Table I.
Summary of studies included in the present literature review.
| Author, date | Total patients, n | Histological types | Antibody | Quantification of expression | Results | (Ref.) |
|---|---|---|---|---|---|---|
| Saito et al, 2007 | 51 | AA, 19; GBM, 32 | Goat polyclonal anti-survivin (Santa Cruz Biotechnology, Inc., Dallas, TX, USA; dilution 1:100) | Nuclear and cytoplasmic staining were evaluated. ≥1,000 tumor cells were counted/sample in randomly selected fields (magnification, ×400). +ve, >5% cells immunopositive; −ve, ≤5% immunopositive. +ve samples classified as follows: Nuclear +ve; cytoplasmic +ve; and nuclear/cytoplasmic +ve. | Immunoreactive cases, 51/51 (100%): Cytoplasmic, 23 cases (45%); nuclear, 10 cases (20%); both, 18 cases (35%). Localization survivin vs. Ki67/MiB-1 expression, P=0.6798; survivin nuclear +ve vs. cytoplasmic +ve, P=0.796; nuclear/cytoplasmic group survival time was shorter vs. nuclear or cytoplasmic alone (P=0.0001); survivin localization (nuclear/cytoplasmic vs. nuclear or cytoplasmic alone) associated with OS (P<0.001). | (9) |
| Xie et al, 2006 | 56 | Primary GBM, 30; secondary GBM, 26 | Rabbit polyclonal anti-survivin (catalog no., NB-500-201 K3; Novus Biologicals LLC, Littleton, CO, USA; dilution, 1:300; cytoplasmic detection); rabbit polyclonal anti-survivin (catalog no., sc-10811; Santa Cruz Biotechnology, Inc.; dilution, 1:400; nuclear | Staining was evaluated semi-quantitatively. Staining score was obtained as the proportion of immunopositive cells: -, negative; +, staining in <25% cells; ++, staining in 25–50%; +++, staining in 51–75%; ++++, staining >75%. detection) | Immunoreactive cases: Cytoplasmic, 37/56 cases (66%); nuclear, 43/56 cases (77%). Survivin-C expression in primary vs. secondary GBM, 83% vs. 46% (P<0.001); survivin-N expression primary vs. secondary GBM, 73% vs. 81% (P=0.51). Overall expression of cytoplasmic and nuclear survivin in 15 cases was concordant between precursor lesion vs. secondary GBM; expression level of survivin-C was higher in secondary GBM, no difference in survivin-N. Survivin-N vs. clinicopathological features, P>0.05; survivin-C vs. tumor size, P<0.01; survivin-C vs. other clinico-pathological features, P>0.05; mean progression time (months) between precursor lesion and secondary GBM was shorter in cytoplasmic +ve vs. −ve cases (P<0.05); survivin-C vs. AI, P<0.001; survivin-N vs. AI, P>0.05. | (10) |
| Shirai et al, 2009 | 66 | GBM, 66 | Anti-survivin antibody (Novus Biologicals LLC; dilution, 1:300) | Cell nuclei and cytoplasms of >500 cells evaluated. Nuclear and cytoplasmic survivin scores evaluated with cell positivity and SI: 0, no staining; 1,<50% of cell positivity and any intensity; 2, >50% of cell positivity and weak to moderate intensity; 3, >50% cell positivity and strong intensity. | Immunoreactive cases: Cytoplasmic, 58/66 (87.9%); nuclear, 47/66 (71.2%). Survivin-C score of 0, 8 patients (12.1%); 1, 47 patients (71.2%); 2, 6 patients (9.1%); 3, 5 patients (7.6%); survivin-C not associated with prognosis. Survivin-N score of 0,19 patients (28.8%); 1, 26 patients (39.4%); 2, 9 patients (13.6%); 3, 12 patients (18.2%); 3-year OS rate of survivin-N lower for score 3 vs. 2 (P=0.0003); survivin-N +ve predictor of OS (P=0.003; multivariate analysis). | (11) |
