PO Stains 1 PDF

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11A1 14-3-3sigma protein (stratifin) 15-PGDH 2-succino-cysteine (pending) 3 beta hydroxysteroid

dehydrogenase / HSD3B1 and HSD3B2 45M1 5-hmC (pending) 7 AAD / 7-amino-actinomycin D A beta
42 ABCC2 ABL Acid fast / Auramine-rhodamine Acid phosphatase Acridine orange ACSM1 ACTH
(pending) Actin - alpha cardiac Actin - general Actin - muscle specific Actin, alpha smooth muscle
type Adenovirus Adipophilin (pending) AF4 AGR2 Akt Albumin Alcian blue ALK Alkaline
phosphatase Alpha fetoprotein (AFP) Alpha-1-antichymotrypsin Alpha-1-antitrypsin Alpha-
lactalbumin Alpha-synuclein AMACR AML1 AMY1A amylase (pending) Amyloid beta and amyloid beta
precursor protein Androgen receptor (AR) Annexin A1 (pending) Annexin A10 AP2 beta APC API2-
MALT1 Apolipoprotein D (apoD) Argentaffin Arginase1 ARID1A ARID2 Asbestos ATDX
(ATRX) ATM B72.3 BAP1 Bcl-xL BCL10 (pending) BCL2 BCL6 BCOR (pending) BCR-
ABL Beclin1 BerEP4 / EpCAM Beta catenin Beta-2-microglobulin BG7 BG8 Bielschowsky Bile
(pending) Biotin Blood group antigens (A, B, H) BMP BOB1 Bodian silver
(pending) Bombesin Brachyury BRAF BRAF-melanoma BRCA1 BRCA2 BUB1B Butyrate esterase
(4-methylumbelliferyl butyrate) (pending) c-MET C1q (pending) C3 (pending) C3d (pending) C4d
(pending) C5b9 (pending) CA 19-
9 CA125 Cadherins Calcitonin Calcium Caldesmon Calponin Calretinin CAMTA1 Carbonic
anhydrase IX Caspase 3 Caspase 7 Caspase 8 Caspase 9 Caspases Cathepsin B Cathepsin
K CCR1 CCR2 CCR3 CCR4 CCR5 CCR6 CCR7 CCR8 CCR9 CDC2 / CDK1 CDH17
(pending) CDK4 CDX2 CEA / CD66e Cell cycle Ceramide Chaperones Chloroacetate
esterase Chromaffin Chromogranin CK 8/18 (pending) Claudin 6 Claudin1 Claudin18 Claudin4
(pending) Claudin5 Claudin7 Claudins - general Clusterin Collagen Collagen - type II Collagen type
IV Collagen XVII Congo red Copper Crystal Violet (pending) CXCL13
(pending) CXCL16 CXCR2 CXCR3 CXCR5 Cyclin D1 Cyclins Cyclooxygenase 2 (COX2) cyfra 21-1
(pending) Cytochrome c oxidase (COX) Cytokeratin 1 (CK1, K1) Cytokeratin 10 (CK10, K10) Cytokeratin 11
(CK11, K11) Cytokeratin 12 (CK12, K12) Cytokeratin 13 (CK13, K13) Cytokeratin 14 (CK14, K14) Cytokeratin
15 (CK15, K15) Cytokeratin 16 (CK16, K16) Cytokeratin 17 (CK17, K17) Cytokeratin 18 (CK18,
K18) Cytokeratin 19 (CK19, K19) Cytokeratin 2 (CK2, K2) Cytokeratin 20 (CK20, K20) Cytokeratin 21 (CK21,
K21) Cytokeratin 22 (CK22, K22) Cytokeratin 23 (CK23, K23) Cytokeratin 24 (CK24, K24) Cytokeratin 3 (CK3,
K3) Cytokeratin 34 beta E12 Cytokeratin 35 beta H11 Cytokeratin 4 (CK4, K4) Cytokeratin 5/6 Cytokeratin
5/6 and CK5 Cytokeratin 7 (CK7, K7) Cytokeratin 8 (CK8, K8) Cytokeratin 9 (CK9, K9) Cytokeratin
AE1 Cytokeratin AE1 / AE3 Cytokeratin AE3 Cytokeratin CAM 5.2 Cytokeratin KL-1 Cytokeratin MNF
116 Cytokeratins (CK) - general Cytomegalovirus (CMV) D2-40 (Podoplanin) DBA-
44 DCC deltaNp63 Desmin Desmogleins Dicer Diff-Quik (pending) DOG1 DOPA
reaction DPC4 Dupan-2 (pending) Dynactin1 Dystrophin (pending) E selectin E-
cadherin E1AF E2A EBER1 and EBER2 EGFR eIF-4F EKH4 keratin (pending) Elastic
fibers Elongin EMB (eosin and methylene blue) (pending) Endothelin-1 Epithelial membrane antigen
(EMA) Epstein-Barr virus ERCC1 ERG Estrogen receptor ETS1 ETV1 EWSR1 EZH2 Factor VIII
related antigen Factor XIIIa Fascin Ferritin FGFR3 FHIT Fibrinogen (pending) Filaggrin Fite acid-
fast stain (pending) FLI1 FLT3 FMC7 FN1 (pending) Follicular dendritic cell secreted protein
(FDCSP) Fontana-Masson FOXA1 FoxJ1 (pending) FOXL2 FOXP3 FSH (pending) Fumarate
Hydratase (FH), S-(2-succino) cysteine (2SC) Galectin3 Gastrin (pending) GATA3 GCET (pending) GH
(pending) Giemsa stain Glial fibrillary acidic protein (GFAP) Glucagon (pending) GLUT-
4 GLUT1 Glutamine synthetase (pending) Glycosaminoglycans Glypican
3 GMS GNAQ GNAS Gram stain Granzyme B Granzyme M Grimelius Gross cystic disease fluid
protein 15 (GCDFP-15) H3K27me3 Hales colloidal iron HAM 56 Hamartin Hansel stain HBME HBsAg
(pending) hCG HE4 HEG1 (pending) Helicobacter pylori antibody Hemoglobin A
(pending) HepPar1 HER2 (c-erbB2) breast HER2 stomach/GE junction HES1 HGAL HHV8 /
KSHV HIF1a (pending) HIK1083 HIV p24 hKIM1 (pending) HLA-DR HLA-G HMB45 HMGA2 HNF-
1B HNF1β (pending) Hotchkiss-McManus (pending) HPC2 HRAS Hsp90 (pending) HSV
(pending) HTLV-1 Human papillomavirus Human placental lactogen ICE IDH1 IFITM1 IFITM1
(pending) IgA (pending) IgD (pending) IgG IgG (pending) IgG4 IgH IgM
(pending) IL8 IMP3 IMP3 (pending) ING1 ING2 ING3 Inhibin A Inhibin B INI1 /
SMARCB1 INSM1 insulin (pending) Integrins Interleukins Involucrin (pending) Iodine
(pending) Iron ISL1 JAK Jones methenamine
silver Jun JunB Kappa Ki67 KIT KRAS Ku70 Ku80 L
selectin Lambda Laminin Lecithin Lectins Leder stain LEF-1 LEF1 (pending) LFABP
(pending) LH (pending) Light Chain 3B (LC3B) LIN28 Lipase (pending) Lipochrome (lipofuscin)
pigments LMO2 LMP Luxol fast blue Lysozyme MAC 387 Machiavello
(pending) MALT1 Mammaglobin MAP2 (pending) Martius scarlet blue trichrome Maspin MAST2 May-
Grunwald-Giemsa MCL1 (pending) MCPyV (pending) MDM2 MDR / CD243 MED12 MEF2B
(pending) MelanA / MART1 Melanin Menin Mesothelin Metalloproteinases (MMP) Methylene blue
(pending) MGMT MHC class II Microphthalmia transcription factor (MITF) Microsatellite
instability MLH1 MLL / ALL1 Movat pentachrome (pending) MRP2
(pending) MSH1 MSH2 MSH6 MSI testing Lynch syndrome / colorectal cancer MTAP
(pending) mTOR MUC2 MUC3 (MUC3A and MUC3B) MUC4 (pending) MUC5AC MUC6 MUC7
(pending) Mucins Multidrug resistance associated protein (MRP) Multigene products MUM1 /
IRF4 MYB MYC Myeloperoxidase MyoD1 Myogenin Myoglobin Myosin N-myc NADH
(pending) NapsinA NB84 (pending) NCCT (pending) Nek2 Nephrin (NPHS1) NESP55+
(pending) Nestin (pending) NeuN Neurofibromin Neurofilament Neuron specific enolase (NSE) NF
2 NF1 NFKB NKX2.2 NKX3.1 Nonspecific esterase NPM-ALK fusion protein NRAS Nucleophosmin
(NPM) NUTM1 Occludin p (pending) OCT 3/4 OCT2 Oil Red O Olig2 OPA1 Orcein
(pending) ORM1 (pending) OSCAR cytokeratin Osteocalcin (pending) P selectin p120
catenin p16 p21 p27 p53 p57 kip2 p63 Pan-TRK (EPR17341) [NTRK] Pancreatic
polypeptide PARP Parvalbumin (pending) PAS (Periodic Acid-Schiff) PAS Hematoxylin (PASH)
(pending) PAX2 PAX3 PAX5 PAX7 PAX8 PBK PCA3 PCNA PDGF PDL1 22C3 PDL1
SP142 PDL1 SP142 (Pending) PDL1 SP263 (Pending) PDS5B PDX1 (pending) Pentachrome
stain Perforin (pending) PGP9.5 (pending) PHF1 Phosphohistone H3 Phosphotungstic acid-hematoxylin
(PTAH) PHOX2B (pending) PIK3CA (pending) PKD1 PKD2 PKD3 PLA2R
(pending) PLAG1 PLAP PLEKHA7 PMEL17 PML-RAR α PMS2 PPARγ Prealbumin
(pending) PRKAR1A (pending) Progesterone receptor Programmed death-1 (PD-1) Prolactin
(pending) Prostate specific antigen (PSA) Prostate specific membrane antigen (PSMA) Prostatic acid
phosphatase (PAP) Prostein / P501S PROX1 PTEN PTH (pending) PU.1 RAD51 Rb RCC Reg
IV Renin RET Reticulin Retinoic acid, all-trans ROS1 RRM1 RUNX1 S100 S100A1 S100A1
(pending) S100P SALL4 SDH (pending) SDHB (succinate dehydrogenase) Serglycin (SRGN) Serum
amyloid A (SAA) SF1 SF1 (pending) SGOL1 SHP-1 Sialyl-Tn antigen Silica Sirius
red SIRT1 SMAD2 (pending) SMARCA4/BRG1 Smooth muscle myosin heavy chain /
SMMHC Smoothelin Somatostatin (pending) SOX10 SOX11 SOX2 SOX9 SPan-1 (pending) Special
AT-rich sequence-binding protein 2 (SATB2) SSTR2A STAT3 STAT6 Steiner (pending) STMN1
(pending) Sudan Black B Survivin SV40 (pending) Synaptophysin SYT (pending) T cell leukemia /
lymphoma protein 1 (TCL1) T-bet TAK1 / MAP3K7 Tamm Horsfall protein (pending) Tau TCF4
(pending) TCRαβ (pending) TCRγδ (pending) TCRβF1 (pending) TCRγ
(pending) TdT Telomerase Tenascin TERT (pending) TFE3 TFF1 (pending) Thioflavin S
(pending) Thioflavin T (pending) Thrombomodulin Thyroglobulin TIA1 Tissue of origin / unknown
primary TLE3 (pending) TMB toluidine blue (pending) Topoisomerase II alpha (TOP2A) Toxoplasma
(pending) Transducin-like enhancer of split 1 (TLE1) TRAP (Tartrate resistant acid phosphatase) Treponema
IHC (pending) Trichrome Trypsin (pending) Tryptase TSC1 and TSC2 TSH
(pending) TTF1 Tuberin Tubulin Tumor necrosis factor Twist1 Tyrosinase Ubiquitin Urates / uric
acid Uroplakin II Uroplakin II (pending) Uroplakin III VEGF VEGF-
D VEGFR3 Villin Villin Vimentin VIP (pending) Vitronectin von Hippel Lindau (VHL) von Willebrand
factor (vWF) VS38 (pending) VZV (Varicella-Zoster Virus) (pending) Warthin-Starry silver
stain wnt Wright-Giemsa stain WT1 WWTR1 YAP1 ZAP70 (pending) ZEB1 ZO1 (pending)
11A1
Table of Contents
Definition / general | Clinical features | Uses by pathologists
Definition / general
Procollagen 11A1 is overexpressed in desmoplastic stroma (Int J Oncol 2012;40:1447)
Note: 11A1 also refers to a mitochondrial cytochrome P450 enzyme (Lipids 2008;43:1127)
Note: Slc11a1 refers to solute carrier family 11, a different entity (WikiGenes)
Clinical features
Essential for normal skeletal development; mutations cause Marshall and Stickler syndromes, both characterized by
craniofacial abnormalities, nearsightedness and hearing deficiencies (Matrix Biol 2008;27:330)
Uses by pathologists
May be marker of desmoplasia
14-3-3sigma protein (stratifin)
Table of Contents
Definition / general | Clinical features | Diagrams / tables | Uses by pathologists | Microscopic (histologic)
images | Positive staining - normal | Positive staining - disease | Negative stains
Member of highly conserved family of 14-3-3 acidic proteins present in all eukaryotic organisms (Wikipedia)
Transcriptionally activated by p53 after DNA damage; facilitates DNA repair during G2 arrest (Oncogene 2006;25:4559)
Considered a tumor suppressor with reduced expression in some cancers (inactivated by promoter hypermethylation, Mod
Pathol 2005;18:340, Am J Clin Pathol 2010;133:232), and increased expression causes resistance to some antitumor agents
(Am J Transl Res 2009;1:326)
Clinical features
Down regulation is associated with poor outcome in intrahepatic cholangiocarcinoma (Hum Pathol 2007;38:1014)
Increased expression associated with poor prognosis in breast cancer (Cancer Biomark 2009;5:215, also poorer response to
neoadjuvant chemotherapy, Breast Cancer Res Treat 2012;134:229), nasopharyngeal carcinoma-undifferentiated (Oncol Rep
2010;24:949), pancreatic cancer (BMC Cancer 2010;10:598), stomach cancer (BMC Cancer 2011;11:397)
Diagrams / tables
Function in DNA
damage
response
None at this time
Microscopic (histologic) images
Images hosted on other servers:

Breast: normal Lung: non-small Lung: Oral cavity: Oral cancer (fig Stomach:
to invasive cell cancer adenocarcinoma normal to 1B) normal and
carcinoma carcinoma carcinoma
Positive staining - normal

Breast and prostate periductal and periglandular cells, urothelium, uterus (strong in squamous epithelium, weak in
endometrial and endocervical glands)
Myoepithelial marker in breast (Am J Surg Pathol 2005;29:347)
Positive staining - disease

Bladder urothelial carcinoma (98%), breast carcinoma (23%), cervical squamous cell carcinoma (67%), endometrial
adenocarcinoma (57%), ovarian carcinoma (33%), prostatic adenocarcinoma (55%), renal carcinoma (12%), testicular
tumors (27%)
Negative stains
Kidney (sporadic expression in tubules), germinal cells of ovary and testis
15-PGDH
Table of Contents
Definition / general | Diagrams / tables | Uses by pathologists | Microscopic (histologic) images | Positive staining -
normal | Positive staining - disease
NAD(+) dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), also called HPGD
Enzyme that inactives prostaglandin (PG) E2 by oxidizing its hydroxyl group to a ketone, leading to loss of biological
activity
A metabolic antagonist of cyclooxygenase-2 (COX2), a rate-limiting enzyme in biosynthesis of PGE2 (Biochem Pharmacol
2011;82:1352)
Regulated by NSAIDs (Prostaglandins Other Lipid Mediat 2011;96:37, Arch Biochem Biophys 2009;487:139)
Acts as a tumor suppressor in bladder (Am J Pathol 2010;176:1462), breast (Cancer Res 2006;66:7818), colorectal (J Korean
Soc Coloproctol 2012;28:253), lung (Carcinogenesis 2005;26:65, Prostaglandins Other Lipid Mediat 2007;83:203) and stomach
cancer (World J Gastroenterol 2012;18:1028); also in pituitary adenoma (Oncol Rep 2012;28:714)
H. pylori may promote gastric carcinogenesis by suppressing 15-PGDH (Cancer Prev Res (Phila) 2013;6:349)
In breast cancer, 15-PDGH also associated with aggressive behavior (J Pathol 2012;226:674)
Diagrams / tables
PGE2 synthesis,
degradation and
regulation
Apocrine marker for benign and most malignant apocrine breast lesions

Bladder: normal (left) and carcinoma Breast: benign apocrine and malignant lesions

