Follicular lymphoma and diffuse large B-cell lymphoma with BCL2 and IRF4 rearrangements in adult patients.

Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) with concurrent BCL2 and IRF4 rearrangements are rare. It is unclear whether such cases should be classified as large B- cell lymphoma with IRF4 rearrangement or FL/DLBCL-not otherwise specified. We identified 5 adult patients (FL, N = 3 and FL/DLBCL, N = 2) with concurrent BCL2 and IRF4 rearrangements. The median age at presentation was 77 years, and three patients presented with advanced stage disease. Both nodal and extranodal sites were involved and involvement was not limited to head and neck region. With a median follow-up of 18 months, 1 patient died and 4 patients were alive, including 3 who received chemotherapy and 1 who was observed. The neoplasms were histologically heterogeneous, including grade 2 and 3 FL and DLBCL. Four cases coexpressed CD10, BCL6, BCL2 and MUM1/IRF4. The Ki67 labelling index ranged from 20% to 95%. In 4 patients, the percentage of cells with BCL2 rearrangement was equal to or slightly greater than the cells harboring IRF4 rearrangement. Two cases underwent next generation sequencing tailored for lymphoid neoplasms. Both lacked mutations involving IRF4 and NF-kB pathway genes that are frequently detected in large B-cell lymphoma with IRF4 rearrangement, and one case showed DLBCL-EZH2 type mutations, including KMT2D and BCL2 mutations, similar to 2 previously reported DLBCL with BCL2 and IRF4 rearrangements. Adults with FL and FL/DLBCL with BCL2 and IRF4 rearrangements display clinicopathologic and mutational features more akin to FL and DLBCL and should not be characterized as large B-cell lymphoma with IRF4 rearrangement.

Genomic landscape of Epstein-Barr virus-positive extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue.

Epstein-Barr virus (EBV)-positive extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT lymphomas) were initially described in solid organ transplant recipients, and, more recently, in other immunodeficiency settings. The overall prevalence of EBV-positive MALT lymphomas has not been established, and little is known with respect to their genomic characteristics. Eight EBV-positive MALT lymphomas were identified, including 1 case found after screening a series of 88 consecutive MALT lymphomas with EBER in situ hybridization (1%). The genomic landscape was assessed in 7 of the 8 cases with a targeted high throughput sequencing panel and array comparative genomic hybridization. Results were compared to published data for MALT lymphomas. Of the 8 cases, 6 occurred post-transplant, 1 in the setting of primary immunodeficiency, and 1 case was age-related. Single pathogenic/likely pathogenic mutations were identified in 4 of 7 cases, including mutations in IRF8, BRAF, TNFAIP3, and SMARCA4. Other than TNFAIP3, these genes are mutated in <3% of EBV-negative MALT lymphomas. Copy number abnormalities were identified in 6 of 7 cases with a median of 6 gains and 2 losses per case, including 4 cases with gains in regions encompassing several IRF family or interacting genes (IRF2BP2, IRF2, and IRF4). There was no evidence of trisomies of chromosomes 3 or 18. In summary, EBV-positive MALT lymphomas are rare and, like other MALT lymphomas, are usually genetically non-complex. Conversely, while EBV-negative MALT lymphomas typically show mutational abnormalities in the NF-κB pathway, other than the 1 TNFAIP3-mutated case, no other NF-κB pathway mutations were identified in the EBV-positive cases. EBV-positive MALT lymphomas often have either mutations or copy number abnormalities in IRF family or interacting genes, suggesting that this pathway may play a role in these lymphomas.

A rare case of atypical chronic myeloid leukemia associated with t(8;22)(p11.2;q11.2)/ BCR-FGFR1 rearrangement: A case report and literature review.

Myeloid/lymphoid neoplasm with t(8;22)(p11.2;q11.2)/BCR-FGFR1 is an extremely rare diagnosis, with few reported cases to date. In contrast to other FGFR1-partner rearrangements that are associated with chronic eosinophilic leukemia, acute myeloid leukemia, and/or lymphoblastic lymphoma, patients with BCR-FGFR1 have a myeloproliferative disorder that closely resembles chronic myeloid leukemia (CML). The current report describes a rare case of a 61 year old man with an atypical CML phenotype associated with t(8;22)(p11.2;q11.2)/BCR-FGFR1. A literature review is presented to enhance the awareness of this rare diagnostic entity.

