Lymph nodes - not lymphoma
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Last revised 13 July 2006
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See also Lymphomas: B cell and plasma cell neoplasms and Lymphomas: 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)
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
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)
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)
Positive stains: strong and dense bcl6 and CD10
Negative stains: bcl2
Mantle zone: small B cells surrounding pale staining germinal centers
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
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
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
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
Vessels: blood enters and leaves lymph node at hilus
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
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)
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
Micro: mainly present in primary and secondary follicular centers
References: B cell antigen presentation, B cell differentiation
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
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
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
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
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
Positive stains: Giemsa and toluidine blue (purple granules), Leder stain, microphthalmia transcription factor, tryptase; also CD2, CD25, CD45, CD68, CD117
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)
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
Positive stains: CD1a, S100, vimentin, Langerin, variable CD68
Negative stains: CD21, CD35 and CD86
EM: 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
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
Positive stains: CD68 (macrophages containing pigment)
DD: MFH, follicular dendritic cell tumor, spindle cell melanoma, Kaposi’s sarcoma
Presence of asbestos bodies in hilar lymph nodes after bleach digestion correlates with heavy lung burden (Mod Path 1990;3:513)
Thoracic lymph node may have higher asbestos burden than lung in non-occupationally exposed individuals (Am J Ind Med 2000;37:169)
Asbestosis in asbestos exposed individuals is associated with mediastinal adenopathy (Clin Radiol 1992;45:340)
Decidual reaction / ectopic decidua in lymph nodes
Rare
Often discovered in pregnant woman with cervical squamous cell carcinoma requiring hysterectomy and lymphadenectomy
A particular problem differentiating from squamous cell carcinoma during frozen section (Archives 2005;129:e117)
Derive from endometriosis or mesenchymal cells under the influence of pregnancy hormones
Case reports: lymph node with decidua and metastatic squamous cell carcinoma (J Surg Oncol 1988;38:126)
Gross: compact mass in lymph node
Micro: subcapsular or superficial cortical nodules of relatively uniform, loosely cohesive cells with distinct cell membranes, abundant amphophilic cytoplasm with variable vacuoles, round vesicular nuclei and occasional nucleoli; may have occasional bizarre, hyperchromatic nuclei; no intercellular bridges, no dyskeratosis, no keratin pearls, no mitotic activity, no desmoplasia
Negative stains: keratin
DD: metastatic squamous cell carcinoma (small, irregular nests with well circumscribed borders of tightly cohesive, polygonal cells with small, dark staining nuclei and pleomorphism)
Not common
May cause enlargement of lymph nodes
Case report: woman in 40’s with ileocecal valve and nodal involvement by endometriosis
Micro: endometrial type glands and stroma, usually within center of node; may undergo decidual reaction; variable hemorrhage; rarely has smooth muscle component
Positive stains: keratin, EMA, ER, PR, CD10 (stroma)
Epithelium inclusions in lymph nodes
May coexist with breast micrometastases
In axilla, may be due to pre-sentinel lymph node biopsy breast massage (AJSP 2004;28:1641)
Case reports: squamous epithelial cyst in axillary node removed for lobular breast carcinoma (Archives 2004;128:361), benign cystic epithelial choristoma in celiac node (Hum Path 1987;18:866)
Micro: single or tubules of epithelial cells in subcapsular sinus of draining lymph node after surgical or needle manipulation; also hemosiderin laden macrophages and damaged erythrocytes; breast epithelial inclusions may show apocrine metaplasia, sclerosing adenosis, epithelial hyperplasia
Positive stains: breast - myoepithelial markers (p63, S100, smooth muscle actin)
DD: metastatic carcinoma
References: AJCP 2000;113:259, AJSP 2003;27:513; Archives 2003;127:e25 (axillary inclusions)
Case reports: 34 year old woman with gold injections for rheumatoid arthritis (J Clin Pathol 2001;54:562), simulating microcalcifications on mammogram (Hum Path 1988;19:992)
Micro: reactive node with variable infarction
DD: lymphoma
Case reports: 49 year old woman with lymphadenopathy after single infusion of iron dextran (J Clin Pathol 1968;21:492)
Portal lymphadenopathy due to lipofuscin pigment is associated with primary biliary cirrhosis and other chronic cholestatic conditions (J Clin Pathol 1989;42:1160)
Micro: lipofuscin pigment present in sinus histiocytes
Often associated with extramedullary hematopoiesis when present in lymph nodes
Case reports: mimicking metastatic breast carcinoma in axillary node (Archives 2002;126:618)
Positive stains: CD31, CD61, vWF
Negative stains: keratin, CD68
DD: multinucleated histiocytes (larger, more cytoplasm, vesicular nuclei that are not multilobated, CD68+)
Yellow brown spindle bodies in mesenteric nodes may be due to melanosis coli (Histopathology 1978;2:47)
Case reports: presence in colonic mucosa and pericolonic lymph nodes (Archives 2004;128:565)
Mesothelial cell inclusions in lymph nodes
Rare
Usually mediastinal or abdominal lymph nodes (Mod Path 1996;9:879)
Often missed on routine H&E sections (AJSP 1999;23:1264)
Hyperplastic mesothelial cells in nodal tissue may derive from reactive serosal mesothelium that is dislodged into draining lymphatics (Archives 2000;124:609); often associated with serosal fluid collection (pericardial, pleural, abdominal) at time of nodal biopsy (Hum Path 1998;29:339), including episodes of intraperitoneal hemorrhage and ascites (Pathology 2001;33:239), perhaps because effusion allows for mesothelial cell migration into lymphatics (Diagn Cytopathol 2003;29:163)
Micro: single cells or small clusters of cells in nodal sinuses with well defined cells borders and mesothelial windows, abundant cytoplasm, bland nuclei; no mitotic figures
Positive stains: keratin (perinuclear)
Negative stains: EMA, CD15, CEA, B72.3
EM: long microvilli
DD: metastatic carcinoma or mesothelioma
References: AJCP 1990;93:741
Mullerian inclusions / cysts in lymph nodes
Also called endosalpingiosis
Pelvic lymph nodes of women, also rarely mediastinal and pelvic nodes in males
Present in 5-41% of intra-abdominal nodes of women (Am J Obstet Gynecol 1978;130:813), 20% of women with gynecologic malignancies in paraaortic/pelvic nodes (Gynecol Oncol 2000;78:242)
May be due to metaplastic proliferation of peritoneal mesothelium
May represent metastatic ovarian serous borderline tumors, particularly if present in nodes that drain ovary (AJSP 2000;24:710), although no definite prognostic significance (AJSP 2006;30:614)
May have endometriotic foci elsewhere (Archives 2005;129:e218)
Case report: 64 year old woman with endosalpingiosis and psammoma bodies in intramammary lymph node presenting as mammographic calcifications (Archives 1995;119:841)
Micro: capsular or parenchymal involvement by small round glands or cysts lined by bland, serous (mullerian), cuboidal-columnar epithelium with simple architecture; psammoma bodies are common; may undergo squamous metaplasia; no/rare mitotic figures, no/mild atypia, no desmoplastic stroma, no endometrial stroma
Positive stains: mucin
DD: metastatic adenocarcinoma (atypia, desmoplasia, mitosis, usually no ciliated cells)
Incidence in axillary nodes is 7% per patient and 0.5% per node in one study (AJCP 1994;102:102)
Presence in sentinel nodes in melanoma patients is associated with cutaneous nevi (AJCP 2004;121:58) and congenital cutaneous nevi (Am J Dermatopathol 2002;24:1)
May represent benign metastases from intradermal nevus in area of lymphatic drainage (AJCP 1985;84:220)
Micro: single cells, linear arrangements or aggregates of small, round/oval nevus cells with moderate pale/clear cytoplasm, round nuclei with fine chromatin, no prominent nucleoli or pleomorphism, usually within fibrous capsule and trabeculae, but also within nodal parenchyma (AJSP 2003;27:673) or surrounding a small vessel (AJSP 1996;20:834); no angiolymphatic invasion, no mitotic figures, no prominent melanin pigment
Cytology: nodules of uniform nevoid cells, but also possibly atypical melanocytic cells from dermatopathic lymphadenopathy (Diagn Cytopathol 2004;31:180)
Positive stains: S100, MART1, tyrosinase, p16 (Virchows Arch 2003;443:745)
Negative stains: HMB45 (occasionally is very focal), Ki-67 (<1%)
DD: metastatic carcinoma or melanoma (usually not confined to capsule, atypia, mitotic figures, different immunostaining), Spitz nevus (larger cells with abundant eosinophilic cytoplasm, vesicular nuclei with prominent nucleoli), blue nevus (also spindled/dendritic cells with heavy pigmentation)
References: AJSP 2002;26:1351 (immunostains)
Blue nevus
May be incidental in axillary node dissection for breast carcinoma (AJSP 1984;8:907)
May be associated with blue nevus in regional skin (Histopathology 1977;1:451)
May need to bleach sections
Case reports: blue nevus of nodal capsule #1 (AJCP 1984;81:367); #2 (Pathologica 1992;84:547)
Gross: black streaks in nodal capsule
Micro: focal blue nevus cells in capsule or along fibrous trabeculae; cells are heavily pigmented dendritic and bipolar nevus cells, mixed with macrophages; no atypia, no mitotic figures
