Pathology and diagnosis of follicular lymphoma and related entities

Pathology (- xxxx) xxx(xxx), xxx

LY M P H O M A 2 0 2 0 : A N U P D AT E

Pathology and diagnosis of follicular lymphoma and related entities CARA RANDALL, YURI FEDORIW Department of Pathology and Laboratory Medicine, Division of Hematopathology, University of North Carolina, NC Cancer Hospital, Chapel Hill, NC, USA

Summary Follicular lymphoma (FL) is an indolent, mature B-cell neoplasm classically characterised by the t(14;18)(q32;q21) with constitutive overexpression of the anti-apoptotic protein, BCL2. Most cases present in older adults with slowly progressive lymphadenopathy and follow an indolent clinical course. Typical morphology shows an expansile follicular proliferation with tumour expression of germinal centre markers, and bone marrow involvement at diagnosis is frequent. However, in the recent past, efforts to understand the biological and clinical heterogeneity of FL has effected significant change to the diagnostic approach. While morphological grade, assessed by enumerating large ‘centroblasts’ in the neoplastic follicles, generally correlates with outcome in systemic nodal FL, variants with high-grade morphology but indolent clinical behaviour have been identified. Given the clinical implications of these FL variants, knowledge of their clinical and histopathological defining features is of paramount importance to the pathologist. Furthermore, as with many areas of diagnostic oncology, precursors to FL have been identified and described with measurable rates of progression to bona fide lymphoma. Accurate diagnosis of these early lesions can often prevent unnecessary therapy and guide appropriate monitoring for disease progression. This review aims to summarise these key pathological and diagnostic features of FL. We further highlight the biological underpinnings of FL that will likely affect the classification, diagnosis, and treatment of patients with lymphoma. Key words: Hematopathology; lymphoma; follicular lymphoma; BCL2; t(14;18). Received 2 August, revised 11 September, accepted 16 September 2019 Available online: xxx

INTRODUCTION Systemic follicular lymphoma (FL) comprises approximately 20% of all lymphoma diagnoses and is the second most common mature B-cell neoplasm, following diffuse large Bcell lymphoma (DLBCL). It most commonly affects white men and women, has a median age at diagnosis of 63 years, and is extremely rare in children and adolescents. FL has a favourable prognosis with an 88.4% survival rate at 5 years.1

Patients generally present with widespread nodal disease and may have splenic, bone marrow or peripheral blood involvement at the time of presentation. In most patients, FL follows a chronic relapsing course and disease burden often ebbs and flows without treatment, though a subset of patients will progress rapidly with transformation to an aggressive lymphoma.2,3 Insights into the molecular pathogenesis of FL and appreciation of FL variants and precursor lesions have significantly impacted care for patients. Often subtle morphological differences between aggressive and indolent FL subtypes are important to recognise for both prognostic and predictive purposes. This review summarises the current classification of FL, with a focus on clinical, histopathological, and molecular features that define relevant disease subtypes and variants.

SYSTEMIC (NODAL) FOLLICULAR LYMPHOMA Biology Follicular lymphoma arises from germinal centre (GC) B cells that have undergone preceding oncogenic events contributing to lymphomagenesis. One of the earliest of these events is the t(14;18)(q32;q21) translocation between the immunoglobulin heavy chain (IGH) gene promotor regions and the B cell lymphoma/leukaemia 2 (BCL2) protooncogene leading to constitutive expression of BCL2. While not definitional, the translocation is identified in most cases (80–90%)4–6 of FL. The acquisition of this translocation occurs in the bone marrow during heavy chain rearrangement, well before the maturing B cells enter the GCs in the lymph node.7,8 Under physiological conditions, B cells lack BCL2 and undergo apoptosis if outcompeted during somatic hypermutation and selection. Given their abnormal expression of BCL2, B cells with t(14;18) can escape the normal apoptotic process allowing for prolonged life spans and acquisition of additional oncogenic events. There are minor alternate translocations that juxtapose the immunoglobin light chain promotors to BCL2 [t(2;18) and t(18;22)], resulting in similar abnormal expression of BCL2 on naïve B cells.4 Importantly, t(14;18) alone is not sufficient to cause lymphoma, as 50–70% of healthy individuals have detectable levels of this translocation in their blood.9–11 Additionally, t(14;18) is the sole cytogenetic abnormality in <10% of FL cases, supporting the need for additional chromosomal abnormalities and/or mutational events.4 Finally, cases with a characteristic FL immunophenotype that lack t(14;18), some

