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Lymphoma - B cell neoplasms

Follicular lymphoma-general


Reviewer: Nikhil Sangle, M.D., University of Utah and ARUP Laboratories (see Reviewers page)
Revised: 7 February 2012, last major update January 2011
Copyright: (c) 2001-2011, PathologyOutlines.com, Inc.

General
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● Most common type of non-Hodgkin's lymphoma; usually indolent

Terminology
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● Also called follicular center cell lymphoma
● Graded 1-3 (low grade to high grade)

Epidemiology
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● Most common form of non-Hodgkin lymphoma in US (45% of all cases)
● Lower incidence in Asians (Cancer Causes Control 1996;7:224), African-Americans (J Natl Cancer Inst 2000;92:1240)
● Median age 55 years; rare under age 20 years

Etiology
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● 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
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● 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)

Prognosis
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FLIP2 study identifies 5 risk factors for progression:
● Beta2-microglobulin > upper limit of normal
● Bone marrow involvement
● Hemogloblin < 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
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● 53 year old Japanese woman with crystals in tumor cells (Hum Pathol 2002;33:1141)
● Grade 1 tumor with Burkitt translocations and aggressive clinical course (Arch Pathol Lab Med 2004;128:210)

Treatment
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● Radiation for stage I/II disease
● Rituximab plus chemotherapy (World J Gastroenterol 2010;16:5543, J Hematol Oncol 2009;2:14)
● Autologous hematopoietic stem cell transplantation for salvage therapy or transformed disease (Biol Blood Marrow Transplant 2010;16:443)

Clinical images
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Eyebrow lesion (Stage IV disease)

Gross images
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Tumor of lymph nodes

Micro (lymph node) description
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● Nodal effacement by closely packed follicles containing small cleaved cells without nucleoli (centrocytes) and larger non-cleaved 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 40x (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)

Micro images - General
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Various 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 (AFIP 3rd Series Vol 14)

   
Back to back arrangement of poorly defined follicles with no cell polarization and no tingible body macrophages. There is more variation in follicular size in second image (AFIP 3rd Series Vol 14)

   
Ill defined follicles fade and coalesce at periphery, more noticable on right (AFIP 3rd Series Vol 14)

   
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 (AFIP 3rd Series Vol 14)


   
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 (AFIP 3rd Series Vol 14)


Micro images - Cases that may appear reactive
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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 (AFIP 3rd Series Vol 14).


       
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) (AFIP 3rd Series Vol 14).



Follicular lymphoma with thick lymphocytic mantles around the follicles - this unusual case resembles mantle cell lymphoma (AFIP 3rd Series Vol 14).


Follicular lymphoma with incomplete effacement of nodal architecture - neoplastic sinusoids are closely packed and ill defined, but residual sinusoids are present on the right (AFIP 3rd Series Vol 14).

Micro images - Follicular lymphoma versus hyperplasia
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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 (AFIP 3rd Series Vol 14)

   
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 (AFIP 3rd Series Vol 14).


Follicular lymphoma: large cells are aggregated focally, simulating cellular polarization (AFIP 3rd Series Vol 14).


Follicular lymphoma: no cellular polarization is present; cells are small, cleaved and fairly monotonous; no tingible body macrophages are present (AFIP 3rd Series Vol 14).


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 (AFIP 3rd Series Vol 14).


Reactive hyperplasia: the germinal center is polarized, with a dark zone at the top and pale zone at the bottom. The dark zone contains primarily centroblasts (large noncleaved cells with a thin rim of basophilic cytoplasm and round vesicular nuclei). There are numerous mitotic figures and tingible body macrophages. The pale zone contains primiarly centrocytes (small cleaved cells with scant cytoplasm and irregular angulated nuclei) (AFIP 3rd Series Vol 14).

   
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 (AFIP 3rd Series Vol 14).

   
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) (AFIP 3rd Series Vol 14).

Micro images - Variants
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Cases with pleomorphic CD30+ cells


Case report above with Burkitt's translocation


With marginal zone differentiation


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.

Micro images - Bone marrow
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Bone marrow involvement is bcl2+

Micro images - Grading
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Comparison of grades 1, 2 and 3

Micro images - Stains
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CD5 stains T cells surrounding follicular lymphoma


Strong nuclear and cytoplasmic bcl2 staining, due to t(14;18) (AFIP 3rd Series Vol 14)

   
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) (AFIP 3rd Series Vol 14)


Various stains

Virtual slides
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Lymph node tumors: grade 1 and grade 2

Bone marrow tumor

Peripheral smear description
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● Cells have scant cytoplasm, cleaved nucleus
● Recommended to confirm that cells are neoplastic with flow cytometry

Positive stains
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● CD10, CD19, CD20 (strong), CD79a, bcl2 within follicles, bcl6 (Am J Surg Pathol 2000;24:846)
● CD30+ cells in 30% (Arch Pathol Lab Med 2001;125:1036)
● Variable surface immunoglobulin (intense in bone marrow)
Note: CD10 frequently is weak/negative in interfollicular infiltrates and in grade III follicular lymphomas (Am J Clin Pathol 2001;115:862)
Note: CD10 is sensitive and specific for follicular lymphoma among small B cell lymphomas in multiparameter flow cytometry (Am J Clin Pathol 2002;117:291)
● Variable CD11c, CD23, CD25, CD43

Negative stains
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● CD5 (although mixed T cells are often present), cyclin D1

Flow cytometry description
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● 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 description
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● 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 images
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The bcl2 gene on chromosome 18 is translocated to chromosome 14 directly adjacent to the immunoglobulin heavy chain gene (AFIP 3rd Series Vol 14)

Fusion gene diagram and FISH

PCR gels

Videos
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bone marrow biopsy, grade 2 lymphoma of lymph node

Differential diagnosis
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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)
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
Follicular colonization by other low grade lymphomas: histologic and immunohistochemical patterns of other lymphomas
SLL/CLL in bone marrow: no cleaved nuclei, CD5+, CD23+, weak surface Ig-, CD10-

End of Lymphoma - B cell neoplasms > Follicular lymphoma-general


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