Non-Hodgkin Lymphomas

Non-Hodgkin lymphomas (NHLs) are a diverse group of hematologic malignancies that are clonal proliferative disorders of mature or progenitor B cells, T cells, or natural killer (NK) cells. Most pediatric cases are aggressive and high-grade (but curable); in adults, low-grade subtypes are more common. Like Hodgkin lymphoma, which has distinct pathologic features and treatments, NHL often presents with constitutional signs of fever, night sweats, and weight loss. Clinical features include lymphadenopathy and hepatosplenomegaly, but some individuals present with extranodal involvement and abnormal lab findings. B-cell NHLs include diffuse large B-cell lymphoma, follicular lymphoma, Burkitt lymphoma, mantle cell lymphoma, and marginal zone lymphoma. T-cell NHLs include adult T-cell lymphoma and mycosis fungoides. Diagnosis is made by lymph node biopsy, bone marrow biopsy, or both. Management is with chemotherapy or targeted drugs. Radiation therapy is used in adults but not in children, and stem cell transplantation is used for patients with aggressive disease.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Non-Hodgkin lymphomas (NHLs) are a diverse group of hematologic malignancies that are clonal proliferative disorders of mature or progenitor B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells, T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells, or natural killer (NK) cells.

Epidemiology

  • Incidence in the United States: > 70,000 cases annually (6th most common cancer in the United States)
  • Accounts for 4% of all cancers:
    • Most common: hematopoietic cancer
    • Increasing incidence for unknown reasons; some related to infection (e.g., HIV)
    • NHLs are significantly more common than Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma.
  • Occurs in both children and adults:
    • In children:
      • Tumors are usually extranodal and often leukemic.
      • Subtypes are high grade and aggressive, but 5-year survival rates are > 85%.
      • Most common subtypes are Burkitt lymphoma and lymphoblastic leukemia/lymphoma
    • In adults:
      • Incidence increases with age; median, 67 years
      • Most common subtypes in adults: follicular, diffuse large B cell, and chronic lymphocytic leukemia Chronic Lymphocytic Leukemia Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia/small lymphocytic lymphoma ( CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia/SLL)
  • Seen in individuals of all races and socioeconomic status
  • Types: 
    • Approximately 85% of NHLs are of B-cell origin.
    • Most others are derived from T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells.
    • NK-cell lymphoma is rare.

Etiology

  • Exact etiology unknown
  • Increased risk with
    • Viral infections:
      • EBV: Burkitt lymphoma, others
      • Human T-cell leukemia/lymphotropic virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview (HTLV-1)
      • Hepatitis C virus Hepatitis C Virus Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). Hepatitis C virus is an RNA virus and a member of the genus Hepacivirus and the family Flaviviridae. The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C Virus: lymphoplasmacytic lymphoma
      • HIV
      • HHV-8
    • Helicobacter Helicobacter Helicobacter pylori is a gram-negative bacterium that causes gastric infection. It is the most well known and clinically significant species of Helicobacter. Transmission is believed to occur by ingestion of contaminated food or water; therefore, a higher prevalence of infection is seen in areas with poor sanitation. Helicobacter pylori gastritis Gastritis Gastritis refers to inflammation of the gastric mucosa. Gastritis may occur suddenly (acute gastritis) or slowly over time (chronic gastritis). Gastritis may be asymptomatic or with symptoms, including burning abdominal pain (which either worsens or improves with eating), dyspepsia, nausea, and vomiting. Gastritis: marginal zone lymphoma of the MALT type (mucosa-associated lymphoid tumor ( MALToma MALToma Extranodal marginal zone lymphoma (EMZL) of mucosa-associated lymphoid tissue (also called MALToma, MALT lymphoma, and pseudolymphoma) is a group of non-Hodgkin's lymphomas that have historically been grouped together because they appear to arise from postgerminal center marginal zone B cells and share a similar immunophenotype. MALT Lymphoma)) 
    • Chronic inflammatory conditions or autoimmune diseases:
      • Hashimoto thyroiditis Thyroiditis Thyroiditis is a catchall term used to describe a variety of conditions that have inflammation of the thyroid gland in common. It includes pathologies that cause an acute illness with severe thyroid pain (e.g., subacute thyroiditis and infectious thyroiditis) as well as conditions in which there is no clinically evident inflammation and the manifestations primarily reflect thyroid dysfunction or a goiter (e.g., painless thyroiditis and fibrous Riedel's thyroiditis). Thyroiditis: marginal zone lymphoma
      • Sjögren syndrome: marginal zone lymphoma
      • Celiac sprue
      • Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis
      • Systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus
    • Immunodeficiency:
      • Ataxia-telangiectasia Ataxia-telangiectasia Ataxia-telangiectasia, also known as Louis-Bar syndrome, is a neurocutaneous syndrome, which involves multiple systems but mainly affects the neurological system. Ataxia-telangiectasia is an autosomal recessive genetic disorder caused by a mutation in the ATM gene (ATM serine/threonine kinase or the ataxia-telangiectasia mutated gene). Ataxia-telangiectasia syndrome
      • Common variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables immunodeficiency disease
      • HIV: diffuse large B-cell lymphoma, Burkitt lymphoma
      • Iatrogenic immunosuppression
    • Chemical and drug exposures:
      • Prior chemotherapy or radiation therapy
      • Phenytoin
      • Dioxin (phenoxy herbicides)
    • Genetic factors: Some single nucleotide polymorphisms are associated with ↑ risk of NHL.

