The pathobiology of follicular lymphoma

Abstract

Follicular lymphoma is one of the most frequent lymphomas. Histologically, it is characterized by a follicular (nodular) growth pattern of centrocytes and centroblasts; mixed with variable immune microenvironment cells. Clinically, it is characterized by diffuse lymphadenopathy, bone marrow involvement, and splenomegaly. It is biologically and clinically heterogeneous. In most patients it is indolent, but others have a more aggressive evolution with relapses; and transformation to diffuse large B-cell lymphoma. Tumorigenesis includes an asymptomatic preclinical phase in which premalignant B-lymphocytes with the t(14;18) chromosomal translocation acquire additional genetic alterations in the germinal centers, and clonal evolution occurs, although not all the cells progress to the tumor stage. This manuscript reviews the pathobiology and clinicopathological characteristics of follicular lymphoma. It includes a description of the physiology of the germinal center, the genetic alterations of BCL2 and BCL6, the mutational profile, the immune checkpoint, precision medicine, and highlights in the lymphoma classification. In addition, a comment and review on artificial intelligence and machine (deep) learning are made.

Subtypes of follicular lymphoma

The lymphoma classification of lymphoid neoplasms, as revised in 2017, included more than 80 mature lymphoid neoplasms that were divided into three main subtypes: Hodgkin, B-cell, and T-cell lymphomas.^1,2 The broad categories of mature B-cell neoplasms are shown in Figure 1. In this classification, each lymphoma subtype arises or has a stage of differentiation from a particular compartment of the immune system. Therefore, the classification is based in part on the physiological cell counterpart or cell of origin. For example, follicular lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma would arise from the germinal centers.

Fig. 1.

Cell-of-origin and classification of mature B-cell neoplasms

The different lymphoma subtypes are classified based on their histological architecture, cellular morphology, immunophenotype, genetic characteristics, and correspondence to the normal stages of B-cell development, such as naïve, germinal center, and post germinal center cells. Follicular lymphoma comprises germinal center B-cells similar to those found in secondary lymphoid follicles. It is composed of a mixture of small (centrocytes) and larger neoplastic cells (centroblasts) that have the t(14;18)/IGH::BCL2 fusion gene.

Follicular lymphoma is one of the most frequent lymphomas. Follicular lymphoma represents approximately 5% of all hematological neoplasms, and around 20 to 25% of all new non-Hodgkin lymphomas in western countries.³ As reported by Yoshino T. et al., the incidence of lymphoma has rapidly increased over the last 40 years in Japan, reaching a frequency comparable to that of Western countries.⁴

The follicular lymphoma category comprises the following entities: follicular lymphoma (including in situ follicular neoplasia, and duodenal-type follicular lymphoma), BCL2-R–negative CD23-positive follicle center lymphoma, primary cutaneous follicle center lymphoma, pediatric-type follicular lymphoma, and testicular follicular lymphoma.^5-9

Structure and function of the germinal center

Figure 2 shows a simplified version of the dynamics of the germinal center. The germinal center of lymphoid follicles is the place where activated B-lymphocytes acquire the diversity of immunoglobulin genes using the somatic hypermutation (SHM) mechanism; as a result, high-affinity antibodies are created. In that specialized immune microenvironment, B-lymphocytes also undergo class switch recombination (CSR) to create antibodies with specialized effector functions.¹⁰

Fig. 2.