Dural Extranodal Marginal Zone Lymphoma in an XRCC2 Mutation Carrier.

Dural extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is a rare entity without an associated recurrent genetic abnormality. Only one case has been described in a woman with history of breast carcinoma without a known genetic predisposition. Here, we report a case of a 56-year-old woman heterozygous for XRCC2 mutation with a history of Graves' disease and bilateral breast carcinomas, who was found to have a diffusely infiltrative extra-axial mass in the high parietal convexity with infiltration into the adjacent superior sagittal sinus. The morphologic, immunophenotypic, and molecular findings were diagnostic of MALT lymphoma. Staging bone marrow demonstrated involvement by the neoplasm. Although the study was limited to only the clinically significant laboratory evaluation, it may serve as an important addition to the current knowledge of the pathogenic potential of a loss of function mutation in this rarely reported cancer predisposition gene.

Detection of a cryptic NUP214/ABL1 gene fusion by mate-pair sequencing (MPseq) in a newly diagnosed case of pediatric T-lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm involving the bone marrow and blood that accounts for ∼15% of childhood and 25% of adult ALL. Whereas multiple, recurrent genetic abnormalities have been described in T-ALL, their clinical significance is unclear or controversial. Importantly, ABL1 rearrangements, most commonly described in BCR/ABL1-positive B-ALL and BCR-ABL1-like B-ALL, have been observed in T-ALL and may respond to tyrosine kinase inhibitor (TKI) therapy. We describe a newly diagnosed case of pediatric T-ALL with a fluorescence in situ hybridization abnormality suggesting a partial ABL1 deletion by a BCR/ABL1 dual-color dual-fusion probe but that demonstrated a normal result using an ABL1 break-apart probe. Mate-pair sequencing (MPseq), a next-generation sequencing (NGS)-based technology utilized to detect copy number and structural abnormalities with high resolution and precision throughout the genome, was performed and revealed a NUP214/ABL1 gene fusion that has been demonstrated to be sensitive to TKI therapy. This case demonstrates the power of MPseq to resolve chromosomal abnormalities unappreciable by traditional cytogenetic methodologies and highlights the clinical value of this novel NGS-based technology.

Eomes+T-betlow CD8+ T Cells Are Functionally Impaired and Are Associated with Poor Clinical Outcome in Patients with Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a devastating blood cancer with poor prognosis. Immunotherapy targeting inhibitory pathways to unleash the antileukemia T-cell response is a promising strategy for the treatment of leukemia, but we must first understand the underlying molecular mechanisms. Eomesodermin (Eomes) and T-bet are both T-box transcription factors that regulate CD8+ T-cell responses in a context-specific manner. Here, we examined the role of these transcription factors in CD8+ T-cell immunity in AML patients. We report that the frequency of Eomes+T-betlow CD8+ T cells increased in newly diagnosed AML. This cell subset produced fewer cytokines and displayed reduced killing capacity, whereas depletion of Eomes by siRNA reversed these functional defects. Furthermore, Eomes bound the promoter of T-cell immunoglobulin and ITIM domain (TIGIT) and positively regulated the expression of this inhibitory receptor on patient-derived T cells. A high frequency of Eomes+T-betlow CD8+ T cells was associated with poor response to induction chemotherapy and shorter overall survival in AML patients. These findings have significant clinical implications as they not only identify a predictive and prognostic biomarker for AML, but they also provide an important target for effective leukemia therapeutics. SIGNIFICANCE: These findings reveal that a high frequency of Eomes+T-betlow CD8+ T cells predicts poor clinical outcome in AML and that targeting Eomes may provide a therapeutic benefit against AML.

Florid splenic γ/δ T-cell proliferation in patients with splenomegaly and cytopenias: a "high stakes" diagnostic challenge.

