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Stains Chapter
Reviewer: Nat Pernick, M.D. (see Reviewers page)
Revised: 4 May 2013
Copyright: (c) 2002-2012, PathologyOutlines.com, Inc.
See also CD Markers chapter
Table of Contents - Stains
General: IHC basics IHC procedure common panels enzyme cytochemistry
3 beta 7 AAD 11A1 14-3-3sigma 15-PGDH 45M1
A: A beta 42 abl acid fast acid phosphatase ACSM1 acridine orange actin-general actin-alpha cardiac actin-alpha smooth muscle, actin-muscle specific AE1-AE3 (cytokeratin) AF-4 albumin alcian blue ALK alkaline phosphatase ALL1 alpha-1-antichymotrypsin alpha-1-antitrypsin alpha-fetoprotein alpha-lactalbumin AMACR AML1 androgen receptor APC API2-MALT1 Apolipoprotein D argentaffin argyrophilic asbestos ATM auramine-rhodamine
B: B72.3 bcl1 bcl2 bcl6 bclXl bcr-abl Beclin1 BerEP4 beta-2-microglobulin beta-catenin BG7 BG8 Bielschovsky biotin blood group antigens BMP BOB.1 brachyury BRAF BRCA1 BRCA2
C:
c-kit c-MET c-myc CA125 cadherins calcium caldesmon calponin calretinin CAM5.2 carbonic anhydrase IX caspases cathepsin B CCR1 CCR2 CCR3 CCR4 CCR5 CCR6 CCR7 CCR8 CDC2 CDX2 CEA ceramide chaperones chloroacetate esterase chromaffin chromogranin claudins claudin1 claudin6 claudin7 claudin18 clusterin CMV collagen collagen II collagen XVII Congo Red CXCR2 CXCR3 CXCR5 cyclins Cyclin D1 cyclooxygenase 2
Cytokeratins: general CK1 CK2 CK3 CK4 CK5 CK6 CK7 CK8 CK9 CK10 CK11 CK12 CK13 CK14 CK15 CK16 CK17 CK18 CK19 CK20 CK21 CK22 CK23 CK24 34betaE12 35betaH11 AE1, AE3 AE1-AE3 CAM5.2 KL-1 MNF116 OSCAR
D: D2-40 DBA-44 DCC deltaNp63 desmogleins desmin DOG1 DOPA reaction DPC4 dynactin 1
E: E1AF E2A E-cadherin EBER1 EGFR eIF-4F elastic fibers elongin EMA endothelin-1 EpCAM Epstein Barr virus (EBV) erbB2 ERCC1 ERG estrogen receptor ets1 ETV1 ETV6-NTRK3 EWS
F: Factor VIII Factor XIIIa Fas/CD95 Fas ligand/CD178 fascin ferritin FGFR3 FLI-1 FLT3 FMC7 Fontana-Masson FOXA1
G: galectin3 GATA3 GCDFP-15 GFAP Giemsa GLUT1 GLUT4 glycophorin A glycosoaminoglycans glypican 3 granzyme B GMS gram stain Grimelius
H: Hales colloidal iron HAM56 hamartin Hansel HBME hCG HE4 Helicobacter pylori HepPar1 HER2 HGAL HHF35 HHV8 HIV p24 HLA-DR HLA-G HMB45 HPC2 HPL HPV hSNF5
I : ICAM-1 ICE IgG4 IgH Inhibin A Inhibin B INI1 integrins interleukins IRF4 iron
L : lambda laminin LANA lecithin lectins Leder Leu7 LIN28 lipid lipochrome LMO2 LMP Luxol fast blue lysozyme
M: MAC387 MALT1 MART1 Martius maspin May-Grunwald-Giemsa MDM2 mdr MelanA melanin menin mesothelin metalloproteinases (MMP) MIB1 mic2 microphthalmia transcription factor microsatellite instability MLH1 MOC31 MRP MSA MSH 1&2 mTOR mucins MUC1 MUC2 MUC3 MUC4 MUC5AC MUC6 MUM1 myeloperoxiase MyoD1 myogenin myoglobin myosin
N: N-CAM n-myc NapsinA neu neurofilament neurofibromin neuron specific enolase NF2 NF-KB nonspecific esterase NPM-ALK nucleophosmin
P: P glycoprotein p16 p21 p27 p40 p53 p57 p63 P504S PAP PARP PAS PAX5 PAX7 PAX8 PCA3 PCNA PD-1 PDGF PECAM1 Pentachrome phosphohistone H3 podoplanin PKD1 PKD2 PKD3 PLAG1 PLAP PLEKHA7 PML-RARα PPARγ progesterone receptor PSA PSAP PTAH PTEN PU.1
R: Rb RCC Reg IV RET reticulin retinoic acid RUNX1
S: S100 S100P SALL4 selectin E selectin L selectin P SHP-1 Sialyl-Tn silica Sirius red SIRT1 smoothelin SOX2 Sudan Black B survivin synaptophysin
T : tattoo tau T-bet TdT telomerase tenascin thrombomodulin thyroglobulin TIA1 TOP2A TRAP trichrome tryptase TTF1 tuberin tubulin tumor necrosis factor tyrosinase
U : ubiquitin unknown primary uric acid uroplakin III
V : VCAM-1 VEGF VEGFR3 VHL villin vimentin vitronectin vWF
W : Warthin-Starry wnt Wright-Giemsa WT1
Y :
Z : Ziehl-Neelsen Cell cycle In-situ hybridization may be specific for
hepatocellular carcinoma or hepatoid areas of combined
hepatocellular-cholangiocarcinoma (AJSP
2002;26:989) Anaplastic lymphoma kinase gene at 2p23; Also called
CD246 Membrane spanning tyrosine kinase receptor, member of
insulin receptor family Ligand is growth factor pleiotrophin 3' end contains catalytic domain of tyrosine kinase t(2;5) associated with T cell anaplastic lymphoma via
fusion of ALK and nucleophosmin protein Has important role in brain development ALK+ primary anaplastic large cell lymphomas have
favorable prognostic significance ALK- cases of primary anaplastic large cell lymphoma
are associated with trisomy 2 (Mod
Path 2005;18:235) Positive staining (normal): normal small intestine, T cells; weakly positive in
brain, colon, prostate Positive staining (disease): T or null cell anaplastic lymphomas (some),
inflammatory myofibroblastic tumor (AJSP
2001;25:1364, AJSP
2001;25:761) Negative staining: fibromatosis, GIST, nodular fasciitis, normal lymphoid tissue Alkaline phosphatase Membrane bound glycoproteins, with hepatic, osseous,
renal and placental isoenzymes See PLAP Positive staining (normal): osteoblasts Positive staining (disease): mononuclear stromal cells from giant cell tumor of
bone and soft tissue (Hum
Path 2005;36:945) ALL1 Gene at 11q23 also called MLL (mixed lineage leukemia),
HRX, Htrx (from Drosophila trithorax protein) Affected by self-fusion translocation of
t(11;11)(q23;q23) Self fusion causes the gene to be dominant negative
by fusing with other genes Trisomy causes loss of function of the gene, leading
to B cells with both lymphoid and myeloid phenotypes Self fusion involves “Alu” sequences, which are
conserved elements of repetitive DNA in non-protein coding region There are 1 million copies of Alu sequences in human
genome, each about 300 base pairs in length Alu mediated recombination causes partial duplication
of the ALL1 gene ALL1 tumors:
usually CD10 negative, CD19+, with lymphoid and myeloid markers Bone marrow transplantation recommended in childhood
ALL with t(4;11)(q23;q23) due to otherwise poor prognosis 90% of all cases with ALL abnormalities are t(4;11),
t(9;11), t(11;19) Accounts for 5-10% of acute leukemias, usually M4 or
M5 Present in 60% of infants < 1 year with ALL Abnormal expression in 10% of ALL, 6% of AML, 80% of
secondary leukemia after topoisomerase II inhibitor treatment Acute phase plasma protease inhibitor, mainly
produced by liver Homologous to alpha-1-antitrypsin Positive staining: histiocytes, reticulum cells Micro images: pancreatoblastoma:
C - positive staining last updated October 2008 Enzyme
that inhibits proteases, particularly elastase (which digests lung tissue),
which is secreted by neutrophils during inflammation Genetic deficiency (due to
folding errors, IUBMB Life
2008 Sep 10 [Epub ahead of print]),
causes emphysema (Orphanet
J Rare Dis 2008; 3:16), cirrhosis
(Am J Gastroenterol
2008;103:2136), panniculitis (Dermatol Clin 2008;26:447) Homologous to alpha-1-antichymotrypsin Positive staining (normal): histiocytes, reticulum cells, gallbladder,
hepatocytes, small intestinal enterocytes (J
Clin Invest 1993;92:2022) Positive staining (disease): various sites-angiosarcoma (hyaline globules), granular cell tumor
(J Oral Pathol Med
2000;29:284, Mod Path 1996;9:888), histiocytic lymphoma, MFH, pleomorphic adenoma (epithelium), Rosai-Dorfman
disease (focal); bile duct-adenoma-(cytoplasmic inclusions, Int J Surg Pathol
2008;16:218),
bladder-yolk sac
tumor of urachus; bone-giant cell tumor, cervix-decidual
reaction; eye-oncocytoma of conjunctiiva; kidney-renal
cell carcinoma-clear cell type; liver- alpha-1-antitrypsin
deficiency (cytoplasmic inclusions), focal nodular hyperplasia, hepatoblastoma
(40%, Appl Immunohistochem Mol
Morphol 2008;16:140), hepatocellular adenoma
(cytoplasmic globules), hepatocellular carcinoma, undifferentiated embryonal
sarcoma; lung-bronchioloalveolar carcinoma (Clara cells in non-mucinous types); ovary-endodermal
teratoma, MMMT and yolk sac tumor (hyaline droplets, Hum Path 1982;13:930); pancreas-cystic fibrosis (mucous
globules), neuroendocrine tumor and solid pseudopapillary tumor (AJSP 2000;24:1361); skin-atypical fibroxanthoma; testis-papillary cystadenoma, Sertoli cell tumor and yolk
sac tumor (hyaline globules); thyroid-papillary thyroid carcinoma (AJSP 1996;20:956) Micro images: liver-alpha-1-antitrypsin
deficiency; liver-undifferentiated
embryonal sarcoma; lymph
node-Kikuchi’s lymphadenitis; pancreas-solid
pseudopapillary tumor #1; #2;
#3; pancreatoblastoma:
fig B; peripheral
giant cell granuloma References: Wikipedia Alpha-lactalbumin Major protein of human milk Specific to breast tissue (normal, malignant,
fibrocystic) and hydradenoma papilliferum of vulva Alpha MethylAcyl
Coenzyme A Racemase; also called P504S Identified from prostate adenocarcinoma by cDNA
library subtraction coupled with high throughput microarray screening of human
prostatic tissue Also expressed in colorectal adenocarcinoma and other
malignancies, but not in normal appearing small and large intestinal mucosa A mitochondrial and peroxisomal enzyme involved in
beta-oxidation of dietary branched-chain fatty acids and fatty acid derivatives
(including bile acid intermediates) Sensitive (82-95%) and relatively specific for
prostate carcinoma vs. benign prostate (AJSP
2001;25:1397, AJSP
2002;26:1588) In prostate carcinoma, is strongly positive, usually
diffuse, regardless of Gleason grade Relatively specific - benign prostate is usually
negative or only focal/weakly positive; however partial atrophy and crowded
benign glands may be positive (AJSP
2005;29:874) Most specific if circumferential luminal to
subluminal and diffuse cytoplasmic staining Uses:
identify small foci of prostatic adenocarcinoma, in conjunction with 34 beta
E12 or p63 (AJSP
2002;26:1169), may identify a subset of AAH with a premalignant
potential (AJSP
2002;26:921) Positive staining (disease): prostatic adenocarcinoma and high grade PIN; partial
prostatic atrophy and crowded benign prostatic glands may be positive (AJSP
2005;29:874); also overexpressed
in lymphomas and cervical, colorectal adenocarcinoma (69-83%, AJSP
2005;29:890), breast, gastric,
liver, ovarian, renal cell carcinomas (AJSP
2002;26:926), urothelial carcinoma (30%), primary (65%) and
secondary (from colorectum) bladder adenocarcinomas (Mod
Path 2005;18:1217) Negative staining: benign prostate (usually, see exceptions under positive staining),
atypical adenomatous hyperplasia (usually, 10% are positive, AJSP
2002;26:921); small intestinal
adenocarcinoma (usually, only 4-6% are positive, AJSP
2005;29:890) Micro images: fig
3a: primary bladder adenocarcinoma (diffusely+) vs. 3b: secondary from
colorectum (focal+) AML1 Gene at 21q22 is DNA binding component of AML1/CBF
beta transcription factor complex, most frequent target of translocations in
AML via t(8;21) [AML1-ETO]; t(12;21); t(3;21) [AML1-EVI1] Fusion products (below) suppress normal AML1 mediated
transactivating activity Normal AML1 required to establish fetal liver-derived
definitive hematopoiesis (stem cells to definitive hematopoietic elements) APC Adenomatous polyposis coli gene on 5q21, tumor
suppressor gene, autosomal dominant Important for familial adenomatous polyposis and
Gardner syndromes Binds to (a) microtubule bundles and promotes cell
migration and adhesion, (b) beta-catenin (cytoskeletal protein) in a cellular
adhesion complex including E-cadherin, part of Wnt signaling pathway Beta-catenin is also bound to a T cell
factor-lymphoid enhancer factor (Tcf-Lef), which activates other genes,
stimulates cell proliferation and inhibits apoptosis APC accelerates the proteasome-mediated degradation
of beta-catenin, which reduces its role as a transactivating factor for the
Tcf-Lef pathway Mutations in APC produce elevated levels of
Tcf4-beta-catenin, which stimulates a transcriptional response that initiates
polyp formation and eventually malignant growth APC is considered a gatekeeper gene since it directs
activity downstream of different pathways Colon:
mutations play critical role in tumorigenesis (mutations in APC or beta-catenin
present in 90% of colon cancers) API2-MALT1 Fusion protein associated with MALT lymphoma (50%);
rarely with diffuse large B cell lymphoma Due to t(11;18)(q21;q21) - API2 and MALT1 May lead to increased inhibition of
apoptosis, helping MALT lymphoma cells to survive References:
Mod
Path 2003;16:1232 (colorectal lymphoma), Hum
Path 2003;34:1212 (diffuse large B cell lymphoma) Apolipoprotein D (apoD) Member of lipocalin superfamily of proteins involved
in transport of cholesterol, steroid hormones and other small hydrophobic
molecules Correlates with cell cycle inhibition in various
situations including cellular senescence High levels in fibrocystic breast disease and HDL,
but produced by almost all tissues in body Expression upregulated in nonneoplastic regenerating
peripheral nerve compared to normal, then downregulated during transformation
to MPNST (Hum
Path 2005;36:987) Argentaffin cells/tissues contains a substance (such
as catecholamines, indolamines) that reduces silver and other metallic salts to metallic silver, staining brown or
black Argentaffin stains are: Fontana-Masson, Schmorl's,
Autofluorescence, diazonium salt Argyrophilic cells/tissues contain a substance that
reduces silver solution to metallic silver after exposure to an extraneous
reducing agent, such as hydroquinone or formalin Argyrophilic stains: Grimelius (with Bouin's fixative), Churukian-Schenk’s modification, Pascual's Special type of long-thin silica crystal, usually
from mineral group chrysotile Highly fibrogenic in tissue Called ferruginous bodies in tissue - fibers coated
with protein-iron-calcium matrix, giving them a shish-kebab appearance;
highlighted with iron stain Image: Asbestos
body, unstained Image: Asbestos
bodies, iron stain ATM Ataxia telangiectasia mutation Mutations cause suboptimal induction of p53 dependent
signaling after exposure to DNA damaging agents, which causes an increase in
mitotic recombination Definition:
monoclonal antibody that recognizes tumor-associated glyocoprotein 72 (TAG-72),
a mucin-like sugar and protein complex on the surface of many cancer cells Antibody is directed against the Sialyl-Tn blood
group antigen Intrepretation: cytoplasmic staining Uses: (1) distinguish pulmonary adenocarcinoma (positive)
from mesothelioma (negative) as part of a panel (Diag Cytopathol 1997;17:115) (2)
distinguish carcinoma in cytology specimens (positive) from benign effusions
(usually negative, but may have focal staining, J
Clin Pathol 1990; 43:1026, Acta
Cytol 1987;31:537, Diag
Cytopathol 2007;35:300) (3)
confirm diagnosis of breast apocrine carcinoma (APMIS 2006;114:712) Positive
staining (normal tissue): colonic
mucosa (Hum Pathol 1989;20:994), endometrium-secretory, endometriosis (J
Clin Endocrinol Metab 1993;76:1075), gastric/duodenal goblet cells-coarsely granular, gastric/duodenal epithelium-finely
granular (Diagn Cytopathol
2005;33:381) Positive staining (malignancies): angiosarcoma-epithelioid, breast apocrine carcinoma (92%), breast ductal
carcinoma, colonic adenocarcinoma, endometrial carcinoma, esophageal squamous
cell carcinoma, lung adenocarcinoma, ovarian serous tumors and implants,
pancreatic ductal adenocarcinoma and intraductal oncocytic papillary neoplasm, prostatic
adenocarcinoma, salivary gland carcinoma including duct carcinoma,
mucoepidermoid carcinoma (Laryngoscope
1994;104:304)
and malignant mixed tumor; testicular
ovarian surface epithelial-like tumor, testicular serous papillary carcinoma, vulvar
Paget’s disease Negative
staining (normal tissue): mesothelial
cells, most benign cells except colon, duodenum, endometrium, gastric Negative staining (disease): adrenocortical adenoma, adrenocortical carcinoma,
anaplastic meningioma, lung small cell carcinoma, mesothelial cell inclusions
in lymph nodes, mesothelial cysts in the kidney, mesothelioma, ovarian adnexal
tumor of probable wolffian origin, ovarian primary retroperitoneal mucinous
cystadenoma, ovarian small cell carcinoma-hypercalcemic type Micro images: bronchioalveolar
carcinoma of lung: A-H&E, B-cytoplasmic staining for CEA, C-cytoplasmic
staining for B72.3 Protein fusion product formed by t(9;22)(q34;q11),
called the Philadelphia chromosome Either p210 or p185 hybrid proteins p210 formed by bcr from 5' to b2/b3 of M (major)-bcr
joined to second exon of c-abl (between IA and IB); has constitutive tyrosine
kinase activity; associated with chronic myelogenous leukemia p185 formed by bcr from 5' to m (minor)-bcr; more
potent tyrosine kinase than p210; associated with ALL or AML abl overexpression causes resistance to apoptosis
induced by Fas, ceramide or chemotherapy Found in 25% adult ALL, 5% pediatric ALL; 95%+ of
patients with CML Poor prognostic factor in pediatric ALL Forms light chain of HLA molecule Present on surface of all nucleated cells Increased levels in multiple myeloma Beta 2 microglobulin amyloidosis is related to renal
dialysis, increasing with duration of therapy and patient age Gene is also called CTNNB1 Physiology:
cytoplasmic protein normally adjacent to cell membrane, where it interacts with
cytoplasmic domains of E-cadherin; E-cadherin and beta-catenin complex is
connected to cytoskeletal actin by alpha-catenin; thus beta-catenin stabilizes
E-cadherin, and participates in cell-cell adhesion mediated by E-cadherin Important regulator of cell growth Beta-catenin and T cell factor (Tcf) are also distal
components of the highly conserved Wnt pathway that govern cell fate and
proliferation in lower organisms; binds to APC; also binds to a T cell
factor-lymphoid enhancer factor (Tcf-Lef), which activates other genes,
stimulates cell proliferation and inhibits apoptosis; APC accelerates the
proteasome-mediated degradation of beta-catenin, which reduces its role as a
transactivating factor for the Tcf-Lef pathway Mutations:
mutations in APC produce elevated levels of Tcf4-beta-catenin, which stimulates
a transcriptional response that initiates polyp formation and eventually
malignant growth; mutations in beta-catenin itself can cause its activation Colon:
plays critical role in tumorigenesis (mutations in APC or beta-catenin present
in 90% of colon cancers) Uterus:
endometrioid endometrial carcinoma is associated with beta-catenin mutations Interpretation: nuclear staining is significant
in fibroblasts, nuclear or cytoplasmic staining is significant in epithelial
cells Uses: (1) distinguish
mesenteric fibromatosis (positive with nuclear staining due to mutations in
APC/beta-catenin pathway causing nuclear accumulation) from GIST tumors
(negative) and sclerosing mesenteritis (negative, AJSP
