Teresio Motta

Marker Expression in Peripheral T-Cell Lymphoma: A Proposed Clinical-Pathologic Prognostic Score

PURPOSEnAlthough peripheral T-cell lymphoma, unspecified (PTCL/U), is the most common T-cell tumor in Western countries, no study to date has been based on the application of a wide panel of markers to a large series of patients and assessed the impact of phenotype on survival. We evaluated the expression of 19 markers in 148 PTCLs/U and 45 PTCLs of the angioimmunoblastic type (AILD).nnnPATIENTS AND METHODSnThe analysis was performed on tissue microarrays by immunohistochemistry and in situ hybridization. Clinical data were available in 93 PTCL/U patients, most of whom had been included in a previous study proposing a prognostic index (PIT).nnnRESULTSnAn aberrant phenotype with frequent loss of CD5 and/or CD7 was typical for PTCLs, irrespective of whether they were U or AILD. Aberrantly expressed proteins rarely included CD20, CD15, and CD30. Positivity for Epstein-Barr virus-associated small RNAs and CD15 expression emerged as adverse prognostic factors. Among PTCLs/U, the proliferation-associated protein Ki-67 turned out to be prognostically relevant and was integrated in a new predictive score, incorporating age (> 60 years), high lactate dehydrogenase, poor performance status, and Ki-67 > or = 80%. This score was associated with the patient outcome (P < .0001) and was found to be more robust than PIT (P = .0043) in the present series.nnnCONCLUSIONnOur retrospective analysis shows a wide range of protein expression in PTCLs and proposes a new prognostic index. The latter represents one of the first examples of mixed score (including patient- and tumor-specific factors) applied to malignant lymphomas and may be the basis for future prospective therapeutic trials.

Epstein-Barr virus-negative lymphoproliferate disorders in long-term survivors after heart, kidney, and liver transplant.

BACKGROUNDnSolid organ transplant patients undergoing long-term immunosuppression have high risk of developing lymphomas. The pathogenesis of the late-occurring posttransplantation lymphoproliferative disorders (PTLD) have not yet been extensively investigated.nnnMETHODSnWe studied 15 patients who developed PTLD after a median of 79 months (range 22-156 months) after organ transplant. Clonality, presence of Epstein-Barr virus (EBV) genome, and genetic lesions were evaluated by Southern blot analysis or polymerase chain reaction.nnnRESULTSnAll monomorphic PTLD and two of three polymorphic PTLD showed a monoclonal pattern. Overall, 44% of samples demonstrated the presence of the EBV genome. Within monomorphic PTLD, the EBV-positive lymphomas were even lower (31%). A c-myc gene rearrangement was found in two cases (13%), whereas none of the 15 samples so far investigated showed bcl-1, bcl-2, or bcl-6 rearrangement. The modulation of immunosuppression was ineffective in all patients with monomorphic PTLD independent of the presence of the EBV genome. The clinical outcome after chemotherapy was poor because of infectious complications and resistant disease. With a median follow-up of 4 months, the median survival time of these patients was 7 months.nnnCONCLUSIONSnLate occurring lymphomas could be considered an entity distinct from PTLD, occurring within 1 year of transplant, because they show a histological and clinical presentation similar to lymphomas of immunocompetent subjects, are frequently negative for the EBV genome, are invariably clonal, and may rearrange the c-myc oncogene. New therapeutic strategies are required to reduce the mortality rate, and new modalities of long-lasting immunosuppression are called for.

Lymphomas occurring late after solid-organ transplantation: Influence of treatment on the clinical outcome

Background. Posttransplant lymphoproliferative disorders (PTLDs) that occur late after solid-organ transplantation are usually a monoclonal proliferation frequently characterized by the lack of the Epstein-Barr virus genome in tumor cells. The clinical outcome and the best management for patients who present with late PTLDs still remain unclear. Patients and Methods. Thirty patients who developed PTLDs more than 12 months (range 13–156) after heart, kidney, or liver transplantation were retrospectively evaluated. Median age was 36.7 years (range 1–70). Fifty-five percent of patients presented with advanced-stage (III–IV) lymphoma, 43% of patients presented with B symptoms, and 40% of patients showed extranodal involvement. Twenty-four cases (75%) were categorized as monoclonal monomorphic PTLD. Results. Three patients died of progressive multiorgan failure before any treatment was initiated. Overall, 17 (63%) patients obtained a clinical response (14 patients had complete remission [CR] and 3 patients had partial remission [PR]). Eight (47%) patients are still alive and in CR, two (12%) patients died in CR, and seven (41%) patients relapsed. With a median follow-up of 6 months (range 0.5–42.8), the median overall survival was 6.2 months. Both clinical response and survival were significantly influenced by the treatment. Indeed, all patients treated for limited disease with surgery or radiotherapy in combination with modulation of immunosuppression obtained CR and are still alive and in CR. On the contrary, 33% of patients who received chemotherapy obtained a clinical response, whereas 15% of patients who received chemotherapy showed progressive disease and 50% of patients who received chemotherapy died of toxicity (infectious or multiorgan failure). Conclusions. We suggest that patients with late PTLDs and limited disease may benefit from local treatment. For patients who require chemotherapy, we suggest that it should be administered to minimize the risk of infection complications.

