High Ki-67 Proliferation Index Research Articles

Multifocal and Multicentric Breast Carcinoma: A Significantly More Aggressive Tumor than Unifocal Breast Cancer.

There are still many questions that surround multifocal or multicentric breast carcinoma (MMBC). The aim of this study was to analyze the clinicopathological characteristics of MMBC and provide feasible suggestions for therapy. A total of 156 cases of MMBC in 3,597 invasive ductal breast carcinomas were collected and reviewed. Some factors related with prognosis such as tumor size, lymph node metastasis and others were assessed in each tumor focus, and mismatches among foci were recorded. The majority of MMBC had aggregate dimensions over 2 cm (85.90%). The rate of axillary lymph node metastasis was 56.41% (88/156) compared to unifocal tumors of 33.01% (1,136/3,441). Most cases had higher Ki-67 proliferative indices (91/156). Mismatches in ER status were present in 6 cases, PR in 4 cases, proliferative index (Ki-67) in 9 cases and HER2-positive status in 2 cases. The larger aggregate dimension of tumor, the higher metastatic rate of axillary lymph node and the high Ki-67 proliferative index seen in most cases, suggest that MMBC is biologically more aggressive than unifocal breast cancer. In addition, every focus should be tested owing to the existence of different expressions of immunostaining between foci.

Abstract 3937: Diversity index as a novel predictor of tumor progression in breast cancer

Abstract Intratumoral genetic heterogeneity leads to tumor progression and therapeutic resistance. However, due to the difficulty associated with its assessment, application of intratumoral genetic heterogeneity as a prognostic or predictive marker is limited. We investigated the significance of Shannon diversity index as a tool for measuring genetic heterogeneity by performing fluorescence in situ hybridization of c-Myc gene in invasive breast cancers, and correlated the Shannon diversity index for c-Myc copy number variation with clinicopathologic features of tumor including patient survival. Shannon index for c-Myc copy number variation strongly correlated with average c-Myc copy number and was significantly higher in tumors with c-Myc genetic or regional heterogeneity than in those without c-Myc amplification. High Shannon index was associated with high histologic grade, lymphovascular invasion, p53 overexpression, high Ki-67 proliferation index, hormone receptor negativity, and HER2 amplification. In survival analyses, c-Myc amplification or c-Myc copy number gain was not associated with patient survival. However, a high level of Shannon index was associated with poor disease-free survival. In subgroup analyses, it was found to be an adverse prognostic factor in hormone receptor-positive group, but not in hormone receptor-negative group. In a validation set, high Shannon diversity index for c-Myc copy number variation was also found to be associated with poor survival of the patients. We further investigated the correlation with clinicopathologic features and predictive power of Shannon index using another gene, fibroblast growth factor receptor 1 (FGFR1) and observed that high Shannon index for FGFR1 gene copy number variation was an independent prognostic factor for poor clinical outcome in a whole group and in hormone receptor-positive subgroup. In conclusion, this study demonstrated that higher diversity index was associated with adverse pathologic parameters of breast cancer and poor clinical outcome suggesting that Shannon diversity index, which represents intratumoral genetic heterogeneity, can be used as a potential biomarker for tumor progression and prognostication in patients with breast cancer. Citation Format: Yul Ri Chung, Hyun Jeong Kim, Young A Kim, Mee Soo Chang, Ki-Tae Hwang, So Yeon Park. Diversity index as a novel predictor of tumor progression in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3937. doi:10.1158/1538-7445.AM2017-3937

Phosphohistone-H3 and Ki67: Useful Markers in Differentiating Dermatofibroma From Dermatofibrosarcoma Protuberans and Atypical Fibrohistiocytic Lesions.

