Non-Hodgkin Lymphoma (NHL)

How to Cite This Chapter: Lepic K, Crowther M, Warzocha K. Non-Hodgkin Lymphoma (NHL). McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. Accessed April 24, 2024.
Last Updated: June 8, 2019
Last Reviewed: June 8, 2019
Chapter Information

Definition, Etiology, PathogenesisTop

Non-Hodgkin lymphomas (NHLs) are a group of neoplasms characterized by the clonal proliferation of lymphoid cells at various stages of B-cell or less commonly T-cell or natural killer (NK)-cell differentiation. NHLs are the sixth most prevalent type of cancer in adults. Factors showing a documented causal relationship with the development of NHL include environmental factors (exposure to benzene, ionizing radiation), viral infections (human T-lymphotropic virus type I, Epstein-Barr virus [EBV], HIV, human herpesvirus 8, hepatitis C virus), bacterial infections (Helicobacter pylori), autoimmune diseases, immunodeficiencies (including immunosuppressive treatment after transplant), and prior chemotherapy (particularly when combined with radiotherapy).

The World Health Organization (WHO) histologic classification includes >30 NHL subtypes:

1) B-lymphoblastic and T-lymphoblastic leukemia/lymphoma (B/T-ALL/LBL) (see Acute Lymphoblastic Leukemia).

2) Mature B-cell neoplasms (80%-90%): Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), hairy cell leukemia (HCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL) and its variants, Burkitt lymphoma (BL), and other types.

3) Mature T-cell and NK-cell neoplasms: Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), large granular lymphocytic leukemia (LGLL), mycosis fungoides (MF), and other types.

Clinical Features and Natural HistoryTop

1. General symptoms: Table 1.

2. Lymphadenopathy: Lymph nodes are usually painless and the overlying skin is unchanged. Typically, they are >1 cm in diameter and have a tendency to form conglomerates. Lymph nodes usually enlarge slowly, and temporary decreases in their size may be observed. Massive lymphadenopathy may cause superior vena cava syndrome as well as pleural effusions, ascites, and edema of the lower extremities. Rapid enlargement should suggest high-grade characteristics, as seen, for example, with BL.

3. Manifestations of extranodal tumors: Abdominal pain caused by enlargement of the spleen or liver; jaundice caused by liver infiltration; gastrointestinal bleeding, obstruction, and malabsorption that may be caused by gastrointestinal NHL; and other symptoms caused by infiltrates in various organs (eg, skin, central nervous system [CNS]).

4. Staging: Table 1.

5. Natural history: The prognosis and clinical management in NHL are based on the following classification:

1) Indolent NHLs (about half of cases): The majority of small B-cell NHLs, including FL, CLL/SLL, LPL/WM, MZL, and a few T-cell NHLs (MF, LGLL); these develop mainly in the elderly and present with generalized lymphadenopathy, bone marrow and peripheral blood involvement, and (frequently) splenic and hepatic involvement. General symptoms are rare. Indolent NHL may transform into aggressive NHL, and it is usually characterized by slow progression of signs and symptoms, with survival for most types measured in years. The most common indolent NHL is FL (10%-20% of NHLs).

2) Aggressive NHLs (about half of cases): DLBCL (most common, 30%-35% of NHLs) and MCL, as well as the majority of T-cell lymphomas. Untreated patients survive from a few to several months.

3) Highly aggressive NHLs: ALL/LBL and BL. Untreated patients survive from several weeks to a few months.


Diagnostic Tests

1. Histologic and immunohistochemical examination of an involved lymph node or organ specimens (excisional biopsy or multiple core biopsies).

2. Studies performed to identify nodal and extranodal lesions (required for staging):

1) Contrast-enhanced computed tomography (CT) of the chest, abdomen, and pelvis (in fluorodeoxyglucose [FDG]-avid NHL and as the only imaging test in primarily extranodal NHL, CLL/SLL, LPL/WM, MZL).

2) Positron emission tomography (PET)-CT should be considered in the case of FDG-avid NHL.

3) Bone marrow aspiration and biopsy.

4) Depending on the subtype and signs/symptoms, it may be necessary to perform endoscopy, cerebrospinal fluid examination, or other studies.

3. Laboratory studies:

1) Complete blood count (CBC).

2) Other: Renal and liver function tests and lactate dehydrogenase levels, beta2-microglobulin; serum protein electrophoresis and immunoglobulins concentration, direct antiglobulin (Coombs) tests; HIV, hepatitis B or C virus, EBV.

4. Electrocardiography (ECG) and echocardiography are indicated in every patient in whom treatment with anthracyclines is planned and in the elderly.

5. Cytogenetic studies and molecular studies are performed for those lymphomas that have identifiable abnormalities.

Diagnostic Criteria

Diagnosis is made on the basis of histologic and immunohistochemical examination of an entire lymph node or a specimen of an involved organ.

