The Ki-67 proliferation antigen in meningiomas. Experience in 600 cases

Summary. Background. Meningiomas are mostly benign tumours that can be cured by surgical resection. Because meningiomas tend to recur, long term management in patients with subtotal tumour resection remains controversial. Previous studies have shown that the proliferation potential of meningiomas by Ki-67 labelling indices (LI) might predict their natural history. The purpose of this study was to analyse the reliability of Ki-67-labelling index in predicting the behaviour of meningiomas, and to help the neurosurgeon in establishing better follow up criteria and long term management strategies for these patients. Method. From 1990 to 2000 1328 meningiomas have been operated in our Neurosurgical Department. A total of 600 tumours were examined immunohistochemically using the Mib-1 monoclonal antibody. Clinical charts of the patients including surgical, histological and follow up records, as well as imaging studies were analysed retrospectively. Ki-67 LI were correlated with neuroradiological findings, 3D volumetric studies, histological subtype, recurrence-free survival, grade of resection, consistency of tumour tissue, location, osseous involvement, en plaque appearance, vascularity and progesterone-receptor status. Findings. Among the 600 patients analysed, there were 66% females (mean LI 3.8%) and 34% males (mean LI 5.7%), including 20 neurofibromatosis-type-2 (NF-II) patients with a mean LI of 5.2%. Histological grading revealed 91% WHO°I meningiomas (mean LI 3.28%), 7% WHO°II (mean LI 9.95%) and 2% WHO°III (mean LI 12.18%). Labelling indices in recurrent meningiomas increased from initial resection to a fourth local resection. A significant correlation between negative progesteron-receptor status and high tumour vascularity with high Ki-67 LI was seen. Ki67 was not a statistically significant predictor of survival time in totally excised WHO°I meningiomas. Interpretation. Mib-1 is one important tool in addition to routine histological evaluation, but a combination of clinical factors and particularly the extent of surgical resection, along with the biological features of the tumour, should influence the decision of the neurosurgeon to the patient follow up.     

Immunohistochemical study of p53 and Ki-67 antigen expression in bladder carcinoma]

We examined the relationship between the expression of mutant p53 and Ki-67 antigens in urinary bladder transitional cell carcinoma and the pathological and clinical findings. Tissues were obtained from 28 patients with bladder carcinoma who underwent total or partial cystectomy. An ABC immunostaining method and two primary antibodies (DO-7 and MIB-1 antibodies) were used. The percentages of p53 and Ki-67 antigen-positive cells to the total number of cells were regarded as the p53 and Ki-67 labeling indices (LI) respectively. There were no statistically significant correlations between p53 LI and the histological grade or stage, although p53 LI increased slightly in the high grade and high stage group. There was a statistically significant correlation between Ki-67 LI and the histological grade and stage (p < 0.05). The correlation between p53 LI and Ki-67 LI was linear. Some cases had a p53 LI below the mean even though the Ki-67 LI was higher. The clinical course was characteristic of superficial bladder carcinoma initially, but progressed to invasive bladder carcinoma over the next several years. These results suggest that even cases initially diagnosed as superficial bladder carcinoma with a low p53 LI may progress to invasive bladder carcinoma in subsequent years. Therefore, it is important that the patient be followed-up.     

P27Kip1 and Ki-67 expression analysis in transitional cell carcinoma of the bladder

P27^Kip1 protein is a cell cycle inhibitor which blocks the transition of cells from G1 to S phase, while Ki-67 is the most specific marker of proliferative activity. Both proteins are independent predictors of clinical outcome in various neoplasms. The aim of the study was to assess the prognostic value of p27^Kip1 and Ki-67 expression in urothelial bladder tumours. P27^Kip1 and Ki-67 expressions were evaluated immunohistochemically in archival samples of 45 superficial and 26 invasive transitional cell carcinomas obtained by a transurethral resection. In the patients with superficial tumours, disease-free survival (DFS) was positively influenced by good histological differentiation as well as by concurrent high p27^Kip1 and low Ki-67 expression. Multivariate analysis has confirmed that tumour grade and p27^Kip1/Ki-67 status were independent predictors of DFS (p=0.028 and p=0.029, respectively). P27^Kip1 or Ki-67 expressions did not influence overall survival. We conclude that a variable combined of p27^Kip1 and Ki-67 expressions is a better predictor of DFS in superficial bladder tumours than either protein alone.     

