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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0000000000000030
Review Articles

Follicular Dendritic Cell Pattern in Early Lymphomas Involving Follicles

Carbone, Antonino MD*; Gloghini, Annunziata PhD

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Author Information

*Department of Pathology, Centro di Riferimento Oncologico Aviano, Istituto Nazionale Tumori, IRCCS, Aviano

Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS, Istituto Nazionale Tumori, Milano, Italy

This paper is based on the study of lymphomas of follicular origin diagnosed by the authors during a 20-year period (from 1986 to 2005) at the Centro di Riferimento Oncologico of Aviano, Italy. The paper is also based on the observation of early neoplastic lymphoid lesions diagnosed by one of the authors (A.C.) from 2010 to 2013 at the Centro di Riferimento Oncologico of Aviano, Italy. All cases were diagnosed and studied by combining H&E and immunohistochemical stainings. Selected subsets of these cases were studied by molecular genetics.

This work was supported in part by an Institutional grant to A.C. from the Centro di Riferimento Oncologico of Aviano for an intramural project on “Molecular Medicine”. The authors have no funding or conflicts of interest to disclose.

Reprints: Antonino Carbone, MD, Department of Pathology, Centro di Riferimento Oncologico Aviano, Istituto Nazionale Tumori, IRCCS, Via F. Gallini 2, 33081 Aviano, Italy (e-mail: acarbone@cro.it).

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Abstract

This article reviews the most typical follicular dendritic cell (FDC) patterns displayed by early lymphomas involving follicles. In in situ follicular lymphoma, FDCs form a well-developed round (spherical) dendritic meshwork with a sharp outline. Other patterns that can be seen include contracted/distorted/disintegrated FDC meshworks. In early mantle cell lymphoma with mantle zone pattern, FDCs compose an ill-outlined and loosely arranged “centrifugal” meshwork. In marginal zone lymphoma, the FDC meshwork forms a relatively well-developed nodular meshwork with irregular outlines. In nodular lymphocyte predominant (LP) Hodgkin lymphoma, LP tumor cells are localized within an environment with prominent FDC meshwork and rare or absent LP cells outside the nodules. In angioimmunoblastic T-cell lymphoma (AITL), scattered regressed germinal centers are usually noted, although hyperplastic germinal centers are seen during the early stages of the disease (EAITL). Identifying the FDC meshwork, mainly in association with blood vessels, constitutes one of the most typical findings of the disease. In conclusion, the morphologic pattern of the FDC meshwork in early lymphomas of follicular origin is heterogenous and differs according to the lymphoma subtypes. These FDC patterns are recognizable in the most typical cases when the lymphoma is in its early stage and still maintains a follicular/nodular pattern of growth. The FDC patterns seen in the CD21 and CD23 stains contribute to the recognition of early stages of lymphomas involving follicles. Conversely, tumor cell immunostains for BCL2, cyclin D1, and other stains form the basis for the definition of lymphoma subtypes.

The lymphoid follicle is a structure made of B and T lymphoid cells within a meshwork of follicular dendritic cells (FDCs). The FDCs define the locus of germinal center (GC) formation and serve as antigen-retaining cells for GC B cells, antigen-specific T cells, and antigen-specific B cells. GC B cells take up antigen from FDC, process it, and present it to antigen-specific T cells (reviewed in Carbone et al1 and Rezk et al2).

GC-derived lymphomas include follicular lymphoma (FL), nodular lymphocytic predominant Hodgkin lymphoma (NLPHL), and angioimmunoblastic T-cell lymphoma (AITL). Other lymphomas of presumed follicular origin comprise mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL) (Fig. 1A). Within the microenvironment of all these follicle-derived lymphomas, tumor cells show a strict topographical and functional relationship with FDC, together with reactive lymphoid and stromal cells.1,2 In FL, the tumor cells reside and proliferate in follicular structures in close association with FDCs, even when the infiltrate localize in the bone marrow and in nonlymphoid organs. The FDCs are thought to represent newly generated cells arising during lymphoma growth and progression, although they remain non-neoplastic bystander cells.3 In FL, FDCs possess a possible role in the stimulation and proliferation of the neoplastic B cells.3,4 In AITL, the exuberant proliferation of the FDC network can be directly induced by tumor cells through IL-21 and CXCL13 release and is also sustained by the release of proinflammatory mediators by bystander myeloid cells.5