Primary nodal marginal zone B-cell lymphoma: clinical features and prognostic assessment of a rare disease

This study defined the clinical features and assessed the prognosis of 47 patients (17 males, 30 females, median age 63u2003years) with primary nodal marginal zone B‐cell lymphoma. Forty‐five per cent had stage IV disease. Hepatitis C virus serology was positive in 24%. According to the Follicular Lymphoma International Prognostic Index (FLIPI), 33% were classified as low‐risk, 34% as intermediate‐risk, and 33% as high‐risk. The 5‐year overall survival (OS) was 69%. In univariate analysis worse OS was associated with: FLIPI (Pu2003=u20030·02), ageu2003>u200360u2003years (Pu2003=u20030·05) and raised lactate dehydrogenase (Pu2003=u20030·05). In multivariate analysis, only FLIPI predicted a worse OS (Pu2003=u20030·02).

Reactive perivascular T-cell infiltrate predicts survival in primary central nervous system B-cell lymphomas

Well‐established histopathological prognostic factors are lacking in primary central nervous system (CNS) lymphomas (PCNSL). The present study investigated the presence and prognostic role of tumour necrosis (TN) and reactive perivascular T‐cell infiltrate (RPVI), defined as a rim of small reactive T‐lymphocytes occurring alone or located between the vascular wall and large neoplastic cells, in tumour samples from 100 immunocompetent patients with PCNSL. World Health Organization histotypes of the patients were: 96 diffuse large B‐cell lymphomas, two Burkitt‐like lymphomas, one anaplastic large T‐cell lymphoma and one unclassified B‐cell lymphoma. TN was observed in 24 (24%) cases and RPVI in 26 (36%) of 73 assessable cases. Patients with RPVI‐positive lesions exhibited a significantly better overall survival (OS) than patients with RPVI‐negative lymphoma, particularly among patients treated with high‐dose methotrexate‐based chemotherapy (3‐year OS: 59u2003±u200314% vs. 42u2003±u20039%, Pu2003=u20030·02). By contrast, the presence of TN did not demonstrate prognostic significance. Multivariate analysis confirmed an independent association between RPVI and survival. In conclusion, the presence of RPVI is independently associated with survival in PCNSL. This parameter can be easily and routinely assessed at diagnosis on histopathological specimens.

Gela histological scoring system for post-treatment biopsies of patients with gastric MALT lymphoma is feasible and reliable in routine practice

The International Extranodal Lymphoma Study Group (IELSG) promoted this study to determine the inter‐observer agreement in the application of the Groupe d Etude des Lymphomes de l Adulte (GELA) histological scoring system for evaluating residual disease in post‐treatment gastric biopsies of patients with gastric Mucosa‐Associated Lymphoid Tissue (MALT) lymphoma (GML). Twenty‐one patients with Helicobacter pylori ‐associated GML and treated with anti‐H. pylori therapies were considered. A total of 154 biopsy sets from follow‐up endoscopic procedures after H. pylori eradication were examined independently by seven pathologists from four European countries, following histological criteria suggested by the GELA scoring system. The overall concordance rate was 83% with a kappa value of 0·64, indicating a significant agreement among the seven observers. Most non‐concordant responses clustered across the border of complete remission (CR) and probable minimal residual disease (pMRD), a distinction that does not imply critical clinical impact. Accordingly, when the analysis considered CR/pMRD as a single entity, the responses showed an overall concordance rate of 89% with kappa value of 0·83, thus indicating a high degree of inter‐observer agreement. This study provides additional validation of the GELA histological grading system. This scheme can therefore be recommended in routine practice and deserves to be used in prospective clinical trials.

The modified International Prognostic Index can predict the outcome of localized primary intestinal lymphoma of both extranodal marginal zone B-cell and diffuse large B-cell histologies.

