Diagnostic and therapeutic pathways for lymphoma patients: expert consensus through Nominal Group Technique and Delphi methodology

BackgroundSomatostatin receptors (SSTR) and chemokine receptor CXCR4 are expressed in lymphomas, while the abundance is known to be heterogeneous in different subtypes of lymphomas. Targeting tumor cells expressing these receptors might add to therapeutic opportunities while radiolabeled ligands for both imaging and therapy have been developed. The aim of this study was to establish SSTR subtype 2, 3 and 5 and also CXCR4 status immunohistochemically in six different lymphoma subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), mucosa-associated marginal B-cell lymphoma (MALT), Hodgkin lymphoma (HL) and peripheral T-cell lymphoma (PTCL).Material and MethodsThis study included a total of 103 lymphoma patients (24 DLBCL, 22 FL, 18 HL, 9 MALT, 20 MCL and 10 PTCL) diagnosed in the Southwest hospital district of Finland during 2010-2019. SSTR 2, 3 and 5 and CXCR4 expression was analyzed immunohistochemically (IHC) in lymphoma samples obtained from local archival Biobank tissue repository. Immunopositivity of each receptor was scored on a four-point scale accounting for staining intensity and proportion of positively stained tumor cells.ResultsOf different SSTR subtypes SSTR2 immunopositivity was most common and seen predominantly at the cell membrane of the malignant cells in 46-56% of DLBCL, HL and FL. CXCR4 co-expression was frequently present in these cases. SSTR3 and SSTR5 IHC were negative in DLBCL and FL but in HL SSTR expression was more heterogenous and SSTR3 and SSTR5 positivity was found in cytoplasm in 35% and 25% of cases. 2/4 blastoid MCL variants and one pleomorphic MCL variant had positive CXCR4 IHC whilst all other MCL cases (85%) were negative for all receptors. 30% (n=3) of the PTCL patients had positive SSTR5 IHC and CXCR4. MALT lymphomas were negative for all receptors.ConclusionSSTR2 and CXCR4 are found in DLBCL, FL and HL and co-expression of these receptors is common. Although in general expression of SSTRs and CXCR4 is heterogenous and very low in some subtypes such as MCL and MALT there are also patients with abundant expression. The latter are candidates for trials studying SSTR2 and/or CXCR4 based treatments in the future.

Historical review of lymphomas.

Diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) constitute two distinct subtypes of non-Hodgkin lymphoma (NHL) associated with considerable morbidity and mortality. Marked diversities with regard to molecular biology and clinical features are recognized in different subsets of the two lymphomas. Because these differences could be related to the location of the lymphoma, it is of interest to investigate the clinical and histopathological features of DLBCL and MCL involving the ocular adnexal region (i.e. the orbit, eyelids, conjunctiva, lacrimal gland and lacrimal sac). Similarly, the lacrimal gland is the only glandular structure within the orbit. Because the lacrimal gland represents an important part of the immunological system, it is of interest to investigate lymphomas involving this location with regard to clinical and histological characteristics. To characterize the clinical and histopathological features of Danish patients with DLBCL of the ocular adnexal region between 1980 and 2009 and of Danish ocular adnexal MCL patients from 1980 to 2005. Furthermore, the aim of this PhD was to review all specimens from patients with lymphoma of the lacrimal gland in Denmark between 1975 and 2009 to determine the distribution of lymphoma subtypes of the lacrimal gland and to describe the clinicopathological features of these patients. A total of 34 patients with DLBCL and 21 with MCL of the ocular adnexal region were identified. Twenty-seven patients had lacrimal gland lymphoma, including four DLBCLs and three MCLs from studies I and II. Elderly patients predominated in all three groups, with median ages of 78, 75 and 69 years in the DLBCL, the MCL and the lacrimal gland lymphoma groups, respectively. MCL patients had a preponderance of males, whereas females prevailed among lacrimal gland lymphoma patients. The orbit was the most common site of involvement in DLBCL and MCL. Most DLBCL patients had unilateral involvement, while MCL patients had a high frequency of bilateral involvement. Similarly, localized lymphoma was relatively frequently seen in DLBCL patients in contrast to the predominance of disseminated lymphoma in the MCL group. The majority of lacrimal gland lymphomas were low grade, and the distribution of subtypes was as follows: extranodal marginal zone lymphoma, 10 (37%); follicular lymphoma, 5 (19%); DLBCL, 4 (15%); MCL, 3 (11%); chronic lymphocytic leukaemia/small lymphatic lymphoma, 2 (7%); and unclassified B-cell lymphoma, 3 (11%). The overall survival rates at 3 and 5 years for the entire study group of DLBCL were 42% and 20%, whereas 58% and 22% of MCL patients were alive 3 and 5 years after the time of diagnosis. The 5-year overall survival rate of lacrimal gland lymphoma patients was 70%. Concordant bone marrow involvement and the International Prognostic Index score were predictive factors for the overall survival in the DLBCL group in Cox regression analysis. Rituximab-containing chemotherapy was associated with an improved survival rate in MCL patients. Diffuse large B-cell lymphoma and MCL involving the ocular adnexal region and lymphoma of the lacrimal gland are prevalent among elderly patients. The overall prognosis in DLBCL and MCL was poor, whereas the prognosis for lacrimal gland lymphoma patients was relatively good. Concordant bone marrow involvement and the International Prognostic Index score were independent predictive factors for mortality in the DLBCL group. Chemotherapy containing rituximab significantly improved survival in the MCL group.