2002; 26:1296) (2) distinguish deep fibromatoses (diffuse or rarely
focal nuclear staining) from low grade fibromyxoid sarcoma and other
myofibroblastic or fibroblastic tumors/sarcomas (negative for nuclear staining,
AJSP
2005;29:653) Positive staining (normal): fibroblasts and endothelial cells
(cytoplasmic-membranous staining) Positive staining (disease): desmoid-type fibromatosis, solitary fibrous tumors
(nuclear staining in 33%, remainder had membranous or membranous/cytoplasmic
staining, Archives
2005;129:776); endometrioid
carcinoma of endometrium and ovary, particularly squamous morules (Hum
Path 2005;36:605) Negative staining: GIST, sclerosing mesenteritis, low grade fibromyxoid sarcoma,
myofibroblastic or fibroblastic tumors Micro images: patterns
of staining in solitary fibrous tumor; highly
malignant adult hepatic blastoma - fig A: ferritin; B: alpha-fetoprotein; C:
HepPar1; D: CK8; E: p53; F: beta-catenin Highlights neurofibrillary tangles Interpretation: H&E shows optically clear nuclei or biotin-rich intranuclear
inclusions; presence of biotin may cause false positive staining with
avidin-peroxidase method Positive staining (normal): pregnancy-related endometrium Positive staining (disease): granulosa cell tumor-like variant of endometrioid
carcinoma of ovary (Archives 2005;129:1288); also endometriotic cysts,
morule-forming endometrioid carcinoma Micro images: granulosa
cell tumor-like variant of endometrioid carcinoma of ovary (figure 2C) Blood group antigens (A, B, H) Glycolipids in cell membranes of RBCs and epithelial
cells BMP Bone Morphogenetic
Proteins Members of transforming growth factor-beta (TGF-beta)
superfamily (20 types cloned through October 2005) Used for intercellular signals including cell growth
and differentiation Ubiquitous in embryonic development; also involved in
apoptosis Blocking their activity in chickens leads to duck
feet Deletion causes lack of mesoderm development, lack of
sperm development, eye/kidney deformities, misshapen feet Overexpression associated with fibrodysplasia
ossificans progressiva, various bone and soft tissue sarcomas Colonic adenocarcinoma: BMP5 and BMP6 prominent in cytoplasm of tumor cells,
BMP2 and BMP4 strongly expressed in surrounding mesenchymal cells (Archives
2005;129:1347) Cadherins See also E-cadherin, N-cadherin Molecules that establish links between adjacent cells
by forming zipper like structures at adherens junctions Linked to cytoskeleton via catenins (cadherin to beta
catenin, beta catenin to alpha catenin, alpha catenin to actin) to stabilize adherens
junction Homophilic interactions (like-like) causes clustering
of embryonic cells with others from same tissue Loss of cadherins may be first step in giving cells
invasive properties With routine staining, calcium forms a blue-black
lake with hematoxylin, usually with sharp edges. von Kossa method: silver is substituted for calcium in calcium salts; light or a
photographic developer turns the silver black; only stains calcium bound to an
anion such as phosphate or carbonate; most useful when large amounts of
phosphates and carbonates are present, as with bone Alizarin red S forms an orange-red lake with calcium at a pH of 4.2; works best with
small amounts of calcium such as in Michaelis-Gutman bodies; this method is
used on Dupont ACA analyzer to measure serum calcium photometrically Azan stain
used to distinguish osteoid from mineralized bone. Micro images: malakoplakia
of bladder (von Kossa calcium stain) Caldesmon binds calcium, calmodulin, tropomyosin and
actin, and regulates smooth muscle contraction (Int
J Biochem Cell Biol 1997;29:1047) h-caldesmon is its high molecular
weight isoform, found in smooth muscle cells; l-caldesmon isoform is
distributed in non-muscle cells (J Biol Chem 1991;266:355) Uses: (1) very useful to distinguish smooth muscle
cells/lesions (positive) from myofibroblastic cells/lesions (negative or only a
few cells positive, AJCP 2000;114:746, Am
J Dermatopathol 2006;28:105) (2) distinguish uterine leiomyoma or leiomyosarcoma
(positive) from endometrial stromal tumors (negative, AJSP
2001;25:455), but endometrial
stromal tumors may have focal smooth muscle differentiation (AJSP
2002;26:1142) (3) sensitive and specific for epithelioid peritoneal
mesothelioma (positive) versus ovarian serous carcinoma (negative, AJSP
2007;31:1139)
and epithelioid pleural mesothelioma (positive) versus pulmonary adenocarcinoma
(negative, AJSP
2006;30:463) Note: may be negative in epithelioid smooth muscle tumors
of uterus (AJSP
2006;30:319) Positive staining (normal): smooth muscle cells (vascular, visceral) Positive staining (disease): angioleiomyoma
(Hum
Path 2007;38:645), gastrointestinal stomal tumor (61%, Pathol
Oncol Res 2005;11:11),
glomus tumor (Hum
Path 1999;30:392), inflammatory
myofibroblastic tumor (focal, AJSP
2006;30:1502),
leiomyoma/leiomyomatosis (Eur
J Gynaecol Oncol 2004;25:481),
leiomyosarcoma (AJSP
2004;28:178 and
references above, but see Appl
Immunohistochem Mol Morphol 2001;9:302),
myopericytoma (AJSP
2006;30:104),
perivascular epithelioid cell tumors (Int
J Gynecol Pathol 2005;24:341) Negative staining (normal): endometrium, endometrial stroma, myofibroblasts (J
Submicrosc Cytol Pathol 2005;37:231), pericytes Negative staining (disease): endometrial stromal tumor (references above),
fibromatosis, myofibroblastoma
(Pathology
2005;37:144),
myofibroblastic lesions (Int
J Surg Pathol 2005;13:57),
nodular fasciitis, rhabdomyosarcoma (AJSP
2005;29:1106), synovial sarcoma (AJSP
2002;26:1434) Micro images: colon-pericrytal
fibroblast sheath (fig A); leiomyosarcoma
#1; #2-bladder
(fig 2); lipoleiomyosarcoma
(fig 4); mixed
tumor of vagina-stromal cells (fig d) Actin filament associated regulatory protein h1 (basic) isoform is smooth muscle specific, but a
late stage smooth muscle marker; described below h2 isoform is found in smooth muscle and non muscle
cells; not described below Uses: (1) identify myoepithelial cells in breast lesions (Histopathology
2005;47:202)
(2) help differentiate breast collagenous spherulosis
(positive) from adenoid cystic carcinoma (negative, Mod Path 2006;19:1351), although adenoid cystic carcinoma
is calponin positive in salivary gland tumors (Archives 1999;123:801) Positive staining (normal): smooth muscle, myoepithelial cells (most but not
all, Breast Cancer Res 2003;5:R151), myofibroblasts (AJSP
2003;27:82,
Proc Natl Acad Sci USA 1993;90:999); also keratinocytes and nerve fibers
(Virchows
Arch 2000;437:58), choroidal non-vascular
smooth muscle cells (J Anat 2005;207:381) Positive staining (disease): atypical fibroxanthoma (30%, Virchows
Arch 2002;440:404),
benign fibrous histiocytoma (65%), collagenous spherulosis (Mod Path 2006;19:1351), DFSP (40%), fibromatosis (Am
J Dermatopathol 2006;28:105), fibrosarcoma (60%), glomus tumor (AJSP
2002;26:301),
leiomyoma, leiomyosarcoma, MFH of bone (47%, J Clin Pathol 2002;55:853), MPNST (40%), myoepithelioma-skin, myofibroblastic lesions, myofibroblasts in
desmoplastic stroma of carcinomas, nodular fasciitis, solitary fibrous tumor
(70%), synovial sarcoma (Histopathology
2003;42:588) Negative staining (disease): adenoid cystic carcinoma Micro images: breast - adenoid
cystic carcinoma (fig e) versus collagenous spherulosis (fig j); adenomyoepithelioma
(fig I); myoepithelial cells
#1; #2;
phyllodes
tumor-malignant, metastatic (fig d); sclerosing
lobular hyperplasia salivary gland - adenoid
cystic carcinoma-submandibular gland; basal
cell adenoma; epithelial-myoepithelial
carcinoma other - hidradenoma
papilliferum; MFH
of bone (fig B, F); pleomorphic
adenoma of nasal cavity (fig 4b) CDC2 / CDK1 Also called Cyclin Dependent Kinase
1 Member of cyclin dependent kinase family, which
regulates phase transitions and checkpoints within the cell cycle Nuclear protein that is subunit of M phase promoting
factor, together with cyclin B subunit Not expressed in normal esophagus; rare to occasional
expression in Barrett’s esophagus with low grade dysplasia, increasing to
diffuse expression in 95% with high grade dysplasia; expression correlates with
progression of esophageal adenocarcinoma in cell lines (AJSP
2005;29:390) EM-1521, a CDC2/CDK1 inhibitor, is theoretical
antitumor therapy for esophageal adenocarcinoma Low levels associated with reduced survival in mantle
cell lymphoma (Mod
Path 2005;18:1223) Interpretation: staining in mantle cell lymphoma is predominantly cytoplasmic and
partial nuclear Positive staining (normal): germinal center (but not mantle zone) of benign
lymph nodes Micro images: staining
in tonsil (fig 2b), mantle cell lymphoma (2e/2f) Ceramide Members of the class of neutral glycosphingolipids Basic units of sphingolipids Are sphingoids attached via their amino groups to a
long chain fatty acyl group Fabry’s disease: abnormally accumulate Chaperones Proteins which help other proteins fold correctly by
transient binding to interactive surfaces (hydrophobic areas), which otherwise
might aggregate Name is accurate since it has no actual positive
effect but prevents negative effects Important after environmental stress which causes
proteins to unfold As a translated protein grows, it becomes
increasingly available to chaperones; the protein is released into the
intracellular space only when it is folded enough to prevent aggregation Also called specific esterase, naphthol AS-D
chloroacetate esterase Useful for demonstrating myeloid differentiation,
although negative in 25% of cases, particularly with immature granulocytic and
monocytic neoplasms (Archives
2005;129:32) Enzyme cytochemistry-positive: AML-M1, M2, microgranular M3; granulocytic sarcomas,
neutrophils Enzyme cytochemistry-negative: ALL Chromaffin cells have cytoplasmic granules that
appear brown when fixed with a dichromate solution Traditionally associated with adrenal medulla or
extraadrenal paraganglion tissues (pheochromocytomas) Types of stains for chromaffin include: Modified
Giemsa, Schmorl's, Wiesel's Claudins Multigene family of integral membrane proteins active
in tight junction formation and function At least 24 known members, expressed in tissue
specific pattern; usually cells from a specific organ express multiple claudin
proteins Variation in expression associated with malignant
tumors Positive staining (normal): epithelial and endothelial cells Clusterin Glycoprotein implicated in apoptosis and other
cellular functions Strongly expressed in follicular dendritic cell
tumors, weak/no expression in other dendritic cell tumors Among spindle cell neoplasms, has high sensitivity
and specificity for follicular dendritic cell tumors (Mod
Path 2005;18:260) Positive stains (disease): anaplastic large cell lymphoma (80-100% of systemic
cases, 40-60% of primary cutaneous cases), diffuse large B cell lymphoma (12%),
carcinomas of breast, colon, pancreas, prostate Micro images: follicular
dendritic cell tumor: H&E and clusterin (b/e) c-MET Gene at 7q31-34; receptor for hepatocyte growth
factor receptor A tyrosine kinase that mediates cell motility,
proliferation, invasiveness, angiogenesis and morphogenetic differentiation Activating mutations are present in papillary renal
cell carcinoma; missense mutation in 6% of thyroid carcinoma (papillary,
follicular and medullary, AJSP
2005;29:544); high levels of MET
mRNA and protein expressed in papillary thyroid carcinoma Positive staining (disease): melanoma, melanocytic lesions Proto-oncogene at 8q24.1 produces short lived nuclear
phosphoprotein Overexpressed by t(8;14)(q24;q32.3), t(8;22);(q24;11)
and t(2;8);(p11-12;q24), which translocate c-myc gene next to immunoglobulin
genes in Burkitt’s lymphoma Gene expressed in virtually all eukaryotic cells;
expression usually tightly controlled Immediate early growth response gene; rapidly induced
when quiescent cells receive a signal to divide; required for cells to enter S
phase By itself, binds DNA poorly; forms stable sequence
specific DNA binding heterodimers with max; myc-max recognizes E-box sequence
CACGTG and activates transcription of nearby growth promoting genes Has leucine zipper motif: leucine residues that
project from every other turn of the alpha helix (every 7th amino acid is
leucine), which interdigitates with another leucine zipper In humans, deletion causes embryonic death t(8;14) also frequent in AIDS-related lymphomas,
diffuse large-cell lymphomas, posttransplant lymphoproliferative disease, B-ALL
(leukemic counterpart of Burkitt's lymphoma) t(8;14)(q24;q11) present in 10-15% T-ALL Breast cancer: amplified in 20-30% of cases; associated with HER2 amplification and
poor outcome (Hum
Path 2005;36:634) Burkitt’s lymphoma: 90% have translocation of c-myc or variants; translocation causes
continuous stimulation by adjacent enhancer element of immunoglobulin gene or
mutations in myc gene regulatory sequences, that leads to increased
constitutive levels; continuous growth stimulation may lead to polyclonal pre-B
proliferations, then clonal proliferations, usually ALL-L3 Lung-small cell carcinoma: amplified Neuroblastoma: amplified Type I collagen: dermis, tendons and bone Type II collagen: cartilage Type III collagen: fetal skin, scars, arterial walls Type IV collagen: normal constituent of basement membrane surrounding noninvasive
glandular epithelium There is discontinuous or complete absence of
basement membrane staining surrounding colonic adenocarcinoma, AJSP
2002;26:206 Uses:
double immunostaining of type IV collagen with cytokeratin is useful to detect
microinvasion in VIN or CIN (Archives
2005;129:747) Micro images: double
immunostaining with cytokeratin #1; #2 Collagen - type II Specific marker of normal and neoplastic chondrocytes Specific and sensitive for mesenchymal
chondrosarcomas vs. other small cell sarcomas except chondroblastic small cell
osteosarcomas (Mod
Path 2005;18:1088) Micro images: mesenchymal
chondrosarcoma - a1-c1: H&E; a2-c2: vimentin; a3-c3: S100; a4-c4: collagen
type II Also called amyloid stain Must examine stained tissue with standard and
polarized light Amyloid under polarized light has apple green
birefringence, based on the molecule being in an antiparallel beta-pleated
sheet. Note:
non-amyloid related green birefringence can occur due to excess dye retained by
the tissue Micro images: medullary
carcinoma of thyroid gland-staining lower right; amyloid in
adrenal gland; primary
localized laryngeal amyloidosis (polarized light-fig F); amyloid
tumor of breast - fig 1: coarse calcifications of right breast; 2: H&E; 3:
Congo red staining; 4: Congo red under polarized light; cardiac
amyloidosis under polarized light Also called CD183 Receptor for some chemokines; binding of chemokines
to CD183 induces integrin activation, cytoskeletal changes and chemotactic
migration in inflammation-associated effector T cells CD183+ T cells detected in inflamed tissues of
patients afflicted with juvenile rheumatoid arthritis, multiple sclerosis,
sarcoidosis, hepatitis C Positive staining (normal): T cells in inflamed tissue, eosinophils,
plasmacytoid dendritic cells, hematopoietic progenitors Negative staining: naďve T cells in peripheral blood Cyclins Regulatory subunits of cyclin dependent kinases
(CDKs) Control the passage of proliferating cells through
key checkpoints in the cell cycle (G1 to S, G2 to M) through overexpression of
positive growth regulators such as cyclin dependent kinases (CDKs) and underexpression
of inhibitory growth regulators, such as CDK inhibitors Cyclooxygenase 2 (COX2) Cyclooxygenases 1 (COX1) and 2 (COX2), also known as
prostaglandin H synthase, catalyze formation of prostaglandin from arachidonic
acid COX1 is constitutive form of enzyme on 9q; COX2 is
inducible isoform on 1q, has 61% sequence homology with COX1 Regulated by mitogens, tumor promoters, cytokines,
serum, free fatty acids, NSAIDs, selective COX2 inhibitors Increased expression associated with poor clinical
outcome in stage I/II non-small cell lung carcinoma (Archives
2005;129:1113), possibly poorer
outcome in follicular thyroid carcinoma (Archives
2005;129:736) Interpretation: cytoplasmic staining Positive staining (normal): endothelial cells Positive staining (disease): breast, colorectal, esophageal, liver, lung, ovary,
pancreas, prostate, skin, stomach tumors Micro images: lung
adenocarcinoma (A: COX2+; B: COX2-; C: endothelial cells are positive control);
fig
7-staining in follicular carcinoma; arachidonic
acid pathway Definition:
family of water-insoluble intracytoplasmic structural proteins that are the
dominant intermediate filament proteins of epithelial and hair forming cells;
also present in epithelial tumors Within a cell, form a dense network radiating from
the nucleus to the plasma membrane Act as cytoplasmic scaffold that gives epithelial
cells the ability to sustain mechanical and non-mechanical stress Keratin intermediate filaments are highly dynamic
structures and are reorganized during mitosis and apoptosis; reorganization is
mediated by posttranslational phosphorylation, glycosylation,
transglutamination and proteolysis, or through interaction with 14-3-3 or other
proteins Expression depends on cell type and differentiation
status Over 25 subtypes are defined based on
molecular weight (40 to 68 kDa) and isoelectric pH (5 to 8) Moll catalog number (Cell
1982;31:11) ranges from 1
(highest molecular weight) to 23 (lowest molecular weight) New nomenclature exists (J Cell Biol 2006;174:169) Divided into Type I (acidic; CK10, CK12-19, 40-56.5
kDa) and Type II (neutral-basic, CK1-CK8, 53-67 kDa) Type I genes are expressed at 17q21.2, type II genes
at 12q13.13 Proteins are obligate heteropolymers with equimolar
amounts of type I and type II proteins that form functional filaments, such as
CK8/18, CK5/14, CK1/10 Also divided into low molecular weight (CAM 5.2, 34
beta E11) and high molecular weight (34 beta E12); pankeratin cocktails contain
AE1 and AE3 and possibly also CAM 5.2 Genes are KRT1 for keratin 1, KRT2 for keratin 2,
etc. Uses: (1) diagnose epithelial (cytokeratin+) versus
nonepithelial cells / tumors (usually cytokeratin negative but there are many
exceptions) (2) diagnose particular types of epithelial tumors
based on staining patterns of particular cytokeratins - dot like staining is
suggestive of neuroendocrine tumors (3) in rebiopsies of tumors, don’t assume that all
keratin+ cells are residual tumor cells (AJSP
2007;31:390) Negative
staining (usually): endothelium, mesenchymal
