Skull base plasmacytoma in young patients aged below 40 years: Radiological perspectives and clinical outcomes.

BACKGROUND: Plasmacytoma of the skull base is a rare manifestation of plasma cell neoplasm with only a few cases documented in literature involving young adults. Plasmacytoma can be an isolated solitary lesion or a secondary manifestation of multiple myeloma (MM). In this study, we report the clinical and radiological characteristics, management, and outcomes of patients under the age of 40 who presented with skull base plasmacytoma and associated neurological manifestations. Additionally, we share our experience in treating a rare case of skull base plasmacytoma diagnosed during pregnancy, in which the patient exhibited a favorable response to myeloma treatment initiated after delivery. CASE SERIES: Four patients were identified, comprising one pregnant female and three male patients, with a median age of 36 years (range 33-37 years). The main presenting symptoms were headache, dizziness, and cranial nerve palsy. All patients received underwent systemic myeloma therapy and radiotherapy with three patients also underwent autologous stem cell transplantation (ASCT). Notably, all patients achieved complete remission. CONCLUSION: Skull base plasmacytoma represents a rare manifestation of plasma cell neoplasms, underscoring the importance of considering it in the differential diagnosis of skull base lesions to ensure early intervention and avoid potential serious complications. Throughout our series, the cornerstone of therapy involved radiotherapy, systemic myeloma therapy, and ASCT, all of which elicited a favorable response in every case.

Concurrent Presentation of Hairy Cell Leukemia and Mantle Cell Lymphoma (Leukemic Non-Nodal Variant): An Extremely Rare Composite Lymphoma.

Herein, we describe the clinicopathologic and genetic characteristics of the first report of simultaneous bone marrow involvement by classical hairy cell leukemia (HCL) and leukemic non-nodal variant of mantle cell lymphoma (L-NN-MCL) with t(11;14)(q13;q32) with BRAF mutation and deletion of TP53. A 40-year-old asymptomatic man was investigated for incidental neutropenia and thrombocytopenia. Flow cytometry showed two distinct monotypic B-cell populations: one expressed CD19 (bright), CD20 (bright), FMC7, CD103, CD25, CD11c, CD123, and IgD (bright) and showed kappa light chain restriction (bright), consistent with HCL and the other kappa-restricted CD5/CD10-negative B-cell population with distinctive immunophenotypic features. The bone marrow biopsy is infiltrated by an abnormal B-lymphoid infiltrate with different patterns of infiltration in different marrow areas. Fluorescence in situ hybridization (FISH) analysis revealed a CCND1/IGH rearrangement, t(11;14)(q13;q32), and deletion of TP53. The BRAF V600E missense mutation was detected by quantitative real-time polymerase chain reaction (PCR). The diagnosis of a composite B-cell neoplasm was composed of HCL together with a second CD5/CD10-negative monotypic B-cell population, with CCND1/IGH fusion, favoring the 2016 WHO new category of L-NN-MCL (CD5/SOX11-negative). Treatment with cladribine and rituximab normalized the blood counts within 6 weeks without significant side effects. L-NN-MCL is one of the smoldering MCL subtypes, recently listed in WHO 2016 as a separate variant, with a particular set of unique features and a less aggressive clinical course compared to classical MCL. To date, the clinicopathological features (including the bone marrow findings) of L-NN-MCL have not been sufficiently characterized in the literature. We describe the first report of synchronous presentation of HCL and L-NN-MCL. This case represents a real challenge from the biologic, diagnostic and therapeutic point of views, due to extremely rare combination of two distinct uncommon B-cell neoplasms. The study of composite lymphomas offers the opportunity to evaluate the etiology and the clonal interrelationship involved in the pathogenesis/evolution of lymphomas.

Assessing Bone Marrow Activity with [18F]FLT PET in Patients with Essential Thrombocythemia and Prefibrotic Myelofibrosis: A Proof of Concept.

