Publications by authors named "Christiane Copie-Bergman"

104 Publications

High-grade Follicular Lymphomas Exhibit Clinicopathologic, Cytogenetic, and Molecular Diversity Extending Beyond Grades 3A and 3B.

Am J Surg Pathol 2021 10;45(10):1324-1336

Pathology and Tumor Immunology, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm U1068, CNRS UMR7258, Aix-Marseille University, Marseille.

Although follicular lymphoma (FL) is usually graded as FL1-2, FL3A, and FL3B, some borderline cases can be observed and led us to investigate the clinicopathologic diversity of grade 3 FL (FL3). Among 2449 FL patients enrolled in Lymphoma Study Association (LYSA) trials, 1921 cases with sufficient material underwent a central pathologic review. The resulting diagnoses comprised 89.6% FL1-2 (n=1723), 7.2% FL3A (n=138), and 0.5% purely follicular FL3B (n=9). The remaining 51 unclassifiable cases (2.7%) exhibited high-grade features but did not meet WHO criteria for either FL3A or FL3B; and were considered as "unconventional" high-grade FL (FL3U). FL3U morphological pattern consisted of nodular proliferation of large cleaved cells or small-sized to medium-sized blast cells. Compared with FL3A, FL3U exhibited higher MUM1 and Ki67 expression, less BCL2 breaks and more BCL6 rearrangements, together with a higher number of cases without any BCL2, BCL6 or MYC rearrangement. FL3U harbored less frequent mutations in BCL2, KMT2D, KMT2B, and CREBBP than FL3A. MYC and BCL2 were less frequently mutated in FL3U than FL3B. Rituximab cyclophosphamide, doxorubicin, vincristine, and prednisone treated FL3U patients had a worse survival than FL1-2 patients with similar follicular lymphoma international prognostic index and treatment. These results suggest that high-grade FLs encompass a heterogeneous spectrum of tumors with variable morphology and genomic alterations, including FL3U cases that do not strictly fit WHO criteria for either FL3A or FL3B, and display a worse outcome than FL1-2. The distinction of FL3U may be useful to allow a better comprehension of high-grade FLs and to design clinical trials.
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http://dx.doi.org/10.1097/PAS.0000000000001726DOI Listing
October 2021

Plasticity of Mature B Cells Between Follicular and Classic Hodgkin Lymphomas: A Series of 22 Cases Expanding the Spectrum of Transdifferentiation.

Am J Surg Pathol 2021 Jul 15. Epub 2021 Jul 15.

Multi-site Pathology Department Hematology Department, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite Université Claude Bernard Lyon-1 Pathology Department, Centre Léon Berard, Lyon Institut National de la Santé et de la Recherche Médicale, Unité 1065, Centre Me[Combining Acute Accent]diterrane[Combining Acute Accent]en de Me[Combining Acute Accent]decine Mole[Combining Acute Accent]culaire (C3M), Team 10, Nice Pathology Department, Centre Hospitalier et Universitaire de Montpellier, Hôpital Gui De Chauliac, Montpellier Pathology Department, Centre de Recherche en Cancérologie de Toulouse-Purpan, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse CRCL, INSERM U1052-CNRS UMR5286, Faculté de Médecine Lyon-Sud, Université Claude Bernard Lyon-1, Oullins Pathology Department, Assistance Publique des Hôpitaux de Paris, Hôpital Ambroise Paré, Université Paris Saclay, Boulogne-Billancourt Pathology Department, Assistance Publique des Hôpitaux de Paris, Hôpital Henri Mondor, Université Paris-Est, Créteil, France.

Follicular lymphoma and classic Hodgkin lymphoma can be associated in composite and/or sequential lymphomas. Common IGH and BCL2 rearrangements have already been identified between both contingents of these entities, but mutation profiles have not yet been investigated. The main objective of this study was to analyze the transdifferentiation process that may occur between Hodgkin and follicular contingents in sequential and composite lymphomas to better characterize these entities. From 2004 to 2020, a retrospective multicentric study was performed, including 9 composite and 13 sequential lymphomas. Clinical data were retrospectively collected. Fluorescent in situ hybridization of BCL2 and BCL6 rearrangements, polymerase chain reaction of IGH and IGK rearrangements, next-generation sequencing of IGK rearrangement, and targeted next-generation sequencing (TNGS) on a panel of genes frequently mutated in lymphomas were performed on each contingent of composite and sequential lymphomas. For TNGS, each contingent was isolated by laser capture microdissection. Clinical presentation and evolution were more aggressive in sequential than composite lymphomas. By fluorescent in situ hybridization, common rearrangements of BCL6 and BCL2 were identified between both contingents. Similarly, a common clonal relationship was established by evaluating IGH and IGK rearrangement by polymerase chain reaction or next-generation sequencing. By TNGS, the same pathogenic variants were identified in both contingents in the following genes: CREBBP, KMT2D, BCL2, EP300, SF3B1, SOCS1, ARID1A, and BCOR. Specific pathogenic variants for each contingent were also identified: XPO1 for Hodgkin lymphoma contingent and FOXO1, TNFRSF14 for follicular lymphoma contingent. This study reinforces the hypothesis of a transdifferentiation process between Hodgkin and follicular contingent of sequential/composite lymphomas.
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http://dx.doi.org/10.1097/PAS.0000000000001780DOI Listing
July 2021

The alternative RelB NF-κB subunit is a novel critical player in diffuse large B-cell lymphoma.

Blood 2021 07 7. Epub 2021 Jul 7.

Université de Paris, NF-kappaB, Différenciation et Cancer, Paris, France

Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid malignancy affecting adults. NF-kB transcription factor family is activated by two main pathways, the canonical and the alternative NF-kB activation pathways with different functions. The alternative NF-kB pathway leads to the activation of the transcriptionally active RelB NF-kB subunit. Alternative NF-kB activation status and its role in DLBCL pathogenesis remain undefined. Here, we reveal a frequent activation of RelB in a large cohort of DLBCL patients and cell lines, independently of their ABC or GCB subtypes. RelB activity defines a new subset of DLBCL patients with a peculiar gene expression profile and mutational pattern. Importantly, RelB activation does not correlate with the MCD genetic subtype, enriched for ABC tumors carrying MYD88L265P and CD79B mutations that cooperatively activate canonical NF-kB, thus indicating that current genetic tools to evaluate NF-kB activity in DLBCL do not provide information on the alternative NF-kB activation. Further, the newly defined RelB-positive subgroup of DLBCL patients exhibits a dismal outcome following immunochemotherapy. Functional studies revealed that RelB confers DLBCL cell resistance to DNA-damage induced apoptosis in response to doxorubicin, a genotoxic agent used in front-line treatment for DLBCL. We also show that RelB positivity is associated with high expression of cIAP2. Altogether, RelB activation can be used to refine the prognostic stratification of DLBCL and may contribute to subvert the therapeutic DNA damage response in a segment of DLBCL patients.
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http://dx.doi.org/10.1182/blood.2020010039DOI Listing
July 2021

Genetic Characterization and Clinical Features of Negative Gastric Mucosa-Associated Lymphoid Tissue Lymphoma.

