Gene Summary

Gene:TNFRSF8; tumor necrosis factor receptor superfamily, member 8
Aliases: CD30, Ki-1, D1S166E
Summary:The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is expressed by activated, but not by resting, T and B cells. TRAF2 and TRAF5 can interact with this receptor, and mediate the signal transduction that leads to the activation of NF-kappaB. This receptor is a positive regulator of apoptosis, and also has been shown to limit the proliferative potential of autoreactive CD8 effector T cells and protect the body against autoimmunity. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:tumor necrosis factor receptor superfamily member 8
Source:NCBIAccessed: 06 August, 2015


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TNFRSF8 (cancer-related)

Boddicker RL, Kip NS, Xing X, et al.
The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma.
Blood. 2015; 125(20):3118-27 [PubMed] Article available free on PMC after 14/05/2016 Related Publications
Peripheral T-cell lymphomas (PTCLs) are generally aggressive non-Hodgkin lymphomas with poor overall survival rates following standard therapy. One-third of PTCLs express interferon regulatory factor-4 (IRF4), a tightly regulated transcription factor involved in lymphocyte growth and differentiation. IRF4 drives tumor growth in several lymphoid malignancies and has been proposed as a candidate therapeutic target. Because direct IRF4 inhibitors are not clinically available, we sought to characterize the mechanism by which IRF4 expression is regulated in PTCLs. We demonstrated that IRF4 is constitutively expressed in PTCL cells and drives Myc expression and proliferation. Using an inhibitor screen, we identified nuclear factor κB (NF-κB) as a candidate regulator of IRF4 expression and cell proliferation. We then demonstrated that the NF-κB subunits p52 and RelB were transcriptional activators of IRF4. Further analysis showed that activation of CD30 promotes p52 and RelB activity and subsequent IRF4 expression. Finally, we showed that IRF4 transcriptionally regulates CD30 expression. Taken together, these data demonstrate a novel positive feedback loop involving CD30, NF-κB, and IRF4; further evidence for this mechanism was demonstrated in human PTCL tissue samples. Accordingly, NF-κB inhibitors may represent a clinical means to disrupt this feedback loop in IRF4-positive PTCLs.

Uccini S, Al-Jadiry MF, Scarpino S, et al.
Epstein-Barr virus-positive diffuse large B-cell lymphoma in children: a disease reminiscent of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly.
Hum Pathol. 2015; 46(5):716-24 [PubMed] Related Publications
Pediatric Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV+ DLBCL) is a rare disease in nonimmunocompromised hosts. In a review of 231 cases of malignant lymphoma (87 Hodgkin lymphoma and 144 non-Hodgkin lymphoma) occurring in Iraqi children, 7 cases (5% of NHLs) were classified as EBV+ DLBCL. Six children presented with nodal disease, and 1 presented with extranodal localization (bone). In all cases, the disease was at an advanced clinical stage (III/IV). Evidence of immunodeficiency (Evans syndrome and selective IgA deficiency) was observed in a single case. Two cases were "monomorphic" with immunoblastic histology, and 5 cases were "polymorphic" with histologic aspects reminiscent of nodular lymphocyte-predominant Hodgkin lymphoma (2 cases) and of CD30+ classical Hodgkin lymphoma (3 cases). In all cases, tumor cells were EBV infected (EBER+/LMP-1+), were medium-large B-cells (CD20+/CD79a+/PAX-5+/BOB-1+/OCT-2+) of non-germinal center (non-GC) origin (CD10-/MUM-1+), and had high proliferative activity (50%-70%). Chromosomal translocations involving BCL2, MYC, and IGH genes were not observed. IGH monoclonality could be demonstrated in 3 of 3 investigated cases. Six cases of EBV-negative DLBCL (4% of NHL) were present in the same series. All had monomorphic histology with centroblastic/immunoblastic morphology; 3 cases were of GC type and 3 of non-GC type. Our findings indicate that in Iraq, DLBCLs are 9% of NHLs. Moreover, 2 different types of the disease do exist; the EBV-positive cases, with strong histologic and immunohistochemical resemblance with EBV+ DLBCL of the elderly, and the EBV-negative cases, which are similar to the pediatric DLBCL usually observed in Western populations.

de la Garza Bravo MM, Patel KP, Loghavi S, et al.
Shared clonality in distinctive lesions of lymphomatoid papulosis and mycosis fungoides occurring in the same patients suggests a common origin.
Hum Pathol. 2015; 46(4):558-69 [PubMed] Related Publications
Lymphomatoid papulosis (LyP) lies within the spectrum of primary cutaneous CD30-positive lymphoproliferative disorders. Approximately 10% to 15% of patients with LyP develop other lymphomas, most commonly mycosis fungoides (MF), suggesting a biological relationship between these distinctive diseases. Here, we describe the clinical and histopathologic features of 11 patients who had both LyP and MF, including a total of 30 biopsy specimens (14 LyP and 16 MF). Clinically, LyP lesions were characterized by clustered papules undergoing spontaneous regression and were classified as type A (n = 11), type C (n = 2), or type D (n = 1). All cases of MF were characterized clinically by patch/plaque disease, were stage I or II at the time of diagnosis, and consisted of a CD4-predominant epidermotropic T-cell infiltrate. We used polymerase chain reaction-based methods to assess the TCR-β chain (TCRB) and TCR-γ chain (TCRG) in both LyP and MF lesions of all patients. Monoclonal TCR gene rearrangements were detected in 13 LyP lesions from 10 of 11 patients and in 14 MF lesions from 10 of 11 patients. All 10 patients in whom their skin lesions carried monoclonal TCR gene rearrangements exhibited overlapping clones in both their LyP and MF lesions; additional non-overlapping clones were identified in 3 LyP lesions from 2 patients and 1 MF lesion from another patient. The demonstration of shared monoclonal T-cell receptor gene rearrangements in LyP and MF lesions in almost all patients suggests a common origin between these distinctive clinicopathological diseases.

