Isolated Follicles Enriched for Centroblasts and Lacking t(14;18)/BCL2 in Lymphoid Tissue: Diagnostic and Clinical Implications

2016-03-18 14:05:47

PLOS One; 18 March 2016: DOI: 10.1371/journal.pone.0151735

Grant E. Nybakken , Rajeev Bala , Dita Gratzinger , Carol D. Jones , James L. Zehnder , Charles D. Bangs , Athena Cherry , Roger A. Warnke , Yasodha Natkunam


We sought to address the significance of isolated follicles that exhibit atypical morphologic features that may be mistaken for lymphoma in a background of reactive lymphoid tissue. Seven cases that demonstrated centroblast-predominant isolated follicles and absent BCL2 staining in otherwise-normal lymph nodes were studied. Four of seven cases showed clonal B-cell proliferations amid a polyclonal B cell background; all cases lacked the IGH-BCL2 translocation and BCL2 protein expression. Although three patients had invasive breast carcinoma at other sites, none were associated with systemic lymphoma up to 44 months after diagnosis. The immunoarchitectural features of these highly unusual cases raise the question of whether a predominance of centroblasts and/or absence of BCL2 expression could represent a precursor lesion or atypical reactive phenomenon. Differentiating such cases from follicular lymphoma or another mimic is critical, lest patients with indolent proliferations be exposed to unnecessarily aggressive treatment.


Unusual growth patterns of atypical large cells associated with lymph node follicles have been previously described and range from reactive hyperplasias to germinotropic lymphomas. In recent years, recognition of aberrant strong coexpression of the germinal center marker CD10 and the anti-apoptotic protein BCL2, has been described within isolated secondary follicles of otherwise-normal lymph nodes. Since its recognition, this phenomenon, variously termed ‘in situ localization of follicular lymphoma’, ‘follicular lymphoma in situ’ (FLIS) or ‘follicular lymphoma-like lesion of uncertain clinical significance’, has been described in histologically unremarkable lymph nodes from healthy patients, normal lymph nodes in patients with a prior or concurrent diagnosis of follicular lymphoma (FL), lymph nodes involved by a variety of other hematolymphoid malignancies, and lymph nodes removed during the evaluation of non-hematolymphoid neoplasms.

he clinical significance of FLIS is still of uncertain significance, particularly because numerous studies have reported the presence of non-neoplastic cells that harbor IGH-BCL2 gene rearrangements in the peripheral blood and tissues of patients with no evidence of FL. Diagnostic criteria for identifying FLIS and guidelines for distinguishing this pattern of involvement from cases of partial lymph node involvement by FL have been proposed in an attempt to stratify patients into risk groups. To date the reported cases in the literature contain aberrant strong coexpression of CD10 and BCL2 within follicles containing predominantly centrocytes amid otherwise-normal lymph nodes.

Herein, we report seven cases characterized by isolated abnormal follicles composed of atypical centroblasts within otherwise-normal lymph nodes that show significant differences from previously described cases. Detailed morphologic and immunophenotypic characterization was undertaken, and in cases with sufficient tissue, cytogenetics and molecular studies for clonal IGH@ gene rearrangements were performed. The diagnostic challenges and clinical implications of these unusual findings are described.

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Key Words

Lymph Nodes | Lymphomas | B Cells | Follicular Lymphoma | Fluorescent in situ Hybridization | Cancer detection and diagnosis | Follicular dendritic cells | Breast Tumors