Stains F-Z
Printer Friendly Version
(routine stains, immunostains and molecular markers)
Last revised 7 October 2007
Copyright © 2002-2007 PathologyOutlines.com, Inc.
See also CD Marker chapters
Bold and underlined topics are hypertext links
Links in green are to free full text-no registration journal articles
Advertisement
Note: stains/proteins are in alphabetical order, with numbers before letters, and ignoring dashes and spaces
Stains A-E, including general information
F G H I J K L M N O P Q R S T U V W X Y Z
Interpretation: cytoplasmic stain; endothelium acts as a positive internal control
Positive staining (normal): endothelial cells, megakaryocytes, platelets, mast cells
Positive staining (disease): vascular tumors
Factor XIIIa
Fibrohistiocytic marker
FADD
Fas (CD95) Associated protein with Death Domain
Not the same protein as Fas
Part of Fas and TNFR1 pathways:
In Fas pathway, death domain portion of Fas recruits FADD
In TNFR1 pathway, TNFR1 binds TRADD, which acts as an adaptor protein to recruit FADD
FAS-FADD and TNFR1-TRADD-FADD recruit FLICE to receptor signaling complex, eventually induce apoptosis
FAK
See focal adhesion kinase
Fas
See CD95
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
References: Hum Path 2005;36:741
Fas ligand
See CD178
Fat stains
See Oil Red O
Fatty acid synthase
Multifunctional enzyme complex at 17q25 involved in de novo synthesis of saturated fatty acids
Catalyzes conversion of acetyl-CoA and malonyl-CoA into long chain fatty acids via NADPH
Inhibitors are being evaluated as potential therapeutic agents due to toxicity to human cancer cells in vitro
Stronger expression in melanoma vs. nevi; higher for melanoma Clark levels IV/V vs. I/II and Breslow thickness 0.75 mm+ vs. < 0.75 mm; also high in congenital melanocytic nevi (Mod Path 2005;18:1107)
Positive staining (disease): carcinoma of breast, colon, endometrium, ovary, prostate; melanoma
Fc gamma RIIb
Part of t(1;22)(q22;q11) with lambda light chain
Associated with follicular lymphoma
References: more information #1; #2
Ferritin
fes
Tyrosine kinase / signal transducer at 15q25-26
FEV
Gene at 2q33 mutated in Ewing’s sarcoma/PNET
fgr
Tyrosine kinase / signal transducer at 1p36.1-36.2
FHIT
Fragile HIstidine Triad gene
Putative tumor suppressor gene
Deleted in tumors of GI, lung, head/neck
FKHR
Fused with PAX7 gene via t(1;13)(p36;q14) in alveolar rhabdomyosarcoma.
FLI-1
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
FLICE/MACH
Member of ICE protease family
MACH = Mort1/FADD Associated CED-3 Homolog
Dominant-negative isoforms block both CD95 and TNF induced apoptosis
Apparently is recruited as a proenzyme to the receptor signaling complex by CD95-FADD and TNFR1- TRADD-FADD
Autoactivates in 2 steps: (1) abstraction of one of its two death effector domains (DED) into receptor complex may relieve autoinhibition caused by interaction between two DED domains, which would prime FLICE/MAH for (2) second trans-cleavage activation step, brought about by close proximity of other recruited pro-FLACH/MACH molecules. This would lead to release of active FLICE/MACH
FLT3
Class III receptor tyrosine kinase preferentially expressed on hematopoietic progenitor cells
Activated FLT3 activates signal transduction pathways involved in proliferation of pluripotent and progenitor cells
Internal tandem duplication reported in acute myeloid leukemia (20%), myelodysplasia (3%); D835 mutation present in AML (7%), myelodysplasia (3%), ALL (3%)
References: Archives 2005;129:1299
FMC7
Late B cell differentiation marker
Positive staining: mantle cell lymphoma, hairy cell leukemia, prolymphocytic leukemia
