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Histopathology and bcl-2 immunohistochemistry of in situ follicular lymphoma. (A-B) Low-power view of H&E- stained (A) and bcl-2 – stained (B) sections showing preserved nodal architecture with open sinuses and prominent paracortex. In B, focal germinal centers (GCs) stain strongly positive for bcl-2, 25 ϫ (case no. 4). (C-D) In this case, most follicles have sharply demarcated lymphoid cuffs resembling reactive GCs (C; H&E). A bcl-2 stain (D) reveals a variable number of cells strongly positive for bcl-2, with some GCs containing only rare bcl-2 ϩ cells. Note
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From 1992 to 2000, we identified 23 lymph node biopsies with focal germinal centers (GCs) containing centrocytes staining strongly for bcl-2 protein, whereas most of the remaining lymph node showed bcl-2-negative follicular hyperplasia. We propose the designation in situ localization of follicular lymphoma (FL) for this phenomenon. In 2 additional...
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Context 1
... identified 23 lymph node biopsies that showed atypical follicular hyperplasia on hematoxylin and eosin (H&E)-stained sections, but contained focal GCs strongly positive for bcl-2 by immunohistochemical staining (Figure 1). In these lymph nodes the remaining GCs in the same lymph node were bcl-2 . ...
Context 2
... was also a spectrum in the number of the positive cells identified within affected follicles. Some of the involved GCs contained only a few positive cells in a background of bcl-2 centrocytes and centroblasts, whereas others were more exten- sively replaced by bcl-2 centrocytes (Figure 1). In all cases, the bcl-2 staining in the abnormal follicles was notable for its high-level and uniform intensity. ...
Context 3
... microdissected the bcl-2 follicles and bcl-2 follicles from the same lymph node, and analyzed them in parallel by IgH FRIII-PCR and BCL2/JH PCR. The results are shown in Figure 2 and Table 3. Figure 1 (I,J) shows bcl-2-stained sections before and after LCM of bcl-2 follicles. DNA was prepared from microdissected GCs and used for PCR analysis. ...
Citations
... 12,13 By definition, ISFN involves GC of normal reactive lymph nodes and the cells express strongly CD10 and BCL2 but show a very low proliferation rate. 14 Another closely related lesion is duodenal-type follicular lymphoma (DTFL), which is morphologically and immunophenotypically indistinguishable from cFL and characterized by restricted involvement of intestinal mucosa and usually lack of extraintestinal manifestations, although rarely local lymph node involvement has been reported. 15,16 Another feature of FL is the constitutive expression of activation-induced cytidine deaminase (AID), which mediates the process of somatic hypermutation (SHM) and class switch recombination (CSR), leading to genomic instability and accumulation of genetic alterations. ...
Follicular lymphoma (FL) is a neoplasm derived from germinal center B cells, composed of centrocytes and centroblasts with at least a focal follicular growth pattern. The t(14;18) translocation together with epigenetic deregulation through recurrent genetic alterations are now recognized as the hallmark of FL. Nevertheless, FL is a heterogeneous disease clinically, morphologically, and biologically. The existence of FL lacking the t(14;18) chromosomal alteration highlights the complex pathogenesis of FL, and indicates that there are alternative pathogenetic mechanisms that can induce a neoplasm with follicular center B-cell phenotype. According to their clinical presentation t(14;18)-negative FL can be divided in three broad groups; nodal presentation, extranodal presentation, and those affecting predominantly children and young adults. Recent studies have shed some light into the genetic alterations of t(14;18)-negative FL. Within the group of t(14;18)-negative FL with nodal presentation, cases with STAT6 mutations are increasingly recognized as a distinctive molecular subgroup, often co-occurring with CREBBP and/or TNFRSF14 mutations. FL with BCL6 rearrangement shows clinicopathological similarities with the t(14;18)-positive counterpart. In contrast, t(14;18)-negative FL in extranodal sites are characterized mainly by TNFRSF14 mutations in the absence of chromatin modifying gene mutations. FL in children have unique molecular landscape when compared to adults. Pediatric-type follicular lymphoma (PTFL) is characterized by MAP2K1, TNFRSF14 and/or IRF8 mutations, whereas large B-cell lymphoma with IRF4 rearrangement is now recognized as a distinct entity different from PTFL. Ultimately, the better understanding of FL biology and heterogeneity should help to understand the clinical differences and help guiding patient management and treatment decisions.
