL, a definitive diagnosis requires additional studies including tissue biopsy and immunohistochemistry, in addition to biochemical investigations and radiological workup to establish the diagnosis and exclude similar conditions. In conclusion, FNAC is a very useful, simple, rapid and reliable procedure for diagnosis of the lymphoma. FNAC provided the earliest clue to diagnosis of PBL, which was later confirmed by tissue biopsy., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper., (Copyright © 2021 by S. Karger AG, Basel.)

Histiocytic disorders are an exceptionally rare group of diseases with diverse manifestations and a paucity of approved treatments, thereby leading to various challenges in their diagnosis and management. With the discovery of novel molecular targets and the incorporation of targeted agents in the management of various adult histiocytic disorders, their management has become increasingly complex. In an attempt to improve the understanding of the clinical features and management of common adult histiocytic disorders (Langerhans cell histiocytosis, Erdheim-Chester disease, Rosai-Dorfman disease, and hemophagocytic lymphohistiocytosis), we created this document based on existing literature and expert opinion., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Objectives: According to recent guidelines, a diagnosis of celiac disease (CD) can be made without a biopsy, especially in children. There are no enough studies despite high prevalence and differences in genetic, race, and cultures. Therefore, we examined the correlation between tissue transglutaminase (TTG) and duodenal biopsy changes in our region because we are identical and different from others in culture, environment, and habits, and the correlation is same as that in different regions., Methods: A retrospective cohort study at the Ministry of National Guard Health Affaires (NGHA) health care facilities that are distributed throughout kingdom of Saudi Arabia from April 19, 2015, till March 29, 2018. This study used the BESTCARE system that includes data from all NGHA facilities; data from 513 patients with CD were collected. All patients diagnosed with celiac disease aged 15 years or more, confirmed by improvement on gluten-free diet (GFD), and were not on GFD before endoscopy or serology test or both of them were included in the study, and the TTG IgA level was measured at the same time or within 2-3 months of biopsy date. The exclusion criteria were negative duodenal biopsy, which is less than 2; patients with negative biopsy and negative serology; patients who were on GFD before testing, and any patients known to have immunity diseases or illness causing mucosal changes. The TTG IgA level was measured in IU/ mL and was labeled as negative (<20 IU/mL) and positive (≥ 20 IU/mL) based on the cutoff value. However, Intestinal biopsy findings were identified as Marsh classification groups., Results: One hundred thirty-four patients who met the inclusion criteria were included in the study. Median age of our sample was 24 years (16-37 years). Among these, 99 (73.88%) were female patients, whereas male patients were only 35 (26.12%). Histopathologic investigation of intestinal biopsy were Marsh 0 group was 16 cases (11.9%), Marsh 1 group was 8 cases (6%), Marsh 2 group was 4 cases (3%), Marsh 3a group was 32 cases (23.9%), Marsh 3b group was 64 cases (47.8%), and Marsh 3c group was 10 cases (7.5%). The TTG IgA antibody serology groups were <20 IU/mL in 13 cases (9.7%) and ≥20 IU/mL in 121 cases (90.3%). Among all patients with CD who had negative biopsy (Marsh 0 group), 16 (100%) of them had positive TTG IgA antibody. However, among patients with Marsh 1 group biopsy, 5 (62.5%) cases had negative TTG IgA antibody compared with 3 (37.5%) positive cases. Of the four cases (100%) with Marsh 2 group, all of them had positive TTG IgA antibody. However, in Marsh 3a group biopsy, 3 (9.4%) cases had negative TTG IgA antibody compared with 29 (90.6%) cases with positive TTG IgA antibody. Furthermore, among the patients with Marsh 3b group biopsy, 5 (7.8%) had negative antibody and 59 (92.2%) had positive serology. Of all biopsies of Marsh 3c group, 10 (100 %) had positive TTG IgA antibody., Conclusions: In perspective of high prevalence of CD in KSA, even more than western countries, we can pretend that positive TTG antibody tests can be applied for the diagnosis of CD without biopsy, particularly in symptomatic patients along with high titer, that is, 5-10 times the upper limit of normal (ULN). However, to validate it further, we need larger prospective studies in which duodenal biopsies should be taken according to recommended protocol and should be interpreted by experienced pathologist. Furthermore, biopsy is still needed in patients who do not show clinical improvement on a gluten-free diet and in cases with mildly or moderately elevated TTG IgA., Competing Interests: Conflict of Interest None declared., (© 2020 Ibrahim S. Alharbi, Abdul Monem Sweid, Muhammad Yousuf Memon, Saeed Alshieban, Ameirah Alanazi, published by Sciendo.)

