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Stains Chapter
Reviewer: Nat Pernick, M.D., PathologyOutlines.com, Inc. (see Reviewers
page)
Revised: 24 January 2012
Copyright: (c) 2002-2012, PathologyOutlines.com, Inc.
See also CD Markers chapter
Note: many stains NOT listed in the table of contents can be accessed by clicking on the first letter of their name below; they will be added to the table of contents as they are updated. Stains are listed in alphabetical order, with spaces and dashes before numbers, and numbers before letters.
Table of Contents - Stains
General: IHC basics, IHC procedure, common panels, enzyme cytochemistry
3 beta, 7 AAD, 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, alpha-1-antichymotrypsin, alpha-1-antitrypsin, alpha-fetoprotein, AMACR, androgen receptor, argentaffin, argyrophilic, asbestos, auramine-rhodamine
B: B72.3, bcl1, bcl2, bcl6, bclXl, bcr-abl, Ber-EP4, beta-2-microglobulin, beta-catenin, BG7, BG8, Bielschovsky, biotin, BOB.1, brachyury, BRAF, BRCA1, BRCA2
C:
c-kit, c-myc, CA125, calcium, caldesmon, calponin, calretinin, CAM5.2, caspases, CCR1, CDX2, CEA, chloroacetate esterase, chromaffin, chromogranin, claudin1, claudin7, claudin18, collagen, collagen XVII, Congo Red, CXCR2, CXCR5, Cyclin D1
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, deltaNp63, desmin, DPC4, DOG1
E: E-cadherin, EBER1, EGFR, elastic fibers, EMA, Epstein Barr virus (EBV), ERG, estrogen receptor
F: Factor VIII, Factor XIIIa, Fas/CD95, Fas ligand/CD178, ferritin, FLI-1, FMC7, Fontana-Masson
G: galectin3 GATA3 GCDFP-15 GFAP Giemsa glypican 3 GMS gram stain
H: Hansel Helicobacter pylori HE4 HER2 HGAL HHF35
J :
K : kappa Ki-67 Kras KSHV/HHV8
L : lambda laminin Leder LIN28 lysozyme
N: N-CAM Neuron specific enolase O
P: P glycoprotein p40, p53 p57 p63 P504S, PAX8 phosphohistone H3 podoplanin progesterone receptor
R: Rb RCC Reg IV RET reticulin retinoic acid
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 T-bet TdT thrombomodulin thyroglobulin TOP2A TRAP trichrome TTF-1
U : unknown primary uroplakin III
Y :
Z : Ziehl-Neelsen, Cell cycle
Primary references AIB1 Also called
SRC3, TRAM1 Member of steroid receptor coactivator 1 family at
20q12 Involved in cell proliferation, migration and
differentiation References: Hum
Path 2005;36:777 (colorectal carcinoma) 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 Alpha Part
of t(6;11)(p21;q12); TFEB and Alpha; renal neoplasm of children and young
adults (AJSP
2005;29:230) Gene
is at 11q12; lacks introns or splice signals; does not code for a functioning
protein Can
detect using DNA PCR as an alternative to RT-PCR since Alpha lacks splice
signals Nuclear
stain 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-naphthyl acetate /
alpha-naphthyl butyrate See Non specific esterase Alpha-naphthyl chloroacetate
esterase Note: staining is opposite of alpha-naphthyl acetate Positive staining: granulocytes Negative staining: monocytes and lymphocytes 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+) AMF Autocrine motility factor Induces the directed and random migration of AMF
producing tumor cells Expression of its receptor correlates with stage and
recurrence in bladder carcinoma Expression of its receptor is associated with down
regulation of E-cadherin AMH Anti-Mullerian Hormone High serum levels associated with granulosa cell
tumors of ovary and testis Positive staining (normal): prepubertal Sertoli cells Negative staining: pubertal Sertoli cells 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) AP-1 Activator protein 1, a transcription factor complex
composed of proteins that bind to AP-1 DNA recognition elements, which induces
expression of genes controlling cell growth and apoptosis Includes 4 subfamilies Jun, Fos, Maf and ATF, which
function as a complex of homodimers and heterodimers AP-2 Family of 5 transcription factors, all homologous 50
kDa proteins: AP-2alpha, AP-2beta, AP-2gamma, AP-2delta and AP-2epsilon,
encoded by separate genes These transcription factors homo- or heterodimerize
and transactivate their target genes by binding to GC-rich sequences in their
promoter regions AP-2alpha represent CK18+ breast glandular epithelial
cells and AP-2gamma represent smooth muscle actin+ myoepithelial cells in
non-neoplastic breast tissue and DCIS have distinct spatial distribution in non-neoplastic
