Trends in Bone Marrow Sampling and Core Biopsy Specimen Adequacy in the United States and Canada: A Multicenter Study.

OBJECTIVES: To assess bone marrow (BM) sampling in academic medical centers. METHODS: Data from 6,374 BM samples obtained in 32 centers in 2001 and 2011, including core length (CL), were analyzed. RESULTS: BM included a biopsy (BMB; 93%) specimen, aspirate (BMA; 92%) specimen, or both (83%). The median (SD) CL was 12 (8.5) mm, and evaluable marrow was 9 (7.6) mm. Tissue contraction due to processing was 15%. BMB specimens were longer in adults younger than 60 years, men, and bilateral, staging, and baseline samples. Only 4% of BMB and 2% of BMB/BMA samples were deemed inadequate for diagnosis. BM for plasma cell dyscrasias, nonphysician operators, and ancillary studies usage increased, while bilateral sampling decreased over the decade. BM-related quality assurance programs are infrequent. CONCLUSIONS: CL is shorter than recommended and varies with patient age and sex, clinical circumstances, and center experience. While pathologists render diagnoses on most cases irrespective of CL, BMB yield improvement is desirable.

Histoplasmosis-Induced Hemophagocytic Lymphohistiocytosis in an Adult Patient: A Case Report and Review of the Literature.

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threating immune dysregulation syndrome characterized by persistent activation of the mononuclear phagocytic system leading to uncontrolled systemic hyperinflammatory response. The proliferation and activation of histiocytes and lymphocytes lead to production of large amounts of cytokines, also called cytokine storm. Hematopoietic and lymphoid tissues are directly involved while other organs are damaged by circulating cytokines. Primary HLH is attributed to genetic defects of the immune system and secondary HLH is usually seen in adults secondary to malignancy, infection, or autoimmune diseases. Zoonotic diseases including fungal infections are an important cause of HLH. Secondary HLH can delay the recognition of the underlying zoonoses. We report the case of a 61-year-old female with history of rheumatoid arthritis with histoplasmosis associated hemophagocytic lymphohistiocytosis.

Hemophagocytic Lymphohistiocytosis and Bone Marrow Hemophagocytosis: A 5-Year Institutional Experience at a Tertiary Care Hospital.

OBJECTIVE: The purpose of this study was to correlate the significance of bone marrow hemophagocytosis and analyze outcome data in patients with suspected hemophagocytic lymphohistiocytosis (HLH) at a tertiary care hospital during the course of 5 years. METHODS: The pathology database of State University of New York Upstate Medical University, Syracuse, was searched for the terms "hemophagocytosis," "hemophagocytic syndrome," and "hemophagocytic lymphohistiocytosis" encompassing the period January 2009-December 2014. Bone marrow aspirate and biopsy specimens, along with ancillary laboratory studies, clinical course, and outcome data, were reviewed for each case. RESULTS: Of the 23 patients included in our study, HLH was diagnosed in 14 (60.8%). Bone marrow hemophagocytosis (HPC) was seen in a higher proportion of patients (78.5%) who were diagnosed as having HLH; however, 55.5% of the patients who were not diagnosed as having HLH also showed evidence of bone marrow HPC. Patients with malignancy-associated HLH had a markedly worse outcome compared with patients with nonmalignancy-associated HLH. CONCLUSIONS: Although bone marrow HPC is fairly sensitive, it is not specific to establish a diagnosis of HLH. A high index of clinical suspicion together with early diagnosis and treatment is imperative to improve outcomes in patients suspected of having HLH.

Erythroid blast crisis in chronic myelogenous leukemia: Case report and review of literature.

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder where over a period of time 15-20% of patients show blastic transformation with majority transforming into acute myeloid leukemia, most of which are of granulocytic lineage. Erythroid blast phase of CML is relatively rare with the incidence ranging from 0-10%. Further the incidence of acute erythroid leukemia by itself is fairly low amongst all acute leukemias. We report a case of 41-year-old patient with CML who failed to achieve cytogenetic remission, transformed to acute erythroid leukemia and eventually succumbed to the disease over a short period of time. Related literature is also reviewed.