Epithelial dysplasia (ED) grading systems are criticized for low reliability. The effects of diagnostic tests or stains on reducing examiner variability in grading ED of the upper aerodigestive tract have not been investigated. The study aim was to examine the effectiveness of cytokeratin 19 (K19) immunostain on enhancing inter and intraexaminer reliability of ED grading and to reiterate the relation of K19 positivity with epithelial keratinization. The study sample consisted of 122 paraffin blocks that fulfilled the inclusion criteria. Each paraffin block had three sections cut: one immunostained for K19 and two for hematoxylin and eosin stain (H&E). Each examiner graded the study sample in six rounds; three using H&E stain only and three using paired K19-H&E stains. The study examiners were three American-Board certified practicing oral pathologists. The results were analyzed using Krippendorff's alpha, ROC curve, Chi square test and binary logistic regression. Upon the use of paired K19-H&E stains the results showed that the intraexaminer reliability coefficients of grading were improved from 0.70, 0.69, 0.78 to 0.73, 0.88, 0.91 for examiners 1, 2, and 3 respectively. Reliability coefficients for inter-examiners improved from 0.55 to 0.73 (Krippendorff alpha). The accuracy of identifying the diseased cases (high-grade dysplasia) increased from 0.82 to 0.94 (ROC curve). Binary logistic regression revealed that K19 positivity is negatively associated with hyperkeratinization of surface epithelium (P = 0.001). To conclude, for grading non-keratinized epithelial dysplastic lesions of the upper aerodigestive tract, paired K19-H&E stains proved to reduce inter and intra-examiner variability by highlighting the extension of dysplastic epithelial cells within epithelial thickness, thus identifying the involved epithelial third and assigning a more reliable and better reproducible grade.

Primary brain tumors are a leading cause of cancer-related morbidity and mortality in children. Glioblastoma (GBM) is a high-grade astrocytoma that occurs in both children and adults and is associated with a poor prognosis. Despite extensive study in recent years, the clinical management of these tumors has remained largely unchanged, consisting of surgical resection, conventional chemotherapy, and radiotherapy. Although the etiology and genomic drivers in GBM are diverse, constitutional mismatch repair-deficiency (CMMRD) syndrome is a rare, recessively inherited disease with a predisposition to gliomagenesis. CMMRD results from biallelic mutations in one of the mismatch repair genes including mutL homolog 1 ( MLH1 ), mutS homolog 2 ( MSH2 ), mutS homolog 6 ( MSH6 ), and post-meiotic segregation increased 2 ( PMS2 ). In this report, we present the case of a 5-year-old female with GBM and CMMRD due to an MSH6 homozygous c.1883G>A mutation, who continues to experience an exceptional and durable response (9 months) to the immune checkpoint inhibitor (ICPI) nivolumab. Our patient presented with acute neurologic decline and increased intracranial pressure. Neuroimaging studies revealed a large left frontoparietal mass requiring neurosurgical decompression and resection. Histopathologic analyses resulted in a diagnosis of de novo GBM that was BRAF wild type and negative for programmed death-ligand 1 protein expression. She received standard-of-care treatment with surgery, radiation therapy, and temozolomide; however, the tumor recurred 3 months after the initial diagnosis. Molecular analyses of tumor and blood tissues revealed an MSH6 homozygous c.1883G>A mutation consistent with CMMRD. Given her CMMRD status, she was treated with nivolumab (3 mg/kg doses every 2 weeks for 36 weeks) and showed a 60% reduction in tumor size, improved clinical symptoms, and an ongoing durable response lasting 10 months to date. Our study highlights a durable response to the ICPI nivolumab in a pediatric patient with recurrent/refractory CMMRD-associated GBM. We show that incorporating genomic and/or molecular testing for CMMRD into routine pediatric oncology clinical care can identify a subset of patients likely to benefit from ICPI. KEY POINTS: Constitutional mismatch repair-deficiency (CMMRD) syndrome, alternatively known as biallelic mismatch repair deficiency syndrome, occurs in subset of pediatric cancer patients, including those with primary brain tumors.Patients from Arab and other developing countries are predicted to have higher incidence of CMMRD due to high prevalence of consanguinity.Integration of molecular and/or genomic testing into routine clinical care for pediatric cancer patients is important to identify patients with CMMRD syndrome.Patient with CMMRD-associated cancers may show increased responsiveness to immune checkpoint inhibitors.To the authors' knowledge, this is the first report in the Arab world of a durable response to immune checkpoint inhibitors in a pediatric glioblastoma patient., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Background: Chronic lymphocytic leukemia and chronic myeloid leukemia are the most common types of adult leukemia. However, it is rare for the same patient to suffer from both. Richter's transformation to diffuse large B-cell lymphoma is frequently observed in chronic lymphocytic leukemia. Purine analog therapy and the presence of trisomy 12, and CCND1 gene rearrangement have been linked to increased risk of Richter's transformation. The coexistence of chronic myeloid leukemia and diffuse large B-cell lymphoma in the same patient is extremely rare, with only nine reported cases. Here, we describe the first reported case of concurrent chronic myeloid leukemia and diffuse large B-cell lymphoma in a background of chronic lymphocytic leukemia., Case Presentation: A 60-year-old Saudi man known to have diabetes, hypertension, and chronic active hepatitis B was diagnosed as having Rai stage II chronic lymphocytic leukemia, with trisomy 12 and rearrangement of the CCND1 gene in December 2012. He required no therapy until January 2016 when he developed significant anemia, thrombocytopenia, and constitutional symptoms. He received six cycles of fludarabine, cyclophosphamide, and rituximab, after which he achieved complete remission. One month later, he presented with progressive leukocytosis (mostly neutrophilia) and splenomegaly. Fluorescence in situ hybridization from bone marrow aspirate was positive for translocation (9;22) and reverse transcription polymerase chain reaction detected BCR-ABL fusion gene consistent with chronic myeloid leukemia. He had no morphologic or immunophenotypic evidence of chronic lymphocytic leukemia at the time. Imatinib, a first-line tyrosine kinase inhibitor, was started. Eight months later, a screening imaging revealed new liver lesions, which were confirmed to be diffuse large B-cell lymphoma., Conclusions: In chronic lymphocytic leukemia, progressive leukocytosis and splenomegaly caused by emerging chronic myeloid leukemia can be easily overlooked. It is unlikely that chronic myeloid leukemia arose as a result of clonal evolution secondary to fludarabine treatment given the very short interval after receiving fludarabine. It is also unlikely that imatinib contributed to the development of diffuse large B-cell lymphoma; rather, diffuse large B-cell lymphoma arose as a result of Richter's transformation. Fludarabine, trisomy 12, and CCND1 gene rearrangement might have increased the risk of Richter's transformation in this patient.