Dynamics of B-lymphocytes in the germinal centers; and a stepwise evolution model of follicular lymphoma

The germinal center reaction is crucial in humoral immunity, during which somatically mutated B-lymphocytes and plasma cells with high-affinity receptors are generated. The initiation and formation of mature germinal centers follows a series of phases including early initiation (antigen activation), late initiation (T cell migration into follicle, and appearance of early germinal centre), and proliferation and establishment (appearance of mature germinal center). Each phase is characterized by a different expression and/or functional requirement of molecules, NFKB and MYC are necessary in the initiation stages, while BCL6, SPIB, and BACH2 in late initiation and mature stages. This figure shows the dynamics of the germinal center reaction and selection of high-affinity antibody mutants. Antigen-activated B-lymphocytes undergo clonal expansion in the dark zone, during proliferation, somatic hypermutation (SHM) introduces basepair changes into the V(D)J region of the variable region (IgV) genes of immunoglobulin. In the light zone, with the help of follicular dendritic cells (FDCs) and T follicular helper (Tfh) cells, B-lymphocytes with improved-modified B-cell receptor (BCR) high-affinity are positively selected. Then, some will recirculate into the dark zone, undergo class switch recombination (CSR), or differentiate into plasma cells or memory B-lymphocytes. In the light zone, B-lymphocytes with unfavorable antibodies that are unable to capture enough antigen undergo apoptosis.

In the early immune response, in the border between the B-cell and T-cell zones, the antigen-activated B and T-lymphocytes are committed to differentiate into germinal center B-cells and T follicular helper (Tfh) cells. The migration into the follicle is facilitated by BCL6 in the case of B-cells, which happens after the Tfh cells have moved into the follicle. B-lymphocytes differentiate into blasts that proliferate until filling the follicle.^10-14 When the germinal center matures, there is polarization into two different microenvironments, the dark and light zones. In the dark zone, B-lymphocytes proliferate extremely rapidly; and generate a large quantity of mutations in immunoglobulin (SHM). Then, dark zone B-lymphocytes differentiate into light zone B-lymphocytes. There, the ones with high-affinity antibodies are selected; and instructed to recirculate to the dark zone to undergo further SHM (process mediated by MYC, and REL); or to differentiate into memory or plasma cells.^10-14 Follicular lymphoma is characterized by an immune microenvironment that includes all the components of the germinal center. The germinal center B-cell origin of follicular lymphoma is also supported by the identification of ongoing somatic hypermutation of the immunoglobulin heavy chain variable region (IGVH) of t(14;18)-positive lymphoma cells.^15-19

Clinicopathological characteristics of follicular lymphoma

Follicular lymphoma originates or has a differentiation stage of germinal B-lymphocytes; and in most cases grows in a follicular (nodular) architectural pattern. Follicular lymphoma is clinically indolent in most cases and is associated with a favorable outcome. Nevertheless, in a fraction of patients, the disease behaves more aggressively with progression, and adverse outcomes. Because of the use of rituximab, outcomes of the follicular lymphoma patients have improved significantly, with around 80% of the patients having an overall survival above 10 years.³ Prognostic factors include the Follicular Lymphoma International Prognostic Index (FLIPI) that includes age, nodal sites, LDH, hemoglobin, and stage variables²⁰ and is also valid in the rituximab era;²¹ the PRIMA prognostic index (PRIMA-PI) that uses B2-microglobulin,^22,23 tumor grade (probably grade 1-3 A versus 3B),^24-28 and microenvironment,^29-49 among others.

From a clinical perspective, follicular lymphoma in adults and children is different. Pediatric-type follicular lymphoma is characterized by a low-stage disease (I/II), involvement of the head and neck region, high histological grade,³ absence of BCL2 rearrangement, mutations of MAP2K1 and TNFRSF14, and a high rate of cure.^50-53

Pathogenesis

The pathogenesis of follicular lymphoma is multifactorial; and involves a series of steps in which a B lymphocyte acquires genetic and epigenetic alterations that lead to malignant transformation.⁵⁴ The molecular changes can occur at different compartments of the immune system, including the bone marrow where BCL2 rearrangement occurs in precursor B-cells; or in the germinal centers of secondary lymphoid organs where somatic mutations and class switch recombination occurs.⁵⁴

