RPL22

Gene Summary

Gene:RPL22; ribosomal protein L22
Aliases: EAP, L22, HBP15, HBP15/L22
Location:1p36.31
Summary:Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a cytoplasmic ribosomal protein that is a component of the 60S subunit. The protein belongs to the L22E family of ribosomal proteins. Its initiating methionine residue is post-translationally removed. The protein can bind specifically to Epstein-Barr virus-encoded RNAs (EBERs) 1 and 2. The mouse protein has been shown to be capable of binding to heparin. Transcript variants utilizing alternative polyA signals exist. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. It was previously thought that this gene mapped to 3q26 and that it was fused to the acute myeloid leukemia 1 (AML1) gene located at 21q22 in some therapy-related myelodysplastic syndrome patients with 3;21 translocations; however, these fusions actually involve a ribosomal protein L22 pseudogene located at 3q26, and this gene actually maps to 1p36.3-p36.2. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:60S ribosomal protein L22
HPRD
Source:NCBIAccessed: 17 August, 2015

Ontology:

What does this gene/protein do?
Show (21)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Immunohistochemistry
  • DNA, Viral
  • T-Cell Lymphoma
  • T-Lymphocytes
  • Gene Expression
  • Herpesvirus 4, Human
  • Herpesviridae Infections
  • Cancer Gene Expression Regulation
  • Transcription Factors
  • Neoplastic Cell Transformation
  • TP53
  • RNA-Binding Proteins
  • Squamous Cell Carcinoma
  • Mutation
  • Chromosome 3
  • Base Sequence
  • Molecular Sequence Data
  • Cancer DNA
  • Phenotype
  • Nasopharyngeal Cancer
  • Chromosome 1
  • Cancer RNA
  • Neoplasm Proteins
  • Polymerase Chain Reaction
  • Diffuse Large B-Cell Lymphoma
  • Paranasal Sinus and Nasal Cavity Cancer
  • Epstein-Barr Virus Infections
  • Cell Line
  • Viral RNA
  • Adolescents
  • Childhood Cancer
  • Core Binding Factor Alpha 2 Subunit
  • B-Cell Lymphoma
  • Gene Rearrangement
  • Proteins
  • Natural Killer Cells
  • Immunophenotyping
  • In Situ Hybridization
  • Proto-Oncogene Proteins
  • DNA-Binding Proteins
Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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: RPL22 (cancer-related)

Ferreira AM, Tuominen I, van Dijk-Bos K, et al.
High frequency of RPL22 mutations in microsatellite-unstable colorectal and endometrial tumors.
Hum Mutat. 2014; 35(12):1442-5 [PubMed] Related Publications
Ribosomal Protein L22 (RPL22) encodes a protein that is a component of the 60S subunit of the ribosome. Variants in this gene have recently been linked to cancer development. Mutations in an A8 repeat in exon 2 were found in a recent study in 52% of microsatellite-unstable endometrial tumors. These tumors are particularly prone to mutations in repeats due to mismatch repair deficiency. We screened this coding repeat in our collection of microsatellite-unstable endometrial tumors (EC) and colorectal tumors (CRC). We found 50% mutation frequency for EC and 77% mutation frequency for CRC. These results confirm the previous study on the involvement of RPL22 in EC and, more importantly, reports for the first time such high mutation frequency in this gene in colorectal cancer. Furthermore, considering the high mutation frequency found, our data point toward an important role for RPL22 in microsatellite instability carcinogenesis.

Yang M, Sun H, He J, et al.
Interaction of ribosomal protein L22 with casein kinase 2α: a novel mechanism for understanding the biology of non-small cell lung cancer.
Oncol Rep. 2014; 32(1):139-44 [PubMed] Related Publications
Dysfunction of ribosomal proteins (RPs) may play an important role in molecular tumorigenesis, such as lung cancer, acting in extraribosomal functions. Many protein-protein interaction studies and genetic screens have confirmed the extraribosomal capacity of RPs. As reported, ribosomal protein L22 (RPL22) dysfunction could increase cancer risk. In the present study, we examined RPL22-protein complexes in lung cancer cells. Tandem affinity purification (TAP) was used to screen the RPL22-protein complexes, and GST pull-down experiments and confocal microscopy were used to assess the protein-protein interaction. The experiment of kinase assay was used to study the function of the RPL22-protein complexes. The results showed that several differentially expressed proteins were isolated and identified by LC-MS/MS, which revealed that one of the protein complexes included casein kinase 2α (CK2α). RPL22 and CK2α interact in vitro. RPL22 also inhibited CK2α substrate phosphorylation in vitro. This is the first report of the RPL22-CK2α relationship in lung cancer. Dysregulated CK2 may impact cell proliferation and apoptosis, key features of cancer cell biology. Our results indicate that RPL22 may be a candidate anticancer agent due to its CK2α-binding and -inhibitory functions in human lung cancer.

Ménard V, Lévesque E, Chen S, et al.
Expression of UGT2B7 is driven by two mutually exclusive promoters and alternative splicing in human tissues: changes from prenatal life to adulthood and in kidney cancer.
Pharmacogenet Genomics. 2013; 23(12):684-96 [PubMed] Related Publications
OBJECTIVE: UDP-glucuronosyltransferase 2B7 (UGT2B7) plays a major detoxification role in commonly prescribed drugs and endogenous lipophilic molecules. Additional exons and multiple alternative splicing events (ASEs) at the UGT2B7 locus were recently discovered.
MATERIALS AND METHODS: Novel and classical ASEs were quantified in 27 human tissues, as well as in fetal and tumoral tissues. The activity of the alternative UGT2B7 promoters was studied in cell lines.
RESULTS: UGT2B7 expression is driven by an alternate promoter 1a associated with transcripts containing exon 1b, which is located ∼44 kb upstream of the known promoter 1 associated with transcripts containing exon 1 required for enzyme activity. The exon 1 was expressed most abundantly in the liver and gastrointestinal tract, whereas exon 1b was expressed predominantly in other extrahepatic tissues. Experimental evidence indicated endogenous translation that yields alternative UGT2B7s derived from the use of exon 1b are enzymatically inactive. Alternate 5' ASE predominates in fetal tissues (kidney, lung) and kidney tumor samples compared with normal adult kidney. These changes further correlate with reduced glucuronidation in neoplastic kidneys. This differential expression pattern was further confirmed using four liver and kidney cell lines and was consistent with the differential usage of alternate promoters in hepatic (promoter 1) and kidney cells (1a).
CONCLUSION: UGT2B7 is characterized by two mutually exclusive exons 1, both flanked by a unique 5' promoter region. Data also indicated a switch toward functional enzyme upon maturation in the kidney and reversal of this process in neoplastic cells, considerably modifying the glucuronidation potential across human tissues and cells.

