High tissue expression of tumour-associated trypsin inhibitor (TATI) associates with a more favourable prognosis in gastric cancer

AIMS: The tumour-associated trypsin inhibitor (TATI) is a 6-kDa protease inhibitor with potential inhibitory effects on tissue degradation. In serum, increased levels have been associated with adverse prognosis in different forms of cancer. We assessed the tumour tissue expression and prognostic value of TATI in a surgically treated, single-institution series of patients with gastric cancer. METHODS AND RESULTS: Using a monoclonal anti-TATI antibody, immunohistochemistry was performed on formalin-fixed paraffin-embedded tumour specimens from 336 patients. TATI expression was observed in 265 (79%) of the tumours. There was a significant association between high TATI expression and low stage (P = 0.007), superficial tumours (P = 0.005), and absence of nodal (P = 0.015) and of distant metastases (P = 0.022). In univariate analysis, patients with high TATI expression had a significantly more favourable 5-year cumulative survival compared with patients with negative to moderate immunostaining (43% and 28%, respectively, P = 0.006). On multivariate survival analysis stratified for estimated cure of surgery, stage (P < 0.0001) and age (P = 0.022) at the time of surgery were independent prognostic factors. CONCLUSIONS: High TATI expression in tumour tissue was detected more frequently in patients with early-stage gastric cancer and seems to correlate with a favourable outcome.     

CD151 expression can predict cancer progression in clear cell renal cell carcinoma

Yoo S H, Lee K, Chae J Y & Moon K C
(2011) Histopathology  58 , 191–197
CD151 expression can predict cancer progression in clear cell renal cell carcinoma Aims: CD151 is known to be implicated in cancer progression and metastasis. The aim was to evaluate the expression of CD151 in clear cell renal cell carcinoma (CCRCC) and to assess its prognostic significance. Methods and results: The expression of CD151 was evaluated in 489 cases of CCRCC by immunohistochemistry. Immunoreactivity was classified into four categories (minimal, 0–10% positive cells; focal, 10–50% positive cells; diffuse moderate, >50% positive cells with moderate staining intensity; diffuse strong, >50% positive cells with strong staining). To determine the statistical significance of CD151 expression in CCRCC, all cases were divided into two groups based on their CD151 expression level: a CD151‐low group (n = 257; minimal and focal) and a CD151‐high group (n = 232; diffuse). Expression of CD151 was correlated positively with pT, pN, pM categories, pathological tumour–node–metastasis (pTNM) stage, nuclear grade, tumour size and patient’s age. The CD151‐high group had significantly shorter cancer‐specific survival (P < 0.001) and progression‐free survival (P < 0.001) times. Furthermore, multivariate analysis showed that CD151 expression was an independent predictor for tumour progression in patients with CCRCC (P = 0.040). Conclusions: High CD151 expression is associated with advanced stage and high nuclear grade in CCRCC. CD151 is a prognostic marker for tumour progression in CCRCC patients.     

Clinicopathological correlates and prognostic significance of glutathione S-transferase Pi expression in 468 patients after potentially curative resection of node-positive colonic cancer

Tan K L, Jankova L, Chan C, Fung C L‐S, Clarke C, Lin B P C, Robertson G, Molloy M, Chapuis P H, Bokey L, Dent O F & Clarke S J
(2011) Histopathology  59 , 1057–1070
Clinicopathological correlates and prognostic significance of glutathione S‐transferase Pi expression in 468 patients after potentially curative resection of node‐positive colonic cancer Aims: This study investigated the association between glutathione S‐transferase Pi (GST Pi) expression, histopathology and overall survival in 468 patients after resection of stage C colonic adenocarcinoma. Methods and results: Data were drawn from a prospective hospital registry of consecutive bowel cancer resections with a minimum follow‐up of 5 years. Nuclear and cytoplasmic GST Pi expression, assessed by both intensity of staining and percentage of stained cells at both the central part of the tumour and the invasive tumour front, were evaluated retrospectively by tissue microarray immunohistochemistry on archival specimens. The most effective measure of GST Pi expression was the percentage of immunostained nuclei in central tumour tissue, where >40% stained was associated significantly with high grade, invasion beyond the muscularis propria, involvement of a free serosal surface or apical node, and invasion into an adjacent organ or structure. After adjustment of other predictors, GST Pi expression remained independently prognostic for reduced overall survival (hazard ratio 1.4, P = 0.002). Conclusions: In patients with clinicopathological stage C colonic cancer, GST Pi expression is associated with features of tumour aggressiveness and with reduced overall survival. Further appropriately designed studies should aim to discover whether GST Pi can predict response to adjuvant chemotherapy.     