EM: uniform round nevus cells with indented nuclei, dispersed chromatin, randomly oriented cytoplasmic fibrils and a few mature melanosomes (Cancer 1982;49:269)
DD: melanoma
Prosthesis related changes in lymph nodes
See also silicone below
May be an incidental finding at radical prostatectomy (J Clin Pathol 2002;55:623)
Case reports: post-shoulder joint replacement (AJCP 1993;99:314), post-hip replacement with coexisting metastatic prostate adenocarcinoma to same lymph node (Hum Path 1998;29:95), due to chromium in hip prosthesis (Acta Cytol 2003;47:270)
Micro: sinuses distended by large macrophages with abundant granular PAS+ eosinophilic cytoplasm representing polyethylene (AJSP 1989;13:1050); may contain black specks which resemble “dirt”; pelvic lymph nodes in patients with cobalt-chromium or titanium hip implants may have heavy metal microparticles or polyethylene particles with associated florid sinus histiocytosis (AJSP 1994;18:83)
Positive stains: PAS+ polyethylene particles
DD: metastatic melanoma (J Surg Oncol 1995;60:128)
Salivary gland inclusions in lymph nodes
Extremely common in cervical nodes
Ducts and acini are common within intraparotid lymph nodes
May undergo all pathologic processes of normal salivary gland tissue, most commonly Warthin’s tumor (Am J Otolaryngol 2005;26:96)
Case reports: sialometaplasia arising within parotid gland inclusions #1 (AJCP 1986;86:116); #2 (J Clin Pathol 2004;57:1335), adenoid cystic carcinoma apparently arising from salivary gland inclusions (Laryngorhinootologie. 2006 Feb 21; [Epub ahead of print])
Micro: salivary gland ducts (lined by double layer of epithelium and myoepithelium) and acini (with zymogen granules)
Presence of silicone in lymph node is due to injection of liquid silicone or implantation of bag-gel prosthesis for mammary augmentation
Either an incidental finding or causes painful / enlarged lymph node
May be associated with granulomatous inflammation (Histol Histopathol 1997;12:1003)
Case reports: associated with silicone elastomer prosthesis (Hum Path 1980;11:240), foot joint prosthesis (J Clin Pathol 2000;53:549)
Micro: scattered cells to sheets of foamy macrophages and refractile droplets of clear material; usually refractile material consistent with silicone, less commonly polygonal foreign material consistent with polyurethrane; may have giant cells and vacuolated cells
DD: sinus histiocytosis with massive lymphadenopathy
References: AJSP 2005;29:506, AJSP 1988;12:484
Exposure to low concentrations of quartz may cause hilar node fibrosis (Occup Environ Med 1998;55:383)
Case reports: stone splitter presenting with enlarged supraclavicular node (Respirology 1998;3:281)
Micro: sclerohyaline nodule, fibrinoid necrosis, birefringent crystals
EM: longitudinal splitting and breakage of collagen fibrils, deposition of flocculent electron-dense material around collagen fibrils
References: Hum Path 1985;16:393
Often present in hilum of inguinal lymph and axillary nodes, with fibrovascular tissue
May be related to prominent hilar vascularity (Virchows Arch A Pathol Anat Histopathol 1985;406:261)
Smooth muscle cells may also be present in capsule and trabeculae (Anat Rec 1975;183:517)
Nodal parenchyma is usually uninvolved
No clinical significance
Squamous epithelium inclusions in lymph nodes
Also called lymphoepithelial cyst
Most common in upper cervical nodes
Depending on location, may be a branchial pouch derivative or derive from metaplastic calyceal urothelium (Hum Path 1990;21:1239)
Case reports: axillary nodes of breast cancer patients #1 (Archives 2004;128:361), #2 (Archives 2003;127:e25), #3 (Pathol Res Pract 1999;195:263), cystic lymphoepithelial lesions of peripancreatic nodes (Surg Today 1999;29:467)
Micro: small cystic structures lined by well differentiated squamous epithelium
DD: metastatic well differentiated squamous cell carcinoma (often undergoes cystic change)
May cause lymphadenopathy, usually resolves spontaneously
Pigment initially within keratinocytes, fibroblasts, macrophages and mast cells; later only within dermal fibroblasts surrounded by connective tissue; eventually tattoo ink appears in regional lymph nodes
Melanoma patients should be questioned regarding history of tattoos, particularly prior to sentinel node treatment (Int Semin Surg Oncol 2005;2:28)
Histologic confirmation of melanoma in nodes is necessary to avoid unnecessary surgery (Dermatol Surg 1996;22:92)
Case reports: patient with melanoma and adjacent tattoo (Dermatol Online J 2005;11:14); scapular tattoo with pigment in axillary node (Dermatology 2001;203:342), tattoo and localized lymphadenopathy (Cutis 2001;67:471)
DD: melanoma (S100+, positive Fontana Masson stain for melanin)
Ectopic thymus may be present in supraclavicular nodes
Micro: lymphoid stroma with Hassall’s corpuscles
DD: metastatic squamous cell carcinoma
Thyroid follicles in lymph nodes
1-3% of cervical nodes
Micro: capsular or subcapsular involvement with 20-30 normal appearing colloid filled thyroid follicles
DD: metastatic papillary carcinoma (assume metastatic unless see small aggregate of follicles that are round/oval, loosely arranged with no papillae, normal sized nuclei and nucleoli, fine chromatin, no crowded nuclei, no stromal reaction, no psammoma bodies)
Also called Hamazaki-Wesenberg bodies
More common in deep abdominal than superficial nodes
At autopsy, present in 35% of mesenteric nodes and 11% of mediastinal nodes (J Clin Pathol 1979;32:52)
No association with age, gender or disease
May resemble yeast (Archives 1987;111:555)
Micro: small, spindled structures within nodal sinuses or macrophages or lying free
Positive stains: PAS
EM: appear to represent giant lysosomal residual bodies with hemosiderin or lipofuscin
Primary immunodeficiency disorders
Either humoral (B cell related), cell-mediated (T cell related) or defects in phagocytes / accessory immune system
Diagnosis requires laboratory testing (including immunoglobulins), delayed-type skin reactions and lymphocyte testing
Lymph node biopsies provide quantitative information
Humoral based disease - medullary plasma cells and no/reduced cortical centers
Cell-mediated based disease - reduced paracortical areas
Autoimmune lymphoproliferative syndrome in lymph nodes
Also called Canale-Smith syndrome
First named in 1995 (Cell 1995;81:935)
Inherited disorder due to defects in Fas/CD95/Apo-1 mediated apoptosis
Childhood onset of lymphadenopathy, hepatosplenomegaly, hypergammaglobulinemia and autoimmunity; also cytopenias and increased risk of lymphoma (Hematology 2006;11:15)
40% have histologic features of sinus histiocytosis with massive lymphadenopathy (AJSP 2005;29:903)
Type I: functional defects of FAS gene
Type II: functional FAS deficiency but no FAS gene mutations
Case reports: 6 month old girl with cervical lymphadenopathy, hepatosplenomegaly and gammadelta+ T cell blasts (AJSP 2003;27:546); 4 year old girl with type II syndrome and clonal immunoblasts but no evidence of lymphoma (AJSP 1999;23:829); due to FasL mutation (Blood 2006 Apr 20; [Epub ahead of print])
Micro: paracortical hyperplasia, expanded interfollicular areas; polyclonal plasmacytosis; frequent mitotic figures; often florid follicular hyperplasia with focal progressive transformation of germinal centers; occasional follicular involution
Positive stains: T cells - CD3, CD57, usually alphabeta T cell receptor; also perforin, TIA1, CD57
Negative stains: T cells - CD4, CD8; also CD25, CD45RO
Molecular: mutation in death domain of FAS gene
DD: sinus histiocytosis with massive lymphadenopathy, lymphoma
References: Am J Pathol 1998;153:1541, OMIM 601859
Chronic granulomatous disease in lymph nodes
Due to congenital enzymatic defect of NADPH oxidase in granulocytes and monocytes
White blood cells cannot generate superoxide ion which kills microorganisms in lysosomes
Either Y linked or autosomal recessive
Diagnose with nitro blue tetrazolium test (almost always positive)
Clinically, patients have recurrent lymphadenitis, hepatosplenomegaly, skin rash, pulmonary edema
Laboratory: anemia, leukocytosis, hypergammaglobulinemia
Case reports: child with Hansenula polymorpha infection (Archives 1980;104:290)
Micro: granulomas with central necrosis in lymph nodes and other organs; pigment laden histiocytes
Cytology: necrotizing granuloma, pigmented histiocytes (Diagn Cytopathol 1991;7:57)
EM: pigment is lipofuscin, apparently from lysosomes (Pediatr Pathol 1992;12:839)
DD: cat-scratch disease, lymphogranuloma venereum
References: eMedicine, MedlinePlus
Also called Mo1 deficiency
Micro: severe lymph node hypoplasia with small, poorly delineated germinal centers
References: Hum Path 1988;19:753, eMedicine
Omenn’s syndrome in lymph nodes
Rare, autosomal recessive form of severe combined immunodeficiency of infancy
Recurrent infections, early diffuse erythrodermia, failure to thrive, protracted diarrhea, hepatosplenomegaly, elevated serum IgE and eosinophilia, lymphadenopathy, oligoclonal T cell expansions
Often recombinase activating gene mutations (Clin Immunol 2005;116:246)
Also increased circulating and infiltrating activated T cells that are unable to proliferate in response to mitogenic stimuli
Micro: total effacement of nodal architecture with no distinct cortex and no follicles; also B cell depletion and accumulation of interdigitating reticulum cells (AJSP 1995;19:1082)
Positive stains: up to 50% of lymphocytes express CD30 (AJSP 1996;20:773)
References: eMedicine, OMIM 603554
Infectious/parasitic disorders
Rare; associated with poor dental hygiene (is a normal inhabitant of the oral cavity)
Causes lymphadenopathy
Gram stain: gram positive, filamentous branching bacteria
Treatment: appropriate dental care and antibiotics
Case reports: 12 year old girl with retroperitoneal tumor with rib involvement (Eur J Pediatr Surg 2005;15:38)
Gross: tan-white cut surface, multiple pinpoint white spots
Micro: marked capsular fibrotic thickening with thick fibrous bands dividing nodes into nodules; also follicular hyperplasia, marked interfollicular fibrosis and multiple interfollicular microabscesses containing focal Actinomyces colonies with classic sulfur granules (may require deeper levels to identify); no palisading of histiocytes around the abscesses; numerous macrophages are present in germinal centers
