Background
Primary atypical hyperplasia | Number of AH cases excised | Overall carcinoma | Invasive carcinoma | Ductal carcinoma in situ | Risk factors | References |
---|---|---|---|---|---|---|
ADH | 62 cases | 9 cases (14.5%) | 2 cases (3.2%) | 7 cases (11.3%) | Personal/family history breast cancer | [60] |
ALH | 73 | 13 (17.8%) | 5 (6.8%) | 8 (11.0%) | [61] | |
ADH | 104 | 22 (21.2%) | 3 (2.9%) | 19 (18.3%) | [62] | |
ADH | 76 | 21 (27.6%) | 3 (3.9%) | 18 (23.7%) | [63] | |
ADH | 61 | 19 (31.2%) | 5 (8.2%) | 14 ((23.0%) | [64] | |
ALH | 97 | 21 (21.6%) | 6 (6.2%) | 15 (15.5%) | [65] | |
ADH (9 gauge) | 74 | 16 (21.6%) | 2 (2.7%) | 14 (18.9%) | [66] | |
ADH | 101 | 20 (19.8%) | 3 (3.0%) | 17 (16.8%) | Number of ADH foci | [67] |
ADH | 65 | 11 (16.9%) | 5 (7.7%) | 6 (9.2%) | Increasing age | [68] |
ALH | 40 | 11 (27.5%) | 4 (10.0%) | 7 (17.5%) | [69] | |
Mean | 21.97% ± 1.7 | 5.47% ± 0.84 | 16.52% ± 1.55 |
Type of atypical hyperplasia | Number of cases | Follow-up | Overall carcinoma | Invasive carcinoma | DCIS | Relative risk | References |
---|---|---|---|---|---|---|---|
AH | 331 | Mean—13.7 years | 18.4% | 16.0% | 2.4% | Overall—3.88 ALH—3.67 ADH—3.83 ALH + ADH—7.10 | [4] |
AH | 668 | Median—17 years | 21.4% | 17.4% | 3.0% | All AH—4.34 ALH—4.76 ADH—3.93 ALH + ADH—4.36 | [5] |
ALH ADH | 126 150 | Mean—17.5 years | 12.0% 12.7% | 12.0% 12.7% | ALH—4.2 ADH—4.3 | [1] | |
ALH | 316 | Mean—17 years | ALH—12.8% ALH + DIALH—21.3% ALH/no DIALH-7.7% DIALH—6.1% | ALH—12.8% ALH + DIALH—21.3% ALH/no DIALH-7.7% DIALH—6.1% | ALH—4.3 ALH + DIALH-6.8 ALH/no DIALH-2.7 DIALH—2.1 | [14] | |
ADH | 82 | Mean—12.4 years | 9.8% | 9.8% | [70] | ||
ALH | ALH all—252 ALH alone—161 ALH + DIALH—76 ALH + ADH—15 | ALH all—20% ALH alone—16% ALH + DIALH—24% ALH + ADH—40% | ALH all—20% ALH alone—16% ALH + DIALH—24% ALH + ADH—40% | Invasive carcinoma—3.1 | [2] |
Methods
Literature search and criteria for identification of tissue specimens
Results and discussion
Numerical chromosomal changes in atypical hyperplasia
Chromosome | Alteration | Normal breast | Atypical hyperplasia | DCIS | Invasive carcinoma | References |
---|---|---|---|---|---|---|
1 | Chromosome copy number—FISH | Normal compliment | ALH—no gain or loss | Gain 100% | Gain 100% | [20] |
1 | Ploidy, FISH | Normal content | ADH—aneusomy, 100.0% | Gain, 72.7% Loss, 9.1% | Gain, 87.5% | [71] |
1 | Chromosome copy number, FISH | Signal number—1.14 | ADH—increased copy number, signal number 1.50 | Increased, copy number, signal number 1.95 | Increased copy number, signal number 1.74 | [23] |
16 | Chromosome copy number—FISH | Borderline loss | ALH—gain, 50% | Gain, 100% | Gain, 100% | [20] |
17 | Chromosome copy number—FISH | Normal compliment | ALH—borderline loss, 50% | True gain, 100% | True gain, 100% | [20] |
17 | Ploidy, FISH | Normal content | ADH—no loss or gain | Gain, 45.5% Loss, 45.5% | Gain, 50.0% | [71] |
