Non-Hodgkin lymphomas

Lymphomas are malignancies that arise from lymphocytes and are classified as either Hodgkin lymphomas (characterized by Reed-Sternberg cells) or non-Hodgkin lymphomas (NHLs), which comprise all other types of lymphoma. NHLs are further classified according to cell type, i.e., B cells, T cells, and natural killer (NK) cells; location (nodal or extranodal); and tumor grade. Low-grade tumors originate from mature cells that have a slow growth rate and an indolent clinical course. The most common low-grade B-cell lymphoma is follicular lymphoma, while the most common low-grade T-cell lymphomas are cutaneous T-cell lymphomas, such as mycosis fungoides. High-grade tumors have a rapid growth rate and an aggressive clinical course. Certain subtypes of NHL, such as Burkitt lymphoma, are more common in children and young adults than in older adults. NHL is diagnosed by obtaining a biopsy of the affected tissue and carrying out a detailed assessment, including immunophenotyping, genetics, and molecular testing. These studies allow for the identification of specific NHL subtypes, which guides treatment. Generally, treatment involves a combination of chemotherapy and radiation therapy. Patients with high-grade NHLs and those with low-grade tumors and limited disease are treated with curative intent. Patients with advanced, low-grade tumors who experience symptoms usually receive palliative treatment.

• Incidence: NHL is the most common hematopoietic neoplasm. [1]
• Age
  • The incidence of all NHLs increases with age; the peak incidence is in those aged > 50 years.
  • High-grade lymphomas are most common in children and young adults (20–40 years).

Epidemiological data refers to the US, unless otherwise specified.

• Chromosomal translocations: most commonly t(14;18)
• Infections [2]
  • EBV
  • HIV
  • HTLV-1
  • HCV
  • Helicobacter pylori: associated with gastric lymphoma, e.g., MALT lymphoma, diffuse large B-cell lymphoma (DLBCL)
• Autoimmune diseases: Hashimoto thyroiditis, rheumatoid arthritis
• Immunodeficiency: congenital immunodeficiencies, AIDS, history of chemotherapy and/or immunosuppressive therapy
• Environmental factors: aromatic hydrocarbons (e.g., benzene), radiation

B-cell lymphomas (85% of all NHLs)

Burkitt lymphoma is most common in kids.

T-cell lymphomas (15% of all NHL)

Think of an aggressive man to remember that the occurrence of mantle cell lymphoma is greater in men and that the disease has an aggressive course.

Hair can get TRAPped in the hairdryer: hairy cell leukemia, TRAP stain, dry tap.

• Nodal disease: typically painless lymphadenopathy associated with fatigue and weakness (multiple noncontiguous lymph nodes may be involved) ; [12][13]
  • High grade
    • Rapidly growing mass/nodes
    • Constitutional symptoms or B symptoms (i.e., weight loss, fever, night sweats)
  • Low grade
    • Slow-growing or undulant lymphadenopathy (over months or years)
    • Hepatosplenomegaly
    • Cytopenias: Patients may present with anemia or bleeding, or have an increased susceptibility to infections.

• Extranodal disease (primary or secondary): The symptoms are highly dependent on the affected tissue; B symptoms are common. [12][13]
  • GI tract: e.g., early satiety, GI bleeding
  • Neurological involvement: e.g., headache, focal neurologic symptoms
  • Primary cutaneous NHL or secondary skin infiltration: e.g., rash, plaques, tumors, ulcers
  • Thyroid involvement (rare): e.g., nodules, goiter
• Oncologic emergencies/paraneoplastic syndromes [12][13]
  • Examples include tumor lysis syndrome, hypercalcemia, spinal cord compression, superior vena cava syndrome, cardiac tamponade, lymphomatous meningitis, and a CNS mass.
  • See “Oncologic emergencies” for detailed information on the management of these conditions.

See ”Differential diagnosis of B symptoms”, “Enlarged lymph nodes”, and “Differential diagnosis of granulomatous disease” for more information.

Extranodal masses

• Thymoma
• Teratoma (and other germ cell tumors)
• Thyroid neoplasm

The 4 T's of anterior mediastinal masses: Thymoma, Teratoma (and other germ cell tumors), Thyroid neoplasm, and Terrible lymphoma.