DD: cat scratch disease and lymphogranuloma venereum (palisading histiocytes present), syphilis (fibrotic capsule, but also prominent plasma cells)
References: Archives 2000;124:1502
Bacillary angiomatosis in lymph nodes
Caused by Bartonella (formerly Rochalimaea) henselae, which also causes cat-scratch disease
May also be caused by Bartonella quintana (Ann N Y Acad Sci 2005;1063:302)
Almost all patients are HIV+ or otherwise immunosuppressed
May have multiple red/violet skin lesions resembling Kaposi’s sarcoma, but also involves lymph nodes and spleen
Bacterial reservoir is domestic cats (transmit to humans) and cat fleas (transmit to other cats)
May appear neoplastic, but is reactive
Gram stain: small, curved, motile, gram-negative rod that is difficult to culture
Diagnosis: PCR
Treatment: erythromycin, other macrolides or doxycycline are very effective
Case reports: 17 year old renal transplant patient (Archives 2004;128:e12)
Micro: focal nodal effacement by multiple coalescing intranodal clusters of small blood vessels, lined by epithelioid endothelial cells with pale cytoplasm; may have focal nuclear atypia; interstitium contains abundant eosinophilic to amphophilic, amorphous or granular material containing aggregates of bacteria (highlighted by Warthin-Starry stain); also neutrophils
DD: Kaposi’s sarcoma (cleft-like vessels, spindled endothelial cells, no bacteria), epithelioid hemangioma or hemangioendothelioma (eosinophilic and vacuolated cytoplasm, no amorphous/granular material)
References: AJSP 1991;15:430, eMedicine
Post vaccination bacille Calmette-Guerin infection occurs in 1% of infants, although swelling usually subsides (Braz J Med Biol Res 2004;37:697)
Patients with normal immunity have complete recovery after postvaccination bCG infection after excision of infected lymph node; immunosuppressed patients may require antiTB therapy to avoid fatal disseminated infection (AJCP 2000;113:703)
Treatment: surgery for large (3 cm) nodes, anti-TB therapy for small (1 cm) nodes (J Ayub Med Coll Abbottabad 2005;17:16), but see The Internet Journal of Infectious Diseases 2004;3(2) (no need for surgery)
Case reports: 3 month old Chinese baby post bcg vaccination, cervical lymphadenitis post-bCG for bladder cancer (Respiration 2001;68:420)
Micro (patients with normal immunity): multiple epithelioid granulomas and Langhans giant cells; variable suppuration, minimal caseous necrosis, few acid-fast bacteria identified with Ziehl-Neelsen stain
Micro (immunosuppressed patients): histiocytes with abundant gray cytoplasm containing numerous acid-fast bacilli, plump nuclei
Cytology: poorly to moderately cellular smears of epithelioid histiocytes in a granuloma pattern with occasional multinucleated Langerhans-type giant cells, lymphocytes and neutrophils; background is finely granular with necrotic debris; isolated calcified spherules
(Diagn Cytopathol 2001;25:134); may be heavy involvement of acid fast bacilli (CytoJournal 2004;1:6)
References: Postgrad Med J 2002;78:327
Due to Brucella abortus, melitensis or suis
Either occupational or food-related (milk and cheese)
Fever, hepatosplenomegaly, rarely lymphadenopathy
Case reports: B. melitensis with subsequent Kikuchi-Fujimoto disease #1 (In Vivo 2003;17:51), #2 (Sangre (Barc) 1992;37:201)
Diagnosis: culture, PCR, serology
Micro: follicular hyperplasia, clusters of epithelioid histiocytes that may form large noncaseating granulomas; also eosinophils, plasma cells, immunoblasts
DD: Hodgkin’s lymphoma
Brugia malayi is a filarial nematode that affects lymphatics
Infections with zoonotic Brugia species are uncommon in US
Adult reproductive period is up to 9 years (J Trop Med Hyg 1994;97:269)
Case reports: patient in Rhode Island (USA) with florid monocytoid B cell proliferation (AJCP 1996;105:384); patient in Michigan (USA) with zoonotic infection (AJSP 1993;17:1058)
Micro: worm present (50 microns-male, 75 to 100 microns-female) with thin (1 micron) cuticle, small number of muscle cells and paired uterine tubes; hyperplastic follicles with focal granulomatous reaction (Am J Trop Med Hyg 1988;39:185, Am J Trop Med Hyg 1986;35:1205)
Cat-scratch disease in lymph nodes
Caused by Bartonella (formerly Rochalimaea) henselae (AJCP 1994;101:607), harbored by kittens and young cats; transmitted between cats by cat flea (but not from cats to humans)
Adults or children (85% under age 18) infected by cat claws contaminated with infected flea feces; 24K cases/year in US (most common cause of chronic benign lymphadenopathy)
Cutaneous red papule 7-12 days after contact that may become crusted or pustular, with enlargement of cervical or axillary nodes
May have necrotizing granulomas in liver, spleen or bone
Usually resolves spontaneously; erythromycin or other macrolides may be given
Rare complications are granulomatous conjunctivitis, thrombocytopenic purpura, CNS disease (Eur J Intern Med 2005;16:610)
Historical criteria: exposure to cat and presence of scratch or dermal/eye lesion; positive cat scratch disease antigen skin test; regional lymphadenopathy with negative culture for other possible causes; characteristic changes in nodal biopsy
Case reports: 16 year old African American teenager with tender cervical adenopathy (Archives 2005;129:1065), coinfection with M. tuberculosis in HIV+ patient (J Infect 2003;46:244)
Gram stain: pleomorphic, curved, gram negative coccobacillus; catalase negative, oxidase negative; difficult to culture, but prolonged incubation is helpful (J Clin Microbiol 2002;40:3620)
Diagnosis: PCR (AJCP 2001;115:900, Archives 2003;127:706, J Clin Microbiol 2005;43:3800), serology, immunofluorescence (Clin Diagn Lab Immunol 2003;10:686), possibly culture
Micro: early - histiocytes and follicular hyperplasia; intermediate - capsulitis and subcapsular granulomas; late - abscesses; in general, necrosis is often stellate with neutrophils, surrounded by palisading histiocytes; paracortical vascular proliferation; sinuses are often packed with monocytoid B cells, but no epithelioid cells are present; small rods may be present with silver stain around small blood vessels and lymphatics
Skin shows dermal necrosis surrounded by histiocytes; also multinucleated giant cells, lymphocytes and eosinophils
Positive stains: Warthin-Starry
EM: extracellular bacteria form small groups within bundles of collagen fibrils; bacteria are gram-negative pleomorphic rods, with thick and homogeneous cell walls (AJCP 1987;87:739)
DD: lymphogranuloma venereum (similar necrosis pattern but affects inguinal nodes), toxoplasmosis (also has monocytoid B cells), tularemia (usually constitutional symptoms, no well defined rim of histiocytes), Yersinia, Mycobacterium avium intracellulare (no zonation, bacteria are acid-fast positive), brucellosis, fungi, Kikuchi’s syndrome (no neutrophils)
References: eMedicine
Coccidioides immitis in lymph nodes
Also called San Jaquin Valley Fever
Dimorphic fungus with distinct yeast and mold stages
Endemic to Lower Sonoran Desert (southwest US, Central and South America)
Usually self-limiting, but more severe disease in immunocompromised hosts
Diagnosis: culture (grows on all media); has enteroarthric conidia (alternating segments of hyphae undergo autolysis, while surviving segments form infective barrel shaped multinucleate arthroconidia)
Case reports: 27 year old man on steroids for clinical pneumonia with enlarged paratracheal lymph node (Archives 2005;129:699)
Micro: thick-walled spherules 20-150 microns containing 3-5 micron endospores, surrounded by a giant cell granulomatous reaction
References: eMedicine #1; #2
C. ovis is associated with sheep contact in rural Australia; can cause cervical adenopathy with mild constitutional symptoms and necrotizing granulomas in lymph nodes
Small gram positive organism
Case reports: C. ovis associated with raw milk ingestion in US (AJCP 1981;76:486); C. pseudotuberculosis associated with farm animal contact (Pathology 1997;29:231), shepherd with painful groin mass (Med Clin (Barc) 1995;104:699)
Associated with Kawasaki disease (J Med Assoc Thai 2005;88:436, Southeast Asian J Trop Med Public Health 2000;31:190)
Case reports: with lymph node infarction (BMC Clin Pathol 2005;5:11)
References: Centers for Disease Control and Prevention
Epstein Barr virus in lymph nodes
Causes infectious mononucleosis (typical cases); other viruses may cause atypical cases
Classic clinical features are teenager/young adult with fever, sore throat, cervical adenopathy and mild hepatitis; peripheral blood shows atypical lymphocytes (CD8+ cytotoxic T cells)
Lymph nodes should usually NOT be biopsied as diagnosis is clinical and serologic
Atypical cases (lymphadenopathy but no fever, no sore threat, no splenomegaly) may be biopsied to rule out lymphoma
Fatal cases of infectious mononucleosis are associated with monoclonal or biclonal EBV (AJCP 2002;117:582)
Associated with histiocytic necrotizing lymphadenitis (Kikuchi’s disease) in Taiwan (AJCP 2000;113:774)
EBV RNA also present in Peruvian patients in nonneoplastic lymph nodes in B and T cells (Mod Path 1993;6:729)
May cause post-transplant lymphoproliferative disorders (see Lymphomas-non B cell), also Hodgkin’s and some non-Hodgkin’s lymphomas
Case reports: extensive necrosis (Pathol Res Pract 2004;200:53), extensive nodal infarction (Int J Surg Pathol 2002;10:223)
Micro: partial architectural effacement due to marked sinusoidal and capsular/extranodal infiltration by immunoblasts that often have Reed-Sternberg like features and atypia; follicular hyperplasia with ragged or mottled edges, follicles have tingible body macrophages and marked mitotic activity; also polymorphous inflammatory cells; early infections have prominent monocytoid B cell reaction and no epithelioid cells (AJSP 2005;29:595); necrosis is usually minimal, but may be extensive in immunocompromised.