... The 5 th World Health Organization (WHO) classification defines ISFN as partial or complete colonization of some GCs by follicular B cells with IGH::BCL2 and strong BCL2 expression in otherwise normal reactive LNs or lymphoid tissues at extranodal sites. 6,18 ISFN was first described as follicular lymphoma in situ (FLIS) by Cong et al. in 2002 and was subsequently defined more strictly by Jegalian et al. in 2011. 19,20 This entity was included as FLIS in the 4 th WHO classification; however, given the limited clinical and prognostic impact, the term "neoplasia" rather than "lymphoma" was preferred. ...
Follicular lymphoma (FL) is an indolent B-cell lymphoma with a germinal center (GC) B cell phenotype that typically harbors t(14;18)(q32;q21). t(14;18) juxtaposes IGH on 14q32 and BCL2 on 18q21, resulting in overexpression of the anti-apoptotic BCL2 protein. However, t(14;18) is also found in the peripheral blood or lymphoid nodes (LNs) of otherwise healthy individuals. Moreover, overt FL has several additional gene alterations involved in epigenetic modification, JAK/STAT signaling, immune modulation, and NF-κB signaling, indicating multi-step lymphomagenesis in FL. There are two early or precursory lesions of FL: t(14;18)-positive cells in the peripheral blood of otherwise healthy individuals and in situ follicular B-cell neoplasm (ISFN). t(14;18)-positive cells are found in 10%–50% of healthy populations, and their incidence and frequency increase with age. The detection of t(14;18) in peripheral blood is a predictive factor for an increased risk of overt FL development. In contrast, ISFN is a histopathologically recognizable precursory lesion, in which t(14;18)-positive cells are confined to the GC of otherwise reactive LNs. ISFN is usually detected incidentally, with an incidence ranging from 2.0% to 3.2%. Occasional ISFN cases have concurrent or metachronous clonally related overt FL or aggressive B-cell lymphoma of a GC phenotype. t(14;18)-positive cells in peripheral blood and isolated ISFN, by themselves, are asymptomatic with limited clinical significance; however, investigations of t(14;18)-positive precursory or early lesions offer meaningful insights into the pathogenesis of FL. This review summarizes the epidemiology, clinical features, pathology, and genetics of precursory or early lesions of FL.
... This condition was first described in 2002 [7]. It was detected through immunohistochemical findings and molecular clonality analysis, as there is no disruption of surrounding tissue, and the lymph node architecture is preserved [7]. ...
... This condition was first described in 2002 [7]. It was detected through immunohistochemical findings and molecular clonality analysis, as there is no disruption of surrounding tissue, and the lymph node architecture is preserved [7]. In 2016, the World Health Organization recognized this condition in their new classification guidelines, along with in situ mantle cell neoplasia [1]. ...
Introduction: Precursor lymphoid lesions have long been recognized in hematopathology. Monoclonal B-cell lymphocytosis has been established as a precursor to CLL, and NK-cell enteropathy was recently identified as a lymphoproliferative disease mimicking NKT-cell lymphoma in the digestive tract. Neither of these lesions requires treatment without transformation to a more aggressive form.
... Histologically, the condition may be suspected owing to the monotonous appearance of a few or a number of GCs that are mainly harboring centrocytes. However, these changes are easily overlooked and ISFN is usually recognized only upon BCL2 staining revealing the partial or complete colonization of GCs by strongly BCL2 positive B cells (Figure 1) [18]. As a rule, CD10 expression-in contrast with reactive follicles-is also unusually strong. ...
Simple Summary
In this paper, we give an overview on the classification of Follicular lymphoma as modified in the 5th edition of the WHO classification of haematolymphoid tumors and discuss new data regarding the biological background of the classification.
Abstract
The conceptual description of Follicular lymphoma (FL) in the 5th edition of the World Health Organization (WHO) classification of haematolymphoid tumors (WHO-HAEM5) has undergone significant revision. The vast majority of FL (85%) with a follicular growth pattern are composed of centrocytes and centroblasts, harbor the t(14;18)(q32;q21) translocation and are now termed classic FL (cFL). They are set apart from three related subtypes, FL with predominantly follicular growth pattern, FL with unusual cytological features (uFL) and follicular large B-cell lymphoma (FLBCL). In contrast to the revised 4th edition of the WHO classification of haematolymphoid tumors (WHO-HAEM4R), grading of cFL is no longer mandatory. FL with a predominantly diffuse growth pattern had been previously recognized in WHO-HAEM4R. It frequently occurs as a large tumor in the inguinal region and is associated with CD23 expression. An absence of the IGH::BCL2 fusion and frequent STAT6 mutations along with 1p36 deletion or TNFRSF14 mutation is typical. The newly introduced subtype of uFL includes two subsets that significantly diverge from cFL: one with “blastoid” and one with “large centrocyte” variant cytological features. uFL more frequently displays variant immunophenotypic and genotypic features. FLBCL is largely identical to WHO-HAEM4R FL grade 3B and renaming was done for reasons of consistency throughout the classification. In-situ follicular B-cell neoplasm, pediatric-type FL, duodenal-type FL and primary cutaneous follicle center lymphoma are categorized as discrete entities. In addition, novel findings concerning underlying biological mechanisms in the pathogenesis of early and systemic follicular lymphoma will be presented.
