MPIG6B Gene-Related Myelofibrosis: A Rare Inherited Disease That Is Frequently Described in Arab Population.

The megakaryocyte and platelet inhibitory receptor gene G6P (MPIG6B) is located on chromosome 6p21.33. It encodes G6b-B; an inhibitory receptor expressed on the surface of platelets. It regulates platelets production, aggregation, and activation. We describe a case of a 31-year-old man who presented with a long history of thrombocytopenia, anemia, and hepatosplenomegaly. The patient received multiple blood transfusions and his clinical course was stable. A bone marrow biopsy showed morphologic features similar to primary myelofibrosis. Whole exome sequencing study was performed and revealed homozygous pathogenic mutation in exon 2 of MPIG6B gene (c.324C > A, p.Cys108Ter) that is the second reported case in literature. In this report, we describe the main clinical and pathologic features of this disease and review the literature of previously documented cases.

Pancytopenia with aplastic anemia in systemic lupus erythematosus: case series and literature review.

Aplastic anemia (AA) is a rare, potentially catastrophic hematopoiesis failure manifested by pancytopenia and bone marrow aplasia. AA occurrence in Systemic Lupus Erythematosus (SLE) patients is extremely rare. The diagnosis may be delayed due to other possible pancytopenia etiologies. Confirmation of peripheral cytopenias diagnosis necessitates a bone marrow aspiration. The management of AA is challenging, and the literature reported using glucocorticoids, danazol, plasmapheresis, cyclophosphamide, intravenous immunoglobulin, and cyclosporine. We report two cases of SLE patients who presented with pancytopenia, with bone marrow biopsy confirmed AA. One case was treated with cyclophosphamide but unfortunately succumbed to Acute Respiratory Distress Syndrome (ARDS), while the other case was managed with rituximab with a good response. Interestingly, both patients were on azathioprine before the diagnosis of AA. A comprehensive search for reported cases of AA in PubMed, Scopus, and the Directory of Open Access Journals databases was performed to enhance the understanding of the diagnostic and management challenges associated with AA in SLE, facilitating ongoing exploration and research in this field. The decision to do a BM aspiration and biopsy is recommended for SLE patients with an abrupt decline in blood counts and previously stable blood counts.

Genetic predisposition to early mycosis fungoides: investigating genetic polymorphisms in tissue-resident memory T-cell genes.

OBJECTIVES: Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma; it arises from tissue-resident memory T-cells (TRM). In the present study, we investigated potential functional genetic variations that may predispose MF development. METHODS: A case-control study was conducted using whole-exome sequencing, with a focus on genes that are essential to TRM function. RESULTS: We included 21 patients and 19 healthy subjects in the study. Single nucleotide polymorphisms in the following genes were significantly more common in patients than in healthy subjects: GZMB, HLA-DRB1, CD103, and NOTCH1. Moreover, the number of patients carrying single nucleotide polymorphisms in LAG3, NR4A2, and CD26L was significantly greater in the patient group than in the control group. CONCLUSIONS: The presence of genetic variations in one or more TRM functional gene may predispose patients to develop MF. Further studies involving a larger patient population and a comparative analysis of protein expression will be necessary to validate these findings.

Myelodysplastic Syndromes and Myelodysplastic Syndromes/Myeloproliferative Neoplasms: A Real-World Experience From a Developing Country.

PURPOSE: Myelodysplastic syndromes (MDS) include a heterogeneous group of clonal bone marrow disorders characterized by ineffective hematopoiesis. They manifest as dysplasia in bone marrow hemopoietic elements associated with peripheral cytopenias with variable risk of AML transformation. PATIENTS AND METHODS: We analyzed retrospectively registry data collected prospectively from patients with primary MDS and patients with MDS/myeloproliferative neoplasm (MPN) in the Jordan University Hospital between January 2007 and September 2021. The registry captured epidemiologic information such as date of diagnosis, age, gender, date of AML transformation, cytogenetics, MDS subtype, risk group according to Revised International Prognostic Scoring System, and survival. The registry also captured baseline ferritin, B12, and lactate dehydrogenase levels. RESULTS: A total of 112 patients with MDS and MDS/MPN were included in the registry. Median age at diagnosis was 59 years. The male-to-female ratio was about 1.2. In a multivariate cox regression model, baseline serum ferritin significantly affected survival as patients with levels exceeding 1,000 µg/L had a risk of death three times higher compared with those with <1,000 µg/L levels (P < .05). CONCLUSION: To our knowledge, our study is the first comprehensive study examining the epidemiology and prognostic factors in patients with MDS and patients with MDS/MPN in Jordan. Our results show that MDS and MDS/MPN epidemiology in Jordan is different compared with Western countries. Our results also show that baseline serum ferritin levels can be used as a prognostic marker for patients with MDS.