Cytology: greater than usual numbers of large immunoblastic lymphocytes; also polymorphic immunoblasts; pattern is not specific (Diagn Cytopathol 1990;6:323)
Positive stains: Reed-Sternberg like immunoblasts are usually CD20+, CD15-, CD30- (may be focally CD30+, AJCP 1990;93:698); also preservation of underlying reticulin architecture (AJSP 1987;11:122)
Negative stains: CD15 (for Reed-Sternberg like cells)
DD: Hodgkin’s lymphoma (nodular distortion, mixed inflammatory cells), anaplastic large cell lymphoma (lymphomas have atypical cells throughout the lymph node, not confined to the sinuses as with EBV), drug reactions, post-vaccination, other viral infections
References: eMedicine, Centers for Disease Control and Prevention
Severe chronic active EBV infection
Rare, life threatening
Criteria: chronic or recurrent infectious mononucleosis-like symptoms lasting more than 6 months and high titers of EBV antibodies
Case report: 62 year old woman with fatal disease (J Korean Med Sci 2004;19:453)
Haemophilus influenzae in lymph nodes
Common infection in patients with agammaglobulinemia, as they patients are prone to infection by encapsulated organisms
Other common causes of infectious lymphadenopathy in children are Staph and Strep species
Diagnosis: culture on chocolate agar
Case reports: 17 year old boy with X linked agammaglobulinemia and H. influenzae cervical adenopathy (Archives 2005;129:100)
Micro: enlarged node with dense collagenous stroma containing scattered lymphocytes and occasional neutrophils; epithelioid granulomas with occasional multinucleated giant cells; no necrosis; no organisms identified with special stains
HSV lymphadenitis is very uncommon
Usually inguinal nodes (AJCP 1991;95:709)
Often associated with hematopoietic malignancies
Case report: lymphadenitis before appearance of cutaneous vulvar lesions (Archives 1985;109:1043), with mantle cell lymphoma (Archives 2006;130:536), CLL/SLL patient with HSV infection resembling Richter’s transformation (Am J Hematol 2001;68:287), patient with immunodeficiency (Clin Infect Dis 2002;34:1)
Micro: well circumscribed necrosis, follicular and paracortical hyperplasia; cells have intranuclear inclusions, particularly at edge of necrotic areas; also marked immunoblasts, T cell hyperplasia
Positive stains: HSV
EM: intranuclear and cytoplasmic virus particles
References: AJSP 1990;14:571, Histopathology 1991;19:355
Infection in infancy causes exanthem subitum (HHV-6B), a mild infection
Two patients with fever, fatigue, generalized lymphadenopathy and elevated liver enzymes (Mod Path 2004;17:1427)
May be associated with some cases of histiocytic necrotizing lymphadenitis/Kikuchi’s (Diagn Mol Pathol 2006;15:49)
Micro: T cells in expanded paracortical areas with intranuclear and cytoplasmic inclusions
Positive stains: HHV6
EM: cytoplasmic and nuclear viral particles
Molecular: HHV6 by PCR
References: Indian J Pediatr 2004;71:89
Human herpesvirus 8 / Kaposi’s sarcoma associated herpesvirus
High prevalence in East Africa
Associated with Kaposi’s sarcoma (Mod Path 2004;17:456); in endemic regions of Africa, association is regardless of HIV status (Hum Path 2006;37:23)
Also associated with primary effusion lymphoma, plasmablastic lymphoma, some cases of multicentric Castleman’s disease
Note: most lymphomas are HHV8-, even in HHV8+ patients
Not associated with Kikuchi’s disease (Hum Path 2003;34:130), despite earlier study to the contrary (Hum Path 1998;29:1091)
May clinically mimic tuberculosis
Micro: chronic suppurative lesion; granulomatous process or widespread nodal necrosis with diffuse sinus histiocytosis
Positive stains: GMS or PAS
References: Centers for Disease Control and prevention
Besides changes below, HIV+ patients also have mycobacterial infections and associated pseudotumors, Kaposi’s sarcoma, bacillary angiomatosis, lymphoma and fungal infections
Downregulation of Fas/CD95 is present (Archives 2002;126:28)
Chronic lymphadenopathy syndrome: unexplained enlargement of nodes of 2+ extrainguinal sites for 3+ months, in patient at risk for AIDS; 25% develop AIDS at followup with weight loss and cachexia
Micro: florid reactive hyperplasia (may be serrated, serpentine or dumbbell shaped) containing tingible body macrophages and plasma cells; follicle lysis often present (invagination of mantle lymphocytes into germinal centers, giving them a moth-eaten appearance, also called explosive follicular hyperplasia); also monocytoid B cells in sinuses; interfollicular area shows vascular proliferation and abundant plasma cells, granulocytes and macrophages; also neutrophils and dermatopathic lymphadenopathy; interfollicular zone shows vascular proliferation, which may progress to Kaposi’s sarcoma; occasional polykaryocytes; nodes may also show eventual profound lymphocyte depletion and resemble Castleman’s disease
Positive stains: p24 (HIV core protein), CD8 > CD4 lymphocytes (inversion of usual ratio)
EM: prominent follicular dendritic cells
References: Webpath tutorial
Parasites may continue in lymph nodes after clinical cure (J Infect 2003;47:77)
Case reports: atypical presentation with hepatitis and adenopathy in disseminated disease (Trans R Soc Trop Med Hyg 2006;100:79)
Micro: granulomas with abundant plasma cells, focal fibrosis, variable necrosis, leishmanian amastigotes (by immunostain)
Cytology: polymorphous lymphocytes, histiocytes, plasma cells, giant cells and tingible body macrophages; amastigote forms within histiocytes and multinucleated giant cells and extracellularly (Acta Cytol 2005;49:286)
References: AJCP 1994;102:11. eMedicine
Diagnosis: PCR, immunofluorescence
Case reports: with coexisting tuberculosis (Lepr Rev 1999;70:345)
Micro: lepromatous leprosy exhibits large, pale, round histiocytes without granulomas and with no/rare necrosis
Positive stains: acid-fast (modified Ziehl-Neelsen)
DD: lymphoma (clinically, Lepr Rev 2005;76:87)
Lymphogranuloma venereum in lymph nodes
Sexually transmitted disease caused by Chlamydia trachomatis serotypes L1, L2 and L3
Endemic in tropical areas, rare in industrialized countries
Recent outbreak in Western Europe among male homosexuals (Rev Prat 2005;55:1747), also in Bahamas associated with crack cocaine and HIV (Sex Transm Dis 2002;29:253)
Three clinical stages (see references below)
Diagnosis: PCR; previously Frei test (delayed hypersensitivity skin test using “lygranum” chlamydial antigen)
Treatment: doxycycline for 21 days
Micro: early - tiny necrotic foci with neutrophils; late - stellate abscesses surrounded by pale epithelioid cells; abscesses may merge, and sinus tracts may develop; macrophages may have organisms within vacuoles
EM: elementary and reticulate bodies
DD: cat-scratch disease (J Clin Microbiol 2000;38:2062), atypical mycobacteria, tularemia
References: Mod Path 1995;8:924, MedlinePlus, eMedicine, Wikipedia
Fatal measles cases in South African in 1976-1982 were associated with malnutrition; caused depletion of T cell zones (S Afr Med J 1985;68:858)
Measles associated lymphopenia may be due to apoptosis of uninfected lymphocytes (Arch Virol 2000;145:905)
Live attenuated vaccine may cause regional lymphadenopathy
Case reports: 14 month old boy with familial immunodeficiency and necrotizing lymphadenitis with Warthin-Finkeldey type giant cells after measles vaccination (Ultrastruct Pathol 1980;1:243)
Micro: polykaryocytes; Warthin-Findeldey giant cells in germinal cells have large nuclei and B cells markers; in interfollicular areas they have small hyperchromatic nuclei and T cell markers (Pathol Int 1994;44:442)
Mycobacteria-atypical / other than TB or leprosy in lymph nodes
Common cause of granulomatous lymphadenitis
Typically lateral nodes in mid-neck; without therapy, drainage occurs years with scarring and contractures
Causes chronic cervical lymphadenitis in childhood (Indian J Med Sci 2003;57:12, Pediatr Dermatol 2004;21:24), often M. avium (Clin Infect Dis 2004;39:450, Int J Pediatr Otorhinolaryngol 2000;53:187)
Report of endemic infections in Czechoslovakia (Tubercle 1980;61:207)
Case reports: M. avium-intracellulare in axillary node of HIV+ infant (Indian J Med Microbiol 2005;23:192); M. bohemicum (Pediatr Infect Dis J 2002;21:982); M. celatum (Diagn Microbiol Infect Dis 2004;49:19), M. chelonei (J Clin Pathol 1973;26:422), M. fortuitum (Br J Dermatol 2004;151:1096), M. malmoense (Eur J Clin Microbiol Infect Dis 2004;23:567), M. scrofulaceum (Ala Med 1989;59:19)
Diagnosis: PCR (J Clin Microbiol 2004;42:2644), culture
Treatment: excision of node, antibiotics
Micro: caseating granulomas with suppurative changes; granulomas often ill-defined, irregular or serpinginous; often Langhans type giant cells; variable plasma cells and neutrophils; immunosuppressed patients may develop a spindle cell pseudotumor
Positive stains: acid-fast stain
References: eMedicine #1; #2; J Clin Pathol 1998;51:925
Mycobacterium kansasii in lymph nodes
Associated with pulmonary infection in late stage AIDS with thoracic nodal involvement (Archives 2003;127:554)
Gram stain: long, coarsely beaded, with frequently folded ends; often within histiocytes
Diagnosis: culture is slow; often confection with several species, including M. avium intracellulare complex
Case reports: 57 year old man with diabetes, with pseudo-Gaucher cells (J Clin Pathol 2005;58:1113); HIV negative patient (Thorax 1993;48:672)
Micro: granulomas with granular eosinophilic necrosis, neutrophilic abscesses, spindle cell proliferations
Positive stains: acid-fast
References: eMedicine
Mycobacterial spindle cell pseudotumor in lymph nodes
HIV+ patients, often involvement of many sites
Also infants after bCG vaccination (Zhonghua Bing Li Xue Za Zhi 2001;30:89, free full text) and post-transplant (AJCP 1985;83:524)
Spindle cells are macrophages with large amounts of mycobacteria (AJSP 1992;16:276)
Intraoperative touch imprints may demonstrate numerous intracellular organisms (Archives 1995;119:811)
Treatment: antiretroviral therapy for HIV, antibiotics
Micro: nodes show partial/complete effacement by storiform pattern of bland spindle cells, some with vacuoles; also numerous vessels lined by plump endothelial cells, plasma cells and lymphocytes; no multinucleated tumor cells, no foamy histiocytes
Cytology: spindle cell proliferation resembling Kaposi’s sarcoma, no foamy histiocytes (Acta Cytol 1995;39:125)
Positive stains: spindle cells - CD45, CD68, HLA-DR, S100; also desmin; Ziehl-Neelsen - numerous bacteria identified
DD: Kaposi’s sarcoma (fascicular spindle cells, slit-like spaces, mitotic figures, no granular or acidophilic cytoplasm; spindle cells are CD31+ and CD34+ but S100- and CD68-, AJSP 1999;23:656), smooth muscle tumor
In adults, parvovirus B19 infection is associated with fever (81%), arthralgia/myalgia (62%), skin rash (48%), general fatigue (43%), lymphadenopathy (38%) and edema (38%) (Intern Med 2002;41:295)
May be associated with hemophagocytic syndrome (Br J Haematol 1997;96:868)
Diagnosis: PCR, immunohistochemistry
Case reports: 16 year old girl with cervical lymphadenopathy, fever and fatigue (J Clin Pathol 2005;58:872)
Micro: massive nodular histiocytic proliferation resembling Kikuchi’s disease with prominent apoptosis but no necrosis; one case showed florid reactive hyperplasia with paracortical expansion, neutrophils and hemophagocytosis (Pathol Int 1998;48:829.
