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
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 lambda)
B cell antigen receptor loci may have 4 types of modification - (1) recombination of variable, diversity and joining regions (VDJ); (2) somatic hypermutation of V segments; (3) immunoglobulin heavy chain gene class switching; and (4) receptor editing
Early B cell precursor is TdT+, CD34+, HLA-DR+; then undergoes heavy (H) chain rearrangement and adds CD19; then adds CD10; then adds IgM heavy chain; then adds light (L) chain rearrangement and adds cytoplasmic IgM with heavy and light chains; then expresses IgM and IgD with the same binding site; then adds CD20 (now called preB cell); then adds surface Ig; then adds CD21 and CD22 and drops TdT (now called B cell)
If B cell encounters an antigen that interacts with its variable region, it becomes a plasma cell
Precursor B cells contain immunoglobulin related components but not immunoglobulin; express CD179a and CD179b (precursor to light chains) as part of their pre-B cell receptor, which disappears when replaced with conventional light chains
B cells express surface immunoglobulin, which is associated with CD79a/CD79b complex to form a B cell antigen receptor complex
IgH (heavy chain of immunoglobulin): encoded at 14q32; variable portion coded by VDJ genes
IgL (light chain of immunoglobulin): kappa on 2p11, lambda on 22q11; no diversity region is present
Heavy chain isotype switch: determines if immunoglobulin is IgM, IgD, IgG1-4, IgA1-2 or IgE (9 constant regions); mediated by switch genes
B cell lymphomas: clonal light chain rearrangement is usually specific for the presence of a B cell neoplasm
Diagrams: immunoglobulin; B cell differentiation; heavy chain gene rearrangement
Micro: mainly present in primary and secondary follicular centers
Micro images: various images
References: B cell antigen presentation
Develop from bone marrow, become prothymocytes, then migrate to thymus gland, where self-recognizing T cells are eliminated
T cell receptors (TCR) are either alpha/beta (95%) or gamma/delta (5%) heterodimers
T cells mediate reactions to soluble antigens and some particulate antigens
Precursor cell is TdT+, CD34+, HLA-DR+; then drops HLA-DR; then adds CD2, CD5, CD7 (early thymocyte) while undergoing gamma/beta chain rearrangement; then adds CD1 and drops CD34; now a common thymocyte; then undergoes beta/alpha chain rearrangement and adds CD4 and CD8; then splits into helper or cytotoxic T cell, without TdT, CD1, CD5 and CD7; has CD2, CD3, CD4 (helper) or CD8 (cytotoxic)
T alpha and delta genes are on 14q11; T beta is on 7q34; T gamma is on 7p15 (note: there are only 10 V regions, so a polyclonal population of cells can appear oligoclonal)
90% of peripheral T-cell lymphomas have rearrangements of T-alpha, beta and gamma genes, including all cases of mycosis fungoides and Sezary syndrome
Note: T cell clonality is seen in AIDS and congenital immunodeficiency syndromes, but does NOT indicate malignancy
Note: rarely a clonal band may comigrate with the germline band; solution - use 2-3 restriction enzymes (HindIII, EcoRI, BamHI)
Note: T cells and NK cells arise from a common progenitor that expresses CD3 epsilon and cannot develop into B cells
Diagrams: antigen presentation #1; #2; T cell differentiation
Micro: mainly present in paracortex of lymph node; little cytoplasm, small, round/irregular nuclei with dark and condensed chromatin; may have blastic forms with moderate cytoplasm, irregular nuclei and marginal nucleoli
Micro images: attacking tumor cells; 3D image
NK cells (Natural Killer cells)
Distinct group of non-T, non-B lymphocytes
Capable of lysing certain target cells without prior activation or major histocompatibility complex restriction
Believed important in defense against viral and bacterial infections and tumor cells as well as immunomodulation and regulation of hematopoiesis
Granules contain perforin (forms pores in cell membrane of target cells through which granzymes enter and induce apoptosis)
Activated by interferons or cytokines
Comprise 5-20% of peripheral blood lymphocytes
If target cell has class I MHC, then NK cell's killer cell inhibitory receptor (KIR) inhibits cytolysis
Micro: large granular lymphocytes
Positive stains: CD56 (>90%, adhesion molecule), CD57 (unknown
function), CD16 (>90%, low affinity IgG Fc receptor / FC
RIII
that is responsible for antibody dependent cellular cytotoxicity in NK cells
and also expressed on neutrophils and monocyte subset); also cytoplasmic (not
surface) CD3, CD2, CD7, CD8, CD11b, CD11c, perforin, granzyme B, TIA-1
Negative stains: CD3 (surface), immunoglobulins
EM images: NK cells
See also discussion in Spleen chapter
Present in T cell areas (World J Surg Oncol 2003;1:25)
Micro: difficult to detect; distinct cytoplasmic boundaries, faintly granular cytoplasm, large pale nuclei; some cells are elongated and resemble fibroblasts
Micro images: mast cells in subcapsular and medullary sinuses; mast cell (stain unknown)
Positive stains: Giemsa and toluidine blue (purple granules), Leder stain, microphthalmia transcription factor, tryptase; also CD2, CD25, CD45, CD68, CD117
EM images: various images
Includes antigen presenting cells (dendritic cells and Langerhans cells) and antigen processing cells (monocytes, macrophages)
Histiocytes: monocytes, macrophages, Langerhans cells and dendritic cells
Fibroblastic reticulum cells
Stromal support cells
Micro: spindled cells in the parafollicular and deep cortex
Positive stains: vimentin, smooth muscle actin, desmin, alkaline phosphatase, CD68 (focal), keratin (some)
Negative stains: CD21, CD35, S100, EBV
EM: filaments with focal condensations
Follicular dendritic cells
Associated with germinal centers
Have complex cell processes joined by desmosomes, but no Birbeck’s granules
Control B cell maturation and isotype switching
FDC like cells can be produced from monocytes (BMC Immunol 2005;6:23)
Upregulated by Tamoxifin treatment for breast cancer (Am J Pathol 2003;163:1313)
Micro images: CD14+ follicular dendritic cells in appendix
Positive stains: CD21, CD35; also fascin, ER, epidermal growth factor receptor, CD11b, CD14, CD19, CD20; variable S100, EBV, CD68
Negative stains: CD1a, keratin
Interdigitating dendritic cells
Associated with interfollicular (T cell) zones in lymphoid tissue
Micro: may cause the paracortex to look mottled; resemble Langerhans cells; abundant, clear and pale cytoplasm with ill defined borders; have large and bizarre nucleus with deep clefts and folds; delicate almost transparent chromatin, inconspicuous nucleoli
Positive stains: S100, vimentin, fascin, CD45RB, CD68 (focal), variable CD1a (AJSP 1998;22:1048, AJCP 2001;115:589); also CD13
Negative stains: CD21, CD35, B and T cell markers, actin, desmin, keratin
EM: have complex cell processes that interdigitate with T cells, but NO desmosomes and NO Birbeck granules
Indeterminate cells
Resemble Langerhans cells but NO Birbeck’s granules
Derived from Langerhans cells or interstitial dendritic cells, reside in skin and mucosa
Migrate into local lymphoid tissue after antigen capture
Positive stains: CD1a, S100, fascin
Interstitial dendritic cell
Counterpart of Langerhans cell in parenchymal organs (excluding cornea and brain)
Langerhans cells
Related to interdigitating dendritic cells and dermal dendrocytes
Micro images: Langerhans cell histiocytosis #1; #2 of bone; #3 of temporal bone
Positive stains: CD1a, S100, vimentin, Langerin, variable CD68
Negative stains: CD21, CD35 and CD86
EM: Birbeck’s granules
EM images: various images; Birbeck’s granules
Macrophages
Process antigens via phagocytosis
Related to circulatory monocytes
Are present throughout the lymph node
May contain thyroglobulin in lymph nodes draining thyroid tumors (J Clin Pathol 2001;54:314)
Micro: abundant cytoplasm with medium to large nuclei with vesicular chromatin; tingible body macrophages have clear cytoplasm and contain apoptotic bodies, which gives node a starry sky pattern
Micro images: monocyte; macrophages (with pigment) and plasma cells; tingible body macrophage #1; #2; thyroglobulin+ histiocytes
Positive stains: CD68, lysozyme
Sinus lining cells
Also called littoral cells, particularly in spleen
Have endothelial and macrophage properties
Normal lymphoid cells undergo rearrangements within their antigen receptor genes, causing specificity for the immunoglobulin or T cell receptor that they produce
Monoclonal proliferations are presumed to be neoplastic; polyclonal populations are not
Apoptosis helps eliminate B cells producing antibodies with low avidity
Lymphoid stem cell: TdT+, CD34+, HLA-DR+, then develops along B or T cell pathway
Age related changes in lymph nodes
Germinal centers are more common in infants and children, decrease in young adults, often absent in elderly
Germinal centers are more common in mesenteric and cervical lymph nodes
Hyaline deposits increased with age
Peripheral lymph nodes, with little antigenic stimulation, often have replacement by fat, particularly in axillary, cubital and popliteal nodes
Lymphocyte depletion, fibrosis and hyaline deposits are associated with chronic disease, particularly cancer
References: Am J Pathol 1975;78:7, J Clin Pathol 1980;33:454
Inclusions, pigment or ectopic cells or tissue
Adipose tissue metaplasia in lymph nodes
Very common, particularly in external iliac and obturator nodes (see also Age related changes)
May cause masses up to 10 cm
Common in intrapulmonary lymph nodes
Due to coal dust, smoke or pollution