Dermatofibromas (DF) are common, benign, skin tumors, usually easily differentiated from dermatofibrosarcoma protuberans (DFSP) by the presence of a relative low cellularity, lesser degree of infiltration of subcutaneous tissue, and immunohistochemical pattern (eg, FXIIIa in DF and CD34 in DFSP). Atypical fibrohistiocytic lesions (AFL) have features intermediate to DF and DFSP (trunk location, storiform pattern, infiltration of the subcutaneous tissue, and focal expression of both CD34 and Factor XIIIa). It is unclear if mitotic counts/degree of proliferation is helpful to distinguish DF from DFSP. To study the mitotic rate and proliferation index in DF, AFL/DFSP, anti-ki67, and anti-PHH3 were performed on 10 cases of DF (including 4 cellular DF), 10 standard DFSP, and 2 AFL. The proliferation index and mitotic figures were counted per square millimeter in a "hotspot" (in a fashion similar to mitotic counts in melanoma). All cases of DF showed much higher Ki67 proliferation index (P = 0.0001) along with increased mitotic figures both on H&E and with anti-PHH3 (P = 0.0001) when compared to AFL/DFSP. Our data indicate that DF has a higher proliferation index and mitotic counts when compared to superficial/peripheral portion of AFL and DFSP. This finding may be helpful in the differential diagnosis among these fibrohistiocytic lesions.

Analysis of various potential prognostic markers and survival data in clear cell renal cell carcinoma.

ABSTRACTPurpose Clear cell renal cell cancers frequently harbor Von Hippel-Lindau gene mutations, leading to stabilization of the hypoxia-inducible factors (HIFs) and their target genes. In this study, we investigated the relationship between vascular endothelial growth factor (VEGF), HIF-1α, HIF-2α, p53 positivity, microvessel density, and Ki-67 rates with prognostic histopathologic factors (Fuhrman nuclear grade, stage, and sarcomatoid differentiation) and survival in clear cell renal cell carcinomas.Material and Methods Seventy-two nephrectomy specimens diagnosed as clear cell renal cell carcinoma between 2000 and 2012 were reevaluated. Immunohistochemically VEGF, HIF-1α, HIF-2α, p53, CD34 (for microvessel density evaluation), and Ki-67 antibodies were applied to the tumor areas. The relationships of these antibodies with prognostic factors and survival rates were evaluated with statistical analyses.Results Mean survival time was 105.6 months in patients with ccRCC. Patients with high expression of VEGF, HIF-1α and HIF-2α positivity, a high Ki-67 proliferation index, and a high microvessel density evaluation score had a shorter survival time (p<0.05).Conclusions Our findings supported that with the use of these immunohistochemical markers, prognosis of renal cell carcinoma may be predicted at the first step of patient management. New treatment modalities targeted to HIF-1α and HIF-2α might be planned as well as VEGF-targeted therapies in the management of clear cell renal cell carcinomas.

Lymph node metastasis of presacral ependymoblastoma in a young child

Ependymoblastoma presenting outside the brain is rare in children. The overwhelming majority of presacral ependymal tumors are of the benign myxpapillary type. We present a case of ependymoblastoma in the presacral region of a four-year old child. The patient presented with a presacral mass and ipsilateral inguinal lymph node metastasis. Both masses revealed histologic and immunophenotypic features of ependymoblastoma associated with myxoid areas and high Ki-67 proliferation index. The masses were excised and the patient remained well for a year after diagnosis with no other therapy. This report emphasizes ependymoblastoma as rare entity in the differential diagnosis of presacral tumors in children and, up to our knowledge, the first report of inguinal lymph node metastasis of ependymoblastoma.

Immunohistochemical profiling including beta-catenin in conjunctival melanocytic lesions

Conjunctival melanocytic lesions encompass a group of clinically diverse, benign to malignant, neoplasms that may contain overlapping histopathological features, making definitive diagnosis challenging in some cases. In this series, we compared multiple immunohistochemical (IHC) markers in 11 conjunctival nevi, 10 primary acquired melanosis (PAM) lesions, and 11 conjunctival melanomas. Immunostains included the melanocytic markers HMB-45 and Melan-A, as well as the proliferative marker Ki-67. Loss of beta-catenin expression has been associated with more aggressive clinical disease in cutaneous melanoma, but its status in conjunctival melanocytic lesions is not known, therefore we incorporated beta-catenin immunohistochemical staining in our study. In this series, conjunctival melanomas had a higher Ki-67 proliferative index and HMB-45 immunoreactivity than did PAM lesions and conjunctival nevi (P<0.001). Melan-A was highly expressed in all 3 groups. Beta-catenin was more strongly expressed in melanomas and nevi than in PAM (P<0.001). There was high inter-grader reliability (Kappa=0.53). Overall, IHC labeling of HMB-45 and Ki-67 is increased in conjunctival melanomas compared to PAM or conjunctival nevi. Beta-catenin, an IHC marker previously unstudied in conjunctival melanocytic lesions, is not preferentially expressed in benign lesions and may play a different role in conjunctival atypia than it does in cutaneous melanoma.