Splenic γ/δ T-cell proliferation is rare, and correct diagnosis is critical for adequate clinical management. Two splenectomy cases from patients with splenomegaly and cytopenias were studied by morphological evaluation, extensive immunophenotyping, FISH and molecular studies. The clinicopathologic findings were compared with splenic T γ/δ neoplasia, notably hepatosplenic T-cell lymphoma (HSTL) and T-cell large granular lymphocytic leukemia (TLGL) of the variety T γ/δ. The enlarged spleens showed expanded red pulp with markedly increased γ/δ T cells, which share significant to complete overlapping morphology and immunophenotype with the neoplastic γ/δ T cells in HSTL and γ/δ TLGL. However, they were polyclonal by molecular study and showed no evidence of isochromosome 7q. Splenectomy alone led to long-term clinical remission in both patients. Two florid reactive splenic γ/δ T-cell proliferations mimicking γ/δ T-cell neoplasia were reported for the first time in English literature. Recognition of this exceedingly rare phenomenon is critical in prevention of misdiagnosis with potentially catastrophic consequences.

Orbital Epstein-Barr Virus-Positive Polymorphic B-Cell Lymphoproliferative Disorder in an Apparently Immunocompetent Woman.

We report a rare case of Epstein-Barr virus (EBV)-positive polymorphic B-cell lymphoproliferative disorder (LPD) involving the lacrimal gland of a 28-year-old, apparently immunocompetent woman. She presented with a chief complaint of orbital swelling and tenderness and was found to have a lesion involving the right lacrimal gland and distal superior and lateral rectus muscles. Histology of the lesion revealed histiocytes with pleomorphic nuclei, reactive lymphocytes, and scattered cells that resembled the Reed-Sternberg (R-S) cells of classical Hodgkin lymphoma. The R-S-like cells were positive for PAX5 and CD30 and negative for CD15, supporting a diagnosis of polymorphic B-cell LPD. In situ hybridization for EBV-encoded RNA demonstrated the presence of EBV. Most EBV-positive polymorphic B-cell LPDs are associated with immunodeficiency. However, the patient described is HIV-negative and has no identifiable defects in immunoglobulin levels or cell-mediated immunity. This raises the question of whether she has an underlying immunodeficiency resulting from subtle changes in T-cell physiology, or whether chronic EBV infection contributed to her immune dysfunction through an unclear mechanism. The orbital mass partially regressed with chemotherapy, and the patient has done well clinically with no recurrence of this EBV-LPD for over 2 years.

Clinical Implications of CD30 Expression in Aggressive B-Cell Lymphomas.

BACKGROUND: US Food and Drug Administration approval of brentuximab vedotin for treatment of CD30-positive relapsed/refractory lymphomas, including classical Hodgkin lymphoma and anaplastic large cell lymphoma, initiated significant interest in researching CD30 expression in other therapy-resistant or relapsed lymphomas. We evaluated CD30 expression in 116 cases of aggressive B-cell lymphomas diagnosed at Penn State Milton S. Hershey Medical Center between 2000 and 2012 with the purpose of assessing the benefit of treatment with brentuximab. PATIENTS AND METHODS: We studied CD30 expression in types of aggressive B-cell lymphomas not previously studied, including Burkitt lymphoma, high-grade (grade III) follicular lymphoma, mixed grade III follicular lymphoma/diffuse large B-cell lymphoma (DLBCL), posttransplantation lymphoproliferative disease large B-cell lymphoma, and primary mediastinal large B-cell lymphoma. RESULTS: CD30 expression was found in 37.5% of DLBCL and 46.2% of other non-DLBCL aggressive B-cell lymphomas. CONCLUSION: Expression of CD30 in patients with both DLBCL and other aggressive B-cell lymphomas and the absence of MYC oncogene-driven proliferation in the majority of these tumors suggests that brentuximab may be a particularly effective form of targeted therapy in the subset of patients with high CD30 expression.

Cutaneous involvement in multiple myeloma (MM): A case series with clinicopathologic correlation.

BACKGROUND: Disease-specific skin lesions are rare in patients with multiple myeloma (MM). OBJECTIVE: We sought to further characterize the clinical and pathologic features of patients with cutaneous involvement with MM. METHODS: We identified 13 patients with cutaneous lesions of MM. RESULTS: Cutaneous lesions consisted of pink, red, and violaceous papules, nodules, and/or plaques that varied in size. Histopathology revealed atypical plasma cells with occasional plasmablastic features. MM had aggressive biologic features and was at an advanced stage in the majority of patients. Despite aggressive management, including chemotherapy and stem-cell transplantation, most patients died of progressive disease within a few months after the development of cutaneous lesions. LIMITATIONS: The study group was relatively small. CONCLUSIONS: Cutaneous involvement with MM is associated with aggressive biologic behavior and short survival.