Cancers (Basel) 2021 Jun 15;13(12). Epub 2021 Jun 15.

Department of Pathology, Division of Cellular and Molecular Pathology, University of Cambridge, Cambridge CB2 1TN, UK.

Background: In Western countries, the prevalence of gastric mucosa-associated lymphoid tissue (MALT) lymphoma has declined over the last three decades. Contemporaneously, negative gastric MALT lymphoma is increasingly encountered, and their genetic basis and clinical features remain elusive.

Methods: A total of 57 cases of negative gastric MALT lymphoma were reviewed and investigated for chromosome translocation by fluorescence in-situ hybridization and for somatic mutations by the targeted sequencing of 93 genes.

Results: translocation, most likely t(11;18)(q21;q21)/ was detected in 39% (22/57) cases, and translocation was further seen in 12 -negative cases, together accounting for 60% of the cohort. Targeted sequencing was successful in 35 cases, and showed frequent mutations in NF-κB signaling pathways ( = 23%, = 9%, = 9%), together affecting 14 cases (40%). The NF-κB pathway mutations were mutually exclusive from , albeit not translocation, altogether occurring in 86% of cases. There was no significant correlation between the genetic changes and clinicopathological parameters. The patients showed a median of progression-free survival (PFS) of 66.3 months, and a significant superior PFS when treated with systemic versus antibiotic therapy ( = 0.004).

Conclusion: negative gastric MALT lymphoma is characterized by highly frequent genetic changes in the NF-κB signaling pathways.
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http://dx.doi.org/10.3390/cancers13122993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232676PMC
June 2021

c-Rel Is the Pivotal NF-κB Subunit in Germinal Center Diffuse Large B-Cell Lymphoma: A LYSA Study.

Front Oncol 2021 20;11:638897. Epub 2021 Apr 20.

CNRS UMR-7276, INSERM U1262, CRIBL, University of Limoges, and Hematology Laboratory of Dupuytren Hospital University Center (CHU) of Limoges, Limoges, France.

Relationships between c-Rel and GCB-DLBCLs remain unclear. We found that strong c-Rel DNA-binding activity was mostly found in GCBs on two independent series of 48 DLBCLs and 66 DLBCLs, the latter issued from the GHEDI series. c-Rel DNA-binding activity was associated with increased mRNA expression. Extending the study to the whole GHEDI and Lenz DLBCL published series of 202 and 233 cases, it was found that the c-Rel gene expression profile (GEP) overlapped partially (12%) but only with the GCB GEP and not with the GEP of ABC-DLBCLs. Cases with both overexpression of mRNA and c-Rel GEP were defined as those having a c-Rel signature. These cases were GCBs in 88 and 83% of the GHEDI or Lenz's DLBCL series respectively. The c-Rel signature was also associated with various recurrent GCB-DLBCL genetic events, including gains, translocation, , , , and mutations and with the EZB GCB genetic subtype. By CGH array, the c-Rel signature was specifically correlated with 2p15-16.1 amplification that includes XPO1, BCL11A, and USP34 and with the 22q11.22 deletion that covers IGLL5 and PRAME. The total number of gene copy number aberrations, so-called genomic imbalance complexity, was decreased in cases with the c-Rel signature. These cases exhibited a better overall survival. Functionally, overexpression of c-Rel induced its constitutive nuclear localization and protected cells against apoptosis while its repression tended to increase cell death. These results show that, clinically and biologically, c-Rel is the pivotal NF-B subunit in the GCB-DLBCL subgroup. Functionally, c-Rel overexpression could directly promote DLBCL tumorigenesis without need for further activation signals.
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http://dx.doi.org/10.3389/fonc.2021.638897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095348PMC
April 2021

The landscape of copy number variations in classical Hodgkin lymphoma: a joint KU Leuven and LYSA study on cell-free DNA.

Blood Adv 2021 04;5(7):1991-2002

Department of Human Genetics and.

The low abundance of Hodgkin/Reed-Sternberg (HRS) cells in lymph node biopsies in classical Hodgkin lymphoma (cHL) complicates the analysis of somatic genetic alterations in HRS cells. As circulating cell-free DNA (cfDNA) contains circulating tumor DNA (ctDNA) from HRS cells, we prospectively collected cfDNA from 177 patients with newly diagnosed, mostly early-stage cHL in a monocentric study at Leuven, Belgium (n = 59) and the multicentric BREACH study by Lymphoma Study Association (n = 118). To catalog the patterns and frequencies of genomic copy number aberrations (CNAs), cfDNA was sequenced at low coverage (0.26×), and data were analyzed with ichorCNA to yield read depth-based copy number profiles and estimated clonal fractions in cfDNA. At diagnosis, the cfDNA concentration, estimated clonal fraction, and ctDNA concentration were significantly higher in cHL cases than controls. More than 90% of patients exhibited CNAs in cfDNA. The most frequent gains encompassed 2p16 (69%), 5p14 (50%), 12q13 (50%), 9p24 (50%), 5q (44%), 17q (43%), 2q (41%). Losses mostly affected 13q (57%), 6q25-q27 (55%), 4q35 (50%), 11q23 (44%), 8p21 (43%). In addition, we identified loss of 3p13-p26 and of 12q21-q24 and gain of 15q21-q26 as novel recurrent CNAs in cHL. At diagnosis, ctDNA concentration was associated with advanced disease, male sex, extensive nodal disease, elevated erythrocyte sedimentation rate, metabolic tumor volume, and HRS cell burden. CNAs and ctDNA rapidly diminished upon treatment initiation, and persistence of CNAs was associated with increased probability of relapse. This study endorses the development of ctDNA as gateway to the HRS genome and substrate for early disease response evaluation.
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http://dx.doi.org/10.1182/bloodadvances.2020003039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045498PMC
April 2021

No evidence for a pathogen associated with pulmonary MALT lymphoma: a metagenomics investigation.

Infect Agent Cancer 2021 Feb 6;16(1):10. Epub 2021 Feb 6.

