Primary renal angiosarcoma with extensive hemorrhage: CT and MRI findings.

Primary angiosarcomas of the kidney are very rare, but highly aggressive tumors showing poor prognosis. Patients frequently complain of flank pain, hematuria, or a palpable mass. We present a case of primary renal angiosarcoma occurring in a 61-year-old man. CT images depicted a huge exophytic mass (16 cm in diameter) in the right kidney, exhibiting extensive hemorrhage. The mass showed centripetal peripheral nodular enhancement on dynamic contrast-enhanced images. Furthermore, MR imaging revealed a tangled mesh of tumor vessels in the periphery of the mass. We suggest its inclusion in the differential diagnosis of cases of hemorrhagic renal tumors with prominent vasculature.

B7-H3 and B7-H4 expression in phyllodes tumors of the breast detected by RNA in situ hybridization and immunohistochemistry: Association with clinicopathological features and T-cell infiltration.

Phyllodes tumors are rare biphasic breast tumors with the potential for both local recurrence and distant metastasis. The aberrant expression of B7-H3 and B7-H4 B7 molecules could be potential targets for future development of immunotherapeutic approaches. This work was undertaken to evaluate the expression of B7-H3 and B7-H4 in phyllodes tumors and assess the association with the grade and clinical behavior of phyllodes tumors. In addition, the roles of B7-H3 and B7-H4 in the regulation of tumor immune surveillance were evaluated by assessing the relationship between B7-H3/B7-H4 expression and T-cell infiltration. The messenger RNA and protein expression of B7-H3/B7-H4 were determined by RNAscope in situ hybridization and immunohistochemistry, respectively, in 101 phyllodes tumors (60 benign, 26 borderline, and 15 malignant) using a tissue microarray. Immunohistochemistry for CD3 and CD8 was also performed. B7-H3 messenger RNA and protein appeared to be concentrated mainly in the stromal compartment of phyllodes tumors. However, B7-H4 messenger RNA and protein were undetectable in the stromal compartment of phyllodes tumors. Stromal B7-H3 messenger RNA and protein expression were noted in 10 (16.7%) and 31 (51.7%) of 60 benign phyllodes tumors, 12 (46.1%) and 20 (76.9%) of 26 borderline phyllodes tumors, and 10 (66.7%) and 13 (86.7%) of 15 malignant phyllodes tumors, respectively. Stromal B7-H3 messenger RNA and protein expression increased as phyllodes tumors progressed from benign to borderline and finally to the malignant grade (Pearson's R = 0.411, p < 0.001 and Pearson's R = 0.293, p = 0.003, respectively). The recurrence rate was higher in the stromal B7-H3 messenger RNA or protein-positive group than in the negative group, but this difference was not significant. Stromal B7-H3 protein expression inversely correlated with the densities of CD3+ and CD8+ T-cell infiltrates ( p = 0.001 and p = 0.027, respectively). These results suggest that B7-H3 is involved in the progression of phyllodes tumors and may contribute to their immune surveillance.

Expression of matrix metalloproteinases and their inhibitors in different immunohistochemical-based molecular subtypes of breast cancer.

BACKGROUND: Metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) are involved in several key pathways of tumor growth, invasion and metastasis, but little is known about their expression according to different molecular subtypes of breast cancer. The aims of this study were to assess the prevalence and clinical significance of MMP and TIMP expression in invasive breast cancer and to determine its association with immunohistochemical-based molecular classification. METHODS: Tissue microarray sections were immunostained for estrogen receptor-α (ER-α), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR) and with specific antibodies against MMP-1, 2, 7, 9, 11, 13, and 14 and TIMP-1, 2, and 3. Based on the immunostaining data from five of the markers used (ER-α, PR, HER2, EGFR and CK5/6), three major subtypes (123 luminal A, 31 basal-like, and 17 HER2-overexpressing) were selected. RESULTS: Statistically significant differences in the expression of MMPs and TIMPs among the three subtypes were found in tumoral MMP7 (P = 0.005), tumoral MMP-9 (P = 0.000), tumoral MMP-13 (P = 0.016) and stromal MMP-13 (P = 0.016). The incidence of tumoral MMP-9 expression in the HER2-overexpressing subtype was significantly higher than in the luminal A subtype (P = 0.021). Tumoral MMP-9 and stromal MMP-13 expression were significantly higher in the HER2-overexpressing subtype than in the basal-like subtype (P = 0.000 and P = 0.016, respectively). Tumoral MMP-7 expression was significantly higher in the basal-like subtype compared to luminal A (P = 0.007) and HER2-overexpressing subtype (P = 0.004). Tumoral MMP-13 showed a higher expression in the basal-like subtype than in the HER2-overexpressing subtype (P = 0.010). In multivariate analysis, stage and stromal MMP-1 expression were significantly related to overall survival. Stage was of independent prognostic significance for disease-free survival. CONCLUSION: We found some variations in MMP and TIMP expression among the immunohistochemical-based molecular subtypes of breast carcinomas, suggesting differences in their tumor pathophysiology. Additional studies are needed to determine the mechanisms underlying the differences of MMP and TIMP expression in the molecular subtypes for the development of specific therapeutic targets for breast cancer subtypes.