Necrotizing lymphadenitis (Kikuchi-Fujimoto disease) [14]

• Etiology: unknown
• Epidemiology
  • Rare; most commonly reported in Asian population
  • Sex: ♀ > ♂
  • Mean age: 30 years
• Clinical features: painful cervical lymphadenopathy and fever
• Diagnostics: Lymph node biopsy shows single or multiple necrotic foci, histiocytic cellular infiltration, without granulocytic involvement.
• Treatment: typically resolves spontaneously within 1–4 months of onset without treatment

The differential diagnoses listed here are not exhaustive.

Approach [15][16][17]

• Suspect NHL in patients with suggestive clinical or laboratory features.
• Confirm the diagnosis and determine the subtype via lymph node and/or tissue biopsies.
• Stage and classify the disease (see “Staging of NHL”), e.g.:
  • Imaging studies: to determine the extent of the disease and detect possible CNS involvement
  • Bone marrow aspiration and biopsy: to detect bone marrow involvement

The clinical presentation of patients with NHL varies (e.g., nodal symptoms, extranodal symptoms, oncologic emergencies, or paraneoplastic syndromes); therefore, clinicians must maintain a high index of suspicion to facilitate early diagnosis.

Laboratory studies [16]

• Routine laboratory studies
  • CBC: may show anemia, thrombocytopenia; WBC count may be high or low (commonly leukopenia, lymphocytosis)
  • BMP: may show abnormal renal function [18]
  • Serum calcium: may show hypercalcemia
  • Liver chemistries: may be abnormal in patients with liver infiltration or primary hepatic lymphoma [19]
• Markers of disease activity [16][20]
  • Uric acid: usually elevated
  • LDH: usually elevated
  • Serum β2-microglobulin: may be elevated
  • Others: CRP, ESR
• Viral serologies
  • HIV screening
  • Additional studies can be suggestive of the underlying etiology (e.g., hepatitis B and C, EBV, HTLV-1).

Confirmatory diagnostics tests [13][15][17]

Histopathological studies are required to diagnose lymphoma. Large samples are preferred as intact tissue architecture is required to classify the subtype. If initial biopsy results are negative in patients with symptoms that are highly suggestive of lymphoma, consider obtaining a larger biopsy sample and repeating the studies.

Selection of biopsy sample

• Nodal disease
  • Select the most appropriate node for biopsy (e.g., a node with significant, progressive, and persistent enlargement).
  • Imaging methods such as CT and PET-CT may be used to select a site (see “Staging of NHL”).
  • Techniques [17]
    • Preferred: excisional lymph node biopsy or core needle biopsy
    • Alternative: incisional lymph node biopsy
    • Avoid fine-needle aspiration biopsy.
• Extranodal disease
  • Excisional tissue biopsies are recommended.
  • Biopsies frequently require guidance, e.g., with endoscopy or using ultrasound.

Histopathology and specialized studies

These studies help determine the subtype of NHL.

• Histopathology: provides a detailed morphology of individual proliferating cells and a description of the pattern of lymph node (or tissue) infiltration (e.g., nodular, diffuse)
• Immunophenotype (e.g., flow cytometry, immunohistochemistry)
  • Detects surface antigens, determines the specific cell type (B cell/T cell), and identifies specific markers
  • Possible findings include:
    • B-cell lymphomas: CD20 positive
    • T-cell lymphomas: CD3 positive
• Genetic studies
  • Cytogenetics (karyotype, FISH): can identify chromosomal abnormalities, e.g., t(14;18) in follicular lymphoma
  • Molecular testing (e.g., PCR): can detect clonality, e.g., in B-cell receptors or T-cell receptors

It is important to identify CD20-positive lymphomas, as patients may benefit from targeted therapy with CD20 antibodies (e.g., rituximab).

Staging [15]

• Imaging
  • Indicated in all patients for staging and to assess response to therapy
  • Choice of imaging modality depends on the suspected subtype of NHL (uptake of FDG varies between subtypes)
    • FDG-avid NHLs (most subtypes): PET-CT
    • Non-FDG-avid NHLs : CT whole body with contrast
• Bone marrow aspiration and biopsy: indicated in most newly diagnosed patients with NHL
• Assessment of CNS involvement
  • Indications
    • Patients considered high-risk for CNS involvement [21]
    • Primary CNS lymphoma
    • Patients with neurological signs and symptoms
    • Patients with HIV
  • Recommended modalities include:
    • Imaging (MRI or CT brain)
    • Lumbar puncture with CSF assessment (cytology; detection of EBV DNA)

Classification [15]

