t(14:18) translocation involving IGH & BCL2 gene
↓
Overexpression of BCL-2 antiapoptotic protein
↓
B-cell do not undergo apoptosis
Tumorigenesis starts in precursor B cells and becomes full-blown tumour when the cells reach the GC maturation step.
FL is preceded by an asymptomatic preclinical phase in which premalignant B cells carrying a t(14;18) chromosomal translocation accumulate additional genetic alterations, although not all of these cells progress to the tumour phase.
Origin of mature B cell lymphomas:
B cell lymphomas are cancers that develop from the malignant transformation of B lymphocytes at various stages of ontogeny. Most are of mature B cell origin, and revolve around the germinal centre (GC) reaction, a critical step in which B cells are subject to intense proliferation and genomic remodelling processes — namely, somatic hypermutation and class-switch recombination — to generate memory B cells and plasma B cells that produce high-affinity antibodies. From naive B cells to memory B cells, most differentiation steps are associated with a malignant B cell subtype (defined as the cell of origin (COO)) on the basis of classic histological definitions and gene expression profiling. The COO assumes that B cell malignancies are ‘frozen’ at a given B cell differentiation stage arising in a particular location of the B cell follicle. For example, follicular lymphoma (FL) is a follicle-related B cell lymphoma that is considered the malignant counterpart of normal ‘frozen’ GC B cells. Unmutated mantle cell lymphoma (UM-MCL) originates from mantle zone B cells, marginal zone lymphoma (MZL) resembles marginal zone B cells whereas Burkitt lymphoma (BL) resembles dark zone B cells. Based on the COO, distinct diffuse large B cell lymphoma (DLBCL) molecular subtypes are defined as not otherwise specified DLBCL (DLBCL NOS), whereas, the GC B cell-like DLBCL corresponds to B cells that are arrested at various stages of the GC transit (from dark zone to light zone B cells) and the activated B cell-like DLBCL seems to derive from GC B cells en route to plasma cell differentiation, resembling plasmablasts. BCR, B cell receptor; FDC, follicular dendritic cell; M-MCL, mutated mantle cell lymphoma; MHC, major histocompatibility complex; TCR, T cell receptor; TFH, follicular T helper. | Basso, K. & Dalla-Favera, R. Germinal centres and B cell lymphomagenesis. Nat. Rev. Immunol. 15, 172–184 (2015). Return to ref 44 in article
Disease progression:
Primary overt follicular lymphoma (FL) emerges from early mutated cancer precursor cells (CPCs) engaged in a dynamic process of re-entry into the germinal centre (GC), evolving and disseminating over decades in asymptomatic individuals. Such early clones are also likely at the origin of post-treatment relapses. FL-like cells (FLLCs) are present in most healthy individuals and will never progress to FL (despite dissemination to different organs and sharing some genotypic and phenotypic features with FL). By contrast, CPCs are more evolved and committed to ultimately give rise to FL. In situ follicular neoplasia (ISFN) represents an early precursor lesion that might progress into FL at a low rate of progression (5%), although its relationship with CPCs remains unknown. In FL, spatial and temporal genomic analysis revealed that relapse events (relapse 2) or transformation to faster-growing high-grade FL (t-FL; relapse 3) arise predominantly by divergent evolution of a common mutated CPC that clonally diverges through the acquisition of distinct genetic events. Relapse events (that is, relapse 1) arising from a direct clonal evolution of the dominant FL clones present at the diagnosis also exist and characterize mostly early progression specimens. HSPC, haematopoietic stem and precursor cell. | Gascoyne, J. et al. Follicular lymphoma: State-of-the-art ICML workshop in Lugano 2015. Hematol. Oncol. 35, 397–407 (2017). Return to ref 255 in article
Histopathology:
a | Microscopic features of the normal germinal centre environment. Three stains simultaneously detect different proteins in formalin-fixed, paraffin-embedded sections of a reactive lymph node. Triple staining for CD20 (teal), CD3 (purple) and Ki67 (yellow, indicating proliferation) cells shows the topographic relationship between CD3+ T cells, CD20+ B cells, and Ki67+ follicular cells. Ki67+ cells co-express CD20. Magnification ×20. b | Multiplexed immunohistochemistry shows that the neoplastic nodules are composed of CD20+ B cells (teal). CD3+ T cells (purple) are mainly interfollicular, whereas Ki67+ cells (yellow) are within the follicles and co-express CD20. Magnification ×10. | Carbone, A., Roulland, S., Gloghini, A., Younes, A., von Keudell, G., López-Guillermo, A., & Fitzgibbon, J. (2019). Follicular lymphoma. Nature Reviews Disease Primers, 5(1), 83. https://doi.org/10.1038/s41572-019-0132-x
Clinical features
Most patients with FL have no obvious symptoms of the disease at the time of diagnosis.
Painless generalised lymphadenopathy (enlarging over months):
Bulky disease: Transverse diameter of tumour mass > 10 cm and confers a poorer prognosis in early-stage patients.
