Pretreatment evaluation and staging of non-Hodgkin lymphomas

INTRODUCTION — Non-Hodgkin lymphomas (NHL) are a diverse group of lymphoid malignancies that vary according to the underlying pathobiology, natural history, preferred treatment, and prognosis. Pretreatment evaluation for a patient with a newly diagnosed NHL must establish the histologic subtype (table 1), disease stage (ie, extent and sites of disease) (table 2), and medical fitness.

This topic addresses the general pretreatment evaluation of a patient with a newly diagnosed NHL, including clinical and laboratory studies, imaging, and disease staging. Importantly, certain aspects of the pretreatment evaluation vary according to the specific subtype of NHL; such details are presented with the initial treatment of the specific lymphoma category.

CLINICAL AND LABORATORY EVALUATION

Clinical — The history should consider constitutional symptoms (eg, unexplained fevers, sweats, unintended weight loss) and neurologic complaints (eg, headache, altered vision, motor or sensory complaints). Symptoms related to heart, lung, kidney, and liver disease and other comorbid conditions should be assessed.

Physical examination should evaluate lymph node-bearing areas (including Waldeyer's ring), liver, and spleen and should screen for neurologic abnormalities.

Medical fitness — Fitness for treatment is assessed by clinical evaluation and performance status. For some patients, use of an assessment instrument for comorbid illnesses or geriatric consultation may be helpful for judging fitness.

●Performance status – Performance status is a measure of a patient's functional capacity. Assessment of performance status may affect the choice of treatment and is associated with outcomes for many lymphomas.

Karnofsky performance status (KPS) and the Eastern Cooperative Oncology Group (ECOG) performance status are most commonly used as instruments to judge performance status (table 3A-B).

●Comorbid conditions – For patients with significant conditions identified by clinical evaluation, an instrument for assessing the severity of comorbid illnesses, such as the Charlson comorbidity index (table 4), can be useful.

Comprehensive geriatric assessment may be helpful for judging fitness of certain older patients. (See "Comprehensive geriatric assessment for patients with cancer".)

Laboratory studies — Laboratory studies for patients with newly diagnosed NHL should include:

●Complete blood count (CBC) and blood smear – CBC, including differential count and evaluation of the blood smear.

The presence of atypical cells on the blood smear (picture 1) suggests lymphomatous involvement of bone marrow, which is most common with indolent lymphomas, such as follicular lymphoma.

●Serum chemistries – Chemistry studies should include:

•Electrolytes – Including calcium, phosphorus, and uric acid.

•Kidney function tests – Blood urea nitrogen (BUN) and creatinine.

•Liver function tests – Including alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and albumin.

Kidney function tests are important for choosing treatment, since many agents are nephrotoxic and/or excreted through the kidney (table 5). (See "Nephrotoxicity of chemotherapy and other cytotoxic agents" and "Nephrotoxicity of molecularly targeted agents and immunotherapy".)

High levels of uric acid, calcium, potassium, phosphorus, and serum creatinine may indicate spontaneous tumor lysis syndrome (TLS), which is more common with aggressive tumors (eg, diffuse large B cell lymphoma [DLBCL], Burkitt lymphoma, high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 gene rearrangements); TLS requires urgent management before initiating chemotherapy, because treatment will further exacerbate TLS. (See "Tumor lysis syndrome: Prevention and treatment".)

Elevated BUN or creatinine may also indicate bilateral ureteral obstruction caused by retroperitoneal nodes.

●Serum protein electrophoresis (SPEP) and/or serum viscosity – SPEP, serum viscosity, and/or beta-2 globulin should be obtained in selected cases.

•SPEP – Patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) should have a pretreatment SPEP to document a circulating monoclonal paraprotein or hypogammaglobulinemia, which may be associated with increased risk for infection. Patients with lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM) may have a serum immunoglobulin (Ig) M paraprotein. (See "Laboratory methods for analyzing monoclonal proteins" and "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma" and "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia".)

•Serum viscosity – Serum viscosity may be increased due to elevated serum IgM (eg, in LPL/WM) or, rarely, elevated IgA. Viscosity should be evaluated urgently in patients with symptoms suspicious of hyperviscosity (eg, blurry vision, headache, vertigo). (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Hyperviscosity syndrome'.)

