Lipponen P

Hyaluronan expression in gastric cancer cells is associated with local and nodal spread and reduced survival rate

SummaryHyaluronan (HA), an extracellular high-molecular-mass polysaccharide, is supposed to be involved in the growth and progression of malignant tumours. We studied the cellular expression of HA in 215 operated stage I–IV gastric cancer patients using a specific biotinylated probe. Most (93%) of the tumours showed HA staining in their parenchyma, whereas the stroma inside and around the tumour was stained in every case. When HA expression was compared with the clinical and histological features of the tumours, a strong staining intensity in the tumour parenchyma was found to be associated with deep tumour invasion (pT3 or 4) and with mixed type of Laurén. A high proportion of HA-positive cells of all neoplastic cells was significantly associated with deep tumour invasion, nodal metastasis, positive lymphatic invasion, poor differentiation grade, as well as with inferior prognosis in univariate survival analysis. However, in multivariate analysis, only pT, pN, and vascular and lymphatic invasion emerged as independent predictors of survival in gastric cancer. The results indicate that ectopic HA expression is a frequent feature of gastric adenocarcinoma, and is associated with tumour progression and poor survival rate.

Prognostic Value of MIB-1 Score, p53, EGFr, Mitotic Index and Papillary Status in Primary Superficial (Stage pTa/T1) Bladder Cancer: A Prospective Comparative Study

Objective: A prospective randomized study was undertaken to determine whether cell proliferation indices (M/V index, MIB1), papillary status, the expression of p53 and epidermal growth factor receptor (EGFr) have prognostic value in superficial (pTa–pT1) bladder cancer (SBC). Methods: 207 patients with primary SBC were followed up over a period of 4.9 (range 3.7–6.0) years. M/V index and papillary status were assessed by light microscopy, and expression of MIB1, p53 and EGFr was assessed by immunohistochemistry. The results of histopathological analyses were related to the survival data of the patients. Results: Using univariate analysis, stage (p < 0.001), grade (p < 0.001), papillary status (p < 0.001), MIB1 (p < 0.001), M/V index (p < 0.001), EGFr (p < 0.001) and p53 (p = 0.002) were significant predictors of progression. Using multivariate analysis, MIB-1 score and papillary status were independent predictors of progressive disease and cancer-specific survival. Tumor grade was the only independent predictor of recurrence. Conclusion: Evaluation of tumor cell proliferation rate by M/V index or by MIB1 immunohistochemistry and assessment of papillary status by light microscopy are useful prognostic tools in tailoring treatment and follow-up schedule of patients with SBC.

Expression of cyclins A and D and p21 (waf1/cip1) proteins in renal cell cancer and their relation to clinicopathological variables and patient survival

SummaryWe have studied 118 renal cell carcinomas to analyse the expressions of cyclins A and D1 and p21(waf1/cip1), and their relationship to clinical and histopathological parameters as well as to clinical outcome. Cyclins A and D1 and cyclin-dependent kinase inhibitor p21(waf1/cip1) were not expressed in normal renal tissue. Staining signals of cyclin D1 and p21(waf1/cip1) were always nuclear but cyclin A was also expressed in the cytoplasm of the tumour cells. The mean (range) fractions of cyclin A, cyclin D1 and p21(waf1/cip1)-positive tumour cells were 2.2% (range 0–20%), 23.3% (range 0–90%) and 6.8% (range 0–70%) respectively. The expression of cyclin A was related to venous invasion, high nuclear grade, high mitotic rate, high Ki-67 and high PCNA expressions (P ≤ 0.006 for all). The expression of cyclin D1 was linked with age over 65 years, low nuclear grade and high p53 expression (P ≤ 0.05 for all). An inverse correlation was present between p21(waf1/cip1) and cyclin D1 (P = 0.011). Cyclin A predicted survival in the entire study group (P = 0.0014), in T1–4/N0–2/M0 (P = 0.0007) and in T1–2/N0/M0 tumours (P = 0.0007). Cyclin A was also a powerful predictor of disease-free survival in T1–4/N0/M0 (P = 0.0027) tumours (P = 0.0007). Cyclin D1 and p21(waf1/cip1) were not significantly related to survival or disease-free survival in any of the groups. In the entire material the independent prognostic factors were the presence of distant metastases (relative risk (RR) 5.16, P < 0.001), T category (RR 2.68, P < 0.001), Ki-67 expression (RR 1.02, P = 0.026) and cyclin A expression (RR 1.12, P = 0.001). The independent predictors in T1–4/N0/M0 tumours were T-category (RR 2.67, P = 0.001) and cyclin A (RR 1.21, P < 0.001), and in T1–2/N0/M0 tumours the only significant predictor was cyclin A (RR 1.19, P = 0.0002). In renal cell carcinoma, cyclin A is a powerful and independent prognostic factor in all clinical stages of the disease, whereas cyclin D1 and p21(waf1/cip1) have no prognostic value.