Brown NA, Ross CW, Gudjonsson JE, et al.
Subcutaneous panniculitis-like T-cell lymphoma with bone marrow involvement.
Am J Clin Pathol. 2015; 143(2):265-73 [PubMed] Related Publications
OBJECTIVES: To describe a rare case of subcutaneous panniculitis-like T-cell lymphoma (SPTCL) with morphologic and immunophenotypic evidence of bone marrow involvement.
METHODS: Biopsy specimens of skin and subcutis and bone marrow were examined using H&E-stained sections. Immunohistochemical studies for CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30, CD56, and granzyme B were reviewed. In addition, T-cell receptor γ gene rearrangement studies were performed.
RESULTS: A bone marrow core biopsy demonstrated several lymphohistiocytic aggregates containing atypical, cytotoxic T cells that rimmed adipocytes and were associated with karyorrhexis. These T cells were morphologically and immunophenotypically identical to a concurrent SPTCL, expressing CD2, CD3, CD7, CD8, and granzyme B but with diminished CD5 expression.
CONCLUSIONS: SPTCL may rarely involve the bone marrow. Bone marrow infiltrates show a similar morphologic and immunophenotypic appearance to those in the subcutaneous fibroadipose tissue, including rimming of adipocytes by neoplastic lymphocytes.

Nevet MJ, Zuckerman T, Sahar D, Bergman R
Transformation of Sézary syndrome into CD30+ anaplastic large T-cell lymphoma after alemtuzumab therapy with evidence of clonal unity.
Am J Dermatopathol. 2015; 37(1):73-7 [PubMed] Related Publications
Alemtuzumab is a humanized mouse antibody targeting the CD52 cell surface, which has been effective in patients with advanced stage mycosis fungoides (MF) including erythrodermic MF and Sézary syndrome. There are a few descriptions of large cell transformation after its administration. A young patient with an acute onset of Sézary syndrome treated initially unsuccessfully with fludarabine and cyclophosphamide and later on successfully with alemtuzumab has been described. Three weeks after the beginning of therapy, however, she developed transformed T-cell lymphoma indistinguishable from CD30 anaplastic large-cell lymphoma. After bone marrow transplantation, the transformed CD30 cutaneous T-cell lymphoma recurred as a transformed CD30 plaque MF. All 3 types of lesions showed the same T-cell receptor clonal gene rearrangement, which supports the notion that Sézary syndrome, CD30 anaplastic large-cell lymphoma, and MF are interrelated.

Xing X, Feldman AL
Anaplastic large cell lymphomas: ALK positive, ALK negative, and primary cutaneous.
Adv Anat Pathol. 2015; 22(1):29-49 [PubMed] Related Publications
Anaplastic large cell lymphomas (ALCLs) comprise a group of CD30-positive non-Hodgkin lymphomas that generally are of T-cell origin and share common morphologic and phenotypic characteristics. The World Health Organization recognizes 3 entities: primary cutaneous ALCL (pcALCL), anaplastic lymphoma kinase (ALK)-positive ALCL, and, provisionally, ALK-negative ALCL. Despite overlapping pathologic features, these tumors differ in clinical behavior and genetics. pcALCL presents in the skin and, while it may involve locoregional lymph nodes, rarely disseminates. Outcomes typically are excellent. ALK-positive ALCL and ALK-negative ALCL are systemic diseases. ALK-positive ALCLs consistently have chromosomal rearrangements involving the ALK gene with varied gene partners, and generally have a favorable prognosis. ALK-negative ALCLs lack ALK rearrangements and their genetic and clinical features are more variable. A subset of ALK-negative ALCLs has rearrangements in or near the DUSP22 gene and has a favorable prognosis similar to that of ALK-positive ALCL. DUSP22 rearrangements also are seen in a subset of pcALCLs. In this review, we discuss the clinical, morphologic, phenotypic, genetic, and biological features of ALCLs.

Sandoval J, Díaz-Lagares A, Salgado R, et al.
MicroRNA expression profiling and DNA methylation signature for deregulated microRNA in cutaneous T-cell lymphoma.
J Invest Dermatol. 2015; 135(4):1128-37 [PubMed] Related Publications
MicroRNAs usually regulate gene expression negatively, and aberrant expression has been involved in the development of several types of cancers. Microarray profiling of microRNA expression was performed to define a microRNA signature in a series of mycosis fungoides tumor stage (MFt, n=21) and CD30+ primary cutaneous anaplastic large cell lymphoma (CD30+ cALCL, n=11) samples in comparison with inflammatory dermatoses (ID, n=5). Supervised clustering confirmed a distinctive microRNA profile for cutaneous T-cell lymphoma (CTCL) with respect to ID. A 40 microRNA signature was found in MFt including upregulated onco-microRNAs (miR-146a, miR-142-3p/5p, miR-21, miR-181a/b, and miR-155) and downregulated tumor-suppressor microRNAs (miR-200ab/429 cluster, miR-10b, miR-193b, miR-141/200c, and miR-23b/27b). Regarding CD30+ cALCL, 39 differentially expressed microRNAs were identified. Particularly, overexpression of miR-155, miR-21, or miR-142-3p/5p and downregulation of the miR-141/200c clusters were observed. DNA methylation in microRNA gene promoters, as expression regulatory mechanism for deregulated microRNAs, was analyzed using Infinium 450K array and approximately one-third of the differentially expressed microRNAs showed significant DNA methylation differences. Two different microRNA methylation signatures for MFt and CD30+ cALCL were found. Correlation analysis showed an inverse relationship for microRNA promoter methylation and microRNA expression. These results reveal a subgroup-specific epigenetically regulated microRNA signatures for MFt and CD30+ cALCL patients.