18 | Chromosome copy number—FISH | Borderline loss | ALH—borderline loss 50% | Gain, 100% | Borderline gain, 100% | [20] |
Chromosomes 8,11 | FISH | Nipple aspirate fluid mild atypia—20% aneusomy | [72] | |||
Chromosomes 1,8,11 or 17. | FISH | Disomy—100% | Nipple aspirate fluid, marked atypia—100% aneusomy | Nipple aspirate fluid, malignant, 100% aneusomy | [72] | |
Chromosomes 7-12, 17, 18, X | Chromosomal aberrations, cytologic, FISH | 40% of non-proliferative lesions | ADH—100% | 100% (includes DCIS) | [16] | |
Chromosomes 1, 7, 8, 16, 17, X | Chromosome copy number—FISH | ADH—no gains or losses ALH, chromosome 8, 3% triploid | 70% aneuploidy | 100% aneuploidy | [73] | |
Nucleus—nuclear morphometry | Area | Non-proliferative 25.5 | AH—37.4 | 47.9 | 54.9 | [74] |
Perimeter | Non-proliferative 20.6 | AH—24.3 | 27.2 | 29.4 | [74] | |
Maximum diameter | Non-proliferative 7.3 | AH—8.52 | 9.6 | 10.3 | [74] | |
Minimum diameter | Non-proliferative 5.1 | AH—6.0 | 6.9 | 7.4 | [74] | |
Large dark areas | Non-proliferative 0.022 | AH—0.084 | 0.103 | 0.099 | [74] | |
Large light areas | Non-proliferative 0.009 | AH—0.038 | 0.049 | 0.075 | [74] | |
Total stain | Non-proliferative 12.52 | AH—12.38 | 23.73 | 19.72 | [74] | |
DNA content | Normal diploid | ADH—diploid, 33% Type III histogram, 33.3% Aneuploid, 33.3% ALH—diploid, 100% | [75] | |||
DNA content | Nuclear DNA histogram | Diploid | ADH—Type III/IV histogram, 38.1% ALH—diploid | [76] | ||
DNA content | Hyperplasia without atypia-diploid | Aneuploid, 33.3% | Aneuploid, 78.2% | [19] | ||
DNA content | Aneuploidy | AH—aneuploid, 30.8% | Aneuploid, 33.3% | Aneuploid, 88.5% | [77] | |
DNA ploidy | Cytometric assessment | Intraductal proliferation without atypia—euploid | ADH—43% aneuploidy | 71.4%—84.4% aneuploidy | 54.1%—95.6% aneuploidy | [78] |
DNA aneuploidy | DNA histogram | AH—aneuploidy, 71% | Aneuploidy, 71% | [6] | ||
DNA aneuploidy | DNA Index | Non-proliferative—25% aneuploidy | Hyperplasia with atypia—aneuploidy 32% | [79] | ||
Nuclear morphometry | Nuclear area | 13.13 | AH—24.25 | Cribriform—16.16 Comedo—40.23 | 41.30 | [17] |
Nuclear morphometry | Nuclear abnormality | 0.644 | AH—2.261 | Cribriform—0.918 Comedo—2.710 | 1.265 | [17] |
Monoclonality | X-chromosome inactivation assay | 0% monoclonal | AH—51.3% monoclonal | 100% monoclonal | [21] | |
Nucleolar organizer regions | Ag-NOR—IHC | 6.0 | ADH—8.8 ALH—8.6 | 9.0 | 17.7 | [18] |
DNA quantitation | Aneuploidy | Euploid (NABT) | AEH—aneuploidy 50% | Aneuploidy 50% | [80] | |
Mitotic figures | Mitoses/HPF | 3.5 (proliferative disease without atypia) | ADH—6.7 | DCIS—26.5 DCIS in infiltrating carcinoma—51.3 | [81] | |
Chromosomal abnormalities | Cytogenic, FISH | AEH—diploid with structural aberrations | [82] |
Chromosome | Gene | Alteration | Normal breast | Atypical hyperplasia | DCIS | Invasive carcinoma | References |
---|---|---|---|---|---|---|---|
