INTRODUCTION — The initial evaluation of the patient with newly diagnosed non-Hodgkin lymphoma (NHL) must establish the precise histologic subtype, the extent and sites of disease, and general health status, in order to select the optimal treatment.

This topic will address the general pretreatment evaluation of a patient with a newly diagnosed NHL, including laboratory studies and imaging, disease staging, and response assessment.

Of note, the pretreatment evaluation may vary by histologic subtype. Details of the pretreatment evaluation for specific NHL subtypes are presented as part of the discussion of initial treatment. The clinical presentation and basic diagnostic tests are presented separately as well. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Classification of the hematopoietic neoplasms".)

INITIAL LABORATORY STUDIES

Complete blood count and smear — All patients should have a complete blood count (CBC) with white blood cell differential and an evaluation of the peripheral smear.

Detection of atypical cells on the peripheral blood smear may suggest involvement of bone marrow and/or peripheral blood. The presence of malignant cells in the peripheral blood is generally indicative of extensive marrow involvement and is most common with indolent lymphomas, such as follicular lymphoma (picture 1).  

Serum chemistries — All patients with NHL should have baseline electrolytes, blood urea nitrogen (BUN), creatinine, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and albumin. Some patients should have a serum protein electrophoresis (SPEP).

Renal function tests are important as a guide to treatment, since many chemotherapeutic agents are nephrotoxic and/or excreted through the kidney (table 1). High levels of uric acid, calcium, potassium, phosphorus, and serum creatinine may indicate spontaneous tumor lysis syndrome (TLS), especially in patients with clinically aggressive tumors (eg, diffuse large B cell lymphoma [DLBCL], Burkitt lymphoma); TLS requires urgent management before initiating chemotherapy, because treatment will further exacerbate TLS. Elevated BUN or creatinine may also indicate bilateral ureteral obstruction secondary to massive enlargement of retroperitoneal nodes. (See "Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Conventional cytotoxic agents" and "Tumor lysis syndrome: Prevention and treatment" and "Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Molecularly targeted agents and immunotherapies".)

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/Waldenström macroglobulinemia may have a serum immunoglobulin M (IgM) paraprotein that can cause hyperviscosity; serum viscosity should also be evaluated in patients with elevated serum IgM or symptoms suspicious of hyperviscosity (eg, blurry vision, headache, vertigo), which should be evaluated and managed urgently. (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", section on 'Hyperviscosity syndrome'.)

Bone marrow examination — For staging most patients with NHL, a unilateral bone marrow (BM) aspiration and biopsy should be performed. This examination should include histologic examination, special stains, flow cytometry, and/or molecular studies (table 2).

A potential exception is for patients with DLBCL in whom positron emission tomography (PET)/computed tomography (CT) suggests the presence of advanced stage disease. PET is sensitive for detecting BM involvement with DLBCL [1]. However, BM examination should be performed for staging a patient with DLBCL who has no evidence of bone involvement by PET, because PET cannot conclusively rule out the presence of low-volume, diffuse BM involvement. A meta-analysis that included data from 654 patients with newly diagnosed DLBCL estimated the sensitivity and specificity of PET/CT for detection of BM involvement to be 88.7 and 99.8 percent, respectively [2]. Approximately 3 percent of patients with a negative PET/CT had evidence of disease on BM biopsy. In contrast, 12 percent of patients with a negative BM biopsy had evidence of disease on PET/CT.

Lumbar puncture — Patients with highly aggressive NHL (Burkitt lymphoma, adult T cell leukemia-lymphoma, precursor T or B lymphoblastic leukemia/lymphoma), human immunodeficiency virus (HIV)-positive NHL, or aggressive lymphoma (DLBCL, peripheral T cell lymphoma, grade 3b FL, mantle cell lymphoma) who have epidural, bone marrow, testicular, or paranasal sinus involvement, or at least two extranodal disease sites are at risk of having central nervous system (CNS) involvement (table 3) [3]. Such patients should undergo examination of the cerebrospinal fluid (CSF) by lumbar puncture. If performed, CSF should be sent for both cytology and flow cytometry. (See "Clinical presentation and diagnosis of secondary central nervous system lymphoma" and "Lumbar puncture: Technique, indications, contraindications, and complications in adults".)

