Chronic reparative changes in medium-sized vessels in a case of primary cutaneous anaplastic large-cell lymphoma with angioinvasive features and cytotoxic phenotype: new histopathological findings in line with indolent clinical behavior

Angioinvasion/angiodestruction has been reported in a small subset of primary cutaneous anaplastic large-cell lymphomas (PCALCL). Recently, PCALCL with angioinvasive features and cytotoxic phenotype has been characterized as a variant associated with good clinical outcomes despite worrisome histopathologic features. We report a case of PCALCL with angioinvasive features and cytotoxic phenotype associated with reparative changes on the wall of medium-sized vessels involved by the neoplasm, including intimal fibroblastic proliferation and luminal obliteration. This vascular pattern, although previously unreported in PCALCL, is in accordance with the indolent behavior observed in this entity and provides a further link with lymphomatoid papulosis type E.

Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-cell lymphoma and Sezary syndrome.

Signaling through the interleukin 2 receptor (IL-2R) involves phosphorylation of several proteins including Jak3, STAT5, and, in preactivated cells, STAT3. In the present study, we examined the functional status of the IL-2R-associated Jak/STAT pathway in malignant T lymphocytes from advanced skin-based lymphomas: anaplastic large T-cell lymphoma (ALCL) and Sezary syndrome (SzS). Proliferation of three ALCL cell lines (PB-1, 2A, and 2B) was partially inhibited by rapamycin, a blocker of some of the signals mediated by IL-2R, but not by cyclosporin A, FK-506, and prednisone, which suppress signals mediated by the T-cell receptor. All the cell lines expressed on their surface the high-affinity IL-2R (alpha, beta, and gamma c chains). They showed basal, constitutive phosphorylation, and coassociation of Jak3, STAT5, and STAT3. Weak basal phosphorylation of IL-2R gamma c was also detected. In regard to SzS, peripheral blood mononuclear cells from 10 of 14 patients showed basal phosphorylation of Jak3, accompanied by phosphorylation of STAT5 in 9 patients, and STAT3 in 4 patients. However, in vitro overnight culture of SzS cells without exogenous cytokines resulted in markedly decreased Jak3 and STAT5 phosphorylation, which could be reversed by stimulation with IL-2. This indicates that the basal phosphorylation of Jak3 and STAT5 in freshly isolated SzS cells is induced rather than constitutive. The basal activation of the Jak/STAT pathway involved in IL-2R signal transduction in ALCL and SzS cells reported here suggests that this pathway may play a role in the pathogenesis of cutaneous T-cell lymphomas, although the mechanism (induced versus constitutive) may vary between different lymphoma types.

Studies on the adhesion properties of the liver-metastatic murine RAW117 large-cell lymphoma cells: Roles of $\beta\sb3$ integrin

Metastasis is the major cause of death in cancer patients. Since many cancers show organ-preference of metastasis, elucidation of the underlying mechanisms of metastasis will benefit diagnosis or treatment of metastatic diseases. Adhesion mechanisms are thought to be involved in organ-preference of metastasis, because metastatic cells show organ preference in adhering to organ-derived microvascular endothelial cells. The adhesion molecules in this process remain largely unidentified. I have examined a series of murine RAW117 large-cell lymphoma cells variants selected in vivo for liver-colonizing properties ($\rm{H10{>>}L17>P}$). The highly liver-metastatic H10 cells were found to differentially express much higher levels of integrin $\alpha\rm\sb{v}\beta\sb3$ than L17 or P cells. H10 cells also adhered at higher rates to vitronectin and fibronectin than to fibrinogen, fibrin, laminin and type I collagen, and adhered at significantly higher rates to (GRGDS)$\sb4$ than to monomeric RGD-peptides. In contrast, P and L17 cells did not adhere well to the above substrates. H10 cells also spread well on vitronectin and migrated toward vitronectin concentration gradients. Pretreament of H10 cells with anti-$\beta\sb3$ monoclonal antibodies resulted in significant decreases in adhesion of H10 cells to vitronectin and immobilized (GRGDS)$\sb4$, and reduced the formation of experimental liver metastases in syngeneic Balb/c mice.^ Adhesion of RAW117 cells under hydrodynamic shear stresses was also studied because tumor cell adhesion occurs under fluid shear stresses in target organ microvessels. Similar to their properties found with static adhesion assays, H10 cells stabilized their hydrodynamic adhesion to vitronectin, fibronectin and (GRGDS)$\sb4$ much more quickly than P or L17 cells. Unlike their static adhesion properties, RAW117 cells showed differential adhesion stabilization to liver-sinusoidal endothelial cell-derived extracellular matrix ($\rm{H10{>>}L17>P}$). Although not supporting static adhesion of RAW117 cells, monomeric RGD-peptides mediated adhesion stabilization of H10 cells but not L17 or P cells. Integrin $\rm\alpha\sb{v}\beta\sb3$ was found to be involved in stabilizing H10 cell adhesion to vitronectin, (GRGDS)$\sb4$, monomeric RGD-peptide R1, and liver sinusoidal endothelial cell-derived extracellular matrix.^ This study is the first to provide evidence that integrin $\rm\alpha\sb{v}\beta\sb3$ is differentially expressed in liver-metastatic lymphoma cells and involved in differential adhesion of these cells. The results indicate that strong static adhesion and especially the unique hydrodynamic adhesion of RAW117 cells to the RGD-containing substrates correlate with liver-metastatic potentials. Thus, integrin $\rm\alpha\sb{v}\beta\sb3$ may play an important role in liver-preferential metastasis of RAW117 large-cell lymphoma cells. ^