Negative staining: Chronic lymphocytic leukemia
fms
macrophage colony stimulating factor (M-CSF) receptor; also called CSF-1R, at 5q33-34
Promotes proliferation and differentiation of monocytes-macrophages
Mutations cause constitutive receptor transduction; associated with hematopoietic diseases, including myelodysplastic syndrome
Positive staining (normal): macrophages and their precursors
Positive staining (disease): choriocarcinoma, some AML
Focal adhesion kinase (FAK)
Protein tyrosine kinase, 125 kDa, that regulates antiapoptotic signaling
Binding of extracellular matrix molecules to integrins from endothelial cells causes recruitment of signaling molecules src, focal adhesion kinase, phospholipase C-gamma and basic-FGF to focal adhesion complexes, and modulates ability of endothelial cells to respond to growth factors
Positive staining (disease): invasive breast carcinoma (particularly high grade tumors, Mod Path 2005;18:1289), high grade sarcoma
Fontana-Masson
Melanin stain; difficult to interpret faint staining in sparsely positive cells
Melanin granules reduce ammonia-silver nitrate and turn black
Formaldehyde induced fluorescence
Demonstrates catecholamines and indolamines
Biogenic amines plus formaldehyde vapors from heating form highly fluorescent derivatives
fos
Protein at 14q21-22 that binds DNA in complex with jun; an immediate early response gene
FRAP
FKBP Rapamycin Associated Protein
Also called mTOR or RAFT
Founding member of the phosphatidylinositol kinase-related kinase family
Sensor of physiological signals that regulate cell growth, including nutrients, cAMP levels, and osmotic stress
Affects transcription, translation, and autophagy.
Ability to mediate osmotic stress response may be via an intermediate mitochondrial dysfunction, Proc Natl Acad Sci USA 2002;99:4319
Fusin
T lymphocyte surface protein and key attachment site for HIV; works with CD4
Receptors that promote exchange of GTP for GDP bound to G alpha subunit, then dissociation of alpha GTP
and G beta gamma from receptor and each other; then alpha GTP or G beta gamma regulate effector protein; then GTP becomes GDP and alpha GDP reassociates with G beta gamma to turn off the signal
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
Reference: Mod Path 2005;18:1264 (prognostic significance in lung squamous cell and adenocarcinoma)
Gangliosides
GM1: on intestinal epithelial cell surface; bound by B unit of choleragen (Vibrio cholera toxin)
Gastrin releasing peptide
Appear at weak 15 of gestation
Relatively specific to neoplastic and non-neoplastic endocrine cells of the lung
Gelatinase B
See MMP-9
Gemori methamine silver
See GMS
Giemsa stain
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)
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
Gomori methenamine silver
Special stain for detecting fungi and Pneumocystis carini
Stains cell walls and outlines these organisms; may have artefactual background staining
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)
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
Gross cystic disease fluid protein 15 (GCDFP-15)
Glycoprotein originally isolated in human breast gross cystic fluid
Positive staining (disease): lobular breast carcinoma (90%), primary breast carcinomas (72%), metastatic breast carcinoma (80%); also salivary gland and prostate carcinoma, apocrine differentiation
Growth factor receptors
Typically have extracellular ligand binding domain, a transmembrane domain and a cytoplasmic domain with a tyrosine kinase domain
Alterations (amplification, mutation, rearrangement) may lead to constitutive activation in absence of ligand.