Insulin-like growth factor-II mRNA-binding protein 3 expression in effusion cytology: a marker for metastatic adenocarcinoma cells and a potential prognostic indicator in gastric adenocarcinoma.

OBJECTIVE: The aim of our study was to identify the diagnostic value of insulin-like growth factor-II mRNA-binding protein 3 (IMP3) in distinguishing metastatic adenocarcinoma cells (MAC) from reactive mesothelial cells (RMC) in effusions. We also investigated the role of IMP3 as a prognostic indicator for patients with malignant effusion. STUDY DESIGN: A total of 156 cell block specimens, including 116 malignant effusions with MAC and 40 benign effusions with RMC, were subjected to immunocytochemical staining for IMP3. RESULTS: Immunocytochemical studies showed positive staining for IMP3 in 91 of 116 (78.4%) cases of MAC and in 3 of 40 (7.5%) cases of RMC. With regard to distinguishing MAC from RMC, the IMP3 reactivity was found to be 78.4% sensitive and 92.5% specific with a positive predictive value of 96.8% and a negative predictive value of 59.7%. Diffuse IMP3 expression (>25%) in MAC from patients with gastric adenocarcinoma was associated with shorter survival (p = 0.001). CONCLUSION: Our data suggest that IMP3 is a helpful marker for differentiating MAC from RMC, and that diffuse IMP3 expression is a poor prognostic indicator in patients with gastric adenocarcinoma and malignant effusion.

Diagnostic usefulness of MUC1 and MUC4 for distinguishing between metastatic adenocarcinoma cells and reactive mesothelial cells in effusion cell blocks.

OBJECTIVE: The aim of our study was to determine the diagnostic value of MUC1 and MUC4 for distinguishing between metastatic adenocarcinoma cells (MAC) and reactive mesothelial cells (RMC) in effusion fluids. STUDY DESIGN: A total of 237 cell block specimens from pleural and peritoneal effusions, including 196 malignant effusions with MAC and 41 benign effusions with RMC, were stained with antibodies against MUC1 and MUC4. Membranous staining with or without cytoplasmic staining was considered to be positive. RESULTS: MUC1 immunoreactivity was observed in 194 (99.0%) of 196 cases of MAC and in 20 (48.8%) of 41 cases of RMC. MUC4 immunoreactivity was observed in 174 (88.8%) of 196 cases of MAC and in 4 (9.8%) of 41 cases of RMC. For distinguishing MAC from RMC, the MUC1 reactivity was found to be 99.0% sensitive and 51.2% specific with a positive predictive value of 90.7% and a negative predictive value of 91.3%. The sensitivity of MUC4 for MAC was 88.8%, the specificity was 90.2%, the negative predictive value was 62.7%, and the positive predictive value was 97.8%. CONCLUSION: Our data suggest that MUC4 appears to be a sensitive and specific marker for differentiating between MAC and RMC.

Combined epithelioid trophoblastic tumor and contralateral synchronous adenocarcinoma of the lungs in a 69-year-old man.

An epithelioid trophoblastic tumor (ETT) is a form of gestational trophoblastic neoplasms that arise from trophoblasts. The tumor generally occurs in women of reproductive age and has a characteristic growth pattern and immunohistochemical profile. We present an extremely rare case of a primary ETT occurring in the lungs with an adenocarcinoma in the contralateral lung as synchronous double primary lung cancers in a 69-year-old man who had no history of a remote malignancy. He underwent adjuvant radiotherapy to both lungs after a staged thoracoscopic wedge resection and was doing well without recurrence or metastasis up to last follow-up.