| Jung et al, 2012 | 62 | GBM, 62 | Anti-survivin (Lab Vision Corp, Fremont, CA, USA; catalog no., MS-1202; dilution, 1:25; microwave; cytoplasmic/nuclear detection) | SI score (0, −ve; 1, weak, but detectable; 2, moderate; 3, strong) and percentage of immunoreactive stains were automatically analyzed by Tissue Mine. H-score = Sum of percentages of positively stained cells × weighted staining intensity. | Immunoreactive cases: uncertain. Hierarchical clustering of the patients into two groups; no significant difference in clinical characteristics, but difference in survival rate. Survivin-N identified as 1/10 proteins whose expression was significantly different between the two groups (P=0.0295; Student's t-test). | (12) |
| Zhen et al, 2005 | 83 | PA, 17; DA, 16; EPAII, 5; OAII, 4; AA, 11; OAIII, 4; EPA, 3; GBM, 12; MB, 9; NB, 2. | Goat polyclonal anti-survivin (Santa Cruz Biotechnology, Inc.; dilution, 1:100) | IRS = percentage of survivin +ve cells (0, <1%; 1, 1–25%; 2, 26–50%; 3, 51–75%; 4, >75%) × SI (0, no staining; 1, weak; 2, moderate; 3, strong). | Immunoreactive cases, 48/83 (57.8%); IRS in 83 cases, 3.75±3.89. IRS by WHO grade: Grade I, 1.29±2.62; grade II, 2.56±3.44; grade III, 4.78±3.89; grade IV 6.04±3.78. Survivin IRS grade I vs. grade III, P=0.023; grade II vs. grade IV, P=0.011; grade I vs. grade IV, P<0.001. Survivin IRS associated with PCNA PI (P<0.001). PCNA PI was higher in survivin +ve groups (P<0.001). AI expression in survivin +ve vs. −ve groups, P=0.108; survivin was inversely associated with AI (P<0.001). Overall daily growth significantly higher in survivin +ve vs. −ve group (P=0.001), with +ve association with survivin IRS (P<0.001). | (13) |
| Liu et al 2006 | 102 | DA, 19; AA, 16; GBM, 43; NBT, 24 | Rabbit polyclonal anti-survivin (catalog no., BIRC5; R&D Systems, Inc., Minneapolis, MN, USA; dilution, 1:500) | Cytoplasmic and nuclear staining were scored separately. Survivin-C, 0–3 scoring used (combined intensity and extent of cells stained). Survivin-N LI: +ve cells in 1,000 tumor cells starting from the highest labeling region. | Immunoreactive cases: uncertain. Mean value survivin-C: DA, 0.7±0.9; AA, 0.7±0.6; GBM, 1.4±0.9. Mean value survivin-N: DA, 0.6±0.7; AA, 2.5±2.5; GBM, 7.2±6.4. Survivin-C: DA vs. AA, P=0.0678; DA vs. GBM, P=0.0233; AA vs. GBM, P=0.0216. Survivin-N: DA vs. AA, P=0.0030; DA vs. GBM, P=0.0001; AA vs. GBM, P=0.0241. Survivin-C and survivin-N vs. tumor grade, P=0.028 and P<0.0001, respectively. Survivin-C vs. Ki67/MiB-1, P=0.0298; survivin-N vs. Ki67/MiB-1, P<0.0001. | (14) |
| Habberstad et al, 2011 | 27 | AA, 27 | Rabbit monoclonal anti-survivin (clone, EP2880Y; Abcam, Cambridge, MA, USA; dilution, 1:250) | LI = percentage of immunoreactive cells/total cells. Determined by counting ≥1000 tumor cells or 3 HPFs. | Immunoreactive cases: 27/27 (100%). Survivin located in cytoplasm and nucleus; only nuclear positivity was recorded. Survivin associated with mitotic activity (P=0.010), Ki67/MiB-1 (P<0.001) and other markers [pHH3, mitosin and DNA topoisomerase IIα (P<0.05)]. Survivin not associated with survival (P>0.05). | (15) |