gstp1
Gene directs formation of glutathione S transferase protein, which detoxifies environmental carcinogens by reduction
Inactivated by hypermethylation
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
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
HBME
Marker of mesothelial cells, named after laboratory of Dr. Hector Battifora and MEsothelioma
Also positive in various thyroid carcinomas
hc2
Positive in hairy cell leukemia, activated B and T cells, plasma cells
hcg
human chorionic gonadotrophin
Glycoprotein with alpha and beta subunits, used to detect pregnancy
Positive staining (disease): choriocarcinoma, syncytiotrophoblast cells in other tumors
Negative staining: exaggerated placental sites, placental site nodules, placental site trophoblastic tumors, epithelioid trophoblastic tumors
Heat shock proteins
See hsp
Hemosiderin
Hemoglobin breakdown product that contains iron
Heparanase
Expressed in metastatic gastric carcinoma to lymph nodes (95), primary gastric carcinoma (47%), not in normal gastric epithelial cells (Mod Path 2005;18:205)
Degrades heparan sulfate, a principal component of basement membranes, functional receptor complexes that facilitate signal transduction, and the extracellular matrix
Hepatocyte growth factor (HGF)
Only ligand for c-MET
Pleiotropic growth factor that promotes cell proliferation, motility and morphogenesis; also has important roles in normal development, organ regeneration and tumor development
Positive staining (disease): melanoma, melanocytic lesions
Hep Par1 antibody
Hepatocyte Paraffin 1; Also called Hep
Recognizes mitochondrial antigen of hepatocytes
Highly sensitive (92%); negative in higher nuclear grade tumors, AJSP 2002;26:978
Moderately specific; false positive cases were CK7+ or CK20+ (adenocarcinoma), chromogranin+ or synaptophysin+ (neuroendocrine)
Interpretation: granular cytoplasmic staining
Uses: determine hepatocellular origin, particularly in panel with alpha-fetoprotein and CEA or CD10 (canalicular pattern, more specific than Hep Par1)
Positive staining (disease): most hepatocellular carcinomas, some nonhepatocellular carcinomas metastatic to liver
Negative staining: bile duct adenoma
HER2
Also called neu, c-erbB2, p185HER2
Proto-oncogene on #17q11-21 for human epidermal growth factor receptor 2
Member of HER/erbB family, which encodes 185 kDa transmembrane tyrosine kinase receptor proteins (also epidermal growth factor receptor, HER3 and HER4), whose activation causes a cascade of intracellular enzymatic pathways, which can cause cell transformation
Overexpression is an independent adverse prognostic factor in several cancers; usually attributed to amplification of HER2 gene
Tumor expression of HER2 is discordant at nuclear, cytoplasm and cell surface levels, which highlights limitations of immunohistochemistry alone (AJSP 2005;29:1125, pancreatic adenocarcinoma)
HER2 - Breast
Expression is regulated by transcription activation in normal breast
Protein overexpression is associated with gene amplification (at 17q21); note - chromosome 17 polysomy without HER2 amplification doesn’t appear to affect HER2 expression (AJSP 2005;29:1221)
Overexpressed in 20-30% of female breast cancers; associated with comedocarcinoma, aggressive tumors, also intraductal tumor spreading (Hum Path 2002;33:21); usually not due to chromosome 17 aneusomy (Mod Path 2002;15:137)
Amplification causes 90% of cases of HER2 overexpression
Amplification determines eligibility for Herceptin (trastuzumab - anti-HER2 antibody) treatment for breast cancer, but only weak / variable association with poorer prognosis /survival) or response to chemotherapy
85% concordance between immunohistochemistry and FISH in breast carcinoma
HER2 is often amplified in ADH and DCIS, suggesting involvement in initiation of breast carcinogenesis (Mod Path 2002;15:116)
Associated with c-myc amplification (Hum Path 2005;36:634)
10% of ER+ DCIS cases were also HER2+ and were high nuclear grade (Mod Path 2005;18:615)
Vulvar Paget’s disease: overexpression is common in primary and recurrent disease (Mod Path 2005;18:354)
Predominantly determined using immunostaining; relevant staining (3+) is strong, complete membranous staining of tumor cells evident at low power; can be confirmed by Fluorescence In Situ Hybridization (FISH, more sensitive but more expensive and difficult to distinguish in situ from invasive lesions) and Chromogenic In Situ Hybridization (CISH, Mod Path 2002;15:657, Mod Path 2005;18:1015)
Compare intensity to 3+ control slide with negative normal epithelium
For node negative patients, FISH and IHC results were generally similar with some discrepant cases (Archives 2001;125:746)