Differentially Expressed Genes in Matched Normal, Cancer, and Lymph Node Metastases Predict Clinical Outcomes in Patients With Breast Cancer.

Genome-wide screening of transcriptional changes among normal, cancer, and nodal metastases provides insights into the molecular basis of breast cancer (BC) progression and metastasis. To identify transcriptional changes and differentially expressed genes (DEGs) in the metastatic progression of BC and to determine the prognostic role of these DEGs in clinical outcome, we compared transcriptome profiling in matched normal, cancer, and lymph node metastatic tissues of 7 patients with estrogen receptor-positive, HER2-negative BC by using massive parallel RNA sequencing. The global profiles of gene expression in cancer and nodal metastases were highly correlated (r=0.962, P<0.001). In 6 (85.8%) patients, cancer and corresponding nodal metastases from the same patient clustered together. We identified 1522 and 664 DEGs between normal and cancer and between cancer and nodal metastases, respectively. The DEGs in normal versus cancer and cancer versus nodal metastases were significantly clustered in 1 and 8 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, respectively. The chemokine signaling pathway was the most significant pathway in the cancer-to-nodal metastasis transition (false discovery rate=2.15E-13). The expression of 2 dysregulated RAC2 and PTGDS genes was confirmed by quantitative real-time polymerase chain reaction and immunohistochemistry. Interestingly, the lower RAC2 and PTGDS expression were associated with significantly worse disease-free survival in patients with BC. Our results show a high concordance of gene expression in BC and their nodal metastases, and identify DEGs associated with the metastatic progression of BC. The DEGs identified in this study represent novel biomarkers for predicting the prognosis of patients with BC.

Case report: IgG4-related renal disease co-existing with retroperitoneal fibrosis.

A 51-year-old woman visited our clinic for orthopnea, chest discomfort, and facial and leg edema. Acute kidney injury and pleural effusion were diagnosed and she received hemodialysis. This is a rare case of IgG4-related disease diagnosed by renal biopsy in the patient with retroperitoneal fibrosis and severe acute kidney injury, which progressed rapidly and required hemodialysis without markedly elevated serum IgG4 level and urinary tract obstruction. Immunostaining of a kidney biopsy revealed IgG4-related renal disease and magnetic resonance imaging showed retroperitoneal fibrosis in the paraspinal and presacral areas. After 3 days of glucocorticoid treatment, renal function and bilateral pleural effusion were restored. Another 2 months of glucocorticoid treatment decreased the extent of retroperitoneal fibrosis on follow-up abdominal computed tomography. IgG4-related disease is a recently recognized fibro-inflammatory condition with a dense lymphoplasmacytic infiltration of IgG4-positive plasma cells. The kidney and retroperitoneum are the frequently associated organs in IgG4-related disease. This case shows that IgG4-related disease can involve the kidney and/or other organs and be diagnosed by kidney biopsy.

Tendon-Inspired Nanotopographic Scaffold for Tissue Regeneration in Rotator Cuff Injuries.

Acute and chronic rotator cuff (RC) tears are common etiologies of shoulder disabilities. Despite the advanced surgical techniques and graft materials available for tendon repair, the high re-tear rate remains a critical challenge in RC healing. Inspired by the highly organized nanotopography of the extracellular matrix (ECM) in tendon tissue of the shoulder, nanotopographic scaffolds are developed using polycaprolactone for the repair and regeneration of RC tendons. The scaffolds show appropriate flexibility and mechanical properties for application in tendon tissue regeneration. It is found that the highly aligned nanotopographic cues of scaffolds could sensitively control and improve the morphology, attachment, proliferation, and differentiation of tendon-derived cells as well as promote their wound healing capacity in vitro. In particular, this study showed that the scaffolds could promote tendon regeneration along the direction of the nanotopography in the rabbit models of acute and chronic RC tears. Nanotopographic scaffold-augmented rotator cuff repair showed a more appropriate healing pattern compared to the control groups in a rabbit RC tear model. We demonstrated that the tendon ECM-like nanoscale structural cues of the tendon-inspired patch may induce the more aligned tissue regeneration of the underlying tissues including tendon-to-bone interface.

Human papilloma virus identification in ocular surface squamous neoplasia by p16 immunohistochemistry and DNA chip test: A strobe-compliant article.

