CREBBP and STAT6 co-mutation and 16p13 and 1p36 loss define the t(14;18)-negative diffuse variant of follicular lymphoma.

The diffuse variant of follicular lymphoma (dFL) is a rare variant of FL lacking t(14;18) that was first described in 2009. In this study, we use a comprehensive approach to define unifying pathologic and genetic features through gold-standard pathologic review, FISH, SNP-microarray, and next-generation sequencing of 16 cases of dFL. We found unique morphologic features, including interstitial sclerosis, microfollicle formation, and rounded nuclear cytology, confirmed absence of t(14;18) and recurrent deletion of 1p36, and showed a novel association with deletion/CN-LOH of 16p13 (inclusive of CREBBP, CIITA, and SOCS1). Mutational profiling demonstrated near-uniform mutations in CREBBP and STAT6, with clonal dominance of CREBBP, among other mutations typical of germinal-center B-cell lymphomas. Frequent CREBBP and CIITA codeletion/mutation suggested a mechanism for immune evasion, while subclonal STAT6 activating mutations with concurrent SOCS1 loss suggested a mechanism of BCL-xL/BCL2L1 upregulation in the absence of BCL2 rearrangements. A review of the literature showed significant enrichment for 16p13 and 1p36 loss/CN-LOH, STAT6 mutation, and CREBBP and STAT6 comutation in dFL, as compared with conventional FL. With this comprehensive approach, our study demonstrates confirmatory and novel genetic associations that can aid in the diagnosis and subclassification of this rare type of lymphoma.

Rituximab-Induced Splenic Rupture and Cytokine Release.

BACKGROUND: Rituximab is a therapeutic monoclonal antibody that is used for many different lymphomas. Post-marketing surveillance has revealed that the risk of fatal reaction with rituximab use is extremely low. Splenic rupture and cytokine release syndrome are rare fatal adverse events related to the use of therapeutic monoclonal antibodies, especially in aggressive malignancies with high tumor burden. CASE REPORT: A 55-year-old woman presented with abdominal pain and type B symptoms and was diagnosed with mantle cell lymphoma. Initial peripheral blood flow cytometry showed findings that mimicked features of chronic lymphocytic leukemia. Further treatment with rituximab led to catastrophic treatment complications that proved to be fatal for the patient. CONCLUSIONS: Severe cytokine release syndrome associated with biologics carries a very high morbidity and case fatality rate. With this case report we aim to present the diagnostic challenge with small B-cell neoplasms, especially mantle cell lymphoma and chronic lymphocytic lymphomas, and underscore the importance of thorough risk assessment for reactions prior to treatment initiation.

Immunoblastic follicular lymphoma: a very unusual transformation of low-grade follicular lymphoma.

A 73-year-old man, in clinical remission 17 years after radiation therapy for a localized low-grade follicular lymphoma (FL), developed extensive lymphadenopathy, ascites, and splenomegaly with splenic masses. Axillary lymph node biopsy showed FL composed of nodules of centrocytes side by side with nodules of immunoblasts rather than centroblasts. Immunophenotyping revealed conventional FL markers (BCL-2, BCL-6, and CD10) as well as MUM-1 in the immunoblastic component, suggesting postgerminal center differentiation. Fluorescence in situ hybridization showed t(14;18) in both centrocytic and immunoblastic components and a copy gain of BCL-6 predominantly in the immunoblastic component. Areas of centrocytic and of immunoblastic nodules were macrodissected separately and underwent molecular evaluation for immunoglobulin heavy chain gene rearrangement. Identical base-pair peaks were found, attesting to their clonal identity. This case represents a very unusual example of transformation of a low-grade FL to a nodular immunoblastic FL.

A rare case of acute lymphoblastic leukemia in a patient with light chain (AL) amyloidosis treated with lenalidomide.

Lenalidomide belongs to a novel class of drugs called Immunomodulators which are now being used for the treatment of plasma cell dyscrasias with variable degrees of efficacy and toxicity. Though Second Primary Malignancies (SPM) have been a concern with its use, the benefits of the treatment outweigh the risks. The leukemogenic risk seems to be potentiated especially when combined with alkylating agents and the SPMs documented are predominantly myeloblastic. To date there are no reported cases of new lymphocytic leukemias in AL amyloidosis, regardless of whether undergone treatment or not. We present a case of AL amylodosis who was treated with lenalidomide and subsequently developed acute lymphoblastic leukemia.

Transformation of the 5q- syndrome to acute lymphoblastic leukemia: a report of two cases and review of the literature.

Myelodysplastic syndrome (MDS) with an isolated deletion of the long arm of chromosome 5 (5q- syndrome) is a distinct subtype of MDS with an indolent course that rarely transforms to acute leukemia. Deletion of the long arm of chromosome 5 has also been reported in rare cases of de novo B-lymphoblastic leukemia. We present two cases of 5q- syndrome with a similar and unusual course of transformation to lymphoblastic leukemia while on Lenalidomide. These two patients achieved an initial response; however, later acquired a second cytogenetic abnormality, became refractory to treatment and evolved into acute leukemia. At the time of transformation, both patients had recurrence of the 5q- abnormality. Review of the literature and the mechanisms of transformation of the 5q-syndrome into an acute leukemia are discussed. Although the relationship between the events in our cases remains unclear, the intriguing similarity between the two cases raises a question whether immune modulators can alter the natural course of MDS. To our knowledge, no similar cases were previously reported in the literature.

Percentage of {gamma}{delta} T cells in panniculitis by paraffin immunohistochemical analysis.

