Frequency of Synaptic Autoantibody Accompaniments and Neurological Manifestations of Thymoma.

IMPORTANCE: Thymoma is commonly recognized in association with paraneoplastic autoimmune myasthenia gravis (MG), an IgG-mediated impairment of synaptic transmission targeting the nicotinic acetylcholine receptor of muscle. Newly identified synaptic autoantibodies may expand the serological profile of thymoma. OBJECTIVE: To investigate the frequency of potentially pathogenic neural synaptic autoantibodies in patients with thymoma. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively identified patients with histopathologically confirmed thymoma and serum available to test for synaptic autoantibodies (collected 1986-2014) at the Mayo Clinic Neuroimmunology Laboratory. We identified and classified 193 patients with thymoma into 4 groups: (1) lacking neurological autoimmunity (n = 43); (2) isolated MG (n = 98); (3) MG plus additional autoimmune neurological manifestations (n = 26); and (4) neurological autoimmunity other than MG (n = 26). MAIN OUTCOMES AND MEASURES: Clinical presentation and serum profile of autoantibodies reactive with molecularly defined synaptic plasma membrane proteins of muscle, peripheral, and central nervous systems. RESULTS: Of the 193 patients with thymoma, mean patient age was 52 years and did not significantly differ by sex (106 women) or group. Myasthenia gravis was the most prevalent clinical manifestation (64%) followed by dysautonomia (16 patients [8%]) and encephalopathy (15 patients [8%]); 164 patients (85%) had at least 1 synaptic autoantibody, and 63 of these patients (38%) had at least 1 more. Muscle acetylcholine receptor was most frequent (78%), followed by ganglionic acetylcholine receptor (20%), voltage-gated Kv1 potassium channel-complex (13%), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (5%). Less frequent were aquaporin-4, voltage-gated Kv1 potassium channel-complex related proteins (leucine-rich glioma-inactivated 1 and contactin-associated protein-like 2), glycine receptor, and γ-aminobutyric acid-A receptor. Synaptic autoantibodies were significantly more frequent in patients with neurological autoimmunity than in those without and were most frequent in patients with neurological manifestations other than or in addition to MG. CONCLUSIONS AND RELEVANCE: Synaptic autoantibodies, particularly those reactive with ion channels of the ligand-gated nicotinic acetylcholine receptor superfamily (namely α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, glycine, and γ-aminobutyric acid-A receptors), were prevalent in patients with thymoma. Autoantibodies of this extended spectrum may enhance autoimmune serological testing as an aid to preoperative thymoma diagnosis. Detection of currently known synaptic autoantibody specificities absent from this profile have potential algorithmic usefulness as negative predictors for thymoma (as recognized for neuronal voltage-gated calcium channel autoantibodies).

Co-existent cutaneous cryptococcosis of the forearm and cutaneous alternariosis of the leg in patient with metastatic thymoma.

BACKGROUND: Cryptococcosis and alternariosis are rare opportunistic infections often observed in immunocompromised patients. Because Cryptococcus and Alternaria are ubiquitous fungi found in soil, the presence of fungi in the dermis has to be observed on histological examination to confirm a real cutaneous, invasive, infection. PATIENT: We report the first case of concomitant cutaneous cryptococcosis and cutaneous alternariosis, in an immunocompromised patient treated for a metastatic thymoma. CONCLUSION: This observation underlines the fact that the possible co-existence of several rare infections in immunocompromised patients should take into consideration pathogen identification in order to adapt the therapy to individual patient requirements.

Thymic carcinoma with a defective Epstein-Barr virus encoding the BZLF1 trans-activator.

The diagnosis of Epstein-Barr virus (EBV)-associated carcinomas is often heralded by high antibody titers to the viral replicative antigens, suggesting EBV reactivation may be a factor in tumor evolution. EBV DNA and nuclear antigen was detected in a newly diagnosed thymic carcinoma. Polymerase chain reaction analysis revealed the presence of a rearranged EBV DNA fragment, BamHI WZhet. This rearrangement is found in a defective EBV that up-regulates the BZLF1 (BamHI Z leftward reading frame) gene product in vitro and induces the EBV lytic cycle. Molecular analysis of the EBV termini demonstrated low levels of the lytic (linear) genomic configuration among a predominantly latent (episomal) population at diagnosis. The episomal populations were of uniform molecular weight at diagnosis and relapse, indicating clonal tumor expansion from a single EBV-infected progenitor. The presence within malignant epithelium of defective virus that can disrupt EBV latency, and perhaps cellular gene regulation, suggests a potential mechanism for EBV reactivation and concurrent malignant progression.