Keratin 7 expression in colorectal cancer – freak of nature or significant finding?

Harbaum L, Pollheimer M J, Kornprat P, Lindtner R A, Schlemmer A, Rehak P & Langner C
(2011) Histopathology 59 , 225–234 Keratin 7 expression in colorectal cancer – freak of nature or significant finding? Aims: To assess the prevalence of keratin 7 (K7) expression in colorectal cancer and to correlate findings with clinicopathological parameters and patients' outcome. Method and results: A total of 370 patients were evaluated for K7 expression by immunohistochemistry using a tissue microarray technique. K7 expression was scored semiquantitatively as either focal (<10%), moderate (10–50%) or extensive (>50%). In all, 32 (9%) tumours were immunoreactive for K7, with five cases showing extensive, four moderate and 23 focal expression, respectively. K7 expression was associated with poor tumour differentiation (P = 0.005) and the extent of tumour budding (P = 0.02). In whole sections, K7 immunoreactivity prevailed in single cells and small clusters of cells at the invasion front. Analysis of serial sections showed that K7‐positive cells colocalized with keratin 20, whereas they lacked immunoreactivity for E‐cadherin, MUC2 and MIB‐1. Disease progression occurred in 52% of patients with K7‐positive tumours and 41% with K7‐negative tumours (P = 0.19); 48% of patients with K7‐positive tumours but only 33% with K7‐negative tumours died of disease (P = 0.06). Conclusions: Aberrant expression of K7 in budding cancer cells represents a modification of the epithelial phenotype (‘epithelial–epithelial transition’: EET) which may be linked to gains in motility and invasive potential.     

Clinicopathological correlates and prognostic significance of maspin expression in 450 patients after potentially curative resection of node‐positive colonic cancer

Fung C L‐S, Chan C, Jankova L, Dent O F, Robertson G, Molloy M, Bokey L, Chapuis P H, Lin B P C & Clarke S J
(2010) Histopathology 56 , 319–330 Clinicopathological correlates and prognostic significance of maspin expression in 450 patients after potentially curative resection of node‐positive colonic cancer Aims: The tumour suppressor maspin has been investigated for its association with conventional histopathological features in colorectal cancer and for its potential as an independent predictor of survival and response to adjuvant chemotherapy. The aim of this study was to examine associations between maspin expression, other histopathology and survival in a large consecutive series of patients after potentially curative resection of node‐positive colonic adenocarcinoma. Methods and results: Nuclear and cytoplasmic maspin expression in both superficial and deep parts of the tumour were assessed retrospectively by tissue microarray and immunohistochemistry in specimens from 450 patients whose other histopathology had been recorded in a prospective hospital registry of large bowel cancer resections from 1971 to 2001 with a minimum follow‐up of 5 years. Among 13 clinicopathological features examined, the only associations that persisted across all four maspin assessments were stronger expression in right‐ than in left‐sided tumours (P = 0.001–0.011) and stronger expression in high‐grade tumours (P < 0.001–0.007). There was no significant association between intensity of maspin expression and overall survival. Conclusions: In this large and thoroughly documented series of patients with clinicopathological stage C colonic tumour, maspin expression was correlated with few other conventional histopathology variables and was not a significant prognostic factor.     

