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Purpose: Farnesyltransferase (Ftase) was identified by gene-expression profiling and by preclinical evaluation in in vitro and in vivo mantle cell lymphoma (MCL) models as a rational therapeutic target in MCL, one of the most refractory B-cell lymphomas. We conducted a multicenter phase II study of a potent Ftase inhibitor, tipifarnib, in patients with relapsed or refractory MCL.Methods: Tipifarnib was administered at 300 mg orally twice daily for the first 21 days of each 28-day cycle for 4 cycles, and in case of response for 6 cycles. Study endpoints were objective response at 4 and 6 cycles, progression free survival (PFS), overall survival, and toxicity. Prediction of response was retrospectively evaluated in the initial tumor biopsy by the RASGRP1/APTX gene expression ratio, and the AKAP13 expression level.Results: Eleven patients (median age, 71 years) were enrolled. Patients received a median number of three prior therapies (range 1-11). Nine patients completed at least 3 cycles of tipifarnib. No grade III-IV hematological toxicities were recorded. One patient presented a complete response (CR) after 4 and a persistent CR at 6 cycles (ORR = 9%). Median PFS was 3 months (range 0.7-14.2). The RASGRP1/APTX gene expression ratio was higher in the responder (n = 1) while the AKAP13 expression was higher in the non-responders (n = 2). This corresponds to the expected result for predicting response to tipifarnib.Conclusion: Treatment with tipifarnib relapsed or refractory MCL is associated with low response rates. Limited gene expression studies suggest that response may be associated with molecular targets. [ABSTRACT FROM AUTHOR]

Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is driven by aberrant activation of the B-cell receptor (BCR) and the TLR/MyD88 signaling pathways. The heat-shock protein HSP110 is a candidate for their regulation as it stabilizes MyD88. However, its role in overall BCR signaling remains unknown. Here, we used first-in-class HSP110 inhibitors to address this question. HSP110 inhibitors decreased the survival of several ABC-DLBCL cell lines in vitro and in vivo, and reduced the phosphorylation of BCR signaling kinases, including BTK and SYK. We identified an interaction between HSP110 and SYK and demonstrated that HSP110 promotes SYK phosphorylation. Finally, the combination of the HSP110 inhibitor with the PI3K inhibitor copanlisib decreases SYK/BTK and AKT phosphorylation synergistically, leading to suppression of tumor growth in cell line xenografts and strong reduction in patient-derived xenografts. In conclusion, by regulating the BCR/TLR signaling pathway, HSP110 inhibitors are potential drug candidates for ABC-DLBCL patients., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

In the 2022, WHO and ICC classifications, myeloid/lymphoid neoplasms with eosinophilia (M/LN-eo) and tyrosine kinase gene fusions represent rare hematologic malignancies driven by rearrangements of PDGFRA, PDGFRB, FGFR1, JAK2, FLT3, and ETV6::ABL1 fusion. Eosinophilia is the most constant finding, whereas the clinicopathological features are quite heterogeneous, presenting as Chronic eosinophilic leukemia (CEL) NOS, myelodysplastic/myeloproliferative neoplasm (MDS/MPN), MDS, MPN, systemic mastocytosis (SM), T or B cell acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL), acute myeloid leukemia (AML), blastic phase of MPN, or mixed phenotype acute leukemia (MPAL). Extramedullary involvement at diagnosis or during progression is common. Here, we report a very unusual case of myeloid/lymphoid neoplasm with ETV6::FLT3 fusion with a nodal presentation without associated eosinophilia. Our case draws attention to diagnostic pitfalls in these rare entities., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Many neoplasms remain unclassified after histopathological examination, which requires further molecular analysis. To this regard, mesenchymal neoplasms are particularly challenging due to the combination of their rarity and the large number of subtypes, and many entities still lack robust diagnostic hallmarks. RNA transcriptomic profiles have proven to be a reliable basis for the classification of previously unclassified tumors and notably for mesenchymal neoplasms. Using exome-based RNA capture sequencing on more than 5000 samples of archival material (formalin-fixed, paraffin-embedded), the combination of expression profiles analyzes (including several clustering methods), fusion genes, and small nucleotide variations has been developed at the Centre Léon Bérard (CLB) in Lyon for the molecular diagnosis of challenging neoplasms and the discovery of new entities. The molecular basis of the technique, the protocol, and the bioinformatics algorithms used are described herein, as well as its advantages and limitations., (© 2022 Wiley Periodicals LLC.)