Analysis of oncogenic progression in a radiation leukemia virus model.

The mechanism by which non-oncogene-bearing, slowly transforming retroviruses induce leukemia is not well understood, but appears to represent a multi-step process. Cell lines have been isolated following in vitro infection of lymphoid cells with radiation leukemia virus (RadLV) and they have been used to develop a two-step model for leukemia development. Thymic tumors were induced when one of the cell lines, C1-V13D, was inoculated into CBA/H mouse thymus. Upon reisolation of C1-V13D cells after one, two and three passages through thymus, individual cloned cell lines displayed increased tumorigenic potential compared with the non-tumorigenic parental line. Southern analysis has been used to track any genetic changes occurring while cells undergo further transformation and become increasingly tumorigenic. Specifically, retrovirus integration has been monitored in clones derived from C1-V13D at the primary, secondary and tertiary passage through thymus using probes specific for long terminal repeat (LTR), gag, pol and env genes of RadLV. The data indicate multiple ecotropic retrovirus integration sites in C1-V13D cells. Primary thymic tumors also showed the integration of a new recombinant or defective virus. There was no evidence that new ecotropic retrovirus integration had occurred during subsequent passage of primary tumors through the thymus, i.e. during the progression to oncogenesis. All data indicate an important role for the thymic environment in the development of a fully transformed cell.

Evolution of feline leukemia virus variant genomes with insertions, deletions, and defective envelope genes in infected cats with tumors.

In order to study retroviral variation, selection, and viral correlates of in vivo pathogenicity, we documented the evolution of feline leukemia virus (FeLV) variants in cats that died with thymic lymphoma after infection with molecularly cloned subgroup A FeLV. Using genomic DNA from cat necropsy samples, we employed PCR to amplify and clone the envelope gene, which is a major determinant of the specific pathogenicity of different FeLV variants. In the envelope gene, mutations encoded scattered amino acid changes that did not cluster into clearly definable variable regions; however, characterization of these terminal variant sequences revealed a predominance of G-to-A and A-to-G nucleotide substitutions. Additionally, some cats harbored variants with recombinant subgroup B-like envelope genes, while the major variant from one cat had a 12-bp insertion in a region previously characterized as an immunodeficiency-inducing determinant. Finally, proviruses from tumor DNA frequently possessed envelope genes predicted to encode a protein truncated in the N-terminal half because of either premature termination codons or deletions ranging from 29 to 1,666 bp. In contrast, all envelope genes cloned from the bone marrow of one cat were predicted to encode full-length envelope product, and only a minority of proviral clones from a cat that did not develop a tumor had defective envelope genes. Thus, in the cat, viruses evolved from subgroup A FeLV that had point mutations, insertions, deletions, or recombinant envelope genes. Furthermore, defective variants were particularly prominent in T-cell tumors.

Radiation leukemia virus-induced thymic lymphomas express a restricted repertoire of T-cell receptor V beta gene products.

We have investigated the phenotypic changes that take place during the process of neoplastic transformation in the thymocytes of C57BL/Ka mice infected by the radiation leukemia virus (RadLV). By the combined use of antibodies against the envelope glycoprotein gp70 of RadLV, the transformation-associated cell surface marker 1C11, and the CD3-T-cell receptor (TCR) complex, we found that in the RadLV-infected thymus, the earliest expression of viral gp70 is in 1C11hi cells; a small but significant percentage of these cells also express CD3. A first wave of viral replication, manifested by the expression of high levels of gp70 in thymocytes (over 70% positive), reaches a peak at 2 weeks; during this period, no significant changes are observed in the expression of 1C11 or CD3. The population of gp70+ cells is drastically reduced at 3 to 4 weeks after infection. However, a second cohort of gp70+ cells appears after 4 weeks, and these cells express high levels of 1C11 and TCR determinants as well. RadLV-induced lymphomas differ from normal thymocytes in their CD4 CD8 phenotype, with domination by one or more subsets. Characterization of TCR gene rearrangements in RadLV-induced lymphomas shows that most of these tumors are clonal or oligoclonal with respect to the J beta 2 TCR gene, while the J beta 1 TCR gene is rearranged in a minority (4 of 11) of lymphomas. TCR V beta repertoire analysis of 12 tumors reveals that 6 (50%) express exclusively the V beta 6 gene product, 2 (17%) are V beta 5+, and 1 (8%) each are V beta 8+ and V beta 9+. In normal C57BL/Ka mice, V beta 6 is expressed on 12%, V beta 5 is expressed on 9%, V beta 8 is expressed on 22%, and V beta 9 is expressed on 4% of TCRhi thymocytes. Thus, it appears that RadLV-induced thymic lymphomas are not randomly selected with respect to expressed TCR V beta type.

