Lymphoma & related disorders
Mature B cell neoplasms
Follicular lymphoma
Unusual morphologic patterns of follicular lymphoma
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Deputy Editor-in-Chief: Genevieve M. Crane, M.D., Ph.D.
Last author update: 4 April 2022
Last staff update: 4 April 2022
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PubMed Search: Follicular lymphoma unusual variants
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Diagrams / tables | Clinical features | Diagnosis | Prognostic factors | Case reports | Treatment | Frozen section description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Khanlari M, Thakral B, Chapman J. Unusual morphologic patterns of follicular lymphoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomafollicularunusual.html. Accessed April 26th, 2024.
Definition / general
- Follicular lymphoma (FL) is a neoplasm composed of germinal center B cells (centrocytes and centroblasts in varying proportions), usually (but not always) distributed in a follicular pattern
- Distinct biologic variants of FL have identifiable clinical and histopathologic features that help their recognition in clinical practice; examples include pediatric type FL, primary cutaneous follicular center cell lymphoma, primary testicular FL and duodenal type FL
- Unusual morphologic patterns can also be seen in cases of FL and do not represent biologically distinct variants of FL; these FL may not be easily recognizable due to histopathologic overlap with other B cell lymphomas and are discussed in this chapter (see Table 1)
Essential features
- FL with Castleman-like changes:
- Castleman-like changes with B cell markers, BCL2 and germinal center markers
- FL with plasmacytic differentiation and IgG4 positive plasma cells:
- FL with associated increased and monotypic plasma cells
- FL with marginal zone (MZ) differentiation involving mucosa associated lymphoid tissue (MALT) sites:
- Marginal zone differentiation
- Monocytoid B cells
- Lymphoepithelial lesions
- Plasmacytic differentiation
- FL negative for CD10, positive for MUM1 and with BCL6 abnormalities:
- More frequent diffuse proliferation and grade 3B compared with conventional FL
- Usually lack BCL2 rearrangement
- MUM1 expression and BCL6 abnormalities (translocation, amplification)
- EBV positive FL:
- Morphology and immunophenotype similar to the conventional type of FL
- EBER is positive in ~100% of cases
- Floral variant of FL:
- Irregular neoplastic follicles with expanded, prominent mantle zone lymphocytes penetrating the neoplastic follicles
ICD coding
Epidemiology
- FL with Castleman-like changes:
- Incidence: infrequent
- Probably more common in practice than reported in the literature
- Essential to be familiar with this variant as Castleman-like changes may mask the underlying lymphoma (Hum Pathol 2017;68:136)
- FL with plasmacytic differentiation and IgG4 positive plasma cells:
- ∼3.5% of FL show plasmacytic differentiation (Am J Clin Pathol 1985;84:283, Virchows Arch A Pathol Anat Histol 1981;394:119, Mod Pathol 2010;23:71)
- FL with marginal zone differentiation involving MALT sites:
- FL with marginal zone differentiation seen in ~9% of cases (Leuk Lymphoma 2011;52:804)
- FL negative for CD10 and expressing MUM1 (Blood 2007;109:3076):
- Elderly patients
- M > F
- EBV positive FL (Am J Hematol 2019;94:E62, Mod Pathol 2017;30:519):
- Uncommon, prevalence of ~2.5% in an unselected cohort of FL
- No association with prior history of immunosuppression, gender or age
- Floral variant of FL:
- First described by Osborne and Butler (Am J Clin Pathol 1987;88:264)
- In a study by Kojima et al., 13 cases were reported (1992 - April 2006) (APMIS 2006;114:626)
Diagrams / tables
Table 1
| FL with Castleman-like changes |
| FL with plasmacytic differentiation with or without IgG4 positive plasma cells |
| FL with marginal zone differentiation, typically involving MALT sites |
| FL negative for CD10, positive for MUM1 with BCL6 abnormalities |