Classification

  • Subtypes are classified by:
    • Cell of origin
    • Morphology
    • Immunophenotype
    • Genetic and molecular profiles
    • Clinical features
  • Classified into 5 broad categories by the WHO:
    • Precursor B-cell neoplasms: precursor B-cell acute lymphoblastic leukemia Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia/lymphoma (ALL/LBL) are hematologic malignancies characterized by the uncontrolled proliferation of lymphoid precursor cells. Acute lymphoblastic leukemia/lymphoma, the most common forms of cancer affecting children, show the presence of increased lymphoblasts. Acute Lymphoblastic Leukemia/lymphoma (B-ALL))
    • Peripheral B-cell neoplasms:
      • CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia/SLL
      • Marginal zone lymphomas
      • Mantle cell lymphoma
      • Diffuse large B-cell lymphoma (DLBCL)
      • Burkitt lymphoma
    • Precursor T-cell neoplasms: precursor T-cell acute lymphoblastic leukemia Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia/lymphoma (ALL/LBL) are hematologic malignancies characterized by the uncontrolled proliferation of lymphoid precursor cells. Acute lymphoblastic leukemia/lymphoma, the most common forms of cancer affecting children, show the presence of increased lymphoblasts. Acute Lymphoblastic Leukemia/lymphoma
    • Peripheral T-cell and NK-cell neoplasms :
      • T-cell prolymphocytic leukemia
      • Mycosis fungoides/Sézary syndrome
      • Peripheral T-cell lymphoma, unspecified
      • Adult T-cell leukemia/lymphoma
      • Extranodal NK/T-cell lymphoma
      • NK-cell leukemia
    • Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma (all subtypes)
  • Lymphomas can also be classified in other ways:
    • Nodal (⅔) or extranodal (⅓)
    • Aggressive (60%) or indolent (40%)

Pathophysiology

The pathogenesis of NHL involves multiple genetic lesions that affect proto-oncogenes and tumor suppressor genes. Abnormal cells also appear to escape immune surveillance.

Pathogenesis

  • Genetic translocations put a proto-oncogene next to a gene that is active in lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes, resulting in the overexpression of transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription factors:
    • t(14;18) causes ↑ expression of BCL2 (follicular cell lymphoma)
    • t(8;14) causes ↑ expression of c-MYC (Burkitt lymphoma)
    • t(11;14) causes ↑ expression of cyclin D1 (mantle cell lymphoma)
  • Either precursor or mature cells may be involved.
  • Stage of lymphocyte differentiation at which oncogenic event occurs → disease presentation and outcome

