Non-Hodgkin lymphoma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

Non Hodgkin's Lymphoma 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.

Pathogenesis

• 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 include the following:
  • Mature B-cell neoplasms:
    • Burkitt lymphoma
    • Diffuse large B cell lymphoma
    • Mantle cell lymphoma
    • Small lymphocytic lymphoma
    • Follicular lymphoma
    • Extranodal marginal zone lymphoma
    • Splenic marginal zone lymphoma
    • Lymphoplasmacytic lymphoma
  • Mature T and NK neoplasms:
    • Adult T-cell lymphoma
    • Mycosis fungoides
    • Sezary syndrome
    • Peripheral T cell lymphoma

Genetics

Different subtypes of non Hodgkin lymphoma and their genetic involvements::

		Pathophysiology	Symptoms	History	Physical Examination	Laboratory Findings
						Immunochemistry	Blood work	Biospy
B cell lymphoma	Mantle cell lymphoma	CD5 positive antigen in pregerminal center of B-cell Chromosomal translocation at t(11:14) Over-express cyclin D1	Stage IV disease B symptoms, Generalized lymphadenopathy Abdominal distention Fatigue Extranodal involvement of gastrointtestinal (GI) tract, lungs, and central nervous system (CNS)	History of Night sweats Weight Loss	Generalized lymphadenopathy Hepato-splenomegaly Mental Retardation Less commonly Palpable masses in skin, breast, and salivary glands	CD5+ B-cell antigen positive CD19 CD20 CD22 Cyclin D1 is overexpressed.	CBC Anemia and cytopenias are secondary to bone marrow infiltration Lymphocytosis > 4000/µL Elevated LDH	Germinal centers filled by small-to-medium atypical lymphocytes. Nodular appearance may be evident from expansion of the mantle zone in 30-50% of patients early in the disease.
	Nodal marginal zone B-cell lymphoma	Arise from memory B cells. Include Splenic marginal zone lymphoma Nodal marginal zone lymphoma Extranodal marginal zone lymphoma. Stimulation of antigen receptor by autoantigen and co-stimulatory molecule CD40.	Depends largely on its location Gastric marginal zone lymphoma Dyspepsia Abdominal pain Hemorrhage	Chronic infectious conditions or autoimmune processes, such as H pylori gastritis Hashimoto thyroiditis Sjögren syndrome.		AE1/AE3 B-cell markers CD20, CD79a, CD10, CD23, and bcl-2 are expressed		Follicular cells in reactive zone Centrocyte like cells in marginal zone lymphoma
	Splenic marginal zone lymphoma	Clonal rearrangements of the immunoglobulin genes (heavy and light chains) . Deletion 7q21-32 Translocations of the CDK6 gene located at 7q21.				CD20 CD79a		B-cells replace the normal white pulp of the spleen. The neoplastic cells compromise Small lymphocytes Transformed blasts Sinus invasion Epithelial histocytes Plasmacytic differentiation of neoplastic cells. Splenic Hilar Lymph Nodes Involved hilar lymph nodes adjacent to the spleen show an effaced architecture without preservation of the marginal zone seen in the spleen Bone Marrow Biopsy Splenic marginal zone lymphoma in bone marrow displays a nodular pattern with morphology similar to what is observed in the splenic hilar lymph nodes.
	Hairy cell leukemia	Production of cytokines, such as TNF alpha and IL-2R, provide important stimuli for malignant B cells proliferation in hairy cell leukemia. The p38-MAPK-JNK cascade The MEK-ERK cascade The Phosphatidylinositol 3 kinase (PI3K)-AKT cascade	Fever Night sweats Fatigue Easy bruising or bleeding Generalized weakness Weight loss Recurrent infections Early satiety	Review occupational history related to sawdust exposure Review any exposure to radiations Review any exposure to herbicides or diesel	Pallor, Petechiae Splenomegaly	Annexin A1 CD20 CD25 CD103 CD19 CD11c FMC7	Tartrate-resistant acid phosphatase positive CBC Decreased hemoglobin concentration Decreased platelets count	Small cells with "fried egg"-like appearance Well-demarcated thread-like cytoplasmic extensions Clear cytoplasm Central round nucleus Peri-nuclear clearing ("water-clear rim" appearance)