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with a characteristic diffuse growth pattern, harbour alternate oncogenic and genomic profiles (see section Morphology). The GC environment is highly mutagenic, as naïve B cells are under constant pressure for selection via high-affinity immunoglobulin and undergo cycles of genomic rearrangement and proliferation. Because of aberrant BCL2 expression, precursor FL cells survive for prolonged periods in the GC, where some of them experience additional events that halt maturation. These cells, which retain GC functionality via expression of proteins such as B cell lymphoma 6 (BCL6) and activation-induced cytidine deaminase (AID), have been termed follicular lymphoma-like cells (FLLCs).5,12 These FLLCs may have a centroblast or centrocyte phenotype, depending on the stage of their maturation arrest in the GC. Interestingly, some FLLCs undergo class-switch recombination but retain IgM/IgD surface expression, a phenomenon known as the allelic paradox.5,6,12–14 These cells are not obligatory FL precursors, but are hypothesised to exit and reenter the GC repeatedly, accumulating additional genomic aberrations until they become committed FL precursors. The committed precursors may then travel to secondary lymphoid organs and/or bone marrow, becoming early histological lesions or overt FL; or they may undergo further malignant evolution, creating subclones that present later in the disease course as clinically distinct entities such as transformed follicular lymphoma.5,6,14 In some patients, in situ follicular lymphoma (ISFL), overt FL and transformed FL have been shown to lack a clonal relationship, supporting the theory that multiple committed precursors may undergo unique changes creating different malignant clones in various sites.15,16 Characterisation of the post-t(14;18) lymphomagenic events that occur within the FLLCs and committed FL precursors has proven complex, but there are known secondary chromosomal alterations and molecular derangements of epigenetic modification, B cell receptor signalling, cell cycle regulation and immune evasion. Recurrent chromosomal aberrations include copy number changes of multiple chromosomes, most notably loss of 1p36, 6q and 17p, and gains of 1q, 7, 8, 12q, 18q and X, in addition to duplication of the der(18)t(14;18). Losses of 6q and 17p are strongly associated with poor outcomes and transformation to higher grade disease.17–21 Changes involving 1p36 (contains TNFRSF14) are seen in all forms of FL, but are enriched in the diffuse morphological variant and paediatric-type follicular lymphoma (see section Paediatric-type follicular lymphoma).22,23 Dysregulation of gene expression and transcription is an important component of follicular lymphoma pathogenesis. Mutations in one or more genes encoding the histonemodifying enzymes KMT2D (MLL2), CREBBP, EZH2 and EP300, in addition to MEF2B (transcription factor) and ARID1A (component of the SWI-SNF complex), have been found in up to 90% of FL cases. In approximately 10–20% of FL cases, CARD11, which encodes a protein in the B cell receptor signalling pathway, shows gain-of-function mutations. Downstream of B cell signalling, the transcription factor FOXO1 is constitutively activated by a missense gain of function mutation in 5–10% of cases.15,24–27 When evaluated in toto, this spectrum of molecular genetic changes accounts for increased cell proliferation and survival, decreased differentiation, and impaired T-cell activation and immune response. In most cases, the number of genetic alterations increases proportional to morphological grade.

