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Reactive B cell rich lymphoid proliferations that can mimic lymphoma

Authors: Roman Segura-Rivera, M.D., Mario L. Marques-Piubelli, M.D., Roberto N. Miranda, M.D.

Editorial Board Member: Julie Feldstein, M.D.

Last staff update: 23 August 2023 (update in progress)

Copyright: 2022-2023, PathologyOutlines.com, Inc.

PubMed Search: Reactive B cell rich lymphoid proliferations

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Table of Contents

Cite this page: Segura-Rivera R, Marques-Piubelli ML, Miranda RN. Reactive B cell rich lymphoid proliferations that can mimic lymphoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphnodesreactivebcellrichlymphprolif.html. Accessed September 22nd, 2023.

Definition / general

Heterogeneous group of nonneoplastic proliferations that mimic B cell lymphomas and affect lymphoid tissue in nodal or extranodal sites

Essential features

Heterogeneous group of nonneoplastic proliferations that mimic B cell lymphomas and affect lymphoid tissue in nodal or extranodal sites
3 different main patterns
- Nodal and extranodal follicular proliferations
- Nodal and extranodal nodular proliferations
- Nodal and extranodal immunoblastic proliferations

Nodal follicular / nodular proliferations

Florid follicular hyperplasia (Hematol Oncol Clin North Am 2009;23:729)

Increased number of widely spaced primary and secondary follicles
- Florid cases usually involve medulla
Follicles show uneven size and shape
Hyperplastic germinal centers (GC) comprise a mixture of centroblasts and centrocytes with brisk mitoses, reactive T cells, follicular dendritic cells (FDCs) and tingible body macrophages (Ann Diagn Pathol 2020;44:151421)
- B lymphocytes
  - Centroblasts
    - Mainly in the dark zone of GC
    - 3 - 4x size of small lymphocytes
    - Large vesicular nuclei, 1 - 3 peripheral nucleoli
  - Centrocytes
    - Mainly in the light zone of GC
    - Small to intermediate sized cells with cleaved, hyperchromatic nuclei and small or absent nucleolus
  - Both centroblasts and centrocytes are BCL6+, CD10+, LMO2+, HGAL / GCET+, OCT2+
- T lymphocytes
  - Small and round
  - CD3+ and BCL2+
  - Subset of T helper cells (TFH): polarized CD4+, PD-1 / CD279+, BCL6+, CD10+, CXCL13+, ICOS+
- Follicular dendritic cells (FDCs)
  - Few (usually ~1%)
  - 2 square shaped and adjacent nuclei (kissing cells) with vesicular chromatin
    - May display small nucleolus
  - Long cytoplasmic processes
  - CD21+, CD23+ or CD35+
- Tingible body macrophages
  - Display oval or twisted vesicular nuclei
  - Abundant pale cytoplasm containing karyorrhectic nuclei
  - Impart a starry sky pattern when prominent
  - CD4+, CD68+ or CD163+
Well developed mantle zones
Distinction from germinal centers
- Composed predominantly of small lymphocytes and IgD+
No or limited extension outside the capsule into perinodal soft tissue
Location can suggest underlying disease and additional workup is necessary to confirm the diagnosis (Pediatr Clin North Am 2002;49:1009)
- Cervical: infectious mononucleosis
- Posterior cervical: toxoplasmosis
- Parotid, submaxillary, epitrochlear: HIV infection
- Cervical and axillary: cat scratch disease, dermatopathic lymphadenitis
- Inguinal: sexually transmitted diseases
Immunoarchitecture (Ann Diagn Pathol 2020;44:151421, Clin Lab Med 2021;41:433)
- Lymphoid follicles express B cell antigens
- Primary follicles
  - Small lymphocytes
  - BCL2+, Ki67 (usually < 10%), BCL6- and CD10-
- Secondary follicles
  - GCs are BCL2-
    - TFH cells: subset of T cells in germinal centers are BCL2 positive and occasionally are increased
      - May mimic follicular lymphoma
    - Pediatric type follicular lymphoma (FL) is BCL2 negative
      - FOXP1 is positive in GC cells of pediatric FL (Virchows Arch 2019;475:771)
  - High proliferation Ki67
    - Polarization (centroblast rich dark zone and a centrocyte rich pale zone)
    - Low Ki67 proliferation rate within a germinal center should always be considered atypical and suspicious for follicular lymphoma
  - BCL6+ and CD10+ are restricted to GCs, minimal in interfollicular areas
Flow cytometry
- Polytypic B cells; CD10+, T cell antigens-
Polymerase chain reaction (PCR)
- Polyclonal immunoglobulin heavy chain gene rearrangement
- No evidence of t(14;18)(q32;q21) or IGH::BCL2 fusion