Service de Pneumologie et Oncologie thoracique, Centre de référence des maladies pulmonaires rares, AP-HP, Hôpital Tenon and GRC#4 Theranoscan, Sorbonne Université, Paris, France.

Mucosa-associated lymphoid tissue (MALT) lymphoma is generally associated with chronic antigen stimulation: auto-antigens or of microbial origin. Only one study suggested association between Achromobacter xylosoxidans and pulmonary MALT lymphoma. We aimed to investigate the presence of virus or any infectious agents in pulmonary MALT lymphoma by using metagenomic next-generation sequencing (mNGS).All lung samples were centrally reviewed. The t(11;18) (q21;q21) was evaluated by FISH analysis. The snap frozen large lung biopsies were analyzed by mNGS. After lung biopsies homogenization total nucleic acids (RNA and DNA) were extracted, amplified and classified according to their taxonomic assignment, after exclusion of host DNA.We included 13 samples from pulmonary MALT lymphoma (mean age: 60.3 years, 7 women, 3 with auto-immune background) and 10 controls. The diagnosis of MALT lymphoma was confirmed for the 13 samples, 3 showed API2-MALT1 translocation (23%). No evidence of the presence of a specific pathogen was clearly identified in the group of patients with pulmonary MALT lymphoma. We identifiedA. xylosoxidans sequence in 4/13 patients and in 4/10 controls.This study did not find evidence for a DNA or RNA virus, a fungi, a parasite or a bacteria associated with pulmonary MALT lymphoma either in the stroma or in tumor cells.
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http://dx.doi.org/10.1186/s13027-021-00351-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868019PMC
February 2021

Follicular lymphoma t(14;18)-negative is genetically a heterogeneous disease.

Blood Adv 2020 11;4(22):5652-5665

Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen-Comprehensive Cancer Center, University Hospital Tübingen, Tübingen, Germany.

Fifty-five cases of t(14;18)- follicular lymphoma (FL) were genetically characterized by targeted sequencing and copy number (CN) arrays. t(14;18)- FL predominated in women (M/F 1:2); patients often presented during early clinical stages (71%), and had excellent prognoses. Overall, t(14;18)- FL displayed CN alterations (CNAs) and gene mutations carried by conventional t(14;18)+ FL (cFL), but with different frequencies. The most frequently mutated gene was STAT6 (57%) followed by CREBBP (49%), TNFRSF14 (39%), and KMT2D (27%). t(14;18)- FL showed significantly more STAT6 mutations and lacked MYD88, NOTCH2, MEF2B, and MAP2K1 mutations compared with cFL, nodal marginal zone lymphoma (NMZL), and pediatric-type FL (PTFL). We identified 2 molecular clusters. Cluster A was characterized by TNFRSF14 mutations/1p36 alterations (96%) and frequent mutations in epigenetic regulators, with recurrent loss of 6q21-24 sharing many features with cFL. Cluster B showed few genetic alterations; however, a subgroup with STAT6 mutations concurrent with CREBBP mutations/16p alterations without TNFRSF14 and EZH2 mutations was noted (65%). These 2 molecular clusters did not distinguish cases by inguinal localization, growth pattern, or presence of STAT6 mutations. BCL6 rearrangements were demonstrated in 10 of 45 (22%) cases and did not cluster together. Cases with predominantly inguinal presentation (20 of 50; 40%) had a higher frequency of diffuse growth pattern, STAT6 mutations, CD23 expression, and a lower number of CNAs, in comparison with noninguinal cases (5.1 vs 9.1 alterations per case; P < .05). STAT6 mutations showed a positive correlation with CD23 expression (P < .001). In summary, t(14;18)- FL is genetically a heterogeneous disorder with features that differ from cFL, NMZL, and PTFL.
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http://dx.doi.org/10.1182/bloodadvances.2020002944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686888PMC
November 2020

Effectiveness and Safety of Subcutaneous Rituximab for Patients With Gastric MALT Lymphoma: A Case-Control Comparison With Intravenous Rituximab.

Clin Lymphoma Myeloma Leuk 2021 01 24;21(1):e32-e38. Epub 2020 Aug 24.

Department of Gastroenterology, Groupe Hospitalier Henri Mondor-Albert Chennevier, APHP, EC2M3-EA7375, Université Paris Est Créteil, Creteil, France. Electronic address:

Introduction: Rituximab is a standard treatment for gastric mucosa-associated lymphoid tissue (MALT) lymphoma (GML). We sought to compare the effectiveness and safety of subcutaneous and intravenous rituximab in a retrospective case-control study.

Patients And Methods: All consecutive patients with GML treated with subcutaneous rituximab between January 2017 and December 2018 were included and compared to 3 matched control patients (based on Ann Arbor classification, presence of t(11;18) translocation, history of treatment, and type of current treatment) treated with intravenous rituximab between January 2000 and December 2018. Patients with t(11;18) translocation were treated with rituximab in combination with chlorambucil; the other patients were treated with rituximab alone. Effectiveness was assessed at week 52, and safety was assessed through weeks 0 to 52 and compared by the chi-square test.

Results: Twenty-five patients were included in the subcutaneous rituximab group and 75 in the intravenous group. There was no difference between the groups in complete remission (78% vs. 76%, P = .99) or overall response rates (91% vs. 89%, P = .99) at week 52. Safety profiles were similar in both groups, with a significant decrease in postinduction grade 2 injection-related reactions and outpatient hospital length of stay in the subcutaneous rituximab group.

Conclusion: In a small case-control study, we did not find any difference in the effectiveness or safety profiles between subcutaneously and intravenously delivered rituximab for the treatment of patients with GML. We found a decrease in postinduction grade 2 injection-related reactions and outpatient hospital length of stay in the subcutaneous rituximab group.
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http://dx.doi.org/10.1016/j.clml.2020.08.014DOI Listing
January 2021

APRIL-producing eosinophils are involved in gastric MALT lymphomagenesis induced by Helicobacter sp infection.

Sci Rep 2020 09 9;10(1):14858. Epub 2020 Sep 9.

Univ. Bordeaux, INSERM, BaRITOn, U1053, 33000, Bordeaux, France.