Case reports: 45 year old man with GIST tumor and pericolic nodes containing hyphae-like structures, but actually composed of mineral deposits (Archives 2005;129:e97), 66 year old man with pulmonary carcinoma and branching septate hyphae-like structures containing iron (Archives 1994;118:95), 31 year old woman with pulmonary blastoma and PAS+, GMS+, iron+ pseudofungi in mediastinal nodes with granulomatous response (Korean J Pathol 2004;38:64), PAS+ but GMS negative, composed of iron, phosphorus and calcium (Archives 1991;115:1166)
Micro: confined to sinuses of otherwise normal appearing lymph nodes; usually no association with acute or granulomatous inflammation; hyphae have more variable thickness and branching angles than true fungi
Positive stains: Perls iron, von Kossa (calcium); variable PAS
Negative stains: GMS
EM: septation and branching due to fractures of pseudofungi
DD: calcific deposits on collagen fibers, Gamna-Gandy bodies, calcified small branching blood vessels
Due to Treponema pallidum
Primary syphilis
Solitary inguinal lymphadenopathy associated with syphilitic chancre
Diagnosis: PCR (including FNA of inguinal nodes, Lancet 2002;360:388), Southern blotting, immunostains
Micro: capsular and pericapsular fibrosis, follicular hyperplasia, diffuse interfollicular plasma cells, prominent endarteritis outside the capsule; noncaseating granulomas and abscesses are rare; spirochetes easiest to identify within blood vessel walls
Positive stains: Warthin-Starry, immunostains
Secondary syphilis
Micro: follicular hyperplasia
Tertiary syphilis
Localized lymph node enlargement
Common obligate intracellular parasite (Toxoplasma gondii) that is either asymptomatic, causes lymphadenitis or produces an acute infection during pregnancy that may damage fetus
Also called Piringer-Kuchinka lymphadenitis
Transmitted from cat feces (kitty litter) or undercooked meat
Commonly involves posterior cervical nodes of young women, but should be considered in differential diagnosis of tonsillitis, adenoid hyperplasia and chronic neck lymphadenopathy (Kulak Burun Bogaz Ihtis Derg 2004;13:132)
Case reports: due to family rabbit (AJCP 1990;94:107), diagnosis by direct immunofluorescence (J Clin Pathol 1977;30:847), causing granulomatous common variable immunodeficiency (Clin Exp Immunol 2004;137:578)
Diagnosis: based on morphology and serology (IgM antibody), as PCR and immunostains are usually negative in lymph nodes; high IgG avidity only in patients who developed lymphadenopathy at least 4 months earlier (J Clin Microbiol 2004;42:4627)
Treatment: pyrimethamine and either sulfadiazine or clindamycin
Micro: well preserved nodal architecture; marked follicular hyperplasia with frequent mitotic figures and phagocytosis of nuclear debris, small noncaseating epithelioid granulomas with indistinct margins (presence within germinal centers is fairly specific for toxoplasmosis), distention of sinuses by monocytoid B cell with immunoblasts and plasma cells in medulla; occasionally granulomas exhibit necrosis or have frequent Langhans giant cells
Recommended diagnostic criteria are either (1) florid reactive follicular hyperplasia, clusters of epithelioid histiocytes and focal sinusoidal distention by monocytoid B cells (Pathol Int 2001;51:619) or (2) microgranulomas, absence of giant cells, lower than “grade 2 macrogranuloma” and follicular hyperplasia (J Clin Pathol 2005;58:1143)
Cytology: epithelioid microgranulomas (small clusters of epithelioid histiocytes with abundant, pale staining and homogenous cytoplasm and eccentric, oval nuclei, but no necrosis, giant cells or neutrophils) are characteristic (Acta Cytol 2005;49:139); also reactive hyperplasia and tachyzoites within lymphocytes (Acta Med Croatica 2005;59:153); pap stain may demonstrate parasite on FNA (Acta Cytol 2003;47:299)
DD: lymphocyte predominant Hodgkin’s lymphoma, sinus histiocytosis with massive lymphadenopathy (Leuk Lymphoma 2004;45:1037), other infections
References: US Department of Agriculture, Univ of Texas Medical Branch, eMedicine, J Clin Pathol 1961;14: 565
See also extensive discussion in Lung-nontumor chapter
Usually nodal involvement of cervical region (scrofula), often with draining sinus to skin
Generalized TB in AIDS cases at autopsy show thoracic or abdominal nodal involvement in almost all cases, although TB often not diagnosed prior to death (Archives 2000;124:1267)
Needle biopsy of enlarged nodes may be helpful in smear negative, HIV+ patients with suspected TB (Int J Tuberc Lung Dis 2005;9:220)
Case reports: with metastatic breast carcinoma in axillary node (World J Surg Oncol 2003;1:3), with Hodgkin’s lymphoma (Med Klin (Munich) 2006;101:500), coinfection with Trichomonad tenax (Hum Path 2000;31:1317), 8 year old boy with chronic renal failure and mediastinal nodal TB (Clin Exp Nephrol 2006;10:152)
Diagnosis: PCR (preferred, J Clin Pathol 2000;53:355), ligase chain reaction (Scand J Infect Dis 2004;36:724), immunostains or culture
Gross: large multinodular mass that resembles carcinoma with multiple foci of caseous necrosis
Micro: either multiple small epithelioid granulomas or huge epithelioid granulomas with prominent Langhans giant cells and central necrosis
References: J Clin Pathol 1988;41:93 (HIV+ patients with TB lymphadenitis in Uganda)
Caused by Francisella tularensis, a gram negative coccobacilli found in rodents, rabbits, and hares, transmitted by ticks and deer flies
Commonly due to food and water contamination by rodents, hunting hares (Med Clin (Barc) 2002;119:455) and mosquito bites (Emerg Infect Dis 2002;8:956)
Also a virulent, potential biowarfare agent
Symptoms: sudden fever, chills, headaches, diarrhea, muscle aches, joint pain, dry cough, progressive weakness; also pneumonia, skin/mouth ulcers, lymphadenopathy, eye involvement
Ulceroglandular form: prominent lymphadenopathy of either axilla (mammalian vectors, such as handling rabbits) or cervical/inguinal regions (arthropod vectors)
Diagnosis: rise in titers, PCR (Mod Path 2004;17:489), immunofluorescence (Scand J Infect Dis 2004;36:785)
Micro: early - reactive changes; second week - abscess with variable epithelioid cell reaction; fourth week - caseous necrosis, diffuse lymphadenitis; late - granulomatous reactions that may resemble TB; often extracapsular inflammation
DD: tuberculosis (acid-fast), sarcoidosis, toxoplasmosis
References: Archives 1986;110:42, Centers for Disease Control and Prevention, eMedicine
Post-smallpox vaccination may cause enlarged and painful adenopathy, up to 6 cm in 29% at 10 days (Vaccine 2006;24:476)
Usually supraclavicular nodes on side of vaccination
Micro: paracortical expansion with eosinophils, plasma cells and immunoblasts; also vascular changes and focal necrosis
Whipple’s disease in lymph nodes
Rare; due to infection by Tropheryma whipplei, present in soil and sewage but not animals
Typically affects farmers and outdoor workers
Symptoms include diarrhea, malabsorption, weight loss, fever, arthralgias; also occasional CNS and cardiac involvement
May cause marked enlargement of mesenteric and periaortic lymph nodes; enlargement of peripheral lymph nodes may occur early
Diagnosis requires massive involvement of node plus intense PAS+ staining (small aggregates of PAS+ macrophages are nonspecific) or PCR
Treatment: IV penicillin and streptomycin or third generalization cephalosporin for 10-14 days, plus cotrimoxazone for 1 year
Gram stain: gram positive bacteria
Case reports: 55 year old woman with mesenteric lymphadenopathy and a monoclonal B cell proliferation (Archives 2003;127:1619)
Micro: nodal architecture obscured by ill defined lipogranulomas; involvement of sinuses by macrophages with foamy cytoplasm
Positive stains: PAS+ diastase resistant bacilli within histiocytes, immunostains for bacteria (AJCP 2002;118:742)
Negative stains: Ziehl-Neelsen
Molecular: PCR to confirm diagnosis (AJCP 2001;116:898, difficult to culture)
EM: rod like organisms
DD: Fabry’s disease
Yersinia enterocolitica in lymph nodes
Clinical picture usually resembles acute appendicitis, but laparotomy often shows mesenteric lymphadenitis (Pediatr Surg Int 1998;13:2)
Similar to Y. pseudotuberculosis
Usually self-limited
Gram stain: gram negative, polymorphic, coccoid or ovoid mobile bacteria
Diagnosis: PCR, cultures
Case reports: 46 year old woman with weight loss and abdominal lymphadenopathy (Radiologe 1998;38:37)
Micro: capsular thickening and edema; immunoblasts and plasma cells in cortical and paracortical region; large lymphocytes within sinuses, germinal center hyperplasia; no granulomas (unlike Y. pseudotuberculosis)
References: Centers for Disease Control and Prevention, eMedicine #1, #2
Yersinia pestis in lymph nodes
Infection is usually limited to lymph nodes (“bubo”, as in bubonic plague)
Pneumonic plague occurs if bacterial are aerosolized
Micro: depletion of lymphocytes, edema, necrosis, foamy macrophages; bacteria may involve blood vessels
Positive stains: Yersinia immunostain (AJCP 2002;117:205)
References: eMedicine, Wikipedia
Yersinia pseudotuberculosis in lymph nodes
Clinical picture usually resembles acute appendicitis with possible abdominal mass (Eur J Pediatr Surg 1997;7:180), but laparotomy often shows mesenteric lymphadenitis
Usually self-limited, but may be associated with Kawasaki’s disease (Kansenshogaku Zasshi 2005;79:895, Acta Paediatr 1997;86:661)
Ampicillin reduces fetal excretion of bacteria, but provides no clinical benefit (Pediatr Infect Dis J 1988;7:686)
Gram stain: gram negative, polymorphic, coccoid or ovoid mobile bacteria
Diagnosis: PCR, cultures
Gross: inflammation of terminal ileum and cecum
Micro: capsular thickening and edema; granulomas with central necrosis and microabscesses; immunoblasts and plasma cells in cortical and paracortical region, large lymphocytes within sinuses, germinal center hyperplasia
References: AJCP 1979;71:631, eMedicine
Inflammatory disorders (non-infectious)
Reactive conditions in lymph nodes - general
Not clonal
Contain mixtures of cells
No/minimal cytologic atypia
Usually considered benign if no mass lesion or architectural effacement at low power
Clonal processes are usually, but not always neoplastic, and polyclonal processes are usually, but not always, benign
Acute nonspecific lymphadenitis
Rarely biopsied
Suppurative lymphadenitis is associated with Staphylococcal infections, mesenteric lymphadenitis, cat-scratch disease and Lymphogranuloma venereum
Necrosis is associated with bubonic plague, anthrax, tularemia, typhoid fever, melioidosis and Kikuchi’s disease
Micro: dilated sinuses, dilated vessels, neutrophils and capsular edema
Adult onset of Still’s disease in lymph nodes
Still’s disease is an acute febrile form of juvenile rheumatoid arthritis of unknown etiology; rare in adults
Adult onset cases have multicentric lymphadenopathy (often cervical) in 50-90% of patients, spiking fever, evanescent rash, arthritis, arthralgias and various organ involvement
