Distinct clonal identities of B-ALLs arising after lenolidomide therapy for multiple myeloma.

Patients with multiple myeloma (MM) who are treated with lenalidomide rarely develop a secondary B-cell acute lymphoblastic leukemia (B-ALL). The clonal and biological relationship between these sequential malignancies is not yet clear. We identified 17 patients with MM treated with lenalidomide, who subsequently developed B-ALL. Patient samples were evaluated through sequencing, cytogenetics/fluorescence in situ hybridization (FISH), immunohistochemical (IHC) staining, and immunoglobulin heavy chain (IgH) clonality assessment. Samples were assessed for shared mutations and recurrently mutated genes. Through whole exome sequencing and cytogenetics/FISH analysis of 7 paired samples (MM vs matched B-ALL), no mutational overlap between samples was observed. Unique dominant IgH clonotypes between the tumors were observed in 5 paired MM/B-ALL samples. Across all 17 B-ALL samples, 14 (83%) had a TP53 variant detected. Three MM samples with sufficient sequencing depth (>500×) revealed rare cells (average of 0.6% variant allele frequency, or 1.2% of cells) with the same TP53 variant identified in the subsequent B-ALL sample. A lack of mutational overlap between MM and B-ALL samples shows that B-ALL developed as a second malignancy arising from a founding population of cells that likely represented unrelated clonal hematopoiesis caused by a TP53 mutation. The recurrent variants in TP53 in the B-ALL samples suggest a common path for malignant transformation that may be similar to that of TP53-mutant, treatment-related acute myeloid leukemia. The presence of rare cells containing TP53 variants in bone marrow at the initiation of lenalidomide treatment suggests that cellular populations containing TP53 variants expand in the presence of lenalidomide to increase the likelihood of B-ALL development.

Adult T-Cell Leukemia-Lymphoma Presenting Concurrently with Myelopathy.

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus. Of the approximate ten to twenty million people currently infected worldwide, 4-9% of infected individuals develop adult T-cell leukemia/lymphoma (ATLL) or HTLV-associated myelopathy/tropical spastic paresis (HAM/TSP) in their lifetime. The current report is based on a patient who presented concurrently with CD30+ lymphoma subtype ATLL and HAM/TSP. The patient's ATLL responded to brentuximab-vedotin-based chemotherapy; however, HAM/TSP did not improve. The patient's peripheral blood mononuclear cells were cultured and injected into immunodeficient mice, and the mice developed massive organ involvement and chronic lymphocytic leukemia-subtype ATLL. This case study is novel in the findings of concurrent development of ATLL and HAM/TSP, the response to brentuximab-vedotin chemotherapy, and the use HTLV-1 helix basic zipper protein-targeted probe for RNAscope for diagnosis.

Deaths, panic, lockdowns and US equity markets: The case of COVID-19 pandemic.

This study investigates the impact of COVID-19 pandemic on the microstructure of US equity markets. In particular, we explain the liquidity and volatility dynamics via indexes that capture multiple dimensions of the pandemic. Our results suggest that increases in confirmed cases and deaths due to coronavirus are associated with a significant increase in market illiquidity and volatility. Similarly, declining sentiment and the implementations of restrictions and lockdowns contribute to the deterioration of liquidity and stability of markets.

Bone Marrow Biopsy Needle Type Affects Core Biopsy Specimen Length and Quality and Aspirate Hemodilution.

Objectives: Bone marrow biopsies are essential for evaluating patients with suspected or confirmed hematopoietic disorders or malignancies, but little is known about how biopsy needle type affects biopsy length and/or quality. We sought to compare bone marrow biopsy quality in specimens obtained with two different needles. Methods: A retrospective analysis was performed on bone marrow specimens obtained with manual single-bevel (n = 114) or triple-bevel (n = 166) needles. The lengths of evaluable marrow, core quality, and aspirate quality were assessed by blinded hematopathologists. Results: The triple-bevel needle produced 1.33-mm shorter lengths of evaluable marrow than the single-bevel needle and was five times less likely to produce a specimen rated as "adequate" and 4.2 times more likely to produce crush artifact. The triple-bevel needle was also 2.4 times more likely to produce hemodilute aspirates. Conclusions: Bone marrow biopsy needle type affects the length of evaluable marrow and quality of core and aspirate specimens.

Immunophenotypic Variations in Mantle Cell Lymphoma and Their Impact on Clinical Behavior and Outcome.