Deregulation of PAX-5 by translocation of the Emu enhancer of the IgH locus adjacent to two alternative PAX-5 promoters in a diffuse large-cell lymphoma.

Analyses of the human PAX-5 locus and of the 5' region of the mouse Pax-5 gene revealed that transcription from two distinct promoters results in splicing of two alternative 5' exons to the common coding sequences of exons 2-10. Transcription from the upstream promoter initiates downstream of a TATA box and occurs predominantly in B-lymphocytes, whereas the TATA-less downstream promoter is active in all Pax-5-expressing tissues. The human PAX-5 gene is located on chromosome 9 in region p13, which is involved in t(9;14)(pl3;q32) translocations recurring in small lymphocytic lymphomas of the plasmacytoid subtype and in derived large-cell lymphomas. A previous molecular analysis of a t(9;14) breakpoint from a diffuse large-cell lymphoma (KIS-1) demonstrated that the immunoglobulin heavy-chain (IgH) locus on 14q32 was juxtaposed to chromosome 9p13 sequences of unknown function [Ohno, H., Furukawa, T., Fukuhara, S., Zong, S. Q., Kamesaki, H., Shows, T. B., Le Beau, M. M., McKeithan, T. W., Kawakami, T. & Honjo, T. (1990) Proc. Natl. Acad. Sci. USA 87,628-632]. Here we show that the KIS-1 translocation breakpoint is located 1807 base pairs upstream of exon 1A of PAX-5, thus bringing the potent Emu enhancer of the IgH gene into close proximity of the PAX-5 promoters. These data suggest that deregulation of PAX-5 gene transcription by the t(9;14)(pl3;q32) translocation contributes to the pathogenesis of small lymphocytic lymphomas with plasmacytoid differentiation.

T-cell lymphoma in the tongue of a dog with cutaneous and striated forelimb muscle involvement