May be associated with storiform pattern of histiocytes that resembles a neoplasm (Hum Path 1998;29:851)
Associated with silica, although often no history of industrial exposure
Associated with hyalinization in nodes of elderly Japanese (Histol Histopathol 2003;18:1169)
Case reports: causing mediastinal lymphadenopathy resembling TB (Eur J Intern Med 2003;14:444)
Micro: fine anthracotic pigment; may be associated with storiform pattern of spindle cells that extend outside capsule and surround nerve; also nodal hyaline scars and polarizable material suggestive of silica
Micro images: anthracosis #1; #2; #3
Virtual slides: anthracosis #1; #2 with TB
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)
Micro images: not necessarily lymph node - asbestos body #1; #2 with iron stain
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
Micro images: patient with cervical carcinoma; decidua in placenta; decidua in cervix
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
Micro images: endometriosis of ileocecal value and nodal inclusions; endometriosis of unknown lymph node; see also above case report
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
Micro images: (1) cystic epithelial inclusions; (2) heterotopic mammary ducts; (3) figure 1-squamous inclusion cysts (inset CK5/6); 2: p63; (4) left-benign tubular epithelial inclusions; right-infiltrating carcinoma
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
Micro images: infracted tissue; reticulin stain shows preservation of nodal architecture
DD: lymphoma
Case reports: 49 year old woman with lymphadenopathy after single infusion of iron dextran (J Clin Pathol 1968;21:492)
Micro images: hyperplasia of histiocytes and increased plasma cells; Perl’s iron stain shows staining of histiocytes in sinuses
Virtual slides: hemochromatosis
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)
Micro images: various images; megakaryocytes in bone marrow #1; #2
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)
Micro images: pigment in colonic mucosa and colonic lymph nodes
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
Micro images: hyperplastic mesothelial cells in nodal sinuses #1; #2 (stains)
Positive stains: keratin (perinuclear)
Negative stains: EMA, CD15, CEA, B72.3
EM: long microvilli
EM images: long slender microvilli, perinuclear intermediate filaments and cell junctions
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
Micro images: endosalpingiosis #1; #2 and serous borderline tumor; endocervical-type inclusions; not lymph node - glands lined by tubal type epithelium #1; #2
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)
Micro images: (1) left-benign nevus cells, right-infiltrating lobular carcinoma; (2) benign nevus cells within capsule and vessel of perinodal adipose tissue
Virtual slides: nevus cells in lymph node
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
Micro images: not lymph node - cellular blue nevus; amelanotic blue nevus
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)
Micro images: sinus histiocytosis and histiocytes with multiple spindled particles
Positive stains: PAS+ polyethylene particles
EM images: particles are 1 micron
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)
Micro: sialometaplasia - extensive squamous metaplasia of intranodal inclusions #1; #2; metaplastic lobules express smooth muscle actin at periphery
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
Micro images: germinal centers surrounded by sinuses containing multinucleated giant cells with refractile silicone material; multinucleated giant cells containing refractile silicone and intracytoplasmic asteroid bodies; silicone leakage next to striated muscle; silicone particles in cystic spaces and within a foreign body type giant cell (arrow)
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
Micro images: silicotic nodule of lung; site unknown - silica crystals (polarized light)
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
Micro images: (1) intranodal cystic epithelial inclusions in breast node; (2) axillary intranodal cyst (figure 1: H&E, inset CK5/6; 2: p63)
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)
Micro images: preserved nodal architecture with pigment; dark pigment within sinuses; pigment within macrophages
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
Micro images: mesenteric node shows histiocytes and heavily stained round, oval and spindled yellow bodies in a sinus
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
Micro images: tuberculoid type granuloma #1; #2
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
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)
Micro images: H&E and S100
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
Micro images: various images; cervical cytology
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
Micro images: AIDS patient #1; #2; figures 1/2: confluent nodular areas with proliferating vessels; 3: solid clusters of plump endothelial cells without lumina; inset: granular and amorphous material; 4: Southern blot with B henselae probe (specimen-tubes 1,3,5,7; positive control-tube 9)
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)
Micro images: macrophages and neutrophils in necrotic background; Ziehl-Neelsen stain shows intra- and extracellular bacilli
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
Virtual slides: brucellosis
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)
Diagrams: life-cycle
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)
Micro images: blood smear
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
Gross images: lesion on finger
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
Micro images: (1) necrotizing granulomas surrounded by palisading histiocytes; (3) various images as part of case history; (5) stellate microabscesses in axillary nodes (PDF file); (6) Warthin-Starry stain; (7) immunofluorescence; (8) figures 1/2: stellate-shaped abscess with central necrosis and neutrophils, surrounded by granulomatous inflammation; 3: Warthin-Starry stain (also inset) highlights bacteria; 4: immunohistochemical stain is also positive
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
Micro images: (1) images from Arizona (Southwest US) case history; (2) figure 1: CT scan; 2: H&E shows spherules filled with endospores; 3: wooly white mold on blood agar plate after 5 days; 4: Lacto-phenol cotton blue stain shows characteristic enteroarthric conidia formation
not necessarily lymph node - (3) spherules within giant cell; (4) spherule with endospores; (5) large spherules; (6) various images
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)
Micro images: infracted lymph node; congestion of perinodal vessels
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)
Micro images: peripheral smear shows atypical lymphocytes #1; #2
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)
Micro images: above case report (PDF file)
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
Micro images: patient with agammaglobulinemia; gram stain
EM images: rod with capsule
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
Micro images: (1) parafollicular expansion; (2) interfollicular infiltrate of immunoblasts, centroblasts, small lymphocytes and occasional histiocytes and venule with prominent endothelial cells; (3) with mantle cell lymphoma - 2: HSV inclusions, 3: CD20, inclusions at arrow, 4: HSV1/2 immunostain); (4) various images of tonsillar HSV infection
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)
Micro images: HHV8 immunostain (site unknown)
May clinically mimic tuberculosis
Micro: chronic suppurative lesion; granulomatous process or widespread nodal necrosis with diffuse sinus histiocytosis
Micro images: granuloma of histoplasmosis
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
Micro images: HIV lymphadenitis; p24 staining; Fas/CD95 staining
Virtual slides: lymphocyte depleted lymph node
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)
Micro images: adrenal gland; liver; small bowel; site unknown
EM images: amastigote of Leishmania
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
Micro images: well developed germinal centers with lymphocytic cuff, paracortex is almost devoid of lymphocytes; foamy histiocytes contain M. leprae
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
Micro images: site unknown - image #1; #2
Virtual slides: lymphogranuloma venereum
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)
Micro images: measles lymphadenitis
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
Gross images: central caseation in node involved by M. avium intracellulare; cervical node involved by M. chelonei
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
Micro images: M. avium-intracellulare - central necrosis and Langhans giant cells / inset-Ziehl-Neelsen stain shows irregular rods; Ziehl-Neelsen stain shows macrophages stuffed with acid fast bacilli; axillary node aspirate in HIV+ infant; M. chelonei - caseous granuloma #1; #2
Virtual slides: Mycobacterium avium-intracellulare; acid-fast stain
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
Micro images: various images #1; #2; #3 (from above case report); bacteria in vitro #1; #2; #3
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) 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
Case reports: 35 year old HIV+ man with diffuse lymphadenopathy (Case of Week #218)
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)
Micro images: site unknown (Ziehl-Neelsen stain)