Velusamy T, Kiel MJ, Sahasrabuddhe AA, et al.
A novel recurrent NPM1-TYK2 gene fusion in cutaneous CD30-positive lymphoproliferative disorders.
Blood. 2014; 124(25):3768-71 [PubMed] Related Publications
The spectrum of cutaneous CD30-positive lymphoproliferative disorders (LPDs) includes lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Chromosomal translocations targeting tyrosine kinases in CD30-positive LPDs have not been described. Using whole-transcriptome sequencing, we identified a chimeric fusion involving NPM1 (5q35) and TYK2 (19p13) that encodes an NPM1-TYK2 protein containing the oligomerization domain of NPM1 and an intact catalytic domain in TYK2. Fluorescence in situ hybridization revealed NPM1-TYK2 fusions in 2 of 47 (4%) primary cases of CD30-positive LPDs and was absent in other mature T-cell neoplasms (n = 151). Functionally, NPM1-TYK2 induced constitutive TYK2, signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activation. Conversely, a kinase-defective NPM1-TYK2 mutant abrogated STAT1/3/5 signaling. Finally, short hairpin RNA-mediated silencing of TYK2 abrogated lymphoma cell growth. This is the first report of recurrent translocations involving TYK2, and it highlights the novel therapeutic opportunities in the treatment of CD30-positive LPDs with TYK2 translocations.

Bossard C, Dobay MP, Parrens M, et al.
Immunohistochemistry as a valuable tool to assess CD30 expression in peripheral T-cell lymphomas: high correlation with mRNA levels.
Blood. 2014; 124(19):2983-6 [PubMed] Related Publications
The extended use of brentuximab-vedotin was reported for CD30(+) nonanaplastic peripheral T-cell lymphomas (PTCLs) with promising efficacy. CD30 status assessment is thus a critical factor for therapeutic decision, but the reliability of immunohistochemistry (IHC) in evaluating its expression remains to be defined. This prompted us to investigate the correlation between semiquantitative CD30 protein assessment by IHC and messenger RNA (mRNA) assessment by microarrays in a cohort of 376 noncutaneous PTCLs representative of the main entities. By IHC, CD30 expression was heterogeneous across and within entities and significantly associated with large tumor cell size. In addition to 100% anaplastic large-cell lymphomas, 57% of other PTCL entities were CD30-positive at a 5% threshold. CD30 protein expression was highly correlated to mRNA levels. mRNA levels were bimodal, separating high from low CD30-expressing PTCL cases. We conclude that IHC is a valuable tool in clinical practice to assess CD30 expression in PTCLs.

Jiang X, Yin W, Song J, et al.
Primary central nervous system extranodal NK/T cell lymphoma, nasal type, with antecedent hemophagocytic syndrome in a child.
Pediatr Dev Pathol. 2014 Nov-Dec; 17(6):482-6 [PubMed] Related Publications
Primary central nervous system (CNS) extranodal natural killer (NK)/T-cell lymphoma, nasal type (NKTCL), is an exceedingly uncommon entity. Here, we present a case of CNS NKTCL that manifested initially as hemophagocytic syndrome 4 months earlier in a 13-year-old girl. Histological examination revealed the cerebellum mass was composed of large-sized and atypical tumor cells, with an angiocentric and angiodestructive growth pattern and prominent necrosis. The tumor cells exhibited marked pleomorphism with conspicuous nucleoli and prominent mitotic activity. Immunohistochemical staining showed the tumor cells were positive for CD45, CD2, CD3ε, CD30, CD43, CD56, and granzyme B. Epstein-Barr virus--encoded ribonucleic acid was expressed in almost all of the nuclei of the lymphoma cells. The T-cell receptor γ chain gene rearrangement study showed no evidence of a clonal rearrangement. The patient was treated with etoposide and dexamethasone and died a few days after the operation. As far as we know, this case is the 1st pediatric and female patient of primary CNS NKTCL with antecedent hemophagocytic syndrome, which highlights the clinical data and is helpful for the diagnosis of this tumor.

Takata K, Hong ME, Sitthinamsuwan P, et al.
Primary cutaneous NK/T-cell lymphoma, nasal type and CD56-positive peripheral T-cell lymphoma: a cellular lineage and clinicopathologic study of 60 patients from Asia.
Am J Surg Pathol. 2015; 39(1):1-12 [PubMed] Related Publications
Primary cutaneous, extranodal natural killer/T-cell lymphoma, nasal type (PC-ENKTL), is a rare Epstein-Barr virus (EBV)-associated neoplasm with poorly defined clinicopathologic features. We performed a multinational retrospective study of PC-ENKTL and CD56-positive EBV-negative peripheral T-cell lymphoma (PC-CD56+PTCL) in Asia in an attempt to elucidate their clinicopathologic features. Using immunohistochemistry for T-cell receptors (TCRs), in situ hybridization for EBV, and TCR gene rearrangement, we classified 60 tumors into 51 with PC-ENKTL (20 of NK-cell, 17 T-cell, and 14 indeterminate lineages) and 9 with PC-CD56+PTCL. Tumors of T-cell origin accounted for 46% of PC-ENKTLs with half of these cases being TCR-silent. As compared with T-lineage tumors, PC-ENKTLs of NK-cell lineage had more frequent involvement of regional lymph nodes and more frequently CD8-negative and CD56-positive. Cases of PC-ENKTL showed more frequent tumor necrosis, younger age, and a higher frequency of CD16 and CD30 expression than cases of PC-CD56+PTCL. CD56-positive T-lineage PC-ENKTL tumors (n=8) had more localized disease in the TNM (tumor-node-metastasis) staging and were more often of γδ T-cell origin compared with cases of PC-CD56+PTCL (n=9). PC-ENKTLs and PC-CD56+PTCLs were equally aggressive, with a 5-year overall survival rate of 25%. Tumor necrosis and CD16 expression may serve as useful surrogates for differentiating PC-ENKTL from PC-CD56+PTCL. A single lesion, an elevated lactate dehydrogenase level, and the presence of B symptoms were independent poor prognostic factors for PC-ENKTL in multivariate analysis. Further studies with more cases are warranted to delineate the clinicopathologic features and significance of EBV in these rare lymphomas.