Colon: normal Colon: normal Liver: normal Lung: normal and carcinoma
and cancer

Prostate: normal Stomach: normal and cancer Synovium:

healthy and
inflamed

Synovium: Uterus: endometrial adenocarcinoma

rheumatoid
arthritis

Apocrine sweat glands; various epithelium

Apocrine benign and malignant breast lesions (Mol Oncol 2009;3:220, Mol Cell Proteomics 2006;5:462)
2-succino-cysteine (pending)
Table of Contents
[Pending]
3 beta hydroxysteroid dehydrogenase / HSD3B1 and HSD3B2
Table of Contents
Definition / general | Diagrams / tables | Uses by pathologists | Microscopic (histologic) images | Positive staining -
normal | Positive staining - disease | Negative staining
Critical enzyme in biosynthesis of all steroid hormones; catalyzes conversions of progesterone from pregnenolone, 17-
hydroxyprogesterone from 17-hydroxypregnenolone and androstenedione from dehydroepiandrosterone (Wikipedia)
Also called hydroxyl-δ-5-steroid dehydrogenase
Isomerase 1 (HSD3B1) localizes generally to placenta and nonsteroidogenic tissue; isomerase 2 (HSD3B2) generallly
localizes to adrenal gland, gonads and steroidogenic tissue
Located on inner mitochondrial membrane; acts as both a dehydrogenase and an isomerase, due to a conformational
change (Biochemistry 2011;50:11015)
Transcription in adrenal gland regulated by farnesoid X receptor (Mol Cell Endocrinol 2009;299:153)
Mutations cause rare form of congenital adrenal hyperplasia (Horm Res Paediatr 2012;77:334, Rev Med Liege
2004;59:485, Gene 2012;503:215)
Diagrams / tables
Steroid
synthesis chart
Identify adenocortical tissue origin (Arch Pathol Lab Med 2002;126:1118)
Note: fetal adrenal gland lacks 3 beta hydroxysteroid dehydrogenase
Confirm trophoblastic origin

3 beta-hydroxysteroid Adrenal gland Placental villi
dehydrogenase zona fasciculata
immunohistology (fig B)
in adrenal gland

Adrenocortical tissue, placental intermediate trophoblast and syncytiotrophoblast (Am J Surg Pathol 2008;32:236); testicular
Leydig cells

Trophoblastic tumors (HSD3B1 - Am J Surg Pathol 2008;32:236, Int J Gynecol Cancer 2013;23:343)
Negative staining
Normal seminiferous tubules, fetal adrenal gland
45M1
Table of Contents
Definition / general | Uses by pathologists | Case reports | Microscopic (histologic) images | Positive staining -
Antibody against MUC5AC, a gastric mucin, with epitope located in the C-terminal cysteine-rich part (FEBS J 2008;275:481)
To detect gastric mucins
Case reports
58 year old man with recurrence of gastric cancer with mucin phenotype (Surg Today 2007;37:325)
78 year old man with 45M1+ ampullary signet-ring cell carcinoma and ampullary adenocarcinoma (JOP 2011;12:162)
Ampulla of Vater: coexisting signet-ring cell carcinoma and adenocarcinoma (45M1+, fig 4)

Bowel Pancreas: mucous gland hyperplasia (45M1+)
Stomach (distal):

Gastric epithelium

Barrett’s esophagus and intestinal metaplasia of gastroesophageal junction (Am J Surg Pathol 2001;25:87)
Mucous gland hyperplasia of pancreas (J Carcinog 2005;4:9)
Distal stomach super-minute well-differentiated adenocarcinoma lesions (J Carcinog 2005;4:14)
Negative staining
Mature small intestinal goblet cells
5-hmC (pending)
Table of Contents
[Pending]
7 AAD / 7-amino-actinomycin D
Table of Contents
Definition / general | Diagrams / tables | Uses by pathologists | Positive staining - normal | Negative staining
Fluorescent dye that binds DNA and is excited by a 488 nm laser, commonly used in flow cytometry
Intact cells exclude 7 AAD, but dead or apoptotic cells that have lost membrane intergrity allow 7 AAD entry, which binds
to DNA (Wikipedia, Nat Protoc 2007;2:187)
Diagrams / tables
7 AAD
fluorescence
Used in flow cytometry to reduce non-specific staining by eliminating 7 AAD positive cells (dead cells) from further analysis
Can use to exclude dead sperm (Andrologia 2010;42:20)

Dead cells: allow entry of dye, which binds DNA and fluoresces with 488 nm laser commonly used in flow cytometry
Negative staining
Viable cells (do not allow entry of dye into cell)
A beta 42
Table of Contents
Definition / general | Clinical features | Diagrams / tables | Microscopic (histologic) images
Aβ42 is generated by sequential processing of β-amyloid precursor protein (APP) by beta and gamma secretase, which
likely has a causative role in Alzheimer's disease (AD)
Aβ42 is main constituent of amyloid plaque in brains of patients with Alzheimer disease; has 2 common isoforms: Aβ40 is
more common, Aβ42 is more amyloidogenic and may lead to formation of plaques (Alzheimers Res Ther 2012;4:9)
Production of Aβ42 is enhanced by familial AD mutations in presenilin 1 (PS1) and PS2, as well as by some familial AD
mutations in APP (J Biol Chem 2011;286:15240)
Clinical features
Aβ42 is target of therapeutic strategies
Elevated Aβ42 also occurs in aged, non-demented with cerebral atherosclerosis (Curr Alzheimer Res 2013;10:785)
CSF levels of Aβ42 may predict clinical progression to AD in some patients (Alzheimers Dement 2012;12:481)
Diagrams / tables
Apolipoprotein E / Aβ interaction pathways

and therapeutic approaches

Brain tissue of Alzheimer's disease

patient
ABCC2
Table of Contents
Definition / general | Essential features | Terminology | Pathophysiology | Clinical features | Interpretation | Uses by
pathologists | Prognostic factors | Microscopic (histologic) description | Microscopic (histologic) images | Positive
staining - normal | Positive staining - disease | Negative staining | Molecular / cytogenetics description | Board
review style question #1 | Board review answer #1
Adenosine triphosphate (ATP) binding cassette subfamily C member 2 (ABCC2) belongs to the C subfamily of the ABC
transmembrane protein transporters
It is located on chromosome 10 (Nat Rev Cancer 2010;10:147)
ABCC transporters are involved in active drug transportation
Contributes to chemotherapy resistance in some tumors by what is thought to be drug efflux mechanisms
Also called multidrug resistant protein 2 (MRP2)
Essential features
Diagnostically, ABCC2 is to be used together with morphology to subtype papillary renal cell carcinomas according to
the proposed biological classification
ABCC2 has prognostic significance in some tumors, particularly papillary renal cell carcinoma, as well as breast, colon,
ovary and fallopian tube
Might have predictive significance as has been implicated in chemotherapy resistance
Terminology
Adenosine triphosphate (ATP) binding cassette subfamily C member 2 (ABCC2)
Multidrug resistance associated protein 2 (MRP2)
Canalicular multispecific organic anion transporter 1 (CMOAT1)
Canalicular multidrug resistance protein (cMRP)
ABC30
Dubin-Johnson syndrome (DJS)
Pathophysiology
ABC transporters have 7 subfamilies
ABCC2 belongs to the C subfamily, also known as multidrug resistance protein family (Nat Rev Cancer 2010;10:147)
They are involved in active drug transportation
ABCC2 contributes to chemotherapy resistance through active ATP dependent efflux of drugs (Nat Rev Cancer 2010;10:147)
Some studies indicate that they play a role in tumor biology beyond the efflux properties (Nat Rev Cancer 2010;10:147)
Transporters are ATP dependent
Cells enriched in ABC transporters are reported to be larger than average and hold numerous mitochondria to
compensate for high energy demand needed for the transporter properties
This could contribute to the oncocytic nature of some of the reported ABCC2 high tumors (Curr Cancer Drug Targets
2005;5:457)
Renal drug transporters, including ABCC2, are upregulated downstream to the NRF2-ARE pathway that is enriched
in papillary renal cell carcinoma type 2 (N Engl J Med 2016;374:135, Toxicol In Vitro 2015;29:884)
Clinical features
Germline mutations in ABCC2 are associated with autosomal recessive Dubin-Johnson syndrome
It is characterized by impaired secretion of conjugated bilirubin by hepatocytes
Grossly, the liver is black in appearance
Microscopically, there is accumulation of dark, coarsely granular pigment in the centrilobular zone
Electron microscopy shows the pigment accumulating in lysosomes
These patients are usually asymptomatic, with incidental detection of hyperbilirubinemia (Talaga: Dubin Johnson
Syndrome, 2019)
Interpretation
Cytoplasmic staining consistently observed in all reported tumors and normal tissue
Additional nuclear staining reported in breast, ovary and fallopian tube
Papillary renal cell carcinoma subtyping: in the proposed combined morphological and molecular classification of
papillary renal cell carcinoma, ABCC2 plays an important role in making the distinction between subtypes 1, 2, 3 and 4
(oncocytic low grade) (Am J Surg Pathol 2017;41:1618)
Prognostic factors
Papillary renal cell carcinoma subtypes show different prognosis: on univariate and multivariate analysis, types 1 and 4
showed indolent behavior with significantly better outcome than types 2 and 3 (Am J Surg Pathol 2017;41:1618, Eur Urol
Focus 2018;4:740)
Prognostic and predictive marker for other tumors
ABCC2 immunohistochemistry is reported as having prognostic value and potential predictive value (associated with
chemotherapy resistance) in colon carcinoma, ovarian carcinoma, fallopian tube carcinoma and breast carcinoma
(Gynecol Oncol 2006;100:239, Clin Cancer Res 2000;6:2401, Clin Cancer Res 2006;12:7149, Pathol Oncol Res 2012;18:331, Arch
Gynecol Obstet 2013;287:563)
Possible predictive value in metastatic papillary renal cell carcinoma type 2 (Mol Oncol 2018;12:1673)
Microscopic (histologic) description

Papillary renal cell carcinoma subtypes (Am J Surg Pathol 2017;41:1618):
Type 1 shows complete absence of ABCC2 staining
Type 2 exhibits strong diffuse staining equal to or stronger than the background renal tubules
Type 3 shows patchy staining weaker than the normal renal tubules
Type 4 (oncocytic low grade type) has a distinct morphology with reverse polarity nuclear pattern and shows a strong
diffuse ABCC2 staining pattern; however, unlike type 2, they harbor GATA3+ nuclear staining (Am J Surg Pathol 2019
May 22 [Epub ahead of print])
Type 3 can be difficult to distinguish from type 1 on morphology alone without ABCC2 immunohistochemistry ancillary
testing
Contributed by Rola Saleeb, M.D., Ph.D.

Papillary renal cell carcinoma type 1 Papillary renal cell carcinoma type 2

Papillary renal cell carcinoma type 3 Papillary renal cell carcinoma type 4

Renal tubules (cytoplasmic)
Liver bile canaliculi (bile canaliculi expression)
Cerebral cortex (cytoplasmic)
Squamous epithelium (cytoplasmic)
Pancreatic acini (cytoplasmic)
Normal fallopian tube epithelium (cytoplasmic)

Papillary renal cell carcinoma subtypes 2, 3 and 4 (cytoplasmic)
Colon adenocarcinoma (cytoplasmic)
Ovarian cancer (cytoplasmic and nuclear)
Breast carcinoma (cytoplasmic and nuclear)
Fallopian tube carcinoma (cytoplasmic and nuclear)
Negative staining
Papillary renal cell carcinoma type 1
Glomeruli
Lymph nodes
Endocrine pancreas
Molecular / cytogenetics description

Molecular analysis of papillary renal cell carcinoma showed statistically significant very high ABCC2 gene expression by
RNA sequencing platform in papillary renal cell carcinoma type 2 in comparison with type 1
Data was based on The Cancer Genome Atlas papillary cohort (Eur Urol Focus 2018;4:740)
Studies on colon cancer, breast carcinoma, fallopian tube carcinoma and ovarian carcinoma showed correlation
between ABCC2 gene expression by polymerase chain reaction and clinical outcomes, as well as chemotherapy
resistance (Gynecol Oncol 2006;100:239, Clin Cancer Res 2000;6:2401, Clin Cancer Res 2006;12:7149, Pathol Oncol Res
2012;18:331, Arch Gynecol Obstet 2013;287:563)
Board review style question #1

A 56 year old man has an incidentally discovered renal mass, 4 cm in size. He was treated with partial nephrectomy.
Microscopic examination shows a papillary renal cell carcinoma. You run an immunopanel including ABCC2 stain. Which
pattern of staining reflects indolent tumor behavior?
A. Complete absence of ABCC2 staining in both the tumor and the surrounding kidney
B. Complete absence of ABCC2 staining in the tumor with preserved staining in renal tubules
C. Strong diffuse staining equal to or stronger than the surrounding renal tubules
D. Weak patchy staining, slightly weaker than the surrounding renal tubules
Board review answer #1

B. Complete absence of ABCC2 staining in the tumor with preserved staining in renal tubules. Papillary renal cell carcinoma
type 1 shows complete absence of ABCC2 staining, while type 3 shows patchy weak staining and type 2 shows strong
diffuse staining. Type 1 tumors with low ABCC2 levels by both mRNA and immunohistochemistry analysis have been shown
in multiple studies to have excellent outcomes.
Reference: ABCC2
Comment Here
ABL
Table of Contents
Definition / general | Clinical features | Diagrams / tables | Microscopic (histologic) images
Also called c-abl
Gene at 9q34.1, named after ABelson murine Leukemia virus
Abelson family of nonreceptor tyrosine kinases, ABL1 and ABL2, transduces diverse extracellular signals to protein
networks that control proliferation, survival, migration and invasion (Nat Rev Cancer 2013;13:559)
Dysregulated tyrosine kinase activates a network of signals that contributes to cytokine independent growth, resistance to
apoptosis and genetic instability (Cancer Control 2009;16:100)
Also regulates BMP2 induced osteogenesis (J Biol Chem 2013;288:24503)
Clinical features
Commonly overexpressed in chronic myelogenous leukemia (CML), due to t(9;22)(q34;q11), the Philadelphia
chromosome, which produces the BCR-ABL fusion gene; BCR-ABL transcript can be demonstrated with RT-PCR
Also occurs in Philadelphia chromosome+ AML, a rare aggressive leukemia distinct from CML (Am J Clin Pathol
2007;127:642) and Philadelphia chromosome+ acute lymphoblastic leukemia (Hematology Am Soc Hematol Educ Program
2009;371:81)
Not present in atypical CML, juvenile myelomonocytic leukemia, other chronic myeloid neoplasms
Inhibited by imatinib mesylate (Gleevec, STI571), a treatment for CML
Overexpression of c-Abl predicts unfavorable outcome in epithelial ovarian cancer (Gynecol Oncol 2013;131:69)
Diagrams / tables
t(9;22)
Liver:
Hepatocellular
carcinoma
Acid fast / Auramine-rhodamine
Table of Contents
Definition / general | Methods | Microscopic (histologic) images | Videos
Acid fast refers to microorganisms whose cell wall has a high lipid content of mycolic acids and long chain fatty acids,
which traditionally is considered to cause them to bind and retain the complex basic dye carbol-fuchsin even after strong
decolorization with acid-alcohol (thus "acid-fast") (Wikipedia)
Hänscheid et. al. believe auramine O actually binds to nucleic acids, not to the cell wall (see Lancet Infect Dis
2007;7:236, J Microbiol Methods 2008;74:119)
Partially acid fast organisms exhibit both acid fast and non-acid fast bacilli and filaments in a single strain
Standardization recommended for interpretation (Hum Pathol 2012;43:1845)
Sputum smears may misidentify acid-fast bacilli as Mycobacterium tuberculosis in HIV+ patients (J Acquir Immune Defic
Syndr 2013;63:168)
Acid fast organisms include Mycobacteria, oocysts of Cryptosporidium parvum, Cyclospora, Isospora; also hooklets of
cysticerci
Partially acid fast organisms include Actinomyces: Dietzia (Int J Syst Evol Microbiol 2006;56:1667), Gordonia (Emerg Infect Dis
2000;6:382), Nocardiae (Surg Infect (Larchmt) 2012;13:163), Rhodococcus (South Med J 1991;84:1217), Tsukamurella (J Med
Case Rep 2008;2:207); also rarely Mycobacterium peregrinum (J Clin Microbiol 2005;43:2015)
Note: nucleic acid based tests can rapidly detect and speciate mycobacteria (Arch Pathol Lab Med 2008;132:1333, Thorax
2008;63:317)
Methods
Ziehl-Neelsen (classic): common method; bacteria stain bright red due to retention of carbol-fuchsin dye; background
is methylene blue counterstain; procedure involves heat (#1, #2)
Ziehl-Neelsen (modified bleach): may be more sensitive than classic stain (Acta Cytol 2008;52:325,J Cytol 2012;29:165)
Ziehl-Neelsen (modified for stool specimens): does not require heating (Centers for Disease Control)
Kinyoun: common method; uses more concentrated fuchsin dye and lipid solvent, but no heat; bacteria stain bright red
against green background (#1, #2)
Fite: to detect M. leprae (leprosy) and Rhodococcus (Diagn Cytopathol 2001;24:244); combines peanut / vegetable oil with
xylene to minimize exposure of bacteria cell wall to organic solvents and protect precarious acid-fastness of organism
(#1, #2)
Ellis and Zabrowarny: protocol excludes phenol; procedure (J Clin Pathol 1993;46:559)
Auramine-rhodamine: mixture of Auramine O and Rhodamine B dyes, auramine binds to mycolic acid in cell wall;
detection requires a fluorescence microscope (mercury vapor lamp or LED), but is most sensitive stain for mycobacteria
(Hum Pathol 1984;15:1085, PLoS One 2011;6:e22495); saves time in searching for microorganisms (Clin Infect Dis
2008;47:203); procedure
Water filters are recommended to reduce false positives due to non-TB mycobacteria (Appl Environ Microbiol
2007;73:6296)
Cryptosporidium:

Oocysts: modified acid-fast stain Stool specimen Oocysts:

(Ziehl-Neelsen) auramine-
rhodamine stain
Cyclospora:

Acid-fast stain Modified acid-
fast stain
Isospora:
Videos
Acid phosphatase
Table of Contents
Definition / general | Essential features | Terminology | Interpretation | Uses by pathologists | Microscopic
(histologic) description | Microscopic (histologic) images | Positive staining - normal | Positive staining -
disease | Negative staining | Board review style question #1 | Board review answer #1
Acid phosphatase is not a single enzyme but rather a group of enzymes that hydrolyze and release phosphate group from
different substrates
By definition, they function best in an acidic environment and are normally localized in the lysosomes (Mol Pathol
2002;55:65)
In muscle biopsies, the acid phosphatase stain is an enzyme histochemical stain that relies on endogenous acid
phosphatase activity in the muscle specimen to hydrolyze the artificial naphthol AS-B1 phosphate substrate into naphthol,
producing a brick red reaction product (Dubowitz: Muscle Biopsy: A Practical Approach, 4th Edition, 2013)
Therefore, the acid phosphatase stain must be performed on cryosections of snap-frozen fresh muscle tissue
Acid phosphatase should be differentiated from the antibody based immunohistochemical stains Prostatic Acid
Phosphatase (PAP or PSAP) and Tartrate Resistant Acid Phosphatase (TRAP)
PAP is a marker for prostate cancer (Biochem Mol Biol Int 1994;33:567)
TRAP is a marker for osteoclasts (Calcif Tissue Int 1982;34:285)
Essential features
In muscle biopsies, acid phosphatase stain is mainly used to highlight macrophages, red rimmed vacuoles in inclusion
body myositis, lysosome storage disorders and other hereditary or acquired vacuolar myopathies associated with
abnormal lysosomal activity
Terminology
Nonspecific acid phosphatase(s)
Interpretation
Lysosomes
Highlights degenerating fibers and macrophages (Dubowitz: Muscle Biopsy: A Practical Approach, 4th Edition, 2013)
Detects muscle disorders with lysosomal abnormalities, including lysosomal storage diseases and variable hereditary or
acquired vacuolar myopathies associated with lysosomal dysfunction or excessive autophagic activity; see disease
specific references under Positive staining - disease section

Staining of lipofuscin in myofiber is punctate granular, predominantly subsarcolemmal (Dubowitz: Muscle Biopsy: A Practical
Approach, 4th Edition, 2013)
Staining of lysosomes or lysosomal vacuoles in myofiber is punctate and predominantly sarcoplasmic; see disease
specific references under Positive staining - disease section
Staining of degenerating myofibers and paraspinal myofibers is a weak diffuse blush in the sarcoplasm
Staining of macrophages is strong cytoplasmic
Contributed by Chunyu "Hunter" Cai, M.D., Ph.D.