Objectives: This study aims to assess the value of FLT-PET as a non-invasive tool to differentiate between patients with ET and Pre-PMF. This study is a pilot study to have a proof of concept only. Methods: This is a prospective, interventional study where a total of 12 patients were included. Each patient underwent FLT PET imaging as well as bone marrow examination (gold standard). In addition, semi-quantitative (SUVmax and SUVmean) measurements of FLT uptake in the liver, spleen, and Lspine, SUVmean, as well as the Total Lesion Glycolysis (TLG) of the Lspine were performed. Results from the two patient cohorts were compared using = Kruskal-Wallis statistical test. A P-value of <.05 is considered to be statistically significant. Results: The differences in FLT SUVmax and SUVmean measurements in the three organs (liver, spleen, and LSpine) between the ET and Pre-PMF patients were not statistically significant (P > .05). In contrast, TLG measurements in the LSpine were statistically different (P = .013), and therefore, compared to gold standard bone marrow results, TLG can separate ET and Pre-PMF patients. Conclusion: This study is a proof of concept about the potential to discriminate between ET and pre-PMF patients in a non-invasive way. TLG of the LSpine in FLT PET images is a potential quantitative parameter to distinguish between ET and pre-PMF patients.

Downregulation of Lymphoid enhancer-binding factor 1 (LEF-1) expression (by immunohistochemistry and/ flow cytometry) in chronic Lymphocytic Leukemia with atypical immunophenotypic and cytologic features.

INTRODUCTION: Lymphoid enhancer-binding factor 1 (LEF-1) overexpression has been recently remarkably reported in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and has shown utility in distinguishing CLL/SLL from other B-cell lymphomas. CLL has a well-defined immunophenotype, yet, some cases of CLL demonstrate atypical morphology/ phenotype reflected by low Matutes score (atypical CLL). Till date, LEF1 expression has not been systematically studied in cases of CLL with atypical features. METHODS: In this study, LEF-1 expression was assessed by two different techniques, (immunohistochemistry and flow cytometry), to investigate the expression profile of LEF-1 in cases of CLL/SLL, in comparison with other low-grade B-lymphomas and CLL with atypical features, including atypical immunophenotype and CLL with increased prolymphocytes or morphologically atypical cells. RESULTS: We found that LEF-1 expression is downregulated in CLL with atypical immunophenotype/features compared to classic CLL; Chi-Square P < .0001. The ratio for LEF-1 expression in malignant B-cells/NK (by flow cytometry) in CLL/SLL with classic immunophenotype was higher than atypical CLL and is significantly higher in other small B-cell lymphomas (P < .01). Absence of LEF-1 expression in CLL/SLL is correlated (P < .05) with downregulation of CD5, CD23, CD200, expression of FMC7, brighter expression of CD79b, brighter expression of surface light chain, increased prolymphocytes and lower Matutes score. CONCLUSION: As downregulation of LEF-1 expression is well correlated with atypical CLL, we suggest adding LEF-1 to Matutes score as a beneficial marker to differentiate classic from atypical CLL LEF-1 could also serve as a potential prognostic indicator for CLL clinical course.

Composite Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Mantle Cell Lymphoma; Small Cell Variant: A Real Diagnostic Challenge. Case Presentation and Review of Literature.

BACKGROUND Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL) both have a common origin arising from mature CD5+ B-lymphocytes. Their distinction is crucial since MCL is a considerably more aggressive disease. Composite lymphoma consisting of CLL/SLL and MCL has been rarely reported. This type of composite lymphoma may be under-diagnosed as the 2 neoplasms have many features in common, both morphologically and immunophenotypically. CASE REPORT We report the case of a 57-year-old male patient who presented with a 4-month history of recurrent abdominal pain and distention with hepatosplenomegaly. Peripheral blood showed a high leukocytes count (46.7×10³/uL) with marked lymphocytosis of 35.0×10³/uL, mostly small mature-looking, with some showing nuclear irregularities, with approximately 3% prolymphocytes. Immunophenotyping by flow cytometry and immunohistochemistry revealed 2 immunophenotypically distinct abnormal CD5+monotypic B-cell populations. Fluorescence in situ hybridization (FISH) on peripheral blood demonstrated IGH/CCND1 rearrangement consistent with t(11;14) in 65% of cells analyzed. Accordingly, based on compilation of findings from morphology, flow cytometry, immunohistochemistry, and FISH, A diagnosis of composite lymphoma consisting of MCL; small cell variant and CLL/SLL was concluded. CONCLUSIONS We describe a case of composite lymphoma of MCL (small cell variant) and CLL/SLL that emphasizes the crucial role of the multiparametric approach, including vigilant cyto-histopathologic examination, immunophenotyping by flow cytometry and immunohistochemistry, as well as genetic testing, to achieve the correct diagnosis.