Background: Second primary cancers (SPC) account for 18% of all cancers. We used the enhanced medical/health data mining tool ConSoRe to search aggregated data, analyze electronic patient records (EPR), and better characterize patients with SPC., Methods: This retrospective cohort study used ConSoRe to identify EPRs from patients with SPC referred to the regional cancer center Leon Bérard from 1993 to 2017, and examined characteristics of patients with SPC, frequencies of first primary cancer (FPC) localization in the global population of patients with SPC, and time to SPC. Data set was extracted on January 1, 2018., Results: Among 296,530 EPRs, we identified 157,187 patients with FPC, including 13,002 (8%) patients with SPC. Between 2000 and 2010, the rate of SPC was 34%, and 52% of SPC were identified in the last years (2010-2017). In men, main cancers were head and neck cancer, lymphoma, and prostate carcinoma accounting for 15.6%, 12.8%, and 10.5% of FPC, while the three most common SPC were head and neck cancer (13.2%), lung cancer (11.8%) and lymphoma (9.2%). In women, breast cancers, lymphoma, and skin cancers accounted for 48.8%, 8%, and 5.1% of first cancers, and for 31.1%, 7% and 6% of SPC., Conclusion: The data mining tool ConSoRe contributes to access to real world data, and to better characterize patients with SPC. Expanding such approach to any comprehensive center will allow a global overview of the follow-up of patients with cancer, and help to improve long-term management and adapt surveillance., (© 2021. Japan Society of Clinical Oncology.)

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., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Cholesterol granuloma (CG) is a foreign body-type granuloma that forms in response to cholesterol crystals. Its etiology and pathogenesis are unclear. 18F-FDG is not a tumor-specific agent. Fibroblasts, macrophages, and multinucleated giant cells also take up 18F-FDG. Like sarcoid granulomas or fibrous dysplasia, CG avidly takes up 18F-FDG and can mimic tumor involvement. We present 2 cases of histologically proven CG, which has been misinterpreted as active residual Hodgkin lymphoma lesion., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

While outcome for pediatric T lymphoblastic lymphoma (T-LL) has improved with acute leukemia-type therapy, survival after relapse remains rare. Few prognostic markers have been identified: NOTCH1 and/or FBXW7 ( N/F ) mutations identify good prognosis T-LL and high-level minimal disseminated disease (MDD) is reported to be of poor prognosis. We evaluated MDD and/or MRD status by 8-color flow cytometry and/or digital droplet PCR in 82 pediatric T-LL treated according to the EURO-LB02 prednisone reference arm. Both techniques gave identical results for values ≥0.1%, allowing compilation. Unlike historical studies, an MDD threshold of 1% had no prognostic significance. The 54% (42/78) of patients with MDD ≥0.1% had a relatively favorable outcome (5-y overall survival [OS] 97.6% versus 80.6%, P = 0.015, 5-y event-free-survival [EFS] 95.2% versus 80.6%, P = 0.049). MDD lower than 0.1% had no impact in N/F mutated T-LL, but identified the N/F germline patient with a high risk of relapse. Combining oncogenetic and MDD status identified 86% of patients (n = 49) with an excellent outcome and 14% of N/F germline/MDD <0.1% patients (n = 8) with poor prognosis (5y-OS 95.9% versus 37.5%, P < 0.001; 5y-EFS 93.9% versus 37.5%, P < 0.001). If confirmed by prospective studies, MDD and N/F mutational status would allow identification of a subset of patients who merit consideration for alternative front-line treatment., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

