PCR-based immunoglobulin (Ig)/T-cell receptor (TCR) clonality testing in suspected lymphoproliferations has largely been standardized and has consequently become technically feasible in a routine diagnostic setting. Standardization of the pre-analytical and post-analytical phases is now essential to prevent misinterpretation and incorrect conclusions derived from clonality data. As clonality testing is not a quantitative assay, but rather concerns recognition of molecular patterns, guidelines for reliable interpretation and reporting are mandatory. Here, the EuroClonality (BIOMED-2) consortium summarizes important pre- and post-analytical aspects of clonality testing, provides guidelines for interpretation of clonality testing results, and presents a uniform way to report the results of the Ig/TCR assays. Starting from an immunobiological concept, two levels to report Ig/TCR profiles are discerned: the technical description of individual (multiplex) PCR reactions and the overall molecular conclusion for B and T cells. Collectively, the EuroClonality (BIOMED-2) guidelines and consensus reporting system should help to improve the general performance level of clonality assessment and interpretation, which will directly impact on routine clinical management (standardized best-practice) in patients with suspected lymphoproliferations.
Angioimmunoblastic T-cell lymphoma (AITL) is an uncommon, but aggressive nodal peripheral T-cell lymphoma. Little is known of its biology and its natural history has been poorly studied. We report the first comprehensive study on the natural history/histologic progression of AITL by reviewing consecutive biopsies in 31 cases. Immunostaining for CD3, CD20, CD10 and CD21, CD23, CNA-42, CD4, CD8, and Ki 67, in situ hybridization for Epstein-Barr virus (EBV)-encoded RNA and polymerase chain reaction for T-clonality and B-clonality were performed. Histologic progression from AITL with limited nodal involvement and hyperplastic follicles (pattern I) to typical AITL with or without regressed follicles (patterns II and III) was observed in 7 cases, one of which relapsed subsequently as pattern I. Thirteen cases showed typical AITL at presentation and follow-up. Eleven cases where polymerase chain reaction results for T-cell receptor-gamma gene rearrangement were directly compared showed an identical band-size in the initial and follow-up biopsies. Seven cases (23%) developed EBV-associated B-cell lymphomas [5 diffuse large B-cell lymphoma (DLBCL) and 2 classic Hodgkin lymphoma]. In 4 cases, a dominant B-cell clone was observed in biopsies lacking evidence of DLBCL. A single case was complicated by EBV-negative DLBCL, whereas another with large cell transformation had a T-cell phenotype. In conclusion, AITL represents a clonal T-cell proliferation with a stable T-cell clone throughout the disease. Partial nodal involvement with hyperplastic follicles is seen in early AITL and at relapse. When "morphologic high-grade transformation" occurs, it is usually due to a secondary (often EBV-associated) B-cell lymphoma, rather than a T-cell neoplasm.
Synovial Sarcoma consistently harbors t(X;18) resulting in SS18-SSX1, SS18-SSX2 and rarely SS18-SSX4 fusion transcripts. Of 328 cases included in our study, synovial sarcoma was either the primary diagnosis or was very high in the differential diagnosis in 134 cases: of these, amplifiable cDNA was obtained from 131. SS18-SSX fusion products were found in 126 (96%) cases (74 SS18-SSX1, 52 SS18-SSX2), using quantitative and 120 by conventional reverse transcriptase-polymerase chain reaction (RT-PCR). One hundred and one cases in a tissue microarray, analyzed by fluorescence in situ hybridization (FISH), revealed that 87 (86%) showed SS18 rearrangement: four RT-PCR positive cases, reported as negative for FISH, showed loss of one spectrum green signal, and 15 cases had multiple copies of the SS18 gene: both findings are potentially problematic when interpreting results. One of three cases, not analyzed by RT-PCR reaction owing to poor quality RNA, was positive by FISH. SS18-SSX1 was present in 56 monophasic and 18 biphasic synovial sarcoma: SS18-SSX2 was detected in 41 monophasic and 11 biphasic synovial sarcoma. Poorly differentiated areas were identified in 44 cases (31%). There was no statistically significant association between biphasic, monophasic and fusion type. Five cases were negative for SS18 rearrangement by all methods, three of which were pleural-sited neoplasms. Following clinical input, a diagnosis of mesothelioma was favored in one case, a sarcoma, not otherwise specified in another and a solitary fibrous tumor in the third case. The possibility of a malignant peripheral nerve sheath tumor could not be excluded in the other two cases. We concluded that the employment of a combination of molecular approaches is a powerful aid to diagnosing synovial sarcoma giving at least 96% sensitivity and 100% specificity but results must be interpreted in the light of other modalities such as clinical findings and immunohistochemical data.
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