Cell of Origin (Table 2.1)
Cellular origin is a major defining feature of cancers in general. Likewise, normal counterpart is one of the defining features of lymphomas in the World Health Organization classification, and non‐Hodgkin lymphoma entities are primarily stratified according to their cellular derivation from B cells compared with T or NK cells.
In the B‐cell lineage, stages of normal B‐cell differentiation proceed through successive steps that occur in distinct microenvironments, are associated with genetic events, modification of gene expression profiles and immunophenotypes and to some extent morphology, and there is a relatively good correspondence of many B‐cell neoplasms to normal counterparts [112].
In contrast, the cellular immune system comprises multiple functional subsets featuring functional plasticity, and NK/T‐cell activation and differentiation do not encompass acquired genetic traits. One important level of dichotomy is between the innate and the acquired immune systems which comprise distinct cellular subsets with different physiological properties, and the derived neoplasms broadly feature different characteristics, emphasizing the concept that cellular derivation is an important determinant of lymphoma biology (Figure 2.3). Innate immune cells comprise NK cells, γδ T cells and a minor subset of αβ T cells. These cells preferentially distributed at the interface with external antigenic stimuli (skin and mucosae) provide immediate immune responses which are not restricted by antigen recognition in the context of MHC presentation, and lack immunological memory. NK cells lack TCR gene rearrangements and lack membrane TCR expression. NK cells share some markers with T cells such as CD2, CD7, CD45RO, and cytoplasmic (but not surface) CD3. NK cells are usually CD4–/CD8– but may be CD8+, and they express one or several of the “NK‐associated” antigens (CD11b, CD16, CD56, CD57, NK receptors), which are, however, not entirely specific. γδ T cells (CD4‐CD8‐ or more rarely CD4–/CD8+) comprise less than 5% of T cells and are preferentially distributed in the skin, mucosae, and to the splenic red pulp. Both NK cells and γδ T cells express cytotoxic proteins, T‐cell intracellular antigen‐1 (a marker of cytotoxic cells in general), perforin and granzyme B (both expressed upon activation and not in the resting stage). The majority of T lymphocytes are αβ T cells, which recognize the antigen in a MHC‐restricted fashion in the presence of an antigen‐presenting cell, and constitute the adaptative immune system, which is characterized by specificity and memory of the immunological response.
Figure 2.3 Cellular derivation of T‐cell and NK‐cell lymphomas from the innate and adaptive immune systems. ALCL, anaplastic large‐cell lymphoma; ALK, anaplastic lymphoma kinase; EBV, Epstein–Barr virus; LPD, lymphoproliferative disorders; NK, natural killer; TCL, T‐cell lymphoma; TFH, T follicular helper cells; TH1, 2, T lymphocyte 1, 2; Treg, T‐regulatory cells.
Source: Adapted from de Leval and Gaulard [122].
Neoplasms derived from the innate immune system comprise several mostly extranodal cytotoxic malignancies, which are overall rare and, with the exception of the usually indolent chronic leukemias of NK cells or large granular lymphocytes, often have a highly aggressive behavior and poor outcome. Innate‐type lymphomas may occur in young individuals and some entities, such as ENKTL, are defined by their association to EBV infection. Together with the cytotoxic features of the malignant cells and/or EBV infection, these diseases may not uncommonly be associated to necrosis and a hemophagocytic syndrome [113]. Although there might be a predilection for derivation from NK compared with γδ compared with αβ T cells in distinct entities, only the NK‐cell leukemias and primary cutaneous γδ T‐cell lymphomas are by definition homogeneous in terms of cellular lineage. Interestingly, there is marked overlap in the mutational landscapes of these different innate lymphoid neoplasms. Mutation‐induced activation of the JAK–STAT pathway is highly recurrent among those [114], and inactivation of the SETD2 histone methyltransferase appears to be tightly linked to entities derived from gamma‐delta T cells, MEITL, and HSTL [23, 54, 114].
It is also remarkable that extranodal PTCL entities tend to have a predilection for development in peculiar organs. Accordingly, distinct extranodal PTCL entities have a gene expression signature component that is organ specific [115, 116]. In some instances, the association reflects derivation from a subset of organ‐specific lymphocytes, or lymphocytes with peculiar homing properties. For example, EATL and MEITL are derived from intraepithelial lymphocytes of the intestinal mucosa. Most cases of HSTL derive from functionally immature cytotoxic γδ T cells of the splenic pool with Vδ1 gene usage. Epidermotropic mycosis fungoides, which is the most common cutaneous lymphoma, is associated with an expansion of lymphoid cells with homing properties to the skin. Altogether, this suggests the importance of tissue‐specific factors in sustaining or promoting tumor growth. Interestingly, a feature common to extranodal PTCL entities is the rarity of dissemination to the bone marrow and the lymph nodes.
The majority of mature T‐cell neoplasms are derived from alpha‐beta T cells that normally comprise CD4+ (mainly helper) and CD8+ (mainly cytotoxic) subsets, and tend to involve primarily lymph nodes. The discovery that the clonal T cells of AITL a shared the gene expression profile and immunophenotype of normal Tfh cells, represented a major step forward in the deciphering of the neoplastic to normal cell counterpart relatedness of mature nodal T‐cell lymphomas [61]. This important notion is now incorporated in the definition of the disease and in the current classification scheme, where cellular derivation from Tfh cells is the defining feature of a large group of mature CD4+ T cells. Importantly, this group of diseases defined by a common immunophenotype appears to be associated with clinical features reflecting the functional properties of the neoplastic cells and have in common a characteristic mutational landscape resulting in epigenetic deregulation and activation of receptor signaling pathways [112, 117]. Subsequently, unsupervised analysis of genome‐wide molecular profiles identified two distinct molecular subgroups of PTCL‐NOS, defined by the overexpression of GATA3 or TBX21 (t‐bet) and associated target genes. GATA3 and TBX21 are master regulators of gene expression profiles in Th cells skewing Th polarization into Th2 and Th1 differentiation pathways, respectively, suggesting that a large proportion of PTCL, NOS are related to either Th1 or Th2 lineage derivation. Moreover, both subgroups tend to correlate with different prognoses, and are associated with distinct structural genomic alterations and point mutations [6]. The neoplastic cells in HTLV1‐associated T‐cell lymphoma/leukemia often exhibit a T‐regulatory phenotype with frequent expression of FOXP3 transcription factor.
The notion of cellular derivation and normal cell counterpart has often been used interchangeably, implying that the driver oncogenic mutation target distinct subsets of mature T cells. This concept was recently challenged by novel data, which have highlighted a more complex picture. In the case of so‐called “lymphomas derived from Tfh cells,” experimental data and observations in humans have clearly demonstrated that, while early mutations in epigenetic modifiers may occur in early hematopoietic progenitors ahead of the lymphoid versus myeloid commitment, second‐line mutations occur in such primed cells engaged in the lymphoid lineage and are responsible for driving the Tfh differentiation of the neoplastic cells [118]. Hence, Tfh cells are better viewed as the normal cell counterpart, rather than the cell of origin. In the case of ALK‐positive ALCL, experimental data in a mouse model have suggested that it may arise in progenitor cells [119]. In ATLL associated with HTLV1 infection, expression of the Treg immune profile (positivity for CCR4 chemokine receptor and nuclear FoxP3) found in a subset of the cases [120], has led to the suggestion that ATLL may derive from Treg cells. However, some cases may express CD8 or lose CD4 expression, and it has been shown that FoxP3 is induced by HBZ, and the Treg phenotype can be induced by FoxP3 [121]; thus ATLL does not