The Role of Integrated Positron Emission Tomography/Computed Tomography (PET/CT) and Bone Marrow Examination in Staging Large B-Cell Lymphoma.

INTRODUCTION: In the era of routine use of positron emission tomography/computed tomography (PET/CT) for staging, it is not yet clear whether PET/CT can replace bone marrow biopsy for the assessment of bone marrow involvement in large B-cell lymphoma. OBJECTIVES: To compare the clinical utility of bone marrow biopsy and PET/CT scanning in the staging of large B-cell lymphoma. METHODS: This was a retrospective analysis of all patients who presented to single center over a 4-year period with large B-cell lymphoma who had concurrent PET/CT and bone marrow biopsy performed in the assessment and staging of the lymphoma. RESULTS: Out of 89 patients, 24 had bone marrow involvement either by PET/CT, by bone marrow biopsy, or by both. Bone marrow biopsy identified 12 patients (sensitivity 50%, specificity 100%, negative predictive value 84%), whereas PET/CT identified 23 patients (sensitivity 96%, specificity 100%, negative predictive value 98%). No patients were upstaged by the bone marrow biopsy result, and no patients had their treatment plan changed based on the bone marrow biopsy result. CONCLUSION: The results show that PET-CT is more sensitive and has better negative predictive value than bone marrow biopsy. This suggests that PET-CT could replace bone marrow biopsy in detecting bone marrow involvement for staging of large B-cell lymphoma.

A study of 18F-FLT positron emission tomography/computed tomography imaging in cases of prefibrotic/early primary myelofibrosis and essential thrombocythemia.

The objectives of this research project are to study in patients with primary myelofibrosis (PMF) and Essential Thrombocythemia (ET); (1) the uptake patterns of FLT-PET (FLT-PET) and its value in diagnosing, staging, and treatment response monitoring of malignant hematopoiesis, (2) compare imaging findings from FLT-PET with bone marrow biopsy (standard of care), and (3) associate FLT-PET uptake patterns with genetic makeup such as JAK2 (Janus kinase 2), CALR (Calreticulin), MPL (myeloproliferative leukemia protein), Triple negative disease, and allele burden.This trial is registered in ClinicalTrials.gov with number NCT03116542. Protocol version: Mar 2017.

Plasma Cell Myeloma with an Aggressive Clinical Course and Anaplastic Morphology in a 22-Year-Old Patient: A Case Report and Review of Literature.

BACKGROUND Plasma cell myeloma is a neoplastic plasma cell disorder that usually presents after the fifth decade of life; it is rarely described in younger population especially under 30 years of age. However, there are conflicting reports in the literature about the clinical behavior and overall survival in younger age groups. In approximately 2% of plasma cell myeloma, the morphology of the neoplastic cells is highly pleomorphic, quite anaplastic, and may resemble metastatic tumor cells. While this poses a challenge for morphological interpretation during diagnosis, it has been demonstrated that bone marrow morphologic features (including diffuse sheet growth pattern, immature cell morphology and high mitotic index) significantly correlates with high risk disease. Moreover, there is limited description available about the morphology of the neoplastic cells when correlating the age at presentation with the clinical outcome/biological behavior; hence, the need to report and collect such cases. CASE REPORT We report a case of plasma cell myeloma in a 22-year-old male who presented with non-specific clinical features and posed a diagnostic challenge during clinical, radiological, and laboratory examination. The pathology specimens showed anaplastic morphology. Unfortunately, after diagnosis, despite treatment with brotezomib, his disease had an aggressive clinical course and he passed away 4 months after diagnosis. CONCLUSIONS Although plasma cell myeloma is rare in patients younger than 30 years, it must be considered in the differential diagnosis and investigated properly especially in patients with clinical suspicion of a metastatic non-hematological tumor. The anaplastic variant in a young patient is a diagnostic challenge and is associated with bizarre morphology, aggressive presentation, adverse cytogenetics, resistance to chemotherapy, and poor, short-term, survival.