Immunohistochemical Expression of mTOR in Multiple Myeloma: Retrospective Analysis of 31 Cases, a Clinicopathological Study.

The mammalian target of rapamycin (mTOR) pathway regulates several cellular processes and is implicated in an increasing number of neoplasms. In an attempt to explore the role of mTOR pathway in multiple myeloma, we analyzed immunohistochemical (IHC) expression of mTOR and p-mTOR (phosphorylated-mTOR) in 31 multiple myeloma patients and correlated the results with clinical parameters. On univariate analysis, there was a very high correlation between IHC expression of mTOR and p-mTOR using rabbit monoclonal antibodies that detect endogenous level of total mTOR protein and m-TOR protein phosphorylated at Ser 2448 respectively. Expression of both of these biomarkers was associated mostly with male gender. Further, older patients showed a trend towards having more mTOR positive tumors. No statistically significant difference was noted in mTOR expression between chemotherapy naïve and relapsed patients. Based on our results, we hypothesize that targeted therapy with mTOR inhibitors may have a role as an additional novel component in a subset of multiple myeloma patients.

Immunohistochemical expression of mTOR in germinal center and nongerminal center group of diffuse large B-cell lymphoma: a clinicopathological study.

BACKGROUND: The mammalian target of rapamycin (mTOR) pathway regulates many major cellular processes and is implicated in an increasing number of neoplasms, including lymphoma. PATIENTS AND METHODS: We correlated immunohistochemical expression of mTOR with germinal center and nongerminal center phenotype, B cell lymphoma-2 (bcl-2) and cellular homolog of the retroviral v-myconcogene (c-myc) expression, and International Prognostic Index (IPI) score in 31 patients with diffuse large B-cell lymphoma (DLBCL). RESULTS: Virtually all patients in our study with high mTOR scores had a germinal center phenotype. Furthermore within the germinal center subgroup, patients with high mTOR scores were associated with higher IPI scores (P < .001). CONCLUSION: Based on our results we propose that within the category of germinal center phenotype of DLBCL, mTOR expression might help identify a subset of patients with potentially more aggressive tumors who might benefit from use of targeted therapy using mTOR inhibitors.

Biclonal chronic lymphocytic leukemia presenting as skin lesion.

Chronic lymphocytic leukemia (CLL) is by far the most common mature B-cell leukemia in Western countries. Some patients with CLL present with manifestations of extra medullary disease. We report a case of biclonal CLL/small lymphocytic lymphoma in an elderly patient who initially presented with skin lesions, no other systemic symptoms, and normal white cell count. Skin biopsy revealed concurrence of basal cell carcinoma and a nodular dermal infiltrate with immunophenotype consistent with CLL/small lymphocytic lymphoma. Polymerase chain reaction assay for immunoglobulin heavy chain gene rearrangement revealed the presence of 2 distinct B-cell clones in the peripheral blood. The clinicopathological characterization of this case is presented here.

Activation of mammalian target of rapamycin in diffuse large B-cell lymphoma: a clinicopathological study.

Cell signaling by a highly conserved serine/threonine kinase mammalian target of rapamycin (mTOR) has been shown to play a critical role in cell proliferation. We analyzed the immunohistochemical expression of mTOR, pmTOR and bcl-2 in 55 patients with diffuse large B-cell lymphoma and correlated it with clinical parameters and clinical outcomes. On univariate analysis, higher expression of mTOR was associated with male gender, older age, and higher IPI score. Patients with a high total mTOR score showed a trend toward shorter survival. Based on our results we propose that use of targeted therapy with mTOR inhibitors, in a subset of diffuse large B-cell lymphoma patients may help improve patient survival.

Expression of signal transducer and activator of transcription 3 (STAT3) in primary central nervous system diffuse large B-cell lymphoma: a retrospective analysis of 17 cases.