In the stepwise evolution model of follicular lymphoma,³ the evolution follows three steps: healthy or subclinical disease, primary tumor, and relapse (Figure 2). The t(14;18) occurs in the bone marrow. FL-like cells (FLLCs) are in most healthy individuals and are characterized by t(14;18). Follicular lymphoma emerges from early mutated cancer precursor cells (CPCs) engaging in a dynamic process of reentry into the germinal center, evolving and disseminating over decades in asymptomatic individuals.³ Such early clones are likely responsible for posttreatment relapses. In situ follicular neoplasia (ISFN) represents an early precursor lesion that may progress into follicular lymphoma at a low rate of progression.³

Follicular lymphoma neoplasia is characterized by a mixture of small cleaved B-lymphocytes (known as centrocytes); and larger noncleaved B-lymphocytes (known as centroblasts); and a tumor immune microenvironment that mimics the structure of the secondary follicles⁵⁵ (Table 1). This dynamic structure comprises reticular cells, follicular dendritic cells (FDC), T follicular helper (Tfh) cells, FOXP3-positive T follicular regulatory (Tfr) cells, and macrophages.¹³ Table 1 shows the grading. The histological pattern is follicular (>75%), follicular and diffuse (25-75%), focally follicular/predominantly diffuse (<25%), and diffuse (0% of follicular).²

Table 1. Grading and mutational landscape of follicular lymphoma.

Grading of follicular lymphoma
Grade	CB:HPF	Characteristics
1	0-5	CD10+, BCL2+, and BLC2 translocation+ in 90% of cases
2	6-15	CD10+, BCL2+, and BLC2 translocation+ in 90% of cases
3A	>15	Presence of centrocytes, CD10+, BCL2+, and BLC2 translocation+ in 75% of cases
3B	>15	Absence of centrocytes (diffuse areas of centroblasts), CD10+, BCL2+, and BLC2 translocation+ in few cases
Mutational profile
Gene	%	Function / Effect
KMT2D	80-90	Loss of function; histone modification
IgHV, IgLV	75-90	Gain of function; BCR signaling and proliferation
CREBBP	33-70	Loss of function; histone modification
BCL2	0.5	Gain of function; anti-apoptosis
TNFRSF14	20-50	Loss of function; immune evasion
BCL6	47	Gain of function; tumor progression
H1-2, H1-4	44	Loss of function; chromatin remodeling
RRAGC	17	gain of function; mTOR survival
EZH2	7-30	Gain of function; histone modification
TNFAIP3	2-26	Loss of function; survival
Prognosis
m7-FLIPI	EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP and CARD11
Genetically-targeted therapy
Tazemetostat	EZH2 inhibitor
Duvelisib	PI3K inhibitor
Copanlisib	PI3K inhibitor
Ibrutinib	CARD11 and FOXO1 mutation+ cases
Vorinostat	CREBBP and EP300 mutation+ cases
Pidilizumab	PD-L1

Table based on the work of Carbone A. et al. and Stevenson FK. et al.^3,143

Follicular lymphoma progresses into transformation to diffuse large B-cell lymphoma (associated to TP53 mutation); and high-grade B-cell lymphoma with double-hit BCL2 and MYC rearrangement in most cases.⁵⁶ Nevertheless, transformation to Epstein–Barr virus-related Hodgkin-like lymphoma has been described.⁵⁷ Other rarer forms also include classic Hodgkin lymphoma, histiocytic/dendritic sarcoma, and high-grade B-cell lymphoma with double-hit TdT+.⁵⁶

B-cell leukemia/lymphoma 2 (BCL2)

Most follicular lymphoma cases overexpress the apoptosis regulator Bcl-2, also known as B-cell leukemia/lymphoma 2 (BCL2), which is located at the 18q21.33 chromosomal location. BCL2 overexpression in most cases is due to the translocation t(14;18)(q32;q21) that locates the BCL2 gene under the control of the IgH locus (85-90 percent of Follicular lymphoma cases). Other uncommon but equivalent translocations involving BCL2 are the kappa light chain gene on chromosome 2 resulting in t(2;18)(p11;q21); and the lambda light chain gene on chromosome 22 resulting in t(18;22)(q21;q21).^58,59 In this rearrangement process, RAG1 and RAG2 are involved as they mediate breaks in pre-B cells.⁶⁰