•Beta-2 microglobulin – For patients with follicular lymphoma, beta-2 microglobulin is used for certain prognostic instruments. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma", section on 'PRIMA prognostic index (PRIMA-PI)'.)

●HIV – All patients should be tested for HIV, as documentation of HIV infection may affect diagnosis, treatment, and prognosis. (See "Screening and diagnostic testing for HIV infection".)

In patients with HIV infection, systemic NHL and primary central nervous system (CNS) lymphoma are AIDS-defining malignancies. (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology".)

●Hepatitis serologies – Testing for hepatitis B or hepatitis C is important for selected patients, as the underlying infection or its hepatic and hematologic complications can affect NHL management.

Treatment of the viral hepatitis should be considered before or at the time of initiating treatment for the lymphoma. (See "Hepatitis B virus: Overview of management", section on 'Patients receiving immunosuppressive therapy' and "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Deciding when to treat'.)

•Hepatitis B – All patients who may receive rituximab should be tested for hepatitis B because of the risk of hepatitis B reactivation. Testing includes hepatitis B surface antigen (HBsAg) and antibodies against hepatitis B core antigen (anti-HBc); for patients who are HBsAg positive, testing for HBeAg, anti-HBe, and an HBV DNA level should be evaluated.

Antiviral therapy for infected patients should start before treatment commences and continue for months after chemotherapy [1,2]. Reactivation of hepatitis B virus during chemotherapy, which occurs in 20 to 50 percent of HBsAg carriers, can be associated with a high mortality despite antiviral treatment [3,4]. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Patients who are not infected may benefit from hepatitis B vaccination.

•Hepatitis C – Some experts test all patients for hepatitis C, while some limit testing to patients with marginal zone lymphoma. Serologic testing for hepatitis C should include both antibody testing and hepatitis C RNA assays. (See "Screening and diagnosis of chronic hepatitis C virus infection", section on 'Diagnostic techniques'.)

Infection with hepatitis B or hepatitis C may have a causal relationship with certain cases of NHL [5-8].

●Pregnancy testing – All women of child-bearing potential should have pregnancy testing.

Fertility preservation is discussed below. (See 'Fertility preservation' below.)

CLINICAL TESTING — Heart function should be evaluated for patients with known heart disease and for those who may receive cardiotoxic treatments. Bone marrow examination or evaluation for nervous system involvement is performed in selected patients.

Cardiac function — Echocardiogram or radionuclide ventriculogram (RVG or MUGA) should be used to assess cardiac ejection fraction if the patient may be treated with an anthracycline or receive mediastinal irradiation. Cardiac function testing may not be necessary if the patient is young, has no history of heart disease, and is going to get a relatively small dose of an anthracycline. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

Bone marrow examination — Bone marrow (BM) examination is needed in only limited circumstances, because positron emission tomography (PET)/computed tomography (CT) is sensitive for detecting BM involvement by NHL.

We perform a unilateral BM examination, including microscopy, special stains, flow cytometry, and/or molecular studies (table 6) to:

●Exclude systemic disease in a patient with apparent stage I disease

●Evaluate possible discordant histology (eg, transformation of follicular lymphoma)

●Investigate abnormal blood counts in patients without an alternative explanation

For most NHL histologic subtypes, the ability of PET/CT to accurately detect BM involvement is not well-defined [9,10]. However, for diffuse large B cell lymphoma (DLBCL), PET is highly specific for detecting lymphomatous BM involvement; nevertheless, normal BM on PET does not exclude BM involvement by DLBCL because it may miss diffuse, low-volume (10 to 20 percent of marrow) disease. In a meta-analysis that included data from seven studies with a total of 654 patients with newly diagnosed DLBCL, PET had moderate sensitivity (88.7 percent) and high specificity (99.8 percent) for detecting BM involvement [11]. Approximately 3 percent of patients with involvement on BM biopsy had a negative PET, while 13 percent with involvement on PET had a negative BM biopsy.

The role of BM biopsy for response assessment in most NHL is also very limited [12].

Central nervous system (CNS) — CNS involvement should be investigated for patients with abnormal findings on neurologic examination, new neurologic symptoms, or those with certain histologic categories or clinical features.

A multimodal approach can detect both parenchymal and leptomeningeal involvement. We obtain magnetic resonance imaging (MRI; with and without gadolinium contrast) and lumbar puncture (LP), but a CT with intravenous contrast is acceptable for patients who cannot undergo MRI because of an implanted metallic device.