... While the first may represent the very initial steps of MCL lymphomagenesis, the latter would correspond to the early or partial lymph node involvement of a conventional MCL, similarly to what has been already described for follicular lymphomas [8]. In line with this, it is the recent detection of clonal B cells restricted to the germinal centers carrying the t(14;18) translocation [9,10], a phenomenon which could be interpreted as an early step in the lymphomagenesis of follicular lymphoma, possibly corresponding to ISMCN, www.pacificejournals.com/apalm eISSN: 2349-6983; pISSN: 2394-6466 and referred to as follicular lymphoma in situ (FLIS) [9]. ...
... In line with this, it is the recent detection of clonal B cells restricted to the germinal centers carrying the t(14;18) translocation [9,10], a phenomenon which could be interpreted as an early step in the lymphomagenesis of follicular lymphoma, possibly corresponding to ISMCN, www.pacificejournals.com/apalm eISSN: 2349-6983; pISSN: 2394-6466 and referred to as follicular lymphoma in situ (FLIS) [9]. As the existence of very tiny clones carrying the t(11;14) translocation with no evidence of progression to overt lymphoma has been found in the peripheral blood of 7% of healthy individuals [11], ISMCNs could reasonably correspond to their tissue counterpart. ...
A 55-year-old gentleman presented to our hospital with a single inguinal adenopathy, and no other clinical symptoms or signs. An excisional lymph node biopsy was performed. Pathologic evaluation demonstrated follicular center site which stained positive for CD20, CD10, Bcl-2, Bcl-6, and mantle zone cells which demonstrated Cyclin D1 (CCND1) positivity, partial SOX11 positivity and no expression of CD5, suggesting the diagnosis of composite lymphoma comprising follicular lymphoma (FL) with in situ mantle cell neoplasia (ISMCN), the latter previously referred as in situ mantle cell lymphoma (MCLIS). FL is known as indolent non-Hodgkin lymphoma; however, the clinical significance of a coexisting ISMCN continues to be elusive, and optimal management of these patients remains largely unknown. This paper reports a new case of this extremely uncommon condition and also discusses reviews of the literature including advances in molecular pathogenesis and lymphoma genomics with the aim to offer novel insights into this rare hematological malignancy.
... In situ follicular neoplasia (ISFN) is characterized by a monoclonal proliferation of B-cells carrying t(14;18) confined to the GC [37,38]. Clinically, ISFN is an incidental finding with a low risk of progression to FL. ISFN is usually diagnosed incidentally in a reactive-looking lymph node with preserved nodal architecture, open sinuses, and well-defined GCs with intact mantle zones. ...
Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are indolent mature B-cell neoplasms with variable clinical presentation and distinct histopathologic features. Recent advances in the biology and molecular characteristics of these lymphomas have further expanded our understanding of the heterogeneous nature of these lymphomas, with increasing recognition of specific disease entities within the broader categories of FL and MZL. Here, we discuss the conclusions of the 2022 International Consensus Classification of Mature Lymphoid Neoplasms (2022 ICC) dealing with FL, and review differences with the proposed WHO 5th Edition classification. We review issues related to grading and alternative forms of FL especially those lacking the genetic hallmark of FL, the t(14;18) chromosomal alteration. Among them, t(14;18)-negative CD23 ⁺ follicle center lymphoma has been proposed by the 2022 ICC as a provisional entity. Other follicle center–derived lymphomas such as pediatric-type follicular lymphoma, testicular follicular lymphoma, primary cutaneous follicle center lymphoma, and large B-cell lymphoma with IRF4 rearrangement are considered distinct entities separate from conventional FL. Importantly, large B-cell lymphoma with IRF4 rearrangement introduced as a provisional entity in the WHO 2017 is upgraded to a definite entity in the 2022 ICC. We also discuss diagnostic strategies for recognition of MZLs including splenic MZL, extranodal MZL (MALT lymphoma), and primary nodal MZL. The importance of molecular studies in the distinction among marginal zone lymphoma subtypes is emphasized, as well as their value in the differential diagnosis with other B-cell lymphomas.