Mechanisms by which FL can manipulate its environment to promote tumour growth while maintaining immune evasion have also been identified. The tumour microenvironment of FL is unique, recapitulating the normal GC, including non-neoplastic T cells, dendritic cells, macrophages, and sometimes non-neoplastic B cells. However, the normal homeostatic balance of each cellular component is perturbed in the neoplastic follicles of FL. Follicular T helper cells (Tfh) are enriched in FL, with both an overall increase and increase in the relative abundance of T regulatory cells (Treg). CCL17 and CCL22 produced by the neoplastic B cells promote the migration of Treg cells, normally a minor part of GCs, to the tumour microenvironment. The Treg lymphocytes dampen antitumor immune response, and CREBBP mutations are associated with decreased expression of MHC class II molecules.27 FL-associated stromal cells release CXCL12, attracting FL B cells to the growing tumour.28–30 Stromal cells are further activated via production of cytokines such as TNF-a, which are upregulated in the setting of TNFRS14/ 1p36 loss.31 TNFRS14-negative FL B cells are also resistant to FAS-mediated apoptosis.32 Some studies33,34 have suggested that the composition of the microenvironment can be prognostic, and even IHC for Treg subsets and tumourassociated macrophage scoring have shown promise,35,36 through these tools are not yet in use for clinical purposes. Morphology Classic FL is characterised by crowded neoplastic follicles effacing the normal nodal architecture. In contrast to reactive GCs, neoplastic follicles are similarly sized, non-polarised, have attenuated or absent mantle zones, and lack tingiblebody macrophages. FL is composed of centrocytes and/or centroblasts, with the proportion of centroblasts defining the grade. Centrocytes are small to medium-size lymphocytes with irregular nuclear contours (cleaved cells), relatively condensed chromatin and scant cytoplasm. Centroblasts are large cells (usually 3 times that of a resting lymphocyte) with round to oval nuclei, multiple peripherally located nucleoli and some measure of identifiable cytoplasm. Centroblasts can be challenging to distinguish from follicular dendritic cells, which also have large round nuclei but, in comparison, have dispersed, nearly clear chromatin with a single eosinophilic nucleolus, a heavier nuclear membrane and indistinct cytoplasm (Fig. 1). Grade 1–2 (low-grade) FL cases contain <15 centroblasts per high power microscopic field (hpf), evaluated in 10 different follicles. A single hpf is defined as a 40×, 0.159 mm2 field, and the evaluated follicles should be representative of the whole, rather than focused on those with higher numbers of centroblasts. It is not recommended to separate grades 1 and 2, as the distinction is not reproducible, and their clinical courses are similar. Grade 3 FL is characterised by 15 centroblasts per high power field, and is further separated into grade 3A, those cases with background centrocytes, and grade 3B, in which the follicles are composed entirely of centroblasts. If a single case is composed mostly of grade 1–2 FL with a distinct area of grade 3 disease, the diagnoses should be listed in conjunction. Importantly, grade 3B cytology with a diffuse growth pattern warrants the diagnosis of diffuse large B-cell lymphoma (DLBCL). Most FL cases are low-grade (grade 1–2), and a pure grade 3B FL is rare, as most cases will have some diffuse

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FOLLICULAR LYMPHOMA

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Classic morphological features of follicular lymphoma. (A) The lymph node architecture is replaced by irregular ‘back-to-back’ follicles with attenuated mantle zones (H&E). (B) High-power images of a malignant follicle primarily composed of small, irregularly shaped neoplastic cells (centrocytes), scattered large centroblasts (arrows), and rare follicular dendritic cells (arrowheads) (H&E).

Fig. 1

component and therefore will be classified as grade 3B FL and DLBCL. Immunohistochemistry and grading In addition to pan-B-cell markers such as CD19, CD20, and CD79a, the tumour cells in typical FL cases are positive for the GC markers CD10 and BCL6 and show characteristic coexpression of BCL2, a combination not seen in reactive GCs (Fig. 2). However, there are cases of BCL2-negative FL, which are often associated with a late GC immunophenotype, expressing IRF4/MUM1 and lacking CD10. Often these are high grade tumours or specific variants which lack t(14;18) (see below); therefore, BCL2 negativity does not exclude FL. In addition, BCL2 should be interpreted in conjunction with CD10, as primary follicles and background T-cells are also positive for BCL2. Some cases of FL, especially those with

divergent differentiation, may lose expression of the GC markers CD10 and/or BCL6. HGAL and LMO2 are additional GC markers which, when available, may also be helpful (see section Morphological variants below). CD21 and CD23 are helpful in identifying the follicular architecture, especially in small biopsies, and highlight follicular dendritic cell meshworks which are often more irregular than those seen in normal follicles.2 CD5 is rarely expressed in FL, but when positive, is associated with a higher rate of transformation to DLBCL and shorter progression-free survival.37 Mirroring the centroblast count, Ki-67 increases with grade. Grade 1–2 tumours have a Ki-67 rate <20%, while most grade 3B tumors have >70% positivity. There are rare cases of low-grade tumours with high Ki-67 that have clinical outcomes similar to grade 3 FL; therefore, Ki-67 is an important adjunct for morphological assessment.2,38

Fig. 2 Immunohistochemical profile of nodal follicular lymphoma. (A) H&E stained sections reveal abnormal follicular architecture, (B) highlighted by CD10. (C) The neoplastic follicles aberrantly express BCL2, and (D) show haphazard and atypically low expression of Ki-67.

