In hepatocellular carcinoma (HCC), studies from Ito et al.1
indicated that 14 of 20 (70%) HCC tissues showed nuclear staining of survivin, whereas non-tumor tissues showed little survivin staining. Nuclear survivin expression strongly correlated with the proliferation index.1
Similarly, studies from Moon et al.4
showed that 22 of 35 (63%) survivin-positive specimens (total = 47) showed punctate nuclear staining in HCC cells. In contrast, nonmalignant hepatocytes showed only cytoplasmic staining. HCC specimens with nuclear survivin expression showed the highest PCNA (proliferating cell nuclear antigen) labeling index and correlated with tumor cell de-differentiation.4
Recently, Fields et al.8
reported that immunohistochemical analyses of 72 hepatocellular carcinoma by tissue microarray indicated 43% frequency of nuclear survivin expression, which correlated with nuclear grade, microvascular invasion, mitotic rate, MIB-1 index, local recurrence and diseasefree survival. These observations are consistent with the previous finding that survivin interacts with Cdk4 in (growing) HCC cell lines,1
which leads to the nuclear translocation of survivin.21
Overexpression of survivin resulted in a decrease in the G0
phase and an increase in the S-phase.1
Blocking nuclear transport suppressed survivin nuclear translocation and S-phase shift.21
These studies suggest that nuclear translocation of survivin might be a prerequisite for cancer cell proliferation whereas the cytoplasmic presence of survivin may be associated with cell survival but not cell proliferation. It should be pointed out that the IHC images provided in the study by Moon and Tarnawski4
for nuclear or cytoplasmic expression of survivin seem to be convincing.
In esophageal squamous cell carcinoma (SCC), nuclear expression of survivin was detected in 67 of 84 (80%) specimens.2
The mean patient survival (28 months) for this group was significantly less than that for patients without survivin expression in the tumor cell nuclei (108 months). In contrast, the tumors with cytoplasmic survivin staining had no prognostic significance.2
Whether the latter conclusion was derived from the 7 specimens with only cytoplasmic staining of survivin or from all the 53 specimens with cytoplasmic staining of survivin (46 of 53 with both) is not clear in the study. We should mention that one is unable to appreciate the nuclear or cytoplasmic staining of survivin because the IHC images are in a black and white format.
In ovarian carcinoma, Cohen et al.3
reported that 36 of 49 (74%) specimens showed nuclear expression of survivin, which correlated significantly with high tumor grade, histologic type and mutant p53, but not with disease-free survival. We should mention that the nuclear staining of survivin provided in the IHC images is convincing. Recently, however, Tringler et al.
immunohistochemically analyzed 15 cystadenomas, 15 borderline tumors and 12 cystadenocarcinomas of the ovary. Eighty-seven percent of adenomas/borderline tumors showed survivin-positivity in the nucleus but only 42% for carcinomas, which is statistically significant. This observation suggests that nuclear localization of survivin is more common in benign or borderline tumors than in malignant serous tumors of the ovary.9
In mantle cell lymphoma (MCL), Martinez et al.5
reported that 80 specimens examined showed 5–95% of nuclear survivin expression. Selected MCL cell lines and tumor specimens were used for the confirmation of survivin localization by Western blot as well. The nuclear expression level of survivin was significantly associated with proliferative activity; overall patient survival was significantly shorter in patients with high survivin expression in the cell nucleus.5
It should be emphasized that the results from Martinez et al.5
are not only confirmed by Western blots but the IHC images provided in the study are also convincing.
In gastroenteropancreatic neuroendocrine tumor (GEP-NET), Grabowski et al. (personal communication) found that among 104 GEP-NET patients, 29 patients with localized well-differentiated GEP-NETs without recurrence or tumor-associated deaths, survivin was not expressed in tumor cell nuclei. In contrast, 15 of 60 (25%) patients with advanced metastatic GEP-NETs expressed survivin in cancer cell nuclei (Dr. Hans Scherubl et al., personal communication). Those 15 patients had a statistically significant worse prognosis (survival of 8 vs. 115 months). Their results suggest that nuclear survivin expression was inversely correlated with tumor differentiation and grade. Although 44 of 47 well-differentiated tumors were nuclear survivin-negative, 12 of 13 undifferentiated tumors were nuclear survivin-positive (Dr. Hans Scherubl et al., personal communication).
In non-small cell lung cancer (NSCLC), immunohistochemistry analyses of 48 cancer samples showed 32 cases (67%) with nuclear survivin-positivity, 39 cases (83%) with cytoplasmic survivin-positivity and 19 cases (44%) with survivin-positive staining in both cytoplasm and nucleus. These authors found that nuclear survivin expression was significantly associated with poor survival, whereas cytoplasmic staining of survivin was not.7
They proposed that nuclear presence of survivin might be an important prognostic marker for patients with NSCLC.
In cholangiocarcinoma, Javle et al.6
reported that among 24 consecutive cases of cholangiocarcinoma, cytoplasmic survivin was detectable in 13 cases and nuclear survivin in 11. Among these, strong (>50% of cells positive) cytoplasmic survivin expression was seen in 6 cases and strong (>50% of cells positive) nuclear expression of survivin in 4. Patients with strong nuclear survivin had a median survival of 11 months, which was significantly lower than that for patients with weak nuclear survivin expression (20 months, p