Atsaves V, Lekakis L, Drakos E, et al.
The oncogenic JUNB/CD30 axis contributes to cell cycle deregulation in ALK+ anaplastic large cell lymphoma.
Br J Haematol. 2014; 167(4):514-23 [PubMed] Related Publications
Anaplastic lymphoma kinase (ALK)+ anaplastic large cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35) resulting in expression of NPM1(NPM)-ALK oncogenic kinase. The latter is capable of activating ERK kinase, which upregulates JUNB expression through ETS1. JUNB, in turn, interacts with the TNFRSF8 (CD30) gene promoter and induces CD30 (TNFRSF8) overexpression. However, the role of CD30 overexpression in ALK+ ALCL oncogenesis remains unknown. Here we show that the JUNB gene is frequently amplified in ALK+ ALCL, suggesting gene amplification as an additional underlying mechanism for JUNB overexpression. Silencing of JUNB resulted in reduced cell growth and colony formation associated with decreased activator protein-1 activity and G1/S and G2/M cell cycle arrest. These effects were linked to decreased CD30 levels, downregulation of CCNA2 (Cyclin A), CCND2 (Cyclin D2) and CCND3 (Cyclin D3) and upregulation of cyclin-dependent kinase inhibitors CDKN2A (p14) and CDKN1A (p21), but not CDKN1B (p27). Similar cell cycle changes were observed following the knock-down of TNFRSF8 gene or blockade of its function using anti-CD30 antibodies, which were associated with upregulation of CDKN2A and CDKN1A, but not CDKN1B. These findings indicate that JUNB may partly operate through CD30 signalling. Silencing of JUNB also sensitized NPM1-ALCL+ cells to standard chemotherapeutic agents. Our findings uncover the oncogenic role of the JUNB/CD30 axis and its potential as therapeutic target in ALK+ ALCL.

Slack GW, Steidl C, Sehn LH, Gascoyne RD
CD30 expression in de novo diffuse large B-cell lymphoma: a population-based study from British Columbia.
Br J Haematol. 2014; 167(5):608-17 [PubMed] Related Publications
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with variable therapeutic responses and alternative therapies are needed for patients with unfavourable treatment outcomes after standard treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). One promising candidate is brentuximab vedotin, an antibody-drug conjugate targeting CD30-expressing cells. However, CD30 (TNFRSF8) expression patterns in DLBCL are not well described thus far. Here, we examined CD30 expression in a population-based cohort of immunocompetent patients from British Columbia with de novo DLBCL using immunohistochemistry. 385 cases of formalin-fixed paraffin-embedded DLBCL in tissue microarrays were evaluated. 95 cases (25%) harboured CD30+ tumour cells. Using a > 0% cut-off, CD30 expression was predictive of superior 5-year progression-free survival within R-CHOP treated germinal centre B-cell-like (GCB) DLBCL (86% vs. 64%, P = 0·020), which was independent of the International Prognostic Index. Epstein-Barr virus (EBV) was identified in 11 (3%) cases, all of which were non-GCB (P = 0·001) and almost exclusively positive for CD30 expression (10/11) (P < 0·001). We conclude CD30 is expressed in a substantial proportion of DLBCL and CD30 immunohistochemistry may be a useful prognostic marker in R-CHOP treated GCB-DLBCL. The significant association of CD30 with EBV-positive non-GCB DLBCL suggests a distinct pathobiology for these cases.

Mehrotra M, Medeiros LJ, Luthra R, et al.
Identification of putative pathogenic microRNA and its downstream targets in anaplastic lymphoma kinase-negative anaplastic large cell lymphoma.
Hum Pathol. 2014; 45(10):1995-2005 [PubMed] Related Publications
Anaplastic large cell lymphomas (ALCL) are tumors of T/null-cell lineage characterized by uniform CD30 expression. The 2008 World Health Organization classification subdivided ALCLs into 2 groups: anaplastic lymphoma kinase (ALK)-positive (established entity) and ALK-negative (proposed new entity) ALCL. The genetic basis for the pathogenesis of newly categorized ALK- ALCL is poorly understood. In this study, we used microRNA microarray analysis to identify differentially expressed microRNAs in ALK+ and ALK- ALCL. ALK- ALCL showed significantly higher expression of miR-155 (0.888 ± 0.228) compared with ALK+ ALCL (0.0565 ± 0.009) on microarray and by quantitative real-time polymerase chain reaction in ALK- ALCL compared with ALK+ ALCL (P < .05) with a strong correlation between the 2 platforms (R = 0.9, P < .0003). A novel in situ hybridization method allows direct visualization of expression patterns and relative quantitation of miR-155 (mean score, 2.3 versus 1.3; P = .01) for the first time in tissue sections of ALCL. Among computationally predicted targets of miR-155, we identified ZNF652 (r = -0.57, P = .05), BACH1 (r = 0.88, P = .02), RBAK (r = 0.81, P = .05), TRIM32 (r = 0.92, P = .01), E2F2 (r = 0.81, P = .05), and TP53INP1 (r = -0.31, P = .03) as genes whose expression by quantitative real-time polymerase chain reaction correlated significantly with the level of miR-155 in ALCL tumor tissue.