PCNA and Ki-67 as Prognostic Markers in Human Parathyroid Carcinomas

Background: It is widely accepted that histological diagnosis of parathyroid tumors is established with great difficulty. Carcinomas cannot be reliably separated from adenomas by histology alone. In this study, immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and Ki-67 was determined in 10 cases of parathyroid carcinomas, labeling indices (LIs) were calculated, and the results were correlated with the clinical outcomes.Methods: Ten cases of formalin-fixed, paraffin-embedded tissue with surgically resected parathyroid carcinoma were used. Immunohistochemical staining for PCNA and Ki-67 was performed and the LIs were calculated. We also examined whether LI could become a useful marker for parathyroid carcinomas.Results: Although nine patients with minimally invasive growth without recurrence of the tumor showed a low LI for both markers, one patient with a widely invasive neoplasm, and who died, had a high LI.Conclusions: These results suggested that the LI of PCNA and Ki-67, in addition to the histological appearance, may be markers of the biological behavior of parathyroid carcinomas. However, this study was on a small scale, so it may be valuable to repeat these studies in a larger group of patients with better defined histological criteria.     

Relationships between Ki-67 labelling index,amplification of the epidermal growth factor receptor gene,and prognosis in human glioblastomas

Summary The aim of this study was to determine possible relationships between Ki-67 labelling index (Ki-67 LI), amplification of the epidermal growth factor receptor (EGFR) gene, and prognosis in human glioblastomas. Ki-67 LI was determined on cryosections of biopsy specimens of 20 human glioblastomas with a mouse antihuman Ki-67 monoclonal antibody. Amplification of the EGFR gene was determined by slot blot and Southern blot analyses of DNA extracted from the tumour biopsies. The Ki-67 LI was higher in the glioblastoma group with EGFR gene amplification (8 tumours, median value of Ki-67 LI 4.2, range 0.4–24.6) than in those without EGFR gene amplification (12 tumours, median value of Ki-67 LI 0.8, range 0.2–11.8) (0.05 p<0.1). The glioblastoma patients with Ki-67 LI>1.5 (10 tumours) had a statistically significant shorter survival than those with Ki-67 LI<1.5 (10 tumours) (p<0.05). The glioblastoma patients with EGFR gene amplification lived shorter time than those without EGFR gene amplification (p>0.05).     

Correlation of thymidine phosphorylase staining and the Ki-67 labeling index to clinicopathologic factors and hepatic metastasis in patients with colorectal cancer

Purpose. Our aim was to investigate the thymidine phosphorylase (TdRPase) expression and Ki-67 labeling index (LI) of primary tumors of colorectal cancer and hepatic metastases immunochemically and to evaluate the relationship of these parameters to various clinicopathologic factors and hepatic metastasis. Methods. We performed immunochemical studies in 74 patients with colorectal cancer, using anti-TdRPase antibody and MIB-1 antibody. Results. TdRPase expression and a Ki-67 LI ≧30% in primary lesions were significantly more common in patients with lymphatic invasion (ly), venous invasion (v), lymph node involvement (n), and hepatic metastasis. A Ki-67 LI ≧ 30% of the primary tumor was associated with a significantly higher frequency of metachronous liver metastasis. In the same patients, the mean Ki-67 LI was 24.3 ± 17.9 for primary lesions and 5.0 ± 4.2 for hepatic metastases, this difference being significant. Conclusions. These results indicate that TdRPase expression and the Ki-67 LI are related to various clinicopathologic factors, suggesting their usefulness as indices of tumor malignancy. We suggest that the Ki-67 LI of primary colorectal cancer could be an important predictor of the future development of metachronous liver metastasis. Received: January 10, 2001 / Accepted: November 20, 2001     

The correlation of Ki-67 staining indices with tumour doubling times in regrowing non-functioning pituitary adenomas

