II mRNA-binding Protein 3 Expression Research Articles

Insulin-like Growth Factor II mRNA-binding Protein 3 is a Highly Sensitive Marker for Intravascular Large B-cell Lymphoma: Immunohistochemical Analysis of 152 Pathology Specimens From 88 Patients.

Intravascular large B-cell lymphoma (IVLBCL) is a rare type of aggressive extranodal large B-cell lymphoma characterized by the selective growth of lymphoma cells within the lumina of blood vessels, particularly capillaries. IVLBCL lacks mass formation, and its diagnosis can be challenging. We analyzed the utility of insulin-like growth factor II mRNA-binding protein 3 (IMP3) immunohistochemistry for IVLBCL diagnosis in various organs. Double staining with paired box 5 (PAX5) was performed for validation. Overall, 152 pathological specimens (111 positive and 41 negative for IVLBCL) obtained from 88 patients with a diagnosis of IVLBCL were stained for IMP3 and IMP3/PAX5. As negative controls, 40 pathology specimens from 38 patients with no history of IVLBCL or other B-cell lymphomas were stained for IMP3, which comprised 31 benign pathological specimens from 29 patients in whom malignancy was suspected, 7 cases of appendicitis with intravascular and/or intralymphatic lymphoid proliferations, and 2 cases of intravascular natural killer/T-cell lymphoma. All mononuclear cells with cytoplasmic staining were considered positive for IMP3 expression, but expression restricted to germinal center B cells was excluded from evaluation. All 111 IVLBCL pathological specimens were positive for IMP3 and IMP3/PAX5. In addition, 11 of the 41 specimens originally diagnosed as IVLBCL-negative showed IMP3/PAX5 double-positive cells, raising the suspicion of IVLBCL. However, of the 40 negative control samples, IMP3-positive non-germinal center B cells were detected in only 2 samples ( P = 0.0131) and no intravascular IMP3-positive B cells suspicious for IVLBCL were identified. Altogether, IMP3 immunohistochemistry is a highly sensitive marker of IVLBCL and can be a helpful adjunct for IVLBCL diagnosis.

The utility of IMP3 immunohistochemical staining in differentiating nodular lymphocyte predominant Hodgkin Lymphoma from T-Cell/Histiocyte-Rich large B-Cell lymphoma

IntroductionNodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and T cell/histiocyte-rich large B-cell lymphoma (THRLBCL) have overlapping histological features that make their diagnosis challenging. Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is a recently proposed diagnostic marker for Hodgkin’s lymphoma. The aim of this study was to determine the ability of IMP3 in differentiating NLPHL from THRLBCL.MethodsIn this retrospective study, the formalin-fixed paraffin-embedded blocks from 56 patients (28 NLPHL and 28 large B cell lymphoma (LBCL, including 16 THRLBCL and 12 DLBCL, NOS) cases based on immunohistochemistry (IHC) were included. Sample sections were stained for IMP3 using IHC method. Moderate to strong staining in at least 10% of tumor cells was considered positive IMP3 expression.ResultsThe mean age of the patients was 41.25 ± 16.08 years old. The majority of the patients were male. There was a significant age difference between NLPHL (34.61 ± 16.44 years old) and LBCL (47.89 ± 12.85 years) groups (p = 0.001). No significant difference was seen in gender and site between NLPHL and LBCL groups. The expression of IMP3 was mainly strong in LBCL group, while it was heterogeneously distributed among NLPHL samples ranging from weak to strong (p < 0.001). It was determined that strong IMP3 expression at 55.00% can differentiate LBCL from NLPHL with 71.4% sensitivity and 71.4% specificity.ConclusionOur findings showed that IMP3 may be a good complement in differentiating NLPHL cases from THRLBCL.

A Promising Diagnostic Role of Immunohistochemical Expression of Insulin-Like Growth Factor II mRNA Binding Protein 3 (IMP3) in Pancreatic Lesions Using Endoscopic Ultrasound-Guided Fine Needle Aspiration (EUS-FNA) Cytology.