FDA approved assays give comparable results when strictly handled (Archives 2004;128:627)
Staining pattern:
0 (negative) - no staining or membrane staining in <10% of tumor cells
1+ (negative) - faint membrane staining in > 10% of tumor cells; only part of membrane is stained
2+ (weak positive) - weak/moderate complete membrane staining in >10% of tumor cells
3+ (strong positive) - strong complete membrane staining in >10% of tumor cells
IHC stain scores of 0/1+ (negative/weak) or 3+ (strong) are predictive of FISH results (negative and positive amplification respectively); 2+ is not predictive and has significant interobserver variability (Mod Path 2001;14:1079); suggested to perform FISH or PCR for 2+ tests (will occasionally show amplification, PCR accuracy increased by laser-assisted microdissection, AJSP 2003;27:1565; but see Hum Path 2003;34:1043)
GOLDFISH (gold-facilitated autometallographic in situ hybridization): highly reproducible interpretation of scoring (AJSP 2002;26:908)
Interpretation: strong cell membrane staining around entire cell is associated with gene amplification
References: Mod Path 2001;14:213, Mod Path 2000;13:1239 (FISH correlates with IHC), Mod Path 2000;13:866, Mod Path 2000;13:37, Mod Path 2001;14:677, Archives 2003;127:549 (quality assurance), Hum Path 2005;36:250 (quality assurance)
HHF / HHF-35
Also called muscle actin
Positive staining (normal): smooth and skeletal muscle, pericytes, myoepithelial cells, myofibroblasts
Positive staining (disease): rhabdomyosarcoma
HHV-8
Human herpes virus 8
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
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)
Associated with 3 HIV associated lymphoproliferative disorders - primary effusion lymphoma, multicentric Castleman’s disease, multicentric Castleman’s disease-associated plasmablastic lymphoma
HIV p24
HLA-DR (Ia)
Positive staining (disease): AML-M3, AML-M6
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
HMB45
Human Melanoma Black, discovered by Dr. Allen Gown
Monoclonal antibody originally identified from melanoma abstract, recognizes melanosomal glycoprotein gp100
Identifies oncofetal glycoconjugate associated with immature melanosomes and probably related to the tyrosinase enzymatic system, J Histochem Cytochem 1992;40:207
Note: invasive melanomas with paradoxical maturation show at least focal deep HMB-45 reactivity, in contrast to nevi which are negative
Melan-A and MART-1 appear to be superior to HMB-45 in evaluating sentinel lymph nodes for melanoma, AJSP 2001;25:1039
Uses: confirmation of melanoma
Positive staining (normal): junctional melanocytes, scattered mononuclear cells in normal lymph nodes, rare nevus cells
Positive staining (disease): angiomyolipoma, tuberous sclerosis complex components, melanomas (85-90%), soft part sarcomas, sugar tumor of lung, lymphangioleiomyomatosis, pheochromocytomas (30%), pigmented nerve sheath tumors, Spitz nevi, cellular blue nevi
Negative staining: epithelial malignant peripheral nerve sheath tumors, spindle cell melanomas (usually), desmoplastic melanoma (usually), oral mucosal melanomas, adult melanocytes
Note: 50% of HMB45 negative melanoma cells have premelanosomes on EM
hMLH1 and hMSH2
Mismatch repair gene;
Mutations in these genes account for 70% of hereditary nonpolyposis colon cancer cases; also hPMS1, hPMS2, hMSH3 mutations
Inactivation causes high levels of microsatellite instability, which alters the cell’s ability to repair errors normally produced during DNA replication
Inactivation often occurs by methylation of its promoter in colon and gastric cancer
Associated with hereditary nonpolyposis colon cancer (90% of cases) and 15% of sporadic colorectal carcinoma
Homeobox genes
Genes that are similar across species at the nucleotide and amino acid level and determine the body’s basic organization
Produce transcription factors; mutations may cause limbs sprouted from the head
The position of the genes reflects the anterior to posterior site and timing of developmental expression
There are sharp boundaries in expression of these proteins
hox 11
Gene at 10q24, amplified in t(10;14)(q24;q11), seen in 7% of T-ALL
hSNF5/INI1
Inactivation associated with malignant rhabdoid tumors of kidney, atypical rhabdoid and teratoid tumor, as well as congenital disseminated malignant rhabdoid tumor and cerebellar tumor mimicking medulloblastoma, AJSP 2002;26:266
Hsp (heat shock proteins)
Induction of these proteins, by tumor necrosis factor and others, confers resistance to many agents which induce apoptosis in hematopoietic cells
Hsp 27
Expressed in upper epidermal layer of skin
Molecular chaperone involved in regulation of cell growth and differentiation