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There is some debate concerning the biological relatedness of low-grade (grade 1–2) and grade 3 FL. As previously mentioned (see section Biology), most cases of FL, especially grade 1–2 cases, are characterised by t(14;18). The frequency of t(14;18) decreases in higher grade cases, with the lowest incidence in grade 3B cases, especially those with concomitant DLBCL.38 These grade 3B, t(14;18)-negative cases often show BCL6 rearrangements or amplification of the BCL6 locus (3q27), and lose immunohistochemical expression of CD10.39–42 Grade 3A cases are morphologically, immunohistochemically, and molecularly similar to grade 1–2 FL. Gene expression profiling studies generally suggest that grade 3A FL is more closely related to grade 1–2 FL than grade 3B. However, grade 3B FL shares many signatures with DLBCL, although it remains distinct from DLBCL and related to FL when assessed as a pure 3B FL.38,43 Morphological variants Numerous morphological growth patterns have been identified in FL. The diffuse pattern is of note as it can be seen in combination with classic follicular morphology or as a nearly pure pattern (Fig. 3). The latter is particularly important as it associated with t(14;18) negativity, BCL2 negativity and chromosomal deletion 1p36 (the TNFRSF14 locus).23 The presence of focal microfollicles, retained CD10 positivity, and often CD23 expression facilitate discrimination from other mature B-cell lymphomas. Diffuse FL often forms large tumours located in the inguinal region but behaves indolently. Even when present in conjunction with classic follicular morphology, the WHO recommends delineating the proportion of diffuse component by quartiles when given adequate tissue for evaluation. The clinical significance of a mixed diffuse and follicular pattern is uncertain, as clinical outcomes are similar in all groups. Of note, interfollicular spread of neoplastic cells does not constitute a diffuse pattern.2 Additional morphological patterns include floral, hyaline vascular, blastoid, and those with divergent differentiation,

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such as marginal zone (MZ) and plasmacytic. The floral pattern is characterised by invagination of mantle zone lymphocytes into the neoplastic follicles, creating an irregular, serrated appearance reminiscent of progressively transformed GCs. Therefore, the process may be mistaken for a reactive phenomenon. In addition, the presence of CD5+ mantle cells within the follicles and rare reported instances of CD5+ floral FL can complicate immunohistochemical evaluation and lead to erroneous diagnosis.44,45 The hyaline vascular variant has many of the typical features of hyalinevascular Castleman disease, including ‘onion-skinning’ of the mantle zone lymphocytes, hyalinisation of blood vessels within follicles, and follicle twinning. The mantle zones are less clearly defined in hyaline-vascular FL, and the neoplastic follicles contain more lymphocytes than the involuted follicles of Castleman disease.46 In approximately 10% of FL, cytological and architectural changes suggestive of marginal zone lymphoma (MZL) are present.47,48 These cases have monocytoid neoplastic cells with moderate amounts of clear to lightly basophilic cytoplasm that are most prominent in the interfollicular zones. The monocytoid cells may also constitute a portion of cells within the neoplastic follicles themselves, raising the differential of MZL with follicular colonisation (Table 1). Immunohistochemical and cytogenetic techniques can be employed to differentiate FL and MZL when there are overlapping features. CD10 and BCL2 are often maintained in the monocytoid cells of FL with MZ differentiation; however, CD10 and BCL6 may be lost, especially in the interfollicular component, and BCL2 positivity alone is not specific for FL (or any other B-cell lymphoma). Alternative GC markers HGAL and LMO2 have been shown to be highly sensitive and specific for FL and are useful in differentiating FL with MZ features from MZL with follicular colonisation, especially when there is a prominent interfollicular component, though these stains are not widely available.45,49,50 In many cases of FL with t(14;18), the monocytoid areas maintain t(14;18), and FISH testing may be useful in scenarios where access to alternative GC markers is limited.47 While considered definitional in cases of

Fig. 3 (A) Diffuse pattern of low-grade follicular lymphoma compared to (B) diffuse large B cell lymphoma (H&E). Careful and clear reporting of diffuse lymphomas is necessary to avoid miscommunication of clinically relevant distinctions.

