Follicular lymphoma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2]

Overview

Genes involved in the pathogenesis of follicular lymphoma include BCL-2 and BCL-6. The most common cause is reciprocal translocation t(14;18)(q32;q21). The progression to follicular lymphoma involves microRNAs (miRNAs). On microscopic histopathological analysis, centrocytes, centroblasts along with various non-neoplastic cells including T cells, follicular dendritic cells, and macrophages are the characteristic findings of follicular lymphoma.

Pathophysiology

Physiology

  • Follicular lymphoma is the second most common non-Hodgkin lymphoma.[3].
  • The disease is characterized by the clonal proliferation of neoplastic lymphoid cells that share morphological, immunophenotypic and molecular genetic attributes of germinal centre B-cells.
  • The development of follicular lymphoma tumors in adults is dependent upon the overexpression of B-cell leukemia/lymphoma 2 (BCL-2) located on chromosome band 18q21.
  • BCL-2 is an oncogene that blocks programmed cell death (apoptosis). As such, overexpression results in prolonged cell survival.
  • These tumours contain a mixture of neoplastic centrocytes and centroblasts along with various non-neoplastic cells including T-cells, follicular dendritic cells, and macrophages.
  • Follicular lymphoma can be designated as low grade (1 and 2) or higher grade (3A and 3B) disease, depending on the number of centroblasts per high-power field.

Pathogenisis

  • The most common cause is reciprocal translocation between (14;18)(q32;q21) in 80-85% of cases.[4]
  • This somatic rearrangement is initiated within the bone marrow during B-cell lymphopoiesis and results from immunoglobulin heavy chain gene (IGH) rearrangement.
  • The t(14;18) translocation leads to placement of the B cell lymphoma 2 (BCL2) gene under the influence of transcriptional enhancers associated with IGH, resulting in overexpression of anti-apoptotic BCL2 leading to increased cell survival and uncontrolled cell proliferation in germinal centers.[5][6][7]
  • BCL2, along with other anti-apoptotic proteins, inhibits apoptosis by binding and neutralizing activated pro-apoptotic proteins including the mitochondrial outer membrane permeabilizers BAX and BAK, as well as the intracellular stress sensors which activate BAX and BAK.
  • Mutations in chromatin-modifying genes occur, affecting histone methyltransferases, histone acetyltransferases or histone linker proteins.
  • These mutations act to promote increased proliferation of B cells.
  • Genes encoding components of vacuolar H+-ATPase, or RRAGC, a guanine nucleotide binding protein, regulate the mTOR activation.
  • Mutations in these genes upregulate mTOR (mammalian target of rapamycin) signaling in FL cells. These mutations are found in approximately 15 to 20 percent of cases.
  • Upregulated mTOR directs many cellular processes including growth, differentiation, survival, and adhesion or cellular migration, and resulting in follicular lymphoma development.
  • KMT2D, CREBBP, EZH2, EP300, HIST1H1E, KMT2C, ARID1A, and SMARCA4 are some of the other genomes which undergo mutations in a very few cases.
  • The tumor microenvironment comprised of T cells and dendritic cells, may influence the development and progression of Follicular lymphoma.
  • Communication between the tumor cells and the microenvironment involves chemokines, chemokine receptors and adhesion molecules, the balance of which determines whether there is tumor cell growth promotion or inhibition.
  • MicroRNA expression- short non-coding RNAs named microRNAs (miRNAs) have important functions in follicular lymphoma biology.[8]
  • In malignant B cells miRNAs participate in pathways fundamental to B cell development like:

Genetics

Gross Pathology

Microscopic Pathology

The tumor is composed of follicles containing a mixture of the following[14]:

  • Centrocytes (small cleaved cells without nucleoli)
  • Centroblasts (larger noncleaved cells with moderate cytoplasm, open chromatin and multiple nucleoli)
  • These follicles are surrounded by non-malignant cells, mostly T-cells.

Within the follicles, centrocytes typically predominate; centroblasts are usually scarce.