The oncogenic events involved in breast implant-associated anaplastic large cell lymphoma (BI-ALCL) remain elusive. To clarify this point, we have characterized the genomic landscape of 34 BI-ALCLs (15 tumor and 19 in situ subtypes) collected from 54 BI-ALCL patients diagnosed through the French Lymphopath network. Whole-exome sequencing (n = 22, with paired tumor/germline DNA) and/or targeted deep sequencing (n = 24) showed recurrent mutations of epigenetic modifiers in 74% of cases, involving notably KMT2C (26%), KMT2D (9%), CHD2 (15%), and CREBBP (15%). KMT2D and KMT2C mutations correlated with a loss of H3K4 mono- and trimethylation by immunohistochemistry. Twenty cases (59%) showed mutations in ≥1 member of the JAK/STAT pathway, including STAT3 (38%), JAK1 (18%), and STAT5B (3%), and in negative regulators, including SOCS3 (6%), SOCS1 (3%), and PTPN1 (3%). These mutations were more frequent in tumor-type samples than in situ samples (P = .038). All BI-ALCLs expressed pSTAT3, regardless of the mutational status of genes in the JAK/STAT pathway. Mutations in the EOMES gene (12%) involved in lymphocyte development, PI3K-AKT/mTOR (6%), and loss-of-function mutations in TP53 (12%) were also identified. Copy-number aberration (CNA) analysis identified recurrent alterations, including gains on chromosomes 2, 9p, 12p, and 21 and losses on 4q, 8p, 15, 16, and 20. Regions of CNA encompassed genes involved in the JAK/STAT pathway and epigenetic regulators. Our results show that the BI-ALCL genomic landscape is characterized by not only JAK/STAT activating mutations but also loss-of-function alterations of epigenetic modifiers., (© 2020 by The American Society of Hematology.)

Rare cases of hematological precursor neoplasms fulfill the diagnostic criteria of mixed phenotype acute leukemia (MPAL), characterized by expression patterns of at least two hematopoietic lineages, for which a highly aggressive behavior was reported. We present a series of 11 pediatric non-leukemic MPAL identified among 146 precursor lymphoblastic lymphomas included in the prospective trial Euro-LBL 02. Paraffin-embedded biopsies of 10 cases were suitable for molecular analyses using OncoScan assay (n = 7), fluorescence in situ hybridization (FISH; n = 7) or both (n = 5). Except for one case with biallelic KMT2A (MLL) breaks, all cases analyzed by FISH lacked the most common translocations defining molecular subsets of lymphoblastic leukemia/lymphomas. Two non-leukemic B-myeloid MPALs showed the typical genomic profile of hyperdiploid precursor B-cell lymphoblastic leukemia with gains of chromosomes 4, 6, 10, 14, 18, and 21. One B-T MPAL showed typical aberrations of T-cell lymphoblastic lymphoma, such as copy number neutral loss of heterozygosity (CNN-LOH) at 9p targeting a 9p21.3 deletion of CDKN2A and 11q12.2-qter affecting the ATM gene. ATM was also mutated in a T-myeloid MPAL case with additional loss at 7q21.2-q36.3 and mutation of NRAS, two alterations common in myeloid disorders. No recurrent regions of CNN-LOH were observed. The outcome under treatment was good with all patients being alive in first complete remission after treatment according to a protocol for precursor lymphoblastic lymphoma (follow-up 3-10 years, median: 4.9 years). In summary, the present series of non-leukemic MPALs widely lacked recurrently reported translocations in lymphoid/myeloid neoplasias and showed heterogeneous spectrum of chromosomal imbalances., (© 2018 Wiley Periodicals, Inc.)

Activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive lymphoproliferative disorder involving chronic NF-κB activation. Several mutations in the BCR and MyD88 signaling pathway components, such as MyD88 L265P, are implicated in this aberrant activation. Among heat shock proteins, HSP110 has recently been identified as a prosurvival and/or proliferation factor in many cancers, but its role in ABC-DLBCL survival mechanisms remained to be established. We observed that short hairpin RNA-mediated HSP110 silencing decreased the survival of several ABC-DLBCL cell lines and decreased immunoglobulin M-MyD88 co-localization and subsequent NF-κB signaling. Conversely, overexpression of HSP110 in ABC-DLBCL or non-DLBCL cell lines increased NF-κB signaling, indicating a tight interplay between HSP110 and the NF-κB pathway. By using immunoprecipitation and proximity ligation assays, we identified an interaction between HSP110 and both wild-type MyD88 and MyD88 L265P. HSP110 stabilized both MyD88 forms with a stronger effect on MyD88 L265P, thus facilitating chronic NF-κB activation. Finally, HSP110 expression was higher in lymph node biopsies from patients with ABC-DLBCL than in normal reactive lymph nodes, and a strong correlation was found between the level of HSP110 and MyD88. In conclusion, we identified HSP110 as a regulator of NF-κB signaling through MyD88 stabilization in ABC-DLBCL. This finding reveals HSP110 as a new potential therapeutic target in ABC-DLBCL., (© 2018 by The American Society of Hematology.)

Purpose To prospectively assess the clinical impact of expert review of lymphoma diagnosis in France. Materials and Methods From January 2010 to December 2013, 42,145 samples from patients with newly diagnosed or suspected lymphomas were reviewed, according to the 2008 WHO classification, in real time by experts through the Lymphopath Network. Changes in diagnosis between referral and expert review were classified as major or minor according to their potential impact on patient care. Results The 42,145 reviewed samples comprised 36,920 newly diagnosed mature lymphomas, 321 precursor lymphoid neoplasms, 314 myeloid disorders, and 200 nonhematopoietic neoplasms, with 4,390 benign lesions. There were 4,352 cutaneous and 32,568 noncutaneous lymphomas. The most common mature noncutaneous lymphomas were diffuse large B-cell lymphomas (32.4%), follicular lymphomas (15.3%), classic Hodgkin lymphomas (13%), peripheral T-cell lymphomas (6.3%) of which angioimmunoblastic T-cell lymphomas (2.3%) were the most frequent, and mucosa-associated lymphoid tissue lymphomas (5.8%). A diagnostic change between referral and expert review occurred in 19.7% of patients, with an estimated impact on patient care for 17.4% of patients. This rate was significantly higher for patients sent with a provisional diagnosis seeking expert second opinion (37.8%) than for patients sent with a formal diagnosis (3.7%). The most frequent discrepancies were misclassifications in lymphoma subtype (41.3%), with 12.3% being misclassifications among small B-cell lymphoma entities. Fewer than 2% of changes were between benign and malignant lymphoid conditions. Minor changes (2.3%) mostly consisted of follicular lymphoma misgrading and diffuse large B-cell lymphoma subtype misclassification. Conclusion To our knowledge, this study provides the largest ever description of the distribution of lymphoma entities in a western country and highlights how expert review significantly contributes to a precise lymphoma diagnosis and optimal clinical management in a proportion of patients.

Histiocytoses are rare and heterogeneous disease sharing histology, characterized by accumulation of histiocytes. They may be inherited or sporadic, and related to the accumulation of endo- or exogenous material in macrophages or to macrophage activation. Recent discoveries have shown that some histiocytoses, such as Langerhans cell histiocytosis or Erdheim-Chester disease, previously considered as idiopathic or inflammatory were clonal myeloid proliferations. This review presents the general classification of histiocytoses, and describes diagnostic and molecular criteria of idiopathic histiocytoses and histiocytic neoplasms., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Long-term primary CNS lymphoma (PCNSL) survivors could have multiple adverse prognostic factors at diagnosis such as age, performance status (PS), site of the tumour (deep vs superficial), lactate dehydrogenase (LDH) level and CSF protein level. Whether these five prognostic factors integrated in the International Extranodal Lymphoma Study Group (IELSG) score have a time-dependent effect is questionable. Among 132 PCNSL patients treated at our institution between 1984 and 2006, 91 available patients for IELSG score were evaluated by time-segmented analysis. Of the 91 patients, 21% had 0-1, 59% had 2-3 and 20% had 4-5 adverse IELSG prognostic scores. With a median follow-up of 102 months, the median overall survival (OS) of the 91 patients with the five prognostic factors of IELSG score was 33 months (95% CI, 17 to 55) compared with 14 months (95% CI, 3 to 23) for the remaining 41 patients whose CSF protein level was lacking in the IELSG score. These 41 patients who did not have lumbar puncture presented a poorer PS at diagnosis and a lower treatment response rate. While confirming the prognostic value of the IELSG score, we observed a time-dependent effect of age, PS and tumour site; all three lost their prognostic value after 6 months from diagnosis, while LDH remained a constant predictor of OS. No prognostic impact of CSF protein level was reported. Patients with older age, poor PS and deep brain involvement are at risk of death during the first months after diagnosis but could have a favourable long-term outcome after the treatment period. New prognostic factors predicting long-term outcome remain to be determined., (Copyright © 2012 John Wiley & Sons, Ltd.)