Summary In order to improve our ability to predict the regrowth of nonfunctioning pituitary adenomas, we tried to assess the correlation between growth fractions with Ki-67 and PCNA (proliferating cell nuclear antigen) and tumour doubling times in regrowing tumours, and also to find out any difference of growth fractions between the regrowing and the cured cases.In 33 patients with non-functioning pituitary adenomas, 14 cases including 11 with cavernous sinus invasion showed residual tumour on MRI after the operation (regrowing group) and 19 cases had no tumour regrowth on MRI within 5 years after the operation (cured group). Immunocytochemical studies were done with monoclonal antibodies (anti-PCNA, anti-Ki-67: MIB-1). The growth fraction of each tumour was estimated by calculating the ratio of the positive nuclei to the total number of tumour cells with the aid of an image analyser (Mac SCOPE). The tumour doubling times were estimated from serial CT or MRI with the aid of the image analyser (NIH image).Ki-67 staining indices ranged from 0.2% to 1.5% (n = 14, 0.86±0.10%; mean±SEM) in the regrowing group, and from 0.1% to 0.5% (n = 19, 0.23±0.03%) in the cured group. PCNA staining indices of the regrowing group ranged from 0.6% to 24% (n = 14, 3.7±1.6%). In the regrowing group, the tumour doubling times ranged from 200 to 2550 days (930±180 days), and showed a significant inverse correlation with Ki-67 staining indices, but no correlation with PCNA staining indices. The regrowing group showed a significantly higher Ki-67 staining index (n = 14, 0.86±0.10%) than the cured group (n = 19, 0.23±0.03%) (p<0.01).These results indicate that immunocytochemical studies using MIB-1 may be better than those with PCNA for the prediction of regrowth in non-functioning pituitary adenomas. Immunocytochemical study with MIB-1 could lead to the accurate prediction of the rapid regrowing lesions in non-functioning adenomas.     

Early recurrence of benign meningioma correlates with expression of mini-chromosome maintenance-2 protein

We have investigated the potential utility of monoclonal antibodies against mini-chromosome maintenance-2 protein (Mcm2) in predicting meningioma recurrence. MCM proteins are members of the DNA-binding prereplicative complex and are essential for eukaryotic DNA replication. They are present throughout the cell cycle, but are down-regulated in quiescence and cell differentiation, making them specific markers of proliferating cells. We analysed 10 benign meningiomas that subsequently recurred within a 5-year period, together with 20 matched non-recurrent benign meningiomas. There was no significant correlation between histological subtype, mitotic count or Ki-67 labelling index and tumour recurrence. We observed that whilst the average Mcm2 labelling index (LI) of the tumour section as a whole (LI(Ave)) is not significantly different between recurrent and nonrecurrent meningiomas, the Mcm2 labelling index in the area of highest proliferative activity within the tumour section (LI(Max)) is significantly higher in recurrent meningiomas (p < 0.0001). Seven out of the 10 recurrent meningiomas displayed a Mcm2 LI((Max) greater than 30%, compared to 0 out of 20 for non-recurrent tumours. In conclusion, these results suggest that analysis of Mcm2 expression may facilitate identification of patients with a high risk of meningioma recurrence, for whom adjuvant radiotherapy may be of benefit.     

Expression of Ki-67 in squamous cell carcinoma of the penis

OBJECTIVE: To investigate the Ki-67 labelling index (LI) as a prognostic factor for the outcome of penile carcinoma, as in squamous cell carcinoma (SCC) of the larynx the expression of this marker correlates with histological features indicative of prognosis. PATIENTS AND METHODS: We retrospectively analysed the records of 44 patients in whom primary SCC of the penis was treated with amputation and bilateral lymphadenectomy (pT1, in 24, pT2 in 20, pN+ in 10; G1 in 12, G2 in 28 and G3 in four). During a mean follow-up of 35.6 months, four patients had disease progression. Tumour tissue was stained immunohistochemically using the streptavidin-biotin method. The mean Ki-67 LI was defined as the percentage of total tumour cells that were Ki-67-positive. The results were compared with pathological tumour stage, grade, nodal status and clinical disease progression. RESULTS: The mean (range) Ki-67 LI was 40.5 (6.4-93.0)%; a high mean Ki-67 LI was significantly inversely correlated with tumour differentiation (P < 0.005) and there was a tendency for a high Ki-67 LI to be associated with advanced local tumour stage, nodal metastasis and clinical disease progression, but these correlations were not statistically significant (P = 0.07, 0.07 and 0.06, respectively). CONCLUSIONS: The Ki-67 LI is correlated with tumour grade in penile cancer, and may indicate a greater risk of nodal metastasis.     