High levels of microRNA-21 in the stroma of colorectal cancers predict short disease-free survival in stage II colon cancer patients

Approximately 25% of all patients with stage II colorectal cancer will experience recurrent disease and subsequently die within 5 years. MicroRNA-21 (miR-21) is upregulated in several cancer types and has been associated with survival in colon cancer. In the present study we developed a robust in situ hybridization assay using high-affinity Locked Nucleic Acid (LNA) probes that specifically detect miR-21 in formalin-fixed paraffin embedded (FFPE) tissue samples. The expression of miR-21 was analyzed by in situ hybridization on 130 stage II colon and 67 stage II rectal cancer specimens. The miR-21 signal was revealed as a blue chromogenic reaction, predominantly observed in fibroblast-like cells located in the stromal compartment of the tumors. The expression levels were measured using image analysis. The miR-21 signal was determined as the total blue area (TB), or the area fraction relative to the nuclear density (TBR) obtained using a red nuclear stain. High TBR (and TB) estimates of miR-21 expression correlated significantly with shorter disease-free survival (p = 0.004, HR = 1.28, 95% CI: 1.06–1.55) in the stage II colon cancer patient group, whereas no significant correlation with disease-free survival was observed in the stage II rectal cancer group. In multivariate analysis both TB and TBR estimates were independent of other clinical parameters (age, gender, total leukocyte count, K-RAS mutational status and MSI). We conclude that miR-21 is primarily a stromal microRNA, which when measured by image analysis identifies a subgroup of stage II colon cancer patients with short disease-free survival.     

p53 mutations in gastric and colorectal cancers in Texas Hispanics versus Anglos

Gastric cancer is more than twice as common in Hispanics as in Anglos in Texas, while colorectal cancer is almost twice as common in Anglos as Hispanics. To test the hypothesis that mutations in the p53 tumour suppressor gene are involved in these differences, we examined 131 gastric and 138 colorectal cancers from Hispanic and Anglo patients from South Texas and Mexico using immunohistochemistry (IHC) as a screening assay for p53 mutations. The fraction of p53 positive cases was not significantly different in gastric cancers from Hispanics compared to Anglos (43% versus 61%, respectively, p=0.13) or in colorectal cancer (57% versus 58%, respectively, p=1.0), suggesting that p53 mutations are not involved in causing the different incidences of these cancers in these populations. In addition, the types of p53 mutations arising in gastric tumours from Hispanic patients were consistent with those reported in gastric tumours in other populations. Sequencing of mutations in five gastric cancers revealed two G: C to A: T transitions, two A: T to G: C transitions and one complex deletion. In contrast with findings in studies in other tumour types, neither stage nor survival was associated with p53 positive staining by IHC in either gastric or colorectal tumours in this study. Positive p53 immunostaining was associated with the diffuse histological subtype in gastric carcinoma (p=0.05) and high histological grade in colorectal carcinoma (p=0.04).     

The impact of CpG island methylator phenotype and microsatellite instability on tumour budding in colorectal cancer

Zlobec I, Bihl M P, Foerster A, Rufle A & Lugli A
(2012) Histopathology  61, 777–787 The impact of CpG island methylator phenotype and microsatellite instability on tumour budding in colorectal cancer Aims: In colorectal cancer, tumour budding, a process likened to epithelial mesenchymal transition, is an adverse prognostic factor which is rarely found in tumours with high‐level microsatellite instability (MSI‐H). Cases with MSI‐H or high‐level CpG island methylator phenotype (CIMP‐H) have similar histomorphological features, yet seemingly opposite prognosis. We hypothesized that tumour budding is related to CIMP, thus partially explaining this prognostic difference. Methods and results: MSI, KRAS, BRAF, CIMP and 0⁶‐methylguanine‐DNA methyltransferase (MGMT) were investigated in tissues from 127 colorectal cancer patients. Tumour budding was scored using pan‐cytokeratin‐stained whole tissue sections within the densest area of buds (×40). Tumour budding was not associated with KRAS, BRAF, MGMT or CIMP, but was correlated inversely with MSI‐H (P = 0.0049). Multivariate survival time analysis revealed that tumour budding was independent of all five molecular features and was predicted by MSI status [odds ratio (OR): 4.29, 95% confidence interval (CI) 1.5–12.1; P = 0.006)], but not CIMP (OR: 0.81, 95% CI 0.3–2.5; P = 0.714). Conclusions: These findings underline that MSI, rather than CIMP, plays a role in conferring a tumour budding phenotype. Budding retains its unfavourable prognostic effect independently of these five molecular features. Continued efforts to standardize the assessment of tumour budding are necessary to integrate this feature into daily diagnostic routine.     

