Francesco Bacci

Myeloid sarcoma: clinico-pathologic, phenotypic and cytogenetic analysis of 92 adult patients.

Myeloid sarcoma (MS) is a rare neoplasm whose knowledge is largely based on case reports and/or technically dated contributions. Ninety-two MSs in adulthood with clinical data available were evaluated both morphologically and immunohistochemically. Seventy-four cases were also studied by fluorescent in situ hybridization on tissue sections and/or conventional karyotyping on bone marrow or peripheral blood. Histologically, 50% of the tumors were of the blastic type, 43.5% either monoblastic or myelomonocytic and 6.5% corresponded to different histotypes. CD68/KP1 was the most commonly expressed marker (100%), followed by myeloperoxidase (83.6%), CD117 (80.4%), CD99 (54.3%), CD68/PG-M1 (51%), CD34 (43.4%), terminal-deoxy-nucleotidyl-transferase (31.5%), CD56 (13%), CD61/linker for activation of T cells (2.2%), CD30 (2.2%) and CD4 (1.1%). Foci of plasmacytoid monocyte differentiation were observed in intestinal cases carrying inv16. Chromosomal aberrations were detected in about 54% of cases: monosomy 7(10.8%), trisomy 8(10.4%) and mixed lineage leukemia-splitting (8.5%) were the commonest abnormalities, whereas t(8;21) was rare (2.2%). The behavior was dramatic irrespective of presentation, age, sex, phenotype and cytogenetics. Most if not all, long survivors received bone-marrow transplantation. The present report expands the spectrum of our knowledge showing that MS has frequent monoblastic/myelomonocytic differentiation, displays distinctive phenotypic profile, carries chromosomal aberrations other than t(8;21), and requires supra-maximal therapy.

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

PURPOSE Although 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). PATIENTS AND METHODS The 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). RESULTS An 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. CONCLUSION Our 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.

Role of [18F]Fluorodeoxyglucose Positron Emission Tomography Scan in the Follow-Up of Lymphoma

PURPOSE In lymphoma, [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) is routinely used for initial staging, early evaluation of treatment response, and identification of disease relapse. However, there are no prospective studies investigating the value of serial FDG-PET over time in patients in complete remission. PATIENTS AND METHODS All patients with lymphoma who achieved the first complete remission were prospectively enrolled onto the study and scheduled for serial FDG-PET scans at 6, 12, 18, and 24 months; further scans were then carried out on an annual basis. Overall, the population included 421 patients (160 patients with Hodgkins lymphoma [HL], 183 patients with aggressive non-Hodgkins lymphoma [NHL], and 78 patients with indolent follicular NHL). All patients had a regular follow-up evaluation, including complete clinical and laboratory evaluation, and final assessment of any suspect FDG-PET findings using other imaging procedures (computed tomography [CT] scan) and/or biopsy and/or clinical evolution. FDG-PET findings were reported as positive for relapse, inconclusive (when equivocal), or negative for relapse. RESULTS PET enabled documentation of lymphoma relapse in 41 cases at 6 months, in 30 cases at 12 months, in 26 cases at 18 months, in 10 cases at 24 months, and in 11 cases at more than 36 months. All 36 patients with inconclusive positive PET underwent biopsy; only 12 (33%) of 36 patients had a concomitant suggestion of positivity on CT. A lymphoma relapse was diagnosed in 24 (66%) of 36 patients. CONCLUSION Our results confirm FDG-PET as a valid tool for follow-up of patients with HL and NHL. In patients with inconclusive positive results, histologic confirmation plays an important role in identifying true relapse.

A phase II trial of CHOP chemotherapy followed by yttrium 90 ibritumomab tiuxetan (Zevalin) for previously untreated elderly diffuse large B-cell lymphoma patients

BACKGROUND A prospective, single-arm, open-label, nonrandomized phase II combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus radioimmunotherapy trial was conducted to evaluate the efficacy and safety in untreated elderly diffuse large B-cell lymphoma (DLBCL) patients. PATIENTS AND METHODS From February 2005 to April 2006, in our institute we treated 20 eligible elderly (age > or =60 years) patients with previously untreated DLBCL using a novel regimen consisting of six cycles of CHOP chemotherapy followed 6-10 weeks later by (90)Y ibritumomab tiuxetan. RESULTS The overall response rate to the entire treatment regimen was 100%, including 95% complete remission (CR) and 5% partial remission. Four (80%) of the five patients who achieved less than a CR with CHOP improved their remission status after radioimmunotherapy. With a median follow-up of 15 months, the 2-year progression-free survival was estimated to be 75%, with a 2-year overall survival of 95%. The (90)Y ibritumomab tiuxetan toxicity included grade > or =3 hematologic toxicity in 12 of 20 patients; the most common grade > or =3 toxic effects were neutropenia (12 patients) and thrombocytopenia (7 patients). Transfusions of red blood cells and/or platelets were given to one patient. CONCLUSION This study has established the feasibility, tolerability, and efficacy of this regimen for elderly patients with DLBCL.

Cytoplasmic mutated nucleophosmin (NPM) defines the molecular status of a significant fraction of myeloid sarcomas.