Correlation between the Ki-67 proliferation index and response to radiation therapy in small cell lung cancer

BackgroundIn the breast cancer, the decision whether to administer adjuvant therapy is increasingly influenced by the Ki-67 proliferation index. In the present retrospective study, we investigated if this index could predict the therapeutic response to radiation therapy in small cell lung cancer (SCLC).MethodsData from 19 SCLC patients who received thoracic radiation therapy were included. Clinical staging was assessed using the TNM classification system (UICC, 2009; cstage IIA/IIB/IIIA/IIIB = 3/1/7/8). Ki-67 was detected using immunostained tumour sections and the Ki-67 proliferation index was determined using e-Count software. Radiation therapy was administered at total doses of 45–60 Gy. A total of 16 of the 19 patients received chemotherapy.ResultsPatients were divided into two groups, one with a Ki-67 proliferation index ≥79.77% (group 1, 8 cases) and the other with a Ki-67 proliferation index <79.77% (group 2, 11 cases). Following radiation therapy, a complete response (CR) was observed in six cases from group 1 (75.0%) and three cases from group 2 (27.3%). The Ki-67 proliferation index was significantly correlated with the CR rate (P = 0.05), which was significantly higher in group 1 than in group 2 (P = 0.04). The median survival time was 516 days for all patients, and the survival rates did not differ significantly between groups 1 and 2.ConclusionsOur study is the first to evaluate the correlation between the Ki-67 proliferation index and SCLC tumour response to radiation therapy. Our findings suggest that a high Ki-67 proliferation index might represent a predictive factor for increased tumour radiosensitivity.

Clinicopathologic and Prognostic Significance of Transducin-Like Enhancer of Split 1 Protein Expression in Invasive Breast Cancer.

PurposeTransducin-like enhancer of split 1 (TLE1) is a member of the TLE family of transcriptional co-repressors that control the transcription of a wide range of genes. We investigated the prognostic significance of TLE1 protein expression in breast cancers by using immunohistochemistry and explored the relationship of TLE1 with clinicopathological parameters.MethodsImmunohistochemistry was performed on 456 cases of breast cancer tiled on tissue microarrays. The relationship between TLE1 expression in normal breast specimens and ductal carcinoma in situ (DCIS) was also analyzed.ResultsTLE1 was highly expressed in 57 of 456 (12.5%) carcinoma samples. TLE1 was more frequently expressed in DCIS and invasive breast cancers than in normal breast tissue (p=0.002). High expression of TLE1 significantly correlated with negative lymph node (LN) metastasis (p=0.007), high histologic grade (p<0.001), estrogen receptor negativity (p<0.001), progesterone receptor negativity (p<0.001), human epidermal growth factor receptor 2 (HER2) positivity (p<0.001), and high Ki-67 proliferation index (p<0.001). Based on intrinsic subtypes, high TLE1 expression was strongly associated with HER2+ and triple-negative breast cancers (TNBC) (p<0.001). Survival analysis demonstrated no significant association between TLE1 expression and disease-free survival (DFS) (p=0.167) or overall survival (OS) (p=0.286). In subgroup analyses, no correlation was found between TLE1 expression and DFS or OS according to LN status or intrinsic subtype.ConclusionHigh TLE1 expression is significantly associated with the HER2+ and TNBC subtypes. This is the first study documenting immunohistochemical expression of TLE1 in invasive breast cancer and its association with clinicopathological parameters, prognosis, and intrinsic subtype.

MicroRNA-222 Expression as a Predictive Marker for Tumor Progression in Hormone Receptor-Positive Breast Cancer.