Natural killer (NK) cell lymphoblastic leukaemia/lymphoma is a rare haemopoietic tumour currently defined in the 2008 WHO classification under the category of acute leukaemias of ambiguous lineage. A diagnosis of this type of leukaemia is considered in cases expressing CD56 along with immature T-cell-associated markers such as CD2 and CD7 with absence of B-cell and myeloid markers; in addition, blastic plasmacytoid dendritic cell leukaemia should be excluded. Prior to 2008, these precursor NK cell lymphoblastic leukaemias/lymphomas were categorized as myeloid/NK cell acute leukaemia with a phenotype identical to acute myeloid leukaemia with minimal differentiation. While the new classification has merit in having excluded myeloid expression, there is still persistent confusion in the literature and on a practical level with regard to precursor NK cell neoplasms. There is a paucity of recent case reports in the literature after the new WHO classification of this neoplasm. Due to the rarity of this neoplasm, an accurate pathological diagnosis is often difficult. In this article, we describe a case of precursor NK cell lymphoblastic leukaemia/lymphoma presenting with unique morphological features and conflicting immunophenotypes. We also review all case reports of this neoplasm after the WHO 2008 classification.

We describe the case of a young man with therapy-naive chronic myeloid leukemia who did not initially have any peripheral blood or bone marrow excess blasts but presented with extramedullary myeloid blast crises involving the central nervous system and multiple lymph nodes. Conventional cytogenetic tests were positive for t(9;22)(q34:q11) as well as for trisomy 8, 14 and 21 and del(16q). The patient's peripheral blood and bone marrow were positive for the BCR-ABL oncogene when analyzed by fluorescence in situ hybridization and polymerase chain reaction. He achieved good clinical, radiological, cytogenetic and molecular response to acute myeloid leukemia induction chemotherapy combined with 16 doses of triple intrathecal chemotherapy and oral dasatinib (second-generation tyrosine kinase inhibitor) treatment. Due to his poor general condition, he was treated with 24 Gy of whole-brain radiation therapy, as allogeneic stem cell transplantation was not feasible. Although extramedullary CNS blast crises are usually associated with a very poor outcome, our patient remains in complete cytogenetic and molecular remission, on single-agent dasatinib, 4 years after the diagnosis with no current evidence of active extramedullary disease. This suggests that dasatinib has a role in controlling not only chronic-phase chronic myeloid leukemia, but also its CNS blast crisis.

Turnaround time is an important quality indicator in surgical pathology. Retrospective analysis of three data points in September 2014, January 2015, and February 2015 showed that on average, about a quarter (24%) of routine surgical pathology cases (26%, 19%, and 27% respectively) are not reported on time and do not meet the accepted level of the College of American Pathologists' (CAP) standard turnaround time, which states at least 90% of routine surgical pathology cases should be reported and verified within two days. Our daily observation supported by a root cause analysis exercise revealed that subprocesses including slide allocation and delivery to pathologists, slide review by pathologists, report editing by transcriptionists, and report verification by pathologists are where most delays occur. Thus, to tackle these process issues we developed a quality improvement project using the model of improvement methods to streamline the sample flow process and avoid unjustified reporting delay. The improvement ideas included developing a time log sheet to be attached with all pathology requests, and sending a daily reminder email followed by a phonecall to all pathologists to verify completed reports on the same day. These intervention elements were tested using multiple PDSA cycles resulting in a very noticeable improvement, with more than 94% of all routine cases reported in less than two days, meeting and exceeding the CAP standards. Such noticeable improvement in turnaround of surgical pathology reports will eventually lead to improving the quality and safety of patient care outcome, including diagnosing patients on time, developing the appropriate treatment plan, and avoiding unjustified complications resulting in morbidity and mortality due to delayed reports.