• Lugano classification is the preferred classification method for primary nodal NHL.
  • Imaging is used to assess the number and location of affected lymph nodes, tumor bulk, and liver and spleen involvement.
  • Bone marrow biopsy to assess bone marrow involvement
  • The disease is then classified as either:
    • Limited disease (stage I + II): one node or conglomerate (stage I), or ≥ 2 nodes or conglomerates on one side of the diaphragm (stage II)
    • Advanced disease (stage III + IV): nodes on both sides of the diaphragm or supradiaphragmatic nodes with splenic involvement (stage III), or diffuse or disseminated disease (stage IV)
  • See “Lugano classification of lymphomas” for more information.
• Previously, a version of the Cotswolds-modified Ann Arbor system was used, excluding the presence of B symptoms.

Most patients with newly diagnosed NHL require chemotherapy, radiotherapy, or both. In some patients with indolent NHLs, such as follicular lymphoma, occasionally a watch and wait strategy can be used. Consultation with a hematologist-oncologist is essential for planning and initiating treatment.

Approach [16][22]

• Perform prechemotherapy screening.
• Select treatment based on the subtype of NHL, staging, and prognosis
  • Most patients will receive treatment with systemic chemotherapy and/or radiotherapy.
    • Low-grade NHL (initial stages): Consider radiotherapy with curative intent.
    • Low-grade NHL (advanced stages): usually palliative chemotherapy
    • High-grade NHL: usually chemotherapy with curative intent
  • Select patients may benefit from additional interventions, including splenectomy and hematopoietic stem cell transplantation (HSCT).
• Provide supportive treatment: see also “Principles of cancer care.”
  • Adequate hydration and nutrition
  • Management of chemotherapy-induced nausea and vomiting and other side effects of chemotherapy
  • DVT prophylaxis
  • Consider prophylaxis for tumor lysis syndrome. [23]

Prechemotherapy screening is essential in all patients receiving chemotherapy for NHL to adequately adjust chemotherapeutic doses according to patients' hepatic, renal, and cardiac function.

Medical therapy

Treatment options [22]

• Radiotherapy
  • May be curative or palliative
  • Can be conventional or in form of radioimmunotherapy, in which engineered monoclonal antibodies that are specific for tumor antigens are bound to radioactive nucleotides, which results in higher doses of radiation reaching the target cancer cells and less off-target effects.
• Systemic chemotherapy: Regimens usually include combinations of chemotherapeutic agents, steroids, and immunotherapy.
  • Antifolates: high-dose methotrexate ; (in combination with leucovorin) for primary CNS lymphoma
  • Alkylating agents: e.g., cyclophosphamide (C)
  • Topoisomerase II inhibitors: e.g., etoposide (E), doxorubicin/hydroxydaunorubicin (H)
  • Alkaloids: e.g., vincristine/oncovin (V/O)
  • Steroids: e.g., prednisolone (P), dexamethasone
  • Immunotherapy: e.g., rituximab (R)
• Intrathecal chemotherapy: Intrathecal methotrexate can be considered for leptomeningeal involvement.

Specific regimens [16][22]

Below is a summary of some of the common treatment regimens found in the literature for select NHL subtypes; these regimens are intended to provide an overview only and treatment decisions should be tailored to the patient and the features of the disease (e.g., specific mutations, location, extent).

CHOP is the most common regimen in NHL, with the addition of rituximab (CD20 antibody) for B-cell neoplasms (R-CHOP).

Some new therapies are emerging as part of the management of certain types of NHLs, including targeted therapies (e.g., ibrutinib) and monoclonal antibodies (e.g., mogamulizumab). If available, a specialist may choose to use them depending on the individual evaluation of each patient.

Additional therapies [22][24]

• Surgery
  • Splenectomy: Consider in select patients with B-cell lymphomas with splenic involvement (e.g., splenic MZL, hairy cell leukemia).
  • Surgical resection: Consider in select patients with specific NHL subtypes.
• HSCT
  • Consider in relapsing or refractory disease for some NHL subtypes, e.g., DLBCL, mantle cell lymphoma, mature T-cell lymphoma.

• Typically, the prognosis of NHL is worse than that of Hodgkin lymphoma. [25]
  • Low-grade lymphomas: median survival of 6–10 years
  • High-grade lymphomas: survival typically several months (years in less aggressive variants)
• Indicators of poor prognosis: old age, number of involved nodal and extranodal sites, ↑ LDH, ↑ beta2 microglobulin [26]