Joseph A. Sparano, MD


October 23, 2001


A 42-year-old female presented with left supraclavicular lymphadenopathy and no clinical symptoms. Biopsy of the lymph node revealed follicular mixed non-Hodgkin's lymphoma with an increased large cell component (> 15/hpf). Immunophenotyping confirmed the diagnosis. Bone marrow is negative. A right breast mass was found on computed tomography (CT); biopsy revealed diffuse large-cell lymphoma. Axillary and periaortic lymphadenopathy was found, with a bulky right iliac node measuring 8 cm in diameter; the right iliac lymphadenopathy was causing right hydronephrosis.

Renal scan revealed a nonfunctioning right kidney. The spleen was enlarged to 22 cm with multiple hypodense lesions noted. Creatinine upon presentation was 2.0, but with hydration decreased to 1.3. Lactic dehydrogenase (LDH) was just above 500 (upper limit of normal, 500), and performance status was 1.

The patient was treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). After 2 cycles, all of the lesions decreased in size except for the right iliac nodes. After the 4th cycle, all of the lesions disappeared except for the right iliac node, which now measured 6 cm. The spleen remained mildly enlarged to 15 cm, but all splenic lesions disappeared. The patient was then given another 2 cycles of CHOP. After the 6th cycle, the right iliac node still persists; positron-emission tomography (PET) scan revealed no increased uptake except at the area of the right iliac node.

A review of the films by an interventional radiologist determined that the node was inaccessible by CT-guided biopsy but was accessible by surgery.

Three options were offered to the patient: (1) surgical biopsy, (2) local radiation therapy, and (3) 2 more cycles of CHOP with rituximab. The patient chose the 3rd option. After the 8th cycle of CHOP (with 2 doses of rituximab), the right iliac node persists, with increased uptake by PET scan limited to the right iliac lymph node.

What should be done at this point? Repeat biopsy? Local radiation? Stem-cell transplantation?

Response from Joseph A. Sparano, MD

This 42-year-old woman has either a follicular mixed or a large-cell lymphoma: some areas are consistent with diffuse large-cell lymphoma, but one area is consistent with persistent bulky adenopathy and mild-moderate splenomegaly (with resolved focal splenic lesions). Using the Revised European and American Lymphoma (REAL) classification, the diagnosis seems to be most consistent with follicle center lymphoma, follicular, grade 3. The age-adjusted International Prognostic Index (IPI) score is at least 2, which is associated with a 5-year survival of about 45% (although few patients in the IPI analysis had this specific histologic type).

The patient has had a response to CHOP x 8 cycles, the last 2 given with rituximab. Persistent radiographic abnormalities include a 6-cm right iliac node (that is accessible to biopsy only by surgery), with increased uptake seen on PET scan only in the right iliac node.

This difficult case raises several important questions outlined below. Although a number of phase 3 trials have been performed in order to address some of these questions, the majority of patients in such studies had diffuse large-cell lymphoma.

Response from Joseph A. Sparano, MD

An excisional biopsy of the entire node or lesion provides means to achieve an accurate histologic diagnosis; fine-needle aspiration or core biopsy may yield inaccurate results. Although an excisional biopsy of the supraclavicular node was performed, it is unclear what type of biopsy was performed of the breast, casting some doubt about whether this site consisted of pure diffuse large-cell lymphoma.

Response from Joseph A. Sparano, MD

Notwithstanding the biopsy issue cited above, discordant histology may be seen in up to 15% to 20% of patients, especially in those who have follicular lymphoma with mixed cell types.

Response from Joseph A. Sparano, MD

Compared with those who have pure diffuse large-cell lymphoma, a follicular component is associated with bcl-2 overexpression in about 85% of cases and carries a higher risk of relapse.

Response from Joseph A. Sparano, MD

Persisting lesions measuring more than 3 cm are more likely to harbor residual lymphoma.

Response from Joseph A. Sparano, MD

Activity seen on fluoro-2-deoxy-D-glucose (FDG) PET is suggestive of persistent disease, although false positives and false negatives may be seen. Anecdotally, I have seen false-positive cases in patients with HIV disease who had follicular hyperplasia without lymphoma.

Response from Joseph A. Sparano, MD

Two trials have evaluated the role of involved field irradiation plus chemotherapy. A Southwest Oncology Group (SWOG) trial demonstrated that CHOP x 3 plus radiation therapy (RT) was more effective than CHOP x 8 in patients with non-bulky stage 1 or 2 disease.[1] Similarly, an Eastern Cooperative Oncology Group (ECOG) trial demonstrated that CHOP x 6-8 cycles plus RT was more effective than CHOP alone in patients with bulky stage 2 (usually mediastinal) disease who achieved complete response to therapy.[2] However, all patients in the study who had a partial response received RT, making it difficult to evaluate its role in this setting.

Response from Joseph A. Sparano, MD

An interim analysis of a phase 3 trial performed by the Groupe d'Etude des Lymphomes de L'Adulte (GELA; trial LNH 98-5) recently indicated a significantly improved complete response (CR) rate (76% vs 60%), an event-free survival rate (69% vs 49%), and a 1-year survival rate (83% vs 68%) in 328 elderly patients (60-80 years of age) treated with rituximab plus CHOP compared with CHOP alone.[3] Other trials with a similar design are currently in progress, including a study being performed by ECOG (E4494); a similar trial performed by ECOG that included 630 patients has not yet demonstrated any benefit for rituximab in this setting. E4494 also evaluated the role of maintenance rituximab in responders, an approach that was not evaluated in the GELA study. Thus, it remains unclear whether rituximab plays any role in patients with high-risk IPI features (aside from advanced age).

Response from Joseph A. Sparano, MD

Several studies have found no benefit for high-dose therapy plus stem-cell transplantation compared with CHOP.[4,5,6] A subset analysis of 1 study, however, showed a benefit for high-dose therapy in patients with IPI high-risk features.[7] Another study demonstrated an advantage for high-dose sequential therapy, a treatment approach that was different from that employed in other trials evaluating high-dose therapy.[8] No randomized trials have specifically addressed the issue of high-dose therapy in partial responders or in patients with follicular histology.

Response from Joseph A. Sparano, MD

The options presented to this patient were certainly reasonable, and indicate the lack of evidence-based research supporting any particular choice. In this young patient in otherwise good condition, I would favor having the most information possible in formulating a management plan, specifically via biopsy of the iliac node and possibly splenectomy. Persistent follicular lymphoma would favor administration of rituximab, perhaps in conjunction with irradiation, whereas persistent large-cell lymphoma would favor administration of irradiation, rituximab plus irradiation, or perhaps high-dose therapy.


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