Immunohistochemical Expression of p16INK4A, Ki-67, and Mcm2 Proteins in Gastrointestinal Stromal Tumors: Prognostic Implications and Correlations with Risk Stratification of NIH Consensus Criteria

Background Inactivation of p16^INK4A promotes G1/S progression of cell cycle. Minichromosome maintenance protein-2 (Mcm2), a novel cell proliferation marker, is known to better correlate with clinical outcomes than Ki-67 in many carcinomas. Since gastrointestinal stromal tumors (GISTs) sometimes remains challenging in prognostication, we analyzed the utility of these three markers in GISTs.Methods Immunohistochemistry was performed in tissue microarrays of 277 primary GISTs and correlated with NIH consensus criteria and clinical outcomes.Results The increment of NIH risk levels significantly correlated with increasing labeling indices (LI) of both Ki-67 (P <.001) and Mcm2 (P <.001) and loss of p16^INK4A expression (P <.035). However, the latter aberration did occur in 23% of very low/low-risk GISTs. The relationship between Mcm2 and Ki-67 LIs could be modeled as linear (P <.001, r = 0.697), while Mcm2 LI was considerably higher (P <.001) with a stepwise escalation related to risk levels. Ki-67 LI >5% (P <.0001) and Mcm2 LI >10% (P <.0001) were strongly predictive of inferior disease-specific survival (DSS), while aberrant loss of p16^INK4A only reached a trend (P = .0954). In multivariate analyses, independent adverse factors of DSS were high-risk category (RR = 16.93, P <.0001), metastatic disease (RR = 4.12, P = .0015), Ki-67 LI >5% (RR = 3.55, P = .001), and presence of epithelioid histology (RR = 2.17, P = .0308).Conclusions Prognostic efficacy of NIH consensus criteria is substantiated. P16^INK4A deregulation can occur early in GIST tumorigenesis and marginally correlates with patient survival. Despite Ki-67 LI being an independent prognosticator, simultaneous detection of Mcm2 is recommended as a prognostic adjunct of GISTs, given its better sensitivity and stepwise escalation with increasing risk levels.     

Prognostic factors in intracranial ependymomas in children

OBJECT: The occurrence of intracranial ependymomas in children is relatively infrequent, and their prognostic factors are still controversial, especially regarding histological composition. METHODS: A retrospective study was conducted of 37 children treated during the last 20 years for intracranial ependymomas at the H?pital de la Timone. Both univariate and multivariate statistical analyses were performed to assess the prognostic relevance of patient age and sex, extent of tumor removal, location of the tumor (supratentorial compared with infratentorial, median compared with lateral), tumor histological composition, and adjuvant therapies in affecting the 5-year progression-free survival (PFS) rate and overall survival (OS) rate. The following histopathological features, either alone or in combination, were analyzed: endothelial proliferation, necrosis, loss of differentiating structures (present compared with absent), the number of mitotic figures per 10 hpf, and cellularity (number of nuclei/5 hpf). In addition, immunohistochemical detection of Ki-67 antigen was performed and the Ki-67 labeling index (LI) evaluated in all cases. The 5-year OS and PFS rates were 45% and 25%, respectively (median follow up 34 months). Four patients died of disease without remission (median 163 days) and disease in 21 patients relapsed: 18 in situ and three both in situ and distantly. On univariate analysis total surgical resection and median infratentorial location were associated with a better outcome (p < 0.002) for both OS and PFS. Loss of differentiating structures was associated with poor prognosis (p < 0.008) and the combination of necrosis, endothelial proliferation, and mitotic index greater than 5 was also a negative predictive factor for both OS (p < 0.002) and PFS (p = 0.02). The PFS time was shorter in patients younger than 4 years of age and in patients in whom a Ki-67 LI greater than 1 was found (p = 0.03 and 0.006, respectively). Adjuvant radiotherapy and chemotherapy were not relevant to prognosis. Moreover, among the 15 patients in whom total excision was achieved, OS was better in those who did not receive adjuvant therapies. In contrast, adjuvant therapies significantly enhanced PFS time in patients in whom tumor excision was incomplete. CONCLUSIONS: This study and analysis of the literature further highlight that total tumor removal is the treatment of choice for ependymomas in children. Postoperative measurement of residual tumor is required, especially because a subgroup of patients might be treated by surgery alone. Median infratentorial ependymomas have to be distinguished from the lateral type. Appropriate and reproducible histological parameters and Ki-67 LI are of interest as predictors of outcome.     