cells Micro images: cytokeratin
network of cell #1; #2
(CK8, 18, 19) Highest molecular weight keratin (67-68 kDa) Produced by KRT1 gene in complex manner (PLoS Genet 2006;2:e93) Associates with CK10 Keratin 1b is expressed in eccrine sweat glands (J Invest Dermatol 2005;125:428) Reduced expression in HPV infection (Cancer Res 1990;50:3709) Mutations are associated with epidermolytic
hyperkeratosis / bullous congenital ichthyosiform erythroderma (Dermatol Online J 2006;12:6), Greither’s syndrome (J
Am Acad Dermatol 2005;53:S225), striate
palmoplantar keratoderma (J Invest Dermatol 2002;118:838) Uses: no significant clinical use by pathologists Positive staining (normal): endothelial cells, skin and other squamous
epithelium (suprabasal spinous and granular layers), thymic Hassal’s corpuscle Positive staining (disease): angiosarcoma (73%), epithelioid hemangioendothelioma
(100%), epithelioid sarcoma (70%), hemangioma (often), schwannoma (62%),
squamous cell carcinomas-keratinizing, synovial sarcoma (28%), vascular tumors
(greater in well versus poorly differentiated tumors) Micro images: eccrine
sweat gland expression References:
Hum
Path 2001;32:873, OMIM 139350 Molecular weight (CK2e) is 65.5-65.8 kDa Associates with CK10 (UniProtKB) Mutations cause ichthyosis bullosa of Siemens (Br
J Dermatol 2005;152:1353) K2e (epidermis) and K2p (palate) are encoded by
separate genes, with < 75% identity at primary structural level; thus, are
not true isoforms, although they cannot be distinguished by conventional 2D
electrophoresis (HopkinsMedicine) Uses: no significant clinical use by pathologists Positive staining (normal): skin (upper spinous and granular cells, Br
J Dermatol 1999;140:582) References: OMIM 600194,
Exp
Cell Res 1992;202:132 Molecular weight is 64-65 kDa Associates with CK12 Mutations in KRT3 gene may cause Meesmann corneal dystrophy (Cornea
2005;24:928) Uses: no significant clinical use by pathologists Positive staining (normal): corneal epithelium (full thickness), limbus epithelium
(suprabasal) Negative staining: conjunctival epithelium Micro images: suprabasal
staining of limbus epithelium cultured using air-lifting (AL) technique (fig
A/B) References:
OMIM 148043 Molecular weight is 59 kDa Associates with CK13 Downregulated in head and neck squamous cell
carcinoma (Acta
Otolaryngol 2006;126:967) Uses: no significant clinical use by pathologists Case reports: mutation in KRT4 gene causes white sponge nevus (Br
J Dermatol 2003;148:1125) Positive staining (normal): suprabasal cells of nonkeratinized stratified
squamous epithelium of esophagus and cornea; also anus, larynx, pharynx, tongue
(J Biol Chem 1998;273:23912) Micro images: epidermis
before and after treatment with retinoic acid References:
OMIM 123940 Molecular weight is 58 kDa Major partner is CK14, but related to cytokeratin 6
(antibodies are often to CK5/6) Common antibody is 34BE12 Mutations may cause epidermolysis bullosa simplex (Hum Mutat 2006;27:719), Dowling-Degos disease (Am J Hum Genet 2006;78:510) Important in tooth enamel formation (J Biol Chem 2003;278:20293) Interpretation: diffuse cytoplasmic staining with perinuclear enhancement (AJSP
2001;25:43) Uses: (1) helps defines a basal-like subtype of invasive
ductal carcinoma of the breast that is usually CK5/6+, ER-, PR-, HER2-, EGFR+
with poorer prognosis (Clin Cancer Res 2006;12:1533); associated with premenopausal
African American women (JAMA
2006;295:2492), BRCA1 (J Natl Cancer Inst 2003;95:1482, Mod Path 2005;18:1321) and brain metastases (AJSP
2006;30:1097) (2) defines a DCIS subtype with poorer prognosis (Hum
Path 2007;38:197); (3) distinguish breast usual ductal hyperplasia
(strong staining) from solid papillary DCIS (negative, Hum
Path 2006;37:787) (4) p63+ and CK5/6+ poorly differentiated metastatic
carcinomas are likely to have squamous carcinoma primaries (AJCP
2001;116:823) (5) distinguish
epithelioid mesothelioma (CK5/6+ cytoplasmic staining with perinuclear
enhancement) from lung adenocarcinoma (usually CK5/6 negative, Histopathology
2006;48:223); also in pleural effusions (Diagn
Cytopathol 2006;34:801) (6) distinguish cutaneous spindled squamous cell
carcinoma (CK5/6+ in 100%) from superficial epithelioid sarcoma (rare focal
positivity, Cutan
Pathol 2003;30:114) Cytokeratin 5 (continued) Positive staining (normal): breast myoepithelial cells, cornea (Exp
Eye Res 2004;78:1137),
mesothelium, nail unit of adults (Br
J Dermatol 2004;151:362),
prostate basal cells (J
Pathol 2001;195:563) skin (basal layer), salivary glands (basal layer), spermatogenic cells (Mol
Reprod Dev 2002;61:1),
squamous epithelium (basal cells), urothelium (basal layer, Mol Cell Proteomics 2002;1:269) Positive staining (not carcinoma): cutaneous amyloidosis (primary and secondary, Arch
Dermatol Res 2004;296:83), epithelioid sarcoma (rare to 30%, focal, Archives 2003;127:1161), mesothelioma (references above), salivary gland
tumors, thymoma Positive staining (carcinoma): adrenocortical neoplasms (adenoma and carcinoma,
pediatric-75%, AJSP
2003;27:867), basal cell, breast-basal subtype (references above),
endometrial adenocarcinoma (50%), lung
(adenocarcinoma-12 to 56%, Hum
Path 2006;37:542; squamous cell (87-100%, AJSP
2003;27:150), ovarian
adenocarcinoma (25%), pancreatic adenocarcinoma (38%), squamous cell (all sites),
urothelial (62%) Negative staining: colonic adenocarcinoma, gastric adenocarcinoma, germ cell tumor,
hepatocellular carcinoma, large cell neuroendocrine carcinoma, small cell
carcinoma (usually), renal cell carcinoma, synovial sarcoma (biphasic), thyroid
tumors Micro images: breast carcinoma-basal
subtype in BRCA1 patient; breast-various;
gallbladder
adenosquamous carcinoma; mesothelioma #1;
#2;
#3-deciduoid
(fig 5); ovarian
serous carcinoma (fig b); pancreas-adenosquamous
carcinoma; skin (normal);
squamous cell
carcinoma-oral (fig a); benign
epithelial inclusions of axillary lymph nodes - fig 1: CK5/6+; 2: p63+; various
images #1 (squamous cell-fig 1A, urothelial-fig 1C, thymoma-fig 1E, salivary
gland adenoid cystic-fig 1G); #2
(ovary-fig 2A, endometrioid adenocarcinoma of uterus-fig 2C, infiltrating ductal
carcinoma of breast-fig 2E) Contributed by Leica Microsystems, Biosystems Division - mesothelioma-Cytokeratin
5 (XM26) with intense cytoplasmic and membranous staining References: Mod
Path 2002;15:6-free full text, OMIM 148040 Molecular weight is 56 kDa; major isoform is 6A Related to cytokeratin 5 (Hopkinsmedicine) Paired with CK16 and CK17 Mutations cause pachyonychia congenita (Ann
N Y Acad Sci 2006;1082:56) Upregulated in conjunctiva in Sjogren's syndrome (Exp
Eye Res 2003;77:17) and in cornea in keratoconus (Invest Ophthalmol Vis Sci 2003;44:2466) Marker of hyperproliferative and activated
keratinocytes found in psoriasis (Dermatology
2000;201:15),
wound healing and other
inflammatory disorders (J Invest Dermatol 2001;116:330) Uses: (1) helps defines a basal-like subtype of invasive
ductal carcinoma of the breast that is usually CK5/6+, ER-, PR-, HER2-, EGFR+
with poorer prognosis (Clin Cancer Res 2006;12:1533); associated with premenopausal
African American women (JAMA
2006;295:2492), BRCA1 (J Natl Cancer Inst 2003;95:1482) and brain metastases (AJSP
2006;30:1097) (2) defines a DCIS subtype with poorer prognosis (Hum
Path 2007;38:197); (3) distinguish breast usual ductal hyperplasia
(strong staining) from solid papillary DCIS (negative, Hum
Path 2006;37:787) (4) p63+ and CK5/6+ poorly differentiated metastatic
carcinomas are likely to have squamous carcinoma primaries (AJCP
2001;116:823) (5) distinguish
epithelioid mesothelioma (CK5/6+ cytoplasmic staining with perinuclear
enhancement) from lung adenocarcinoma (usually CK5/6 negative, Histopathology
2006;48:223); also in pleural effusions (Diagn
Cytopathol 2006;34:801) (6) distinguish cutaneous spindled squamous cell
carcinoma (CK5/6+ in 100%) from superficial epithelioid sarcoma (rare focal
positivity, Positive staining (normal): esophagus, epidermal and epithelial
glands, hair and nails, oral mucosa, stomach, tongue (filiform papillae) Positive staining (disease): psoriasis, other skin disorders (see above) Micro images: breast
carcinoma-basal subtype in BRCA1 patient; gallbladder
adenosquamous carcinoma; keratoconus (fig A), normal
cornea (fig D); mesothelioma-deciduoid
(fig 5); ovarian
serous carcinoma (fig b); pancreas-adenosquamous
carcinoma; skin-various
images; squamous
cell carcinoma-oral (fig a); benign
epithelial inclusions of axillary lymph nodes - fig 1: CK5/6+; 2: p63+; various
images #1 (squamous cell-fig 1A, urothelial-fig 1C, thymoma-fig 1E, salivary
gland adenoid cystic-fig 1G); #2
(ovary-fig 2A, endometrioid adenocarcinoma of uterus-fig 2C, infiltrating
ductal carcinoma of breast-fig 2E) References:
OMIM 148041,
Wikipedia, J Invest Dermatol 2000;115:795 Low molecular weight keratin (52.5-53.5 kDa) Usually paired with cytokeratin 18 Component of nuclear inclusions of rhabdoid tumors
(composed of tangled CK8 and vimentin) and Mallory bodies Mutated in malignant rhabdoid tumor (Mod
Path 2002;15:146-free full text), chronic pancreatitis (9%, Dig
Liver Dis 2003;35:416), liver disease (Proc Natl Acad Sci USA 2003;100:6063) May protect hepatocytes from oxidative stress Cleaved by Chlamydia during infection to permit
vacuole expansion necessary for replication (Infect Immun 2004;72:3863) Uses: (1) confirm epithelial nature of tissue / tumors (2) assess sentinel lymph nodes in colon carcinoma (Scand
J Gastroenterol 2006;41:1073) Positive staining (normal): simple type (single layer) epithelium including
breast ducts (luminal cells), gallbladder, intestine, liver (hepatocytes and
bile ductules), pancreas, prostate (basal cells and secretory cells) Positive staining (not carcinoma): ameloblastoma (stellate reticulum-like areas, Oral
Dis 1999;5:111),
autoimmune hepatitis (90%, Acta
Cytol 2007;51:61), Mallory bodies (J Cell Biol 2005;171:931), rhabdoid tumor (references above) Positive staining (carcinoma): bile duct, breast (invasive ductal and DCIS),
hepatocellular, neuroendocrine, pancreatic, prostate, renal cell, squamous cell
(cervix-57%, Hum
Path 2004;35:546; oral cancers-62% from smears, Eur
J Cancer B Oral Oncol 1994;30B:405), stomach (97%, Hum
Path 2004;35:576) Negative staining: adamantinoma of long bone (Histopathology
1994;25:71), smooth
muscle tumors (although may be false positives, Pathol
Res Pract 2007;203:31) Micro images: hepatic
blastoma-adult (fig D); hepatocytes
(residual) are CK8+ in embryonal sarcoma of liver; liver
disease (various); malignant
rhabdoid tumor (fig c); prostatic
adenocarcinoma-top and benign prostate-bottom; squamous cell
carcinoma-oral (fig c/d); various carcinomas (breast,
colon, lung-squamous cell, prostate) Contributed by Leica Microsystems, Biosystems Division - colon
(normal)-Cytokeratin 8/18 (5D3) with intense cytoplasmic and membranous
staining References:
OMIM 148060 Molecular weight of 64 kDa (HopkinsMedicine) Partner may be CK1 Regulated by dermal fibroblasts (J Invest Dermatol 1999;112:483) Mutations cause epidermolytic palmoplantar
keratoderma (J
Invest Dermatol 1998;111:1207) Uses: no significant clinical use by pathologists Positive staining (normal): suprabasal epidermis of palms and soles (J Invest Dermatol 1999;112:483), spermatogenic cells (Mol
Reprod Dev 2002;61:1) References: OMIM 607606, Wikipedia Molecular weight of 56.5 kDa Partner of CK1 CK1 and CK10 are present in suprabasal terminally
differentiating cells Mutations in CK10 or CK1 cause epidermolytic
hyperkeratosis / bullous
congenital ichthyosiform erythroderma Brocq (Hum
Mol Genet. 2006;15:1133, Dermatol Online J 2006;12:6); defects of CK10-CK1 protein network cause structural
instability and weakness of keratinocytes, causing blistering,
hyperproliferation and hyperkeratosis CK10 is putative autoantigen in chronic, antibiotic
resistant Lyme arthritis (J
Immunol 2006;177:2486) Uses: (1) helps distinguish inflammatory linear verrucous epidermal nevus (higher
CK10) from psoriasis (Eur J Dermatol 2004;14:216) (2) increase indicates a response to treatment for
psoriasis (Am
Acad Dermatol 2004;51:257). Positive staining (normal): epidermal spinous and granular cell layers Positive staining (disease): cervical squamous cell carcinoma-keratinizing (Hum
Path 2004;35:546) References: OMIM 148080 Very little information is present on CK11 Uses: no significant clinical use by pathologists Positive staining (normal): keratinizing epidermal squamous cells Molecular weight is 53.5 kDa Pairs with CK3 Maintains corneal epithelial integrity (Invest
Ophthalmol Vis Sci 1996;37:2572) Mutations cause Meesmann corneal dystrophy (Am J Hum Genet 1997;61:1268) Uses: no significant clinical use by pathologists Positive staining (normal): conjunctival limbic suprabasal epithelial cells and
corneal basal and suprabasal layers (Invest Ophthalmol Vis Sci 2006;47:1359) References:
OMIM 601687 Molecular weight is 53 kDa Pairs with CK4 Marker of mature but non-keratinized squamous
epithelium Downregulated in squamous cell carcinoma of head and
neck (Oral
Oncol 2005;41:183) and other sites (Virchows
Arch A Pathol Anat Histopathol 1991;418:249) Sensitive marker for retinoid
bioactivity in skin warts of renal transplant recipients (Arch
Dermatol 2002;138:61) Mutation causes familial white sponge nevus (J
Dent Res 2001;80:919) Cable piliated Burkholderia cepacia binds to
cytokeratin 13 of epithelial cells (Infect Immun 2000;68:1787) Uses: no significant clinical use by pathologists Positive staining (normal): suprabasal layers of non-cornified stratified
epithelium, including squamous (non-keratinized) epithelia of cervix,
esophagus, larynx, oral cavity, tonsils, urothelium, and respiratory-type
epithelium Positive staining (disease): Brenner tumor, squamous metaplasia,
squamous cell carcinoma (10%), urothelial carcinoma (well differentiated) Negative staining: epidermis References:
OMIM 148065,
Gene
1998;215:269 Molecular weight of 50 kDa Partner is CK5 May be detected by cytokeratin 34BE12 CK5/6+ or CK14+ tumors define a basal subtype of DCIS
(Mod
Path 2006;19:1506) or invasive breast
carcinoma; represents 9% of sporadic invasive ductal breast cancers, ER-, PR-,
HER2-, high grade, poor prognosis (Mod Path 2005;18:1321, Eur
J Cancer 2006;42:3149 but see Clin Cancer Res 2004;10:5988-not poor prognosis), associated with BRCA1 (Clin Cancer Res 2005;11:5175) In cervix, loss of expression is associated with high
grade SIL and high risk HPV (Hum
Path 2001;32:1351) Prostate tumors with distinct basal cells on H&E
that are negative for 34BE12 are also negative for CK14 (Pathol
Res Pract 2006;202:651 Mutations cause epidermolysis bullosa simplex (J Invest Dermatol 2006;126:773), Naegeli syndrome / dermatopathia pigmentosa reticularis (no
fingerprints, OMIM 161000) Uses: (1) distinguish parathyroid oxyphil adenoma (CK14+)
from carcinoma (CK14-, AJSP
2002;26:344) (2) distinguish breast papilloma (stronger and more
diffuse CK14 staining) from papillary DCIS (AJSP
2005;29:625) (3) distinguish sinonasal squamous cell carcinoma
(poorly differentiated or nonkeratinizing, both CK14+) from sinonasal
undifferentiated carcinoma or nasopharyngeal carcinoma (CK14-, AJSP
2002;26:1597) Positive staining (normal): hair follicles (Br
J Dermatol 2004;150:860), basal keratinocytes in stratified epithelium (various
tissue/organs), myoepithelial cells (breast and salivary gland), thyroid
oncocytes Positive staining (not carcinoma): breast papilloma (see above), odontogenic neoplasms (Oral
Dis 2003;9:1), parathyroid oxyphil adenoma (see above), pseudoepitheliomatous hyperplasia-spinous and
superficial layers of oral mucosa with paracoccidioidomycosis (Med
Mycol 2006;44:399), renal and other oncocytoma (Histopathology
2001;39:455), thymoma, trichoblastoma Positive staining (carcinoma): basal cell (Am
J Dermatopathol 2001;23:501), breast-basal
phenotype (see above), salivary gland tumors except acinic cell carcinoma (Pathologica
2006;98:147),
squamous cell carcinoma
(esophagus-Nepal
Med Coll J 2006;8:75 and other sites-Histopathology
2001;39:9), squamous
differentiation in urothelial (J Clin Pathol 1997;50:1032) and other tumors Negative staining: normal oral mucosa, most renal cell carcinomas Micro images: breast-normal;
breast
carcinoma #1 is CK14+ (fig C); gallbladder
adenosquamous carcinoma; skin-normal
#1; #2;
skin
in epidermolysis bullosa simplex patients; squamous cell
carcinoma #1-oral (fig e/f); mesothelioma;
squamoid
areas are CK14+ in urothelial carcinoma References:
OMIM 148066 Molecular weight of 50 kDa (HopkinsMedicine) Downregulated in activated keratinocytes in
psoriasis, hypertrophic scars and skin injury (J Invest Dermatol 1999;112:362, Exp
Cell Res 2000;254:80 Uses: no significant clinical use by pathologists Positive staining (normal): conjunctiva (basal cells) and cornea limbus
epithelial cells (basal and suprabasal cells, Invest
Ophthalmol Vis Sci 2006;47:4780), fetal epidermis and nail, hair follicle bulge and follicular stem
cells (Clin
Exp Dermatol 2006;31:807), oral mucosa, skin-deep rete ridges (Differentiation
2004;72:387,
stratified epithelium-basal regions (cervix-Am
J Pathol 1993;142:403, esophagus-Mol Cell Biol 2004;24:3168) Positive staining (disease): Paget’s disease-extramammary (small, compressed
keratinocytes, Histopathology
2006;48:723),
sebaceomas (J
Cutan Pathol 2006;33:634), trichoepithelioma (63-100%, Eur
J Dermatol 1999;9:363, J
Cutan Pathol 1999;26:113) Negative staining: cornea (central), sebaceous carcinomas and sebaceous neoplasms in
Muir-Torre syndrome Micro images: skin (external root
sheath); skin (K15
in red); various
epithelia References:
OMIM 148030 Molecular weight of 48 kDa (HopkinsMedicine) Paired with keratin 6 Activated keratinocytes produce keratin 6, 16, 17,
not normally present (Am
J Pathol 1998;152:1133) Upregulated in benign keratinocyte hyperplasia, including psoriasis; prepsoriatic skin
may be converted to a distinct adult tissue type resembling hard palate (J Investig Dermatol Symp Proc 2006;11:16) Also upregulated in stress
incontinence in periurethral vaginal wall (Hum
Reprod 2006;21:22), conjunctival epithelium in Sjogren’s syndrome (Exp
Eye Res 2003;77:17) Downregulated in cervical squamous carcinoma (Virology
2005;331:269) Mutations are associated with pachyonychia congenita (Nat
Genet 1995;9:273) and focal
non-epidermolytic palmoplantar keratoderma (Hum