| EBV positive FL |
| Floral variant of FL |
Clinical features
- Similar to those of usual type FL
Diagnosis
- Constitutional symptoms: fatigue, fever or night sweats, weight loss or recurrent infections
- Diagnostic imaging: enlarged lymph nodes, nodules / lesions / infiltration in extranodal sites
- Tissue biopsy / excision (lymph node / extranodal sites)
- Laboratory tests: peripheral blood exam / bone marrow biopsy (especially in staging) / lumbar puncture
- Reference: Am J Hematol 2018;93:296
Prognostic factors
- FL negative for CD10 and expressing MUM1 (Blood 2007;109:3076):
- Relatively poor prognosis
- EBV positive FL (Am J Hematol 2019;94:E62):
- Inferior overall survival when adjusted for age or sex
Case reports
- 32 year old man presented with tonsillar hypertrophy in laryngoscopy and underwent a low temperature plasma tonsillectomy (Diagn Pathol 2019;14:70)
- 74 year old woman presented with a 4 year history of squamous cell carcinoma of the skin and regional lymphadenopathy; biopsy of the postauricular lymph node was performed (Virchows Arch A Pathol Anat Histopathol 1985;405:473)
- 77 year old woman presented with left foot swelling attributed to an insect bite; Doppler ultrasound was negative for deep venous thrombosis but the study revealed left inguinal lymphadenopathy (Hum Pathol 2017;68:136)
Treatment
- More studies are needed to evaluate the response to the standard therapy for FL
Frozen section description
- Same histologic features (see Microscopic description)
- Cytogenetics, flow cytometry, preparation of imprints should be considered
Microscopic (histologic) description
- FL with Castleman-like changes (Hum Pathol 2017;68:136):
- Small and atrophic neoplastic follicles
- Atretic and hyalinized germinal centers
- Concentric mantle zones
- Increased interfollicular vascularity
- Penetrating hyalinized blood vessels
- FL with plasmacytic differentiation and IgG4 positive plasma cells (Mod Pathol 2010;23:71):
- FL with associated increased and monotypic plasma cells
- B cells and plasma cells show the same light chain expression, thus supporting a common clonal relationship
- 2 distinct types:
- Predominantly interfollicular distribution of plasma cells, these cases show BCL2 rearrangements and are considered to be FL with plasmacytic differentiation
- Predominantly intrafollicular plasma cell distribution; these cases tend not to show BCL2 rearrangements and some evidence supports that these cases may not represent neoplastic FL with plasmacytic differentiation but show biologic overlap with marginal zone lymphomas
- Can lack CD10 expression but retain expression of BCL6 and other germinal center markers such as LMO2, HGAL, etc.
- 2 distinct types:
- FL with marginal zone differentiation involving MALT sites:
- Marginal zone differentiation variable, characterized by a perifollicular band of monocytoid B cells rimming the neoplastic follicles
- Monocytoid B cells are represented by:
- Round to slightly irregular nuclei
- Moderate amount of clear cytoplasm
- Pale appearance at low magnification
- Lymphoepithelial lesions are prominent
- Plasmacytic differentiation with monotypic interfollicular plasma cells
- FL negative for CD10, positive for MUM1 and with BCL6 abnormalities (Blood 2007;109:3076):
- More frequent diffuse proliferation compared with conventional FL
- More frequent grade 3B in follicular foci
- More frequently shows component of diffuse large B cell lymphoma (DLBCL)
- Usually lacks BCL2 rearrangement
- Frequently expresses MUM1 and cytoplasmic light chain
- More frequent BCL6 abnormalities (translocation, amplification)
- EBV positive FL:
- Histologically and immunophenotypically indistinguishable from nodal FL
- Floral variant of FL:
- Neoplastic follicles are irregular in shape
- Expanded, prominent mantle zone lymphocytes surround follicles
- Mantle zone lymphocytes penetrate neoplastic follicles
Microscopic (histologic) images
Contributed by Jennifer Chapman, M.D.
