Pathobiology of Classical Hodgkin Lymphoma

Abstract

The World Health Organization has acknowledged the malignant nature of classical Hodgkin lymphoma (cHL), which encompasses four histological subtypes. The diagnosis of cHL is based on the detection of malignant Hodgkin and Reed-Sternberg cells (HRSC) confirmed by immunophenotyping and the detection of growth patterns specific to each histological subtype. The pathologic HRSC arise from germinal center or immediate postgerminal cells that lack detectable immunoglobulin/B-cell antigen receptor expression, with a consequent loss of B-cell identity; very few cHL cases are of T-cell origin. To escape apoptosis, which normally occurs in B cells with nonfunctioning antigen receptor machinery, HRSC develop concurrent antiapoptotic mechanisms by activation of nuclear factor-ĸB or are rescued by Epstein-Barr virus infection. HRSC are characterized by a variable and inconstant immunophenotype, with a remarkable loss of lineage-specific cell antigens and expression of antigens of other cell lineages. The master plan of B-cell identity in HRSC is disturbed not only at the immunoglobulin expression level, but also at the transcriptional factor level. HRSC are further characterized by profound cell cycle deregulation with futile replication, multinucleation and poly- and aneuploidy. Here, we review pathobiological aspects of cHL with respect to lymphomagenesis and routine diagnostics.

Clonal Relationship of Classical Hodgkin Lymphoma and Its Recurrences

“…Hodgkin and Reed-Sternberg cells are known for their defective cell cycle and apoptosis regulation, which enables them to escape therapy (reviewed in ref. 7), a theory which is supported by our finding of clonally related recurrences. Another hypothesis focuses on the existence of tumor stem cells in HL.…”

“…3, 11, 14, 15, and 20), and late recurrences in 17 patients (no. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. In 1 case (no.…”

“…Both B cell origin and monoclonality of Hodgkin and Reed-Sternberg cells have been established (reviewed in ref. 7). It has also been shown that in composite lymphomas, consisting of an HL and a so-called "non-HL" (NHL), a clonal relationship between both components can exist (8)(9)(10)(11), but studies on the clonal relationship of recurrent HL have so far been limited to case reports (12).…”

Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin's lymphoma

“…8-11 Importantly, the transforming lymphomagenesis events in both FL and cHL probably occur during the socalled germinal center (GC) reaction, 12,13 which is the most important step in B-cell maturation during T-cell dependent antigen responses.…”

Livin Expression by Semi-quantitative Immuno-flourecent Staining in Hodgkin Lymphoma: A Promising Marker or a Leading Role in Pathogenesis?

“…Although HL in general has a favorable prognosis but more molecular studies are required for the refractory and relapsed patients [9][10][11][12] to discover the unresolved molecular pathobiological issues of HL [2,13,14]. Recently, advances in molecular profiling of HRS cells have shown that this small number of malignant cells have a potential role in the HL pathogenesis through different pathways like providing a typical microenvironment by secretion of cytokines and chemokines (CCL5, CCL17, CCL22, IL5, TGF-β, PDGF, IL2, IL6 [2,4,15], deregulating of transcription factor network [2], and escaping from apoptosis [13,15,16].…”