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follicular lymphoma

Thursday 20 October 2005

Definition: Follicular lymphoma is the 2nd most common B-cell non-Hodgkin lymphoma after diffuse large B-cell lymphoma. It comprises up to 20% of lymphoma in adults in the USA and in Western Europe. As the name implies the lymphoma takes a “follicular” or nodular pattern of growth with or without diffuse areas. This form of lymphoma is almost always a disease of adults with very rare examples documented in the pediatric age group.


- hyalin vascular Castleman disease vs follicular lymphoma

Digital cases

- In lymph node : Nodal follicular lymphoma

  • HPC:243 : Follicular lymphoma in lymph node.
  • HPC:288 : Follicular lymphoma in lymph node.
  • HPC:331 : Nodal follicular lymphoma, grade 1.
  • HPC:354 : Chronic lymphocytic lymphoma-like follicular lymphoma.

- In bone marrow

  • HPC:280 : Follicular lymphoma in bone marrow.
  • UI:759 : Follicular lymphoma in bone marrow.

- Extranodal follicular lymphoma

  • HPC:310 : Thyroid follicular lymphoma.
  • HPC:310 : Parotidal follicular lymphoma (Follicular lymphoma of a salivary gland).


- PathPedia
- Pleural fluid with follicular lymphoma on Flickr


-  nodal follicular lymphoma
- digestive follicular lymphoma
- splenic follicular lymphoma
- medullary follicular lymphoma

Neoplastic follicles

A neoplastic follicle is a round to oval structure comprised of follicular center B-cells distributed evenly throughout the follicle with no definition of “light” or “dark” zones of a normal lymphoid follicle. This lack of “polarity” of smaller and larger cells is a helpful morphologic finding in distinguishing a neoplastic follicle from a benign reactive follicle. Also, neoplastic follicles generally either have no mantle zones or reduced, thin, or incomplete mantle zones around follicles.

Generally, neoplastic follicles are regular, back-to-back with similar shapes and sizes but neoplastic follicles can be heterogeneous with small and large follicles next to each other. The nodal architecture is effaced by numerous nodules without an obvious boundary between cortex and medulla. The neoplastic follicles show a monotonous population of cells with no light or dark zones and lack any significant mantle zones. A predominant population of larger cells in this neoplastic follicle without any light or dark zones and lack of any obvious mantle zone around the follicle can be observed.

The neoplastic follicles consist of a variable mixture of centrocytes and centroblasts. Centrocytes, also known as cleaved cells, are small to large cells with irregular nuclei that often show nuclear clefts, indentations, and grooves without any nucleoli. The cells contain scant cytoplasm and nuclei often appear “stretched toffee” like and twisted. In contrast, centroblasts (large non-cleaved cells) are larger cells with scant to moderate cytoplasm and round to oval nuclei with open chromatin and small to distinct nucleoli.

Typical “centrocytes” have often elongated and irregular nuclei that may show linear clefts and small chromocenters but no nucleoli. Centrocytes can be small or large but all share the same basic individual morphology.


Follicular lymphoma is graded based on the number of centroblasts present in neoplastic follicles in 10 high power fields (40x fields). A practical approach of low grade versus high grade is clinically significant but a 3-tier system of grading is allowed. Grade 1 follicles contain up to 5 larger centroblasts in a 40x field whereas in a grade 2 lymphoma up 15 centroblasts are allowed. More than 15 centroblasts in a 40x field are seen in grade 3/3 (high grade) follicular lymphoma.

Low grade lymphomas may be reported as grade 1-2/3 rather than strictly as grade 1/3 or 2/3 since it can be very difficult to count exact number of centroblasts in a neoplastic follicle and in up to 10 such follicles.

In grade 3/3 follicular lymphoma, most of the cells are centroblasts both small and large. Not only centroblasts are generally bigger but the defining characteristic is the quality of nuclear chromatin which is open and vesicular in appearance. High grade (grade 3/3) follicular lymphoma is generally treated with regimens used for diffuse large B-cell lymphoma.