1p32 |
MYC1
| MSI/LOH | 8.3% | [33] | |||
1q | CGH | ADH—gain 11.1% | [35] | ||||
1q | Chromosome copy number, CGH | ADH—gain 33.3% | Gain, 60% | Gain, 80% | [83] | ||
1q32-42/D1S549, D1S213 | LOH (proportion) | 2% | ADH with cancer, 29% | 52% | 44% | [32] | |
1q32-42/D1S549 | MSI/LOH | AH—25.0% | [33] | ||||
1q32-qter | CGH | ADH—high-level amplification | [7] | ||||
2p11.2 | CGH | ALH—gains, 50% | [84] | ||||
2q35/D2S362 | LOH | ADH non-cancerous breast—none ADH cancerous breast—6% | Non-comedo—6% Comedo—9% | [85] | |||
3p |
rhoA, cdc25A
| CGH | ADH—gains | [83] | |||
3p24/D3S1298 | MSI/LOH | AH—8.3% | [33] | ||||
3p22ter | CGH | ADH gain, 67% | Gain, 60% | [83] | |||
3q11-q21 | CGH | ADH loss, 11.1% | [35] | ||||
5p | CGH | Gain | Gain | Gain | [7] | ||
5p14 | CGH | ADH—high-level amplification | [7] | ||||
5q32-33.1 |
CSF1R
| CGH | ALH—gain | [84] | |||
6q | Chromosomal imbalance, CGH | ALH—gain, 36% | Gain, 22% | Gain, 2% | [86] | ||
6qter/D6S417 | LOH | ADH non-cancerous breast—6% ADH cancerous breast—9% | Non-comedo—17% Comedo—11% | [85] | |||
6g21ter | CGH | ADH—gain, 33.3% | Gain, 40% | Gain, 60% | [83] | ||
6q27-qter |
SEN6
| FISH, cytogenetic | ADH—large deletion present | [87] | |||
7p11.2-p11.1 | CGH | ALH—Loss, 83.3% | [84] | ||||
7p12-15 |
EGFR
| Microsatellite analysis | 30.0% | ADH of cancer subject—80% | 100.0% | 100.0% | [88] |
7p22-qter | CGH | ADH—high-level amplification | [7] | ||||
7q35ter | CGH | ADH—gain, 33.3% | Gain, 40% | [83] | |||
8p |
NRG1 (just distal to region)
| CGH | ADH—loss | Loss | Loss | [7] | |
8p/D8S339 | LOH | ADH with cancer—≥ 25% | ≥35% | [34] | |||
8p12-pter | CGH | ADH—Loss, 11.1% | [35] | ||||
8q | CGH | ADH—high-level amplification | [7] | ||||
8q21-qter | CGH | ADH—gain, 11.1% | [35] | ||||
8q24 |
MYC
| ADH—gain, 66.0% | Gain, 60% | Gain, 80% | [83] | ||
8q24 |
MTSS1; MYC
| AI | 0.0% | ADH—35% | 29% | 13%—37% | [89] |
9p/D9S157 | LOH | ADH non-cancerous breast—8% | Non-comedo—10% Comedo—11% | [85] | |||
9p21 | AI | 5% | ADH—8% | 16% | 11%–28% | [89] | |
10q25ter | CGH | ADH—gain, 33.3% | Gain, 40% | Gain, 80% | [83] | ||
10q26 | CGH | ADH-high-level amplification | [7] | ||||
11p15/D11S988 | LOH | ADH non-cancerous breast—15% ADH cancerous breast—38% | Non-comedo—18% Comedo—19% | [85] | |||
11p15 |
THO1
| LOH (proportion) | ADH with cancer—8% | 37% | 28% | [32] | |
11q12-13 | CGH | ADH—gain, 11.1% | [35] | ||||
11q13(PYGM) |
PYGM
| LOH | None | ADH—8.5% | 27.6% | [90] | |
11q13 |
INT-2 or PYGM
| LOH | ALH—10.5% | 33.3% | [91] | ||
11q13 | CGH | ADH—gain, 33.3% | Gain, 40% | Gain, 80% | [83] | ||
11q13.1 | AI | 0.0% | ADH—8% | 9% | 21%–30% | [89] | |
11q13/11q22-23/D11s1818, D11s1819 |
PYGM
| LOH (proportion) | ADH with cancer—11% | 35% | 57% | [32] | |
11q23.3 | AI | 4% | ADH—8% | 21% | 25%–50% | [89] | |
11q24ter | CGH | ADH—gain, 33.3% | Gain, 20% | Gain, 40% | [83] | ||