The BCL2 oncogene is a suppressor of apoptosis (prevents caspase activation) in many types of cells,⁶¹ and as a result the cells have increased survival. Nevertheless, the BCL2 overexpression is not sufficient for developing lymphoma as this translocation has been found in healthy individuals.^62-64 In addition to BCL2, follicular lymphoma has increased expression of other antiapoptotic factors such as BCL-XL and MCL1; and lower expression of proapoptotic factors such as BAX and BAD. Both BAX and BAD are the major initiators of apoptosis; they aggregate into the mitochondrial membrane and release cytochrome c into the cytoplasm. As a result, there is an activation of caspase-9 and then caspase-3. Active caspase-3 is responsible for apoptotic chromatin condensation and DNA fragmentation.^65-68 Therefore, the result is a promotion of cell survival⁶⁹ (Figure 3).

Fig. 3.

Pathogenesis of follicular lymphoma

The pathogenesis of follicular lymphoma is multifactorial; and involves a series of steps in which a B lymphocyte acquires genetic and epigenetic alterations that lead to the malignant transformation. The pathobiology includes genetic alterations in BCL2 and BCL6, a mutational profile, and changes in the immune microenvironment and the immune checkpoint. On the left, a characteristic low-grade follicular lymphoma is shown. This case was characterized by a nodular proliferation of centrocytes, which had a classical phenotype with positivity of CD20, CD10, BCL6, and BCL2, and a mesh of CD21 follicular dendritic cells. CNAs, copy number alterations.

BCL2 rearrangement-negative follicular lymphoma represents less than 10% of the cases, and their protein expression of BCL2 is decreased or absent in comparison to the follicular lymphoma with BCL2 translocation.⁷⁰ Usually, the rearrangement-negative follicular lymphoma cases are characterized by having a predominantly diffuse histological pattern; or a nodular/follicular growth pattern with a high histological grade (usually 3b). Interestingly, as described by Katzenberger T and Siddiqi IN et al.,^71,72 these predominantly diffuse follicular lymphoma cases are atypical, have variable protein expression of BCL2, high protein expression of CD23, copy number losses of 1p36 locus, and mutations of TNF receptor superfamily member 14 (TNFRSF14) and STAT6 mutation.

BCL6 transcription repressor

Follicular lymphoma cases with a histological grade 3B appear closer to diffuse large B-cell lymphoma than low-grade follicular lymphoma.²⁴ Cytogenetic studies found that could be characterized by t(14;18) affecting the BCL2 gene, the presence of 3q27 rearrangement involving the BCL6 gene, and others.²⁴ Although initially it was thought that the BCL2 and BCL6 rearrangements were mutually exclusive. Nowadays, there are cases of double-positive rearrangement exist.^73-76 B-cell lymphoma 6 protein (BCL6) is a transcriptional repressor that plays a role in the formation of the germinal center and in antibody affinity maturation. The mechanism of repression is by binding to the BCL6-binding site (5’-TTCCTAGAA-3’) or by repressing the transcriptional activity of other transcription factors.⁷⁷ BCL6 is responsible for the suppression in B-lymphocytes of the germinal centers of genes associated with cell differentiation, apoptosis (TP53), cell cycle control (allowing them to proliferate), and inflammation. BCL6 upregulates Activation-induced cytidine deaminase (AICDA, also known as AID), which is responsible for germinal center-associated somatic hypermutation (SHM).^32,77-83 BCL6-null mice lack germinal centers.^84,85 Therefore, BCL6 is a key oncogene in B-cell lymphomagenesis.⁸⁶

