Emerging issues after the recognition of in situ follicular lymphoma

This article reviews knowledge derived from the introduction of the concept of in situ follicular lymphoma (FL). The following questions are addressed: (1) How should in situ lymphomas be defined and diagnosed? (2) Is in situ lymphoma an early step of lymphomagenesis? (3) Is the concept of early neoplasia applicable to the lymphoma setting? (4) How should patients with in situ lymphoma be managed? The commonly used term of in situ FL, also called FL in situ (FLIS), has been adopted to define a B-cell lymphoid neoplasia with an intrafollicular growth pattern. The neoplastic B cells are localized within the germinal center, without invasion of surrounding structures. Pathological diagnosis requires recognizing strong immunostaining of BCL2 and CD10 by neoplastic B cells inside the affected follicles. Fluorescence in situ hybridization (FISH) analysis for t(14;18) is mandatory in doubtful cases in which immunohistochemistry data are ambiguous. In situ FL is probably the earliest stage of development of FL, while the concept of "early" lymphoma is applicable when minimal disease extends beyond the boundaries of the follicular compartment. From a clinical point of view, in situ FL has an uncertain clinical behavior and unknown risk to progression to overt lymphoma. How to approach and monitor patients with in situ FL is currently uncertain. An asymptomatic patient with stage 1 in situ FL requires the same treatment plan as an asymptomatic patient with stage 1 conventional FL. For patients with concomitant overt malignancy, therapy must be applied according to the malignant counterpart.