PurposeThe microRNA-221/222 (miR-221/222) gene cluster has been reported to be associated with the promotion of epithelial-mesenchymal transition (EMT), downregulation of estrogen receptor-α, and tamoxifen resistance in breast cancer. We studied the expression of miR-222 in human breast cancer samples to analyze its relationship with clinicopathologic features of the tumor, including estrogen receptor status, expression of EMT markers, and clinical outcomes.MethodsQuantitative real-time polymerase chain reaction was performed to detect the expression of miR-222 in 197 invasive breast cancers. Expression of EMT markers (vimentin, smooth muscle actin, osteonectin, N-cadherin, and E-cadherin) was evaluated using immunohistochemistry.ResultsHigh miR-222 levels were associated with high T stage, high histologic grade, high Ki-67 proliferation index, and HER2 gene amplification. Its expression was significantly higher in the luminal B and human epidermal growth factor receptor 2-positive (HER2+) subtypes than in the luminal A and triple-negative subtypes. In the hormone receptor-positive subgroup, there was a significant negative correlation between miR-222 and estrogen receptor expression, and miR-222 expression was associated with EMT marker expression. In the group as a whole, high miR-222 expression was not associated with clinical outcome. However, subgroup analyses by hormone receptor status revealed that high miR-222 expression was a poor prognostic factor in the hormone receptor-positive subgroup, but not in the hormone receptor-negative subgroup.ConclusionThis study showed that miR-222 is associated with down-regulation of the estrogen receptor, EMT, and tumor progression in hormone receptor-positive breast cancer, indicating that miR-222 might be associated with endocrine therapy resistance and poor clinical outcome in hormone receptor-positive breast cancer.

Anaplastic lymphoma kinase expression and gene alterations in glioblastoma: correlations with clinical outcome

AimsTo study anaplastic lymphoma kinase (ALK) protein expression and possible underlying gene alterations in glioblastoma (GBM), correlating them with clinical outcome.MethodsWe studied ALK immunohistochemical expression and fluorescent in situ hybridisation...

Prognostic significance of centromere 17 copy number gain in breast cancer depends on breast cancer subtype

Increased copy number of chromosome enumeration probe (CEP) targeting centromere 17 is frequently encountered during HER2 in situ hybridization (ISH) in breast cancer. The aim of this study was to clarify the clinicopathologic significance of CEP17 copy number gain in a relatively large series of breast cancer patients. We analyzed 945 cases of invasive breast cancers whose HER2 fluorescence ISH reports were available from 2004 to 2011 at a single institution and evaluated the association of CEP17 copy number gain with clinicopathologic features of tumors and patient survival. We detected 186 (19.7%) cases of CEP17 copy number gain (CEP17≥3.0) among 945 invasive breast cancers. In survival analysis, CEP17 copy number gain was not associated with disease-free survival of the patients in the whole group. Nonetheless, it was found to be an independent adverse prognostic factor in the HER2-negative group but not in the HER2-positive group. In further subgroup analyses, CEP17 copy number gain was revealed as an independent poor prognostic factor in HER2-negative and hormone receptor-positive breast cancers, and it was associated with aggressive histologic variables including high T stage, high histologic grade, lymphovascular invasion, p53 overexpression, and high Ki-67 proliferative index. In conclusion, we found that elevated CEP17 count can serve as a prognostic marker in luminal/HER2-negative subtype of invasive breast cancer. We advocate the use of the dual-colored fluorescence ISH using CEP17 rather than the single-colored one because it gives additional valuable information on CEP17 copy number alterations.

Prognostic Value of a Category Based on Electron Microscopic Features of Clival Chordomas.

Skull base chordomas are clinically malignant because of the difficulty of total removal and the high recurrence rate. Because the disease-free survival after surgery is currently unpredictable, there is a need for new parameters, obtained from histologic analyses of the resection specimen, that allows a risk stratification of patients with chordoma. In recent years, electron microscopic diagnoses were introduced into the clinical practice for the diagnosis of chordoma in our department. Clinical outcomes and electron microscopic features were retrospectively reviewed in the study. The electron micrograph shows that clival chordoma can be divided into cell-dense type (CDT) and matrix-rich type (MRT). Of all the patients with chordoma, complete data from 27 patients were obtained. There were 12 patients in the CDT group and 15 patients in the MRT group. The paraffin-embedded tissue samples were stained with Ki-67 antibody. The prognostic values of electron microscopic classification were compared between the 2 groups. There were no statistical differences in the gender (P= 0.704) and age distribution (P= 0.243) between the 2 groups. There was also no statistical difference concerning the constitution of primitive tumors and recurrent tumors between the 2 groups (P= 0.706). The CDT group had a higher mortality rate than the MRT group (P= 0.037). The tumors in the CDT group were prone to recurrence and the need for reoperation within 1 year after surgery, which is statistically different from that in the MRT group (P < 0.001). Chordoma tumors of 23 patients (85.2%) stained positive for Ki-67. CDT chordomas had a higher Ki-67 proliferation index than the MRT chordomas (P= 0.013). The present study demonstrates the utility of the ultrastructural features in the prognostic outcome of patients with chordoma. According to the ultrastructures of chordomas, they can be divided into CDT and MRT. CDT chordoma cells have a more aggressive proliferative ability. Patients with CDT have a poor prognostic factor in clival chordoma, which has a higher risk of recurrence and a shorter survival.