Poor prognosis and short survival of patients harboring pancreatic cancer emerge how advanced disease it is. In a trial to achieve the earliest and most accurate diagnosis to manage this progressive disease, we proposed that using endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) with an adjuvant diagnostic immunohistochemical marker would give better diagnostic results. IMP3 has gained recently wide attention, as many studies found that IMP3 has not only diagnostic but also prognostic role in different types of malignancies. This prospective work is to assess the diagnostic role of EUS-FNA combined with the immunohistochemical expression of IMP3 on different benign and malignant pancreatic lesions. The included pancreatic lesions (n = 140) were obtained by EUS-FNA technique and stained for IMP3 immunohistochemically. Paraffin blocks from patients who underwent excision (n = 92) or core biopsies (n = 48) were performed for confirming diagnosis. The combined method for diagnosis showed that IMP3 was positive in 78.7%, 91.7%, 100% PAC, mucinous neoplasm with high grade dysplasia, and IPMN with high grade dysplasia, respectively, while almost all benign lesions showed negative IMP3. Also, this method showed sensitivity (78.26%), specificity (95.83%), and accuracy (84.3%). EUS-FNA cytology with IMP3 could be a reliable diagnostic tool especially for assessment of malignant pancreatic lesions.

Expression of Insulin-like Growth Factor II mRNA-binding Protein 3 in Gallbladder Carcinoma.

Emerging evidence suggests that Insulin-like growth factor II mRNA-binding protein 3 (IMP3) promotes tumor progression in several human malignancies. We investigated whether IMP3 expression has clinicopathological and prognostic significance in gallbladder adenocarcinoma (GBAC). We examined immunohistochemical IMP3 expression in 204 GBACs and its associations with clinicopathological parameters and patient outcomes. The majority (87.7%) of GBACs exhibited at least focal cytoplasmic and membranous IMP3 immunoreactivity. Tumor-specific IMP3 expression highlighted proper muscle invasion, which was not detected in the corresponding hematoxylin and eosin-stained slides. This finding upgraded pathological tumor stage (pT) from pT1a to pT1b in four well-differentiated GBACs. High IMP3 expression was associated with high histological grade, advanced stage, and lymphatic invasion, as well as worse overall survival. Tumor-specific IMP3 expression in GBAC is helpful in determining the tumor extent, especially in well-differentiated tumors. High IMP3 expression reflects aggressive oncogenic behavior of GBAC. IMP3 expression may be used as a diagnostic and prognostic marker in GBAC.

Significance of Insulin-Like Growth Factor II Mrna-Binding Protein 3 (IMP3) Expression in Selected Thyroid Lesions

Background: Differentiation of benign from malignant follicular thyroid lesions remains difficult and the ability of molecular markers to differentiate between them still unclear. The aim of this study was to evaluate the usefulness of IMP3 expression to distinguish benign from malignant thyroid lesions. Methods: This is a retrospective study upon selected 57 thyroid lesions designated as; 7 cases of Hashimoto thyroiditis (HT), 10 cases of hyperplastic nodules (HN), 15 cases of follicular thyroid adenoma (FTA), 13 cases of conventional papillary thyroid carcinoma (PTC), 6 cases of follicular variant of papillary thyroid carcinoma (FV-PTC), and 6 cases of follicular thyroid carcinoma (FTC). Immunohistochemistry was applied on formalin-fixed, paraffin-embeded tissue blocks using IMP3. clinicopathological data were reviewed from patients' pathological reports and correlated with IMP3 expression. Results: IMP3 positivity was seen in1/7 cases (14.3%) of HT, 2/10 cases (20%) of HN, 4/15 cases (26.7%) of FTA, 12/13 cases of PTC, and in all (100%) FV-PTC & FTC cases. IMP3 staining was significantly increased from normal thyroid tissue up to malignant tumors (P<0.01). IMP3 showed 96% sensitivity and 78.1% specificity for malignant tumors. IMP3 expression was positively correlated with grade and tumor size in malignant cases (P<0.05). No significant correlation was found in IMP3 expression with patient age, sex, capsular invasion, lymphatic/vascular invasion, lymph node metastasis, distant metastasis and TNM stage. Conclusions: IMP3 is a potential diagnostic marker for thyroid cancer and can be a promising marker for distinguishing benign from malignant follicular patterned thyroid lesions.

Prognostic value of IMP3 immunohistochemical expression in triple negative breast cancer.