Mol Genet 1995;4:1875) Uses: no significant clinical use by pathologists Positive staining (normal): hair, nail and glands of epidermis;
melanocytes (Am
J Dermatopathol 2005;27:476); esophagus Positive staining (disease): keratoderma of the palms (strong, Acta
Dermatovenerol Croat 2005;13:206), skin damage (suprabasal keratinocytes), tympanic membrane-annular region (Acta
Otolaryngol 1993;113:345) Positive staining (carcinoma): breast-invasive (10%, Am
J Pathol 1991;138:751), squamous cell carcinoma in situ of skin-clear cell type (J
Cutan Pathol 2007;34:226), Negative staining: normal breast Micro images: oral
cavity (normal) References: OMIM 148067 Molecular weight of 48 kDa Basal type cytokeratin (also 34betaE12, CK5/6, CK14)
of complex epithelia but not in stratified or simple epithelia (Eur
J Cell Biol 1992;59:127) Rapidly induced in wounded stratified epithelia (also
CK 6, CK16); regulates cell growth through binding to the adaptor protein
14-3-3sigma (Nature
2006;441:362) Mutations cause pachyonychia congenita type 2 (J
Dermatol 2006;33:161) or steatocystoma
multiplex (Br
J Dermatol 1998;139:475) Uses: (1) distinguish pancreatobiliary adenocarcinoma
(CK17+) from extra-pancreatobiliary nonmucinous adenocarcinoma (CK17-, AJSP
2005;29:359) (2) distinguish cholangiocarcinoma (60% are CK17+)
from hepatocellular carcinoma (CK17-, J Gastrointestin Liver Dis 2006;15:9) (3) distinguish renal urothelial carcinoma (CK5/CK6+,
CK17+, vimentin-) from collecting duct carcinoma (CK5/CK6-, CK17-, vimentin+, AJSP
2005;29:747) (4) considered a marker of or associated with the
basal phenotype (also CK 5/6, CK 14) of invasive or in situ ductal carcinoma of
breast (Mod
Path 2006;19:1506) (5) sensitive marker of sentinel nodal metastases by
RT-PCR in oral squamous cell carcinoma (Clin Cancer Res 2006;12:2498) Positive staining (normal): basal cells of complex epithelia, breast
myoepithelial cells (references above), cervical reserve and immature
metaplastic cells (Cancer
1999;87:87), hair shaft epithelia (Am
J Dermatopathol 1997;19:335), nail beds (NCBI), sebaceous glands (Oncol
Rep 2006;16:295), urothelial metaplasia (Int
J Gynecol Pathol 1999;18:125) Positive staining (carcinoma): basal cell of skin (J
Dermatol Sci 1998;17:15), breast (references above), cervical (J Clin Pathol 1999;52:41), cervical squamous intraepithelial
lesions (Cancer
1999;87:87),
cholangiocarcinoma (intrahepatic, Pathologe
2006;27:244), laryngeal
premalignant changes or squamous cell carcinoma (Ann
Otol Rhinol Laryngol 2004;113:821),
pancreatobiliary (AJCP
2001;115:695), squamous cell of
head and neck (Anticancer
Res 2005;25:2675), thyroid (Hum
Path 1999;30:1166), urothelial (references
above) Negative staining: gastric adenocarcinoma (Hum
Path 2004;35:576) Micro images: breast myoepithelial
hyperplasia (fig 1j); squamous cell carcinoma References:
OMIM 148069 Molecular weight is 45 kDa (HopkinsMedicine) Pairs with CK8 Ethanol causes CK8/18+ Mallory body like inclusions
by (a) causing oxidative stress, which (b) inhibits proteasomes that normally
remove ubiquinated cytokeratins, which (c) causes accumulation of ubiquinated
cytokeratins (Exp
Mol Pathol 2006;81:191) Various CK8/CK18 mutations may increase susceptibility
to liver disease (Gastroenterology
2005;129:885) including cryptogenic cirrhosis (J Clin Invest 1997;99:19) Is a marker of fetal mid-face (primary palate) growth
and fusion (J Dent Res 2005;84:69) Interacts with enteropathogenic E. coli secreted protein F (EspF) and is redistributed
after infection (Cell Microbiol 2004;6:987) In Chagas’ disease, FLY domain on surface of
trypomastigotes binds to CK18, promotes its reorganization and causes increase
in number of parasites/cell (Exp
Cell Res 2007;313:210, J Biol Chem 2001;276:19382) Interacts strongly with HPV16 E1=E4 protein (J Virol 2004;78:821) Uses: (1) serum tumor marker for breast cancer (AJCP
2005;123:66)
and T3/T4 bladder carcinoma (Clin
Biochem 2002;35:327) (2) an airway
epithelial cell autoantigen associated with nonallergic asthma; a possible
serum marker (also CK19) for toluene diisocyanate-induced asthma among exposed
workers (Yonsei Med J 2006;47:773) (3) RT-PCR to assess sentinel lymph nodes in colon
carcinoma (Scand
J Gastroenterol 2006;41:1073) and lymph
nodes of gastric carcinoma (World J Gastroenterol 2005;11:6530) (4) loss of expression in breast carcinoma may be a
poor prognostic factor (Clin Cancer Res 2004;10:2670) (5) cleaved
cytokeratin-18 is a marker of apoptosis (J Histochem Cytochem 2005;53:229, Oncoserve
online) Cytokeratin 18 (continued) Positive staining (normal): simple (i.e. non stratified) epithelial cells,
eccrine glands (J
Cutan Pathol 2007;34:226), endothelium of veins, venules and lymphatics (Hum
Path 2000;31:1062), trophoblast
(Archives 2002;126:1480) Positive staining (not carcinoma): ameloblastoma-peripheral (Oral
Diseases-OnlineEarly Articles), breast (references
above), chordoma (56%, Mod
Path 1997;10:545), endothelium of synovial
tissue with rheumatic disease (Br J Rheumatol 1993;32:676), epithelioid hemangioendothelioma (100%) and
angiosarcoma (epithelioid-50%, nonepithelioid-20%, Hum
Path 2000;31:1062), hepatoblastoma
(epithelial areas, Pediatr
Dev Pathol 2006;9:196),
hepatoid adenocarcinoma (AJSP
2003;27:1302), inflammatory myofibroblastic
tumor (AJSP
2006;30:1502), Mallory bodies (J Cell Biol 2005;171:931), papillary tumor of pineal region (J
Neuropathol Exp Neurol 2006;65:1004), urothelial
metaplasia (Int
J Gynecol Pathol 1999;18:125) Positive staining (carcinoma): adenocarcinoma (various), gastric (Hum
Path 2004;35:576), hepatocellular
(including imprints in 83%, Acta
Cytol 2007;51:61), large
cell neuroendocrine (AJCP
2006;125:682), Negative staining: squamous
cell carcinoma (Histopathology
1993;23:45) Micro images: breast-infiltrating
ductal carcinoma #1; #2; choroid
plexus papilloma; colon
(normal); liver
and bile ducts are CK18+; neuroendocrine
carcinoma (unknown site); placenta;
breast and lung carcinoma
and normal prostate Contributed by Leica Microsystems, Biosystems Division - colon
(normal)-Cytokeratin 8/18 (5D3) with intense cytoplasmic and membranous staining References: OMIM 148070 Molecular weight is 40 kDa (smallest cytokeratin) Often coexpressed with CK7 Present in both simple and complex epithelium Involved in the organization of myofibers; links
contractile apparatus to dystrophin at costameres of striated muscle (also CK8,
Mol Biol Cell 2005;16:4280) Polymorphisms of CK19 pseudogene are associated with
primary biliary cirrhosis (Hepatol
Res 2003;25:281) Uses: (1) confirm diagnosis of papillary thyroid carcinoma
in cytology or equivocal cases (Archives 2003;127:579, Mod
Path 2006;19:1631); help
distinguish follicular variant of papillary thyroid carcinoma (CK19+) from (a)
follicular adenoma (CK19-, Endocr
Pathol 2006;17:213, AJCP
2006;126:700 but see AJCP
2001;116:696),
(b) hyalinizing trabecular
adenoma (CK19-, AJSP
2006;30:1269), (c) Grave’s disease (weak/negative CK19, Endocr
Pathol 2005;16:63), (d) multinodular goiter with papillary areas (Endocr
Pathol 2002;13:207); note that CK19 may stain benign thyroid lesions (2) distinguish hepatocellular carcinoma (CK19-) from
either hepatoid adenocarcinoma metastatic to liver (CK19+, AJSP
2003;27:1302) or cholangiocarcinoma (CK19+, J Gastrointestin Liver Dis 2006;15:9, AJCP
2006;125:519) (3) distinguish chordoma (CK19+) from parachordoma
(CK19-, Ann
Diagn Pathol 1997;1:3) (4) poor prognostic factor in pancreatic endocrine
neoplasms (AJSP
2004;28:1145, AJSP
2006;30:1588), hepatocellular carcinoma (Histopathology
2006;49:138, Cancer
Sci 2003;94:851) (5) presence of CK19+ peripheral blood tumor cells or
CK19+ fragments is a poor prognostic factor for breast cancer (predicts CNS relapse, Breast Cancer Res 2006;8:R36), non-small cell lung carcinoma (Ann
N Y Acad Sci 2006;1075:244, Cancer
2006;107:2842) (6) RT-PCR detects nodal and marrow metastases in
various carcinomas - bladder carcinoma (poorer survival, Clin Cancer Res 2005;11:3773), breast (Anticancer
Res 2006;26:3855, Jpn J Clin Oncol 2003;33:167), gastric (World J Gastroenterol 2006;12:5219), head and neck squamous cell (Br
J Cancer 2006;94:1164), skin (Br
J Dermatol 2003;149:998); note that pelvic lymph nodes may have false positives (Int
J Cancer 2007;120:1842) (7) RT-PCR detects peripheral blood tumor cells in
carcinoma of cervix (Gynecol
Oncol 2002;85:148), colon (Gut
2002;50:530),
gallbladder (Rev
Med Chil 2004;132:1489), pancreatic carcinoma (World J Gastroenterol 2007;13:257); the significance of these tumor
cells is unclear (Ann Oncol 2005;16:1845) Cytokeratin 19 (continued) (8) possible urine screening test for bladder
carcinoma (J Egypt Natl Canc Inst 2006;18:82) (9) an airway
epithelial cell autoantigen associated with nonallergic asthma; a possible
serum marker (also CK18) for toluene diisocyanate-induced asthma among exposed
workers (Yonsei Med J 2006;47:773) Positive staining (normal): anal transition zone (Histopathology
1995;26:39), bile ducts and ductules, breast (ductal and
secretory cells), colon, conjunctiva (Invest Ophthalmol Vis Sci 2006;47:4780), GI epithelium, hair follicles (J Invest Dermatol 1989;92:707), muscle fibers, myoepithelium, nipple epidermis,
pancreatic ducts (Pancreas 2005;30:158), salivary gland acini (Res
Commun Mol Pathol Pharmacol 1998;101:115),
squamous epithelium (basal layers, BMC Cancer 2006;6:10), sweat glands, umbilical cord, urothelium Positive staining (not carcinoma): adamantinoma (Pathol
Int 2000;50:801),
ameloblastoma (stellate reticulum-like areas, Bull Tokyo Dent Coll 2002;43:13), cholesteatoma (Histol
Histopathol 2007;22:37), chordoma
(references above), hepatoblastoma (embryonal subtype, Pediatr
Dev Pathol 2006;9:196), oral dysplasia (Zhonghua
Kou Qiang Yi Xue Za Zhi 2002;37:187),
posterior polymorphous corneal dystrophy (Exp
Eye Res 2007;84:680), pulmonary interstitial pneumonia-hyaline membranes
(some, Pathology
2003;35:120),
synovial sarcoma (Histopathology
1998;33:501), syringocystadenoma papilliferum of skin (Br
J Dermatol 2002;147:936) Positive staining (carcinoma): anal (Virchows
Arch 2001;439:782), breast (Med
Mol Morphol 2006;39:8),
cholangiocarcinoma (references above), endometrial
(Gynecol
Oncol 2006;100:355), hepatoid adenocarcinoma
(references above), lung (Histopathology
2004;45:125), Paget’s
disease (extramammary, Histopathology
2006;48:723), pancreatic
ductal (references above), renal cell (collecting duct-Appl
Immunohistochem Mol Morphol 2002;10:332, mucinous & tubular spindle cell-Virchows
Arch 2005;447:978, medullary, papillary,
tubulocystic and urothelial-AJSP
2005;29:747), squamous cell (various sites-Histopathology
1993;23:45), thyroid
papillary (references above) Negative stains: cornea (Cornea
2003;22:533), hepatocytes (Hepatology
1996;23:476), hepatocellular carcinoma (usually), pancreatic
islets, parachordoma, thyroid hyalinizing trabecular adenoma,
trichilemmoma (Br
J Dermatol 2003;149:99) Micro images: ameloblastoma
(various images);
cholangiocarcinoma
with lymphoepithelioma-like component; clear
cell odontogenic carcinoma (fig 7b); colonic
adenomcarcinoma; endolymphatic
sac tumor; pancreatic
ductal carcinoma (fig D); renal
low grade tubular-mucinous neoplasm; squamous cell
carcinoma-oral (fig b); stomach-complete
intestinal metaplasia; thyroid
papillary carcinoma #1; #2-follicular
variant (fig d); thyroid
lesions-various; thyroid
nodular goiter has focal CK19+ (fig i) References: OMIM 148020,
UniProtKB Present in brown rats, not humans No information is available as of Apr07 Molecular weight of 48 kDa Minimal information is available as of Apr07 Uses: no significant clinical use by pathologists Positive staining (normal): cornea of mice (Eur
J Cell Biol 2006;85:803) Positive staining (disease): pancreatic carcinoma (Genes
Chromosomes Cancer 2001;30:123) References: OMIM 606194 Molecular weight of 55 kDa (predicted) Minimal information is available as of Apr07 Uses: no significant clinical use by pathologists Positive staining (normal): keratinocytes, colon, placenta, spleen; less
expression in thymus and testis (J Invest Dermatol 2002;119:692) References: OMIM 607742 One of several possible clones for CK8 An antibody to low molecular weight (LMW)
cytokeratins - more commonly used LMW antibodies are CAM 5.2, CK8 and AE1 Uses (for this clone): (1) to distinguish sebaceous carcinoma (35 beta H11+)
from squamous cell or basal cell carcinoma (35 beta H11 neg, Pathol
Res Pract 1993;189:888) (2) to distinguish choroid plexus papilloma (35 beta
H11+) from choroid plexus carcinoma (35 beta H11 neg, Arq
Neuropsiquiatr 2004;62:600) Positive staining (normal): prostate luminal cells (Virchows
Arch A Pathol Anat Histopathol 1992;421:157), skin-sebaceous glands (J
Dermatol 1994;21:553), skin-sweat glands (Arch
Dermatol Res 1993;285:6) Positive staining (carcinoma): non-squamous carcinomas including cervical
adenocarcinoma (Am
J Obstet Gynecol 1992;166:1655), Paget’s
cells (Gynecol
Oncol 1992;46:216), prostate (Virchows
Arch A Pathol Anat Histopathol 1992;421:157), sebaceous carcinoma (references above) Negative staining: basal cell and squamous cell carcinoma (references above) Usually used in a cytokeratin cocktail with AE3 (see AE1-AE3) Detects high molecular weight CK10, 14, 15 and CK16
and low molecular weight CK19; these are acidic (type I) cytokeratins Uses:
highlight bile ducts in liver transplant rejection, particularly if
inflammation present (J Clin Pathol 1994;47:303) Positive staining (normal): most epithelium; including bile ducts, bronchial
gland secretory cells (Histol
Histopathol 2005;20:865) Positive staining (disease): most carcinomas, including biliary tumors (benign or
malignant, AJSP
1988;12:187); also
mesothelioma (AJCP
1987;88:610) Negative staining: adrenocortical carcinoma, basal cell carcinoma, hepatocytes,
hepatocellular carcinoma (AJCP
1985;84:697) Micro images: breast
adenomyoepithelioma #1 (glandular cells are AE1+, myoepithelial cells are
negative); liver-bile
ducts in severe acute rejection with dense lymphoid infiltrate: H&E (top),
AE1 (bottom); liver-bile
ducts in chronic rejection #1 with dense lymphoid infiltrate: H&E (top), AE1
(bottom); #2
References:
J Cell Biol 1984;98:1388, J Cell Biol 1982;95:580 Often used in a cytokeratin cocktail with AE1 (see AE1-AE3) Detects high molecular weight CK1, 2, 3, 4, 5 and CK6
and low molecular weight CK7 and CK8; these are basic (type II) cytokeratins Often considered a high molecular weight antibody
(CK1-CK6 are high molecular weight, CK7-CK8 are low molecular weight) Another high molecular weight keratin is 34 beta E12 Caution: AE3 is also the name of a chloride/bicarbonate anion exchanger (Biochem J 2003;371:687) Positive staining (normal): most epithelium; also nodal reticulum cells (Archives 2002;126:248) Positive staining (disease): most carcinomas; also adrenocortical oncocytoma (AJSP
1998;22:603, lichen amyloidosus
and macular amyloidosis (J
Eur Acad Dermatol Venereol 2004;18:305), pterygium (Yan
Ke Xue Bao 2000;16:48) Micro images: nodal
reticulum cells References:
J Cell Biol 1984;98:1388, J Cell Biol 1982;95:580 Broad spectrum keratin antibody for CK1-4, 10-11 (Jpn J Clin Oncol 1998;28:480) or CK1, 2, 5-8, 11, 14, 16-18 (Abcam) Not used as frequently as AE1-AE3 Uses: (1) detect tumor cells in bone marrow (Jpn J Clin Oncol 1998;28:480) (2) detect micrometastases in lymph nodes (Mod
Path 2002;15:641, free full text) (2) label tumor cells for flow cytometry from
archival specimens (AJCP
1998;110:227) Positive staining (normal): most epithelium (J
Invest Dermatol 1983;81:351) Positive staining (disease): most carcinomas; also craniopharyngioma (Acta
Neurochir (Wien) 2001;143:147), liver epithelial neoplasms (Am
J Pathol 1987;127:530) Micro images: breast
carcinoma metastases to axillary nodes Broad-spectrum cytokeratin marker which stains high
and low molecular weight cytokeratins (CK 5, 6, 8, 17 and probably 19) Uses: (1) detect micrometastases in lymph nodes (BJU
Int 2006;98:70) (2) detect positive margins in Mohs’ surgery (Dermatol
Surg 2003;29:375) (3) double immunostaining with laminin or collagen
type IV is useful to detect microinvasion in VIN or CIN (Archives 2005;129:747) Positive stains (normal): most epithelial cells, including lung type II
epithelial cells (Am J Respir Cell Mol Biol 1998;18:786), trophoblast (Acta
Obstet Gynecol Scand 2003;82:722), uterine smooth muscle (Histopathology
1995;27:407) Positive stains (disease): most carcinomas (J Histochem Cytochem 2001;49:1369), mesothelioma (Am
J Dermatopathol 1997;19:261),
pituitary adenoma (Eur J Endocrinol 2003;148:357) Negative stains: myofibroblastic tumors (or weak, J
Cutan Pathol 2003;30:393) Micro images: adenocarcinoma-pleural
effusion; anaplastic
thyroid carcinoma is MNF116+ (fig A); breast-infiltrating
ductal carcinoma; carcinoma
in situ and invasive (various)-double immunostaining with collagen type IV #1;
#2;
cardiac
myxoma with glandular differentiation; primary
cutaneous localized amyloidosis: MNF 116 stains the amyloid (fig 3) Micro images: lung
transplantation patient with CMV mimicking carcinoma (fig 5/6) Micro images: Contributed by Leica Microsystems, Biosystems Division - placenta-CMV
early gene RNA using probe (PB0614)-in situ hybridization DCC Tumor suppressor gene at 18q; “Deleted in Colon
Cancer” Related structurally to cell adhesion molecules Important prognostic marker in stage II colon cancer Desmogleins Constituents of desmosomes that anchor intermediate
filaments Autoantibodies to desmoglein-3 cause pemphigus
vulgaris Autoantibodies to desmoglein-1 cause pemphigus
foliaceus (more superficial) DOPA reaction For melanocytic cells Presence of tyrosinase is determine by deposition of
brown pigment Also called MADH4, SMAD4 Tumor suppressor gene on 18q21.1 that mediates the
downstream effect of the TGF-beta superfamily signaling, resulting in growth
inhibition and apoptosis Inactivation relatively specific for pancreatic
adenocarcinoma, but only 55% sensitive in usual pancreatic ductal
adenocarcinomas and 34% sensitive in ampullary carcinoma; may not be
inactivated in IPMN associated colloid carcinoma (Mod
Path 2005;18:1034) Mutations in 20% of colorectal carcinomas Interpretation: staining is primarily cytoplasmic; adjacent pancreatic stroma also
stains in benign and malignant mucinous cystic neoplasms Use: loss
of expression specific for pancreatic malignancy (in-situ or invasive) vs.