Long-range mapping of Mis-2, a common provirus integration site identified in murine leukemia virus-induced thymomas and located 160 kilobase pairs downstream of Myb.

The nondefective Moloney murine leukemia virus (MuLV) induces clonal or oligoclonal T-cell tumors in mice or rats. The proviruses of these nondefective MuLVs have been shown to act as insertion mutagens most frequently activating an adjacent cellular gene involved in cell growth control. Mutations by provirus insertions, recognized as common provirus integration sites, have been instrumental in identifying novel cellular genes involved in tumor formation. We have searched for new common provirus integration sites in Moloney MuLV-induced thymomas. Using cellular sequences flanking a provirus cloned from one of these tumors, we found one region, designated Mis-2, which was the target of provirus integration in a low (3%) percentage of these tumors. Mis-2 was mapped on mouse chromosome 10, approximately 160 kbp downstream of myb. The Mis-2 region may contain a novel gene involved in tumor development.

BCR-ABL and v-abl oncogenes induce distinct patterns of thymic lymphoma involving different lymphocyte subsets.

The human BCR-ABL oncogenes encoded by the Philadelphia chromosome (Ph) affect the pathogenesis of diverse types of leukemia and yet are rarely associated with T-lymphoid leukemia. To determine whether BCR-ABL kinases are inefficient in transforming T lymphocytes, BCR-ABL-expressing retroviruses were injected intrathymically into mice. Thymomas that expressed BCR-ABL kinase developed after a relatively long latent period. In most thymomas, deletion of 3' proviral sequences resulted in loss of tk-neo and occasionally caused expression of kinase-active carboxy-terminally truncated BCR-ABL oncoprotein. In contrast, deletion of 3' proviral sequences was not observed in thymomas induced with Abelson murine leukemia virus (A-MuLV). BCR-ABL viruses induced distinct patterns of disease and involved different thymocyte subsets than A-MuLV and Moloney murine leukemia virus (Mo-MuLV). While Mo-MuLV only induced Thy-1+ thymomas, v-abl- and BCR-ABL-induced thymomas often contained mixed populations of B220+ and Thy-1+ lymphocytes in the same tumor. In most v-abl and BCR-ABL tumors, Thy-1+ lymphoid cells expressed CD8 and a continuum of CD4 ranging from negative to positive. Conversely, Mo-MuLV thymomas contained distinct populations of CD4+ cells that were either CD8+ or CD8-. A-MuLV-transformed T-lymphoid cells did not express the CD3/T-cell receptor complex, while BCR-ABL tumors were CD3+. Thus, BCR-ABL viruses preferentially induce somewhat more differentiated T lymphocytes than are transformed by A-MuLV. Furthermore, rare B220+ lymphocytes may represent preferred v-abl and BCR-ABL transformation targets in the thymus.

Coincident involvement of flvi-2, c-myc, and novel env genes in natural and experimental lymphosarcomas induced by feline leukemia virus.

The flvi-2 locus is a target of insertional mutagenesis in thymic lymphosarcomas induced by feline leukemia virus (FeLV). flvi-2 encodes the gene bmi-1, whose product is implicated as a myc-collaborator in the induction of B- and T-cell lymphoma. We have examined the involvement of flvi-2 and myc in natural and experimentally induced FeLV-positive feline lymphosarcomas which are heterogeneous in anatomical origin, geographic origin, and strain of FeLV involved. We further compared these findings with previous reports of novel FeLV env genes in the same tumors. The results show that proviral insertion at flvi-2 occurs commonly in natural and experimental feline thymic lymphosarcomas of diverse origins [52% overall], and that alterations in c-myc commonly accompany insertional mutagenesis of flvi-2 [54% overall]. However, 46% of tumors with flvi-2 insertions apparently lack involvement of c-myc. These observations support the hypothesis that interruption of flvi-2 may be an early event in a multistep cascade, one possibility for completion of which is activation of c-myc. Interruption of flvi-2 was not observed in nonthymic lymphosarcomas of alimentary or multicentric origin, although c-myc may be involved. A proportion of both thymic and nonthymic tumors have been shown previously to contain FeLV proviruses with recombinant or mutant env genes. Our findings strongly implicate the insertional mutagenesis of flvi-2, the activation of c-myc, and the emergence of novel env genes in FeLV-mediated lymphomagenesis, particularly in the induction of thymic lymphosarcoma. The data show that these events may overlap, but do not necessarily occur concurrently.