Summary. We have previously reported on the efficacy of a modified International Prognostic Index (MIPI) in predicting the outcome of patients with primary gastric lymphoma. This prompted the retrospective analysis of a large series of patients with primary intestinal lymphoma (PIL) of both diffuse large B‐cell (DLCL) and low‐grade (extranodal marginal zone B‐cell lymphoma, MZL) histology. Clinical records of 122 patients with localized primary intestinal lymphoma of MZL (n=35) and DLCL (n=87) histology, confirmed by an ad hoc expert panel of pathologists, were reviewed. Forty‐nine patients were treated with single therapy, while 72 received combined‐modality treatment, which included surgery followed by a short‐term chemotherapy. MIPI was included in a multivariate prognostic analysis for overall survival (OS) and event‐free survival (EFS). Sixty‐five patients (75%) with DLCL and 22 with MZL(65%) achieved complete remission. After a median follow‐up of 42u2003months (range 6–163u2003months), 5‐year estimates of OS and EFS were 68% and 50% for DLCL and 65% and 26% for MZL. OS varied according to MIPI, from, respectively, 86% and 87% for DLCL and MZL patients with 0–1 risk factor to 50% and 32% for patients with >u200a1 risk factor (P=0·01 and P=0·02). Similar results were obtained for EFS. Cox regression analysis showed an unfavourable MIPI to be the only independent predictor of shorter EFS. This retrospective study shows that stage‐MIPI can be a reliable prognostic indicator for PIL of both low‐grade MZL and diffuse large B‐cell histology, enabling the early identification of patients at higher risk of failure.

Unexpected remission of acute myeloid leukaemia after GM‐CSF

Summary. The administration of granulocyte‐monocyte colony‐stimulating factor (GM‐CSF) was associated with complete clinical and haematological response in an adult patient with minimally differentiated acute myeloid leukaemia who presented with pneumonia and moderate neutropenia, but no blast cells in the peripheral blood. The response lasted 9 months. At relapse, a second GM‐CSF course resulted in a very good partial remission lasting 5 months, although differences in the kinetics of haemoglobin, neutrophil and platelet recovery were noted. Subsequent recurrences were managed with chemotherapy, a complete remission being obtained twice more and lastly consolidated with myeloablative chemo‐radiotherapy supported by a peripheral blood stem cell autograft. This report suggests that GM‐CSF should be further investigated as a therapeutic agent in selected cases of AML.

Immunoreactivity for cyclin D3 is frequently detectable in high-grade primary gastric lymphomas in the absence of the t(6;14)(p21.1;q32.3) chromosomal translocation

Cyclin D3 plays a pivotal role in controlling the physiological progression from the G1 to the S phase of the cell cycle. Recent data suggest that cyclin D3 may be deregulated in extranodal non‐Hodgkins lymphomas (NHLs) as a consequence of the t(6;14)(p21.1;q32.3) translocation. The present study investigated for the first time by dual‐colour fluorescence in situ hybridization (FISH) on interphase nuclei and immunohistochemistry the prevalence of the t(6;14) translocation and cyclin D3 immunoreactivity (IR) in a series of 29 stage I–IIE primary gastric NHLs (PGLs). No case showed the t(6;14) translocation. However, in five (17.2%) cases (two extranodal marginal zone lymphomas of MALT type, LGM; one diffuse large‐cell lymphoma with a MALT component, DLCLM; and two diffuse large‐cell lymphomas without a MALT component, DLCL), three to four cyclin D3 signals were detected by FISH. Co‐hybridization with probes specific for the centromeric region and long arm of chromosome 6 indicated trisomy in one case (DLCL), whereas in the remaining four cases the pattern was highly suggestive of the presence of an isochromosome 6p. One (12.5%) case of LGM, six (75%) cases of DLCLM, and seven (53.8%) cases of DLCL (p = 0.0378) were immunoreactive for cyclin D3. Cyclin D3 IR was detected in two (40%) of the five cases with extra cyclin D3 signals and in 12 of the remaining 24 cases (50%, p = 1.000). These results suggest that the t(6;14) may represent a rare event in the pathogenesis of PGL and that cyclin D3 deregulation is most likely the result of epigenetic mechanisms. Copyright

Gastric MALT lymphomas prospective LY03 randomised cooperative trial: preliminary results of the molecular follow-up

GASTRIC MALT LYMPHOMAS PROSPECTIVE LY03 RANDOMISED COOPERATIVE TRIAL: PRELIMINARY RESULTS OF THE MOLECULAR FOLLOW-UP Francesco Bertoni1,2, Annarita Conconi1,3, Carlo Capella4, Teresio Motta5, Roberto Giardini6, Maurilio Ponzoni7, Ennio Pedrinis8, Domenico Novero9, Paolo Rinaldi10, Giovanni Cazzaniga11, Andrea Biondi11, Andrew Wotherspoon12, Barry William Hancock13, Paul Smith14, Robert Souhami15, Finbarr E. Cotter 2, Franco Cavalli1, and Emanuele Zucca1 On behalf of the International Extranodal Lymphoma Study Group (IELSG) and the United Kingdom Lymphoma Group (UKLG).