The roles of the inflammatory response and production of a proliferation-inducing ligand (APRIL) cytokine in gastric mucosa-associated lymphoid tissue (MALT) lymphomagenesis induced by Helicobacter species infection are not clearly understood. We characterized the gastric mucosal inflammatory response associated with gastric MALT lymphoma (GML) and identified APRIL-producing cells in two model systems: an APRIL transgenic mouse model of GML induced by Helicobacter infection (Tg-hAPRIL) and human gastric biopsy samples from Helicobacter pylori-infected GML patients. In the mouse model, polarization of T helper 1 (tbet), T helper 2 (gata3), and regulatory T cell (foxp3) responses was evaluated by quantitative PCR. In humans, a significant increase in april gene expression was observed in GML compared to gastritis. APRIL-producing cells were eosinophilic polynuclear cells located within lymphoid infiltrates, and tumoral B lymphocytes were targeted by APRIL. Together, the results of this study demonstrate that the Treg-balanced inflammatory environment is important for gastric lymphomagenesis induced by Helicobacter species, and suggest the pro-tumorigenic potential of APRIL-producing eosinophils.
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http://dx.doi.org/10.1038/s41598-020-71792-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481773PMC
September 2020

Gene expression profiling of gray zone lymphoma.

Blood Adv 2020 06;4(11):2523-2535

Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada.

Gray zone lymphoma (GZL), a B-cell lymphoma with features intermediate between large B-cell lymphoma (LBCL) and classic Hodgkin lymphoma (cHL), is a rare and poorly defined entity. Alongside GZL, a subset of Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) has been described with polymorphic/GZL-like morphology (polymorphic-EBV-L). To fill the important gap in our understanding of the pathogenic process underlying these entities, we performed a gene expression study of a large international cohort of GZL and polymorphic-EBV-L, combined with cHL and primary mediastinal large B-cell lymphoma (PMBCL) cases. In an unsupervised principal component analysis, GZL cases presented with intermediate scores in a spectrum between cHL and PMBCL, whereas polymorphic-EBV-L clustered distinctly. The main biological pathways underlying the GZL spectrum were related to cell cycle, reflecting tumor cell content, and extracellular matrix signatures related to the cellular tumor microenvironment. Differential expression analysis and phenotypic characterization of the tumor microenvironment highlighted the predominance of regulatory macrophages in GZL compared with cHL and PMBCL. Two distinct subtypes of GZL were distinguishable that were phenotypically reminiscent of PMBCL and DLBCL, and we observed an association of PMBCL-type GZL with clinical presentation in the "thymic" anatomic niche. In summary, gene expression profiling (GEP) enabled us to add precision to the GZL spectrum, describe the biological distinction compared with polymorphic-EBV-L, and distinguish cases with and without thymic involvement as 2 subgroups of GZL, namely PMBCL-like and DLBCL-like GZL.
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http://dx.doi.org/10.1182/bloodadvances.2020001923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284085PMC
June 2020

Combining gene expression profiling and machine learning to diagnose B-cell non-Hodgkin lymphoma.

Blood Cancer J 2020 05 22;10(5):59. Epub 2020 May 22.

INSERM U1245, Centre Henri Becquerel, UNIROUEN, University of Normandie, Rouen, France.

Non-Hodgkin B-cell lymphomas (B-NHLs) are a highly heterogeneous group of mature B-cell malignancies. Their classification thus requires skillful evaluation by expert hematopathologists, but the risk of error remains higher in these tumors than in many other areas of pathology. To facilitate diagnosis, we have thus developed a gene expression assay able to discriminate the seven most frequent B-cell NHL categories. This assay relies on the combination of ligation-dependent RT-PCR and next-generation sequencing, and addresses the expression of more than 130 genetic markers. It was designed to retrieve the main gene expression signatures of B-NHL cells and their microenvironment. The classification is handled by a random forest algorithm which we trained and validated on a large cohort of more than 400 annotated cases of different histology. Its clinical relevance was verified through its capacity to prevent important misclassification in low grade lymphomas and to retrieve clinically important characteristics in high grade lymphomas including the cell-of-origin signatures and the MYC and BCL2 expression levels. This accurate pan-B-NHL predictor, which allows a systematic evaluation of numerous diagnostic and prognostic markers, could thus be proposed as a complement to conventional histology to guide the management of patients and facilitate their stratification into clinical trials.
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http://dx.doi.org/10.1038/s41408-020-0322-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244768PMC
May 2020

PTPN11 mutations in canine and human disseminated histiocytic sarcoma.

Int J Cancer 2020 09 8;147(6):1657-1665. Epub 2020 Apr 8.

Faculty of Medicine, CNRS-University of Rennes 1, UMR6290, Institute of Genetics and Development of Rennes, SFR Biosit, Rennes, France.

In humans, histiocytic sarcoma (HS) is an aggressive cancer involving histiocytes. Its rarity and heterogeneity explain that treatment remains a challenge. Sharing high clinical and histopathological similarities with human HS, the canine HS is conversely frequent in specific breeds and thus constitutes a unique spontaneous model for human HS to decipher the genetic bases and to explore therapeutic options. We identified sequence alterations in the MAPK pathway in at least 63.9% (71/111) of HS cases with mutually exclusive BRAF (0.9%; 1/111), KRAS (7.2%; 8/111) and PTPN11 (56.75%; 63/111) mutations concentrated at hotspots common to human cancers. Recurrent PTPN11 mutations are associated to visceral disseminated HS subtype in dogs, the most aggressive clinical presentation. We then identified PTPN11 mutations in 3/19 (15.7%) human HS patients. Thus, we propose PTPN11 mutations as key events for a specific subset of human and canine HS: the visceral disseminated form. Finally, by testing drugs targeting the MAPK pathway in eight canine HS cell lines, we identified a better anti-proliferation activity of MEK inhibitors than PTPN11 inhibitors in canine HS neoplastic cells. In combination, these results illustrate the relevance of naturally affected dogs in deciphering genetic mechanisms and selecting efficient targeted therapies for such rare and aggressive cancers in humans.
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http://dx.doi.org/10.1002/ijc.32991DOI Listing
September 2020

Composite and sequential lymphoma between classical Hodgkin lymphoma and primary mediastinal lymphoma/diffuse large B-cell lymphoma, a clinico-pathological series of 25 cases.

Br J Haematol 2020 04 6;189(2):244-256. Epub 2020 Feb 6.

Department of Haematology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite cedex, France.

Composite and sequential lymphomas involving both classical Hodgkin lymphoma (CHL) and primary mediastinal B-cell lymphoma (PMBCL) are rare phenomena. Beyond the relevant biological interest raised by these cases, treatments and outcome data are poorly covered in the recent literature. This retrospective analysis describes the pathological and clinical characteristics of 10 composite and 15 sequential cases included after a central pathological review. At diagnosis, 70% of the composite lymphomas presented a disseminated and extranodal disease. Among the 15 sequential lymphomas, 12 were CHL at first occurrence and three were PMBCL. Based on their clinical evolution, these sequential lymphomas could be divided into early (i.e., diagnosis of second lymphoma within a year) and late [(i.e., a second lymphoma occurrence occurring after a long period of complete remission]). All composite cases were alive in complete remission after a median follow-up of 34 months. If the early sequential lymphoma presented a particularly poor outcome with a median overall survival shorter than one year, the late cases were efficiently salvaged. Further molecular studies are needed to describe the underlying biology of these rare diseases, possibly representing the extreme of tumour cell plasticity found in grey-zone lymphoma.
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http://dx.doi.org/10.1111/bjh.16331DOI Listing
April 2020

Colonic mucosa-associated lymphoid tissue lymphoma: a case series.