Difficult to diagnosis due to non-specific findings, including fever of unknown origin; histopathology may change dramatically during course of disease
Micro: various patterns: (a) paracortical hyperplasia with prominent vasculature, scattered immunoblasts and inflammatory cells; (b) paracortical hyperplasia with massive sinus histiocytosis and S100+ histiocyte aggregates; (c) exuberant immunoblasts with high mitotic activity; (d) distinct follicular hyperplasia
DD: peripheral T cell lymphoma (Int J Surg Pathol 2002;10:197), Castleman’s disease-hyaline vascular variant (Clin Rheumatol 1999;18:485)
References: J Clin Pathol 2004;57:1052
Allergic granulomatosis in lymph nodes
Case reports: cases consistent with Churg-Strauss disease (chronic asthma, allergic rhinitis and eosinophilia) but limited to lymph nodes (Archives 2001;125:954, J Pediatr Hematol Oncol 2000;22:468)
Treatment: prednisone
Micro: infiltration of lymph nodes with histiocytic granulomas and eosinophils
Positive stains: preserved B and T cell areas in a reactive lymph node
Negative stains: CD15, CD30
DD: lymphoma, Kimura’s disease (no granulomas), sarcoidosis (no eosinophilic abscesses), Wegener’s granulomatosis (different clinical presentation)
References: eMedicine #1, #2
Lymph node involvement present in up to 1/3 of generalized primary and secondary cases; also in 22% of uremic patients (Ren Fail 2000;22:613)
Usually AL type if isolated amyloidosis or AA type in reactive systemic amyloidosis or uremic patients (Hum Path 1986;17:1245)
May be associated with monoclonal light chains from lymphoma (Ann Oncol 1997;8:267)
Case reports: recurrent, isolated lymph node amyloidosis (Archives 1991;115:948)
Micro: amorphous appearing salmon-colored material; often vascular deposition; may be coexisting lymphoma, plasmacytoma or metastatic medullary carcinoma of thyroid
Cytology: either flocculent material or irregularly shaped fragments with scalloped and pointed edges; amorphous fragments (eosinophilic to blue/green with Pap stain, deep blue with Diff-Quik) are acellular and associated with connective tissue; may have florid giant cell reaction (Acta Cytol 1999;43:746)
Positive stains: apple green birefringence with Congo red stain
EM: clusters of round/oval nodules, often enclosed with cytoplasmic processes of macrophages or reticulum cells; fibrils are nonbranching, 7.5 nm in diameter, form parallel bundles close to cytoplasmic membranes (Histol Histopathol 1986;1:277)
DD: proteinaceous lymphadenopathy (resembles but is not amyloid), hyaline deposits (Congo red negative), sclerosis (trichrome positive)
Angiolymphoid hyperplasia with eosinophilia in lymph nodes
Rare benign vascular tumor
Also called epithelioid hemangioma
Distinct from Kimura’s disease (AJSP 1988;12:843, An Bras Dermatol 2006;81)
Multiple small nodules of skin and subcutaneous tissue of head and neck of young adults, more commonly women
Associated with peripheral blood eosinophilia in 20% of patients
May have history of trauma/scratching
Most intradermal lesions are up to 2 cm, subcutaneous lesions are up to 10 cm
Uncommonly affects regional lymph nodes (more common in Kimura’s disease)
Treatment: excision, cryotherapy, pulsed dye laser therapy, intralesional steroids, interferon or cytotoxic agents
Case reports: within deep mediastinal, abdominal and intramammary nodes and associated with raised CA-125 levels (Virchows Arch 2006;448:366), with coexisting Kimura’s disease (Int J Dermatol 2006;45:139)
Micro: solitary or multiple benign cutaneous nodules comprised of immature and mature vascular structures with epithelioid endothelial cells and an infiltrate of eosinophils, histiocytes, lymphocytes, and mast cells; no eosinophilic folliculolysis, no IgE deposits in germinal centers
DD: Hodgkin’s lymphoma (AJCP 1987;88:236), Kimura’s disease (young Asian men, presents with lymphadenopathy with variable soft tissue mass and major salivary gland involvement, usually subcutaneous or deeper, almost always peripheral eosinophilia, usually elevated serum IgE, no epithelioid endothelial cells, has dense hyaline fibrosis in lymph nodes with vascularization of germinal centers, polykaryocytes, eosinophilic abscess and necrosis of germinal centers)
References: eMedicine
Castleman’s disease in lymph nodes
Also called giant lymph node hyperplasia, angiofollicular hyperplasia
Rare; etiology unknown
Usually adults, but may occur in children
Clinically either solitary or multicentric
Solitary disease has mass in mediastinum or other sites up to 15 cm; mass is round and well circumscribed, 90% are hyaline-vascular variant, unicentric and asymptomatic; plasma cell variant may present with fever, anemia, night sweats, weight loss, elevated sedimentation rate and hypergammaglobulinemia; treatment is surgical excision
Multicentric disease is almost always plasma cell variant, with generalized lymphadenopathy and possible splenic involvement; resembles angioimmunoblastic lymphadenopathy
Multicentric disease may be associated with POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein and Skin)
In children, multicentric disease occurs in girls (75%), is usually plasma cell variant (63%), has good response to steroids (Mod Path 1996;9:1135)
Plasma cell variant is associated with HHV8 infection, with an accumulation of HHV8+ lymphocytes in mantle zone leading to dissolution of the germinal center (AJSP 2003;27:91)
May have associated angiomyoid, vascular or follicular dendritic cell neoplasms (AJSP 1997;21:1295, AJSP 1990;14:603)
Associated with paraneoplastic pemphigus (Arch Dermatol 2005;141:1285) and other paraneoplastic syndromes (Pediatr Blood Cancer 2005 Jul 26 [Epub ahead of print])
Poor prognostic factors: (a) multicentric disease (may cause renal or pulmonary complications; may develop Kaposi’s sarcoma or lymphoma); (b) expression of HHV8 viral IL6 (AJCP 2002;117:268)
Case reports: hyaline vascular variant - 53 year old man (Archives 2005;129:945), 38 year old woman with mediastinal mass (Archives 2001;125:964), 2 patients with systemic symptoms (J Clin Pathol 1983;36:1005), with coexisting follicular dendritic cell tumor (AJSP 1994;18:517), with calcifying fibrous pseudotumor after FNA (J Clin Pathol 1999;52:547), 12 year old girl with fatal disease and thymic involvement (Mod Path 1993;6:776), with HHV8 and EBV coinfection (Haematologica 2005;90 Suppl:ECR35)
plasma cell variant - with coexisting plasmacytoma (Archives 1986;110:157), associated with refractory anemia that resolved after nodal excision (J Clin Pathol 1978;31:757), associated with systemic amyloidosis (J Clin Pathol 1997;50:965)
plasmablastic variant - fatal HHV8 associated variant in HIV negative man (AJSP 2006;30:123)
Treatment: solitary lesions - surgical excision; multicentric lesions - optimal treatment is unknown, possibly methotrexate in patients with coexisting rheumatoid arthritis (Clin Rheumatol 2006 Mar 30; [Epub ahead of print])
Castleman’s disease in lymph nodes (continued)
Micro:
hyaline vascular (angiofollicular) variant - common (90%); prominent follicles within lymphoid tissue and absence of sinuses; follicles have marked vascular proliferation with thick and hyalinized walls and hyalinization of germinal centers, which resemble Hassall’s corpuscles of thymus or splenic white pulp, but are actually regressed (involuted) germinal centers; a capillary frequently penetrates the follicle; large cells with prominent nucleoli are follicular dendritic cells (CD21+, CD35+); concentric layering of peripheral lymphocytes resembles onion-skin; prominent interfollicular stroma with frequent hyperplastic post-capillary venules and plasma cells, eosinophils, immunoblasts and plasmacytoid monocytes
lymphoid subtype of hyaline vascular variant has marked expansion of mantle zone and smaller germinal centers, and resembles mantle zone hyperplasia, follicular lymphoma and mantle cell lymphoma
plasma cell variant - follicular hyperplasia with large germinal centers; diffuse plasma cells between follicles, often with Russell bodies; no hyaline-vascular changes present; center of follicle has amorphic eosinophilic material (fibrin, immune complexes)
plasmablastic variant - mantle zone has numerous large cells (2x lymphocytes) with moderate amphophilic cytoplasm, large vesicular nuclei, 1-2 prominent nucleoli (Blood 2000;95:1406)
multicentric disease - HIV negative patient with coexisting Kaposi’s sarcoma post-cyclosporin for minimal change nephropathy (BMC Blood Disord 2003;3:3), HIV+ but HHV8 negative (BMC Infect Dis 2003;3:20)
Positive stains: HHV8 (often)
Negative stains: usually no light chain restriction in plasma cells
Molecular: usually not clonal; HMGIC rearrangement in one case (AJSP 2002;26:662), clonal karyotypic abnormality in one case (AJSP 2000;24:882)
DD: HIV lymphadenopathy, mantle cell lymphoma
References: AJCP 1996;105:268, J Clin Pathol 1972;25:306
Non-specific finding
Micro: follicular hyperplasia, prominent post-capillary venules, immunoblasts, plasma cells, histiocytes, fibrosis
Clofazimine-induced changes in lymph nodes
Clofazimine is an anti-leprosy drug
Gross: black discoloration of lymph nodes, omentum and peritoneum (Lepr Rev 2004;75:171, Pathology 1993;25:24)
Micro: marked interfollicular plasmacytosis and scattered crystal-storing histiocytes; crystals are clear, colorless and elongated with irregular ends; also plasmacytosis; frozen section shows red crystals with bright-red birefringence
Negative stains: PAS, IgG, IgA, IgM, kappa, lambda
References: AJSP 2000;24:129
Also called lipomelanosis reticularis of Pautrier
Nodal hyperplasia secondary to generalized dermatitis, particularly with exfoliation
May occur in any skin disorder with itching and scratching
No features, other than tumor cells, predict associated mycosis fungoides (AJSP 1981;5:343)
In Japanese patients, associated with fever and multicentricity in most cases; less commonly with autoimmune disease, drug hypersensitivity reactions or angioimmunoblastic T cell lymphoma (Int J Surg Pathol 2004;12:127, free full text)
Rarely occurs with no clinical skin disease (Archives 1988;112:1145)
Case reports: associated with tattoo (Cutis 2001;67:471), affected parotid node with coexisting Warthin’s tumor (ORL J Otorhinolaryngol Relat Spec 2001;63:385)
Gross: enlarged lymph node with bulging, yellow cut surface; black pigment (melanin) may be present
Micro: nodular expansion of interfollicular region due to histiocytes containing melanin pigment and fat, Langerhans cells and interdigitating dendritic cells; often prominent post-capillary venules, plasma cells, follicular hyperplasia, eosinophils
DD: Hodgkin’s lymphoma, mycosis fungoides (cerebriform lymphocytes), monocytic leukemia, Langerhans cell histiocytosis
Drug hypersensitivity in lymph nodes
Generalized lymphadenopathy, skin rash, fever and peripheral eosinophilia due to antiepilepsy drugs (phenytoin is common)
