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Follicular Lymphoma Revisited

Departments of Medicine (Oncology) and Radiation Oncology, Stanford University School of Medicine, Stanford, CA

The last quarter century has seen significant advances in the management and understanding of many human malignancies. This is especially true for the malignant lymphomas. The invitation to reflect on a report from Stanford, published 25 years ago, and the changes that have occurred since then, is a rare opportunity to look at what we have learned about the follicular non-Hodgkin's lymphomas, generally, and their histologic and clinical transformation, specifically.

It is useful to divide the Editorial into three parts: diagnostic advances, management advances, and transformation, of both the follicular lymphomas, but, also of the physicians who care for them.

DIAGNOSTIC ADVANCES

Nomenclature and classification changes that have occurred during the last 25 years may or may not be considered an advance. The Rappaport classification, which used the terms "nodular, lymphocytic, and histiocytic," and degrees of "differentiation," have been replaced by terminology now considered more immunologically and biologically correct.

Clearly, immunologic surface markers, such as CD10 and CD5, and cytogenetics such as t(14;18) assist in the differential diagnosis of low-grade lymphocytic disorders. Light chain restriction and gene rearrangement studies recognize clonality and provide insight into the transformation process.

Pathologists have attempted to provide criteria for separating various grades of follicular lymphomas and for distinguishing follicular from diffuse categories, though these remain imperfect. However, for purposes of identifying the transformation events of follicular lymphomas, the predominance of large cells and diffuse patterns is usually accurate, but can be subjective, and vary among pathologists and major centers and, therefore, in reported studies.

MANAGEMENT ADVANCES

There have been dramatic changes and many advances in managing patients with non-Hodgkin's lymphomas, including those with follicular subtypes and those who have transformed, clinically and histologically. Diagnostic methods and procedures, which currently include bone marrow biopsy, bone marrow and peripheral-blood cell flow studies, computed tomography, and positron emission tomography scanning, are widely utilized. Past methods, not often used today, but which were enlightening in understanding and managing the disease, included lower extremity lymphangiography and diagnostic exploratory laparotomy with splenectomy.

Staging systems, primarily the Ann Arbor system, have evolved, which gave important prognostic information valuable for most of the malignant lymphomas, though least of all for follicular non-Hodgkin's lymphomas. More useful systems now include the FLIPI system, among others.

Significant changes and advances in therapy, primarily with chemotherapy, have occurred in this quarter century. Improved radiotherapy equipment and approaches have also been introduced and remain important in the management of these patients. Low-dose irradiation, with as little 2 Gy for two consecutive daily doses, is especially useful for palliation. Transplantation, usually with autologous stem cells from the bone marrow or peripheral blood has been widely used, but its indications remain to be defined.

The development of monoclonal antibodies, especially the anti–CD-20 hybridized product rituximab, has been a most important advance in the management of the B-cell lymphomas, including the transformed follicular lymphomas. Combining radiation with monoclonal antibodies—radioimmunotherapy—can be especially successful for patients with follicular lymphoma who have transformed to higher grade disease.

The widespread use of clinical trials, by major centers and cooperative groups, if properly controlled and randomized, is a major advance in developing and understanding the management advances of the past 25 years.

TRANSFORMATION OF FOLLICULAR NON-HODGKIN'S LYMPHOMA

The clinical and histological transformation of a low-grade follicular lymphoma is the most significant event that can occur in a patient with this disease. The true frequency of this event is difficult to determine and varies between approximately 15% and 60% among series in the literature. The spread of the reported frequency depends on the denominator chosen. If all patients in a database are used, the transformation rate will be low. If the denominator only includes patients who have had a second biopsy, the rate will be higher; if second biopsies are performed only for patients who are suspected of transformation by their clinical, laboratory, and imaging abnormalities, the rate will be much higher. The highest rates will be seen in autopsy series of those patients who died of their lymphoma. In a large, but old series (N = 1,269), the author reported that of the 162 patients who had follicular lymphoma during life, only two had follicular disease at autopsy.

It may well be that patients do not often die directly of follicular lymphoma, but of the transformation that may occur or of treatment effects, primarily bone marrow failure and infection.

Several unique clinical situations resulting from transformed follicular lymphoma may occur, and clinicians must remain alert to recognize them. A patient may be treated for diffuse large-cell lymphoma, having transformed from a follicular subtype in an apparent remission of some duration, and have a recurrence of the low-grade follicular disease, which is rarely, if ever, cured by the treatment of the diffuse lymphoma. Biopsy of the recurrence should be done, when the clinical situation suggests itself and treated appropriately. Some patients will present initially with both a follicular low-grade lymphoma and a transformed site, so that the true stage and extent of each disease type may be difficult to ascertain. The treatment for the diffuse large-cell disease may result in its cure, but the follicular disease is likely to recur sometime in the future. Occasionally, a patient with diffuse large-cell lymphoma will have a long duration of complete remission after chemotherapy and recurrence 10 or more years later, usually in a different site. One can postulate that there is an underlying follicular lymphoma, which has transformed a second time, and should again respond to the initial chemotherapy if tolerated.

Perhaps the dramatic and significant transformation when discussing patients with follicular lymphoma has been the experience, approach, and management of these patients by the current generation of oncologists. It remains to be established whether patients with follicular non-Hodgkin's lymphoma can be cured of their disease, or even if their overall survival has increased by any specific therapy. Despite their advanced age at diagnosis, survival can be long, with medians improving to 15 years or more during the last 10 to 15 years.

Yet, the current generation of oncologists rarely observe these patients without treatment, many receiving the cyclophosphamide, doxorubicin, oncovin, prednisone regimen, and virtually all receive rituximab.

A recent review of the Stanford experience presented at the 2007 American Society of Hematology meeting by Daryl Tan, MD, and Sandra Horning, MD, makes several important observations and provocative conclusions. Overall survival has improved to a median of 18 years, before the current use of rituximab in primary therapy. The "watchful waiting" (or no initial therapy) group, fully half of all patients initially seen, though selected, has the best overall survival, and the treatment-naïve patients have the longest survival following transformation.

In this author's opinion, the experience and skill of the physician in recognizing which patients should be treated when and how is the major factor in the quality and length of survival of patients with follicular lymphoma. Many patients can be managed with little or no therapy for prolonged periods. The presence of lymphadenopathy is often asymptomatic, waxes and wanes, and does not have to be treated aggressively. It is essential to remain alert to transformation of the disease, which must be treated with all available tools. Anthracyclines are important when transformation occurs, and probably rituximab as well. Certainly, the patient must have adequate performance status and bone marrow reserve to accept successful treatment for the more aggressive and life-threatening transformed lymphoma.

In conclusion, reflecting on our report of transformation of follicular lymphoma, of 25 years ago, and the 50 years’ experience of the author, this event remains a most important one in the course and life of a patient with follicular lymphoma, but so is the attitude, skill, and judgment of the physician managing these special patients.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

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This Article Full Text (PDF) From JCO 1983 Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Rosenberg, S. A. Search for Related Content PubMed Articles by Rosenberg, S. A. Related Articles Related Article