Leuk Lymphoma 2020 03 6;61(3):582-587. Epub 2019 Nov 6.

Department of Gastroenterology, Groupe Hospitalier Henri Mondor-Albert Chenevier, APHP, Créteil, France.

Primary colonic mucosa-associated lymphoid tissue (MALT) lymphoma accounts for less than 0.5% of all colon cancers. We report 9 cases of colonic MALT lymphomas (median follow up: 9 [IQR 1-26] years). The disease was multi-focal in 4 patients: the most frequent sites were the cecum in 4 and the rectum in 3 patients. The main endoscopic finding was a polypoid lesion. The treatment modalities were rituximab +/- an alkylating agent ( = 5), an alkylating agent alone ( = 2), surgical resection ( = 1), and endoscopic resection ( = 1). Remission was achieved in 8 cases. Three patients relapsed, and 2 were re-treated. At the end of the study period, 67% of the patients were in remission. All patients were symptom-free. This current series of colonic MALT lymphomas shows the indolent nature of the disease, which may be treated with various modalities.
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http://dx.doi.org/10.1080/10428194.2019.1686501DOI Listing
March 2020

Refining diffuse large B-cell lymphoma subgroups using integrated analysis of molecular profiles.

EBioMedicine 2019 Oct 21;48:58-69. Epub 2019 Oct 21.

Inserm U1245, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France. Electronic address:

Background: Gene expression profiling (GEP), next-generation sequencing (NGS) and copy number variation (CNV) analysis have led to an increasingly detailed characterization of the genomic profiles of DLBCL. The aim of this study was to perform a fully integrated analysis of mutational, genomic, and expression profiles to refine DLBCL subtypes. A comparison of our model with two recently published integrative DLBCL classifiers was carried out, in order to best reflect the current state of genomic subtypes.

Methods: 223 patients with de novo DLBCL from the prospective, multicenter and randomized LNH-03B LYSA clinical trials were included. GEP data was obtained using Affymetrix GeneChip arrays, mutational profiles were established by Lymphopanel NGS targeting 34 key genes, CNV analysis was obtained by array CGH, and FISH and IHC were performed. Unsupervised independent component analysis (ICA) was applied to GEP data and integrated analysis of multi-level molecular data associated with each component (gene signature) was performed.

Findings: ICA identified 38 components reflecting transcriptomic variability across our DLBCL cohort. Many of the components were closely related to well-known DLBCL features such as cell-of-origin, stromal and MYC signatures. A component linked to gain of 19q13 locus, among other genomic alterations, was significantly correlated with poor OS and PFS. Through this integrated analysis, a high degree of heterogeneity was highlighted among previously described DLBCL subtypes.

Interpretation: The results of this integrated analysis enable a global and multi-level view of DLBCL, as well as improve our understanding of DLBCL subgroups.
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http://dx.doi.org/10.1016/j.ebiom.2019.09.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838437PMC
October 2019

Prognostic Significance of Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma: A Study by the Lunenburg Lymphoma Biomarker Consortium.

J Clin Oncol 2019 12 9;37(35):3359-3368. Epub 2019 Sep 9.

BC Cancer, Vancouver, British Columbia, Canada.

Purpose: rearrangement (-R) occurs in approximately 10% of diffuse large B-cell lymphomas (DLBCLs) and has been associated with poor prognosis in many studies. The impact of R on prognosis may be influenced by the partner gene (immunoglobulin [IG] or a non-IG gene). We evaluated a large cohort of patients through the Lunenburg Lymphoma Biomarker Consortium to validate the prognostic significance of (single-, double-, and triple-hit status) in DLBCL within the context of the partner gene.

Methods: The study cohort included patients with histologically confirmed DLBCL morphology derived from large prospective trials and patient registries in Europe and North America who were uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy or the like. Fluorescence in situ hybridization for the , , , and IG heavy and light chain loci was used, and results were correlated with clinical outcomes.

Results: A total of 5,117 patients were identified of whom 2,383 (47%) had biopsy material available to assess for -R. -R was present in 264 (11%) of 2,383 patients and was associated with a significantly shorter progression-free and overall survival, with a strong time-dependent effect within the first 24 months after diagnosis. The adverse prognostic impact of R was only evident in patients with a concurrent rearrangement of and/or and an IG partner (hazard ratio, 2.4; 95% CI, 1.6 to 3.6; < .001).

Conclusion: The negative prognostic impact of -R in DLBCL is largely observed in patients with double hit/triple-hit disease in which is translocated to an IG partner, and this effect is restricted to the first 2 years after diagnosis. Our results suggest that diagnostic strategies should be adopted to identify this high-risk cohort, and risk-adjusted therapeutic approaches should be refined further.
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http://dx.doi.org/10.1200/JCO.19.00743DOI Listing
December 2019

Defining signatures of peripheral T-cell lymphoma with a targeted 20-marker gene expression profiling assay.

Haematologica 2020 06 5;105(6):1582-1592. Epub 2019 Sep 5.

INSERM U955 and Université Paris-Est, Créteil, France

Peripheral T-cell lymphoma comprises a heterogeneous group of mature non-Hodgkin lymphomas. Their diagnosis is challenging, with up to 30% of cases remaining unclassifiable and referred to as "not otherwise specified". We developed a reverse transcriptase-multiplex ligation-dependent probe amplification gene expression profiling assay to differentiate the main T-cell lymphoma entities and to study the heterogeneity of the "not specified" category. The test evaluates the expression of 20 genes, including 17 markers relevant to T-cell immunology and lymphoma biopathology, one Epstein-Barr virus-related transcript, and variants of (G17V) and (R172K/T). By unsupervised hierarchical clustering, our assay accurately identified 21 of 21 ALK-positive anaplastic large cell lymphomas, 16 of 16 extranodal natural killer (NK)/T-cell lymphomas, 6 of 6 hepatosplenic T-cell lymphomas, and 13 of 13 adult T-cell leukemia/lymphomas. ALK-negative anaplastic lymphomas (n=34) segregated into one cytotoxic cluster (n=10) and one non-cytotoxic cluster expressing Th2 markers (n=24) and enriched in -rearranged cases. The 63 T-derived lymphomas divided into two subgroups according to a predominant T (n=50) or an enrichment in Th2 (n=13) signatures. We next developed a support vector machine predictor which attributed a molecular class to 27 of 77 not specified T-cell lymphomas: 17 T, five cytotoxic ALK-negative anaplastic and five NK/T-cell lymphomas. Among the remaining cases, we identified two cell-of-origin subgroups corresponding to cytotoxic/Th1 (n=19) and Th2 (n=24) signatures. A reproducibility test on 40 cases yielded a 90% concordance between three independent laboratories. This study demonstrates the applicability of a simple gene expression assay for the classification of peripheral T-cell lymphomas. Its applicability to routinely-fixed samples makes it an attractive adjunct in diagnostic practice.
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http://dx.doi.org/10.3324/haematol.2019.226647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271600PMC
June 2020

