Lymphoma and plasma cell neoplasms
Follicular lymphoma
General

Author: Nikhil Sangle, M.D. (see Authors page)

Revised: 3 April 2017, last major update January 2011

Copyright: (c) 2001-2017, PathologyOutlines.com, Inc.

PubMed Search: follicular lymphoma

Cite this page: Follicular lymphoma - General. PathologyOutlines.com website. http://pathologyoutlines.com/topic/lymphomafollicular.html. Accessed June 24th, 2017.
Definition / general
  • Most common type of non-Hodgkin lymphoma; usually indolent
Terminology
  • Also called follicular center cell lymphoma
  • Graded 1 - 3 (low grade to high grade)
Epidemiology
Etiology
  • Originates from germinal/follicular center B cells
  • t(14;18)(q32;q21), which occurs in 90% of cases, causes overexpression of BCL2, a protein of the mitochondrial membrane, which prevents cells in follicular center from undergoing apoptosis
Clinical features
  • Generalized painless lymphadenopathy; may have history of waxing and waning lymphadenopathy
  • Marrow involvement common (85% have paratrabecular lymphoid aggregates); with marrow involvement, 40% have tumor cells in blood, which may resemble CLL
  • 10% have peripheral lymphocytosis
  • Occasional involvement of splenic white pulp and hepatic portal triads
  • Indolent; historically median survival was 8 years with 5 year survival of 72%; may be higher now with newer treatments
  • Transformation to diffuse large B cell lymphoma occurs in 20 - 30%, rarely to Burkitt / Burkitt-like lymphoma or B cell ALL; survival < 1 year for either type of transformation; rarely, blastic / blastoid transformation (Am J Surg Pathol 2000;24:525); transformation due to additional but inconsistent chromosomal abnormalities (Hum Pathol 2003;34:915), with gene expression pattern resembling germinal center diffuse large B cell lymphoma (Hematology Am Soc Hematol Educ Program 2009:532)
Prognostic factors
  • FLIP2 study identifies 5 risk factors for progression:
    • Beta2 microglobulin > upper limit of normal
    • Bone marrow involvement
    • Hemoglobin < 12g/dl
    • Longest diameter of the largest involved node > 6 cm
    • Age > 60 years
  • 5 year progression free survival, based on number of risk factors is: 0 risk factors: 80%; 1 - 2 risk factors: 51%; 3 - 5 risk factors: 19% (J Clin Oncol 2009;27:4555)
Case reports
Treatment
Clinical images

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Eyebrow lesion (stage IV disease)

Gross images

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Tumor of lymph nodes

Microscopic (histologic) description
  • Nodal effacement by closely packed follicles containing small cleaved cells without nucleoli (centrocytes) and larger noncleaved cells with moderate cytoplasm, open chromatin and multiple nucleoli (centroblasts)
  • Minimal or no apoptotic cells or tingible body macrophages
  • Attenuated or absent mantle zones
  • Often is interfollicular involvement or capsular infiltration
  • Rarely large areas of necrosis, dense fibrous bands
  • Diffuse pattern: defined as complete absence of CD21 / CD23 positive follicular dendritic cells; usually centrocyte-type cells; follicular areas present in larger biopsy specimens; same staining and molecular patterns as classic follicular lymphoma, but histologically may resemble mantle cell lymphoma
  • Floral pattern: not a diagnostic term; nodules are surrounded and infiltrated by small lymphocytes of the follicular mantle, resulting in an unusual serrated configuration that resembles progressive transformation of germinal centers and lymphocyte predominance Hodgkin lymphoma; occasionally CD5 positive, but usually CD10 positive with BCL2 rearrangement (Am J Clin Pathol 2000;114:912)
  • Incipient: monoclonal proliferation of germinal center cells within a lymph node follicle that is also immunoreactive for B cell antigens, CD10, BCL6 and BCL2 with IgH rearrangement (Hum Pathol 2001;32:1410)
  • With marginal zone differentiation: tumors are primary follicular cell (not primary marginal zone) since BCL2 immunoreactive, have t(14;18) and are same clone as follicular center cell (Mod Pathol 2001;14:191)
  • Bone marrow: usually paratrabecular involvement by CD20+ CD10+ BCL2+ cells; rarely (5%) has follicular pattern (Am J Clin Pathol 2002;118:780); may recapitulate neoplastic follicle or have "reverse germinal center" pattern with transforming cells on periphery of lymphoid cluster; may have foci of transformation resembling Reed-Sternberg cells with cleaved nuclei
  • Grading: graded as 1, 2 or 3 based on average number of intrafollicular centroblasts per field, by counting ten 40× (0.159 mm2) fields (WHO); important to differentiate grades 1/2 vs. grade 3; grade 1: 0 - 5, grade 2: 6 - 15, grade 3: > 15 centroblasts/HPF (grade 3A - centrocytes present, grade 3B - solid sheets of centroblasts)
  • WHO recommends reporting as follicular (> 75% follicular architecture), follicular and diffuse (25 - 75% follicular), focally follicular / predominantly diffuse (< 25% follicular) or diffuse (0% follicular), although this may not have clinical significance (Leuk Lymphoma 2009;50:900)
  • Note: grade 3 with diffuse areas should be reported as diffuse large B cell lymphoma with follicular lymphoma (grade 1 - 2, 3A or 3B)
Microscopic (histologic) images

