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(A) Classic RS cells and the main RS cell variants including lacunar and mononuclear cells. (B) A typical example of the diagnostic Reed-Sternberg (RS) cell (top) and a typical example of the L&H (lymphocytic & histiocytic) cell: a large cell with abundant clear cytoplasm contains a multilobated nucleus with small, prominent nucleoli (bottom).
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Hodgkin's lymphoma is a relatively uncommon malignancy that predominantly effects young adults. It became the first human cancer to be cured with combination chemotherapy. Unfortunately, many cured patients do not live their expected lifespan because of long-term lethal effects of therapy. Novel treatment strategies based on our understanding of Ho...
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... fibrosis), the mixed subtype representing those cases that did not fit into the other subtypes. The classification also included the definition of the lymphocyte and histiocyte (L&H) cells, and three RS cell variants: the lacunar cell variant, specifically detectable in nodular sclerosis, the pleomorphic variant and the mononuclear variant (Fig. 1). However, in daily practice, most pathol- ogists and clinicians used the classification presented at the meeting on HL held in Rye, New York. 5 The Rye classification combined the six groups of the Lukes and Butler's classification into four major histological subtypes: lymphocytic predominance, nodular sclerosis, mixed cellularity, ...
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We retrospectively reviewed 139 stage I-II HL patients who were diagnosed and followed up in an Italian northern region (Liguria) from 1995 to 2007, and who received either chemotherapy (CT) alone (mainly doxorubicin, bleomycin, vinblastine, and dacarbazine; ABVD) or a combined modality treatment (chemotherapy + radiotherapy, CT + RT). The two ther...
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... El linfoma de Hodgkin presenta una distribución bimodal, siendo en adultos más agresiva y generalmente de tipo celularidad mixta (13) , es inusual su presentación como adenopatía única por 4 años, sin presentar síntomas B, ni la diseminación ordenada que lo caracteriza. Su histología presenta las células de Reed-Sternberg en escasa cantidad en el marco de un infiltrado inflamatorio (14,15) . ...
Describimos el caso de un paciente portador de Desorden Linfoproliferativo Germinotrópico (DLG) Asociado a Virus Epstein Baar (EBV) y herpesvirus 8 (HHV8/KSVH), el primer reporte de esta entidad se realizo en la revista Blood del año 2002 (1) y a la fecha se han descrito alrededor de 20 casos (2,3); esta clasificada dentro de los desordenes linfoproliferativos asociados al herpesvirus 8 (HHV8/KSVH) (4)(5). Clínicamente se caracteriza por presentarse en pacientes inmunocompetentes, como una adenopatía localizada, de curso indolente, con respuesta favorable a la quimioterapia, radioterapia o escisión quirúrgica (6). Histológicamente se observan plasmablastos que marcan positivo a EBV y HHV8/KSVH formando agregados confluentes que tienden a invadir los centros germinales (germinotropismo) (6); al hacer la microdisección de los plasmablastos y estudio cadena de reacción de polimesasa (PCR), muestran un patrón policlonal u oligoclonal, por esto es catalogado como un “desorden” y no como una neoplasia propiamente dicha (6). La linfomagenesis esta dada por la co-infección de una célula B de origen centrogerminal; inicialmente tenemos a las células B como reservorio latente del HHV8/KSVH y posteriormente recibe el “second genetic hit” por el Virus Epstein Barr (EBV) (7), desarrollando en un paciente inmunocompetente el DLG.
... 4 Classic Hodgkin Lymphoma (cHL) represents a unique example among human lymphomas in that the putative malignant cells, i.e. the mononucleated Hodgkin cells and the giant multinucleated Reed-Sternberg cells, account for a striking minority, usually 0.1-3.0% of the total cell population in HL-involved tissues. [5][6][7] H-RS cells are interspersed among a heterogeneous population of non-malignant reactive cells mainly including T-cells, eosinophils, neutrophils, B-lymphocytes, plasma cells, histiocytes and stromal cells. [5][6][7] There are several mechanisms whereby chemokines might play an important role in the pathophysiology of HL. ...