Lin SJ, Chang KP, Hsu CW, et al.
Low-molecular-mass secretome profiling identifies C-C motif chemokine 5 as a potential plasma biomarker and therapeutic target for nasopharyngeal carcinoma.
J Proteomics. 2013; 94:186-201 [PubMed] Related Publications
UNLABELLED: Cancer cell secretome profiling has been shown to be a promising strategy for identifying potential body fluid-accessible cancer biomarkers and therapeutic targets. However, very few reports have investigated low-molecular-mass (LMr) proteins (<15kDa) in the cancer cell secretome. In the present study, we applied tricine-SDS-gel-assisted fractionation in conjunction with LC-MS/MS to systemically identify LMr proteins in the secretomes of three nasopharyngeal carcinoma (NPC) cell lines. We examined two NPC tissue transcriptome datasets to identify LMr genes/proteins that are highly upregulated in NPC tissues and also secreted/released from NPC cells, obtaining 35 candidates. We verified the overexpression of four targets (LSM2, SUMO1, RPL22, and CCL5) in NPC tissues by immunohistochemistry and demonstrated elevated plasma levels of two targets (S100A2 and CCL5) in NPC patients by ELISA. Notably, plasma CCL5 showed good power (AUC 0.801) for discriminating NPC patients from healthy controls. Additionally, functional assays revealed that CCL5 promoted migration of NPC cells, an effect that was effectively blocked by CCL5-neutralizing antibodies and maraviroc, a CCL5 receptor antagonist. Collectively, our data indicate the feasibility of the tricine-SDS-gel/LC-MS/MS approach for efficient identification of LMr proteins from cancer cell secretomes, and suggest that CCL5 is a potential plasma biomarker and therapeutic target for NPC.
BIOLOGICAL SIGNIFICANCE: Both LMr proteome and cancer cell secretome represent attractive reservoirs for discovery of cancer biomarkers and therapeutic targets. Our present study provides evidence for the practicality of using the tricine-SDS-PAGE/LC-MS/MS approach for in-depth identification of LMr proteins from the NPC cell secretomes, leading to the discovery of CCL5 as a potential plasma biomarker and therapeutic target for NPC. We believe that the modified GeLC-MS/MS approach used here can be further applied to explore extremely low-abundance, extracellular LMr proteins with important biological functions in other cell lines and biospecimens.

Yang M, Sun H, Wang H, et al.
Down-regulation of ribosomal protein L22 in non-small cell lung cancer.
Med Oncol. 2013; 30(3):646 [PubMed] Related Publications
Ribosomal protein L22 (RPL22), an RNA-binding protein, is a constituent of the 60S large ribosomal subunit. As reported, RPL22 is not required in protein synthesis, and mutations of RPL22 were the main cause of macrolide resistance in bacteria. In vertebrates, RPL22 mutation might increase the proliferation of cells and then increase cancer risk. However, to our knowledge, RPL22 has not been implicated in any lung diseases, especially in lung cancer. In this study, we compared the expression of RPL22 gene in non-small cell lung cancer (NSCLC) tissues, plasma as well as human lung cancer cell line LTEP-a-2 with that in normal lung tissues and cells, using real-time RT-qPCR, Western blot, quantitative immunohistochemistry analysis, and ELISA. Our studies showed that the expression of RPL22 was significantly down-regulated in mRNA and protein expression level in NSCLC; however, there was no significant difference of RPL22 levels in plasma between normal and NSCLC patients. Further analysis indicated that down-regulation of RPL22 might be involved in the carcinogenesis of NSCLC, yet not an effective biomarker in plasma for early diagnosis.

Novetsky AP, Zighelboim I, Thompson DM, et al.
Frequent mutations in the RPL22 gene and its clinical and functional implications.
Gynecol Oncol. 2013; 128(3):470-4 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To determine the frequency and spectrum of mutations in RPL22 a gene identified by The Cancer Genome Atlas (TCGA) as mutated in endometrioid endometrial cancer, and determine the relationship between RPL22 defects and clinicopathologic features.
METHODS: Direct sequencing of the entire coding region of the RPL22 cDNA and exons 2/4 was performed in tumors with/without microsatellite instability (MSI). RPL22 expression was assessed by immunofluorescence microscopy in the KLE, RL952 and AN3CA cell lines, wildtype, heterozygous and homozygous mutants, respectively. Relationships between RPL22 mutation and clinicopathological features were assessed using Chi-squared analysis and Student's t test. Progression-free survival (PFS) was calculated from the date of diagnosis to the date of recurrence.
RESULTS: A single nucleotide deletion in an A8 coding repeat was identified in exon 2 of the RPL22 gene in 116/226 (52%) of MSI-high tumors. No mutations were identified in MSI-stable tumors. Only 2% of the tumors expressed a homozygous A deletion. RPL22 mutation was not associated with stage, grade, race and lymphovascular space invasion. Women whose tumors harbored RPL22 mutations were significantly older (67 vs. 63years, p=0.005). There was no difference in PFS between patients with the wildtype and mutant genotypes.
CONCLUSIONS: RPL22 is frequently mutated in MSI-high endometrioid endometrial cancers. The A8 mutation identified was not reported in the whole exome sequences analyzed by the TCGA. The demonstration of frequent mutation in RPL22 may point to a limitation of the exome capture and next generation sequencing analysis methods for some mononucleotide string mutations. Functional assessment of the RPL22 knockdown may be warranted.

Rao S, Lee SY, Gutierrez A, et al.
Inactivation of ribosomal protein L22 promotes transformation by induction of the stemness factor, Lin28B.
Blood. 2012; 120(18):3764-73 [PubMed] Free Access to Full Article Related Publications
Ribosomal protein (RP) mutations in diseases such as 5q- syndrome both disrupt hematopoiesis and increase the risk of developing hematologic malignancy. However, the mechanism by which RP mutations increase cancer risk has remained an important unanswered question. We show here that monoallelic, germline inactivation of the ribosomal protein L22 (Rpl22) predisposes T-lineage progenitors to transformation. Indeed, RPL22 was found to be inactivated in ∼ 10% of human T-acute lymphoblastic leukemias. Moreover, monoallelic loss of Rpl22 accelerates development of thymic lymphoma in both a mouse model of T-cell malignancy and in acute transformation assays in vitro. We show that Rpl22 inactivation enhances transformation potential through induction of the stemness factor, Lin28B. Our finding that Rpl22 inactivation promotes transformation by inducing expression of Lin28B provides the first insight into the mechanistic basis by which mutations in Rpl22, and perhaps some other RP genes, increases cancer risk.