CONTEXT.­: Immunophenotypic variations in mantle cell lymphoma (MCL) from the classic CD5+/CD10-/CD23-/FMC-7+ immunophenotype have been reported in the literature, but correlation with clinical behavior and outcome has not been fully studied. OBJECTIVE.­: To investigate clinicopathologic and prognostic differences between immunophenotypically aberrant MCL and immunophenotypically typical MCL. DESIGN.­: We evaluated differences in clinical presentation, laboratory parameters, prognostic indices, response to initial treatment, and progression-free and overall survival between patients with aberrant MCL and patients with immunophenotypically typical MCL. RESULTS.­: There were 158 patients with newly diagnosed cyclin D1 or t(11;14)(q13;q32)+ MCL identified in the original search, of which, 29 patients (18%) showed immunophenotypic aberrancies, with CD23 coexpression being the most common. When compared with 33 randomly selected patients with immunophenotypically typical MCL, statistically significant differences were seen in white blood cell counts ( P = .02), in the presence of absolute lymphocytosis ( P = .03), in the MCL International Prognostic Index score ( P = .02), and in response to initial treatment ( P = .04). The "immunophenotypic status" of the MCL was the only independent factor associated with response to treatment ( P = .05), but not with the MCL International Prognostic Index score, absolute lymphocytosis, or white blood cell count. No significant differences were seen for progression-free or overall survival. CONCLUSIONS.­: Immunophenotypic variations in MCL are associated with differences in clinical presentation and response to therapy when compared with immunophenotypically typical MCL. However, with current intensive frontline immunochemotherapy, immunophenotypic aberrations do not appear to affect progression-free or overall survival.

Role of Weight-Bearing Exercises in the Treatment of Post-Menopausal Osteoporosis.

OBJECTIVE: To determine the change in T-score of post-menopausal osteoporosis patients with weight-bearing exercises. STUDY DESIGN: A quasi-experimental study. PLACE AND DURATION OF STUDY: Physiotherapy Department and Orthopedic Unit I, Mayo Hospital, Lahore, from May to October 2014. METHODOLOGY: Two hundred and seventy-four patients were randomly divided into two groups according to inclusion and exclusion criteria using non-probability purposive sampling technique. The group 1 was treated by medication and weightbearing exercises and group 2 was given medication alone. The dual energy X-ray absorptiometry (DEXA)scan was used tofind the T-score before and after treatment and improvement was compared. A p-value less than 0.05 was taken as significant. RESULTS: The results showed that improvement was occurred in both groups after treatment. The DEXAscan median values after treatment were changed to 3.00 (0) for group 1 (exercises and medication) and 2.00 (1) for group 2 (medication). CONCLUSION: The physical activity along with medication play vital role in the treatment of post-menopausal osteoporosis than medication alone.

Severe Cytomegalovirus Gastritis During Natalizumab-Mediated Immunosuppression.

We report a 35-year-old female receiving natalizumab as monotherapy for multiple sclerosis who subsequently developed severe cytomegalovirus gastritis. As cytomegalovirus gastritis has not been previously described during natalizumab treatment, we discuss the biological plausibility of this potential association and avenues for further study.

PRDM1 expression levels in marginal zone lymphoma and lymphoplasmacytic lymphoma.

PRDM1 (BLIMP1) is a transcription repressor protein shown to be involved in B-cell differentiation into plasma cells. Marginal zone lymphomas (MZL) and lymphoplasmacytic lymphomas (LPL) are B cell lymphomas that both show some degree of plasmacytic differentiation and thus can sometimes constitute a difficult differential diagnosis. In this study, we investigated if MZL and LPL have abnormalities in the expression of PRDM1 beta and if there are any differences in expression between these two entities. After interrogating 42 samples (15 marginal zone lymphomas, 9 lymphoplasmacytic lymphomas, 3 follicular lymphomas, and 13 normal/control samples), we have found that a significant percentage of MZL and LPL cases harbor abnormalities (67% and 44%, respectively) involving the PRDM1-ß transcript (P=0.004). By immunohistochemistry, PRDM1 positive staining (>5%) was more common in MZL. We conclude that PRDM1-ß may play a role in the pathogenesis of these low-grade lymphomas with plasmacytic differentiation.

CD4-positive diffuse large B-cell lymphoma: A variant with aggressive clinical potential.