Prognostic significance of p27Kip1 expression in colorectal cancer: a clinico-pathological characterization

This study has evaluated the expression of the cyclin-dependent kinase inhibitor p27^Kip1 in 89 colorectal cancers (CRCs) using immunohistochemistry and has related p27 levels to clinico-pathological characteristics, tumour cell proliferation, and the expression of other G1–S transition regulatory proteins. Low levels of p27 were common in CRCs; 11 per cent of the tumours expressed very low levels and 44 per cent had p27 labelling indices (LIs) below 50 per cent. Except for depth of tumour invasion, no significant correlation was found between p27 expression and Dukes' stage, differentiation, growth pattern, tumour type or lymphocytic infiltration. Interestingly, tumours expressing low or very low p27 LIs were predominantly found in the right colon (p=0·026). Expression of p27 was a strong predictor of survival, both in univariate and in multivariate survival analyses; patients with tumours of p27 LI less than 50 per cent had an impaired prognosis (p=0·0069). p27 expression did not correlate with tumour cell proliferation, or with expression of cyclin D1 or the retinoblastoma protein (pRb). These findings support the view that p27 not merely controls cell cycle progression, but might be associated with other mechanisms responsible for aggressive tumour behaviour in colorectal cancer. Copyright © 1999 John Wiley & Sons, Ltd.     

Is step section necessary for determination of complete pathological response in rectal cancer patients treated with preoperative chemoradiotherapy?

Park S Y, Chang H J, Kim D Y, Jung K H, Kim S Y, Park J W, Oh J H, Lim S‐B, Choi H S & Jeong S‐Y
(2011) Histopathology 59 , 650–659 Is step section necessary for determination of complete pathological response in rectal cancer patients treated with preoperative chemoradiotherapy? Aims: To assess the efficacy of the step section for determination of pathological complete response (pCR) in rectal cancer treated with preoperative chemoradiotherapy (CRT). Methods and results: Of 709 patients with rectal cancer who received preoperative CRT, 88 were initially diagnosed as having pCR. These 88 patients were re‐evaluated after two‐level step sections of the entire tumour by using Dworak’s regression grade. Additional serial step sections revealed residual tumour cells in seven of 88 patients (7.95%), all of whom were upgraded to regression grade 3 (near total regression) from regression grade 4 (total regression). Of these seven patients, one (14.3%) showed tumour recurrence, compared with 11 of 81 (13.6%) patients with a final regression grade of 4. Neither recurrence rate nor disease‐free survival rate differed significantly between these two groups (P > 0.5). Calcification was significantly more frequent in grade 3 than in grade four patients (71.4% versus 32.1%; P = 0.037), and acellular mucin pools were associated with better disease‐free survival (P = 0.022). Conclusions: Stratifying patient outcome by final regression grade after step section did not yield different outcomes in patients with initial pCR. If residual tumour cells are not identified on initial meticulous examination, further processing of step sections is not necessary.     

Alpha-methylacyl-CoA racemase (AMACR/P504S) protein expression in urothelial carcinoma of the upper urinary tract correlates with tumour progression