Cell-Cycle Regulators and the Ki-67 Labeling Index Can Predict the Response to Chemoradiotherapy and the Survival of Patients With Locally Advanced Squamous Cell Carcinoma of the Esophagus

Background: We investigated whether aberrant p53 and p16 expression, the Ki-67 labeling index (LI), and int-2/cyclin D1 gene amplification predict the response to chemoradiotherapy (CRT) in patients with locally advanced esophageal squamous cell carcinoma (ESCC).Methods: p53 and p16 expression status, the Ki-67 LI, and int-2/cyclin D1 amplification were assessed by immunohistochemical staining and slot blot analysis in pretreatment endoscopic biopsy specimens of 41 patients with T4 or M1 Lym (distant lymph node metastasis) ESCC. All patients received a course of chemotherapy (5-fluorouracil and cisplatin) with radiotherapy.Results: The CRT therapeutic response rate was 71%, and resection after CRT was successful in 15 of the cases in which the CRT effect was significant. The cumulative survival rate after CRT in the p53-negative patients was significantly higher than in the p53-positive patients (P = .037). The mean Ki-67 LI in the CRT response cases was significantly higher than in the CRT no-response cases (P = .023). Multivariate regression analysis revealed high Ki-67 LI to be an independent variable linked to a pathologic complete response to CRT (P = .033). The cumulative survival rate after CRT in the group that was p53-negative and int-2/cyclin D1 amplification-positive was significantly higher than in the other groups (P = .008).Conclusions: Evaluating predictive factors in pretreatment endoscopic biopsy specimens may allow selection of more suitable multimodal treatment for ESCC patients and improve their quality of life.     

Cellular proliferation in prostatic adenocarcinoma as assessed by bromodeoxyuridine uptake and Ki-67 and PCNA expression

Prostatic carcinomas vary in their biological potential, even when stratified by grade and stage. Measurement of cellular proliferation by various methods has been shown to correlate with outcome for several human cancers, including prostatic carcinoma. Uptake of bromodeoxyuridine (BrdUrd), a thymidine analogue, has been accepted as a measure of cellular proliferative rate. However, the technique is somewhat complex, requiring incubation with fresh tissue. We compared cellular proliferation as measured by BrdUrd uptake with two more simple immunohistochemical methods in 44 prostatic adenocarcinoma specimens and correlated the results with standard clinical parameters. The tissue was obtained via needle biopsy, channel transurethral resection, and radical prostatectomy. Specimens were incubated in vitro with BrdUrd and then fixed and paraffin embedded. Sections were immunohistochemically stained with antibodies to BrdUrd, proliferating cell nuclear antigen (PCNA), and Ki-67. At least 1,000 cells were scored, and a labeling index (LI) was calculated (number of positive cells/total number of cells). The mean LI determined by all three indices was low (BrdUrd = 3.0, PCNA = 7.0, Ki-67 = 3.4), consistent with the knowledge that prostatic tumors grow slowly. In 36 patients who had not been treated at the time of analysis, the LI as determined by all three methods correlated well with clinical stage and pathological grade. Furthermore, the LIs discriminated between those with tumor confined to the prostate and those with extension to the seminal vesicles, lymph nodes, or bone (P = 0.003, 0.004, 0.008 for BrdUrd, PCNA, and Ki-67, respectively). The LIs for PCNA and Ki-67 correlated well with that for BrdUrd (r = 0.84; r = 0.85), while the LIs for Ki-67 and PCNA correlated slightly less well with each other (r = 0.78). PCNA and Ki-67 expression appear to reflect essentially the same biological process as BrdUrd uptake. Either can substitute for BrdUrd as a measure of cellular proliferation, and Ki-67 seems to offer the fewest technical problems.     