Other genetic alterations

Cytogenetic and whole-genome copy number and LOH analyses have shown that in follicular lymphoma, the most frequent areas of gains are located at chromosomes 1, 6p, 7, 8, 12q, X, and 18q/dup, and of losses of 1p, 6q, 10q, and 17p² (Figure 3). Several genomic changes affect the 1p36 locus, which includes the TNFRSF14 gene, and include copy number losses, copy neutral loss of heterozygosity (CN-LOH, acquired uniparental disomy), and mutations. These changes are associated with poor prognosis.^87-89 Deletions of 6q are found in around 20% of the cases, and these changes are usually associated with an unfavorable prognosis.^88,90,91 The abnormalities of chromosome 3 include the 3q27 locus and involve the BCL6 gene; and are associated with BCL2 rearrangement-negative cases.^24,73

MYC translocations are commonly acquired and are present in 25% of transformed follicular lymphoma cases.^92,93 Recently, it has been reported that cases with BCL6 rearrangement and/or BCL6 gain (with cases of BCL2 rearrangement and/or of copy number gain excluded) correlated with favorable progression-free survival.⁷⁵ BCL6 rearrangement-positive follicular lymphoma is characterized by higher rates of grade 3A, and MUM1 expression and less interfollicular spread pattern.⁷⁵

Mutational landscape

The mutational landscape of follicular lymphoma has been analyzed by several groups using next-generation sequencing (NGS). The NGS workflow contains three steps: library preparation, sequencing, and analysis. The analysis tech-workflow includes primary, secondary, including mutation calling, and tertiary with annotation, and data interpretation and prioritization. Differences in highlighting high-confidence calls are a relevant issue to be solved.

Several groups have focused on the analysis of histone and chromatin-modifying genes. In order of frequency, the most mutated in follicular lymphoma were KMT2D, CREBBP, EZH2, EP300, HIST1H1E, KMT2C, ARID1A, and SMARCA4.^93-101 Interestingly, it has been reported that CREBBP and EZH2 mutations are an early event in the pathogenesis, whereas KMT2D and TNFRSF14 would occur later.^94,97,102

An important pathway that is also mutated is mTOR, such as RRAGC, which is important for the activation of the pathway.¹⁰³ Interestingly, activating RRAGC mutations would promote lymphomagenesis by interacting with the microenvironment.¹⁰⁴

Mutations of the B-cell receptor pathway are also found, including BTK; and CD79B, which control many functions of B-lymphocytes such as cell growth, differentiation, survival, and migration.¹⁰⁵

Transformed follicular lymphoma is associated with TP53 mutations, and they are not usually found at diagnosis; but are found in subsequent biopsies before transformation.^106-108

In order of frequency (Table 1), the most frequently mutated genes in follicular lymphoma are KMT2D (80-90%) as a loss of function (histone modification, proliferation); IgHV and IgLV, gain of function (75-90%, BCR signaling, proliferation); CREBBP (33-70%), loss of function (histone modification), BCL2 (50%), gain of function (suppression of apoptosis, survival); TNFRSF14 (20-50%), loss of function (increased BCR signaling, immune evasion); BCL6 (47%), gain of function (transcription factor, tumor progression); H1-2, H1-4 (44%), loss of function (chromatin remodeling); RRAGC (17%), gain of function (mTORC1 survival signal); EZH2 (7-30%), gain of function (histone modification), and TNFAIP3 (2-26%), loss of function (loss of tumor suppressor, survival)³ (Table 1) (Figure 3).

