Neural correlates of evaluations of non-binary social feedback: An EEG study.

PURPOSE: In complex and diverse social circumstances, decision making is affected by social feedback. Although previous studies have examined the electrophysiological correlates of social feedback with a binary valence, those related to non-binary feedback, or the magnitude of social feedback, remain unclear. This study investigated the electrophysiological correlates of non-binary social feedback and subsequent action selection processing. METHODS: Participants were asked to complete a Gabor patch direction judgment task in which they were required to make judgments before and after receiving social feedback. They were informed that the feedback stimuli represented the degree to which other participants made the same choice. RESULTS & CONCLUSION: The results revealed that feedback that was highly concordant with the participant's judgments elicited greater P300 activity, which was associated with the fulfillment of expectations regarding social reward. Moreover, moderately concordant feedback induced stronger theta band power, which may indicate monitoring of subjective conflict. Temporal changes in theta power during feedback phase may also relate to adjustments in prediction error. Additionally, when an initial judgment was maintained following social feedback, we observed a stronger increase in beta power, indicating an association with post-social-feedback action processing.

Partial Molar Pregnancy Presenting as a Tubal Ectopic Pregnancy.

Background: Tubal molar pregnancy is extremely rare, with no more than 200 cases reported in the literature. The incidence is approximated at 1.5 per 1,000,000 pregnancies. Case: We report the case of a 22-year-old woman with an overall initial stable clinical presentation who was noted to have a ruptured ectopic pregnancy. She was surgically treated, and pathology revealed partial hydatidiform molar ectopic pregnancy. At the time of surgical intervention, the treating physicians had not considered molar ectopic pregnancy within the differential diagnosis, since this is a very rare presentation. Once the pathology was discovered, the patient was contacted to be scheduled for close follow-up and counseling to reduce progression to choriocarcinomas. Conclusion: This case report highlights the importance of sending, reviewing, and following up on pathologic specimens for all patients undergoing surgical intervention for presumed ectopic pregnancy and ensuring that appropriate follow-up is in place for those patients.

BRD3-NUTM1-expressing NUT carcinoma of lung on endobronchial ultrasound-guided transbronchial needle aspiration cytology, a diagnostic pitfall.

BACKGROUND: Nuclear protein in testis (NUT) carcinoma (NC) is an aggressive type of poorly differentiated carcinoma with a variable degree of squamous differentiation. NC is defined by the presence of BRD-NUT fusion oncogenes, the most common fusion form being the BRD4-NUTM1 gene. Variant rearrangements involving the BRD3 and NSD3 genes. Variant rearrangements involving the BRD3 and NSD3 genes occur in approximately one-third of the cases. AIMS: This is the first case regarding the study of cytological features of NC of the lung with BRD3-NUTM1 fusion. MATERIALS AND METHODS: A 36-year-old female with chest heaviness and shortness of breath was found to have a right-sided pleural effusion; she was non-smoker and denied any significant past medical illness. CT-chest revealed an 8.5 cm heterogeneous mass in the right and mid-upper lung. She underwent endobronchial ultrasound-guided (EBUS) transbronchial fine-needle aspiration (FNA) of the lung mass. Thoracocentesis was performed, and pleural fluid was sent to the laboratory for cytological evaluation RESULTS: The cytopathological findings showed atypical squamoid cells with variably prominent single or multiple nucleoli. Monotonous-looking cells with high nuclear to cytoplasmic ratio and hyperchromasia were also present. The atypical squamoid cells showed abundant clear to eosinophilic cytoplasm with rare individual cell keratinization and focal keratin pearl formation. The atypical cells were positive for CK7, p40, p63, mCEA and equivocal for NUT-specific antibody. The cytopathological findings were consistent with squamous cell carcinoma with focal keratinization. The Fusion Panel-Solid Tumor (50 genes) revealed BRD3-NUTM1 fusion gene. Diagnosis was amended to pulmonary NC. DISCUSSION: NC is a diagnostic challenge for pathologists as it can morphologically mimic undifferentiated carcinoma, squamous cell carcinoma, or neuroendocrine carcinoma. The challenge is not how to diagnose NC but rather determining when to include it in the differential diagnosis and perform the diagnostic molecular tests (FISH or NGS) or IHC study for NUT-specific antibody. CONCLUSION: When a specimen demonstrates a dual cell population of squamoid cells and primitive-looking tumor cells in the wrong clinical context (i.e., young patient with no smoking history), further molecular profiling is warranted to include the differential of a primary NC of the lung. The cytological features of NC itself have rarely been documented and moreover, that of a primary NC of the lung with BRD3-NUTM1 fusion has never been reported. We herein report cytological findings of a primary NC of the lung with BRD3-NUTM1 fusion gene.

