Unusual Morphologic Presentations of CLL/SLL

Lessons From the Friday Unknowns

Nodal involvement by chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL) is often characterized by a diffuse proliferation of predominantly small lymphocytes and proliferation centers, composed of prolymphocytes and paraimmunoblasts.

In rare instances, CLL/SLL cases can demonstrate unusual patterns of infiltration, mimicking other lymphoid neoplasms such as T-cell lymphoma, mantle cell lymphoma and marginal zone lymphoma.

Below is a brief illustration of each of these unusual patterns of infiltration:

A. CLL/SLL with a T-cell rich background

Low power evaluation of this case shows a diffuse lymphocytic infiltrate with indiscernible proliferation centers.

On higher power, cells are small with admixed paraimmunoblasts and prolymphocytes.

CD3 imunohistochemical (IHC) stain highlights numerous background T-cells with no morphologic atypia.


No aberrant loss of CD5 or CD7 expression is identified by IHC stains.


PAX5 IHC stain highlights scattered B-cells, spread out throughout the core, with a noticeable absence of B-cell aggregates or compartments.


CD21 IHC stain is negative for residual follicular dendritic cells, and Ki67 proliferation index is ~30%.


A small CD5-positive monoclonal B-cell population with an immunophenotype characteristic of CLL/SLL cells was identified by flow cytometry analysis. No aberrant T-cell population was detected.

Upper row: Flow cytometry analysis plots showing an aberrant B-cell population (pink) expressing CD19, CD20 (dim), CD22 (dim) and CD23 | Lower row: Aberrant B-cell population (blue) expressing CD5 and lambda light-chain restriction

These findings taken together with an established history of CLL/SLL, are supportive of persistent CLL/SLL. This case illustrates a rare presentation of CLL/SLL with a T-cell rich background, which could be misinterpreted as an atypical T-cell proliferation, especially when coupled with a moderate to high Ki67 proliferation index (most likely reflecting reactive background T-cells in this case).

In ~10% of CLL/SLL cases, neoplastic cells are confined to the mantle zones, or interfollicular/ marginal zones surrounding benign lymphoid follicles, in either nodal or extranodal sites (1-3). In such cases, recognition of proliferation centers, coupled with a CD5/CD23 positive monoclonal B-cell population help establish the correct diagnosis:

B. CLL/SLL with Mantle Zone Pattern of Infiltration

Low power view reveals a neoplastic lymphocytic infiltrate with a somewhat nodular pattern of infiltration.

High power examination reveals a predominant population of small lymphocytes with admixed prolymphocytes and paraimmunoblasts. Residual germinal centers are also seen.

CD20 stain highlights neoplastic B-cells with a vague follicular and peri-follicular pattern of infiltration.


CD3 stain highlights background T-cells.


In comparison to CD3, CD5 stain highlights T-cells AND neoplastic B-cells.


On higher power, CD5 dim expression in a mantle zone pattern surrounding residual germinal centers (cells between dotted circles), is reminiscent of mantle cell lymphoma, mantle zone pattern.

CD23 stain highlights the neoplastic B-cells, in addition to follicular dendritic cells in residual germinal centers.


Ki67 stain is characteristically high in residual reactive germinal centers (GC), and highlights numerous background proliferation centers (PC).

The differential diagnosis in this case includes mantle cell lymphoma. However, in contrast to CLL/ SLL, mantle cell lymphoma is composed of a monotonous population of lymphoid cells devoid of prolymphocytes and paraimmunoblasts. Flow cytometry analysis of a concurrent specimen showed typical CLL/SLL immunophenotype. In addition, Cyclin-D1 and SOX11 IHC stains were negative, supporting the diagnosis of CLL/SLL with mantle zone pattern of infiltration.

C. CLL/SLL with an Inter-follicular/Marginal Zone Pattern of Infiltration

Low power view shows germinal centers (GC) with adjacent interfollicular proliferation centers (PC)

Higher power evaluation of a proliferation center (left) reveals numerous paraimmunoblasts (black arrows) and prolymphocytes (red arrows). Evaluation of a germinal center (right) on the other hand reveals numerous centroblasts admixed with centrocytes and tangible body macrophages.

Left: Proliferation center, black arrows indicate paraimmunoblasts and red arrow prolymphocytes| Right: Germinal center

The differential diagnosis in this case includes nodal marginal zone lymphoma, which is often composed of small cells with abundant clear cytoplasm, and lacks prolymphocytes and paraimmunoblasts.

This inter-follicular/marginal pattern of infiltration seen in this case may be explained, in part, by the putative origin of CLL/SLL from a CD5/CD23 positive recirculating pre-germinal center B-cell, which resides or homes to the marginal zone. However, the retention of these patterns in extra-nodal sites in reported cases, and the presence of disseminated disease in most cases argue against this explanation. Alternatively, the neoplastic cells may secrete cytokines that induce germinal center formation, at least in extra-nodal sites (3).

Link to digital slides of above discussed cases (A, B, C): https://bit.ly/2QsRzkS (Slides labeled cases 1, 2 & 3)

Suggested read: https://www.nature.com/articles/3880214


(1) Nguyen DT, Diamond LW, Schwonzen M, Bohlen H, Diehl V. Chronic lymphocytic leukemia with an interfollicular architecture: avoiding diagnostic confusion with monocytoid B-cell lymphoma. Leuk Lymphoma 1995;18:179–84.

(2) Ellison DJ, Nathwani BN, Cho SY, Martin SE. Interfollicular small lymphocytic lymphoma: the diagnostic significance of pseudofollicles. Hum Pathol 1989;20:1108–18.

(3) Gupta D, Lim MS, Medeiros LJ, Elenitoba-Johnson KS. Small lymphocytic lymphoma with perifollicular, marginal zone, or interfollicular distribution. Mod Pathol. 2000 Nov;13(11):1161–6.



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Siba El Hussein, MD

Siba El Hussein, MD

Hematopathology | Cytopathology | Molecular pathology | Digital pathology | Data science | Machine learning