Progressive transformation of germinal centers (PTGC) (Virchows Arch 2019;475:771)

Single or few large (4 - 5x normal) lymphoid follicles with mantle cells extensively indenting into GCs
Background lymph node exhibits reactive follicular hyperplasia (RFH)
Negative for rosetting by PD-1+ cells (TFH) around large B cells
GCs remnants rarely show tingible body macrophages
Morphological changes seem to proceed gradually
- Early stages show hyperplastic GCs
- Fusion of GCs within one single follicle (usually 2 - 3x size)
- Inward migration of mantle zone small B cells into the germinal center
- Later stages: dissolution of GCs results in islands or scattered centrocytes and centroblasts with follicular dendritic cells among small mantle zone B cells
Immunoarchitecture
- Preserved B and T cell compartments of lymph node and prominent follicular pattern
- Both GC and mantle zone cells express pan-B cell antigens
- Mantle cells: BCL2+, IgD+, BCL6- and CD10-
- Disrupted GCs: BCL6+, CD10+, BCL2- and IgD-
- CD21, CD23 or CD35 show disruption of FDCs meshwork
- IgG4+ plasma cells: ~40 - 50% of cases
Flow cytometry
- Polytypic B cells
Genetic testing
- Polyclonal IGH rearrangements

Hyaline vascular Castleman disease (HVCD)

Young adults (Blood 2017;129:1658)
- Usually < 30 years old
- Can also affect children
Numerous follicles in cortex and medulla of lymph node or extramedullary sites
Obliteration of subcapsular and interfollicular sinuses
≥ 2 germinal centers in follicle (also known as twinning)
Follicles typically large with regressed (or involuted) germinal centers
- Mostly composed of FDCs with few lymphocytes
- Mantle zones prominent
- FDCs often hyperplastic and can show dysplasia
Many follicles show so called lollipop features
- Concentric rings of mantle zone lymphocytes (onion skin appearance)
- Sclerotic blood vessels radially traversing into germinal center
Interfollicular or stromal component is also important (J Clin Exp Hematop 2022;62:60)
- Increased number of high endothelial venules with hyalinized walls
- Stromal component can predominate with only a few hyaline vascular follicles
Clusters of plasmacytoid dendritic cells can occur
Plasma cells and immunoblasts are not abundant in HVCD
- More common and abundant in plasma cell Castleman disease (PCCD)
Immunohistochemistry
- HHV8 is absent
- Polytypic B, T cells and plasma cells
- Increased FDCs in involuted germinal centers
  - CD21+, CD23+, CD35+ or EGFR+
- Dysplastic FDCs often stain variably for FDC markers
Differential diagnosis
- Classic Hodgkin lymphoma concurrent with Castleman disease (Virchows Arch 2020;477:437)
  - Diagnosis is established upon identification of Hodgkin Reed-Sternberg (HRS) cells with usual phenotype
- Castleman-like follicles in infectious lymphadenopathies
  - Changes are focal and sinuses are open