Prognostic value of the expression of Ki-67, CD44 and vascular endothelial growth factor, and microvessel invasion, in renal cell carcinoma

OBJECTIVE: To determine if use of cell proliferation, cell adhesion, level of angiogenesis-related factors and presence of microscopic vascular invasion (MVI) could better predict the biological behaviour of renal cell carcinoma (RCC), which has a widely variable clinical outcome despite the use of conventional prognostic factors (staging and grading). MATERIALS AND METHODS: The expression of Ki-67, CD44H and vascular endothelial growth factor (VEGF) were assessed immunohistochemically in formalin-fixed, paraffin-embedded tissues from 48 RCCs, using a Ki-67 labelling index (LI), CD44 LI and level of VEGF expression, respectively. In addition all the pathological slides were reviewed retrospectively for the presence and absence of MVI. The prognostic value of all the variables assessed was then evaluated, and correlated with the usual prognostic variables and cancer-specific survival. RESULTS: Univariate analysis of cancer-specific survival showed that tumour stage (P < 0.001), tumour size (P = 0.005), metastasis, MVI, Ki-67 LI, CD44H LI and VEGF expression (all P < 0.001) were predictors of tumour-related death. There was a statistical correlation between CD44H LI and each of Ki-67 LI (r = 0.61), expression level of VEGF (r = 0.72) and presence of MVI (r = 0.71). Independent predictors of cancer-specific survival in a multivariate analysis were: in all patients with RCC, the MVI (P = 0.003) and VEGF expression (P = 0.01); in those with no metastases, MVI (P = 0.01); in patients with no MVI, VEGF (P = 0.04); and in patients with MVI, Ki-67 LI (P = 0.003). No independent predictor was identified in patient with metastases. CONCLUSION: This study suggests that cell proliferation, cell adhesion, the level of VEGF expression and the presence of MVI represent a complex tumour-host interaction that may favour the progression of RCC. Cell proliferation, CD44H and VEGF expression appear to be powerful markers for identifying patients with an adverse prognosis.     

Different types of postoperative diabetes insipidus and the relation to basal and stimulated serum prolactin levels in patients with hypothalamo-hypophyseal tumorous lesions

Summary To evaluate the interrelationships between anterior pituitary function and the antidiuretic system in patients harbouring hypothalamo-hypophyseal tumorous lesions, combined anterior pituitary stimulation tests were performed in the pre (n=192 patients) and postoperative (n=151 patients) state. Basal and stimulated plasma antidiuretic hormone, serum as well as urinary osmolality and diuresis were analyzed to determine the residual functional capacity of the antidiuretic system. In 106 patients with non-prolactin (PRL) secreting tumours basal and stimulated PRL secretion of the residual anterior pituitary was studied pre- and postoperatively.It was found that in the preoperative state latent (n=12 patients) or manifest (n=10 patients) types of diabetes insipidus (DI) were related to a significant decrease of maximal stimulated levels of thyroid stimulating hormone as well as basal and maximal stimulated levels of follicle stimulating hormone relative to patients without DI. In the postoperative state DI lasting longer than 10 days (n=51 patients) was associated with decreased basal and maximal stimulated concentrations of cortisol, luteinizing and follicle stimulating hormone, whereas basal and maximal stimulated levels of PRL were significantly increased compared to those patients without DI (n=61 patients). Decompression (n=65 procedures) via the transnasal route was related with a lower frequency of the more severe types of DI (n=7 patients) and a significant decrease of basal and maximal PRL levels in patients with non-PRL secreting tumours. The transcranial approach (n=86 procedures) caused a higher rate of severe DI types (n=33 patients) and an increase of PRL secretion from the residual anterior pituitary lobe. Patients without DI or DI of mild severity (n=50), as a group, had a significant decrease of basal and maximal PRL levels compared with preoperative values (preoperative: basal =14.3±1.5 ng/ml, max=31.4±1.5 ng/ml, postoperative: basal= 9.6±1.1 ng/ml, max=24.9±2.9 ng/ml). In patients with severer degrees of DI (n=40) PRL levels were significantly increased, respectively (preoperative: basal=15.3±3.1 ng/ml, max= 23.9±7.6 ng/ml, postoperative; basal=19.7±3.4 ng/ml, max= 38.6±7.9 ng/ml).It was concluded that in the surgical treatment of non-PRL secreting hypothalamo-hypophyseal lesions the results of early postoperative assessment of basal and stimulated PRL levels may predict the type of postoperative DI. However, the residual capacity of the antidiuretic system is not affected by the functional state of the anterior pituitary lobe in patients with these lesions.     