Adult onset acid Central core Cystinosis distal Degenerating Hydroxychloroquine

maltase myopathy myopathy myofibers myopathy
deficiency

Inclusion body Infant onset acid Lupus myositis Myophagocytosis Normal muscle
myositis maltase
deficiency

Stains lysosomes in myofibers, which are inconspicuous in normal fibers
Stains lipofuscin in muscle fibers, which are usually subsarcolemmally located and increase with age
Increased in paraspinal muscles (Muscle Nerve 2015;52:45)

Degenerating and regenerating myofibers (J Neurol Sci 1977;33:95)
Macrophages (Muscle Nerve 1995;18:242)
Rimmed vacuoles in inclusion body myositis (Ann Neurol 1988;23:258)
Acid maltase deficiency/Pompe disease/Glycogen storage disease type II (Acta Neuropathol Commun 2014;2:2)
Vacuoles in cystinosis distal vacuolar myopathy (Ann Neurol 1994;35:181)
Vacuoles in X-linked myopathy with excessive autophagy (XMEA) (Biomed Res Int 2018;2018:5069042)
Vacuoles in Danon disease (J Neuropathol Exp Neurol 2005;64:513)
Chloroquine and hydroxychloroquine induced myopathy (Am J Med 1987;82:447)
Colchicine induced myopathy (Acta Neuropathol 2002;103:100)
Chronic vitamin E deficiency (Ann N Y Acad Sci 1982;393:84)
Negative staining
Other types of glycogen storage diseases besides acid maltase deficiency (GSD II) (J Clin Neurosci 2015;22:1674)

Which of the following components in muscle fiber stains acid phosphatase?
A. Lipid droplet
B. Lysosome
C. Mitochondria
D. Myosin filament
E. Sarcoplasmic reticulum

B. Lysosome
Comment Here
Reference: Acid phosphatase
Acridine orange
Table of Contents
Definition / general | Uses by pathologists | Microscopic (histologic) images
Nucleic acid, selective fluorescent cationic dye useful for cell cycle determination (Wikipedia)
Cell-permeable, interacts with DNA by intercalation and with RNA by electrostatic attraction
Accumulates in intracellular acidic vesicles, especially lysosomes, in an acidity-dependent manner; anti-tumor effect due
to its marked and prolonged accumulation in acidic lysosomes of cancer cells (Curr Pharm Des 2012;18:1414)
For diagnosis in exfoliative cytology of bladder carcinoma (Int Urol Nephrol 2012;44:1375), oral cavity carcinoma (Indian J
Dent Res 2011;22:649)
Part of photodynamic therapy to treat musculoskeletal sarcoma and spare normal surrounding tissue (Clin Orthop Relat Res
2013;471:792, J Bone Joint Surg Br 2010;92:760)
To identify small numbers of bacteria and microorganisms under fluorescent light, including mycobacteria (Indian J Pathol
Microbiol 2010;53:894) and malaria parasites (Ann Trop Med Parasitol 2002;96:643)
In fertility testing, is part of sperm chromatin structural assay, which reflects sperm chromatin denaturation (J Assist Reprod
Genet 2009;26:591)
To determine gender by examining Barr bodies in buccal smears (J Forensic Dent Sci 2012;4:66)
To identify engulfed apoptotic cells, because it fluoresences upon engulfment

Bacilli and cocci Buccal smear Buccal smear Mycobacteria

clusters (female) (male)

Oral cavity: Oral cavity: Sperm: Sperm: Trypanosomes
normal cells squamous cell chromatin hyaluronic acid
carcinoma
ACSM1
Table of Contents
Definition / general | Clinical features | Uses by pathologists | Microscopic (histologic) images | Positive staining -
normal | Positive staining - disease
First discovered in 2001, also called MACS1 (J Biol Chem 2001;276:35961), acyl-CoA synthetase medium-chain family
member 1
Encodes enzyme catalyzing activation of medium chain length fatty acids (OMIM #614357)
Present on chromosome 16p12-13
Clinical features
Breast apocrine marker (Mol Cell Proteomics 2008;7:1795)
Schizophrenia susceptibility gene (J Psychiatr Res 2010;44:748)
Atlas of Genetics and Cytogenetics
GeneCards
Marker of apocrine breast lesions (benign and malignant)

Various normal Benign breast Invasive breast Kidney tubules

tissues apocrine lesions apocrine (second image
carcinoma in slideshow)

Monocytes (IUBMB Life 2006;58:435)
Esophagus

Breast - benign and malignant apocrine lesions (Mol Oncol 2009;3:220)
ACTH (pending)
Table of Contents
[Pending]
Actin - alpha cardiac
Table of Contents
Definition / general | Diagrams / tables | Microscopic (histologic) images | Positive staining - normal | Positive
staining - disease | Negative staining
Also called ACTC1
Two types of alpha sarcomeric / striated actin: alpha cardiac type and alpha skeletal muscle type; both are expressed
in cardiac and skeletal muscle, but the proportions vary at different developmental periods (J Biol Chem 1994;269:12212) or
with disease (Rapid Commun Mass Spectrom 2003;17:1467)
Existence of two actin isoforms and their conformational differences may be part of tuning regulatory mechanism, by which
the cardiac muscle cells can maintain their biological function under pathological conditions (Biochem Biophys Res Commun
2008;368:696)
Mutations in alpha cardiac actin may cause dilated or hypertrophic cardiomyopathy (J Mol Cell Cardiol 2000;32:1687, J Biol
Chem 2006;281:16777); location of mutations correlate with type of functional change (PLoS One 2012;7:e36821)
Mutations may cause familial atrial septal defects (Hum Mol Genet 2008;17:256) due to reduced ACTC1 expression inducing
cardiomyocyte apoptosis (Circ J 2010;74:2410)
Diagrams / tables
Cardiac actin
mutations
related to
cardiomyopathies

Various images

Myocardium (adult and fetal), skeletal muscle (fetal), skeletal muscle (adult-muscle spindle myocytes) and vascular
smooth muscle (occasional)

Skeletal muscle (regenerating skeletal muscle cells, Differentiation 1996;60:245), Duchenne muscular dystrophy,
degenerative atrophy (Virchows Arch 2006;449:175), rhabdomyosacoma, Wilm tumor-rhabdomyomatous cells
Extraocular skeletal muscle in skeletal muscle alpha-actin disease (Neuromuscul Disord 2008;18:953)
Occasional smooth muscle tumors
Negative staining
Skeletal muscle (adult, but muscle spindle myocytes are positive)
Actin - general
Table of Contents
Definition / general | Pathophysiology | Clinical features | Diagrams / tables | Microscopic (histologic) images
Globular protein that forms microfilaments; found in all eukaryotic cells except nematode sperm (Wikipedia)
Highly conserved, differs by at most 20% between algae and humans
Participates in more protein-protein interactions than any known protein
Pathophysiology
The monomeric subunit of microfilaments, one of 3 major components of cytoskeleton (also microtubules and intermediate
filaments); also a component of thin filaments (part of contractile apparatus of muscle cells)
Can transition between monomeric (G-actin) and filamentous (F-actin) states under control of nucleotide hydrolysis, ions,
and actin-binding proteins (Annu Rev Biophys 2011;40:169)
Mammalian muscle cells contain alpha and gamma smooth muscle actin, alpha cardiac actin and alpha skeletal actin
Mammalian nonmuscle cells contain beta cytoplasmic actin and gamma cytoplasmic actin
Functions in all cells:
Forms part of cytoskeleton, which gives mechanical support to cell and is part of signal transduction
Assists with motility and phagocytosis
Helps myosins transport organelles and other substances through cell
Actin cytoskeleton may act as sensor and mediator of apoptosis (Bioarchitecture 2012;2:75)
Function in muscle cells: contraction
Actin cap: recently characterized cytoskeletal organelle composed of thick and highly contractile acto-myosin filaments
anchored to apical surface of interphase nucleus (Soft Matter 2013;9:5516)
Clinical features
Persistence of high titers of anti-actin serum antibodies is associated with disease activity in autoimmune hepatitis
(Hepatology 2013;59:592)
Diagrams / tables

Actin and Helical structure G-actin to F- Animation of

myosin in of F-actin actin transition muscle
muscle contraction

Various images
Actin - muscle specific
Table of Contents
Definition / general | Uses by pathologists | Microscopic (histologic) images | Positive staining - normal | Positive
staining - disease | Negative staining
Discovered in 1987 (Am J Pathol 1987;126:51); also called HHF35, MSA
Recognizes all alpha actins (skeletal, smooth, cardiac) and gamma smooth muscle actin; but not beta cytoplasmic or
gamma cytoplasmic actin (the latter is also called non-muscle actin)
Recognizes actin expressed in all cells with muscle differentiation (cardiac, smooth and skeletal muscle), myoepithelial
cells, myofibroblasts, pericytes and myogenic tumors (Am J Clin Pathol 1991;96:32)
Identify skeletal muscle (Tumori 2007;93:198, J Cutan Pathol 2007;34:352) and smooth muscle cells (Eur Respir J 2001;17:316)
in normal tissue or various disease entities
Classify tumors with smooth or skeletal muscle, pericytes, myofibroblasts (Cardiovasc Pathol 2006;15:91) or myoepithelial
cells
Differentiate leiomyosarcoma (MSA+, keratin-) from spindle cell carcinoma (MSA-, keratin+, Am J Otolaryngol 2005;26:201)

Endometriosis

Myofibroblastoma: Myofibroblastoma: lymph node Prostate: normal
breast (fig d) smooth muscle
stroma

Rhabdomyo- Rhabdomyo- Glomus tumor

sarcoma: CNS, sarcoma: oral
embryonal (fig 4) cavity

Cardiac muscle, decidua, myoepithelial cells (although calponin and vimentin may be better, Braz Dent J 2007;18:192),
myofibroblasts, pericytes, skeletal muscle, smooth muscle and vascular smooth muscle

Adenoid cystic carcinoma-myoepithelial component (J Oral Maxillofac Surg 2006;64:415)
Angiomyolipoma
Cardiac rhabdomyoma
Chondroblastoma (35%, Hum Pathol 1997;28:316)
Endometriosis-smooth muscle (Hum Reprod 2000;15:767)
Fibromatosis (Acta Cytol 1991;35:403)
Giant cell tumor of bone (Ultrastruct Pathol 2013;37:183)
Glioblastoma multiforme (occasional)
Glomus tumor (Hum Pathol 1999;30:1259)
Inflammatory myofibroblastic tumor (Mod Pathol 2001;14:784)
Leiomyoma (Int J Gynecol Pathol 1995;14:134)
Leiomyosarcoma (80-100%, J Pak Med Assoc 2005;55:138, APMIS 1997;105:793, Histopathology 2013;63:194)
Malignant fibrous histiocytoma (30%, J Clin Pathol 2003;56:666)
Mucinous cystic neoplasm (ovarian type stroma, Saudi Med J 2013;34:80), although most studies report smooth muscle actin
(Am J Surg Pathol 1999;23:1)
Myoepithelioma (Zhonghua Bing Li Xue Za Zhi 2005;34:211)
Myofibroblastic sarcoma (Chin Med J (Engl) 2007;120:363, Hum Pathol 2008;39:846)
Myofibroblastoma (variable)
Myofibroma (Histopathology 2012;60:E1)
Myopericytoma (Hum Pathol 2010;41:1500)
Osteosarcoma (Am J Clin Pathol 2000;113:663)
Perivascular epithelioid cell tumors (Diagn Pathol 2012;7:183), although most studies report smooth muscle actin
Pleomorphic adenoma (Hum Pathol 1991;22:1206)
Rhabdomyosarcoma (but MyoD1 and myogenin are more specific / sensitive, Am J Surg Pathol 2006;30:962)
Sinonasal-type hemangiopericytoma (Head Neck 2005;27:124, Am J Surg Pathol 2003;27:737)
Solitary fibrous tumor (variable staining, Mod Pathol 1997;10:443)
Negative staining
Angiomyofibroblastoma (Pathol Int 1995;45:487), mesothelioma-epithelioid (Am J Surg Pathol 2006;30:463)
Actin, alpha smooth muscle type
Table of Contents
Definition / general | Terminology | Clinical features | Interpretation | Uses by pathologists | Microscopic (histologic)
images | Positive staining - normal | Positive staining - disease | Negative staining
Discovered in 1986 (J Cell Biol 1986;103:2787)
Antibodies to alpha smooth muscle actin do not detect the other actin isoforms
Terminology
Also called smooth muscle actin, SMA; clone 1A4 or sm-1
Clinical features
No apparent deficiency in intestinal pseudoobstruction (J Clin Pathol 2004;57:1168)
May predict aggressive behavior in cutaneous basal cell carcinoma (Hum Pathol 2010;41:1128) and pancreatic ductal
adenocarcinoma (Pancreas 2010 May 7 [Epub ahead of print])
Predictor of good prognosis in lung adenocarcinoma (Mod Pathol 2009;22:776)
A potential prognostic factor in idiopathic pulmonary fibrosis (Clinics (Sao Paulo) 2012;67:1039)
Interpretation
Membranous or cytoplasmic staining
Identify smooth muscle cells and myofibroblasts in normal, reactive (Am J Respir Cell Mol Biol 1999;20:582) or neoplastic
tissue (Am J Dermatopathol 2006;28:105)
Identify myoepithelial cells in normal, neoplastic or diseased breast, salivary glands or sweat glands; may be helpful to rule
out invasion; may be particularly important in cytology specimens (Anticancer Res 2003;23:4175)
Identify pericytes to correlate with hematogenous metastasis and prognosis (Oncology 2005;69:159)
Help distinguish pleuropulmonary desmoid tumors (SMA+) from solitary fibrous tumor (SMA-, Arch Pathol Lab Med
2006;130:1503)
Note: in breast papillary lesions, p63 is more sensitive and specific because smooth muscle actin also stains stromal cells
(J Clin Pathol 2007;60:315)
Images from Pathout server:

Leiomyosarcoma: Sinonasal
cervix hemangiopericytoma
Images from other servers:

Ameloblastic carcinoma Bladder: Bone: glomus Breast:

PEComa tumor myoepithelial
cells (fig C/G)

Breast: Colon (left to right): carcinosarcoma; leiomyoma (top); Colon and small
leiomyoma Peutz Jeghers polyp (fig 4) intestine: normal
and intestinal
pseudoobstruction

Crohn disease: Eye: MFH of Heart: fetus with Heart scar tissue
obliterative conjunctiva (top heart block
muscularization left)

Inflammatory myofibroblastic tumor Kidney (left to right): atypical

(left to right): bone, gallbladder, epithelioid angiomyolipoma (two
salivary gland (fig 3b) images), focal segmental
glomerulosclerosis

Leiomyosarcoma (left to right): Liver: Lung: COPD

bladder (fig C), esophagus glomangioma
(fig 5)

Lung: Myofibroblastic sarcoma Myofibroblastic sarcoma

lymphangio- (left: smooth muscle actin, (left: smooth muscle actin,
leiomyomatosis right: calponin) right MIB-1)

Normal: breast Normal: breast Normal: decidual Normal: eye

myoepithelial myoepithelial stromal cells choroid and
cell disruptions cells sclera