Table 1. Differential diagnosis between florid follicular hyperplasia and B cell lymphomas with follicular formation
Feature	Florid follicular hyperplasia	Follicular lymphoma	Marginal zone lymphoma	Mantle cell lymphoma, mantle zone pattern
Follicles	Enlarged, with prominent GCs and distinct mantle zones	Variably sized surrounded by faint mantle zones	Nodules with remnants of GCs surrounded by monocytoid cells	Thickened mantle zones
Density	Low, widely spaced	Back to back	Variable; may be confluent	Variable
Size	Uneven	Uniform	Variable	Uniform
Borders of GC	Sharp, well defined	Fainted, crack artifact	Blurry	Sharp, well defined
Distribution	Cortical predominance; florid cases involve medulla	Cortex and medulla	Cortex and medulla	Even distribution throughout cortex and medulla
Extension to perinodal fat	Absent or unusual	Often present	Often present	Uncommon
Mantle zone	Present, well developed	Attenuated to absent	Generally absent	Expanded in mantle zone pattern
Marginal zone	Can be hyperplastic	Absent	Expanded, may coalesce	Absent
Germinal center cells			Colonized by monocytoid cells	Absent
Tingible body macrophages	Present and common	Decreased or absent	Decreased or absent	Variable
Polarization	Present	Absent	Absent	Variable
Cytologic features	Centroblasts, centrocytes and macrophages	Centroblasts and centrocytes in various proportions	Monocytoid and plasmacytoid; scattered large cells	Small and intermediate centrocyte-like cells; few large cells
Immunoarchitecture
BCL2	Negative in GCs	Positive in germinal centers of FL grades 1 - 2; 50% in FL grade 3	Positive in neoplastic cells; GC remnants are negative	Positive in mantle zones
BCL6, CD10	Positive, restricted to GCs	Positive in GCs and interfollicular areas	Negative, GC remnants positive	Positive, restricted to GCs
Ki67	High proliferation rate; polarized in GCs	Low, nonpolarized	Low, nonpolarized	Variable in mantle zones
CD21, CD23, CD35	FDC meshworks preserved	FDC meshworks preserved	Distorted FDC meshworks	FDC meshworks preserved
Common positive markers	BCL6, LMO2, OCT2, HGAL	CD10, BCL2, BCL6, LMO2	CD43, MNDA, CD5-/+	Cyclin D1, SOX11, CD5
Common negative markers	CD3, BCL2	CD5, cyclin D1	CD10, cyclin D1, SOX11	CD10-, CD23- in mantle zones
Flow cytometry	Polytypic	Monotypic surface Ig; CD10 positive	Monotypic surface Ig; CD10 neg; CD5 neg or weak	Monotypic surface Ig; CD5 positive

Table 2. Differential diagnosis between progressive transformation of germinal centers and lymphomas with large nodules
Feature	Progressive transformation of germinal center	Nodular predominant Hodgkin lymphoma (patterns A / B)	Lymphocyte rich classic Hodgkin lymphoma, nodular variant
Follicles
Size	Scattered large nodules	Nodules larger than PTGC	Moderately enlarged
Germinal centers	Variably disrupted or involuted	Absent	Present within neoplastic nodules
Centrocytes and centroblasts	Decreased; scattered, BCL2-	Absent	In residual GCs
Mantle zone cells	Inward growth into GCs, BCL2+ and IgD+	Absent	Expanded
Reactive follicular hyperplasia	Present at background	Absent or focal	Absent or focal
Immunoarchitecture
T follicular helper cells rosettes (PD-1+)	Absent	Present	May be present
IgG4+ plasma cells	In 40 - 50% of cases	Absent	Absent
Large B cells	Rare immunoblasts	LP cells (popcorn cells)	Present, HRS cells
Immunophenotype	IgG+	CD20+, CD45+, OCT2+, EMA+/-, PAX5+ strong, IgD-/+	CD30+, CD45-, CD15+, PAX5+ dim, OCT2-, EMA-, CD20-