Mechanisms that contribute to non-Hodgkin lymphomas

  • Chromosomal translocations (e.g., t(11:14) in mantle cell lymphoma))
  • Unbalanced chromosomal alterations: (e.g., CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia/SLL)
    • Recognized by genomic sequencing
    • Associated with tumor progression and adverse outcomes
  • Somatic mutations: 
    • Some are clonal: present in all cells of the lymphoma (suggesting early involvement in pathogenic events)
    • Many are “drivers”: found in only a subset of lymphoma cells (suggesting acquisition later in the pathogenesis)
  • Epigenetic modifications: mutations affecting genes that regulate histone modifications
  • Genome damage: aberrant rearrangement and/or DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure repair
  • Oncogenic viruses: introduce foreign genes into their target cells

Differences in mechanism from solid tumors

  • The NHL genome is relatively stable (unlike random genomic instability seen with solid tumors).
  • Microsatellite instability (due to defects in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure mismatch repair genes) is infrequent as compared with solid tumors.

Clinical Presentation

Most lymphomas present with painless lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy with variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables peripheral blood, bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow, GI, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, or CNS involvement.

Aggressive “high-grade” lymphomas

  • Rapidly growing mass (painless)
  • Constitutional “B” symptoms:
    • Low-grade fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Night sweats
    • Weight loss
  • Fatigue
  • Enlarged mediastinal and retroperitoneal nodes can produce pressure on:
    • Superior vena cava → facial swelling and dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
    • Biliary tree compression → jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice
    • Compression of ureters → hydronephrosis Hydronephrosis Hydronephrosis is dilation of the renal collecting system as a result of the obstruction of urine outflow. Hydronephrosis can be unilateral or bilateral. Nephrolithiasis is the most common cause of hydronephrosis in young adults, while prostatic hyperplasia and neoplasm are seen in older patients. Hydronephrosis
    • Bowel obstruction
  • Pleural effusions
  • May have leukemic manifestations (involvement of bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow or peripheral blood)
  • Infrequent mediastinal involvement

Indolent “low-grade” lymphomas

  • Insidious onset
  • Painless peripheral lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy 
  • Hepatomegaly or splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly
  • Cytopenias:
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview (33%)
    • Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia
    • Thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia

Cutaneous T-cell lymphoma

  • Diffuse erythema
  • Discrete papules, plaques, and nodules
Mycosis fungoides

Mycosis fungoides in a 40-year-old man with a generalized rash

Image: “Mycosis fungoides in a 40-year-old man manifested as generalized atrophic patches” by F1000Research. License: CC BY 4.0

Diagnosis and Staging

Adequate diagnosis requires histologic examination, immunophenotyping, genotyping, and consideration of the clinical features. Staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis is similar to that for Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma.

Diagnosis

  • History including B symptoms and past or present history of:
    • HIV risk factors
    • Hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus or C
  • Physical exam and imaging as above
  • Excisional lymph node biopsy if palpable nodes are present:
    • Immunohistochemistry defines the distribution of T and B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells.
    • Cytogenetic and mutational analysis:
      • t(14;18) seen with follicular lymphoma
      • MYD88 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in lymphoblastic lymphoma
  • Initial laboratory workup
    • CBC with WBC differential and platelet count
    • Tests for hypogammaglobulinemia: 
      • Approximately 15% of patients at diagnosis
      • Increases the risk of bacterial infection
      • May require IV immune globulin replacement
    • Other labs:
      • Electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes
      • Renal function: BUN/creatinine
      • Liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests
      • LDH
      • Uric acid level
      • Testing for HIV, hepatitis B, and hepatitis C, if indicated
  • Bone marrow biopsy
  • Endoscopy/gastroscopy if biopsy needed in suspected GI involvement
  • Lumbar puncture if:
    • CNS symptoms
    • Positive bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow
    • Aggressive lymphoma (large-cell, lymphoblastic, or Burkitt lymphoma types)
  • Thoracocentesis or paracentesis if pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion or ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites
  • Imaging:
    • Chest radiography
    • CT of abdomen, pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 "hip" bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis, chest:
      • Not only for staging; also used for guided biopsy if needed 
      • Also used for assessment of response to therapy
    • PET if large-cell lymphoma
    • MRI of brain and spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord if neurologic symptoms are present

Staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis of NHL

Table: Stages
Stage I Involvement of a single lymph node group or single extralymphatic organ
Stage II Involvement of ≥ 2 lymph node groups on the same side of the diaphragm Diaphragm The diaphragm is a large, dome-shaped muscle that separates the thoracic cavity from the abdominal cavity. The diaphragm consists of muscle fibers and a large central tendon, which is divided into right and left parts. As the primary muscle of inspiration, the diaphragm contributes 75% of the total inspiratory muscle force. Diaphragm
Stage III Involvement of lymph nodes, spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen or both, on both sides of the diaphragm Diaphragm The diaphragm is a large, dome-shaped muscle that separates the thoracic cavity from the abdominal cavity. The diaphragm consists of muscle fibers and a large central tendon, which is divided into right and left parts. As the primary muscle of inspiration, the diaphragm contributes 75% of the total inspiratory muscle force. Diaphragm
Stage IV Diffuse or disseminated involvement of ≥ 1 extralymphatic organs ( liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow, lung) with or without lymph node involvement
  • A subscript “E” is used if limited extranodal extension is found. 
  • A subscript “X” designates bulky disease:
    • No cutoff for treatment purposes
    • Follicular lymphoma bulky disease is 6 cm.
    • Diffuse large B-cell lymphoma bulky disease is 6–10 cm
  • Unlike Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma, B symptoms are not incorporated into NHL staging.
Hodgkin disease staging

Staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis of NHL (same as that for Hodgkin disease)

Image by Lecturio.

Management and Prognosis

Treatment is based on many factors, including histologic subtype, stage, and comorbidities. CD19 is highly expressed in nearly all B-cell malignancies, making it an attractive receptor for novel targeted therapies.

Management

  • Stage I (localized disease):
    • Regional radiation: possible cure in 40%
    • Short course of chemotherapy
    • For stage I lymphoblastic lymphoma or Burkitt lymphoma: intensive combination chemotherapy with meningeal prophylaxis
  • For advanced disease (stage II, III, IV, or B symptoms), therapy often consists of:
    • Radiation therapy:
      • May be used to limit the number of cycles of chemoimmunotherapy
      • Localized treatment for residual sites of bulk disease
    • Immunotherapy:
      • Anti-CD20 monoclonal antibody therapies may delay the need for myelosuppressive chemotherapy.
      • Monoclonal antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins targeting CD20: rituximab, obinutuzumab, ofatumumab
    • Chemotherapy: R-CHOP ) Rituximab (anti-CD20 monoclonal antibody) plus Cyclophosphamide, Hydroxydaunorubicin, vincristine (Oncovin), and Prednisone
    • Targeted drugs:
      • BTK (Bruton tyrosine kinase) inhibitors for follicular, mantle cell, and marginal zone NHL: ibrutinib, acalabrutinib, and zanubrutinib
      • CD19-targeted immunotherapies (e.g., blinatumomab)
      • Bispecific antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins against CD19 and CD3 are in early trials.
      • Chimeric antigen receptor (CAR)–modified T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells: autologous T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells that have been genetically engineered to recognize a tumor antigen (e.g., CD19)—potential cure for refractory DLBCL
    • Hematopoietic stem cell transplantation is used for:
      • Peripheral T-cell NHL
      • Primary CNS lymphoma
      • NHL without remission at the end of therapy or with relapse after chemotherapy
  • Follicular lymphoma:
    • Treated only if the disorder is causing problems
    • Chemotherapy with bendamustine plus rituximab (efficacy equal to that of R-CHOP, but less toxicity)

Prognosis

High-grade NHLs are aggressive but have a better prognosis, whereas low-grade NHLs progress slowly but are difficult to cure.

