Follicular lymphoma and marginal zone lymphoma: how many diseases?

FL is a B-cell neoplasm derived from germinal center (GC) cells that is largely composed of a mixture of cleaved centrocytes (CC) and non-cleaved centroblasts (CB). Conventional FL involves mainly nodal sites and is characterized by a clonal proliferation of follicle center cells harboring t(14;18) and exhibiting a follicular growth pattern. Other commonly involved sites include bone marrow, spleen, and gastrointestinal tract. Distinct FL forms have been described based upon age, anatomic sites, characteristic morphological features, and the presence or absence of the t(14;18) chromosomal alteration. Among them, early in situ lesions of FL have been recognized as indolent disorders closely related to conventional FL. The new category of t(14;18)-negative CD23+ follicle center lymphoma (FCL), which can have a follicular as well as a diffuse growth pattern, has been proposed by the 2022 ICC as a provisional entity [2]. Other variants of FL such as pediatric-type follicular lymphoma (PTFL), testicular follicular lymphoma (TFL), primary cutaneous follicle center lymphoma (PCFL), and large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) are considered as distinct entities separate from conventional FL in the 2022 ICC [2].

Conventional follicular lymphomaMorphological features

FL is characterized by effacement of normal lymph node architecture by closely packed neoplastic follicles with loss of polarization, absence of body macrophages, and attenuated mantle zones. The neoplastic cells are characteristically a mixture of CC and CB. The 3rd and 4th edition World Health Organization (WHO) classifications of lymphomas [1, 4] recommended FL grading based on the number of CB per high-power field (HPF): grade 1 < 5CB/HPF; grade 2 = 5 to 15 CB/HPF; and grade 3 or high-grade > 15 CB/HPF. Grade 3 is subdivided into grades 3A and 3B; the latter is assigned to FL cases, where neoplastic follicles are essentially composed of sheets of CB. Moreover, because grades 1 and 2 comprise a morphologic continuum and are both clinically indolent, the designation grade 1–2 (low-grade FL) was introduced and widely used [1, 4]. However, FL grading based on strict counting methods of CB and CC (cells that may exhibit variation in their cytological features) lacks reproducibility and its clinical impact, especially between grades 1, 2, and 3A, appears to be less significant in the era of rituximab. Therefore, the 5th edition of the WHO [3] proposes grading to be optional in FL, gathering grades 1, 2, and 3A as classic FL, whereas FL grade 3B was renamed as follicular large B-cell lymphoma (FLBL). Although, the 2022 ICC [2] recognizes the biological relationship between grades 1, 2, and 3A, and acknowledges some difficulties in FL grading, the consensus among clinicians was to retain histologic grading, in part to allow for investigation of the response of new agents. Whether patients with grade 3A have a more adverse prognosis [5, 6] or deserve different management remains debatable and needs to be re-evaluated in the future, given evolving non-cytotoxic therapeutic approaches [5,6,7,8,9]. Of note, some FLs are composed of neoplastic cells that are not classic CB but rather small-sized blasts/blastoid cells or large cleaved cells/large centrocytes that do not strictly fit the FL3A or FL3B 2017 WHO criteria [10]. Based on the challenges in distinguishing FL 3A and 3B, the 2022 ICC recommends that emphasis should be placed on ancillary studies in conjunction with morphological assessment. The demonstration of BCL2 rearrangement (BCL2-R) and CD10 expression both favor grade 3A [2]. The 5th edition WHO recommends the name of FL with uncommon features (uFL) for these and other cases with variant morphology [3]. FL commonly has a follicular growth pattern sustained by a follicular dendritic cell (FDC) network. Sometimes more and less extended diffuse areas can be observed. Diagnostic reports traditionally identify the growth pattern, with designation as mainly follicular pattern (at least 75%); FL with follicular and diffuse pattern (25–75%); predominantly diffuse (< 25%); and totally diffuse (no follicles). Moreover, t(14;18)-negative CD23+ FCL, often having a diffuse growth pattern, should be also distinguished from conventional FL (see below). As recommended in the last WHO 2017 [1] and 2022 ICC [2], the presence of entirely or predominantly diffuse areas, in cases with high-grade cytology, will support a diagnosis of diffuse large B-cell lymphomas (DLBCL). However, treatment decisions in individual patients should not be based on pathology information alone but rather on integration of clinical and pathologic data [3].

In addition, several cytologic variants including FL with marginal zone B-cell differentiation (monocytoid-like cells), floral variant, or sclerosing variant (Castleman-like features) of FL have been described but are not separated from conventional FL. Other cytologic FL variants are less commonly seen.

Phenotype

FL cells express the pan B-lymphocyte antigens (CD19, CD20, CD22, CD79a, PAX-5) and IgM with or without IgD. Similar to normal GC cells, FL cells express CD10 and BCL6, usually stronger in the neoplastic follicles than in interfollicular areas. Moreover, a subset of FL especially grade 3B can be negative for CD10 and/or BCL6. In this context, other GC markers including GCET1, HGAL (GCET2), LMO2, and/or MEF2B should be performed to establish a GC phenotype and rule out other B-cell lymphoma diagnoses.

