Chronic T-Cell

Overview of Chronic/Mature T-Cell Leukemia/Lymphoma

Definition: A heterogeneous group of lymphoid neoplasms derived from mature (post-thymic) T lymphocytes or natural killer (NK) cells. These disorders can present as leukemias (primarily involving the blood and bone marrow) or lymphomas (primarily involving lymph nodes and other tissues)
Key Features:
- Clonal Proliferation: These are malignant disorders arising from a single, genetically abnormal T cell or NK cell that proliferates uncontrollably
- Mature T-Cell Phenotype: The cells express markers characteristic of mature T cells or NK cells (e.g., CD3, CD4, CD8)
- Variable Morphology: The cells may have variable size, shape, and nuclear features
- Extranodal Involvement: Many of these lymphomas can involve extranodal sites, such as the skin, gastrointestinal tract, and liver
Classification: The World Health Organization (WHO) classification system is used to categorize these disorders based on clinical, morphological, immunophenotypic, and genetic features. T-cell and NK-cell neoplasms can be broadly classified into:
- T-cell lymphomas
- T-cell leukemias
- NK-cell lymphomas/leukemias

Key Disorders

Large Granular Lymphocytic Leukemia (LGL Leukemia):
- Definition: A chronic lymphoproliferative disorder characterized by a sustained increase in large granular lymphocytes (LGLs) in the peripheral blood. There are two main subtypes:
  - T-LGL Leukemia: More common; derived from cytotoxic T cells (CD3+, CD8+)
  - NK-LGL Leukemia: Less common; derived from natural killer cells (CD3-, CD56+)
- Pathophysiology:
  - Clonal proliferation of LGLs with cytotoxic activity
  - Associated with STAT3 mutations in many cases
- Clinical Features:
  - Often asymptomatic or mild symptoms
  - Fatigue
  - Neutropenia: Increased susceptibility to infections
  - Anemia: Due to pure red cell aplasia (PRCA) or other mechanisms
  - Splenomegaly (less common)
  - Association with autoimmune disorders (e.g., rheumatoid arthritis)
- Laboratory Findings:
  - CBC:
    - Lymphocytosis with increased LGLs (typically >2.0 x 10^9/L)
    - Neutropenia
    - Anemia
  - Peripheral Blood Smear:
    - Large granular lymphocytes with abundant cytoplasm and azurophilic granules
  - Immunophenotyping:
    - T-LGL Leukemia: CD3+, CD8+, CD57+, CD16+, TCRαβ+
    - NK-LGL Leukemia: CD3-, CD56+, CD16+, CD57+, TCR silent
  - Bone Marrow Examination:
    - Infiltration of the bone marrow by LGLs
  - Molecular Testing:
    - STAT3 mutations (in some cases)
- Treatment:
  - Many patients with asymptomatic LGL leukemia do not require treatment
  - Immunosuppressive Therapy:
    - Methotrexate, cyclosporine, corticosteroids
    - Used to treat cytopenias and autoimmune manifestations
  - Cyclophosphamide or fludarabine:
    - May be used in patients with more aggressive disease
  - Splenectomy:
    - May be considered in patients with symptomatic splenomegaly or cytopenias
Sézary Syndrome (SS):
- Definition: A rare and aggressive form of cutaneous T-cell lymphoma (CTCL) characterized by widespread skin involvement, lymphadenopathy, and the presence of malignant T cells (Sézary cells) in the skin, lymph nodes, and peripheral blood
- Pathophysiology:
  - Clonal proliferation of malignant CD4+ T helper cells with skin-homing properties
  - Cells infiltrate the skin, causing erythroderma (generalized redness and scaling of the skin) and plaques
- Clinical Features:
  - Erythroderma: Generalized redness and scaling of the skin
  - Intense Pruritus (itching)
  - Lymphadenopathy: Swollen lymph nodes
  - Sézary cells in the skin and peripheral blood
  - Hepatosplenomegaly (enlarged liver and spleen)
- Laboratory Findings:
  - CBC:
    - Leukocytosis with lymphocytosis
    - Eosinophilia
  - Peripheral Blood Smear:
    - Sézary cells: Lymphocytes with cerebriform (brain-like) nuclei
  - Immunophenotyping:
    - CD3+, CD4+, CD45RO+, CD7- (loss of CD7 is a common finding)
    - Abnormal T cell receptor expression
  - Skin Biopsy:
    - Confirms the diagnosis of CTCL and demonstrates the presence of Sézary cells in the skin
  - T Cell Receptor (TCR) Gene Rearrangement Studies:
    - Demonstrates clonality of the T cell population
- Treatment:
  - Skin-Directed Therapies:
    - Topical corticosteroids
    - Phototherapy (PUVA, UVB)
    - Topical chemotherapy (e.g., mechlorethamine)
  - Systemic Therapies:
    - Extracorporeal photopheresis (ECP): Treats the blood outside the body with ultraviolet light to kill malignant cells
    - Interferon-alpha
    - Histone deacetylase (HDAC) inhibitors (e.g., vorinostat, romidepsin)
    - Chemotherapy (e.g., CHOP)
    - Mogamulizumab: An anti-CCR4 monoclonal antibody
  - Stem Cell Transplantation
Hodgkin Lymphoma (HL):
- Definition: A type of lymphoma characterized by the presence of Reed-Sternberg cells (large, abnormal lymphocytes)
- Distinction from other lymphomas: Hodgkin Lymphoma spreads predictably and is more treatable
- Classical Hodgkin Lymphoma (cHL): The most common subtype, characterized by the presence of Reed-Sternberg cells and their variants in a background of reactive inflammatory cells. Subtypes of cHL include nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted
- Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL): A less common subtype characterized by lymphocyte-predominant Reed-Sternberg cells (L&H cells) and a different immunophenotype
- Pathophysiology:
  - Arises from germinal center or post-germinal center B cells
  - Reed-Sternberg cells secrete cytokines that attract and activate other immune cells, leading to the formation of a tumor microenvironment
- Clinical Features:
  - Painless Lymphadenopathy: Often in the cervical (neck) or mediastinal (chest) region
  - B Symptoms: Fever, night sweats, weight loss
  - Pruritus (itching)
  - Fatigue
- Laboratory Findings:
  - CBC: Variable; may be normal or show anemia, leukocytosis, or lymphopenia
  - Peripheral Blood Smear: Usually normal; may show eosinophilia
  - Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP): Often elevated
  - Lymph Node Biopsy: Essential for diagnosis
    - Presence of Reed-Sternberg cells (hallmark of HL)
    - Immunohistochemistry:
      - Reed-Sternberg cells in cHL: CD30+, CD15+, PAX5+, CD45-
      - L&H cells in NLPHL: CD20+, BCL6+, CD45+, CD30-, CD15-
  - Imaging Studies (CT Scan, PET/CT): To stage the disease and assess the extent of involvement
- Treatment:
  - Chemotherapy:
    - ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)
    - BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone)
  - Radiation Therapy:
    - May be used in combination with chemotherapy
  - Brentuximab Vedotin:
    - An anti-CD30 antibody-drug conjugate used for relapsed or refractory HL
  - Nivolumab and Pembrolizumab:
    - PD-1 inhibitors used for relapsed or refractory HL
  - Hematopoietic Stem Cell Transplantation (HSCT):
    - May be considered for relapsed or refractory disease