HIV serologies — Systemic NHL and primary CNS lymphoma are AIDS-defining malignancies. Approximately 25 to 40 percent of HIV-1 seropositive patients eventually develop a malignancy that, in approximately 10 percent of cases, is NHL. Compared with non-HIV-infected patients, seropositivity for HIV-1 increases the risk of development of a lymphoma approximately 100-fold over that of the seronegative population. (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology".)

All patients with newly diagnosed lymphoma should be asked about HIV risk factors. If risk factors are present, patients should undergo serologic testing for HIV. Some clinicians perform serologic testing for HIV in all patients with certain NHL subtypes.

Hepatitis B and C serology — We suggest that patients with newly diagnosed NHL be tested for both hepatitis B and hepatitis C. Serologic testing for hepatitis B should include assessment of hepatitis B surface antigen (HBsAg) and antibodies against hepatitis B core antigen (anti-HBc); further testing should include HBeAg, anti-HBe, and an HBV DNA level if the patient is HBsAg positive. Serologic testing for hepatitis C should include both antibody testing and hepatitis C RNA assays. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy" and "Screening and diagnosis of chronic hepatitis C virus infection", section on 'Diagnostic techniques'.)

Hepatitis B and hepatitis C may have a causal relationship with NHL [4-10]. Hematologic and hepatic complications of these infections can affect treatment of NHL [11]. In addition, these patients should be considered for treatment directed at their hepatitis infection. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Deciding when to treat' and "Extrahepatic manifestations of hepatitis C virus infection", section on 'Lymphoma' and "Hepatitis B virus: Overview of management", section on 'Indications for antiviral therapy' and "Hepatitis B virus: Overview of management".)

Reactivation of hepatitis B virus during chemotherapy, which can be associated with a high mortality despite anti-viral treatment, occurs in 20 to 50 percent of HBsAg carriers [12,13]. Screening for hepatitis B infection (eg, hepatitis B surface antigen and hepatitis B core antibody) should be considered at the time of lymphoma diagnosis to allow for prophylactic anti-viral therapy in infected patients starting before and continuing for a number of months after chemotherapy [14,15]. Those not infected may benefit from hepatitis B vaccination. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Fertility preservation — An overall discussion of fertility issues should be undertaken in patients of childbearing age prior to the initiation of treatment, including the possibility of sperm or fertilized ovum banking. (See "Overview of fertility and reproductive hormone preservation prior to gonadotoxic therapy or surgery".)

ROUTINE IMAGING STUDIES

Choice of imaging modality — Positron emission tomography with computed tomography (PET/CT) is preferred for staging fluorodeoxyglucose (FDG)-avid nodal lymphomas, while CT alone is preferred for FDG-nonavid and variably FDG-avid histologies [1,16].

For these purposes, essentially all nodal lymphoma histologies are considered FDG-avid except the following:

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

●Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia

●Mycosis fungoides

●Marginal zone lymphoma

Although PET/CT is generally not useful for staging these more indolent histologies, it may be helpful in some circumstances (eg, to identify a preferred biopsy site if aggressive transformation is suspected) [17].

A dedicated contrast-enhanced CT scan may be required in addition to the PET/CT to define the extent of disease in special situations, such as in the setting of lymphadenopathy close to bowel or if there is compression or thrombosis of blood vessels. Additional tests may be helpful in the evaluation of specific disease sites. (See 'CT scanning' below and 'Evaluation of specific sites' below.)

PET scanning — PET scanning using 18F-fluorodeoxyglucose (¹⁸F-FDG) can be performed as an independent study or can be fused with a near-simultaneous CT scan into a single image (ie, integrated PET/CT imaging). Integrated PET/CT is preferred, when available, because it allows for more exact anatomic localization of abnormal isotope (ie, ¹⁸F-FDG) uptake. In addition, for typically FDG-avid tumors, integrated PET/CT scanning results in more accurate staging than CT alone, PET alone, or PET read alongside with CT [18-22].

