Chronic lymphocytic leukemia: the pathologist's view of lymph node microenvironment

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Chronic lymphocytic leukemia (CLL), an indolent B-cell malignancy frequently diagnosed in the elderly, is characterized by the relentless accumulation of CD5+ monoclonal B cells that proliferate in the appropriate tissue microenvironments. Despite many advances achieved by molecular and functional studies, our knowledge of the reciprocal relationship between the CLL cell and its microenvironment at the tissue level is still largely incomplete. In this review we present the relevant current information on the tissue microenvironmental features of CLL, focusing on the events that appear to occur in the lymph node. Special attention is devoted to analyzing the properties of both neoplastic and nonneoplastic bystander cells within proliferation centers, the mysterious structures that likely represent the actual proliferative compartment.

Section snippets

Histopathology and immunophenotype of CLL

The architecture of CLL lymph nodes is usually effaced and exhibits small, if any, residual germinal centers; more rarely, CLL infiltration has an interfollicular pattern, where germinal centers are more evident.2 The predominant diffuse population of small cells with clumped chromatin, regular nuclei, and scant cytoplasm is spaced out by vaguely nodular, clear-looking structures called proliferation centers (PC). The composition of PC encompasses a wider spectrum of neoplastic cells, including

Properties of CLL microenvironment

When considering the relationship between CLL cells and their microenvironment, we should take into account two main concepts. First, BM and secondary lymphoid organs have a different and yet imperfectly defined cellular and molecular milieu.1 Second, the dialog between microenvironment and neoplastic B cells is not necessarily unidirectional; rather, signals generated by each counterpart imply a feedback response generated by the target cell. Major players of microenvironmental stimuli are

Pathology of CLL–microenvironment interactions

The above-mentioned mechanisms are derived from in vitro models using flow cytometry and molecular methods, which brings up the question of how the physical interaction among CLL cells and microenvironmental players can be visualized. Available data are scant, especially considering the mysterious nature of PC.

Focusing on neoplastic B cells, immunohistochemistry has revealed that CLL cells are immunoreactive for BAFF-receptor, namely BAFF3 or BR-3. Although these studies have been performed in

Microenvironmental features of proliferation centers

PC are easily recognized in tissues involved by CLL, especially in lymph nodes; however, these structures remain largely unknown and apparently do not have a physiological counterpart in nonneoplastic lymphoid tissues.

PC are obviously characterized by increased proliferation rate (Figure 2) and express CD5, bcl-2, CD71, HLA-DC, and HLA-DR, whereas IgD, p27, and CD9 are down-regulated. Compared with the surrounding “classical” small CLL cells, PC preferentially or more strongly express MUM1/IRF4+

Conclusions

Despite significant advances in the understanding of CLL pathogenesis, studies have clarified the reciprocal relationships between neoplastic B cells and microenvironmental components. These issues are even more important when we analyze the tissues involved. The lymph node environment and especially the origin, nature, and properties of PC must be extensively studied because this anatomical structure represents the actual site of active replication and the ensuing acquisition of new genetic

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