Monroe SC, Jo SY, Sanders DS, et al.
MLL-AF9 and MLL-ENL alter the dynamic association of transcriptional regulators with genes critical for leukemia.
Exp Hematol. 2011; 39(1):77-86.e1-5 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: The aim of this study was to better understand how mixed lineage leukemia (MLL) fusion proteins deregulate the expression of genes critical for leukemia.
MATERIALS AND METHODS: The transforming domain of one of the most common MLL fusion partners, AF9, was immunopurified after expression in myeloblastic M1 cells, and associating proteins were identified by mass spectrometric analysis. Chromatin immunoprecipitation followed by quantitative polymerase chain reaction was used to determine how binding of associating proteins compare across Hoxa9 and Meis1 in cell lines with and without MLL fusion proteins and how binding is altered during gene down-regulation and differentiation.
RESULTS: Consistent with earlier purifications of ENL and AF4 from 293 cells, the 90 amino acid C-terminal domain of AF9 associates with many other MLL translocation partners including Enl, Af4, Laf4, Af5q31, Ell, and Af10. This complex, termed elongation assisting proteins (EAPs), also contains the RNA polymerase II C-terminal domain kinase Cdk9/Cyclin T1/T2 (pTEFb) and the histone H3 lysine 79 methyltransferase Dot1L. Myeloid cells transformed by MLL fusions show higher levels and a broader distribution of EAP components at genes critical for leukemia. Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented.
CONCLUSIONS: The findings suggest that MLL fusion proteins deregulate genes critical for leukemia by excessive recruitment and impaired dissociation of EAP from target loci.

Li D, Ping Y, Xu F, et al.
Construction of a star-shaped copolymer as a vector for FGF receptor-mediated gene delivery in vitro and in vivo.
Biomacromolecules. 2010; 11(9):2221-9 [PubMed] Related Publications
The success of cancer gene therapy highly relies on the gene delivery vector with high transfection activity and low toxicity. In the present study, eight-armed polyethylene glycol (EAP) and low molecular weight (LMW) polyethylenimine (PEI) were used as basic units to construct the architecture of a new star-shaped EAP-PEI copolymer (EAPP). MC11, a peptide capable of selectively binding fibroblast growth factor receptor (FGFR) on tumor cell membranes, was further conjugated to EAPP to produce the vector EAPP-MC11 (EAPPM) to enhance tumor targetability. This tumor-targeting vector EAPPM was observed to retard the plasmids mobility at a nitrogen/phosphorus (N/P) ratio of 3. The vector could efficiently condense plasmids within 300 nm nanoparticles with a positive zeta potential at the N/P ratio of 20 or above. While the cytotoxicity of EAPPM polyplexes was similar to that of LMW PEI, it was significantly lower than that of PEI (25 kDa) in HepG2 and PC3 cell lines. In vitro gene transfection with pDNA mediated by EAPPM showed that the transfection efficiency increased 15 times in HepG2 cells but remained at a similar level in PC3 cells in comparison with that of EAPP. By systemic injection of EAPPM/pDNA complexes into a HepG2-bearing mice model, luciferase expression detected in lung, liver, and tumor tissues demonstrated EAPPM could deliver in a targeted manner a reporter gene into tumor tissues, where the luciferase expression of EAPPM was 4 times higher than that of EAPP and even 23 times higher than that of PEI (25 kDa). Furthermore, it was found that the systemic delivery of EAPPM/pCSK-α-interferon complexes in vivo were much more effective in inhibiting tumor growth than EAPP or PEI (25 kDa). These results clearly show that EAPPM is an efficient and safe vector for FGFR-mediated targeted gene delivery both in vitro and in vivo. With low cytotoxicity and high targetability, EAPPM may have great potential as a delivery vector for future cancer gene therapy applications.

Kawamoto K, Nakamura S, Iwashita A, et al.
Clinicopathological characteristics of primary gastric T-cell lymphoma.
Histopathology. 2009; 55(6):641-53 [PubMed] Related Publications
AIMS: To investigate the clinicopathological characteristics of 20 primary gastric T-cell lymphoma (GTCL) cases without human T-lymphotropic virus type I infection in Japan, a non-endemic area for coeliac disease.
METHODS AND RESULTS: Fifteen cases had no history of persistent diarrhoea or severe hypoproteinaemia. Histologically, 13 cases (65%) consisted of large cell lymphoma and seven (35%) were of medium-sized cells. Intraepithelial lymphoma cell invasion was found in three cases (15%). Two of 10 surgical cases (20%) showed intramucosal tumour cell spreading with enteropathy-like features. Helicobacter pylori CagA gene was detected in three of 10 cases (30%). The lymphoma cells of all 20 cases were positive for CD3 and/or TCRbetaF1 and negative for CD56. CD4- and CD8- lymphoma was found in 11 cases (55%), CD4+ lymphoma in seven (35%) and CD8+ lymphoma in two (10%). CD30+, CD5+ and CD25+ lymphomas were detected in nine (45%), 10 (50%) and 11 (55%) cases, respectively. Five-year survival of the 16 available cases was 54%. Early clinical stage and medium-sized cell lymphoma were significantly (P < 0.05) better prognostic factors.
CONCLUSIONS: Patients with GTCL exhibit distinct clinicopathological findings and prognoses from those with enteropathy-associated T-cell lymphomas. GTCL may be mainly derived from lamina propria and parafollicular T cells.

Van Slycke S, Caiazzo R, Pigny P, et al.
Local-regional recurrence of sporadic or syndromic abdominal extra-adrenal paraganglioma: incidence, characteristics, and outcome.
Surgery. 2009; 146(6):986-92 [PubMed] Related Publications
BACKGROUND: Operative excision of abdominal extra-adrenal paragangliomas (EAPs) does not preclude the late development of local-regional recurrence. We describe the incidence, characteristics, and outcome of this rarely reported feature.
METHODS: Retrospective analysis of local-regional recurrence that occurred during follow-up of 51 consecutive patients operated for a sporadic (n = 26) or hereditary (n = 25) EAP.
RESULTS: Seven patients with a sporadic or syndromic EAP (n = 4: von Hippel-Lindau syndrome and SDHB, SDHC, and SDHD gene mutations) underwent reoperation for a local-regional recurrence after a median time of 46 months (interquartile range [IQR], 16-100). The Kaplan-Meier estimated incidence of local-regional recurrence (+/- standard error of the mean) reached 15% +/- 7% at 5 years and 23% +/- 9% after 10 years. Recurrent EAPs were all secreting and 38% provoked clinical symptoms. New lesions were smaller than the primary EAP (P = .01) and more often associated with lymph node metastases (43% vs 4%, P = .01). Operative excision seemed complete in 5 patients. Clinical remission was maintained in 4 patients after a median follow-up of 57 months (IQR, 22-102).
CONCLUSION: Local-regional recurrence of sporadic and syndromic EAPs is frequent and may be delayed beyond 10 years, requiring lifelong follow-up after the initial operation. When technically feasible, operative excision can lead to prolonged remission.