LP, including cytology and flow cytometry, should be performed in patients who have a substantial risk of involvement of the CNS, based on histologic category or certain clinical features (table 7):

●Highly aggressive NHL – Examples of highly aggressive NHL associated with increased risk for CNS involvement include:

•Burkitt lymphoma

•Adult T cell leukemia-lymphoma

•Acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL)

•High grade lymphoma with MYC and BCL2 and/or BCL6 gene rearrangement

●HIV-positive NHL – Most types of HIV-related NHL are associated with increased risk for CNS involvement.

●Higher-risk for CNS involvement – Patients with DLBCL, peripheral T cell lymphoma (PTCL), grade 3b follicular lymphoma, or mantle cell lymphoma with one of the following features:

•Epidural, bone marrow, testicular, or paranasal sinus involvement

•≥2 extranodal disease sites

Increased risk for CNS involvement by NHL is discussed separately. (See "Secondary central nervous system lymphoma: Clinical features and diagnosis" and "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Central nervous system (CNS) evaluation'.)

Fertility preservation — Fertility preservation, including sperm or fertilized ovum banking, should be discussed with patients of childbearing age prior to initiating treatment. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

IMAGING

Choice of imaging modality — The choice of imaging modality is influenced by the histologic subtype of NHL:

●Positron emission tomography (PET)/computed tomography (CT) – Whole-body PET, using 18F-fluorodeoxyglucose (¹⁸F-FDG), with concurrent CT is preferred for evaluation and staging of most NHL subtypes [13-17].

In special situations (eg, blood vessel compression/thrombosis, lymphadenopathy close to bowel), a dedicated contrast-enhanced CT or other studies may be needed in addition to PET/CT. (See 'Evaluation of specific sites' below.)

Although most categories of nodal NHL are FDG-avid, certain histologic subtypes are variably FDG-avid or non-avid [9,10]. PET has inconsistent usefulness for these and other indolent lymphomas, but it may be helpful in some circumstances (eg, to identify a preferred biopsy site if aggressive transformation is suspected). Examples of variably FDG-avid categories include:

•Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)

•Lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM)

•Mycosis fungoides (MF)

•Marginal zone lymphoma (MZL)

●Computed tomography – CT of chest, abdomen, and pelvis with intravenous contrast or oral contrast is used to define the extent of disease for FDG-non-avid or variably FDG-avid histologies (described above). CT of the neck should be performed, as clinically indicated.

Positron emission tomography (PET) — PET is used for initial staging of most types of NHL and is a key component of assessing response to therapy.

PET combined with near-simultaneous CT identifies lymphoma-related uptake for many histologic categories (discussed above) and can help to distinguish it from non-lymphomatous activity (eg, infection, inflammation). PET is highly sensitive and specific for detecting NHL in nodal and extranodal sites and it has variable reliability for detecting bone marrow involvement, as discussed above. (See 'Bone marrow examination' above.)

Standardized uptake value (SUV) is a semi-quantitative method for assessing PET activity [18]. SUV analysis is useful because uptake of the radiolabeled tracer, 2-deoxy-2-[¹⁸F] fluoro-D-glucose (FDG), varies with the amount of injected FDG, patient size, and among different organs/tissues. For most histologic categories of NHL, uptake by involved lymph nodes and some locations (eg, Waldeyer's ring, certain extranodal sites) is generally greater than PET activity of the mediastinal blood pool and/or liver [9].

The use of PET for assessing response to treatment using the five-point (Deauville score) is incorporated into the Lugano criteria (table 8) [9,10] and is discussed separately. (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'End-of-treatment PET'.)

The following studies have investigated FDG-avidity of various NHL histologic subtypes:

●PET revealed at least one FDG-avid site in 718 of 766 patients (94 percent) in one study of patients with NHL or Hodgkin lymphoma [19]. The frequency of FDG-avidity varied by histologic subtype:

•FDG-avid – FDG-avidity was present in all cases of Burkitt lymphoma, mantle cell lymphoma (MCL), nodal MZL, lymphoblastic lymphoma, and Hodgkin lymphoma. FDG-avidity was also high in patients with DLBCL (97 percent) and follicular lymphoma (FL; 95 percent).

•FDG-variable – Lower rates of FDG-avidity were seen in T cell lymphoma (85 percent), CLL/SLL (83 percent) and extranodal MZL (55 percent).