Myelodysplastic syndrome with t(6;9)(p22;q34.1)/DEK-NUP214 better classified as acute myeloid leukemia? A multicenter study of 107 cases.

t(6;9)(p22;q34.1)/DEK-NUP214 is a recurrent genetic abnormality that occurs in 1-2% of patients with acute myeloid leukemia (AML), and rarely in myelodysplastic syndrome (MDS). It has been suggested by others that all myeloid neoplasms with t(6;9)/DEK-NUP214 may be considered as AML, even when blast count is <20%. In this study, we compared the clinicopathologic features of 107 patients with myeloid neoplasms harboring t(6;9)/DEK-NUP214: 33 MDS and 74 AML. Compared with patients with AML, patients with MDS were older (p = 0.10), had a lower white blood cell count (p = 0.0017), a lower blast count in the peripheral blood (p < 0.0001) and bone marrow (p < 0.0001), a higher platelet count (p = 0.022), and a lower frequency of FLT3-ITD mutation (p = 0.01). In addition, basophilia was not a common feature in the patients of this cohort. Although there was no difference in overall survival between MDS and AML patients (p = 0.18) in the entire cohort, the survival curves did show a trend toward favorable survival in MDS patients. Multivariate analyses showed that initial diagnosis of MDS vs. AML and allogeneic hematopoietic stem cell transplantation were prognostic factors for survival of patients with t(6;9)/DEK-NUP214 (p = 0.008 and p < 0.0001, respectively). Our data suggest that MDS with t(6;9)/DEK-NUP214 is prognostically not equivalent to AML with t(6;9)/DEK-NUP214. These data also show that stem cell transplantation greatly improves the survival of MDS and AML patients with myeloid neoplasms associated with t(6;9)/DEK-NUP214.

Hepatic involvement by T-cell neoplasms: a clinicopathologic study of 40 cases.

Hepatic involvement by a T-cell neoplasm is rare and often challenging to diagnose in liver biopsies. We collected 40 cases of T-cell neoplasms diagnosed in the liver from five large academic institutions to assess the clinicopathologic features. The patients included 11 women and 29 men, with a median age of 54 (range: 2-75) years and a high mortality rate (31/37, 83.8%). Fourteen (35%) patients were diagnosed with hepatosplenic T-cell lymphoma (HSTCL), 13 (32.5%) peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), and 13 (32.5%) other types of T-cell neoplasms. Patients with HSTCL were much younger and had worse survival than PTCL-NOS and other T-cell neoplasms (P < 0.05). On imaging studies, 20 cases (50%) showed abnormalities, including 10 with mass lesions that correlated with normal or cholestatic pattern enzyme elevation. Histomorphological analysis revealed four main patterns; with the exception of mass forming lesions (pattern 4; n = 8), cases with sinusoidal predominant (pattern 1; n = 12), portal predominant with sinusoidal infiltrates (pattern 2; n = 13) or lobular aggregates (pattern 3; n = 5) demonstrated small to medium lymphocytes resembling a reactive/inflammatory process. In addition, we described two cases of T-cell large granular lymphocytic leukemia that mimicked HSTCL, and a case of aggressive post-transplant lymphoproliferative disorder that developed after chronic Epstein-barr virus (EBV) infection, suggesting the importance of EBV testing in some lymphoma cases. As the largest cohort of T-cell neoplasms in liver, our study provides critical data on disease frequency, distribution, and clinicopathologic features that are essential for accurate diagnosis.

Successful treatment of lipofibromatosis-like neural tumor of the lumbar spine with an NTRK-fusion inhibitor.