12p13-pter | CGH | ADH—high-level amplification | [7] | ||||
12q24 | CGH | ADH—gain, 33.3% | Gain, 20% | Gain, 80% | [83] | ||
13q11-22 | CGH | ADH—loss, 66% | Loss—100% | Loss—100% | [83] | ||
13q13/D13S137 | LOH | ADH non-cancerous breast—13% ADH cancerous breast—9% | Non-comedo—17% Comedo—13% | [85] | |||
13q32-q34 | CGH | ADH—high-level amplification | [7] | ||||
14q11.2-q12 | CGH | ADH—high-level amplification | [7] | ||||
14q24/D14S62 | LOH | ADH non-cancerous breast—none ADH cancerous breast—12% | Non-comedo—16% Comedo—18% | [85] | |||
14q32 | CGH | ADH—gain, 33.3% | Gain, 20% | Gain, 40% | [83] | ||
14q32.33 |
ATK1
| CGH | ALH- gain | [84] | |||
15q23-25 |
c-src -1
| CGH | ADH—gain, 67% | [83] | |||
15q25-qter | CGH | ADH—high-level amplification | [7] | ||||
15q26 | CGH | ADH—gain, 66.0% | Gain, 40% | Gain, 100% | [83] | ||
16p | Chromosome copy number, CGH | ALH—loss, 57% loss | Loss, 6% | Loss, 1%–13% | [86] | ||
16p | Chromosome copy number/CGH | ADH—gain, 33.3% | Gain, 80% | Gain, 100% | [83] | ||
16q | LOH | Atypical hyperplasia—50% | 71.4% | [92] | |||
16q |
CDH1
| LOH Mutation | ALH—7.7% ALH—frameshift mutation, 7.7% | [93] | |||
16q |
Matrix metalloproteinase 2, NME3
| CGH | ADH—loss, 33.3% | [83] | |||
16q | CGH | ADH—loss, 55.5% | [35] | ||||
16q | CGH | ALH—loss, 36% | Loss, 17% | Loss, 25%–67% | [86] | ||
16q |
CDH1, E2F4, WWOX
| CGH | ADH—loss | Loss | Loss | [7] | |
16q/D16S413 | LOH | Atypical ductal hyperplasia—55.6% | [94] | ||||
16q/D16S422 |
CDH13
| LOH | ADH with cancer—≥25% | ≥35% | [34] | ||
16q21-q23.1 |
CDH1
| CGH | ALH—loss, 25% | [84] | |||
16q21-24/D16s265, D16s402, D16s413, D16s512 | LOH (proportion) | 2% | ADH—52% | 63% | 78% | [32] | |
17p | CGH | ADH—loss 22.2% | [35] | ||||
17p |
P53
| CGH | ADH—loss | Loss | Loss | [7] | |
17p13/D17S796 | Close to P53 | LOH | ADH in normal adjacent to cancer—33.3% | 100% | 100% | [95] | |
17p13/D17S960 | P53 candidate gene | LOH | ADH non-cancerous breast—11% ADH cancerous breast—8% | Non-comedo—31% Comedo—37% | [85] | ||
17p13.1 |
TP53
| Microsatellite alterations | AH—16.6% | [33] | |||
17p13.1/D17s796, D17s525 |
TP53
| LOH (proportion) | ADH with cancer—6% | 42% | 59% | [32] | |
P53 |
TP53
| Mutations | ADH—mutations in 50% | [46] | |||
17p13.2/D17S796 | Within 2 cM of p53 | LOH | ADH—25.0% | [94] | |||
17q |
HER-2/neu, GRB7, TBX2, STARD3, MLN64/
CAB1, and ESTIMAGE68400
| CGH | ADH—gain | [7] | |||
17q11/NF1 | LOH | ADH non-cancerous breast—14% ADH cancerous breast—10% | Non-comedo—27% Comedo—15% | [85] | |||
17q21 | AI | 0.0% | ADH—7% | 30% | 19%–27% | [89] | |
17q21/D17S579 | Region of BRCA1
| MSI/LOH | AH—8.3% | [33] | |||
D17S8000 |
BRCA1
| LOH | ADH ≥25% | [34] | |||
20p11.2-p13 | CGH | ADH—high-level amplification | [7] | ||||
20q |
AIB1, TFAP2C, STK15
| CGH | ADH—gain | Gain | Gain | [7] | |
20q | Chromosomal copy number alterations/CGH | None | ADH –amplified 100% | 100% show amplification | 100% show amplification | [96] | |