Castleman-like changes
Castleman-like changes
Floral variant
Floral variant
Follicular lymphoma negative for CD10 and expressing MUM1
Cytology description
- Variable mixture of centrocytes and centroblasts
- Centrocytes
- Small to large
- Angulated nuclei
- Dense chromatin
- Scant cytoplasm
- Centroblasts
- Large cells with oval nuclei
- Vesicular chromatin
- 1 - 3 nucleoli
- Moderate cytoplasm
- > 3 times the size of lymphocytes
- Differentiate from follicular dendritic cells
- Large round nuclei
- Dispersed, nearly clear chromatin
- Single eosinophilic nucleolus
- Indistinct cytoplasm
- Centrocytes
- Absent / rare tingible body macrophages
- Reference: Jaffe: Hematopathology, 2nd Edition, 2016
Positive stains
- FL with Castleman-like changes:
- FL with plasmacytic differentiation and IgG4 positive plasma cells:
- Immunophenotype similar to that of nodal FL
- Plasmacytic differentiation: cytoplasmic light chain restriction among interfollicular neoplastic plasma cells
- IgG4 positive plasma cells may be increased: > 100/high power field and IgG4:IgG ratio > 40%
- FL with marginal zone differentiation involving MALT sites:
- FL negative for CD10 and expressing MUM1 (Blood 2007;109:3076):
- EBV positive FL (Am J Hematol 2019;94:E62):
- Floral variant of FL:
Negative stains
- FL with Castleman-like changes:
- FL with marginal zone differentiation involving MALT sites:
- FL negative for CD10 and expressing MUM1 (Blood 2007;109:3076):
- Floral variant of FL:
Molecular / cytogenetics description
- FL with Castleman-like changes:
- Positive for t(14;18)(q32;q21) or BCL2 rearrangements (Pathology 2017;49:544)
- FL with plasmacytic differentiation and IgG4 positive plasma cells (Mod Pathol 2010;23:71):
- BCL2 rearrangements
- Present in monotypic plasma cells with an interfollicular distribution
- Absent in monotypic plasma cells with prominent intrafollicular distribution
- BCL2 rearrangements
- FL with marginal zone differentiation involving MALT sites:
- BCL2 rearrangements seen in both the follicular and marginal zone components (Mod Pathol 2001;14:191)
- Pitfall: FL involving MALT sites show IGH-BCL2 rearrangements less frequently than typical (nodal) FL (J Clin Pathol 2008;61:377, Am J Surg Pathol 2009;33:22)
- BCL2 rearrangements seen in both the follicular and marginal zone components (Mod Pathol 2001;14:191)
- FL negative for CD10 and expressing MUM1 (Blood 2007;109:3076):
- Frequently lacks IGH-BCL2 translocation
- BCL6 gene abnormalities (translocation or amplification) in the majority of cases
- BCL2 gene amplification (in ~50% of cases)
- EBV positive FL:
- t(14;18)(q32;q21) translocation in ~85% of cases (Mod Pathol 2017;30:519)
- Floral variant of FL:
- t(14;18)(q32;q21) translocation
Sample pathology report
- Lymph node, cervical, excision:
- Follicular lymphoma, low grade, with Castleman-like changes (see comment)
- Comment: Sections of the lymph node show a follicular lymphocytic proliferation, with a dense, atypical lymphocytic infiltrate. In most lymph node areas, sections reveal the presence of lymphoid follicles containing predominantly small, slightly angulated lymphocytes having irregular nuclei. In many of the follicles, the central areas of the follicle are nearly fully occupied by histiocytic / dendritic cells, with surrounding mantle zones prominent, giving an appearance of atretic follicles and imparting a distinctly Castleman-like appearance. The interfollicular regions of the lymph node show scattered plasma cells, in which a variable degree of plasma cell enlargement is present. Eosinophilic staining collagenous material is present around blood vessels and extensively in the lymph node capsule.