... The early lesions within the lymphoid tissue accepted by the 4th edition of the World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues are "in situ" follicular neoplasia and "in situ" mantle cell neoplasia [2] that could actually be considered as the tissue counterpart of circulating elements with t(14;18) and t (11;14) rearrangements (Table 1). "In situ" follicular neoplasia (ISFN) is defined as partial or total colonization of germinal centers by clonal B cells carrying the BCL2 translocation characteristic of follicular lymphoma (FL) in a lymph node where the overall architecture is preserved [3,4]. ISFN is characterized by lack of polarization, closely packed centrocytes with very few, if present, centroblasts, although it is not commonly recognizable in routine H&E-stained sections [3]; this condition is frequently identified by an intense immunoreactivity for germinal center markers (e.g., CD10) and aberrant positivity for BCL2, along with a low proliferation index. ...
... "In situ" follicular neoplasia (ISFN) is defined as partial or total colonization of germinal centers by clonal B cells carrying the BCL2 translocation characteristic of follicular lymphoma (FL) in a lymph node where the overall architecture is preserved [3,4]. ISFN is characterized by lack of polarization, closely packed centrocytes with very few, if present, centroblasts, although it is not commonly recognizable in routine H&E-stained sections [3]; this condition is frequently identified by an intense immunoreactivity for germinal center markers (e.g., CD10) and aberrant positivity for BCL2, along with a low proliferation index. ISFN must be distinguished from partial involvement by follicular lymphoma (pFL), where an architectural distortion is observed. ...
Lymphoproliferative neoplasms of uncertain biological significance are increasingly encountered due to widespread usage of immunophenotypic and molecular techniques. Considering that clearer biological criteria and patient management have been established for B-cell lymphoproliferative diseases of undetermined significance occurring in the peripheral blood, many issues are still obscure for early lesions detected in lymphoid tissues. Regardless that some categories of lymphoproliferative neoplasms of uncertain biological significance have been recognized by the 4th edition of the WHO, other anecdotal early lymphoproliferative lesions still remain fully undefined. Some early lesions frequently originate from the germinal center, including atypical germinal centers BCL2-negative, an early pattern of large B-cell lymphoma with IRF4 rearrangement, and “in situ” high-grade B lymphomas. Moreover, other early lymphoproliferative lesions arise outside the germinal center and include those developing within the setting of monocytoid B-cell hyperplasia, but they also can be directly or indirectly associated with chronic inflammations. This review aims to summarize the concepts discussed during the IV Workshop organized by the Italian Group of Hematopathology, focus on the state-of-the-art on B-cell lymphoproliferative neoplasms of uncertain biological significance, and offer operative insights to pathologists and clinicians in routine diagnostics.
... Still, abnormal, bright BCL2-positive B-cells are identified within lymphoid follicles [1]. These BCL2-positive B-cells are confined to follicles and represent colonization of pre-existing germinal centers by monoclonal BCL2-rearranged B-cells [27,28]. Because a subset of these patients will have FL in other sites at the time of diagnosis of in situ follicular neoplasia, these patients should be staged. ...
Follicular lymphoma (FL) is the most common indolent B-cell lymphoma and originates from germinal center B-cells (centrocytes and centroblasts) of the lymphoid follicle. Tumorigenesis is believed to initiate early in precursor B-cells in the bone marrow (BM) that acquire the t(14;18)(q32;q21). These cells later migrate to lymph nodes to continue their maturation through the germinal center reaction, at which time they acquire additional genetic and epigeneticabnormalities that promote lymphomagenesis. FLs are heterogeneous in terms of their clinicopathologic features. Most FLs are indolent and clinically characterized by peripheral lymphadenopathy with involvement of the spleen, BM, and peripheral blood in a substantial subset of patients, sometimes accompanied by constitutional symptoms and laboratory abnormalities. Diagnosis is established by the histopathologic identification of a B-cell proliferation usually distributed in an at least partially follicular pattern, typically, but not always, in a lymph node biopsy. The B-cell proliferation is biologically of germinal center cell origin, thus shows an expression of germinal center-associated antigens as detected by immunophenotyping. Although many cases of FLs are typical and histopathologic features are straightforward, the biologic and histopathologic variability of FL is wide, and an accurate diagnosis of FL over this disease spectrum requires knowledge of morphologic variants that can mimic other lymphomas, and rarely non-hematologic malignancies, clinically unique variants, and pitfalls in the interpretation of ancillary studies. The overall survival for most patients is prolonged, but relapses are frequent. The treatment landscape in FL now includes the application of immunotherapy and targeted therapy in addition to chemotherapy.