Deauville score — A positive PET scan is determined by the Deauville score (also known as the 5-point scale), which is a visual method of standardizing the interpretation of post-treatment PET scans for primary nodal lymphoma and enables harmonization of scans using different machines at different centers [23,24].

The Deauville score uses a patient's FDG uptake in the mediastinal blood pool and liver as internal controls. FDG uptake is always present in these two sites, with higher levels consistently seen in the liver. The Deauville score interprets the most intense FDG uptake in a site of disease as follows [1,16,24] (table 4):

●1 – No uptake

●2 – Uptake ≤ mediastinal blood pool

●3 – Uptake > mediastinal blood pool but ≤ liver

●4 – Uptake moderately more than liver uptake, at any site

●5 – Uptake markedly higher than liver (ie, two to three times the maximum standardized uptake value [SUV] in the liver) and/or new lesions

●X – New areas of uptake unlikely to be related to lymphoma

The PET scan identifies the location of lymphoma-related uptake and distinguishes it from physiologic uptake and/or other causes of increased FDG uptake (eg, infection, inflammation) according to distribution and/or CT characteristics. PET appears to be highly sensitive and specific for detecting NHL in nodal and extranodal sites [25,26], although its reliability for detection of bone marrow involvement is variable [27,28].

Using this method, a Deauville score of 1 or 2 is consistent with a complete metabolic response [1]. Interpretation of a Deauville score of 3 depends on the clinical context. For most patients undergoing a post-treatment PET/CT after standard therapy, a score of 3 probably represents a complete metabolic response. In contrast, a score of 3 might be suboptimal in a patient being evaluated mid-treatment. Scores of 4 or 5 represent residual metabolic disease.

The FDG uptake in some normal anatomic locations (eg, Waldeyer's ring, certain extranodal sites) is greater than the mediastinal blood pool and/or liver. In addition, FDG uptake may be abnormally increased in the spleen or marrow following stimulation with chemotherapy or growth factors (eg, G-CSF). In such situations, a complete molecular response may be inferred if uptake at sites of initial involvement is less than surrounding normal tissue [1].

Different Deauville score cutoffs may be used in clinical trials that incorporate PET scanning into treatment planning. As an example, studies designed to evaluate dose escalation in patients without a complete remission at a prespecified time point may choose a higher cutoff (eg, Deauville score 3) above which escalation would occur. In contrast, studies designed to evaluate treatment deescalation may choose a lower cutoff (eg, Deauville score 2).

The ∆SUVmax is an alternative semi-quantitative method of evaluating PET response in lymphoma. However, calculation of ∆SUVmax requires baseline images with an institution specific dose calibrator. While the Deauville score provides the clinician with a prognostic measure that is more easily interpreted than the ∆SUVmax, an international retrospective study suggested that the latter had superior interobserver reproducibility and performance [29].

Initial PET evaluation — Initial PET/CT serves to determine the stage of disease at diagnosis and to provide a baseline study to determine response to treatment.

Integrated PET/CT is preferred for staging of FDG-avid nodal lymphomas. In general, PET scanning is useful for staging the clinically aggressive and highly aggressive NHL variants (eg, diffuse large B cell lymphoma [DLBCL], Burkitt lymphoma/leukemia), some clinically indolent variants (eg, follicular lymphoma), and most Hodgkin lymphoma subtypes. Its usefulness in the other indolent lymphomas remains unclear [1,16,17,30-35]. The most common FDG-nonavid histologies are presented above. (See 'Choice of imaging modality' above.)

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

●In a single center study of patients with NHL or Hodgkin lymphoma diagnosed between 2001 and 2008, at least one FDG-avid site was detected on PET scan in 718 of 766 patients (94 percent) [36]. The frequency of FDG-avidity varied by histologic subtype:

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

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

●In another study, PET scanning detected disease in at least one location in 98 to 100 percent of patients with pathologically proven DLBCL, mantle cell lymphoma, Hodgkin lymphoma, and follicular lymphoma, but was less often able to detect disease in patients with marginal zone and peripheral T cell lymphoma [28].