Hoe SL, Lee ES, Khoo AS, Peh SC
p53 and nasopharyngeal carcinoma: a Malaysian study.
Pathology. 2009; 41(6):561-5 [PubMed] Related Publications
AIMS: Nasopharyngeal carcinoma (NPC) is a common malignancy among men in Malaysia. To determine the role of p53 in NPC, we screened for p53 mutations and evaluated the protein expression levels in samples from local patients with NPC.
METHODS: Fifty-three formalin-fixed, paraffin-embedded nasopharyngeal carcinoma tissue blocks were chosen for this study. The presence of Epstein-Barr virus (EBV) was determined by in situ hybridisation using an EBER probe. p53 protein expression was detected using immunohistochemistry. Simultaneously, amplifications by PCR were performed for p53 exons 5 to 8, followed by mutation screening via single strand conformation polymorphism (SSCP). Sequencing of all the four exons was performed in five samples with mobility shift. To rule out false negative results by SSCP, 13 samples with p53 overexpression and five samples with low p53 expression were randomly selected and sequenced.
RESULTS: There was no mutation found in exons 5 to 8 in all the samples despite 46 (87%) of them having high p53 levels. EBV was detected in 51 (96%) out of 53 samples. There was no statistically significant association between p53 expression level and EBV presence.
CONCLUSIONS: High-intensity staining for p53 by immunohistochemistry was common in our series of NPC tissue samples but was not associated with 'hot spot' mutations of exons 5-8 of the gene. We did not find a significant relationship between the expression level of p53 and presence of EBV. Our study confirms that mutation of the DNA-binding domain of p53 is rare in NPC.

Samanta M, Takada K
Modulation of innate immunity system by Epstein-Barr virus-encoded non-coding RNA and oncogenesis.
Cancer Sci. 2010; 101(1):29-35 [PubMed] Related Publications
Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) are polyA-, non-coding RNAs that are expressed abundantly in all forms of cells latently infected with EBV. EBERs (EBER1 and EBER2) contribute to the clonal proliferation of EBV-negative Burkitt's lymphoma (BL) cells in soft agar, tumorigenicity in SCID mice, up-regulation of the bcl-2 oncoprotein, resistance to apoptosis, and maintenance of malignant phenotypes in BL cells. EBERs induce the expression of interleukin (IL)-10 in BL cells, insulin-like growth factor 1 (IGF-I) in gastric and nasopharyngeal carcinoma cells, IL-9 in T cells, and IL-6 in lymphoblastoid cell lines. Additionally, each of these cytokines acts as an autocrine growth factor. In BL cells, EBERs bind the double-stranded RNA-activated protein kinase PKR, inhibit its phosphorylation, and thereby prevent IFN-alpha-mediated apoptosis. In epithelial cells, EBERs confer resistance to Fas-mediated apoptosis by blocking PKR activity. EBERs form complexes with PKR, ribosomal protein L22, lupus erythematosis-associated antigen (La), and retinoic acid-inducible gene I (RIG-I). In BL cells, EBERs activate RIG-I signaling and induce the expression of type-I IFNs and interferon stimulated genes (ISGs) through the activation of RIG-I substrates, nuclear factor-kappa B (NF-kappaB), and IFN regulatory factor 3 (IRF-3), and anti-inflamatory cytokine IL-10 through IRF-3 but not NF-kappaB signaling. EBERs also play critical roles in the growth transformation of B lymphocytes. Although EBER1 and EBER2 exhibit similarities in their primary (54%) and secondary structures, recent findings have shown that recombinant EBVs carrying only the EBER2 gene play a greater role in the growth transformation of B lymphocytes than EBVs carrying only the EBER1 gene. Thus, EBERs play multiple roles in various cell types, and we present a model that highlights the functions of EBERs in EBV-mediated oncogenesis in BL cells.

Shinozaki A, Ushiku T, Fukayama M
Prominent Mott cell proliferation in Epstein-Barr virus-associated gastric carcinoma.
Hum Pathol. 2010; 41(1):134-8 [PubMed] Related Publications
The proliferation of Mott cells (plasma cells with multiple Russell bodies) is rarely observed in nonhematopoietic tumors, and no reports of this phenomenon in malignant epithelial neoplasms have been published. We present 2 cases of gastric carcinoma associated with prominent Mott cell proliferation. Histologically, both tumors consisted of extensive lymphoplasmacytic infiltration and numerous Mott cells with dysplastic epithelial cells. The epithelial cells showed overt cytologic atypia; infiltrating cells did not show cytologic atypia, immunoglobulin light chain restriction, or clonal immunoglobulin gene rearrangement. In situ hybridization for Epstein-Barr virus (EBV)-encoded small RNA (EBER) labeled the carcinoma cells but not the lymphoplasmacytic cells. The Mott cell accumulation was a reactive phenomenon in gastric carcinoma associated with EBV. The differential diagnosis included primary gastric lymphoma and nonneoplastic conditions such as Russell body gastritis; EBER in situ hybridization was helpful in their differentiation.

Wang J, Chen C, Lau S, et al.
CD3-positive large B-cell lymphoma.
Am J Surg Pathol. 2009; 33(4):505-12 [PubMed] Related Publications
It is not uncommon for some B-lineage non-Hodgkin lymphomas (NHLs) to aberrantly coexpress T-cell markers, particularly CD5, as well as CD7, CD2, CD4, and/or CD8 in rare cases. Cases of CD3-positive B-cell NHL, however, have not previously been described in the literature. We present 4 cases of large B-cell lymphoma aberrantly coexpressing T-cell marker CD3 and B-lineage markers as well as demonstrating clonal rearrangement of the immunoglobulin genes but not the gamma T-cell receptor gene. To our knowledge, this represents the first series report of B-cell NHL coexpressing T-lineage-specific marker CD3. The identification of such cases indicates that the use of CD3 antibody alone in paraffin sections may lead to an incorrect determination of cell lineage in some B-cell NHL. Immunohistochemistry using additional cell lineage specific markers or molecular analysis for antigen receptor gene rearrangements are necessary for correct determination of the cell lineage in such cases.