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General (AFIP images):

Uniform nodularity with back to back arrangement and little variation in size and shape of follicles; follicles are also present in perinodal adipose tissue

Back to back arrangement of poorly defined follicles with no cell polarization and no tingible body macrophages (more variation in follicular size in second image)


Ill defined follicles fade and coalesce at periphery, more noticable on right

Left: vague follicules show peripheral fading / coalescence,
capsular infiltration (not in the form of follicles) is seen at upper left
Right: neoplastic follicles breach the capsule and are present in
perinodal adipose, which strongly favors a diagnosis of follicular
lymphoma over reactive follicular hyperplasia


Left: follicles vary considerably in size, and lack well defined
mantle zones, neoplastic follicles are present in adipose in upper left
Right: follicles vary widely in size and shape, and are surrounded by
thin mantles in this case, no tingible body macrophages are present



Cases that may appear reactive (AFIP images):

Follicular lymphoma with thick
lymphocytic mantles around the
follicles (this unusual case
resembles mantle cell lymphoma)

Follicular lymphoma with incomplete effacement
of nodal architecture - neoplastic sinusoids are
closely packed and ill defined, but residual
sinusoids are present on the right

Left: follicular lymphoma with broad interfollicular zones - follicles are separated by broad
lymphoid stroma; however, this is neoplastic based on the lack of cellular polarization,
the lack of tingible body macrophages, and cellular monotony at high power (not shown)
Right: this case appears reactive, due to a well defined mantle zone and prominent interfollicular tissue;
neoplastic features include spillage of lymphoid infiltrate into perinodal tissue (upper left) and cellular
monotony on high power (not shown); ancillary techniques may be needed to confirm the diagnosis


Left: follicular lymphoma with lymphocytic mantles around the follicles - follicles
are surrounded by thin mantles, but are neoplastic based on uniform staining of
germinal centers (reflecting monotonous cells) and lack of tingible body macrophages;
Middle / right: follicles have thin discrete mantles, some with serrated outlines;
however, they are neoplastic due to follicular crowding and cellular monotony on high power (not shown)



Follicular lymphoma versus hyperplasia (AFIP images):

Reactive follicular hyperplasia: note that the germinal centers are
surrounded by mantle zones and show cellular polarization
(i.e., aggregation of large follicular center cells and tingible body
macrophages opposite the eccentric lymphoid (mantle) cap;
in the image at right, the reactive follicles are frequently irregular and
surrounded by discrete mantles, with a "starry sky"
appearance due to tingible body macrophages

Hyperplastic lymphoid follicles (left) compared to neoplastic follicles (right) -
characteristic reactive features are cellular polarization (left), based on an
eccentric mantle cap, a pale zone and a dark zone; some tingle body
macrophages are present; the neoplastic follicle (right) lacks
cellular poliarization and tingible body macrophages

Follicular lymphoma:
large cells are aggregated
focally, simulating
cellular polarization

