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Lymphoid aggregates (benign)

Author: Barina Aqil, M.D.

Editorial Board Member: Anamarija M. Perry, M.D.

Deputy Editor-in-Chief: Genevieve M. Crane, M.D., Ph.D.

Last author update: 15 November 2023

Last staff update: 15 November 2023

Copyright: 2002-2024, PathologyOutlines.com, Inc.

PubMed Search: Lymphoid aggregates bone marrow

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Table of Contents

Cite this page: Aqil B. Lymphoid aggregates (benign). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/bonemarrowlymphoidaggregates.html. Accessed April 26th, 2024.

Definition / general

Benign lymphoid aggregates are composed predominantly of small lymphocytes
Some benign lymphoid aggregates may have germinal centers made up of centrocytes and centroblasts

Essential features

Presence of lymphoid aggregates in the bone marrow biopsy should be evaluated to exclude lymphoproliferative disorders / lymphoma
Morphology is of paramount importance for the decision to perform ancillary tests
Small size (< 600 μm), nonparatrabecular location, confined borders, paucity of B cells are usually supportive of benign lymphoid aggregates
Ancillary modalities such as flow cytometry and molecular studies have their diagnostic limitations and should be taken into consideration when making a diagnosis

Epidemiology

Benign lymphoid aggregates seen in only 1 - 2% of bone marrow biopsy specimens
More frequently seen in autopsy specimens

Etiology

Benign lymphoid aggregates are seen in association with the following (J Clin Pathol 1999;52:294, Virchows Arch A Pathol Anat Histopathol 1991;419:261, Leuk Res 2002;26:525, Am J Clin Pathol 1999;112:844, Eur Respir J 2009;34:405, Blood 2011;117:6438, Mod Pathol 2015;28:367, J Clin Pathol 1993;46:955, Br J Haematol 2016;172:923, Haematologica 2017;102:364)

Advanced age
Tobacco use
Autoimmune diseases	Rheumatoid arthritis, systemic lupus erythematosus
Autoimmune lymphoproliferative syndrome with germline FAS mutation
Inflammatory conditions
Infectious diseases	HIV, hepatitis C virus, hepatitis B virus, mycobacteria, fungal or bacterial and cytomegalovirus infections
Myeloproliferative neoplasms	Polycythemia vera, primary myelofibrosis, systemic mastocytosis
Myelodysplastic syndromes
POEMS syndromes Polyneuropathy Organomegaly Endocrinopathy M protein Skin changes TEMPI syndromes Telangiectasias Elevated erythropoietin and erythrocytosis Monoclonal gammopathy Perinephric fluid collections Intrapulmonary shunting
Rituximab and chimeric antigen receptor T cells (CAR T) treatment
Idiopathic hypereosinophilic syndrome

Clinical features

Usually, no prior history of lymphoproliferative disorder; however, even if there is a history, that does not necessarily signify the presence of lymphoid aggregates as malignant
Mean age of presentation is in the sixth decade (Hum Pathol 2013;44:512)
Incidence increases with age (Hum Pathol 2013;44:512)

Diagnosis

Incidental finding on bone marrow examination

Prognostic factors

In all ages, up to 33% of cases may have subsequent malignant lymphoid aggregates in bone marrow or other evidence of lymphoma or lymphoproliferative disorders (Blood 1974;43:389)
If initial biopsy showed atypical lymphoid aggregates, then follow up with bone marrow biopsy should be suggested

Treatment

No treatment for benign lymphoid aggregates

Microscopic (histologic) description

Lymphoid aggregates are assessed based on the location (intertrabecular / paratrabecular), size and appearance of lymphocyte population
Characteristics of benign lymphoid aggregates (J Clin Pathol 1999;52:294, Virchows Arch A Pathol Anat Histopathol 1991;419:261, J Pathol 1997;181:451, J Pathol 1996;178:447)
- Small size (< 600 μm)
- Uniform configuration
- Distinct outline
- Nonparatrabecular location
- Becomes smaller or disappears in deeper sections of the specimen
- Lack of cytologic atypia
- Negative for clonality (exception in autoimmune diseases)

5 different patterns are described for the T cell and B cell distribution in the lymphoid aggregates (Hum Pathol 2013;44:512)

Patterns	CD3+ T cells / CD20+ B cells
1	Predominantly T cells
2	Mixture of T and B cells, haphazard arrangement
3	T cell core surrounded by few B cells
4	B cell core surrounded by T cells
5	Predominantly composed of B cells