Normal: liver (fetal)

Placenta accreta Plexiform Pleomorphic Salivary gland

(fig 3) fibrohistiocytic sarcoma / MFH duct carcinoma
tumor

Salivary gland Stomach: left-gastric carcinoma- Submandibular

sialometaplasia diffuse type (fig A); right-gastric gland - adenoid
in parotid node carcinoma-intestinal type (fig A) cystic carcinoma
Images from Nature.com:

Breast: basal- Breast: cellular Breast: adenoid cystic carcinoma

like carcinoma fibroadenoma (fig B) vs collagenous spherulosis
(fig A) (fig G)

Neuroblastoma

Lung: adenocarcinoma, subepithelial Liver: epithelioid

myofibroblasts angiomyolipoma

Breast myoepithelial cells (most, Breast Cancer Res 2003;5:R151, Proc Natl Acad Sci U S A 1993;90:999)
Chondrocytes (Folia Biol (Praha) 2006;52:167), choroidal non-vascular smooth muscle cells (J Anat 2005;207:381)
Decidual stromal cells (Hum Reprod 1999;14:1599), fibroblastic reticulum cells (J Cancer Res Clin Oncol 1981;101:149)
Glomus coccygeum (Arch Pathol Lab Med 1999;123:905), hepatic stellate cells (Virchows Arch 1997;430:195)
Myofibroblasts (except alveolar - J Histochem Cytochem 1992;40:1955, and some granulation tissue / scars - Lab Invest
1989;60:275, Int J Legal Med 1992;105:99)
Osteoblasts (J Orthop Res 2002;20:622)
Pericytes (J Histochem Cytochem 1989;37:315)
Salivary glands
Smooth muscle and vascular smooth muscle (Proc Natl Acad Sci U S A 1981;78:298)
Sweat glands and tracheobronchial glands (J Histochem Cytochem 1988;36:659)

Adenoid cystic carcinoma (Arch Pathol Lab Med 1999;123:801)
Angiomyofibroblastoma (occasionally focal, Hum Pathol 1997;28:1046, J Med Case Rep 2010;4:79)
Angiomyolipoma (J Egypt Natl Canc Inst 2013;25:125)
Atypical teratoid / rhabdoid tumor (J Neurosurg 1996;85:56, Brain Tumor Pathol 2008;25:79)
Breast: intraductal carcinoma (PLoS One 2013;8:e57773)
Cellular angiofibroma (focal, 41% Mod Pathol 2011;24:82)
Collagenous spherulosis (Mod Pathol 2006;19:1351)
COPD: large airways have increased expression of SMA (Respir Res 2011;12:48)
Endometrial stromal sarcoma (65%, Gynecol Oncol 2004;92:71)
Endometriosis-stroma (Pathol Int 2003;53:371, Pathol Int 2013;63:429)
Epithelial-myoepithelial carcinoma (Am J Surg Pathol 2007;31:44)
Epithelioid sarcoma-proximal type (33%, Am J Surg Pathol 1997;21:130, 15%, Mod Pathol 2001;14:655)
Fibromatosis (56%, Am J Surg Pathol 2002;26:1296)
Fibroblastic reticulum cell tumor (Am J Surg Pathol 1998;22:1048)
Gastric carcinoma stromal cells (J Clin Pathol 2002;55:741)
GIST (45%, Am J Surg Pathol 2002;26:1296, Am J Pathol 1990;136:771)
Glomus tumor (Hum Pathol 1999;30:1259, Am J Pathol 1990;136:771)
Granulosa cell tumors of ovary-adult (variable, Mod Pathol 1995;8:25)
Hemangiopericytoma (Am J Surg Pathol 2003;27:737)
Kidney-focal segmental glomerulosclerosis (Braz J Med Biol Res 2001;34:985)
Inflammatory myofibroblastic tumor (Ann Diagn Pathol 2001;5:335, Am J Surg Pathol 1992;16:896, Turk J Gastroenterol
2012;23:399)
Leiomyoma
Leiomyosarcoma (Int J Gynecol Pathol 2011;30:236, Anticancer Res 2005;25:1559)
Liposarcoma (focal in 45%, Am J Surg Pathol 2004;28:1257)
Maligant fibrous histiocytoma (J Clin Pathol 2003;56:666)
Melanoma-desmoplastic and non-desmoplastic sarcomatoid,(Am J Dermatopathol 1999;21:537, J Clin Pathol 1996;49:950)
Mesothelioma-sarcomatoid (60%, Histopathology 2003;42:270)
Myoepithelioma (Hum Pathol 2004;35:14)
Myofibroblastic sarcoma (Chin Med J (Engl) 2007;120:363, Int J Oral Sci 2012;4:170)
Nodular fasciitis (Ann Diagn Pathol 2002;6:94)
Ossifying fibromyxoid tumor (some, J Laryngol Otol 1993;107:75; 6%, Am J Surg Pathol 2011;35:1615)
Pancreatic stellate cells post-obstruction (J Surg Res 2003;114:6)
Plexiform fibrohistiocytic tumor (Histopathology 1991;19:503)
Plexiform fibromyxoma (Am J Surg Pathol 2009;33:1624)
Pulmonary lymphangioleiomyomatosis (J Clin Pathol 1993;46:479, Tohoku J Exp Med 2003;199:119)
Renal mixed epithelial and stromal tumor (Arch Pathol Lab Med 2006;130:80, Beijing Da Xue Xue Bao 2008;40:415)
Rhabdomyoma (focal / rare, Hum Pathol 1993;24:754, Hum Pathol 1993;24:608)
Rhabdomyosarcoma, alveolar (Korean J Ophthalmol 2006;20:70)
Rhabdomyosarcoma embryonal (botryoid type, Pediatr Dev Pathol 2005;8:427)
Spindle cell carcinoma (Am J Surg Pathol 2001;25:1009)
Synovial sarcoma (25%, Mod Pathol 2007;20:760)
Negative staining
Normal tissue:
Cardiac muscle (positive during development, J Cell Sci 2007;120:229)
Skeletal muscle (J Cell Biol 1985;100:807)
Disease:
Carcinomas (usually)
Myofibroblastoma (occasionally focally positive, Pathology 2005;37:144, Am J Surg Pathol 2001;25:1022)
Schwannoma, solitary fibrous tumor (Arch Pathol Lab Med 2006;130:1503)
Adenovirus
Table of Contents
Definition / general | Essential features | Pathophysiology | Clinical features | Interpretation | Uses by
pathologists | Microscopic (histologic) images | Positive staining - disease | Electron microscopy
images | Molecular / cytogenetics description | Additional references | Board review style question #1 | Board review
answer #1
Anti-adenovirus is a cocktail of mouse monoclonal antibodies derived from cell culture supernatant
Essential features
Anti-adenovirus is a cocktail of mouse monoclonal antibodies with nuclear and cytoplasmic staining pattern
False positives are extremely uncommon
Most false negatives (cases with positive viral cytopathic effect and negative IHC) result from exhaustion of the diagnostic
tissue
Pathophysiology
Double stranded DNA viruses with linear genome capped by proteins at both 5' ends with nonenveloped capsule
Adenovirus produces nuclear inclusions without cytomegaly
Virus binds to coxsackie adenovirus receptor or major histocompatibility class I molecule followed by viral internalization
Viral replication cycle takes about 32 - 36 hours and up to 10,000 virions can be produced; new virions remain in cell until
it degenerates and lyses (Tille: Bailey & Scott's Diagnostic Microbiology, 13th Edition, 2013)
Clinical features
Adenoviruses are spread via aerosols, in fecal matter or through close contact
Adenovirus infection is especially common in military barracks and college dormitories
Children under 14 and immunocompromised patients including transplant recipients are especially vulnerable
Interpretation
Nuclear and cytoplasmic
False positives are extremely uncommon
Most false negatives (cases with positive viral cytopathic effect and negative IHC) result from exhaustion of the diagnostic
tissue (Am J Clin Pathol 2017;147:96)
Other limitations of this and other IHC tests are fixation time of tissues, dilution factor of antibody, retrieval method utilized
and incubation time; optimal performance should be established through positive and negative controls
Various commercially available antibodies used for immunohistochemistry may not provide complete coverage against all
51 serotypes of adenovirus; diagnosis need to be confirmed by polymerase chain reaction or electron microscopy
Detection of adenovirus in solid organ transplant patients
Solid organ transplant recipients (Virchows Arch 2015;467:603)
Renal allograft recipients (Clin J Am Soc Nephrol 2012;7:1884)
Small bowel transplantation (Arch Pathol Lab Med 2008;132:703)
Adenovirus hepatitis in the adult allograft liver (Transplantation 1997;64:1483)
Detection of adenovirus in hematopoietic stem cell transplant patients (Leuk Lymphoma 2004;45:873)
Contributed by Vikas Mehta M.D. and Maria M Picken, M.D., Ph.D.

Nuclear and cytoplasmic expression

Adenovirus infection in pediatric solid organ and hematopoietic stem cell transplantation (Curr Infect Dis Rep 2012;14:658)
Electron microscopy images
Contributed by Maria M Picken, M.D., Ph.D.
Crystalline array

Gene amplification or DNA in situ hybridization can be used for identification
Additional references
Emerg Infect Dis 2010;16:769, J Clin Microbiol 2006;44:3371

The immunohistochemical staining pattern of adenovirus in adenovirus nephritis is
A. Cytoplasmic
B. Dot-like
C. Nuclear
D. Nuclear and cytoplasmic

D. Nuclear and cytoplasmic
Reference: Stains - adenovirus
Comment here
Adipophilin (pending)
Table of Contents
(pending)
AF4
Table of Contents
Definition / general | Microscopic (histologic) images
Member of protein family implicated in childhood lymphoblastic leukemia, FRAXE (Fragile X E site) intellectual disability
and ataxia, also called AF4/FMR2 family, member 1 (GeneCards)
Transcriptional activator at 4q21 involved in transcriptional elongation
Has central role in RNA Pol II mediated transcription and phosphorylation-dependent regulatory mechanisms (Biochem J
2011;438:649)
MLL-AF4 translocation of t(4;11)(q21;q23 ) is common in infantile acute lymphoblastic leukemia (Genes Chromosomes
Cancer 2013;52:954); rarely acute megakaryoblastic leukemia (Eur J Haematol 2009;83:149)
AF4 complex provides several activities that could activate RNA polymerase II; in contrast, AF4-MLL protein disturbs the
fine-tuned activation cycle of promoter-arrested RNA Pol II, and causes altered histone methylation signatures (Leukemia
2011;25:135)

CNS: left-cerebellum; right-cortex Breast

carcinoma
(second image)
AGR2
Table of Contents
Definition / general | Clinical features | Microscopic (histologic) images
Anterior gradient protein 2
Member of protein disulfide isomerase family; homolog of African clawed frog (Xenopus laevis) gene XAG2
Secreted peptide known to promote cell metastasis (Exp Cell Res 2012;318:1788, Exp Mol Med 2011;43:91)
Localizes in endoplasmic reticulum of normal intestinal epithelial cells and is essential for in vivo production of mucus;
mediates processing of MUC2 through formation of mixed disulfide bonds (Cancer Res 2011;71:7091)
Clinical features
May have important role in glioblastoma growth and vascularity (Cell Biochem Biophys 2013;67:1487)
Tumor expression may have prognostic value in breast (Zhonghua Bing Li Xue Za Zhi 2008;37:109), lung (Osaka City Med J
2012;58:13), ovarian (Pathology 2013;45:49) and prostate carcinomas (Mod Pathol 2013;26:849)
Serum levels may have prognostic value in colorectal (Int J Mol Sci 2012;13:4367) and lung carcinomas (Cancer Biomark
2011-2012;10:101)

Esophagus: Ovary: Pancreas:

adenocarcinoma mucinous normal and
carcinoma malignant
Akt
Table of Contents
Definition / general | Terminology | Pathophysiology | Clinical features | Uses by pathologists | Microscopic
(histologic) images | Virtual slides | Positive staining - normal | Positive staining - disease | Negative
staining | Additional references
The Akt family is comprised of 3 closely related serine / threonine protein kinases (Akt1, Akt2 and Akt3), which regulate
many processes including metabolism, proliferation, cell survival, growth, inhibition of apoptosis and angiogenesis
These kinases phosphorylate serine or threonine residues on a range of downstream substrates
They are activated by various factors such as insulin, PI3K, IGF1
Akt was named after a cell transforming retrovirus isolated from a spontaneous thymoma in AKR mice (Proc Natl Acad Sci U
S A 1987;84:5034)
Due to its involvement in various cellular processes that promote cell survival and growth, the AKT pathway is a major
target for cancer drug discovery
Terminology
"Akt" usually refers to Akt1
AKT1 is also called RAC-alpha serine / threonine protein kinase, v-akt murine thymoma viral oncogene homolog 1, and
protein kinase B (PKB), and is encoded by the AKT1 gene
Pathophysiology
Akt regulates glucose uptake by mediating insulin induced translocation of the glucose transporter to the cell surface
Akt plays a role as a key modulator of the AKT-mTOR signaling pathway, which controls a variety of cellular processes
including new neuron integration during adult neurogenesis, correct neuron positioning, dendritic development and
synapse formation (Protein Data Bank)
The protein activity of Akt is stimulated by phosphorylation at 2 regulatory sites, Thr308 and Ser473 (OMIM - 164730)
Akt is normally expressed in the cytoplasm, nucleus and cell membrane; upon activation it translocates to the nucleus
(Abcam)
Clinical features
Akt is associated with tumor cell survival, proliferation and invasiveness
The activation of Akt is one of the most frequent alterations observed in human cancer and tumor cells
Tumor cells that have constantly active Akt may depend on Akt for survival, so understanding Akt and its pathways is
important
A mosaic activating mutation (c. 49G→A, p.Glu17Lys) in AKT1 is associated with Proteus Syndrome, which causes
overgrowth of skin, connective tissue, brain and other tissues (Wikipedia - Protein kinase B)
AKT-GSK3B signaling is a target of lithium and has been implicated in the pathogenesis of mood disorders, and has a role
in schizophrenia (Nat Genet 2004;36:131)
A somatic mutation at amino acid 17 of AKT1, resulting in glutamic acid to lysine substitution, has been observed in
human breast, colorectal and ovarian cancers
This mutation activates AKT1 and localizes it to the plasma membrane, stimulating downstream signaling, resulting in
cell transformation and induction of leukemia in mice (Nature 2007;448:439)
Mutations resulting in upregulation of AKT1 phosphorylated at Thr308 have been shown to be involved in Cowden
syndrome (Am J Hum Genet 2013;92:76)
Dysregulation of the AKT1 pathway may be important in the pathogenesis of intrahepatic cholangiocarcinoma (Mod Pathol
2012;25:131)
Akt pathway may induce autophagy in cancer cells (J Biol Chem 2012;287:25325)
Mice models:
A combination of activated Ras and Akt induced high grade gliomas with the histologic features of human glioblastoma
after gene transfer to neural progenitors (Nat Genet 2000;25:55)
Akt1 null mice are smaller than wild type littermates, and have shorter lifespan upon exposure to genotoxic stress
Males have increased spontaneous apoptosis in testes and thymus (Genes Dev 2001;15:2203)
In a cardiac specific Akt transgenic mouse model, Akt overexpression produced cardiac hypertrophy at the molecular
and histologic levels, with a significant increase in cardiomyocyte cell size and concentric left ventricular hypertrophy
Akt transgenic mice also showed a remarkable increase in cardiac contractility compared with wild type (Proc Natl Acad
Sci U S A 2002;99:12333)
Akt1 / Akt2 double knockout mice showed severe growth deficiency and died shortly after birth
These mice displayed impaired skin development due to a proliferation defect, skeletal muscle atrophy due to a marked
decrease in individual muscle cell size, and impaired bone development (Genes Dev 2003;17:1352)
Akt1 deficient mice showed alterations in the expression of genes in the prefrontal cortex involved in synaptic function,
neuronal development, myelination and actin polymerization (Proc Natl Acad Sci U S A 2006;103:16906)
Pathways involving AKT signaling are upregulated in a variety of cancers
Phosphorylation of Akt1 is associated with a poor prognosis in early breast cancer
Tumors with high levels of Akt1 have been associated with tamoxifen and doxorubicin resistance, resulting in poor
prognostic outcome (J Pathol 2012;227:481)
Images hosted on Other server:

Various images, testis Various images, liver
Virtual slides
Images hosted on Other server:

Various images, breast ductal

carcinoma

Uterus, cervix, ovary, testis, lung, liver (adult), lymph node, brain (fetal), peripheral blood mononuclear cells

Most malignancies show moderate to strong nuclear AKT staining
Negative staining
Brain (adult), hair follicle, liver (fetal), bone, colon muscle, nasopharynx, T cells
Human Protein Atlas - Akt1, GeneCards - Akt1
Albumin
Table of Contents
Definition / general | Clinical features | Microscopic (histologic) images
Most common serum protein
65K protein produced by ALB gene on #4, by liver (Wikipedia)
50% of total plasma protein content; usual serum concentration of 40 g/L
Binds to water, bilirubin, calcium, fatty acids, hormones (acts as carrier protein), potassium, sodium, and various drugs
Main function of serum albumin is to regulate blood colloidal osmotic pressure
Bovine serum albumin (BSA): plasma protein from cows that maintains osmotic pressure in blood plasma for proper
distribution of body fluids between intravascular compartments and body tissues
Rarely used as IHC marker for liver
Clinical features
Laboratory:
For serum albumin measure, most instrument systems do NOT have satisfactory total-error performance (Arch Pathol
Lab Med 2013;137:912)
Serum albumin may be a low cost diagnostic marker for tuberculosis in HIV+ patients eligible for antiretroviral therapy
(Bioimpacts 2013;3:123)
In type 2 diabetes patients with stable angina and chronic total coronary occlusion, increased serum glycated albumin
levels are associated with impaired coronary collateral growth (Cardiovasc Diabetol 2013;12:165)
Deficiency causes familial dysalbuminemic hyperthyroxinemia (MIM:103600)
Surgical pathology
Albumin in-situ hybridization may be specific for hepatocellular carcinoma or hepatoid areas of combined
hepatocellular-cholangiocarcinoma (Am J Surg Pathol 2002;26:989), although other markers are more commonly used

