Categories
ORGAN SYSTEMS

Follicular lymphoma (FL)

Introduction

Systemic neoplasm of the lymphoid tissue displaying germinal centre (GC) B cell differentiation.

  • FL represents ~5% of all haematological neoplasms
  • #2 non-Hodgkin lymphoma (~20–25%) (M/C diffuse large B-cell lymphoma)
  • FL is an indolent (low-grade) lymphoma
f2.large_
Bowzyk Al-Naeeb, A., Ajithkumar, T., Behan, S., & Hodson, D. J. (2018). Non-Hodgkin lymphoma. BMJ, 362, k3204. https://doi.org/10.1136/bmj.k3204

Pathophysiology

Genetic hallmark: t(14:18) translocation (>85% cases)

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:

41572_2019_132_fig1_html
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:

41572_2019_132_fig2_html
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:

41572_2019_132_fig4_html
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):

  • M/C sites: Mediastinal/neck nodes (60%) >> splenic > axillary > abdominal > hilar/inguinofemoral
  • 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
non-hodgkin-lymphoma
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

 

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)
    • “extranodal”
    • (largest deposit is >10 cm large (“bulky disease”), or whether the mediastinum is wider than ⅓ of the chest on a chest X-ray)

 

St.Jude’s/Murphy classification: Pediatric NHL


Management

41572_2019_132_fig7_html
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

Chemoimmunotherapy (CI): R-CHOP regimen (cures 50%‐60% cases):

  • Rituximab
  • Cyclophosphamide (adv effect: hemorrhagic cystitis)
  • Doxorubicin
  • Vincristine (adv. effect: peripheral neuropathy)
  • Prednisone

Prognosis

International prognostic index (IPI):

  • Age > 60 years
  • ↑ Serum lactate dehydrogenase (LDH)
  • Performance status ≥ 2 (ECOG) or ≤70 (Karnofsky)
  • Ann Arbor Stage III/IV
  • ≥ 2 sites of extranodal involvement

Summary:

41572_2019_140_figa_html
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

Leave a Reply