
Lymph nodes-not lymphoma
Last revised 21 July 2008
Last major update June 2006
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See also Lymphoma-B cell and plasma cell neoplasms and Lymphoma-non B cell
Table of contents
Primary references, images needed, embryology, normal anatomy, normal cell population, B cells, T cells, NK cells, mast cells, accessory immune system, normal development, age related changes
Inclusions, pigment, ectopic cells or tissue: adipose tissue, anthracosis, asbestos bodies, decidual reaction, endometriosis, epithelial, gold, iron, lipofuscin, megakaryocytes, melanosis, mesothelial, mullerian, nevus cells, prosthesis related, salivary gland, silicone, silicosis, smooth muscle, squamous epithelium, tattoo, thymus, thyroid follicles, yellow bodies
Primary immunodeficiency disorders: general, autoimmune lymphoproliferative syndrome, chronic granulomatous disease, CR3 deficiency, Omenn’s syndrome
Infectious/parasitic disorders: actinomyces, bacillary angiomatosis, bCG, brucellosis, Brugia, cat-scratch, Coccidiodes, Corynebacteria, denge fever, EBV, hemophilus influenza, herpes simplex, HHV6, HHV8/KSHV, histoplasmosis, HIV, Leishmania, leprosy, lymphogranuloma venereum, measles, mycobacteria-atypical, mycobacterial spindle cell pseudotumor, parvovirus B19, pseudofungi, syphilis, toxoplasmosis, tuberculosis, tularemia, vaccinia, Whipple’s disease, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis
Inflammatory disorders: reactive-general, acute nonspecific lymphadenitis, adult onset Still’s disease, allergic granulomatosis, amyloid, angiolymphoid hyperplasia with eosinophilia, Castleman’s disease, chronic lymphadenitis, Clofazimine, dermatopathic lymphadenitis, drug hypersensitivity, erythrophagocytosis, extramedullary hematopoiesis, follicular hyperplasia, granulomatous, hemophagocytic lymphohistiocytosis, hyaline deposits, infarction, inflammatory pseudotumor, Kawasaki, Kikuchi’s, Kimura’s disease, lipogranuloma, lymphedema, mantle cell/marginal zone hyperplasia, monocytoid B cell hyperplasia, plasmacytosis, polykaryocytes, post-lymphangiography granuloma, post-transplant, progressive transformation of germinal centers, rheumatoid arthritis, sarcoidosis, sinus histiocytosis, sinus histiocytosis with massive lymphadenopathy, Sjogren’s syndrome, SLE, systemic sclerosis, vascular transformation of sinuses, vasculitis, venolymphatic angiodysplasia
Neoplasms (not lymphoma): ALL, AML, angioimmunoblastic lymphadenopathy, angiolipomatous hyperplasia, angiomyolipoma, angiomyomatous hamartoma, angiosarcoma, CML, epithelioid hemangioendothelioma, Erdheim-Chester disease, fibroblastic reticulum cell sarcoma, follicular dendritic cell sarcoma, hemangioma, histiocytic sarcoma, indeterminate cell tumors, interdigitating dendritic/reticulum cell sarcoma, Kaposi’s sarcoma, Langerhans cell histiocytosis, leiomyoma, lymphangioma, lymphangiomyomatosis, lymphoma, malignant histiocytosis, mastocytosis, metastases to lymph nodes, myofibroblastoma, plasmacytoma
Miscellaneous: grossing, lymph node dissection
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
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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
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
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; #2; cortex and medulla #1; #2; reticular network (silver stain); various images
Normal cell population of lymph node
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 disease; Russell bodies #1; #2
EM images: plasma cell #1; #2
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: immunoglobulin; B cell differentiation #1; #2; heavy chain gene rearrangement
Micro: mainly present in primary and secondary follicular centers
Micro images: various images; 3D image
References: B cell antigen presentation
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; #2; T 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 cells; 3D image
NK cells (Natural Killer cells)
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 / FC
RIII 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
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 sinuses; mast cell (stain unknown); mast cells in systemic mastocytosis; mast 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
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
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
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 appendix; ER+ 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
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
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
Counterpart of Langerhans cell in parenchymal organs (excluding cornea and brain)
Langerhans cells
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; #2; Birbeck’s granules
Macrophages
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: monocyte; macrophages (with pigment) and plasma cells; tingible body macrophage #1; #2; thyroglobulin+ histiocytes
Positive stains: CD68, lysozyme
Sinus lining cells
Also called littoral cells, particularly in spleen
Have endothelial and macrophage properties
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
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
Very common, particularly in external iliac and obturator nodes (see also Age related changes)
May cause masses up to 10 cm
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