Lymph nodes-not lymphoma

Last revised 21 July 2008

Last major update June 2006

Copyright © 2006-2008, PathologyOutlines.com, Inc.

Reviewed by William D. DePond, MD (see Reviewers Page)
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See also Lymphoma-B cell and plasma cell neoplasms and Lymphoma-non B cell

 

 

 

Table of contents

Primary referencesimages neededembryologynormal anatomynormal cell populationB cells,  T cellsNK cellsmast cellsaccessory immune systemnormal developmentage related changes 

Inclusions, pigment, ectopic cells or tissue: adipose tissueanthracosisasbestos bodiesdecidual reactionendometriosisepithelialgoldironlipofuscinmegakaryocytesmelanosis,  mesothelialmulleriannevus cellsprosthesis related, salivary glandsiliconesilicosis,  smooth musclesquamous epitheliumtattoothymusthyroid folliclesyellow bodies

Primary immunodeficiency disorders: general,  autoimmune lymphoproliferative syndromechronic granulomatous diseaseCR3 deficiencyOmenn’s syndrome

Infectious/parasitic disorders: actinomycesbacillary angiomatosisbCGbrucellosisBrugiacat-scratchCoccidiodesCorynebacteriadenge feverEBVhemophilus influenzaherpes simplexHHV6HHV8/KSHVhistoplasmosisHIVLeishmanialeprosylymphogranuloma venereummeaslesmycobacteria-atypicalmycobacterial spindle cell pseudotumorparvovirus B19pseudofungisyphilistoxoplasmosistuberculosistularemiavaccinia,  Whipple’s diseaseYersinia enterocoliticaYersinia pestisYersinia pseudotuberculosis

Inflammatory disorders: reactive-generalacute nonspecific lymphadenitisadult onset Still’s diseaseallergic granulomatosisamyloidangiolymphoid hyperplasia with eosinophilia,  Castleman’s diseasechronic lymphadenitisClofaziminedermatopathic lymphadenitisdrug hypersensitivityerythrophagocytosisextramedullary hematopoiesisfollicular hyperplasiagranulomatoushemophagocytic lymphohistiocytosishyaline deposits,  infarctioninflammatory pseudotumor, Kawasaki,  Kikuchi’s,  Kimura’s diseaselipogranulomalymphedemamantle cell/marginal zone hyperplasiamonocytoid B cell hyperplasiaplasmacytosispolykaryocytespost-lymphangiography granulomapost-transplantprogressive transformation of germinal centersrheumatoid arthritis,  sarcoidosissinus histiocytosissinus histiocytosis with massive lymphadenopathySjogren’s syndrome,  SLEsystemic sclerosisvascular transformation of sinusesvasculitisvenolymphatic angiodysplasia

Neoplasms (not lymphoma): ALLAMLangioimmunoblastic lymphadenopathyangiolipomatous hyperplasiaangiomyolipomaangiomyomatous hamartomaangiosarcomaCMLepithelioid hemangioendotheliomaErdheim-Chester diseasefibroblastic reticulum cell sarcomafollicular dendritic cell sarcomahemangiomahistiocytic sarcomaindeterminate cell tumorsinterdigitating dendritic/reticulum cell sarcoma,  Kaposi’s sarcomaLangerhans cell histiocytosisleiomyomalymphangiomalymphangiomyomatosislymphomamalignant histiocytosismastocytosismetastases to lymph nodes,  myofibroblastomaplasmacytoma 

Miscellaneous: grossinglymph node dissection

 

Primary references

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American Journal of Clinical Pathology (AJCP), August 1975 to May 2006

American Journal of Pathology (free after 6 months), January 1990 to June 2006

American Journal of Surgical Pathology (AJSP), March 1977 to June 2006

Archives of Pathology and Lab Medicine (Archives), January 1976 to May 2006

BMC Clinical Pathology, 20 June 2001 to 23 May 2006

Human Pathology (Hum Path), March 1970 to June 2006

Journal of Clinical Pathology (free after 1 year) Sept 1965 to June 2006

Modern Pathology (Mod Path), January 1988 to June 2006

Rosai, J:  Ackerman’s Surgical Pathology (9th Ed); Mosby, 2004

Sternberg, S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins, 2004
Sternberg: Histology for Pathologists (2nd Ed); 1997

University of Pittsburgh Medical Center Case Reports, cases 1-470

Warnke: Tumors of the Lymph Nodes and Spleen (Atlas of Tumor Pathology, 3rd Series, Vol. 14; 1995)

Journal search terms: lymph node

 

Images needed of lymph nodes

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We welcome your contributions of digital images, which we will post in the appropriate section of this chapter, and which help pathologists worldwide who use this website

To contribute, email your digital images (GIF or JPG, any size) to Dr. Pernick at info@PathologyOutlines.com.  We will list your name as a contributor unless you want to be anonymous.  Click here for more information.