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The morphologic pattern of the FDC meshwork in overt lymphomas of follicular origin is heterogenous and differs according to the lymphoma subtypes.6 The FDC patterns, as described for FL and MCL,7,8 are reminiscent of the distribution pattern of FDC meshwork seen in the GC or the mantle zone of the reactive lymphoid follicle, respectively.9 The FDC patterns shown by FL, MCL, and the other lymphomas of follicular origin have recently been reviewed with special attention to overt lymphomas.2

The 2008 “WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues” has addressed the problem of early events in the evolution of lymphoid neoplasia. Early lymphomas have been recognized for GC-derived lymphomas and other lymphomas of presumed follicular origin.10–12

On the basis of personal observation of early neoplastic lymphoid lesions diagnosed and studied by combining hematoxylin and eosin and immunohistochemical stainings, and molecular genetics,10 this article reviews the most typical FDC patterns displayed by early lymphomas involving follicles and documents the FDC network patterns in the CD21 and CD23 immunostains in the in situ or early lymphoma subtypes recognized by the 2008 WHO classification proposal.11 Examples of early lymphoma subtypes include in situ/early FL, early MCL, early MZL, early NLPHL, and early AITL. This review indicates that the morphologic patterns of the FDC meshwork in early lymphomas of follicular origin are heterogenous and differ according to the lymphoma subtypes. These FDC patterns are uniformly recognizable in the most typical cases when the lymphoma is in its early stage and still maintains a follicular/nodular pattern of growth.

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FOLLICULAR DENDRITIC CELL: MAIN FEATURES AND FUNCTIONS

The origin of FDCs has been the subject of debates and speculations and remains unclear to date.2 FDC are specialized nonlymphoid stromal cells of mesenchymal origin, located in the peripheral lymphoid tissues, particularly in the B-cell-dependent areas. However, the existence of ubiquitous undifferentiated progenitors has been hypothesized13 (reviewed also in Cyster et al14). In healthy conditions, FDCs are located in lymphoid primary follicles (primary FDCs), or in secondary follicles (secondary FDCs). Maturation from primary to secondary FDCs is guaranteed by cytokines such as linfotoxin (LT) α1β1, α1β2, α2β1, α3, and tumor necrosis factor (TNF) α. A major role is played by LT and TNF. The latter directly binds the tumor necrosis factor receptor-1 (TNFR1) expressed by FDC precursors. This finding is probably sufficient for FDC maturation. The formation of secondary FDCs is also because of the presence of Fc γ RIIb on their membrane that binds integrin ligands, specifically the intercellular adhesion molecule-1 (ICAM-1) and the vascular cell adhesion molecule-1 (VCAM-1). Integrin signals mediated by FDCs are important for the GC B-cell persistence, because integrin-FDC signals are required for centrocyte selection.15

Classic FDC immunophenotype includes the expression of S-100 protein, CD21, CD23, and CD35. Other markers reported to be highly sensitive but not specific to FDCs include clusterin16 and podoplanin.17 Fibroblast markers such as VCAM-1, ICAM-1, 1B10 ND 3C8, and adhesion markers such as BP-3 and mucosal vascular address in cell adhesion molecule-1 (MadCAM-1) are also expressed by FDC.