PAX5 and TDT-Negative B-Acute Lymphoblastic Leukemia with Unusual Genetic Mutations: A Case Report.

B-acute lymphoblastic leukemia (B-ALL) is commonly encountered in clinical practice. Patients present with increased percentage of lymphoblasts in bone marrow and/or peripheral blood. Immunophenotypic study by flow cytometry or immunohistochemistry is essential to establish the diagnosis. Paired box-5 (PAX5) is a B cell lineage protein and terminal deoxynucleotidyl transferase (TDT) is an immature marker, both of which are routinely tested in the pathologic workup of acute leukemia. In this report, we describe a case of B-ALL in a 37-year-old woman in which both PAX5 and TDT were negative. Next-generation sequencing test detected mutations in DNA methyltransferase 3 α and Fms related receptor tyrosine kinase 3 genes, which are frequently mutated in acute myeloid leukemia rather than B-ALL. The constellation of these rare findings in a single case signifies the importance of examining a wide panel of markers when the diagnosis of ALL is suspected.

Programmed Death Ligand-1 is Frequently Expressed in Primary Acute Myeloid Leukemia and B-Acute Lymphoblastic Leukemia.

BACKGROUND: The introduction of checkpoint inhibitors in solid cancer therapy showed successful results. The role of Programmed Death-1/Programmed Death-Ligand 1 (PD1/PD-L1) in hematologic malignancies is currently being investigated and clinical trials are ongoing. Preliminary findings showed conflicting results. In this study, we examined the degree of PD-L1 and PD-L2 expression in primary acute leukemia patients. METHODS: Flow cytometry expression of PD-L1 and PD-L2 was evaluated in de novo acute leukemia in the collaborating institutions between 2018 - 2020. RESULTS: One hundred forty patients were identified. PD-L1 was positive in 34/70 (49%) of AML, 25/50 (50%) of B-ALL, and none (0/20) of T-ALL patients. In contrast, PD-L2 was solely expressed in eight (19%) AML patients. The expression of PD-L1 showed statistically significant correlation with the type of acute leukemia (AML and B-ALL > T-ALL, p < 0.001) and with age group (adults > children, p = 0.048), but not with blast count, immunophenotype or cytogenetic mutations. The positivity for PD-L1 was associated with worse overall survival in AML, but not in B-ALL. CONCLUSIONS: The expression of PD-L1 is common among newly diagnosed AML and B-ALL patients and is not restricted to relapsed cases as previously described. PD-L2 is less commonly expressed and is accompanied by PD-L1 expression. Positive PD-L1 patients may benefit from treatment with immune checkpoint inhibitors, especially in AML. Further studies are recommended.

The Expression of the Senescence-Associated Biomarker Lamin B1 in Human Breast Cancer.

Senescence is a major response to cancer chemotherapy and has been linked to unfavorable therapy outcomes. Lamin B1 is a component of the nuclear lamina that plays a pivotal role in chromatin stability. Downregulation of lamin B1 represents an established biomarker for cellular senescence. However, the protein expression level of lamin B1 in malignant tissue, particularly of the breast, has not been previously described. In this work, we investigated lamin B1 protein expression in normal breast epithelium, malignant breast tissue (including adjacent non-malignant tissue) and in malignant tissue exposed to neoadjuvant chemotherapy (NAC) using immunohistochemistry (IHC) in three patient groups (n = 15, n = 87, and n = 43, respectively). Our results indicate that lamin B1 mean positive expression was 93% in normal breast epithelium and 88% in malignant breast cells, but significantly decreased (mean: 55%, p < 0.001) in malignant breast tissue after exposure to NAC, suggestive of senescence induction. No significant association between lamin B1 expression and other clinicopathological characteristics or survival of breast cancer patients was recorded. To our knowledge, this is the first report that established the baseline protein expression level of lamin B1 in normal and malignant breast tissue, and its reduction following exposure to chemotherapy. In conclusion, lamin B1 downregulation can be used reliably as a component of multiple biomarker batteries to identify therapy-induced senescence (TIS) in clinical cancer.

Immunohistochemical Expression Patterns of CD45RO, p105/p50, JAK3, TOX, and IL-17 in Early-Stage Mycosis Fungoides.