Alpha-methylacyl-CoA racemase (AMACR/P504S) is a useful biomarker of prostate cancer. We evaluated the expression of AMACR in upper urinary tract urothelial carcinomas with respect to associations with tumour stage, grade and metastasis-free survival. A total of 268 tumours were investigated immunohistochemically using a tissue microarray technique. AMACR expression was noted in 127 of 261 (48.7%) evaluated tumours and was associated with high tumour stage [58 of 139 (41.7%) pTa/pT1 vs. 69 of 122 (56.6%) pT2–pT4, P=0.019] and high tumour grade [44 of 137 (32.1%) low vs. 83 of 124 (66.9%) high grade, P<0.001]. In addition, AMACR expression was associated with the presence of tumour necrosis (P<0.001) and marked stromal desmoplasia (P=0.0026). This correlation indicates that increased AMACR expression might be related to hypoxia-induced changes in cancer cell metabolism, such as increased dependence on fatty acid oxidation for energy generation. Progressive disease was observed in 73 of 183 (39.9%) patients with solitary invasive carcinomas and was associated with AMACR expression (P=0.017). Multivariate analysis, however, proved only pT-stage >1 (P<0.001) and high tumour grade (P<0.001) to be independent predictors of patient outcome. In conclusion, AMACR expression correlated with advanced tumour stage and grade and may serve as an additional prognostic indicator in upper urinary tract urothelial cancer.     

Expression of p21WAF1 in Astler-Coller stage B2 colorectal cancer is associated with survival benefit from 5FU-based adjuvant chemotherapy

In several, but not all, previous studies, positive p21^WAF1 expression has been suggested as an indicator of a good prognosis in patients with stage III/IV colorectal cancer. However, it is not known whether the same is true for stage B2 patients. The purpose of this study is to assess the influence of p21^WAF1 expression in tumor cells on disease-free survival (DFS) and overall survival (OS) of Astler–Coller stage B2 and C patients with colorectal cancer who underwent 5-fluorouracil-based adjuvant chemotherapy. Nuclear p21^WAF1 was detected by immunohistochemistry in tissue microarrays from 275 colorectal cancers. The expression of p21^WAF1 was associated with DFS (p = 0.025) and OS (p = 0.008) in the subgroup of stage B2 patients that was treated with adjuvant chemotherapy. In multivariate analysis, it remained the only independent prognostic parameter in relation to DFS and OS (p = 0.035 and p = 0.02, respectively). In the subgroup of 72 stage B2 patients with positive p21^WAF1 expression but not in the subgroup of 61 stage B2 patients with negative p21^WAF1 expression, adjuvant chemotherapy was associated with better DFS (85% 5-year survival versus 65% without chemotherapy, p = 0.03) and OS (96% versus 82%, p = 0.014). In the combined stage B2 and C group of patients treated with adjuvant chemotherapy, positive p21^WAF1 expression was also associated with better DFS and OS (p = 0.03, p = 0.002, respectively). Expression of p21^WAF1 in colorectal tumor cells identifies a subgroup of Astler–Coller stage B2 patients who could benefit significantly from 5FU-based chemotherapy and may improve the selection of patients for adjuvant chemotherapy.     

Nuclear expression of N-cadherin correlates with poor prognosis of nasopharyngeal carcinoma

Luo W‐R, Wu A‐B, Fang W‐Y, Li S‐Y & Yao K‐T (2012) Histopathology  61, 237–246 Nuclear expression of N‐cadherin correlates with poor prognosis of nasopharyngeal carcinoma Aims: To investigate the aberrant expression of N‐cadherin in nasopharyngeal carcinoma (NPC) and its prognostic significance. Methods and results: Immunohistochemical staining for N‐cadherin protein was performed on tissue microarray (TMA) from 122 NPC patients. Cytoplasmic N‐cadherin was observed in 42.6% and nuclear N‐cadherin in 45.1% of NPC tissues. High expression of cytoplasmic and nuclear N‐cadherin was associated with a majority of the clinicopathological variables, including lymph node metastasis, distant metastasis and clinical stage. Cytoplasmic N‐cadherin was associated positively with nuclear N‐cadherin expression (P = 0.000). In univariate analysis, cytoplasmic N‐cadherin showed no significant impact on patient prognosis. In contrast, the overall survival was significantly shorter in patients with high nuclear N‐cadherin than those with low levels of staining (P = 0.002). A high expression of nuclear N‐cadherin predicted poorer survival in patients with late stage disease (P = 0.033), but not those with early tumour stage. In addition, multivariate analysis showed nuclear N‐cadherin to bean independent prognostic marker for NPC patients (P = 0.024). Conclusions: Nuclear N‐cadherin expression may represent a valuable prognostic marker in NPC patients, especially those with late stage disease.     