Uncommon, occurs within first few months of drug administration, disappears after removal
Rarely is fatal due to pancytopenia or polyarteritis nodosa
Case reports: carbamazepine hypersensitivity (J Clin Pathol 1986;39:1224)
Micro: partial effacement of nodal architecture, infiltration
by histiocytes, immunoblasts (some with atypia), plasma cells, eosinophils and
neutrophils; foci of necrosis
DD: angioimmunoblastic
lymphadenopathy
References: AJSP 1995;19:675 (dilantin)
Erythrophagocytosis in lymph nodes
Present in most axilla lymph nodes to some extent, marked after breast biopsy (AJCP 1988;90:189)
May also be associated with lymphoproliferative disorders
Extramedullary hematopoiesis in lymph nodes
See also megakaryocytes in lymph nodes
Rarely associated with myeloproliferative disorders (Diagn Cytopathol 1993;9:522), but also in healthy patients (Arch Otolaryngol 1982;108:523)
DD: Hodgkin’s lymphoma
Follicular hyperplasia in lymph nodes
May be due to bacteria, rheumatoid arthritis, lupus (Pathol Int 2000;50:304), viruses (HIV) or associated with Castleman’s disease or progressive transformation of germinal centers (Int J Surg Pathol 2005;13:175)
Lack of light chain expression: usually is associated with lymphoma, but rarely is associated with hyperplasia, often in HIV+ patients (AJCP 2005;124:143)
May have skewing of light chain ratios in germinal center cells compared to mantle cells (AJCP 2003;119:130)
In elderly, cases with interfollicular plasmacytosis are associated with immunologic abnormalities (Pathol Res Pract 1998;194:391)
HLA-DO may distinguish florid follicular hyperplasia from follicular lymphoma by flow cytometry (AJCP 2003;119:842)
Gross: usually less than 1 cm; pink homogenous cut surface; may resemble fat
Micro: nodal architecture is preserved; usually no/minor infiltration of capsule and perinodal adipose tissue; follicles are markedly variable in size and shape; margins are sharply defined and surrounded by a mantle layer of IgD+ small lymphocytes, often with an onion skin pattern, and sometimes primarily on one pole of the follicle; follicles are composed of centrocytes (small) and centroblasts (large); interfollicular lymphocytes differ from follicular lymphocytes; tingible body macrophages (with nuclear debris) and mitotic figures are common; large number of dendritic cells with intact dendritic meshwork by CD21/CD35 staining
Cytology: tingible body macrophages, no lymphoid aggregates, no two-nuclei-like cleaved cells, no/rare prominent nucleoli (Diagn Cytopathol 2006;34:11)
Negative stains: bcl2 (AJCP 2000;114:258), CD10 (Appl Immunohistochem Mol Morphol 2000;8:263), no immunoglobulin heavy chains, no light chain restriction
Molecular: usually no clonality, but rarely is clonal by flow cytometry and molecular methods with no clinical evidence of lymphoma - they cases occurred in normal young males and an HIV+ young woman (AJCP 2004;121:464)
DD: follicular lymphoma (diffuse effacement of nodal architecture, follicles are similar in size and shape and uniformly distributed throughout the node, no tingible body macrophages, cells are similar within and between the follicles, bcl2+ [AJCP 2003;119:145], clonal, t(14;18), light chain restriction, presence of immunoglobulin heavy chains), HIV+ explosive follicular hyperplasia, progressive transformation of germinal centers, Castleman’s disease, rheumatoid lymphadenopathy, syphilitic lymphadenitis, Kimura’s disease
Granulomatous inflammation in lymph nodes
Due to infection (atypical mycobacteria is common), foreign bodies, secondary response to malignancy
Helpful diagnostic features include presence and type of necrosis; presence and type of giant cells; size, shape and distribution of granulomas; other associated changes
These lymph nodes should be cultured
Case reports: 69 year old woman with granulomatous reaction around cholesterol-like clefts, apparently due to draining fluid from an ovarian mucinous cystadenoma (Archives 1985;109:1124)
Hemophagocytic lymphohistiocytosis in lymph nodes
See also erythrophagocytosis above
Generalized, non-malignant histiocytosis with prominent phagocytosis of blood cells causing peripheral blood pancytopenia
Also fever, hepatosplenomegaly, abnormal liver function tests, hypertriglyceridemia, hypofibrinogenemia
May have marrow dyserythropoiesis (J Clin Pathol 2001;54:961)
Either genetic (rare, infants/young children, rapidly fatal, autosomal recessive with family history or parental consanguinity, Pathology 1997;29:92) or acquired (EBV+ immunocompromised patients)
May be due to defects in perforin gene in some patients (Blood 2004;103:1244)
Diagnosis may require repeated sampling of bone marrow, CSF, lymph nodes, liver, spleen
Micro: intact architecture but infiltration by bland histiocytes containing erythrocytes and occasionally lymphocytes and neutrophils; hemophagocytic histiocytes with erythrophagocytosis are present in lymph nodes, bone marrow or spleen
Cytology: benign histiocytes engulfing erythrocytes and platelets, best seen with imprints (Diagn Cytopathol 1988;4:121)
DD: post-transfusion, malignant histiocytosis (atypia, architectural effacement), peripheral T cell lymphoma (atypical T cells)
References: Histiocyte Society, eMedicine, American Society of Hematology
Hyaline deposits in lymph nodes
Also called proteinaceous lymphadenopathy
Often present in stroma of pelvic or abdominal nodes
A nonspecific finding
Increases with age (Am J Pathol 1975;78:7, Histol Histopathol 2003;18:1169), and may reduce nodal function
Associated with rheumatoid arthritis and systemic sclerosis (J Clin Pathol 1994;47:138, Br J Rheumatol 1995;34:1087), hypergammaglobulinemia (Archives 1990;114:34, AJSP 1979;3:137) and post-treatment changes for carcinoma (Histopathology 1996;29:63)
May calcify
Micro: extracellular eosinophilic material resembling amyloid, but Congo Red negative; also hyaline sclerosis of small and mid-sized vessels of lymph nodes and organs (Blood 1995;86:1159)
Positive stains: immunoglobulins
Negative stains: Congo Red
DD: amyloid, hemorrhagic spindle cell tumor with amianthoid fibers
Uncommon
Associated with fever, pain and lymphadenopathy (AJCP 1980;74:687)
Causes: lymphoma, melanoma or granulocytic sarcoma (APMIS 2003;111:1133), venous thrombosis, arterial occlusion in vasculitis (polyarteritis nodosa), emboli (cholesterol-Hum Path 1978;9:597), heart lung transplantation (J Thorac Cardiovasc Surg 1990;99:861), fine needle aspiration (J Clin Pathol 1982;35:855, Diagn Cytopathol 2001;25:104), mediastinoscopy (Ann Thorac Surg 1989;48:247), gold injection (J Clin Pathol 2001;54:562), denge fever with DIC (BMC Clin Pathol 2005;5:11), infectious mononucleosis (Int J Surg Pathol 2002;10:223), parvovirus B19, intestinal volvulus
Examine node carefully (possibly with levels or immunohistochemistry) and follow patient to rule out lymphoma or other malignancies (Histopathology 1986;10:571, Indian J Pathol Microbiol 2005;48:510)
Micro: extensive necrosis with perinodal inflammation and granulation tissue; may retain a rim of viable lymphatic tissue; reticulin architecture is retained
Immunostains: tumor cells may stain with traditional markers (keratin, S100), even if remaining node is necrotic (Archives 2003;127:60), but be cautious (Archives 2003;127:922)
DD: Kikuchi’s disease, mucocutaneous lymph node syndrome, infectious mononucleosis, granulomatous inflammation, malignancy (lymphoma or melanoma)
References: J Clin Pathol 1972;25:689
Inflammatory pseudotumor in lymph nodes
One or many lymph nodes are affected
Often fever, anemia, elevated erythrocyte sedimentation rate, hypergammaglobulinemia, prominent lymphadenopathy
Usually benign / reactive, NOT neoplastic and so distinct from inflammatory myofibroblastic tumor at this site (Hum Path 2001;32:1382)
Case reports: subsequent follicular dendritic cell tumor (Hum Path 2005;36:207), calcified tumor developing after FNA for Castleman’s disease (J Clin Pathol 1999;52:547)
Treatment: steroids, NSAIDs
Micro: varies from case to case; storiform pattern of spindled fibroblasts or myofibroblasts in fibrous stroma of node with extension into lymphoid tissue and perinodal tissue; also vascular proliferation and mixed inflammatory infiltrate of plasma cells, immunoblasts, small lymphocytes, histiocytes, dendritic cells, neutrophils and fibroblasts
Cytology: EBV+ cases may have Reed-Sternberg like cells (Diagn Cytopathol 2002;27:335)
Positive stains: vimentin, CD45/LCA, CD68, actin; also vascular endothelial growth factor (Int J Surg Pathol 2001;9:207), occasionally EBV
Negative stains: ALK, HHV8
Molecular: no clonal T cell receptor gene rearrangements
DD: pseudotumor due to Mycobacterium avium intracellulare in immunocompromised; Kaposi’s sarcoma (involves entire node, has slitlike vascular spaces and extravasated red blood cells), anaplastic large cell lymphoma (AJSP 2000;24:1537)
References: AJCP 1996;105:430, AJSP 1991;15:744, AJSP 1988;12:351, Hum Path 1997;28:332, J Clin Pathol 1995;48:37
Also called mucocutaneous lymph node syndrome
Febrile disorder of unknown etiology usually affecting children
High incidence (39 per 100K children below age 5) in Hong Kong (Hong Kong Med J 2005;11:331)
Fever, pharyngitis and conjunctivitis, erythematous skin rashes, cervical adenopathy (25%); also arthritis (40%), coronary arteritis with persistent damage (15-25%) which may cause death
Treatment: IV gamma globulin, high dose aspirin
Micro: fibrin thrombin in smaller vessels with patchy infarcts (AJSP 1982;6:493)
References: eMedicine
Kikuchi’s disease in lymph nodes
Also called histiocytic necrotizing lymphadenitis, Kikuchi-Fujimoto’s disease
Initially described in Japan and other Asian countries; now worldwide
Young adults with cervical lymphadenopathy (tender or painless) and fever, often leukopenia
Associated with autoimmune disease in children (Microbiol Immunol Infect 2004;37:219)
Usually benign and self-limited (Ann Saudi Med 2005;25:319); 3% recur (AJSP 1995;19:798), rarely is fatal
Etiology unknown, although necrosis is due to apoptosis mediated by cytotoxic T cells (Mod Path 1997;10:231)
Case reports: 17 year old girl with cervical lymphadenopathy, with lupus (Indian J Dermatol Venereol Leprol 2005;71:338, J Cutan Med Surg 2004;8:442), in pregnant woman that responded to steroids (Am J Hematol 2006;81:118), with ruptured silicone breast implant (Archives 1996;120:380), recurrence 12 years later (J Clin Pathol 2000;53:157), with diffuse large B cell lymphoma in remission (Hum Path 2000;31:1328), with hemophagocytic syndrome (J Clin Pathol 2000;53:636, J Korean Med Sci 2003;18:592)
Micro: paracortical, well-circumscribed necrotic lesions, often with a starry-sky appearance; also karryorhexis, fibrin deposits, plasmacytoid monocytes (2-3x size of small lymphocytes, variable cytoplasm, round nuclei with open chromatin, small nucleoli, CD4+) that may resemble lymphoma, T cells (CD8+, cytotoxic phenotype); occasional xanthoma cells; no/rare plasma cells, no neutrophils, no follicular hyperplasia, no atypia; occasionally no overt necrosis (AJSP 1990;14:514)