Background: Primary tongue tumors rarely affect dogs and correspond to 4% of tumors involving the oropharynx. Until now, primary tongue lymphoma had not been reported. However, lymphoma involvement in the skeletal muscle, although quite unusual, was described in the literature in four cases. Cutaneous lymphoma is another rare extranodal manifestation. The objective of this report is to describe a case of T immunophenotype lymphoma occurrence, whose manifestation is atypical, not only because it is situated in the tongue muscle but also because of the subsequent involvement of the striated musculature of the left forelimb and the skin, which showed unfavorable evolution. Case: A female seven-year-old mongrel was seen showing a regular lump in the base of the tongue, 3 cm in diameter, not ulcerated and of fi rm consistency, with halitosis as the only clinical sign of the disease. Incisional biopsy of the lump was performed and histopathology verifi ed that it was large cell lymphoma. The material was sent for immunohistochemical evaluation and was characterized as T immunophenotype lymphoma by positive CD3 and negative CD79a marking. The CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy protocol was established as treatment and after the fi rst chemotherapy session there was partial remission of the mass, measuring 2 cm in diameter. The lump, however, remained stable in the following sessions. Thirty days after the diagnosis of lymphoma, the animal began to show lameness of the left forelimb and swelling near the head of the left humerus. A muscle mass, fi rm in consistency, progressing fast, presented a signifi cant increase, just three weeks after its appearance. Two skin lesions, arcuate, erythematous and pruritic also appeared in the dorsocervical and ventral-abdominal region. Incisional biopsy of these lesions was performed and the histopathological diagnosis confi rmed muscle and cutaneous large cell lymphoma and immunophenotype compatible with T cells (positive CD3 and negative CD79a). Due to disease advance, even during chemotherapy, a rescue protocol of L-asparaginase administration followed by lomustine and prednisone was proposed. Even with the rescue protocol there was no remission of the tumors and the case was classifi ed as progressive. The animal of this report died after completing the fi rst cycle of chemotherapy protocol, with a survival of 92 days. Discussion: Despite the fact that clinical behavior of primary lymphoma in dogs’ skeletal muscle is unknown, it is believed that, as in humans, it can be associated with chronic infl ammation or neoplastic cell invasion by proximity of the tumor or metastasis, which could justify the dissemination of the lymphoma reported here from the tongue to other tissues. However, appearance of concurrent independent lymphomas cannot be ruled out. As observed in the three cases of primary muscular lymphoma, the dog of this report had low response to therapy and short survival. This report presents the fi rst case of lymphoma in tongue with subsequent skin and left forelimb skeletal muscle involvement described in the literature. The clinical outcome corroborates the aggressiveness of muscular lymphoma observed in the other reports and also suggests that both tongue and other skeletal muscle tumors should be included in the differential diagnosis of canine lymphoma.

Ongoing immunoglobulin somatic mutation in germinal center B cell-like but not in activated B cell-like diffuse large cell lymphomas

B cell diffuse large cell lymphoma (B-DLCL) is a heterogeneous group of tumors, based on significant variations in morphology, clinical presentation, and response to treatment. Gene expression profiling has revealed two distinct tumor subtypes of B-DLCL: germinal center B cell-like DLCL and activated B cell-like DLCL. In a separate study, we determined that B-DLCL can also be subdivided into two groups based on the presence or absence of ongoing Ig gene hypermutation. Here, we evaluated the correlation between these B-DLCL subtypes established by the two different methods. Fourteen primary B-DLCL cases were studied by gene expression profiling using DNA microarrays and for the presence of ongoing mutations in their Ig heavy chain gene. All seven cases classified as germinal center B cell-like DLCL by gene expression showed the presence of ongoing mutations in the Ig genes. Five of the seven cases classified by gene expression as activated B cell-like DLCL had no ongoing somatic mutations, whereas, in the remaining two cases, a single point mutation was observed in only 2 of 15 and 21 examined molecular clones of variable heavy (VH) chain gene, respectively. These two cases were distantly related to the rest of the activated B cell-like DLCL tumors by gene expression. Our findings validate the concept that lymphoid malignancies are derived from cells at discrete stages of normal lymphocyte maturation and that the malignant cells retain the genetic program of those normal cells.

Expression of high amounts of the CD117 molecule in a case of B-cell non-Hodgkin's lymphoma carrying the t(14:18) translocation.

The c-kit proto-oncogen (CD117) has been described to be present in normal and neoplastic hemopoietic cells including both myeloid and lymphoid lineages. Among the normal lymphoid cells CD117 expression would be restricted to a small subset of NK-cells, and to early T-cell precursors and it is not expressed by normal B-cells. Regarding chronic lymphoproliferative disorders the only data provided up to now suggests that CD117 expression is restricted to cases of Hodgkin's disease and anaplastic large-cell lymphoma. In the present paper we describe a case of a B-cell chronic lymphoproliferative disorder carrying the t(14:18) translocation as demonstrated by molecular studies, in which the flow cytometric immunophenotypic analysis of both peripheral blood and bone marrow samples revealed the expression of high amounts of the CD117 antigen in the surface of the clonal B-cell population. Further studies are necessary to explore both the functional role of c-kit expression in the neoplastic B-cells from this patient and its potential utility for the diagnosis and follow-up of patients with B-cell non-Hodgkin's lymphoma.

CD30-positive peripheral T-cell lymphomas share molecular and phenotypic features.