BACKGROUND: Lipofibromatosis-like neural tumors (LPF-NT) are a newly identified class of rare mesenchymal neoplasms. Current standard of care therapy is surgical resection alone; there are no chemotherapies or molecular targeted therapies that have been shown to be effective in patients who are not surgical candidates due to either tumor bulk or location. Most LPF-NT harbor NTRK fusions, although the therapeutic significance of these fusions has not been previously demonstrated in this malignancy. Here, we present the first case of a patient with surgically-unresectable LPF-NT successfully treated with medical therapy, specifically the TRK fusion-protein inhibitor entrectinib. CASE PRESENTATION: The patient is a 21 year old man with no co-morbidities who presented for evaluation due to intermittent abdominal pain and was found to have a mass spanning from T12-L2. Biopsy revealed a mesenchymal spindle cell neoplasm and S100 positivity pointed to possible nerve sheath origin. The sample was ultimately found to have an LMNA-NTRK1 fusion, confirming the diagnosis of LP-NFT. Unfortunately, due to the bulk and location of the tumor, surgery was felt to be exceptionally morbid and the patient was treated in a clinical trial with the NTRK inhibitor entrectinib. Surprisingly, he had such a robust clinical response that he was ultimately deemed a surgical candidate and he was successfully taken to surgery. Post-operative pathology revealed > 95% necrosis, demonstrating exceptional sensitivity to the targeted therapy. The patient remains NED and on entrectinib 12 months post-operatively. CONCLUSIONS: The exceptional treatment response of this patient suggests that NTRK fusions are true drivers of the disease. Thus, all patients should be evaluated for NTRK fusions using sensitive methodologies and treatment with TRK fusion-protein inhibitors should be considered in patients who are not candidates for oncologic resection.

Pathological complete response induced by neoadjuvant treatment using BRAF and MEK inhibitors in a patient with unresectable BRAF V600E-mutant malignant melanoma of the gallbladder.

Historically, patients with locally advanced or metastatic melanoma have an extremely poor prognosis. In recent years, major breakthroughs in cutaneous melanoma treatment have led to remarkable improvements in patient outcomes. However, there are limited published data on the efficacy of these novel therapies in the treatment of mucosal melanoma due to rarity of the disease. We report a case of successful neoadjuvant targeted therapy with BRAF and MEK inhibitors followed by radical surgical excision in a patient with advanced malignant melanoma of the gallbladder.

Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggressive B-cell lymphoma.

We studied the global microRNA (miRNA) expression in diffuse large B-cell lymphoma (DLBCL; n = 79), Burkitt lymphoma (BL; n = 36), primary mediastinal B-cell lymphoma (PMBL; n = 12), B-cell lines (n = 11), and normal subsets of naïve B cells, centroblasts (CBs), and peripheral blood B cells along with their corresponding gene expression profiles (GEPs). The normal B-cell subsets have well-defined miRNA signatures. The CB miRNA signature was significantly associated with germinal center B-cell (GCB)-DLBCL compared with activated B-cell (ABC)-DLBCL (P = .002). We identified a 27-miRNA signature that included v-myc avian myelomatosis viral oncogene homolog (MYC) targets and enabled the differentiation of BL from DLBCL, a distinction comparable with the "gold standard" GEP-defined diagnosis. Distinct miRNA signatures were identified for DLBCL subgroups, including GCB-DLBCL, activated B-cell (ABC)-DLBCL, and PMBL. Interestingly, most of the unclassifiable-DLBCL by GEP showed a strong similarity to the ABC-DLBCL by miRNA expression profiling. Consistent results for BL and DLBCL subgroup classification were observed in formalin-fixed, paraffin-embedded tissue, making such tests practical for clinical use. We also identified predictive miRNA biomarker signatures in DLBCL, including high expression of miR-155, which is significantly associated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment failure. This finding was further supported by the observation that high expression of miR-155 sensitizes cells to v-akt murine thymoma viral oncogene homolog-1 inhibitors in vitro, suggesting a novel treatment option for resistant DLBCL.

MicroRNA expression profiling identifies molecular signatures associated with anaplastic large cell lymphoma.