Images are particularly needed for these topics: in lymph node - marginal zone, centroblasts, centrocytes, B cells, T cells, NK cells, macrophages, mast cells, dendritic cells (all types, also EM), littoral cells, CR3 deficiency, Brugia, HIV, mycobacterial spindle cell pseudotumor, parvovirus, pseudofungi, syphilis,  vaccinia, Yersinia (all species), amyloid, chronic lymphadenitis, clofazimine, extramedullary hematopoiesis, hyaline deposits, Kawasaki disease, lipogranuloma, lymphedema, mantle cell/marginal zone hyperplasia, monocytoid B cell hyperplasia, Sjogren’s syndrome, vasculitis, angiolipomatous hamartomas, angiomyomatous hamartoma

 

 

Embryology of lymph node

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Develop from lateral plate mesoderm (on either side of intermediate mesoderm)

   Image: animation of lateral plate mesoderm (slow loading)

First, lymphatic sacs arise from endothelial outgrowths of large central veins at week 5

Second, lymphatic plexus develops from lymphatic sacs

Third, plexuses are invaded by mesenchymal cells that proliferate and aggregate to form lymph nodes

Small collections of lymphoblasts are present by first trimester

By second trimester, cortex is distinguishable from medulla and primary follicles are present

Drawing: development of lymph node

References: Human Anatomy - Pearson

 

Normal anatomy/histology of lymph node

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A secondary lymphoid organ (where B and T cells proliferate in response to exogenous antigen)

Primary lymphoid organs are bone marrow and thymus

Other secondary lymphoid organs are spleen and Peyer’s patches

Tertiary lymphoid organs are tissues with few lymphocytes that recruit more when inflammation is present

Lymph nodes are organized to detect and inactivate foreign antigens present in lymph fluid that drains skin, GI tract and respiratory tract, the major organs in contact with the environment

Gross: ovoid with gray-tan cut surface

Micro: at low power, lymph node structures are capsule, cortex and medulla, follicles, paracortex, sinuses

Afferent lymph vessels: penetrate capsule, enter marginal sinus, communicate with intranodal sinuses, then become efferent vessels, which lack an endothelial lining; intranodal vessels contain littoral cells or histiocytes with phagocytic properties

Capsule: thin fibrous connective tissue covering of lymph node; may be thicker at hilus; connected to fibrous trabeculae which penetrate the node; capsule may contain smooth muscle cells (Anat Rec 1975;183:517)

   Micro images: capsule and subcapsular sinus #1#2

Cortex: subcapsular portion of node with largest number of follicles

Germinal center: contains centroblasts and centrocytes; also macrophages and follicular dendritic cells; surrounded by a mantle zone of small B lymphocytes (which resembles the primary follicle, see below)

   Micro images:  germinal center #1#2#3#4

   Positive stains: strong and dense bcl6 and CD10

   Negative stains: bcl2

Mantle zone: small B cells surrounding pale staining germinal centers

     Micro images: mantle zone #1#2

Marginal zone: light zone on outer rim of mantle zone; contains post-follicular memory B cells derived after stimulation of recirculating cells from T cell dependent antigen

Medulla: portion of node closest to hilum; contains vessels and sinuses and mast cells but minimal number of follicles

Medullary cords: found in hilar region between the sinuses, composed mostly of small B and T lymphocytes

   Micro images: medullary cords and sinuses

Paracortex: tissue between cortical follicles and medulla; mostly dark staining; contains post-capillary venules (lined by high endothelial cells with intraendothelial lymphocytes), dendritic cells and T cells; expands during cell-mediated immunological reactions; has coarse network of reticulin fibers