... [5][6][7] H-RS cells are interspersed among a heterogeneous population of non-malignant reactive cells mainly including T-cells, eosinophils, neutrophils, B-lymphocytes, plasma cells, histiocytes and stromal cells. [5][6][7] There are several mechanisms whereby chemokines might play an important role in the pathophysiology of HL. First, they may exert a direct action on tumor cells by activating signaling pathways implicated in cell survival and proliferation. ...
The expression of CCL5/Rantes by Hodgkin (H) and Reed-Sternberg (RS) cells has been recently documented. In the present study we demonstrated that the CCL5 receptor (CCR5) is constitutively expressed by Hodgkin Lymphoma (HL)-derived cell lines (i.e. L-428, KM-H2, L-1236 and L-540) as shown by immunohistochemistry, flow cytometry and western blotting and also detected by immunohistochemistry on primary H-RS cells from lymph node tissues. sCD40L never significantly affected CCR5 expression, whereas a short exposure to doxorubicin down regulated its expression. CCR5 receptors on HL cell lines were functionally active, since neutralizing anti-CCL5 monoclonal antibodies inhibited basal proliferation of HL-derived cell lines and recombinant CCR5 ligands (CCL3/Mip-1 alpha, CCL4/Mip1 beta and CCL5/Rantes) increased their clonogenic growth. CCL5 secretion by L-1236, L-428 and KM-H2 cells was stimulated by CD40 engagement and also by coculturing L-1236 cells on primary stromal fibroblasts from HL-involved lymph nodes (HLF). Coculture experiments indicated that a direct contact of H-RS cells induces HLF cells to produce CCL5. Supernatants from L-1236, L-428 and KM-H2 cells stimulated migration of purified CD4+ T-cells and eosinophils in vitro. The migratory response to HL-cell lines supernatants was only partially neutralized (CD4+ cells: 70%; esinophils: 36%) by anti-CCL5 antibodies, reinforcing the notion that multiple chemokines are involved in the recruitment of nonmalignant reactive cells in HL tissues. Taken together, our results indicate a possible involvement of the CCR5/CCR5-ligands signaling in the regulation of H-RS cells growth and in the formation/maintenance of the typical tissue microenvironment of HL.
... These reactive cells are not bystander cells, as previously thought. By contrast, they frequently provide survival signals to HRS cells ( Figure 2B) [50]. The role of the microenvironment in supporting the survival and growth of HRS cells is best illustrated by the difficulty of establishing HRS-derived cell lines. ...
... Therefore, it is ironic that the host's own immune cells are providing survival factors to the malignant cells, creating an 'immune-betrayal' phenomenon. Eliminating these reactive cells from the microenvironment may deprive HRS cells from critical survival factors and may lead to their growth arrest and death [50]. ...
The WHO classification of Hodgkin's lymphoma (HL) distinguishes between two major subtypes, classical and nodular lymphocyte predominant HL. Approximately 95% of patients with HL will have the classical HL histology, which is characterized by the presence of rare malignant Hodgkin's and Reed-Sternberg cells among an overwhelming number of benign reactive cells. In recent years, new studies have shed more light on the biological and molecular features of Hodgkin's and Reed-Sternberg cells, providing hope that new targeted therapy may be developed to enhance the cure rate and to reduce treatment-related toxicity. In this review, the current understanding of the pathology and biology of HL will be discussed, as well as the current treatment approaches for patients with classical HL. Future treatment strategies will also be discussed based on our understanding of HL biology.