Triple negative breast cancer (TNBC) account for 12% to 17% of all breast cancers. It is a heterogeneous group of tumors associated with aggressive clinical course. Insulin-like growth factor II mRNA binding protein 3 (IMP3) belongs to a family of insulin-like growth factor type II (IGF2), which plays a key role in the transmission and stabilization of mRNA, cell growth, and migration during embryogenesis. Increased expression of IMP3 is associated with aggressive behavior of different tumor types, advanced clinical stage, distant metastasis, and shorter overall survival (OS).The study included 118 patients with breast carcinoma diagnosed as TNBC and immunohistochemical staining for estrogen receptors (ER), progesterone receptors (PR), epidermal growth factor receptor 2 (HER2/neu), Ki-67, and IMP3 was performed. Correlations between categorical variables were studied using the chi-square and the Mann–Whitney U test. For survival analysis, the Kaplan–Meier method, log-rank test and the Cox proportional hazard regression model were used.Positive expression of IMP3 protein was present in 35.6% of TNBC. The presence of basal morphology was observed in 46.6% of TNBC. Positive IMP3 expression was connected with larger size of tumor, higher clinical stage, and basal morphology (P = .039, P = .034, P < .001). Disease-free survival and OS were significantly shorter in IMP3 positive TNBC.According to results of our study IMP3 expression can be used as negative prognostic factor for triple negative breast carcinomas. Targeting IMP3 molecule could be an effective approach to the management of a triple negative breast cancer with new immunological therapies, which does not yet exist for this group of tumors.

Tumor-specific Expression of Insulin-like Growth Factor II mRNA-binding Protein 3 Independently Predicts Worse Survival of Patients With Adenocarcinoma of the Ampulla of Vater.

Insulin-like growth factor II mRNA-binding protein 3 (IMP3) plays an important role in the adhesion, invasion, and metastasis of tumor cells. Although emerging evidence suggests that IMP3 promotes tumor progression in several malignancies, the expression of IMP3 and its prognostic implication in adenocarcinoma of the ampulla of Vater (AVAC) has not been clarified to date. The IMP3 expression status in 87 AVAC tissues was examined using immunostaining, and its association with various clinicopathological features and outcome of patients with AVAC was investigated. The vast majority (87.4%) of AVAC cases displayed at least focal cytoplasmic and membranous IMP3 immunoreactivity in tumor cells, whereas IMP3 expression was consistently absent from normal biliary epithelial cells. Tumor-specific IMP3 expression was associated with submucosal and pancreatic invasion, which were not identified in the corresponding hematoxylin and eosin-stained slides. This finding led to up-staging of the pathological tumor stage in two cases of well-differentiated AVAC. In addition, high IMP3 expression was significantly associated with a poorly differentiated histology (p=0.026). Survival analyses revealed that high IMP3 expression independently predicted shorter recurrence-free (p=0.003) and overall (p=0.029) survival. Our study demonstrated tumor-specific IMP3 expression in AVAC, which will be helpful in determining invasion depth and tumor extent in patients with well-differentiated tumors, as well as indicating worse survival of patients with AVAC. Our data highlight IMP3 expression status as a potential diagnostic and prognostic marker for AVAC.

Prognostic significance of IMP-3 expression pattern in esophageal squamous cell carcinoma.

Esophageal cancer is one of the most malignant gastroenterological cancers. To improve the treatment outcomes of patients with esophageal squamous cell carcinoma (ESCC), a biomarker capable of predicting the malignant potential of the cancer cells is needed. The aim of the present study was to investigate the relationship between the expression pattern of insulin-like growth factor II m-RNA-binding protein 3 (IMP3), a promising cancer testis antigen for peptide vaccine therapy, in ESCC tumors and the outcomes of patients with ESCC. One hundred and seventy patients with ESCC who underwent a radical transthoracic esophagectomy between 2003 and 2005 at Tokai University Hospital were investigated. IMP3 expression was immunohistochemically analyzed using sections from surgically resected tumor specimens and metastatic lymph nodes. Of the 170 patients, 160 patients (94%) exhibited IMP3 positivity in the cytoplasm of their cancer cells (IMP3-positive group), while 10 patients (6%) were IMP3-negative (IMP3-negative group). No significant difference in the overall survival curves were observed between the IMP3-positive and IMP3-negative groups. When the survival analysis was confined to the 160 IMP3-positive patients, however, an invasive front-type IMP3 expression pattern (IF-type) was seen in 46 patients (29%) and a diffuse-type pattern (D-type) was seen in 114 patients (71%). A multivariate analysis also showed that an IF-type was a prognostic factor (HR =1.618, P=0.049). The overall survival curve for patients with an IF-type was significantly worse than that of D-type patients (P=0.001). An IF-type pattern of IMP3 expression might predict a poor outcome in patients with ESCC.