Micro (skin biopsies): vacuolar interface change with necrotic keratinocytes, dense superficial lymphohistiocytic infiltrate, deep perivascular and interstitial lymphohistiocytic infiltrate; abundant karyorrhectic debris but rare/no neutrophils or plasma cells (AJSP 1999;23:1040, AJSP 1990;14:872)
Cytology: phagocytic histiocytes with peripheral nuclei and plasmacytoid monocytes
Molecular: KSHV/HHV8 present in 0% (Diagn Mol Pathol 2006;15:49) to 23% (Hum Path 1998;29:1091)
EM: tubuloreticular structures and intracytoplasmic rods, similar to lupus
DD: lymphoma with necrosis (involves entire node, lacks plasmacytoid monocytes, atypia present), cat-scratch disease (neutrophils, follicular hyperplasia), lupus lymphadenitis (Hum Path 1989;20:295)
References: AJSP 1994;18:219, Hum Path 1993;24:1114 (plasmacytoid monocytes), J Clin Pathol 1985;38:1252, eMedicine #1, #2
Kimura’s disease in lymph nodes
Chronic inflammatory disorder of unknown etiology
Endemic in Asia, affects young men
Often subcutaneous mass of head and neck (including salivary glands), associated with regional lymphadenopathy but normal overlying skin
Lesions persist and may recur after excision
Laboratory: increased serum IgE, peripheral eosinophilia ((AJSP 1988;12:843)
Treatment: excision, radiation therapy, cyclosporine
Case reports: clonal T cell receptor delta rearrangement (AJSP 2002;26:1083), Japanese boy with epithelioid eosinophilic granulomatous reaction and apoptotic eosinophils (Hum Path 2002;33:561), with coexisting angiolymphoid hyperplasia with eosinophilia (Int J Dermatol 2006;45:139)
Micro: germinal center hyperplasia with polykaryocytes, fibrosis and proteinaceous material in germinal centers; also folliculolysis, interfollicular eosinophils and eosinophilic abscesses; increased paracortical plasma cells; variable hyalinized vessels
Soft tissue lesions show proliferation of thin-walled vessels with eosinophilia
Cytology: polymorphous lymphoid population with significant eosinophils, fragments of collagenous tissue, endothelial cells and occasional polykaryocytes (Acta Cytol 2002;46:357)
Positive stains: IgE reticular networks in germinal centers (AJSP 1989;13:177)
Molecular: may be clonal rearrangement of T cell receptor delta gene
DD: angiolymphoid hyperplasia with eosinophilia (also called epithelioid hemangioma; affects skin of older Caucasian men with multiple small papules, blood vessels are thick walled with prominent epithelioid endothelial cells), progressive transformation of lymph nodes
References: eMedicine
Also called lipophagic granuloma
Secondary to various inflammatory and neoplastic conditions or primary lesion of lymph node
In West, commonly due to mineral oil ingestion or total parenteral nutrition
Case reports: 27 year old woman with prior giant cell tumor (Acta Cytol 2002;46:772)
Micro: giant cells (mono- or multinuclear) with foamy and vacuolated cytoplasm
Either congenital, infectious, obstructive, traumatic or idiopathic
Congenital: also called Milroy’s disease (primary hereditary lymphedema), autosomal dominant (OMIM 153000, 153100, 153200, 153300, 153400)
Infectious: due to Schistosomiasis in endemic areas; occasionally due to minor infection such as furuncle
Obstructive: associated with malignancy or nodal dissection (axilla or groin most common)
Traumatic: may be as minor as sprained ankle
Idiopathic: called lymphedema praecox (if before age 35 years) or tarda
All causes are associated with lymphangitis, cellulitis and recurrent infections
Postmastectomy lymphedema may lead to angiosarcoma
Treatment: elevation of extremity, compression and massage; if necessary, excise thickened skin and replace with skin grafts
Micro: markedly dilated dermal lymphatics, including in lymph nodes; fibrous tissue deposition in overlying skin, subcutaneous tissue and fascia
References: eMedicine #1; #2; #3
Mantle cell / marginal zone hyperplasia in lymph nodes
Gene rearrangement studies and followup recommended to rule out occult lymphoma in cases with clear cells (AJCP 2001;116:550)
Marginal zone hyperplasia is rare (except in mesenteric nodes), but does occur in reactive nodes (APMIS 2002;110:325)
Micro: monomorphic proliferation of small lymphocytes with clear cytoplasm and round nuclei; no pericapsular infiltration, sinuses are identifiable, scattered reactive follicles
Positive stains: bcl2 (by marginal zone B cells, AJSP 2003;27:888)
Negative stains: no light chain restriction
Molecular: usually negative
Monocytoid B cell hyperplasia in lymph nodes
Benign disorders are toxoplasmosis, cat-scratch disease, EBV (AJSP 2005;29:595), HIV (Hum Pathol 1985;16:979), autoimmune disorders, zoonotic Brugia (AJCP 1996;105:384)
Also associated with mantle cell / marginal zone hyperplasia (see above)
Micro: sinuses distended by small lymphoid cells with clear cytoplasm and central, round/oval nuclei; variable neutrophils
DD: peripheral T cell lymphoma, MALT lymphoma, hairy cell leukemia, mastocytosis
References: Pathol Res Pract 1998;194:559
Common in paracolic lymph nodes draining tumor (Virchows Arch A Pathol Anat Histopathol 1987;411:239)
Associated with idiopathic plasmacytic lymphadenopathy, which resembles Castleman’s disease (Int J Surg Pathol 2004;12:25)
Case reports: patient with Sjogren’s syndrome and plasmacytosis resembling myeloma (J Korean Med Sci 2005;20:506)
Micro: well preserved nodal architecture with plasma cells and plasma cell precursors in medullary cords; sinuses are patent
Negative stains: no light chain restriction
Molecular: not clonal
DD: plasmacytic SLL/CLL (diffuse, not just involvement of medullary cords)
Warthin-Finkeldey polykaryocytes are associated with various benign and malignant lymphoid conditions
Initially identified in tonsils of patients with measles
Also present in HIV patients
Case reports: associated with systemic lupus erythematosus (Hum Path 1988;19:1358)
Micro: multinucleated giant cells from 25 to 150 microns, with minimal cytoplasm and up to 60 nuclei
Positive stains: CD3, CD43 (T cells)
References: AJCP 1992;97:179
Post-lymphangiography granuloma in lymph nodes
Lymphangiography may induce a lipogranulomatous reaction in lymph nodes
May persist for months
Micro: distended nodal sinuses contain multi- and mononucleated histiocytes; initially neutrophils, later eosinophils
Post-transplant lymph node changes
Effects due to immunosuppressive drugs
Micro: patterns of lymph node regression: (A) germinal cells may have few/no lymphocytes, no/rare tingible body macrophages, poorly developed mantle zone; (B) crowded follicular dendritic cells with no germinal center lymphocytes or tingible body macrophages; (C): smaller germinal center, irregular shape due to disintegration of follicular dendritic cells, no mantle zone
References: AJSP 1999;23:536
Progressive transformation of germinal centers in lymph nodes
75% males
Usually presents with solitary asymptomatic lymphadenopathy of head and neck; more frequently in elderly in Japan (Int J Surg Pathol 2003;11:101)
May be part of evolutionary spectrum with follicular hyperplasia and follicular lysis, in the resolution of lymphoid hyperplasia by sequential ingression of T cells followed by mantle B cells (AJCP 2003;120:322)
Either self-limited (particularly in young men, AJSP 1992;16:252), or associated with lymphocyte predominant Hodgkin’s lymphoma (AJCP 1990;93:219)
Micro: germinal centers are markedly (3-5x) larger than normal, with indistinct margins; are composed of follicular mantle lymphocytes and extensive follicular dendritic cells; tingible body macrophages are also present; associated with more typical germinal centers; large numbers of T cells are present; may have a few small hyaline-vascular type germinal centers; rarely have T cell rosettes
May have bcl2 expression in mantle B cells
Positive stains: CD20, CD45RA
DD: follicular lymphoma (AJCP 1987;88:264), nodular lymphocyte predominant Hodgkin’s lymphoma (AJSP 1999;23:27), hyaline-vascular Castleman’s disease (APMIS 2005;113:288)
Rheumatoid arthritis in lymph nodes
See also hyaline deposits and gold deposits
Associated with lymphadenopathy during course of disease in 82%, usually axillary (J Int Med Res 2003;31:345)
Lymphadenopathy usually disappears during disease remission
May also have fever, weight loss, anemia
Modestly increased risk of lymphoma, may be due to methotrexate treatment
Micro: follicular hyperplasia with sparse (J Clin Pathol 1990;43:106) vs. active (Acta Pathol Jpn 1990;40:249) proliferative activity, interfollicular plasma cells with Russell bodies, vascular proliferation; capsular lymphocytic infiltrate; may resemble plasma cell variant of Castleman’s disease; often PAS+ extracellular hyaline material; occasionally focal necrosis and microabscesses; may have sarcoid-like granulomas
Negative stains: no light chain restriction in plasma cells (i.e. they are polyclonal)
A multisystemic granulomatous disease that is a diagnosis of exclusion
Occurs worldwide, with increased incidence in Scandinavian countries
Etiology is unclear, although reaction to mycobacteria is suspected
In US, 10-15x more common in blacks vs. whites
Usually lung (hilar nodes), other lymph nodes, eyes, skin and liver, but may affect any organ
Often preceded by erythema nodosum
Associated with hypoparathyroidism, due to PTH-related protein secreted by granulomatous cells
Kveim test: 60-85% sensitive and fairly specific; biopsy of area 4-6 weeks after intradermal inoculation of human spleen extract shows sarcoid-like granuloma; not commonly used due to lack of extract
Case reports: 50 year old African-American HIV+ woman with Hamazaki-Wesenberg bodies (Archives 2003;127:111)
Micro: nodal effacement by small granulomas composed of epithelioid cells with scattered Langhans giant cells and lymphocytes; giant cells are smaller and have fewer nuclei than tuberculosis; necrosis is absent/limited; variable Schaumann bodies, asteroid bodies and calcium oxalate crystals within giant cell cytoplasm; no/rare follicular centers
Asteroid bodies: have star-like cytoplasmic pattern, composed of radiating filamentous arms covered by myelin-like membranes; contain calcium, phosphorous, silica, aluminum; not specific for sarcoidosis
Hamazaki-Wesenberg inclusions: PAS+, yellow-brown, ovoid; may represent large lysosomes with hemosiderin or lipofuscin; present in up to 68% of cases, but not specific for sarcoidosis; may resemble yeast (Archives 1987;111:555)
Schaumann bodies: round, with concentric laminations, contain iron and calcium; not specific for sarcoidosis
Cytology: epithelioid granulomas (Chest 2000;118:928)
DD: tuberculosis, atypical mycobacteria, fungi, leprosy, syphilis, leischmaniasis, brucellosis, tularemia, zirconium, berylliosis, Crohn’s disease, chalazion, talc (Br J Ind Med 1984;41:84), Hodgkin’s lymphoma, nearby neoplasm