Differential Diagnosis

Other causes of general symptoms, lymphadenopathy, or splenomegaly.


The choice of treatment modalities depends on the histologic type and stage of NHL as well as the presence of certain prognostic factors at the onset of the disease (Table 2), performance status, and comorbidities.

Treatment of Indolent NHL

Currently available treatment modalities cannot achieve a radical cure in this group of patients. Exceptions are localized lymphomas (clinical stage I or II), which sometimes may regress spontaneously or may be successfully treated by eradicating the etiologic factor using antimicrobial agents (eg, H pylori in patients with gastric mucosa-associated lymphoid tissue lymphoma) and/or surgical resection of the primary lesion (eg, spleen in patients with splenic MZL) combined with adjuvant radiotherapy and/or chemotherapy. Localized follicular lymphoma can sometimes be cured with radiation alone. Blood and marrow transplant can be used with curative intent in a subset of patients.

Indications for systemic treatment (chemotherapy or immunochemotherapy): Significant constitutional symptoms, progressive bulky disease, significant cytopenia, threatened end-organ function (CNS, gastrointestinal system). In patients who do not require immediate treatment, it should be delayed until symptomatic progression of the disease is observed. Cutaneous NHL may require skin-directed therapy.

Treatment of Aggressive Lymphomas

Lymphoma treatment is an area of active interest with novel agents entering clinical practice. Clinicians are encouraged to enter patients into clinical trials and to refer patients to expert centers where recent advances in therapy are more likely to be available.

1. First-line treatment: Start multiagent chemotherapy as soon as possible in combination with rituximab (in B-cell NHL) and involved field radiotherapy (if necessary).

2. In patients with refractoriness or relapse, use alternative chemotherapy regimens with or without radiotherapy of the remaining active neoplastic tissue followed by autologous hematopoietic stem cell transplant (HSCT) in transplant-eligible patients. Chimeric antigen receptor (CAR) T cells have shown promise for patients with relapsed refractory disease.

Treatment of Highly Aggressive Lymphomas

1. BL: Urgent initiation of intensive multiagent chemotherapy with CNS prophylaxis. Before this treatment, start prevention of tumor lysis syndrome (see Tumor Lysis Syndrome).

2. ALL/LBL: see Acute Lymphoblastic Leukemia.


Indolent lymphomas: Remissions are frequent (>75%) but short-lasting (although up to several years), and cure is very rare. High-grade transformations should be treated as aggressive lymphomas and may result in complete remission of high-grade lesions.

Aggressive lymphomas: Complete remissions are achieved in >75% of treated patients, and long-term survival rates are ~50%. In general, “cure” rates are highest with the most aggressive forms of B-cell lymphomas and lower in the elderly and in patients with comorbid conditions that restrict the use of aggressive chemotherapy regimens.


Table 9.3-3. Lugano (2014) staging system for primarily nodal lymphomas

Clinical stage (CS)



One node or a group of adjacent nodes, or single extranodal lesions without nodal involvement


≥2 nodal groups on the same side of the diaphragm, or CS I/II by nodal extent with limited contiguous extranodal involvement


Nodes on both sides of the diaphragm, or nodes above the diaphragm with spleen involvement


Additional noncontiguous extralymphatic involvement

The tonsils, Waldeyer ring, and spleen are considered nodal tissue.

Additionally in Hodgkin lymphoma: A, no general symptoms; B, general symptoms: unexplained fever (>38°C), drenching night sweats, or weight loss >10% of body weight in the prior 6 months.

a CS II bulky: CS II as above and bulky disease (a single nodal mass of ≥10 cm or >1/3 of the transthoracic diameter at any level of thoracic vertebrae as determined by computed tomography).

Based on J Clin Oncol. 2014;32(27):3059-68.

Table 9.3-4. International prognostic index for non-Hodgkin lymphomas

International prognostic index (IPI) for aggressive NHL

Risk factors

Cutoff value


≤60 years vs >60 years

ECOG performance status (see

<2 vs ≥2

Clinical stage (see table 9.3-3)


Number of extranodal sites involved

≤1 vs >1

Serum LDH level

≤ULN vs >ULN

Risk groups

Number of risk factors

Low risk


Low-intermediate risk


High-intermediate risk


High risk


Follicular lymphoma-specific international prognostic index (FLIPI) for indolent NHL

Risk factors

Cutoff value


≤60 years vs >60 years

Number of extranodal sites involved

≤4 vs >4

Clinical stage (see table 9.3-3)


Hemoglobin level

<12 g/dL vs ≥12 g/dL

Serum LDH level

≤ULN vs >ULN

Risk groups

Number of risk factors

Low risk


Intermediate risk


High risk


ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; NHL, non-Hodgkin lymphoma; ULN, upper limit of normal.

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