Non-Hodgkin Lymphoma Workup

The workup in a patient with suspected non-Hodgkin lymphoma (NHL) should include the following:

• Complete blood cell (CBC) count
• Serum chemistry studies, including lactate dehydrogenase (LDH)
• Serum beta2-microglobulin level
• HIV serology
• Chest radiography
• Computed tomography (CT) scan of the neck, chest, abdomen, and pelvis
• Positron emission tomography (PET) scan
• Excisional lymph node biopsy
• Bone marrow aspirate and biopsy
• Hepatitis B testing in patients in whom rituximab therapy is planned because reactivation has been reported

Other studies may be indicated, depending on the clinical presentation.

In the early stage of disease, patients with NHL may have blood counts within the reference range. As the disease progresses, a CBC count with differential and platelet count in patients with NHL may show the following:

• Anemia secondary to bone marrow infiltration, autoimmune hemolysis (particularly associated with small lymphocytic lymphoma [SLL]/chronic lymphocytic leukemia [CLL]), bleeding, anemia of chronic disease
• Thrombocytopenia, leukopenia, or pancytopenia secondary to bone marrow infiltration or autoimmune cytopenias
• Lymphocytosis with circulating malignant cells (common in patients with low-grade lymphomas)
• Thrombocytosis (paraneoplastic syndrome associated with lymphomas or reactive secondary to blood loss)

Serum chemistry studies may show the following:

• Elevated lactate dehydrogenase (LDH): indicates poor prognosis; correlates with increased tumor burden
• Abnormal liver function test (LFT) results: secondary to hepatic involvement, hypermetabolic tumor growth, chronic inflammation
• Hypercalcemia: in patients with acute form of adult T-cell lymphoma-leukemia (ATLL)

An elevated beta2-microglobulin level may be seen. Elevated levels correlate with a poor prognosis.

Occasionally, NHL is associated with monoclonal gammopathy. A Coombs test may be positive result (especially in SLL/CLL). Hypogammaglobulinemia may be present.

HIV serology should be obtained, especially in patients with diffuse large cell immunoblastic or small noncleaved histologies. HTLV-1 serology should be obtained in patients with ATLL.

A chest radiograph yields positive information in approximately one fourth of patients with NHLs. It may identify hilar or mediastinal adenopathy, pleural or pericardial effusions, and parenchymal involvement. The chest radiograph may demonstrate a bulky mediastinal mass, which is associated with primary mediastinal large B-cell lymphoma or lymphoblastic lymphoma.

Obtain an upper GI series with small bowel follow-through in patients with head and neck involvement (eg, tonsil, base of tongue, nasopharynx, Waldeyer ring) and those with a GI primary lesion.

A CT scan of the neck, chest, abdomen, and pelvis is used to detect enlarged lymph nodes, hepatosplenomegaly, or filling defects in the liver and spleen. Currently, it is the most widely used test for initial staging, assessing treatment response, and conducting follow-up care.^[13]

A bone scan is ordered only in patients with bone pain, elevated alkaline phosphatase, or both. Bone lesions are particularly associated with the acute form of ATLL and diffuse large B-cell lymphomas.

Gallium scans are an option in selected cases of NHL. These scans can detect initial sites of disease, reflect therapy response, and detect early recurrences. This scan is positive in nearly all patients with aggressive and highly aggressive lymphomas and in approximately 50% of patients with indolent lymphomas at diagnosis.

Whole body F-18 2-deoxyglucose (FDG) positron emission tomography (PET) scan can be used for the initial evaluation of patients with NHL; however, this scan is more useful for posttreatment evaluation to differentiate early recurrences or residual disease from fibrosis or necrosis. This PET scan has a higher predictive value for relapse than classic CT scan imaging.^[14] A study by Zinzani et al determined that midtreatment scanning using PET allowed physicians to better make crucial decisions on further treatment.^[15]

A study by Terezakis found that incorporating FDG-PET into CT-based treatement planning in patients with lymphoma resulted in beneficial changes in management, volume definition, and normal tissue dosimetry for a significant amount of patients.^[16]

Obtain an ultrasound of opposite testis in male patients with a testicular primary lesion.

A multiple gated acquisition (MUGA) scan should be performed to measure the left ventricular ejection fraction (LVEF) of patients who are being considered for treatment with anthracyclines.

In general, anthracyclines should not be administered to those patients with LVEF of less than 50%.

Obtain an MRI of the brain and spinal cord of patients who are suspected of having primary CNS lymphoma, lymphomatous meningitis, paraspinal lymphoma, or vertebral body involvement by lymphoma. An MRI scan can also be performed to identify focal areas of marrow involvement in those patients suspected to have bone marrow involvement but in whom random bone marrow biopsy findings have been negative.

A well-processed hematoxylin and eosin (H&E)–stained section of an excised lymph node is the mainstay of pathologic diagnosis. Excisional lymph node biopsy is required because lymphoma diagnosis relies heavily on careful assessment of altered nodal architecture accompanying lymphomatous infiltrates. Fine-needle aspiration (FNA) is insufficient for establishing a diagnosis; needle-core biopsies have a limited role in establishing a diagnosis of NHL.