Left: normal Liver and

liver; right: hepatocellular
negative control carcinoma
Alcian blue
Table of Contents
Definition / general | Uses by pathologists | Clinical features | Microscopic (histologic) images | Positive staining -
Common "routine" stain (not an immunohistochemical stain) to detect mucins (Wikipedia: Alcian Blue Stain [Accessed 8
August 2018])
At pH 2.5, detects acidic mucins
At pH 1.0, detects highly acidic mucins
Stained parts are blue to bluish green
Note: all references below are to pH 2.5 unless otherwise indicated
Stains acid-simple, nonsulfated and acid-simple mesenchymal mucins at pH 2.5, acid-complex sulfated mucins at pH 1.0
and acid-complex connective tissue mucins at pH 0.5; does NOT stain neutral mucins
PAS-Alcian blue may be best pan mucin combination; PAS also stains glycogen, but predigestion with diastase will
remove the glycogen
Alcian blue-high iron diamine detects sulfomucins (brown) and sialomucins (blue)
Clinical features
Procedure (University of Utah)
May be useful in FNA diagnosis of salivary gland pleomorphic adenoma (J Cytol 2012;29:221)
Stains glycosaminoglycan deposits in macular corneal dystrophy (Korean J Ophthalmol 2013;27:454)
Images hosted on Pathout server:

Bladder: Esophagus Esophagus, Barrett: blue staining goblet cells and clear
urothelial staining gastric type surface columnar cells
carcinoma with
gland-like
lumina

Heart: myxoma Kidney: Sacrum, Scrotum: Paget Thyroid gland:

with glandular adenocarcinoma Chordoma: disease signet ring cell
structures (AB-PAS) stroma stains variant of
with Alcian blue follicular
adenoma
Images hosted other servers:

Breast: lobular carcinoma Breast: Esophagus: Esophagus,
(metastatic) and modified Alcian blue mucoepidermoid Barrett and Barrett: GE
stain carcinoma mimics junction
(Alcian blue-
PAS)

Eye: macular Gallbladder: Kidney: Soft tissue:

corneal pyloric mucinous proliferative
dystrophy metaplasia tubular and fasciitis - AB-
spindle cell PAS
carcinoma

Colloid of thyroid gland, goblet cells and mucous glands

Adenocarcinoma, adenosquamous carcinoma, mast cell leukemia (Acta Med Croatica 2013;67:61)
Mucinous tumors, myxedema (dermal mucin), myxoma (mucoid matrix), nodular mucinosis (breast, other) and Paget
disease of scrotum
Negative staining
Lipids / lipid entities (lipoma, liposarcoma), Paget disease of esophagus, squamous cell carcinoma (acantholytic variant-
breast & other sites, pseudoglandular variant-penis & other sites), xanthelasma
ALK
Table of Contents
Definition / general | Pathophysiology | Diagrams / tables | Clinical features | Methods | Microscopic (histologic)
images | Positive staining - normal | Positive staining - tumors | Negative staining | Molecular / cytogenetics images
See also NPM-ALK fusion protein
Anaplastic lymphoma kinase gene is at 2p23; protein is called ALK1, CD246
Membrane spanning tyrosine kinase receptor, member of insulin receptor family
Is NOT the same as Ki-1/CD30, contrary to some references
Interpretation: usually cytoplasmic and nuclear staining
References: OMIM #105590
Pathophysiology
Ligand is growth factor pleiotrophin
3' end contains catalytic domain of tyrosine kinase
Has important role in brain development
Part of ~ 20 translocations associated with large B-cell lymphoma (Int J Clin Exp Pathol 2009;2:508, Adv Hematol
2012;2012:529572), nonsmall cell lung carcinoma (Mol Cancer 2010;9:188), inflammatory myofibroblastic tumor (J Signal
Transduct 2012;2012:123253)
Diagrams / tables

ALK signaling Pathways in ALK+ anaplastic large cell lymphoma
Clinical features
First discovered associated with anaplastic large cell lymphoma in 1994 (Science 1994;263:1281)
t(2;5) is associated with T cell anaplastic lymphoma via fusion of ALK and NPM (nucleophosmin protein), but also variants
(Genes Chromosomes Cancer 2002;34:354)
ALK+ primary anaplastic large cell lymphomas have favorable prognostic significance (Blood 1999;93:3913), including
primary CNS ALCL (Am J Surg Pathol 2003;27:487); also favorable in inflammatory myofibroblastic tumors (Am J Surg Pathol
2007;31:509)
ALK- cases of primary anaplastic large cell lymphoma are associated with trisomy 2 (Mod Pathol 2005;18:235); consensus
criteria for diagnosis are lacking (Am J Clin Pathol 2007;127:707)
ALK mutation may cause hereditary hemorrhagic telangiectasia type 2 (J Dent Res 2006;85:705)
Methods
Prognostic value in anaplastic large cell lymphoma and inflammatory myofibroblastic tumor (see above)
Predictive marker for therapy in nonsmall cell lung cancer (Mod Pathol 2013;26:1468, Mod Pathol 2013;26:1545, Arch Pathol Lab
Med 2012;136:1201)
Differentiate inflammatory myofibroblastic tumor (ALK+) from ALK negative spindled neoplasms in:
Bladder (Mod Pathol 2007;20:592, Urol Ann 2012;4:115)
Female genital tract (Arch Pathol Lab Med 2012;136:623)
Soft tissue (Am J Surg Pathol 2001;25:1364)

Anaplastic Anaplastic lymphoma: various images

lymphoma

Diffuse large B Inflammatory IMT of abdomen IMT of larynx

cell lymphoma myofibroblastic (fig 2C)
(fig B) tumor (IMT) of
bladder

IMT-pelvis Inflammatory Neuroblastoma Renal cell

breast carcinoma with
carcinoma is ALK gene
ALK- rearrangement

Embryonic neurons of central and peripheral nervous systems, weakly positive in adult brain
Normal small intestine, T cells
Weakly positive in colon, prostate
Positive staining - tumors

T/null cell anaplastic lymphomas (most), inflammatory myofibroblastic tumor (variable, Am J Surg Pathol 2001;25:1364, Am J
Surg Pathol 2001;25:761)
Diffuse large B cell lymphoma (rarely, Mod Pathol 2007;20:310)
Low level expression in some rhabdomyosarcomas, lipogenic tumors, Ewing / PNET, MFH, leiomyosarcoma and other
soft tissue tumors (Hum Pathol 2004;35:711)
Rarely renal cell carcinoma (Mod Pathol 2012;25:1516, Korean J Pathol 2013;47:52)
Negative staining
Fibromatosis, GIST, nodular fasciitis and normal lymphoid tissue
Molecular / cytogenetics images
Images hosted on PathOut server:
Images kindly provided by LeicaBiosystems Amsterdam:

ALK / EML4 ALK (2p23)

t(2;2); inv(2)
FISH: ALK+
large cell
lymphoma
Alkaline phosphatase
Table of Contents
Definition / general | Essential features | Terminology | Interpretation | Uses by pathologists | Prognostic
factors | Microscopic (histologic) description | Microscopic (histologic) images | Positive staining - normal | Positive
staining - disease | Negative staining | Board review style question #1 | Board review answer #1
An enzyme histochemical stain that relies on endogenous alkaline phosphatase activity to hydrolyze exogenous alpha
naphthyl acid phosphate substrate to form naphthol, which in turn reacts with fast blue RR salt to form a black reaction
product (Zhou: A Case-Based Guide to Neuromuscular Pathology, 1st Edition, 2020)
Alkaline phosphatase reaction generates air bubbles if the section is cover slipped prematurely; to minimize this, it is
advisable to wait at least 45 minutes before placing the coverslip over the stained section
Essential features
In skeletal muscle, alkaline phosphatase is normally only present in the endothelium of arterioles but not in capillaries,
myofibers or connective tissue (Nature 1962;195:611, J Histochem Cytochem 1970;18:55, Arch Histol Cytol 1998;61:215)
The main use in a skeletal muscle biopsy is to highlight regenerating myofibers and connective tissue injury (Zhou: A Case-
Based Guide to Neuromuscular Pathology, 1st Edition, 2020)
Immune myopathies with perimysial pathology (IMPP), highlighted by alkaline phosphatase, are more commonly
associated with antisynthetase syndrome associated autoantibodies, particularly Jo1 autoantibody; these patients are
more likely to have interstitial lung disease, arthritis, Raynaud phenomenon, mechanic hands and excellent response to
immune modulation therapy (Brain 2015;138:2485, Neurol Neuroimmunol Neuroinflamm 2018;5:e434)
Elsewhere in the body, alkaline phosphatase enzyme activity is also widely present in bone, cartilage, biliary tract, kidney,
intestine and a variety of human tumors (Burstone: Enzyme Histochemistry and Its Application in the Study of Neoplasms, 1st
Edition, 1962)
Terminology
Other names: Gomori alkaline phosphatase stain, nonspecific alkaline phosphatases
Interpretation
Assess for black reaction product
In muscle biopsies:
Identify regenerating myofibers of all causes (not limited to inflammatory myopathies) (J Histochem Cytochem
1970;18:55, Dubowitz: Muscle Biopsy - A Practical Approach, 4th Edition, 2013, Zhou: A Case-Based Guide to Neuromuscular
Pathology, 1st Edition, 2020)
Identify connective tissue injury in immune myopathies with perimysial pathology (IMPP) (Brain 2015;138:2485, Neurol
Neuroimmunol Neuroinflamm 2018;5:e434)
Increased endomysial capillary alkaline phosphatase reactivity is seen in a subset of myositis with poor response to
steroids (Am J Pathol 1980;101:159)
Prognostic factors
Immune myopathies with perimysial pathology (IMPP) are associated with excellent response to immune modulation
therapy (Neurol Neuroimmunol Neuroinflamm 2018;5:e434)
Inflammatory myopathies with high endomysial capillary alkaline phosphatase reactivity responded poorly to steroids (Am
J Pathol 1980;101:159)

Staining pattern varies depending on structure highlighted:
Regenerating fibers: sarcoplasmic (J Histochem Cytochem 1970;18:55)
Arterioles and capillaries: endothelium cytoplasmic (Nature 1962;195:611)
Perimysial connective tissue: connective tissue / collagen (Neurol Neuroimmunol Neuroinflamm 2018;5:e434)
Denervated myofibers: sarcoplasmic (J Histochem Cytochem 1970;18:55)

Contributed by Chunyu "Hunter" Cai, M.D., Ph.D.

Normal muscle Dermatomyositis Dermatomyositis Antisynthetase

Mi2 NXP2 syndrome PL7

Antisynthetase Necrotizing Reducing body

syndrome Jo1 autoimmune myopathy
myopathy
HMGCR

Endothelium of arterioles of skeletal muscle (Nature 1962;195:611, J Histochem Cytochem 1970;18:55, Arch Histol Cytol
1998;61:215)

Connective tissue reactivity:
Perimysial connective tissue in antisynthetase syndrome associate myositis, necrotizing myopathy with anti-HMGCR
autoantibody and a subset of dermatomyositis (Brain 2015;138:2485, Neurol Neuroimmunol Neuroinflamm
2018;5:e434, Neurol Neuroimmunol Neuroinflamm 2015;2:e124)
Myofiber reactivity:
Regenerating fibers of all causes (not limited to inflammatory myopathies) (J Histochem Cytochem 1970;18:55)
Can be seen in a small subset of denervated myofibers in adults with amyotrophic lateral sclerosis or peripheral
neuropathies or young children with infantile spinal muscular atrophy (J Histochem Cytochem 1970;18:55)
Capillary reactivity:
Endomysial capillary reactivity is increased in a subset of dermatomyositis (Am J Pathol 1980;101:159)
Negative staining
Myofibers undergoing active necrosis or phagocytosis
Duchene muscular dystrophy, limb girdle muscular dystrophy or experimental ischemic myopathy do not show perimysial
connective tissue reactivity (Am J Pathol 1980;101:159)

In a normal muscle biopsy specimen, which of the following components stains for alkaline phosphatase?
A. Arterioles
B. Capillaries
C. Connective tissue
D. Muscle fibers
E. Venules

A. Arterioles
Comment Here
Reference: Alkaline phosphatase
Alpha fetoprotein (AFP)
Table of Contents
pathologists | Prognostic factors | Microscopic (histologic) images | Virtual slides | Positive staining -
normal | Positive staining - disease | Negative staining | Board review style question #1 | Board review answer #1
Alpha fetoprotein is a marker related to embryonic development (yolk sac), mainly used for diagnosing germ cell tumors
and liver tumors
Overall specific but not sensitive marker
Essential features
Positive immunostaining in a subset of hepatocellular carcinomas and hepatoblastomas but also found to be positive in
other liver diseases
Positive immunostaining can be found in the various patterns of yolk sac tumor but also can be positive in teratoma
Positive in various tumors with hepatoid differentiation
Terminology
Alpha fetoprotein (AFP)
First detected in high concentrations in human embryonal and fetal serum, named alpha-1 globulin (Scand J Clin Lab Invest
1956;8:174)
Pathophysiology
Part of the albuminoid gene superfamily, gene mapped on chromosome 4 (4q11-q22) (Nucleic Acids Res 1985;13:8007)
Major protein in serum of early mammalian embryos, synthesized at the site of embryonal hematopoiesis: the yolk sac (J
Clin Invest 1967;46:1010)
Function: transport and binding of ligands, growth regulator during embryonic development, immune regulatory functions
(Exp Biol Med (Maywood) 2001;226:377, Annu Rev Med 1977;28:453)
Clinical features
High serum levels in several conditions:
Pregnancy
Hepatic disorders
Malignancies (hepatocellular carcinomas, germ cell tumors - especially with yolk sac tumor components, neoplasms of
endodermal origin - lung, gastric, colon - especially if associated hepatoid foci, liver metastases, pediatric tumors such
as pancreatoblastoma)
History of gastrointestinal / hepatic surgery
Hereditary ataxia telangiectasia, in cases of liver damage by chemotherapy or anesthetics (Annu Rev Med
1977;28:453, Hum Pathol 2008;39:1115, Gastroenterology 1979;77:787, Nat Rev Urol 2016;13:715, JOP 2007;8:55)
Specific serum isoforms: L1, in nonneoplastic liver disease; L2, in yolk sac tumor; L3, in liver cancer
Both L2 and L3 can be elevated in pediatric yolk sac tumor, reflecting both yolk sac and hepatic differentiation (J Pediatr
Surg 1989;24:350)
Elevations in maternal serum and amniotic fluid may indicate fetal abnormalities, including neural tube defects (Am J
Obstet Gynecol 2006;195:1623)
Serum levels drop after birth (still elevated until around 6 months of age, needing care in interpretation); small amounts
still produced in adults (Annu Rev Med 1977;28:453)
Serum AFP increases in 50 - 70% of patients with nonseminoma germ cell tumors; half life is 5 to 7 days; prominent
elevations in pure seminomas usually indicate yolk sac differentiation in metastatic locations; patients should be treated as
having mixed germ cell tumor (Nat Rev Urol 2020;17:201)
Interpretation
Membranous or cytoplasmic staining is expected; granular
Supporting the diagnosis of germ cell tumors (testicular, ovarian or extragonadal), especially those with identifiable yolk
sac tumor foci (Mod Pathol 2005;18:S61)
Supporting the diagnosis of hepatocellular disease (including nonneoplastic diseases such as chronic hepatitis, and
neoplastic diseases such as hepatocellular carcinoma and hepatoblastoma) (World J Gastroenterol 2005;11:5015)
Confirming suspected hepatoid foci within other neoplasms or confirming that tumor cells produce AFP in case of
remarkable elevations of this marker in patient serum (Mod Pathol 1997;10:686)
Prognostic factors
Preoperative levels are prognostic for hepatocellular carcinoma (World J Surg Oncol 2013;11:212)
Normal AFP hepatocellular carcinoma patients were significantly older, had fewer chronic liver conditions such as viral
hepatitis or cirrhosis and had better survival; tumors were smaller, less vascular and well differentiated (J Clin Med
2019;8:E1736)
Part of staging and prognostic grouping in germ cell tumors, correlation with response to treatment, both in testis and
ovary (Biomed Res Int 2019;2019:5030349, Mol Clin Oncol 2015;3:125)
Contributed by João Lobo, M.D., Rui Henrique, M.D., Ph.D.

