Cite this page: Aqil B. Lymphoid aggregates (benign). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/bonemarrowlymphoidaggregates.html. Accessed April 10th, 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 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 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?

1. Infiltrative border, cytologic atypia, B cell rich pattern
2. Large size, nonparatrabecular location, T cell rich pattern
3. Large size, uniform configuration, T cell rich pattern
4. Small size, intertrabecular location, no cytologic atypia

Board review style answer

1

1. 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.

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?

1. CD10+, BCL6+, BCL2+
2. CD10+, BCL6+, BCL2-
3. HGAL+, BCL6+, BCL2+
4. LMO2+, CD10+, BCL2+

Board review style answer

2

2. 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+.