| Huang et al, 2011 | 91 | DA, 25; AA, 17; GBM, 31; NBT, 18 | Rabbit polyclonal anti-survivin (R&D Systems, Inc.; dilution, 1:600) | Survivin-N LI: Positively stained nuclei in 1,000 cells. Survivin-N characterized into two groups: <3% stained nuclei or ≥3% stained nuclei. | Immunoreactive cases: DA, 10/25 (40.0%); AA, 9/17 (52.9%); GBM, 25/31 (80.7%); NBT, 0/18 (0%). Survivin-N significantly higher in GBM (10.3±5.3) and AA (3.1±2.2) vs. DA (1.6±2.3) (P<0.001). Survivin-N was a prognostic factor in disease-specific survival (log rank, P<0.001; Cox regression analysis, P=0.023) and in progression-free survival (log rank, P<0.001; Cox regression analysis, P=0.032). | (16) |
| Medina Villaamil et al, 2011 | 26 | PA, 1; DA, 5; GBM, 5; GC, 11; RG, 6 | Mouse monoclonal IgG2a survivin (clone, D-8; Santa Cruz Biotechnology, Inc.; dilution, 1:100) | IRS = percentage of +ve cells (0, <1%; 1, 1–25%; 2, 26–50%; 3, 51–75%; 4, >75%) × SI (1, weak; 2, moderate; 3, strong). | Immunoreactive cases: PA, 0/1 (0%); DA, 0/5 (0%); GBM, 1/5 (20%); GC, 2/11 (18%); RG, 0/6 (0%). No significant difference in expression of survivin among the tissue samples (P>0.05). | (17) |
| Mellai et al, 2008 | 20 | GBM, 20 | Rabbit polyclonal anti-survivin (catalog no., NB-500-201 K3; dilution, 1:500; Novus Biologicals LLC) | LI (each area) = percentage of positively stained cells in ≥1,000 cells. | Immunoreactive cases: 20/20 (100%). Survivin variably stained nuclei in viable areas; cytoplasmic staining inconstant and irregular, so nuclear staining considered for comparative evaluation. SI lower for survivin expression vs. Ki67. Positive association survivin vs. Ki67/MiB-1 (P=0.0001). No inverse association with AI (P=0.1547). No association with survival. | (18) |
| Preusser et al, 2005 | 104 | GBM, 104 | Rabbit polyclonal anti-survivin (clone, FL-142; catalog no., sc-10811; Santa Cruz Biotechnology, Inc.; dilution, 1:300) | Fraction of labeled tumor cell nuclei expressed as a percentage; 500 tumor cell nuclei were evaluated per specimen in fields with the highest density of immunopositive nuclei. Cut-off for survivin, ≤/>14. | Immunoreactive cases: 104/104 (100%). No survivin expression in NBT; faint cytoplasmic expression in some cells. Survivin index range, 2.4–44.0%. Association survivin index vs. Ki67/MiB-1 and DNA topoisomerase IIα (P<0.0001). Survivin did not associate with AI (P=0.498) or OS (P=0.6368). In survivin expressing cells, 91.08% co-expressed Ki67, and 58.85% of Ki67/MiB-1 expressing cells co-expressed survivin. | (19) |
| Preusser et al, 2005 | 63 | EPAII, 44; EPAIII, 19 | Polyclonal rabbit anti-survivin (clone, FL-142; catalog no., sc-10811; dilution, 1:300; Santa Cruz Biotechnology, Inc.) | Fraction of labeled tumor cell nuclei expressed as a percentage; 500 tumor cell nuclei evaluated in fields with highest density of immunopositive nuclei. Median cut-off value: Low (≤6.4%) and high (>6.4%) survivin expression. | Immunoreactive cases: 63/63 (100%). Faint cytoplasmic expression in a few tumor cells. Expression: Overall, 0.6–43.2%; grade II, 0.6–35.8%; grade III, 2.8–43.2%. Mean survivin-expressing nuclei co-expressing with Ki67, 92.2%; mean Ki67-expressing tumor cell nuclei co-expressing survivin, 62.9%. Ki67/MiB-1 index higher vs. survivin index (P<0.001). Increased survivin associated with grade III (P=0.003). Survivin index associated with Ki67/MiB-1 and DNA topoisomerase IIα (P<0.001). Survivin index associated with OS (P=0.0032; univariate analysis, but not independent prognostic factor in multivariate analysis). | (20) |