Chan CM, Wong SC, Lam MY, et al.
Proteomic comparison of nasopharyngeal cancer cell lines C666-1 and NP69 identifies down-regulation of annexin II and beta2-tubulin for nasopharyngeal carcinoma.
Arch Pathol Lab Med. 2008; 132(4):675-83 [PubMed] Related Publications
CONTEXT: Nasopharyngeal carcinoma (NPC), common in southern China and North Africa, has a complex etiology involving interplay between viral, environmental, and hereditary factors and is almost constantly associated with the Epstein-Barr virus. Since the prognosis of locally advanced and metastatic diseases is poor, increased understanding of the pathogenesis of NPC would be important for discovering novel markers for patients' management.
OBJECTIVES: To compare the proteomic expression profile between an Epstein-Barr virus-associated NPC cell line (C666-1) and a normal NP cell line (NP69). The proteins with differential expression were analyzed in 40 undifferentiated NPC paraffin-embedded specimens.
DESIGN: Differentially expressed proteins discovered between the two cell lines were identified by mass spectrometry. After confirmation by immunocytochemical staining, their expression in patient samples was measured using 40 pairs of undifferentiated NPCs together with their adjacent normal epithelia.
RESULTS: Proteomic findings indicated that adenosine triphosphate synthase alpha chain was up-regulated, whereas annexin II, annexin V, beta(2)-tubulin, and profilin 1 were down-regulated. After confirming the results in agar-processed cell lines, annexin II and beta(2)-tubulin expression were found to be lower in tumor cells than in adjacent normal epithelial cells in 100% and 90% of the patients' specimens, respectively. Finally, annexin II down-regulation was positively associated with lymph node metastasis, suggesting that it may be a prognostic factor in NPC.
CONCLUSIONS: The results suggest that annexin II and beta(2)-tubulin down-regulation is important in NPC formation and may represent potential targets for further investigations.

Dongiovanni D, Daniele L, Barone C, et al.
Gefitinib (ZD1839): therapy in selected patients with non-small cell lung cancer (NSCLC)?
Lung Cancer. 2008; 61(1):73-81 [PubMed] Related Publications
PURPOSE: To evaluate response rate, toxicity and epidermal growth factor (EGFR) mutations and gene copy number as outcome predictive factors in Italian patients with non-small cell lung cancer (NSCLC) treated with gefitinib (Iressa) in an expanded access program (EAP).
PATIENTS AND METHODS: A total of 137 patients with advanced NSCLC received gefitinib as first line treatment or after failure of chemotherapy. In 43 cases, tissue specimens were available for EGFR status evaluation: immunohistochemical (IHC) for EGFR, fluorescence in situ hybridisation (FISH) or Chromogenic in situ hybridisation (CISH)-(ISH) analysis for EGFR and HER2 gene copy number, and PCR-DNA sequencing for mutational analysis of EGFR were performed.
RESULTS: In the study population, response rate (PR) was 13%; disease stabilization (DS) 26%; overall disease control rate 39%; median survival 6.3 months and time to progression 2.7 months. Toxicity was mild (G3 skin toxicity in 3% and G3 liver toxicity in 4% of patients). An EGFR-mutation was detected in 9/43 patients: Eight deletions in exon 19 and 1 missense mutation in exon 21. Increased gene copy number for EGFR and/or HER2 was detected in 17/43 patients. Response rate was significantly higher in women, non-smokers, in mutation carriers than in wild type carriers, in EGFR-trisomy/polysomy carriers and HER2-trisomy/polysomy carriers.
CONCLUSIONS: In this study, response rate and toxicity to gefitinib treatment were consistent with previously reported data for whites. Female gender, absence of smoking history, EGFR-mutations, EGFR and HER2-polysomy were significantly associated with response to gefitinib therapy in NSCLC patients.

García-Cosío M, Santón A, Martín P, et al.
Analysis of Epstein-Barr virus strains and variants in classical Hodgkin's lymphoma by laser microdissection.
Histol Histopathol. 2008; 23(2):209-17 [PubMed] Related Publications
Epstein-Barr virus (EBV) seems to have an etiological role in the pathogenesis of classical Hodgkin's lymphoma (cHL). Studies of whole tissue DNA by polymerase-chain reaction (PCR) have shown a considerable number of cHL cases with co-infections by different EBV strains and variants, which apparently contradict the clonality of EBV in cHL previously demonstrated by Southern blot analysis. Due to the paucity of HRS cells in HL tissues, studies on single cell DNA are necessary to identify the specific cellular location (HRS cells and/or bystander B lymphocytes) of the EBV strains and variants present in tissue specimens. In the current study, the presence of EBV was determined by PCR of the 3' end of the LMP-1 gene and EBNA-3C gene in whole tissue and, consecutively, in isolated cells from 26 cases of cHL: 10 HIV-positive and 16 sporadic cHL cases. EBV EBERs were present in all but 2 sporadic cHL cases, which were used as negative controls. At isolated cell level, EBNA-3C gene PCR was more sensitive. Indeed, from the cHL cases in which dual-infection was present, it was observed that, in most of them, HRS cells were infected by type 1 virus, and B lymphocytes were co-infected by both types, which points towards EBV infection occurring early in cHL development. Moreover, the finding of 2 cases with dual-infection in HRS may suggest that, in a small percentage of cHL cases, HRS cells derive from different neoplastic clones, or that HRS cells are superinfected by other viral types after the establishment of the neoplastic clone.

Wang J, Geng SA, Su Z, et al.
Rearranged T-cell receptor gene and positive Epstein-Barr virus-encoded nuclear RNA in an extranodal NK/T-cell lymphoma with cutaneous manifestation only: case study.
Clin Exp Dermatol. 2007; 32(6):744-8 [PubMed] Related Publications
Natural killer (NK)/cytotoxic T-cell lymphoma, a new type of cutaneous neoplasm, has been described recently in the World Health Organization/European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas. We report an 11-year-old boy who had had erythematous plaques and blisters on his face and hands for 4 years and infiltrating plaques and necrosis on his extremities for 4 months. Routine clinical and laboratory examinations found no primary nasal involvement. Biopsies taken from nasal mucosa and skin showed that the tumour only involved dermis and subcutaneous tissue, and the infiltrated lymphohistiocytic tumour cells were CD56+, TIA+, CD45RO+ and CD30+. In situ hybridization for EBV-encoded nuclear RNA was positive. Clonal T-cell receptor-gamma2 gene rearrangement was positive. A diagnosis of extranodal NK/T-cell lymphoma, nasal type, was made. This is a rare case, with slow course and survival for >51 months with the presentation only occurring in the skin.