●In another study, PET detected disease in at least one location in 98 to 100 percent of patients with pathologically proven DLBCL, MCL, Hodgkin lymphoma, and FL, but it was less often able to detect disease in patients with MZL and peripheral T cell lymphoma [20].

●A study that used CT and/or MRI to confirm sites of involvement reported that PET identified >97 percent of disease sites identified by CT or MRI in Hodgkin lymphoma and aggressive or highly aggressive NHL [21]. PET was less sensitive for the detection of lesions in the indolent NHL variants, with sensitivities of 91, 82, and 50 percent for FL, extranodal MZL of MALT tissue, and SLL/splenic marginal zone lymphoma, respectively.

Computed tomography (CT) — Contrast-enhanced CT is often preferred for imaging variably FDG-avid or nonavid histologic subtypes [9,10]. For any histologic category, a dedicated contrast-enhanced CT can help to define the extent of disease in special situations, such as lymphadenopathy close to bowel or if there is compression or thrombosis of blood vessels. (See 'Choice of imaging modality' above.)

When CT is used for staging, the initial evaluation should include a contrast-enhanced CT scan of the chest, abdomen, and pelvis (image 1 and image 2). A dedicated CT of the neck may be necessary for patients with cervical and/or supraclavicular nodal involvement on physical examination.

The report should include bidirectional measurements of the six largest nodes, nodal masses, or other lymphomatous lesions from different body regions [9]; involved nodes should have a longest diameter >1.5 cm, and extranodal disease should have a longest diameter >1 cm. Response to treatment can be assessed with subsequent imaging, using the six chosen lesions; other lesions (eg, cutaneous lesions, pleural or pericardial effusions, ascites) are generally considered non-measurable disease.

EVALUATION OF SPECIFIC SITES — Specific evaluation of the gastrointestinal (GI) tract, liver, spleen, central nervous system (CNS), skeleton, or genitourinary (GU) tract is generally reserved for patients with symptoms or those at high risk for involvement of these sites.

Gastrointestinal tract — Evaluation of the GI tract with imaging or endoscopy is indicated for patients with symptoms that suggest GI involvement (table 9).

Endoscopic procedures are helpful in tumor localization and staging (eg, endoscopic ultrasound), detection of bleeding lesions, and in the obtaining of biopsy specimens in patients with GI lymphoma (picture 2 and picture 3). CT (image 3 and image 4) is useful for simultaneously evaluating mucosal lesions and assessing the extraluminal extent of lesions and associated adenopathy. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas", section on 'Diagnostic evaluation' and "Mantle cell lymphoma: Initial management", section on 'Pretreatment evaluation'.)

Liver and spleen — Estimation of liver and spleen size (reported as centimeters below the costal margin in the midclavicular line) should be recorded with the initial physical examination of all patients with newly diagnosed NHL. Normal liver and spleen size do not rule out involvement, while hepatic or splenic enlargement in a patient with NHL is not always due to lymphoma.

●Liver – For staging purposes in fluorodeoxyglucose (FDG)-avid histologies, liver involvement is determined by positron emission tomography (PET)/computed tomography (CT) demonstrating diffusely increased or focal FDG uptake, with or without focal or disseminated nodules [9,10]. Clinical hepatic enlargement alone, with or without abnormalities of liver function tests (LFTs), is not adequate. A percutaneous liver biopsy may be indicated if there are abnormalities of LFTs or liver imaging in patients with FDG-non-avid histologies who would otherwise have been classified as having stage I disease.

●Spleen – Splenic involvement in FDG-avid histologies is determined by PET/CT that reveals one of the following: homogeneous splenomegaly >13 cm, diffuse infiltration with miliary lesions, focal nodular lesions, or a large solitary mass. Although some advocate fine needle aspiration biopsy of the spleen under radiologic guidance, this is generally not recommended, because of the increased risk of bleeding [22,23].

Skeletal imaging — For patients with bony pain and/or suspicion of a pathologic fracture, imaging with plain films, CT, and/or magnetic resonance imaging (MRI) should be performed, as clinically indicated. Routine bone imaging is generally not performed for asymptomatic patients with NHL.

For suspected spinal cord compression, urgent MRI of the entire spinal column is indicated, since multiple sites may be involved. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression", section on 'Magnetic resonance imaging of the spine'.)