Prepubertal Prepubertal Prepubertal Prepubertal Metastatic yolk Metastatic yolk

testicular yolk testicular yolk testicular yolk testicular yolk sac tumor sac tumor, AFP
sac tumor sac tumor, AFP sac tumor sac tumor, AFP

Testicular mixed Testicular mixed Fetal liver Fetal liver, AFP Hepatoblastoma Hepatoblastoma,
germ cell tumor germ cell tumor, AFP
AFP
Virtual slides

Ovarian yolk sac Yolk sac tumor

tumor, AFP in undescended
testis, AFP

Well fixed and nonautolyzed embryonal liver is a reliable positive control
Early gut, yolk sac; nonspecific background reaction frequent in necrotic and cystic areas, since it is a protein secreted in
serum (Int J Dev Biol 2012;56:755)
Low expression in normal adult liver (EBioMedicine 2018;33:57)
Yolk sac tumor (62%)
Specific marker but less sensitive than glypican 3 (glypican 3 stains 97% of solid yolk sac tumors, which can mimic
seminoma) (Pathology 2018;50:88)
In primitive patterns, usually with a strong granular cytoplasmic positivity, especially in intracellular lumina; can be
positive in hyaline globules, although this is not frequent (Hum Pathol 1988;19:995)
In classical patterns, staining may be heterogeneous but is consistent
In somatic glandular patterns, staining is incomplete, more focal or absent, difficult to identify at low power
(Histopathology 2014;65:51)
Positive foci within embryoid bodies or embryonal carcinoma reflect differentiation into yolk sac tumor (Acta Pathol
Microbiol Immunol Scand A 1983;91:165)
Hepatocellular carcinoma (2 - 62%)
Specific but not a sensitive marker (Hum Pathol 2002;33:1175)
Infantile hemangioendothelioma can show expression (Hum Pathol 2010;41:763)
Cirrhosis, chronic hepatitis B and other liver diseases can show low level expression in liver (EBioMedicine 2018;33:57)
Reports of positivity in multiple tumors with hepatoid or enteric differentiation or of pediatric origin, such as enteroblastic
gastric carcinoma, lung carcinoma, gallbladder carcinoma, colon carcinoma, sex cord stromal tumors like Sertoli-Leydig
tumors, among others (Case Rep Pathol 2018;2018:3620293, Respir Med 2016;119:175, JOP 2007;8:55, summarized in World J
Gastroenterol 2013;19:321)
Negative staining
Germ cell neoplasia in situ (GCNIS)
Seminoma
Embryonal carcinoma
Choriocarcinoma
Gonadoblastoma
Spermatocytic tumor
Teratoma: can be positive in some epithelial components (20%) (Acta Pathol Microbiol Immunol Scand A 1983;91:165)
Hepatoblastoma (15%): not significantly associated with subtype (Eur J Cancer 2012;48:1853)
Cholangiocarcinoma
Metastatic adenocarcinomas to the liver (5%)
Which of the following is true about the immunohistochemical expression of AFP?
A. It can be positive in other liver diseases besides hepatocellular carcinoma and hepatoblastoma
B. It is more sensitive than glypican 3 for diagnosing yolk sac tumor
C. Nuclear staining is expected
D. Seminomas are typically positive
E. Teratomas are invariably negative
A. It can be positive in other liver diseases besides hepatocellular carcinoma and hepatoblastoma. It is a specific marker but
less sensitive than glypican 3. Seminomas are typically negative. Cytoplasmic or membrane staining is expected. Teratomas
may show positivity in certain epithelial elements. Other liver diseases and liver tumors can show positive immunostaining,
including metastatic disease to the liver.
Comment Here
Reference: Alpha fetoprotein (AFP)
Alpha-1-antichymotrypsin
Table of Contents
Definition / general | Clinical features | Uses by pathologists | Microscopic (histologic) images | Positive staining -
normal | Positive staining - tumors
Also called α1-ACT
Acute phase protein / plasma protease inhibitor, mainly produced by liver in response to cytokines such as oncostatin M
May limit tissue damage produced by excessive inflammation associated proteolysis
Also localizes to nuclei of hepatic cells to control chromatin condensation and proliferation (Gastroenterology 2013;144:818)
Homologous to alpha-1-antitrypsin
Chymotrypsin is digestive enzyme produced by pancreas
Clinical features
Heart: has role in pathophysiology of heart failure (Circ Heart Fail 2013;6:853)
Kidney: part of plasma molecular profile associated with acute cellular renal allograft rejection (Transplantation 2011;92:388)
Skin: has role in skin repair (J Biol Chem 2011;286:28889)
Umbilical cord: may help differentiate between stillborns and liveborns (Pathol Res Pract 2009;205:534)
Marker for acinic / acinar cell carcinoma in breast (Case Rep Oncol Med 2013;2013:372947), pancreas, salivary gland

Breast: primary Pancreas: Skin: nevi and Stomach: hepatoid
acinic cell pancreatoblastoma melanoma adenocarcinoma (fig C)
carcinoma (fig F) (fig C)

Histiocytes, reticulum cells
Positive staining - tumors

Acinic / acinar cell carcinomas of breast, pancreas, salivary gland tumors
Hepatoid adenocarcinoma of stomach (World J Gastroenterol 2013;19:4437)
Solid-pseudopapillay neoplasm of pancreas
Alpha-1-antitrypsin
Table of Contents
Definition / general | Clinical features | Laboratory | Diagrams / tables | Uses by pathologists | Microscopic
(histologic) images | Positive staining - normal | Positive staining - disease
Acute phase plasma protein predominantly derived from liver which inhibits neutrophil elastase
Most abundant circulating serine protease inhibitor
Elastase digests lung tissue and is secreted by neutrophils during inflammation (Wikipedia)
Member of serpin superfamily; homologous to alpha-1-antichymotrypsin
Clinical features
Common genetic deficiency, see Liver nontumor chapter
Occurs in 1 per 2,500-5,000 newborns in Western Europe / USA
Incidence is highly dependent on Scandinavian descent within the population
Disorder due to folding errors (IUBMB Life 2009;61:1)
Causes emphysema (Orphanet J Rare Dis 2008;3:16), chronic hepatitis (Hum Pathol 2012;43:753) or cirrhosis (Am J
Gastroenterol 2008;103:2136, Clin Gastroenterol Hepatol 2012;10:575)
In liver, mutant Z gene synthesizes mutant Z protein, which folds abnormally and accumulates, rather than being
secreted; accumulated protein causes liver injury, cirrhosis, hepatocellular carcinoma (Curr Gastroenterol Rep
2014;16:367)
Also associated with bronchiectasis, vasculitis (including granulomatosis with polyangiitis (Wegener's), Rheumatol Int
2014;34:553), panniculitis (Dermatol Clin 2008;26:447, Respir Med 2014;108:338)
Treatment include intravenous augmentation therapy (Orphanet J Rare Dis 2013;8:149) including Proliastin® (BMC Clin
Pharmacol 2010;10:13), liver transplant (Liver Transpl 2013;19:1370)
Laboratory
Screening tests use dried blood spots (J Bras Pneumol 2013;39:547)
Evaluation for genetic deficiency involves quantitation of serum A1A protein and characterization of genetic
polymorphisms (Am J Clin Pathol 2012;138:398)
Diagrams / tables

Structure Polymer of AAT

molecules
Immunohistochemistry marker of alpha-1-antitrypsin genetic disease in hepatocytes
Also marker of normal histiocytes and hepatocytes
Images hosted on Pathout server:
Liver-alpha-1-antitrypsin deficiency-
Pancreas-solid
papillary
neoplasm is
A1A+

Liver-H&E PAS+ diastase resistant inclusions Pancreatoblastoma
(fig B)

Histiocytes, reticulum cells, gallbladder, hepatocytes, small intestinal enterocytes (J Clin Invest 1993;92:2022)

Various sites: angiosarcoma (hyaline globules), granular cell tumor (J Oral Pathol Med 2000;29:284, Mod Pathol 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 (club cells in non-mucinous types)
Ovary: endodermal teratoma, MMMT and yolk sac tumor (hyaline droplets, Hum Pathol 1982;13:930)
Pancreas: cystic fibrosis (mucous globules), neuroendocrine tumor, solid papillary neoplasm (not specific, Am J Surg
Pathol 2000;24:1361, Case of Week #121)
Skin: atypical fibroxanthoma
Testis: papillary cystadenoma, Sertoli cell tumor and yolk sac tumor (hyaline globules)
Thyroid: papillary thyroid carcinoma (Am J Surg Pathol 1996;20:956)
Alpha-lactalbumin
Table of Contents
Definition / general | Uses by pathologists
Main whey protein in human and cow's milk (Wikipedia)
Helps synthesize lactose from glucose and galactose in mammary gland (Arch Latinoam Nutr 2012;62:6)
Specific to breast tissue (normal, malignant, fibrocystic) and hydradenoma papilliferum of vulva, but not a common
immunostain
GCDFP-15 is more specific for metastatic breast cancer than alpha-lactalbumin (Hum Pathol 1989;20:281)
Alpha-synuclein
Table of Contents
Definition / general | Uses by pathologists | Clinical features | Microscopic (histologic) images | Positive
stains | Additional references
Member of the synuclein family of soluble proteins (alpha-synuclein, beta-synuclein and gamma-synuclein) that are
commonly present in CNS of vertebrates
Expressed in the neocortex, hippocampus, substantia niagra, thalamus and cerebellum
Main location is within the presynaptic terminals of neurons in both membrane-bound and cytosolic free forms
Can be seen in neuroglial cells and melanocytic cells; highly expressed in the neuronal mitochondria of the olfactory bulb,
hippocampus, striatum and thalamus
Three isoforms have been isolated by alternative splicing
Most research is the full length isoform with 140 amino acids
Others are alpha-synuclein-112 and alpha-synuclein-126 (Wikipedia)
Diagnosis of (a) Parkinson disease (PD) / brainstem predominant type of Lewy body disease, and (b) dementia with Lewy
bodies (DLB), the two most frequent synucleinopathies.
These neurodegenerative multisystem disorders have widespread occurrence of α-synuclein containing deposits in the
central, peripheral, and autonomic systems. For both, staging/classification systems are based on semiquantitative
assessment of the distribution and progression pattern of α-synuclein pathology, which are considered to be linked to
clinical dysfunction (Biochimica et Biophysica Acta;2009:1792;730, Int J Clin Exp Pathol 2014;7:1714, Mov Disord 2016;31:193
Clinical features
Forms insoluble aggregates in the group of pathological disorders known as synucleopathies, characterized by:
Formation of neuronal Lewy bodies and Lewy neurites in idiopathic Parkinson disease and dementia with Lewy bodies
Oligodendroglial cytoplasmic inclusions in multiple system atrophy
Large axonal spheroids in several rarer neuroaxonal dystrophies
Both the sporadic and the familial form of Alzheimer disease also demonstrate alpha-synuclein protein
In recent years, several studies have shown that alpha-synuclein aggregation can also be detected outside the central
nervous system, particularly in the enteric nervous system of the gastrointestinal tract of PD patients using
immunohistochemistry
This has the potential to enable an early diagnosis of the disease as well as enhance the neuroprotective effects of the
available therapeutic modalities
Images hosted on PathOut servers:

Lewy body in Parkinson disease Cellular inclusions and

neuritis plaques
In cortex: (A) no staining and (B) synaptic staining; In substantia nigra: neurons with (C) > S-immunoreactive (IR) aggregates
(arrows), (D) >S-IR neurites / neuropil threads (arrowheads), and (E) > S-IR macrophages (open arrow); (F) punctate cytoplasmic
labeling; (G) punctate cytoplasmic labeling with ovoid inclusions; (H) multiple rounded inclusions; and (I) extracellular Lewy
bodyYlike inclusion.
Positive stains
Brain tissue: neocortex, hippocampus, substantia niagra, thalamus and cerebellum (within the presynaptic terminals of
neurons in both membrane bound and cytosolic free forms)
Olfactory bulb, hippocampus, striatum and thalamus (highly expressed in mitochondria)
Also neuroglial cells, melanocytic cells
Acta Neuropathol 2008;116:277, Acta Neuropathol 2016;131:49, J Neuropathol Exp Neurol 2008;67:125, J Neuropathol Exp Neurol
2010;69:40, Neuropathology 2016;36:187, Acta Neuropathol 2015;130:93, Parkinsonism Relat Disord 2014;20:1329
AMACR
Table of Contents
pathologists | Prognostic factors | Microscopic (histologic) images | Positive staining - normal | Positive staining -
disease | Negative staining | Additional references | Board review style question #1 | Board review answer #1 | Board
review style question #2 | Board review answer #2 | Board review style question #3 | Board review answer #3 | Board
review style question #4 | Board review answer #4
Alpha methyacyl CoA racemase (AMACR) is a mitochondrial and peroxisomal enzyme, a 382 amino acid protein essential
in lipid metabolism, encoded by a 1621 bp sequence gene, located on chromosome 5p13 (J Clin Pathol 2003;56:892)
One of the most widely used markers of prostate carcinoma, because this protein is upregulated in prostate carcinoma
and not found in benign prostate tissue (J Clin Pathol 2003;56:892, Am J Surg Pathol 2014;38:e6)
Essential features
Cytoplasmic expression is seen in prostate adenocarcinoma (80%), colon adenocarcinoma (90%) and in many other
cancers, including ovarian, lung cancers, lymphoma and melanoma (Am J Surg Pathol 2002;26:926)
Terminology
P504S (antibody against AMACR)
Pathophysiology
AMACR catalyzes the racemization of alpha methyl branched carboxylic coenzyme A thioesters and this enzyme is
essential in the oxidation of bile acid intermediates and branched chain fatty acids (J Clin Pathol 2003;56:892)
Phytanic acid, present in red meat and dairy products, is one of the primary substrates of AMACR and has been found to
be elevated in prostate adenocarcinoma (Prostate 2011;71:498)
AMACR is important in the pharmacological activation of ibuprofen and related drugs (Bioorg Chem 2019;92:103264)
Clinical features
Adult onset sensory motor neuropathy is developed due to mutations in the AMACR gene, associated with reduced
enzyme activity (J Clin Pathol 2003;56:892)
Diets rich in dairy products and red meat increases the risk for developing prostate cancer, because dairy products and
red meat are the major dietary sources of the branched chain fatty acid substrates of AMACR / P504S (J Clin Pathol
2003;56:892)
AMACR gene polymorphisms (D175G and M9V polymorphisms) are thought to affect the expression of the enzyme and
might be risk factors for prostate cancer (Asian Pac J Cancer Prev 2015;16:1857, Prostate 2008;68:1373)
Interpretation
Cytoplasmic granular staining pattern
Used to aid in the diagnosis of prostatic adenocarcinoma with a strong granular cytoplasmic staining in luminal cells;
however, can be positive in benign mimics (J Clin Pathol 2003;56:892, Am J Surg Pathol 2014;38:e6)
Overexpression of AMACR in combination with absence of basal cell markers (p63 or high molecular weight
cytokeratin [HMWCK]) is typical of prostatic adenocarcinoma (Am J Surg Pathol 2007;31:889)
A triple stain cocktail using a brown chromogen for basal cell markers (both p63 and HMWCK) and a red chromogen for
AMACR is shown to be better than basal cell markers by themselves and supports rational usage of tissue (Am J Surg
Pathol 2014;38:e6)
Prognostic factors
It has been shown that high expression of AMACR might represent an adverse prognostic factor in different types of
tumors, such as gastric adenocarcinoma, hepatocellular carcinoma, gallbladder carcinoma, nasopharyngeal carcinoma,
gastrointestinal stromal tumor and myxofibrosarcoma (Int J Med Sci 2018;15:638, Tumour Biol 2014;35:7983, J Clin Pathol
2014;67:974)
Contributed by Jonathan Epstein, M.D., Debra Zynger, M.D.