   Micro images: paracortex;  post-capillary venule of paracortex

Primary follicle: round aggregates of small, dark staining lymphocytes, usually near the capsule, within a network of follicular dendritic cell processes; no germinal center present

Secondary follicle: arise from primary follicles that develops germinal centers (see below) due to antigenic stimulation of B cells and production of antibodies; contains pale staining germinal center which may be polarized towards site of antigen entry; contains B cells, follicular dendritic cells (CD21+, CD35+) and tingible body macrophages

   Micro images: germinal center #1#2

Sinuses: carry lymph from afferent to efferent lymphatics; subcapsular sinus is below capsule and partially lined by endothelium; becomes “medullary” as it approaches the hilum and is lined by macrophages

   Micro images: subcapsular sinus #1;  #2

Vessels: blood enters and leaves lymph node at hilus

 

Drawings: lymph node structures #1#2#3#4

Micro images: low power #1;  #2cortex and medulla #1#2reticular network (silver stain)various images

 

Normal cell population of lymph node

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See also specific cell types below

Centroblasts: large non-cleaved follicular center cells (B cells) with moderate amounts of basophilic cytoplasm, large round nuclei, open chromatin, multiple peripheral nucleoli; frequent mitotic figures

     Micro images: centroblast-like cells in diffuse large B cell lymphoma

Centrocytes: large and small cleaved follicular center cells (B cells) with scant cytoplasm and inconspicuous nucleoli

Plasma cells: abundant basophilic cytoplasm (due to high content of rough endoplasmic reticulum) with paranuclear hof (highlighted by Giemsa stain, due to Golgi apparatus); have eccentrically placed nucleus with spoke wheel (clock face) chromatin due to small clumps of chromatin on nuclear membrane in an otherwise round and clear nucleus; may have Russell bodies (intracytoplasmic PAS+ globules)

     Micro images: plasma cells #1 (arrows)#2#3;  in Castleman’s diseaseRussell bodies #1#2

     EM images: plasma cell #1#2

 

B cells

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Develop from stem cells of yolk sac, fetal liver, spleen and bone marrow

B cells mediate reactions to lipopolysaccharides and other macromolecules with repetitive features

B cells express surface immunoglobulin (Ig), which is composed of 2 heavy (H) and 2 light (L) chains (either kappa or gamma)

B cell antigen receptor loci may have 4 types of modification - (1) recombination of variable, diversity and joining regions (VDJ); (2) somatic hypermutation of V segments; (3) immunoglobulin heavy chain gene class switching; and (4) receptor editing

 

Early B cell precursor is TdT+, CD34+, HLA-DR+; then undergoes heavy (H) chain rearrangement and adds CD19; then adds CD10; then adds IgM heavy chain; then adds light (L) chain rearrangement and adds cytoplasmic IgM with heavy and light chains; then expresses IgM and IgD with the same binding site; then adds CD20 (now called preB cell); then adds surface Ig; then adds CD21 and CD22 and drops TdT (now called B cell)

If B cell encounters an antigen that interacts with its variable region, it becomes a plasma cell

 

Precursor B cells contain immunoglobulin related components but not immunoglobulin; express CD179a and CD179b (precursor to light chains) as part of their pre-B cell receptor, which disappears when replaced with conventional light chains

B cells express surface immunoglobulin, which is associated with CD79a/CD79b complex to form a B cell antigen receptor complex

IgH (heavy chain of immunoglobulin): encoded at 14q32; variable portion coded by VDJ genes

IgL (light chain of immunoglobulin): kappa on 2p11, lambda on 22q11; no diversity region is present

Heavy chain isotype switch: determines if immunoglobulin is IgM, IgD, IgG1-4, IgA1-2 or IgE (9 constant regions); mediated by switch genes

B cell lymphomas: clonal light chain rearrangement is usually specific for the presence of a B cell neoplasm

 

Diagrams: immunoglobulinB cell differentiation #1;  #2heavy chain gene rearrangement

Micro: mainly present in primary and secondary follicular centers

Micro images:  various images3D image

References: B cell antigen presentation

 

T cells

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Develop from bone marrow, become prothymocytes, then migrate to thymus gland, where self-recognizing T cells are eliminated

T cell receptors (TCR) are either alpha/beta (95%) or gamma/delta (5%) heterodimers