benign process, particularly helpful in biopsies (AJCP
2001;116:831); expression in PanIN may predict its expression in a
subsequent invasive ductal adenocarcinoma, and distinguish recurrent or
persistent adenocarcinoma from a second primary adenocarcinoma, Hum
Path 2001; 32:638 Positive staining (normal): normal pancreatic ducts, islets and acini; Positive staining (tumor): carcinoma in situ in mucinous cystic neoplasms Negative staining: invasive mucinous cystic neoplasms (AJSP
2000;24:1544), some
in-situ and invasive pancreatic adenocarcinomas Micro images: DPC4
staining in invasive ampullary carcinoma and high grade dysplasia; Micro images: staining
in pancreatic lesions - PANIN, invasive disease, IPMN Gene at 17q12 translocated in Ewing’s sarcoma/PNET E2A Transcriptional factor at 19p13.3 that binds DNA E2A- PBX1 Fusion protein found in 25% of early pre-B ALL, 5-7%
of pediatric ALL via t(1;19)(q23;p13) N terminal of protein has E2A, C terminal has PBX-1 Transcriptional transactivator; precise mechanism not
known Poor prognostic factor in childhood ALL, although
some t(1;19) translocations in pediatric ALL lack E2A-PBX1 expression and have
better prognosis Associated with L1 subtype of ALL; positive for CD9,
CD10, CD19 EBV encoded RNA; nuclear RNA portions of EBER 1 and 2
genes Interpretation: nuclear stain Micro images: Contributed by Leica Microsystems, Biosystems Division - Hodgkin’s
lymphoma-in situ hybridization using EBER probe (PB0589) Calcium-dependent transmembrane epithelial protein
that promotes intercellular adhesion molecule Its loss is associated with invasive carcinoma Tumor suppressor gene CDH1 is at 16q22.1 Abnormal function in carcinomas may facilitate cellular
detachment leading to metastasis Interpretation: normal pattern is membranous staining Uses:
distinguish LCIS from DCIS in indeterminate cases (AJSP
2001;25:229) Bladder:
Reduced expression in invasive bladder carcinoma Breast cancer: Absent expression in lobular carcinoma and LCIS; reduced expression in
ductal carcinoma; positive expression in small cell carcinoma (AJSP
2001; 2001;25:831) and DCIS (AJSP
2001;25:229) Stomach: signet
ring carcinomas negative for E-cadherin expression Colonic adenocarcinoma: Diminished membranous staining compared to adenomas
with misplaced epithelium (AJSP
2002;26:206) Micro images: Paget’s
disease of breast - Paget cells are CK7+, E-cadherin negative; inflammatory
carcinoma of breast - A: tumor emboli in dermal lymphatic; B: membranous E
cadherin staining; (2) A:
inflammatory carcinoma with lobular histology (H&E); B: membranous E
cadherin staining Epidermal Growth
Factor Receptor; also called HER1, c-erb-B1; on 7p Member of epidermal growth factor receptor family
(also HER2) 170 kDa transmembrane receptor that induces tyrosine
kinase activity affecting cell growth Activated by epidermal growth factor and transforming
growth factor alpha Lung adenocarcinoma patients with specific mutations
may have clinical response to gefitinib (targets EGFR kinase) Brain: amplification
is favorable prognostic factor in glioblastoma multiforme (Archives
2005;129:624) Breast: 6%
of breast carcinomas show EGFR amplification (7-18 copies) associated with EGRF
protein overexpression but not HER2 status; patients may be responsive to EGFR
therapy (Mod
Path 2005;18:1027) Colon:
present in 60-80% of colorectal carcinomas, but these tumors lack gene
amplification (Mod
Path 2005;18:1350), and patients
don’t respond to gefitinib Lung: mutations are associated with terminal respiratory
unit type adenocarcinoma of lung (AJSP
2005;29:633); EGRF tyrosine kinase inhibitors (gefitinib) show
rapid clinical response in 10% of lung cancer patients Positive staining (normal): endometrial stromal cells Positive staining (disease): endometrial stromal sarcoma (AJSP
2005;29:485); also adenosarcoma,
MMMT, squamous cell carcinoma of lung, 80% of non-small cell lung cancers Micro images: amplification
by FISH in glioblastoma multiforme; immunostains
and amplification in breast carcinoma; immunostaining
in colorectal carcinoma; chromogenic
in situ hybridization in colorectal carcinoma Also called Verfoeff-van Gieson Stains elastic fibers black Outlines elastic lamina of muscular arteries and
media of aorta Background is trichrome Micro images: normal
aorta, media with parallel elastic fibers, van Gieson stain; angiolymphatic
invasion in infiltrating ductal carcinoma of breast; not
angiolymphatic invasion Elongin Transcription elongation factor; negatively regulated
by von Hippel Lindau protein Increases rate of elongation by suppressing RNA
polymerase pausing Heterotrimer of A, B and C subunits VHL product competes with subunit A for binding with
BC, causing more "pausing", less transcription A: catalytic subunit of ABC complex; competes with
VHL for binding of Elongin (homologous coding region) B: positive regulator of Elongin C: positive regulator of Elongin; similar to E. coli
termination factor Rho's RNA binding region, so binding of nascent RNA may be
important Endothelin-1 Vasoconstrictor protein associated with hypertension
in African-Americans See also EBER1 above Strongly associated with sinonasal (NK) lymphomas Associated with monoclonal B cell lymphoproliferative
disorder (high grade) and immunosuppression (methotrexate) for autoimmune
disease Expresses LMP1, which prevents apoptosis via bcl2
interaction Expresses EBER1, which transactivates host genes ERCC1 Excision Repair
Cross-Complementation group 1 DNA repair gene Genetic polymorphisms may affect patient response to
platinum-based chemotherapy in non-small cell lung carcinoma (Clin Lung Cancer 2009;10:118,
Clin
Cancer Res 2004;10:4939, Eur
J Cardiothorac Surg 2008;33:805) Diagrams: nucleotide
excision repair Two subtypes: ER-alpha and ER-beta ER-alpha: “classic” functions of ER; may render
breast epithelium susceptible to proliferative stimulation of estrogen;
expressed in breast and endometrium ER-beta: “housekeeping” functions; expressed in
normal ovary and granulosa cells; carcinoma of breast, colon, prostate Both alpha and beta share highly conserved DNA
binding domain and commonly interact with estrogen-regulating factors, but may
affect different genes Presence
of estrogen (type alpha) and progesterone receptors correlates best with
response to anti-estrogen treatment (tamoxifen or others) or chemotherapy, only
weakly with prognosis; presence is associated with better differentiated
tumors, older age Evaluate
% of tumor nuclei stained and intensity of staining (none, weak, moderate,
strong) Immunostaining
now done on paraffin fixed tissue (previously required fresh tissue) Metastases
to skin are often positive for androgen receptor, even if ER-, PR- (Mod
Path 2000;13:119) Antigen
retrieval techniques are required for ER if glyoxal fixative is used (Hum
Path 2004;35:1058) Compared
to ER, PR staining adds only a limited amount of additional predictive
information for response to hormonal therapy (Mod
Path 2004;17:1545) Interpretation: nuclear stain; cytoplasmic staining only is a negative result Uses: (1)
in breast cancer, predicts response to tamoxifen or other anti-estrogens; also
prognostic marker for survival (ER+ is favorable); (2) relatively specific for
breast origin (but numerous exceptions); (3) distinguishes endocervical (ER-)
from endometrial (ER+) adenocarcinomas (AJSP
2002;26:998) Positive staining (disease): breast carcinoma (varies by subtype and tumor
grade); endometrial adenocarcinoma (75%); ovarian serous, mucinous and
endometrioid adenocarcinoma (AJSP 2001;25:667), papillary urothelial
carcinoma of bladder (10-20%) and ovarian transitional cell carcinoma (90%, Archives
2005;129:194) Negative staining: endocervical adenocarcinoma, ovarian clear cell carcinoma Micro
images: peritoneal
fluid from metastatic lobular carcinoma of breast with intraperitoneal
carcinomatosis (fig 3); papillary
urothelial carcinoma of bladder (fig 3), ovarian transitional cell carcinoma
(fig 6); breast
carcinoma metastatic to stomach: ER+ (fig 3a), PR+ (3b); GCDFP-15+ (3c); colloid
carcinoma of breast - ER+, PR+, chromogranin+, synaptophysin+; DCIS
with ER and HER2 double immunostaining Contributed by Leica Microsystems, Biosystems Division - invasive ductal
carcinoma-ER (6F11) with intense nuclear staining References: Hum
Path 2001;32:113 (ER type beta),
Cancer
Res 2002;62:4849 (ER beta cx, a splice variant) ets-1 Proto-oncogene at 11q23-24, Also called v-ets Member of Erythroblastosis virus association Transforming
Sequence family of DNA binding transcription factors, all with a common
84 amino acid sequence called Ets domain; also a specific transcription factor Activates transcription of urokinase-plasminogen
activator, MMP-1, MMP-3, MMP-9, all associated with metastases Present in both tumor and stromal cells Expression induced by acidic and basic vascular
endothelial growth factor, vascular endothelial growth factor, epidermal growth
factor Ovary:
mRNA expression in solid ovarian carcinomas and effusions of serous ovarian
carcinoma is poor prognostic marker, AJSP
2001;25:1493 ETV1 Gene at 7p22 translocated in Ewing’s sarcoma/PNET;
overexpressed in chronic myeloid leukemia and acute myeloid leukemia
transformed from myelodysplastic syndrome EWS At 22q12 Translocations: t(9;22)(q22;q12) with TEC gene on #9 in myxoid
chondrosarcoma t(11;22)(p13;q12) in desmoplastic small round cell
tumor with WT1 gene on #11 t(11;22)(q24;q12) in Ewing’s sarcoma/PNET EWS/FLI-1 Fusion protein of Ewing's sarcoma/PNET localized to
nucleus, associated with t(11;22)(q24;q12) More powerful transcription activator than normal
FLI-1, can transform NIH 3T3 cells EWS-WT1 Fusion protein of desmoplastic small round cell
tumor, associated with t(11;22)(p13;q12) Fusion gene may lose the tumor suppressor effect of
WT1 and gain the transactivation activity of EWS, functioning as a novel
transcription factor that activates expression of target genes normally
repressed by WT1, such as PDGF-A Fascin 55 kDa protein that forms tight and stable
cytoplasmic bundles with filamentous actin Fascin-1: most common type; present in specialized
cells with extensive surfaces or migratory potential, such as neurons, glia,
dendritic cells, macrophages, skeletal and smooth muscle, endothelial cells;
not normal epithelial cells Fascin-2: in retina; fascin-3: in testis Actin-bundling protein with important role in cell
motility and adhesion Overexpression in tumors often associated with
aggressive disease Positive staining (disease): carcinoma of biliary tract, breast, colon, lung, ovary,
pancreas, skin; follicular dendritic cell tumors, Hodgkin’s lymphoma-classic
subtype (highly sensitive), interdigitating dendritic cell tumors Langerhans
cell histiocytosis, urothelial carcinoma (noninvasive papillary or invasive) Negative staining: normal epithelial cells, normal urothelium, benign urothelial lesions Micro images: synovial
sarcoma (positive) References: Hum
Path 2005;36:741 Micro images: highly
malignant adult hepatic blastoma - fig A: ferritin; B: alpha-fetoprotein; C:
HepPar1; D: CK8; E: p53; F: beta-catenin Protein is member of ETS family of DNA binding
transcription factors; gene is fli-1, present on #11q24 Involved in cellular proliferation, tumorigenesis,
embryologic development of blood vessels 90% of Ewing’s sarcoma/primitive neuroectodermal
(PNET) tumors have t(11;22)(q24;q12) which results in fusion of EWS to FLI-1 Sensitive and specific for Ewing’s sarcoma/PNET; also
sensitive/specific for vascular tumors vs. sarcomas, carcinomas or melanomas (AJSP
2001;25:1061) Interpretation: call positive if nuclear staining of 10% of tumor cells (usually is
>50%) and positive internal controls of endothelial cells and small lymphocytes
(AJSP
2001;25:1061) Note:
other vascular tumor markers (CD31, CD34, von Willebrand factor) are membranous
or cytoplasmic stains Note: cytoplasmic
staining present in breast epithelium (benign/malignant) and cutaneous eccrine
glands Uses:
differentiate Ewing’s sarcoma/PNET of kidney (positive) from blastema
predominant Wilms’ tumor (negative); diagnosis of vascular tumors Positive staining (normal): endothelial cells, T cells, small lymphocytes Positive staining (disease): Ewing’s sarcoma/PNET, vascular tumors, lymphomas Negative staining: blastema predominant Wilms’ tumor; carcinomas, melanomas, non-vascular
sarcomas; muscle, nerve, fibroblasts Late B cell differentiation marker Positive staining: mantle cell lymphoma, hairy cell leukemia, prolymphocytic leukemia Negative staining: Chronic lymphocytic leukemia Melanin stain; difficult to interpret faint staining
in sparsely positive cells Melanin granules reduce ammonia-silver nitrate and
turn black Micro images: melanoma Galectin-3 Member of carbohydrate-binding protein family known
as lectins One of 14 galectins, which function as cell receptors
for N-acetyl-lactosamine moieties present on most extracellular matrix
components) Also member of the beta-galactoside-binding protein
family that plays an important role in cell-cell adhesion, cell-matrix interactions,
macrophage activation, angiogenesis, metastasis, apoptosis Uses: in
one study, Gal-3+ with Ki-67 > 6% was associated with parathyroid carcinomas
vs. adenomas (Hum
Path 2005;36:908) Positive staining (normal): endothelial cells, peripheral nerve,
folliculostellate cells of adenohypophysis Positive staining (disease): tumors of thyroid, head and neck, liver, colon, prolactinomas;
parathyroid carcinoma; rarely in reactive of hyperplastic parathyroid lesions Micro images: galectin-3
staining in lung squamous and adenocarcinoma Reference: Mod
Path 2005;18:1264 (prognostic significance in lung squamous cell and
adenocarcinoma) As a hematology stain, works best with alcohol fixed
smears As a histology stain, detects mast cells and
microorganisms, such as Giardia or Helicobacter A "Romanowsky-type" stain, composed of
mixtures of methylene blue, azure, and eosin compounds Methylene blue is a metachromatic stain, meaning that
some tissue components (mast cell granules ,cartilage, mucin, amyloid) stain
purple and not blue Glial fibrillary acidic protein
(GFAP) Intermediate filament for astrocytes (normal,
reactive, neoplastic) Positive staining (disease): CNS tumors, colonic schwannoma (AJSP
2001;25:846) Micro images: myxopapillary
ependymoma of broad ligament (fig 8b) GLUT1 Facilitative glucose transporter; activated by
hypoxia-sensing cellular pathways; may sustain cellular metabolism via
glycolysis when hypoxia is present Positive staining (normal): red blood cells, blood-brain barrier, perineurium Positive staining (disease): various carcinomas, including fallopian tube
carcinomas (Archives
2005;129:651) Negative staining: benign epithelium GLUT-4 Glucose transporter 4 Highly expressed in mitochondria-rich (oxyphil) cells
in normal/neoplastic tissue, including gastric parietal cells, Hashimoto
thyroiditis, Hurthle cell adenomas and carcinomas, occasional oxyphil
parathyroid hyperplasias, occasional oxyphil parathyroid adenomas, renal
oncocytomas, salivary gland oncycytomas, Warthin tumors, hibernomas Glycophorin A Also called CD235a Positive staining: erythroid cells, AML-M6 Negative staining: AML M0-M5, M7 Glycosaminoglycans Heteropolysaccharides which contain an N-acetylated
hexosamine in a characteristic repeating disaccharide unit involving alternate
1,4- and 1,3-linkages consisting of either N-acetylglucosamine or
N-acetylgalactosamine GMS Special stain for detecting fungi and Pneumocystis
carini Stains cell walls and outlines these organisms; may
have artefactual background staining Micro images: Pneumocystis
carinii; Cryptococcus
neoformans; Coccidioides
immitis; Aspergillus
fumigatus Gram stain Stain to detect and differentiate bacteria Method: Apply crystal violet, then iodine, then decolorize by
alcohol/acetone, then counterstain by safranin/fuchsin Gram positive bacteria retain the crystal
violet-iodine complex after decolorization, are not counterstained, and appear
purple Gram negative bacteria have a different cell wall
structure, don’t retain the crystal violet-iodine complex after decolorization,
and so are counterstained by safranin/fuchsin and appear pink/red Paraffin sections: Use neutral red instead of safranin; gram negative
organisms usually stain poorly because their bacterial wall lipid is removed in
tissue processing Note: with hematoxylin and eosin staining on paraffin
sections, bacteria appear as blue rods or cocci regardless of gram reaction;
colonies appear as fuzzy blue clusters Rapid diagnostic strategy for bronchioalveolar lavage
samples consists of Gram stain and bacterial ATP assay (Archives 2005;129:78) Not suitable for burn wound surfaces (Archives 2003;127:1485) Micro images: Fungi - Fusarium
in peritoneal fluid Gram positive tissue sections - Bacillus
anthracis in CSF; Lactobacillus
osteomyelitis; methicillin
resistant Staphylococcus aureus (MRSA) pneumonia; Mycobacterium
abscessus (soft tissue) References: J Clin Pathol 1979;32:187, University
of Utah method, University of
Nottingham method Granzyme B Enzyme associated with cytotoxic T lymphocytes;
induces apoptosis in target cells of these lymphocytes Grimelius Micro images: breast carcinoma - focal
Grimelius+ cells in neuroendocrine DCIS; infiltrating
ductal carcinoma with focal Grimelius+ cells; Grimelius
stain+ colloid carcinoma #1; #2 Kidney tumors: stain must have pH between 1.5 and 2.0 Clear cell and papillary renal carcinoma have focal,
coarse, droplike staining Note: hemosiderin in any tumors will also stain
positive Uses:
Helpful in distinguishing chromophobe renal cell carcinoma (intensely positive
in large percentage of cells with reticular staining) from oncocytoma (usually
negative; if positive - fewer cells with less intensity and dustlike staining) HAM 56 Stains histiocytes, endothelium, adenocarcinoma Negative staining: osteoclast-like giant cells Micro images: giant
cell tumor of bone - mononuclear cells are positive (fig 1B); giant
cell tumor of tendon sheath - mononuclear and giant cells are positive (fig 2B) Also called TSC1 On 9q34 Mutations cause tuberous sclerosis, an autosomal
dominant disease beginning in infancy or early childhood with mental
retardation and seizures, angiomyolipomas, subependymal giant cell tumors,
cutaneous angiofibromas, cardiac rhabdomyomas, lymphangioleiomyomatosis and
multifocal multinodular pneumocyte hyperplasia Broadly expressed in many organs and tissues,
including myometrium and most smooth muscle Negative regulator of cell cycle – inhibits cell
proliferation Inactivation causes benign neoplasms in patients with
tuberous sclerosis complex Combination of eosin and methylene blue Uses:
detect eosinophiluria (eosinophils in urine) - eosinophils are bright red or
pink (New Engl J Med 1986;315:1516) More sensitive in urine than Wright’s stain (Arch Pathol Lab Med
1989;113:1256), alkaline
erythrocin B or naphthalene black (Biochem
Histochem 1993;68:146) Positive staining (disease): eosinophils, usually associated with drug-induced
acute interstitial nephritis, but also with eosinophilic cystitis,
atheroembolic renal disease, schistosomiasis, rapidly progressive
glomerulonephritis, acute prostatitis, postinfectious glomerulonephritis and
acute cystitis Micro images: image Sources for Hansel stain testing (advertisements): Lide Labs HBME Marker of mesothelial cells, named after laboratory
of Dr. Hector Battifora and MEsothelioma Also positive in various thyroid carcinomas HHV8 / KSHV top HIV p24 Micro images: placental
staining in HIV+ mothers HLA-G Non-classical MHC class I antigen that interacts with
NK cells, can present nonamer peptides and binds CD8 analogous to classic HLA
class 1 proteins May play a role in maternal tolerance toward fetal
tissue Sensitive and specific for intermediate trophoblast
in all types of gestational trophoblastic tissue (including tumors) in initial
study, AJSP
2002;26:914 Focal staining in melanoma, renal cell carcinoma,