... These circulating translocation-positive cells are most likely equivalent to those of in situ follicular neoplasia (ISFN) in lymph nodes (LNs) identified incidentally by BCL2 immunohistochemistry [3,4]. The B-cell follicles involved by ISFN usually display only subtle changes that are not readily identifiable using conventional H&E staining but are recognised by strong BCL2 staining in germinal centre B-cells [5]. Generally, few ISFNs progress into an overt B-cell lymphoma. ...
In situ follicular neoplasia (ISFN) is usually an occasional incidental finding in lymph nodes by BCL2 immunohistochemistry, and its true scale is unknown. We have identified 6 cases of follicular lymphoma (FL) with a history of solid neoplasm 4–16 years ago, from which ISFN was identified widely in the surgically cleared lymph nodes (LNs). Using clone-specific PCR and BaseScope in situ hybridisation with primers or probes specific to the VDJ or BCL2-IGHJ junction sequence, we confirmed the clonal identity among different ISFNs and overt-FL in each of the 4 cases successfully investigated. Mutation analyses of overt-FL by targeted next-generation sequencing identified multiple potential pathogenic changes involving CREBBP, EZH2, KMT2D, TNFRS14 and STAT6. Further investigations of these mutations in paired ISFNs using Fluidigm PCR and Illumina sequencing showed the presence of the FL associated mutations in early lesions for 2 of the 6 cases investigated (CREBBP and KMT2D in one case and STAT6 in the other), with one case displaying stepwise accumulation of its observed mutations. Remarkably, there were considerable divergences in BCL2 variants among different ISFN involved lymph nodes in all 4 cases successfully investigated, indicating ongoing intraclonal diversification by somatic hypermutation machinery. Our findings demonstrate widespread distribution of ISFN lesions, further implicating their dynamic nature with the neoplastic cells undergoing active trafficking and clonal evolution.
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... In situ follicular neoplasia (ISFN), initially described as "in situ localization of follicular lymphoma" is considered a precursor clonal process with potential to develop FL [9]. ISFN has been reported up to 2.3-3.2% of otherwise reactive lymph nodes [10,11]. ...
Warthin tumor is one of the most common benign salivary gland tumors. Overt lymphoma is known to occur in the lymphoid stroma of Warthin tumor. In situ follicular neoplasia is difficult to identify in routine histologic examination of lymphoid tissue and has not been reported in association with Warthin tumor. Our objective is to determine the prevalence of overt malignant lymphoma and in situ follicular neoplasia in Warthin tumor. We conducted a retrospective histological evaluation of 89 sequential Warthin tumor cases with available slides and blocks from the years 2010–2019. Of these, 84 cases were subjected to immunohistochemical testing, while 5 cases had been previously worked up for the suspicion of lymphoma. We identified two additional cases of lymphoid neoplasia associated with Warthin tumor including small lymphocytic lymphoma/chronic lymphocytic leukemia (n = 1) and in situ follicular neoplasia (n = 1) in addition to previously reported case of follicular lymphoma included in this study. The prevalence rate of first-time detected lymphoid neoplasia in Warthin tumor is 3.4%. The prevalence rate of overt lymphoma is 2.2%, while the prevalence of in situ follicular neoplasia is 1.1%. We propose histologic criteria to identify small lymphocytic lymphoma and follicular lymphoma in Warthin tumor. These include a monotonous interfollicular expansion of small lymphocytes and germinal centers composed of a monotonous population of lymphocytes without polarity or tingible body macrophages respectively. It is very important for pathologists to perform a diligent morphological examination and perform immunohistochemistry in suspected cases to identify subtle involvement of Warthin tumor by lymphoma. In patients with involvement of Warthin tumor by in situ follicular neoplasia, concurrent lymphoma in the same tissue and other sites should be considered. Patients without overt lymphoma elsewhere likely have a low risk of progression to follicular lymphoma. The low prevalence of in situ follicular neoplasia in Warthin tumor, combined with the low rate of clinical progression to lymphoma, make routine screening of Warthin tumor for in situ follicular neoplasia unnecessary.