breast epithelia References: Mod
Path 2005;18:431 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 ARP Arginine Rich
Protein, 3p21 Deleted or mutated in 50% of sporadic renal cell
carcinomas ARPP a protein including an Ankyrin Repeat PEST
motif and Proline-rich region Homologous to cardiac ankyrin-repeat protein and
diabetes-related ankyrin repeat protein May act as molecular link between myofibrillar
stretch-induced signaling pathway and muscle gene expression Expressed exclusively in striated muscle (in normal
human tissue), within I band of sarcomere Positive staining (disease): rhabdomyosarcoma (89%), epithelioid sarcoma (60%,
focal/weak or strong), Ewing’s sarcoma (20%, focal/weak), malignant fibrous
histiocytoma (10%, focal/weak), synovial sarcoma (10%, focal/weak) Interpretation: definitive cytoplasmic staining is required (nuclear staining is
nonspecific) References:
Hum
Path 2005;36:620 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 Autocrine motility factor Produced by neoplasms; induces in vitro migration of
tumor cells Autotaxin Motility factor in melanoma cells Last revised 29 March 2009 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 BAG1 Also called RAP46 Expressed by estrogen receptor positive breast
cancers Basement membrane Composed of type IV collagen and laminin BAT-26 Highly sensitive to microsatellite instability in
colorectal carcinomas Bauhinia purpurea (BPA) Positive staining (normal): granulocytes, macrophages, germinal center
lymphocytes Positive staining (disease): Reed-Sternberg cells bax Member of bcl2 family; has pro-apoptotic activity An increase in the ratio of bax to bcl2 promotes
cellular apoptosis Promotes apoptosis by either forming homodimers or
binding with and inhibiting bcl2 BB4 See CD138 in
the CD Markers chapter B-CAM B cell surface adhesion molecule at 19q13.2-13.3 Forms the Lutheran blood group gene by alternative
splicing Overexpressed in ovarian carcinoma bcl3 Located at 14q32, part of t(14;v)(q32;v) bcl-X bcl2 like protein Has 2 transcripts which either induce (bcl-Xs) or
protect (bcl-Xl) against apoptosis Thus, factors involved in RNA splicing may regulate
apoptosis by differential splicing bcl-Xs Shorter
transcript of bcl-X Induces apoptosis bcr Gene present at 22q11 - breakpoint cluster
region 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 BDCA-2 Specific marker for plasmacytic dendritic cells,
present in CD4+ CD56+ hematodermic tumors (Hum
Path 2005;36:1020) Antibody to cell membrane glycoproteins; does not
react with cytokeratin Use: 100%
sensitive, 91% specific for lung adenocarcinoma vs. mesothelioma; strong
membrane staining; recommended threshold of 2% of cells with lateral
membrane staining to call positive, AJSP
2001;25:43 Positive staining (normal): non-neoplastic epithelial cells Positive staining (disease): lung adenocarcinomas; mammary Paget's disease,
trichoepithelioma, dermatofibroma, basal cell carcinoma, carcinomas Negative staining: non-basal layers of squamous epithelium 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 Beta-catenin (continued) 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 Beta-tubulin, class III Marker for high-grade neuroendocrine pulmonary tumors
(one study), other neuronal and neuroblastic tumors (medulloblastomas,
retinoblastoma, neuroblastomas [olfactory, sympathetic], pheochromocytomas) 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) BMP2 Potent inducer of osteoblastic differentiation; BMP4 Bone Morphogenic
Protein 4 Powerful signaling protein, made by lymphocytes Potent inducer of osteoblastic differentiation; helps
developing embryo build its skeleton Abnormalities cause fibrodysplasia ossificans
progressiva (FOP), in which the slightest injury to tendons, ligaments or muscles
causes severe inflammation and formation of cartilage or bone at site of injury Tumor suppressor gene at 17q21; 220 kDa nuclear
phosphoprotein, 1863 amino acids, 7.8 kb mRNA Interacts with RAD51; may facilitate homologous
recombination in bypass of stalled replication forks Loss of functional BRCA1 or BRCA2 leads to activation
of p53, causing cell cycle arrest or apoptosis; if p53 if inactivated,
proliferation results in progressive accumulation of DNA damage and increased
frequency of malignancy Overexpression suppresses estrogen receptor