An improved prediction of follicular lymphoma using a targeted sequencing panel, known as m7-FLIPI, has also been designed. The calculator can be accessed at https://www.german-lymphoma-alliance.de/box.php?action=box.boilerplate.detail&site=scores&boilerplatePk=BD7B559B-C5CF-DF40-19B1-4E214D787FFA (Accessed on March 30, 2023). This panel included seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP and CARD11), FLIPI, and Eastern Cooperative Oncology Group (ECOG) performance status.¹⁰⁹

The mutational profile of t(14;18) negative Follicular lymphoma has recently been described,⁵³ and it has been found to be heterogeneous. The differences between stage I versus III/IV follicular lymphoma have also been analyzed.¹¹⁰

Finally, one of the few genetically targeted therapies available is tazemetostat. It is an inhibitor of EZH2 approved by the FDA that provided a favorable overall response rate in the case of EZH2 mutation.¹¹¹

Immune checkpoint and tumor immune microenvironment

The knowledge of the composition and role of the tumor microenvironment (TME), host immune response, and immune checkpoint has recently advanced. Follicular lymphoma cells are mixed with a TME milieu of nonmalignant immune, stromal, and extracellular components, which create a bidirectional interaction between the follicular lymphoma neoplastic cells and the immune microenvironment.^41,112,113

Since the identification of the role of the immune microenvironment in follicular lymphoma by gene expression arrays, many publications have analyzed several components of the microenvironment that were found to have prognostic relevance. The components highlighted are immune gene-signature, macrophages, CD4-positive T-lymphocytes, CD8-positive cytotoxic T-lymphocytes, FOXP-positive regulatory T-lymphocytes (Tregs), PD-1, and PD-1 ligands, TNFRSF14 (HVEM), BTLA, CSF1R, IL-10, and microvessel density, among others. In summary, the data indicate that markers of M2-like tumor-associated macrophages (TAMs) and microvessels (angiogenesis) are associated with an unfavorable prognosis. Conversely, FOXP3 (Tregs), PD-1 (Tfh), and CD8 (Tc) are associated with a favorable clinical evolution.^29-49 Some components of the microenvironment are also related to the histological transformation, such as high levels of tumor-associated CD68-positive and PD-L1-positive macrophages (TAMs)¹¹⁴ (Figure 3 and 4).

Fig. 4.

The immune response in follicular lymphoma

The immune response is central to the pathobiology of follicular lymphoma. The work of LLMPP³⁶ identified two immune responses related to the host immune response with predictive value; the immune response type 2 was characterized by genes associated with tumor-associated macrophages. Further work using the same gene expression dataset confirmed the results, including several pathway analyses using gene set enrichment analysis (GSEA). Interestingly, macrophages increased in the progression from low- to high-grade follicular lymphoma but also in the transformation to diffuse large B-cell lymphoma, including the creation of 3D networks.^34,35,142

A recent study analyzed the CSF-1/CSF1R pathway using an in vitro analysis and an in vivo follicular lymphoma xenograft mouse model. The results were validated in a series of human follicular lymphoma by immunohistochemistry. The crosstalk between follicular lymphoma B-lymphocytes, macrophages, and follicular dendritic cells was analyzed. This result supported the role of macrophages in follicular lymphoma pathogenesis; and indicated that CSF1R may be relevant as a prognostic factor cooperating with anti-CD20 immunotherapy.⁴⁸

Precision medicine

The management of patients with relapse or refractory follicular lymphoma is changing. Cases with EZH2 mutations (in codon Y646, A682, or A692) with no alternative treatment options can be treated with tazemetostat, which is an antineoplastic agent and a potent and selective inhibitor of EZH2. Other drugs are duvelisib (PI3K inhibitor), umbralisib (multikinase inhibitors), and copanlisib (PI3K inhibitor). Nevertheless, FDA approval of the lymphoma medicine umbralisib has been withdrawn due to safety concerns.^115,116

FDA has also granted accelerated approval to axicabtagene ciloleucel (Yescarta) for relapsed or refractory follicular lymphoma, which is an immunotherapy medicine (a CD19-directed chimeric antigen receptor (CAR) T-cell therapy).^115,116

Other possible targets are ibrutinib (CARD11 and FOXO1 mutation), pidilizumab (PD-L1 expression), and vorinostat (CREBBP and EP300 mutation)¹¹⁷ (Table 1).