Genitourinary tract — The GU tract (eg, kidney, testis, ovary) is involved in approximately 10 percent of patients with NHL at initial diagnosis.

GU involvement is associated with increased risk for involvement of the CNS, as described above. (See 'Central nervous system (CNS)' above.)

●Kidney – The kidney is the most common site of GU involvement by NHL and is most often seen in patients with aggressive and highly aggressive histologic subtypes.

Renal involvement is often seen on CT as multiple discrete masses, or diffuse infiltration causing renal enlargement (image 5). Isolated masses are less common.

●Testis or ovary – Testis or ovary involvement usually occurs in patients with diffuse large B cell NHL (DLBCL).

While most GU lesions are identified by CT, patients with an abnormality on testicular examination should have testicular ultrasound (US) (image 6). Patients with testicular lymphoma should also have US of the apparently uninvolved testicle, to evaluate for contralateral disease. (See "Initial treatment of limited stage diffuse large B cell lymphoma", section on 'Testicular'.)

Less common GU lesions include mural thickening of the bladder or a ureter, or mass lesions of the uterus, cervix, or prostate.

STAGING — The Lugano classification is used for staging most patients with NHL, but some categories use distinctive staging systems. (See "Primary cutaneous follicle center lymphoma".)

The Lugano classification focuses on the number of tumor sites (nodal and extranodal) and their location (table 2) and was derived from the Ann Arbor staging system.

●Stage I – Lymphoma involving a single lymph node region (stage I), or a single extralymphatic organ or site (stage IE) without nodal involvement. A single lymph node region can include one node or a group of adjacent nodes (figure 1).

●Stage II – Two or more nodal regions on the same side of the diaphragm (stage II), or stage I or II by nodal involvement with limited contiguous extranodal involvement (stage IIE).

●Stage III – Lymph node involvement on both sides of the diaphragm.

●Stage IV – Diffuse or disseminated involvement of one or more extralymphatic organs (eg, liver, bone marrow, lung), with or without associated node involvement.

Noteworthy points for staging NHLs according to the Lugano system include:

●Constitutional symptoms – Systemic "B" symptoms (fever, sweats, weight loss) are not incorporated into the staging of NHL, in contrast with classic Hodgkin lymphoma (cHL), because they are not independent prognostic factors for patients with NHL.

●Extranodal involvement – The subscript "E" is used if limited extranodal extension is documented; multiple sites/more widespread extranodal disease is designated stage IV.

●Spleen – Disease involving the spleen is considered nodal, rather than extranodal.

●Bulky/large tumor masses – The Lugano classification requires a recording of the largest tumor diameter. Criteria for bulky disease vary by histology and no cutoff has been validated using modern treatment [9,10], but cutoffs of 6 cm and 6 to 10 cm are used for follicular lymphoma and DLBCL, respectively.

Most types of NHLs spread hematogenously, rather than by contiguous lymphatic extension (as occurs with cHL); as a result, disease stage is less important prognostically for NHL than for cHL. As an example, treatment of stage III and stage IV is generally very similar. Nevertheless, staging of NHL is important to identify patients with early-stage disease who can be treated with local therapy or with combined modality treatment (ie, chemotherapy plus radiation therapy).

PROGNOSIS — Prognosis for patients with NHL is greatly affected by histopathology, but it is less influenced by clinical parameters such as age, extranodal disease, performance status, and stage (I/II versus III/IV).

Within specific NHL categories, prognosis is related to aspects of tumor cell biology, such as cytogenetics, immunophenotype, growth fraction, or cytokine production. Tumor burden is important prognostically and may affect treatment for NHL (eg, use of adjuvant radiotherapy to sites of bulky disease), but it may not be accurately reflected in the disease stage, which depends only upon the location and number of disease sites.

Prognostic instruments that can be valuable for NHL include:

●International Prognostic Index (IPI) – The IPI (table 10) has value with all categories of NHL. (See "Prognosis of diffuse large B cell lymphoma", section on 'International Prognostic Index'.)

●Disease-specific – Disease-specific prognostic scores incorporate variables of tumor biology for specific NHL variants, such as the Follicular Lymphoma International Prognostic Index (FLIPI) (table 11) and the NK/T cell lymphoma prognostic index (table 12). (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma", section on 'Follicular lymphoma IPI (FLIPI)'.)

