Indeed, Tregs may limit the inflammatory spur of additional cells of the immune system (including T effectors) by liberating IL-10 and TGF-b, and this beneficial effect may prevail on the impairment of an effective T-cell-mediated response, as far as the outcome of HL is concerned (Physique 5). of characteristic multinucleated giant cells within an inflammatory milieu. These cellstermed Reed-Sternberg (RS) or diagnostic cellsrepresent the body of the tumor; they measure 2060m in diameter and display a large rim of cytoplasm and at least two nuclei with acidophilic or amphophilic nucleoli, covering more than 50% of the nuclear area (Physique 1). The tumoral population also includes a variable number of mononuclear elementsHodgkin’s cells (HCs)showing comparable cytological features to RS cells and neoplastic cell variants, each corresponding to a specific subtype of HL. Molecular studies have only recently shown that in most if not all CAL-130 cases RS cells, Hodgkin’s cells, and cell variants belong to the same clonal population, which is derived from peripheral B cell [19]. Accordingly, the disease has been included among malignant lymphomas, and the term Hodgkin’s lymphoma has been proposed [1012]. == Physique 1. == Histopathological features of classical Hodgkin lymphoma (cHL). At CAL-130 morphology (H&E staining), it is possible to distinguish nodular sclerosis (NS)*, mixed cellularity (MC), lymphocyte rich (LR), and lymphocyte-depleted (LD) subtypes. At immunophenotyping, cHL is typically CD15+, CD30+, possibly EBER+, and CD20-/+(Olympus BX41 microscope, Olympus CAMEDIA C-7070 camera, magnification 400, colours balanced after acquisition with Adobe Photoshop). *Note the typical Reed-Sternberg cells in the insets. However, although HRS cells are B lymphoid cells, they are unlike any normal B cell. Furthermore, their characteristics definitely contrast with a possible stem cell potential. Interestingly, it was recently shown that both the L428 and KM-H2 HL cell lines contained rare B-cell subpopulations responsible for the generation and maintenance of the predominant HRS cell population [13]. Intriguingly, the B cells within the HL cell lines expressed immunoglobulin light chain, the memory B-cell antigen CD27, and the stem cell marker aldehyde dehydrogenase (ALDH) [13]. Grippingly, CD27+/ALDH++B-cells, clonally related to lymph node HRS cells, were also detected in the blood of HL patients. Indeed, though the significance of such circulating clonotypic B-cells has to be defined, the authors suggested that they may be the initiating cells for HL [13]. Although regarded as diagnostic, RS cells are not exclusive to HL because comparable elements can be seen in reactive lesions (such as infectious mononucleosis), B and T cell lymphomas, carcinomas, melanomas, and sarcomas [14]. Thus, the presence of an appropriate cellular backgroundalong with the results of immunophenotypingis basic for the diagnosis. The reactive milieu, which can form up to 99% of the total population examined, consists of small lymphocytes, histiocytes, epithelioid histiocytes, neutrophils, eosinophils, plasma cells, and fibroblasts in different proportions, depending on the histological subtype of HL. It is sustained by an autocrine and/or paracrine production of several cytokines including, among others, IL-5, IL-8, IL-9, CCL-5, and CCL-28 (see below). The LMAN2L antibody release of these molecules is also responsible for most of the symptoms recorded in patients with HL, in addition to the ability of the neoplastic cells to escape from growth controls and immunosurveillance. More recently, it has been proposed that hepatocyte growth factor and c-MET might constitute an additional signaling pathway between RS cells and the reactive cellular background, affecting adhesion, proliferation, and the survival of RS cells [15]. == 1.1. Histopathological Classification == In 1832, Sir Thomas Hodgkin provided the first macroscopic description of the process in a paper entitled On some morbid appearances of the absorbent glands and spleen. In 1898 and 1902, Carl Sternberg and Dorothy Reed independently described the typical diagnostic cells. In 1944, Jackson and Parker proposed the first comprehensive classification of the tumor (Table 1). However, this classification was subsequently found to be clinically irrelevant because most patients belonged to the granulomatous subtype and the response to treatment varied greatly from case to case. == Table 1. == Hodgkin’s lymphoma (HL) classification schemes. *This includes a nodular (common) and a diffuse (rare) form CAL-130 in contrast to the REAL classification. In 1956, Smetana and Cohen identified a histopathological variant of granulomatous Hodgkin disease (HD), which had a.
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