| Ridley et al, 2008 | 65 | EPAII/III, 65 | Rabbit polyclonal anti-survivin (catalog no., sc-10811; Santa Cruz Biotechnology, Inc.; dilution, 1:1,000) | LI = percentage of immunopositive tumor cell nuclei exhibiting nuclear staining / total number cells evaluated. Tumors were categorized into low (≤1%), intermediate (2–4%) and high (≥5%) survivin expression levels. | Immunoreactive cases: 65/65 (100%). Mean LI, 1.1%; median LI, 0.5% (range, <1–6%). Low expression, 51 tumors (79%); intermediate expression, 11 (17%); high expression, 3 (4%). Survivin clearly associated with Ki67/MiB-1 (P<0.001). Survivin had no prognostic value (OS, P=0.110; EFS, P=0.360). Increased LI survivin associated with grade III tumors (P<0.001). | (21) |
| Kogiku et al, 2008 | 99 | LGA, 18; AA, 34; GBM, 47 | Produced own antibody; see Uematsu et al (17) | Survivin index = percentage immunostained cells per 200 cells in 5 fields of view. Low index, ≤50% cells stained; high index, >50% cells stained. | Immunoreactive cases: uncertain. Antiserum detected cytoplasmic and nuclear survivin. Survivin associated with prognosis (P<0.0001; univariate analysis). Median survival shorter for high vs. low index (P<0.0001). Survivin was a predictor of survival in high- (grade IV, P=0.0207) and low-grade (grades II and III, P=0.0004) glioma. Survivin remained significant in the multivariate analysis (P<0.0269). Survivin index associated with age (P=0.0017), KPS score (P=0.0006), tumor grade (P=0.0002) and Ki67/MiB-1 (P=0.0002) Survivin was not associated with EGFR (P=0.0573). | (22) |
| Rousseau et al, 2006 | 15 | Gangliogliomas, 15 | Polyclonal anti-survivin (Novus Biologicals LLC; dilution, 1:500) | Evaluated using LI. Proportion of immunoreactive cells for survivin was quantified as a percentage of the neoplastic glial component. | Immunoreactive cases: 6/15 (40%). Survivin detected only in glial cells. Relapsing lesions were all (5/5) immunopositive (2 originally not immunoreactive). No detectable survivin/<1% immunoreactivity in 11/14 tumors (all low-grade). Gangliogliomas (n=5), >5% immunopositive cells: 4, malignant; 1, relapsing low-grade. Immunopositivity for survivin increased with the Ki67/MiB-1 LI. | (23) |
| Uematsu et al, 2005 | 29 | DA, 9; AA, 12; GBM, 8 | Prepared own antiserum: Polyclonal anti-survivin (dilution, 1:250). Obtained from human neuroblastoma using RT-PCR with specific primers | Survivin index = percentage of immunostained cells per 200 cells in 5 fields per section. Low survivin, ≤80%; high survivin, >80%. | Immunoreactive cases: 29/29 (100%). Survivin undetectable around gliosis and in NBT. Mean % immunoreactive cells: DA, 70.0%; AA, 81.3%; GBM, 85.0%. Increase in survivin +ve cells inversely associated with OS time (P=0.049). Survival time shorter for patients with a high expression vs. low expression (P=0.003). No association between survivin and Ki67/MiB-1 (P=0.065). Difference between survival time in DA and AA patients with high vs. low survivin index (P=0.007). Survivin associated with survival (P=0.036; multivariate analysis). | (24) |
