Follicular lymphoma

Follicular lymphoma is the most frequent type of lymphoma in the western countries and usually presents as a disseminated disease with Ann Arbor stage III and IV.1 The follicular lymphoma cells in a great majority of affected lymph nodes proliferate only in follicular fashion, supported by follicular dendritic cells, and preferentially colonize paratrabecular areas in the bone marrow, suggesting a prominent dependency on homing to certain microenvironments. The term follicular colonization was used originally by Isaacson et ale to designate centrocyte-like cells of mucosa-associated lymphoid tissue lymphoma populating benign follicles. We illustrate in this article that this term may also be appropriate for follicular lymphoma when it populates otherwise benign follicles within the cortex of the architecturally normal lymph node.

We describe 4 patients with follicular lymphoma and evidence of follicular colonization in otherwise benign lymph node. The first patient had been diagnosed previously with follicular lymphoma, grade 2, while the follicular colonization was found in mesocolic lymph nodes of the colon resected for adenocarcinoma. The second patient had a diagnosis of follicular lymphoma made on a bone marrow biopsy that showed typical paratrabecular infiltrates, which were positive for both CD10 and Bcl-6. This patient also had a single enlarged cervical lymph node that showed focal follicular colonization only. In addition, flow cytometric analysis of the lymph node showed a monoclonal CD10-positive/CD5-negative B-cell population. No other enlarged lymph nodes were found. The third patient had retroperitoneal and inguinal lymphadenopathy. The biopsy of the inguinal node showed follicular colonization only. However, within the deeper sections of the same lymph node classic follicular lymphoma, grade 2, was identified. The fourth patient had a follicular lymphoma, grade 1, diagnosed in the cervical lymph node and enlarged inguinal lymph node, which showed follicular colonization only (Figure 1, original magnifications x20 [left] and X100 [right]). Bone marrow was also involved.

All lymph nodes with follicular colonization had a small number of small follicles in their normal anatomical location; in addition, 2 of 4 had focal paracortical hyperplasia. Most germinal centers were variably populated by small cleaved cells, which were strongly positive for Bcl2 and CD10. Normal germinal center cells are positive for CD10 and negative for Bcl-2. That these are not T lymphocytes was confirmed by CD3 immunostaining, which showed only occasional T cells in the germinal centers (Figure 1, G and H). The populated follicles were not enlarged, and some of the smallest germinal centers showed denser populations of neoplastic cells than the larger follicles (Figure 1, D and F).

Pruneri et al3 recently described an "incipient follicular lymphoma," a follicular lymphoma which involved only 1 follicle in an otherwise benign, reactive lymph node. No other evidence of follicular lymphoma was found in their patient. Follicular colonization by follicular lymphoma and incipient follicular lymphoma are very similar; however, only 1 follicle was involved by incipient follicular lymphoma, and only 1 patient has been described to date. Hence, it is difficult to make comparisons with certainty. The only morphologic difference appears to be that almost all cells in the germinal center were neoplastic, and this single follicle was lacking a distinct mantle zone. Follicular colonization by follicular lymphoma in our cases showed a variable degree of germinal center involvement, which was apparent by Bcl-2 immunostaining (Figure 1, A-D). Also, distinct mantle zones were present in all our cases.

Both in the case of a previously described incipient follicular lymphoma and in our 4 cases, the neoplastic cells stained very intensely with Bcl-2 immunostaining, even stronger than mantle zones or T cells. It is possible that there are cases that do not show such a strong overexpression of Bcl-2, but such cases would probably be missed, because this was the most prominent aberrant feature of the involved follicles. In retrospect, the germinal centers with follicular colonization by follicular lymphoma have a more uniform population of centrocytes (Figure 1, B); however, the morphologic features are focal and subtle, and to look for them without using Bcl-2 immunostaining would be a difficult task in otherwise benign lymph nodes.

The importance of identifying follicular colonization in the absence of classic follicular lymphoma is that it may prompt further evaluation of the same lymph node, which could have a diagnostic lesion in deeper sections, and it may have relevance for appropriate staging or further clinical evaluation of the patient. It has to be stressed that in most cases this entity cannot be determined by morphologic examination alone. The follicles have normal localization, good mantle zones, and may contain many residual benign germinal center cells. Therefore, the use of Bcl-2 even in morphologically benign lymph nodes may be justifiable in an appropriate clinical setting.

References

1. Federico M, Vitolo U, Zinzani PL, et al. Prognosis of follicular lymphoma: a predictive model based on a retrospective analysis of 987 cases. Blood. 2000; 95:783-789.'

2. Isaacson PG, Wotherspoon AC, Diss T, Pan LX. Follicular colonization in 13

cell lymphoma of mucosa-associated lymphoid tissue. Am I Surg PathoL 1991; 15:819-828.

3. Pruneri G, Mazzarol G, Manzotti M, Viale G. Monoclonal proliferation of germinal center cells (incipient follicular lymphoma) in an axillary lymph node of a melanoma patient. Hum Pathol. 2001;32:1410-1413.

Emina Torlakovic, MD; Goran Torlakovic, MD

Accepted for publication April 19, 2002.

From the Department of Pathology, The Norwegian Radium Hospital, Oslo, Norway.

Reprints: Emina Torlakovic, MD, Department of Pathology, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway (e-mail: emina.torlakovic@labmed.uio.no).

Copyright College of American Pathologists Sep 2002
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