Follicular lymphoma: no cellular
polarization is present; cells are small,
cleaved and fairly monotonous; no
tingible body macrophages are present

Follicular lymphoma: the neoplastic follicle is
dominanted by centrocytes (small cleaved cells with
scant cytoplasm and angulated nuclei); arrows point
to follicular dendritic cells, which have an indistinct
cell border, open chromatin and a small distinct nucleolus


Reactive follicular hyperplasia

Left: tingible body macrophages, containing phagocytosed cellular debris, are common in reactive follicles, and create a "starry sky" appearance on low power; right: neoplastic follicles usually lack tingible body macrophages

Unusual follicular lymphoma with prominent tingible body macrophages that makes it appear reactive (left); however, low power shows follicle crowding and lack of well defined mantles (right)



Variants:

With prominent follicular dendritic cells,
characterized by indistinct cell borders,
delicate nuclear membranes, open chromatin,
small distinct nucleoi and occasional binucleation;
in addition, the small cleaved cells have only subtle cleaving



Stains (AFIP images):

Strong nuclear and cytoplasmic BCL2 staining, due to t(14;18)

Left: the follicles show a fairly monotonous population of large cells, but no tingible body macrophages; Right: BCL2 stains the follicles, as well as the non-neoplastic mantle and interfollicular zones (their normal staining pattern)



Images hosted on other servers:

General:

Lymph node involved by lymphoma

Various images



Variants:

Cases with pleomorphic CD30+ cells

Case report above with Burkitt translocation



Bone marrow:

Bone marrow involvement is BCL2+



Grading:

Comparison of grades 1, 2 and 3



Stains:

CD5 stains T cells surrounding follicular lymphoma

Various stains

Peripheral smear description
  • Cells have scant cytoplasm, cleaved nucleus
  • Recommended to confirm that cells are neoplastic with flow cytometry
Positive stains
Negative stains
Flow cytometry description
  • CD10+ cells with high BCL2 predicts follicular lymphoma vs. reactive hyperplasia, but may also occur in some diffuse large B cell lymphomas (Am J Clin Pathol 2003;119:145)
Molecular / cytogenetics description
  • t(14;18)(q32;q21) affecting IgH and BCL2: occurs in 90%, but also present in diffuse large B cell lymphoma; causes overexpression of BCL2, which prevents cells in follicular center from undergoing apoptosis; however BCL2 overexpression is not specific for follicular lymphoma and often occurs in marginal zone hyperplasia in spleen, abdominal lymph nodes and ileal lymphoid tissue (Am J Surg Pathol 2003;27:888, Arch Pathol Lab Med 2008;132:1355)
  • All cases have clonal rearranged immunoglobulin genes
Molecular / cytogenetics images

Images hosted on PathOut server:

BCL2 gene on chromosome 18
is translocated to chromosome 14
directly adjacent to immunoglobulin
heavy chain gene (AFIP)



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Fusion gene diagram and FISH

PCR gels

Videos


Histopathology bone marrow - Follicular lymphoma


Histopathology lymph node - Follicular lymphoma, grade 2
Differential diagnosis
  • Follicular colonization by other low grade lymphomas: histologic and immunohistochemical patterns of other lymphomas
  • Mantle cell lymphoma with diffuse pattern: CD5+, cyclin D1+, CD43+, CD10-
  • Marginal zone B cell lymphoma: no follicular pattern; CD10-
  • Peripheral T cell lymphoma: rarely contains sharply demarcated follicles with abundant follicular dendritic cells; CD4+, BCL6+, CD10+, T cell receptor rearrangements
  • Reactive hyperplasia: normal nodal architecture, follicles vary considerably in size and shape, have sharply defined margins, surrounded by a mantle zone, follicle contains mixture of centrocytes and centroblasts, cleaved cells are restricted to follicles, numerous mitoses and tingible body macrophages are present; BCL2 immunostaining is absent from follicles, cases are typically are CD20+ BCL2 negative / dim by flow cytometry (Am J Clin Pathol 2000;114:258)
  • SLL / CLL in bone marrow: no cleaved nuclei, CD5+, CD23+, weak surface Ig-, CD10-