Peripheral T-cell lymphoma, not otherwise specified is a heterogeneous group of aggressive neoplasms with indistinct borders. By gene expression profiling we previously reported unsupervised clusters of peripheral T-cell lymphomas, not otherwise specified correlating with CD30 expression. In this work we extended the analysis of peripheral T-cell lymphoma molecular profiles to prototypical CD30(+) peripheral T-cell lymphomas (anaplastic large cell lymphomas), and validated mRNA expression profiles at the protein level. Existing transcriptomic datasets from peripheral T-cell lymphomas, not otherwise specified and anaplastic large cell lymphomas were reanalyzed. Twenty-one markers were selected for immunohistochemical validation on 80 peripheral T-cell lymphoma samples (not otherwise specified, CD30(+) and CD30(-); anaplastic large cell lymphomas, ALK(+) and ALK(-)), and differences between subgroups were assessed. Clinical follow-up was recorded. Compared to CD30(-) tumors, CD30(+) peripheral T-cell lymphomas, not otherwise specified were significantly enriched in ALK(-) anaplastic large cell lymphoma-related genes. By immunohistochemistry, CD30(+) peripheral T-cell lymphomas, not otherwise specified differed significantly from CD30(-) samples [down-regulated expression of T-cell receptor-associated proximal tyrosine kinases (Lck, Fyn, Itk) and of proteins involved in T-cell differentiation/activation (CD69, ICOS, CD52, NFATc2); upregulation of JunB and MUM1], while overlapping with anaplastic large cell lymphomas. CD30(-) peripheral T-cell lymphomas, not otherwise specified tended to have an inferior clinical outcome compared to the CD30(+) subgroups. In conclusion, we show molecular and phenotypic features common to CD30(+) peripheral T-cell lymphomas, and significant differences between CD30(-) and CD30(+) peripheral T-cell lymphomas, not otherwise specified, suggesting that CD30 expression might delineate two biologically distinct subgroups.

Frequent somatic hypermutation of the 5' noncoding region of the BCL6 gene in B-cell lymphoma.

The BCL6 gene encodes a zinc-finger transcription factor and is altered by chromosomal arrangements in its 5' noncoding region in approximately 30% of diffuse large-cell lymphoma (DLCL). We report here that, in 22/30 (73%) DLCL and 7/15 (47%) follicular lymphoma (FL), but not in other tumor types, the BCL6 gene is also altered by multiple (1.4 x 10(-3) -1.6 x 10(-2) per bp), often biallelic, mutations clustering in its 5' noncoding region. These mutations are of somatic origin and are found in cases displaying either normal or rearranged BLC6 alleles indicating their independence from chromosomal rearrangements and linkage to immunoglobulin genes. These alterations identify a mechanism of genetic instability in malignant B cells and may have been selected during lymphomagenesis for their role in altering BCL6 expression.

Primary diffuse large B-cell lymphoma or lymphomatoid granulomatosis grade 3: a still-puzzling diagnosis in autopsy

Primary lung lymphoma is a rare entity accounting for approximately 0.3% of all primary neoplasia of the lung and includes diffuse large B-cell lymphoma (DLBL) and lymphomatoid granulomatosis (LYG). Considering that clinical features may be similar, whereas epidemiology, morphology, and radiological features are different, the authors report a case of a middle-aged man who presented multiple pulmonary nodules in the lower lobes and groundglass opacities scattered bilaterally on computed tomography. Clinically, he presented a consumptive syndrome with respiratory failure and pleurisy, which progressed until death. The autopsy findings were consistent with lymphomatoid granulomatosis (LYG) grade 3/ diffuse large B-cell lymphoma (DLBL). The authors call attention to the difficulty of establishing an accurate diagnosis, mainly when the demonstration of EBV-infected atypical B-cells fails.

Primary cutaneous CD4+ small-/medium-sized pleomorphic T-cell lymphoma: a cutaneous nodular proliferation of pleomorphic T lymphocytes of undetermined significance? A study of 136 cases