●In a third study, using CT and/or magnetic resonance imaging (MRI) to confirm sites of involvement, PET identified >97 percent of disease sites identified by CT or MRI in Hodgkin lymphoma and aggressive or highly aggressive NHL [34]. PET was less sensitive for the detection of lesions in the indolent NHL variants, with sensitivities of 91, 82, and 50 percent for follicular lymphoma, extranodal marginal zone lymphoma of MALT tissue, and SLL/splenic marginal zone lymphoma, respectively.

Data are limited regarding the ability of PET/CT to detect bone marrow (BM) involvement for most NHL histologic subtypes [1,16]. In DLBCL, PET/CT is highly specific and more sensitive than BM biopsy for the detection of BM involvement at the time of diagnosis, but may miss diffuse, low-volume (10 to 20 percent of marrow) BM involvement. 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 the detection of BM involvement [2]. Approximately 3 percent of patients with involvement on BM biopsy had a negative PET scan, while 13 percent with involvement on PET scan had a negative BM biopsy. Thus, for patients with DLBCL, normal BM on PET scan cannot rule out the presence of BM involvement, but FDG uptake in the BM on PET scan is highly specific for lymphomatous BM involvement. (See 'Bone marrow examination' above.)

Evaluating response to treatment — Integrated PET/CT scanning improves the accuracy of determining treatment response in patients with typically FDG-avid lymphomas and has been incorporated into the Lugano criteria (table 5) [1,16]. Its effect on the prognostic value of the International Prognostic Index (table 6) is unknown [37], and there is no evidence that the results of routine scanning outside of clinical trials can be successfully used to alter treatment with an improvement in outcome [38-40]. Response criteria are discussed in more detail separately. (See 'Response assessment' below.)

For FDG-avid histologies, PET scanning should be performed at least three weeks and preferably at six to eight weeks after chemotherapy or chemoimmunotherapy and 8 to 12 weeks after radiation or chemoradiotherapy. PET scans are interpreted using the 5-point Deauville score. (See 'Deauville score' above.)

For FDG-nonavid or variable avidity histologies, a mass on CT that has decreased in size but persists is considered at best a partial response in the absence of biopsy documenting absence of lymphoma. The term "complete response, unconfirmed" is no longer used.

Numerous studies have documented that PET scanning detects actively metabolizing tumor in residual masses following or during chemotherapy, and that persistent abnormal uptake predicts for early relapse and/or reduced survival [41-48]. Examples of this observation are presented below.

●In one study, 90 patients with newly diagnosed aggressive NHL were prospectively explored with PET prior to, after two cycles, and following completion of chemotherapy [49]. Patients achieving PET-negative status after two cycles of chemotherapy, in comparison to those who were PET-positive at this same time period, had a significantly higher rate of complete remission (83 versus 58 percent) and greater estimated two-year overall survival (90 versus 61 percent). Results from other studies have been mixed with some concluding that a positive early interim PET scan is a strong and independent predictor of disease progression [50-52] and others not finding such a correlation [53].

●Although an interim PET scan may have prognostic value, there are concerns about the reproducibility of PET scan interpretation and at this time, no prospectively validated criteria for interim PET scan interpretation. A review of positive interim PET scans from the Eastern Cooperative Oncology Group (ECOG) trial E3404 showed only moderate reproducibility between three expert nuclear medicine physicians [54].

●Following completion of treatment, some patients with NHL may have residual masses on CT scanning containing only fibrotic tissue or non-viable tumor. Such patients may be erroneously considered as not having achieved complete remission. Functional imaging of these sites using PET scanning or combined PET/CT scanning appears to be able to resolve these issues in most cases [55,56]. However, PET-positive disease at the completion of treatment requires a tissue biopsy or further evaluation, as some of these patients remain in prolonged remission.