Increased expression of minichromosome maintenance protein 2 in active inflammatory bowel disease

OBJECTIVE: Minichromosome maintenance protein 2 (Mcm2) is an accurate indicator of cell cycle entry in tissue samples, but its expression in inflammatory bowel disease (IBD) has not previously been investigated. We have used immunohistochemistry to assess the expression of Mcm2, in comparison to the existing proliferation marker Ki-67, in active IBD and IBD without inflammatory activity. MATERIALS AND METHODS: For this experimental study, sections from colonic biopsy and resection specimens of 48 patients with IBD (5 inactive/quiescent Crohn's disease (CD), 13 active CD, 19 inactive/quiescent ulcerative colitis (UC) and 11 active UC) and 15 normal controls were immunostained with antibodies to Mcm2 and Ki-67. The percentage of immunopositive epithelial nuclei was determined by calculating a labelling index (LI) for entire glands and for gland thirds (superficial, middle and basal). RESULTS: The Mcm2 LI was significantly increased in the superficial third of glands in active vs. inactive/quiescent UC (P < 0.0001) and active vs. inactive/quiescent CD (P = 0.001). The Mcm2 LI was significantly greater than the Ki-67 LI in active IBD, both in entire glands (P < 0.0001) and in the superficial third of glands (UC, P = 0.001; CD, P = 0.0002). Mcm2 LIs for entire glands were significantly higher in UC (all cases) compared to CD (all cases) (P = 0.032). CONCLUSIONS: There is increased cell cycle entry, as indicated by expression of Mcm2 and to a lesser extent Ki-67, in the superficial third of colonic glands in active IBD compared to inactive/quiescent IBD. Detection of Mcm2 may contribute to improved histological assessment of small tissue biopsies and may enable the development of a direct stool-based test for detection of active IBD and potentially for assessment of disease activity.     

Proliferation potential of spinal meningiomas

Objectives: The goal of the present study was to quantitatively assess the proliferation index and progesterone receptor status of spinal versus intracranial meningiomas and to determine if these biological indicators can describe the clinical behavior of these tumors. This information could provide the spinal surgeon with important additional information concerning surgical management and follow-up recommendations for the individual patient. Methods: The study group consisted of 26 patients with spinal and 241 patients with intracranial meningiomas. Patients with atypical or anaplastic tumors as well as with neurofibromatosis type II were excluded from the study. Furthermore both groups were matched according to age, sex and resection grade (total resection according the Simpson classification). Proliferation index (Ki-67 Labelling index [LI]) and progesterone-receptor (PR) status of spinal and intracranial meningiomas were compared. Clinical charts including surgical and histological records and imaging studies were reviewed. Correlations with histological subtype, intratumoral calcifications, tumor vascularity and recurrence-free survival were analyzed. Results: Compared to the spinal group with a mean Ki-67 LI of 2.48% and a positive PR-status of 46%, proliferation rates of intracranial meningiomas were significant higher (Ki-67 LI 3.6%; P-value 0.041). No significant difference in PR status was seen (spinal PR-status 46%, P-value 0.261). Furthermore spinal meningiomas were less vascularized and showed less intratumoral calcifications. Time to recurrence was similar in spinal and intracranial tumors. Conclusion: Spinal and intracranial meningiomas differ in their proliferation activity but not in their PR status. However, despite lower proliferation rates, time to recurrence in spinal and cranial meningiomas is comparable in totally excised tumors. Further studies are needed to determine the role of other biological indicators in spinal meningioma growth and response to therapy.     