Pathobiology and highlights in the lymphoma classification

Recently, there have been advances in the understanding of the pathobiology of follicular lymphoma, which has led to changes and/or highlights in the classification of small B-cell lymphoid neoplasms of ICC 2022.⁵

• Histological grades are maintained as previously.² In case of follicular lymphoma grade 3, the presence of rearrangement of BCL2 and CD10 positivity favor grade 3A against 3B. In young cases, grade 3B and MUM1 (IRF4) positivity should recommend analysis of IRF4 alteration. Routine molecular testing is not necessary; but could be recommended in selected patients (EZH2 inhibitors).

• BCL2-R negative; CD23-positive follicle center lymphoma is classified as a type of follicle center lymphoma. This type can have a histological diffuse pattern, is located in the pelvic/inguinal zone, and usually has STAT6 mutations.

• Primary cutaneous follicle center lymphoma has molecular and cytogenetic characteristics different from those of other follicular lymphoma.

• Testicular follicular lymphoma is recognized as a distinct form in young boys.

Advances in the pathobiology of Follicular lymphoma have also been translated into the WHO-HAEM5 as described by Alaggio R. et al..⁹

• The term classic follicular lymphoma (cFL) is used and is separated from follicular large B-cell lymphoma (FLBL); and follicular lymphoma with uncommon features (uFL). The classic FL is the most frequent (85%), has a follicular pattern, comprises centrocytes and centroblasts, and is characterized by the t(14;18) (q32;q21) translocation that is associated with the IGH::BCL2 fusion. Of note, in cFL, grading is no longer mandatory.

• Follicular lymphoma grade 3B equals FLBL.

• The uFL includes the “blastoid”; and the predominantly diffuse growth pattern (which corresponds to the BCL2 rearrangement-negative, CD23-positive follicle center cell lymphoma).

Artificial intelligence

The birth of artificial intelligence (AI) was denoted by Alan Turing’s seminal work “Computing Machinery and Intelligence”,¹¹⁸ which described AI as systems that act like humans. AI is the engineering of intelligent computer programs.¹¹⁹ AI combines computer science and robust datasets to solve problems.¹²⁰ Using both machine learning and deep learning, it is possible to make predictions and classifications based on input data. A turning point in AI has been the release of OpenAI’s ChatGPT, which is a trained conversational model.¹²¹ Nevertheless, it is important to point out that thinking and making our own decisions is what makes us humans. Letting machines think for us makes us less free; and less conscious. Therefore, no machine should be made in the likeness of the human mind.

From 2015, there has been an exponential increase in the number of publications that use deep learning in the pathology field in Japan. Examples include gastrointestinal pathology,¹²² precision medicine,¹²³ urothelial carcinoma,¹²⁴ ocular pathology,¹²⁵ esophageal cancer,¹²⁶ lung cancer,¹²⁷ thyroid cytology,¹²⁸ intestinal diseases,^122,129-135 sarcoma,¹³⁶ hematological,^137-140 among others. In the field of malignant lymphoma, Miyoshi H and Ohshima K et al. showed how deep learning was capable of high-level computer-aided diagnosis based on H&E slides, including diffuse large B-cell lymphoma, follicular lymphoma, and reactive lymphoid hyperplasia;¹⁴¹ and Hashimoto N and Takeuchi I et al. analyzed several malignant lymphoma cases using immunohistochemical patterns.¹³⁸ In case of follicular lymphoma, the pathobiology has also been described using machine learning and neural networks, predicting the prognosis based on immune checkpoint and other oncogenes.^34,35,142 In conclusion, the pathobiology of neoplasia and follicular lymphoma is being analyzed using new technology.

Conclusions

Follicular lymphoma is one of the most frequent lymphomas, and is a heterogeneous disease, both clinically and genetically. It is characterized by the t(14;18) with the IGH::BCL2 rearrangement, but additional genetic changes and changes in the microenvironment are necessary for the pathogenesis. The importance of other genetic changes as prognostic markers remains to be further developed.