The complementary role of insulin-like growth factor II mRNA-binding protein 3 (IMP3) in diagnosis of Hodgkin's lymphoma

BackgroundHodgkin's Lymphoma (HL) is a peculiar subtype of lymphoid malignancies. The etiology of HL is still unknown. Insulin-like growth factor II mRNA-binding Protein 3 (IMP3) is a member of IMP family. In HL, IMP3 is expressed in the cytoplasmic compartment of the tumor cells (in both HRS cells & LP cells) against completely negative background of non-tumor cells except for residual germinal centers. Materials & MethodsOf 51 cases of Hodgkin's lymphoma (HL) referred to surgical pathology laboratory at oncology center, Mansoura University (OCMU), Egypt. All cases were stained for CD20, CD3, CD15, CD30 and IMP3. Regarding IMP3 antibody, The slides were then incubated with the Anti-IMP3, mouse monoclonal antibody (1:200, clone sc-365640, concentrated, California) that was used as primary antibody for IMP3 detection for 1 hour at room temperature, followed by incubation with the secondary antibody, poly HRP (horseradish peroxidase), conjugate for mouse/rabbit, for 20 minutes. ResultsIMP3 showed cytoplasmic immunoreactivity in 43 (83%) cases while 8 cases were negative. The sensitivity of combined CD30 & CD15, combined CD30 & IMP3, combined CD15 & IMP3 were 96%, 98% and 94% respectively. On the other hand, the sensitivity of CD30, CD15 and IMP3 alone were 92.2%, 68.6% and 84.3% respectively. All 23 studied cases of NSCHL, all the 17 cases of MCCHL, 7 out of 8 cases of LRCHL and the only case of LDCHL had predominant T-lymphocytes in their background. On the other hand, the 2 cases of NLPHL and only case of LRCHL had predominant B-lymphocytes in their background. ConclusionIMP3 is a novel marker that is expressed in large proportion of both types of HL against nearly negative background. It has no significant increase in sensitivity in detection of the tumor cells when combined with CD30. There are insignificant relations between IMP3 expression and different clinicopathological parameters. Further studies about IMP3 on a large scale of cases are required to confirm its mechanistic role in generation of HL.

Upregulation of insulin-like growth factor II mRNA-binding protein 3 (IMP3) has negative prognostic impact on early invasive (pT1) adenocarcinoma of the esophagus.

Therapeutic decisions in esophageal adenocarcinomas (EAC) restricted to mucosa (pT1a) or submucosa (pT1b) depend mainly on classic histomorphology-based criteria like tumor grading or lymphovascular invasion with limited success. There is a strong need for reliable pre-therapeutical biomarker-based evaluation also applicable on endoscopically obtained biopsies. Patients who underwent esophagectomy due to EAC in a high volume center between 1999 and 2016 were included. Tissue microarrays (TMA) were retrospectively established from the formalin-fixed and paraffin-embedded material of the resected specimens and immunohistochemically stained using a monoclonal primary antibody specific for IMP3. IMP3 staining intensity was scored manually according to a 3-tier-scoring system (negative, weak and strong). 371 EACs were interpretable for analysis. 109 patients (29%) had early invasive (pT1a/pT1b) and 262 patients (71%) locally advanced EAC (> pT2). 259 EACs (70%) revealed positive immunostaining for IMP3 including 167 strongly and 92 weakly positive. Early EAC had significantly lower IMP3 expression compared to advanced tumor stages (p < 0.0001). IMP3 positive pT1 EAC revealed higher levels of lymph node metastases (LNM) (p = 0.0001) and pT1b tumors showed higher rates of IMP3 positivity compared to pT1a (p = 0.007). Subdividing the submucosa in thirds, there was a significant trend for higher IMP3 expression with deeper tumor infiltration from pT1a to pT1b (sm3) (p = 0.0001). There was an association between IMP3 expression and shortened survival in pT1 EAC (p = 0.038). IMP3 expression correlates with depth of tumor infiltration, rate of LNM and is associated with worse outcome. Thus, IMP3 might be useful for therapeutic decisions in early-invasive EAC.

