Abstract
“T and NK-cell lymphoid proliferations and lymphomas” comprise nine groups with distinct cell origins, differentiation states, clinical features, localization, and cytomorphology. Most correspond to specific T or NK lineage. Still, few have a hybrid or indeterminate phenotype, including extranodal NK and T-cell lymphoma, EBV+ nodal T/NK-cell lymphoma, chronic active EBV disease, and severe mosquito bite allergy. The distinction between T- and NK cells is sometimes unclear. The main categories are Mature T-cell and NK-cell leukemias, Primary cutaneous T-cell lymphoid proliferations and lymphomas (CTCL), Intestinal T- and NK-cell lymphoid proliferations and lymphomas, Nodal T-Follicular Helper Cell Lymphomas, Peripheral T-cell lymphomas (PTCLs), EBV-related mature T-cell and NK-cell neoplasms, and Extranodal NK/T-cell lymphoma (ENKTL). HL comprises classical HL (cHL) and nodular lymphocyte predominant HL (NLPHL) subtypes.
TopMature T-Cell And Nk-Cell Leukemias
Mature T- and NK-cell neoplasms present primarily as leukemia and include the following entities:
- 1.
T-prolymphocytic leukemia (T-PLL) is rare accounting for ~2% of all small lymphocytic leukemias in adults with a median age of 61. It typically presents with splenomegaly, lymphadenopathy, and leucocytosis frequently >100x109 /l. Less commonly, other organs and skin are involved. Up to 30% of patients are asymptomatic at diagnosis. (Sabattini, 2022). It arises from mature, antigen-experienced, non-conventional memory T-cells.
Most T-PLL have aberrant TCL1A or MTCP1 protooncogenes expression, leading to overexpression of TCL1 and non-productive TCR-A rearrangement and the transition of naïve T-cells into an expanding pool of memory T cells. The TCR-mediated activation is the genetic hallmark of TPLL. Protein kinase B Akt1 activation and nuclear transport promote cell proliferation. (Shi & Jevremovic, 2022)
The diagnostic criteria and workup of T-PLL include major and minor criteria as outlined in Table 1. The recommended workup is summarized in Table 14.2(Staber et al., 2019).
Table 1. Requirements to establish the diagnosis of T-PLL (Staber et al., 2019)
| Major Criteria | Minor Criteria (At Least One Required) |
| >5×109/L TPLL cells in peripheral blood or bone marrow | Abnormalities involving chromosome 11 (11q22.3; ATM) |
| T-cell clonality by PCR for TRB/TRG or by flow cytometry | Chromosome 8 abnormalities: idic(8)(p11), t(8;8), trisomy 8q |
| Abnormalities of 14q32 or Xq28 genes OR expression of TCL1A/B, or MTCP1* | Abnormalities in chromosomes 5,12,13, 22, or complex karyotype |
| Involvement of T-PLL specific site (e.g., splenomegaly, effusions) |
Cases without TCL1A, TCL1B, or MTCP1 rearrangement or their respective overexpression constitute a TCL1-family negative T-PLL.
Key Terms in this Chapter
Epigenetic Therapies for Lymphoma: Emerging therapies that target epigenetic modifications, including DNA methylation, histone modifications, and RNA regulation. They include several classes according to their genetic target e.g. Inhibitors of DNA Methyltransferases (DNMTs), Histone Deacetylase (HDAC) Inhibitors, and Protein Arginine Methyltransferase (PRMT) Inhibitors. They offer exciting prospects for improving lymphoma treatment.
Transdifferentiation In Lymphoid Neoplasms: A lineage reprogramming in which one mature somatic cell transforms into another without undergoing an intermediate pluripotent or progenitor cell type. It can occur with some lymphoid tumors, such as follicular lymphoma and chronic lymphoid leukemia/small lymphocytic leukemia (CLL/SLL), where a subsequent histiocytic sarcoma shares molecular/genetic features with the lymphoid neoplasm. Its current uses include disease modeling and drug discovery , gene therapy, and regenerative medicine .
Immunotherapy: Potentiates the body’s immune system to recognize and eliminate cancer cells. It has several types according to their mechanisms. Monoclonal Antibodies target lymphoma cells, directly or by tagging them for destruction by immune cells. Immunomodulating drugs enhance the immune system’s function, Immune checkpoint inhibitors block proteins that suppress the immune response. CAR T-cell therapy uses genetically modified patients’ T cells to express chimeric antigen receptors that recognize lymphoma cells.
Targeted Next-Generation Sequencing (t-NGS): This molecular technique allows simultaneous assessment of somatic mutations and TCR gene rearrangements. It is more specific (100%) than T-cell clonality assessment (41.7%-45.5%) and provides a reliable basis for diagnosis even in samples with partially degraded DNA.
Induced Pluripotent Stem Cells (iPSCS): Reprogrammed somatic cells to an embryonic-like cell state. They can develop from many cell types, such as fibroblasts and blood cells. They provide the clinical advantages of high expansion capacity and pluripotency, allowing their differentiation to any desired cell type.
The: T -cell receptor ß constant region 1 (TRBC1): This plays a crucial role in the diagnostic work-up of T-cell malignancies. Using a monoclonal antibody specific for human TRBC1 in flow cytometry immunophenotyping assays provides a low-cost, robust, and highly specific test to detect clonality of immunophenotypically distinct T-cell populations. The detection of discrete clonal T-cell populations may lead to the identification of T-cell clones of uncertain clinical significance (T-CUS).
IgM Flare: A transient increase in serum IgM levels after treatment with rituximab or other anti-CD20 monoclonal antibodies. It occurs in 30% to 80% of WM patients and may exacerbate complications related to the high levels of monoclonal IgM.