Prognostic factors in gastric cancer: the value of vascular invasion, mitotic rate and lymphoplasmacytic infiltration

A retrospective analysis of 321 gastric cancer patients was made to assess the prognostic value of TNM classification, tumour differentiation, Laurén classification, proliferative rate, inflammatory reaction and tumour invasion in vascular or neural structures of the gastric wall. The TNM classification showed the strongest correlation with survival in univariate and multivariate analyses (P < 0.0001). The invasion in lymphatic or vascular system and Laurén classification were also independent prognosticators in multivariate analysis (P < 0.05). In univariate analysis, the WHO-grade, the size and the location of the tumour and perinueral invasion were significant prognostic factors (P < 0.01), as were the infiltration of lymphocytes and plasma cells in the tumour (P < 0.05). On the other hand, the mitotic indices reflecting the proliferative activity of the tumour cells showed no significant correlation with the prognosis. The results indicate that the prognostic power of the TNM classification can be further increased by assessment of the above special histological features in gastric cancer.

p21/WAF1 expression in human colorectal carcinoma: association with p53, transcription factor AP-2 and prognosis

Summaryp21/WAF1 expression was studied in a series of 162 colorectal carcinoma patients and its relation to p53- and activator protein (AP)-2 expressions and to stage as well as survival was assessed. p21 expression was moderate or intense in 33% of the tumours, and 53% of the tumours had moderate or strong p53 staining intensity. Eighty-nine percent of the tumours showed a weak cytoplasmic AP-2 signal. As expected, p21 and p53 stainings were inversely related to each other (P < 0.001). There was a significant positive association between p21 and AP-2 expression levels (P = 0.01). p21 intensity and percentage were higher in Dukes’ A and B stages (P < 0.001). The cancer-related survival and recurrence-free survival (RFS) rates were significantly lower among patients with a low signal for p21 (P < 0.001) and low p21 percentage in tumour epithelium (P < 0.001). High p53 staining intensity in tumour epithelium predicted poor survival (P = 0.01) and RFS (P = 0.003). In the multivariate analysis, p21 percentage distribution independently predicted cancer-related survival in all cases, and p21 expression intensity in T1–4/N0–3/M0 and T1–3/N0/M0 cases. p21 percentage distribution was an independent predictor of RFS in all and T1–3/ N0/M0 cases. AP-2 staining did not reach any prognostic significance. These results suggest that the immunohistochemical detection of cyclin-dependent kinase inhibitor p21 could be used to predict more precisely the outcome of colorectal cancer patients.

Expression of CD44 and Variant Proteins in Human Colorectal Cancer and Its Relevance for Prognosis

BACKGROUND CD44 is a cell adhesion molecule often expressed in the form of various splice variants. The role of standard CD44 isoform (CD44s) and its variants in colorectal carcinogenesis is partly conflicting. Therefore, we compared the expression of CD44s (hermes-3) and its splice variants (v3 and v6) with traditional prognostic factors in 194 colorectal cancer patients treated at Kuopio University Hospital and followed up for a mean of 14 years. METHODS Formalin-fixed, paraffin-embedded tissue sections from 194 patients with colorectal carcinoma were examined immunohistochemically to detect the expression of different forms of CD44. The hypothesis that CD44s, CD44v3, and CD44v6 expression intensities and distribution in cancer cells correlated with survival was tested with the log-rank test, hazard ratios, and their confidence intervals. RESULTS In high-grade tumours CD44s and CD44v6 expression intensities and CD44s percentages were stronger than in low-grade tumours. CD44v6, CD44v3, and CD44s expression intensities in tumour epithelium were also stronger in Dukes C and D tumours than in A and B tumours. In the univariate survival analysis patients with strong CD44s, CD44v3, and CD44v6 expression intensities in tumour epithelium had lower cancer-related survival than the patients who had weak CD44s, CD44v3, and CD44v6 expression intensities. Recurrence-free survival was also shorter in patients with intense signals for CD44v3 and CD44v6 in tumour epithelium. In the multivariate analysis the CD44v6 expression intensity in tumour epithelium predicted independently both cancer-related and recurrence-free survival in T1-4N0-3M0 and T1-3N0M0 cases. In addition, the CD44v3 expression intensity in tumour epithelium was a significant predictor of RFS in T1-3N0M0 cases. CONCLUSIONS These results strongly suggest that the CD44 splice variants v6 and v3 have prognostic significance in colorectal cancer.

Usefulness of History-Taking, Physical Examination and Diagnostic Scoring in Acute Renal Colic