Lymphomagenesis in AKR.Fv-1b congenic mice.

In the AKR.Fv-1b congenic strain the Fv-1n allele of the AKR/J mice was substituted with the Fv-1b allele, thereby limiting viral replication and spread of the endogenous N-tropic murine leukemia virus. As a result of this genetic change AKR.Fv-1b mice develop a low spontaneous incidence (7%) of T-cell lymphomas and about 28% of Ly-1+ B-cell lymphomas are observed in old mice. Characteristic changes in thymus subpopulations of AKR/J mice (related to the formation of the dual tropic mink cell focus inducing (MCF) type virus in the thymus) were not observed in the thymus of AKR.Fv-1b mice. In contrast to the low susceptibility to spontaneous T-cell lymphoma development, these mice were highly sensitive to fractionated irradiation or to radiation leukemia virus (a mixture of N- and B-tropic viruses) induced T-cell lymphoma. Potential lymphoma cells (that would ultimately develop into Ly-1+ B-cell lymphomas) were demonstrated in bone marrow and spleens of 16-24-month-old mice. Analysis of the Ly-1+ IgM+ B-cell population in spleens of 18-month-old mice revealed a significant increase in this population (35% versus 2% in young spleens). The spontaneous Ly-1+ B-cell lymphoma incidence could be enhanced (up to 77%) by in vivo administration of anti-CD8 monoclonal antibody or IL-4 to 18-month-old mice. Virological analysis of T/B-cell lymphomas for class I MCF viruses indicated that Class I MCF development was tightly correlated with T-lymphoma development (except radiation induced tumors that showed no MCF provirus involvement). In contrast, Ly-1+ B-cell lymphoma development was independent of Class I MCF pathogenic virus involvement.

flvi-2, a target of retroviral insertional mutagenesis in feline thymic lymphosarcomas, encodes bmi-1.

LC-FeLV is a myc-containing strain of feline leukemia virus which induces thymic lymphosarcoma in the domestic cat with short latency. A locus in feline DNA, termed flvi-2, is commonly interrupted in naturally occurring and experimentally induced thymic lymphosarcomas containing LC-FeLV; thus, interruption of a gene encoded by flvi-2 may cooperate with the myc oncogene in the induction of T-cell tumors by LC-FeLV. Clones homologous to flvi-2 have been isolated from a normal human thymus cDNA library. Nucleotide sequence analysis of the cDNA clones demonstrates that flvi-2 encodes bmi-1, a gene previously identified as a target for MoMuLV integration and as a myc-collaborator in retrovirally-induced B-cell lymphomas in E mu-myc transgenic mice. In feline thymic lymphomas, retroviral integrations occur downstream of the gene, and result in enhanced expression of a bmi-1 transcript of normal size. These findings demonstrate the interruption of bmi-1 in natural as well as experimentally induced tumors, implicate the activation of bmi-1 in the induction of T-cell as well as B-cell lymphoma, and support the premise that bmi-1 functions as a myc collaborator.

Use of transgenic mice reveals cell-specific transformation by a simian virus 40 T-antigen amino-terminal mutant.