FDC’s main functions comprise: (1) histoarchitecture organization of lymphoid follicles, (2) antigen trapping and presentation, (3) organization of apoptotic “waste” removing, and (4) self-immunity prevention.18 Organizing functions of FDCs are chemokine dependent. In detail, FDCs produce chemokines including CXCL13 and the stromal-derived factor-1 (SDF-1). CXCL13, also known as B-cell chemoattractant (BCL), is a molecule produced by FDCs and by the follicular stromal cells. The binding of CXCL13 with its receptor, CXCR5, which is expressed by B cells, is critical for B-cell migration into the GC light zone.13 It is interesting to note that CXCL13 production strongly depends on LT α1β2 production. On the contrary, CXCL13 directly induces LT α1β2 expression by naive B cells, creating a positive feedback loop to augment the CXCL13 production.13 Upon activation, CXCL13 can bind CXCR5, also expressed on Tfh, to augment the production of immunoglobulins by follicular B-cell. SDF-1, instead, has a role in leukocytes activation and in proinflammation signaling; it is produced by dark zone sparse FDCs, and it is involved directly in B cells positioning into the GC dark zone by the linking to its receptor CXCR4. FDCs are defined as professional antigen-presenting cells, because they trap immunocomplexes, transported by naive B cells, through immunoglobulin constant portion receptor (FcR) and complement receptor C3. As a consequence, FDCs present antigens to GC B cells to generate memory B cells or plasma cells, also thanks to GC T cells, which cooperate with FDCs to allow B-cell differentiation. In fact, FDCs are able to interact with T cells also thanks to costimulatory molecules: CD80 and CD86 bind CD28 on T cells allowing recognition, binding, and signal transduction. In conclusion, it is possible to affirm that FDCs, B and T cells are mutually dependent. The immune complexes are held on FDCs surface by Fc receptors such as CD23 and CD32 or by complement receptors such as CD21 and CD35 (reviewed in Rezk et al2). FDCs’ ability to catch antigens is also guaranteed by their dendritic cytoplasmic extensions that augment the cellular surface. These “arms” create a network laminin-correlated. In fact, it has been demonstrated by IHC that the expression of laminin parallels the FDC networks as identified by an antibody against FDCs called DRC-1.19

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FOLLICULAR DENDRITIC CELL PATTERNS IN REACTIVE LYMPHOID FOLLICLES

In reactive lymphoid follicle, the meshwork of immunostained FDCs is localized more densely in GC than in the mantle zone. Rounded collections of cohesive FDCs are seen in the GC, whereas irregularly shaped meshwork of poorly cohesive FDCs are evident in the mantle zone.4 FDCs tend to localize in the GC and progressively decrease in number toward the mantle zone (Fig. 1B). The patterns of FDC distribution, usually recognizable in reactive lymphoid follicles, include typical tight/dense meshwork pattern, polarized FDC meshwork pattern, and expanded FDC meshwork with extension into the mantle zones.2

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EARLY LYMPHOMAS OF FOLLICULAR ORIGIN: DIAGNOSIS

Lymphomas of follicular origin can be readily recognized on the basis of several stains such as: CD20, BCL2, CD10, BCL6, cyclin D1, CD3, PD1, and CD4. Use of Ki67, κ, λ, IgD, and IgM can provide additional diagnostic information, if needed in any given case. The diagnosis of early or in situ stage of FL and MCL, early MZL, early NLPHL, and AITL is not based on the findings in the CD21 and CD23 immunostains. CD21 and CD 23 stains can help in the diagnostic process, but are not required to make a final diagnosis.

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FOLLICULAR DENDRITIC CELL PATTERNS IN EARLY LYMPHOMAS OF FOLLICULAR ORIGIN

Follicular Lymphoma

FLs are derived from GC B cells and maintain the gene expression program of this stage of differentiation.20 Unlike normal GC B cells, FLs express BCL2 as a result of the characteristic t(14;18) translocation. In in situ FL, the neoplastic cells are localized “in the place” that is occupied by the normal counterpart of the tumor cell, without invasion of the surrounding structures.10,21 A precise pathologic diagnosis of in situ FL requires the recognition of the following histologic and immunohistochemical features: (1) a preserved general architecture of the lymph node; (2) the presence of affected follicles that are usually scattered; and (3) immunohistologic detection of GC B cells that show strongly positive staining for BCL2 and CD10. Immunohistochemically, in the involved follicles strongly positive BCL2+ cells are confined only to GCs and are not seen in the interfollicular region or elsewhere in the lymph node and other lymphoid tissues.22–24

The abnormal follicles involved in in situ FL have monotonous-appearing GCs surrounded by well-preserved mantle zones. The intrafollicular BCL2-positive GC B cells are located within the meshwork of the CD23+ FDC and coexpress BCL6 and CD20 and are CD3 negative. The proliferation index rate, as assessed by Ki67, is low. The FDC meshwork usually form a well-developed “spherical” dendritic meshwork with a sharp outline highlighting well-preserved mantle zone. Other patterns that can be seen include contracted/distorted/disintegrated FDC meshworks (Figs. 2, 3). As compared with in situ FL, the neoplastic follicles involved by early overt FL usually have thinner mantle zones and higher proliferation index rate; however, they have a similar FDC pattern with a well-developed round spherical meshwork (Fig. 4).