	Plasma cell myeloma
	Diffuse large B-cell lymphoma	Germinal centre B-cell-like (GCB) Activated B-cell-like (ABC). B cell receptor (BCR) signalling B cell migration/adhesion Cell-cell interactions in immune niches Production and class-switching of immunoglobulins					Neutropenia Anemia Hypergammaglobulinemia	Centroblastic Medium-to-large-sized lymphocytes Monomorphic Immunoblastic:: > 90% immunoblasts Trapezoid shaped large lymphoid cells with significant basophilic cytoplasm Anaplastic: Very large cells with a round, oval, or polygonal shape that may resemble Reed-Sternberg cells of Hodgkin's lymphoma or Anaplastic Large cell Lymphoma.
	Burkitt lymphoma	Translocation of chromosome 8 myc locus with 3 possible partners (accounting for 90% of translocations): The Ig heavy chain region on chromosome 14: t(8;14) The kappa light chain locus on chromosome 2: t(2;8) The lambda light chain locus on chromosome 22: t(8;22)	Fever Night sweats Unexplained weight loss Swollen lymph nodes in the neck, axilla, or groin		Proptosis Jaw mass Abdominal masses Ascites Peripheral lymphadenopathy	CD19 CD20, CD22 CD10 BCL6. BCL2 and TdT.		Medium-sized (~1.5-2x the size of a RBC) with uniform size ("monotonous") -- key feature (i.e. tumor nuclei size similar to that of histiocytes or endothelial cells) Round nucleus Small nucleoli basophilic cytoplasm Brisk mitotic rate and apoptotic activity Cellular outline usually appears squared off "Starry-sky pattern": The stars in the pattern are tingible-body macrophages (macrophages containing apoptotic tumor cells) The tumour cells are the sky
T cell lymphoma	T-cell granular lymphocytic leukemia	Disregulation of signaling pathways: FAS/FAS-L Phosphatidylinositol-3 kinase (PI3K), Mitogen-activated proteinkinase/extracellular signal-regulated kinase (MAPK/ERK)	Symptoms of T-cell large granular lymphocyte leukemia may include the following: Generalised weakness and fatigue Anorexia Joint pain Night sweating Epistaxis Bone pain Dyspnea		Usually appear pale and malnourished. Cardiac flow murmur High-grade fever Hepatomegaly Splenomegaly	CD3+ TCRαβ+ CD4- CD8+	Neutropenia Anemia Hypergammaglobulinemia	Clonal rearrangements of the T-cell receptor (TCR) gene Chronic (> 6 months) elevation in large granular lymphocytes (LGLs) in the peripheral blood Large granular lymphocyte count greater than 2.0 × 109/L Lymphocytosis (typically 2-20x109/L)
	Mycosis fungoides / Sézary syndrome		Epidermal atrophy or poikiloderma Generalized itching(pruritus) Pain in the affected area of the skin. Insomnia Red (erythematous) patches scattered over the skin of the trunk and the extremities Weight loss Lymphadenopathy Malaise and fatigue Anemia May progress to Sezary syndrome (Skin involvement plus hematogenous dissemination)		Cutaneous manifestaions
	Subcutaneous panniculitis-like T-cell lymphoma
	Enteropathy-type intestinal T-cell lymphoma
	Anaplastic large cell lymphoma
	Aggressive NK-cell leukemia

Associated Conditions

Conditions associated with [disease name] include:

• [Condition 1]
• [Condition 2]
• [Condition 3]

Gross Pathology

On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Genetics

The development of Non-Hodgkin lymphoma is the result of multiple genetic mutations such as:

• Mutations of the B-cell receptor genes and NFKB pathway
• RNA splicing mutations in the small lymphocytic lymphoma
• Genetic mutations in histone formation:
  • MLL2
  • MEF2B
  • EZH2
  • CREBBP
  • EP300
  • MLL2

Gross Pathology

On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].