Lymphoma is the fifth most common type of cancer in the United States, with 74,490 new cases estimated in 2009. Approximately 15% of patients with lymphoma have Hodgkin lymphoma; the remainder have one of the non-Hodgkin lymphomas. The incidence of non-Hodgkin lymphoma has increased steadily over recent decades. This chapter reviews the epidemiology, classification, clinical features, pathology, diagnostic evaluation, staging and prognosis, and treatment of Hodgkin and non-Hodgkin lymphoma. Other topics discussed include the acute and chronic effects of therapy for Hodgkin disease, as well as the subtypes of non-Hodgkin lymphomas, including indolent B cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, marginal-zone lymphoma, diffuse large B cell lymphoma (DLBCL), primary central nervous system lymphoma (PCNSL), Burkitt lymphoma, and HIV-related non-Hodgkin lymphoma. Figures illustrate the cellular appearance of Hodgkin lymphoma subtypes and DLBCL, diagnosis of DLBCL subtypes by gene expression, computed tomography and plain chest film in primary mediastinal cell lymphoma, MRI of the brain in PCNSL, and gene expression and gene expression predictors of survival among patients with DLBCL treated with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine [Oncovin], and prednisone (R-CHOP). Tables describe the Ann Arbor classification and the Cotswold modification for staging of lymphoma; the International Prognostic Score for advanced Hodgkin lymphoma; the World Health Organization classification of hematopoietic neoplasms; chromosomal translocations in non-Hodgkin lymphoma; the Eastern Cooperative Oncology Group performance scale; the International Prognostic Index for aggressive non-Hodgkin lymphoma; and the Follicular Lymphoma International Prognostic Index. This chapter has 185 references. This review contains 9 tables, 7 figures and 185 references

Autoimmune Diseases and Prognosis across Lymphoma Subtypes

Lenalidomide Is Effective in Heavily Pretreated Non Hodgkin Lymphoma (NHL): Analysis of a Retrospective Data Collection

Optimisation of metabolic criteria in the prognostic assessment in patients with lymphoma. A multicentre study.