Nodal immunoblastic proliferations

Infectious mononucleosis (Semin Diagn Pathol 2018;35:54, Virchows Arch 2019;475:771)

Caused by acute Epstein-Barr virus (EBV) infection
Histologic changes are variable and depend on disease duration
- Early stage: reactive follicles, with mild paracortical expansion
- Progression: follicles sparse due to interfollicular expansion
- Advanced stage: follicles may become effaced, with interfollicular expansion
Interfollicular areas with numerous immunoblasts or mixed infiltrate
- Immunoblasts can be dispersed or abundant
- Lymphocytes range from small to intermediate and large in size
- Plasma cells, plasmacytoid cells and histiocytes are variably present, less frequently accompanied by eosinophils
- Sinuses are regularly occupied by immunoblasts, monocytoid B cells and histiocytes
Immunoblasts can be binucleated, mimicking HRS
- Intact nodal architecture admixed with B and T immunoblasts are indicative of a reactive process
Focal necrosis may be present
Immunohistochemistry
- HRS-like cells are CD45+, CD15-, CD30+ (weak) admixed with B and T immunoblasts
- EBV latency type 3 (Semin Diagn Pathol 2018;35:54)
  - EBV encoded RNA (EBER) present in numerous infected cells, ranging from small and intermediate lymphocytes to HRS-like immunoblasts
  - EBNA1+, EBNA2 variable and EBNA3+
  - LMP1+ and LMP2+
- Most lymphocytes in the background are CD8+, TIA1+

Herpesvirus lymphadenitis (Virchows Arch 2019;475:771)

Uncommon complication from either primary exposure or reactivation (more common)
Prominent immunoblastic paracortical hyperplasia
- Similar to infectious mononucleosis
Sharply circumscribed areas of necrosis and sinus histiocytosis
Adjacent to areas of necrosis
- Multinucleated cells with ground glass chromatin and intranuclear viral inclusions (halo)
Herpes simplex virus (HSV) immunohistochemistry confirms the diagnosis

Cytomegalovirus lymphadenitis (Virchows Arch 2019;475:771)

Morphologic features overlapping with those described in other viral infections
Monocytoid B cell hyperplasia is frequent
Characteristic owl eye central intranuclear inclusions with a halo
Cells infected with cytomegalovirus (CMV) often are T cells or endothelial cells
Diagnosis can be established utilizing CMV immunohistochemical stain

Table 3. Differential diagnosis between nodal B cell immunoblastic proliferation and lymphomas
Feature	Infectious mononucleosis	Classic Hodgkin lymphoma	Diffuse large B cell lymphoma, EBV+
Nodal compartment	Paracortical	Diffuse effacement	Diffuse effacement
Neoplastic cells	Not present	Scattered large cells; confluent in nodular sclerosis syncytial variant	Abundant large cells; diffuse pattern
Background lymphocytes
B cells	Small to intermediate	Small	Small
T cells	CD8+, small to intermediate	CD4+, small	CD8+, small
Monocytoid B cells hyperplasia	Often present	Absent	Absent
Plasma cells	Variably present	Few	Not frequent
Histiocytes	Variably present	Variable	Variable
Eosinophils	Rare	Present, often abundant	May be present
Necrosis	Focally present	Often present in nodular sclerosis subtype	May be present
Immunoarchitecture
EBV latency type	Type III	Type II	Type I
EBER	Positive in most cells	Positive in HRS cells	Positive in large cells
LMP1	Positive, fewer small and large cells (less sensitive)	Restricted to HRS cells in positive cases	If positive, restricted to large neoplastic cells
EBNA2	Mostly positive	Negative	Negative
EBNA3	Positive	Negative	Negative
CD20	Positive in large cells	Faint reactivity in HRS cells in ~20% of cases	Positive in large cells
CD3	Positive in small lymphocytes	Negative in HRS cells	Negative in large cells
CD30	Positive in HRS-like cells, usually dim	Positive in HRS cells, strong	May be positive in neoplastic cells
CD45	Positive in most cells	Negative in HRS cells	Positive in neoplastic cells
CD4, PD-1, ICOS, CXCL13	Negative in immunoblasts	Negative in HRS cells	Negative in neoplastic cells
CD21	Present only in GCs	Present only in residual GCs	Absent
Diagnostic molecular testing	Polyclonal B and T cells	Polyclonal B and T cells	Monoclonal IGH gene rearrangements