Kim SH, Cheong JW, Park KH, et al.
Comparison of ataxia-telangiectasia mutated protein expression in diffuse large B-cell lymphomas of primary central nervous system and non-central nervous system origin.
Arch Pathol Lab Med. 2007; 131(3):457-67 [PubMed] Related Publications
CONTEXT: The ataxia-telangiectasia mutated (ATM) gene encodes a nuclear 370-kd phosphoprotein known to be associated with chromosomal regions containing double-strand breaks. The mutations in the ATM gene may be involved in the development of some subtypes of sporadic lymphomas and leukemias. In primary central nervous system diffuse large B-cell lymphomas (PCNS DLBCLs), the pathogenetic role of ATM mutation has not been investigated.
OBJECTIVE: To investigate ATM protein expression in PCNS DLBCLs, in comparison with that in non-central nervous system (non-CNS) DLBCLs and to study the relationship of ATM protein loss with several clinicopathologic parameters.
DESIGN: This study included 42 cases of PCNS DLBCL and 33 cases of non-CNS DLBCL from immunocompetent patients. The ATM protein loss was analyzed by immunohistochemical staining. For the subclassification of DLBCL and analysis of the relationship between ATM and other prognostic markers, we performed immunohistochemical evaluation to detect the following markers: Bcl-6, CD10, multiple myeloma-1, CD138, Bcl-2, Ki-67, and p53.
RESULTS: The loss of ATM expression was statistically more frequent in PCNS DLBCLs (21/42 cases [50.0%]) than in non-CNS DLBCLs (0/33 cases [0.0%]; P < .001). The loss of ATM expression was not a prognostic marker in PCNS DLBCLs (P = .64). The loss of ATM expression had a strong correlation with the germinal center B-cell-like subtype (P = .01), a low Ki-67 labeling index (P = .03), and low Bcl-2 expression (P = .01) among several clinicopathologic parameters.
CONCLUSIONS: Our results suggest that the ATM protein is more strongly correlated with PCNS DLBCL lymphomagenesis than with non-CNS DLBCLs, especially in germinal center B-cell-like subtypes demonstrating low Ki-67 labeling indexes and low Bcl-2 expression.

Chun SM, Kim YL, Choi HB, et al.
Identification of leukemia-specific fusion gene transcripts with a novel oligonucleotide array.
Mol Diagn Ther. 2007; 11(1):21-8 [PubMed] Related Publications
BACKGROUND: Identification of specific chromosomal translocations is essential for the diagnosis and prognosis of leukemia. In this study, we employ DNA microarray technology to detect chromosomal aberrations in patients with chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), as well as in leukemic cell lines.
METHODS: Reverse transcription using a random 9-mer primer was performed with total RNA from patients and leukemic cells lines. Multiplex PCR reactions using four groups of primer sets were then performed for amplification of cDNA from reverse-transcribed total RNA samples. Normal and fusion sequences were distinguished by hybridization of the amplified cDNA to a selective oligonucleotide array (SOA) containing 20-30mer synthetic probes. A total of 23 sets of oligomers were fabricated on glass slides for the detection of normal and fusion genes, as follows: BCR/ABL, AML/EAP, AML/ETO, AML/MDS, PML/RARA, NUMA1/RARA, PLZF/RARA, and CBFB/MYH.
RESULTS: Gene translocation in leukemia was effectively identified with the SOA containing various leukemia-specific fusion and normal control sequences. Leukemic fusion sequences from patients and cell lines hybridized specifically to their complementary probes. The probe sets differing by approximately 50% at their 5' or 3' ends could distinguish between normal and fusion sequences. The entire process of detection was completed within 8 hours using the SOA method.
CONCLUSIONS: Probe sets on SOA can effectively discriminate between leukemia-specific fusion and normal sequences with a chip hybridization procedure. The oligonucleotide array presents several advantages in identifying leukemic gene translocations, such as multiplex screening, relatively low cost, and speed.

Yin CC, Cortes J, Barkoh B, et al.
t(3;21)(q26;q22) in myeloid leukemia: an aggressive syndrome of blast transformation associated with hydroxyurea or antimetabolite therapy.
Cancer. 2006; 106(8):1730-8 [PubMed] Related Publications
BACKGROUND: The t(3;21)(q26;q22) translocation is associated with myeloid leukemias and results in a chimeric oncoprotein containing AML1/RUNX1 variably fused to EAP, MDS1, and/or EVI1.
METHODS: The current study describes what to the authors' knowledge is the first large case series reported to date of 26 t(3;21)(q26;q22)-associated leukemias, in which 24 cases arose after chemotherapy. Conventional G-band karyotyping and flow cytometry immunophenotyping were performed. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to detect fusion transcripts between AML1 and EAP, MDS1, or EVI1, followed by DNA sequencing.
RESULTS: In all 16 patients with chronic myeloproliferative disorders, including 14 with chronic myelogenous leukemia (CML), the occurrence of t(3;21) heralded myeloid blast transformation. Fifteen (93%) patients had been previously treated with hydroxyurea. Eight patients with chronic myeloproliferative disorders (CMPD) were found to have t(3;21) with t(9;22) as the sole cytogenetic abnormality; in 5 other patients this was accompanied by trisomy 8. Among 10 cases of t(3;21)-associated acute myeloid leukemia, 8 were secondary tumors after chemotherapy for other neoplasms that had been treated with regimens including fludarabine and 5-fluorouracil in 3 patients each and etoposide in 2 patients. The immunophenotype of the blasts in all 22 tested cases was similar, with uniform expression of myeloid markers and CD34 and variable expression of CD7 and CD9, but minimal morphological myeloid maturation. Dysplastic micromegakaryocytes and bone marrow fibrosis were observed predominantly in CMPD cases. RT-PCR followed by DNA sequencing showed that the AML1-/MDS1-/EVI1 (AME) fusion transcript was detected in all 5 cases assessed. Among the patients with CMPD, 8 died of disease (at a median of 6.5 mos) and 5 achieved disease remission with bone marrow transplantation. Among patients with acute myeloid leukemia/myelodysplastic syndrome, 7 died of disease (at a median of 2 mos) and 2 had persistent leukemia with short follow-up.
CONCLUSIONS: Activation of AME through t(3;21) defines a highly aggressive, therapy-related leukemic blast syndrome. Prior treatment with hydroxyurea or other antimetabolites is implicated as a contributory cause.