Patients with skin nodules characterized by the infiltrate of pleomorphic small/medium T lymphocytes are currently classified as "primary cutaneous CD4+ small-/medium-sized pleomorphic T-cell lymphoma" (SMPTCL) or as T-cell pseudolymphoma. The distinction is often arbitrary, and patients with similar clinicopathologic features have been included in both groups. We studied 136 patients (male:female = 1:1; median age: 53 years, age range: 3-90 years) with cutaneous lesions that could be classified as small-/medium-sized pleomorphic T-cell lymphoma according to current diagnostic criteria. All but 3 patients presented with solitary nodules located mostly on the head and neck area (75%). Histopathologic features were characterized by nonepidermotropic, nodular, or diffuse infiltrates of small- to medium-sized pleomorphic T lymphocytes. A monoclonal rearrangement of the T-cell receptor-gamma gene was found in 60% of tested cases. Follow-up data available for 45 patients revealed that 41 of them were alive without lymphoma after a median time of 63 months (range: 1-357 months), whereas 4 were alive with cutaneous disease (range: 2-16 months). The incongruity between the indolent clinical course and the worrying histopathologic and molecular features poses difficulties in classifying these cases unambiguously as benign or malignant, and it may be better to refer to them with a descriptive term such as "cutaneous nodular proliferation of pleomorphic T lymphocytes of undetermined significance," rather than forcing them into one or the other category. On the other hand, irrespective of the name given to these equivocal cutaneous lymphoid proliferations, published data support a nonaggressive therapeutic strategy, particularly for patients presenting with solitary lesions.

Identification of novel target genes in different subtypes of cutaneous T-cell lymphoma

Ihon T-solulymfoomat (cutaneous T-cell lymphoma, CTCL) ovat ryhmä imukudossyöpiä, joiden esiintyvyys on nousussa erityisesti länsimaissa. Taudin syntymekanismit ovat suurelta osin tuntemattomat, diagnostiikka on vaikeaa ja siksi usein viivästynyttä eikä parantavaa hoitoa ole. CTCL ilmenee iho-oirein, vaikka syöpäsolut eivät ole iholla normaalisti esiintyviä soluja, vaan elimistön puolustusjärjestelmän soluja, jotka ovat tuntemattomasta syystä vaeltaneet iholle. Syöpäsolut ovat kypsiä T-auttajasoluja (Th-soluja) ja ilmentävät tyypin 2 immuunivasteelle ominaisia sytokiineja. Kromosomaalinen epästabiilius on tautiryhmän keskeinen piirre. CTCL-potilailla on lisääntynyt riski sairastua myös muihin syöpiin, erityisesti keuhkosyöpään ja non-Hodgkin –lymfoomiin. Väitöskirjatutkimuksen tavoitteena oli havaita CTCL:n syntymekanismeja selvittäviä kromosomi- ja geenimuutoksia. Erityisesti tavoitteena oli identifioida molekyylejä, jotka soveltuisivat diagnostisiksi merkkiaineiksi tai täsmähoidon kohteeksi. Työssä on tutkittu kahta tautiryhmän yleisintä muotoa, mycosis fungoidesta (MF) ja Sezaryn syndroomaa (SS) sekä harvinaisempaa vaikeasti diagnosoitavaa subkutaanista pannikuliitin kaltaista T-solulymfoomaa (SPTL). Lisäksi on tutkittu CTCL:ään liittyvää keuhkosyöpää ja verrattu sitä tavalliseen (primaariin) keuhkosyöpään. Tutkimusmenetelminä on käytetty esimerkiksi molekyylisytogeneettisiä metodeja ja mikrosiruja. Väitöskirjatyössä havaittiin ensimmäinen CTCL:lle ominainen toistuva geenitason muutos: puutos- tai katkoskohta NAV3-geenissä. Tämän geenipoikkeavuuden havaittiin esiintyvän useissa taudin alaryhmissä (MF, SS, SPTL). NAV3-geenipuutoksen osoittaminen FISH-tekniikalla on sovellettavissa kliiniseen diagnostiikkaan. Tutkimukset geenipuutoksen aiheuttamista toiminnallisista seurauksista ovat käynnissä. Työssä saatiin myös uutta tietoa taudin syntymekanismeista havaitsemalla useiden Th1-tyypin immuunivasteelle ominaisten geenien alentunut ilmeneminen CTCL-potilailla. Tämän lisäksi potilasnäytteissä havaittiin eräiden solun pinta-antigeenien lisääntynyt ilmeneminen, mikä luo pohjan uusien vasta-ainepohjaisten täsmähoitojen kehittämiselle. Väitöskirjatutkimuksessa todettiin myös CTCL:ään liittyvän keuhkosyövän eroavan kromosomi- ja geenimuutosten suhteen verrokkikeuhkosyövästä, mikä jatkossa antaa aiheen tutkia syöpäkantasolujen merkitystä CTCL:n ja sen liitännäiskasvainten kehittymisen taustalla.