Prognostic significance of proliferation activity and neuroendocrine differentiation to predict treatment failure after radical prostatectomy

OBJECTIVES: Neuroendocrine (NE) cells in prostate cancer may influence tumor cell proliferation in a paracrine fashion. The aims of this study were to clarify the prognostic value of tumor cell proliferation and NE tumor cell differentiation in prostate cancer after radical prostatectomy, and to compare these parameters with each other. MATERIAL AND METHODS: Specimens were pooled from a total of 528 patients treated with radical prostatectomy without neoadjuvant hormonal therapy between 1996 and 2003. NE differentiation (NED) was determined by immunohistochemistry using antibodies directed against chromogranin A (CgA), and was scored as either NE-negative (0-1+) or -positive (2-3+). Tumor cell proliferation was assessed by means of the Ki-67 labeling index (Ki-67 LI). The mean post-surgical follow-up period was 49 months (range 10-116 months). Any subsequent rise in prostate-specific antigen (PSA) level was regarded as reflecting disease progression. The prognostic values of Ki-67 and CgA were comparatively analyzed using multivariate Cox regression. RESULTS: NED was present in 6.1% of tumors. The mean Ki-67 LI was significantly higher in the CgA-positive group in comparison with CgA-negative specimens (6.6% vs 5.0%; p=0.029). The Ki-67 LI showed the highest correlations with Gleason score and pathological tumor stage (r=0.31 and r=0.3, respectively). NED was found to have the strongest association with pathological tumor stage (r=0.2). Multivariate analysis determined Gleason score > or =7 (4+3) [hazard ratio (HR) 3.04], NED (HR 1.89), lymph node metastases (HR 1.84), preoperative PSA level>20 ng/ml (HR 1.66), and Ki-67 LI > or = 5% (HR 1.62) to be significant predictors of biochemical progression. CONCLUSION: Our results identify Ki-67 LI and NED as additional prognostic markers after radical prostatectomy.     

The prognostic value of proliferating cell nuclear antigen,Ki-67 and nucleolar organizer region in transitional cell carcinoma of the bladder

Objectives: To investigate the value of proliferating cell nuclear antigen(PCNA), Ki-67 antigen labelling indices and nucleolar organizer region(NOR) score in relation to histological grade, stage, recurrence andprogression of the bladder tumor.Materials and methods: Tissue specimens from 77 bladder cancer patients(43 superficial, 34 invasive) were immunostained with PCNA and Ki-67 andstained with AgNOR. Thirteen specimens of normal bladder mucosa servedas controls.Results: In comparison to normal bladder mucosa the values of the threeindicators were significantly greater (p < 0.001). There was a significantrelationship between PCNA, Ki-67 indices, AgNOR scores and grade andstage of the tumor (p < 0.001). All indicators also correlated with each other(p < 0.001). The Kaplan-Meier curves for recurrence-progression freesurvival revealed that patients with a PCNA labelling index >36.22%, Ki-67labelling index >29.68% and AgNOR score > 3.34 had a worse prognosis thanthose with <36.22%, <29.68% and <3.34, respectively.Conclusions: PCNA, Ki-67 indices and AgNOR scores correlated with eachother and with tumor grade and stage. These proliferation markers maygive objective and accurate information about the biological behavior ofbladder transitional cell carcinoma.     

Growth rate of human pituitary adenomas

The immunohistological detection of a proliferation-associated nuclear antigen by the monoclonal antibody Ki-67 allows the determination of the growth fraction in human cell populations. In this study, biopsy specimens of 31 pituitary adenomas representing all major endocrine types were examined. All adenomas contained proliferating cells and the percentage of nuclei that were immunoreactive to Ki-67 ranged from 0.1% to 3.7%. Low values (0.1% to 1.0%) were present in 11 endocrine-inactive adenomas and higher values (1.1% to 1.5%) were found in six acromegalic patients. The percentages of Ki-67-positive cells in 12 prolactinomas and two adenomas from patients with Cushing's disease covered the entire range (0.1% to 3.7%). Preoperative bromocriptine treatment of prolactinomas did not influence Ki-67 expression. Invasive adenomas, as determined by preoperative computerized tomography, surgical observation, and histological examination of the sella dura demonstrated significantly higher Ki-67 values (average 1.15%) than noninvasive adenomas (average 0.60%). Determination of the incidence of proliferating cells by Ki-67 immunoreactivity represents a new tool for intraoperative quantitative assessment of tumor growth characteristics and may aid in the planning of adjuvant therapy and estimation of prognosis.