Important Considerations

These are simplified overviews, and many of these disorders have subtypes and variations
Differential diagnosis in this area can be challenging, and often requires integration of clinical, morphological, immunophenotypic, cytogenetic, and molecular data.
Treatment is evolving rapidly, with new targeted therapies and immunotherapies becoming available.

Key Terms

Lymphoid Neoplasm: Malignancy originating from lymphocytes
T Cells: Lymphocytes responsible for cell-mediated immunity
B Cells: Lymphocytes responsible for humoral immunity (antibody production)
NK Cells: Large granular lymphocytes involved in innate immunity
Lymphoma: Malignancy primarily involving lymph nodes and other lymphoid tissues
Leukemia: Malignancy primarily involving the bone marrow and peripheral blood
Large Granular Lymphocytic Leukemia (LGL Leukemia): Leukemia of LGLs
Sézary Syndrome (SS): Aggressive cutaneous T-cell lymphoma
Hodgkin Lymphoma (HL): Lymphoma characterized by Reed-Sternberg cells
Reed-Sternberg Cells: Large, abnormal lymphocytes characteristic of Hodgkin lymphoma
Immunophenotyping: Identification of cell surface markers using flow cytometry
Cytogenetic Analysis: The study of chromosomes and their abnormalities
Molecular Testing: Techniques to detect gene mutations and fusion genes

Chronic B-Cell

Plasma Cell