Analysis of IMP3 expression in primary tumor and stromal cells in patients with colorectal cancer.

Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is an oncofetal protein upregulated in tumor cells during carcinogenesis. The aim of the present study was to investigate the expression status of IMP3 in colorectal cancer (CRC) tissues and its clinical significance. Immunostaining was performed in 130 CRC samples, the association of IMP3 expression with clinicopathological characteristics was assessed and 58 patients were selected for survival analysis. To the best of our knowledge, the present study describes for the first time the expression of IMP3 in tumor stromal components of CRC. Stromal expression of IMP3 was detected in 24/130 (18.5%) CRC tissue specimens and was associated with tumor-node-metastasis (TNM) stage (stage III–IV, P=0.003), lymph node metastasis (P=0.006), lympho-vascular invasion (P=0.003), tumor border (P=0.013). Tumoral expression of IMP3 was detected in 94/130 (72.3%) of CRC specimens and was associated with T classification (T3-T4, P=0.027), tumor-node-metastasis (TNM) stage (stage III–IV, P=0.011), lymph node metastasis (P=0.048), tumor budding (>10 buds, P=0.005). Further study indicated that patients with IMP3 expressed in tumor cells and tumor stroma tend to have poorer overall survival rates (P=0.02 and P=0.06, respectively). Moreover, tumoral expression of IMP3 and TNM stage were identified to be independent prognostic factors in CRC. IMP3 was not only expressed in tumor cells but also in stroma cells. Stromal expression of IMP3 was associated with lymph node metastasis and advanced tumor TNM stage. Moreover, the survival analysis indicated that there is a significant association between IMP3 expression in tumor cells and a poorer overall survival rate in patients with CRC. The expression of IMP3 maybe a predicted factor for CRC patient.

Insulin-like growth factor II mRNA binding protein 3 expression in the non-muscle invasive bladder cancer and its relationships with the prognosis

Objective To investigate the expression of insulin-like growth factor Ⅱ mRNA binding protein 3 (IMP3) in non-muscle invasive bladder cancer and its relationship with the tumor recurrence and progression. Methods IMP3 protein expression was detected by immunohistochemistry in 130 cases of non-muscle invasive bladder cancer specimens who underwent transurethral resection the first time at Beijing Chao-Yang hospital, from October 2010 to October 2013. Besides, we analyzed 20 cases of muscle-invasive samples and 20 benign tissues adjacent to cancer as control. The 130 patients were followed up by telephone and other methods. According to the UICC-TNM standard.Survival analysis was calculated by using the Kaplan-Meier method, and the difference in survival curves was analyzed by using the log-rank test. For multiple analyses, The Cox proportional hazards regression model was used. Results The positive expression rate of IMP3 in 130 patients with non-muscle invasive bladder cancer was 59.2% (77/130), of which 30.0% (39/130) was weak expression, 29.2% (38/130) was strong. However there was 80.0% (16 /20) in muscle-invasive specimens, of which 20.0% (4/20) was weak, 60.0% (12/20) was strong (P=0.011). IMP3 was not detected in all benign tissues adjacent to cancer (P<0.001). All the 130 patients were followed-up for 5 to 69 months , 45 cases experienced disease recurrence, 20 patients had progressed and 12 cases died.IMP3 expression was significantly related to higher tumor stage (P<0.001), high tumor grade (P=0.014), and tumor recurrence (P=0.003). Kaplan-Meier plots and log-rank tests showed that patients with IMP3-positive tumors had a lower disease-free survival (P=0.002) and progression-free survival rate (P=0.010) than those with IMP3-negative tumors. In the multivariable Cox analysis, we found that IMP3 protein was an independent predictor of disease-free survival (P=0.010) in non-muscle invasive urothelial carcinoma of bladder. Conclusions IMP3 was not expressed in benign tissue adjacent to cancer, whereas highly expressed in bladder cancer, and high IMP3 expression is an independent prognostic factor in NMIBC that can identify the patients with a high potential to relapse. Key words: Insulin-like growth factor Ⅱ mRNA binding protein 3(IMP3); Non-muscle invasive bladder cancer(NMIBC); Prognosis

IMP3 and p16 expression in squamous cell carcinoma of the head and neck: A comparative immunohistochemical analysis.