- Immunohistochemical studies show positive staining for CD20, PAX5, BCL2 and BCL6 and are negative for CD3, CD5, cyclin D1 and HHV8. Cyclin D1 highlights endothelial cells, as well as histiocytic / dendritic cells. CD35 highlights numerous follicular dendritic cell meshworks in the areas of follicle formation and highlights the sclerotic centers. Few CD138 positive plasma cells are identified, which are polytypic by kappa and lambda immunohistochemical and in situ hybridization study. Congo red stain is negative for birefringent material.
- By in situ hybridization analysis for Epstein-Barr virus encoded RNA (EBER), the neoplastic cells are negative for EBER.
- Fluorescence in situ hybridization (FISH) reports IGH-BCL2 fusion (25% nuclei), BCL6 rearrangement (30% nuclei) and no evidence of MYC rearrangement.
Differential diagnosis
- FL with Castleman-like changes (Hum Pathol 2017;68:136, Mod Pathol 2018;31:429):
- Overlapping features with Castleman disease; however, features favoring FL include:
- FL with plasmacytic differentiation and IgG4 positive plasma cells:
- Overlapping features with marginal zone lymphoma
- Immunophenotype in neoplastic cells is similar to that of nodal FL
- Distinction of these entities typically requires extensive immunophenotyping and FISH studies to assess for IGH-BCL2 translocation
- FL with marginal zone differentiation involving MALT sites:
- Overlapping features with marginal zone lymphoma; features favoring FL include:
- t(14;18) negative follicular lymphoma:
- Shows aberrations more similar to nodal marginal zone lymphoma
- Floral variant of FL:
- Progressive transformation of germinal centers (PTGC) (APMIS 2006;114:626):
- Marginal zone lymphoma (MZL) with follicular colonization (Leuk Lymphoma 2021;62:1116):
- In FL, floral variant:
- In MZL with follicular colonization:
- In follicles colonized with MZL:
- Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) (APMIS 2006;114:626):
- Presence of centroblasts in FL versus popcorn cells in NLPHL
- CD10+, CD20+, BCL2+ immunophenotype in FL versus CD10-, CD20+, BCL2- in NLPHL
- Absence of T cell rosette around cells in FL (APMIS 2006;114:626, Am J Clin Pathol 1987;88:264)
Board review style question #1
Which of the following follicular lymphomas or variants more commonly has BCL2 rearrangement?
- Follicular lymphoma with Castleman-like changes
- Large B cell lymphoma with IRF4 rearrangement
- Pediatric follicular lymphoma
- Testicular follicular lymphoma
Board review style answer #1
A. Follicular lymphoma with Castleman-like changes
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Reference: Unusual morphologic patterns of follicular lymphoma
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Reference: Unusual morphologic patterns of follicular lymphoma
Board review style question #2
A 50 year old man presented with abdominal pain for 1 month. Physical examination and laboratory tests were within normal limits. An imaging study showed multiple masses, the largest one measuring 10.5 x 5.0 cm. The patient underwent an excisional biopsy of one of the lymph nodes. The cut section of the lymph node showed lymphoid nodules, some surrounding atrophic follicles. Flow cytometry showed an aberrant CD10+ B cell population, positive for cytoplasmic CD22 and CD79a and negative for surface or cytoplasmic immunoglobulin, CD5 and CD23. Fluorescence in situ hybridization (FISH) analysis showed an IGH-BCL2 fusion gene consistent with t(14;18)(q32;q21). Which of the following options is the best correct option in this case?
- Cyclin D1 is positive in lymphocytes in the lymphoid nodule
- IgD is is positive in lymphocytes in the lymphoid nodule
- Ki67 proliferation index is expected to be high in lymphoid nodules
- Lymphoid cells in lymphoid nodules are expected to be positive for CD10, CD79a, BCL2 and BCL6
Board review style answer #2
D. Lymphoid cells in lymphoid nodules are expected to be positive for CD10, CD79a, BCL2 and BCL6
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Reference: Unusual morphologic patterns of follicular lymphoma
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Reference: Unusual morphologic patterns of follicular lymphoma