●Treatment-specific – Treatment-specific prognostic scores incorporate variables that reflect interactions among patient, tumor, and the therapeutic regimen [24]. An example is cell of origin analysis, which is associated with outcomes for patients with DLBCL treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). (See "Prognosis of diffuse large B cell lymphoma", section on 'Cell of origin studies'.)

Further discussion of prognosis for specific categories of NHL is presented separately. As examples:

●Diffuse large B cell lymphoma (see "Prognosis of diffuse large B cell lymphoma")

●Follicular lymphoma (see "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma", section on 'Prognosis')

●Peripheral T cell lymphoma (see "Clinical manifestations, pathologic features, and diagnosis of peripheral T cell lymphoma, not otherwise specified", section on 'Prognosis')

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lymphoma diagnosis and staging".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Lymphoma (The Basics)")

●Beyond the Basics topics (see "Patient education: Follicular lymphoma in adults (Beyond the Basics)" and "Patient education: Diffuse large B cell lymphoma in adults (Beyond the Basics)")

SUMMARY

●Importance of pretreatment evaluation – Management of the patient with newly diagnosed non-Hodgkin lymphoma (NHL) is based on histologic subtype (table 1), disease stage (table 2), and medical fitness.

●Clinical and laboratory evaluation – Evaluation includes (see 'Clinical and laboratory evaluation' above):

•History – Constitutional symptoms (fevers, sweats, weight loss), neurologic complaints, symptoms related to comorbid conditions (eg, heart, lung, kidney, liver disease), and performance status (table 3A-B).

•Examination – Evaluation of lymph node-bearing areas, liver, spleen, and neurologic findings.

•Laboratory – Testing includes:

-Hematology – Complete blood count with differential

-Serum chemistries – Electrolytes, kidney and liver function tests, lactate dehydrogenase, uric acid

-Infectious – HIV testing (all patients) and hepatitis B and hepatitis C testing (selected patients) (see 'Laboratory studies' above)

●Clinical testing – For selected patients:

•Cardiac – Ejection fraction by echocardiogram or radionuclide ventriculogram for patients with heart disease or who may receive mediastinal radiation or anthracycline-based therapy. (See 'Cardiac function' above.)

•Bone marrow (BM) – BM examination is obtained to (see 'Bone marrow examination' above):

-Exclude systemic disease in a patient with apparent stage I disease

-Investigate unexplained cytopenias

•Central nervous system (CNS) – CNS should be evaluated for patients with neurologic findings, certain histologic categories (eg, highly aggressive subtypes, AIDS-related NHL), or clinical features (eg, epidural, bone marrow, testicular, paranasal sinus involvement, or ≥2 extranodal disease sites). Evaluation includes magnetic resonance imaging (MRI) and/or lumbar puncture (LP). (See 'Central nervous system (CNS)' above.)

•Fertility preservation – Fertility preservation, including sperm or fertilized oocyte preservation, should be discussed with patients of childbearing age. (See 'Fertility preservation' above.)

●Imaging – Choice of imaging varies with the histologic category:

•Positron emission tomography (PET)/computed tomography (CT) – PET/CT is preferred for staging most types of NHL, but some more indolent histologic types are variably PET-avid or non-avid, such as (see 'Positron emission tomography (PET)' above):

-Chronic lymphocytic leukemia/small lymphocytic lymphoma

-Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia

-Mycosis fungoides

-Marginal zone lymphoma

•Computed tomography – CT of chest, abdomen, and pelvis with intravenous contrast or oral contrast may be more useful for staging variably PET-avid categories (above) and for defining disease of any category that involves lymphadenopathy close to bowel or blood vessels. (See 'Computed tomography (CT)' above.)

●Evaluation of specific sites – Special testing for involvement of gastrointestinal tract, bone, and genitourinary system is described above. (See 'Evaluation of specific sites' above.)

●Staging – The Lugano classification (table 2) uses clinical examination and PET/CT to stage NHL (see 'Staging' above):

•Stage I – Single lymph node region (stage I), or a single extralymphatic organ or site (stage IE) without nodal involvement (figure 1)

•Stage II – Two or more involved node regions on the same side of the diaphragm (stage II) or with localized involvement of an extralymphatic organ or site (stage IIE)

•Stage III – Nodal involvement on both sides of the diaphragm

•Stage IV – Diffuse or disseminated involvement of one or more extralymphatic organs (eg, liver, bone marrow, lung), with or without associated lymph node involvement