Shaver AC, Ma L, Vnencak-Jones C, et al.
Transformation of small B-cell lymphoma into large cell CD30⁺, CD4⁺, Epstein-Barr virus-negative lymphoma.
Arch Pathol Lab Med. 2014; 138(8):1101-5 [PubMed] Related Publications
We report here 2 separate cases in which patients with known low-grade B-cell lymphomas presented with transformed lesions that were CD30⁺, CD4⁺, Epstein-Barr virus negative, and negative or focally weak for a wide range of B-cell, T-cell, and histiocytic/dendritic cell markers. In each case the transformed lymphoma possessed an identical pattern of immunoglobulin heavy chain and/or BCL2 rearrangement to the corresponding original low-grade B-cell lymphoma, confirming their identity as transformed B-cell lymphoma. A review of the relevant literature reveals that, to our knowledge, no transformed B-cell lymphomas with this immunophenotype have been previously reported, which creates the opportunity for potential errors of diagnosis. These cases highlight the importance of correlation with the patient's history and with molecular genetic results in rendering an accurate diagnosis.

Choe JY, Bisig B, de Leval L, Jeon YK
Primary γδ T cell lymphoma of the lung: report of a case with features suggesting derivation from intraepithelial γδ T lymphocytes.
Virchows Arch. 2014; 465(6):731-6 [PubMed] Related Publications
T cell lymphoma of γδ T cell origin is a rare disease that mainly involves extranodal sites and shows aggressive clinical behavior. Here, we report a case of primary γδ T cell lymphoma of the lungs with epitheliotropism in the respiratory epithelium, a feature somewhat reminiscent of what is observed in enteropathy-associated T cell lymphoma. A 63-year-old man presented with chest pain and dyspnea on exertion, weight loss, and general weakness. On a positron emission tomography (PET) scan, multiple hypermetabolic lesions were found in both lungs. Microscopic examination of the wedge lung biopsy revealed nodular infiltration of monomorphic, medium- to large-sized atypical lymphocytes with round nuclei, coarse chromatin, and a variable amount of clear to eosinophilic cytoplasm. Of note, intraepithelial lymphocytosis by atypical lymphoid cells was observed in the respiratory epithelium within and around the nodule. Immunohistochemically, the tumor cells were CD3+, TCRβF1-, TCRγ+, CD5-, CD7+, CD20-, CD79a-, CD30-, CD4-, CD8-, CD10-, BCL6-, CD21-, CD56+, CD57-, and CD138-, and expressed cytotoxic molecules. Epstein-Barr virus (EBV) was not detected by an in situ hybridization assay for EBV-encoded RNA. Interestingly, CD103 was expressed by a subset of tumor cells, especially those infiltrating the epithelium. T cell clonality was detected by multiplex PCR analysis of TRG and TRD gene rearrangements. After 2 months of systemic chemotherapy, PET scan showed regression of the size and metabolic activity of the lesions. This case represents a unique γδ T cell lymphoma of the lungs showing epitheliotropism by CD103+ γδ T cells that is suggestive of tissue-resident γδ T cells as the cell of origin.

Parrilla Castellar ER, Jaffe ES, Said JW, et al.
ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes.
Blood. 2014; 124(9):1473-80 [PubMed] Article available free on PMC after 28/08/2015 Related Publications
Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a CD30-positive T-cell non-Hodgkin lymphoma that morphologically resembles ALK-positive ALCL but lacks chromosomal rearrangements of the ALK gene. The genetic and clinical heterogeneity of ALK-negative ALCL has not been delineated. We performed immunohistochemistry and fluorescence in situ hybridization on 73 ALK-negative ALCLs and 32 ALK-positive ALCLs and evaluated the associations among pathology, genetics, and clinical outcome. Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCLs, respectively. These rearrangements were mutually exclusive and were absent in ALK-positive ALCLs. Five-year overall survival rates were 85% for ALK-positive ALCLs, 90% for DUSP22-rearranged ALCLs, 17% for TP63-rearranged ALCLs, and 42% for cases lacking all 3 genetic markers (P < .0001). Hazard ratios for death in these 4 groups after adjusting for International Prognostic Index and age were 1.0 (reference group), 0.58, 8.63, and 4.16, respectively (P = 7.10 × 10(-5)). These results were similar when restricted to patients receiving anthracycline-based chemotherapy, as well as to patients not receiving stem cell transplantation. Thus, ALK-negative ALCL is a genetically heterogeneous disease with widely disparate outcomes following standard therapy. DUSP22 and TP63 rearrangements may serve as predictive biomarkers to help guide patient management.