Clinical Impact of Genomic Diversity From Early to Advanced Hepatocellular Carcinoma.

Hepatology 2020 01 12;71(1):164-182. Epub 2019 Aug 12.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Functional Genomics of Solid Tumors Laboratory, Paris, France.

To date, genomic analyses of hepatocellular carcinoma (HCC) have been limited to early stages obtained from liver resection. We aim to describe the genomic profiling of HCC from early to advanced stages. We analyzed 801 HCC from 720 patients (410 resections, 137 transplantations, 122 percutaneous ablations, and 52 noncurative) for 190 gene expressions and for 31 gene mutations. Forty-one advanced HCC and 156 whole exome of Barcelona Clinic Liver Cancer (BCLC) 0/A were analyzed by whole-exome sequencing. Genomic profiling was correlated with tumor stages, clinical features, and survival. Our cohort included patients classified in BCLC stage 0 (9.4%), A (59.5%), B (16.2%), and C (14.9%). Among the overall 801 HCC, the most frequently mutated genes were telomerase reverse transcriptase (TERT) (58.1%), catenin beta 1 (CTNNB1) (30.7%), tumor protein 53 (TP53; 18.7%), AT-rich interaction domain 1A (ARID1A) (13%), albumin (11.4%), apolipoprotein B (APOB) (9.4%), and AXIN1 (9.2%). Advanced-stage HCC (BCLC B/C) showed higher frequencies of splicing factor 3b subunit 1 (SF3B1) (P = 0.0003), TP53 (P = 0.0006), and RB Transcriptional Corepressor 1 mutations (P = 0.03). G1-G6 transcriptomic classification and the molecular prognostic 5-gene score showed different distributions according to the stage of the disease and the type of treatment with an enrichment of G3 (P < 0.0001), poor prognostic score (P < 0.0001), and increased proliferation and dedifferentiation at the transcriptomic level in advanced HCC. The 5-gene score predicted survival in patients treated by resection (P < 0.0001) and ablation (P = 0.01) and in advanced HCC (P = 0.04). Twenty-two percent of advanced HCC harbored potentially druggable genetic alterations, and MET amplification was associated with complete tumor response in patients with advanced HCC treated by a specific MET inhibitor. Conclusion: Genomic analysis across the different stages of HCC revealed the mechanisms of tumor progression and helped to identify biomarkers of response to targeted therapies.
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http://dx.doi.org/10.1002/hep.30811DOI Listing
January 2020

Deregulation of miRNA in -Induced Gastric MALT Lymphoma: From Mice to Human.

J Clin Med 2019 Jun 13;8(6). Epub 2019 Jun 13.

INSERM, Université Bordeaux, UMR1053 Bordeaux Research in Translational Oncology, BaRITOn, 33000 Bordeaux, France.

Gastric MALT lymphoma (GML) is directly caused by infection but occurs only in a small number of infected subjects. Mechanisms underlying the initiation and progression of GML remain unclear. MicroRNAs (miRNAs) are small non-coding RNAs that are now considered as major players in inflammation and carcinogenesis, acting as oncogenes or tumor suppressors. Previous laboratory studies have shown in a GML mouse model that overexpression of a distinct set of five miRNAs (miR-21a, miR-135b, miR-142a, miR-150, miR-155) could play a critical role in the pathogenesis of GML. Our goal was to compare the miRNA expression profile obtained in the GML mouse model to that in human GML (11 cases of GML compared to 17 cases of gastritis control population). RTqPCR on the five dysregulated miRNAs in the GML mouse model and PCR array followed by RTqPCR confirmation showed that four miRNAs were up-regulated (miR-150, miR-155, miR-196a, miR-138) and two miRNAs down-regulated (miR-153, miR-7) in the stomachs of GML patients vs. gastritis control population. The analysis of their validated targets allowed us to postulate that these miRNAs (except miR-138) could act synergistically in a common signaling cascade promoting lymphomagenesis and could be involved in the pathogenesis of GML.
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http://dx.doi.org/10.3390/jcm8060845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616415PMC
June 2019

Isolated 5' Signals Are an Atypical Pattern To Be Considered as Positive for ALK Rearrangement: A Brief Report of Three Cases and Review of the Literature.

Transl Oncol 2019 May 22;12(5):784-787. Epub 2019 Mar 22.

Department of Pathology, HUPC, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris 75014, France. Electronic address:

Anaplastic lymphoma kinase (ALK) rearrangement is reported in 3% to 8% of patients with lung adenocarcinoma and can be detected by fluorescent in situ hybridization (FISH) or indirectly by immunohistochemistry. In FISH assay, isolated 5' signal (loss of 3' signal) is usually considered negative. We report three young nonsmoking patients with stage IV lung adenocarcinoma. Strong ALK expression in tumor cells detected by immunohistochemistry was observed in all cases, but FISH revealed an isolated 5' signal pattern. Massive parallel "next-generation" sequencing was performed in two patients and confirmed ALK rearrangement. The three patients were treated and responded to crizotinib after 14, 10, and 31 months.
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http://dx.doi.org/10.1016/j.tranon.2019.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434406PMC
May 2019

GAPDH Expression Predicts the Response to R-CHOP, the Tumor Metabolic Status, and the Response of DLBCL Patients to Metabolic Inhibitors.

Cell Metab 2019 06 28;29(6):1243-1257.e10. Epub 2019 Feb 28.

CHU Dinant Godinne, UcL Namur, Yvoir, Belgium.