Perioperative Risk Assessment of Patients with Gliomatosis Cerebri

Gliomatosis cerebri is a rare diffusely infiltrating malignant glial neoplasm. Presenting symptoms include seizures, neurologic deficits, and frequently symptoms related to increased intracranial pressure (ICP). Surgical intervention, including brain biopsy, may induce worsening of these neurologic symptoms. We reviewed our database to identify prognostic and risk factors for perioperative deterioration specifically associated with elevated ICP. Between 2006 and 2014, 78 patients were treated for gliomatosis cerebri. Ten patients required perioperative emergent treatment for elevated ICP. The clinical course and outcome of these 10 patients (study group) were characterized and compared with the remaining 68 patients. The study group patients developed life-threatening symptoms of increased ICP and required urgent decompressive craniectomy (n= 5 urgent decompressive craniectomy after biopsy, n= 2 urgent decompressive craniectomy on admission) or aggressive medical therapy (n= 3). Demographic and clinical variables were similar in both groups. In patients with severe symptoms of increased ICP, enhancing tumor volume was significantly greater than in asymptomatic patients. Radiologic evidence of obliteration of the basal cisterns and herniation was more common in symptomatic patients. The proliferation index in the biopsy specimens of tumors was also significantly higher in patients with symptomatic ICP elevation. Clinical symptoms and radiologic appearance suggestive of elevated ICP at presentation, volume of contrast enhancement, and high Ki-67 proliferation index may predict the need for aggressive rapid treatment to control ICP in a small but significant subset of patients with GC. Further studies are needed to clarify the biologic basis for the unusual clinical course in these tumors.

Diagnosis of Gastrointestinal Stromal Tumors Using Endoscopic Ultrasound Guided Fine Needle Aspiration: The Value of Cellblock and Immunohistochemistry

Introduction: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal (GI) tract. Their clinical management depends on their risk assessment based on tumor size, location, mitotic count, proliferation index, and histologic grade. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is a common procedure for diagnosing GIST. A recent study reported a discrepancy of immunohistochemical results between the cytology and the surgical resection due to the cytolyte fixation of cytology material. The aim of this study was to analyze our experience on EUS-FNA for establishing diagnosis and malignant risk evaluation of GIST. Methods: A retrospective analysis of adult EUS-FNA of submucosal lesions in the upper GI tract was performed (n=9). Specimens were obtained using a 22 G procore, or a 25 G sharkcore needle from stomach (n=6), duodenum (n=1), esophagus (n=1) and rectum (n=1). Results: The tumor size ranged from 1.3-6.4 cm. All cases yielded sufficient material for cytologic and histological evaluation. Four cases (44.4%) were diagnosed as GIST based on histologic and immunohistochemical findings (positive for CD117 and CD34, negative for desmin, smooth muscle actin, and S-100). One case was classified as high grade, high risk GIST based on mitotic rate (15/5mm2) and high Ki-67 proliferation index (25%). The subsequent resection confirmed the cytology impression. Two cases were classified as low grade and low risk (Ki-67 < 5%). The remaining two cases were diagnostic or suggestive of leiomyomas (n=1, 11.1%) or normal smooth muscle cells (n=1, 11.1%). Conclusion: In this limited sample, EUS-FNA of GI submucosal lesions yielded sufficient material for cellblock preparation and immunohistochemistry to establish the diagnosis of GIST and to perform the evaluation of tumor grade and risk, using either the procore or sharkcore needles. We use formalin as the fixative solution for all cellblock material. There was no discrepancy between the cytology and surgical specimens on CD117 and CD34.