Xu J, Wei S
Breast implant-associated anaplastic large cell lymphoma: review of a distinct clinicopathologic entity.
Arch Pathol Lab Med. 2014; 138(6):842-6 [PubMed] Related Publications
Primary breast anaplastic large cell lymphoma (ALCL) is rare but is more commonly seen in patients with implants; fewer than 50 cases of breast implant-associated ALCL have been reported in the English language literature. Breast implant-associated ALCL is not a disease of the breast parenchyma, but instead is a disease of the fibrous capsule surrounding the implant. The patients usually present with an effusion around the implant and, rarely, with a solid mass. Morphologically, the neoplastic cells are large, epithelioid, and pleomorphic, with abundant cytoplasm, vesicular irregular nuclei, and frequent mitoses. Occasional "hallmark" cells may be present. The lesional cells typically show strong and diffuse immunoreactivity for CD30 and often express T-cell markers, cytotoxic-associated antigens, and epithelial membrane antigen. Almost all reported cases are negative for anaplastic lymphoma kinase. Molecular genetic analyses have demonstrated T-cell receptor gene rearrangements. The differential diagnosis essentially includes poorly differentiated carcinoma, other lymphomas, and chronic inflammation. Once a diagnosis of lymphoma is established, it is important to exclude systemic anaplastic lymphoma kinase-negative ALCL involving the breast, primary cutaneous ALCL, and other CD30(+) lymphoproliferative disorders. The patients with effusion-associated ALCL often have an indolent course and excellent prognosis, responding well to excision of the fibrous capsule around the implant (capsulectomy) and implant removal. In contrast, patients who present with a distinct mass may have a more aggressive course and poor prognosis, requiring chemotherapy and/or radiation therapy.

Kempf W, Kazakov DV, Rütten A, et al.
Primary cutaneous follicle center lymphoma with diffuse CD30 expression: a report of 4 cases of a rare variant.
J Am Acad Dermatol. 2014; 71(3):548-54 [PubMed] Related Publications
BACKGROUND: CD30 is expressed in aggressive and Epstein-Barr virus-associated forms of B-cell non-Hodgkin lymphomas, but is rarely expressed by the majority of tumor cells in primary cutaneous B-cell lymphomas (CBCLs). The expression of CD30 in CBCLs may be at risk for misinterpretation as an unequivocal indicator of a highly aggressive form of the disease.
OBJECTIVE: We report 4 cases of low malignant primary cutaneous follicle center lymphoma (PCFCL) with diffuse and strong expression of CD30 by the majority of neoplastic cells.
RESULTS: The patients included 3 men and 1 woman with tumors on the scalp (3 patients) and chest wall (1 patient). The histologic examinations revealed a mixed, diffuse, and follicular growth pattern with CD20(+), bcl-6(+), and bcl-2(-) tumor cells. Seventy percent to 90% of the tumor cells expressed CD30. Clonal rearrangement of immunoglobulin heavy chain genes was found in 1 of 4 cases. None of the 3 cases yielded positivity for Epstein-Barr virus RNA.
LIMITATIONS: The study is limited by the small number of patients.
CONCLUSIONS: This rare variant of CD30(+) PCFCL needs be distinguished from CD30(+) aggressive B-cell lymphomas. CD30 in this variant of CBCLs may serve as a therapeutic target for anti-CD30 antibody-based strategies.

Eyre TA, Khan D, Hall GW, Collins GP
Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma: current and future perspectives in adult and paediatric disease.
Eur J Haematol. 2014; 93(6):455-68 [PubMed] Related Publications
Anaplastic large cell lymphoma (ALCL) is a rare T-cell lymphoma seen in both adults and children. ALCL is associated with a characteristic chromosomal translocation, t(2;5)(p23;35) which fuses the anaplastic lymphoma kinase (ALK) gene on chromosome 2 with the nucleophosmin (NPM) gene on chromosome 5, resulting in a NPM-ALK fusion protein, ALK over-expression and constitutive tyrosine kinase activity. This aggressive lymphoma is more prevalent in males and can present with extranodal involvement (lung, skin and marrow infiltration) and haemophagocytic lymphohistocytosis. The long-term overall survival is approximately 70-90% in children and over 70% in adults. Staging systems and prognostic risk factors are different in both childhood and adult ALCL. Treatment in adults is typically anthracycline-based, with autologous stem cell transplantation (ASCT) salvaging patients in relapsed disease. There is evidence for ALL-like therapy or intensive, pulsed anthracycline-based induction in children. ASCT, allogeneic SCT and vinblastine maintenance are all considered reasonable options in relapsed childhood disease. The anti-CD30 immunoconjugate Brentuximab Vedotin and the specific ALK inhibitor Crizotinib are changing the treatment paradigm in ALCL (ALK-positive or negative) and ALK-positive ALCL respectively. Both agents have shown encouraging responses in relapsed ALCL. It remains to be seen how these novel agents are used, but it is very possible that they may improve overall responses and survival in both children and adults. This review highlights the presentation, histopathological features, prognostic factors, and evidence-based treatment approaches in the first line and relapsed setting in ALK-positive ALCL. The review concludes by discussing the novel approaches using Brentuximab and Crizotinib which are being tested in clinical trials.

Wang Y, Gu X, Zhang G, et al.
SATB1 overexpression promotes malignant T-cell proliferation in cutaneous CD30+ lymphoproliferative disease by repressing p21.
Blood. 2014; 123(22):3452-61 [PubMed] Related Publications
Cutaneous CD30(+) lymphoproliferative disease (CD30(+)LPD), characterized by the presence of CD30(+) anaplastic large T cells, comprises the second most common group of cutaneous T-cell lymphoma (CTCL). However, little is known about the pathobiology of the CD30(+) lymphoma cells, as well as the mechanisms of disease progression. Here we report that Special AT-rich region binding protein 1 (SATB1), a thymocyte specific chromatin organizer, is over-expressed in CD30(+) lymphoma cells in most CD30(+)LPDs, and its expression is upregulated during disease progression. Our findings show that SATB1 silencing in CD30(+)LPD cells leads to G1 cell cycle arrest mediated by p21 activation. Using chromatin immunoprecipitation, luciferase assays, and mutational analysis, we demonstrate that SATB1 directly regulates the transcription of p21 in a p53-independent manner. Moreover, DNA demethylation on a specific CpG-rich region of the SATB1 promoter is associated with the upregulation of SATB1 during disease progression. These experiments define a novel SATB1-p21 pathway in malignant CD30(+) T lymphocytes, which provides novel molecular insights into the pathogenesis of CD30(+)LPDs and possibly leads to new therapies.