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease treated with anti-CD20-based immuno-chemotherapy (R-CHOP). We identified that low levels of GAPDH predict a poor response to R-CHOP treatment. Importantly, we demonstrated that GAPDH lymphomas use OxPhos metabolism and rely on mTORC1 signaling and glutaminolysis. Consistently, disruptors of OxPhos metabolism (phenformin) or glutaminolysis (L-asparaginase) induce cytotoxic responses in GAPDH B cells and improve GAPDH B cell-lymphoma-bearing mice survival, while they are low or not efficient on GAPDH B cell lymphomas. Ultimately, we selected four GAPDH DLBCL patients, who were refractory to all anti-CD20-based therapies, and targeted DLBCL metabolism using L-asparaginase (K), mTOR inhibitor (T), and metformin (M) (called KTM therapy). Three out of the four patients presented a complete response upon one cycle of KTM. These findings establish that the GAPDH expression level predicts DLBCL patients' response to R-CHOP treatment and their sensitivity to specific metabolic inhibitors.
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http://dx.doi.org/10.1016/j.cmet.2019.02.002DOI Listing
June 2019

Gray-zone Lymphoma Between cHL and Large B-Cell Lymphoma: A Histopathologic Series From the LYSA.

Am J Surg Pathol 2019 03;43(3):341-351

INSERM1052, CNRS 5286, Lyon-Sud Charles Mérieux Lyon-1 Faculty, Claude Bernard University.

Gray-zone lymphoma (GZL) with features intermediate between classic Hodgkin lymphoma (cHL) and large B-cell lymphoma (LBCL) was introduced as a provisional entity into the World Health Organization classification in 2008. However, as diagnostic criteria are imprecise, reliable identification of GZL cases remains challenging. Here, we describe the histopathologic features of 139 GZL cases from a retrospective Lymphoma Study Association (LYSA) study with the goal to improve classification accuracy. Inclusion criteria were based on literature review and an expert consensus opinion of the LYSA hematopathologist panel. We observed 86 cases with a morphology more closely related to cHL, but with an LBCL immunophenotype based on strong and homogenous B-cell marker expression (CD20 and/or CD79a, OCT2, BOB1, PAX5) on all tumor cells (cHL-like GZL). Fifty-three cases were morphologically more closely related to LBCL but harbored a cHL immunophenotype (LBCL-like GZL). Importantly, we observed a continuous morphologic and immunophenotypic spectrum within these 2 GZL categories. The majority of cases presented genetic immune escape features with CD274/PDCD1LG2 and/or CIITA structural variants by fluorescence in situ hybridization. Patients without mediastinal involvement at diagnosis (17%) were older than those with mediastinal tumors (median: 56 vs. 39 y). Cases associated with Epstein-Barr virus (24%) presented with similar patient characteristics and outcome as Epstein-Barr virus negative cases. In summary, we provide refined diagnostic criteria that contribute to a more precise pathologic and clinical characterization of GZL within a broad spectrum from cHL-like to LBCL-like disease.
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http://dx.doi.org/10.1097/PAS.0000000000001198DOI Listing
March 2019

Cyclin D1-positive Mediastinal Large B-Cell Lymphoma With Copy Number Gains of CCND1 Gene: A Study of 3 Cases With Nonmediastinal Disease.

Am J Surg Pathol 2019 01;43(1):110-120

Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen, University Hospital Tübingen, Eberhard-Karls-University, Tübingen, Germany.

Primary mediastinal large B-cell lymphoma (PMBL) is a mature large B-cell lymphoma of putative thymic B-cell origin involving the mediastinum with younger age distribution and better prognosis than diffuse large B-cell lymphoma (DLBCL), not otherwise specified. Recently, based on gene expression profile analysis and morphologic findings, cases of PMBL without mediastinal involvement have been reported. In this study, we analyzed 3 cases of nodal DLBCL with morphologic features of PMBL presenting in submandibular or supraclavicular lymph nodes, in middle-aged to elderly patients, 2 of them without clinical or radiologic evidence of mediastinal involvement. The 3 patients presented with stage I/II disease and had excellent response to R-CHOP/R-EPOCH therapy. The 3 cases showed MAL expression and were positive for CD23 and/or CD30. All 3 cases expressed cyclin D1 with copy number gains of CCND1 gene but without rearrangement. There was no rearrangement of CIITA or PDL1/PDL2. Reverse transcriptase-multiplex ligation-dependent probe amplification, a mRNA-based gene expression profile analysis revealed high probability of PMBL (87.6%, 98.7%, and 99%) in these 3 cases. Targeted next-generation sequencing analysis showed SOCS1 mutations in the 3 cases, and TNFAIP3 and XPO1 mutations in one, further supporting the diagnosis of PMBL. In conclusion, we report 3 cases of nodal PMBL, 2 of them without mediastinal mass, and expression of cyclin D1 due to copy number gains of CCND1 gene, a diagnostic pitfall with mantle cell lymphoma and DLBCL, not otherwise specified.
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http://dx.doi.org/10.1097/PAS.0000000000001154DOI Listing
January 2019

Multiple Ways to Detect IDH2 Mutations in Angioimmunoblastic T-Cell Lymphoma from Immunohistochemistry to Next-Generation Sequencing.

J Mol Diagn 2018 09 5;20(5):677-685. Epub 2018 Jul 5.

INSERM U955 Équipe 9, Institut Mondor de Recherche Biomédicale, Créteil, France; Université Paris Est, Créteil, France; Département de Pathologie, Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Créteil, France.

Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma associated with chemoresistance and a poor prognosis. Various nonsynonymous mutations in the R172 residue of IDH2 are present in 20% to 30% of AITL patients. In addition to their diagnostic value, these mutations are potentially targetable, especially by isocitrate dehydrogenase (IDH) 2 inhibitor, and therefore their identification in a routine setting is clinically relevant. However, in AITL, the neoplastic cells may be scarce, making the identification of molecular anomalies difficult. We evaluated the diagnostic value of different methods to detect IDH2 mutations in formalin-fixed, paraffin-embedded tumor samples. Immunohistochemistry with an anti-IDH2 R172K antibody, Sanger sequencing, high-resolution melting PCR, allele-specific real-time quantitative PCR, and next-generation sequencing (NGS) were applied to biopsy specimens from 42 AITL patients. We demonstrate that the IDH2 R172K antibody is specific to this amino acid substitution and highly sensitive for the detection of the IDH2 variant, the most frequent substitution in this disease. In our study, NGS and allele-specific real-time quantitative PCR displayed a good sensitivity, detecting 96% and 92% of IDH2 mutations, respectively, in contrast to Sanger sequencing and high-resolution melting PCR, which showed a significantly lower detection rate (58% and 42%, respectively). These results suggest that a combination of immunohistochemistry and AS-PCR or NGS should be considered for the identification of IDH2 mutations in AITL in a routine setting.
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http://dx.doi.org/10.1016/j.jmoldx.2018.05.012DOI Listing
September 2018

Double-hit DLBCL: should we limit FISH testing?

