PATHOLOGICA 2020;112:1-16; DOI: 10.32074/1591-951X-35-19 Review The broad landscape of follicular lymphoma: Part I Stefano Fratoni1, Magda Zanelli2, Maurizio Zizzo3,4, Francesca Sanguedolce5, Valentina Aimola6, Giulia Cerrone6, Linda Ricci7, Alessandra Filosa8, Giovanni Martino9, Stefano Ascani10 1 Department of Anatomic Pathology, St. Eugenio Hospital of Rome, Rome, Italy; 2 Pathology Unit, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Italy; 3 Surgical Oncology Unit, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Italy; 4 Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy; 5 Pathology Unit, Azienda Ospedaliero-Universitaria - Ospedali Riuniti di Foggia, Italy; 6 Pathology Unit, University of Cagliari, Italy; 7 Pathology Unit, University of Siena, Italy; 8 Pathology Unit, Ospedale di Ascoli Piceno, Ascoli, Italy; 9 Hematology Unit, CREO, Azienda Ospedaliera di Perugia, University of Perugia, Italy; 10 Pathology Unit, Azienda Ospedaliera Santa Maria Terni, University of Perugia, Terni, Italy Summary Follicular lymphoma is a neoplasm derived from follicle center B cells, typically both cen- trocytes and centroblasts, in variable proportions according to the lymphoma grading. The pattern of growth may be entirely follicular, follicular and diffuse, and rarely completely dif- fuse. It represents the second most common non-Hodgkin lymphoma, after diffuse large B-cell lymphoma and is the most common low-grade mature B-cell lymphoma in western countries. In the majority of cases, follicular lymphoma is a nodal tumor, occurring in adults and frequently associated with the translocation t(14;18)(q32;q21)/IGH-BCL2. However, in recent years the spectrum of follicular lymphoma has expanded and small subsets of follicular lymphoma, which differ from common follicular lymphoma, have been identified Received and accepted: December 8, 2019 and included in the current 2017 WHO classification. The aim of our review is to describe Published online: January 22, 2020 the broad spectrum of follicular lymphoma, pointing out that the identification of distinct clinicopathological variants of follicular lymphoma is relevant for patient outcomes and Correspondence choice of treatment. Maurizio Zizzo Surgical Oncology Unit, Azienda Unità Sani- Key words: follicular lymphoma, B-cell, centrocyte, centroblast taria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy E-mail: [email protected] Conflict of interest Introduction The Authors declare no conflict of interest. Follicular lymphoma (FL) is the most common low-grade mature How to cite this article: Fratoni S, B-cell lymphoma in western countries, representing 20% to 30% of all Zanelli M, Zizzo M, et al. The broad non-Hodgkin lymphomas 1. It is defined as a neoplasm composed of landscape of follicular lymphoma: Part I. germinal center (GC) B cells, recapitulating the cellular composition and Pathologica 2020;112:1-16. https://doi. architecture of normal lymphoid follicle 1. It usually affects adults, with org/10.32074/1591-951X-35-19. a median age in the 6th decade of life1. The updated 2017 World Health © Copyright by Società Italiana di Anatomia Pato- Organization (WHO) Classification includes critical news about FL 1. In logica e Citopatologia Diagnostica, Divisione Itali- recent years, the histological and clinical spectrum of GC derived B-cell ana della International Academy of Pathology neoplasms has expanded, leading to the conclusion that FL represents OPEN ACCESS a far more heterogeneous entity than originally appreciated. Some var- iants are associated with age, and others with anatomic site, morpho- This is an open access article distributed in accordance logical pattern and genetic features. Clinical and biological variants of with the CC-BY-NC-ND (Creative Commons Attribution- NonCommercial-NoDerivatives 4.0 International) license. FL exist, expanding the disease spectrum. Identification of biologically The article can be used by giving appropriate credit and distinct variants has prognostic and predictive value for patients and will mentioning the license, but only for non-commercial purposes and only in the original version. For further be likely more relevant in the future. In the present review we illustrate FL information: https://creativecommons.org/licenses/by-nc- variants encountered in diagnostic practice. Surgical pathologists and nd/4.0/deed.en hematopathologists should be aware of the broad FL landscape, in order 2 S. Fratoni et al. sent. Centrocytes are small cells with cleaved nuclei, inconspicuous nucleoli and scant cytoplasm. Cen- troblasts show vesicular chromatin with 1 to 3 small nucleoli located near the nuclear membrane. Unlike reactive GC (in the secondary phase of development) in which centrocytes and