transactivation 185delAG and
5382insC are common in Ashkenazi Jews BRCA1 and BRCA2 mutations in Ashkenazi Jews have 2%
prevalence vs. 0.1% of rest of population Breast:
normally expressed at puberty and pregnancy; interacts with cyclin dependent
kinases; inhibits tumor growth in cell culture Accounts for 5% (age <40 years) to 1% (age 50-70
years) of breast cancer cases in general population Patients with BRCA1 or BRCA2 mutation have a 35%-80%
lifetime risk of breast cancer by age 70; usually high grade, aneuploid, with
basal / myoepithelial phenotype (P-cadherin+, EDGF receptor+, ER-, HER2-) Higher risk with 300 T>G mutation However, BRCA1 or BRCA2 mutation is also associated
with medullary carcinoma of breast (more favorable prognosis) Colon:
relative risk of 4.0 for adenocarcinoma Ovary: 30-60%
lifetime risk of adenocarcinoma in women with mutations; usually associated
with serous cystadenocarcinoma; often younger age and high stage; BRCA
mutations cause 90% of hereditary cases of ovarian carcinomas, which account
for 10% of all ovarian carcinomas Prostate:
relative risk of 3.0 for adenocarcinoma References:
OMIM 113705,
Mod
Path 2005;18:1305, Hum
Path 2005;36:861 (hereditary ovarian cancer) Tumor suppressor gene at 13q12-13 Interacts with RAD51; may facilitate homologous
recombination in bypass of stalled replication forks Loss of functional BRCA1 or BRCA2 leads to activation
of p53, causing cell cycle arrest or apoptosis; if p53 if inactivated,
proliferation results in progressive accumulation of DNA damage and increased
frequency of malignancy 6174delT in BRCA2common in Ashkenazi Jews BRCA1 and BRCA2 mutations in Ashkenazi Jews have 2%
prevalence vs. 0.1% of rest of population Breast:
patients with BRCA1 or BRCA2 mutation have a 35%-80% lifetime risk of breast
cancer by age 70; usually high grade, aneuploid, but ER+, PR+ Higher risk with 4486 G>T mutation Men with BRCA2 mutation have higher risk of breast
cancer also Ovary:
15%-27% lifetime risk of adenocarcinoma in women with mutations; often younger
patients with high stage tumors; BRCA mutations cause 90% of hereditary cases
of ovarian carcinomas, which account for 10% of all ovarian carcinomas References:
OMIM 600185,
Mod
Path 2005;18:1305, Hum
Path 2005;36:861 (hereditary ovarian cancer) BTK Bruton's tyrosine kinase Required for B cell differentiation beyond pro-B
stage Also mediates B cell receptor mediated apoptosis Mutations cause X linked agammaglobulinemia, in which
there is no B cell development Single chain glycoprotein at 3q41-42, expressed on
myeloid cells, endothelial cells, hematopoietic progenitor cells, platelets May enhance phagocytosis upon interaction with
soluble defense collagens Note: distinguished from cC1qR (identical with the
chaperone protein calreticulin) and molecular designated gC1qR (binds the
globular domain of C1q) GGT deficiencies are associated with glutathionuria,
cysteine depletion Positive staining (normal): renal tubular epithelium, pancreas, epididymis,
seminal vesicles, vascular endothelium, macrophages, B cell subsets, activated
T cells Negative expression: hepatocytes 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 CAI Inhibits calcium influx and calcium influx mediated
pathways including arachidonic acid release and tyrosine phosphorylation In vitro, inhibits proliferation, adhesion, motility,
MMP-2 production and density independent growth of human tumor cell lines Has anti-angiogenic abilities 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) can Gene at 9q34 Translocated in some AML cases Cathepsins A group of lysosomal proteinases or endopeptidases
found in aqueous extracts of a variety of animal tissue Function optimally within an acidic pH range Cathepsin B Lysosomal cysteine protease related to tumor
invasiveness Inhibited by cystatin C (an endogenous cysteine
protease inhibitor) Usually acts only in cell cytoplasm, but in malignant
tumors, is secreted extracellularly and degrades extracellular matrix so tumor
cells can invade Associated with focal adhesions Highest staining at invasive edge of tumor Associated with invasive properties of tumors; may
degrade basement membrane High expression associated with poor disease free
survival in gliomas (Hum
Path 2005;36:1008) Brain:
inhibitors prevent infiltration of glioblastoma cells into normal brain in vivo Colon:
predicts poor prognosis in colonic carcinoma CCR5 Also called CD195 Macrophage surface receptor and attachment site for
HIV and SIV, with CXCR4 (CD184); works with CD4 Receptor for CD8 chemokines RANTES, MIP 1-alpha and
MIP 1-beta. 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) CDH1 Gene encodes E-cadherin protein Inactivating mutations may be a risk factor for
diffuse gastric carcinoma CDKs Cyclin dependent kinases Cell cycle progression is regulated by complexes
formed between cyclins and CDKs CDK4 Gene is at 12q13-15 Binds to D type cyclins in G1 phase of cell cycle,
controls G1-S transition via phosphorylation of retinoblastoma gene; inhibited
by p16INK4a Amplified in well differentiated liposarcoma and
dedifferentiated liposarcoma (amplification detected by comparative genomic
hybridization, qualitative PCR, FISH; also immunostain which correlates with
gene amplification Uses:
distinguish well differentiated liposarcoma (positive) from benign adipose
tumors (negative) and dedifferentiated liposarcoma (positive) from poorly
differentiated sarcomas (negative); CDK4 is more specific but less sensitive
than MDM2 (AJSP
2005;29:1340) CDK6 Binds to D type cyclins in G1 phase of cell cycle,
controls G1-S transition via phosphorylation of retinoblastoma gene; inhibited
by p16INK4a CED-3 Required for apoptosis in C. elegans Negatively regulated by CED-9 (bcl2) Analogous to caspases (ICE and family) in mammals CED-4 Required for apoptosis in C. elegans; no known mammalian counterpart Negatively regulated by CED-9 (bcl2) and bcl-xL Overexpression causes apoptosis in cells which
normally survive Loss of function mutations prevent normal cell death Biochemically links bcl2 and ICE/FLICE CED-9 bcl2 homolog in C. elegans CENP-F Also known as mitosin Member of CENP centromere protein family, involved in
formation of centromere and organization of kinetochore during mitosis Interpretation: staining in mantle cell lymphoma is nuclear Micro images: staining
in tonsil (fig 2c), mantle cell lymphoma (2g) 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 CHEK2 Gene encodes cell-cycle checkpoint kinase implicated
in DNA repair processes involving BRCA1 and p53 Mutation CHEK2*1100delC, which lacks kinase activity,
seen in 5.1% of breast cancer patients without BRCA1 or BRCA2 mutations vs.
1.1% of healthy individuals Mutation CHEK2*1100delC confers estimated 2 x risk of
breast cancer in women without BRCA1 or BRCA2 mutations; no increased risk in
patients with BRCA1 or BRCA2 mutations, Nat
Genet 2002;31:55 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 CHOP 12q13 Also called GADD153, DDIT3 Transcription factor translocated via
t(12;16)(q13;p11) in 90% of myxoid or round cell liposarcomas 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 CNA.42 Follicular dendritic cell marker More sensitive but less specific than CD21 or CD35 Positive staining (normal): mononuclear cells, follicular dendritic cells Positive staining (disease): Reed-Sternberg cells, some sarcomas 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 stains See Trichrome 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 Complexity A possible theory of attack for tumor cells Normal cells have redundant pathways to transmit
information from outside the cell to the cytoplasm or nucleus Normal cells also have cross talk between signaling
systems, and can modulate parallel pathways to respond to chemical challenges Cancer cells may become dependent on specific signal
transduction pathways for survival, making them more sensitive to agents that
target a key regulatory signal pathway, while normal cells are unaffected 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 Connexin 43 Also called Cx43 Allows direct gap junctional intercellular
communication Associated with growth control and neoplasia
suppression Up regulated by retinoic acid Positive staining (normal): diffuse suprabasal staining of upper aerodigestic
tract squamous mucosa (apparent marker of squamous cell differentiation) Expression progressively decreases in dysplasia to
well differentiated to poorly differentiated squamous cell carcinomas COX2 See cyclooxygenase 2 (below) CPP-32 Proenzyme activated by ICE and granzyme B (a
cytotoxic T cell granule serine protease) Activation is controlled by physical isolation of
