Follicular lymphoma in situ: clinical implications and comparisons with partial involvement by follicular lymphoma

Abstract

Follicular lymphoma in situ (FLIS) was first described nearly a decade ago, but its clinical significance remains uncertain. We reevaluated our original series and more recently diagnosed cases to develop criteria for the distinction of FLIS from partial involvement by follicular lymphoma (PFL). A total of 34 cases of FLIS were identified, most often as an incidental finding in a reactive lymph node. Six of 34 patients had prior or concurrent FL, and 5 of 34 had FLIS composite with another lymphoma. Of patients with negative staging at diagnosis and available follow-up (21 patients), only one (5%) developed FL (follow-up: median, 41 months; range, 10-118 months). Follow-up was not available in 2 cases. Fluorescence in situ hybridization for BCL2 gene rearrangement was positive in all 17 cases tested. PFL patients were more likely to develop FL, diagnosed in 9 of 17 (53%) who were untreated. Six patients with PFL were treated with local radiation therapy (4) or rituximab (2) and remained with no evidence of disease. FLIS can be reliably distinguished from PFL and has a very low rate of progression to clinically significant FL. FLIS may represent the tissue counterpart of circulating t(14;18)-positive B cells.

Figure 1

FLIS. (A-B) H&E-stained (A) and BCL2-stained (B) sections of LN showing replacement of a germinal center by centrocytes with uniformly intense positivity for BCL2. The surrounding mantle cuff is intact and shows relatively weak BCL2 positivity. Original magnification ×200. (C-D) FLIS in an LN stained for BCL2 (C) and CD10 (D). The single involved follicle is strongly positive for BCL2 and CD10. Mantle zone B cells and T cells show less intense BCL2 positivity. Normal germinal centers are BCL2⁻ and only dimly CD10⁺. Original magnification ×40. (E-G) Several examples of FLIS patterns. (E-F) LNs with overall intact architecture but with the minority (E) or majority (F) of follicle centers involved by FLIS. Original magnification ×20. The individual follicles exhibit various degrees of involvement by FLIS cells (G), and a similar pattern is seen in a case from a patient who had a prior history of follicular lymphoma (H; case 23 in Table 3). Original magnification ×40.

Figure 2

Partial LN involvement by FL. (A-B) In distinction from FLIS, the follicles are expanded in size (A), and clustered in 1 portion of the LN, as highlighted by CD20 immunohistochemistry (B). (C) CD10 staining shows that the margins of the atypical follicles are slightly blurred and not sharply defined. (D) The BCL2 stain is more variable in intensity than is typical for FLIS. Original magnification ×20.

Figure 3

BCL2⁻ FL with an in situ FLIS component. (A-B) The LN exhibits a proliferation of large follicles lacking polarization, highlighted by the CD20 stain (B). (C-D) A CD10 stain (C) demonstrates more intense staining of the FLIS component than the FL component, and the BCL2 stain (D) highlights the intensely staining FLIS component, whereas the FL is BCL2⁻. (E-F) A MIB-1 stain (E) identifies a low proliferation rate within the abnormal follicle, and a CD3 stain (F) reveals admixed T cells. Original magnification ×40. Case 29 in Table 3.

Figure 4

FISH of FLIS. (Top panels) Two FLIS follicles stained for BCL2. FISH was examined in follicular and interfollicular areas. Within the FLIS follicle, a cell shows a split red and green signal, indicating a BCL2 break (top right). (Bottom panels) Cells with split signals are seen only in involved follicle, to right of dotted line, and not in uninvolved areas, to left of dotted line. The involved follicle is shown at higher power (bottom right).