CD4 expression is rare in diffuse large B-cell lymphoma (DLBCL), with 4 previously reported cases. Its significance is uncertain. We report five patients with CD4(+) DLBCL and one CD4(+) primary mediastinal large B-cell lymphoma. Cases were identified by searching the electronic database of the department; each was reviewed. Average age was 56 years. Neoplastic cells expressed CD20 (5/6 tested cases). BCL2/BCL6 expression were seen in 3/3 tested cases, suggesting a germinal center origin. Additionally, expression of T-cell antigens CD2 and CD5 was noted in 2/2 and CD7 in 1/1 tested case. CD3 was negative in all. Lymph nodes were commonly involved (67%). Patients received chemotherapy +/- radiation (6/6) and bone marrow transplant (2/6). Average survival was 44.2 mo. CD4 expression in DLBCL raises questions of lineage commitment. CD4(+) DLBCL is rare; care should be exercised not to diagnose these as T-cell lymphomas. A subset behaves aggressively.

Clinical presentation, progression, and outcome of patients with clonal B-cell counts of less than 5 × 10(9)/l, 5 to 10 × 10(9)/l, and more than 10 × 10(9)/l and chronic lymphocytic leukemia immunophenotype.

OBJECTIVES: The flow cytometric evaluation of peripheral lymphocytosis has led to a dramatic increase in the diagnosis of early stage chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL). Few studies exist to better delineate the natural history and differences between MBL and CLL. METHODS: Applying the recently updated B-lymphocyte threshold of 5 × 10(9) B lymphocytes/L for the diagnosis of CLL, we evaluated the differences in initial presentation, disease progression, time to treatment (TTT), and 10-year overall survival rates between patients with less than 5 × 10 × 10(9)/L, 5 to 10 × 10(9)/L, and more than 10 × 10(9)/L B cells. These clinical/treatment parameters were also compared among the MBL, 5 to 10 CLL Rai stage 0, and more than 10 CLL Rai stage 0 groups. RESULTS: In total, 310 patients were included, with 67 in the less than 5, 75 in the 5 to 10, and 168 in the more than 10 B-cell groups. Statistically significant differences were seen when comparing the 5 to 10 and more than 10 B-cell groups regarding anemia (P = .021 for median hemoglobin; P = .028 for anemia <11 g/dL), platelet count (P = .041 for median platelet count), splenomegaly (P = .013), initial management plan (P = .012 for observation; P = .0021 for treatment with chemotherapy), and TTT (P = .0033). No statistically significant difference was seen among the MBL, 5 to 10, and more than 10 CLL Rai stage 0 groups regarding TTT and 10-year overall survival. CONCLUSIONS: Findings suggest that patients with B-cell counts of 5 to 10 × 10(9)/L behave clinically more similar to patients with B-cell counts of less than 5 × 10(9)/L.

Mast cell leukemia with prolonged survival on PKC412/midostaurin.

Mast cell leukemia (MCL) is a rare and aggressive form of systemic mastocytosis. There are approximately 50 reported cases since 1950s. MCL is refractory to cytoreduction chemotherapy and the average survival is only six months. We report a MCL case in a 71 year-old woman with high tumor load at the initial presentation in 2005, who did not respond to either interleukin-2 or dasatinib therapy. After enrolled in a clinical trial of PKC412 (or Midostaurin) with a daily dose of 100 mg, the patient responded well to PKC412 and became transfusion independent in three months. Since then, her disease had been stably controlled. This is the first report of a high-tumor-load MCL case which achieved prolonged survival (101 months) by PKC 412. The 101-month overall survival is the longest among reported MCL cases in the English literature.

CD163 immunohistochemistry is superior to CD68 in predicting outcome in classical Hodgkin lymphoma.

OBJECTIVES: In recent years, research has increasingly focused on the microenvironment of classical Hodgkin lymphoma (CHL) as a predictor of treatment outcome. The focus of this study was to assess the interobserver reproducibility in interpreting macrophage-associated immunohistochemistry (IHC) for CD68 and CD163 in a retrospective cohort of 88 patients with CHL. METHODS: Staining results were correlated with clinical outcome in all patients and those with a high international prognostic score (IPS). RESULTS: The intraclass correlation (ICC) for the five hematopathologists interpreting the IHC was stronger for CD163 (0.70) than for CD68 (0.50). Using a cutoff of 25% mean macrophage reactivity and including all patients, a statistically significant difference in overall survival (OS) was seen only for CD163 (P = .0006) and not for CD68 (P = .414). Patients with a mean CD163 reactivity of 25% or more had a median OS of 71 months vs 101 months for patients with less than 25% reactivity. CD163 retained statistical significance in multivariate analysis. In patients with advanced-stage CHL with high IPS, OS was also significantly worse for those with a mean CD163 reactivity of 25% or higher. CONCLUSIONS: Our study confirms previous reports of a prognostic role of tumor-infiltrating macrophages in CHL, but only for CD163. Although most of the literature supports an increasing role of macrophage IHC as a predictor of clinical outcome, successful clinical translation will require a standardized method and reporting system.