Anaplastic large-cell lymphomas (ALCLs) encompass at least 2 systemic diseases distinguished by the presence or absence of anaplastic lymphoma kinase (ALK) expression. We performed genome-wide microRNA (miRNA) profiling on 33 ALK-positive (ALK[+]) ALCLs, 25 ALK-negative (ALK[-]) ALCLs, 9 angioimmunoblastic T-cell lymphomas, 11 peripheral T-cell lymphomas not otherwise specified (PTCLNOS), and normal T cells, and demonstrated that ALCLs express many of the miRNAs that are highly expressed in normal T cells with the prominent exception of miR-146a. Unsupervised hierarchical clustering demonstrated distinct clustering of ALCL, PTCL-NOS, and the AITL subtype of PTCL. Cases of ALK(+) ALCL and ALK(-) ALCL were interspersed in unsupervised analysis, suggesting a close relationship at the molecular level. We identified an miRNA signature of 7 miRNAs (5 upregulated: miR-512-3p, miR-886-5p, miR-886-3p, miR-708, miR-135b; 2 downregulated: miR-146a, miR-155) significantly associated with ALK(+) ALCL cases. In addition, we derived an 11-miRNA signature (4 upregulated: miR-210, miR-197, miR-191, miR-512-3p; 7 downregulated: miR-451, miR-146a, miR-22, miR-455-3p, miR-455-5p, miR-143, miR-494) that differentiates ALK(-) ALCL from other PTCLs. Our in vitro studies identified a set of 32 miRNAs associated with ALK expression. Of these, the miR-17∼92 cluster and its paralogues were also highly expressed in ALK(+) ALCL and may represent important downstream effectors of the ALK oncogenic pathway.

Quantitative proteomics reveals that miR-155 regulates the PI3K-AKT pathway in diffuse large B-cell lymphoma.

The aberrant expression of microRNA-155 (miR-155), which has emerged as having a significant impact on the biological characteristics of lymphocytes, plays important roles in B-cell malignancies, such as diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common non-Hodgkin's lymphoma in the adult population, accounting for approximately 40% of newly diagnosed non-Hodgkin's lymphoma cases globally. To determine the specific function of miR-155, a quantitative proteomics approach was applied to examine the inhibitory effects of miR-155 on protein synthesis in DLBCL cells. PIK3R1 (p85α), a negative regulator of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway, was identified as a direct target of miR-155. A luciferase reporter was repressed through the direct interaction of miR-155 and the p85α 3'-untranslated region, and overexpression of miR-155 down-regulated both the transcription and translation of p85α. The PI3K-AKT signaling pathway was highly activated by the sustained overexpression of miR-155 in DHL16 cells, whereas knockdown of miR-155 in OCI-Ly3 cells diminished AKT activity. Taken together, our results reveal a novel target involved in miR-155 biological characteristics and provide a molecular link between the overexpression of miR-155 and the activation of PI3K-AKT in DLBCL.

Genome-wide miRNA profiling of mantle cell lymphoma reveals a distinct subgroup with poor prognosis.

miRNA deregulation has been implicated in the pathogenesis of mantle cell lymphoma (MCL). Using a high-throughput quantitative real-time PCR platform, we performed miRNA profiling on cyclin D1-positive MCL (n = 30) and cyclin D1-negative MCL (n = 7) and compared them with small lymphocytic leukemia/lymphoma (n = 12), aggressive B-cell lymphomas (n = 138), normal B-cell subsets, and stromal cells. We identified a 19-miRNA classifier that included 6 up-regulated miRNAs and 13 down regulated miRNA that was able to distinguish MCL from other aggressive lymphomas. Some of the up-regulated miRNAs are highly expressed in naive B cells. This miRNA classifier showed consistent results in formalin-fixed paraffin-embedded tissues and was able to distinguish cyclin D1-negative MCL from other lymphomas. A 26-miRNA classifier could distinguish MCL from small lymphocytic leukemia/lymphoma, dominated by 23 up-regulated miRNAs in MCL. Unsupervised hierarchical clustering of MCL patients demonstrated a cluster characterized by high expression of miRNAs from the polycistronic miR17-92 cluster and its paralogs, miR-106a-363 and miR-106b-25, and associated with high proliferation gene signature. The other clusters showed enrichment of stroma-associated miRNAs, and also had higher expression of stroma-associated genes. Our clinical outcome analysis in the present study suggested that miRNAs can serve as prognosticators.

Molecular distinctions between pediatric and adult mature B-cell non-Hodgkin lymphomas identified through genomic profiling.

Burkitt lymphoma (BL) predominates in pediatric patients, whereas diffuse large B-cell lymphoma (DLBCL) is uncommon. In contrast to adults, BL and DLBCL are treated similarly in children and both entities have superior outcomes in children compared with adults. Gene expression profiling (GEP) and miRNA expression profiling clearly differentiated pediatric DLBCL from BL, forming distinct clusters regardless of patient age. However, pathway analysis of GEP data identified minor differences between corresponding pediatric and adult tumors. Predominance (6:1) of the germinal center B-cell subtype to activated B-cell subtype was found among pediatric DLBCL. Two cases were molecularly classified as primary mediastinal B-cell lymphoma. We observed frequent abnormalities in 8q24 in pediatric DLBCL, including MYC rearrangement in 31% (5 of 16) and gain or amplification in 50% (6 of 12) nonrearranged cases. MYC rearrangement was present in 96% (23 of 24) BL cases. Array-based CGH analysis identified abnormalities that are shared between adult and pediatric DLBCL (+12q15, +19q13, -6q), and abnormalities unique to the pediatric cases (-4p14, -19q13.32, +16p11.2), suggesting distinct pathogenetic mechanisms relative to age. Elucidation of the underlying target genes may provide insight into factors that modulate outcome and could provide potential novel therapeutic targets with less toxicity for pediatric patients with B-cell non-Hodgkin lymphoma.