Prostate adenocarcinoma, triple RCC papillary type 1 with AMACR

stain

Kidney:
Epithelial cells of the proximal tubules show strong and distinct granular cytoplasmic staining (The Human Protein Atlas:
AMACR [Accessed 21 April 2020])
Epithelial cells of the distal tubules show a weak granular cytoplasmic staining reaction
GI / liver:
Hepatocytes and epithelium of the gastrointestinal tract show moderate cytoplasmic staining

Prostate:
Prostatic adenocarcinoma: majority are positive with sensitivity from 82% to 100% (Am J Surg Pathol 2014;38:e6, Am J
Surg Pathol 2007;31:889, Am J Surg Pathol 2003;27:772)
High grade prostatic intraepithelial neoplasia (HGPIN) (J Urol 2006;175:820, Int J Clin Exp Pathol 2009;2:327)
Partial atrophy: can also lack basal cell expression (Am J Surg Pathol 2008;32:851)
Adenosis and other small glandular proliferations: on needle biopsy 64% of cases of crowded glands are positive and
most had patchy or patchy / negative basal cells (Am J Surg Pathol 2005;29:874)
Kidney:
Papillary renal cell carcinoma (Am J Surg Pathol 2014;38:e35)
MiTF-TFE translocation associated renal cell carcinoma (Am J Surg Pathol 2014;38:e35)
Urothelial tract:
Urothelial carcinoma in situ (sensitivity 73% and specificity 97%) (Diagn Pathol 2019;14:91)
Nephrogenic adenoma: can also be negative for basal cell markers (Ann Diagn Pathol 2019;38:11, Hum Pathol 2019;94:11)
Clear cell adenocarcinoma
Skene gland adenocarcinoma (Am J Surg Pathol 2018;42:1513)
Gynecologic:
Mesonephric carcinoma
Clear cell carcinoma (Appl Immunohistochem Mol Morphol 2019 Jul 29 [Epub ahead of print])
GI / liver:
Barrett esophagus, ulcerative colitis, Crohn's disease: marker of dysplasia and carcinoma (Am J Surg Pathol
2006;30:871, J Clin Diagn Res 2017;11:EC35, Twitter: Andres Matoso [Accessed 21 April 2020])
Gastric adenocarcinoma
Colonic adenocarcinoma (J Clin Diagn Res 2016;10:EC10)
Melanoma / dysplastic nevi: might distinguish from conventional melanocytic nevi (Tumour Biol 2014;35:12015)
Negative staining
Kidney:
Clear cell renal cell carcinoma
Clear cell papillary renal cell carcinoma
Chromophobe renal cell carcinoma
Metanephric adenoma
Wilms tumor
Prostate:
Nonneoplastic prostatic tissue (Int J Clin Exp Pathol 2009;2:327, Am J Surg Pathol 2014;38:e6, Am J Surg Pathol
2007;31:889, Am J Surg Pathol 2003;27:772)
Urothelial tract:
Nonneoplastic urothelium
Papillary cystadenoma of the epididymis and broad ligament: 20% may weakly express (Am J Surg Pathol 2014;38:713)
Hum Pathol 2004;35:1272, Am J Surg Pathol 2020;44:673, Am J Surg Pathol 2016;40:202, Mod Pathol 2004;17:307, Am J Surg Pathol
2003;27:1128

Biopsy of a lymph node shows metastasis of an unknown tumor. Which immunohistochemical panel is consistent with
primary prostate carcinoma?
A. AE1 / AE3-, S100+, MelanA+, AMACR+

B. AMACR+, CDX2+, CK20+
C. AMACR+, p63-, HMWCK-, NKX3.1+
D. AMACR+, p63+, HMWCK+, NKX3.1-

C. AMACR+, p63-, HMWCK-, NKX3.1+
Comment Here
Reference: AMACR

Transurethral resection of the urinary bladder reveals a neoplastic proliferation, composed of small glandular structures,
which are positive for AMACR and NKX3.1. What is the diagnosis?
A. Adenocarcinoma of the urinary bladder, intestinal type

B. Clear cell adenocarcinoma urinary bladder
C. Invasive urothelial carcinoma
D. Prostate adenocarcinoma (metastatic or direct invasion)

D. Prostate adenocarcinoma (metastatic or direct invasion)
Comment Here
Reference: AMACR
Biopsy of the paraaortal lymph node of a 60 year old man shows metastatic tumor (figure A), which is positive for 34 beta
E12 (figure B) and AMACR (figure C) but negative for NKX3.1 (figure D). The tumor is also positive for GATA and CK7 (not
shown) but negative for CDX2 (not shown). What is the diagnosis?
A. Metastatic colorectal adenocarcinoma

B. Metastatic prostate adenocarcinoma
C. Metastatic squamous cell carcinoma
D. Metastatic urothelial cell carcinoma

D. Metastatic urothelial cell carcinoma
Comment Here
Reference: AMACR

In the resection specimen of the urinary bladder of a 60 year old man with known invasive high grade urothelial cell
carcinoma and multifocal carcinoma in situ, a glandular and cystic lesion was found under the urothelial lining (see image).
The lesion is positive for PAX8 and AMACR. What is the diagnosis?
A. Invasive urothelial cell carcinoma

B. Metastatic colorectal adenocarcinoma
C. Metastatic prostate adenocarcinoma
D. Nephrogenic adenoma

D. Nephrogenic adenoma
Comment Here
Reference: AMACR
AML1
Table of Contents
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)
AMY1A
Table of Contents
Definition / general | Clinical features | Uses by pathologists | Positive staining - disease | Negative staining
Also known as amylase alpha 1A
Amylases are secreted proteins that hydrolyze 1,4-alpha-glucoside bonds in oligosaccharides and polysaccharides, the
first step in digestion of dietary starch and glycogen
Humans have cluster of several amylase genes expressed at high levels in salivary gland or pancreas (NCBI Gene)
Clinical features
AMY1 genes show extensive copy number variation, which is directly proportional to salivary α-amylase content in saliva
(J Nutrigenet Nutrigenomics 2012;5:117)
Gene is deleted in chromophobe renal cell carcinoma but not oncocytoma
Differentiate oncocytoma (AMY1A+) from chromophobe renal cell carcinoma (both classic and eosinophilic variants are
negative, Am J Surg Pathol 2013;37:1824)

Oncocytoma
Negative staining
Renal carcinomas: chromophone, clear cell, papillary
amylase (pending)
Table of Contents
[Pending]
Amyloid beta and amyloid beta precursor protein

Table of Contents
Definition / general | Essential features | Terminology | Epidemiology | Sites | Pathophysiology | Etiology | Clinical
features | Diagnosis | Laboratory | Radiology description | Prognostic factors | Case
reports | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Positive
stains | Negative stains | Flow cytometry description | Electron microscopy description | Molecular / cytogenetics
description | Differential diagnosis | Additional references
Amyloid beta (A4) precursor protein (APP) is part of the type 1 transmembrane protein family
The APP gene is located on chromosome 21 and encodes for a cell surface receptor and transmembrane precursor
protein
There are three homologs of APP: APP, APLP1 and APLP2 (Mol Neurodegener 2011;6:27)
Cleavage of APP sequentially by beta secretase (rate limiting step) and gamma secretase produces beta amyloid (amyloid
beta, A4, Abeta) peptides of 40 - 43 amino acids, as well as other peptides that have transcriptional, antimicrobial, or
antifungal activities (Curr Opin Neurol 2000;13:377)
The beta amyloid sequence is unique to APP and is not present in APLP1 or APLP2
Cleavage of the precursor protein by gamma secretase is not precise and thus generates different forms of beta amyloid
with Abeta40 being the most abundant, accounting for 80 - 90% of the beta amyloid that is produced (J Alzheimers Dis
2010;19:311)
Beta amyloid peptides polymerize to form oligomers that then form fibrils or plaques
Oligomers and fibrils of beta amyloid are deposited in the brain and in the cerebrovascular system; these deposits lead to
the development of Alzheimer disease and cerebral amyloid angiopathy
The Abeta42 form accounts for 5 - 10% of the amyloid beta peptides but is more hydrophilic and prone to fibril formation; it
is the main form that is deposited in the brain
Beta amyloid oligomers are also seen in inclusion body myositis and lewy body dementia
Mutations in the APP gene lead to autosomal dominant / familial Alzheimer disease type 1, that accounts for less than 5%
of Alzheimer cases and comprises 10 - 15% of early onset familial Alzheimer disease (Eur Neurol 1995;35:8, Am J Hum
Genet 1999;65:664, Genet Med 2011;13:597)
Mutations in APP also lead to autosomal dominant hereditary cerebral hemorrhage with amyloidosis-Dutch type
(Neuropathology 2005;25:288)
Essential features
Amyloid beta precursor protein is cleaved into several peptides with different functions, including beta amyloid
There are several forms of beta amyloid peptides that aggregate to form oligomers and fibrils that are deposited in the
brain and cerebral vasculature causing disease
Studies suggest that beta amyloid oligomers, not the fibrils, are the neurotoxic form (J Neurosci 1999;19:8876, Nature
2002;418:291, PNAS 1998;95:6448)
Mutations in APP lead to autosomal dominant Alzheimer disease and hereditary cerebral hemorrhage with amyloidosis-
Dutch type, a type of cerebral amyloid angiopathy
The association of beta amyloid deposits to the degree of dementia is weak at best
Beta amyloid deposits in the brain and vasculature can be found in healthy, cognitively normal people
Terminology
Amyloid beta precursor protein is also known as APP, AAA, AD1, PN2, ABPP, APPI, CVAP, ABETA, PN-II, CTFgamma
Beta amyloid is also referred to as amyloid beta, Abeta, or A4
Epidemiology
The prevalence of beta amyloid deposits in the brain ranges between 0 and 47% in cognitively normal elderly people and
between 68 and 100% in those with Alzheimer disease (Neurology 2009;73:754, Alzheimers Dement 2010;6:221, Neurology
2012;79:1636, J Nucl Med 2009;50:878)
Vascular beta amyloid has been detected in 27% of cognitively normal controls and 78% of patients with cerebral amyloid
angiopathy (Mov Disord 2003;18:81, Folia Neuropathol 2013;51:120)
Sites
The amyloid beta precursor protein is expressed in central nervous system as well as other normal tissues
Beta amyloid oligomers and fibrils are generally found in the central nervous system and cerebral vasculature
Pathophysiology
Beta amyloid peptides produced by cleavage of APP polymerize to form oligomers and then fibrils or plaques
The accumulation of beta amyloid plaques in the brain (extracellular) and in the media and adventitia of medium and small
arteries of the cerebral cortex and leptomeninges contributes to the development and progression of Alzheimer disease
and cerebral amyloid angiopathy (Curr Med Chem 2009;16:2498)
Recent studies have suggested that the oligomeric form of beta amyloid is the neurotoxic form that contributes to the
pathology of beta amyloid
The apolipoprotein E E4 allele is speculated to prevent the suppression of amyloid production or the clearance of amyloid
Etiology
Some beta amyloid peptides are unstable in free form and thus polymerize to form fibrils and plaques
Accumulation of amyloid plaques in the brain is dependent on the rate of production and clearance out of the brain
Neurotoxicity of beta amyloid and Tau (a microtubule-associated protein) deposits are thought to contribute significantly to
Alzheimer disease, but the etiology of Alzheimer disease and cerebral amyloid angiopathy is not known
Clinical features
Alzheimer disease: progressive memory loss and cognitive impairment, mood and personality changes, depression,
anxiety – in part due to the accumulation of beta amyloid deposits in the brain
Cerebral amyloid angiopathy: dementia, intracranial hemorrhage – due to beta amyloid deposits in the vasculature
Diagnosis
Beta amyloid can be detected using Congo red staining, immunohistochemical staining or PET imaging
Alzheimer disease: the presence of beta amyloid plaques and neurofibrillary tangles is essential for the diagnosis of
Alzheimer disease (Alzheimer Dementia 2012;8:1) but is not pathognomonic for the disease – beta amyloid plaques may be
seen in normal aging and neurofibrillary tangles can be present in other neurodegenerative disorders
Cerebral amyloid angiopathy: clinical and MRI evidence of hemorrhage or hematomas with cortical biopsy
demonstrating vascular amyloid deposition (Ann Neruol 2004;55:250)
Histologic evaluation of vessels is required for definitive diagnosis

Laboratory
Levels of beta amyloid are generally low in the cerebrospinal fluid of Alzheimer patients and cerebral amyloid angiopathic
patients
Radiology description
Guidelines for the use of PET imaging in differentiating Alzheimer disease from other types of dementia are set by the
Amyloid Imaging Taskforce
PET imaging uses 3 FDA approved beta amyloid tracers (florbetapir F 18, flutemetamol F18 and florbetaben F18) to
detect beta amyloid deposits in the brain (Arch Neurol 2011;68:1404, JAMA 2011;305:275, Alzheimer Dis Assoc Disord 2012;26:8)
Prognostic factors
Mutations in APP that lead to early onset Alzheimer disease result in a more aggressive disease and rapid course
Cerebral amyloid angiopathy:

Lobar intracranial hemorrhages have a better prognosis than hypertensive deep ganglionic bleeds
25 - 40% recurrence rate, which are associated with increased mortality (up to 40%); patients are at highest risk in the
first year
Case reports
Cerebral amyloid angiopathy-related inflammation (Case Rep Neurol Med 2015;2015:483020)
Misdiagnosis of inclusion body myositis (J Med Case Rep 2015;9:169)
Sporadic cerebral amyloid angiopathy with giant cell reaction (Acta Neuropathol 1990;81:95)
Treatment
There are no effective therapies for APP or the accumulation of beta amyloid
Symptomatic treatment of Alzheimer disease include drugs that modulate neurotransmitters (Ach and NMDA) and
psychotropic medications
Treatment of cerebral amyloid angiopathy includes standard therapy for intracranial hemorrhage, steroids and
immunosuppressants for patients with co-existing vasculitis

Beta amyloid:
Extracellular cortical deposits
Pink amorphous extracellular material surrounded by a halo
May also be surrounded by dystrophic / degenerating neurites and reactive glia, cotton wool plaques, amyloid lakes,
subpial bands
Homogenous, eosinophilic substance in vessel wall, may have a smudged appearance; fibrinoid necrosis in amyloid-
laden vessels
Yellow-green birefringence with Congo red stain and polarization
Immunohistochemical staining for APP is cytoplasmic

Subcellular localization in golgi apparatus of APP seen in human cell line U-2 OS
H&E showing beta amyloid deposit in Alzheimer disease
H&E and Congo Red staining of beta amyloid deposits in cerebral blood vessels
Enhancement of formic acid (FA)-mediated amyloid beta peptide antigen retrieval
IHC of beta amyloiddeposits in the cerebral cortex and blood vessels
Virtual slides

Cancer tissue samples - colorectal, breast, prostate, lung, testis found under "protein expression"
Positive stains
Weak to moderate APP staining in neuronal cells
Weak positive APP staining has also been noted in other normal tissues such as the GI tract and male reproductive
system
Weak to moderate cytoplasmic APP staining is seen in many malignant tissues with strong staining noted in some
testicular and urothelial cancer tissues
Negative stains
APP: normal liver and skeletal tissue
Flow cytometry description

Currently experimental for the detection of beta amyloid oligomers (J Alzheimers Dis 2007;11:117)
Electron microscopy description

Beta amyloid plaques on EM appear as a dense core of star-like beta amyloid fibril bundles surrounded by dystrophic
neurites, activated microglia and reactive astrocytes (Tosoni A., Barbiano di Belgiojoso G. and Nebuloni M.: Electron
Microscopy in the Diagnosis of Amyloidosis, 2011)

Pathogenic mutations in APP are generally missense or nonsense mutations (but can also include deletions, insertions
and splice site mutations) and mainly occur in exons 16 and 17
Clinical sequence analysis or mutation scanning may be performed for the entire gene or restricted to exons 16 and 17
only
Duplication mutations of APP are detected by FISH analysis and account for less than 1% of the pathogenic mutations in
APP (Nat Genet 2006;38:24)
Differential diagnosis
Alzheimer disease
Cerebral amyloid angiopathy
Cerebral aneurysms
Choriocarcinoma
CNS tumors
Hypertension
Lewy body disease
Senile dementia
Neuroimage Clin 2013;2:356, Neurol 2007;68:1718, The Human Protein Atlas
Androgen receptor (AR)
Table of Contents
Definition / general | Essential features | Pathophysiology | Diagnosis | Clinical features | Uses by
pathologists | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Positive staining -
normal | Positive staining - disease | Negative staining | Additional references | Board review style question
#1 | Board review answer #1
Androgen receptor (AR) is a member of the superfamily of ligand responsive transcription regulators
It functions in the nucleus where it is believed to act as a transcriptional regulator mediating the action of androgens
918 amino acid protein encoded by a single copy gene on X q11 - q12
Essential features
Expressed variably by both ER / PR+ as well as ER / PR- breast cancers
Most useful for triple negative breast cancer, luminal androgen subtype
Detected by IHC or gene classifier (molecular testing)
Predicts favorable prognosis in early stage disease based on current studies, some controversy exists
Ongoing trials to study the effect of androgen receptor targeted therapy in
AR+ triple negative breast cancer
Hormone receptor positive metastatic breast cancer
HER2+ metastatic breast cancer
Pathophysiology
Expressed in two types of mammary epithelial cells:
Metaplastic apocrine cells (lack ER / PR)
Luminal epithelial cells (5 - 30%) (co-expressed with ER / PR)
Diagnosis
May be detected by gene classifier or IHC
Any nuclear IHC staining in tumor cells is considered as positive result but further subdivided into subgroups with 1 - 10%
and > 10% positive staining
Clinical features
Expressed variably depending on tumor subtype:
ER+ breast tumors: 67 - 88%
All molecular apocrine tumors
12 - 50% of ER- classic invasive ductal carcinoma
Triple negative breast tumors: 6.6 - 75%; range due to variable cutoffs, source of antibody and methodologies, highest
expression in luminal androgen receptor subtype (Breast Cancer Res Treat 2011;130:477, Clin Cancer Res 2011;17:1867, Clin
Cancer Res 2013;19:5505, Clin Adv Hematol Oncol 2016;14:186)
Predicts favorable prognosis based on some studies, however controversy exists
Apocrine marker
Breast carcinoma marker helpful in determining primary site of metastases
Paget disease marker
Sebaceous carcinoma marker; may help differentiate from squamous cell and basal cell carcinomas (Am J Clin Pathol
2010;134:22)
Treatment
In addition to neoadjuvant chemotherapy, patients with AR+ tumors may benefit from AR targeted therapies such as
bicalutamide (AR antagonist) or enzalutamide (AR inhibitor) (ascopost: Targeting the Androgen Receptor in Breast Cancer
[Accessed 8 May, 2018])
Newer therapies are underway

Nuclear stain in tumor cells is quantified

Contributed by Monika Roychowdhury, M.D. Case of the Week #214

Skin metastatic Androgen receptor Skin metastatic Androgen receptor Salivary gland AR-
breast in metastatic breast breast in metastatic breast low grade cribriform
carcinoma 20x carcinoma 20x carcinoma 40x carcinoma 40x cystadenocarcinoma

Breast: apocrine Breast: apocrine Prostate carcinoma Spindle cell

DCIS metaplasia metastatic to bone lipoma
Skin apocrine and sebaceous glands (J Invest Dermatol 1991;97:264), prostate basal cells (J Steroid Biochem Mol Biol
1992;41:693)
Early male and female fetal gonads (Hum Reprod 2004;19:1659)
Also oral mucosa

