Principles of identification and malignancy
There is a strict rule in immuno-oncology: malignant cell transformation is non-random (selective) in nature. Each tumor cell is a lymphocyte that has arrested at a specific stage of maturation.
To precisely determine the cell of origin of a tumor, immunophenotyping is used. Using fluorochrome-conjugated monoclonal antibodies, specialists detect membrane markers (CD antigens). For example, markers CD19 and CD20 indicate B-cell lineage, while CD138 indicates plasma cells. Meanwhile, lymphomas originating from follicular B lymphocytes form follicular lymphomas, and those from extrafollicular ones form diffuse lymphomas.
B-cell tumors: from lymphoblasts to plasmacytes
B-cell tumors encompass various stages of lymphopoiesis—from pro-B cells to mature antibody producers. Diseases developing from antibody-producing cells are of particular interest:
- Waldenström macroglobulinemia. Develops from lymphoblasts that already secrete IgM but have not yet become plasmacytes. The tumor is localized in lymphoid organs.
- Multiple myeloma. The source is fully differentiated plasma cells producing IgG, IgA, or IgE. They migrate to the bone marrow, which is why the disease frequently leads to bone tissue destruction.
Chronic B-cell lymphocytic leukemia is singled out separately, with B1a lymphocytes (IgM+ cells with the CD5 marker) serving as its substrate. A paradox arises: normally, B1 cells recirculate poorly and reside in serous cavities and barrier tissues, but in leukemia, their behavior changes dramatically.
Thymic tumors and T-cell lymphomas
T-cell tumors largely depend on processes occurring in the thymus:
- From double-negative CD4-CD8- cells (subcapsular), acute T-lymphoblastic leukemia (T-ALL) develops. Malignancy occurs even before the cell rearranges the V-genes of its receptor (TCR).
- Lymphomas do not develop from CD4+CD8+ thymocytes (cortical) at all—presumably due to their extremely high susceptibility to apoptosis.
- Human thymic lymphomas themselves are rare, but thymomas—tumors of epithelial origin—do occur. Benign thymomas are frequently accompanied by severe myasthenia gravis. In malignant variants, epithelial cells lose the ability to interact with thymocytes, causing the thymus to become depleted of lymphoid elements.
Most T-cell lymphomas (e.g., mycosis fungoides and Sézary syndrome) are formed by CD4+ T cells and involve the skin. This phenomenon is explained by the presence of the CLA molecule (cutaneous lymphocyte antigen), which is not expressed on CD8+ cells. CLA binds to E-selectin on the vascular endothelium and E-cadherin on keratinocytes, providing targeted homing of tumor cells to the skin.
Lymphogranulomatosis (Hodgkin's disease)
Lymphogranulomatosis differs from classical lymphomas. Tumor cells (Reed-Sternberg and Hodgkin cells) are scarce and diffusely scattered. They express the CD30 marker and combine features of both B lymphocytes and myeloid lineage cells. Today, they are considered to be malignant dendritic cells.
The disease has two prominent clinical variants:
- Lymphocyte-rich: the lesion contains many actively proliferating T cells (likely due to an altered antigen presentation form).
- Nodular sclerosis: lymphocytes are scarce and non-proliferating, and the malignant process spreads to the stroma.
Briefly: answers to topical questions
What histological variants of lymphogranulomatosis (Hodgkin's disease) are distinguished in the modern classification?
The WHO classification (2017) distinguishes two main types of Hodgkin lymphoma: nodular lymphocyte-predominant and classical. Classical lymphoma includes the following histological variants:
- nodular sclerosis variant (types I and II);
- mixed cellularity variant;
- lymphocyte-rich classical variant, corresponding to the old term "lymphocyte predominance";
- lymphocyte-depleted variant.
What genetic mechanisms, besides chromosomal rearrangements, lead to oncogene activation in lymphomas?
In addition to chromosomal translocations, gene mutations and viral stimulation lead to oncogene activation in lymphoproliferative processes. The following mechanisms are distinguished:
- Gene mutations—point mutations in genomic DNA (including in coding regions) arising under the action of carcinogens or radiation.
- Insertional mutagenesis—integration of viral DNA into the host cell oncogene, leading to its activation.
- Oncogene transduction—incorporation of a cellular oncogene into the viral genome with subsequent expression upon infection of another host.
With which oncogenic viruses is the development of lymphoproliferative diseases associated?
Lymphoproliferative diseases are associated with the following viruses:
- Epstein-Barr virus — Burkitt lymphoma and lymphogranulomatosis (Hodgkin's disease); it is also the cause of infectious mononucleosis;
- HTLV-1 virus — adult T-cell leukemia/lymphoma;
- HTLV-2 virus — isolated from a patient with hairy cell leukemia;
- HIV — HIV-associated lymphomas.
What specific chromosomal translocations are characteristic of follicular lymphoma and Burkitt lymphoma?
These lymphomas are characterized by specific translocations leading to the relocation of proto-oncogenes to immunoglobulin gene loci.
| Disease | Chromosomal translocation | Involved genes |
|---|---|---|
| Follicular lymphoma | t(14;18) | Relocation of the bcl-2 proto-oncogene (chromosome 18) to the IGH gene (chromosome 14) |
| Burkitt lymphoma | t(8;14) | Relocation of the c-myc proto-oncogene (chromosome 8) to the IGH gene (chromosome 14) |
In Burkitt lymphoma, alternative translocations of a chromosome 8 fragment to chromosome 2 (to the IGK gene locus) or to chromosome 22 (to the IGL gene locus) are also possible.
How to memorize B-cell tumor markers: Waldenström macroglobulinemia is associated with the secretion of Ig"M" (the letter M is present in both words), whereas Multiple myeloma consists of plasmacytes producing the remaining classes (IgG, IgA, IgE).
Class and exam questions
Why do T-cell lymphomas (mycosis fungoides, Sézary syndrome) frequently localize specifically to the skin?
Tumor CD4+ T cells express the CLA molecule, which ensures homing to the skin. It binds to vascular E-selectin and keratinocyte E-cadherin.
Which cells serve as the cellular source of Hodgkin's lymphoma?
The substrate of Hodgkin's disease is Hodgkin and Reed-Sternberg cells bearing the CD30 marker. Currently, they are considered malignant dendritic cells.
Can tumors develop from cortical thymocytes?
No, lymphomas originating from double-positive (CD4+CD8+) thymocytes are unknown. This is attributed to their high susceptibility to apoptosis.
What is the mechanism of oncogene activation in lymphoproliferative disorders?
Proto-oncogenes turn into oncogenes due to the loss of normal expression regulation. Most frequently, this occurs during their spatial relocation during chromosomal rearrangements.
What else to study on this topic
- Correspondence of specific lymphomas to normal lymphocyte developmental stages
- Role of CLA, E-selectin, and E-cadherin molecules in lymphocyte migration
- Mechanisms of thymoma development and their association with myasthenia gravis
- Differences between Waldenström macroglobulinemia and multiple myeloma
- Role of the microenvironment and stroma in variants of Hodgkin lymphoma
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