Extranodal follicular proliferations

Florid reactive lymphoid hyperplasia

Most cases represent reactive tertiary lymphoid tissue and may be associated either with an infectious agent, autoimmune phenomena or chronic repetitive trauma; these processes may lead to extranodal marginal zone lymphoma (Pathology 2020;52:15)
- Stomach: Helicobacter pylori
- Skin: Borrelia burgdorferi
- Conjunctiva: Chlamydia psittaci
- Cervix: Chlamydia trachomatis
- Small intestine: Campylobacter jejuni
- Lung: Achromobacter xylosoxidans
- Gallbladder: extrahepatic biliary obstruction
- Thyroid: Hashimoto thyroiditis
- Salivary gland: Sjögren syndrome
Differential diagnosis with marginal zone lymphoma can be challenging in some cases
- Cutaneous reactive lymphoid hyperplasia must be also distinguished from primary cutaneous follicular center lymphoma (see table) (Arch Pathol Lab Med 2018;142:1313)
- Florid reactive lymphoid hyperplasia of the female reproductive tract
  - Cervix is the most frequent affected site, followed by endometrium and vulva (Int J Gynecol Pathol 2022;41:459)
Most cases show lymphoid infiltrate with superficial distribution, with or without ulceration
Architecture varies from patchy and nodular to diffuse, with secondary follicles in most cases
- Tends to imitate lymph nodes organization, with a B follicular and T interfollicular compartments
Cytologically composed by small lymphocytes and polytypic plasma cells, with variable number of granulocytes and histiocytes in the background
Scattered large CD30+ immunoblasts are present in the majority of cases
Clonal IGH rearrangement is not uncommon, although patients are free of lymphoma on follow up (Arch Pathol Lab Med 2018;142:1313)

Table 4. Differential diagnosis between cutaneous follicular hyperplasia and B cell lymphomas
Feature	Reactive follicular hyperplasia	Primary cutaneous follicular center lymphoma	Primary cutaneous marginal zone lymphoma
Infiltrate	Denser in superficial dermis, wedge shaped	Denser in deep dermis, Grenz zone	Vertical orientation around follicles
Follicular architecture	Present, uneven shapes and size	Follicular or diffuse pattern	Pale nodules, some residual germinal centers
Mantle zone	Present, well developed	Attenuated to absent	Absent
Marginal zone	Generally absent	Absent	Expanded, may coalesce
Germinal center cells			Colonized by monocytoid cells
Tingible body macrophages	Present	Absent	Present in GC remnants
Polarization	Present	Absent	Absent
Cytologic features	Centrocytes and centroblasts	Centroblasts and centrocytes	Monocytoid cells, few large cells; plasma cells
Immunoarchitecture	B and T compartments preserved	Effaced, B cell predominant	Effaced, B cell predominant
BCL2	Negative in germinal centers	Negative in germinal centers	Positive in neoplastic cells; GC remnants are negative
BCL6	Positive, restricted to GCs	Positive in both GCs and interfollicular areas	Negative, GC remnants positive
Ki67	High and polarized in GCs	Low, nonpolarized	Low, nonpolarized
CD21, CD23, CD35	FDC meshworks preserved	FDC meshworks preserved	Distorted FDC meshworks
Light chain restriction	Absent	May be present	Present in plasmacytoid lymphocytes or mature plasma cells
Positive IgH / IgK clonality assays	No	Yes	Yes

Extranodal immunoblastic proliferations

EBV positive mucocutaneous ulcer (Surg Pathol Clin 2023;16:213)