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), 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
Micro images: pseudofungi
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
Micro images: cervical lymph node involvement with granulomas
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)
Diagrams: life cycle
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)
Micro images: various images #1; #2; #3; #4; #5; follicular hyperplasia and epithelioid granulomas; enlarged and irregular follicles; germinal center shows apoptosis/necrosis and mitotic figures; epithelioid histiocytes #1 and necrotic fragments; #2; #3; #4 (no reticulin present); monocytoid cells #1; #2; plasma cells in nodal capsule; toxoplasma cyst at margin of follicle; direct immunofluorescence shows trophozoite-like bodies (arrows);
tachyzoites - site unknown #1; #2 (various images)
Virtual slides: toxoplasmosis
DD: lymphocyte predominant Hodgkin’s lymphoma, sinus histiocytosis with massive lymphadenopathy (Leuk Lymphoma 2004;45:1037), other infections
References: US Department of Agriculture, 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
Gross images: multinodular mass #1; #2; #3; #4
Micro: either multiple small epithelioid granulomas or huge epithelioid granulomas with prominent Langhans giant cells and central necrosis
Micro images: granulomatous reaction #1; #2 (inset-Ziehl Neelsen stain); #3; #4; #5; non-caseous necrosis with prominent nuclear debris; macrophages around foci of necrosis; with metastatic adenocarcinoma; Ziehl-Neelsen stain in HIV+ patient with TB
Virtual slides: TB #1; #2 with anthracosis
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)
Gross/clinical images: girl with ulcerating lymphadenitis in Kosovo
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
Micro images: various images #1; #2 with case report
Virtual slides: necrotizing granulomatous 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
Micro images: nodal biopsies (figures 3 and 4); abdominal node (figure 2); immunofluorescence (blue-bacteria, green-nuclei, red-vimentin)
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
EM images: trilaminar cell wall; phagosomes (red arrows), bacteria (yellow arrows)
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)
EM images: Yersinia enterocolitica
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
Micro images: medullary necrosis; safety pin appearance of bacteria
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
Micro images: site unknown
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
Micro images: various images; image
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
Micro images: acute lymphadenitis
Virtual slide: acute lymphadenitis
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
Micro images: various images #1; #2
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
Micro images: various images
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
Micro images: not lymph node - laryngeal amyloid exhibits apple-green birefringence with Congo red stain and polarized light
Virtual slides: amyloidosis (spleen)
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
Micro images: ear; wrist lesion; arm mass with intense eosinophilia and prominent vessels lined by prominent endothelial cells with occasional cytoplasmic vacuoles (figure 3-arrow); colon lesion #1; #2; #3 (elastic stain shows distortion and reduplication of internal elastic lamina); site unknown #1-enlarged endothelial cells with eosinophils and lymphocytes; #2-left: inflammatory infiltrate with vascular proliferation, right: prominent endothelial cells without atypia
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 lymphoproliferative disorder of unknown etiology
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; cases with 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; 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)
Castleman’s disease in lymph nodes (continued)
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 2006;47:616)
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 - Case of the Week #93, 53 year old man with supraclavicular lymphadenopathy (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), with HHV8 and EBV coinfection during pregnancy (Haematologica 2005;90 Suppl:ECR35), HIV negative patient with coexisting Kaposi’s sarcoma post-cyclosporin for minimal change nephropathy (BMC Blood Disord 2003;3:3)
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), HIV+ but HHV8 negative (BMC Infect Dis 2003;3:20)
mixed variant - 12 year old girl with fatal disease and thymic involvement (Mod Path 1993;6:776)
plasmablastic variant - fatal HHV8 associated variant in HIV negative man (AJSP 2006;30:123)
Castleman’s disease in lymph nodes (continued)
Treatment: solitary lesions - surgical excision; multicentric lesions - optimal treatment unknown, possibly methotrexate in patients with coexisting rheumatoid arthritis (Clin Rheumatol 2007;26:1148), possibly anti-IL6 therapy (Intern Med 2007;46:771)
Gross: tan-pink tissue with calcifications #1; #2
Micro:
hyaline vascular (angiofollicular) variant - common (90%); prominent follicles within lymphoid tissue and no sinuses; low power targetoid pattern; 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+, Diagn Cytopathol 2000;22:230); 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)
mixed hyaline vascular and plasma cell variant
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)
Castleman’s disease in lymph nodes (continued)
Micro images: hyaline vascular variant - (1) probable early lesion #1 - a lymphocyte cuff surrounds a pale central area of concentric hyalinized cells, and a small vessel penetrates the cuff and enters the central area #1; #2; various images; (4) cuff of lymphocytes surrounds thick walled vessel #1; #2; #3; (8) onion-skin pattern of lymphocytes with abnormal vasculature and multinucleated follicular dendritic cells; (9) follicle has two pale centers, one irregular; vessel enters from below; (10) figure 1: follicular hyperplasia with concentric mantle zones; 2: interfollicular zones have prominent vascular proliferation; 3: targetoid lymphocytes in mantle zone of hyalinized follicles with an occasional capillary penetrating radially into the germinal centers; (11) figure 1: CT scan; 2: 7 cm tumor with rib and vertebrae; 3: scrape shows cellular material with discohesive cells containing high N/C ratios; 4: H&E shows expanded mantle zone with small lymphocytes arranged in concentric layers; (12) almost total obliteration of subcapsular sinus; (13) center of follicle has prominent vessel; (14) reticulin stain shows profusion of small vessels #1; #2; (16) extensive proliferation of small, thick walled vessels with prominent endothelial cells; (17) various images; (18) with Kaposi’s sarcoma in HIV negative patient receiving cyclosporine A for minimal change nephropathy; (19) with Ki-67 staining
Images contributed by Dr. Jack D. Sublett II, University of Arkansas for Medical Sciences - onion skin pattern #1; #2
Case of the Week: low/medium power - figure 1; figure 2; figure 3; low power targetoid pattern; lollipop appearance; onion skin pattern of lymphocytes
high power - figure 4; figure 5
plasma cell variant - interfollicular space shows numerous mature plasma cells #1; #2; #3
plasmablastic variant - plasmablastic and plasma cell variant
Castleman’s disease in lymph nodes (continued)
Cytology: large histiocytic cells with nuclei resembling crumpled tissue paper are seen in a background of small lymphocytes (Cytopathology 2007;18:168)
Positive stains: HHV8 (plasma cell variant, AJSP 2003;27:91)
Negative stains: usually no light chain restriction in plasma cells
Molecular: usually polyclonal (Histopathology 2006;48:233); HMGIC rearrangement in one case (AJSP 2002;26:662), clonal karyotypic abnormality in one case (AJSP 2000;24:882)
DD: follicular lymphoma, follicular hyperplasia, progressive transformation of germinal centers (APMIS 2005;113:288), HIV lymphadenopathy, mantle cell lymphoma.
References: AJCP 1996;105:268, J Clin Pathol 1972;25:306, Acta Oncol 2004;43:698
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
Micro images: various images; dermatopathic lymphadenopathy #1; #2; #3; #4; #5; dendritic cells are CAM 5.2+
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
Micro images: carbamazepine hypersensitivity - (1) small
lymphoid follicle with marked interfollicular edema; (2) polymorphous
infiltrate of immunoblasts, macrophages and plasma cells; (3) interfollicular
necrosis, immunoblasts and macrophages; (5) interfollicular
Reed-Sternberg like cell; (6) immunoblasts
and mitotic figures; (7) reticulin
stain shows numerous vascular channels
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
Micro images: not lymph node - erythrophagocytosis by AML M4/M5
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)
Micro images: Liver with extramedullary hematopoiesis #1; #2
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)
Micro images: follicular hyperplasia #1; #2; #3; #4 (tingible body macrophages); #5; #6; #7; various images
Diagrams: various patterns
Virtual slides: follicular hyperplasia #1 (acute lymphadenitis); #2 (florid but benign)
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)
Gross images: extensive involvement by granuloma and fibrosis
Micro images: lymphangiogram contrast media in lymph node #1; #2; #3
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)
Micro images: bone marrow #1; #2 with case report