- BCL6

  • In a lymph node both benign and neoplastic follicle center cells show nuclear staining for the transcription factor BCL6. Thus, BCL6 severs as an excellent immunohistochemical marker for follicular center cells, whether benign or malignant.
  • Typically, increased numbers of neoplastic follicle center cells are identified outside the neoplastic follicles and can be identified using immunostaining for BCL6 or CD10.
  • The “follicular” cells in the interfollicular zone are generally small centrocytes but sheets of larger cells can also be seen and constitute the presence of a diffuse large cell lymphoma “component” in a follicular lymphoma.
  • Scattered larger BCL6+ cells outside the follicles does not constitute the “diffuse large B-cell lymphoma” definition. To be qualified as diffuse large B-cell lymphoma it must be composed of a predominant population of larger cells packed together in a sheet-like pattern.
  • The most useful diagnostic value of BCL6 immunostaining is in identification of follicular B-cells whether benign or neoplastic and whether inside or outside of follicles.

- BCL2

  • Benign lymphoid follicular center cells DO NOT show expression of bcl-2 oncoprotein whereas up to 85-90% of low grade follicular lymphoma and a lesser proportion of high grade follicular lymphoma show coexpression of bcl-2. Thus, expression of bcl-2 by follicular B-cells (arrow) is a feature of lymphoma and not benign follicular center cells.
  • Care must be taken not to mistake for the normal expression of bcl-2 by T-cells present within lymphoid follicles, by mantle zone B-cells, and by T and B-cells in the interfollicular zone.
  • Also, bcl-2 expression is NOT diagnostic of a follicular lymphoma as many other B and T-cell lymphomas express bcl-2 oncoprotein.
  • The most useful diagnostic value of bcl-2 immunostaining is in differentiating benign follicles from neoplastic ones.
  • The partial nodal involvement by a follicular lymphoma can be missed if neoplastic follicles constitute a smaller proportion of all follicles. The diagnostic morphologic finding is the lack of polarity in neoplastic follicles and the absence of any significant mantle zones around follicles.
  • Bcl-2 expression is less common in grade 3 follicular lymphoma.

- CD21

  • Immunostaining for the follicular dendritic cell marker CD21 can be very helpful in two situations: in identifying a follicular architecture in an apparent diffuse pattern and in identifying abnormal follicles as neoplastic follicles in early follicular lymphoma sometimes called “in-situ” follicular lymphoma.
  • In follicular lymphomas the follicular dendritic cell network is commonly disrupted by expansion of neoplastic follicle center cells as seen in this case.
  • In benign reactive follicles, however, a diffuse meshwork of CD21+ follicular dendritic cells is present evenly throughout the follicle.

Differential diagnosis

- lymphoid nodular hyperplasia
- hyalin vascular Castleman disease


Follicular lymphomas present the second most frequent subtype of nodal lymphoid malignancy in Western Europe.

The annual incidence of this disease has rapidly increased during recent decades and has risen from 2–3/100 000 during the 1950s to 5–7/100 000 recently.


Diagnosis should always be based on a surgical specimen/excisional lymph node biopsy. Core biopsies should only be performed in patients without easily acessable lymph nodes (e.g. retroperitoneal bulk). Fine-needle aspiration is inappropriate for a reliable diagnosis.

The histological report should give the diagnosis according to the WHO classification.


Grading is performed according to the number of blast per high-power field (grade 1–2: ≤15 blasts, grade 3: >15 blasts). Follicular lymphoma grade 3B (with sheets of blasts) is considered an aggressive lymphoma and treated alike (see "Clinical Practice Guidelines for diffuse large B-cell lymphoma").

When possible additional biopsy material should be stored fresh frozen to allow additional molecular (currently still scientific) analyses.


- Pan-B+
- CD10+/-
- CD5-
- sIg+

Putative cell of origin: Centrocytes / centroblasts of germinal centre origin with somatic hypermutation of the IgV genes and ongoing mutations (antigen driven stimulation).