Inhibition of poly(ADP-ribose) polymerase (PARP) and ataxia telangiectasia mutated (ATM) on the chemosensitivity of mantle cell lymphoma to agents that induce DNA strand breaks.

There is a high incidence of genomic aberration of ataxia telangiectasia mutated (ATM) and genes encoding proteins involved in the ATM pathway in mantle cell lymphoma (MCL). It has been shown that poly(ADP-ribose) polymerase inhibitor (PARPi) strongly enhances the cytotoxicity of agents, causing single-strand DNA breaks in cells with impaired homologous recombination repair. Here, we show that PARPi AG14361 potentiates the cytotoxicity induced by topotecan treatment in MCL cell lines, which was not dependent on either TP53 or CHEK2 status. Inhibition and/or knockdown of ATM and BRCA2 did not potentiate the cytotoxic effect of treatment with PARPi and topotecan. With loss of function of ATM, other kinases can still mediate activation of ATM substrates as demonstrated by continued phosphorylation of CHEK2 (Thr-68), although attenuated and delayed. These results suggest that PARPi may enhance the therapeutic efficacy of DNA damaging agents on MCL through TP53-independent mechanisms without requiring the inhibition of either ATM or BRCA2.

The miR-17-92 microRNA cluster is regulated by multiple mechanisms in B-cell malignancies.

A cluster of six microRNAs (miRNAs), miR-17-92, is processed from the transcript of C13orf25, a gene amplified in some lymphomas and solid tumors. We find that levels of the miRNAs in the cluster do not vary entirely in parallel with each other or with the primary RNA in B-cell lines or normal cells, suggesting that processing or stability of the miRNAs is differentially regulated. Using luciferase reporter assays, we identified the region required for maximum promoter activity. Additional deletions and mutations indicated that the promoter is regulated by the collaborative activity of several transcription factors, most of which individually have only a moderate effect; mutation of a cluster of putative SP1-binding sites, however, reduces promoter activity by 70%. MYC is known to regulate C13orf25; surprisingly, mutation of a putative promoter MYC-binding site enhanced promoter activity. We found that the inhibitory MYC family member MXI1 bound to this region. The chromatin structure of a >22.5-kb region encompassing the gene contains peaks of activating histone marks, suggesting the presence of enhancers, and we confirmed that at least two regions have enhancer activity. Because the miR-17-92 cluster acts as an important oncogene in several cancers and targets genes important in regulating cell proliferation and survival, further studies of its transcriptional control are warranted.

Integrated profiling of diffuse large B-cell lymphoma with 7q gain.

To characterize diffuse large B-cell lymphoma (DLBCL) with chromosome 7 gains, we combined clinical data with genomic, RNA and miRNA profiling. Gains were associated with age >60 years, female gender, a trend for higher complete response rate, lower death rate, and better overall survival in patients treated with R-CHOP. Lesions were inversely associated with bone marrow involvement and number of extra-nodal sites. Differentially expressed transcripts were enriched of genes belonging to specific pathways and miRNAs targets. MIR96, MIR182, MIR589, MIR25 were shown significantly up-regulated in 7q+ DLBCL by real-time PCR.

UNiquant, a program for quantitative proteomics analysis using stable isotope labeling.

