The basis and rational use of molecular genetic testing in mature B-cell lymphomas.

An increasing number of neoplasms are associated with variably specific genetic abnormalities. This is best exemplified by hematological malignancies, in which there is a growing list of entities that are defined by their genetic lesion(s); this is not (yet) the case in mature B-cell lymphomas. However, enhanced insights into the pathogenesis of this large and diverse group of lymphomas have emerged with the ongoing unraveling of a plethora of fascinating genetic abnormalities. The purpose of this review is to synthesize well-recognized data and nascent discoveries in our understanding of the genetic basis of a spectrum of mature B-cell lymphomas, and how this may be applied to contemporary clinical practice. Despite the explosion of new and exciting knowledge in this arena, with the potential for enhanced diagnostic and prognostic strategies, it is essential to remain cognizant of the limitations (and complexity) of genetic investigations, so that assays can be developed and used both judiciously and rationally.

Coexisting follicular and mantle cell lymphoma with each having an in situ component: A novel, curious, and complex consultation case of coincidental, composite, colonizing lymphoma.

A diagnosis of composite lymphoma is typically prompted by the observation of morphologic discordance. We present a case of a spleen revealing histologic features of follicular lymphoma, without any indication of a second lymphoma. Immunohistochemical stains supported this diagnosis and showed the follicular lymphoma to be BCL2-. However, these studies revealed 2 additional unexpected findings: cyclin D1+ mantle zone cells surrounding neoplastic and reactive follicles (indicative of in situ mantle cell lymphoma) and BCL2-bright, histologically nonneoplastic follicles (indicative of in situ follicular lymphoma). ImmunoFISH and microdissection and polymerase chain reaction analysis documented the clonal nature of the cyclin D1+ mantle zones and illustrated clonal independence from the follicular lymphoma. This case illustrates an uncommon and unusual composite follicular and mantle cell lymphoma, with the follicular lymphoma accompanied by an in situ component, whereas the only manifestation of the mantle cell lymphoma was in situ.

Utility of fascin and JunB in distinguishing nodular lymphocyte predominant from classical lymphocyte-rich Hodgkin lymphoma.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) and lymphocyte-rich classical Hodgkin lymphoma (LRCHL), although clinically and morphologically similar, differ biologically and in prognosis. Immunolabeling of Reed-Sternberg (RS) cells in LRCHL and lymphocytic and/or histiocytic variants (L&H cells) in NLPHL is often required to help distinguish between the 2 variants. Our aim was to evaluate fascin (a distinct 55-kd actin-bundling protein) and JunB (an activator protein-1 family transcription factor) to differentiate NLPHL from LRCHL. A total of 35 archival cases of NLPHL (n = 24) and LRCHL (n = 11) from adults and children were studied. Slides were reviewed for all cases and clinical, morphologic, and immunohistochemical features were evaluated. Each case was immunostained for fascin and JunB, and immunoreactivity of RS cells, L&H cells, and background lymphocytes were recorded. Whereas occasional L&H cells were weakly positive for fascin in 3 out of 24 (12.5%) cases of NLPHL, RS cells in LRCHL were positive for fascin in 11 out of 11 (100%) cases with a strong cytoplasmic staining pattern. JunB was positive in 10 out of 24 (41.7%) of NLPHL cases, and 11 out of 11 (100%) of LRCHL cases, showing a stippled and/or diffuse nuclear staining pattern. In addition to L & H Cells, JunB also stained small background lymphocytes, particularly in areas of progressively transformed germinal centers of NLPHL. Either stains when tested alone, if negative, or with rare L&H cell weak positivity for fascin, is indicative of NLPHL. The L&H cells of NLPHL cases were negative for concomitant staining in 24 out of 24 (100%) cases. Concomitant positive staining of classic RS cells for fascin and JunB was found in 11 out of 11 (100%) of LRCHL cases. Although fascin positivity alone supports the diagnosis of LRCHL, concomitant positivity offers stronger support and is less likely to lead to a false conclusion if aberrant fascin staining were to be encountered in a case of NLPHL. Staining for fascin and JunB provides a basis for distinguishing NLPHL from LRCHL and offers an alternative to other antibody profiles.

IMP-3 is differentially expressed in normal and neoplastic lymphoid tissue.