20q13 | CGH | ADH—gain, 100% | Gain-100% | Gain, 100% | [83] | ||
20q13 region | Chromosomal copy number | None | ADH—amplified 100% | Amplified- 100% | Amplified, 100% | [96] | |
22q | CGH | ADH—gain 67% | Gain- 60% | Gain, 80% | [83] | ||
22q | Chromosomal imbalance/CGH | ALH—43% | Loss, 28% | 13%–20% | [86] | ||
22q11.1 | CGH | ALH—loss, 50% | [84] | ||||
Xp | CGH | ADH—loss | Loss | Loss | [7] | ||
Xq | CGH | ADH—gain | Gain | Gain | [7] |
Gene | Analysis | Gene function | Normal breast | Atypical hyperplasia | DCIS | Invasive carcinoma | References | |
---|---|---|---|---|---|---|---|---|
APC | MSP | Regulates myc and cyclin D1 expression, cell cycle entry and progression | Tissue invasion and metastases | 15% | 65% | 72% | 84% | [8] |
APC | MSP | Tissue invasion and metastases | 7% | ADH—27% | 34% | 38% | [43] | |
β-catenin (CTNNB1) | MSP | Regulates coordination of cell–cell adhesion and gene transcription | 10% | 19% | 34% | 44% | [8] | |
BRCA1 | Promoter methylation | Tumor suppressor gene, DNA repair, transcriptional regulation | Limitless replicative potential | 18% | 22% | 29% | [97] | |
CDH1 | Methylation | Epithelial cell–cell adhesion, suppresses invasion and metastasis | Tissue invasion and metastases | ALH—100.0% | 92.9% | [42] | ||
CDH1 | MSP | Tissue invasion and metastases | 15% | ADH—35% | 50% | 65% | [8] | |
Cyclin D2 | Methylation | Cell cycle regulation | Limitless replicative potential | Unmethylated | ADH—endoscopy, 16.7% ADH—ductal lavage, 30.0% | 28.6% | 50.0% | [98] |
Cyclin D2 | Methylation | Unmethylated normal breast | ADH—endoscopy, 16.7% | 33.3% | 42.1% | [98] | ||
Cyclin D2 | Methylation | Benign ductal lavage—6.7% | Atypia—ductal lavage, 30.0% | 100% | [98] | |||
DLEC1 | Methylation | 7% | ADH—33% | 37% | 40% | [43] | ||
ESR1 | MSP | Regulation of cell proliferation | Self-sufficiency in growth signals | 40% | ADH—48% | 34% | 51% | [8] |
14-3-3σ | MSP analysis | Cell cycle regulation | Limitless replicative potential | Unmethylated | 38% | 83% | 96% | [99] |
GRIN2B | Methylation | 0% | 3% | 23% | 32% | [43] | ||
GSTPI | MSP | Drug metabolism | 5% | ADH—10% | 16% | 19% | [8] | |
HIN-1 | Methylation | Tumor suppressor function, regulates cell cycle progression and apoptosis | Insensitivity to antigrowth signals | 3% | ADH—23% | 34% | 36% | [43] |
HOXA1 | Methylation | Regulates gene expression, morphogenesis, differentiation | 13% | ADH—43% | 80% | 76% | [43] | |
MINT17 | Methylation Index | 16% | 24% | 26% | 30% | [100] | ||
MINT31 | Methylation Index | 5% | 10% | 21% | 13% | [100] | ||
MTIG | MSP | 0% | ADH—7% | 14% | 32% | [43] | ||
p16INK4A
| Methylation | Cell cycle regulation | Limitless replicative potential | 7.5% (UDH) | 35.0% | Low grade, 50% High grade, 66% | Low grade, 71.4% High grade, 75.0% | [101] |