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)
Micro images: rheumatoid arthritis and systemic sclerosis - hyaline deposits in interfollicular areas; extensive replacement of node by eosinophilic material #1 (also focal calcification); #2; node replaced by sarcoid like granulomas with prominent hyaline material
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
Micro images: various images of infracted nodes with lymphoma; associated with denge fever #1; #2; #3 (CD20+); post-gold injection #1; #2; upper pole shows loss of follicles, few lymphocytes and distended sinuses; traumatic hilar vein (top right) is related to fibrinous extravasation; deeper level of hilar vein shows thrombus
superficial lymph nodes - early infarction with small thrombosed veins and perinodal neutrophils; thrombosed vein next to node; organizing thrombus of hilar vein; recanalizing thrombus of hilar vein; infarct at 16 days-lymphocytes survive beneath sinus, perinodal infiltrate is present; retention of reticulin
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)
Micro images: tumor has hilar location in node; spindle cells, plasma cells, lymphocytes and vascular proliferation; interface between calcified tumor and lymph node; hyalinized collagenous tissue with psammoma bodies and scattered spindle cells; A: perivascular fibrosis; B: perivascular hyalinization of small vessels; C: intravascular fibrin thrombi; D: transmural lymphocytic infiltrate in pericapsular vessel
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 women with cervical lymphadenopathy (tender or painless), 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: Case of the Week #89, 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, phagocytic and foamy histiocytes, T cells (CD8+, cytotoxic phenotype); 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)
Micro images: various images #1; #2; Case of Week #89 - #1; #2; #3; #4; #5; #6; lymph node with necrosis and lymphohistiocytic infiltrate; necrotic focus #1; #2; #3; #4; well preserved cells, pyknotic cells and histiocytes at edge of necrosis; mixed inflammatory infiltrate includes histiocytes with necrotic debris; histiocytes with ingested nuclear debris #1; #2; with SLE #1; #2; resembling signet ring carcinoma of stomach (inset CD68+ histiocytes); reticulin stain shows preserved vessel outlines
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
EM images: histiocytes with myelin figures (HC), lymphocytes (L) and plasmacytoid cells (P) and transformed lymphocytes #1 (TL); #2 with tubuloreticular structures (TRS)-inset
DD: lymphoma with necrosis (involves entire node, atypia present, no plasmacytoid monocytes), cat-scratch disease (history of cat exposure with initial skin papule; neutrophils, follicular hyperplasia), lupus lymphadenitis (paracortical necrosis, hematoxylin bodies, history of lupus-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
Micro images: various images #1 (skin); #2 (skin and lymph node); skin #1; #2; #3
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
Micro images: dilated lymphatic spaces lined by endothelium
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
Micro images: measles #1; #2; various images of ileum
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
Micro images: various images
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
Micro images: follicular hyperplasia with eosinophilic material in interfollicular areas; extensive replacement by focally calcified eosinophilic material; sarcoid-like granulomas with intervening hyaline like material; rounded, well separated follicles with expanded paracortex; follicular center composed primarily of centrocytes, with no/rare tingible body macrophages or mitotic figures; interdigitating dendritic cells (CD1+) are associated with small lymphocytes
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)
Gross images: bilateral hilar adenopathy #1; #2; #3; lymph node
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)
Micro images: classic sarcoid granuloma #1; #2; various images #1; #2; various images with necrosis; asteroid bodies; numerous granulomas (figure D); figure 1: CT scan of lungs; 2: noncaseating granulomas and yellow-brown oval structures in sinuses (Hamazaki-Wesenberg inclusions); 3: GMS; 4: Fontana-Masson silver stain
Cytology images: epithelioid granuloma
Virtual slides: sarcoidosis
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
References: eMedicine #1; #2
Sinus histiocytosis in lymph nodes
Also called sinus hyperplasia
Nonspecific finding associated with various etiologies (benign or malignant), including post-prosthesis
May represent pregranulomatous phase of sarcoidosis (Acta Histochem 2006;107:473)
Rarely occurs in pelvic nodes of prostate cancer and axillary nodes of breast cancer patients (Cancer 1997;80:277)
Case reports: resembling carcinoma (AJCP 1989;92:509, Int J Clin Oncol 2003;8:184), parvovirus (J Clin Pathol 2005;58:872), post-arthroplasty (Arch Gynecol Obstet 2004;269:217, J Urol 1997;158:128)
Micro: dilated and prominent sinuses, often containing increased macrophages or sinus lining cells; may resemble signet ring carcinoma cells, but lack atypia and are mucin negative
Cytology: polygonal histiocytes with rounded nuclei (Acta Cytol 1998;42:1347)
Micro images: various images #1; #2; sinus histiocytosis #1; #3 (associated with thyroid carcinoma); #5
Sinus histiocytosis with massive lymphadenopathy
Also called Rosai-Dorfman disease
Massive painless bilateral lymph node enlargement in neck, of unknown etiology
Rare; 25% involve extranodal sites (skin, upper respiratory tract, bone), but massive lymphadenopathy is usually also present
Associated with fever, leukocytosis, anemia, elevated sedimentation rate, polyclonal hypergammaglobulinemia
Usually age 20 years or less, but can affect any age
Initial cases from South Africa; now from US, Western Europe, Africa and Caribbean
May spontaneously resolve; extranodal cases may persist for decades
May cause death due to amyloidosis, involvement of a vital organ, or immunologic abnormalities
May coexist with lymphoma in same node (Mod Path 2000;13:414)
Treatment: none in most cases
Case reports: presenting as thyroid mass (Archives 2003;127:e197), associated with nodular lymphocyte predominant Hodgkin’s lymphoma (Hum Path 1995;26:1378), 16 month old boy (J Clin Pathol 1973;26:463)
Gross: matted lymph nodes with prominent fibrosis; gray to yellow cut surface
Micro: capsular and pericapsular inflammation and fibrosis; dilated sinuses filled with large histiocytes containing intact lymphocytes (emperipolesis, lymphocytophagocytosis) and with extremely large, round, vesicular nuclei with a delicate nuclear membrane and prominent nucleoli; histiocytes may exhibit atypia and be multinucleated; polyclonal plasma cells and lymphocytes; plasma cells frequently surround prominent high endothelial venules; remaining node contains plasma cells with Russell bodies; no/rare internodal fibrosis; distinctive features are emperipolesis, plasma cells, distention of nodal sinuses
Cytology: histiocytes with large nuclei and emperipolesis; lymphocytes are within cytoplasmic vacuoles; histiocytes may have atypia; also reactive lymphocytes (Diagn Cytopathol 2001;24:42)
Micro images: various images; extensive replacement of nodal architecture by pale staining cells; histiocytes fill a nodal sinus #1; #2; #3; #4; #5; #6; distended sinus contains lymphocytes with ingested lymphocytes #1; #2 (orbit); thyroid nodule
Positive stains: S100, CD68; also CD30, CD14, oil red O
Negative stains: CD1a, EBV, CD21
Molecular: not clonal
DD: sinus histiocytosis (no emperipolesis, S100 negative), Langerhans cell histiocytosis (prominent eosinophils, smaller nuclei with central grooves, indistinct nucleoli, no lymphophagocytosis although may have erythrophagocytosis, CD1a+), leprosy, metastatic melanoma, prosthesis related changes, toxoplasmosis (Leuk Lymphoma 2004;45:1037)
Sjogren’s syndrome in lymph nodes
Increased risk of lymphoma, usually B cell or low grade (MALT), may transform to aggressive large cell lymphoma
Evolution to lymphoma if architectural effacement and expanding clusters of monocytoid B cells; or monotypic plasma cells
Micro: follicular hyperplasia with interfollicular plasmacytosis; may have partial nodal effacement by interfollicular macrophages, plasma cells, immunoblasts and small lymphocytes; sinuses may contain monocytoid B cells
Negative stains: plasma cells are polyclonal
DD: rheumatoid arthritis
References: eMedicine
Systemic lupus erythematosus in lymph nodes
Most SLE patients have cervical lymphadenopathy
Case reports: with coexisting Kukuchi's disease (Int J Dermatol 2006;45:454), with coexisting Castleman's disease (J Rheumatol 1999;26:1400)
Micro: architectural preservation, but follicular hyperplasia with variable sized follicles, increased vascularity, interfollicular immunoblasts and plasma cells; often well circumscribed areas of paracortical necrosis with necrosis of small vessels (APMIS 2001;109:141); occasionally DNA deposition/hematoxylin bodies (hematoxyphilic material) in stroma, sinuses and blood vessel walls; may have giant follicles (APMIS 2005;113:558), often disarray of follicular dendritic cell network (Pathol Int 2000;50:304), no/rare granulomas, no/rare neutrophils
Cytology: typical and atypical immunoblasts, plasma cells, occasional Reed-Sternberg like cells and dispersed hematoxylin bodies (Acta Cytol 2000;44:67)
Micro images: necrotizing lymphadenopathy #1; #2