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FOLLICULAR LYMPHOMA

Table 1

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Classic features of follicular lymphoma identified in other lymphoma subtypes and variants

Classic feature of FL:

Also identified in:

‘Follicular’/nodular growth pattern

MZL with follicular colonisation CLL/SLL with prominent proliferation centres

CD10 and/or BCL6 expression

DLBCL, germinal centre subtype Burkitt lymphoma Rarely in other low-grade B-cell lymphomas, like MCL T-cell lymphomas of T-follicular centre immunophenotype

t(14;18)

Subset of DLBCL Rarely in B-ALL and CLL/SLL

Paratrabecular bone marrow involvement

Many morphologically low-grade B-cell lymphomas, specifically MZL and less frequently LPL and MCL

B-ALL, B-cell acute lymphoblastic leukaemia; CLL/SLL, chronic lymphocytic leukaemia/small lymphocytic lymphoma; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; LPL, lymphoplasmacytic lymphoma; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma.

lymphoplasmacytic lymphoma, plasmacytic differentiation occurs in many small B-cell lymphomas, including FL. Two architectural patterns of FL with plasmacytic differentiation have been described. Interfollicular clonal plasmacytic differentiation is associated with BCL2 rearrangement, most commonly t(14;18). An intrafollicular or perifollicular proliferation of clonally related plasma cells most often occurs in BCL2 non-rearranged cases. In both settings, the neoplastic follicular cells generally maintain GC markers, with CD10 lost more often than BCL6.51,52 Bone marrow involvement The bone marrow is involved by systemic FL in approximately 30–40% of low-grade cases and is often present at the time of diagnosis. FL typically causes paratrabecular aggregates of neoplastic cells, sometimes with follicle formation, though interstitial nodules are often seen in conjunction with paratrabecular disease (Fig. 4). Given the predominantly paratrabecular nature of the aggregates and their associated follicular dendritic cell meshworks, the neoplastic cells often do not aspirate well. Flow cytometric analysis fails to detect a monoclonal B-cell population in the majority of bone marrow specimens histologically involved by FL in a paratrabecular pattern.53 In addition, CD10 can be difficult to interpret in the bone marrow by IHC, as many myeloid cells are positive for CD10. Therefore, even in the presence of a negative flow cytometric study, paratrabecular aggregates of lymphocytes

should be carefully evaluated, and an immunohistochemical panel including CD20, BCL6 and BCL2 is often adequate to capture typical FL. This is particularly important as 10–25% of patients with low grade FL in the bone marrow have grade 3 FL or DLBCL in tissue.54 Occasionally, bone marrow involvement by FL may be the only evidence of a transformed FL in patients presenting with DLBCL elsewhere. Progression and transformation Progression refers to recurrence of FL after therapy, without evolution to a more aggressive lymphoma. As FL is an indolent, non-curable disease, progression occurs often, and the majority of progressed FL do not transform. Transformation is a histological shift most often to DLBCL, with few cases transforming to high grade B-cell lymphoma or lymphoblastic leukaemia/lymphoma, and rarely other aggressive B-cell lymphomas.21,55,56 Approximately 30% of FL will undergo transformation, with a 3% risk per year.57 Gained alterations in MYC and TP53 have been implicated in many cases of transformed FL, and most cases of transformed FL maintain the driver mutations present in the original FL (KMT2D, BCL2, CREBBP, etc.), suggesting clonal evolution of a common progenitor cell. Cases with MYC and BCL2 rearrangements are classified as high-grade B-cell lymphoma with MYC and BCL2/BCL6 rearrangements, or ‘double-hit lymphomas’. This category of lymphoma has a poorer prognosis than DLBCL, not otherwise

Bone marrow involvement. (A) The Wright–Giemsa stained aspirate smear shows increased numbers of small, mature-appearing atypical lymphocytes. (B) Typical bone marrow biopsy findings demonstrate paratrabecular localisation of neoplastic cells (H&E).