| Lin et al, 2012 | 154 | PA, 23; DA, 21; AA, 48; GBM, 62 | Goat polyclonal anti-survivin (clone, c-19; Santa Cruz Biotechnology, Inc.; diluted in 0.1M PBS, 1:200) | For each slide, 10 HPFs were randomly picked for quantification. Survivin IRS (0, −ve; 1–3, weak; 4–12, moderate-strong) was determined by multiplication of SI (0, no staining; 1, weak staining; 2, moderate staining; 3, strong staining) and percentage of +ve tumor cells (0, <1%; 1, 1–25%; 2, 26–50%; 3, 51–75%; 4, >75%). Survivin expression divided into two groups: 1, IRS ≥3; 2, IRS ≤2. | Immunoreactive cases: uncertain. Survivin IRS: Non-neoplastic brain parenchyma, 0.15±0.03; PA, 0.54±0.11; DA, 0.66±0.08; AA, 2.56±0.17; GBM, 4.78±0.26. Median IRS, 3.02±0.48. Survivin expression increased with pathological grade. Survivin was not a significant predictor of survival (P=0.089; multivariate analysis). | (25) |
| Okada et al, 2008 | 27 | BSG, 15; NBSG, 12 | Goat polyclonal anti-survivin (clone, c-19; Santa Cruz Biotechnology, Inc.; dilution, 1:100 in 1% BSA) | +ve staining (+) = definite, but moderate, staining in the tumor. Strong +ve staining (2+), intense immunoreactivity. | Immunoreactive cases: BSG, 8/15 (53.3%); NBSG, 8/12 (66.6%). No association tumor grade vs. survivin expression. | (26) |
| Yeung et al, 2013 | 32 | Pediatric EPA, 19; adult EPA, 13 | Rabbit polyclonal anti-survivin (clone, FL-142, Santa Cruz Biotechnology, Inc.; dilution, 1:200) | Negative (0), no staining or staining equaling background intensity in NBT; moderate (1), definite staining above background intensity in tumor; strong (2), intense immunoreactivity. | Immunoreactive cases: Pediatric, 18/19 (95%); adult, 13/13 (100%). Pediatric results: WHO grade I, 3/19 cases had an SI of 1; grade II, 5/19 and 3/19 cases had SI of 1 and 2, respectively; grade III, 1/19, 3/19 and 4/19 cases had SI of 0, 1 and 2, respectively. Adult results: WHO grade I, 1/13 and 2/13 cases had SI of 1 and 2, respectively; grade II, 7/13 and 3/13 cases had SI of 1 and 2, respectively. No association survivin expression vs. age, gender, location or Ki67. | (27) |
AA, anaplastic astrocytoma; AI, apoptotic index; BSG, brainstem glioma; DA, diffuse astrocytoma WHO grade II; EGFR, epidermal growth factor receptor; EPA, ependymomas; GBM, glioblastoma; GC, gliomatosis cerebri; HPF, high-power field; IRS, immunoreactivity scores; KPS, Karnofsky Performance Scale; LGA, low-grade astrocytoma; LI, labeling index; MB, medulloblastomas; NB, neuroblastomas; NBSG, non-brainstem glioma; NBT, normal brain tissue; OA, oligodendroglioma; OS, overall survival; PA, pilocytic astrocytoma; PCNA PI, proliferating cell nuclear antigen proliferation index; pHH3, mitosis-specific antibody anti-phosphohistone-H3; RG, reactive gliosis; RT-PCR, reverse transcription-polymerase chain reaction; SI, staining intensity; Survivin-C, cytoplasmic survivin; Survivin-N, nuclear survivin; WHO, World Health Organization; +ve, positive; −ve, negative.