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Mantle Cell Lymphoma

MCL is a B-cell neoplasm that usually carries the t(11;14)(q13;q32) translocation that juxtaposes the protooncogene CCND1, which encodes cyclin D1, at chromosome 11q13, to the Ig heavy-chain gene at chromosome 14q32.25 The typical antigen constellation in this lymphoma includes the coexpression of CD5 and CD20 and negativity for CD3, CD10, and CD23. Several growth patterns have been described for MCL including: (1) nodular growth pattern with residual GCs (mantle zone pattern), (2) nodular growth pattern with no residual GCs (mantle cell nodular pattern), (3) nodular growth pattern because of colonization of reactive GCs (follicular colonization pattern), and (4) diffuse pattern with or without residual GCs.11 MCL, in its initial stages usually has a mantle zone pattern, followed by mantle cell nodular pattern.11,21 The t(11;14) translocation is the primary event facilitating the transformation of a B lymphocyte that would initially colonize and expand the mantle cell area of the lymphoid follicles as seen in “in situ” MCL.26

When there is a neoplastic mantle zone pattern, the reactive GCs have preserved tight FDC meshworks, whereas neoplastic zones show a disrupted and fragmented FDC meshwork (Figs. 5, 6). Conversely, as the expansion of the neoplastic mantle zones continue outward, MCL neoplastic nodules with absent FDC meshworks and negative staining for CD21 and CD23 are formed.

FIGURE 5
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FIGURE 6
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Marginal Zone Lymphoma

MZL is an indolent B-cell lymphoma corresponding to post-GC memory B cells that is supposed to derive from the marginal zone and encompass 3 distinct entities: extranodal MZL or mucosa-associated lymphatic tissue (MALT), nodal MZL (NMZL), and splenic MZL (SMZL).27,28 Among marginal zone–derived B-cell lymphomas, early lesions may be observed within the subset of nodal MZL of the splenic type, with tumor cells growing inside an attenuated mantle zone and often around a residual GC. The presence of remnants of FDC meshwork suggests colonized follicles29 (also reviewed in Rezk et al2). Immunohistochemical studies show that the neoplastic lymphocytes are reactive with CD20 and negative for CD3 in all cases. All cases are negative for CD5, CD10, and CD23, whereas CD43 and BCL2 expression on B cells is usually present29 (also reviewed in Rezk et al2). The FDC meshwork is variably distorted and disintegrated when there is follicular colonization.2,27,28 The FDC meshwork is more evident in cases with a nodular/follicular pattern.

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Nodular Lymphocytic Predominant Hodgkin Lymphoma

NLPHL is a monoclonal B-cell neoplasm characterized by a nodular, or a nodular and diffuse proliferation of Reed-Sternberg cell variants, known as popcorn or lymphocyte predominant cells (LP cells). LP cells are characteristically positive for CD20, BCL6, and OCT2.30 The earlier pattern recognized for NLPHL is that described by Fan et al31 as pattern A. In this pattern, the nodules usually contain a prominent FDC meshwork that encompasses the LP cells. In these cases, the neoplastic LP cells are found to be located predominantly within the nodular structures, but rare LP cells extend outside the nodule.31 Recently, we described a novel nodular pattern of NLPHL in which tumor cells reside in an environment reminiscent of lymphoid follicles and do not invade the surrounding space, featuring a “noninvasive pattern.”32,33 LP tumor cells are localized within an environment reminiscent of a secondary follicle or, more frequently, within neoplastic nodules reminiscent of a primary follicle without residual GC. The recognition of this pattern primarily relies on the identification of strongly stained BCL6+ and CD20+ LP tumor cells. CD23 and CD21 immunostaining detects meshworks of FDCs, which entrap the LP cells and the surrounding T-cell rosettes.32–34 Most of the LP cells are ringed by CD3+/CD4+ T cells that express markers such as PD1 and IRF4/MUM1, consistent with a subset of GC T cells.