Expression of S100 Protein in CD4-positive T-cell Lymphomas Is Often Associated With T-cell Prolymphocytic Leukemia.

S100 T-cell lymphomas are infrequent, and except 1 all have been CD4 negative. On the basis of an index case of CD4 S100 T-cell prolymphocytic leukemia (T-PLL), we studied S100 protein expression in 19 additional T-PLLs and 56 other T-cell lymphomas that are usually CD4, including 15 angioimmunoblastic T-cell lymphomas, 24 anaplastic large cell lymphomas (16 ALK and 8 ALK), 7 mycosis fungoides/Sézary syndrome, and 10 peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS). Two additional S100 CD4 PTCL, NOS cases were also reviewed. Thirty percent (6/20) of T-PLLs were S100 compared with 0/56 other T-cell lymphomas with previously unstudied S100 reactivity (40 CD4, 2 CD8, 11 CD4/CD8, 3 unknown) (P=0.0007). There were no significant differences between the S100 and S100 T-PLLs with regard to the male:female ratio (2:1 vs. 1:1), age (71.6±7.7 vs. 65.4±9.3), peripheral blood lymphocyte count (67.2±116.6 vs. 101.1±159.7×10/L), or median survival (463 vs. 578 d, where known). The 2 S100 PTCL, NOS cases occurred in a 7-year-old boy and a 45-year-old woman. Both had involvement of the bone marrow and peripheral blood but were morphologically unlike T-PLL and lacked TCL1 gene rearrangement. These results demonstrate that S100 T-cell lymphomas include a subset that are CD4 and most often, but not exclusively, are T-PLL. Although having diagnostic implications, there were no documented clinical differences between the S100 and S100 T-PLLs.

Gamma-delta T-cell lymphoma arising in a long-standing cutaneous plaque.

The precise classification and characterization of primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) has been hindered by clinical and morphologic features that overlap with other lymphomas, especially subcutaneous panniculitis-like T cell lymphoma (SPTCL). The recent World Health Organization/European Organization for Research and Treatment of Cancer (WHO/EORTC) classification distinguishes the more aggressive PCGD-TCL from the usually indolent SPTCL, however. We report a 30-year-old woman with an indurated violaceous plaque on the left cheek that had been present for several years. Biopsies showed a dense lymphocytic infiltrate involving the subcutis and dermis that consisted mostly of small and medium-sized lymphocytes, some with irregular nuclear contours and dense chromatin. These cells were positive for TIA-1, TCR-gamma and CD8, but negative for beta-F1 and granzyme-B. Staging with positron emission tomography-computed tomography (PET/CT), CBC and bone marrow with flow cytometry identified lymphadenopathy as well as blood and marrow involvement by an abnormal TCRgd-positive T-cell proliferation (Ann Arbor Stage IV). The patient's history of a long-standing lesion in this case is unusual, in that gamma-delta T-cell lymphomas are typically rapidly progressive neoplasms. As such, it raises the possibility of 'transformation' of a long-standing inflammatory process into an overt lymphoma.

Epstein-barr virus-associated extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT Lymphoma) arising in the parotid gland of a child with ataxia telangiectasia.

Hematologic malignancies, in particular T-cell lymphomas/leukemias, are prevalent in patients with ataxia telangiectasia (AT), with most reported cases being clinically aggressive and high grade. Epstein-Barr virus (EBV) is often associated with lymphoid proliferations/neoplasms arising in immunodeficient patients. Reports of low-grade B-cell neoplasms in the ataxia telangiectasia population are extremely rare. Here, we describe a case of EBV-associated extranodal marginal zone lymphoma (mucosa-associated lymphoid tissue lymphoma) of the parotid gland in a 16-year-old boy with AT. In addition, we review the literature of hematologic malignancies in the AT population as well as the occurrence of EBV in mucosa-associated lymphoid tissue lymphoma.

Delay in the administration of all-trans retinoic acid and its effects on early mortality in acute promyelocytic leukemia: final results of a multicentric study in the United States.

Early death (ED) occurs in 10-30% of patients with acute promyelocytic leukemia (APL). Is all-trans retinoic acid (ATRA) promptly given and does it decrease overall early mortality? ATRA was administered within 24h of morphological suspicion in only 44% of the 120 consecutive patients treated in the four collaborating centers. Absence of disseminated intravascular coagulation (p=0.012) and admission to a non-university-affiliated hospital (p=0.032) were independent predictors of ATRA delay. ED occurred in 17% of patients, and was independently correlated only with ICU admission (p=0.002). Our results do not demonstrate that prompt (versus delayed) ATRA administration decreases overall early death.