●In several studies, PET was used to assess the degree of response of aggressive lymphoma to salvage chemotherapy in patients prior to hematopoietic cell transplantation [57-60]. As an example, one of these studies with a median follow-up of four years reported that complete remission was maintained in 83 versus 13 percent of patients with a negative or positive pretransplantation PET study, respectively [57].

CT scanning — As described above, integrated PET/CT is preferred for staging FDG-avid nodal lymphomas, while contrast-enhanced CT alone is preferred for FDG-nonavid and variably FDG-avid histologies [1,16]. A dedicated contrast-enhanced CT scan may be required in additional to the PET/CT to define the extent of disease in special situations, such as in the setting of lymphadenopathy close to bowel or if there is compression or thrombosis of blood vessels. (See 'Choice of imaging modality' above.)

When CT scanning is used for staging purposes, 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 representative of the patient's overall disease burden and include mediastinal and retroperitoneal disease [1]. Involved nodes should have a longest diameter greater than 1.5 cm, and involved extranodal disease should have a longest diameter greater than 1 cm. These six lesions are followed as measureable disease on subsequent imaging. All other lesions are followed as nonmeasured disease (eg, cutaneous lesions, pleural or pericardial effusions, ascites, other nodal disease). (See 'Response assessment' below.)

Typical radiographic findings of lung involvement in NHL include alveolar opacities (consolidation, masses, or nodules) and peribronchial disease. Other thoracic findings include chest wall, pleural, and pericardial involvement. In contrast to patients with Hodgkin lymphoma, parenchymal lung lesions can be seen with no evidence of mediastinal or hilar lymphadenopathy. A study of 181 patients with NHL comparing staging via routine chest radiographs versus chest CT scanning found that the stage was affected in 8.8 percent of patients; however, this did not alter initial therapy [61,62].

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

Gastrointestinal tract — Evaluation of the GI tract with contrast studies or endoscopy is indicated for patients with symptoms that suggest GI involvement (table 7). 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 "Initial treatment of mantle cell lymphoma", section on 'Pretreatment evaluation'.)

Liver and spleen — The initial physical examination should include the measurement of liver and spleen size in centimeters below the costal margin in the midclavicular line. Normal liver and spleen size do not rule out involvement and hepatic or splenic enlargement in a patient with NHL is not always due to lymphoma.

For staging purposes in fluorodeoxyglucose (FDG)-avid histologies, liver involvement is determined by positron emission tomography with computed tomography (PET/CT) demonstrating diffusely increased or focal FDG uptake, with or without focal or disseminated nodules [1,16]. Clinical hepatic enlargement alone with or without abnormalities of liver function tests is not adequate. A percutaneous liver biopsy may be indicated if there are abnormalities on hepatic blood tests or liver scan in patients with FDG-nonavid histologies who would otherwise have been classified as having stage I disease.

Similarly, splenic involvement in FDG-avid histologies is determined by PET/CT demonstrating 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 [63,64].

Central nervous system — Central nervous system (CNS) evaluation via MRI (with and without gadolinium) and/or lumbar puncture is indicated in patients with neurologic symptoms or signs (image 5). This combination of studies evaluates for both parenchymal and leptomeningeal involvement.

CNS involvement may be missed on PET/CT imaging due to the increased physiologic FDG uptake in the normal brain [1,16]. CNS screening studies in patients without CNS symptoms or signs are generally reserved for those patients who are at high risk of CNS involvement. These include patients with bone marrow, testicular, or paranasal sinus involvement, or those with underlying immunodeficiency. (See "Lumbar puncture: Technique, indications, contraindications, and complications in adults" and "Clinical presentation and diagnosis of secondary central nervous system lymphoma", section on 'Neuroimaging'.)