large cell carcinoma of the lung Negative staining: cytotrophoblast, syncytiotrophoblast Human placental lactogen Also called HPL Positive staining: placental site trophoblastic tumors, exaggerated placental sites Negative staining: placental site nodules (or focal), epithelioid trophoblastic tumors (or
focal) ICE Interleukin
1 beta Converting Enzyme; related to ced-3 in C. elegans Formed from cleavage of pro-ICE; then activates
inflammatory cytokine interleukin 1 beta Has early role is signaling pathway for Fas dependent
apoptosis Nuclear substrates: PARP, U1 RNP (U1-70 kDa), nuclear lamins, DNA dependent protein kinase Cytoplasmic substrates: protein kinase C delta, actin / other parts of
cytoskeleton Inhibitors:
p35 (baculovirus protein), CrmA (poxviral protein), aldehydes; no cellular
counterparts known Inhibin A Inhibin is a heterodimeric protein (with alpha and
beta subunits) that inhibits or activates pituitary FSH secretion Serum levels elevated (2x) in women with Down's fetus Positive staining (normal): Sertoli cells (diffuse and strong), granulosa cells,
prostate, brain, adrenal Positive staining (disease): Sex-cord stromal tumors, including Sertoli cell
tumors, adrenocortical tumors, placental and gestational trophoblastic lesions,
granular cell tumors of gallbladder and extrahepatic bile ducts (AJSP
2001;25:1200), some carcinomas Negative staining: primary ovarian carcinomas (usually) Micro images: sex
cord stromal tumor; adrenocortical
oncocytic carcinoma Inhibin B Inhibin is a heterodimeric protein (has alpha and
beta subunits) that inhibits or activates pituitary FSH secretion High serum levels associated with granulosa cell
tumors of ovary and testes Integrins Family of adhesion proteins with various functions,
including major cell surface receptors for extracellular matrix proteins Membrane glycoprotein heterodimer complexes that are
assembled by noncovalent association of alpha and beta subunits, with active
and inactive states; currently are 18 alpha subunits and 8 beta subunits, which
combine to form 24 different integrins Alpha subunit has extracellular domain that binds
matrix molecules; beta subunit has cytoplasmic domain that interacts with actin
cytoskeleton, microfilament-associated proteins and signaling mediators Functions:
(a) homing of progenitor T cells to thymus, (b) differentiation and
proliferation of B and T cells in bone marrow, transcription of genes involved
in cell-cell contacts and endothelial cell migration Activated by intracellular bacteria and by
extracellular ligand binding Inhibited by RGD (arginine-glycine-aspartic acid)
sequence, which blocks integrins from binding to ligands Integrin alpha 2b beta 3 Also called glycoprotein IIa/IIIb, fibrinogen
receptor Platelet integrin that induces platelet aggregation Antibodies to alpha2b beta3 prevent ischemia of
percutaneous coronary angioplasty Integrin alpha 3 beta 2 Fibrinogen forms cross links with this platelet
receptor during platelet aggregation Integrin alpha 4 beta 1 See CD49d Integrin alpha 5 beta 1 Also called CD29, fibronectin receptor Supports assembly of fibronectin matrix Integrin alpha 6 beta 4 Have role in tumor cell migration and invasion in
vitro Reduced expression in invasive bladder CA Principal ligand is laminin-5 protein (component of
epithelial basement membrane) Protein production is characteristic of
basal/myoepithelial type of breast carcinoma Beta4 subunit is only expressed in combination with
alpha 6 subunit Micro images: expression
in breast carcinoma References: Mod
Path 2005;18:1165 (prognostic significance) Integrin alpha v beta 3 Specifically expressed in endothelial cells of newly
formed blood vessels May play a role in central nervous system neoplasms Positive staining (disease): CNS tumors (particularly ependymomas, Hum
Path 2005;36:665) Integrin beta 2 See CD18 Interleukins (IL) Soluble factors which stimulate growth-related
activities of leukocytes as well as other cell types Enhance cell proliferation and differentiation, DNA
synthesis, secretion of other biologically active molecules and responses to
immune and inflammatory stimuli Promote survival of resting T cells which do not
proliferate in response to IL-2, 4 or 7 IL 2, 4 and 7 receptors share a common gamma chain Interleukin 2 (IL-2) Potent inducer of CTLA-4 Potent survival factor for lymphocytes Interleukin 6 (IL-6) Induces thrombocytosis by stimulating thrombopoietin Produced continuously by all mesothelioma cell lines Micro images: IL6+
producing diffuse deciduoid peritoneal mesothelioma Iron Also called hemosiderin (storage iron
granules) See also Hales colloidal iron Perl’s method (Prussian blue stain): hydrochloric acid releases the protein bound to
ferric iron, then potassium ferrocyanide binds with ferric iron to form ferric
ferrocyanide, an insoluble blue compound Hemosiderin may be present in areas of old hemorrhage
or be deposited in tissues with iron overload Hemosiderosis: stored iron does not interfere with
organ function vs. hemochromatosis: iron overload associated with organ failure Micro images: Hemosiderin,
liver, iron stain JAK Family whose members (JAK1-3, Tyk2) are critical for
cytokine signaling Associated with intracytoplasmic portion of cytokine
receptors, which serves as docking site for STAT monomers; activated JAK
activates and phosphorylates the STAT monomers, which then dissociate, dimerize
and migrate to nuclear, where they interact with specific DNA binding elements
and activate transcription of cyclin D1, bcl-Xl, bax, bcl2, c-myc, c-Jun,
c-kit, and IL-10 Jak3: Janus kinase 3, a tyrosine kinase that
activates STAT3 in response to cytokine stimulation Positive staining (disease): ALK+ anaplastic large
cell lymphoma (Hum
Path 2005;36:939) References: Archives
2005;129:990 jun AP-1 protein Gene is at 1p31-32; protein product binds DNA in a complex
with fos JunB At 19p13 Member of Jun family of proteins (also c-Jun and
JunD), that are components of AP-1 transcription factor complex, involved in
cell proliferation and apoptosis May bind with CD30 gene promoter Interpretation: nuclear stain Positive staining (disease): anaplastic large cell lymphoma (ALK+ or negative;
cutaneous or not), classic Hodgkin’s lymphoma, CD30+ diffuse large B cell
lymphoma, lymphomatoid papulosis Negative staining: nodular lymphocyte predominant Hodgkin’s lymphoma, CD30- diffuse large
cell lymphoma Micro images: CD30+
lymphomas; classic
Hodgkin’s lymphoma and anaplastic large cell lymphoma References:
Mod
Path 2005;18:1365) Type of immunoglobulin light chain Kappa/lamba ratio is usually 2:1 Restricted expression of either kappa or lambda
suggests monoclonality and a neoplastic process Micro images: primary
localized laryngeal amyloidosis (kappa-left; lambda-right) Micro images contributed by Leica Microsystems,
Biosytems division: myeloma of
bone marrow with in situ hybridization staining for kappa (left) and
lambda (right) light chains using Kappa Probe (PB0645), Lambda Probe (PB0669)
and Bond Polymer Refine Detection Type of immunoglobulin light chain Kappa/lambda ratio is usually 2:1 Restricted expression of either kappa or lambda
suggests monoclonality and a neoplastic process
Micro images contributed by Leica Microsystems, Biosytems division: myeloma of
bone marrow with in situ hybridization staining for kappa (left) and lambda (right) light chains using Kappa Probe (PB0645), Lambda Probe (PB0669) and Bond Polymer Refine Detection Major component on basement membrane, with type IV
collagen Trimeric glycoproteins (at least 11 types) with
integrin binding site Defects in laminin proteins cause skin blistering and
myocardial diseases Antibodies to laminin inhibit lung branching
morphogenesis Production of alpha-1 laminin by epithelial cells and
mesenchymal cells depends on extent of mesenchymal and epithelial contact with
each other; modulates mesenchymal cell shape Uses:
double immunostaining with cytokeratin is useful to detect microinvasion in VIN
or CIN (Archives
2005;129:747) Micro images:
laminin5
expression in normal breast, DCIS and invasive ductal breast carcinoma LANA Human herpesvirus-8 (HHV8) Latency Associated
Nuclear Antigen Highly expressed during latent HHV8 infection Interacts with pRb, which regulates beginning of S
phase of cell cycle; also inhibits p53 Presence in serum is associated with developing Kaposi’s
sarcoma in immunocompromised individuals Micro images: LANA+
Kaposi’s sarcoma Positive staining (disease): HHV8 associated Kaposi’s sarcoma (endothelial and
spindle cells, 92% sensitive and highly specific), primary effusion lymphoma,
multicentric Castleman’s disease References: Mod
Path 2005;18:463 (LANA vs. HHV8
in Kaposi’s sarcoma) Lecithin Major component of cell membrane, usually outer
surface composed of phosphatidylcholine (phosphocholine and
diglyceride) Lectins Plant-derived proteins that bind specifically to
carbohydrate groups acting as lectin receptors Ulex europeaus lectin combines with H antigen that
corresponds to O blood group Type of enzyme histochemistry Chloroacetate esterase resists effects of formalin
fixation and paraffin embedding Uses:
identify mast cell disorders, myeloid disorders Positive staining (normal): mast cells, myeloid cells Lipochrome (lipofuscin)
pigments Breakdown products within cells from oxidation of
lipids and lipoproteins Also called “wear-and-tear” pigments in heart, liver,
CNS, adrenal cortex (zona reticularis), testis interstitium and seminal vesicle Stains with Sudan black B, long Ziehl-Neelson acid
fast, Schmorl's methods Lipochrome may have strong orange autofluorescence in
formalin-fixed, unstained paraffin sections Micro images: Lipochrome
in liver, H and E stain LMP Latent Membrane
Protein of EBV Interpretation: cytoplasmic or membranous staining Luxol fast blue Myelin stain Based on strong affinity of copper phthalocyanin dye
for phospholipids and choline bases of myelin Use ficin enzymatic retrieval, not heat Positive staining: squamous mucosa; histiocytes Martius scarlet blue trichrome Stains for fresh (orange-yellow), mature (red) or old
(blue) fibrin Micro images: hepatocellular carcinoma and
intravascular tumor - (1) without
thrombus - A: H&E; B: Martius scarlet blue; C: factor XIIIa; D: CD34;
(2) with
thrombus - A: H&E; B: Martius scarlet blue; C: fibrinogen; D: CD34; (3)
tumor
herniation into vessel wall; A: Martius scarlet blue; B: H&E Maspin Tumor suppressor protein with serine protease
inhibition (Serpin) activity at 18q21.3 Directly regulated by p53; inhibits tumor cell
motility, invasion, metastasis and angiogenesis Cervical squamous cell carcinoma: loss of expression
from CIN 3 (HG SIL) to invasive squamous cell carcinoma (Mod
Path 2005;18:1102) Oral squamous cell carcinoma: maspin+ tumors have
longer overall survival than maspin- tumors (Oncogene
2000;19:2398) Positive staining (normal): breast, prostate epithelium Positive staining (disease): ovarian, pancreatic and gastric carcinomas Negative staining: breast carcinomas, prostate carcinomas; normal pancreas Micro images: cervical
CIN 3 (HGSIL) and squamous cell carcinoma May-Grünwald-Giemsa Used for H. pylori; also blood and bone marrow
staining Melanin Pigment normally found in skin, eye, substantia
nigra, melanomas Melanin stains are Fontana-Masson (stains melanin
black) and Schmorl’s method (stains melanin blue-green) Bleaching with potassium permanganate or hydrogen
peroxide is used to remove melanin to examine cellular morphology Note:
pseudomelanin of melanosis coli, usually found in macrophages, is PAS positive;
true melanin is not Micro images: Melanin
pigment in cells of malignant melanoma, Fontana-Masson stain menin Gene at 11q13; mutations cause MEN1 syndrome May regulate transcription of multiple
differentiation regulating genes Menin mutations and allelic loss of 11q13 are also
reported in sporadic carcinoid tumors and sporadic pancreatic endocrine tumors Mesothelin 40 kDa differentiation antigen; precursor protein’s
amino portion is megakaryocytic potentiating factor Cytoplasmic membrane glycoprotein found on surface of
mesothelial cells, mesotheliomas, ovarian carcinomas, pancreatic adenocarcinoma May place a role in cellular adhesion Positive staining (normal): mesothelial cells Positive staining (disease): mesotheliomas, ovarian surface carcinomas Negative staining: benign bile duct lesions Microsatellite instability Changes at (CA)n and (GT)n repeats, associated with
dysfunction of DNA repair mechanisms Involve MLH1, MSH2 proteins Associated with all cases of hereditary nonpolyposis
colorectal cancer and 15% of sporadic colorectal cancers Hallmark of hereditary nonpolyposis colon cancer
(HNPCC) associated tumors is defective mismatch repair, reflect in tumor tissue
as microsatellite instability and loss of mismatch repair proteins MLH1, MSH2,
MSH6, PMS2 Mismatch repair defects found in 15% of sporadic
colorectal cancer in >90% of HNPCC associated cancers Defects present in 65% of adenomas from HNPCC
patients - loss of staining in patient suspected of having HNPCC may be used to
direct mutation analysis (Mod
Path 2005;18:1095) Micro images: loss
of mismatch repair proteins in adenomas from HNPCC patients with disease
causing mutations MSH1 and MSH2 Genes mutated in hereditary nonpolyposis colorectal
carcinoma and sporadic colorectal carcinoma with microsatellite instability Mucins Also called mucopolysaccharides; major glycoprotein
components of mucus under normal circumstances Large, highly glycosylated proteins with repeat
tandem domains rich in serine and threonine sites for O-glycosylation; also
contain glyco-conjugates [mucoproteins, glycoproteins, glycosaminoglycans,
glycolipids] with high content of sialic acid [N-acyl derivative of neuraminic
acid] or sulfated polysaccharide Neuraminic acid is a 9 carbon amino sugar derived
from mannosamine and pyruvate Mucin stains highlight carbohydrate portion of
glycoproteins, not the protein component Best pan mucin combination may be PAS and Alcian blue MUC - epithelial mucins, share a common characteristic
of an elevated number of sequences repeated in tandem, that are different for
each MUC Two main families of MUC genes – gel forming /
secreted mucins at locus 11p15 (MUC2, MUC5AC, MUC5B, MUC6) and membrane-bound
mucins at locus 7q22, 3q and 1q21 (MUC1, MUC3A, MUC3B, MUC4, MUC12, MUC13,
MUC17) Mucin types include acid mucins and
neutral mucins Acid mucins: simple non-sulfated,
simple mesenchymal, complex sulfated and complex connective tissue types Acid-simple non-sulfated: contain sialic acid, found in epithelium
(gallbladder [benign, adenocarcinoma], intestinal metaplasia in stomach);
positive for PAS, Alcian blue at pH 2.5, colloidal iron, and metachromatic
dyes. They resist hyaluronidase digestion. Acid-simple mesenchymal: contain hyaluronic acid and digest with
hyaluronic acid, found in tissue stroma and sarcomas. Positive for Alcian
blue at pH 2.5, colloidal iron, and metachromatic dyes; negative for PAS. Acid-complex sulfated: found in adenocarcinomas; usually
positive for PAS, Alcian blue at pH 1, colloidal iron, mucicarmine, and
metachromatic stains. They resist hyaluronidase digestion Acid-complex connective tissue: found in tissue stroma, cartilage, and bone;
includes chondroitin sulfate, keratan sulfate; Positive
for Alcian blue at pH 0.5; negative for PAS Neutral mucins: GI tract, prostate; stain with PAS only (negative for Alcian blue,
colloidal iron, mucicarmine, or metachromatic dyes); note that thyroglobulin
and other neutral glycoproteins are also PAS positive Mucin stains Alcian blue: stains acid-simple non-sulfated and
acid-simple mesenchymal mucins at pH 2.5, acid-complex sulfated mucins at pH
1.0 and acid-complex connective tissue mucins at pH 0.5; does NOT stain neutral
mucins Colloidal iron: acid mucopolysaccharides attract iron
particles stabilized in ammonia and glycerin; requires formalin fixation; false
positives include phospholipids and free nucleic acids; more specific if
hyaluronidase pre-digestion; stains acid-simple non-sulfated,
acid-simple mesenchymal, acid-complex sulfated mucins. Does NOT stain neutral
mucins or acid-complex connective tissue mucins For chromophobe carcinomas, have diffuse
strong staining with reticular pattern Mucicarmine: Very specific for epithelial mucins,
including adenocarcinomas; although insensitive; stain contains carmine (red coloring material) and aluminum chloride PAS (periodic acid-Schiff): stains glycogen as well as mucins, but
tissue can be pre-digested with diastase to remove glycogen; stains neutral and
acid-simple non-sulfated and acid-complex sulfated mucins; does NOT stain
acid-simple mesenchymal mucins and acid-complex connective tissue mucins References: AJSP
2005;29:881 (MUC expression in salivary gland mucoepidermoid carcinoma) MUC2 Epithelial mucin expressed in intestinal goblet cells
and airway epithelium; gene is at 11p15.5 Relatively specific for predicting colorectal origin
for Paget’s disease (AJSP
2001;25:1469) Gel-forming MUC2 mucin may act as barrier to prevent
infiltration of malignant cells in breast mucinous/colloid carcinoma Positive staining (normal): intestinal and airway epithelium Positive staining (disease): mucinous carcinomas of colon, breast, pancreas,
ovary and stomach Negative staining: stomach, breast ductal and lobular carcinomas Micro images: pregnancy
related carcinoma MUC3 (MUC3A and MUC3B) Upregulated by steroid hormones in vitro Positive staining (disease): invasive breast carcinoma, gastric carcinoma
(associated with poor prognosis) MUC4 Transmembrane or membrane bound mucin that provides a
protective layer of mucus Normally acts as barrier to apical surface of
epithelial cells, playing a protective and regulatory role Positive staining (normal): tracheobronchial mucosa, colon, stomach, cervix and
lung; normal salivary glands Positive staining (disease): pancreatic, colonic, pulmonary and gastric carcinoma MUC5AC Protects epithelium Positive staining (normal): stomach (foveolar epithelium of body and antrum),
tracheobronchial mucosa, endometrium (mucinous metaplasia, eosinophilic
change/metaplasia (Mod Path 2005;18:1243), surface syncytial change, ciliated change in 52%) Positive staining (disease): extramammary Paget disease, but not mammary Paget
disease or normal breast tissue (AJSP
2001;25:1469); mucinous
carcinoma of ovary, diffuse-type gastric carcinoma (83%) Negative staining: normal breast tissue Micro images: poorly
differentiated gastric carcinoma - fig 4a: CK20; 4b: MUC5AC; 4c: MUC6; 4d:
DAS-1; 4e: CDX2; MUC5AC+
endometrioid endometrial adenocarcinoma (fig 1d); MUC5AC
staining in proliferative endometrium with eosinophilic change MUC6 Produces protective glycoprotein coat for gut
epithelia Positive staining (normal): stomach (pyloric glands), gallbladder, colon and
endocervix Positive staining (disease): invasive ductal carcinoma of breast, gastric
carcinomas Negative staining: normal breast tissue Micro images: poorly
differentiated gastric carcinoma - fig 4a: CK20; 4b: MUC5AC; 4c: MUC6; 4d:
DAS-1; 4e: CDX2 Myeloperoxidase Enzyme cytochemistry for myeloperoxidase (not immunohistochemistry)
is the most sensitive and specific stain for myeloid leukemias and granulocytic
sarcoma Stains neutrophils strongly (diffuse granular
pattern), other granulocytes variably Positive staining (enzyme cytochemistry): neutrophils, eosinophils, monocytes (variable),
AML-M1, M2, microgranular M3 Positive staining (immunohistochemistry): granulocytic sarcoma Negative staining (enzyme cytochemistry): lymphocytes, ALL Micro images: granulocytic
sarcoma (immunohistochemistry); myeloid
sarcoma of breast (fig 5) Myogenic transcriptional regulatory protein expressed
early in skeletal muscle differentiation Sensitive but not specific for rhabdomyosarcoma due
to cytoplasmic and non-specific background staining, AJSP
2001;25:1150 Stronger staining in alveolar vs. embryonal