Positive stains: CD11b+ and CD15+ histiocytes; CD8+ T cells, EBV (up to 20%, Int J Surg Pathol 2005;13:273)
DD: Kikuchi’s disease (less prominent follicular hyperplasia and interfollicular plasma cells, more prominent immunoblasts resembling lymphoma), Castleman’s disease (Pathol Res Pract 1997;193:565), polykaryocytes, cat-scratch disease (has neutrophils), lymphogranuloma venereum (has granulomas)
Systemic sclerosis in lymph nodes
Case reports: 29 year old woman with excessive fibrosis of supraclavicular lymph nodes (Rheumatol Int 1993;12:255)
Micro: may have PAS+ extracellular hyaline material (J Clin Pathol 1994;47:138)
Vascular transformation of sinuses in lymph nodes
Also called nodal angiomatosis
Usually found incidentally after resection of a nearby tumor
Benign; all ages
Due to obstruction of lymphatic efferent vessels or venous obstruction (Archives 1990;114:656), or perhaps other angiogenic factors
Case reports: associated with congestive heart failure (G Ital Nefrol 2002;19:60)
Micro: subcapsular and medullary sinuses contain complex network of anastomosing blood vessels of variable sizes with fibrosis; may have irregularly branching vascular slits accompanied by pericytes with maturation towards well-formed vascular channels, may have extravasated red blood cells and interstitial fibrin deposits; reactive, not neoplastic; may also have spindle cell nodules confined to sinus (associated with retroperitoneal nodes removed for renal cell carcinoma); lymphoid parenchyma may show atrophy; no atypia, no PAS+ hyaline globules, no capsular involvement
Micro images: vessels #1; #2; #3; #4
DD: Kaposi’s sarcoma (involvement throughout lymph node including capsule, not just sinuses; well formed and curved spindle cell fascicles, vascular slits are nonbranching; atypia and PAS+ hyaline globules, no fibrosis, patients are HIV+ or African children, AJSP 1991;15:732)
Associated with polyarteritis nodosa, Henoch-Schonlein purpura, Wegener’s granulomatosis, systemic lupus erythematosus, drug hypersensitivity and mucocutaneous lymph node syndrome
Also angioimmunoblastic lymphadenopathy, syphilis
Penetration of inguinal nodes by long saphenous vein or its major branches
May cause varicose veins (Virchows Arch A Pathol Anat Histopathol 1990;417:185)
Neoplasms (excludes lymphoma)
Acute lymphocytic leukemia in lymph nodes
Also called acute lymphoblastic leukemia (ALL)
L3 subtype also called Burkitt’s lymphoma
May have widespread lymphadenopathy and hepatosplenomegaly at diagnosis
Nodal biopsies may be initial diagnostic procedure, although marrow involvement is usually present if tumor in node
Micro: effacement of architecture by primitive cells
Cytology images: lymphoblasts and some lymphocytes
Acute myeloid leukemia / granulocytic sarcoma in lymph nodes
Also called granulocytic sarcoma or chloroma when it forms a mass
See also Leukemia chapter
Diagnosis requires a high degree of suspicion; thin sections are needed to see cytoplasmic granules
Lymphadenopathy may be initial presentation, preceding marrow involvement by months or years
May present with nodal infarction (APMIS 2003;111:1133)
Case reports: chronic myelofibrosis progressing to AML-M7 (Eur J Haematol 2001;67:194)
Gross: may have green hue (“chloroma”) due to myeloperoxidase, which fades on exposure to air
Gross images: retroperitoneal lymphadenopathy; subcutaneous tumor
Micro: cortical or sinusoidal expansion by atypical cells with preservation of follicular centers; blasts are large to medium size with distinct cytoplasmic borders and fine cytoplasmic granules, nuclei have round, folded or lobated nuclei, fine and dispersed chromatin and small to prominent nucleoli; often infiltrate in a single file pattern due to tumor cells insinuating between collagen fibers; often associated with eosinophilic myelocytes; Auer rods may be present (Giemsa stain); variable mitotic figures; may have associated prominent sclerosis
Cytology: cytoplasmic granules in many cells
Micro images: various images (tumor of uterus and retroperitoneal lymph nodes); cells with scant cytoplasm, oval nuclei with stippled chromatin, small nucleoli #1; #2; CD34+; H&E and CD117 (in small bowel)
Virtual slides: AML (without maturation)
Positive stains (on blasts, not other inflammatory cells): myeloperoxidase, lysozyme, chloroacetate esterase (depends on AML subtype), CD43, CD99, CD117
EM: large electron-dense primary cytoplasmic granules and less dense secondary granules; may have ellipsoidal crystalloid granules
DD: lymphoma, Ewing’s sarcoma, Langerhans cell histiocytosis
Angioimmunoblastic lymphadenopathy
See Lymphomas: nonB cell chapter
Angiolipomatous hamartomas in lymph nodes
Associated with Castleman’s disease, hyaline vascular variant (Archives 1986;110:853)
Posterior mediastinum or retroperitoneum
Benign
Treatment: excision
Gross: noncircumscribed single or multiple yellow and fatty nodules up to 15 cm (tan nodules may represent hyaline-vascular Castleman’s disease)
Micro: fibroadipose tissue and haphazard thick walled vessels
Usually retroperitoneal, associated with renal tumor and tuberous sclerosis
May be multifocal
Benign behavior; rare nodal involvement of renal tumors may be due to multifocal tumor, not metastasis (Int J Urol 2000;7:386, Archives 1990;114:65)
Case reports: 34 year old woman with retroperitoneal and nodal tumor (Hinyokika Kiyo 2003;49:611), kidney and nodal involvement (Chang Gung Med J 2003;26:607, Hinyokika Kiyo 2003;49:81, Int Urol Nephrol 2001;33:617)
Micro: haphazard adipose tissue and smooth muscle cells radiating from thick walled vessels; may be epithelioid or pleomorphic
Micro images: perinephric node #1; #2; kidney #1; #2; various images-kidney; HMB45+ smooth muscle cells in kidney
Positive stains: HMB45, MelanA/Mart1
Angiomyomatous hamartomas in lymph nodes
First described in 1992 (AJSP 1992;16:335)
Rare smooth muscle proliferation of inguinal lymph nodes, often of long duration
May have associated limb edema
Usually males, all ages
Benign, excision is curative
Case reports: Case of Week #118, 51 year old with 4 cm mass (Pathol Int 2000;50:655), with significant adipose tissue involvement (Gen Diagn Pathol 1997;143:247)
Gross: enlarged and matted lymph nodes replaced by firm, white tissue
Micro: extensive and multifocal nodal involvement by thick walled hilar blood vessels, often with increased fibrous tissue; nodal parenchyma has haphazard smooth muscle cells in sclerotic stroma; may also be thin or thick walled vessels, fat cells
Micro images: image #1; #2; #3; #4; CD3; CD20
Almost always represents metastatic disease
Case reports: periaortic involvement due to cardiac tumor (Pathology 2001;33:239), inguinal and iliac metastases in retroperitoneal tumor (Eur J Gynaecol Oncol 2000;21:507)
Micro: anastomosing vascular channels, cytologic atypia; may be papillary
Micro images: spinal mass-various images
Chronic myelogenous leukemia in lymph nodes
See also myeloproliferative disorders
Case reports: with tuberculous lymphadenitis (Acta Cytol 2005;49:650)
Micro: mixture of mature and immature myeloid cells
Epithelioid hemangioendothelioma in lymph nodes
Very rare
Must rule out metastastic disease
Treatment: excision; may recur, rare metastases
Case reports: tumor of inguinal node (Virchows Arch A Pathol Anat Histopathol 1986;408:435)
Micro: cords of polygonal or plump spindle cells in a myxohyaline or chondroid matrix; often central necrosis and hyalinization; tumor cells have abundant eosinophilic hyaline cytoplasm with intracytoplasmic vacuoles that may contain red blood cells, mild/moderate nuclear pleomorphism, nuclear pseudoinclusions; rare mitotic figures
Micro images: not necessarily lymph node #1; #2; skin tumor
Positive stains: factor VIII related antigen, CD31, CD33; variable cytokeratin
Negative stains: mucin
DD: metastatic carcinoma, bacillary angiomatosis
Spindle cell variant
Case reports: spindled and epithelioid tumor (AJCP 1986;85:731),
Micro: prominent spindle cell component and reduced hyaline matrix
Erdheim-Chester disease in lymph nodes
See discussion in Bone chapter
Rare non-Langerhans’ cell histiocytosis of bone, with 50% also involving hypothalamic-pituitary axis, lung, heart, retroperitoneum, skin, liver, kidneys, spleen, orbit
Nodal involvement is very rare
Case reports: 50 year old man with nodal involvement (J Clin Pathol 2004;57:1225)
Micro: large foamy histiocytes containing lipid, lymphocytic aggregates, fibrosis; rare Touton-like giant cells
Micro images: various images (C: lymph node); orbital tumor; CNS tumor is CD68+ with rare S100+ cells
Positive stains: CD68
Negative stains: CD1a, S100
Fibroblastic reticulum cell sarcoma in lymph nodes
Rare
Case reports: tumor with mixed dendritic and fibroblastic features (Mod Path 2001;14:1059)
Micro: storiform or fascicular pattern of oval / spindle cells
Micro images: soft tissue tumor-various images
Positive stains: vimentin, desmin, smooth muscle actin
Negative stains: CD21, CD23, CD35
DD: other dendritic cell sarcomas
References: AJSP 1998;22:1048
Follicular dendritic cell sarcoma in lymph nodes
Also called follicular dendritic cell tumor
Rare, first characterized in 1986 (Am J Pathol 1986;122:562)
Often presents as mass or cervical or other superficial lymph nodes of adults, but may involve other nodal or extranodal sites (intra-abdominal, oral or from soft tissue)
May be associated with inflammatory pseudotumor of liver or hyaline-vascular variant of Castleman’s disease
Recurs locally and metastasizes to liver and lung
Intraabdominal tumors are more aggressive