Utility of flow cytometry of cerebrospinal fluid as a screening tool in the diagnosis of central nervous system lymphoma.

CONTEXT: Experiences at our institution show that flow cytometry analysis (FCA) has become routine clinical practice in the workup of patients with altered mental status, even if risk factors are low. OBJECTIVE: To assess diagnostic accuracy of combined FCA and cytology in the diagnosis of central nervous system lymphoma in an unselected patient population with neurologic symptoms, including patients with no history of lymphoma or suspicious radiology. DESIGN: Between 2001 and 2011, cerebrospinal fluid was submitted from 373 patients for lymphoma screening by FCA. The medical records were reviewed for patient symptomatology, history of malignancy, brain imaging, FCA results, cytology results, brain biopsy, and clinical follow-up. RESULTS: A lymphoid malignancy was detected by FCA in 4% of cases. A positive diagnosis was more likely in patients with either a history of hematologic malignancy and/or a suspicious radiology result (P = .009). All patients with no history of lymphoma and no suspicious radiology (n = 102) had negative cytology, and none had a correspondingly positive FCA result. The positive and negative predictive values of combined cytology and FCA in the patients with history of lymphoma and/or abnormal imaging results were 92% and 89%, respectively, when compared with open brain tissue biopsy, and 89% and 86%, respectively, when compared with clinical follow-up. When low-risk patients were included, the positive predictive value remained at 92%, but the negative predictive value dropped to 52% with the open brain biopsy as the reference, and values did not change significantly for the group with clinical follow-up. CONCLUSIONS: Concurrent FCA and cytology are most useful in the appropriate clinical setting, and we propose a triage algorithm for how FCA on cerebrospinal fluid is best used.

Acute EBV infection masquerading as "In-situ Follicular Lymphoma": a pitfall in the differential diagnosis of this entity.

We present the case of a 30 year-old man who was referred for evaluation of diffuse lymphadenopathy. Six weeks prior, he noticed darkening of his urine associated with pale stools, nausea and an eventual 30 lb weight loss within a month. The initial laboratory findings showed elevation of the liver enzymes. A CT scan showed mesenteric and periaortic lymphadenopathy with the largest lymph node measuring 2.8 cm. Other laboratory results were otherwise unremarkable (including a normal LDH) with the exception of positive serum antibodies against Epstein-Barr virus (EBV) associated antigens (IgM+ and IgG+). An excisional biopsy of 4 of the small neck lymph nodes showed a normal architecture with prominent follicles and an intact capsule. But, by immunohistochemistry two of the follicles showed aberrant coexpression of BCL-2, in addition to CD10 and BCL-6. In-situ hybridization for early Epstein-Barr virus mRNA (EBER) and immunohistochemistry for latent membrane protein-1 (LMP-1) stained both scattered positive cells, as well as BCL-2 positive B-cells. Although an original diagnosis of in-situ follicular lymphoma was favored at an outside facility, additional interphase fluorescence in situ hybridization (FISH) studies for t(14;18);(IGH-BCL2) rearrangement (performed on the BCL-2 + follicles microdissected from the tissue block; Abott probe dual colour fusion) and molecular studies (IGH gene rearrangement by PCR, also performed on the microdissected follicles) were negative. Serologic studies (positive EBV antibodies) and immunostains in conjunction with the molecular studies confirmed the reactive nature of the changes. Our case also shows direct immunopathogenic evidence of BCL-2 expression among the EBV-infected cells, which has to our knowledge not been previously documented in vivo. A diagnosis of EBV infection should, therefore, be considered when confronted with BCL-2 expression in germinal centers, particularly in younger individuals, as the diagnosis of FLIS may lead to extensive and invasive haematologic work-ups. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1323656318940068.

Cutaneous myeloid sarcoma: natural history and biology of an uncommon manifestation of acute myeloid leukemia.