rhabdomyosarcomas Interpretation: nuclear immunostaining Positive immunostaining (normal): normal fetal muscle Negative immunostaining: normal adult muscle Myogenin Myogenic transcriptional regulatory protein expressed
early in skeletal muscle differentiation Sensitive and specific for rhabdomyosarcoma Focal nuclear staining in desmoid tumors, infantile
myofibromatosis, synovial sarcoma, infantile fibrosarcoma, entrapped atrophic
or regenerative skeletal muscle, AJSP
2001;25:1150 Interpretation: nuclear immunostaining Positive immunostaining (normal): normal fetal muscle Negative immunostaining: normal adult muscle Micro images: hepatorenal
embryonal rhabdomyosarcoma; desmin (fig4a), myogenin (4b) Myoglobin Oxygen binding protein Positive staining (normal): striated muscle (cardiac, skeletal) Positive staining (disease): rhabdomyosarcoma, other tumors with skeletal muscle
differentiation Myosin Contractile protein exists in smooth muscle form
(non-sarcomeric) and skeletal muscle form (sarcomeric) Neurofilament Major cytoskeletal element in nerve axons and
dendrites Consist of three distinct polypeptides, the
neurofilament triplet Metabolism appears to be disturbed in Alzheimer's
disease, as indicated by the presence of neurofilament epitopes in the
neurofibrillary tangles, and by severe reduction of gene expression for the
light neurofilament subunit of the neurofilament triplet in brains of
Alzheimer's patients Positive staining (normal): neuronal cells Positive staining (disease): central neurocytoma, neuroblastoma, medulloblastoma,
retinoblastoma, Merkel’s cell tumor of skin, pancreatic endocrine neoplasms,
carcinoid tumors, parathyroid tumors Neurofibromin Produces by NF1 gene at 17q11.2 Tumor suppressor gene; member of GTPase activating
protein (GAP) family of RAS regulatory proteins Heterogeneous mutations in neurofibromatosis type 1
(NF1), the most common autosomal dominant inherited disorder in humans (1 per
3000); characterized by benign tumors of peripheral nerves, cafe au lait spots,
retinal hamartomas; also increased risk of malignancy, gastrointestinal stromal
tumors (AJSP
2005;29:1170) Downregulates p21 and Ras, and also links integral
membrane protein with cytoskeleton; mutations cause constitutive RAS activation NF 2 At 22q11-13.1; tumor suppressor protein Produces protein called merlin or schannomin Deleted in soft tissue perineurioma Both copies inactivated in up to 60% of sporadic
meningiomas Often no protein expression in schwannoma May be involved in tumorigenesis of schwannomas and
some meningiomas NFKB Nuclear Factor
Kappa B Transcription factor that is a heterodimer of p50 and
p65/RelA RelA contains TNF-alpha binding sites Activated by TNF, radiation, daunorubicin TNF alpha and IL-1 degrade IKB inhibitory cytoplasmic
retention proteins, leading to rapid nuclear translocation of NKFB Regulates cytokine inducible gene expression,
including hemopoietic growth factors, chemokines and leukocyte adhesion
molecules N-myc Also called MYCN, gene at 2p24 Amplified gene forms double minutes and homogenously
staining regions, and produces excessive N-myc protein Neuroblastoma: amplification (>10 copies by Southern blot or FISH) associated with
poor prognosis and 1p36.3 deletions Nonspecific esterase Also called alpha-naphthyl acetate, alpha-naphthyl
butyrate Note: although abbreviation is NSE, is DIFFERENT from
neuron specific esterase Note: opposite staining for alpha-naphthyl
chloroacetate esterase Positive enzyme cytochemistry: monocytes (inhibited by sodium fluoride), AML-M4, M5,
mature T cells and T-all (cytoplasmic dot), carcinomas, megaloblastic
erythrocytes, cytoplasm focally in AML-M7 Negative enzyme cytochemistry: AML-M0, M1, M2, M3, ALL (usually) Micro images: IgA
myeloma with Auer-rod like inclusions; fig 1: May-Grunwald-Giemsa; 2:
α-naphthyl acetate esterase; 3: EM shows Auer-rod like inclusions and
rough ER; AML
M5b (fig 2) NPM-ALK fusion protein Formed by consistent breakpoints in t(2;5)(p23;q35);
has truncated NPM and ALK proteins Contains only constitutively active catalytic domain
of ALK Fusion protein found in anaplastic large cell
lymphoma (13-50%); when present, can be used to differentiate from Hodgkin’s
lymphoma Patients with fusion protein appear to have better
prognosis Appears to phosphorylate/activate members of multiple
signaling pathways influencing cell proliferation and apoptosis, including ras,
Grb2, Shc, IRS-1, JAK/STAT, PI3-kinase/AKT and FOX03a Nucleophosmin (NPM) Also called B23, numatrin; gene at 5q35 Highly conserved non-ribosomal nucleolar
phosphoprotein involved in assembling preribosomal particles into small and
large ribosomal subunits; binds with high affinity to ss nucleic acids, exhibits
activity that destabilizes the RNA helix and is associated with the most mature
nucleolar preribosomal ribonucleoproteins. May contribute active promoter to NPM-ALK; ALK
promoter is normally silent in lymphoid cells Hypothesis:
IL-2 or T-cell mediated signals activate substrates; with NPM-ALK, get
constitutive activation (note ALCL arises from activated T lymphocytes, which
depend on IL-2 for growth and viability) Fusion protein found in anaplastic large cell
lymphoma (13-50%); when present, can be used to differentiate from Hodgkin’s lymphoma Oil Red O Stain identifies neutral lipids and fatty acids Fresh smears / cryostat sections of tissue are
necessary because alcohols used in tissue processing remove lipids Rapid and simple routine stain Uses: (1) differentiate fibroma from thecoma (not that
important a distinction) (2) diagnose renal cell carcinoma, sebaceous gland
tumors of skin, lipid-rich carcinomas (3) identify fat emboli in lung tissue or clot
sections of peripheral blood Micro images: fat
emboli in lung p16 INK4a Also called MTS1, CDKN2A; at 9p21 near p15INK4b Plays crucial role in regulation of G1-S transition Tumor suppressor gene that inhibits cyclin D
dependent protein kinases CDK4 and CDK6, which prevents phosphorylation of Rb,
which prevents its dissociation from E2F transcription factor; which prevents
cell progression into S phase of cell cycle Frequently silenced in tumors by epigenetic or
genetic abnormalities, including promoter CpG methylation or less often
mutations Cervix:
overexpressed in squamous intraepithelial lesions, particularly HG SIL (97% of
biopsies, Mod
Path 2005;18:267) ALL (pediatric): homozygous deletions noted in 80% of cases with 9p21 abnormalities T-ALL:
deleted in 80% of all cases (even with normal #9) Esophageal carcinoma: high frequency of abnormalities Lymphoma:
p16 gene methylation present in 60% of pulmonary MALT lymphomas; may be early
event (Mod
Path 2005;18:1187); methylation
also associated with Hodgkin’s lymphoma, plaque phase of mycosis fungoides,
monoclonal gammopathy of unknown significance Melanoma:
abnormalities in 50% of sporadic cases Pancreatic carcinoma: high frequency of abnormalities Squamous cell carcinoma, cutaneous: mutations present Micro images: strong
full thickness expression Molecular images: p16
gene methylation in pulmonary MALT lymphomas p21 WAF1/CIP1 Gene at 6p21.2 Negative cell cycle regulator in G2-M phase and G1-S
phase Regulated transcriptionally by p53 p27 kip1 Cyclin dependent kinase inhibitor leading to cell
cycle arrest in G1 phase Member of Cip/Kip family of proteins Loss or reduced expression is associated with poor
outcome in carcinoma of breast, prostate, GI tract and lung Interpretation: nuclear stain PARP Poly (Adenoside
diphosphate Ribose) Polymerase, a nuclear enzyme Involved in DNA repair, genome surveillance and
integrity, predominantly in response to environmental stress Inhibits the Ca/Mg dependent endonuclease An immediate cellular reaction to DNA strand breakage
induced by alkylating agents, ionizing radiation or oxidants; may then mediate
DNA base-excision repair; also is an early step in apoptosis due to cleavage by
CPP32 (caspase 3), which may lead to loss of its inhibitory effect, promoting
apoptosis Positive staining (disease): melanoma (37%) Negative staining: normal melanocytes (only scattered, focal staining) References:
Hum
Path 2005;36:724 (melanoma) PAS (Periodic Acid-Schiff) A special stain, not an immunostain Theory:
substances with nearby glycol groups or their amino or alkylamino derivatives
are oxidized by periodic acid to form dialdehydes, which combine with Schiff's
reagent to form an insoluble magenta compound Used for formalin fixed tissue and enzyme
cytochemistry; can be used for frozen sections with modifications (Eur
J Gynaecol Oncol 1998;19:482. AJSP
1992;16:87) Stains basement membrane (normal and in tumors),
glycogen, some mucins (see below) and mucopolysaccharides A routine stain in brain (with Luxol fast blue),
cornea, kidney, liver and skeletal muscle specimens for nontumor pathology Some mucins (see below) are PASD (PAS
with predigestion with diastase) positive (i.e. stain is present after diastase
predigestion; also called diastase resistant); glycogen is PASD negative (also
called diastase sensitive because diastase removes PAS staining) PAS stains neutral and acid-simple
non-sulfated and acid-complex sulfated mucins PAS does NOT stain acid-simple
mesenchymal mucins and acid-complex connective tissue mucins Also stains various inclusions, bodies,
granules and secretions composed of mucopolysaccharides or mucins Uses: Breast cytology: PASD positive cells with internal structure and producing nuclear
indentation, particularly in dissociated or atypical cells, correlate with
malignant histology (J
Clin Pathol 2001;54:146) Fungi: stains fungal cell walls; PAS+ granule at anterior end of
mature spores is diagnostic of microsporidia (BMC Clin Pathol 2006;6:6) Hematopathology: ALL, AML M5-M7 are PAS+ Kidney: recommended for routine evaluation of renal biopsies due to
basement membrane staining; also useful to diagnose renal cell carcinoma
(stains glycogen, removed by diastase) Liver: routine stain; also stains inclusions of
alpha-1-antitrypsin disease Lung: stains amorphous or granular globules in BAL fluid in
pulmonary alveolar proteinosis (J Clin Pathol 1997;50:981) Muscle biopsies: routine stain to demonstrate glycogen Pancreas: acinar cell carcinoma (PASD+) Parotid glands: zymogen granules are PAS+ Prostate: Cowper’s glands are PASD+ (AJSP
1997;21:550) Skin: eosinophilic globoid
bodies (Kamino bodies) in Spitz nevus are PASD+ PAS (continued) Small intestine: stains Whipple’s disease bacteria (Am
J Clin Pathol 2002;118:742, Hum
Path 2003;34:589); strong cytoplasmic
staining present in microvillous inclusion disease versus linear brush border
staining in normals (AJSP
2002;26:902) Testis:
stains intratubular germ cell neoplasia (AJSP
1994;18:947) and seminoma (PAS+, PASD negative), but not normal
seminiferous tubules Tumors: adenocarcinoma of various sites (mucin is PASD+), alveolar
soft parts sarcoma (PASD+ crystalline structures), apocrine carcinomas,
basement membrane containing tumors (cylindroma [AJSP
2001;25:823], eccrine spiradenoma), clear cell tumors
(stains glycogen), glycogen rich carcinomas, glycogen rich/balloon cell
melanoma (Archives
1998;122:353),
granular cell tumor (cytoplasmic granules), hyaline globules in renal tumors (Hum
Path 1997;28:400), mucinous
tumors, Paget’s disease of breast Other:
stains malakoplakia Enzyme cytochemistry: coarse granular staining Positive staining (normal): basement membrane, fungi, glycogen (removed after
diastase or amylase predigestion), mucins (neutral and
acid-simple non-sulfated and acid-complex sulfated types), surfactant Positive staining (disease): ALL (75%, block staining), alpha-1-antitrypsin
inclusions, alveolar soft part sarcoma (intracytoplasmic crystals), AML-M5a, M6
(60%), M7, basement membrane containing tumors (cylindroma), clear cell tumors,
malakoplakia, renal cell carcinoma (PAS+ glycogen removed with diastase),
parasites Negative staining: mucins (acid-simple mesenchymal and
acid-complex connective tissue types) Micro images: bacteria - atypical
mycobacteria; rhodococcus
#1 is PAS+ in colonic histiocytes (far right); #2 in pulmonary
histiocytes (PASD+); Tropheryma
whipplei in histiocytes in hippocampus (fig 3) blood and marrow elements - various
images brain - acquired
hepatocellular degeneration (with Luxol fast blue) breast cytology - PASD+ malignant
tumors; PASD “not
actually positive” benign tumors CNS -
secretory meningioma
PAS+ inclusions #1; #2 colon - malakoplakia
(fig 3: PAS, 4: calcium stain) cornea - Fuch’s
dystrophy PAS (continued) fungi
- blastomyces;
candida
of esophagus #1; #2;
lung;
tongue;
Coccidioidis
immitis of tongue (fig 4);
cryptococcal
meningitis; histoplasmosis
of colon in HIV+ woman (fig 3); microsporidia;
mucor
#1 of stomach; #2 of skin;
ringworm
(skin) heart - glycogen storage
disease #1; #2 (removed by
diastase) kidney - normal;
Alport’s
syndrome #1; #2 (fetal
glomerulus); amyloidosis
#1; #2;
chronic
pyelonephritis; dense
deposit disease #1; #2;
Fabry’s
disease #1; #2;
focal
segmental glomerulosclerosis; Henoch
Schoenlein purpura; IgA
nephropathy #1; #2;
immunotactoid
glomerulonephritis; membranoproliferative
glomerulonephritis type I #1; #2;
with
crescent; with
doubling of capillary wall; nephronophthisis;
nodular
glomerulosclerosis #1; #2;
#3;
SLE
#1; #2;
#3;
#4;
thrombotic
microangiopathy liver - alpha-1-antitrypsin
deficiency #1; #2;
hepatitis
A with confluent necrosis lung - pneumocystis
pneumonia; pulmonary
alveolar proteinosis: globules (B/D) are PAS+; A/C are H&E; surfactant
in hyaline membrane disease parasites - Acanthamoeba
histolytica #1 (colon); #2
(cornea); #3
(brain); Echinococcus
(fig 2/3) in bone parotid gland - normal skeletal muscle - increased
glycogen (PAS+, PASD-) in desmin related myopathy; PAS+ diastase
sensitive material in McArdle’s disease #1; #2 skin - Fabry’s
disease small intestine - normal (fig 2),
microvillous inclusion disease (fig 3/4) tumors - acinar
cell carcinoma of pancreas; adenocarcinoma
of colon; alveolar soft
parts sarcoma #1, in cervix; #2; clear cell
acanthoma; clear cell carcinoma
of ovary; cylindroma
#1; #2;
eccrine
spiradenoma; endolymphatic
sac papillary tumor of ear; Ewing’s
sarcoma;
glycogen rich carcinoma of breast - fig 1/2: infiltrating nests of atypical
cells with abundant clear cytoplasm; 3: PAS+ granules; 4: PAS staining is
removed by diastase; glycogen rich
urothelial carcinoma; granular
cell tumor; juxtaglomerular
cell tumor of kidney; Kaposi’s
sarcoma; lymphoplasmacytic
lymphoma; mucinous
cystadenoma of ovary; Paget’s
disease-penis; secretory
carcinoma of breast; secretory
meningioma; tubulocystic
carcinoma of kidney Virtual slides: cryptococcus
of brain References: Wikipedia, MacManus (Hoslink), Stainsfile PAX-7 1p36 Transcription factor and member of the PAX family of
developmental control genes Fused with FKHR gene via t(1;13)(p36;q14) in alveolar
rhabdomyosarcoma. PCNA Proliferating
Cell Nuclear Antigen; also called cyclin Nonhistone 36 kDa nuclear protein with a role in DNA
synthesis, DNA repair, and cell cycle progression Coordinates synthesis of both leading and lagging
strands at the replication fork during DNA replication Expression correlates with proliferation activity PDGF Platelet Derived
Growth Factor, also called c-sis Produced and secreted by megakaryocytes, activated
vascular endothelial cells, macrophages, fibroblasts, smooth muscle cells Composed of combinations of A and B isoforms (AA, AB,
BB) PDGF alpha receptor binds to all 3 isoforms; PDGF
beta receptor binds only to BB with high affinity Chondrosarcoma: high expression of PDGF alpha receptor associated with poorer overall
survival, AJSP
2001;25:1520 Ovarian cancer: PDGF alpha receptor expression associated with shorter overall survival Pentachrome stain Stains collagen and mucin in thrombi, plaques Phosphotungstic acid-hematoxylin
(PTAH) Variant of trichrome stain; demonstrates
intracytoplasmic filaments in muscle and glial cells Micro images: myxopapillary
ependymoma of broad ligament (fig 7) PKD1 Gene at 16p13.3 produces polycystin1; gene is
adjacent to TSC2 gene for tuberous sclerosis Mutations can cause autosomal dominant polycystic
kidney disease PKD2 Gene at 4q22 produces polycystin2 Mutations can cause autosomal dominant polycystic
kidney disease PKD3 Mutations can cause autosomal dominant polycystic
kidney disease PLAG1 PLeomorphic
Adenoma Gene 1, at 8q12, often due to t(3;8)(p21;q12) involving
CTNNB1 and PLAG1 genes Proto-oncogene consistently rearranged in pleomorphic
adenomas of salivary glands in both epithelial and myoepithelial cells (Mod
Path 2005;18:1048) Micro images: karyotype,
FISH and CISH PLAP Placental Alkaline
Phosphatase Positive staining (normal): some infantile germ cells until age 1 Positive staining (disease): most germ cell tumors, particularly seminomas; also
breast, lung, ovarian carcinomas (some) PML-RAR alpha Fusion protein present in most cases of AML-M3 due to
t(15;17)(q22;q11-12) Rb Retinoblastoma
gene / protein Tumor suppressor gene at 13q14 Encodes a 110-114 kDa nuclear protein that plays a
crucial role is cell cycle progression by regulating cell cycle arrest at G1-S Active form is hypophosphorylated and binds to E2F
family of transcription factors, which bind to DNA to inhibit transcription Inactive form is phosphorylated via cyclin
D-CDK4/CDK6 complexes, which are inhibited by p16INK4a Rb inactivity [leading to transcription] caused by
(a) loss of p16INK4a causing phosphorylation of Rb, making it inactive; (b) Rb
mutations; (c) Rb hyperphosphorylation; (d) overexpression of cyclin D; (e) DNA
tumor virus SV40 T antigen, adenovirus E1A and HPV-E7 protein Inactive Rb is reactivated by cell cycle specific
phosphatase in M phase Germline mutations or loss predispose to
retinoblastoma and osteosarcoma Somatic mutations cause various tumors Point mutations inhibits Rb-1 and c-myc binding For thyroid neoplasms, follicular adenomas were
usually positive, follicular and papillary carcinomas were usually negative (Mod
Path 2000;13:562) Positive staining (normal): fibroblasts, endothelial cells, lymphoid cells
within thyroid neoplasms Also called RCC Ma (Renal Cell Carcinoma
Marker) Mouse monoclonal antibody generated against crude
microsomal fraction of proximal tubules from normal human kidney Specific for glycoprotein in renal proximal tubular
brush border Sensitive and specific for primary renal cell
carcinoma (AJSP
2001;25:1485); Positive in 93% of primary and 67%-84% of metastatic
renal cell carcinomas Most clear cell (84%) or papillary RCCs were
positive, compared to 0% to 56% of chromophobe carcinomas, 0% sarcomatoid
carcinomas, 0% collecting duct carcinomas, 0% oncocytomas Micro images: pulmonary
adenocarcinoma metastasis (left) to renal cell carcinoma (right) - CK7 (2A);
TTF1 (2B); RCC (2C) Gene at 10q11.2 Receptor tyrosine kinase expressed in neural crest
cells RET ligand is glial-derived neurotrophic factor Activating mutations in 90% of patients with MEN 2A
and 2B and FMTC (familial medullary thyroid carcinoma) Inactivating mutations in Hirschsprung's disease RET/PTC gene arrangement is common in papillary
thyroid carcinoma; also seen in Hashimoto’s thyroiditis Includes RET/PTC1 (60-70%), RET/PTC3 (20-30%) Rare families have FMTC & Hirschsprung's, perhaps
due to tissue-specific modifiers References: Mod
Path 2001;14:246 Reticulin Demonstrates reticular fibers and basement membrane
material Not related to reticulum cells Reticular fibers: thin, usually type III collagen,
widespread in connective tissue throughout the body Basement membrane is composed of type IV collagen and
laminin Both have bound proteoglycans highlighted by silver
stains and PAS Uses: Often not helpful in nonclassic cases Outlines architecture of liver and spleen To diagnose hemangiopericytoma, vascular smooth
muscle, fibrosarcoma or fibrothecoma (stains each cell) vs. endothelial cell
tumors (stains outside of all cells), MPNST (runs parallel to spindle tumor