Immunostains are essential for diagnosis
Case reports: prior inflammatory pseudotumor-like lesion (Hum Path 2005;36:207), tumor with mixed follicular dendritic and fibroblastic features (Mod Path 2001;14:1059), nodal tumor #1 (J Pak Med Assoc 2006;56:137), #2 (Ear Nose Throat J 2004;83:848, free full text), #3 (The Internet Journal of Pathology 2004;3), Case of the Week #81, Case of the Week #1
Micro: fascicles, whorls, or slight storiform patterns; cells may appear syncytial due to interwoven cell processes; cells are oval/spindle, with pseudonuclear inclusions, oval nuclei with vesicular chromatin and small nucleoli; scattered small lymphocytes (T cells); often perivascular lymphocyte cuffing; stroma may be myxoid; occasional multinucleated giant cells, no/rare mitotic activity
Micro images: liver tumor #1; #2 with CD21 and CD35; cecal mass-various images
Cytology images: various images
Positive stains: CD21, CD35; also clusterin (Mod Path 2005;18:260, AJSP 2004;28:988), EMA; variable CD45, CD68, S100, muscle specific actin, vimentin
Negative stains: CD1a, CD45RB, keratin, vascular markers
EM: well developed, long cytoplasmic processes joined by desmosomes; no Birbeck granules
Rare as primary lymph node tumor, usually an extension of soft tissue tumor
May represent a metastasis from epithelioid hemangioma of bone (Int J Surg Pathol 2006;14:9) or pulmonary sclerosing hemangioma (Archives 2003;127:321, Ann Thorac Surg 2005;80:2351)
Case reports: 4 year old boy with inguinal node hemangioma (Archives 1989;113:804), 21 year old woman with hemangiomas of small bowel and local lymph nodes (J Clin Pathol 2000;53:552)
Micro: resembles hemangiomas at other sites; discrete mass lesion, either capillary or cavernous; may be highly cellular or epithelioid
Micro images: hemangioma in mesenteric node; metastatic pulmonary sclerosing hemangioma #1; #2 (figures 3b/3c)
unknown site - epithelioid hemangioma (various images); cavernous hemangioma #1; #2
DD: other vascular tumors, vascular transformation of sinuses (limited to sinuses), Kimura’s disease (inflammatory process with prominent vessels)
References: AJSP 1992;16:335
Histiocytic sarcoma in lymph nodes
By definition, includes only cells of macrophage lineage, not dendritic or Langerhans cells
Rare (< 0.5% of non-Hodgkin’s lymphomas); many previously described “histiocytic” tumors were actually T cell or anaplastic large cell lymphomas
Usually age 30 or less but all ages
Very aggressive; 50% die of disease
Associated with B symptoms (fever, night sweats, 10% or more weight loss), lymphadenopathy hepatosplenomegaly, peripheral blood cytopenia
Diagnosis requires histopathologic evidence of neoplasm and confirmation of cell origin by special studies
Case reports: 39 year old man with idiopathic myelofibrosis and nodal histiocytic sarcoma six months later (Archives 2004;128:1167), complicating rheumatoid arthritis (J Clin Pathol 1986;39:16), head and neck tumor with predominant spindle component (Diagn Pathol 2007;2:7)
Micro: sinus expansion or nodal effacement with sparing of follicles by large cells with variable pleomorphism, abundant eosinophilic cytoplasm, irregular nuclei and prominent nucleoli; may have tumor giant cells, erythrophagocytosis or focal spindling; also necrosis, mitotic figures and inflammatory background
Histiocytic sarcoma in lymph nodes (continued)
Micro images: sinuses distended by malignant histiocytes; cells have vacuolated cytoplasm, atypical nuclei and erythrophagocytosis; figures 3-5 (lymph node); various images (fig 2-7)
Micro images: courtesy of Drs. Charles J. Sailey, Borislav A. Alexiev and John C. Papadimitriou, Maryland (USA): CD163
Positive stains: CD68; also alpha-1-antitrypsin, CD63, CD11b, Cd11c, CD13, CD14, CD15, CD18, CD25, CD32, CD33, CD45, CD163 (Mod Path 2005;18:693), lysozyme, Mac-387; also nonspecific esterase (inhibited by fluoride), acid phosphatase (sensitive to tartrate); variable S100
Negative stains: B and T cell markers, CD1a, keratin, CD21, CD35
Molecular: no immunoglobulin or T cell receptor rearrangement
EM: abundant surface activity, microfilaments, short segments of rough endoplasmic reticulum, scattered haloed granules; no Birbeck granules
DD: metastatic carcinoma and large cell lymphoma (use immunostains to differentiate), reactive histiocytosis, storage diseases (large histiocytes with fine chromatin but minimal atypia)
Indeterminate cell tumors in lymph nodes
Very rare
Usually limited to the skin
Case results: 13 year old girl with skin lesion (Archives 2003;127:748)
Micro: identical to Langerhans cell histiocytosis but without Birbeck’s granules
Micro images: skin lesion
Positive stains: CD1a, S100
Negative stains: CD21, CD35
Interdigitating dendritic cell / reticulum cell sarcoma in lymph nodes
Also called interdigitating dendritic cell tumor
Very rare
Usually arises in lymph nodes with widespread lymphadenopathy, but also in bladder, bowel, intestine, nasopharynx, salivary glands, skin, spleen, testis and tonsils
Aggressive behavior, with half dying of disease after an average of 7 months
Have same morphologic and immunohistochemical features as nonneoplastic interdigitating dendritic cells
Presence of another hematologic neoplasm is common
Case reports: with coexisting SLL in axillary node (Archives 2006;130:544), 20 year old woman with multifocal lymphadenopathy (Archives 1994;118:183), cervical lymph node involvement #1 (Zhonghua Xue Ye Xue Za Zhi 2005;26:232), #2 (Saudi Med J 2002;23:1281), 38 year old woman with cervical lymph node and breast involvement (Virchows Arch 2005;446:546)
Treatment: chemotherapy (Leuk Lymphoma 2002;43:817)
Micro: fascicles or whorls of paracortical tumor cells that spare the follicles and sinuses; tumor cells are large and pleomorphic with abundant pale, eosinophilic cytoplasm and bizarre, grooved nuclei; may have tumor giant cells, mitotic activity, inflammatory infiltrate
Micro images: above case report with SLL; duodenal tumor with nodal metastases
Positive stains: S100, CD68 (variable); also CD45RB, HLA-DR, EMA (Archives 1987;111:337), CD11a, CD18, vimentin
Negative stains: CD1a, CD21, CD35, B cell antigens
EM: interdigitating cytoplasmic processes but no desmosomes or other junctional complexes, no Birbeck granules
DD: Langerhans cell histiocytosis, follicular dendritic cell sarcoma
References: Histopathology 2004;44:283
Kaposi’s sarcoma in lymph nodes
Difficult to detect early involvement; often best diagnosis is “atypical vascular proliferation suggestive of early Kaposi’s sarcoma”
May coexist with leukemia, lymphoma, Castleman’s disease or mycobacterial spindle cell tumor (AJSP 1999;23:656)
Classic form: elderly men of Jewish or Mediterranean descent; skin lesions of lower extremities with only rare nodal involvement; indolent for 10-15 years, then systemic lesions or lymphoreticular malignancies
African (endemic) form: young adults, usually men, with indolent skin involvement, progressive large exophytic or deeply invasive tumors or occasional regional nodal involvement
Childhood form: children 2-13 years, usually boys, HIV negative with lymphadenopathy but usually no skin lesions; death within 1-3 years
HIV associated: usually homosexual men, often disseminated involving mucocutaneous sites, lymph nodes, GI tract and lungs
Transplant associated: local or systemic (Transplant Proc 2004;36:2145, Transplant Proc 2005;37:967)
Case reports: intraparotid lymph node (Laryngoscope 2005;115:861)
Gross: often multifocal
Micro: resembles skin tumors; curved fascicles of spindle cells separated by slitlike vascular spaces with extravasated red blood cells and frequent mitotic figures; spindle cells have pale cytoplasm, elongated nuclei, indistinct nucleoli; often individual cell necrosis; initially subcapsular but extends throughout node and into perinodal tissue; almost always has PAS+ diastase resistant, PTAH+ hyaline globules; may have accompanying lymphocytes, plasma cells, histiocytes and immunoblasts, hemosiderin deposits; may resemble Castleman’s disease
Micro images: peripheral tumor deposits; well circumscribed tumor nodule; well circumscribed tumor and adjacent follicular hyperplasia; well circumscribed tumor with adjacent sinus histiocytosis; interlacing bundles of spindle cells separated by vascular slits containing extravasated red blood cells; extreme vascularity with dilated and blood filled channels; predominantly sinusoidal spread of tumor surrounding follicles with hyperplastic germinal centers; tumor (arrow) extends along sinusoids towards reactive follicles; Kaposi’s sarcoma (upper right), lymphoma (lower left) and plasma cells (arrow)
other sites - PAS+ hyaline globules; CD34 highlights vessels; skin #1; #2
Positive stains: CD31, CD34
Negative stains: muscle specific actin
Molecular: HHV8+ (strong, diffuse, nuclear staining in >10% of tumor cells, Mod Path 2004;17:456)
DD: vascular transformation of sinuses, hemorrhagic spindle cell tumor with amianthoid fibers, vascular tumors, bacillary angiomatosis, inflammatory pseudotumor
References: J Clin Pathol 1977;30:696
Langerhans cell histiocytosis in lymph nodes
Also called eosinophilic granuloma, histiocytosis X, Langerhans cell granulomatosis
Rare disorder of Langerhans cells
See also discussion in bone and lung tumor chapters
Variable clinical picture with single or multiple lesions or disseminated disease
Nodal involvement may be sole manifestation of disease or associated with systemic disease
May also have nodal involvement by lymphoma
