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				Cutaneous manifestaions
	Subcutaneous panniculitis-like T-cell lymphoma
	Enteropathy-type intestinal T-cell lymphoma
	Anaplastic large cell lymphoma
	Aggressive NK-cell leukemia

Differential diagnosis of Lymphocytosis

	Pathophyisiology	Symptoms	History	Physical Examination	Laboratory Findings
AML	Mutation of myeloblast freezes the cell in its immature state and prevent differentiation.	Persistent or frequent infections. Anemia leads to fatigue, paleness, and shortness of breath. Thrombocytopenia leads to bruising or bleeding with minor trauma.	History of pre-existing hematological disorder (e.g aplastic anemia, PNH, myelofibrosis) History of exposure to anti-cancer chemotherapy agents especially alkylating agents History of exposure to ionizing radiation History of occupational exposure to benzene and other aromatic hydrocarbons History of any congenital disorders (e.g Down syndrome, Bloom syndrome)	Bone tenderness Skin manifestations	Immature Myeloblasts on blood smear Flow cytometry +Aur Rods
ALL	Arrest of lymphoblasts. Chromosomal translocations involved 9 and 22, t(9;22) (q34;q11.2) BCR-ABL1 12 and 21, t(12;21)(p13;q22) TEL-AML1 5 and 14, t(5;14)(q31;q32)IL3-IGH 1 and 19 t(1;19)(q23;p13.3) TCF3-PBX1	Generalised weakness and fatigue Frequent or unexplained fever and infections Weight loss and/or loss of appetite Excessive bruising, bleeding from wounds, nosebleeds, petechiae, bone pain, joint pains and dyspnea.	History of cancer History of drug exposure	Lymphadenopathy Hepato-splenomegaly Stridor Pallor Petechiae Bruising Papilledema Nuchar rigidity Cranial nerve palsy Testicular enlargement	Eosinophilia Lymphocytosis Decreased erythrocytes production Thrombocytopenia. Chemistry panels with altered levels of uric acid, creatinine, blood urea nitrogen, potassium, phosphate, calcium, bilirubin, hepatic transaminases and ferritin. A spinal tap will tell if the spinal column and brain has been invaded.
CML	Myeloproliferative expansion of pluripotent stem cells. Philadelphia chromosome resulting from the reciprocal t(9;22)(q34;q11.2) Resulting in a derivative 9q+ and a small 22q-. results in a BCR-ABL fusion gene Ativates numerous downstream targets including c-myc Akt Jun,	Insidious in onset Nonspecific symptoms of fatigue and weight loss. Early satiety and decreased food intake due to splenic compression of stomach Low-grade fever and excessive sweating		Splenomegaly Correlates with granulocyte counts Findings of leukostasis and hyperviscosity. Funduscopy may show papilledema, venous obstruction, and hemorrhages.	WBC counts, exceeding 300,000-600,000 cells/μL Elevated alkaline phosphatase (ALP) Philadelphia (Ph1) chromosome\
CLL	Clonal B cells arrested in the B-cell differentiation pathway, Genetic mutations that promote both malignant leukemic proliferation and apoptotic resistance of mature B cells. Structural genetic mutations involved in the pathogenesis of chronic lymphocytic leukemia include chromosome 13q deletion, chromosome 17p deletion, and chromosome 11q deletion. SF3B1 gene located on chromosome 2 FBXW7 gene located on chromosome 4 MYD88 gene located on chromosome 3 TP53 gene located on chromosome 7 NOTCH1 gene located on chromosome 9 ATM gene located on chromosome 11 CHD2 gene located on chromosome 15	Fever Recurrent bleeding Weight loss Muscle wasting Generalized weakness Anorexia Night sweats Abdominal pain Recurrent infections	Review family history for members with positive history of the disease Review occupational history related to farming Review any exposure to herbicides or insecticides	Skin pallor Palpable cervical lymph nodes Hepatomegaly.	Monoclonality of kappa and lambda producing B cells Presence of smudge cells CBC Absolute lymphocytosis (>5000 cells/μl) Decreased hemoglobin concentration Decreased platelets count Express CD19, CD20, CD23, and CD5 on the cell surface

	Pathophysiology	Symptoms	History	Physical Examination	Laboratory Findings
					CBC	Blood smear	Immunophenotype
Monoclonal B lymphocytosis	Monoclonal population of B lymphocytes <5000 cells/microL	Without other features of Lymphadenopathy Organomegaly Extra-medullary involvement	Active or prior infections History of hematologic malignancy Medications Family history of chronic lymphocytic leukemia (CLL)	Fever Lymphadenopathy Hepatosplenomegaly Joint redness Abdominal pain Lung findings.	Lymphocytosis ≥4000 lymphocytes/microL	Lymphocytes in MBL have no distinguishing appearance Appear as small, mature mononuclear cells.	CD19, CD20, and CD23	Does not require bone marrow examination or imaging for diagnosis
Congenital B cell lymphocytosis
Large granular lymphocyte leukemia	T-cell (T-LGL) Natural killer cell (NK-LGL)	Recurrent infections Fever Night sweats Unintended weight loss Lymphadenopathy			Pancytopenia Splenomegaly		CD3, CD57, CD56 CD3-, CD56+
Chronic lymphocytic leukemia
Sezary syndrome
Mantle cell lymphoma
Follicular lymphoma
Splenic marginal zone lymphoma
Acute lymphoblastic leukemia
Acute Promyelocytic Leukemia
Diffuse Large Cell Lymphoma		Enlarged painful lymph node	Neurological or gastrointestinal manifestations History of environmental and/or infectious disease exposure	Lymphadenopathy Splenomegaly Low-grade fever Pedal edema:

Differential for Eosinophilia

	Pathophysiology	Symptoms	History	Physical Examination	Laboratory Findings
Parasitic Infections	Egg deposition Liberation of antigens of adult worms and eggs Strong inflammatory response characterized by high levels of pro-inflammatory cytokines Interleukins 1, 6, tumor necrosis factor-α, and circulating immune complexes participates in the pathogenesis of the acute phase of the disease	Vary depending on the organism GI STD Neurological Swollen lymph nodes and muscle aches or pains	History of travel	Rash Fever Lymphadenopathy Ulcers	+Stool examination + Serologic testing Urinalysis
Allergy/ Atopic Diseases	Allergic hypersensitivity IgE stimulation	Systemic anaphylaxis Reaction occurs within minutes Leading to symptomatology such as Acute asthma Laryngeal edema Diarrhea Urticaria Shock. Classic examples are penicillin allergy and bee sting allergy. Local anaphylaxis (atopy) About 10% of people have "atopy" and are easily sensitized to allergens that cause a localized reaction when inhaled or ingested. Hay fever Hives, asthma. Classic examples are food allergies and hay fever to ragweed pollen	History consistent with allergy and specific allergens	Eczema (atopic dermatitis) Allergic conjunctivitis Allergic rhinitis Asthma	Increase in eosinophils Serum tryptase positive reaction Testing for specific IgE antigen.
Hypereosinophilic syndromes (HES)	Activation of tyrosine kinases Clonal eosinophilic proliferation Overproduction of eosinophilopoietic cytokines.	Shortness of breath Skin rash Cough Diarrhea Myalgias Fatigue Weight-loss		Skin rash Thickening of the skin (lichenification) Eczema (flexural areas) Dermographism Low-grade fever Raynaud phenomenon Wheezing	Persistently elevated eosinophil count (≥ 1500 eosinophils/mm³) in the blood At least six months without any recognizable cause Involvement of either the heart, nervous system, or bone marrow.
Acute myelogenous leukemias	Mutation of myeloblast freezes the cell in its immature state and prevent differentiation.	Persistent or frequent infections. Anemia leads to fatigue, paleness, and shortness of breath. Thrombocytopenia leads to bruising or bleeding with minor trauma.	History of pre-existing hematological disorder (e.g aplastic anemia, PNH, myelofibrosis) History of exposure to anti-cancer chemotherapy agents especially alkylating agents History of exposure to ionizing radiation History of occupational exposure to benzene and other aromatic hydrocarbons History of any congenital disorders (e.g Down syndrome, Bloom syndrome)	Bone tenderness Skin manifestations	Immature Myeloblasts on blood smear Flow cytometry +Aur Rods
Hodgkin's, T- and B-cell lymphomas)	Reed-Sternberg cell B-cell origin CD30 (Ki-1) and CD15 (Leu-M1) antigens	Painless localized peripheral lymphadenopathy B symptoms	Presence or absence, duration, and severity of other associated systemic symptoms. History of previous malignancy (including other lymphomas) Prior treatment with chemotherapy or radiotherapy Previous immunosuppressive illness Family history of HL or other lymphoproliferative, myeloproliferative, or tissue malignancies.	Palpable, painless lymphadenopathy Superior vena cava Central nervous system (CNS) symptoms Paraneoplastic syndromes including Cerebellar degeneration Neuropathy Guillain-Barre syndrome Multifocal leukoencephalopathy	Fine-needle aspiration Mononucleate and binucleate Reed-Sternberg cells in a background of inflammatory cells Lactate dehydrogenase (LDH) may be increased. ESR elevated Serum creatinine elevated in nephrotic syndrome. Alkaline phosphatase (ALP) increased Hypercalcemia, hypernatremia, and hypoglycemia.
Churg-Strauss (Eosinophilic granulomatosis with polyangiitis)	Complex interaction involving genetic and environmental factors that lead to an inflammatory response involving eosinophils, lymphocytes and giant cells	Prodromal phase: Allergic rhinitis and asthma. Eosinophilic phase: Peripheral eosinophilia and infiltration of eosinophils to lung and GI tract. Vasculitic phase: Small and medium-sized vasculitis and inflammatory granuloma formation. Granulomas can be either vascular or extravascular.	History of allergy	Skin involvement (60%) Nasal polyposis Peripheral neuropathy	P-ANCA positive in most cases Elevated levels of IgE Elevated levels of rheumatoid factor at low titer Hypergammaglobulinemia Biopsy is diagnostic Eosinophilic infiltration Vasculitis of small and medium-sized vessels Granuloma formation.
Systemic mastocytosis	Infiltration of bone marrow by mast cell affecting the peripheral blood and coagulation system. The neoplastic clone of mast cells express abnormal cell surface markers CD25 and/or CD2.	GI Cutaneous Urticaria pigmentosa Musculoskeletal Idiopathic and/or recurrent anaphylactoid reactions	History of/ Associated with Hypereosinophilic syndrome Castleman disease Monoclonal gammopathy Hairy cell leukemia Non-Hodgkin lymphoma Polycythemia vera Primary thrombocythemia	Signs of anemia, Hepatoslenomegaly Lymphadenopathy Urticaria Flushing Osteolysis	CBC Eosinophilia Basophilia Thrombocytosis Monocytosis Total–to–beta-tryptase ratio greater than 20:1 is suggestive. CD117 positive and CD25 and/or CD2 positive. Abnormal mast cells. Larger than normal mast cells Irregularly shaped nuclear outlines Less densely packed mast cell granules

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].