p16INK4A (TSG) | Methylation (MethyLight) | Usual ductal hyperplasia, 7.5% | 35.0% | Low grade, 50.0% High grade, 68.2% | [102] | |||
p16INK4A (TSG) | Percentage methylated (MethyLight) | Tumor suppressor gene | Normal breast/UDH, 7.5% | 35.0% % | Low grade, 50.0% High grad, 66.7% % | 75.0% | [101] | |
p16INK4A (TSG) | IHC protein expression | Normal breast/UDH, 80.0% | 47.5% | Low grade, 33.3% High grade, 30.6% | 18.8% | [101] | ||
RASSF1A | Methylation | Regulates cell cycle, apoptosis | Self-sufficiency in growth signals | 40% | 77% | 89% | 76% | [43] |
RASSF1A | Methylation Index | 39% | 67% | 79% | 76% | [100] | ||
RARβ | MSP | Cell cycle arrest, growth inhibition, apoptosis | Limitless replicative potential | 7% | ADH—7% | 31% | 26% | [43] |
RARβ | Methylation Index | Limitless replicative potential | 16% | 29% | 28% | 22% | [100] | |
RARβ | Methylation | Limitless replicative potential | Unmethylated | ADH—endoscopy, 33.3% ADH—ductal lavage, 30.0% | 50% | 34% | [98] | |
RARβ | Methylated | Tumor suppressor gene | Normal breast tissue, unmethylated | ADH—endoscopy, 33.3% | 14.3% | 60.0% | [98] | |
RARβ | Methylation | Benign breast—4.4% | Atypia—ductal lavage, 30.0% | 100.0% | [98] | |||
SFRP1 | Methylation | 13% | 3% | 26% | 46% | [43] | ||
SFRP4 | Methylation | 0% | ADH—7% | 6% | 18% | [43] | ||
TIMP3 | MSP | Inhibit metalloproteinases, tissue remodeling and tumor cell progression | Tissue invasion and metastases | 45% | ADH—62% | 44% | 56% | [8] |
TMEFF2 | Methylation | 40% | ADH—47% | 86% | 76% | [43] | ||
Twist | Methylation | Modulates p53 | Evading apoptosis | ADH endoscopy—20% methylated ADH—ductal lavage, unmethylated | 28.6% | 42% | [98] |
Gene | Alteration/analysis | Function | Normal breast | Atypical hyperplasia | DCIS | Invasive carcinoma | References |
---|---|---|---|---|---|---|---|
Cox-2 | IHC | ALH—61.4% ADH—23.0% ADH + ALH—53.9% | [103] | ||||
Cyclin A | ISH | Cell cycle regulation, binds and activates CDK2 and CDK1 kinases, and promotes both cell cycle G1/S and G2/M transitions | Benign breast tissue—35.3% | ADH—62.5% | 42.1–46.4% | 77.8% | [104] |
Cyclin D1 | IHC | Normal breast—11.7% PDWA—25.0% | ADH—39.4% | 43.6–47.9% | 48.3% | [105] | |
Cyclin D1 | Gene amplification | Normal breast—15% | 27% | 35% | 25% | [106] | |
Cyclin D1 | IHC | Normal breast—13% | 57% | 50% | 64% | [106] | |
Cyclin D2 | Methylation | A regulatory subunit of CDK4 or CDK6, whose activity is required for cell cycle G1/S transition; involved in the phosphorylation of tumor suppressor protein Rb | Unmethylated normal breast tissue | ADH—endoscopy, 16.7% methylated | 33.3% | 42.1% | [98] |
Cyclin D2 | Methylation | Benign ductal lavage—6.7% | Atypia—ductal lavage, 30.0% methylated | 100.0% | [98] | ||
EGFR (HER-1) | IHC | Regulate cell growth, differentiation, and survival | Non-proliferative—21% | Epithelial hyperplasia with atypia—60% | [79] | ||
EZH2 | IHC | Transcriptional repression | Normal breast—0.0% | ADH without DCIS—10% ADH with DCIS—40.0% | 45% | [52] | |