Objective: The accuracy of the clinical diagnosis of acute renal colic was studied in connection with the survey of acute abdominal pain by the Research Committee of the World Organization of Gastroenterology. The diagnostic efficiency of various clinical symptoms, signs and tests have not previously been analyzed in the diagnosis of acute renal colic, and therefore the study is of potential importance. Methods: 1,333 patients presenting with acute abdominal pain were included in the study. The clinical findings in each patient were recorded in detail, using a predefined structured data collection sheet, and the collected data were compared with the final diagnoses of the patients. Twenty-three clinical history variables, 14 clinical signs and 3 tests were evaluated in a single variable and multivariate analysis. Results: In multivariate logistic regression analysis, the most significant predictors of acute renal colic were urine, tenderness, renal tenderness, duration of pain and appetite. The sensitivity in detecting acute renal colic was 0.84, with a specificity of 0.99 and an efficiency of 0.98. To sum up the contributions of most significant diagnostic factors, a diagnostic score (DS) was built. This score incorporated independent variables, e.g. urine, tenderness, renal tenderness, duration of pain, appetite and sex. The DS reached a sensitivity of 0.89 in detecting acute renal colic, with a specificity of 0.99 and an efficiency of 0.99. Conclusions: The results clearly show that acute abdominal pain with normal appetite, short duration of pain (≤12 h), loin or renal tenderness and hematuria (erythrocytes >10) are indicative of acute renal colic, and therefore, in this particular clinical question, careful history-taking and physical examination are of utmost importance. In our study, the DS system performed well considering the simple nature of its structure. However, to minimize the risk to the patient, we recommend that the DS is used only as an aid in decision-making when there is uncertainty as to the diagnosis of acute renal colic and the need for immediate treatment. In addition, the possibility of obstructive pyelonephritis in combination with renal colic should be considered clinically.

Expression of CD44 standard and variant-v6 proteins in transitional cell bladder tumours and their relation to prognosis during a long-term follow-up.

The expression of the standard CD44 (CD44s) and its v6 isoform (CD44v6) was analysed immunohistochemically in 173 cases of transitional cell bladder cancer. The results of immunohistochemical analyses were related to established prognostic factors and clinical follow‐up data. The expression intensity of CD44s in non‐basal tumour cells was significantly related to TN classification, S‐phase fraction (SPF), mitotic index, grade, density of tumour infiltrating lymphocytes. The expression intensity of CD44v6 in non‐basal tumour cells was inversely related to DNA ploidy, SPF, and mitotic index. The expression intensity of CD44v6 in basal tumour cells was also inversely related to T‐category, grade, papillary status, DNA ploidy, SPF, and mitotic index. Strong expression of CD44s in non‐basal tumour cells was related to unfavourable outcome in univariate analysis (p=0·008), whereas the strong expression of CD44v6 in both non‐basal cells (p=0·005) and basal cells (p=0·0008) was related to high survival probability. In multivariate survival analysis, the expression intensity of CD44v6 was independently related to favourable outcome in muscle invasive tumours, while in superficial tumours, CD44s was an independent prognostic factor. The results suggest that the expression of CD44s and CD44v6 is associated with malignant features and prognosis in bladder cancer. Copyright

Expression of tumour-suppressor gene Rb, apoptosis-suppressing protein Bcl-2 and c-Myc have no independent prognostic value in renal adenocarcinoma

The expression of retinoblastoma (Rb), c-Myc and Bcl-2 proteins was studied by immunohistochemical methods in 104 cases of renal adenocarcinoma. One tumour was completely negative for Rb protein and altered expression pattern was detected in 36% of cases. A low fraction of Rb-positive nuclei was related to high grade (P = 0.016) and high mitotic index (P = 0.012). Twenty-eight per cent of the tumours expressed c-Myc in cancer cell nuclei and 87% showed cytoplasmic positivity. Cytoplasmic expression of c-Myc was related to high grade (P = 0.002), while nuclear expression of c-Myc was related to small tumour diameter (P = 0.034), low T category (P = 0.04), low mitotic index (P = 0.019) and expression of c-ErbB-2 (P = 0.0007). Overexpression of c-myc predicted favourable outcome in M0 tumours (P = 0.0157). Bcl-2 was expressed in 20% of tumours and it was related to small tumour size (P < 0.0001), low T category (P < 0.0001), lack of venous invasion (P = 0.008), node negativity (P = 0.015) and absence of metastasis (P = 0.017). In multivariate analysis the expression of Rb, Bcl-2 and c-Myc had no independent prognostic value over T category (P < 0.001), mitotic index (P = 0.008) and combined nuclear grade (P = 0.056).

Prognostic value of Ki-67 expression in renal cell carcinomas.

OBJECTIVE The aim of the study was to determine the prognostic power of Ki-67 immunostaining in renal cell carcinomas (RCC). METHODS Clinical follow-up data were reviewed in 111 RCC and the results of Ki-67 immunolabelling were correlated to standard prognostic factors and survival data of the patients. RESULTS Ki-67 expression correlated with tumor grade (p < 0.0001) and mitotic activity (p < 0.0001). In survival analysis Ki-67 expression could be used to divide patients into different prognostic groups (p = 0.0003). In separate analysis with M0 tumors Ki-67 immunolabelling was a powerful predictor of survival (p = 0.0016) as well as disease-free survival (DFS; p = 0.0067). In T1-2N0M0 tumors Ki-67 immunolabelling was superior (p = 0.0005) to other prognostic factors in survival analysis as well as in predicting DFS (p = 0.0006). Grade-2 tumors could be separated into distinct prognostic groups according to Ki-67 labelling (p = 0.0098). In Coxs multivariate analysis Ki-67 was an independent prognostic factor in all three subgroups of RCC. CONCLUSIONS The results show that Ki-67 expression is an independent prognostic factor in renal adenocarcinoma and could be applied in defining proper therapy for patients suffering from this malignancy.