eMedicine Specialties > Hematology > Stem Cells and Disorders

Lymphoma, Non-Hodgkin: Differential Diagnoses & Workup

Author: Sanjay Vinjamaram, MD, MPH, Fellow in Hematology/Oncology, Roswell Park Cancer Institute
Coauthor(s): Francisco J Hernandez-Ilizaliturri, MD, Assistant Professor, Departments of Medicine and Immunology, Roswell Park Cancer Institute, State University of New York at Buffalo; Dolores A Estrada, MD, Consulting Staff, Hematology-Oncology, Cancer Care Specialists of Central Illinois; Lakshmi Rajdev, MD, Site Director, Jacobi Medical Center; Assistant Professor, Department of Radiation Oncology, Albert Einstein College of Medicine; Joseph A Sparano, MD, Professor of Medicine, Albert Einstein College of Medicine/Cancer Center; Program Director, Director of Breast Medical Oncology, Department of Internal Medicine, Division of Oncology, Montefiore Medical Center
Contributor Information and Disclosures

Updated: Sep 2, 2009

Differential Diagnoses

Infectious Mononucleosis

Other Problems to Be Considered

The diagnosis of NHL relies on pathological confirmation following appropriate tissue biopsy.
A significant number of medical disorders can be manifested by either local or generalized lymph node enlargement.

The following are some of the conditions that can result in clinical manifestations similar to those observed in lymphoma patients:

• Solid tumor malignancies
  • Metastatic disease to lymph nodes secondary to carcinoma, melanoma, or sarcoma
• Other hematologic malignancies or lymphoproliferative disorders
  • Granulocytic sarcoma
  • Multicentric Castleman disease
• Benign lymph node infiltration or reactive follicular hyperplasia secondary to infection (eg, tuberculosis; other bacterial, fungal, and, rarely, viral infections), and collagen-vascular diseases

Workup

Laboratory Studies

• CBC count with differential and platelet count in patients with non-Hodgkin lymphoma (NHL) may show the following:
  • Counts within the reference range in the early stage of disease
  • 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)
• Chemistries may show the following:
  • Elevated lactate dehydrogenase (LDH) - Poor prognostic factor, correlation 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)
• Beta2-microglobulin may be elevated and correlates with a poor prognosis.
• Occasionally, NHL is associated with monoclonal gammopathy, positive Coombs test result (especially SLL/CLL), and hypogammaglobulinemia.
• 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.

Imaging Studies

• 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.⁴
• A chest radiograph yields positive information in approximately one fourth of patients with NHLs, including identification of hilar or mediastinal adenopathy, pleural or pericardial effusions, and parenchymal involvement.
• Bone scan is only ordered 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 (optional, selected cases) 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.⁵
• 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.
• Obtain an ultrasound of opposite testis in male patients with a testicular primary lesion.
• Multiple gated acquisition (MUGA) scan should be performed to evaluate 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 MRI of the brain and spinal cord of patients who are suspected to have primary CNS lymphoma, lymphomatous meningitis, paraspinal lymphoma, or vertebral body involvement by lymphoma. It 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.

Other Tests

• Immunophenotypic analysis of lymph node, bone marrow, peripheral blood (if positive for neoplastic cells), or a combination of these
  • This study compliments and confirms the results of routine tissue section and may be useful in resolving a diagnostic dilemma in patients with an atypical morphology.
  • 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.
  • This analysis provides information about lineage and clonality, which are complimentary to the histology of a given case.
  • Analysis is also useful for subclassifying certain lymphoma subtypes, which has therapeutic and prognostic importance.
• Cytogenetic studies
  • 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.

Procedures

• Biopsy of peripheral (or most accessible) lymphadenopathy
  • 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.
  • A well-processed hematoxylin and eosin (H&E)–stained section of an excised lymph node is the mainstay of pathologic diagnosis.
• 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, and 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, nasopharyngeal involvement, or patient with 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
  • Patients with neurologic signs and symptoms

Histologic Findings

NHLs are a heterogenous group of lymphoproliferative malignancies with varying morphologic features depending on the specific type of this disorder. 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.

Staging

Staging is important in selecting a treatment and also for 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.
• 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.
• Subscript letters designate involvement of extralymphatic organs, as follows: L, lung; H, liver; P, pleura; O, bone; M, bone marrow; and D, skin. The designation E is used when extranodal lymphoid malignancies arise in tissues that are separate from but near the major lymphatic aggregates.
• In this system, stages I-IV can 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 preceding 6 months before diagnosis, unexplained fever with temperature above 38°C, and drenching night sweats.

IPI and FLIPI score

In addition to staging, risk stratification is important in patients with NHL. Several scoring systems had been developed and validated prospectively in patients with diffuse large B-cell lymphoma (International Prognostic Index, IPI) or follicular B-cell lymphomas (Follicular Lymphoma International Prognostic Index, FLIPI) that can be used to predict the prognosis of patients with B-cell malignancies (see Prognosis).

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