The morphologic changes in early-stage mycosis fungoides (MF) might overlap with benign inflammatory dermatitis (BID). Previous studies have described altered expression patterns of several proteins in MF, but their diagnostic significance is uncertain. This study aims at examining the frequency of expression of CD45RO, NFkB-p105/p50, JAK3, TOX, and IL-17 proteins by immunohistochemistry. The cohorts included 21 patients of early-stage MF and 19 with benign BID as a control group. CD45RO was positive in all patients of MF and BID. NFkB-p105/p50 showed normal cytoplasmic staining, indicating an inactive status in all patients of both groups. JAK3 was positive in 3 (14%) MF and in 17 (89%) BID patients (p = 0.003). TOX was expressed in 19 (90%) and 13 (68%) patients of MF and BID, respectively (p = 0.120). IL-17 was detected in 13 (62%) MF and in 7 (37%) BID patients (p = 0.056). Co-expression of TOX and IL-17 was seen in 11 (52%) MF patients but in only 3 (16%) BID patients, which was statistically significant (p = 0.021). We conclude that a double expression of TOX and IL-17 may support the diagnosis of MF in the right clinicopathologic setting, while none of the immunohistochemical stains alone provided a significant discrimination between MF and BID.

Pitfalls in Assessing Measurable Residual Disease in Plasma Cell Myeloma: a Comparison between Common Laboratory Tests.

BACKGROUND: Measurable residual disease (MRD) in plasma cell myeloma is one of the most important determinants for patients' outcome. Several laboratory tests exist to assess for the presence of MRD with variable accuracy. The aim of this study is to examine the sensitivity of immunofixation electrophoresis (IFE), serum free light chain (FLC), bone marrow immunohistochemistry (IHC), and multicolor flow cytometry (FC) and to address potential caveats of each test. METHODS: Forty patients of plasma cell myeloma who were diagnosed with a positive MRD were retrospectively included in this study. The results of IFE and serum FLC at the time of bone marrow biopsy were collected. RESULTS: In all cases, malignant plasma cells constituted less than 5% of bone marrow cells. MRD was detected by FC in 38 cases (95%) and by IHC in 28 cases (70%). In 2 cases, residual malignant plasma cells appeared in the subcortical area which is difficult to aspirate, and thus they were detected by IHC but not by FC. Among the entire cohort, 38 patients (95%) had positive IFE at the time of bone marrow biopsy, while serum FLC abnormality was detected in 19 patients (48%) only. CONCLUSIONS: Both FC and IFE exhibited high sensitivity in detecting MRD in plasma cell myeloma with comparable results. IFE remains less invasive and less expensive than FC. Despite the lower sensitivity of bone marrow IHC staining, its diagnostic role is essential and can be superior to FC in a subset of cases, for which its routine examination is recommended. Serum FLC test provided the least sensitivity among all tests.

Combined utility of CD177, P53, CD105 and c-kit immunohistochemical stains improves the detection of myelodysplastic syndrome.

The diagnosis of myelodysplastic syndrome (MDS) relies primarily on identifying peripheral blood cytopenia and morphologic dysplasia as well as detecting cytogenetic aberrations in a subset of patients. Accumulating data points to the importance of examining certain immunophenotypic changes characteristic of MDS, most of which are tested by flow cytometry. The role of immunohistochemistry in the diagnostic workup of MDS is less known. In this study, we used immunohistochemistry to survey the expression patterns of CD177, P53, CD105 and c- kit in a cohort of MDS bone marrow specimens (n = 57) and compared the results with a control group of patients who had cytopenia for other benign conditions (n = 49). MDS cases showed significant higher rates of: CD177-loss (13/57, 23% vs 1/49, 2%; P = .0016), P53 overexpression (8/57, 14% vs none; P = .005) and the presence of clusters of CD105-positive cells (6/57, 11% vs none; P = .021). Increased c-kit-positive cells was more common in MDS patients, but not statistically significant (17/57, 30% vs 8/49, 16%; P = .102). On multivariate analysis, only loss of CD177 expression was significantly higher in MDS group (P = .014). These findings suggest that a panel of immunohistochemical stains could serve as an adjunct tool in investigating unexplained cytopenias and warrant further comparative studies with flow cytometry.

Metastatic Dedifferentiated Chondrosarcoma to Thyroid Gland: A Case Report.