Chen KC, Chiang HS, Fang CL
EBER expression of pure urinary bladder lymphoepithelioma-like carcinoma in two unique Asian patients.
Urol Int. 2005; 74(3):280-2 [PubMed] Related Publications
We describe the 2 unique Asian cases of pure urinary bladder lymphoepithelioma-like carcinoma (LELCA). One patient had metastatic pelvic lymphoadenopathy and the other with superficial tumor. The EBER in situ hybridization both showed negative results despite racial or geographical factors might influence the peculiar susceptibility of individuals of Asian ancestry to Epstein-Barr virus-associated lymphoepithelioma-like carcinoma. The 2 patients were treated pertinently with satisfactory outcomes and intravesical BCG instillation is performed to prevent superficial LELCA recurrence rationally.

Huang Y, Tsung JS, Lin CW, Cheng TY
Intrahepatic cholangiocarcinoma with lymphoepithelioma-like carcinoma component.
Ann Clin Lab Sci. 2004; 34(4):476-80 [PubMed] Related Publications
We report an unusual case of intrahepatic cholangiocarcinoma (ICC) with lymphoepithelioma-like carcinoma (LELC) component in a 60-yr-old woman who was found incidentally to have an abdominal mass. Histologically, the tumor showed 2 distinct patterns with dense lymphoplasma cell infiltration. The first pattern, comprising approximately 20% of total tumor volume, showed the features of lymphoepithelioma-like carcinoma, as commonly found in nasopharyngeal carcinoma (NPC). The second pattern was a moderately differentiated cholangiocarcinoma. In situ hybridization for Epstein-Barr virus (EBV)-encoded RNA (EBER) showed positive nuclear labeling of tumor cells in both patterns, but not in surrounding inflammatory cells. By the polymerase chain reaction, the latent membrane protein gene (LMP-1) in this case was shown to have a 30 bp deletion in the C-terminus, a unique feature in high prevalence areas of undifferentiated nasopharyngeal carcinoma, such as in Taiwan. Presence of the EBV genomes and their expression in the cholangiocarcinoma cells suggested that EBV may play an important role in the pathogenesis of ICC with LELC. In this case, it is unclear why only 20% of the glands were transformed into LELC. The mechanism whereby EBV transforms the malignant glands into the distinct morphology resembling NPC warrants further investigation.

Au WY, Srivastava G, Wong KY, et al.
Transformation of diffuse large B-cell lymphoma into pre-B acute lymphoblastic leukemia: clinicopathologic features and clonal relationship.
Hum Pathol. 2004; 35(7):900-3 [PubMed] Related Publications
A patient with fibrosing alveolitis developed a diffuse large B-cell (DLBC) lymphoma that expressed CD20 and CD30. After an initial response, the lymphoma relapsed and was salvaged with further chemotherapy. After another remission of 3 years, a pre-B-cell acute lymphoblastic leukemia (ALL), which expressed CD10, CD19, CD22, CD79a, CD34 and terminal deoxyribonucleotidyl transferase, developed and led to death. Molecular analysis of the immunoglobulin heavy-chain gene showed that the initial lymphoma and its relapse were clonally related. At leukemic relapse, 2 clones related to the initial and relapsed lymphoma clones were present. DLBC lymphomas arise from post-follicle center B cells, whereas ALL arises from pregerminal B cells. Therefore, a direct transformation of DLBC lymphoma to ALL appears unlikely. The overall features suggest instead separate lymphoma and leukemic evolution from a common mutated B-cell precursor rather than transformation of DLBC lymphoma to ALL.

Takahara M, Kishibe K, Bandoh N, et al.
P53, N- and K-Ras, and beta-catenin gene mutations and prognostic factors in nasal NK/T-cell lymphoma from Hokkaido, Japan.
Hum Pathol. 2004; 35(1):86-95 [PubMed] Related Publications
We have shown previously that nasal natural killer (NK)/T-cell lymphoma was associated with Epstein-Barr virus (EBV) and had peculiar clinical features. However, little is known about its biological and genetic changes. The aim of this study is to determine the p53, N- and K-ras, and beta-catenin status in this lymphoma in relation to EBV status and clinical features. The study group consisted of 32 Japanese patients with nasal NK/T-cell lymphoma. The p53 and beta-catenin expression, phenotype, and EBV-oncogenic protein latent membrane protein type 1 (LMP-1) were determined by immunoperoxidase staining. The presence of EBV-encoded small nuclear early region (EBER) RNA was determined by in situ hybridization. The p53 mutations (exons 5 to 9), N- and K-ras mutations (exons 1 and 2), and beta-catenin mutations (exon 3) were analyzed by direct sequencing of the PCR-amplified products that were obtained from laser-microdissected tissues. CD56, CD43, and CD3 were expressed in 32 (100%), in 31 (96%), and in 18 (56%) tumors, respectively. EBER RNA was detected in 31 (96%) tumors. LMP-1 was expressed in 15 (48%) tumors, and p53 and beta-catenin protein were overexpressed in 18 (56%) and 4 (13%) tumors, respectively. Six mutations of the p53 gene, 1 mutation of each N- and K-ras gene, and 8 mutations of beta-catenin gene were detected in 6 (19%), 1 (3%), and 5 (16%) tumors, respectively. The p53 missense mutation was associated with LMP-1 expression (P = 0.038), but not with p53 overexpression. Kaplan-Meier analysis as well as univariate analysis using Cox proportional hazards model showed that high lactate dehydrogenase (LDH) level (P = 0.009, P = 0.0100, respectively), large cell, immunoblastoid polymorphous histology (P = 0.005, P = 0.0162, respectively), and p53 missense mutations (P = 0.021, P = 0.0342, respectively) were significantly related to worse cause-specific survival. Multivariate analysis showed that p53 missense mutation was the most independent among these 3 factors. Although the incidence of thep53, N- and K-ras, and beta-catenin gene mutations is not high, p53 missense mutation has a prognostic value for aggressive course in nasal NK/T-cell lymphoma.