FHIT | IHC/H-score | Controls proliferation and apoptosis | Normal adjacent to cancer, strong and uniform, 100%; 2.95/3.0 | Loss of FHIT protein vs normal | Marked loss of FHIT protein, 75% | Marked loss of FHIT protein, 54%; 0–1.0/3.0 | [107] |
FHIT | mRNA | Normal adjacent to ADH, 86% | 71% | 45% | 29% | [108] | |
FHIT | Western blot | 82% Normal adjacent to AH | 57% | 45% | 27% | [108] | |
HER-2/neu | Amplification FISH | Normal adjacent to ADH, no amplification | ADH—53.8% amplified | 95.5% amplified | 100% amplified | [109] | |
HER-2/neu (C-erbB-2) | IHC | Non-proliferative—15% | Epithelial hyperplasia with atypia—40% | [79] | |||
HER-2/neu (C-erbB-2) | IHC | Ductal hyperplasia without atypia—13.3% | Atypia (mild—severe), 30–56.6% | 31.9% | 17.8% | [110] | |
Myc | IHC | Benign lesions, 31% | 66.7% | 45% | 66.7% | [111] | |
P53 | Sequencing, mutations | ADH—28.6%, insertion, deletion | 34.1% | [45] | |||
P53 | Mutation-gel elect | ADH—1 case | 31.5% | 55.7% | [47] | ||
P53 | SSCP, sequencing; mutation | Normal adjacent to cancer, no mutations | ADH—50% (not adjacent to cancer) | 50% | [46] | ||
RB | IHC | Normal breast, weak staining | ADH, mod/strong—11% | Mod/strong—64% | Mod/strong—47% | [112] | |
Stat3 | IHC | Regulates genes that are involved in cell growth and division, cell movement, and apoptosis | Normal breast, 12.8% | ADH, 30.0% ADH adjacent to breast cancer, 31.15% | [113] | ||
Stat5 | IHC | Normal breast, 17.1% | ADH—31.65% | [113] | |||
Telomere, anaphase bridges | FISH | ADH—16.7% | 18.2% | [114] | |||
Telomerase activity | TRAP signal | Benign breast disease, 14.0% | Atypical hyperplasia, 100%, focal high expression | 92% strong | 94% strong | [115] | |
Telomerase | Human telomerase gene (hTR) | Simple hyperplasia, 16.6% | ADH mild—22% ADH moderate—33.3% ADH severe—60.9% | 85.7% | 91.7% | [116] | |
Telomerase | Human reverse transcriptase gene (hTRT) | Simple hyperplasia, 0.0% | ADH mild—11.1% ADH moderate—25.0% ADH severe—52.1% | 78.6% | 83.3% | [116] | |
α-tubulin | mRNA expression-percent positive | Structural components of centrosomes | Normal breast, 33.3% | ADH—62.5% | 82.5% | 77.5% | [49] |
α-tubulin | Protein expression | Normal breast, 31.7% | ADH—65% | 86.3% | 87.5% | [49] | |
α-tubulin | DNA copy number | Normal breast, 2.05 | ADH—4.31 | 5.54 | 5.15 | [49] | |
Centrosome abnormality-frequency | Normal breast, 0% | ADH—30% | 52.5% | 70.0% | [49] | ||
γ-tubulin | mRNA expression-percent positive | Normal breast, 30.0% | ADH 57.5% | 85.0% | 82.5% | [49] | |
γ-tubulin | Protein expression | Normal breast 35.0% | ADH—58.8% | 86.3% | 85.0% | [49] | |
Ki67 | IHC | Normal breast, 1.5% PBBD without atypia, 3.5% | PBBD with atypia, 16% | Non-high-grade, 6.1% High grade, 17.3% | [54] | ||
Ki67 | IHC | Normal breast, 0.1% Usual hyperplasia, 3.3% | ADH—8.2% | 8.7% | 21.1% | [117] |