Cutaneous T-cell lymphomas with panniculitis-like histologic features have different clinical courses depending on whether they are composed of alphabeta T cells or gammadelta T cells, necessitating their distinction for proper prognostication. However, unlike alphabeta T cells, gammadelta T cells cannot be reliably detected in formalin-fixed, paraffin-embedded sections. We demonstrated that a commercially available antibody can detect gammadelta T cells and examined 2 cases of flow cytometry-proven gammadelta T-cell lymphomas and 15 control cases of nonneoplastic panniculitis. In both lymphomas, the atypical lymphocytes were gammadelta T cells, whereas the reactive lymphocytes were alphabeta T cells. In contrast, nonneoplastic panniculitis had predominantly alphabeta T cells with many fewer and individually scattered gammadelta T cells. The detection of gammadelta T cells in paraffin sections provides a powerful new tool to characterize T cells in lymphomas and inflammation.

Flow cytometric quantitation of natural killer cells and T lymphocytes expressing T-cell receptors alpha/beta and gamma/delta is not helpful in distinguishing benign from malignant body cavity effusions.

BACKGROUND: Quantitation of natural killer (NK) cells in benign and malignant effusions has yielded conflicting results in the past. Studies have claimed higher, lower, and essentially equal percentages of NK cells for benign and malignant effusions. In addition, virtually no literature exists on the numbers and distribution of T lymphocytes expressing T-cell receptor alpha/beta (TCR alpha/beta) and T-cell receptor gamma/delta (TCR gamma/delta) in body effusions. METHODS: Using multicolor flow cytometry and sequential gating techniques, NK cells and T lymphocytes expressing TCR alpha/beta and TCR gamma/delta were identified and quantitated in 30 benign and 30 malignant effusions. RESULTS: No significant difference in percentage of NK cells was found between benign and malignant effusions. The absolute number per miroliter of CD16(+)CD56(+) NK cells was higher in malignant than in benign effusions, but only at a borderline level of statistical significance. T cells expressing TCR alpha/beta far outnumbered those expressing TCR gamma/delta in all effusions, a distribution similar to that in normal adult peripheral blood and lymphoid tissue. The percentages and absolute numbers of these T-cell subsets were the same in benign and malignant effusions. CONCLUSIONS: Enumeration of NK cells and of T lymphocytes expressing TCR alpha/beta or TCR gamma/delta in human body effusions is not helpful in attempting to distinguish between benign and malignant effusions. Values for the two T-lymphocyte subsets in human effusions are, to our knowledge, established for the first time by flow cytometric determination.

Small lymphocytic lymphoma/chronic lymphocytic leukemia in a pelvic myelolipoma.

Myelolipoma is a rare benign tumor composed of mature adipose tissue and normal hematopoietic elements. Extra-adrenal myelolipomas are extremely rare, with approximately 50% of cases occurring in the presacral region. We report a case of an 85 year old woman who presented with small bowel obstruction relating to a pelvic mass detected on computed tomography (CT) scan. At laparotomy, a 12-cm. pre-sacral mass was resected. Histologic examination showed a myelolipoma with dense lymphoid aggregates. On immunostains, the lymphoid aggregates showed positivity for CD20, CD5, and CD23, consistent with small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL). Molecular evaluation confirmed the presence of a clonal B-cell lymphocytic proliferation that did not harbor BCL-2 or BCL-1 gene rearrangements. This case represents the first report of a myelolipoma involved by a non-Hodgkin lymphoma. The unique combination of these findings raises questions about the relationship between the two observed entities. The likeliest scenario is that an unusual benign tumor (myelolipoma) was colonized by a relatively common systemic hematopoietic neoplasm SLL/CLL, producing a collision tumor.

Adhesion- and degranulation-promoting adapter protein is required for efficient thymocyte development and selection.

Adhesion- and degranulation-promoting adapter protein (ADAP) is required in TCR-induced activation and proliferation of peripheral T cells. Loss of ADAP also impairs TCR-initiated inside-out activation of the integrin LFA-1 (CD11a/CD18, alphaLbeta2). In this study, we demonstrate that ADAP-deficient CD4/CD8 double-positive (DP) cells have a diminished ability to proliferate, and that these DP thymocytes up-regulate CD69 poorly in vivo. Moreover, in both MHC class I- and class II-restricted TCR transgenic models, loss of ADAP interferes with both positive and negative selection. ADAP deficiency also impairs the ability of transgene-bearing DP thymocytes to form conjugates with Ag-loaded presenting cells. These findings suggest that ADAP is critical for thymocyte development and selection.

PRAM-1 is required for optimal integrin-dependent neutrophil function.

PML-retinoic acid receptor alpha (RARalpha) regulated adaptor molecule 1 (PRAM-1) is an intracellular adaptor molecule that is upregulated during the induced granulocytic differentiation of promyelocytic leukemic cells and during normal human myelopoiesis. This report describes the generation of PRAM-1-deficient mice and an analysis of the function of this adaptor in neutrophil differentiation and mature neutrophil function. We demonstrate here that neutrophil differentiation is not impaired in PRAM-1-deficient mice and that PRAM-1-deficient neutrophils function normally following engagement of Fcgamma receptors. In contrast, mature PRAM-1-null neutrophils exhibit significant defects in adhesion-dependent reactive oxygen intermediate production and degranulation. Surprisingly, other integrin-dependent responses, such as cell spreading and activation of several signaling pathways, are normal. Together, these findings demonstrate the uncoupling of key integrin-dependent responses in the absence of PRAM-1 and show this adaptor to be critical for select integrin functions in neutrophils.