Mikhail FM, Coignet L, Hatem N, et al.
A novel gene, FGA7, is fused to RUNX1/AML1 in a t(4;21)(q28;q22) in a patient with T-cell acute lymphoblastic leukemia.
Genes Chromosomes Cancer. 2004; 39(2):110-8 [PubMed] Related Publications
AML1 is among the most frequent targets of chromosomal rearrangements in human leukemias. We report here the molecular analysis of a t(4;21)(q28;q22) that has disrupted AML1 in a patient with de novo T-cell acute lymphoblastic leukemia. By using 3'-RACE analysis, we show that this rearrangement results in the fusion of a novel gene immediately downstream of exon 5 or exon 6 of AML1, indicating that the AML1 breakpoint lies in intron 6 and that alternative fusion splice variants are generated. The sequence of the novel gene, located at 4q28, does not have any significant homology with any of the known genes in the human GenBank DNA database. However, the first 118 bases are identical to a part of a human ovarian EST. Also, its high homology with mouse and rat sequences suggests that this sequence most probably represents a part of a novel gene, which we named FGA7 (Fused Gene 7 to AML1). Following the AML1 open reading frame, the FGA7 sequence encodes an unknown protein of 27 amino acids. We isolated three bacterial artificial chromosome (BAC) clones that contain the FGA7 sequence and confirmed the breakpoint of the gene on the patient's metaphase spreads by fluorescence in situ hybridization using these BACs as probes. RT-PCR and Northern blot analyses revealed that FGA7 is expressed in ovarian and skeletal muscle tissues. The predicted AML1-FGA7 chimeric proteins contained a limited number of residues fused to AML1 in a situation similar to that reported for the AML1-EAP fusion that is a product of t(3;21). It is possible that the expression of a constitutively shortened AML1 could compete with full-length AML1 and act as a dominant negative inhibitor of the promoters that the core binding factor activates.

Tinguely M, Rosenquist R, Sundström C, et al.
Analysis of a clonally related mantle cell and Hodgkin lymphoma indicates Epstein-Barr virus infection of a Hodgkin/Reed-Sternberg cell precursor in a germinal center.
Am J Surg Pathol. 2003; 27(11):1483-8 [PubMed] Related Publications
The simultaneous occurrence of a Hodgkin lymphoma (HL) and a non-Hodgkin lymphoma (NHL) is a rare event, and single cell analyses of such composite lymphomas revealed that NHL and Hodgkin/Reed-Sternberg (HRS) tumor cells are frequently descendants of the same tumor clone precursors. Here we present a composite lymphoma consisting of a mantle cell lymphoma (MCL) and an HL with EBV- and EBV+ HRS cells. Analysis of rearranged V genes of single cells revealed a clonal relationship between MCL and HL tumor cells. Although V gene rearrangements of the MCL were unmutated, mutations were observed in HRS cells. Besides mutations shared by all HRS cells, the EBV+ HRS cells carried identical additional mutations. These findings show that both lymphomas derive from a common precursor, most likely a pre germinal center (GC) B cell that already carried some transforming event(s). However, the presence of mutations in the V genes of the HRS cells further corroborates the importance of the GC reaction for the pathogenesis of HL. Importantly, the finding that only a subclone of the HRS clone, defined by a particular mutation pattern, was EBV infected represents a strong indication that EBV infection of the HRS cell precursor happened in the GC.

García-Cosío M, Santón A, Méndez MC, et al.
Nasopharyngeal/nasal type T/NK lymphomas: analysis of 14 cases and review of the literature.
Tumori. 2003 May-Jun; 89(3):278-84 [PubMed] Related Publications
AIMS AND BACKGROUND: Lymphoid malignancies expressing CD56 are rare and most occur in the nasal or nasopharyngeal region. They derive from natural killer cells or from a small subset of T cells that have granular cytoplasm containing molecules that mediate cytotoxic activity: TIA-1, granzyme B and perforin. Both types are closely associated with Epstein-Barr virus.
METHODS: We report the pathologic, immunophenotypic and molecular findings in 14 cases of nasopharyngeal/nasal type T/NK lymphomas.
RESULTS: Clinically, all patients had localized disease and also had symptoms limited to the nose. The neoplastic cells were frequently pleomorphic, and angiocentric growth was common. Combined immunophenotypic and gene rearrangement analyses demonstrated that most of the cases were true NK cell tumors and were either CD56+ and CD3- or CD56+ and CD3+. Immunohistochemical study showed TIA-1 and granzyme B expression in all cases. By in situ hybridization, most of the cases were associated to Epstein-Barr virus, harboring type 1 virus, and polymerase chain reaction amplification across the 30 bp deletion showed high frequency of latent membrane protein-1-deleted variants.
CONCLUSIONS: The nasal type T/NK cell lymphoma shows distinctive clinicopathologic, immunophenotypic and molecular features. These results confirm the important role of Epstein-Barr virus as a local factor in their pathogenesis.

Child FJ, Mitchell TJ, Whittaker SJ, et al.
Blastic natural killer cell and extranodal natural killer cell-like T-cell lymphoma presenting in the skin: report of six cases from the UK.
Br J Dermatol. 2003; 148(3):507-15 [PubMed] Related Publications
BACKGROUND: Some lymphomas express natural killer (NK)-cell markers such as the neural cell adhesion molecule, which is recognized by the CD56 antibody. These lymphomas may present in the skin, but do not represent a homogeneous group. The new World Health Organization classification of lymphoma/leukaemia recognizes several types of NK/T-cell neoplasm, including blastic NK-cell lymphoma, which characteristically presents with cutaneous lesions.
OBJECTIVES: To describe the clinical, pathological and molecular features in six cases of CD56+ lymphoma with cutaneous presentation.
METHODS: The clinical, histopathological and immunophenotypic features of six patients were reviewed. In addition, in situ hybridization (ISH) to identify Epstein-Barr virus (EBV) mRNA, and polymerase chain reaction analysis to identify the presence of a clonal population of T cells or B cells were performed on lesional skin.
RESULTS: All patients presented with widespread nodules and plaques, which in five cases were a characteristic purple colour. Four patients developed disseminated disease, three with neurological involvement. These four patients died between 14 and 46 months following diagnosis (median 30 months). In four of six cases the histopathological and immunohistological features were in keeping with a blastic NK-cell lymphoma. No clonal immunoglobulin heavy chain (IgH) or T-cell receptor (TCR) gene rearrangement was detected in the four cases consistent with an origin from NK cells. A further case fitted the criteria for an extranodal NK/T-cell lymphoma of nasal type and was also the only case to show evidence of EBV mRNA by ISH. A clonal T-cell population was identified in the final case. This patient also exhibited molecular evidence of a clonal B-cell population and a t(14;18) translocation confirmed by sequence analysis.
CONCLUSIONS: Our data confirm that NK-cell lymphomas presenting in the skin are a heterogeneous group, and that in the U.K., blastic NK-cell lymphoma is more common than extranodal NK/T-cell lymphoma of nasal type. These lymphomas pursue an aggressive course, with rapid development of disseminated disease, and resistance to chemotherapy. Detailed immunophenotyping is needed to distinguish the different types. Our molecular data indicate that blastic NK-cell lymphoma cases lack clonal TCR/IgH gene rearrangements consistent with an NK-cell origin. Our ISH findings indicate that EBV plays a pathogenetic role only in extranodal NK/T-cell lymphoma of nasal type.

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