Diffuse follicle center lymphomas (FCL) are diffusely growing, germinal center–derived lymphomas containing predominantly small cleaved B cells or a mix of small cleaved and large B cells. This is the diffuse counterpart of follicular (nodular) lymphomas and may infrequently arise de novo, being considered a variant of follicular lymphoma (FL) (1). However, in most cases, it represents the progression of FL toward a more aggressive form.

Diffuse poorly differentiated lymphocytic lymphoma (Rappaport) (2); Diffuse small cleaved follicle center cell lymphoma (Lukes and Collins) (3); Diffuse centrocytic or centroblastic–centrocytic lymphoma (Kiel) (4); Malignant lymphoma, diffuse, predominantly small cleaved cell (Working Formulation) (5); Follicular cell lymphoma, diffuse, predominantly small-cell (provisional subtype, Revised European-American Lymphoma Classification, or REAL) (6). Diffuse follicle center lymphoma, variant of follicular lymphoma (Tumors of Haematopoietic and Lymphoid Tissues) (WHO) (1).

The changes to the nomenclature and classification of diffuse lymphomas that occurred over the past decade preclude the use of older case series in the study of their epidemiology. Historical studies published before the introduction of immunohistochemistry and genetics may have included lymphoblastic lymphomas or mantle cell lymphomas under the broad category of diffuse lymphomas (7,8,9,10,11,12,13,14,15,16), leaving the epidemiology of diffuse FCL not clearly defined. In the United States, FCLs constitute the second most common non-Hodgkin lymphomas and may present as follicular (nodular), diffuse, or mixed nodular/diffuse (17,18,19). Follicular (nodular) lymphomas as previously noted (Chapter 64) almost never occur in children and rarely before the age of 20 years (19,20,21). Although frequent in Western countries, they are uncommon in Asia and underdeveloped countries (22).

In the course of their progression, about 30% of FLs change from a nodular to a diffuse pattern and, at autopsy, about 70% appear as diffuse lymphomas (23). Therefore, the diffuse lymphomas of cleaved cell type partly represent the progression of former follicular (nodular) lymphomas and partly lymphomas growing in a diffuse pattern from inception. Lymphosarcoma cell leukemia represents the disseminated phase of FCL, follicular or diffuse, and results from the involvement of the bone marrow and peripheral blood.

Diffuse FCL in the WHO classification is described as a variant of FL. It has a diffuse pattern and contains a majority of centrocytes and few centroblasts. In addition, some sign of follicle center origin, such as BCL-2 rearrangement or CD10 immunophenotype, remains (1).

Clinically, the progression of FL is referred to as transformation and requires a change in the architecture from nodular to diffuse and a change in cytology from small to large lymphoma cells (24). Follicular lymphoma grade 1 (WHO) and FL grade 2 (WHO) behave more like each other than like FL grade 3 (WHO) (1). Multiple biopsy specimens from the same patient indicate frequent histologic transitions between FL grades 1 and 2 and FL grade 2, but rarely between FL grade 1 and FL grade 3. Furthermore, a trend for earlier relapse is noted in patients with FL grade 3 versus patients with FL grade 1 or 2 (1). Most oncologists maintain that it is important to note in the pathologic diagnosis the presence of a diffuse growth pattern, indicating a significantly worse prognosis (24,25,26). The WHO classification recommends that diffuse areas should be pointed out according to the REAL classification criteria: predominantly follicular (75% follicular), follicular and diffuse (25% to 75% follicular), and predominantly diffuse (<25% follicular) (1,6). Evidently, the architectural pattern cannot be assessed on fine needle aspirations, which thus are not recommended (24).

The clinical presentation, as in other types of lymphoma, is nonspecific and may include anorexia, malaise, weight loss, fevers, and night sweats. In general, systemic symptoms are more frequent in diffuse than in nodular lymphomas (27). Localized extralymphatic involvement is also more common in diffuse than in nodular lymphomas (27). In one early study, the 5-year survival rate was 74% for patients with follicular (nodular) lymphoma and only 28% for those with diffuse lymphoma, both of cleaved cell type (28). Lymphomas with follicular and diffuse patterns may not behave significantly differently from those with an exclusively follicular pattern (29). Nevertheless, in the large-cell subtype, the presence of diffuse areas indicates a poor prognosis and requires more aggressive chemotherapy.

The noncleaved (centroblastic) cell type of both nodular and diffuse lymphomas has a significantly worse prognosis than does the small cleaved (centrocytic) cell type. The cell size has important prognostic implications. Thus, lymphomas of large-cell types, both nodular and diffuse, are characterized by a far more aggressive clinical course and a significantly worse prognosis than are the corresponding lymphomas of small-cell types. However, despite their highly malignant behavior, large-cell lymphomas initially disseminate less extensively than their small-cell counterparts (see Chapters 67 and 68).