Expression of p16 has been established as a good surrogate marker for high-risk human papillomavirus (HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC) patients, and it has been associated with an improved prognosis, irrespective of the actual HPV status. Conversely, the human insulin-like growth factor II mRNA binding protein 3 (IMP3) has been related to aggressiveness in several types of tumors. The aim of the present study was to investigate and compare p16 and IMP3 as markers of favorable and unfavorable behavior, respectively, in head and neck SCC (HNSCC), with particular reference to the HPV status. Both markers were analyzed by immunohistochemical analysis of 156 HNSCC samples originating from the oropharynx (n=81), oral cavity (n=44), larynx (n=15), hypopharynx (n=10) and nasopharynx (n=6). The HPV status was examined in a randomly selected representative subcohort (n=38) using polymerase chain reaction. Of the 156 HNSCC samples, 81 (51.9%) and 54 (34.6%) were positive for IMP3 and p16, respectively. IMP3 expression (P=0.022), p16 expression (P<0.001) and the combination of these markers (P<0.001) were significantly associated with tumor site. In particular, 69/81 (85%) OPSCC samples were positive for either one or both markers compared with 36/75 (48%) SCC samples from other sites. p16 expression was significantly associated with HPV infection (P=0.017) and a trend towards a negative association between IMP3 expression and HPV infection was observed (P=0.053). The results of the present study suggested that IMP3 and p16 are more frequently expressed in OPSCC compared with other HNSCCs. The prognostic impact of IMP3 on OPSCC remains to be investigated in a larger series with an extended follow-up period.

Prognostic value of high IMP3 expression in solid tumors: a meta-analysis.

BackgroundAccumulated studies have investigated the prognostic role of insulin-like growth factor II mRNA-binding protein 3 (IMP3) in various cancers, but inconsistent and controversial results were obtained. Therefore, we performed a systematic review and meta-analysis to investigate the potential value of IMP3 in the prognostic prediction of human solid tumors.Materials and methodsA systematic literature search in the electronic databases PubMed, Embase, Web of Science, and Cochrane library (updated to April 2016) was conducted to identify eligible studies. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for survival outcomes were calculated and gathered using STATA 12.0 software.ResultsA total of 53 studies containing 8,937 patients with solid tumors were included in this meta-analysis. High IMP3 expression was significantly associated with worse overall survival (OS) of solid tumors (HR =2.08, 95% CI: 1.80–2.42, P<0.001). Similar results were observed in cancer-specific survival (CSS), disease-free survival (DFS), recurrence-free survival (RFS), progression-free survival (PFS), and metastasis-free survival (MFS). Further subgroup analysis stratified by tumor type showed that elevated IMP3 expression was associated with poor OS in renal cell carcinoma (RCC), lung cancer, oral cancer, urothelial carcinoma, hepatocellular carcinoma (HCC), colorectal cancer, pancreatic cancer, gastric cancer, and intrahepatic cholangiocarcinoma (ICC).ConclusionThe current evidence suggests that high IMP3 expression is associated with poor prognosis in most solid tumors. IMP3 is a potential valuable prognostic factor and might serve as a promising biomarker to guide clinical decisions in human solid tumors.

Expression of IMP3 as a marker for predicting poor outcome in gastroenteropancreatic neuroendocrine neoplasms.

The aim of the present study was to investigate the expression and clinical significance of oncofetal protein insulin-like growth factor (IGF) II mRNA-binding protein 3 (IMP3) in the differentiation of gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN). A total of 162 patients who were diagnosed with GEP-NEN, and who underwent surgical or endoscopic resection from January 2006 to March 2013, were enrolled in the study, including 85 cases of grade (G)1 neuroendocrine tumors, 40 cases of G2 neuroendocrine tumors, 28 cases of G3 neuroendocrine carcinomas and 9 cases of mixed stage adenoneuroendocrine carcinomas. The clinical and pathological data were recorded for analysis. The expression of IMP3, cluster of differentiation (CD)44, IGF1 receptor (IGF1R) and matrix metalloproteinase (MMP)2 was determined by immunohistochemistry. SPSS 13.0 software was used for data processing and analyses, and P<0.05 was used to determine significance. Oncofetal protein IMP3 exhibited a high expression rate (74.69%) in GEP-NEN. IMP3-positive cases demonstrated significantly decreased overall and disease-free survival times, as compared with IMP3-negative cases (P=0.012). Overexpression of IMP3 was correlated with tumor grade, clinical stage, tumor size and poor prognosis (all P<0.05). Therefore, patients with overexpressed IMP3 had a poorer prognosis (P<0.01); COX regression analysis revealed that the overexpression of IMP3, the tumor grade, tumor size and metastasis of GEP-NEN were each associated with the clinical outcomes. The results also indicated that the expression rates of CD44, IGF1R and MMP2 in GEP-NEN were 19.75, 53.7 and 55.56%, respectively. While it was negatively associated with the expression of CD44 (r=-0.131; P=0.096), the expression of IMP3 was positively correlated with the expression of IGF1R and MMP2 (r=0.288, P<0.01; r=0.208, P=0.008). In addition, the expression levels of IGF1R and MMP2 were positively associated (r=0.687; P<0.01). In conclusion, high IMP3 expression levels were determined to be associated with a high disease stage in patients with GEP-NEN, thus it may serve as a predictor for metastasis and poor clinical outcomes in GEP-NEN.

Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is a marker that predicts presence of invasion in papillary biliary tumors

Biliary tumors showing intraductal papillary growth (Pap-BTs) include intraductal papillary neoplasm of the bile duct (IPNB) and papillary cholangiocarcinoma (CC). A differential diagnosis between IPNB and papillary CC currently remains challenging. The aim of the present study is to identify histological features and immunohistochemical markers of malignant potential such as tumor invasion in Pap-BTs. Subjects comprised 37 patients with Pap-BT (intrahepatic and perihilar [proximal], 27: 17 noninvasive and 10 invasive; distal, 10: all invasive). We examined histological features and the expression of p53, enhancer of zeste homolog 2, insulin-like growth factor II mRNA-binding protein 3 (IMP3), and DNA methyltransferase-1 in the intraductal area in Pap-BTs. Noninvasive Pap-BT was characterized by the presence of a low-grade dysplastic area, edematous stroma, and the absence of necrosis. The expression of p53, enhancer of zeste homolog 2, IMP3, and DNA methyltransferase-1 was significantly weaker in noninvasive Pap-BTs than in invasive Pap-BTs (P<.01). Diffuse cytoplasmic IMP3 expression was absent in noninvasive Pap-BTs. IMP3 showed the greatest specificity to predict a presence of invasion. A heatmap demonstrated that proximal noninvasive Pap-BTs and distal Pap-BTs may be completely different. In bile duct biopsies, the expression of IMP3 was the most precise predictor of invasion in Pap-BTs. In conclusion, Pap-BTs may be separated into 3 subgroups: (1) proximal noninvasive Pap-BT, corresponding to IPNB; (2) distal invasive Pap-BT, corresponding to papillary CC; and (3) the remaining Pap-BT including IPNB with associated adenocarcinomas, based on histological and immunohistochemical features. IMP3 may be a useful marker for predicting invasion in Pap-BT.

Clinicopathological Implication of Insulin-like Growth Factor-II mRNA-Binding Protein 3 (IMP3) Expression in Gastric Cancer.

The clinicopathological significance of oncofetal mRNA-binding protein, human insulin-like growth factor II mRNA-binding protein 3 (IMP3), in gastric carcinoma (GC) is not fully understood. Tissue microarray blocks with specimens from 346 patients with GC were constructed to evaluate the clinicopathological role of IMP3 expression in GC. These results were validated with an online dataset of 876 patients from the Kaplan-Meier Plotter. Sera from 15 controls and 57 patients with GC were collected in order to compare the levels of serum IMP3 between groups. High expression of IMP3 was significantly associated with poor prognosis. Survival curves from the Kaplan-Meier Plotter showed that high IMP3 expression was significantly related to worse disease-free survival and overall survival. Tissue overexpression of IMP3 might be used as a predictor of advanced disease or lymph node metastasis, and is associated with poorer prognosis in GCs.

Identification of a combined biomarker for malignant transformation in oral submucous fibrosis.

