Stage Information for Adult Non-Hodgkin Lymphoma

Stage is important in selecting a treatment for patients with non-Hodgkin lymphoma (NHL). Chest and abdominal computed tomographic (CT) scans are usually part of the staging evaluation for all lymphoma patients. The staging system is similar to the staging system used for Hodgkin lymphoma. Noncontiguous lymph node involvement, uncommon in Hodgkin lymphoma, is more common among patients with NHL. Involvement of Waldeyer ring, epitrochlear nodes, and the gastrointestinal tract is also more common. Extranodal presentations are more common in NHL. A single extranodal site is occasionally the only site of involvement in patients with diffuse lymphoma. Bone marrow and hepatic involvement are especially common in patients with low-grade lymphomas. Cytologic examination of cerebrospinal fluid may be positive in patients with aggressive NHL. Involvement of hilar and mediastinal lymph nodes is less common than in Hodgkin lymphoma. Mediastinal adenopathy, however, is a prominent feature of lymphoblastic lymphoma and primary mediastinal B-cell lymphoma, entities primarily found in young adults.

The majority of patients with NHL present with advanced (stage III or stage IV) disease that can often be identified with limited staging procedures such as CT scanning and biopsies of the bone marrow and other accessible sites of involvement. Laparoscopic biopsy or laparotomy is not required for staging but may be necessary to establish a diagnosis or histologic type.[1] Positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose can be used for initial staging and for follow-up after therapy as a supplement to CT scanning.[2,3,4,5,6] Interim PET scans after two to four cycles of therapy have not provided reliable prognostic information yet because of problems of interobserver reproducibility in a large cooperative group trial (ECOG-E3404 [NCT00274924]) and lack of difference in outcome between PET-negative and PET-positive/biopsy-negative patients in a single-institution trial.[7,8]

Staging Subclassification System

Table 2. Anatomic Stage/Prognostic Groupsa

The Ann Arbor staging system is commonly used for patients with NHL.[9,10] In this system, stage I, stage II, stage III, and stage IV adult NHL can be subclassified into A and B categories: B for those with well-defined generalized symptoms and A for those without such symptoms. The B designation is given to 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 temperatures above 38° C.
• Drenching night sweats.

Occasionally, specialized staging systems are used. The physician should be aware of the system used in a specific report.

The E designation is used when extranodal lymphoid malignancies arise in tissues separate from, but near, the major lymphatic aggregates. Stage IV refers to disease that is diffusely spread throughout an extranodal site, such as the liver. If pathologic proof of involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed.

Sites are identified by the following notation:

Current practice assigns a clinical stage (CS) based on the findings of the clinical evaluation and a pathologic stage (PS) based on the findings made as a result of invasive procedures beyond the initial biopsy.

For example, on percutaneous biopsy, a patient with inguinal adenopathy and a positive lymphangiogram without systemic symptoms might be found to have involvement of the liver and bone marrow. The precise stage of such a patient would be CS IIA, PS IVA(H+)(M+).

A number of other factors that are not included in the above staging system are important for the staging and prognosis of patients with NHL. These factors include the following:

• Age.
• Performance status.
• Tumor size.
• Lactate dehydrogenase (LDH) values.
• The number of extranodal sites.

To identify subgroups of patients most likely to relapse, an international prognostic index was compiled for 2,031 patients with aggressive NHL.[11] After validation by several cancer centers, the major cooperative groups have used this index in the design of new clinical trials. The model is simple to apply, reproducible, and predicts outcome even after patients have achieved a complete remission. The model identifies five significant risk factors prognostic of overall survival (OS): age (<60 years vs. >60 years), serum LDH (normal vs. elevated), performance status (0 or 1 vs. 2–4), stage (stage I or stage II vs. stage III or stage IV), and extranodal site involvement (0 or 1 vs. 2–4). Patients with two or more risk factors have a less than 50% chance of relapse-free and OS at 5 years. This study also identifies patients at high risk of relapse based on specific sites of involvement, including bone marrow, central nervous system, liver, lung, and spleen. Patients at high risk of relapse may benefit from consolidation therapy or other approaches under clinical evaluation.[11] Molecular profiles of gene expression using DNA microarrays may help to stratify patients in the future for therapies directed at specific targets and to better predict survival after standard chemotherapy.[12,13]

References:

1. Mann GB, Conlon KC, LaQuaglia M, et al.: Emerging role of laparoscopy in the diagnosis of lymphoma. J Clin Oncol 16 (5): 1909-15, 1998.
2. Zijlstra JM, Hoekstra OS, Raijmakers PG, et al.: 18FDG positron emission tomography versus 67Ga scintigraphy as prognostic test during chemotherapy for non-Hodgkin's lymphoma. Br J Haematol 123 (3): 454-62, 2003.
3. Juweid ME, Cheson BD: Role of positron emission tomography in lymphoma. J Clin Oncol 23 (21): 4577-80, 2005.
4. Juweid ME, Stroobants S, Hoekstra OS, et al.: Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 25 (5): 571-8, 2007.
5. Cheson BD, Pfistner B, Juweid ME, et al.: Revised response criteria for malignant lymphoma. J Clin Oncol 25 (5): 579-86, 2007.
6. Terasawa T, Lau J, Bardet S, et al.: Fluorine-18-fluorodeoxyglucose positron emission tomography for interim response assessment of advanced-stage Hodgkin's lymphoma and diffuse large B-cell lymphoma: a systematic review. J Clin Oncol 27 (11): 1906-14, 2009.
7. Horning SJ, Juweid ME, Schöder H, et al.: Interim positron emission tomography scans in diffuse large B-cell lymphoma: an independent expert nuclear medicine evaluation of the Eastern Cooperative Oncology Group E3404 study. Blood 115 (4): 775-7; quiz 918, 2010.
8. Moskowitz CH, Schöder H, Teruya-Feldstein J, et al.: Risk-adapted dose-dense immunochemotherapy determined by interim FDG-PET in Advanced-stage diffuse large B-Cell lymphoma. J Clin Oncol 28 (11): 1896-903, 2010.
9. Lymphoid neoplasms. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 599-628.
10. National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project. Cancer 49 (10): 2112-35, 1982.
11. A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329 (14): 987-94, 1993.
12. Rosenwald A, Wright G, Chan WC, et al.: The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346 (25): 1937-47, 2002.
13. Abramson JS, Shipp MA: Advances in the biology and therapy of diffuse large B-cell lymphoma: moving toward a molecularly targeted approach. Blood 106 (4): 1164-74, 2005.