... raising the possibility that this could provide an alternative mechanism for PTEN loss (Parekh et al, 2000; Vazquez et al, 2000, 2001; Birle et al, 2002; Miller et al, 2002). The malignant Hodgkin and Reed–Sternberg (HRS) cells of Hodgkin lymphoma (HL) are predominantly of B-cell origin and are characterised by the expression of several tumour necrosis factor – receptor family members, including CD30, CD40 and receptor activator of nuclear factor kappa B (RANK) (Carbone et al, 1995; Stein & Hummel, 1999; Fiumara et al, 2001; Younes & Carbone, 2003). We have previously reported that RANK ligand (RANKL) is expressed by HRS cells and therefore is capable of promoting survival by an autocrine manner (Fiumara et al, 2001). ...
... We have previously reported that RANK ligand (RANKL) is expressed by HRS cells and therefore is capable of promoting survival by an autocrine manner (Fiumara et al, 2001). In contrast, CD30L and CD40L are expressed by the surrounding reactive cells and not by HRS cells, providing survival signals in a paracrine manner (Younes & Kadin, 2003). ...
Activation of the phosphatidylinositol 3-kinase (PI(3)K) pathway has been linked with tumour cell growth, survival and resistance to therapy in several cancer types. The active, phosphorylated form of Akt (pAkt) was found to be aberrantly expressed in Hodgkin lymphoma (HL)-derived cell lines and in Hodgkin-Reed-Sternberg (HRS) cells in 27 of 42 (64.3%) of primary lymph node sections of HL, indicative of PI(3)K activity. Akt phosphorylation was not associated with loss of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression, but with its phosphorylation in HL-cell lines, suggesting that its biological function is impaired. Akt phosphorylation was further induced by CD30 ligand (CD30L), CD40L and receptor activator of nuclear factor kappa B (RANK) ligand. The PI(3)K inhibitor LY294002 demonstrated antiproliferative effects in a dose- and time-dependent manner, which was associated with Akt dephosphorylation on Thr308 and Ser473 sites and dephosphorylation of the downstream ribosomal protein S6. LY209002 induced cell cycle arrest in the G0/G1 phase and apoptosis, which were associated with upregulation of MDM2, downregulation of cyclin D1, activation of caspase 9 and poly-ADP-ribose polymerase cleavage. The Akt inhibitor QLT394 also demonstrated antiproliferative effects in a dose- and time-dependent manner, dephosphorylated ribosomal S6 and cleaved caspase 9. Collectively, these data suggest that the aberrant activation of the PI(3)K/Akt survival pathway in HRS cells is not because of loss of PTEN expression. Our data suggest that PTEN phosphorylation and activation of CD30, CD40 and RANK may play a role in activating Akt in HRS cells.
... Novel treatment strategies that are based on our understanding of the biology of Hodgkin's lymphoma will be needed to continue improving the cure rate while reducing treatment-related toxicity. Several new targets have been recently identified for potential novel therapy of Hodgkin's lymphoma, including extracellular signal-regulated kinase (ERK), Akt, and nuclear factor nB (18,19). All these molecular targets have been identified as clients for HSP90 (3,9,20,21). ...
Heat shock protein 90 (HSP90) is a chaperone for several client proteins involved in transcriptional regulation, signal transduction, and cell cycle control. HSP90 is abundantly expressed by a variety of tumor types and has been recently targeted for cancer therapy. The objective of this study was to determine the role of HSP90 in promoting growth and survival of Hodgkin's lymphoma and to determine the molecular consequences of inhibiting HSP90 function by the small-molecule 17-allylamino-17-demethoxy-geldanamycin (17-AAG) in Hodgkin's lymphoma.
HSP90 expression in Hodgkin's lymphoma cell lines was determined by Western blot and in primary lymph node sections from patients with Hodgkin's lymphoma by immunohistochemistry. Cell viability was determined by the 3-(4,5-dimethyl-thiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Apoptosis and cell cycle fractions were determined by flow cytometry. Expression of intracellular proteins was determined by Western blot.
