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Follicular Lymphomas RIGHT off the bat it should be said that lymphomas of follicular center cell origin may have follicular or diffuse growth patterns, or both. In cases of purely diffuse growth, the follicular origin may be inferred from a combination of soft signs: immunophenotype (CD10+), cytogenetic (t[14;18]), and morphologic (the presence of small cleaved B-cells).          It stands to reason that cases with a follicular growth pattern are more indolent: the neoplastic cells must be fairly well differentiated to retain their B-lymphoid ability to self-assemble into follicles. Conversely lymphomas of follicular center cell origin that grow predominantly diffusely have lost a key characteristic of follicle cells, which is a sign of dedifferentiation and a harbinger of more aggressive behavior. This section of the tutorial is devoted to cases with a follicular growth pattern, which are generally lower grade.          Follicular lymphomas (or more formally speaking, follicular center cell lymphomas with a follicular growth pattern) are one of the more common non-Hodgkin's lymphomas in North America. They afflict almost exclusively adults, particularly the middle-aged and elderly. Because the small-cleaved cells of follicular lymphomas know how to circulate in the blood, patients usually present with disseminated lymphadenopathy. Nonetheless these lymphomas have a better prognosis than higher grade lymphomas. Note the presence of both small-cleaved and large cells.         Follicular lymphomas are composed of malignant cells that resemble their equivalents in the normal lymphoid follicle. These cells include small-cleaved cells, large-cleaved cells, and large-non-cleaved cells, where "cleaved" refers to marked nuclear indentations or clefts. Generally these cells have little cytoplasm. The small cells tend to have dark, clumped chromatin and no or inconspicuous nucleoli. The larger cleaved or non-cleaved cells, sometimes called "centroblasts", have more open (clear) chromatin, typically with multiple prominent, bluish nucleoli that tend to cozy up to the nuclear membrane. In contrast, immunoblasts, which are less numerous in follicular lymphomas, have more abundant reddish-blue cytoplasm and prominent, central, reddish nucleoli.       The follicular pattern must be distinguished from other benign and malignant nodular processes, including: Benign reactive follicular hyperplasia Small lymphocytic lymphoma with prominent proliferation centers Mantle cell lymphoma with a nodular growth pattern Nodular lymphocyte predominant Hodgkin’s disease Follicular lymphoma, not benign hyperplasia        One of the more difficult morphologic distinctions in hematopathology can be between reactive follicular hyperplasias and follicular lymphomas. The important points include:

Low Power (Architectural) Benign Malignant Loosely packed follicles Polymorphic follicles Prominent mantle zones Polarized follicles Preserved open sinuses No capsular invasion or transgression Polyclonal light chain expression Non-reactive for BCL-2     Tightly packed follicles Monomorphic follicles Absent or obscured mantle zones Unpolarized follicles Destroyed and constricted sinuses Extension into perinodal soft tissue Monoclonal light chain expression Reactive for BCL-2 High Power (Cytological) Benign Malignant A very high mitotic rate Tingible-body macrophages Between follicles are the usual paracortical lymphoid cells   A lower mitotic rate No tingible-body macrophages Between follicles atypical cleaved cells may be found

Subtypes of Follicular Lymphoma Follicular lymphomas are divided into 3 types according to the ratio of small-cleaved and large cells: Small-cleaved cell type (images) has less than 20-25% large cells, or fewer than 5 large cells per high power field. This lymphoma is rich in small-cleaved cells, which know how to voyage in the blood and are often found there as well as in the marrow and liver. Patients nevertheless have a median survival of 7.5-9 years. As in other low grade lymphomas, however, chemotherapy cannot secure a protracted remission or cure. Mixed small-cleaved and large cell type (images) has between 20-25% and 50% large cells or between 5 and 15 large cells per high power field. Though these lymphomas are also low grade in the Working Formulation, the increased percentage of large cells is associated with a reduced average survival. Large cell type (images) has more than 50% large cells, or more than 15 large cells per high power field. Large cell lymphomas with a follicular growth pattern are uncommon, and the nodularity can be hard to perceive. These lymphomas are the only intermediate grade follicular lymphomas; the five-year survival is less than 50%. Compare the high power morphology of the 3 types.     As with many cancers, follicular lymphomas tend to become more aggressive with time. The percentage of small-cleaved cells may decrease, and the nodularity may grow fainter or vanish. As the proportion of large cells increases, so does the mitotic rate, the tendency to grow diffusely, and the aggressiveness of the lymphoma. In addition, the BCL-2 gene rearrangement is found less frequently. It seems a little mysterious that follicular lymphomas may develop a diffuse growth pattern, but that is part of their malignant potential. As malignant follicular center cells begin to dedifferentiate, they lose their ability to ape the appearance and behavior of their normal counterparts.        Treatment options depend on the stage and grade of the disease. The infrequent patients with early-stage disease may be treated with local radiation, with or without chemotherapy. Patients with more advanced but low-grade disease may remain untreated as long as no symptoms or lymphoma-related organ compromise are present. When treatment becomes necessary, the options include: 1) single-agent alkylator therapy; 2) low-intensity combined chemotherapy without an anthracycline; 3) whole-body irradiation. Large-cell follicular lymphoma is classified as an intermediate-grade lymphoma, and the patients may benefit from the inclusion of an anthracycline in their chemotherapy. Extranodal Involvement Follicular lymphomas frequently involve extra-nodal sites: Bone marrow (image) is involved about a third of the time, most frequently in the small-cleaved type. In all types the deposits tend to be paratrabecular and to be composed mainly of the smaller cells. Peripheral blood involvement is most common in the small-cleaved type. Substantial involvement is usually a late phenomenon. Spleen involvement is seen in about half the patients at laparotomy. The small-cleaved and mixed types infiltrate and transform all the normal splenic follicles, forming innumerable tiny deposits. The large cell type forms large, irregular tumor masses. Liver involvement is noted in about 50% of the cases. Usually the portal triads are affected. Immunology and Genetics Follicular lymphomas are reactive for pan-B-cell markers CD19, CD20, and CD22 in addition to expressing monoclonal light chains. Most cases also react for CD10, which is also seen in lymphoblastic lymphoma but not other low grade lymphomas. No staining for CD5 is seen.     Most cases of follicular lymphoma, especially those rich in small-cleaved cells, have a t(14;18) translocation. This results in a rearranged and constitutively over-expressed gene called BCL-2. The BCL-2 gene product is an inner mitochondrial membrane protein that blocks apoptosis (in plain English, programmed cell death). Although this protein is produced by an unrearranged BCL-2 gene in much benign lymphoid tissue and many lymphomas besides follicular ones, it is not detected in benign, reactive germinal center cells. Thus its presence, as detected by immunostaining, can differentiate malignant from benign follicles. Table of Contents | Next section | Previous section