A Phase II LYSA Study of Obinutuzumab Combined with Lenalidomide for Relapsed or Refractory Aggressive B-Cell Lymphoma

The Epstein–Barr virus (EBV) is linked to various B-cell lymphomas, including Burkitt lymphoma (BL), classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL) at frequencies ranging, by routine techniques, from 5 to 10% of cases in DLBCL to >95% in endemic BL. Using higher-sensitivity methods, we recently detected EBV traces in a few EBV-negative BL cases, possibly suggesting a “hit-and-run” mechanism. Here, we used routine and higher-sensitivity methods (qPCR and ddPCR for conserved EBV genomic regions and miRNAs on microdissected tumor cells; EBNA1 mRNA In situ detection by RNAscope) to assess EBV infection in a larger lymphoma cohort [19 BL, 34 DLBCL, 44 cHL, 50 follicular lymphomas (FL), 10 T-lymphoblastic lymphomas (T-LL), 20 hairy cell leukemias (HCL), 10 mantle cell lymphomas (MCL)], as well as in several lymphoma cell lines (9 cHL and 6 BL). qPCR, ddPCR, and RNAscope consistently documented the presence of multiple EBV nucleic acids in rare tumor cells of several cases EBV-negative by conventional methods that all belonged to lymphoma entities clearly related to EBV (BL, 6/9 cases; cHL, 16/32 cases; DLBCL, 11/30 cases), in contrast to fewer cases (3/47 cases) of FL (where the role of EBV is more elusive) and no cases (0/40) of control lymphomas unrelated to EBV (HCL, T-LL, MCL). Similarly, we revealed traces of EBV infection in 4/5 BL and 6/7 HL cell lines otherwise conventionally classified as EBV negative. Interestingly, additional EBV-positive cases (1 DLBCL, 2 cHL) relapsed as EBV-negative by routine methods while showing EBNA1 expression in rare tumor cells by RNAscope. The relapse specimens were clonally identical to their onset biopsies, indicating that the lymphoma clone can largely loose the EBV genome over time but traces of EBV infection are still detectable by high-sensitivity methods. We suggest EBV may contribute to lymphoma pathogenesis more widely than currently acknowledged.

Phase 1 Study of Radiosensitization Using Bortezomib in Patients with Relapsed Non-Hodgkin's Lymphoma Receiving Radioimmunotherapy

The high incidence of thrombosis in lymphoma is largely due to chronic inflammation and endothelial dysfunction. To elucidate the mechanisms underlying thrombus formation and fibrinolysis, we investigated interactions between circulating endothelial cells and peripheral blood mononuclear cells (MNCs), along with inflammatory signaling pathways, in patients with follicular lymphoma (FL), Hodgkin lymphoma (HL), and diffuse large B-cell lymphoma (DLBCL), independent of the presence of thrombosis, compared to healthy controls by flow cytometry, immunoblotting, and fluorometric assays. We observed increased tissue factor (TF) expression on CD31+ endothelial cells in DLBCL and FL. In DLBCL, inducible nitric oxide synthase expression was elevated in MNCs, while reduced nitrite levels correlated with an advanced clinical stage in patients with thrombosis. In lymphoma, nuclear factor kappa B (NFκB) signaling was activated in MNCs, while signal transducer and activator of transcription 3 (STAT3) activation was increased in DLBCL with thrombosis. Trans-endothelial migration of MNC was enhanced in HL, FL and DLBCL with thrombosis and reduced by inflammatory cytokine tumor necrosis factor alpha (TNF-α) that promoted platelet aggregation like interleukin-6 (IL-6) in HL and FL. Fibrinolytic analyses showed reduced tissue type plasminogen activator in lymphoma, whereas increased urokinase-type plasminogen activator (uPA) was linked to poorer total survival in DLBCL with thrombosis, suggesting a compensatory role in early thrombus resolution. These findings indicate that chronic inflammation promotes endothelial activation, dysregulated fibrinolysis, and increased vascular permeability, contributing to heightened thrombotic risk. This study provides mechanistic insight into lymphoma-associated thrombosis and identifies TF, uPA, and the inflammatory signaling pathways as potential biomarkers and therapeutic targets.