T cells mediate reactions to soluble antigens and some particulate antigens

Precursor cell is TdT+, CD34+, HLA-DR+; then drops HLA-DR; then adds CD2, CD5, CD7 (early thymocyte) while undergoing gamma/beta chain rearrangement; then adds CD1 and drops CD34; now a common thymocyte; then undergoes beta/alpha chain rearrangement and adds CD4 and CD8; then splits into helper or cytotoxic T cell, without TdT, CD1, CD5 and CD7; has CD2, CD3, CD4 (helper) or CD8 (cytotoxic)

 

T alpha and delta genes are on 14q11; T beta is on 7q34; T gamma is on 7p15 (note: there are only 10 V regions, so a polyclonal population of cells can appear oligoclonal)

90% of peripheral T-cell lymphomas have rearrangements of T-alpha, beta and gamma genes, including all cases of mycosis fungoides and Sezary syndrome

Note: T cell clonality is seen in AIDS and congenital immunodeficiency syndromes, but does NOT indicate malignancy

Note: rarely a clonal band may comigrate with the germline band; solution - use 2-3 restriction enzymes (HindIII, EcoRI, BamHI)

Note: T cells and NK cells arise from a common progenitor that expresses CD3 epsilon and cannot develop into B cells

Diagrams: antigen presentation #1#2T cell differentiation

Micro: mainly present in paracortex of lymph node; little cytoplasm, small, round/irregular nuclei with dark and condensed chromatin; may have blastic forms with moderate cytoplasm, irregular nuclei and marginal nucleoli

Micro images: attacking tumor cells3D image

 

NK cells (Natural Killer cells)

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Distinct group of non-T, non-B lymphocytes

Capable of lysing certain target cells without prior activation or major histocompatibility complex restriction

Believed important in defense against viral and bacterial infections and tumor cells as well as immunomodulation and regulation of hematopoiesis

Granules contain perforin (forms pores in cell membrane of target cells through which granzymes enter and induce apoptosis)

Activated by interferons or cytokines

Comprise 5-20% of peripheral blood lymphocytes

If target cell has class I MHC, then NK cell's killer cell inhibitory receptor (KIR) inhibits cytolysis

Diagrams: response to tumor cells

Micro: large granular lymphocytes

Positive stains: CD56 (>90%, adhesion molecule), CD57 (unknown function), CD16 (>90%, low affinity IgG Fc receptor / FCRIII that is responsible for antibody dependent cellular cytotoxicity in NK cells and also expressed on neutrophils and monocyte subset); also cytoplasmic (not surface) CD3, CD2, CD7, CD8, CD11b, CD11c, perforin, granzyme B, TIA-1

Negative stains: CD3 (surface), immunoglobulins

EM images: NK cells

 

Mast cells

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See also discussion in Spleen chapter

Present in T cell areas (World J Surg Oncol 2003;1:25)

Micro: difficult to detect; distinct cytoplasmic boundaries, faintly granular cytoplasm, large pale nuclei; some cells are elongated and resemble fibroblasts

Micro images: mast cells in subcapsular and medullary sinusesmast cell (stain unknown);  mast cells in systemic mastocytosismast cells in bone marrow #1#2

Positive stains: Giemsa and toluidine blue (purple granules), Leder stain, microphthalmia transcription factor, tryptase; also CD2, CD25, CD45, CD68, CD117

EM images: various images

 

Accessory immune system

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Includes antigen presenting cells (dendritic cells and Langerhans cells) and antigen processing cells (monocytes, macrophages)

Histiocytes: monocytes, macrophages, Langerhans cells and dendritic cells

 

Fibroblastic reticulum cells

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Stromal support cells

Micro: spindled cells in the parafollicular and deep cortex

Positive stains: vimentin, smooth muscle actin, desmin, alkaline phosphatase, CD68 (focal), keratin (some)

Negative stains: CD21, CD35, S100, EBV

EM: filaments with focal condensations

 

Follicular dendritic cells

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Associated with germinal centers

Have complex cell processes joined by desmosomes, but no Birbeck’s granules

Control B cell maturation and isotype switching

FDC like cells can be produced from monocytes (BMC Immunol 2005;6:23)

Upregulated by Tamoxifin treatment for breast cancer (Am J Pathol 2003;163:1313)

Micro images: CD14+ follicular dendritic cells in appendixER+ follicular dendritic cells