Most primary central nervous system lymphomas (PCNSL) occurring in immunocompetent patients are diffuse large B-cell lymphomas (DLBCL), characterized by poor prognosis. An activated B-cell (ABC) origin of PCNSL has been postulated based on bcl-6 and MUM-1 expression by majority of these tumors. ABC DLBCL has been functionally subdivided using gene expression profiling and immunohistochemical analysis into STAT3-high and STAT-3 low subsets. A potentially crucial difference between STAT3-high and STAT3-low ABC DLBCL is in the expression of bcl-2 family members. STAT3-high cases are generally bcl-2 low and STAT3-low cases show higher expression of bcl-2. Further mechanisms such as activation of nuclear factor-kappa B (NF-κB) activation seem to be responsible for upregulation of bcl-2 in ABC subtype of DLBCL with an adverse outcome. As deregulation of STAT-3 pathway is known to play a critical role in ABC DLBCL and majority of the PCNSL are of the ABC subtype we studied the immunohistochemical expression of STAT-3 proteins in PCNSL along with other traditional markers (CD10, bcl-6, MUM-1 and bcl-2) in 17 cases of PCNSL occurring in immunocompetent patients. Despite lack of STAT3 expression in all our cases, majority (70%) of the patients with bcl-2 positive PCNSL had an adverse outcome similar to that reported in systemic lymphomas of ABC subtype. Based on our observations we propose that PCNSL represents a distinct subset of ABC diffuse large B-cell lymphomas with low STAT3 expression and perhaps mechanisms other than interaction of STAT-3 and NF-κB pathways may play a role in upregulation of bcl-2 in PCNSL. To the best of our knowledge expression of STAT-3 protein in PCNSL which represents a distinct anatomical subset of ABC DLBCL with a dismal prognosis has not been studied before.

Lepirudin for anticoagulation in patients with heparin-induced thrombocytopenia treated with continuous renal replacement therapy.

Lepirudin is a potent, direct thrombin inhibitor used for anticoagulation in patients with heparin-induced thrombocytopenia type II (HIT). The half-life of lepirudin is prolonged in patients with renal insufficiency. Preliminary studies suggest that it is safe to use lepirudin in patients being treated with intermittent hemodialysis but information regarding its use with continuous renal replacement therapy (CRRT) is scarce. CRRT is used in acute care settings to remove fluid and uremic toxins in patients with renal failure with hemodynamic instability. Patients with HIT, renal failure, and hemodynamic instability pose a complex situation for clinical management. These patients require anticoagulation with nonheparin agents with simultaneous CRRT. There are no guidelines in the literature regarding the management of this patient group. We report our experience with lepirudin at managing four such patients with HIT, being treated with CRRT.

Acute leukemia associated with valproic acid treatment: a novel mechanism for leukemogenesis?

Valproic acid has been previously associated with hematologic toxicity, including a reversible myelodysplasia-like syndrome without chromosomal abnormalities. We now report three cases of acute leukemia with features of secondary leukemia associated with valproic acid therapy: two cases of acute myelogenous leukemia with multilineage dysplasia, one with trisomy 8 and one with monosomy 7, and one case of secondary acute lymphoblastic leukemia with del (7) (q22q34), del (9) (q21.11q22), del (11) (q12q23). One patient had a previous myelodysplastic syndrome while on valproic acid. Valproic acid has been previously shown to be a histone deacetylase inhibitor. Inhibition of histone deacetylase causes a relaxation of chromatin structure and thus increases susceptibility to DNA damage and sensitizes cells to radiation. We propose that valproic acid therapy may lead to secondary leukemia by increasing DNA damage through chronic inhibition of histone deacetylase.

Response of myasthenia gravis to rituximab in a patient with non-Hodgkin lymphoma.

Myasthenia gravis is a B-cell-mediated autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles. The underlying defect is an autoantibody-mediated attack on the acetylcholine receptors (AchRs) at the neuromuscular junction. Rituximab is a genetically engineered chimeric murine/human monoclonal antibody indicated for treatment of patients with low-grade or follicular, CD20-positive, B-cell non-Hodgkin lymphoma. Based on its potential for elimination of auto-reactive B-cell clones, rituximab may have a role in the management of some autoimmune disorders. We report a patient with B-cell, follicular non-Hodgkin lymphoma and a long-standing history of myasthenia gravis and the favorable impact of rituximab on both disorders.