Chapter 105. Malignancies of Lymphoid Cells (Part 17) Evaluation of an adequate biopsy by an expert hematopathologist is sufficient to make a diagnosis of follicular lymphoma. The tumor is composed of small cleaved and large cells in varying proportions organized in a follicular pattern of growth (Fig. 105-7). Confirmation of B cell immunophenotype and the existence of the t(14;18) and abnormal expression of BCL-2 protein are confirmatory. The major differential diagnosis is between lymphoma and reactive follicular hyperplasia. The coexistence of diffuse large B cell lymphoma must be considered. Patients with follicular lymphoma are often subclassified into those with predominantly small cells, those with a mixture of small and large cells, and those with predominantly large cells. While this distinction cannot be made simply or very accurately, these subdivisions do have prognostic significance. Patients with follicular lymphoma with predominantly large cells have a higher proliferative fraction, progress more rapidly, and have a shorter overall survival with simple chemotherapy regimens. Figure 105-7 Follicular lymphoma. The normal nodal architecture is effaced b y nodular expansions of tumor cells. Nodules vary in size and contain predominantly small lymphocytes with cleaved nuclei along with variable numbers of larger cells with vesicular chromatin and prominent nucleoli. The most common presentation for follicular lymphoma is with new, painless lymphadenopathy. Multiple sites of lymphoid involvement are typical, and unusual sites such as epitrochlear nodes are sometimes seen. However, essentially any organ can be involved, and extranodal presentations do occur. Most patients do not have fevers, sweats, or weight loss, and an IPI score of 0 or 1 is found in ~50% of patients. Fewer than 10% of patients have a high (i.e., 4 or 5) IPI score. The staging evaluation for patients with follicular lymphoma should include the studies included in Table 105-11. Follicular Lymphoma: Treatment Follicular lymphoma is one of the malignancies most responsive to chemotherapy and radiotherapy. In addition, tumors in as many as 25% of the patients undergo spontaneous regression—usually transient—without therapy. In an asymptomatic patient, no initial treatment and watchful waiting can be an appropriate management strategy and is particularly likely to be adopted for older patients with advanced stage disease. For patients who do require treatment, single-agent chlorambucil or cyclophosphamide or combination chemotherapy with CVP or CHOP are most frequently used. With adequate treatment, 50–75% of patients will achieve a complete remission. While most patients relapse (median response duration is ~2 years), at least 20% of complete responders will remain in remission for >10 years. For the rare patient (15%) with localized follicular lymphoma, involved field radiotherapy produces long-term disease-free survival in the majority. A number of therapies have been shown to be active in the treatment of patients with follicular lymphoma. These include cytotoxic agents such as fludarabine, and biologic agents such as interferon α, monoclonal antibodies with or without radionuclides, and lymphoma vaccines. In patients treated with a doxorubicin-containing combination chemotherapy regimen, interferon α given to patients in complete remission seems to prolong survival. The monoclonal antibody rituximab can cause objective responses in 35–50% of patients with relapsed follicular lymphoma, and radiolabeled antibodies appear to have response rates well in excess of 50%. The addition of rituximab to CHOP and other effective combination chemotherapy programs is beginning to show prolonged overall survival and a decreased risk of histologic progression. Trials with tumor vaccines have been encouraging. Both autologous and allogeneic hematopoietic stem cell transplantation yield high complete response rates in patients with relapsed follicular lymphoma, and long-term remissions can occur. Patients with follicular lymphoma with a predominance of large cells have a shorter survival when treated with single-agent chemotherapy but seem to benefit from receiving an anthracycline-containing combination chemotherapy regimen plus rituximab. When their disease is treated aggressively, the overall survival for such patients is no lower than for patients with other follicular lymphomas, and the failure-free survival is superior. . Chapter 105. Malignancies of Lymphoid Cells (Part 17) Evaluation of an adequate biopsy by an expert hematopathologist is sufficient to make a diagnosis of follicular lymphoma composed of small cleaved and large cells in varying proportions organized in a follicular pattern of growth (Fig. 105- 7). Confirmation of B cell immunophenotype and the existence of the t(14;18). follicular lymphoma are often subclassified into those with predominantly small cells, those with a mixture of small and large cells, and those with predominantly large cells. While this distinction