centroblasts are polarized in different zones, neoplastic follicles lack polarization in dark and light zones, as confirmed by Ki-67 immu- nostaining. FL is usually positive for CD10, BCL6 and BCL2 and the translocation t(14;18)/IGH-BCL2 com- monly represents its hallmark 1. CD10 and BCL6 can be down regulated in the interfollicular areas, showing a stronger staining in the follicles than in the interfolli- cular zones 1. Many features are helpful to distinguish Figure 1. Lymph node. Follicular lymphoma. Giemsa, 40x FL from reactive follicular hyperplasia (RFH), as brief- magnification. ly illustrated in Table I. However, these features are general diagnostic criteria, which need to be verified case by case, taking into account that exceptions al- to avoid diagnostic pitfalls and obtain more accurate ways do exist. diagnosis. How to easily apply the grading Histopathology of common nodal FL system and report pattern criteria in FL th and diagnostic criteria to differentiate FL according to updated 2017 4 ed. WHO from reactive follicular hyperplasia classification The number of centroblasts within neoplastic follicles FL is a mature B-cell lymphoma of germinal center is the basis for FL grading. WHO classification adopts origin, with strict morphologic criteria and specific im- the grading system initially proposed by Risa Mann munophenotype. At microscopical examination, nodal and Costant Berard in 1983 2. The number of centro- architecture is effaced by closely packed follicles with a blasts in FL varies from follicle to follicle and grading back-to-back distribution (Fig. 1). Sometimes follicles is perfomed by counting the number of centroblasts may be spaced out, irregular, serpiginous, coalescent in 10 follicles, expressed per high-power microscopic or with regressive “Castleman-like” changes. Follicles field (HPF) 1. Ten HPF have to be evaluated within dif- are surrounded by a thin residual mantle zone or they ferent follicles and not be limited to follicles containing can completely lack the mantle. Sometimes the folli- the large amount of centroblasts 1. Grade 1-2 contain cle border is vague, not sharply defined. Neoplastic a predominance of centrocytes (grade 1: 0-5 centro- follicles show a cellular population composed by an blasts/HPF; grade 2: 6-15 centroblasts/HPF) (Fig. 2). admixture of centrocytes with a variable number of The term grade 1-2 FL is preferred as no significant centroblasts; tingible body macrophages are usually clinical differences between grade 1 and grade 2 have rare and a starry sky appearance is commonly ab- been identified. Grade 3 is defined by the presence of Table I. General diagnostic criteria to differentiate FL from RFH. Morphologic Features FL RFH Nodal architecture Partially/totally effaced Preserved Number of follicles High number, randomly distributed; uniform Low; more numerous in the cortex Follicles dark and light zone Polarization lost Polarization preserved Follicles size and shape Uniform; Regular Variable; irregular; elliptical Cellular composition of follicles Monotonous Heterogeneous Mantle zone Scant or absent Well developed Tingible body macrophages Uncommon or absent Many BCL2 immunostaining of follicles Positive (not always) Negative t(14;18)/IGH-BCL2 Present (80%) Absent THE BROAD LANDSCAPE OF FOLLICULAR LYMPHOMA: PART I 3 Table II. FL grading according to updated 2017 4th WHO classification. Grade Proportion of centroblasts Percentage Grade 1-2 [Low grade FL] 0-15 centroblasts/HPF 80-90% Grade 3A > 15 centroblast /HPF (centrocytes present) 10-20% Grade 3B > 15 centroblasts/HPF (follicles entirely composed of large centroblasts) Rare > 15 centroblasts/HPF (area with diffuse pattern of growth; absence of CD21, DLBCL CD23) (DLBCL) diagnosis (Tab. II) 1. However, grading repro- ducibility is low and it has not been easily replaced by the Ki-67/MIB1 proliferation index. Many limitations affect the current grading system, as the following: i) FL may show considerable heterogeneity from area to area, then sampling of follicles is critical (accurate grading can therefore be difficult and not advisable on core needle biopsies); ii) follicles may show a range in cytological composition, so grade 1-2 and grade 3 folli- cles may coexist inside the same lymph node; iii) large centrocytes (large cleaved cells) or small centroblasts may be interpreted differently by individual patholo- gists; iv) counting centroblasts should be rigorous; v) Figure 2. Lymph node. Follicular lymphoma, grade 1-2. Gi- poor tissue handling, fixation or technical processing emsa, 200x magnification. problems may introduce artifacts interfering with grad- ing. These factors underscore the highly subjective nature of FL grading with considerable inter-observer variation.