May 2009
Written by Peter M. Banks, M.D., Director of Hematopathology, Carolinas Medical Center, Charlotte, North Carolina.

Contributing Pathologist
John Koepke, M.D., Northside Hospital, Atlanta, Georgia.

Diagnosis
B-cell malignant lymphoma, of follicular type, with diffuse growth pattern.

Clinical History
This 49 year old woman was found to have asymptomatic enlargement of abdominal lymph nodes. An initial needle biopsy revealed features suggesting a B-cell lymphoma, but without sufficient information to allow definitive classification. Therefore a laparoscopic procedure was performed yielding several sizable samples of tissue.

Microscopy
Sections revealed an abnormal lymphoid proliferation with a perfectly diffuse growth pattern (see Figure 1).

Higher magnification allowed characterization of the cellular composition as small, irregular lymphocytes (small cleaved cells) - see Figures 2 and 3. Rare interspersed follicular dendritic cells, recognizable as delicate vesicular nuclei without apparent cytoplasm, could be recognized at highest magnification (see Figure 3).

Ancillary Studies
Immunohistochemical stains demonstrated strong, uniform expression of CD20 by the tumor cells, with predominant nuclear staining for bcl-6, a marker associated with normal follicle center differentiation (see Figure 4).

Ki-67 marked a moderate percentage of tumor nuclei, indicating an intermediate level of proliferation. Scattered follicular dendritic cells, forming only a very scant network, were positive for CD23 (see Figure 5).
The process was negative for cyclin-D1 by immunohistochemistry.

Fluorescence in-situ hybridization studies using dual fusion two-color methodology with probes for the bcl-2 t(14;18) event were performed at PhenoPath Laboratories in Seattle with positive findings.

Discussion
At least some follicular growth pattern is usually preserved within most lymphomas of low or intermediate grade which show follicle center differentiation, hence the term "follicular" lymphoma. The WHO classification recommends alluding to the percentage follicular versus diffuse growth pattern in cases in which there is not a uniformly manifest follicular pattern (1). In practice however, the problem is just as often a very faintly follicular pattern, not just some particular areas with diffuse growth pattern. Lennert in Germany, in his classic book of 1978, mentioned variations in degree of follicular growth pattern in his category of "centroblastic-centrocytic" lymphomas, with some slight adverse prognostic association with a fainter follicular or diffuse pattern (2). Lukes and Butler, contemporaries of Lennert, emphasized the cell type ("small cleaved") and not the growth pattern in their own lymphoma classification (3).

In cases with a diffuse growth pattern, it is most important to distinguish the process from mantle cell lymphoma. Because mantle cell lymphomas correspond to the normal follicular mantle zone, they too can have interspersed dendritic accessory cells and can even display their own faint follicular growth pattern (see the July 2008 Case of the Month). An immunohistochemical stain for cyclin-D1 should always be employed to exclude the possibility of mantle cell lymphoma before making the diagnosis of follicular lymphoma with diffuse growth pattern. In most cases, the intermixture of some centroblastic larger basophilic cells is strong evidence against mantle cell lymphoma, but in the case under discussion such cells were essentially absent (see Figure 3).

References

1. Nathwani BK, Harris NL, Weisenburger D, Isaacson PG, et al.
   Follicular Lymphoma. p. 162, 163 in World Health Organization Classification of Tumours: Pathology and Genetics - Tumours of the Haematopoietic and Lymphoid Tissues, E.S. Jaffe, N.L. Harris, H. Stein and J. W. Vardiman, editors, 2001, IARC press, Lyon.
2. Lennert K.
   Centroblastic/centrocytic lymphoma. Pp. 302-343 in Malignant Lymphomas Other Than Hodgkin's Disease: Histology, Cytology, Ultrastructure, Immunology. K. Lennert, editor, 1978, Springer, New York.
3. Lukes RJ, Collins RD.
   New approaches to the classification of the lymphomata. Brit J Cancer 1975; 31 (suppl II): 1-28. More online »

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