Rarely have frankly malignant cells (Langerhans cell sarcoma) associated with more aggressive clinical behavior
Hand-Schuller-Christian’s disease: term used previously for more indolent disease of children and young adults
Hashitmoto-Pritzker’s disease: congenital, self limited form
Letterer-Siwe’s disease: systemic disease in infants
Langerhans cells capture antigens and present them to lymphocytes; are considered an immune system “accessory” cell
Langerhans cells are normally present as a few cells in thymus, lymph nodes and skin
Micro: partial effacement of lymph node with preservation of follicular centers but distension of nodal sinuses by Langerhans cells, which are 12-15 microns in diameter with abundant, pale eosinophilic cytoplasm, irregular and elongated nuclei with prominent nuclear grooves and folds, fine chromatin and indistinct nucleoli; occasionally multinucleated; sinuses commonly have foci of necrosis, often surrounded by rim of eosinophils; rarely eosinophilic abscess incite a granulomatous response (J Clin Pathol 2006;59:548); variable mitotic activity
Cytology: high cellularlity, Langerhans cells with nuclear grooves and intranuclear inclusions, numerous eosinophils, lymphocytes, macrophages, neutrophils and giant cells (Acta Cytol 2002;46:753, Chang Gung Med J 2005;28:735)
Micro images: lymph node #1; #2; #3; site unknown; various images; soft tissue mass-cytology
Virtual slides: Langerhans cell histiocytosis
Positive stains: CD1a, S100; also vimentin, langerin, fascin (AJCP 2002;118:335), CD68, CD74, HLA-DR, CD45 (at frozen section); variable CD2 and CD3
Negative stains: CD15, CD45RA, CD45RB, EMA, CD21, CD35
EM: irregular cell membrane and nucleus, Birbeck granules (elongated, zipperlike cytoplasmic structure, 200-400 x 33 nm with double outer sheath), variable lysosomes, no cell junctions
EM images: Birbeck granule
Molecular: variable clonality
DD: sinus histiocytosis with massive lymphadenopathy, Kimura’s disease, cat-scratch disease, hypersensitivity reaction, Erdheim-Chester disease (CD1a negative, focal S100+, no Birbeck granules), lymphoma
References: Pediatr Pathol Lab Med 1997;17:769
Benign
Leiomyomatosis in abdominal nodes is associated with uterine leiomyomas or disseminated peritoneal leiomyomatosis
Intranodal leiomyomas may be associated with HIV
Case reports: leiomyomatosis (Rinsho Byori 1996;44:595)
Micro: partial or complete replacement of node by interlacing fascicles of bland spindle cells with blunt ended nuclei; no nuclear palisading, no amianthoid fibers, no mitotic figures
Positive stains: muscle specific actin
DD: lymphangiomyomatosis, metastatic well differentiated leiomyosarcoma (usually large uterine mass)
References: AJCP 1991;95:858
Usually an extension of soft tissue tumor; rare as primary of lymph node
Micro: noncircumscribed, composed of variable sized endothelial lined lymphatic spaces with proteinaceous fluid; lymphocytes are present in fibrous septa
Cytology: uniform population of small and round lymphocytes with occasional histiocytes, centrocytes, centroblasts and plasma cells; no mitotic figures, no atypia (Acta Cytol 1999;43:442)
Micro images (not lymph node): Factor VIII+ endothelial cells
Lymphangiomyomatosis in lymph nodes
Also called lymphangioleiomyomatosis
Affects women during reproductive years
Associated with pulmonary involvement, angiomyolipoma, tuberous sclerosis
Lung involvement often causes death from pulmonary insufficiency
Rarely is an isolated finding in intra-abdominal lymph nodes
Case reports: 51 year old woman with HMB45 negative retroperitoneal nodal mass (Archives 2003;127:879)
Micro: proliferation of lymphatic channels and smooth muscle cells with clear to eosinophilic cytoplasm
Cytology: relatively large monomorphic spindle cells (Acta Cytol 1997;41:877)
Micro images: HMB45 negative case; various images from lung
Positive stains: HMB45; also muscle specific actin and desmin
DD: metastatic well differentiated leiomyosarcoma (no prominent vascular channels, more atypia and mitotic figures, HMB45 negative)
References: eMedicine
See Lymphomas: B cell and plasma cell neoplasms and Lymphomas: non B cell
Malignant histiocytosis in lymph nodes
A systemic, invasive proliferation of malignant histiocyte-like cells
Traditionally included cases with hemophagocytosis, which is associated with diffuse large B cell lymphoma and T cell lymphomas
Actually represents various conditions, including anaplastic large cell lymphoma and enteropathy associated T cell lymphoma of small bowel
Systemic disease that often involves lymph nodes, but only rarely presents with lymphadenopathy (Cesk Patol 2006;42:34)
See chapters on bone and spleen for more extensive discussion
Micro: variable effacement of nodal architecture by monotonous round/polygonal cells with distinct cell membranes, clear/granular cytoplasm, round/oval nuclei, eosinophils; associated with sclerosis; cells often have perifollicular, perivascular or interfollicular distribution; may have prominent vascular proliferation
Micro images: figure 1: bone marrow, 2: spleen, 3: lymph node (sinusoidal involvement)
Positive stains: highlighting mast cell granules - Giemsa, toluidine blue, polychrome methylene blue, chloroacetate esterase (Leder); cells are immunoreactive for CD68, tryptase, CD117, CD44
DD: normal presence of occasional mast cells, parasitic reaction, Waldenstrom macroglobulinemia, lymphadenitis
Lymph nodes are common site of metastatic disease
Presence of metastases is important for TNM staging
Must determine when examining lymph nodes: tumor present or not; tumor primary or metastatic; possible sites of primary; number of metastatic nodes; size of largest metastatic deposit often helpful; presence of extranodal or vascular involvement
Nodal metastases are common with carcinoma, melanoma or germ cell tumors; rare with CNS tumors and sarcoma (except for angiosarcoma, clear cell sarcoma, epithelioid sarcoma, MFH, rhabdomyosarcoma or synovial sarcoma)
Must also rule out lymphoma; compared to metastatic disease, lymphomas are more likely multifocal with diffuse penetration of vessel wall, minimal necrosis, no nesting, not limited to sinuses, not limited to intravascular invasion; differentiate based on special stains / immunostains (see below), touch preparations (clumping favors carcinoma), EM for epithelial features
Rarely, there is passive transport of benign neoplastic cells to lymph nodes (Archives 2005;129:1317)
Carcinomas usually have cohesive tumor cells, sinus involvement, clearly defined margins with lymphoid tissue; may resemble Hodgkin’s lymphoma due to prominent nucleoli and mixed inflammatory infiltrate
Tumors misinterpreted as lymphoma: nasopharyngeal carcinoma-undifferentiated (tumor cells mix with lymphocytes and tumor does not appear cohesive), melanoma (tumor cells separate from each other within clusters), breast lobular carcinoma (may appear noncohesive), seminoma (inguinal and abdominal nodes)
Recommended stains (by Rosai): first round - CD45/LCA, pan-keratin, S100; second round (as necessary) - CD3 (T cells), CD20 (B cell), EMA, CEA, vimentin, possibly GCDFP15 or lactalbumin (for breast), chromogranin (for neuroendocrine), PSA/PAP (for prostate)
Note: TdT+ lymphoid precursors are present in benign pediatric lymph nodes (AJCP 2002;118:248) and tonsils (AJCP 2001;116:12), causing possible confusion in ALL patients
Site of metastases: upper cervical nodes - associated with upper aerodigestive tract; midcervical nodes - thyroid carcinoma, salivary gland, upper aerodigestive tract; also thymus or ovary; supraclavicular nodes - breast or lung, also stomach, pancreas, prostate, testis; axillary nodes - breast (women), melanoma, lung; inguinal nodes - external genitalia, melanoma
Undetectable primaries with nodal metastases: nasopharynx, retrotonsillar pillars
Post treatment changes: foamy histiocytes, fibrosis, mucin, atypical residual tumor cells
Micro images: passive seeding by metanephric adenoma
Adenocarcinoma - nodal metastases
May represent metastatic ovarian borderline tumor (AJSP 2006;30:739)
Signet ring cells may actual be muciphages (AJSP 1998;22:545)
Breast adenocarcinoma - nodal metastases
Lobular carcinoma may resemble lymphoma, particularly if signet ring cells are present
Micro: ductal - large apocrine-like pleomorphic cells with pink, granular cytoplasm, large nuclei and prominent nucleoli; often cytoplasmic mucin; also comedo, trabecular and papillary patterns
Micro images: micropapillary carcinoma #1; #2; ductal carcinoma
Virtual slides: metastatic breast carcinoma
Hepatocellular carcinoma - nodal metastases
Micro: may produce bile
Melanoma - nodal metastases
Gross images: black staining tissue #1; #2
Micro: often melanin pigment in some tumor cells; balloon cell variant resembles histiocytes, although nuclei are atypical
Mesothelioma - nodal metastases
Nodal involvement may be initial presentation (AJSP 1990;14:872)
Micro: may expand sinuses; cuboidal cells with eosinophilic cytoplasm and central nucleus
Cytology: large dyscohesive cells with abundant pale cytoplasm, ruffled cytoplasmic borders, prominent central nucleoli (AJCP 1992;97:493)
Nasopharyngeal carcinoma, undifferentiated
Also called lymphoepithelial carcinoma
Micro: syncytium of cells with ill defined cytoplasm, vesicular nuclei and prominent nucleoli
Ovarian serous carcinoma - nodal metastases
Micro images: axillary nodal metastasis
Pancreatic adenocarcinoma - nodal metastases
Micro images: usual type, ductal adenocarcinoma
Papillary thyroid carcinoma - nodal metastases