Reduced expression in some hereditary subtypes of ichthyosis (Hum Path 2005;36:686)
hsp 60
Heat shock protein that functions as a small chaperone
hsp 70
Heat shock protein that complexes with p53
hst-1
Also called k-fgf
Angiogenesis growth factor at 11q13.3
Human mobility group gene A2
Upregulated in uterine leiomyomas (Mod Path 2005;18:179)
Human Papilloma Virus
Also called HPV
Detected via PCR or in-situ hybridization
HPV E6 protein induces p53 degradation by a ubiquitin-dependent pathway; also activates host cell telomerase
HPV E7 protein binds retinoblastoma protein, leading to release of E2F transcription factor, then cell cycle progression; E7 also interferes with p21 inhibition of cdk2, causing stimulation of S phase genes cyclin A and E
HPV E5 has antiapoptotic function
Uses: (a) triage specimens with ASCUS into high or low risk; (b) differentiate endocervical (usually positive) from endometrial (usually negative) adenocarcinoma (AJSP 2002;26:998)
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)
Hyaluronic acid
Glycosaminoglycan found in lubricating proteoglycans of synovial fluid, vitreous humor, cartilage, blood vessels, skin, umbilical cord
Linear chain of 2500 repeating disaccharide units in specific linkage, each composed of a N-acetylglucosamine residue linked to glucuronic acid
Present in the capsule of beta hemolytic streptococcus, Group A organisms
Inhibitor of Caspase-3-Activated DNase
Caspase-3 substrate that controls nuclear apoptosis
Has two isoforms: functional 45kDa isoform called ICAD-L/DNA fragmentation factor (DFF 45) and 35kDa isoform called ICAD-S/DFF35
ICAD-deficient murine cells are resistant to apoptotic stimuli and lack typical nuclear changes of apoptosis
Colon cancer: essential to apoptosis of colonic cancer cells, Cancer Res 2002;62:2169
ICAM-1
InterCellular Adhesion Molecule 1; also called CD54
See CD54 (in CD Markers chapter)
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
ICH-1
ICE like protease, encodes 2 transcripts (L & S) which also induce and prevent apoptosis, but appear not to be important in vivo
ICK
Cyclin dependent kinase inhibitor
id2
First transcriptional target of N-myc gene
Neuroblastoma: expression associated with poor outcome, stronger predictor than age < 1 year or number of copies of N-myc gene; Cancer Res 2002;62:301
IGF-II
Expressed in pheochromocytoma and extra-adrenal paragangliomas, as well as some hepatocellular carcinomas
Reference: AJSP 2002;26:945
IgG4
6% of total IgG; least abundant of IgG subclasses
Elevated in serum in allergic or autoimmune disorders
Dysregulation associated with inflammatory pseudotumor (IgG4+ plasma cells) in liver, breast and lung; sclerosing pancreatitis (N Engl J Med 2001;344:732
Positive staining (disease): pemphigus vulgaris, inflammatory pseudotumor, sclerosing pancreatitis
References: Hum Path 2005;36:710 (lung)
Ikb-alpha
Inhibitor of NF KB
Due to its serine phosphorylation, it is ubiquinated, leading to proteosome mediated degradation
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)
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
int-2
“Integration” gene at 11q13
Growth factor similar to basic fibroblast growth factor
Normally expressed only during embryogenesis
int-6
Nuclear protein associated with PML; interacts with the Tax protein product of HTLV-1
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
Also called VLA-4
Helps white blood cells migrate during the inflammatory response
Found normally in basal epidermal layer
Found in suprabasal skin during wound healing and psoriasis
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
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
Also called LFA-1, Mac-1
Present on white blood cells; binds to endothelial proteins
Leukocyte adhesion deficiency type 1: CD18/beta 2 integrin subunit deficiency causes severe leukocytosis, recurrent infections of skin and mucosal surfaces, defective white blood cell adherence, chemotaxis, phagocytosis and bacterial killing
Leukocyte adhesion deficiency type 2: impaired synthesis of fucosylated carbohydrates causes developmental abnormalities, defective neutrophil rolling, leukocytosis, recurrent infections
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
Invadopodia
Plasma membrane protrusions
IRF4
See MUM1
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
Isochromosome 12p
Extra copies of 12 p
Increase in number of copies of 12p is associated with tumor progression and treatment failure in germ cell tumors
Associated with elevated levels of parathyroid related peptide (also on 12p)
Positive staining (disease): germ cell tumors (testicular, ovarian), embryonal rhabdomyosarcoma, neuroepithelioma
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 prod