van Anrooij B, Kluin PM, Oude Elberink JN, Kluin-Nelemans JC
CD30 in systemic mastocytosis.
Immunol Allergy Clin North Am. 2014; 34(2):341-55 [PubMed] Related Publications
CD30 is a transmembrane receptor, normally not expressed by mast cells, which regulates proliferation/apoptosis and antibody responses. Aberrant expression of CD30 by mastocytosis mast cells and interaction with its ligand CD30L (CD153) appears to play an important role in the pathogenesis and clinical presentation of systemic mastocytosis. This article highlights the expression profile and role of CD30 and CD30L in physiologic and pathologic conditions, the applicability of CD30 as a marker for systemic mastocytosis, the consequences of mast cell-expressed CD30, and the possibility of future anti-CD30 based cytoreductive therapies.

Horny HP, Sotlar K, Valent P
Mastocytosis: immunophenotypical features of the transformed mast cells are unique among hematopoietic cells.
Immunol Allergy Clin North Am. 2014; 34(2):315-21 [PubMed] Related Publications
Mastocytosis is a disease of bone marrow origin histologically characterized by compact tissue infiltrates of atypical mast cells never seen in reactive states. Most patients with mastocytosis have transformed mast cells carrying an activating point mutation at codon 816 of KIT and also show an elevated serum tryptase level. In this article immunophenotypical features of mast cells are described. Based on these features, mast cells are not closely related to other myeloid cells. Using the knowledge on aberrantly expressed antigens by mast cells, the hematopathologist should be able to recognize the disease even in the presence of unusual morphologic findings or an associated hematologic non-mast cell lineage disease.

Celegato M, Borghese C, Umezawa K, et al.
The NF-κB inhibitor DHMEQ decreases survival factors, overcomes the protective activity of microenvironment and synergizes with chemotherapy agents in classical Hodgkin lymphoma.
Cancer Lett. 2014; 349(1):26-34 [PubMed] Related Publications
The NF-κB inhibitor DHMEQ has shown preclinical activity in classical Hodgkin Lymphoma (cHL). Here we evaluated if DHMEQ could affect microenvironmental interactions and formation and improve the activity of drugs used in relapsed/refractory cHL. We demonstrated that DHMEQ down-regulated the NF-κB target genes IRF4 and CD40, the secretion of IL-6, CCL5, CCL17 and generated ROS. Cytotoxicity, CD30 down-modulation and CD30 shedding by DHMEQ were prevented by ROS scavenger NAC. DHMEQ overcame stimuli from CD40 engagement and fibroblasts and enhanced doxorubicin, cisplatin and gemcitabine activity. Our results suggest that DHMEQ may be a promising agent for future therapeutic strategies in cHL.

Szablewski V, Laurent-Roussel S, Rethers L, et al.
Atypical fibrous histiocytoma of the skin with CD30 and p80/ALK1 positivity and ALK gene rearrangement.
J Cutan Pathol. 2014; 41(9):715-9 [PubMed] Related Publications
We report the case of a two patients who presented with a solitary, asymptomatic, angiomatoid nodule on the right thigh. Histopathological finding showed a poorly circumscribed lesion, located in the dermis. The morphological aspect strongly suggested the diagnosis of atypical fibrous histiocytoma (AFH), but surprisingly, the neoplastic cells were diffusely CD30+, with a membrane staining devoid of paranuclear dot. The lesions were tested for p80/ALK1 expression. Surprisingly, we found a diffuse cytoplasmic positivity. Interestingly, using break-apart fluorescent in situ hybridization (FISH), we evidenced an ALK rearrangement in nearly 50% of the neoplastic cells. The expression of CD30 and ALK1 with ALK gene rearrangement raised the possibility of three diagnoses: a primary cutaneous anaplastic large cell lymphoma (ALCL), a cutaneous inflammatory myofibroblastic tumor (IMT), an AFH of the skin associated with ALK gene rearrangement and CD30 positivity. The three hypotheses were discussed and finally, although p80/ALK1 expression and cytogenetic abnormalities in fibrous histiocytoma (FH) are not yet reported to the best of our knowledge, we favored the diagnosis of AFH.

Döring C, Hansmann ML, Agostinelli C, et al.
A novel immunohistochemical classifier to distinguish Hodgkin lymphoma from ALK anaplastic large cell lymphoma.
Mod Pathol. 2014; 27(10):1345-54 [PubMed] Related Publications
Classical Hodgkin lymphoma and ALK(-) anaplastic large cell lymphoma share many features like strong CD30 expression and usually loss of B- and T-cell markers. However, their clinical course is dramatically different with curability rates of >90% for classical Hodgkin lymphoma and an unfavorable prognosis for anaplastic large cell lymphoma. Classical Hodgkin lymphoma and ALK(-) anaplastic large cell lymphoma can usually be distinguished by PAX5 expression in the Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma and expression of cytotoxic molecules in tumor cells of anaplastic large cell lymphoma. However, in some cases the differential diagnosis is difficult owing to absence of established markers. To be able to better classify these cases, we reevaluated gene expression data of microdissected tumor cells of both lymphomas for differentially expressed genes. A classifier was established, comprising four genes strongly expressed in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma (MDC/CCL22, CD83, STAT3, and TUBB2B). Applying this classifier to a test cohort, Hodgkin lymphoma was successfully distinguished from ALK(-) anaplastic large cell lymphoma with an accuracy of 97% (43/44). MDC/CCL22, CD83, and STAT3 have also been found to be expressed in antigen-presenting cells. Therefore, based on our established classifier, Hodgkin and Reed-Sternberg cells differ from tumor cells of anaplastic large cell lymphoma, which can successfully be applied for practical purposes in histopathologic diagnostics.