Lymphoproliferative disorder characterized by EBV+ large B cells / Reed-Sternberg-like cells (RS-like cells) cells
Oral mucosa is most common site, followed by skin
- Multiple small lesions within same anatomic region can occur
No systemic symptoms, lymphadenopathy, hepatosplenomegaly or bone marrow involvement
Well circumscribed superficial ulcer with a subjacent polymorphous infiltrate
Deep base shows a sharp demarcation by a dense rim of small lymphocytes
Angioinvasion and high proliferation index may be present
Monoclonal IGH or TCR gene rearrangements can occur in up to a third of cases
Immunohistochemistry
- HRS-like cells: CD45+, CD15- and CD30+ (usually weak)
- Background: B and T cells
- EBV latency type 3 (Semin Diagn Pathol 2018;35:54)
  - EBV encoded RNA (EBER) present in numerous infected cells, ranging from small and intermediate lymphocytes to HRS-like immunoblasts
  - LMP1+, EBNA2+
- Basal rim of T cells are CD8+

Case reports

24 year old man with follicular lymphoid hyperplasia with aggressive behavior in maxilla (Oral Maxillofac Surg 2017;21:475)
40 year old man with infectious mononucleosis that presented as a lymphadenopathy with geographic necrosis (Pathol Res Pract 2004;200:53)
57 year old woman with idiopathic multicentric Castleman disease (TAFRO subtype) (Br J Haematol 2022;196:461)
70 year old woman with atypical follicular hyperplasia after COVID-19 booster (Virchows Arch 2023;482:905)

Microscopic (histologic) images

Contributed by Roberto N. Miranda, M.D. and Roman Segura-Rivera, M.D.

Reactive follicular hyperplasia

Polarized Ki67

Follicular lymphoma

Nonpolarized Ki67

Nodal marginal zone lymphoma

Monocytoid cytology

Mantle cell lymphoma (MCL) with mantle zone pattern

Cyclin D1 (mantle pattern) in MCL

Progressive transformation of germinal centers

CD20 in PTGC

NLPHL

LP cells

Rosetting CD3+ lymphocytes

Castleman disease, hyaline vascular variant

Germinal center in HVCD

Interfollicular expansion

Immunoblasts

Infectious mononucleosis, EBER

EBV positive diffuse large B cell lymphoma

EBER positivity in EBV positive diffuse large B cell lymphoma

Mixed cellularity classic Hodgkin lymphoma (MCCHL)

EBER positivity in mixed cellularity classic Hodgkin lymphoma

EBER positivity in MCCHL

Board review style question #1

Which of the following statements is true about progressive transformation of germinal center (PTGC)?

Centrocytes are increased and have a BCL2+ phenotype
IgG4+ plasma cells are usually absent
Reactive follicular hyperplasia is usually absent in the background
Rosettes of T follicular helper (TFH) cells are usually absent

Board review style answer #1

D. Rosettes of TFH cells are usually absent. Answer B is incorrect because PTGC cases usually present with IgG4+ plasma cells in up to 50% of cases. Answers A and C are incorrect because there is a decrease of centrocytes and reactive follicular hyperplasia in the background.

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Reference: Reactive B cell rich lymphoid proliferations that can mimic lymphoma

Board review style question #2

What latency pattern is more common in infectious mononucleosis?

Type 0: EBER+, LMP1-, EBNA2-
Type I: EBER+, LMP1-, EBNA2-
Type II: EBER+, LMP1+, EBNA2-
Type III: EBER+, LMP1+, EBNA2+

Board review style answer #2

D. Type III: EBER+, LMP1+, EBNA2+. Answers A, B and C are incorrect because the most common latency pattern in infectious mononucleosis is the pattern III, which is characterized by the positivity of EBER, LMP1 and EBNA2.

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Reference: Reactive B cell rich lymphoid proliferations that can mimic lymphoma

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