Fig. 4

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specified, though the prognosis of double-hit lymphoma arising from transformed from FL is unclear. The minority of cases of transformed FL lack t(14;18) and demonstrate an activated B-cell phenotype, being negative for CD10 and BCL6. These cases are more likely to arise from t(14;18)negative follicular lymphoma.14–16,24,58

EARLY LESIONS In situ follicular neoplasia An incidental finding, in situ follicular neoplasia (ISFN) is typically only identifiable by immunohistochemistry. Affected lymphoid tissue maintains normal follicular architecture on an H&E stain; however, strongly BCL2-positive B cells co-expressing CD10 and BCL6 can be demonstrated within GCs. Close examination may reveal a monotonous population of centrocytes, without tingible-body macrophages. The GCs may be partially or totally involved, but there is no extrafollicular spread of lesional cells.59 The cells carry the classic t(14;18) translocation and lack additional genetic alterations found in systemic FL.10 ISFN has been identified in 2–5% of excised lymph nodes, including those excised as part of a solid tumour resection or for suspicion of a haematolymphoid process, a rate far higher than the incidence of systemic FL.60,61 In some cases, patients with nonFL lymphomas, most often B-cell lymphomas, may present with ISFN in the same node.62 The great majority of patients with ISFN will not progress to overt FL, though a clonal relationship can be demonstrated between the in situ and systemic counterparts in the cases that do, suggesting that ISFN may be a tissue-based equivalent to circulating t(14;18)-positive cells.61,63 Partial involvement by follicular lymphoma In contrast to ISFN, partial involvement by FL is appreciable on H&E-stained sections, with features typical of FL such as follicle crowding and lack of well-defined mantle zones apparent in a portion of otherwise normal lymphoid tissue. The uninvolved portions of the lymph node show the typical architecture of a reactive lymph node, with variably-sized, non-crowded follicles and intact paracortex. The immunophenotype is identical to systemic FL. In patients with incidentally discovered partial involvement by FL, approximately 50% will progress to overt FL if untreated,64 and these patients often present with lower stage disease than those with nodal effacement at the time of diagnosis.65

VARIANTS AND RELATED ENTITIES Table 2 summarises the features of FL variants Duodenal-type follicular lymphoma Isolated duodenal involvement by FL represents one of the earliest forms of clinically evident disease. Even so, most cases are discovered incidentally during endoscopies for unrelated symptoms. Involved duodenal mucosa often demonstrates a multifocal granular or nodular appearance, with the highest occurrence rates in the second portion of the duodenum. Histologically, the lamina propria contains defined neoplastic follicles with some extrafollicular spread of infiltrating cells into the surrounding mucosa (Fig. 5).66,67 Primary duodenal FL is usually limited to the mucosa; if

extension into muscularis propria is identified, the duodenal involvement is likely secondary to systemic FL.68 Duodenaltype FL is overwhelmingly low grade (>95% of cases are grade 1–2), and follows an indolent course, with few cases progressing to systemic disease or transforming to a large cell lymphoma. The neoplastic cells share the immunophenotype of classic systemic FL, showing positivity for CD10, BCL2 and/or BCL6. However, follicular dendritic cell meshworks are either absent or typically (though not invariably) restricted to the periphery of the follicles.66,67 Approximately 90% of cases have t(14;18)(q32;q21), but do not show many of the additional karyotypic and molecular changes that are acquired in systemic FL, though a subset of duodenal-type FL have alterations of the TNFRSF14 locus.10,66 This lack of additional oncogenic events likely contributes to the indolent natural history of duodenal-type FL. Interestingly, gene expression profiling suggests a closer relationship to marginal zone lymphoma of extranodal lymphoid tissue (MALT) than to systemic FL, which correlates with the lack of follicular dendritic cell meshworks and IgA heavy chain restriction found in duodenal-type FL.69 Testicular follicular lymphoma Primary testicular FL is a rare entity presenting in paediatric patients as a unilateral testicular mass. Biopsies show neoplastic follicles composed primarily of centroblasts; grade 3A disease is most common. A subset of cases has concomitant DLBCL. The neoplastic follicles may efface the normal seminiferous tubules or show an infiltrative interstitial pattern. Tumour cells are positive for CD20, CD10 and BCL6, but are negative for BCL2 and uniformly lack the characteristic t(11;14) of systemic FL. Rare cases show BCL6 rearrangements. Although the histological grade suggests aggressive behaviour, paediatric patients with primary testicular FL do very well, with some patients undergoing surgery alone. In those with incomplete excision, lowintensity chemotherapy has been shown to be an effective treatment with excellent long-term survival.70,71 The rare adult cases have similar clinicopathological features and outcomes.72 Primary cutaneous follicle centre lymphoma The most common primary cutaneous B-cell lymphoma, primary cutaneous follicle centre lymphoma (PCFCL), presents as plaques and/or nodules generally localised to the head and trunk of adults.73–75 Even in the minority of patients with multifocal cutaneous disease, the prognosis of PCFCL is favourable, with excellent 5-year survival rates and only 10% of cases showing dissemination to extracutaneous sites.74 On microscopic examination, PCFCL preferentially involves the perivascular and periadnexal dermis, occasionally the subcutis, and ranges in architectural pattern from follicular to diffuse. If present, follicles are often less well-formed and in a sparser distribution than in systemic FL, but otherwise resemble classic FL with lack of polarisation, well-formed mantle zones, and tingible-body macrophages (Fig. 6). The proportion of centrocytes and centroblasts varies and classically PCFCL is not histologically graded. However, a primary cutaneous lymphoma with a diffuse proliferation of centroblasts should be classified as DLBCL, leg-type, rather than PCFCL. While this seems somewhat contradictory, the