BackgroundOral submucous fibrosis (OSF) is a chronic progressive disease of the oral cavity that is considered a common potentially malignant disorder in South Asia. Areca nut chewing is the main etiological factor, but its carcinogenic mechanism has yet to be proven. The purpose of this study was to identify the useful biomarkers in predicting high‐risk patients with OSF.MethodsThirty‐six cases of OSF and six cases of normal oral mucosa (NOM) were used for this study. Immunohistochemical staining was performed for Ki67, cyclin D1, p16, p53, β‐catenin, c‐Jun, c‐Met, and insulin‐like growth factor II mRNA‐binding protein 3 (IMP3). The expression patterns of NOM served as guidelines for the scoring system.ResultsThe expression of Ki67, cyclin D1, c‐Met, IMP3, and β‐catenin showed a significant difference between OSF and NOM samples. The combined biomarkers of Ki67 and p16 showed significantly different expression between the transformation and non‐transformation groups. With discriminant analysis, we proposed a noble formula and cutoff value for predicting high‐risk patients with OSF.ConclusionThe notable biomarkers in our present study were Ki67 and p16 showing significantly different expression levels between the transformation and non‐transformation groups. With the identification of high‐risk patients with OSF, we can expect to develop more intensive treatment modalities, leading to the reduction in cancer transformation rate from OSF.

Insulin-like growth factor II messenger RNA-binding protein-3 is an indicator of malignant phyllodes tumor of the breast

The aim of this study was to elucidate the clinicopathological and prognostic significance of the expressions of insulin-like growth factor II mRNA-binding protein-3 (IMP3) and epidermal growth factor receptor (EGFR) in phyllodes tumors (PTs). Immunohistochemical staining for IMP3 and EGFR was performed in 130 cases of primary PTs (83 benign, 28 borderline, 19 malignant), 34 recurrent/metastatic PTs, and 26 fibroadenomas (FAs). Among the primary tumors, a high expression of IMP3 was significantly more frequently present in malignant PTs (17/19, 89%) than in the FAs (0/26, 0%), benign PTs (0/83, 0%) and borderline PTs (3/28, 11%). The recurrent and metastatic lesions of malignant PTs also showed high IMP3 expression (3/5 [60%] and 6/6 [100%], respectively). Most malignant PTs showed strong IMP3 expression at the interductal area or more diffusely, whereas weak and focal (low) expression of IMP3 was limited to the periductal area in FAs and benign PTs. EGFR overexpression was significantly correlated with tumor grade and high IMP3 expression. Overexpressions of IMP3 and EGFR were significantly associated with shorter periods of metastasis-free and disease-free survival. The results suggest that high expressions of IMP3 and EGFR with a characteristic staining pattern may be helpful for both identifying malignant PT and predicting the prognosis of these tumors.

Diagnostic value of IMP3 and mesothelin in differentiating pancreatic ductal adenocarcinoma from chronic pancreatitis

BackgroundThe discrimination between pancreatic ductal adenocarcinoma (PDA) and chronic pancreatitis may be confusing at both clinical and radiologic levels. So, the search for biomarkers able to distinguish both clinical conditions is of great interest. AimThis study was undertaken to assess the value of insulin-like growth factor II mRNA binding protein 3 (IMP3) and mesothelin to differentiate PDA from non-neoplastic/reactive pancreatic duct epithelium. MethodsImmunohistochemical staining for IMP3 and mesothelin was performed on 40 formalin-fixed, paraffin-embedded tissue sections of PDA, 20 biopsies of chronic pancreatitis and 10 normal pancreatic tissue obtained from tumor-free surgical margins. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy were calculated. ResultsIMP3 immunoreactivity was observed in 34 of 40 (85%) cases of PDA. The staining reaction was moderate to strong in 30 (75%) cases and diffuse in 26 (65%) cases. Eighteen of 20 (90%) biopsies of chronic pancreatitis were negative for IMP3, while the other two cases (10%) showed weak and focal IMP3 immunoreactivity. On the other hand, mesothelin demonstrated positive immunoreactivity in 30 of 40 (75%) cases of PDA. The staining reaction was moderate to strong in 24 (60%) cases and diffuse in 22 (55%) cases. Sixteen of 20 (80%) biopsies of chronic pancreatitis were negative for mesothelin, while weak and focal mesothelin staining was detected in the other 4 cases. All normal pancreatic tissues were negative for IMP3 and mesothelin expression. IMP3 showed higher sensitivity (85%) and specificity (90%) than mesothelin (75% and 80%, respectively). ConclusionsOur results showed that IMP3 immunostaining has a higher sensitivity and specificity than mesothelin for the diagnosis of PDA. IMP3 and mesothelin may be useful markers in distinguishing neoplastic from reactive lesions of the pancreas in instances where this is impossible by morphology alone in surgical pathology practice.