In the early phases of NLPHL development in lymph nodes, a number of follicles have a larger size and irregular shape, show a well-preserved mantle zone, and contain scattered LP cells with typical morphology. Immunohistologically, these abnormal follicles contain a prominent FDC meshwork that encompasses reactive GC B cells. This reactive background, dominated by FDCs, is surrounded by an outer zone with smaller non-neoplastic IgD+ B cells. LP cells reside in spherical meshworks of FDCs that are filled with non-neoplastic reactive cells, which also include T cells. LP tumor cells may also be localized within nodules reminiscent of a primary follicle without residual GC. The most important difference between progressively transformed GC (PTGCs) and NLPHL is the presence of LP cells, representing the tumor B-cell population, only in NLPHL. However, NLPHL and PTGC may show a broken-up pattern of FDC and great number of T cells. As benign processes such as PTGC and follicular lysis lead to distorted and disintegrated FDC patterns, the value of the CD23 and CD21 stains is reduced in NLPHL.

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Angioimmunoblastic T-cell Lymphoma

AITL is a peripheral T-cell lymphoma characterized by a systemic disease, a polymorphous infiltrate involving lymph nodes, with a prominent proliferation of high endothelial venules (HEV).35 AITL tumor cells show the phenotype of normal follicular helper T cells expressing CD10, CXCL13, and PD1.1 In early lymph node involvement by AITL, the neoplastic T cells preferentially occupy the B-cell follicles and immediate perifollicular area, sometimes mimicking a FL of B-cell origin.23,36–39 Typically, the tumor cells of AITL have a T-helper cell phenotype expressing CD3, CD4, and frequently CD10, similar to a subset of normal GC-Th cells.38,40 The neoplastic CD4+ T cells represent a minority of the lymph node cell population, their detection being facilitated by the aberrant expression of CD10.

AITL characteristically contains a prominent proliferation of HEV and FDC. Neoplastic cells of AITL form small clusters around FDC meshworks and HEV and are admixed with B cells, eosinophils, and plasma cells. CD21 and CD23 highlight the dense extrafollicular FDC meshwork that mainly surrounds the large blood vessel. The FDC meshworks within the follicles are usually variably distorted and disintegrated (Figs. 7–9).2,10,40

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CONCLUSIONS

In conclusion, tumor cell immunostains for BCL2, cyclin D1, and other stains form the basis for the recognition of the lymphomas of follicular origin. The microenvironmental FDC patterns seen in the CD21 and CD23 stains contribute to the definition of their early stages, especially in ISFL, EMCL, and EAITL subtypes. The FDC patterns recognizable in early lymphomas of follicular origin that may have utility in identifying their early stages include a “spherical pattern,” which highlights well-preserved mantle zones in in situ FL; a “mantle zone”/“centrifugal” pattern in early MCL and a “variably distorted” pattern surrounding HEV in early AITL. These FDC patterns are recognizable in the most typical cases when the lymphoma is in its early stage and still maintains a follicular/nodular pattern of growth. Importantly, because there is considerable variation in the amount/extent of involvement of the follicles (or nodules in NLPHL) in the above lymphomas, diagnostic patterns are not present or do not emerge that would allow clear separation of these lymphomas from each other on the basis of the FDC patterns alone.

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ACKNOWLEDGMENTS

The authors thank B. Canal, P. Ceolin, A. Selva, and L. Zannier from the Department of Pathology, Centro di Riferimento Oncologico Aviano, for the current immunohistochemical assessment of the whole case series of early lymphomas of follicular origin.

The authors also thank Ambra Gualeni from the Department of Diagnostic Pathology, Fondazione IRCCS, Istituto Nazionale Tumori, Milano, for helpful discussion regarding the section on the main features and functions of FDC.

Finally, the authors also thank E. Gislon (Scientific Direction, Centro di Riferimento Oncologico of Aviano, Istituto Nazionale Tumori, IRCSS, Aviano, Italy) for English revision of the manuscript.

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Keywords:

follicular dendritic cell; FDC pattern; lymphomas of follicular origin; germinal center-derived lymphomas; mantle cell lymphoma; early lesion in lymphomas

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