Grading

According to the WHO criteria, the disease is morphologically graded into:[15]

  • Grade 1 (<5 centroblasts per high-power field (hpf))
  • Grade 2 (6–15 centroblasts/hpf)
  • Grade 3 (>15 centroblasts/hpf)
  • Grade 3A (centrocytes still present)
  • Grade 3B (the follicles consist almost entirely of centroblasts)

The WHO 2008 update provided the following grading for follicular lymphoma:

  • Grades 1 and 2 now as low grade follicular lymphoma
  • Grade 3A as high grade follicular lymphoma
  • Grade 3B as diffuse large B Cell lymphoma

References

  1. Lossos IS, Gascoyne RD (2011). "Transformation of follicular lymphoma". Best Pract Res Clin Haematol. 24 (2): 147–63. doi:10.1016/j.beha.2011.02.006. PMC 3112479. PMID 21658615.
  2. Ochando J, Braza MS (2017). "T follicular helper cells: a potential therapeutic target in follicular lymphoma". Oncotarget. 8 (67): 112116–112131. doi:10.18632/oncotarget.22788. PMC 5762384. PMID 29340116.
  3. Kridel R, Sehn LH, Gascoyne RD (2012). "Pathogenesis of follicular lymphoma". J Clin Invest. 122 (10): 3424–31. doi:10.1172/JCI63186. PMC 3461914. PMID 23023713.
  4. Ganapathi KA, Pittaluga S, Odejide OO, Freedman AS, Jaffe ES (2014). "Early lymphoid lesions: conceptual, diagnostic and clinical challenges". Haematologica. 99 (9): 1421–32. doi:10.3324/haematol.2014.107938. PMC 4562530. PMID 25176983.
  5. Biagi JJ, Seymour JF (2002). "Insights into the molecular pathogenesis of follicular lymphoma arising from analysis of geographic variation". Blood. 99 (12): 4265–75. PMID 12036852.
  6. "A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project". Blood. 89 (11): 3909–18. 1997. PMID 9166827.
  7. Lorsbach RB, Shay-Seymore D, Moore J, Banks PM, Hasserjian RP, Sandlund JT; et al. (2002). "Clinicopathologic analysis of follicular lymphoma occurring in children". Blood. 99 (6): 1959–64. PMID 11877266.
  8. Fernández de Larrea C, Martínez-Pozo A, Mercadal S, García A, Gutierrez-García G, Valera A; et al. (2011). "Initial features and outcome of cutaneous and non-cutaneous primary extranodal follicular lymphoma". Br J Haematol. 153 (3): 334–40. doi:10.1111/j.1365-2141.2011.08596.x. PMID 21375524.
  9. 9.0 9.1 Musilova, K; Mraz, M (2014). "MicroRNAs in B cell lymphomas: How a complex biology gets more complex". Leukemia. doi:10.1038/leu.2014.351. PMID 25541152.
  10. Overview at UMDNJ
  11. Bosga-Bouwer AG, van Imhoff GW, Boonstra R; et al. (February 2003). "Follicular lymphoma grade 3B includes 3 cytogenetically defined subgroups with primary t(14;18), 3q27, or other translocations: t(14;18) and 3q27 are mutually exclusive". Blood. 101 (3): 1149–54. doi:10.1182/blood.V101.3.1149. PMID 12529293.
  12. Winberg CD, Nathwani BN, Bearman RM, Rappaport H (1981). "Follicular (nodular) lymphoma during the first two decades of life: a clinicopathologic study of 12 patients". Cancer. 48 (10): 2223–35. PMID 7028244.
  13. Bosga-Bouwer AG, Haralambieva E, Booman M; et al. (November 2005). "BCL6 alternative translocation breakpoint cluster region associated with follicular lymphoma grade 3B". Genes Chromosomes Cancer. 44 (3): 301–4. doi:10.1002/gcc.20246. PMID 16075463.
  14. Anderson T, Chabner BA, Young RC, Berard CW, Garvin AJ, Simon RM; et al. (1982). "Malignant lymphoma. 1. The histology and staging of 473 patients at the National Cancer Institute". Cancer. 50 (12): 2699–707. PMID 7139563.
  15. "Follicular Lymphomas". Retrieved 2008-07-26.