protease Autocatalysis appears to play an important role in
pro-enzyme activation Member of ICE family Cleaves and inactivates PARP Activation is specifically required for apoptosis;
CPP-32 inhibition prevents apoptosis in vivo/vitro CREB Cyclic
adenosine monophosphate Response Element Binding protein A transcription factor Binds with serum response element proteins to mediate
growth factor induction of c-fos by binding to c-fos promoter CSK Tyrosine kinase that negatively regulates LYN and SYK
kinases CTLA-4 Also called CD152 Negative regulator of T cell activation CTLA4 restriction fragment length polymorphisms are
linked to various autoimmune disorders Shares sequence homology with CD28; also shares
ligands CD80 and CD86 with CD28 Positive staining (normal): activated but not resting T cells, activated B cells References:
(123890) 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: naïve 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 Cyclin A Gene is site of integration of part of the hepatitis
B virus in hepatocellular carcinoma Acts from late G1 phase through M phase of cell cycle Forms complex with CDK2 during late G1-S phase, and
with CDC2 during G2-M phase Cyclin B1 G2-M phase regulator Also called bcl1 - “b cell lymphoma #1” Coded by BCL1 / PRAD1 (parathyroid adenoma 1) gene on
#11q13 Responsible for transition to S phase by
phosphorylating the retinoblastoma gene product, which releases transcription
factors to initiate DNA replication Overexpression promotes transformation to a malignant
phenotype; overexpressed in many tumors Interpretation: nuclear stain Uses: (a) Mantle cell lymphoma: characterized by a t(11;14) translocation, which
places the cyclin D1 gene next to an immunoglobulin heavy chain enhancer gene;
among lymphomas, cyclin D1 expression is very specific for mantle cell lymphoma (b) Parathyroid: overexpressed in 18% of parathyroid adenomas, strong staining in
carcinomas Positive staining (nuclear stain): mantle cell lymphoma; various carcinomas, multiple
myeloma (40%), hairy cell leukemia (25%), B-CLL (13%, AJSP 2004;28:801), some
parathyroid adenomas and parathyroid carcinomas Micro images: mantle cell
lymphoma Virtual slides: mantle
cell lymphoma Cyclin D2 Cell cycle regulatory protein that facilitates G1 to
S phase transition Expression associated with poorer prognosis in
diffuse large B cell lymphoma (Mod
Path 2005;18:1377) Positive staining (disease): diffuse large B cell lymphoma (14%) Cyclin D3 Nuclear stain Expression correlates with expression of
phosphorylated (activated) STAT3 (Hum
Path 2005;36:806) Cyclin E A 50-kDa protein that complexes with cdk2 in the late
G1 phase of the cell cycle Interpretation: nuclear staining 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 Cyld1 Tumor suppressor gene at 16p involved in familial
cylindromatosis and sporadic cylindromas Cystatin C Strongest inhibitor of cathepsin B Low expression associated with poor disease free
survival in gliomas (Hum
Path 2005;36:1008) 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) Dihydropyrimidine dehydrogenase Involved in 5-FU metabolism May predict tumor response to 5-FU based therapy in
colorectal carcinoma References: AJSP 2005;29:1304 DNA-PK(cs) Catalytic subunit of DNA dependent protein kinase;
related to ataxia telangiectasia gene Mutations prevent rejoining of DNA double-strand
breaks, including natural gaps between coding regions of antibody genes and DNA
"split ends" from radiation 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 DPP Decapentaplegic protein Member of BMP family that helps establish body and
limb axes in Drosophila DUSP/MKP3 Candidate tumor suppressor gene for pancreatic cancer
at 12q21-q22 Dual specificity phosphatase that binds and
inactivates MAPK1/ERK2; also regulates RAS and MAPK pathways Reduced levels in invasive pancreatic cancer vs.
fairly preserved levels in pancreatic intraepithelial neoplasia; may be
associated with IPMN with mutated KRAS2 (Mod
Path 2005;18:1034) Micro images: staining
in pancreatic lesions - PANIN, invasive disease, IPMN Gene at 17q12 translocated in Ewing’s sarcoma/PNET E2A
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American Journal of Clinical Pathology
American Journal of Surgical Pathology
Archives of Pathology & Laboratory Medicine
Human Pathology
Modern Pathology