Skeletal imaging — Imaging of the bones with plain films, CT, and/or MRI is not routinely performed in NHL, but is indicated in the presence of bony pain and/or suspicion of a pathologic fracture. Bone lesions in NHL are mostly osteolytic on plain films, in contrast to those in patients with Hodgkin lymphoma, which are predominantly osteoblastic (table 8). If there is suspicion of 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 genitourinary (GU) tract (eg, kidney, testis, ovary) is involved in approximately 10 percent of patients at initial diagnosis. While most lesions will be detected on CT scan, testicular ultrasound is indicated for patients with an abnormality on testicular examination. In addition, patients with testicular lymphoma should have an ultrasound examination of the apparently uninvolved testicle to evaluate for contralateral disease. (See "Initial treatment of limited stage diffuse large B cell lymphoma", section on 'Testicular'.)

The most common site of GU involvement is the kidney, usually 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 6). Isolated masses are less common.

The next most common sites of GU involvement are the testis or ovary, usually in patients with diffuse large B cell NHL. Testicular involvement is best evaluated by ultrasound (image 7) [65-67]. Other organs less commonly affected include the bladder or ureter with mural thickening, as well as the uterus, cervix, and prostate with mass lesions.

FUNCTIONAL TESTING — Patients with NHL should undergo functional testing of their heart and lungs prior to the administration of chemotherapy or radiation therapy that may affect these organs. In addition, all patients should be evaluated for their performance status before, during, and after treatment.

Cardiac function — Baseline evaluation of cardiac function (eg, cardiac ejection fraction) should be considered if the patient is likely to be treated with an anthracycline or 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, monitoring, and diagnosis of anthracycline-induced cardiotoxicity" and "Prevention and management of anthracycline cardiotoxicity".)

Pulmonary function — The role of pulmonary function studies (PFTs; eg, diffusing capacity for carbon monoxide) for pretreatment evaluation of NHL is evolving.

Some experts suggest PFTs for a patient who is to be treated with bleomycin. However, PFTs do not reliably to predict bleomycin lung toxicity. We obtain baseline PFTs if this allows for the quantification of any change in pulmonary function during or after treatment. (See "Treatment-related toxicity in men with testicular germ cell tumors", section on 'Pulmonary' and "Bleomycin-induced lung injury".)

Performance status — Performance status is a measure of a patient's functional capacity that can predict survival in patients with cancer and is used as an entry criterion and an adjustment factor for clinical trials of anticancer therapies. A number of metrics have been developed to quantify performance status; among them, the Karnofsky performance status (KPS) and the Eastern Cooperative Oncology Group (ECOG) performance status are the most commonly used (table 9A-B).

STAGING — The Lugano classification is the current staging system used for patients with NHL. The Lugano classification is based on the Ann Arbor staging system, which was originally developed for Hodgkin lymphoma in 1974 and modified in 1988 [68,69]. This staging system focuses on the number of tumor sites (nodal and extranodal) and their location (table 10).

●Stage I refers to NHL 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 refers to two or more involved lymph 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 refers to lymph node involvement on both sides of the diaphragm (stage III).

●Stage IV refers to the presence of diffuse or disseminated involvement of one or more extralymphatic organs (eg, liver, bone marrow, lung), with or without associated lymph node involvement.

The subscript "E" is used if limited extranodal extension is documented; more extensive extranodal disease is designated stage IV. Disease involving the spleen is considered nodal, rather than extranodal. The subscript "X" had been used in the Ann Arbor staging system to designate the presence of bulky disease. Instead of using the designation "X," the Lugano classification requires a recording of the largest tumor diameter. For treatment purposes, criteria for bulky disease vary by histology and no cutoff has been validated using modern treatment [1,16]. However, cutoffs of 6 cm and 6 to 10 cm have been used for follicular lymphoma and diffuse large B cell lymphoma, respectively.

Unlike Hodgkin lymphoma, systemic "B" symptoms (fever, sweats, weight loss) are no longer incorporated into the staging system for NHL. This is primarily because these systemic symptoms have not been independent prognostic factors in patients with NHL.

