Cite this page: Aqil B. Lymphoid aggregates [benign]. PathologyOutlines.com website. //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?
- 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
- 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?
- CD10+, BCL6+, BCL2+
- CD10+, BCL6+, BCL2-
- HGAL+, BCL6+, BCL2+
- LMO2+, CD10+, BCL2+
Board review style answer
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+.