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Table 2

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Follicular lymphoma variants

Variants

Clinical features

Morphology

Immunophenotype

Genetic features

Duodenal-type FL

Often incidentally identified during endoscopy; indolent

Variable grade; follicular pattern

CD10/BCL6+, BCL2+

t(14;18)+

Testicular FL

Indolent

High-grade

CD10/BCL6+, BCL2–

t(14;18)–

Primary cutaneous follicle centre cell lymphoma

Lesions on head and trunk; indolent

Variable cytological spectrum; diffuse to follicular

CD10– if diffuse, + if follicular, BCL2 dim–

t(14;18)–

Paediatric-type FL

Head/neck lymphadenopathy; young males; indolent

High-grade; follicular or serpiginous

CD10/BCL6+, BCL2–

t(14;18)–

LBCL with IRF4 rearrangement

Waldeyer’s ring; indolent

High-grade; diffuse ± follicular

CD10/BCL6+, BCL2+

t(14;18)–

FL, follicular lymphoma; LBCL, large B-cell lymphoma.

Fig. 5

Duodenal-type follicular lymphoma. (A) H&E stained sections of duodenal biopsy showing large neoplastic follicles with (B) uniform staining by CD20.

pattern, rather than formal grading, is necessary for accurate classification. The neoplastic cells of PCFCL are positive for BCL6, with subset positivity for CD10 and negative to weak BCL2 staining. Follicular pattern PCFCL is more likely to be positive for BCL2, but strong BCL2/CD10 co-expression is suggestive of cutaneous involvement by systemic FL.2,50,74,75 PCFCL is predominantly negative for t(14;18) and other BCL2 rearrangements, but positivity has been reported in few cases with follicular architecture, in keeping with BCL2 expression by immunohistochemistry.73 Paediatric-type follicular lymphoma

Fig. 6 Primary cutaneous follicle centre cell lymphoma. Nodular proliferation

of neoplastic follicles in the dermis (H&E), but no expression of BCL2 (inset).

clinical implications are significant as DLBCL, leg-type is an aggressive lymphoma treated with combination chemotherapy. As such, assessment of cell size and architectural

Paediatric-type follicular lymphoma (PTFL) shares some morphological and immunophenotypical characteristics with systemic FL; however, PTFL is biologically distinct, with a disparate genetic profile. Histologically, PTFL is characterised by an entirely follicular pattern with the neoplastic follicles similarly shaped and closely packed, similar to typical systemic FL, though many nodal cases show a distinctive serpiginous pattern. The neoplastic cells are often ‘blastoid’ in appearance, being of intermediate size with fine chromatin and regular oval to round nuclei. There is often abundant apoptosis with associated tingible-body macrophages, which can impart a reactive ‘starry-sky’ appearance to the neoplastic follicles (Fig. 7). As lymph nodes may be partially involved, the distinction between reactive and neoplastic follicles requires examination for normal mantle zones and polarised GCs, both of which are classically absent in PTFL. Centroblasts and centrocytes are often not identified, and therefore PTFL is not graded.2 Marginal zone differentiation has been described in PTFL, though the monocytoid cells are often restricted to a thin rim around the

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Paediatric-type follicular lymphoma. The neoplastic follicle shows expansion of intermediate-sized cells with blastoid morphology and increased numbers of tingible-body macrophages (H&E) without strong BCL2 expression by immunohistochemistry (inset).