Low expression of Granzyme B in colorectal cancer is associated with signs of early metastastic invasion

Salama P, Phillips M, Platell C & Iacopetta B
(2011) Histopathology 59 , 207–215 Low expression of Granzyme B in colorectal cancer is associated with signs of early metastastic invasion Aims: Tumour‐infiltrating forkhead box P3 (FoxP3⁺) regulatory T cells (T_regs) have stronger prognostic significance than cytotoxic CD8⁺ T cells in colorectal cancer (CRC). Because there is evidence that some tumour‐infiltrating CD8⁺ T cells may be inactive, the present study aimed to investigate the prognostic significance of Granzyme B, one of the major effector molecules of T cells. Methods and results: A tissue microarray containing 963 CRCs was stained immunohistochemically for Granzyme B and the level of expression quantified by digital image analysis. Granzyme B expression was higher in tumours with microsatellite instability (P < 0.0001), a dense lymphocytic infiltrate (P < 0.0001) and location in the proximal colon (P = 0.009), but lower in tumours with vascular invasion (P = 0.007), perineural invasion (P =0.041) and positive nodal status (P < 0.001). Elevated expression of Granzyme B was associated with improved survival on univariate analysis (hazard ratio = 0.65; 95% confidence interval 0.51–0.84; P = 0.001), but not in a multivariate model that included stage, vascular invasion and FoxP3⁺ T_reg cell density. Conclusions: Low expression of Granzyme B was associated with early signs of metastasis in CRC. The stronger prognostic significance of FoxP3⁺ T_regs is in keeping with animal models that suggest these cells act as gatekeepers for the release of Granzyme B from CD8⁺ T cells.     

The influence of transforming growth factor-α, cyclooxygenase-2, matrix metalloproteinase (MMP)-7, MMP-9 and CXCR4 proteins involved in epithelial-mesenchymal transition on overall survival of patients with gastric cancer

Fanelli M F, Chinen L T D, Begnami M D, Costa W L Jr, Fregnami J H T, Soares F A & Montagnini A L
(2012) Histopathology  61, 153–161 The influence of transforming growth factor‐α, cyclooxygenase‐2, matrix metalloproteinase (MMP)‐7, MMP‐9 and CXCR4 proteins involved in epithelial–mesenchymal transition on overall survival of patients with gastric cancer Aims: Determination of prognostic parameters that are predictive of survival of gastric cancer (GC) may allow better identification of patients who could benefit from current chemotherapy regimens. To assess the correlation between tumour progression and epithelial–mesenchymal transition (EMT), we assayed the expression levels of selected molecules involved in EMT [CD44, transforming growth factor (TGF)‐α, cyclooxygenase‐2 (COX‐2), matrix metalloproteinase (MMP)‐7, MMP‐9 and C‐X‐C chemokine receptor (CXCR4)], and correlated these with overall patient survival (OS) and disease stage. Methods and results: Medical records and pathological biopsy results of 137 patients with GC were evaluated retrospectively. Spearman’s correlation analysis showed that expression of CXCR4 was correlated significantly with the expression of all other proteins studied. In contrast, COX‐2 expression correlated significantly with the expression of only MMP‐7 (P = 0.011), MMP‐9 (P = 0.015) and CXCR4 (P = 0.013). We observed significant negative correlations between OS and the expression of TGF‐α (P = 0.017), COX‐2 (P < 0.001), CXCR4 (P = 0.010), MMP‐7 (P = 0.020) and MMP‐9 (P = 0.015). On multivariate analysis, only COX‐2 was an independent prognostic factor for OS [hazard ratio (HR) = 3.34; 95% confidence interval (CI): 1.43–9.75; P = 0.002). Conclusions: COX‐2, TGF‐α, MMP‐7, MMP‐9 and CXCR4 are associated with poor OS in gastric cancer.     