We have used the multifunctional transforming protein, simian virus 40 T antigen, as a probe to study the mechanisms of cell growth regulation in the intact organism. T antigen appears to perturb cell growth, at least in part, by stably interacting with specific cellular proteins that function to maintain normal cell growth properties. Experiments in cultured cells indicate that at least three distinct regions of simian virus 40 T antigen have roles in transformation. Two regions correlate with the binding of known cellular proteins, p53, pRB, and p107. A third activity, located near the amino terminus, has been defined genetically but not biochemically. By targeting expression of wild-type and mutant forms of T antigen to distinct cell types in transgenic mice, we have begun to systematically determine which activities play a role in tumorigenesis of each cell type. In this study, we sought to determine the role of the amino-terminal transformation function with such an analysis of the T-antigen mutant dl1135. This protein, which lacks amino acids 17 to 27, retains the p53-, pRB-, and p107-binding activities yet fails to transform cells in culture. To direct expression in transgenic mice, we used the lymphotropic papovavirus transcriptional signals that are specific for B and T lymphocytes and the choroid plexus epithelium of the brain. We show here that although defective in cell culture, dl1135 specifically induced the development of thymic lymphomas in the mouse. Expression of the protein was routinely observed in B- and T-lymphoid cells, although B-cell abnormalities were not observed. Choroid plexus tumors were observed only infrequently; however, dl1135 was not consistently expressed in this tissue. Within a given transgenic line, the penetrance of T-cell tumorigenesis was 100% but appeared to require secondary events, as judged from the clonal nature of the tumors. These experiments suggest that the amino-terminal region of T antigen has a role in the transformation of certain cell types (such as fibroblasts in culture and B lymphocytes) but is dispensable for the transformation of T lymphocytes.

EBER-1 expression in thymic carcinoma.

The Epstein-Barr virus-encoded small nuclear RNA, EBER-1, has been shown to be a suitable target for the in situ hybridization detection of EBV in routinely processed tissue specimens. We evaluated the presence of EBV in thymic carcinoma and invasive thymoma using EBER-1 in situ hybridization on formalin-fixed paraffin-embedded tissue sections. EBER-1 expression was demonstrated in a case of lymphoepithelioma-like thymic carcinoma, but was not detectable in other thymic carcinomas including six squamous cell carcinomas, a clear cell carcinoma and seven invasive thymomas. As reported in three previous cases of EBV-associated thymic carcinoma, lymphoepithelioma-like thymic carcinoma was shown to be closely associated with EBV in our series.

Loss of antigenic epitopes as the result of env gene recombination in retrovirus-induced leukemia in immunocompetent mice.

The murine leukemia virus, E-55+ virus, induces a thymic lymphoma/leukemia in 100% of BALB.K mice infected as adults after a latent period of 4 months or more (Pozsgay et al., Virology 173, 330-334, 1989). Two molecular clones of virus designated E-55+ and E-55- based on their ability to encode the E-55 epitope detected by the monoclonal antibody 55 (mAb 55) were isolated from a leukemic BALB.K mouse inoculated with a biologically cloned E-55+ virus (Chesebro et al., Virology 112, 131-144, 1981). Env gene sequence analysis of E-55+ and E-55- clones showed that the E-55- virus was generated from the E-55+ virus as the result of a recombination between E-55+ virus and the endogenous ecotropic virus, emv-1, carried in the genome of the BALB.K mouse strain. The recombinant E-55- virus is replication competent. This recombination event and the consequential expression of E-55- virus consistently occur in immunocompetent BALB.K mice inoculated with the E-55+ virus and appear to play a role in the loss of epitopes recognized by virus neutralizing antibodies. The loss of these epitopes apparently allows the virus to evade the host immune response.

A common integration locus in type B retrovirus-induced thymic lymphomas.

Type-B leukemogenic retrovirus (TBLV) is a replication-competent type-B thymotropic retrovirus which lacks a transforming gene and whose genome is > 98% homologous to that of type-B mouse mammary tumor virus (MMTV). In contrast to MMTV, which induces mammary adenocarcinomas, TBLV induces a high incidence of T-cell thymic lymphomas in mice after a very short latent period. To investigate the molecular mechanisms by which TBLV induces T-cell lymphomas, we screened TBLV-induced tumor DNA for the frequent disruption of a particular cellular locus by TBLV proviral copies. In approximately 20% of the 55 primary tumors screened, the presence of proviruses in a common integration site was detected. This locus spans at least 53 kb of genomic DNA and maps to the mouse X chromosome. The presence of a functional gene at this locus is suggested by the conservation of nucleotide sequences from this locus among diverse animal species and by the expression of these sequences as mRNA in normal mouse tissues and tumors. The majority (17/18) of TBLV-induced primary tumors examined have elevated levels of this expressed mRNA.

Contributions to transcriptional activity and to viral leukemogenicity made by sequences within and downstream of the MCF13 murine leukemia virus enhancer.