Baseline Characteristics of 3046 Non-Hodgkin's Lymphoma Patients Diagnosed between July 2015 and May 2018: A Report from China Lymphoma Patient Registry (CLAP)

Phase IIa Study of Single-Agent MOR208 in Patients with Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma

Tumors with an excessive amount of stroma have been recognized by pathologists for many decades, for example scirrhous carcinomas of the stomach or breast, fi brolamellar hepatocellular carcinoma, Hodgkin lymphoma (HL) or T-cell/histiocyte-rich large B-cell lymphoma, to name a few. Th e stroma in these tumors is part of their defi nition. Notwithstanding, virtually all tumors contain stromal cells, albeit to varying degrees [1]. Of interest, the nature of the stromal component has also been shown to correlate with prognosis or therapy outcome [1]. In vitro testing has further indicated that stromal cells are active determinants of tumor cell proliferation, diff erentiation and apoptosis [2]. Th erefore, the tumor stroma deservedly has become a major focus of study. Understanding tumor stroma may allow us to devise therapy to counteract its growth-stimulating or stimulate its growthinhibiting characteristics. Recently, novel insights have been gained into the potential role of the stroma in major lymphoma types, especially follicular lymphoma (FL), HL and diff use large B-cell lymphoma (DLBCL). Th e components of the immunological response in FL are clearly associated with survival. Using gene expression analysis, Dave et al . could discern diff erent types of immune response signatures, named immune-response 1 and immune-response 2, respectively [3]. Th e immuneresponse 1 gene signature was shown to be derived from infi ltrating T-cells and to a lesser degree from monocytes, whereas immune-response 2 genes were mainly derived from monocytic cells. Of interest, immune-response 1 genes were correlated with improved survival, whereas immuneresponse 2 genes were correlated with unfavorable survival [3]. However, subsequent studies using tissue microarrays and immunohistochemical methods for characterization of the stromal components have yielded confl icting results with regard to the prognostic impact of infi ltrating cells [4]. Th e latter may partly be due to diff erences in treatment of the patients in the studies [5]. Multiple studies have also indicated that the stromal response in HL is associated with survival diff erences [6]. More specifi cally, gene expression studies indicated that an increased number of infi ltrating macrophages is associated with a less favorable outcome, as demonstrated for FL [7]. Other studies using immunohistochemistry on tissue sections have yielded similar fi ndings [6]. Equally, a stromal gene expression signature can invariably be detected in DLBCL [8 – 10]. DLBCL is molecularly heterogeneous, and can in more than 50% of cases be cured with an anthracycline-based chemotherapy combined with rituximab immunotherapy. Th e addition of immunotherapy improved the survival of patients compared with chemotherapy alone [11]. Th is is true for the two major molecular subtypes of the disease, germinal center B-cell-like and activated B-cell-like [10,12]. However, there still remains an important proportion of patients who cannot be cured with this therapy. Of interest, the stromal component in DLBCL as well as the expression of surface molecules that are important for interaction with stromal cells such as human leukocyte antigen class I and II molecules have proved to be important determinants of survival, irrespective of the molecular subtype [8]. Lenz et al . have shown by gene expression analysis of DLBCL, including expression analysis of fl ow-sorted samples, that especially two types of stromal response determine outcome, called stromal-1 and stromal-2, which result in an improved or worse survival, respectively, for patients treated with immunochemotherapy [10]. Th e stromal-1 response involves connective tissue growth factor and components of the extracellular matrix such as fi bronectin, osteonectin, collagen and laminin isoforms, as well as enzymatic modifi ers of collagen and extracellular matrix components. Th e stromal-2 response consists of genes that encode key regulators of angiogenesis, such as, for example, vascular endothelial growth factor, as well as endothelial cell markers such as CD31, and adipocyte markers. Of interest, the stromal-1 response is mediated by infi ltrating monocyte-derived cells. Th e favorable prognostic impact of monocyte-derived cells suggest another role of these cells in DLBCL compared with FL and HL. In this issue of Leukemia and Lymphoma , Rydstr o m et al . show that expression of CD40 by diff use large B-cell lymphoma, a putative marker for favorable prognosis in DLBCL, is associated with the up-regulation of genes coding for extracellular matrix components as well as proteolytic enzymes, thus approaching the stromal-1 signature [13]. Whether activation through CD40 expressed by diff use large L eu k L ym ph om a D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y 61 .2 21 .3 3. 39 o n 05 /2 0/ 14

Constitutive Chemokine Receptor Expression in B-Cell Non-Hodgkin's Lymphoma.