Non Hodgkin’s Lymphoma (NHL) represents a heterogeneous group of diseases with varied clinical presentation and histological appearance.It arises from cell of the lymphoid system, tumors are mainly derived from B lymphocytes, but are also from T lymphocytes, or natural killer cells. Lymphomas rise from different stages of B and T cell differentiation. Aberrations in the tightly controlled steps of B cell development can lead to oncogenesis. These aberrations are mainly seen in form of chromosomal translocation. About 85% of NHL’s are of B-cell origin and only 15% are derived from T/NK cells. Two specific lymphomas, follicular lymphoma and diffuse large B cell lymphoma, account for about 65% of all non-Hodgkin lymphomas.

• Lymphomas can arise from different stages of B cell development:
• B cell development starts in the primary lymphoid tissue, the bone marrow and subsequent maturation takes place in secondary lymphoid tissue (spleen and lymph nodes).
• At the germinal centers of secondary lymphoid tissue B cells encounter antigens via T cells and then undergo affinity maturation to produce immunoglobulins of high affinity.
• It supports rapid B-cell proliferation for immunoglobulin affinity maturation and production of antibody diversity through two processes know as somatic hypermutation (SHM) and immunoglobulin class switching.
• Both of these processes require rapid cell turnover and multiple double stranded DNA breaks, which is error-prone.
• Somatically acquired genetic alterations ( mainly translocations) of these processes is probably the underlying cause of lymphomagenesis.

• The major subtypes of non-hodgkin lymphoma (NHL) include the following:
  • Mature B-cell neoplasms:
    • Diffuse large B cell lymphoma
    • Follicular lymphoma
    • Burkitt lymphoma
    • Mantle cell lymphoma
    • Hairy cell leukemia
    • Extranodal marginal zone lymphoma
    • Splenic marginal zone lymphoma
    • Plasma cell myeloma
  • Mature T and NK neoplasms:
    • Adult T-cell lymphoma
    • Mycosis fungoides
    • Sezary syndrome
    • Peripheral T cell lymphoma

• About 85% of NHLs are of B-cell origin and only 15% are derived from T/NK cells.^[1]
• The small remainder stems from macrophages.
• These tumors are characterized by the level of differentiation, the size of the cell of origin, the origin cell’s rate of proliferation, and the histological pattern of growth.
• Lymphomas of small lymphocytes generally have a more indolent course than those of large lymphocytes, which may have intermediate-grade or high-grade aggressiveness.
• Two specific lymphomas, follicular lymphoma and diffuse large B cell lymphoma, account for about 65% of all non-Hodgkin lymphomas.
• The gene-expression profiles of almost all non-Hodgkin lymphomas are a reflection of the equivalent healthy cell of origin from which the lymphoma is derived.^[1]
• Follicular lymphoma most commonly results from the t(14;18)(q32;q21) translocation; this translocation places BCL2 (which encodes B-cell CLL/lymphoma 2) under control of the IGH enhancer element, leading to constitutive BCL2 expression.^[2]
• BCL-2 is an anti-apoptotic protein, and the t(14;18)(q32;q21) translocation results in markedly elevated expression of BCL-2, which blocks the healthy germinal center default program of apoptotic cell death and represents a defining pathogenic feature of follicular lymphoma.^[2][3]
• Similarly, mantle cell lymphoma is characterised by the t(11;14)(q13;q32) translocation, which leads to the deregulated expression of cyclin D1.^[4]
• Moreover, burkitt lymphoma overexpresses MYC as a result of the t(8;14)(q24;q32) translocation or variants.
• Recurrent translocations are less common in peripheral T-cell lymphomas than in other types of lymphoma, and examples include the characteristic t(2;5) (p23;q35) translocation seen in anaplastic lymphoma kinase (ALK)-positive anaplastic T-cell lymphoma and the t(5;9)(q33;q22) translocation associated with follicular T-cell lymphoma.^[5]
• Recurrent translocations including t(6;7) (p25;q32) and recurrent gene fusions involving the tumour-suppressor gene TP63 are characteristic of ALK-negative anaplastic T-cell lymphoma.^[5][6]
  

The development of non-Hodgkin lymphoma is the result of multiple genetic mutations such as:^[7][8]

• Mutations of the B-cell receptor genes and NFKB pathway.
• RNA splicing mutations in the small lymphocytic lymphoma.
• Genetic mutations in histone formation:^[9]
  • MLL2
  • MEF2B
  • EZH2
  • CREBBP
  • EP300
  • MLL2
  • KMT2D
• Mutations in CDKN2A alters cell cycle control and affects JAK–STAT signalling.
• Upregulation of key signalling pathways such as CD79B, MYD88, CARD11.
• Block to terminal differentiation such as BCL6 translocations and loss of PRDM1.

• Several conditions are associated with non-Hodgkin’s lymphoma depending on the type. However, Epstein Barr virus, human immunodeficiency virus, and hepatitis C infection are commonly present.

• For information on gross pathology findings of Follicular lymphoma, click here.
• For information on gross pathology findings of Mantle cell lymphoma, click here.
• For information on gross pathology findings of Hairy cell leukemia, click here.
• For information on gross pathology findings of Splenic marginal zone lymphoma, click here.
• For information on gross pathology findings of Mycosis fungoides, click here.
• For information on gross pathology findings of Peripheral T cell lymphoma, click here.

• For information on microscopic pathology findings of Follicular lymphoma, click here.
• For information on microscopic pathology findings of Mantle cell lymphoma, click here.
• For information on microscopic pathology findings of Hairy cell leukemia, click here.
• For information on microscopic pathology findings of Splenic marginal zone lymphoma, click here.
• For information on microscopic pathology findings of Mycosis fungoides, click here.
• For information on microscopic pathology findings of Peripheral T cell lymphoma, click here.

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