Since NHLs most frequently disseminate hematogenously, this staging system has proven to be much less useful than for Hodgkin lymphoma, which disseminates principally by contiguous lymphatic extension. As an example, only 10 percent of patients with follicular lymphoma have localized disease at diagnosis (ie, stage I), and the majority of patients with aggressive lymphomas have advanced stage disease (ie, stage III/IV) at presentation [70]. It is generally accepted that there is little therapeutic benefit in distinguishing between stages III and IV disease in NHL, since treatment options are nearly identical.

Thus, staging is undertaken in NHLs to identify the small numbers of patients with "early stage disease" who can be treated with local therapy or combined modality treatment, and to stratify within histologic subtypes in order to determine prognosis and assess the impact of treatment. (See "Prognosis of diffuse large B cell lymphoma", section on 'Stage-adjusted IPI'.)

RESPONSE ASSESSMENT — Conventional response criteria for NHL define response categories (eg, complete or partial response; stable, and progressive disease) that are based on history, physical examination, laboratory studies, computed tomography (CT) scan, bone marrow evaluation, and positron emission tomography (PET)/CT (table 5), which are incorporated into the Lugano Classification [1].

Some research studies utilize the International Working Group Response Evaluation Criteria in Lymphoma (RECIL) 2017 criteria, but this approach is not currently applied to clinical practice [71].

PET/CT scanning is the preferred imaging modality for response assessment in all nodal lymphoma histologies except those that are not fluorodeoxyglucose (FDG)-avid. (See 'Choice of imaging modality' above.)

The increasing use of biologic agents with immune mechanisms requires flexibility in interpreting disease response to account for seemingly paradoxical or atypical responses, sometimes referred to as "tumor flare." Both conventional and atypical responses are discussed in the following sections. (See 'Atypical responses ("tumor flare")' below.)

Lugano response criteria — Disease response to treatment is defined by the Lugano criteria (table 5) [1,16]. Response categories are:

●Complete response

●Partial response

●No response or stable disease

●Progressive disease

Response to treatment is evaluated by history, physical examination, laboratory studies, and imaging studies. The timing and extent of evaluation and the preferred imaging technique is determined by the underlying histology; further details can be found within the reviews of each specific histology. In general, integrated PET/CT is preferred for response assessment except for FDG-nonavid histologies. (See 'Choice of imaging modality' above.)

Assessment of response in the Lugano classification includes serial measurement of the largest bi-dimensional, perpendicular diameters of up to six target lesions.

RECIL 2017 response criteria — The International Working Group RECIL (Response Evaluation Criteria in Lymphomas) methodology utilizes clinical and imaging results to assess response to lymphoma treatment [71]. RECIL criteria were developed principally for use in certain adult and pediatric clinical trials, but are not currently utilized for clinical practice.

RECIL 2017 differs from the Lugano criteria based on the methodology of lymph node response measurement, adds a category of marginal response, and can accommodate atypical responses to certain lymphoma treatments. (See 'Atypical responses ("tumor flare")' below.)

Atypical responses ("tumor flare") — Treatment with biologic agents that have immune mechanisms of action (eg, lenalidomide, rituximab, brentuximab vedotin, ibrutinib, idelalisib, immune checkpoint inhibitors) may lead to atypical responses that must be distinguished from progressive disease [72]. In a minority of patients, a paradoxical "tumor flare" may be observed within the first weeks of treatment that actually represents a response to therapy. This self-limited response may be manifest as increased size of lymph nodes, lymphocytosis, bone pain, or an increase in serum paraproteins (eg, increased serum IgM and serum viscosity in Waldenstrom macroglobulinemia). In time, many of these responses will convert to partial or complete responses. Because lymphomas may respond more slowly to these agents than to conventional chemotherapy, caution is justified before judging a treatment as ineffective and discontinuing therapy.

PROGNOSIS — Multiple studies have demonstrated that prognosis of NHL is far more dependent on histopathology, being only secondarily influenced by clinical parameters including age, presence of extranodal disease, performance status, and stage (I/II versus III/IV). Since stage usually depends only upon the location and number of disease sites, it is not a true measure of tumor burden, which is clearly an important prognostic determinant in NHL, and may also affect the overall treatment program employed (eg, use of adjuvant radiotherapy to sites of bulky disease).