Frontal glioblastoma multiforme may be biologically distinct from non-frontal and multilobar tumors

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and carries a grim prognosis. Lobar GBM, notably those localized to the frontal lobe, are generally more amenable to complete surgical resection, and may carry a better prognosis. The biology of differently localized GBM has been reported scarcely in terms of prognostic markers, including isocitrate dehydrogenase 1 (IDH1) mutation and O(6)-methylguanine-methyltransferase (MGMT) methylation. To our knowledge, there has been no evaluation in the literature of different proliferation indexes in different GBM locations in the brain. We performed a retrospective evaluation of our prospectively collected database to assess the rate of IDH1 positivity, MGMT methylation and Ki67 index for GBM located in the frontal lobes alone, lobar GBM in other supra-tentorial lobes and multilobar GBM. IDH1 mutated tumors were localized in the frontal lobes in 50.0%, whereas only 20.3% of IDH1 wild-type tumors were localized in the frontal lobe (p=0.006); MGMT methylated tumors were localized in the frontal lobe in 32.0% of the cases. Only 13.75% of the MGMT unmethylated tumors were localized to the frontal lobe (p=0.005); Tumors with higher Ki67 proliferation index were more likely to be localized in the frontal lobe (40.6% vs. 19.5%, p=0.019). This is the largest cohort of GBM assessed for these purposes in the literature. Frontal lobe GBMs may be intrinsically biologically distinct from GBM in other lobes and from multilobar tumors.

Ki67 expression in triple negative breast cancer: Correlation of Ki67 expression with other prognostic factors in breast cancer in Indian patients

Introduction: Triple negative breast cancer ( TNBC) cases are not sensitive to hormonal therapy and till date no specific targeted medication has been found for TNBC. The present study aims to know the expression of Ki67 in TNBC tissues and in non-TNBC tissues using immunohistochemistry and to do correlation analysis of ki 67 expression with other clinicopathological parameters. Material and Methods: The present study was conducted on 160 cases of breast cancer received as specimens from January to august 2016 in the Pathology Department, Sri Guru Ram Das institute of medical sciences, Amritsar. Histopathological typing and grading was done followed by immunohistochemistry for ER, PR, Her2neu and ki67. Results: Ki67-positive expression were identified in 86.6% TNBC cases (including 14 cases of strong Ki67 expression). By contrast, among 130 cases of non-TNBC, 98 cases were Ki67-positive, accounting for 75.3%,(only 2 cases showed strong positivity) indicating a significant difference compared with that in the TNBC group that Ki67 proliferation index was higher in the cases with size >2cm also cases with lymph node metastasis showed high Ki67 proliferation index. Conclusion: Ki-67 index is relatively higher in TNBC than in non-TNBC cases. Ki67 expression correlated with tumor size and lymph node metastasis in breast cancer in the present study. Thus the increased expression of Ki67 may predict the increased proliferation of breast cancer cells, increased invasiveness, faste r rate of growth and the high incidence of lymph node metastasis.

Genomic imbalances and microRNA transcriptional profiles in patients with mycosis fungoides.

Mycosis fungoides is the most common type of primary cutaneous T cell lymphoma. We have evaluated CDKN2A losses and MYC gains/amplifications by FISH analysis, as well as expression of miR-155 and members of the oncogenic cluster miR-17-92 (miR17, miR18a, miR19b, and miR92a) in MF patients with advanced disease. Formalin-fixed paraffin-embedded skin biopsies from 36 patients at diagnosis, 16 with tumoral MF (T-MF), 13 in histological transformation to a large T cell lymphoma (TR-MF), and 7 cases with folliculotropic variant (F-MF), were studied. Twenty cases showed genomic alterations (GAs): 8 (40%) had CDKN2A deletion, 7 (35%) showed MYC gain, and 5 (25%) exhibited both alterations. GAs were more frequently observed in F-MF (p=0.004) and TR-MF (p=0.0001) than T-MF. GAs were significantly higher in cases presenting lesions in head, neck, and lower extremities compared to those observed in trunk and upper extremities (p=0.03), when ≥25% neoplastic cells were CD30 positive (p=0.016) as well as in cases with higher Ki-67 proliferation index (p=0.003). Patients with GAs showed bad response to treatment (p=0.02) and short survival (p=0.04). Furthermore, MF patients showed higher miRNA expression compared to controls (p≤0.0223). T-MF showed higher miR17 and miR-18a expression compared to F-MF and TR-MF (p≤0.0387) while miR19b, miR92a, and miR-155 showed increased levels in F-MF and TR-MF with respect to T-MF (p ≤ 0.0360). Increased expression of miR17 and miR19b in GA group compared to cases without alterations (p≥0.0307) was also detected. Our results add new information about genomic imbalances in MF patients, particularly in F-MF, and extend the present view of miRNA deregulation in this disease.