Micro: may appear as unilocular or multilocular cyst with attenuated lining cells and lack of distinct nuclear features of papillary carcinoma
Positive stains: thyroglobulin
Paraganglia - nodal metastases
Micro images: subcapsular invasion with pleomorphic cells with abundant granular eosinophilic cytoplasm
Plexiform fibrohistiocytic tumor - nodal metastases
Uncommonly metastasizes to lymph nodes (AJSP 1999;23:662)
Micro: multiple plexiform nodules within and external to node; nodules composed of plump fibrohistiocytic cells with multinucleated giant cells
Rhabdomyosarcoma - nodal metastases
Alveolar subtype may first present with nodal involvement
Micro: alveolar subtype - large packets of cells with central dehiscence, cells have moderate eosinophilic cytoplasm, with some rhabdomyoblasts present
Serous borderline tumor - nodal metastases
Case report: 58 year old woman with high grade urothelial carcinoma of bladder and unknown ovary tumor 33 years prior (Archives 2005;129:537)
Micro images: H&E, CK7+
Small cell neuroendocrine carcinoma - nodal metastases
May resemble lymphoma
Micro: minimal cytoplasm, dense chromatin with nuclear molding; often focal necrosis and crush artifact; also Azzopardi phenomena (dense hematoxylin staining of vessel walls)
Squamous cell carcinoma - nodal metastases
Squamous cyst within cervical lymph node should be considered metastatic carcinoma until proven otherwise
Micro: cystic change is common, particularly from head and neck region; often bland-looking squamous cells with only focal atypia
Myofibroblastoma in lymph nodes
Also called palisaded myofibroblastoma, intranodal hemorrhagic spindle cell tumor with amianthoid fibers
Initially described in 1989 (AJSP 1989;13:347, AJSP 1989;13:341)
Amianthoid: having a crystalline appearance like asbestos
Rare; may derive from myofibroblasts (Pathol Int 1998;48:307)
Often solitary, painless inguinal lymph node in adult; also neck and mediastinum
Benign behavior with only rare recurrence; does not metastasize
Treatment: excision
Case reports: 71 year old man with inguinal mass (Archives 2003;127:1040), 48 year old woman with inguinal mass (Chinese Medical Journal 2005;118:1758), 62 year old man with supraclavicular mass, arising in submandibular lymph node (AJCP 1992;97:69), recurrent tumor with metaplastic bone formation in renal transplant patient (Archives 1999;123:433), 45 year old woman (Archives 1989;113:547)
Gross: well circumscribed, up to 5 cm; gray-white-tan with hemorrhage
Micro: may have rim of compressed normal tissue; intersecting bundles of uniform bland spindle cells with myofibroblastic or smooth muscle differentiation, including scant eosinophilic cytoplasm with perinuclear vacuoles and bland fusiform nuclei; focal nuclear palisading may occur; prominent interstitial hemorrhage and hemosiderin; amianthoid fibers (strongly eosinophilic, stellate, extracellular matrix deposits composed of crystalline fibers) may be present with variable calcification and surrounded by mast cells; no/rare mitotic figures, no atypia, no slit-like vascular spaces, no extravasated red blood cells
Micro images: palisaded tumor with amianthoid fibers; various images #1; #2; fascicles of elongated cells with pale cytoplasm and tapered nuclei; early amianthoid fiber formation, in which a vessel is beginning to be surrounded by collagen; overlaying it is an almost fully formed amianthoid structure; both are surrounded by proliferating myofibroblasts; amianthoid fibers composed of a central vessel surrounded by a core of collagen with peripheral spokes, strongly stained by Van Gieson; mast cells surrounding amianthoid fibers are methylene blue+; interstitial cells are smooth muscle actin+; actin stains smooth muscle cells and spokes of amianthoid fibers (arrows)
Cytology: moderately cellular with benign appearing, dissociated, single spindle cell with elongated nuclei, pointed ends and occasional twisted forms; in pale fibrillary matrix with hemosiderin granules, no atypia (Acta Cytol 2002;46:1143)
Positive stains: spindle cells - smooth muscle actin, vimentin, variable factor XIIIa; amianthoid fibers - elastic stains, trichrome, collagen type I/III, smooth muscle actin
Negative stains: S100, synaptophysin, GFAP, Ki-67 (<5%), desmin, EMA, keratin
EM: pinocytotic vesicles, microfilament aggregates, well-developed rough endoplasmic reticulum with dilated cisternae; amianthoid fibers contain collagen fibrils arranged in orderly parallel fashion, long, frequently indented nuclei (Ultrastruct Pathol 1996;20:79)
EM images: spindle cell with indented nuclei and parallel collagen fibrils
DD: (1) Kaposi’s sarcoma (curved fascicles of spindle cells with atypia and PAS+ hyaline globules, brisk mitotic activity, slit-like vessels with extravasated red blood cells), (2) intranodal schwannoma (distinct biphasic pattern, S100+), (3) dendritic cell sarcoma (nests or whorls of plump cells with scattered inflammatory cells, no prominent hemorrhage, no amianthoid fibers, CD21+, CD35+), (4) benign metastasizing leiomyoma (smooth muscle cells are more ovoid with more prominent eosinophilic cytoplasm, no hemorrhage, no amianthoid fibers), (5) spindle cell carcinoma, melanoma or sarcoma (atypia and mitotic figures)
References: J Clin Pathol 1991;44:761
Very rare (<50 reported cases)
Diagnosis of primary plasmacytoma of lymph node requires exclusion of extramedullary plasmacytoma (15% of upper respiratory tract plasmacytomas metastasize to cervical nodes) and myeloma (40% of high stage myelomas metastasize to nodes)
2/3 male; median age 59 years (range 39-76 years)
Often involves cervical nodes
Similar survival to other extramedullary plasmacytomas, although does not progress to myeloma (AJCP 2001;115:119, Hum Path 1997;28:1083)
Treatment: surgery and radiotherapy
Case reports: associated with Castleman’s disease #1 (Archives 1986;110:157), #2 (AJCP 1982;78:541); associated with Sjogren’s syndrome (Pathol Int 1999;49:577), 65 year old man with cervical and submandibular node involvement (Korean J Intern Med 2005;20:183)
Micro: similar to plasmacytomas outside lymph node; dense, monotonous infiltrate of plasma cells that effaces nodal architecture; cells vary from mature to binucleated to anaplastic; plasmablastic if amphophilic to basophilic cytoplasm with small Golgi zone and large vesicular nuclei with prominent central nucleoli; anaplastic if marked pleomorphism and irregular foldings in nuclear membranes; may have amyloid deposits
Micro images: skin - figure 1: atypical plasma cells, 2: plasmablastic, 3: plasmablastic kappa staining, 4: plasmablastic with some kappa staining; figure 1: plasmablastic, 2: CD117+
Positive stains: immunoglobulin light chain restriction; usually positive for CD79a, EMA; variable CD43 and CD45RO
Negative stains: CD45, CD19, CD20, p53, bcl2, EBV
Molecular: negative for KSHV/HHV8
DD: reactive plasmacytosis (often follicular hyperplasia, no light chain restriction), lymphoplasmacytic lymphoma (also has neoplastic small lymphocytes), other low grade lymphomas with plasmacytic differentiation, Castleman’s disease (plasma cell variant)
Miscellaneous
Biopsy the largest and most abnormal regional node
Axillary or cervical nodes are preferred; not inguinal nodes due to frequent inflammatory and fibrotic changes
Frozen sections may confirm involvement of node by a disease process - don’t use to obtain a specific diagnosis because freezing artifacts may hinder diagnosis
Fine needle aspiration may confirm metastatic carcinoma or be used to diagnose lymphoma
Nodes should be received fresh, NOT in formalin or other fixative
Procedure:
- bisect lymph node perpendicular to long axis
- obtain portion for culture if needed from end of node (under sterile conditions)
- obtain touch imprints, fix in ethanol, stain with H&E and Wright’s stain
- sections for formalin or B5 fixation should be 3-4 mm thick to allow for proper fixation
- submit portion for flow cytometry from end of node
- submit portion for cytogenetics, if needed
- avoid squeezing nodes, which may cause changes in histology
- Note: H&E sections are the most important - more important than immunostains!
- EM is helpful only rarely, to diagnose Langerhans histiocytosis or occasionally metastatic tumors
References: AJSP 2001;25:961 (nodes examined for metastatic disease)
See also breast-axillary nodes, breast-sentinel nodes, staging for various malignancies
Most lymph nodes are near the wall of the organ
Be aware of minimal number of nodes required for staging some carcinomas
Either (a) search the fat for nodes while fresh using scissors and forceps and avoid crushing the nodes, or
(b) fix overnight, then search for nodes by shredding the tissue; lymph nodes stand out as white nodules; Carnoy’s solution helps clear the fat
Clearing solutions (such as ethanol, diethyl ether, glacial acetic acid and formalin) may help identify additional lymph nodes (AJSP 1997;21:1387, Archives 2003;127:1552, Archives 2001;125:642)
For each anatomic group, describe the number of nodes, the size of the largest node, and any gross features
Submit all lymph nodes for histology; section node if 5 mm or greater in diameter
For large nodes grossly involved by tumor, only one section needs to be submitted to demonstrate tumor and possible extranodal extension, but save remainder for resampling if necessary
For other large nodes, submission of entire node detects additional metastases in some cases (AJCP 1998;109:571)
Describe number of nodes in each cassette and whether whole or sectioned
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