Prognostic value of ABCG2 in moderately and poorly differentiated intrahepatic cholangiocarcinoma

Larbcharoensub N, Sornmayura P, Sirachainan E, Wilasrusmee C, Wanmoung H & Janvilisri T
(2011) Histopathology 59 , 235–246 Prognostic value of ABCG2 in moderately and poorly differentiated intrahepatic cholangiocarcinoma Aims: Intrahepatic cholangiocarcinoma (ICC) is a primary hepatic malignancy derived from cholangiocytes. The survival rate of ICC patients is very low, and conventional chemotherapy is not effective in prolonging long‐term survival. Adenosine 5′‐triphosphate (ATP)‐binding cassette (ABC) transporters mediate the transport of various substances in several cellular processes. The expression of ABCB1, ABCC1 and ABCG2 has been implicated in multidrug resistance and poor prognosis in several types of cancer. The aim of this study was to examine their expression in normal cholangiocytes and ICC tissues. Methods and results: Immunohistochemistry was employed to evaluate the expression of these transporters in 60 cases of ICC with respect to clinicopathological features and patient outcome. The proportions of cases with loss of ABCB1, ABCC1 and ABCG2 expression were 93.3%, 68.3% and 50%, respectively. Only the loss of ABCG2 was related to a worse prognosis (P = 0.031), and was associated with lymph node involvement (P = 0.003) and higher tumour grade (P = 0.028). Furthermore, multivariate analysis showed that the loss of ABCG2 expression was an independent prognostic factor in patients with moderately or poorly differentiated ICC (P = 0.02). Conclusions: These results suggest that ABCG2 may be involved in cholangiocarcinogenesis; the loss of its expression may enhance tumour progression and contribute to aggressive growth of ICC.     

Prognostic value of the MicroRNA regulators Dicer and Drosha in non-small-cell lung cancer: co-expression of Drosha and miR-126 predicts poor survival

Background

Dicer and Drosha are important enzymes for processing microRNAs. Recent studies have exhibited possible links between expression of different miRNAs, levels of miRNA processing enzymes, and cancer prognosis. We have investigated the prognostic impact of Dicer and Drosha and their correlation with miR-126 expression in a large cohort of non-small cell lung cancer (NSCLC) patients. We aimed to find patient groups within the cohort that might have an advantage of receiving adjunctive therapies.

Methods

Dicer expression in the cytoplasm and Drosha expression in the nucleus were evaluated by manual immunohistochemistry of tissue microarrays (TMAs), including tumor tissue samples from 335 patients with resected stages I to IIIA NSCLC. In addition, in situ hybridizations of TMAs for visualization of miR-126 were performed. Kaplan–Meier analysis was performed, and the log-rank test via SPSS v.22 was used for estimating significance levels.

Results

In patients with normal performance status (ECOG?=?0, n?=?197), high Dicer expression entailed a significantly better prognosis than low Dicer expression (P?=?0.024). Dicer had no significant prognostic value in patients with reduced performance status (ECOG?=?1–2, n?=?138). High Drosha expression was significantly correlated with high levels of the microRNA 126 (miR-126) (P?=?0.004). Drosha/miR-126 co-expression had a significant negative impact on the disease-specific survival (DSS) rate (P?<?0.001). Multivariate analyses revealed that the interaction Dicer*Histology (P?=?0.049) and Drosha/miR-126 co-expression (P?=?0.033) were independent prognostic factors.

Conclusions

In NSCLC patients with normal performance status, Dicer is a positive prognostic factor. The importance of Drosha as a prognostic factor in our material seems to be related to miR-126 and possibly other microRNAs.