Blood 2018 05;131(18):1997-1998

Henri Mondor University Hospital.

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http://dx.doi.org/10.1182/blood-2018-03-836361DOI Listing
May 2018

Total metabolic tumor volume, circulating tumor cells, cell-free DNA: distinct prognostic value in follicular lymphoma.

Blood Adv 2018 04;2(7):807-816

Paris-Est Créteil University, Créteil, France.

Outcomes for follicular lymphoma (FL) have greatly improved, but most patients will ultimately relapse. High total metabolic tumor volume (TMTV), computed from baseline F-fluorodeoxyglucose-positron emission tomography (PET), is associated with shorter progression-free survival (PFS), but circulating tumor cells (CTCs) and cell-free DNA (cfDNA) may also reflect tumor burden and be of prognostic value. The aim of our study was to correlate CTCs and cfDNA with TMTV in FL at diagnosis and to determine their prognostic values. We retrospectively analyzed 133 patients (with previously untreated FL and a baseline PET) from 2 cohorts with either a baseline plasma sample (n = 61) or a bcl2-JH-informative peripheral blood (PB) sample (n = 68). Quantification of circulating bcl2-JH cells and cfDNA was performed by droplet digital polymerase chain reaction. A significant correlation was found between TMTV and both CTCs ( < .0001) and cfDNA ( < .0001). With a median 48-month follow-up, 4-year PFS was lower in patients with TMTV > 510 cm ( = .0004), CTCs >0.0018 PB cells ( = .03), or cfDNA >2550 equivalent-genome/mL ( = .04). In comparison with TMTV alone, no additional prognostic information was obtained by measuring CTCs. In contrast, Cox multivariate analysis, including cfDNA and TMTV, showed that both cfDNA and TMTV remained predictive of outcome. In conclusion, CTCs and cfDNA correlate with TMTV in FL, and all 3 influence patient outcome. PFS was shorter for patients with high cfDNA and TMTV, suggesting that these parameters provide relevant information for tumor-tailored therapy.
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http://dx.doi.org/10.1182/bloodadvances.2017015164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894260PMC
April 2018

Reappraisal of HER2 status in the spectrum of advanced urothelial carcinoma: a need of guidelines for treatment eligibility.

Mod Pathol 2018 08 21;31(8):1270-1281. Epub 2018 Feb 21.

Département Hospitalo-Universitaire (DHU), Virus-Immunité-Cancer (VIC), Université Paris-Est-Créteil, (UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Equipe 7 Translational Research of Genito-Urinary Oncogenesis, INSERM U 955, Créteil, F-94010, France.

Although human epidermal growth factor receptor 2 (HER2) may represent a therapeutic target, its evaluation in urothelial carcinoma of the bladder does not rely on a standardized scoring system by immunohistochemistry or fluorescent in situ hybridization (FISH), as reflected by various methodology in the literature and clinical trials. Our aim was to improve and standardize HER2 amplification detection in bladder cancer. We assessed immunohistochemical criteria derived from 2013 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAPs) guidelines for breast cancer and investigated intratumoral heterogeneity in a retrospective multicentric cohort of 188 patients with locally advanced urothelial carcinoma of the bladder. Immunohistochemistry was performed on 178 primary tumors and 126 lymph node metastases, eligible cases (moderate/strong, complete/incomplete membrane staining) were assessed by FISH. HER2 overexpression was more frequent with 2013 ASCO/CAP than 2007 ASCO/CAP guidelines (p < 0.0001). The rate of positive HER2 FISH was similar between primary tumor and lymph node metastases (8%). Among positive FISH cases, 48% were associated with moderate/strong incomplete membrane staining that were not scored eligible for FISH by 2007 ASCO/CAP criteria. Among 3+ immunohistochemistry score cases, 67% were associated with HER2-positive FISH. Concordance between primary tumors and matched lymph node metastases was moderate for immunohistochemistry (κ = 0.54 (CI 95%, 0.41-0.67)) and FISH (κ = 0.50 (CI 95%, 0.20-0.79)). HER2-positive FISH was more frequent in micropapillary carcinomas (12%) and carcinoma with squamous differentiation (11%) than in pure conventional carcinoma (6%). Intratumoral heterogeneity for HER2 immunohistochemistry was observed in 7% primary tumor and 6% lymph node metastases; 24% positive HER2 FISH presented intratumoral heterogeneity. Our study suggests that HER2 evaluation should include an immunohistochemistry screening step with eligibility for FISH including incomplete/complete and moderate/strong membrane staining. Spatial or temporal intratumoral heterogeneity prompts to perform evaluation on both tumor and lymph node, and for each histological variant observed.
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http://dx.doi.org/10.1038/s41379-018-0023-9DOI Listing
August 2018

Long-term course of precancerous lesions arising in patients with gastric MALT lymphoma.

Dig Liver Dis 2018 Feb 27;50(2):181-188. Epub 2017 Oct 27.

Department of Gastroenterology, Henri Mondor University Hospital, APHP, Creteil F-94010, France; Paris Est-Creteil University (UPEC), Creteil F-94010, France; EC2M3-EA7375 Unit, Creteil, France. Electronic address:

Background And Aims: To evaluate the prevalence and the long-term course of gastric precancerous lesions in patients with GML.

Patients And Methods: In this retrospective single-centre study, we included 179 patients with GML, 70 with gastric diffuse large B-cell lymphoma (GDLBCL) and 152 with Helicobacter pylori-associated gastritis (HpG), from January 1995 to January 2014. The presence of atrophic gastritis, intestinal metaplasia and neoplastic lesion has been assessed at baseline and during follow-up.

Results: Atrophic gastritis was more frequent in the GML group whereas there was also a trend for intestinal metaplasia and gastric dysplasia. In patients with GML, atrophic gastritis, intestinal metaplasia and gastric dysplasia were more frequent in the GML area than in other part of the stomach. During follow-up, the prevalence of atrophic gastritis remained stable overtime whereas intestinal metaplasia and dysplasia tend to increase overtime. In multivariate analysis, the occurrence of dysplasia or carcinoma was associated with the presence of intestinal metaplasia at baseline and male gender.

Conclusion: GML is associated with gastric precancerous lesion to a higher extent than GDLBCL and HpG. Those precancerous lesions do not regress despite achievement of complete remission of GML and tend to increase overtime.
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http://dx.doi.org/10.1016/j.dld.2017.10.014DOI Listing
February 2018
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