Bone marrow aspirate and biopsy

Perform this procedure for staging rather than diagnostic purposes. Bilateral bone marrow aspirate and biopsy should be performed because bone marrow involvement is usually patchy. In bone marrow sections, the neoplastic cells may infiltrate in a focal (ie, paratrabecular or nonparatrabecular, depending on the type of lymphoma), interstitial, or diffuse pattern.

Biopsy of extranodal sites

In approximately 30-35% of adult patients with NHL, the extranodal sites are the primary presenting sites. The most common site is the GI tract.

Processing extranodal biopsy material for lymphoma protocol studies is important whenever suspicion of a hematolymphoid neoplasm exists.

Lumbar puncture for cerebrospinal fluid (CSF) examination should be performed in patients with the following conditions:

• Diffuse aggressive NHL with bone marrow, epidural, testicular, paranasal sinus, or nasopharyngeal involvement, or two or more extranodal sites of disease
• High-grade lymphoblastic lymphoma
• High-grade small noncleaved cell lymphomas (eg, Burkitt and non-Burkitt types)
• HIV-related lymphoma
• Primary CNS lymphoma
• Neurologic signs and symptoms

NHLs are a heterogeneous group of lymphoproliferative malignancies, with varying morphologic features depending on the specific subtype. The abnormal lymphocytes in the lymph node, bone marrow, or extranodal sites can be small cleaved or noncleaved, intermediate, or large cell and can have a follicular or diffuse pattern. In contrast with reactive follicular hyperplasia, lymphomas usually alter the lymph node architecture, and the capsule is usually involved.

Immunophenotypic analysis of lymph node, bone marrow, peripheral blood (if positive for neoplastic cells), or a combination of these complements and confirms the results of routine tissue section and may be useful in resolving a diagnostic dilemma in patients with an atypical morphology.

This analysis provides information about lineage and clonality, which are complementary to the histology of a given case. Analysis is also useful for subclassifying certain lymphoma subtypes, which has therapeutic and prognostic importance.

Immunophenotypic analysis helps to distinguish reactive from neoplastic lymphoid infiltrates, lymphoid from nonlymphoid malignancies, and specific lymphoid neoplasms. Although bcl -2 expression distinguishes follicular lymphoma from reactive follicular hyperplasia, bcl -1 expression strongly favors a diagnosis of mantle cell lymphoma. CD30 expression is important for the recognition of anaplastic large cell lymphoma, and it can also be found in the majority of Hodgkin lymphomas.

These studies have contributed to the understanding of the biology and prognosis of lymphoma. Cytogenetic studies are critical to the discovery of oncogene abnormalities that now are known to be intimately involved in the pathogenesis of NHL.

Staging is important in selecting a treatment and determining prognosis. CT scans of the neck, chest, abdomen, and pelvis, as well as bilateral bone marrow aspirate and biopsy, are necessary to stage the lymphoma. Noncontiguous lymph node involvement, uncommon in Hodgkin disease, is more common among patients with NHL.

The Ann Arbor staging system is the most commonly used staging system for patients with NHL. This system divides NHL into 4 stages, as follows:

• Stage I NHL involves a single lymph node region (I) or localized involvement of a single extralymphatic organ or site (IE)
• Stage II NHL involves 2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extralymphatic organ in addition to criteria for stage II (IIE)
• Stage III involves lymph node regions on both sides of the diaphragm (III) that also may be accompanied by localized involvement of an extralymphatic organ or site (IIIE), spleen (IIIS), or both (IIISE)
• Stage IV represents disseminated or multifocal involvement of one or more extralymphatic sites with or without associated lymph node involvement or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement

In addition to the 4 stage designations, subscript letters designate involvement of extralymphatic organs, as follows:

• L - lung
• H - Liver
• P - Pleura
• B - Bone
• M - Bone marrow
• D - Skin
• E - Extranodal lymphoid malignancies in tissues that are separate from but near the major lymphatic aggregates

The stages can also be appended by A or B designations. Patients with A disease do not have systemic symptoms. The B designation is applied in patients with any of the following symptoms:

• Unexplained loss of more than 10% of body weight in the 6 months before diagnosis
• Unexplained fever with temperature above 38°C
• Drenching night sweats

Risk stratification scoring systems

In addition to staging, risk stratification is important in patients with NHL. Prospectively validated scoring systems that can be used to determine prognosis include the International Prognostic Index (IPI) for patients with diffuse large B-cell lymphoma and the Follicular Lymphoma International Prognostic Index, (FLIPI) for patients with follicular B-cell lymphomas. The greater the number of risk factors present, the higher the risk.

The IPI for NHL is as follows:

• Age older than 60 years
• ECOG grade greater than or equal to 2
• Elevated LDH value
• Two or more extranodal sties
• Ann Arbor stage III or IV

The FLIPI score is as follows:

• Number of nodal sites of 5 or more
• Elevated LDH value
• Age 60 years or older
• Ann Arbor stage III–IV
• Hemoglobin value less than 12 g/dL