Benign lymphoid aggregates show predominantly patterns 1 - 3 with rare cases of patterns 4 and 5
Atypical features described in lymphoid aggregates include large size, infiltrative borders, paratrabecular location and predominance of B cells (patterns 4 and 5)
Patterns 4 and 5 are seen most commonly in lymphomas, with the exception of reactive lymphoid aggregates with BCL6 positive germinal centers (Virchows Arch A Pathol Anat Histopathol 1987;411:543)

Some of the benign lymphoid aggregates have characteristic morphologic findings based on the etiology (Pathologica 1995;87:640, Eur Respir J 2009;34:405, Blood 2011;117:6438, Mod Pathol 2015;28:367, J Clin Pathol 1993;46:955, Haematologica 2017;102:364, Am J Clin Pathol 1999;112:844)

Etiology	Lymphoid aggregate morphologic findings
POEMS syndrome	Composed of mixture of T and B cells, surrounded by lambda / kappa light chain restricted or polytypic plasma cells
Idiopathic hypereosinophilic syndrome	T cell rich aggregates
HIV	Large poorly demarcated lymphoid aggregates with cytologic atypia and histiocytic proliferations
Autoimmune lymphoproliferative syndrome with germline FAS mutation	T cell rich lymphoid aggregates with CD4- / CD8- T cells
Rituximab treatment	T cell rich lymphoid aggregates
CD19 directed CAR T therapy	T cell rich lymphoid aggregates with increased CD8+ T cells

Microscopic (histologic) images

Contributed by Barina Aqil, M.D.

Pattern 1

Pattern 2

Pattern 3

Pattern 4

Pattern 5

Pattern 1 (CD3)

Pattern 2 (CD3)

Pattern 3 (CD3)

Pattern 4 (CD3)

Pattern 5 (CD3)

Pattern 1 (CD20)

Pattern 2 (CD20)

Pattern 3 (CD20)

Pattern 4 (CD20)

Pattern 5 (CD20)

Cytology description

Bone marrow aspirate may show lymphocytosis, consisting of small to medium sized, mature appearing lymphocytes without atypia

Cytology images

Contributed by Barina Aqil, M.D.

Sheet of small lymphocytes

Positive stains

T cells: CD3
B cells: CD20
Germinal centers, if present: CD10, BCL6

Negative stains

CD10, CD23, CD30 are mostly negative
Germinal centers, if present negative for: BCL2

Flow cytometry description

No monotypic B cell or phenotypically aberrant T cell populations identified
Flow cytometry is used to assess the surrogate markers of clonality for B and T cells
Kappa and lambda immunoglobulin light chains are evaluated for monotypic B cells, which includes kappa:lambda ratio > 3 or < 0.5
Neoplastic B cells may also show lack of surface immunoglobulin light chains
Abnormal T cell phenotype is described by abnormal expression patterns of T cell markers; for example, downregulation of surface CD3 expression, loss of CD7 or CD5 as well as a skewed CD4:CD8 ratio or expansion of double positive (CD4+ / CD8+) or double negative (CD4- / CD8-) populations
Clonal T cell or NK cell populations can be evaluated by assessment of TCR Vβ or KIR repertoire, respectively
TCR constant β chain 1 (TRBC1) expression is based on the expression of TCR β chain with either a constant region 1 or a constant region 2 (C1 or C2) on mature αβ T cells
T cell clone is characterized by either a relative increase or a relative decrease in TRBC1+ T cells (Int J Mol Sci 2021;22:1817)

Molecular / cytogenetics description

Molecular tests based on polymerase chain reaction (PCR) are used for detection of immunoglobulin heavy chain (IGH) and light chains or T cell receptor gene rearrangements to identify the clonal nature of lymphoid aggregates and are negative in benign lymphoid aggregates
Cytogenetic analysis: normal karyotype and no abnormal FISH signals

Sample pathology report

Peripheral blood, bone marrow aspirate and left posterior iliac crest, bone marrow core biopsy:
- Normocellular marrow (~30% cellular) with trilineage hematopoiesis and multiple benign lymphoid aggregates (see comment)
- Comment: Flow cytometric immunophenotyping performed on the bone marrow aspirate reveals a polytypic B cell population and a T cell population without evidence of immunophenotypic abnormality based on the markers assayed.
- Microscopic description
  - Peripheral blood smear: normocytic normochromic red blood cells with polychromasia and mild anisopoikilocytosis
  - Neutrophils are adequate with unremarkable morphology; platelets are adequate with unremarkable morphology
  - Bone marrow aspirate smear: the myeloid and erythroid series show progressive maturation with unremarkable morphology
  - No overt increase in blasts, lymphocytes or plasma cells noted; megakaryocytes are present with predominantly unremarkable morphology
  - Bone marrow core biopsy (decalcified): the unilateral bone marrow core biopsy is normocellular for age (~50% cellular)
  - The myeloid and erythroid series show progressive maturation
  - Megakaryocytes are adequately present with unremarkable morphology
  - Multiple interstitial lymphoid aggregates, which are composed predominantly of small lymphocytes, are noted
  - Immunohistochemistry: CD3 and CD20 highlights mixture of interstitially scattered as well as aggregates of CD3+ T cells and CD20+ B cells, with T cell predominance