IMP-3 is a member of the insulin-like growth factor II mRNA binding protein (IMP) family of proteins that play a role in RNA trafficking and stabilization and cell growth and migration during embryogenesis but which are down-regulated in adult tissue. However, IMP-3 has recently been shown to be overexpressed in several epithelial malignancies, with increased expression correlating with aggressive behavior. To our knowledge, there is no published literature evaluating IMP-3 in lymphoid tissue. Accordingly, we immunohistochemically evaluated IMP-3 expression in normal lymphoid tissue and 141 lymphoid neoplasms. Physiologically, IMP-3 expression was restricted to germinal center B cells. Among lymphoid neoplasms, Hodgkin lymphoma demonstrated the highest percentage of positive cases (26/26, 100%) often with bright staining. Burkitt lymphoma was positive in 10 (83%) of 12 cases with moderate to bright staining. Although follicular lymphoma was also positive in a high percentage of cases (12/15, 80%), the intensity was exclusively weak to moderate. Although 22 (85%) of 26 of diffuse large B-cell lymphomas were positive for IMP-3, there was wide variability in staining intensity, which did not correlate with classification into activated B cell versus germinal center B origin. By contrast, lower proportions (8%-20%) of other non-germinal center B lymphoma subtypes were IMP-3-positive. In conclusion, although IMP-3 expression is seemingly restricted to physiologic germinal center B cells, its expression in lymphomas of germinal center B origin is less robust. However, there does appear to be some association with the latter group of lymphomas, which may prove to have diagnostic or therapeutic relevance as the biologic role of IMP-3 is further elucidated.

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.

ZAP70 expression assessed by immunohistochemistry on peripheral blood: a simple prognostic assay for patients with chronic lymphocytic leukemia.

The somatic hypermutational (SHM) status of the immunoglobulin heavy-chain variable (IgVH) gene is a powerful prognostic factor in patients with chronic lymphocytic leukemia (CLL). However, IgVH SHM analysis is not well-suited to routine use in the clinical diagnostic laboratory. ZAP70 expression is a potential surrogate for the absence of SHM. Given the current problems with the standardization of ZAP70 assessment by flow cytometry, we sought an alternative approach, using immunohistochemistry (IHC). The utility of IHC is largely restricted to tissues, precluding its routine application to most patients with CLL who are typically diagnosed based upon peripheral blood (PB) findings. Accordingly, we developed an IHC assay that can be performed on PB. Enriched PB mononuclear cells from 29 patients with CLL were analyzed for ZAP70 expression by IHC on paraffin-embedded cell blocks, using standard techniques. IgVH SHM analysis was performed on all cases, and clinical features recorded. Seventeen specimens (59%) were negative for ZAP70 expression and 12 (41%) were positive for ZAP70 expression. SHM was evident in 20 specimens (69%), and absent in 9 (31%). Seventy-six percent of the specimens (22/29) displayed "concordant" ZAP70 and SHM results, in that 15 (52%) were SHM-positive/ZAP70 negative, whereas 7 (24%) were SHM-negative/ZAP70 positive. ZAP70 expression in this small cohort correlated with poor clinical outcome. Importantly, IHC analysis of ZAP70 in PB is a simple, reliable, robust assay that may have a valuable role in the routine clinical laboratory assessment of patients with CLL.

Primary cardiac lymphoma: utility of multimodality imaging in diagnosis and management.

Primary cardiac lymphoma (PCL) is an extremely rare disease defined as a lymphoma strictly confined to the heart or pericardium without dissemination. We present the case of an 82 yr old male with newly diagnosed PCL and two years of subsequent follow up. This report highlights the utility of a multimodality imaging approach in the diagnosis and management of PCL.

Recent insights into the biology of Hodgkin lymphoma: unraveling the mysteries of the Reed-Sternberg cell.

The microscopic pathology of Hodgkin lymphoma has been recognized for well over a century; however, only in the past 15 years has the enigmatic nature of this peculiar neoplasm been somewhat unraveled. This has been accomplished via a combination of the acquisition, via microdissection, of the prototypically rare malignant cells and their subsequent analysis via a variety of modalities, including genomic studies and expression profiling. This has facilitated the elucidation of the surreptitiously concealed B-cell origin of the cells, their complex but vital relationships with the surrounding micro- and macroenvironment, as well as multiple pathways involved in the pathobiology of this lymphoma. Understanding the intricacies of these intra- and extracellular pathways should allow for the development of less-toxic targeted therapies.

Large natural killer cell lymphoma arising from an indolent natural killer cell large granular lymphocyte proliferation.

Natural killer cell large granular lymphocyte proliferation is a relatively rare disorder that typically runs a chronic, indolent course. We present a patient with a 3 1/2-year history of natural killer cell large granular lymphocyte proliferation terminating in large cell lymphoma with natural killer cell features. The diagnosis of natural killer cell large granular lymphocyte proliferation was based on flow cytometric demonstration of an expanded population of CD3- CD16+/CD56+ lymphocytes in the peripheral blood. The patient experienced various rheumatologic symptoms, but was hematologically stable for 3 1/2 years. He then developed fevers, night sweats, weight loss, and a left lower lobe lung mass. Resection of the mass showed a large cell lymphoma with immunohistochemical positivity for CD2, CD7, CD56, and T-cell intracellular antigen-1, compatible with natural killer cell origin. In situ hybridization for Epstein-Barr virus and polymerase chain reaction analysis for T-cell receptor gene rearrangement were negative. To our knowledge, this is the second documented report of chronic natural killer cell large granular lymphocyte proliferation terminating in an aggressive large natural killer cell lymphoma.