- floral variant of follicular lymphoma (8279627)


Since treatment depends substantially on the stage of the disease initial staging should be thorough particularly in the small proportion of patients with early stages I and II (15%–20%).

Initial work-up should include a CT scan of the neck, thorax, abdomen and pelvis, and a bone marrow aspirate and biopsy. An additional PET is not recommended according to the updated consensus except in rare cases to confirm localized stage I/II disease [IV, C].

A complete blood count, routine blood chemistry including lactate dehydrogenase (LDH) and uric acid as well as screening tests for HIV and hepatitis B and C are required.

The staging is given according to the Ann Arbor system with mention of bulky disease.

For prognostic purposes, a Follicular Lymphoma-specific International Prognostic Index (FLIPI: >4 envolved nodal sites, elevated LDH, age >60 years, advanced stage III/IV, haemoglobin @<@12 g/dl) should be determined [I, A]. A revised FLIPI2 (incorporating β2 microglobulin, diameter of largest lymph node, bone marrow involvement and haemoglobin level) has recently been suggested.

RNA expression analysis suggests a more favourable clinical course in cases with infiltrating T-cells in comparison with cases with non-specific macrophage bystander cells. However, this technique is not yet applicable in clinical routine.

Pediatric follicular lymphoma

Follicular lymphoma in children affects males more than females and, unlike their adult counterparts, often presents with limited stage disease. Even though most are grade 2 or 3, many are curable.

Morphologically, they range from the typical low-power pattern of crowded monomorphic small-to-medium size follicles to large expansive follicles and even “floral variant.”

Phenotypically like adults, most cases are CD10+ and BCL-6+, but unlike adults, are often BCL-2− and most do not have underlying BCL-2/IgH (14;18) translocation.

The small minority with BCL-2 translocations appear to have a worse prognosis.


Aberrant expression of bcl-2 (BCL2), caused by a t(14;18) translocation, is most commonly associated with follicular lymphoma. In a subset of these tumors, additional acquisition of a translocation involving c-myc (MYC) leads to transformation to a high-grade lymphoma.

- t(14;18)(q32;q21) creating BCL2/IGH rearrangement (70-80% of cases) (14q32 and 18q21)

Differential diagnosis

Follicular lymphoma (FL) can exhibit variant histologic patterns that can lead to confusion with other B-cell lymphomas and reactive conditions.

Diagnostic markers such as CD10 and BCL2 may be difficult to interpret in variant FL patterns, and are often diminished or absent in the interfollicular and diffuse components.

See also

- Bone marrow

  • bone marrow anomalies


- Improved demonstration of immunohistochemical prognostic markers for survival in follicular lymphoma cells. Camacho FI, Bellas C, Corbacho C, Caleo A, Arranz-Sáez R, Cannata J, Menárguez J, Sánchez-Verde L, González-Camacho L, Pérez-Martín ME, Martínez-González MA, Alvaro T, Mollejo M, Ruíz-Marcellán C, Montalbán C, Piris MA. Mod Pathol. 2011 Jan 14. PMID: 21240256 [Free]

- Immunoarchitectural Patterns in Follicular Lymphoma: Efficacy of HGAL and LMO2 in the Detection of the Interfollicular and Diffuse Components. Younes SF, Beck AH, Lossos IS, Levy R, Warnke RA, Natkunam Y. Am J Surg Pathol. 2010 Sep;34(9):1266-76. PMID: 20697248

- Prognostic Factors in Follicular Lymphoma. Relander T, Johnson NA, Farinha P, Connors JM, Sehn LH, Gascoyne RD. J Clin Oncol. 2010 Apr 12. PMID: 20385990

- Wang SA, Wang L, Hochberg EP, Muzikansky A, Harris NL, Hasserjian RP. Low Histologic Grade Follicular Lymphoma With High Proliferation Index: Morphologic and Clinical Features. Am J Surg Pathol. 2005 Nov;29(11):1490-1496. PMID: 16224216