The Relationship Between Intracholecystic Papillary-Tubular Neoplasms and Invasive Carcinoma of the Gallbladder.

The term intracholecystic papillary-tubular neoplasm (ICPN) is suggested by some authors for a group of exophytic lesions of the gallbladder. In our study, demographic, pathological, and immunohistochemical features of 45 ICPN cases and their relationship with invasive carcinoma were analyzed. A total of 45 ICPN cases were retrieved out of 7334 cholecystectomies performed between1996 and 2014. Cases were evaluated with regard to demographic, pathological, and immunohistochemical features. Correlation between the clinical and histopathological data and occurrence of invasion was sought. The incidence of ICPN was 0.61% in our series. Invasive carcinoma was observed in 56% of cases. Factors associated with invasion were diffuse high-grade dysplasia (P = .002), papillary growth pattern (P = .001), greatest diameter of the lesion, and high Ki67 proliferation index (P < .0001). Some authors have reported that small intracholecystic exophytic lesions without high-grade dysplasia are considered to be inconsequential. However, there are not enough data concerning the features of large lesions with high-grade dysplasia and their prognoses. Our data suggest that cases with diffuse high-grade dysplasia and tubulopapillary/papillary growth pattern, large tumor size, and high Ki67 proliferation index should be studied for the presence of invasion.

EZH2 Protein Expression and Tumor Response to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer.

Introduction Neoadjuvant chemotherapy (NAC) is the standard treatment for locally advanced breast cancer. However, some tumors will not respond to this treatment due to histological and molecular features. The protein EZH2 (enhancer of zest homolog 2) is a histone methyltransferase that is correlated with poorly differentiated breast carcinomas and aggressive tumor behavior. Purpose The present study evaluated the association between EZH2 expression and response to NAC, and its correlation with HER2 overexpression, estrogen and progesterone receptors (ER, PR) and Ki-67 proliferation index. Methods A total of 60 patients with locally advanced breast cancer treated with NAC were selected for this study. Twenty-three paraffin blocks had not enough material for tissue resection, and were not evaluated. A tissue microarray based in immunohistochemistry (IHC) analysis of EZH2 was performed for the remaining 37 specimens. Patients were divided into two groups based on response to NAC. Results EZH2 expression was significantly associated with markers of poor prognosis such as ER negativity (p = 0.001), PR negativity (p = 0.042) and high Ki-67 proliferation index (p = 0.002). High EZH2 expression was not correlated with the response to NAC. Conclusions Our data suggested that EZH2 protein expression may not correlate with the clinical response to NAC. Other studies with more patients are needed to confirm this observation.

Hypoxia-inducible proteins HIF1α and lactate dehydrogenase LDH5, key markers of anaerobic metabolism, relate with stem cell markers and poor post-radiotherapy outcome in bladder cancer

Purpose: To assess whether anaerobic metabolism, proliferation activity and stem cell content are linked with radioresistance in bladder cancer. Materials and methods: Tissue sections from 66 patients with invasive transitional cell bladder cancer treated with hypofractionated accelerated radiotherapy, was immunohistochemically analyzed for the Hypoxia-Inducible Factor 1α (HIF1α) and the anaerobic glycolysis enzyme lactate dehydrogenase 5 (LDH5). Proliferation index (Ki-67) and stem-cell marker (cluster of differentiation CD44, aldehyde dehydrogenase ALDH1) expression was also examined. Results: Both HIF1α and LDH5 expression were linked with high CD44 stem cell population (p = 0.001 and 0.05, respectively), while high Ki-67 proliferation index was linked with nuclear LDH5 expression (p = 0.03) and high histological grade (p = 0.02). A strong significant association of HIF1α (p = 0.0009) and of LDH5 (p < 0.0001) with poor local relapse free survival (LRFS) was noted, which was also confirmed in multivariate analysis. A significant association with overall survival was also noted. Silencing of lactate dehydrogenase LDHA gene in the human RT112 bladder cancer cell line, or exposure to oxamate (LDH activity inhibitor), resulted in strong radio-sensitization. Conclusions: HIF1α and LDH5 are markers of poor outcome in patients with bladder cancer treated with radiotherapy. Blockage of anaerobic metabolism may prove of importance in clinical radiotherapy.