cells without surrounding them at the poles) Micro images: normal
liver; normal
spleen; leiomyosarcoma;
glomus
tumor (fig 2D); gallbladder
paraganglioma (fig 1b); alveolar
soft parts sarcoma (fig 2a); reticulin
stain outlines each cell in hemangiopericytoma of breast; reticulin
stain demonstrates stroma fibers, but fibers do not completely surround
neoplastic glands in tubular carcinoma of breast Inhibits in vitro transformation of monoctyes to
collagen-producing spindle shaped macrophages, and suppresses type 1 collagen
gene expression in lung fibroblasts Also called Srk Homology domain 2
containing Protein phosphatase 1 Non-transmembrane protein phosphotyrosine phosphatase Modulates intracellular signaling for various
molecules Preliminary study suggests helpful in differentiating
mantle/marginal zone lymphomas (SHP-1+) from follicular lymphomas (SHP-1
negative), AJSP
2001;25:949 Positive staining (normal): mantle zone, marginal zone, interfollicular zone of
lymph node Positive staining (disease): mantle cell lymphoma, marginal zone lymphoma,
SLL/CLL Negative staining: germinal centers (or weak), follicular lymphomas Also called CD 175s Carbohydrate associated with apomucins MUC1, MUC2;
produced in the initial steps of mucin biosynthetic pathway Presence associated with aggressive tumors High pre-operative serum levels predict liver
metastasis and poor prognosis after resection for gastric cancer Definitive Phase III trial of STN vaccine in
metastatic breast cancer patients began 2001 Positive staining (disease): carcinomas Present in minerals and building materials Most forms are inert, cannot be stained in tissue,
can be demonstrated by white birefringence on polarization Most often present in lung, occasionally in lymph
nodes Street drugs for injection are often diluted with
silica or talc Micro images: silica
crystals in silicosis of lung, polarized; polarizable
crystals in lung with intravenous drug use Amyloid stain similar to Congo red Micro images: primary
cutaneous localized amyloidosis - fig 2: Sirius red; 3: cytokeratin MNF References: stainsfile.info Stains lipids in granulocytes; useful if fresh specimens
not available or in patients with myeloperoxidase deficiency Positive enzyme cytochemistry: neutrophils, monocytes (variable), AML-M1, M2,
microgranular M3, negative in ALL Inhibitor of apoptosis protein; may also enhance
proliferative activity of tumor cells Overexpression enhances cell survival Interpretation: cytoplasmic staining Positive staining (normal): fetal tissues Positive staining (disease): hepatocellular carcinoma, endometrial carcinoma Negative staining: most normal, terminally differentiated tissue TRAP (Tartrate resistant acid phosphatase) One of seven isoenzymes with different tissue
distribution TRAP is found in hairy cell leukemia; other acid
phosphatases are found in red blood cells, prostate, white blood cell lysosomes Sensitive and relatively specific for hairy cell
carcinoma when combined with DBA.44 positivity (AJSP
2005;29:474) Positive staining (normal): B lymphocytes of marginal zone, osteoclasts Positive staining (disease): hairy cell leukemia, mantle cell lymphoma (57%), splenic
marginal zone lymphoma (some), primary mediastinal B cell lymphoma (54%),
CLL/SLL (41%), giant cells in giant cell tumor of bone and soft tissue (Hum
Path 2005;36:945) Micro images: giant
cell tumor of bone - mononuclear and giant cells are positive (fig 1D); giant
cell tumor of tendon sheath - mononuclear and giant cells are positive (fig 2C) Usually black, non-polarizable Red tattoo pigment often contains cinnabar (which has
mercury in it) Micro images: Tattoo
pigment in dermis of skin, H and E stain tau Abnormal accumulation of tau protein is seen in
progressive supranuclear palsy, usually in neurons, less often in astrocytes Images: Progressive
supranuclear palsy Telomerase A ribonucleoprotein multisubunit enzyme complex that
functions as a specialized reverse transcriptase, to synthesize telomeric
repeats (TTAGGG) to the 3’ ends of human chromosomes Components of telomerase: RNA template, telomerase
associated protein, human telomerase reverse transcriptase (hTERT) RNA template and telomerase associated protein are
expressed ubiquitously hTERT protein expression is highly regulated,
generally correlates with telomerase activity; reexpression correlates with
laryngeal carcinogenesis (Mod
Path 2005;18:406) Interpretation: hTERT is a nuclear stain Micro images: hTERT expression in larynyx - normal
epithelium (in isolated basal cells); basal
cell hyperplasia (in occasional basal cells); carcinoma
in situ (full thickness staining); squamous
cell carcinoma (present in most cells) Tenascin Also called tenascin C Large glycoprotein of extracellular matrix,
synthesized by fibroblasts, composed of epidermal growth factor like
repetitions May function in epithelial-mesenchymal interactions Expressed during embryogenesis, growth, wound
healing, inflammation Increased in carcinoma of Ampulla of Vater, breast,
colon, lung, prostate Pheochromocytoma: strong expression associated with malignancy, AJSP
2001;25:1419 Also called CD141 Marker of mesotheliomas, endothelial cells and
coagulation factor Cofactor for the thrombin-mediated activation of
protein C Important fibrinolytic inhibitor, as it decreases
activation of plasminogen to plasmin Critical for activation of protein C and initiation
of the protein C anticoagulant pathway Plasma CD141 levels are associated with endothelial
damage Interpretation: predominantly membranous staining Uses: Mesothelioma vs. lung adenocarcinoma: 64% sensitive, 95% specific for mesotheliomas, but
must exclude vasculature; see membranous staining of periphery with isolated
papilla Urothelial carcinoma (positive) vs. renal cell, prostate, endometrial or colonic
carcinoma, AJSP
2001;25:1380 Squamous cell carcinoma (positive), Am
J Clin Pathol 1998;110:385 Positive staining (normal): Endothelial cells, megakaryocytes, platelets,
monocytes, neutrophils, smooth muscle cells, synovial lining cells,
keratinocytes, mesothelial cells Positive staining (disease): epithelial mesotheliomas, urothelial carcinomas,
squamous cell carcinomas Negative staining: adenocarcinoma of colon, endometrium, kidney, lung, kidney, prostate;
sarcomatoid mesotheliomas Large glycoprotein (MW 670K) produced by thyroid
follicular cells; later iodinated to form T3 and T4 Specific marker of thyroid differentiation Micro images: thyroglobulin+
(artifact) lobular breast carcinoma metastatic to thyroid TIA1 Associated with activated cytotoxic T cells Stains collagen blue Phosphotungstic or phosphomolybdic acid is used with
anionic dyes Micro images: chronic
active hepatitis with hepatocyte collapse; cerebral
abscess; scleroderma
with fibrosis of submucosa in stomach Tryptase Dominant protein of human mast cells Negative staining: eosinophils, basophils, neutrophils, lymphocytes, monocytes Tuberin Encoded by TSC2 gene on 16p13.3; adjacent to PKD1
gene for autosomal dominant kidney disease Causes tuberous sclerosis (see TSC1) Homologous to GTPase activating protein Broadly expressed in many organs and tissues,
including myometrium and most smooth muscle Negative regulator of cell cycle – inhibits cell
proliferation Inactivation causes benign neoplasms in patients with
tuberous sclerosis complex Reduced immunostaining is associated with uterine
leiomyomas (Mod
Path 2005;18:179) Tubulin Structural protein involved in assembly of mitotic
spindles Increased expression is associated with increased
mitotic activity Interpretation: cytoplasmic staining in mantle cell lymphoma Positive staining (normal): germinal centers (but not mantle zones) of benign
lymph nodes Micro images: staining
in tonsil (fig 2a), mantle cell lymphoma (2d) Tumor necrosis factor (TNF) Also called cachectin Initiates similar responses as lymphotoxin alpha Secreted by macrophages and lipopolysaccharides or
macrophage activating agents Binds to 55kDa receptor on many cells throughout body Mediators: TRADD, TRAP-1, 55.11 Has many biologic activities; initiate signals for
cell proliferation and apoptosis; required for normal development and function
of immune system; suppresses expression of lipoprotein lipase and anabolic
enzymes in fat In large boluses, modifies coagulation properties of
endothelial cells, activates neutrophils, induces release of inflammatory
cytokines (IL-1), causing cardiovascular collapse In small amounts, causes symptoms of inflammatory response
of bone resorption, fever, anemia, wasting Both triggers apoptosis and activates NFKB which
blocks apoptosis TNF and IL-1 react with hypothalamic receptors,
leading to stimulation of prostaglandin and leukotriene mediated pathways that
reset brains thermoregulatory center Tyrosinase Also called T311 (for immunohistochemistry) Melanocyte specific antigen important in melanin
synthesis and melanosome formation Melanomas:
diffuse reactivity compared to diminished expression towards base in nevi or
melanomas with paradoxical maturation Positive staining (disease): sinonasal melanomas, oral mucosal melanomas,
desmoplastic melanomas, AJSP
2001;25:782 Triggers pathway for protein degradation associated
with turning on and off cell cycle regulators Can turn on cyclin-CDK complexes by destroying its
inhibitor Micro images: neuronal
inclusion staining in motor neuron disease Breast:
BCA225+, CEA-, and CA125- Colon:
CEA+, BCA225-, and CA125- Lung:
BCA225+, CEA+, and CA19-9- Ovary:
CA125+ and CEA- Upper GI tract: CEA+, CA19-9+, and CA125+ Correctly predicts known primary site in 66% of
cases, Am
J Clin Pathol 1997;107:12 Urates / uric acid Uric acid crystals seen in acid urine Urates present in tissue as sodium urate, but soluble
in aqueous solutions and slightly soluble in weak alcoholic solutions, so
tissue must be fixed in 95%/100% alcohol to prevent leaching of urates. Urates are stained black by GMS Sodium urate crystals are birefringent on
polarization Micro images: uric
acid crystals, polarized, with red plate VEGF Vascular Endothelial
Growth Factor Exists in 4 different homodimeric isoforms due to
alternate splicing Potent angiogenic growth factor that stimulates
endothelial cell proliferation and induces microvessel permeability Protein and mRNA are overexpressed in various tumors May have prognostic significance in esophageal
adenocarcinoma (Hum
Path 2005;36:955) VEGF-D Induces angiogenesis and lymphangiogenesis with VEFR
receptor 2 (VEGFR2) and VEGFR3 (also called Flt4) Associated with lymphangiogenesis and lymphatic
metastasis in papillary thyroid carcinoma (Mod
Path 2005;18:1127) Positive staining (normal): thyroid follicular epithelium Micro images: papillary
thyroid carcinoma-diffuse and intense staining (fig 1f) VEGFR3 Vascular Endothelial
Growth Factor Receptor 3 Also called Flt4 Specific marker for lymphatic endothelium Also expressed in blood vascular endothelium of
malignant tumor and granulation tissue Micro images: papillary
thyroid carcinoma (fig 1e) Actin binding protein present in cytoskeleton of
intestinal microvilli; has critical role in maintaining brush border
organization Relatively specific for GI epithelium with brush
border microvilli or adenocarcinomas derived from them Uses: (1)
primary bladder adenocarcinoma vs. colorectal carcinoma to bladder - negative
CDX2 and negative villin suggests bladder primary (Mod
Path 2005;18:1217), (2)
colorectal adenocarcinoma (villin+) vs. ovarian adenocarcinoma (villin-) Positive staining (normal): digestive tract epithelium, renal proximal tubules,
hepatic bile ducts Positive staining (disease): pulmonary adenocarcinomas, renal cell carcinoma,
colonic adenocarcinoma (98%) Negative staining: bronchiolar epithelium, pulmonary alveolar cells, bronchial gland
cells, renal distal tubules Micro images: bladder
adenocarcinoma - (a) secondary colorectal is villin+ as is (b) primary
bladder tumor Vitronectin Positive staining (disease): astrocytomas; giant cells in giant cell tumor of
bone and soft tissue express vitronectin receptor (Hum
Path 2005;36:945) Tumor suppressor gene (autosomal dominant) at
3p25-26, with 3 regions (A, B, C) Familial cases of von Hippel Lindau syndrome are
associated with translocations of this gene Gene is inactivated by hypermethylation of CpG island
in 5' region causing lack of expression of VHL or by mutation in binding region Wild type protein competes with A subunit for binding
to B/C complex; active mutation occurs in homologous sequence region Mutated protein does not bind to elongin B and C
subunits, which allows subunit A to bind, and increases rate of elongation
through suppression of RNA polymerase pausing Abnormalities associated with renal cell carcinoma,
clear cell type Large glycoprotein involved in platelet aggression
and adhesion to subendothelial matrix Somewhat sensitive (50-75%) for vascular tumors;
CD31, CD34 or perhaps FLI-1 are more sensitive Interpretation: cytoplasmic stain; endothelium should be a positive internal control Positive staining (normal tissue): endothelial cells, megakaryocytes, subendothelial
connective matrix; also areas of tumor necrosis and hemorrhage Positive staining (disease): blood vessels in tumors, vascular tumors, metastatic
osteosarcoma Micro images: positive
staining of endothelium (fig 2A) References: Mod
Path 2005;18:388 (expressed in metastatic osteosarcoma)
Primary references
top
American Journal of Clinical Pathology
American Journal of Surgical Pathology
Archives of Pathology & Laboratory Medicine
Human Pathology
Modern Pathology
Human Herpes Virus 8; also known as Kaposi’s Sarcoma-associated
Herpes Virus
Gamma herpesvirus identified as an etiologic agent for Kaposi’s sarcoma in 1994
Latently infects endothelial cells, monocytes and B cells in Kaposi’s sarcoma patients
Associated with 3 HIV associated lymphoproliferative disorders - primary effusion lymphoma, multicentric Castleman’s disease,
multicentric Castleman’s disease-associated plasmablastic lymphoma
Sensitive but not specific for Kaposi’s sarcoma, due to presence in other tumors (including hemangiomas) in immunocompromised (may be present within intratumoral blood mononuclear cells (Mod Path 2005;18:463)
References: Am J Surg Pathol 2002;26:1363
Other images: Hodgkin lymphoma-neoplastic cells have variable cytoplasmic lambda staining, plasma cells have intense staining and histiocytes have weak staining
Stains Helicobacter pylori, spirochetes
Micro images: Spirochetes with Warthin-Starry silver stain
wnt
Beta-catenin and T cell factor (Tcf) are distal components of the highly conserved Wnt pathway that govern cell fate and proliferation in lower organisms.
Wright-Giemsa stain
Also called Wright’s stain
A "Romanowsky-type" stain, composed of mixtures of methylene blue, azure, and eosin compounds
Used to stain peripheral blood smears
Methylene blue is a metachromatic stain, meaning that some tissue components (mast cell granules, cartilage, mucin, amyloid) stain purple and not blue
Micro images: Peripheral blood smear, Wright's stain.
Tumor suppressor gene at 11p13
Protein is transcriptional regulator that apparently inhibits transcription of growth promoting genes
Involved in development of tissues from inner layer of intermediate mesoderm
Interpretation: nuclear stain
Uses: (1) ovarian carcinoma (WT1+) vs. breast/pancreatic carcinoma (WT1 negative)
Positive staining (normal): fallopian tube, kidney, mesothelium, ovarian granulosa cells, Sertoli cells, spleen
Positive staining (disease): acute myeloid leukemia, cystic partially differentiated nephroblastoma, desmoplastic small round cell tumor, malignant mesothelioma, metanephric adenoma, nephrogenic rests, ovarian carcinomas (serous carcinoma [almost all], transitional, small cell, AJSP 2005;29:1034), peritoneal serous carcinoma involving an endometrial polyp-80% (AJSP 2005;29:1074), rhabdoid tumor, Wilm’s tumor
Negative staining: endometrial glands, ovarian mucinous and clear cell carcinomas (Archives 2005;129:85)
Micro images: metanephric adenoma (fig D), ovarian tumor subtypes #1; #2
In non-neoplastic cells, is controlled by proteins that intervene at checkpoints to prevent progression to next phase
Enzymatic activity of protein is activated by phosphorylation, which changes their conformation, and usually leads to more phosphorylation (or kinase) activity
Phosphorylation also creates docking sites on phosphorylated proteins, especially with tyrosine kinases, which recruits other target proteins
Cell cycle: G1 to S (DNA synthesis) to G2 to M (mitosis)
Cells NOT in the cell cycle (in resting phase) are in G0
G1:
(1) pRb (retinoblastoma protein) binds to E2F (transcription factor), which blocks transcription of S phase genes; cells stimulated by extracellular signals cause accumulation of CDK 4-6/cyclin D1 complex, which phosphorylates Rb, reducing its affinity for E2F, causing pRb to dissociate, freeing E2F to activate S phase genes
(2) Ubiquitin, in response to unknown stimulus, binds to and destroys CDK inhibitors, making CDK active
(3) p16 gene (CDKN2) inhibits CDK4-6/cyclin D1 complex, which prevents phosphorylation of Rb, which prevents progression of cell cycle into S phase
S:
Growth factor binds to receptor on outer membrane
Receptor on inner membrane dimerizes, which activates tyrosine or serine/threonine kinases
Dimerized receptor subunits phosphorylate each other on tyrosine residues, creating docking sites for other proteins
Grb2, an adaptor molecule which transfers the activation state, docks to phosphotyrosine and attracts the Sos protein
Sos, a nucleotide exchange factor, attracts Ras
Ras binds to inner membrane by linking to an isoprenyl group (farnesyl): process is called prenylation
Ras binds GTP and becomes activated
Activated Ras is a kinase, which activates Raf-1 via GTP
Somehow Raf-1 is translocated from cytosol to plasma membrane
Ras is inactivated by GAP (GTPase activating protein), which increases Ras's intrinsic GTPase activity
Activated Raf-1 is a kinase, which activates MEK
MEK activates MAPK/ERK (mitogen activated protein kinase / extracellular signal regulated kinase) using ATP
Activated MAPK/ERK directly activates:
(a)ERK1/2 (extracellular signal regulated protein kinases 1 and 2)
(b) BAD (bcl2 family) by phosphorylation
(c) Ribosomal S6 protein kinase (RSK = pp90rsk), which translocates to nucleus and phosphorylates several transcription factors, including jun
(d) Transcription factors (fos)
(e) (alternate pathway) CREB kinase, which phosphorylates and activates CREB at serine 133, which activates intermediate early growth and some delayed response genes with CREB binding sites
Activated MAPK also translocates to nucleus, where it phosphorylates and activates transcription factor ELK-1 at Ser 383
ELK1, with serum response factor, binds to serum response element within IEG promoter to activate IEG genes
Activated fos and jun bind near myc gene, which initiates gene transcription
Activated myc activates other genes, including cyclin D1
Cyclin D1 may initiate progression of cells from S
G2:
M phase promoting factor (MPF) is CDC2 protein kinase plus cyclin B
MPF is inactive when Threonine 14 & Tyrosine 15 are phosphorylates (by Wee1 and Myt1 kinases)
Plx1 extensively phosphorylates CDC25 at mitosis, which activates it
Activated CDC25 dephosphorylates Thr14 & Tyr15 (antagonistic to Wee1 & Myt1), which activates CDC2
M:
Cyclin levels increase
Increased cyclin partially activates CDK (cyclin dependent kinase), which has bound inhibitors
CDK triggers beginning of mitosis (prophase, metaphase)
Ubiquitin is passed from enzymes E1 to E2 to E3 (bucket brigade)
E2: active throughout cell cycle
E3: temporal specificity; is on mitotic spindle, checks if all chromosomes are on spindle. If so, ubiquitin tags an
unknown "tether" protein for proteolysis, which causes anaphase to proceed.
Ubiquitin tags cyclin for proteolysis, which inactivates CDK, and allows mitosis to finish
End of Stains chapter