International Prognostic Index (IPI) factors are associated with a worse prognosis:

  • Age > 60 years
  • Presence of B symptoms
  • Stage III or IV disease
  • Elevated serum LDH
  • Functional status
  • > 1 extranodal site
  • Advanced versus localized disease

Overall 5-year survival for NHLs as a group:

  • 72% for Caucasians and 63% for African Americans
  • Much wider range of survival than for Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma (which has a 5-year survival rate of 85%–90%) because of the heterogeneity in NHLs
  • In DLBCL, prognosis depends on the cell of origin; worse if MYC or BCL gene rearrangements are present 
  • In follicular lymphoma, the disease is responsive but almost always recurs after chemotherapy and/or radiation therapy
    • Most survive 15–20 years
    • 3% transform to DLBCL every year

Complications

  • Some chemotherapies can cause cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Overview of Cardiomyopathies or arrhythmias
  • Myelodysplasia in the 1st 10 years after treatment
  • Acute leukemia due to bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow effects of chemotherapy agents
  • ↑ Risk of secondary cancers with prior radiation to the chest

Comparison of Non-Hodgkin Lymphomas

Table: Comparison of non-Hodgkin lymphomas
Origin Type Risk factors and genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics Epidemiology Pathology and clinical features
B cell (85%–90%) DLBCL Arises sporadically or from the transformation of low-grade lymphoma (e.g., follicular lymphoma)
  • Most common high-grade lymphoma
  • Age: late adulthood
  • Heterogeneous group with different genotypes, prognoses, and responses to therapy
  • 5-year survival: approximately 65%
  • Enlarging lymph node or extranodal mass
  • Extremely aggressive
Follicular lymphoma t(14;18) → overexpression of BCL2 (gene that regulates apoptosis)
  • Most common low-grade lymphoma
  • Age: often in middle age or older
  • Painless lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy
  • Complications: some progress to diffuse large B-cell lymphoma
Burkitt lymphoma
  • Associated with EBV
  • t(8;14) → overexpression of c-MYC
  • Also associated with HIV infection HIV infection Human immunodeficiency virus (HIV), a single-stranded RNA virus belonging to the Retroviridae family, is the etiologic agent of acquired immunodeficiency syndrome (AIDS). The human immunodeficiency virus is a sexually transmitted or blood-borne infection that attacks CD4+ T lymphocyte cells, macrophages, and dendritic cells, leading to eventual immunodeficiency. HIV Infection and AIDS
  • Age: adolescents or young adults
  • In Africa: children in regions where malaria Malaria Malaria is an infectious parasitic disease affecting humans and other animals. Most commonly transmitted via the bite of a female Anopheles mosquito infected with microorganisms of the Plasmodium genus. Patients present with fever, chills, myalgia, headache, and diaphoresis. Malaria and EBV are endemic
  • Starry-sky appearance in histology (many tingible body macrophages)
  • Highly aggressive
Mantle cell lymphoma t(11;14) → overexpression of cyclin D1
  • Age: late adulthood
  • Men > women
  • Painless lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy
  • Highly aggressive, often presents in late-stage disease
MZL
  • Associated with chronic inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation due to autoimmunity Autoimmunity Autoimmunity is a pathologic immune response toward self-antigens, resulting from a combination of factors: immunologic, genetic, and environmental. The immune system is equipped with self-tolerance, allowing immune cells such as T cells and B cells to recognize self-antigens and to not mount a reaction against them. Defects in this mechanism, along with environmental triggers (such as infections) and genetic susceptibility factors (most notable of which are the HLA genes) can lead to autoimmune diseases. Autoimmunity or infection
  • t(11;18) cytogenetic abnormality in 50% of cases
  • Splenic type: associated with hepatitis C
  • Most common indolent B-cell NHL (after follicular lymphoma)
  • Extranodal type (MALTomas): stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach most common (H. pylori gastritis Gastritis Gastritis refers to inflammation of the gastric mucosa. Gastritis may occur suddenly (acute gastritis) or slowly over time (chronic gastritis). Gastritis may be asymptomatic or with symptoms, including burning abdominal pain (which either worsens or improves with eating), dyspepsia, nausea, and vomiting. Gastritis)
  • Other sites of chronic inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation ( skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, thyroid, salivary glands Salivary glands The salivary glands are exocrine glands positioned in and around the oral cavity. These glands are responsible for secreting saliva into the mouth, which aids in digestion. There are 3 major paired salivary glands: the sublingual, submandibular, and parotid glands. Salivary Glands, small bowel)
  • Nodal type: rare form
Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia) MYD88 gene mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in most cases
  • Age: adults
  • Occurs in lymph nodes and bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow
  • Production of an IgM paraprotein is characteristic
  • Can cause hyperviscosity syndrome and stroke
T cell (10%–15%) Adult T-cell lymphoma Associated with retrovirus HTLV-1
  • Age: adults
  • Geographic locations: Japan, West Africa, Caribbean
  • Cutaneous lesions
  • Lytic bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones lesions
  • Hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia
Mycosis fungoides (cutaneous T-cell lymphoma)
  • Unclear cause
  • Many genetic abnormalities found
  • Age: adults
  • Skin patches/plaques
  • Atypical CD4+ cells with cerebriform nuclei in histology
  • Complications: progression to T-cell leukemia
DLBCL: diffuse large B-cell lymphoma
EBV: Epstein-Barr virus Epstein-Barr Virus Epstein-Barr virus (EBV) is a linear, double-stranded DNA virus belonging to the Herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus
HTLV-1: human T-cell leukemia/lymphotropic virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview
MZL: marginal zone lymphoma
MALT: mucosa-associated lymphoid tumor