Fig. 7

up after local excision and chemotherapy.70,76 In contrast to systemic FL and many of the related entities, LBCL with IRF4 rearrangement often shows a diffuse pattern, either as a pure or mixed component, with only a minor subset of cases having a pure follicular pattern. The cytology is similar to PTFL with intermediate-sized cells which may appear blastoid and the neoplastic follicles lack typical centroblasts/ centrocytes; however, mitotic figures and apoptotic debris are minimal, without prominent tingible-body macrophages. Coexpression of BCL6 and IRF4/MUM1, which are mutually exclusive in normal B cells, is a characteristic finding in LBCL with IRF4 rearrangement. CD10 and BCL2 are expressed in the majority of cases, though t(14;18) and other BCL2 rearrangements are absent.2,76,80 Rare cases are CD5positive, especially CD10-negative cases, though double expression of CD5 and CD10 has been reported.81 IRF4 alterations, most often a cryptic IRF4/IGH translocation, characterise LBCL with IRF4 rearrangement, and some cases have additional BCL6 rearrangement.80,82

CONCLUSION neoplastic follicles and lack significant interfollicular spread.70 Plasma cells are infrequent. Any diffuse pattern with high grade cytology excludes the diagnosis of PTFL and constitutes a diagnosis of DLBCL. Most cases of PTFL are CD10 and BCL6 positive, and lack expression of BCL2, correlating with the lack of t(14;18) in these tumours. Ki-67 staining is often high and lacks polarisation in the neoplastic follicles, a helpful feature in excluding reactive follicular hyperplasia.70,76,77 PTFL lacks BCL2 and BCL6 rearrangements, and does not have mutations in the epigenetic modifiers associated with systemic FL (EZH2, CREBBP, etc.).78 Many cases have alterations in 1p36/TNFRSF14 and the MAPK pathway.22,79 Of note, a proportion of PTFL harbour a recurring somatic mutation of the interferon regulatory factor 8 (IRF8) gene,78,79 like TNFRSF14 also involved in germinal centre B-cell development. Taken together, distinguishing PTFL from systemic FL is less challenging than differentiating PTFL from reactive follicular hyperplasia. Given the lack of specific diagnostic features, B-cell receptor gene rearrangement studies are often necessary to establish clonality and recommended in the absence of other convincing findings. PTFL presents with isolated lymphadenopathy, most commonly in the head and neck. Typically occurring in males between 5 and 25 years of age, PTFL can also occur in adult patients, though the disease is rare in this group, and systemic involvement and/or diffuse architecture must be excluded as typical systemic FL and DLBCL are more likely in adult patients. The high proliferative rate and blastoid morphology contrast with the clinically indolent course, with excision alone being curative.2,70,77 Large B-cell lymphoma with IRF4 rearrangement Large B-cell lymphoma (LBCL) with IRF4 rearrangement also occurs most commonly in paediatric patients but lacks male predominance and has a predilection for the lymphoid tissue of Waldeyer’s ring in addition to lymph nodes of the head and neck. Although still a minority, adult cases occur more often than in PTFL. The disease is clinically indolent, with disease-free survival extending up to 10 years of follow-

While classic nodal follicular lymphoma is characterised by archetypal morphological, immunophenotypic, and genomic features, the implications of these findings has significantly changed in the recent past, and meaningful variants have been extracted from what was previously considered a uniform disease. Importantly, many of the FL variants, while demonstrating high-grade histological features, are clinically indolent. Identification of these disease subtypes guides appropriate clinical care and prevents over-treatment with intensive therapeutic regimens. As our understanding of lymphoma biology and microenvironmental factors continues to evolve, so too will the classification of FL, and the demands of pathologists to effectively diagnose and riskstratify these patients. Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. Address for correspondence: Yuri Fedoriw, MD, Department of Pathology and Laboratory Medicine, Division of Hematopathology, University of North Carolina, NC Cancer Hospital C3162, 101 Manning Dr, Chapel Hill, NC, 27599, USA. E-mail: [email protected]

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