Neerja Vajpayee

Plasmablastic Lymphoma in an Immunocompetent Patient

An 84-year-old female was admitted to the State University of New York University Hospital (Syracuse, NY) with complaints of persistent right hip pain for longer than 1 month. Her past medical history was significant for Wolff-Parkinson-White syndrome and osteoarthritis. The physical exam was unremarkable except for some decreased range of motion of the right hip. Computed tomography scan of the abdomen and pelvis showed a massive (8.5 7.0 cm), asymmetric, and heterogeneous mass in the right psoas muscle (Fig 1). Radiologically, the mass appeared to be a well-circumscribed hematoma. Biopsy showed a diffuse infiltrate of large neoplastic cells with plasmablastic (cells with rounded nuclei, coarser chromatin, and smaller two to three nucleoli) and immunoblastic morphology (cells with vesicular enlarged nuclei and single prominent nucleolus, Fig 2A). High proliferative index, frequent apoptosis, and focal necrosis were seen. The neoplastic cells were essentially CD20 negative (Fig 2B) and showed strong positivity with CD138 (Fig 2C) and CD79a (Fig 2D). Additionally kappa light chain restriction was noted by in situ hybridization (Figs 3A, kappa; 3B, lambda). Multiple myeloma oncogene-1 (Fig 3C) showed diffuse strong nuclear positivity and paired box gene-5 (PAX-5; Fig 3D) was positive in more than 50% of the tumor cells. Pancytokeratin, markers for breast carcinoma (GCDFP-15 and mammoglobulin), lung malignancy (TTF-1 and CK-7), melanoma (S-100 and MART-1) and other lymphoid markers (CD10, CD3, CD4, CD8, CD56, CD68, Bcl-6, ALK, and CD30) were all negative. Staining for Epstein-Barr virus (EBV) both by immunohistochemistry (EBV latent member protein 1) and in situ hybridization (EBV-encoded RNA) was also negative. Further staging work-up including computed tomography of the thorax and bone scan were negative. There were no other mass lesions or lymphadenopathy. Serum beta-2 microglobulin was mildly elevated at 2.8 mg/L (normal, 2.3 mg/L), serum albumin was low normal at 3.5 g/dL (normal, 3.4 to 4.8 g/dL), and lactate dehydrogenase was elevated at 800 IU/L. Serum and urine protein electrophoresis were normal without presence of a paraprotein or free light chains. Bone marrow examination did not show any morphologic or phenotypic evidence of plasma cell dyscrasia or lymphoma. Enzyme-linked immunosorbent assay for HIV was negative. There was no history of use of immunosuppressive medications. Based on the clinical presentation, morphology and immunophenotype, the patient was diagnosed as having a extramedullary plasmablastic tumor most consistent with large B-cell lymphoma with plasmablastic differentiation. The patient was started on radiotherapy to palliate pain with the intent of subsequent multiagent chemotherapy. Unfortunately, she developed bowel ischemia and infarction in the radiation field. Her condition subsequently deteriorated and she died 1 month after her admission. Plasmablastic lymphoma (PBL) is a distinctive B-cell neoplasm that shows diffuse proliferation of large neoplastic cells, most of which resemble B-immunoblasts and have immunophenotype of plasma cells. PBL was originally described as a rare variant of diffuse large B cell lymphoma (DLBCL) involving the oral cavity and occurring in the clinical setting of HIV and latent EBV infection. PBL accounts for 2.6% of all HIV-related non-Hodgkin’s lymphomas. The prognosis is poor, with death occurring between 1 and 24 months after diagnosis (average survival time, 6 months). PBL has been described, less commonly, in extraoral locations and immunocompetent settings. Current evidence suggests that DLBCL with plasmablastic differentiation represents a clinically heterogeneous spectrum with different clinicopathologic characteristics representing distinct entities. Important subtypes include PBL of oral mucosa type, PBL with plasmacytic

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.

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.

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.

Trends in Bone Marrow Sampling and Core Biopsy Specimen Adequacy in the United States and CanadaA 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.

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 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.