Differential Diagnosis

  • Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma: malignancy of B lymphocytes B lymphocytes B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells originating in lymph nodes. The disease presents most commonly with lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy (neck most commonly involved), night sweats, weight loss, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and at times, hepatosplenomegaly. Diagnostic testing includes lymph node histologic analysis showing Hodgkin Reed-Sternberg cells, blood tests, CT, and PET. Management is with chemotherapy and radiotherapy.
  • Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma (MM): malignant condition of plasma cells (activated B lymphocytes B lymphocytes B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells) primarily seen in older adults. Monoclonal proliferation of plasma cells followed by osteoclastic activity results in bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones resorption, bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, pathologic fractures, and metabolic disturbances. Diagnosis is established by plasma electrophoresis and bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow biopsy. Treatments are available that slow disease progression, but there is no cure for MM, and the median survival is about 3 years.
  • Nonmalignant lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy: lymph node enlargement (> 1 cm) that is benign and self-limited. Etiologies include infection, autoimmune disorders, and iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy often indicates underlying systemic disease. Diagnosis relies on a thorough medical history, physical examination, and possible biopsy. Management is directed at the underlying infection, malignancy, or other cause.

References

  1. Freedman, A.S., Friedberg, J.W., Aster, J.C. (2020). Clinical presentation and initial evaluation of non-Hodgkin lymphoma. UpToDate. Retrieved November 9, 2021, from https://www.uptodate.com/contents/clinical-presentation-and-initial-evaluation-of-non-hodgkin-lymphoma
  2. Jacobson, C.A., Longo, D.L. (2018). Non-Hodgkin’s lymphoma. In: Jameson, J.L., et al. (Ed.), Harrison’s Principles of Internal Medicine, 20th ed., vol. 1, pp. 769–803. McGraw-Hill Education.
  3. Brown, J.R., Freedman, A.S. (2021). Overview of the pathobiology of the non-Hodgkin lymphomas. UpToDate. Retrieved November 9, 2021, from https://www.uptodate.com/contents/overview-of-the-pathobiology-of-the-non-hodgkin-lymphomas
  4. de Leval, L., Jaffe, E.S. (2020). Lymphoma classification. Cancer J 26:176–185. https://doi.org/10.1097/PPO.0000000000000451
  5. Freedman, A.S., Friedberg, J.W. (2020). Pretreatment evaluation, staging, and response assessment of non-Hodgkin lymphoma. UpToDate. Retrieved November 15, 2021, from https://www.uptodate.com/contents/pretreatment-evaluation-staging-and-response-assessment-of-non-hodgkin-lymphoma
  6. Watkins, M.P., Bartlett, N.L. (2018). CD19-targeted immunotherapies for treatment of patients with non-Hodgkin B-cell lymphomas. Expert Opin Investig Drugs 27:601–611. https://doi.org/10.1080/13543784.2018.1492549
  7. Shanbhag, S., Ambinder, R.F. (2018). Hodgkin lymphoma: a review and update on recent progress. CA Cancer J Clin 68:116–132. Doi: 10.3322/caac.21438

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