Differential diagnosis

Persistent polyclonal B cell lymphocytosis:
- Rare condition of unknown etiology seen in young middle aged women who are usually smokers
- Mostly asymptomatic and are found to have absolute lymphocytosis, elevated serum IgM and binucleated lymphocytes
- Polyclonal B cells detected by flow cytometry
- Rare cases may have lymphadenopathy, hepatomegaly and splenomegaly
- Strong association with human leukocyte antigen DR7 and detection of translocation t(14;18) involving the BCL2 gene has been demonstrated in the literature
Polymorphous reactive lymphoid hyperplasia:
- Characterized by the presence of interstitially increased lymphocytes or lymphoid aggregates in the bone marrow but it is usually focal, random and poorly circumscribed
- Lymphocytes are polymorphous, polytypic and are seen in the background containing plasma cells, immunoblasts, eosinophils and histiocytes
- Found in any age group and is mostly associated with underlying diseases, such as malignancies, postchemotherapy / stem cell transplant, infections and autoimmune disorders (Leuk Res 2013;37:1404)
Systemic polyclonal B immunoblastic proliferation:
- Seen in middle aged to elderly population who present with fever, lymphadenopathy, hepatosplenomegaly and absolute lymphocytosis
- Peripheral blood shows circulating immunoblasts and plasmacytoid cells
- Bone marrow is hypercellular with extensive lymphocytic infiltration mimicking lymphoma
- No immunophenotypic abnormality is detected by flow cytometry
- No detection of IGH and TCR gene rearrangements by molecular studies (Cancer 1988;61:1350, Am J Clin Pathol 1992;98:222)
Malignant lymphoid aggregates:
- Characteristic morphological findings include large / multiple lymphoid aggregates, paratrabecular localization, infiltrative border, distribution around large sinuses with increasing size on deeper sections
- Detection of clonality by flow cytometry and rearrangements by molecular studies

Board review style question #1

What are the features of malignant lymphoid aggregates?

Infiltrative border, cytologic atypia, B cell rich pattern
Large size, nonparatrabecular location, T cell rich pattern
Large size, uniform configuration, T cell rich pattern
Small size, intertrabecular location, no cytologic atypia

Board review style answer #1

A. Infiltrative border, cytologic atypia, B cell rich pattern. Malignant lymphoid aggregates usually have an infiltrative border, show cytologic atypia and are B cell rich (patterns 4 and 5). Answer B is incorrect because malignant lymphoid aggregates are composed predominantly of B cells. Answer C is incorrect because malignant lymphoid aggregates do not have a distinct border and are not usually T cell rich. Answer D is incorrect because malignant lymphoid aggregates demonstrate cytologic atypia and are usually large in size.

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Reference: Lymphoid aggregates (benign)

Board review style question #2

The benign lymphoid aggregate (LA) shows a germinal center composed of centrocytes and centoblasts along with follicular dendritic meshwork (CD21+) on bone marrow core biopsy. Which of the following would be the immunophenotypic profile of the LA?

CD10+, BCL6+, BCL2+
CD10+, BCL6+, BCL2-
HGAL+, BCL6+, BCL2+
LMO2+, CD10+, BCL2+

Board review style answer #2

B. CD10+, BCL6+, BCL2-. Benign lymphoid aggregates with a germinal center on the bone marrow core biopsy will be CD10+, BCL6+, BCL2-. CD10, BCL6, HGAL and LMO2 are germinal center markers and benign (normal) germinal centers are BCL2-, unlike malignant aggregates which are BCL2+. Answer A is incorrect because malignant lymphoid aggregates will be positive for germinal center markers (CD10+, BCL6+) and BCL2+. Answer C is incorrect because malignant lymphoid aggregates will be positive for germinal center markers (BCL6+, HGAL+) as well as BCL2+. Answer D is incorrect because malignant lymphoid aggregates will be positive for germinal center markers (CD10+, LMO2+) as well as BCL2+.

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Reference: Lymphoid aggregates (benign)

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