Cytoplasmic mutated nucleophosmin (NPM) defines the molecular status of a significant fraction of myeloid sarcomas

Molecular Profiling Improves Classification and Prognostication of Nodal Peripheral T-Cell Lymphomas: Results of a Phase III Diagnostic Accuracy Study

PURPOSE The differential diagnosis among the commonest peripheral T-cell lymphomas (PTCLs; ie, PTCL not otherwise specified [NOS], angioimmunoblastic T-cell lymphoma [AITL], and anaplastic large-cell lymphoma [ALCL]) is difficult, with the morphologic and phenotypic features largely overlapping. We performed a phase III diagnostic accuracy study to test the ability of gene expression profiles (GEPs; index test) to identify PTCL subtype. METHODS We studied 244 PTCLs, including 158 PTCLs NOS, 63 AITLs, and 23 ALK-negative ALCLs. The GEP-based classification method was established on a support vector machine algorithm, and the reference standard was an expert pathologic diagnosis according to WHO classification. RESULTS First, we identified molecular signatures (molecular classifier [MC]) discriminating either AITL and ALK-negative ALCL from PTCL NOS in a training set. Of note, the MC was developed in formalin-fixed paraffin-embedded (FFPE) samples and validated in both FFPE and frozen tissues. Second, we found that the overall accuracy of the MC was remarkable: 98% to 77% for AITL and 98% to 93% for ALK-negative ALCL in test and validation sets of patient cases, respectively. Furthermore, we found that the MC significantly improved the prognostic stratification of patients with PTCL. Particularly, it enhanced the distinction of ALK-negative ALCL from PTCL NOS, especially from some CD30+ PTCL NOS with uncertain morphology. Finally, MC discriminated some T-follicular helper (Tfh) PTCL NOS from AITL, providing further evidence that a group of PTCLs NOS shares a Tfh derivation with but is distinct from AITL. CONCLUSION Our findings support the usage of an MC as additional tool in the diagnostic workup of nodal PTCL.

Pathobiology of hodgkin lymphoma.

Despite its well-known histological and clinical features, Hodgkins lymphoma (HL) has recently been the object of intense research activity, leading to a better understanding of its phenotype, molecular characteristics, histogenesis, and possible mechanisms of lymphomagenesis. There is complete consensus on the B-cell derivation of the tumor in most cases, and on the relevance of Epstein-Barr virus infection and defective cytokinesis in at least a proportion of patients. The REAL/WHO classification recognizes a basic distinction between lymphocyte predominance HL (LP-HL) and classic HL (cHL), reflecting the differences in clinical presentation and behavior, morphology, phenotype, and molecular features. cHL has been classified into four subtypes: lymphocyte rich, nodular sclerosing, with mixed cellularity, and lymphocyte depleted. The borders between cHL and anaplastic large-cell lymphoma have become sharper, whereas those between LP-HL and T-cell-rich B-cell lymphoma remain ill defined. Treatments adjusted to the pathobiological characteristics of the tumor in at-risk patients have been proposed and are on the way to being applied.

Peripheral T-cell lymphoma classification: The matter of cellular derivation

Peripheral T-cell lymphomas (PTCLs) represent approximately 12% of all non-Hodgkin’s lymphomas in Western countries. They are quite heterogeneous as far as morphology and phenotype are concerned. Furthermore, until now, PTCLs could not be referred to specific normal counterparts, in contrast to B-cell-derived non-Hodgkin’s lymphomas. In particular, in the last edition of the WHO classification of Tumors of the Hematopoietic and Lymphoid Tissues, for the majority of nodal PTCLs (including the not otherwise specified type and anaplastic large-cell lymphoma), the postulated cell of origin remained undefined. However, in the last few years, high-throughput genomic techniques, especially gene-expression profiling, have allowed us to better define the relationship between some entities and the different T-cell subpopulations. Consequently, it has become possible to clearly define, for example, the association between angioimmunoblastic T-cell lymphoma and T-follicular helper cells. In addition, within PTCLs/not otherwise specified, different subgroups were identified based on their similarity to different cellular counterparts, including T-helper, T-cytotoxic and T-follicular helper cells. In this article, based on their own experience as well as up-to-date literature, the authors revise the concept of PTCL classification by specially focusing on their cellular counterparts and discuss the possible clinical relevance of such an approach.

Pathobiology of Anaplastic Large Cell Lymphoma

The authors revise the concept of anaplastic large cell lymphoma (ALCL) in the light of the recently updated WHO classification of Tumors of Hematopoietic and Lymphoid Tissues both on biological and clinical grounds. The main histological findings are illustrated with special reference to the cytological spectrum that is indeed characteristic of the tumor. The phenotype is reported in detail: the expression of the ALK protein as well as the chromosomal abnormalities is discussed with their potential pathogenetic implications. The clinical features of ALCL are presented by underlining the difference in terms of response to therapy and survival between the ALK-positive and ALK-negative forms. Finally, the biological rationale for potential innovative targeted therapies is presented.

Detection of LIM domain only 2 (LMO2) in normal human tissues and haematopoietic and non-haematopoietic tumours using a newly developed rabbit monoclonal antibody

Agostinelli C, Paterson J C, Gupta R, Righi S, Sandri F, Piccaluga P P, Bacci F, Sabattini E, Pileri S A & Marafioti T 
(2012) Histopathology 61, 33–46