B symptoms:
Fevers, chills, night sweats or unexplained weight loss >10% of body weight
Frequent in patients with advanced-stage or bulky disease
Extranodal involvement: GIT > skin > CNS
M/C extranodal site in FL: Duodenum
The Calgary Guide | http://calgaryguide.ucalgary.ca/
Complications
Aggressive transformation:
FL → diffuse large B-cell lymphoma (DLBCL) (aggressive lymphoma)
Very poor prognosis
Diagnosis
Core-needle/excisional biopsy (no FNAC):
Malignant B-cells organized in follicular pattern
Centrocytes: small lymphocytes with cleaved nuclei
Centroblasts: larger cells with vesicular chromatin and prominent nucleoli
Immunophenotype: CD 79a, CD 79b, B-cell antigens (CD19, CD20, CD21, CD22), CD10, CD 23, Bcl-2
Immunophenotype of follicular lymphoma: Photomicrographs from a single patient of formalin-fixed, paraffin-embedded tissue sections. a | BCL2 immunostaining is intense, showing BCL2+ B cells in follicular areas. Magnification ×10. b | CD23+ follicular dendritic cells are loosely and irregularly aggregated within the neoplastic follicles. Arrows indicate irregularly aggregated follicular dendritic cells. Original magnification ×10. c | Double stain (purple) simultaneously detects BCL2+ B cells and CD23+ follicular dendritic cells that are irregularly aggregated within the neoplastic follicle. Magnification ×15. | Carbone, A., Roulland, S., Gloghini, A., Younes, A., von Keudell, G., López-Guillermo, A., & Fitzgibbon, J. (2019). Follicular lymphoma. Nature Reviews Disease Primers, 5(1), 83. https://doi.org/10.1038/s41572-019-0132-x
In situ follicular neoplasia: Tumour progression from in situ follicular neoplasia to early follicular lymphoma (FL) or overt FL. a | The strongly immunostained BCL2+ B cells are confined to the germinal centre. The BCL2 staining in this population is more intense than that exhibited by the surrounding mantle cells. Magnification ×20. b | A lymph node displaying overt FL and early FL. Magnification ×0.2. c | Foci of early FL in which BCL2+ cells expand outside the follicle without a defined mantle zone. Magnification ×2. d | Foci of overt FL showing intense immunostaining of BCL2 within the neoplastic follicle. Magnification ×2. All panels are of formalin-fixed, paraffin-embedded tissue sections. | Carbone, A., Roulland, S., Gloghini, A., Younes, A., von Keudell, G., López-Guillermo, A., & Fitzgibbon, J. (2019). Follicular lymphoma. Nature Reviews Disease Primers, 5(1), 83. https://doi.org/10.1038/s41572-019-0132-x
Staging
Ann Arbor staging system with Cotswolds modification:
Staging system for lymphomas, both in Hodgkin’s lymphoma (formerly designated Hodgkin’s disease) and non-Hodgkin lymphoma (abbreviated NHL)
Principal stages (determined by location):
Stage I: Single site (nodal/extranodal)
Stage II: ≥ 2 LN on same side of diaphragm (number of anatomic sites should be indicated in a suffix: e.g. II2)
Stage III: LN/structures on both sides of diaphragm:
III1: With/without splenic, hilar, celiac or portal nodes
III2: With paraaortic, iliac or mesenteric nodes
Stage IV: Diffuse, disseminated, several extranodal ± nodal involvement
Modifiers (can be appended to some stages):
A: No B symptoms
B: B symptoms present
S (spleen)
E “extranodal”
X (largest deposit is >10 cm large (“bulky disease”), or whether the mediastinum is wider than ⅓ of the chest on a chest X-ray)
Stage I is involvement of a single lymph node region (I) (mostly the cervical region) or single extralymphatic site (Ie) | By Cancer Research UK – Original email from CRUK, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34333633
Stage I is involvement of a single lymph node region (I) (mostly the cervical region) or single extralymphatic site (Ie) | By Cancer Research UK – Original email from CRUK, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34333665
Stage III is involvement of lymph node regions on both sides of the diaphragm, which may include the spleen (IIIs) or limited contiguous extralymphatic organ or site (IIIe, IIIes) | By Cancer Research UK – Original email from CRUK, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34333711
Stage IV is disseminated involvement of one or more extralymphatic organs. | By Cancer Research UK – Original email from CRUK, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34333755
St.Jude’s/Murphy classification: Pediatric NHL
Management
Standard first-line therapy of follicular lymphoma | Carbone, A., Roulland, S., Gloghini, A., Younes, A., von Keudell, G., López-Guillermo, A., & Fitzgibbon, J. (2019). Follicular lymphoma. Nature Reviews Disease Primers, 5(1), 83. https://doi.org/10.1038/s41572-019-0132-x
Carbone, A., Roulland, S., Gloghini, A., Younes, A., von Keudell, G., López-Guillermo, A., & Fitzgibbon, J. (2019). Follicular lymphoma. Nature Reviews Disease Primers, 5(1), 83. https://doi.org/10.1038/s41572-019-0132-x