A 54-year-old man presented with a pathologic hip fracture secondary to a right femur tumor. A reaming biopsy showed the diagnosis of dedifferentiated chondrosarcoma (DDC). In addition, the patient had a thyroid mass. Fine needle aspirate from the thyroid mass revealed numerous large fragments of cohesive spindle cells with moderate nuclear atypia and brisk mitosis, identical to the femur tumor. Immunohistochemical staining on cell blocks of thyroid aspirate showed positivity for mesenchymal markers and negativity for epithelial and thyroid markers. The metastasis of DDC to the thyroid gland is a very rare incident and has previously been described once in the literature. In this report, we describe the clinical and pathologic findings of this case.

Papillary thyroid carcinoma in a 5-year old child, mimicking lymphoma in presentation.

Thyroid cancer is very rare in children and papillary thyroid carcinoma (PTC) represents the most common type. Patients are frequently in the second decade of life and complain of painless enlargement of the gland. Pediatric PTC has unique clinicopathologic characteristics that make it different from the adult counterpart. The biologic behavior tends to be aggressive and patients frequently present with advanced disease. Herein, we report a case with an unusual presentation. A 5-year-old child manifested with fever, night sweats, cervical lymphadenopathy, and weight loss for 2 months. He also complained of mild cough and shortness of breath. Clinical suspicion of tuberculosis or lymphoma was raised, but laboratory workup was unremarkable. Cervical lymph node excision was done, and the histopathologic examination showed metastatic PTC. The patient underwent surgical and radioactive therapy and remained in complete remission for 5 years. Unfortunately, the disease ultimately relapsed with disseminated metastasis and the patient passed away.

Differential Expression of Androgen Receptor in Type I and Type II Endometrial Carcinomas: A Clinicopathological Analysis and Correlation with Outcome.

OBJECTIVES: Endometrial carcinomas (EC) are the most common gynecological malignancies and are conventionally divided into type I and type II due to diagnostic and prognostic considerations. Female hormone expression in EC is extensively studied; however, data about androgen receptor (AR) expression in EC are sparse. We aimed to study AR expression in different types of EC at our institute and whether it had an impact on patient outcomes. METHODS: A retrospective analysis of EC cases diagnosed and treated from 2010-2019. AR immunohistochemical expression was tested in 52 EC cases (type I = 40; type II = 12). Histological typing was verified according to conventional diagnostic criteria. Only primary EC were included without neoadjuvant therapy. Histologic score was calculated as: stain intensity (graded 0-3) × positive cells percentage (graded 0-4). Level of expression was scored from 0 to 12. RESULTS: The mean age of the selected patients was 60.3 years (range = 31-88 ± 12.6). Recurrence was detected in 11 (21.2%) patients. The outcome was 40 patients were alive without disease, eight alive with disease, three dead of disease, and one dead of other causes. About 62.5% of type I-EC and 25.0% of type II-EC were AR positive. AR expression was analyzed against different clinicopathological parameters including: type (p = 0.005), histotype (p = 0.044); grade (p = 0.035); age group (p = 0.207); menopause (p = 0.086); estrogen receptor (ER) expression (p = 0.284); atypical complex hyperplasia (p = 0.594); tumor stage (p = 0.994); tumor recurrence (p = 0.530); node status (p = 0.110); and outcome (p = 0.202). CONCLUSION: AR expression was higher in type I EC, endometrial endometrioid carcinoma histotype, and with a lower grade. AR expression was not significantly correlated with age, stage, ER, atypical hyperplasia, recurrence, node status, or outcome. Results agree with recent literature that AR expression is associated with better-differentiated EC and may be a potential hormonal therapeutic tool.

The epidemiology of lymphoma in Jordan: A nationwide population study of 4189 cases according to World Health Organization classification system.

OBJECTIVE/BACKGROUND: Lymphoma is a common human cancer that shows a variable geographic incidence worldwide. It is the fourth most common cancer in Jordan. Systemic reports of descriptive epidemiology on lymphoma from the Middle East are limited. METHODS: A nationwide multi-institutional retrospective study was conducted covering all major hospitals and laboratories that provide diagnostic services. We collected data on all cases diagnosed with lymphoma between 2014 and 2019. The included variables were patients' age, gender, anatomic site, and the histologic type according to the World Health Organization classification system. RESULTS: A total of 4189 cases were diagnosed with lymphoma. There was a statistically significant gender difference (p < .05), as 57.5% of patients were males. The peak incidence occurred at age 25-55 years. There were 1,652 (39%) cases of Hodgkin lymphoma (HL) and 2,537 (61%) of non-Hodgkin lymphoma (NHL), where nodular sclerosis (67%) and diffuse large B-cell lymphoma (53%) were the most common subtypes, respectively. The average age-adjusted incidence rates per 100,000 population were 8.01 for all lymphomas, 4.33 for NHL, and 3.16 for HL and all remained stable over the 6 years. CONCLUSION: HL is the most common lymphoma in Jordan, with a percentage higher than most of reported studies in Asian and Western countries. It also shows a unimodal distribution of age-specific incidence rates, with a single peak in young adults. The incidence rate of HL is higher than Eastern countries but comparable to the West. In contrast, NHL demonstrates a lower incidence rate than Western countries but a similar distribution of subtypes, as mature T/natural killer-cell lymphomas were rare.