The determination of prognosis for each of the NHL variants is known to be related to the multiple differences in tumor cell biology (eg, cytogenetics, immunophenotype, growth fraction, cytokine production) found within each of the specific disease variants. It is therefore likely that prognostic indicators in the NHLs will take three semi-independent formats:

●A general prognostic score with value in all of the NHL variants, such as the International Prognostic Index (IPI) (table 6). (See "Prognosis of diffuse large B cell lymphoma", section on 'International Prognostic Index'.)

●A disease-specific prognostic score, with variables reflecting differences in tumor biology for each of the 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)'.)

●A treatment-specific prognostic score, with variables reflecting interactions among patient, tumor, and the therapeutic regimen employed [73]. An example is gene expression profiling, which separates patients with diffuse large B cell lymphoma into categories that are more or less likely to respond to treatment with CHOP-based therapy [74]. (See "Prognosis of diffuse large B cell lymphoma", section on 'Gene expression profiling'.)

Further discussion of prognosis can be found in the topics that discuss the specific histologies of NHL. 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

●The initial evaluation of the patient with suspected non-Hodgkin lymphoma (NHL) must establish the extent and sites of disease (localized or advanced; nodal or extranodal) (table 10) and the performance status of the patient (table 9A-B). The treatment approach and prognosis are strongly dependent on this information.

●The initial workup should include a complete history, including past and present illnesses (eg, hepatitis B, C, HIV risk factors) as well as the presence or absence of systemic "B" symptoms. The physical examination should include emphasis on all node-bearing areas, including Waldeyer's ring, the liver, and spleen. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma".)

●Initial laboratory tests and imaging studies should include, as a minimum (see 'Initial laboratory studies' above and 'Routine imaging studies' above):

•Complete blood count, white cell differential, platelet count

•Tests of renal and hepatic function, including lactate dehydrogenase

•Testing for HIV, hepatitis B, and hepatitis C (in selected patients)

•Electrolytes, uric acid

●Initial imaging both serves to help determine disease stage at diagnosis and to provide a baseline study for comparison to determine response to treatment. Integrated positron emission tomography/computed tomography (PET/CT) is preferred for staging fluorodeoxyglucose (FDG)-avid nodal lymphomas, while CT alone is preferred for FDG-nonavid and variably FDG-avid histologies. For these purposes, essentially all nodal lymphoma histologies are considered FDG-avid except chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, mycosis fungoides, and marginal zone lymphoma. (See 'Choice of imaging modality' above.)

●Specific evaluation of the gastrointestinal tract, liver, spleen, central nervous system, skeleton, or genitourinary tract is reserved for patients with symptoms or those at particularly high risk for involvement of these sites. (See 'Evaluation of specific sites' above.)

●A number of other studies and discussions with the patient need to be undertaken for the following issues:

•Baseline evaluation of cardiac function (eg, cardiac ejection fraction) should be considered if the patient is likely to be treated with an anthracycline or mediastinal irradiation. (See "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity" and "Prevention and management of anthracycline cardiotoxicity".)

•Baseline pulmonary function studies (eg, diffusing capacity for carbon monoxide) should be obtained if the patient is to be treated with bleomycin. (See "Treatment-related toxicity in men with testicular germ cell tumors", section on 'Pulmonary' and "Bleomycin-induced lung injury".)

•An overall discussion of fertility issues should be undertaken in patients of childbearing age prior to the initiation of treatment, including the possibility of sperm or fertilized ovum banking. (See "Overview of fertility and reproductive hormone preservation prior to gonadotoxic therapy or surgery".)

●NHL is staged using the Lugano classification for staging primary nodal lymphoma (table 10). (See 'Staging' above.)

●The timing and extent of disease response evaluation depends at least in part upon the underlying histology and is determined by the Lugano classification response criteria (table 5). (See 'Response assessment' above.)