FL cells typically overexpress BCL2 as a result of the genetic hallmark of FL, t(14;18) IGH::BCL2 translocation. Similar to CD10 staining, the frequency of BCL2 expression is higher in low-grade (85–90%) than in high-grade (50–70%) FL. Overall 10–15% of FL cases, especially grade 3B [10, 11], remain BCL2-negative due to the lack of BCL2-R. The variable expression of BCL2 may also be due to mutations in the BCL2 gene that alter the epitopes recognized by some monoclonal antibodies used for diagnosis. In these “pseudo-negative” cases, other BCL2 antibodies and/or FISH for BCL2-R should be tested [12,13,14].

FL is commonly negative for IRF4/MUM1. However, it can be expressed in some cases, especially with grade 3B cytology. In these particular cases of IRF4/MUM1-positive FL grade 3B, NOTCH1/2 mutations have been reported to be associated with poorer prognosis [15]. In addition, all IRF4/MUM1-positive FL with high-grade cytological features, especially grade 3B and uFL [2, 3], should be evaluated for IRF4 alterations, especially in younger patients to rule out LBCL-IRF4 (see below).

The follicular pattern of FL may be assessed by the identification of FDC networks that are positive for CD21, CD23, and/or CD35, usually absent in cases with diffuse areas. FL with grade 1–2 usually shows a lower Ki-67 proliferation index (PI) than grade 3. However, some FL 1–2 can exhibit a high PI within follicles. The significance of an increased proliferative rate within follicles is not established [16,17,18]. Assessment of PI using Ki67 staining can be difficult because its distribution is not uniform within follicles and its expression may be highly variable between follicular and interfollicular areas. Altogether, Ki67 staining can be specified in diagnostic reports, but still has uncertain clinical significance in isolation [19], and is not required for grading.

Genomics FL with BCL2 rearrangement (BCL2-R)

The t(14;18) (q32;q21) or on rare occasions its variants t(2;18)(p12;q21) or t(18;22)(q21;q11) is the hallmark of conventional FL occurring in 85–90% of cases and leading to the overexpression of anti-apoptotic protein BCL2. Like BCL2 staining, the BCL2-R is more often observed in low-grade than in high-grade FL. However, t(14;18) can also be detected at a very low level in the peripheral blood of healthy adults (referred to as “FL-like cells”) indicating that the translocation alone is not sufficient for the development of FL, and additional genetic alterations are needed for full transformation. In fact, the acquisition of t(14;18) allows FL-like cells to iteratively re-enter GC and engage multiple cycles of somatic hypermutation (SHM), and class switch recombination (CSR) increasing the risk of accumulation of genomic instability. Mutations in epigenetic regulators and chromatin-remodeling genes are the most frequent in conventional FL [20]. Among them, chromatin-remodeling genes such as KMT2D/MLL2, CREBBP, and EP300 mutations represent early drivers of conventional FL. Epigenetic dysregulation comprises gain-of-function mutations of EZH2 that occurs in 25% of cases and may make them good candidates for EZH2 inhibition [21]. Other less frequent epigenetic modifier mutations are seen in ARID1A, MEF2B, and KMT2C genes. BCL2 mutations are common due to AID activity. TNFRSF14 mutations and deletions can be observed. In addition, other mutations involving cell signaling such as STAT6, CARD11, and FOXO1 are less frequently seen. Genomic alterations in TP53 or CDKN2A and MYC translocations are usually associated with high-grade features and/or risk of transformation [22]. According to the literature, MYC and TP53 IHC can be used as a screen for detecting genetic alterations among these genes but sensitivity and specificity vary between studies [23,24,25,26,27]. Moreover, the prognostic value of de novo FL-BCL2R with MYC-R is still controversial. Based on limited data available [28], de novo FL-BCL2R/MYC-R should not be included within the category of high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements. At the moment, investigation for the presence of MYC-R or TP53 mutations is not recommended on a routine basis [29]. In addition, other ancillary genomic studies for prognosis in FL, such as the M7-FLIPI, remain investigational [20, 29, 30].

FL without BCL2 rearrangement (BCL2-R-negative)

BCL2-R-negative FL, representing 10–15% of FL cases, is heterogeneous, both genetically and clinically [31,32,33]. This group includes some conventional FL as well as alternative forms of FL that should be diagnosed separately. At least three groups are recognized: (1) FL with BCL6-R seems to share similar genetic alterations with conventional FL BCL2-R, but at different frequencies [33, 34]. Although studies on FL BCL6-R remain heterogeneous and difficult to compare with FL BCL2-R, such cases have been associated with more aggressive diseases [33, 34]. They show less frequent expression of CD10 and are often positive for MUM1/IRF4 [10, 33,34,35,36]. NOTCH mutations are reported in this group, suggesting overlap with nodal MZL [15]; 2) BCL2-R-negative and BCL6-R-negative cases often lack CD10 and CD23 expression, also raising the question of nodal MZL. In this context, NGS analysis may help in the differential diagnosis; 3) The new provisional entity BCL2-R-negative, CD23+ FCL (see below).