We have identified nucleotide sequences that regulate transcription in both a cell-type-specific and general manner in the long terminal repeat of the MCF13 murine leukemia virus. Besides the enhancer element, we have observed that the region between the enhancer and promoter (DEN) has a profound effect on transcription in different cell types. This effect, however, was dependent on the copy number of enhancer repeats and was detectable in the presence of a single repeat. When two enhancer repeats were present, the effect of DEN on transcription was abrogated except in T cells. DEN also makes a significant contribution to the leukemogenic property of the MCF13 retrovirus. Its deletion from the MCF13 virus dramatically reduced the incidence of thymic lymphoma and increased the latency of disease in comparison with the wild-type virus. This effect was most marked when one rather than two enhancer repeats was present in the mutant viruses. We also observed that the removal of one repeat alone remarkably reduced leukemogenicity by the MCF13 virus. A newly identified protein-binding site (MLPal) located within DEN affects transcription only in T cells, and its deletion attenuates the ability of an MCF13 virus with a single enhancer repeat to induce thymic lymphoma. This observation suggests that the MLPal protein-binding site contributes to the effect of the DEN region on T-cell-specific transcription and viral leukemogenicity. This study identifies the importance of nonenhancer sequences in the long terminal repeat for the oncogenesis of the MCF13 retrovirus.

Patterns of responsiveness of T cell lines and thymocytes reveal waves of specific activity in the post-natal murine thymus.

Antibody binding of CD3, CD4, or CD8 molecules can induce cytoplasmic calcium mobilization in T lymphocytes, usually interpreted as indicating signal transduction. Using such assays, in a CD4+ CD8+ thymocyte line and its single positive progeny we have identified characteristic patterns of responsiveness that are reproducible in vivo in a subpopulation of newborn 'double positive' thymocytes but virtually absent in adult thymuses. In particular, these cells appear to be high responders to the binding of anti-CD3 F(ab)'2 fragments. We have followed the presence of such highly responsive thymocytes in the perinatal period and the first 15 days of life. Intriguingly, these cells populate the newborn thymus in three distinct waves. Such patterns of responsiveness may define early 'selectable' thymocytes.

Diverse classes of T-cell lymphomas arise in T-lymphocyte-inductive epitheliomas of the mouse salivary gland.

During the course of serial transplantations of polyomavirus-induced C3H-Bittner salivary gland epitheliomas in F1-hybrid mice, three tumor sublines were found which gave rise to T-cell lymphomas of host origin. The lymphomas resembled spontaneous AKR/J thymic lymphomas in their expression of lymphoid differentiation antigens, and they may represent sequential stages in the differentiation of immature T lymphocytes. We found no evidence that polyomavirus directly induced the lymphomas, rather, the lymphomagenic events paralleled those which occur in spontaneous AKR/J thymic lymphomas.

Determinants of thymotropism in Kaplan radiation leukemia virus and nucleotide sequence of its envelope region.

Radiation leukemia viruses (RadLVs) are a group of murine leukemia viruses which are induced by radiation and cause T-cell leukemia. Viral clones isolated from the BL/VL3 lymphoid cell line derived from a thymoma show variable tropism and leukemogenic potential. We have constructed chimeric viruses by in vitro recombination between two viruses, a RadLV that is thymotropic and an endogenous ecotropic virus that is nonthymotropic. We show here that, in contrast to thymotropism determinants identified previously, which lie in the long terminal repeat (LTR), it is the envelope region that is responsible for the thymotropism of BL/VL3 RadLV. The nonthymotropic virus which we have rendered thymotropic by transfer of the env region of RadLV in the present study has been shown previously to become thymotropic when the LTR of another thymotropic virus is inserted in its genome. Thus, the LTR and envelope gene may be involved in complementary action to lead to thymotropism.

In situ localization of Epstein-Barr virus in thymic carcinoma.

Epstein-Barr virus (EBV) genome is associated with a variety of lymphoid and epithelial malignancies. EBV DNA has been detected in some cases of thymic carcinoma, but the cellular locus of the virus has never been defined. Detection of EBV has also been reported in normal thymus, thymic lymphoid hyperplasia, and thymoma by some investigators but not by others. In order to better define the association of the virus with benign and malignant thymic tissues and to characterize its cellular locus, we applied a recently developed in situ hybridization technique using a very abundant EBV transcript (EBER1) as target to a variety of thymic tissues. We detected expression of this transcript only in the malignant epithelial cells in one case of thymic lymphoepithelioma-like carcinoma. EBV expression was not detected in six other cases of thymic carcinoma, nor in tissue from 16 normal thymuses, 14 thymomas, and 10 thymic lymphoid hyperplasias.