HSP90 is overexpressed in primary and cultured Hodgkin's lymphoma cells. Inhibition of HSP90 function by 17-AAG showed a time- and dose-dependent growth inhibition of Hodgkin's lymphoma cell lines. 17-AAG induced cell cycle arrest and apoptosis, which were associated with a decrease in cyclin-dependent kinase (CDK) 4, CDK 6, and polo-like kinase 1 (PLK1), and induced apoptosis by caspase-dependent and caspase-independent mechanisms. Furthermore, 17-AAG depleted cellular contents of Akt, decreased extracellular signal-regulated kinase (ERK) phosphorylation, and reduced cellular FLICE-like inhibitory protein levels (FLIP), and thus enhanced the cytotoxic effect of doxorubicin and agonistic anti-tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor antibodies.
Inhibition of HSP90 function induces cell death and enhances the activity of chemotherapy and anti-tumor necrosis factor-related apoptosis-inducing ligand death receptor antibodies, suggesting that targeting HSP90 function might be of therapeutic value in Hodgkin's lymphoma.
CD30, also known as TNFRSF8 (tumor necrosis factor receptor superfamily member 8), is a protein receptor that is heavily glycosylated inside the Golgi apparatus, as well as a tumor marker that is found on the surface of specific cells in the body, including certain immune cells and cancer ones. This review aims to shed light on the critical importance of CD30, from its emergence in the cell to its position in diagnosing various diseases, including Hodgkin lymphoma, where it is expressed on Hodgkin and Reed–Sternberg cells, as well as embryonal carcinoma, anaplastic large cell lymphoma (ALCL), and cutaneous T-cell lymphoma (CTCL). In addition to its role in positive diagnosis, targeting CD30 has been a promising approach treating CD30-positive lymphomas, and there is ongoing research into the potential use of CD30-targeted therapies for autoimmune disorders. We aim to elaborate on CD30’s roles as a tumor marker, supporting thus the hypothesis that this receptor might be the aim of cytostatic treatment.
Hodgkin lymphoma (HL) is a relatively rare cancer, with an estimated 8000 new cases per year in the United States. In the Western world, approximately 95% of patients with HL have a classical HL histology, whereas only 5% have the nodular lymphocyte-predominant HL (NLPHL) histologic subtype. The majority of patients are diagnosed in their late 20s to early 30s, with a fewer patients being diagnosed at a later age. HL is a B-cell lymphoid malignancy, originating from germinal center B lymphocytes.
Epstein-Barr virus (EBV) is a ubiquitous -herpes virus that is a well-established risk factor for Hodgkin's lymphoma, Burkitt's lymphoma, a subset of T cell lymphomas and various tumors of epithelial cell origin with nasopharyngeal carcinoma as the most representative. Furthermore, EBV-associated lymphoproliferative disorders are a well recognized major complication of immune suppression. EBV generally establishes a life-long asymptomatic infection in memory B lymphocytes, by mimicking cellular signaling pathways that regulate antigen-dependent B cell differentiation. In the long-lived memory B lymphocyte pool, the virus is almost completely silent or expresses a very restricted set of latent proteins, evading thus the immune control by EBV-specific effectors. EBV-associated lymphoid and epithelial malignancies are characterized by a peculiar geographic distribution and distinctive epidemiologic and histopathologic and histogenetic features. Moreover, new histogenetic and molecular features have contributed to the recognition and the diagnosis of specific disease categories. The ability of the virus to establish life-long persistent infections in humans and to contribute to cell transformation is related to the biologic properties of a set of EBV-encoded proteins, differently expressed in both normal and transformed cells. In the last decade, our understanding of the latency programs activated by EBV in cellular backgrounds and the function of EBV-encoded proteins has considerably improved. The emerging picture indicates that EBV proteins are able to hijack critical cellular pathways to promote the proliferation and survival of infected cells, while impairing anti-viral immune responses. The recent advances in the elucidation of the mechanisms underlying EBV-induced cell transformation and immune evasion help to design novel treatment approaches for EBV-related malignancies. Moreover, it has been clearly shown that the quantification of circulating EBV DNA is a valuable tool in the diagnosis, clinical monitoring and prognosis of some EBV-associated tumors.