We conducted a retrospective study of patients with cutaneous myeloid sarcoma, from 2 tertiary care institutions. Eighty-three patients presented, with a mean age of 52 years. Diagnosis of myeloid sarcoma in the skin was difficult due to the low frequency of myeloperoxidase and/or CD34+ cases (56% and 19% of tested cases, respectively). Seventy-one of the 83 patients (86%) had ≥ 1 bone marrow biopsy. Twenty-eight (39%) had acute myeloid leukemia with monocytic differentiation. Twenty-three had other de novo acute myeloid leukemia subtypes. Thirteen patients had other myeloid neoplasms, of which 4 ultimately progressed to an acute myeloid leukemia. Seven had no bone marrow malignancy. Ninety-eight percent of the patients received chemotherapy, and approximately 89% died of causes related to their disease. Cutaneous myeloid sarcoma in most cases represents an aggressive manifestation of acute myeloid leukemia. Diagnosis can be challenging due to lack of myeloblast-associated antigen expression in many cases, and difficulty in distinguishing monocyte-lineage blasts from neoplastic and non-neoplastic mature monocytes.

Gastrointestinal lymphomas in a North American population: clinicopathologic features from one major Central-Midwestern United States tertiary care medical center.

BACKGROUND: Gastrointestinal (GI) lymphomas are very common types of extranodal lymphomas, and we hypothesize there are regional differences in subtype, distribution in the GI tract, and epidemiological features among the different populations. METHODS: We retrospectively evaluated the clinical, molecular and histologic features of North American primary and secondary GI lymphomas diagnosed from 2000-2009 seen at our institution. We utilized immunohistochemistry and fluorescence in situ hybridization to further evaluate a subset of the gastric lymphomas. RESULTS: Extranodal marginal zone lymphomas of mucosal associated lymphoid tissue (MALTs) and diffuse large B cell lymphomas (DLBCLs) were the most common subtypes of GI lymphomas. Select gastric DLBCLs (N = 6) and MALTs (N = 13) were further examined for API2-MALT1 and IGH translocations, and P16 and P53 protein expression. Gastric MALTs showed frequent API2-MALT1 (38%) but not IGH translocations (0%), and the DLBCLs showed neither translocation. Expression of P16 and P53 proteins and the proliferative index were compared between high grade gastric lymphomas (gastric DLBCLs) and low grade gastric lymphomas (gastric MALTs). P53 overexpression (P = 0.008) and a high proliferation index [Ki-67] (P = 0.00042) were significantly associated with gastric DLBCL, but no statistically significant difference was observed in P16 expression (p = 0.108) between gastric DLBCL and gastric MALT. CONCLUSION: Our study revealed that GI lymphomas from a Central-Midwestern North American population showed differences and similarities to non-North American cohorts. In addition, API2-MALT1, P16 and P53 abnormalities occurred frequently in gastric lymphomas from this North American population. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1415505838687793.

MIST1-a novel marker of plasmacytic differentiation.

BACKGROUND: Currently available plasma cell markers include CD138 and CD38. However, CD38 is not specific to plasma cells. It is also expressed by many epithelial cells and other hematopoietic cells. In addition, rare CD138-negative PCNs may be exceedingly difficult to diagnose. MIST1 is a transcription factor expressed by mouse and human neoplastic and non-neoplastic plasma cells. Our goals were to compare MIST1 expression to CD38/CD138 in neoplasms with plasmacytic differentiation, assess reactivity in normal samples and nonplasmacytic cell lineages, and to determine whether MIST1 is expressed in CD138-negative PCNs. DESIGN: Eighty-five neoplasms with plasma cell differentiation [marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL), plasmablastic lymphoma (PB), plasma cell neoplasm (PCN)] and 2 non-neoplastic cases (normal marrow) were tested with MIST1 immunohistochemistry. CD138/38 expression for each case was compared with MIST1 reactivity. RESULTS: Plasma cells were MIST1 positive in all cases interrogated. CD38 and/or CD138 expression was reviewed in all cases and found to be concordant in 46/47 (97.8%) of tested cases, with the exception of 1 case of PB that showed MIST1 positivity and no CD138 expression. All other cell lineages were negative, with the exception of MZL and LPL, in which MIST1 highlighted a subset of the lymphocytes, with plasmacytic differentiation. CONCLUSIONS: MIST1 is a sensitive and specific marker of plasmacytic differentiation. CD138+ plasma cells expressed MIST1 in all tested cases; however, 1 PB showed MIST1 positivity and no CD138 expression, suggesting MIST1 may be useful in certain CD138-negative cases. In MZL and LPL, MIST1 highlights a subset of the lymphocytes in lymphomas with plasmacytic differentiation.