The diagnosis of lymphoma, with its associated subtype, is done with a triad of tests:

• The lymph node biopsy
• Immunophenotyping
• Molecular genetics

The most important diagnostic procedure in patients suspected of having lymphoma is the lymph node biopsy.

Many cancers can be diagnosed by inserting a small needle into the tumor mass and withdrawing cells for examination under a microscope. This is called a fine needle aspiration or FNA. For lymphoma diagnosis, however, the preferred technique is removal of the entire affected lymph node for examination by a pathologist.

The pathologist needs to know not only that lymphoma cells are present in the biopsy specimen, but also the architecture of the lymph node and the lymphoma cells within. This requires a pathologist who is experienced in diagnosing lymphomas. Knowing the subtype of lymphoma is crucial for determining long-term prognosis and treatment options.

In addition to examination by a pathologist, the lymph node biopsy will be stained using immunophenotyping for the presence of various cell surface antigens. These are termed cluster of differentiation markers, or CD markers. CD markers help to differentiate B-cell from T-cell lymphomas. The following lists the most common CD markers for lymphomas:

• B-cell (85-90% of lymphomas, including most HD cases): CD10, CD15 (HD only), CD19, CD20, CD22, CD30 (HD only), CD45, and CD38 (mature plasma cells only)
• T-cell (10-15% of lymphomas): CD3, CD4, CD5, CD8

Finally, genetic abnormalities help in determining the subtype of lymphoma and prognosis.

The following lists some of the more common chromosomal translocations identified to date. These may be tested for using a portion of the lymph node biopsy or a bone marrow biopsy (if the bone marrow is involved):

(2;5): 60-85% anaplastic large cell (T-cell) NHL
(8;14): 80% Burkittís lymphoma
(9;14): 50% lymphoplasmacytic lymphoma
(11;14): 70% mantle cell NHL
(11;18): 50% MALT lymphoma
(14;18): rearrangement of the bcl-2 gene ñ 80-90% of follicular NHL

Tests & Diagnosis

Once the diagnosis of lymphoma (with subtype) is confirmed, the patient undergoes a wide variety of tests to evaluate the extent of lymphoma, the prognosis for survival, and to establish baseline organ function prior to treatment.

The extent of lymphoma is determined by:

• Detailed medical history and physical exam
• CT scans (with contrast) of chest, abdomen, and pelvis
• Bilateral bone marrow biopsy
• Complete blood count
• Head CT or MRI, if CNS symptoms are present
• Lumbar puncture, if sinus, periorbital, CNS, or paravertebral involvement
• Endoscopy and Helicobacter pylori status, if gastric lymphoma

Note that the use of PET scans in diagnosis and monitoring lymphoma is increasing. PET stands for positron emission tomography, with the imaging provided by cellular uptake of fluorine-18-fluorodeoxyglucose. Viable cancer cells are able to take up this sugar, while dead or fibrotic cells will not.

This helps clinicians to assess the efficacy of treatment given. Unfortunately, other organs not involved with lymphoma may show up as positive. In addition, lesions smaller than 1 cm are not visualized well with PET scans. As such, PET scans alone are not used for assessing the extent of lymphoma. Integrated PET-CT scans are currently being investigated as a better alternative to CT scans alone.

Patient prognosis is determined by:

• Evaluation of performance status
• Serum LDH, uric acid, and calcium levels
• HIV status
• Beta-2-microglobulin level
• Calculation of the International Prognostic Index (IPI) if NHL. This includes patient age, LDH level, performance status, stage, and presence of extranodal involvement and is an independent predictor of survival.

Baselines are established for the following:

• ECHO or MUGA for cardiac function
• Complete blood count (almost all chemotherapy causes bone marrow suppression)
• Serum electrolytes
• Renal and liver function tests
• Hepatitis B and C status (these infections may reactivate during treatment)
• Pregnancy test in women of child-bearing age (chemotherapy is teratogenic)

Staging Lymphoma

Stage of lymphoma at the time of diagnosis is by far the most important predictor of long-term survival with many types of HD and NHL. Stage is established primarily with CT scans and bone marrow biopsy results. It is most important to distinguish stages I and II (considered to be localized lymphoma) from stages III and IV (which are considered to be disseminated advanced lymphoma).

As will be discussed under treatment, localized lymphoma may be able to be treated with radiation therapy alone. Disseminated disease and many types of high-risk localized disease require systemic treatment with chemotherapy. Interestingly, stages III and IV indolent NHL do not necessarily have a poorer prognosis, as most patients present with stage IV disease but live an average of 10 years from diagnosis.

Some rarer subtypes of lymphoma may utilize different staging systems or not have a specific staging system. This includes enteropathy-type T-cell lymphoma, cutaneous T-cell lymphomas, and splenic lymphomas.

Stages of Lymphoma

The staging system used for most types of both NHL and HD is the Ann Arbor Staging System. It has been in clinical use for more than four decades:

Stage I: One involved lymph node group or single extranodal site
Stage II: Two or more involved lymph node groups on the same side of the diaphragm
Stage III: Multiple lymph node groups involved on both sides of the diaphragm
Stage IV: Diffuse involvement of extra-nodal sites, such as the liver or bone marrow

An A or B is added to the stage number to indicate the presence or absence of the B symptoms as previously described. For example, a person with lymphoma on both sides of the diaphragm with recurrent night sweats and weight loss would be considered to have stage IIIB disease. An X is added to indicate a stage with bulky disease greater than 10 cm. Finally, an E is added to indicate extranodal extension or a single extranodal site of disease.