Chronic Myeloid Leukemia with cryptic Philadelphia translocation and extramedullary B-lymphoid blast phase as an initial presentation.

Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative neoplasm (MPN) characterized by the presence of a reciprocal translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34:q11), resulting in fusion of the break point cluster region (BCR) with the ABL gene, which forms an oncogene, the transcript of which is an oncoprotein with a tyrosine kinase function. In the great majority of CML; BCR/ABL1 is cytogenetically visualized as t(9;22); giving rise to the Ph chromosome, harboring the chimeric gene. Cryptic or masked translocations occur in 2-10% patients with no evidence for the BCR/ABL rearrangement by conventional cytogenetics but are positive by Fluorescence in Situ Hybridization (FISH) and/or reverse transcriptase polymerase chain reaction (RT-PCR). These patients are described as Philadelphia negative (Ph negative) BCR/ABL1- positive CML with the chimeric gene present on the derivative chromosome 22, as in most CML cases, or alternatively on the derivative 9 in rare occasions. In the majority of cases, CML is diagnosed in the chronic phase; it is less frequently diagnosed in accelerated crises, and occasionally, its initial presentation is as acute leukemia. The prevalence of extramedullary blast phase (BP) has been reported to be 7-17% in patients with BP. Surprisingly, no extra-medullary blast crises of B- lymphoid lineage have been reported before among cases of CML as the initial presentation. We report an adult male diagnosed as CML- chronic phase when he was shortly presented with treatment-naive extramedullary B-lymphoid blast crises involving multiple lymph nodes, with no features of acceleration or blast crises in the peripheral blood (PB) and bone marrow (BM). In addition the patient had variant/cryptic Philadelphia translocation. This is the first report of CML, on the best of our knowledge, with extramedullary B-lymphoid blast phase, as initial presentation, that showed a cryptic Ph translocation.

A persistent cough as atypical clinical presentation of intrathoracic extramedullary hematopoiesis (EMH) in a female with thalassemia intermedia.

Extramedullary hematopoiesis (EMH) is a rare disorder, defined as the appearance of hematopoietic elements outside the bone marrow or peripheral blood. The most common sites of EMH are liver and spleen, but it has been documented in other organs such as the mediastinum, lymph nodes, breast, and central nervous system. EMH occurs as a compensatory mechanism for bone marrow dysfunction in severe thalassemia. We report a case of EMH presenting as a posterior mediastinal mass in a 34-year-old woman with thalassemia intermedia with chronic cough and shortness of breath on exertion. The diagnosis of EMH was confirmed by a CT-guided fine needle biopsy. All symptoms disappeared after surgical removal of the mass.

Statural Growth and Prevalence of Endocrinopathies in Relation to Liver Iron Content (LIC) in Adult Patients with Beta Thalassemia Major (BTM) and Sickle Cell Disease (SCD).

Despite regular blood transfusion and iron chelation therapy, growth impairment and pubertal delay are commonly seen in children and adolescents with transfusion-dependent Beta thalassaemia major (BTM) and sickle cell disease (SCD). We evaluated growth parameters and endocrine disorders in relation to the liver iron concentration (LIC) assessed by the Ferriscan® method in a cohort of adults with SCD (n =40) and BTM (n = 52) receiving blood transfusions and iron chelation therapy since early childhood. Before transfusion, hemoglobin concentration had not been less than 9 g/dl in the past 12 years; subcutaneous daily desferrioxamine was administered for all of them since early childhood (2- 5 years of age). All patients were shifted to oral therapy with deferasirox iron chelation, 20 mg/daily for the past 5 years. BTM patients with higher LIC (> 15 mg Fe/g dry weight)  had significantly shorter stature, lower insulin-like growth factor-I SDS (IGF-I SDS), higher alanine transferase (ALT) and  serum ferritin concentrations compared to thalassemic patients with lower LIC.  Patients with SCD with LIC > 8 mg Fe/g dry weight had significantly shorter stature, lower IGF-I SDS and higher ALT compared to SCD patients with lower LIC.  Patients with BTM had significantly shorted final height (Ht-SDS) , IGF-I SDS and FT4 level compared to patients with SCD.  LIC and mean fasting blood glucose (FBG) were significantly higher in patients with BTM compared to those with SCD. The linear regression  analysis showed  a significant correlation between LIC and  serum ferritin level in SCD and BTM. LIC and serum ferritin level were also correlated significantly with IGF-I level in patients with BTM. LIC was correlated significantly with ALT in patients with BTM. In conclusion, the prevalence of endocrinopathies especially hypothyroidism, DM, and hypogonadism were significantly higher in BTM patients versus SCD patients and higher in patients with higher LIC versus those with lower LIC. These complications occurred less frequently, but still considerable, in chronically transfused patients with SCD.