High-grade fever and pancytopenia in an adult patient with common variable immune deficiency.

Fever of unknown origin in patients with common variable immune deficiency (CVID) can be caused by variety of infectious, autoimmune, or malignancy-related etiologies. We present a 52-year-old man with history of CVID, who presented with 3 weeks of persistent high-grade fevers. During admission, he developed severe pancytopenia with shock and multiorgan failure. An extensive workup was performed for typical and atypical infections, autoimmune pathologies, and malignancy. His peripheral blood smear showed marked anisocytosis and poikilocytosis with elevated atypical lymphocytes. Flow cytometry showed markedly elevated CD8 counts, with abnormal CD4/CD8 ratio. Monospot test was negative but real-time polymerase chain reaction showed high Epstein-Barr virus load. Initial clinical suspicion was high for bacterial infections including pneumonia and acute sinusitis complicated by bacteremia and sepsis. Hematologic malignancy was also high on the differentials because of presence of rapidly progressive pancytopenia. The final diagnosis in this case illustrates a rare but potentially fatal disease that can present in CVID patients with persistent fevers and pancytopenia and can be refractory to standard treatment regimen. Because allergy and immunology physicians commonly treat CVID patients, they should be aware of this disease condition including pathophysiology, clinical presentation, laboratory workup, and treatment options.

TP53 pathway analysis in paediatric Burkitt lymphoma reveals increased MDM4 expression as the only TP53 pathway abnormality detected in a subset of cases.

The TP53 (p53) pathway can be inhibited by TP53 mutation or deletion or by MDM2 overexpression. Both occur in Burkitt lymphoma (BL), but many cases lack either abnormality. Expression patterns of the TP53 inhibitor MDM4 have not been reported in BL, and increased MDM4 could deregulate the TP53 pathway in cases without TP53 or MDM2 abnormalities. We investigated TP53 pathway disruption in paediatric BL patient samples (n = 30) by studying MDM4, MDM2, and CDKN1A (p21) protein and mRNA expression; TP53 mutations; TP53 protein expression; and gene copy number abnormalities. MDM4 protein was expressed in 30/30 tumours, and MDM2 protein was weakly expressed in 7/30 (23%). All cases were negative for CDKN1A protein, and CDKN1A mRNA levels were decreased. TP53 mutations were detected in 5/28 (18%) cases and confirmed by sequencing. TP53 protein was expressed in 15/30 (50%) cases, including 7/8 with TP53 genetic alterations. MDM2 protein and mRNA expression levels did not correlate with lack of TP53 genetic changes or TP53 protein expression; however, there was an inverse relationship between detectable TP53 protein expression and MDM4 copy number gains and mRNA expression. The TP53 pathway is deregulated in paediatric BL cases, and increased MDM4 expression may be the primary mechanism in some cases.

Genome wide copy number analysis of paediatric Burkitt lymphoma using formalin-fixed tissues reveals a subset with gain of chromosome 13q and corresponding miRNA over expression.

The majority of paediatric Burkitt lymphoma (pBL) patients that relapse will die of disease, but markers for this high-risk subset are unknown. MYC translocations characterize pBL, but additional genetic changes may relate to prognosis and serve as potential biomarkers. We utilized a molecular inversion probe single nucleotide polymorphism assay to perform high resolution, genome-wide copy number analysis on archival formalin-fixed, paraffin-embedded pBL and germline tissues. We identified copy number abnormalities (CNAs) in 18/28 patients (64%) with a total of 62 CNAs that included 32 gains and 30 copy number losses. We identified seven recurrent CNAs including 1q gain (7/28, 25%), 13q gain (3/28, 11%), and 17p loss (4/28, 14%). The minimum common amplified region on 13q was at 13q31 and included the MIR17HG (MIR17-92) locus. Samples with this gain had higher levels of MIR17 RNA and showed a tendency for early relapse. Tumour-specific uniparental disomy was identified in 32% of cases and usually was recurrent. These results demonstrate that high-resolution copy number analysis can be performed on archival lymphoma tissue specimens, which has significance for the study of rare diseases.