Circulating Hodgkin cells: A clinicopathologic analysis of seven patients and a review of the literature.

INTRODUCTION: Hodgkin cell leukemia is a rare phenomenon in which Hodgkin and Reed-Sternberg cells circulate the peripheral blood. Few cases were reported but no modern case series is available in the literature. METHODS: Peripheral blood smears from patients diagnosed with Hodgkin lymphoma (HL) at our institution were reviewed. Relevant clinical and pathologic parameters were collected and compared with reported cases in the literature. RESULTS: Seven patients were identified over a period of 8 years. All patients were males with a median age of 35 years. The diagnosis was classic HL in six (86%) patients and nodular lymphocyte predominant in one (14%). All patients presented with anemia (100%), and six (86%) had leukopenia and lymphopenia. Circulating Hodgkin cells were few in number and ranged between 2% and 10% of total white blood cells. Mononuclear Hodgkin cells were more common than binucleated Reed-Sternberg cells. All patients were in stage IV disease (100%). Six patients (86%) died within one year of identifying these cells. CONCLUSIONS: Hodgkin cell leukemia is very rare and represents a terminal event in the course of the disease of any histologic subtype. It is strongly associated with poor prognostic factors of HL such as advanced clinical stage, male gender, and the presence of anemia and lymphopenia. Circulating Hodgkin cells are few in number and thus can be missed in routine blood film examination. We describe the morphologic features of leukemic Hodgkin cells in details in order to help pathologists identify them for both diagnostic and research purposes.

Helicobacter pylori Prevalence and Impact: A Histology-Based Report About Children from an Endemic Country.

BACKGROUND: Helicobacter pylori is spreading worldwide with a high prevalence rate in the developing countries. Our primary goal was to measure the histology-based prevalence of Helicobacter pylori infection in children and to quantify its impact on the gastric inflammation and anemia. Our secondary goal was to study possible predictors for the presence of Helicobacter pylori in this cohort. METHODS: A retrospective chart review was performed for children who underwent Esophago-gastro-duodenoscopy at Jordan university hospital in Jordan from 2008 to 2016. Data collected included epidemiological data, indication for endoscopy, endoscopic findings, and laboratory data. The gastric biopsies were re-examined by a pathologist to check for the presence of Helicobacter pylori, the presence of gastritis, and to grade gastritis according to the updated Sydney criteria. RESULTS: A total of 98 children (53 girls-54%) underwent Esophago-gastro-duodenoscopy. The average age was 11.7 years ± 4.7 years. Of them, 53 patients (29 boys-55%) had Helicobacter pylori identified in the gastric biopsy. The histology-based prevalence rate of Helicobacter pylori was 54%. The most common indication for endoscopy was abdominal pain (53%) followed by vomiting (18%). Nodular gastric mucosa was present in 43% of the Helicobacter pylori-positive group, and in only 11% of the Helicobacter pylori-negative group (P-value <0.0.5). Moderate to severe chronic gastritis was seen in 59% of the biopsies of Helicobacter pylori-positive group, compared to 31% in the Helicobacter pylori-negative group (p value <0.05). Presence of anemia was not different between the two groups (p value > 0.05). Presence of endoscopic nodularity, active gastritis by histology, and moderate to severe gastritis by histology were positive predicators for the presence of Helicobacter pylori. (p value <0.05). CONCLUSION: Helicobacter pylori infection in this study cohort of Jordanian children is common, with a histology-based prevalence rate of 54%. Nodularity of the stomach is the most common positive endoscopic feature, and its presence predicts the presence of Helicobacter pylori. Moderate to severe active gastritis is associated with Helicobacter pylori. The presence of Helicobacter pylori does not affect anemia status in this cohort of Jordanian children.