Concomitant Classic Hodgkin Lymphoma of Lymph Node and cMYC-Positive Burkitt Leukemia/Lymphoma of the Bone Marrow Presented Concurrently at the Time of Presentation: A Rare Combination of Discordant Lymphomas.

Discordant lymphoma is rare condition in which different types of malignant lymphomas occurring in different anatomic sites. The two diseases may present clinically as concurrent or sequential disease (10). Herein we are reporting a Pakistani female in her 60s, a carrier of hepatitis B virus with multiple comorbidities presented with cervical lymphadenopathy, diagnosed as Hodgkin's lymphoma, mixed cellularity. During the staging workup, the patient was discovered to have extensive bone marrow (BM) involvement by Burkitt leukaemia/lymphoma (BL). Cytogenetic analysis revealed positivity for t(8;14)(q24;q32) confirmed by Fluorescence In Situ Hybridization (FISH) for IGH/MYC. Epstein-Barr virus (EBV) was demonstrated heavily in our case, with (EBV) DNA of 24,295,560 copies/ml by PCR at time of presentation, in addition, the neoplastic cells in both diagnostic tissues (cervical lymph node and BM) demonstrated positivity for EBV. A diagnosis of concomitant EBV related discordant lymphoma (classical Hodgkin lymphoma (cHL) and Burkitt lymphoma (BL) in leukemic phase was made. Among all reported cases, this case is highly exceptional because it is the first case of discordant/composite lymphoma, with this combination and concomitant presentation. Since we are dealing with a case with an exceptionally rare combination, we found it significant to elaborate more on its clinical features, contributing factors including EBV role, response to treatment, complications, and prognosis.

An Unusual Case of Hepatosplenic αß T-Cell Lymphoma Presenting with Coombs'-Negative Hemolytic Anemia.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare and aggressive extranodal T-cell lymphoma that comprises <5% of peripheral T-cell lymphomas. The majority of cases harbor the γδ T-cell receptor (TCR), but recently, a few cases have been shown to express the αß TCR. Comparison of these two subtypes (αß and γδ) shows similar clinicopathologic and cytogenetic features; however, due to the paucity of reported cases, it is not clear whether they are prognostically distinct entities. We report a case of αß HSTCL with a rather unusual presentation of Coombs'-negative hemolytic anemia. Diagnosis proved challenging due to an unusual blastoid morphology with the absence of typical intrasinusoidal distribution of tumor cells in the bone marrow. This unique case adds to the growing list of this rare subtype of T-cell lymphomas, which warrant urgent attention due to the lack of effective treatment options and dismal prognosis.

Rare aggressive natural killer cell leukemia presented with bone marrow fibrosis - a diagnostic challenge.

Aggressive natural killer cell leukemia is an extraordinary rare aggressive malignant neoplasm of natural killer cells. Although its first recognition as a specific entity was approximately 20 years ago, this leukemia has not yet been satisfactorily characterized as fewer than 200 cases have been reported in the literature and up to our knowledge, this is the first case report in Qatar. Reaching a diagnosis of aggressive natural killer leukemia was a challenging experience, because in addition to being a rare entity, the relative scarcity of circulating neoplastic cells, failure to obtain an adequate aspirate sample sufficient to perform flow cytometric analysis, together with the absence of applicable method to prove NK clonality (as it lack specific clonal marker); our case had atypical confusing presentation of striking increase in bone marrow fibrosis that was misleading and complicated the case further. The bone marrow fibrosis encountered may be related to the neoplastic natural killer cells' chemokine profile and it may raise the awareness for considering aggressive natural killer leukemia within the differential diagnosis of leukemia with heightened marrow fibrosis.