Early lesions of follicular lymphoma

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. BCL2 and CD10 are strongly expressed in the tumor B-cells (almost CC-like cells) confined to the GC. Proliferation is very low as demonstrated by MIB1.

Duodenal-type FL (DFL) is a neoplastic follicular proliferation containing CC-like cells harboring t(14;18) as FL. DFL is often discovered incidentally with a low risk of progression to systemic FL.

Partial involvement of FL (PIFL) is a partial destruction of nodal architecture by enlarged follicles with attenuated/disrupted mantle areas. Neoplastic follicles are similar to FL with atypical B-cells almost CC-like cells positive for t(14;18).

Besides the presence of BCL2-R, early FL lesions share similar genetic alterations as FL but at lower frequencies [39,40,41]. However, DFL is characterized by a chronic inflammation gene signature similar to that of mucosa-associated lymphoid tissue lymphoma (MALT lymphoma) [41, 42]. Interestingly, distinct early lesions or lesions occurring at different sites have been shown to be clonally related suggesting that early clonal cells can recirculate and reach different compartments of lymphoid tissues [41, 43]. Recently, Vogelsberg et al. [44] have demonstrated branched clonal evolution rather than a linear one between early FL lesions and manifest lymphomas, suggesting that ISFN and FL evolve from a common progenitor.

Alternative forms of follicular lymphoma BCL2-R-negative CD23 +follicle center lymphoma (FCL)

In 2009, Katzenberger et al. [45], described a diffuse variant of FL with unusual clinical and pathological features. Subsequently, it was found that these cases frequently carry STAT6 mutations [31]. Further studies reported a close association of CD23 expression with STAT6 mutation, features which correlated with localized disease. Moreover, it was appreciated that at least 30% of the cases were purely follicular [33]. Due to their characteristic, clinical, morphological, and molecular features, the 2022 ICC proposed recognizing these cases as a provisional entity [2]. The specific category of BCL2-R-negative CD23+ FCL is not recognized in the 5th WHO [3], although there is some overlap with the subtype identified as “diffuse variant.” BCL2-R-negative CD23+ FCL is more frequent in women (M:F = 2:1), and often presents with inguinal involvement, but non-inguinal presentations including cervical, axillary, and even retroperitoneum can occur [31]. Patients usually present with low clinical stage. The characteristic histological features are illustrated in Fig. 1. Diagnostic criteria include the absence of the t(14;18), expression of CD23, and at least one GC marker. BCL2 staining is usually negative or weak positive. The molecular profile includes a high frequency of STAT6 and CREBBP co-mutation as well as 1q gain and a recurrent loss 1p36 loss/TNFRS14 abnormalities. The latter has been described at variable frequencies (30–97%) [33, 46]. As noted, CD23 expression is a helpful surrogate marker for the detection of STAT6 mutations [33]. Interestingly, BCL2-R-negative CD23+ FCL without STAT6 mutations carry SOCS1 mutation, which is known to be upstream of STAT6 and thereby contributes to STAT6 activation [33].

Fig. 1figure 1

BCL2-R-negative CD23+ follicle center lymphoma with predominant diffuse growth pattern. Inguinal lymph node with effaced architecture by an atypical lymphoid infiltration with diffuse pattern (A, H&E). Tumors cells are CD20-positive (B), CD10-negative (C), BCL2-negative (D), and CD23-positive (E). CD21 shows no FDC meshwork (F). Interphase fluorescence in situ hybridization (FISH) using BCL2 (G; inset × 6000) and BCL6 (H; inset × 6000) break apart probes are negative

Pediatric-type follicular lymphoma (PTFL)

PTFL was recognized as a definite entity in the WHO 2017 classification [1]. It occurs in children and adolescents, and has an excellent prognosis with conservative management. PTFL is usually characterized by an expanded and serpiginous follicular proliferation of monotonous CB, often with a starry sky pattern and moderate to high proliferation. Neoplastic cells express GC markers whereas BCL2 is typically negative. BCL2-R, BCL6-R, MYC-R, and IRF4-R are negative. The mutational profile is distinct from that observed in conventional FL with a high frequency of MAP2K1 mutations and 1p36/TNFRS14 alterations (30–70%) [47,48,49]. Additional mutations in IRF8, a tumor suppressor gene, are also common in PTFL (15–50%) [49,50,51]. Mutations in epigenetic modifiers are uncommon, in contrast to conventional FL. Among them, KMT2D is the most frequent mutated gene, observed in 16% but alterations in other genes such as CREBBP, EP300, MEF2B, and EZH2 are rare. PTFL frequently shows evidence of marginal zone differentiation, and recent studies support the view that pediatric-type nodal marginal zone lymphoma (pNMZL) is part of the spectrum of PTFL, with both disorders having similar molecular profiles, clinical presentations, and outcomes [51]. Importantly, FISH testing and mutational profile are advised to rule out a diagnosis of conventional grade 3B FL as well as LBCL-IRF4, especially in young patients.

Primary cutaneous follicle center lymphoma (PCFL)

PCFL will be discussed elsewhere in this issue with other cutaneous lymphoproliferative di

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