Histone deacetylase inhibitors in adult patients with diffuse large b-cell lymphoma relapsed/refractory: a phase II study with Panobinostat

Backgrounds:Treatment of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) not eligible to high dose therapy represents an unmet medical need. Panobinostat showed encouraging therapeutic activity in studies conducted in lymphoma cell lines and in vivo in patients with advanced hematologic malignancies.Purpose:FIL-PanAL10 (NCT01523834) is a phase II, prospective multicenter trial of the Fondazione Italiana Linfomi (FIL) to evaluate safety and efficacy of single agent Panobinostat as salvage therapy for R/R DLBCL patients and to evaluate a possible relationships between response and any biological features. Patients and Methods:Patients with R/R DLBCL were included. The treatment plan included 6 induction courses with Panobinostat monotherapy followed by other 6 courses of consolidation. The primary objective was to evaluate Panobinostat activity in terms of overall response (OR); secondary objectives were: CR rate, time to response (TTR), progression-free survival (PFS), safety and feasibility of Panobinostat. We included evaluation of the impact of pharmacogenetics, immunohistochemical patterns and patient’s specific gene expression and mutations as potential predictors of response to Panobinostat as explorative objectives. To this aim a pre-enrollment new tissue biopsy was mandatory. ResultsThirty-five patients, 21 males (60%), were enrolled between June 2011 and March 2014. At the end of induction phase, 7 responses (20%) were observed, including 4 CR (11%), while 28 patients (80%) discontinued treatment due to progressive disease (PD) in 21 (60%) or adverse events in 7 (20%). Median TTR in 9 responders was 2.6 months (range 1.8-12). With a median follow up of 6 months (range 1-34), the estimated 12 months PFS and OS were 27% and 30.5%, respectively. Grade 3-4 thrombocytopenia and neutropenia were the most common toxicities (in 29 (83%) and 12 (34%) patients, respectively. Conclusions The results of this study indicate that Panobinostat might be remarkably active in some patients with R/R DLBCL, showing durable CR

High numbers of DC-SIGN+ dendritic cells in lesional skin of cutaneous T-cell lymphoma

The role of dendritic cells (DCs) in disease progression of primary cutaneous T-cell lymphoma (CTCL) is not well understood. With their unique ability to induce primary immune responses as well as immunotolerance, DCs play a critical role in mediation of anti-tumor immune responses. Tumor-infiltrating DCs have been determined to represent important prognostic factors in a variety of human tumors.

Final Results of a Prospective Evaluation of the Predictive Value of Interim Positron Emission Tomography in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP-14 (SAKK 38/07)

PURPOSE Our main objective was to prospectively determine the prognostic value of [(18)F]fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) after two cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone given every 14 days (R-CHOP-14) under standardized treatment and PET evaluation criteria. PATIENTS AND METHODS Patients with any stage of diffuse large B-cell lymphoma were treated with six cycles of R-CHOP-14 followed by two cycles of rituximab. PET/CT examinations were performed at baseline, after two cycles (and after four cycles if the patient was PET-positive after two cycles), and at the end of treatment. PET/CT examinations were evaluated locally and by central review. The primary end point was event-free survival at 2 years (2-year EFS). RESULTS Median age of the 138 evaluable patients was 58.5 years with a WHO performance status of 0, 1, or 2 in 56%, 36%, or 8% of the patients, respectively. By local assessment, 83 PET/CT scans (60%) were reported as positive and 55 (40%) as negative after two cycles of R-CHOP-14. Two-year EFS was significantly shorter for PET-positive compared with PET-negative patients (48% v 74%; P = .004). Overall survival at 2 years was not significantly different, with 88% for PET-positive versus 91% for PET-negative patients (P = .46). By using central review and the Deauville criteria, 2-year EFS was 41% versus 76% (P < .001) for patients who had interim PET/CT scans after two cycles of R-CHOP-14 and 24% versus 72% (P < .001) for patients who had PET/CT scans at the end of treatment. CONCLUSION Our results confirmed that an interim PET/CT scan has limited prognostic value in patients with diffuse large B-cell lymphoma homogeneously treated with six cycles of R-CHOP-14 in a large prospective trial. At this point, interim PET/CT scanning is not ready for clinical use to guide treatment decisions in individual patients.