     

Cytoplasmic expression of oestrogen receptor beta (ERβ) as a prognostic factor in vulvar squamous cell carcinoma in elderly women

Zannoni G F, Prisco M G, Vellone V G, De Stefano I, Vizzielli G, Tortorella L, Fagotti A, Scambia G & Gallo D
(2011) Histopathology   59 , 909–917 Cytoplasmic expression of oestrogen receptor beta (ERβ) as a prognostic factor in vulvar squamous cell carcinoma in elderly women Aims: To investigate the prognostic value of cytoplasmic oestrogen receptor beta (ERβ) expression in a series of untreated patients with non‐human papillomavirus (HPV)‐related vulvar cancer. Methods and results: Immunohistochemistry was carried out using a polyclonal rabbit anti‐human ERβ antibody. The nuclear and cytoplasmic expression of ERβ was evaluated in 33 patients. Cytoplasmic immunoreactivity was correlated with histopathological and molecular parameters (Ki67, p21), disease‐free survival (DFS) and overall survival (OS). The expression of cytoplasmic ERβ was found to be associated with grade (P = 0.006), while no association was found with any of the remaining variables examined. Cases with high cytoplasmic ERβ expression showed lower DFS and OS compared to cases with low cytoplasmic ERβ (P = 0.007, P = 0.01, respectively). There was also a progressive decline in both the DFS and OS with increasing tumour size (P = 0.05, P = 0.07, respectively) and with increasing depth of infiltration (P = 0.14, P = 0.07, respectively). On multivariate analysis, only tumour size and cytoplasmic ERβ staining retained an independent negative prognostic role for DFS and OS. Conclusions: The assessment of cytoplasmic ERβ expression could be helpful to identify poor prognosis in elderly patients with non‐HPV‐related vulvar squamous cell carcinoma (SCC).     

Cancer stem cell marker CD133+ tumour cells and clinical outcome in rectal cancer

Aims:  The CD133 antigen has been identified as a putative stem cell marker in colorectal cancer tissues. According to the cancer stem cell hypothesis, CD133+ cells determine long-term tumour growth and are therefore suspected of influencing clinical outcome. The aim was to investigate the prognostic value of CD133 expression in rectal cancer patients after preoperative radiation and curative resection.
Methods and results:  The expression of the CD133 stem cell antigen in a series of 73 patients with rectal cancer of various ypTNM stages was analysed by immunohistochemistry on formalin-fixed paraffin-embedded sections. The prognostic value of CD133 expression and other clinicopathological factors was evaluated. On multivariate survival analysis, the proportion of CD133+ cells was a significant ( P  < 0.05) prognostic factor for adverse disease-free survival and overall survival independent of ypTNM stage, tumour differentiation or lymphovascular invasion.
Conclusions:  CD133 stem cell antigen expression correlates with patient survival in rectal cancer, lending support to the current cancer stem cell hypothesis.     

Systematic assessment of the prognostic impact of membranous CD44v6 protein expression in colorectal cancer

Aims:  To assess systematically the membranous expression of CD44v6 in colorectal cancer by immunohistochemistry to determine its prognostic impact, the differential expression between primary and metastatic tumours and expression differences between the tumour centre and invasive front.
Methods and results:  Immunohistochemistry was performed for CD44v6 on two tissue microarrays. The first included 1279 colorectal tumours with full clinicopathological data. The second consisted of 50 matched primary and metastatic tumours sampled from the tumour centre and the invasive margin. A scoring system was tested by multiple observers. Receiver–operating characteristic curve analysis was used for cut-off point determination. Loss of membranous CD44v6 was associated with pT stage ( P  = 0.016; sensitivity 85.8%, specificity 20.1%), lymph node metastasis ( P  = 0.015; sensitivity 52.8%, specificity 55%), an infiltrating tumour margin ( P  < 0.001; sensitivity 71.4%, specificity 40%) and adverse prognosis ( P  = 0.011; hazard ratio 0.79, 95% confidence interval 0.7, 0.9), but was not an independent prognostic factor on multivariable analysis. Loss of expression occurred at the invasive front in both primary and metastatic lesions ( P  < 0.001).
Conclusions:  This study outlines an approach to help standardize the immunohistochemical evaluation of CD44v6 and similar markers in colorectal cancer and highlights a significant role for loss of membranous CD44v6 expression in colorectal cancer progression and prognosis.