Somja J, Bisig B, Bonnet C, et al.
Peripheral T-cell lymphoma with t(6;14)(p25;q11.2) translocation presenting with massive splenomegaly.
Virchows Arch. 2014; 464(6):735-41 [PubMed] Related Publications
Recurrent chromosomal translocations associated to peripheral T-cell lymphomas (PTCL) are rare. Here, we report a case of PTCL, not otherwise specified (NOS) with the karyotype 46,Y,add(X)(p22),t(6;14)(p25;q11) and FISH-proved breakpoints in the IRF4 and TCRAD loci, leading to juxtaposition of both genes. A 64-year-old male patient presented with mild cytopenias and massive splenomegaly. Splenectomy showed diffuse red pulp involvement by a pleomorphic medium- to large-cell T-cell lymphoma with a CD2+ CD3+ CD5- CD7- CD4+ CD8+/- CD30- TCRbeta-F1+ immunophenotype, an activated cytotoxic profile, and strong MUM1 expression. The clinical course was marked by disease progression in the bone marrow under treatment and death at 4 months. In contrast with two t(6;14)(p25;q11.2)-positive lymphomas previously reported to be cytotoxic PTCL, NOS with bone marrow and skin involvement, this case was manifested by massive splenomegaly, expanding the clinical spectrum of PTCLs harboring t(6;14)(p25;q11.2) and supporting consideration of this translocation as a marker of biological aggressiveness.

Kumar A, Younes A
Role of CD30 targeting in malignant lymphoma.
Curr Treat Options Oncol. 2014; 15(2):210-25 [PubMed] Related Publications
CD30 is an important therapeutic target for the treatment of malignant lymphomas. CD30 is a member of the TNF cell receptor superfamily and is highly expressed in a variety of lymphoma subsets, including Hodgkin lymphoma and anaplastic large cell lymphoma. Initial studies evaluated the safety and efficacy of several monoclonal antibodies targeting CD30, with limited success. More recently, the anti-CD30 drug-conjugate brentuximab vedotin produced high response rates with an excellent safety profile. These results lead to the approval of brentuximab vedotin for the treatment of patients with relapsed Hodgkin lymphoma and anaplastic large cell lymphoma. Current studies are focusing on incorporating brentuximab vedotin in front-line regimens and expanding its potential clinical utility in other CD30-expressing malignancies.

Venkataraman G, Mirza MK, Eichenauer DA, Diehl V
Current status of prognostication in classical Hodgkin lymphoma.
Br J Haematol. 2014; 165(3):287-99 [PubMed] Related Publications
Classical Hodgkin lymphoma (cHL) is characterized by a paucity of neoplastic Hodgkin/Reed Sternberg (HRS) cells within a complex cellular milieu that is rendered immunologically incapable of reacting against CD30(+) HRS cells due to a plethora of immune escape mechanisms initiated by the neoplastic cells. Accounting for 25% of all lymphomas and nearly 95% of all Hodgkin lymphomas, patients with cHL are typically young adults. Besides traditional prognostic factors, such as the International Prognostic Index (IPI), newer imaging and ancillary biomarkers (CD68, Galectin-1 and plasma microRNA) have shown promise. Furthermore, the evolution of gene expression profiling (GEP) in recent years has enabled the development of several practically feasible GEP-based predictors with prognostic relevance. This review discusses the current status of clinical prognostication in cHL, the critical role of histological evaluation in light of several mimicking entities, and the relevance of tissue as well as serum biomarkers pertaining to immune escape mechanisms and recent GEP studies.

Piccaluga PP, Tabanelli V, Pileri SA
Molecular genetics of peripheral T-cell lymphomas.
Int J Hematol. 2014; 99(3):219-26 [PubMed] Related Publications
Peripheral T-cell lymphomas (PTCL) are rare neoplasms that in most instances respond poorly to conventional chemotherapies. Four varieties--PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK+ anaplastic T-cell lymphoma (ALCL), and ALK- ALCL--account for about 60 % of them. Their classification is difficult because of the wide spectrum of morphologic features and the lack of robust immunohistochemical markers. Thus, high-throughput technologies can importantly contribute to their better understanding. In particular, gene expression profiling has cleared the borders among PTCL/NOS, ALK- ALCL and AITL. In fact, gene signatures have been developed even from formalin-fixed paraffin-embedded tissue samples that definitely distinguish one tumor from the other(s). This has important practical implications: for instance on routine diagnostics PTCL/NOS expressing CD30 can be easily confused with ALK- ALCL, but has a much worse prognosis. Therefore, the clear-cut distinction between the two conditions is pivotal to understand the results of ongoing trials with Brentuximab Vedotin, targeting the CD30 molecule. Besides improving the diagnosis, molecular studies have provided the rationale for the usage of novel drugs in the setting of PTCLs, such as ALK inhibitors in ALK+ ALCL, anti-angiogenetic drugs in AITL, and tyrosine kinase inhibitors in PTCL/NOS and ALK+ and ALK- ALCLs.

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