Positive stains: CD21, CD35; also fascin, ER, epidermal growth factor receptor, CD11b, CD14, CD19, CD20; variable S100, EBV, CD68

Negative stains: CD1a, keratin

 

Interdigitating dendritic cells

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Associated with interfollicular (T cell) zones in lymphoid tissue

Micro: may cause the paracortex to look mottled; resemble Langerhans cells; abundant, clear and pale cytoplasm with ill defined borders; have large and bizarre nucleus with deep clefts and folds; delicate almost transparent chromatin, inconspicuous nucleoli

Positive stains: S100, vimentin, fascin, CD45RB, CD68 (focal), variable CD1a (AJSP 1998;22:1048, AJCP 2001;115:589); also CD13

Negative stains: CD21, CD35, B and T cell markers, actin, desmin, keratin

EM: have complex cell processes that interdigitate with T cells, but NO desmosomes and NO Birbeck granules

 

Indeterminate cells

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Resemble Langerhans cells but NO Birbeck’s granules

Derived from Langerhans cells or interstitial dendritic cells, reside in skin and mucosa

Migrate into local lymphoid tissue after antigen capture

Positive stains: CD1a, S100, fascin

 

Interstitial dendritic cell

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Counterpart of Langerhans cell in parenchymal organs (excluding cornea and brain)

 

Langerhans cells

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Related to interdigitating dendritic cells and dermal dendrocytes

Micro images: Langerhans cells (site unknown);  Langerhans cell histiocytosis #1;  #2 of bone#3 of temporal bone

Positive stains: CD1a, S100, vimentin, Langerin, variable CD68

Negative stains: CD21, CD35 and CD86

EM: Birbeck’s granules

EM images: various images #1#2Birbeck’s granules

 

Macrophages

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Process antigens via phagocytosis

Related to circulatory monocytes

Are present throughout the lymph node

May contain thyroglobulin in lymph nodes draining thyroid tumors (J Clin Pathol 2001;54:314)

Micro: abundant cytoplasm with medium to large nuclei with vesicular chromatin; tingible body macrophages have clear cytoplasm and contain apoptotic bodies, which gives node a starry sky pattern

Micro images: monocytemacrophages (with pigment) and plasma cells;  tingible body macrophage #1#2thyroglobulin+ histiocytes

Positive stains: CD68, lysozyme

 

Sinus lining cells

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Also called littoral cells, particularly in spleen

Have endothelial and macrophage properties

 

Normal lymphocyte development

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Normal lymphoid cells undergo rearrangements within their antigen receptor genes, causing specificity for the immunoglobulin or T cell receptor that they produce

Monoclonal proliferations are presumed to be neoplastic; polyclonal populations are not

Apoptosis helps eliminate B cells producing antibodies with low avidity

Lymphoid stem cell:  TdT+, CD34+, HLA-DR+, then develops along B or T cell pathway

 

Age related changes in lymph nodes

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Germinal centers are more common in infants and children, decrease in young adults, often absent in elderly

Germinal centers are more common in mesenteric and cervical lymph nodes

Hyaline deposits increased with age

Peripheral lymph nodes, with little antigenic stimulation, often have replacement by fat, particularly in axillary, cubital and popliteal nodes

Lymphocyte depletion, fibrosis and hyaline deposits are associated with chronic disease, particularly cancer

References: Am J Pathol 1975;78:7, J Clin Pathol 1980;33:454

 

 

Inclusions, pigment or ectopic cells or tissue

Adipose tissue metaplasia in lymph nodes

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Very common, particularly in external iliac and obturator nodes (see also Age related changes)

May cause masses up to 10 cm

 

Anthracosis in lymph nodes

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Common in intrapulmonary lymph nodes

Due to coal dust, smoke or pollution

May be associated with storiform pattern of histiocytes that resembles a neoplasm (Hum Path 1998;29:851)

Associated with silica, although often no history of industrial exposure

Associated with hyalinization in nodes of elderly Japanese (Histol Histopathol 2003;18:1169)

Case reports: causing mediastinal lymphadenopathy resembling TB (Eur J Intern Med 2003;14:444)

Micro: fine anthracotic pigment; may be associated with storiform pattern of spindle cells that extend outside capsule and surround nerve; also nodal hyaline scars and polarizable material suggestive of silica

Micro images: anthracosis #1#2#3