The majority of lymphoblastic (precursor cell) neoplasms presents as leukemias. Consequently, the guidelines for lineage determination and subtyping of precursor cell neoplasms were primarily established for flow cytometry methods. Large-scale studies of nonleukemic lymphoblastic lymphomas are lacking so far. We analyzed a large series of pediatric patients with lymphoblastic lymphoma treated within a prospective randomized trial (the Euro-LB 02 study). Among 193 lymphomas, in which a detailed immunohistochemical analysis was carried out, there were several unusual and diagnostically challenging morphologic and immunophenotypical variants. These included 11 lymphomas with mixed phenotypes expressing markers of at least 2 hematopoietic lineages, 7 terminal deoxynucleotide transferase-negative lymphoblastic lymphomas, and 3 undifferentiated hematopoietic neoplasms that could not be assigned to any lineage with certainty. Our data indicate that World Health Organization guidelines for lineage determination and subtyping of precursor cell leukemia need to be adapted before they can be applied to immunohistochemical diagnosis of lymphoma. Using the experience from this cohort we suggest a resource-saving diagnostic staining panel for the immunohistochemical analysis of precursor cell neoplasms in formalin-fixed paraffin-embedded tissue.

There is very limited data on isolated systemic relapses of primary central nervous system lymphomas (PCNSL). We retrospectively reviewed the clinical characteristics and outcome of 10 patients with isolated systemic disease among 209 patients with PCNSL mainly treated with methotrexate-based chemotherapy (CT) with or without radiation therapy (RT). Isolated systemic relapse remained rare (4.8%, 10/209 patients). Median time from initial diagnosis to relapse was 33 months (range, 3-94). Sites of relapse were mostly extranodal. Three patients presented with early extra-cerebral (EC) relapse 3, 5 and 8 months from the beginning of initial treatment, respectively, and 7 patients had later relapses (range, 17-94 months). Treatment at relapse included surgery alone, RT alone, CT with or without radiotherapy, or CT with autologous stem cell transplantation (ASCT). Median overall survival (OS) after relapse was 15.5 months (range, 5.8-24.5) compared to 4.6 months (range, 3.6-6.5) for patients with central nervous system (CNS) relapse (p = 0.35). In conclusion, isolated systemic relapses exist but are infrequent. Early EC relapse suggests the presence of systemic disease undetectable by conventional evaluation at initial diagnosis. Patient follow-up must be prolonged because systemic relapse can occur as late as 10 years after initial diagnosis. Whether EC relapses of PCNSL have a better prognosis than CNS relapses needs to be assessed in a larger cohort., (Copyright © 2010 John Wiley & Sons, Ltd.)

Breast metastases from nonmammary tumors are rare. We report here the first case of pancreatic neuroendocrine carcinoma metastatic to the breast in a patient with possible multiple endocrine neoplasia type 1. The diagnosis was supported by histological examination, immunohistochemistry, and ultrastructural analysis. This observation emphasizes the importance of clinical data for an accurate diagnosis, especially during intraoperative examination. When pathologists are faced with an unusual breast tumor larger than 2 cm, we would recommend freezing and/or saving pieces of tissue for ultrastructural analysis, which might help in the diagnosis.