Stable isotope labeling (SIL) methods coupled with nanoscale liquid chromatography and high resolution tandem mass spectrometry are increasingly useful for elucidation of the proteome-wide differences between multiple biological samples. Development of more effective programs for the sensitive identification of peptide pairs and accurate measurement of the relative peptide/protein abundance are essential for quantitative proteomic analysis. We developed and evaluated the performance of a new program, termed UNiquant, for analyzing quantitative proteomics data using stable isotope labeling. UNiquant was compared with two other programs, MaxQuant and Mascot Distiller, using SILAC-labeled complex proteome mixtures having either known or unknown heavy/light ratios. For the SILAC-labeled Jeko-1 cell proteome digests with known heavy/light ratios (H/L = 1:1, 1:5, and 1:10), UNiquant quantified a similar number of peptide pairs as MaxQuant for the H/L = 1:1 and 1:5 mixtures. In addition, UNiquant quantified significantly more peptides than MaxQuant and Mascot Distiller in the H/L = 1:10 mixtures. UNiquant accurately measured relative peptide/protein abundance without the need for postmeasurement normalization of peptide ratios, which is required by the other programs.

BCL6 promoter interacts with far upstream sequences with greatly enhanced activating histone modifications in germinal center B cells.

BCL6 encodes a transcriptional repressor that is essential for the germinal center (GC) reaction and important in lymphomagenesis. Although its promoter has been well studied, little is known concerning its possible regulation by more distal elements. To gain such information, we mapped critical histone modifications associated with active transcription within BCL6 as well as far upstream sequences at nucleosomal resolution in B-cell lines and in normal naive and GC B cells. Promoter-associated and intronic CpG islands (CGIs) in BCL6 showed a reciprocal pattern of histone modifications. Gene expression correlated with a paradoxical loss from the intronic CGI of histone H3 lysine-4 trimethylation, normally associated with transcription, suggesting that the intronic CGI may interfere with transcription. In an approximately 110-kb region extending 150-260 kb upstream of BCL6, highly active histone modifications were present only in normal GC B cells and a GC B-cell line; this region overlaps with an alternative breakpoint region for chromosomal translocations and contains a GC-specific noncoding RNA gene. By chromosome conformation capture, we determined that the BCL6 promoter interacts with this distant upstream region. It is likely that transcriptional enhancers in this region activate BCL6 and overcome strong autorepression in GC B cells.

Alternative splicing generates a short BCL6 (BCL6S) isoform encoding a compact repressor.

BCL6 gene transcribes two main mRNA isoforms, variant 1 and variant 2, which have distinct transcription start sites. However, these two isoforms encode identical BCL6 protein. Recently, a third variant was sequenced from a human hippocampus cDNA library (DB465062). In this study, we cloned and sequenced a novel BCL6 spliced isoform (BCL6S) which lacks exon 7 that encodes the first two zinc fingers of BCL6. We found a splicing isoform, BCL6S, that excludes exon 7 but retains the last four of the six zinc fingers (ZFs) coding region of the BCL6 gene. BCL6S mRNA and protein were expressed in human cell lines and tissues that expressed BCL6, but accounted for a minor portion of BCL6 transcripts or protein. BCL6S protein was also detectable in BCL6 positive cells. BCL6S could form homodimers or heterodimers with BCL6 and could bind to classical BCL6-binding sites. Luciferase reporter assays demonstrated that BCL6S could effectively repress typical BCL6 target genes. BCL6S is a compact repressor that may have a functional role in normal and neoplastic germinal center B cells.

Gcet1 (centerin), a highly restricted marker for a subset of germinal center-derived lymphomas.

GCET1 (germinal center B cell-expressed transcript-1) gene codes for a serpin expressed in germinal center (GC) B cells. Following the observation that follicular lymphoma cases exhibit an increased level of Gcet1 expression, compared with follicular hyperplasia, we have characterized Gcet1 protein expression in human tissues, cell lines, and a large series of lymphomas. To this end, we have performed immunohistochemical and Western blot analyses using a newly generated monoclonal antibody that is reactive in paraffin-embedded tissues. Our results demonstrate that Gcet1 is expressed exclusively by neoplasms hypothetically to be arrested at the GC stage of differentiation, including follicular lymphoma, nodular lymphocyte predominant Hodgkin lymphoma, and a subset of diffuse large B-cell lymphoma, T-cell/histiocyte rich B-cell lymphoma, and Burkitt lymphoma. Within these tumors, Gcet-1 protein expression is restricted to a subset of GC B cells, establishing the existence of a distinct heterogeneity among normal and neoplastic GC B cells. None of the other B-cell lymphomas, that is, chronic lymphocytic leukemia, splenic marginal zone lymphoma, and mantle cell lymphoma, was Gcet1(+), which underlines the potential utility of Gcet1 expression in lymphoma diagnosis. The results of RNA and protein expression should prompt further investigation into the role of Gcet1 in regulating B-cell survival.