Breast: apocrine metaplasia (100%, J Clin Pathol 1999;52:838) apocrine DCIS (J Clin Pathol 2002;55:14) apocrine carcinoma
(Jpn J Clin Oncol 2012;42:375, Case Rep Pathol 2013;2013:170918), cystic hypersecretory DCIS (Histopathology 2005;46:43),
high grade DCIS, high grade invasive breast carcinoma (primary and metastatic), mammary and extramammary Paget
disease (Mod Pathol 2005;18:1283), PASH spindle cells (Int J Clin Exp Pathol 2009;3:87), sebaceous carcinoma, tall cell-like
tumors (Int J Surg Pathol 2006;14:79)
Associated with better prognosis in all types of breast cancer, and better overall survival in ER+ tumors (PLoS One
2013;8:e82650)
Nasal cavity: nasopharyngeal angiofibroma (75%, Mod Pathol 1998;11:1122, stromal cells in 38% Am J Clin Pathol
2006;125:832)
Ovary: serous tumors (50%), Sertoli-Leydig tumor (Hum Pathol 1997;28:1206), ovarian surface epithelium (higher AR
staining in patients with cervical squamous cell carcinoma, J Ovarian Res 2013;6:85)
Salivary glands: giant cell tumor, salivary duct carcinomas (Am J Clin Pathol 2003;119:801)
Skin: Paget disease, sebaceous carcinoma (Am J Clin Pathol 2010;134:22)
Soft tissue: desmoid tumor (53%, Tohoku J Exp Med 2006;210:189), spindle cell lipoma in men and most women (Arch
Pathol Lab Med 2008;132:81)
Uterus: adenosarcoma (35%), endometrial polyp with atypical features, endometrial stromal nodule, endometrium in
polycystic ovarian syndrome. (Biol Reprod 2002;66:297), leiomyosarcoma (variable, Cancer 2004;101:1455, Tumour Biol
2011;32:451)
Negative staining
Neuroendocrine cells
Adenomatoid tumor, BRCA1 breast carcinoma, breast fibromatosis (Arch Pathol Lab Med 2000;124:276)
Drug Discov Today Dis Mech 2012;9:e19, Wikipedia - Androgen Receptor

Androgen receptor testing is most useful in:
A. ER+, PR+, HER2+ breast tumor

B. ER+, PR+, HER2- breast tumor
C. ER-, PR-, HER2+ breast tumor
D. ER-, PR-, HER2- breast tumor

D. ER-, PR-, HER2- breast tumor
Comment Here
Annexin A1 (pending)
Table of Contents
[Pending]
Annexin A10
Table of Contents
(pending)
AP2 beta
Table of Contents
Definition / general | Pathophysiology | Clinical features | Uses by pathologists | Microscopic (histologic) images
Member of AP2 transcription factor family, which consists of five different yet closely related 50-kDa isoforms
Also called adapter protein 2 beta, TFAP2b (transcription factor AP 2 beta), Activating enhancer-binding protein-2β
Pathophysiology
Regulates expression of many downstream genes, orchestrating a variety of cell processes, particularly cell induction,
differentiation, survival, and proliferation and apoptosis within various developmental contexts (Mol Cancer 2014;13:89, Ann
Thorac Surg 2011;92:1044)
Assembly protein associated with clathrin-coated vesicles, involved in endocytosis and Golgi processing (Genomics
1995;30:94)
Involved in monoaminergic transmission, likely due to a regulatory effect on monoamine oxidase type A and serotonin
transporter (Brain Res 2009;1305 Suppl:S20)
Clinical features
Expression differs in some alveolar rhabdomyosarcoma phenotypes (Int J Cancer 2014;135:1543)
Lung cancer, non small cell type:
Highly expressed in non-small cell lung cancer, poor prognostic factor for adenocarcinoma (Mol Cancer 2014;13:89)
Nucleolar localization may predict poor survival in stage I non-small cell lung cancer (Ann Thorac Surg 2011;92:1044)
Mutations associated with congenital heart disease:
Mutations involved in familial isolated patent ductus arteriosus (J Surg Res 2014;188:466)
Mutations associated with nonfamilial congenital heart disease (Cardiovasc Pathol 2013;22:141)
May have an impact on genetic and early environmental influence on ethanol consumption (J Neural Transm 2010;117:1077)
May be useful for diagnosis of alveolar rhabdomyosarcoma (Histopathology 2009;54:873, J Clin Oncol 2006;24:816)

Non-small cell Lung cancer

lung cancer cells and tumor
tissues
APC
Table of Contents
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
Table of Contents
Definition / general | Additional references
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
Mod Pathol 2003;16:1232
Hum Pathol 2003;34:1212
Apolipoprotein D (apoD)
Table of Contents
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 Pathol 2005;36:987)
Argentaffin
Table of Contents
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
Arginase1
Table of Contents
Definition / general | Uses by pathologists | Microscopic (histologic) images | Positive staining - normal | Positive
staining - disease
Binuclear manganese metalloenzyme that catalyzes hydrolysis of arginine to ornithine and urea (Wikipedia)
Also called liver arginase
Critical regulator of nitric oxide synthesis and vascular function
Defects cause vascular disease, pulmonary disease, infectious disease, immune cell function or cancer
Argininemia: rare autosomal recessive disorder of urea cycle due to mutations in arginase gene; arginine is elevated in
blood and cerebrospinal fluid, causes periodic hyperammonemia, associated with developmental delay, seizures,
intellectual disability, hypotonia, ataxia and progressive spastic quadriplegia (OMIM #207800)
Sensitive and specific marker of benign and malignant hepatocytes (Am J Surg Pathol 2010;34:1147)
Help distinguish hepatocellular carcinoma from metastatic carcinoma (Diagn Pathol 2012;7:149, Am J Clin Pathol
2012;138:203), but also stains cholangiocarcinoma (Oncol Lett 2011;2:1046)

Images hosted on PathOut server:

Contributed by Contributed by
GenomeMe Cell Marque Corporation

Colon (normal), Liver (normal), HCC - nuclear

clone IHC400 clone IHC400 and cytoplasmic
staining

Hepatocellular carcinoma Moderately Liver: benign

differentiated and
HCC hepatocellular
carcinoma

Metastatic Cholangiocarcioma Lung: TB related

colonic granulomas
adenocarcinoma
to liver

Hepatocytes

Cholangiocarcinoma, hepatocellular carcinoma
Granuloma-associated macrophages; lung: type II pneumocytes (FEMS Immunol Med Microbiol 2012;66:265)
Pancreatic adenocarcinoma (13%, Cancer Cytopathol 2012;120:230)
ARID1A
Table of Contents
Definition / general | Clinical features | Diagrams / tables | Microscopic (histologic) images | Positive staining -
normal | Negative stains
AT Rich Interactive Domain 1A (SWI-like) tumor suppressor gene at 1p36.11 encodes BAF250A, a member of the
SWI/SNF ATP-dependent chromatin-remodeling complexes (J Gynecol Oncol 2013;24:376)
Involved in tissue development and cellular differentiation
Inactivation of components of chromatin-remodeling complex are associated with malignancy
Most ARID1A somatic mutations are frame-shift or nonsense mutations that contribute to mRNA decay and loss of
protein expression
5% of ARID1A mutations are in-frame insertions or deletions (indels) that involve only a small stretch of peptides
(Neoplasia 2012;14:986)
Clinical features
Bladder: mutations associated with poor prognosis urothelial carcinomas (PLoS One 2013;8:e62483)
Breast: loss of expression associated with carcinoma ( Tumour Biol 2014;35:4813)
May be due to promoter hypermethylation (PLoS One 2013;8:e53931)
Cervix: loss of expression a poor prognostic factor (Hum Pathol 2013;44:1365)
Loss in 31% of adenocarcinoma / adenosquamous carcinoma (Int J Gynecol Cancer 2012;22:208)
Endocervical-type mucinous borderline tumors may be related to endometrioid tumors based on mutation and loss of
expression of ARID1A (Int J Gynecol Pathol 2012;31:297)
Colorectum: mutated in 39% of microsatellite instability (MSI) cancers (Int J Cancer 2014;135:611 Dec 31)
Esophagus: mutated in 15% of Barrett's related high grade dysplasia or esophageal adenocarcinoma (Oncogene
2014;33:347)
Loss of expression in 12-16% of Barrett's related dysplasia / esophageal adenocarcinoma
Kidney: loss of expression a poor prognostic factor in clear cell carcinoma (Am J Pathol 2013;182:1163)
Neuroblastoma: mutations of ARID1A or ARID1B in 11%; poor prognostic factor (Nat Genet 2013;45:12)
Ovary: loss of expression in 52% of clear cell carcinoma (Mod Pathol 2014;27:983)
Loss of expression may be early event in endometriosis-associated ovarian carcinoma (Int J Mol Sci 2013;14:18824, Int J
Clin Exp Pathol 2012;5:642, Int J Gynecol Cancer 2012;22:1310)
Stomach: loss of expression in gastric carcinoma associated with poor prognosis (PLoS One 2012;7:e40364, Virchows Arch
2012;461:367)
Uterus: loss of expression may play important role in tumor progression of endometrioid carcinoma (Am J Surg Pathol
2013;37:1342)
Loss of expression in 46% of high grade endometrioid carcinomas; associated with mismatch repair deficiency and
normal p53 expression (Mod Pathol 2014;27:255, Mod Pathol 2013;26:1525)
Loss of expression in 20% of endometrial clear cell carcinomas, does not predict prognosis (Mod Pathol 2013;26:1101)
Diagrams / tables

Gene map Regulation of chromatin structure

Cervix: borderline seromucinous Ovary: clear cell Ovary: endometriotic cyst and
tumors carcinoma (A, B) associated well-differentiated
endometrioid carcinoma

Stomach: gastric Uterus: Uterus:

carcinoma endometrioid endometriosis
carcinoma (G-I)

Normal tissue shows ARID1A staining
Negative stains
Various tumors (see above) show loss of ARID1A staining
ARID2
Table of Contents
Definition / general | Diagrams / tables | Clinical features | Microscopic (histologic) description | Resistance
therapies | Molecular / cytogenetics description
ARID2, AT rich interactive domain containing protein 2, functions as a tumor suppressor gene / protein
It is located on chromosome 12q
ARID2 is a subunit of a chromatin remodeling complex
It functions to facilitate ligand dependent transcriptional activity by nuclear receptors (Genes Dev 2005;19:1662, Oncotarget
2011;2:886)
Diagrams / tables
ARID2 associations
Clinical features
ARID2 is associated with melanoma and hepatocellular carcinoma most commonly but has been described in many other
tumors
No studies have described specific histological findings with ARID2 mutations

Detection of ARID2 mutations is not routinely performed in melanocytic proliferations
Inactivation mutations can be detected through whole exome sequencing and microarray
No mechanisms of resistance have been evaluated
Resistance therapies
No resistance therapies have been evaluated

ARID2 mutations causing disease are loss of function mutations
Nonsense mutations are predicted to lack the Zn motifs required for DNA binding
There is some suggestion that UVB may cause some of these mutations leading to melanomagenesis (Cell 2012;150:251)
Asbestos
Table of Contents
Definition / general | Microscopic (histologic) images
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

Asbestos body, Asbestos

unstained bodies, iron
stain
ATDX (ATRX)
Table of Contents
Definition / general | Terminology | Clinical features | Uses by pathologists | Microscopic (histologic) images
Alpha-Thalassemia/intellectual Disability syndrome X-linked
Chromatin remodelling protein important in DNA replication, telomere stability, gene transcription, chromosome
congression and cohesion during cell division (Epigenetics 2013;8:3)
Member of SWI/SNF protein family of DNA dependent ATPases
Is recruited to site of DNA damage; required for efficient checkpoint activation and faithful replication restart (J Biol Chem
2013;288:6342)
Death domain-associated protein (Daxx) cooperates with ATRX
Have essential roles in adenovirus gene expression; illustrates importance of early viral proteins to counteract cellular
chromatin remodelling (Nucleic Acids Res 2013;41:3532)
HSV also represses ATRX (J Virol 2012;86:10093)
Terminology
Previously termed Alpha Thalassemia / Mental Retardation syndrome
Clinical features
Associated with rare genetic disorder ATDX (ATRX) syndrome, which includes developmental delay, cognitive impairment,
various skeletal deformities (PLoS One 2013;8:e85526, Nat Struct Mol Biol 2011;18:769, J Hum Genet 2012;57:73, Eur J Hum Genet
2011;19:717)
Acquired α-thalassemia myelodysplastic syndrome (ATMDS): rare acquired syndrome characterized by somatic point
mutation in ATRX gene in patients with chronic myeloid disorders (Hemoglobin 2012;36:581)
CNS: loss of ATRX expression in 45% of anaplastic astrocytomas, 27% of anaplastic oligoastrocytomas, 10% of
anaplastic oligodendrogliomas (Acta Neuropathol 2013;126:443)
Occurs in pediatric and adult high grade astrocytoma (Mod Pathol 2013;26:1425)
Alternative Lengthening of Telomeres (ALT) is a non-telomerase mechanism of telomere lengthening that occurs in
~10% of cancers overall and is particularly common in astrocytic brain tumors; ATRX may be a repressor of ALT (PLoS
One 2012;7:e50062, Oncotarget 2012;3:1194)
Genetic signatures, including ATRX, may refine classification of gliomas (Oncotarget 2012;3:709)
Pancreas: loss of ATRX is associated with chromosomal instability in pancreatic endocrine tumors and shorter survival
(Gastroenterology 2014;146:453, Horm Cancer 2013;4:165, Mod Pathol 2012;25:1033, Science 2011;333:425)
See clinical features above

Neuroblastoma Pancreas: ALT+ Pancreas: MEN1

tumors microadenoma and
pancreatic neuroendocrine
tumor
ATM
Table of Contents
Definition / general | Diagrams / tables | Clinical features | Uses by pathologists | Microscopic (histologic)
images | Negative staining
Ataxia telangiectasia mutated, gene at 11q21-q22 (Wikipedia)
ATM is protein kinase that activates response to DNA double-strand breaks (Nat Rev Mol Cell Biol 2013;14:197, Front Genet
2013;4:37)
Mutations cause suboptimal induction of p53 dependent signaling after exposure to DNA damaging agents, which causes
an increase in mitotic recombination
Also has functions essential to neuronal survival and normal function but unrelated to DNA damage (Mech Ageing Dev
2013;134:434)
Ataxia telangiectasia:
Rare neurodegenerative disorder due to mutation of protein
Characterized by early-onset, progressive cerebellar ataxia, oculomotor apraxia, choreoathetosis, conjunctival
telangiectasias, immunodeficiency
Also increased risk of malignancy because cells are particularly radiosensitive; increased risk is due to changes occuring
in germline cells and as somatic changes in tumors themselves (Oncogene 2014;33:3351)
Diagrams / tables

ATM controls cellular survival Selected summary of the

in response to DNA damage ATM signaling network
through multiple pathways
Clinical features
CLL: frequently ATM abnormalities (Haematologica 2013;98:1124)
CML: DNA damage-response pathway may determine susceptibility to blast crisis (DNA Repair (Amst) 2013;12:500)
Glioma: may represent a source of radioresistance in glioma stem cells (Oncol Rep 2013 Jul 11 [Epub ahead of print])
Prostate: usually higher levels than normal in prostate carcinoma (Am J Clin Pathol 2004;121:231)
No uses at this time

Prostate: ATM expression Prostate: adenocarcinoma Prostate: adenocarcinoma Prostate: adenocarcinoma
in hyperplastic glands of with low ATM staining with normal ATM expression with high ATM staining.
transitional zone
Negative staining
Loss of 11q21-q22 (ATM) found in nodal, splenic marginal zone and lymphoplasmacytic lymphoma (Mod Pathol
2012;25:651)

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11A1 14-3-3sigma protein (stratifin) 15-PGDH 2-succino-cysteine (pending) 3 beta hydroxysteroid

14-3-3sigma protein (stratifin)

Microscopic (histologic) images

Images hosted on other servers:

Positive staining - normal

Positive staining - disease

Microscopic (histologic) images

Images hosted on other servers:

Prostate: normal Stomach: normal and cancer Synovium:

Synovium: Uterus: endometrial adenocarcinoma

Positive staining - normal

Positive staining - disease

Microscopic (histologic) images

Images hosted on other servers:

Positive staining - normal

Positive staining - disease

Images hosted on other servers:

Bowel Pancreas: mucous gland hyperplasia (45M1+)

Positive staining - normal

Positive staining - disease

Positive staining - normal

Apolipoprotein E / Aβ interaction pathways

Microscopic (histologic) images

Images hosted on other servers:

Brain tissue of Alzheimer's disease

Microscopic (histologic) description

Contributed by Rola Saleeb, M.D., Ph.D.

Positive staining - normal

Positive staining - disease

Molecular / cytogenetics description

Board review style question #1

Board review answer #1

Microscopic (histologic) images

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Acid fast / Auramine-rhodamine

Microscopic (histologic) images

Images hosted on other servers:

Oocysts: modified acid-fast stain Stool specimen Oocysts:

Microscopic (histologic) description

Microscopic (histologic) images

Contributed by Chunyu "Hunter" Cai, M.D., Ph.D.

Adult onset acid Central core Cystinosis distal Degenerating Hydroxychloroquine

Positive staining - normal

Positive staining - disease

Board review style question #1

Board review answer #1

Microscopic (histologic) images

Images hosted on other servers:

Bacilli and cocci Buccal smear Buccal smear Mycobacteria

Microscopic (histologic) images

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Various normal Benign breast Invasive breast Kidney tubules

Positive staining - normal

Positive staining - disease

Actin - alpha cardiac

Microscopic (histologic) images

Images hosted on other servers:

Positive staining - normal

Positive staining - disease

Images hosted on other servers:

Actin and Helical structure G-actin to F- Animation of

Microscopic (histologic) images