The aim of this study was to identify the association between human papilloma virus (HPV) infection and ocular surface squamous neoplasia (OSSN) using p16 immunohistochemistry (IHC) and deoxyribonucleic acid (DNA) chip test.Thirty-eight patients who underwent surgical excision of OSSN were retrospectively studied using tissue samples. The IHC was performed to assess the expression of p16 and DNA chip test was used to detect 24 HPV serotypes.Among the 38 OSSN samples, 32 cases (84.2%) were histopathologically categorized as pre-invasive type and 6 cases (15.8%) as invasive type. The IHC for p16 showed strong positivity in 12 cases (31.6%), whereas it was negative in 26 cases (68.4%). On the other hand, only one case (2.6%) of invasive OSSN was positive for the HPV16 serotype, as assessed by DNA chip test.In OSSN, p16 expression was positive in approximately 1/3rd of the cases, whereas the majority of the 24 HPV serotypes were negative for p16. Our findings suggest that only a weak association exists between HPV infection and OSSN.

Mesenchymal Stem Cells Decrease Tunnel Widening of Anterior Cruciate Ligament Reconstruction in Rabbit Model.

BACKGROUND AND OBJECTIVES: The study investigated the effect of mesenchymal stem cells (MSCs) or fibrin glue on tunnel widening after anterior cruciate ligament (ACL) reconstruction compared with biologic free control without any biologic agents in the rabbit model. METHODS AND RESULTS: ACL reconstructions were performed in 18 New Zealand white rabbits. All animals were divided into 3 groups according to the following reconstruction conditions and euthanized 12 weeks postoperatively for radiologic and histologic analyses. Thirty-two knees (control group=10; fibrin group=11; MSCs group=11) were finally evaluated. On micro-CT scan, mean femoral tunnel widening on oblique-sagittal image was 0.7±0.4 mm in the control group, 0.22±0.1 mm in the fibrin group and 0.25±0.1 mm in the MSCs group (p=0.001). Fibrin group and MSCs group showed significant differences compared with control group (p=0.002, 0.002). Mean tibial tunnel widening on oblique-sagittal image was 0.76±0.5 mm, 0.27±0.1 mm and 0.29±0.2 mm in the control, fibrin and MSCs group. Fibrin and MSCs group showed significant differences compared with control group (p=0.017, 0.014). Hounsfield Units (HU) were not significantly different between 3 groups (p＞0.05). Histological analysis revealed that the architecture of graft in the MSCs group featured hypercellularity and compact collagen deposit. CONCLUSION: ACL reconstruction using MSCs seemed decrease tunnel widening in rabbit model. Further study with large animals is required to confirm efficacy on decreasing tunnel widening.

How Long Should We Wait to Create the Goutallier Stage 2 Fatty Infiltrations in the Rabbit Shoulder for Repairable Rotator Cuff Tear Model?

BACKGROUND: Significant proportion of rotator cuff tears (RCTs) in clinical field are of a kind of repairable tear wherein the degree of fatty infiltration is of Goutallier stage 1 or stage 2. Therefore, the animal model, showing similar fatty infiltration, seems preferable for researches. The purpose of this study is to find out the proper time frame in which there is Goutallier stage 1 or stage 2 fatty infiltration in the rabbit RCT model for the research of repairable RCT in humans. METHODS: Supraspinatus tendon tears were created in forty male New Zealand white rabbits at their right shoulder (n= 8 for each group), and a sham operation on the left shoulder. Rabbits were divided into five groups (2nd, 4th, 6th, 8th, and 12th weeks). Specimens were harvested from the central portion of the supraspinatus muscle for haematoxylin and eosin (H &E) staining, followed by histological and Goutallier grading evaluation. Results are expressed as mean ± standard deviation by Sigma Plot software (version 7.0). RESULTS: At two weeks, mainly lipoblasts were observed around the muscle fibers, and at four weeks these lipoblasts were replaced by mature adipocytes with fatty infiltration amount (2.13 ± 0.35). The degree of muscle atrophy was (1.50 ± 0.53) at four weeks compared to sham group (0.88 ± 0.64) with significant difference (p < 0.05). The inflammatory process appeared as two phases. At two weeks, it was increased with grading value (1.88 ± 0.35). However, in the four-week group, it showed a sharp decrease (0.50 ± 0.53). At six weeks, inflammation reappeared to increase (1.13 ± 0.83). Then, a gradual decline appeared at eight weeks (0.88 ± 0.83) and at 12 weeks (0.50 ± 0.92). CONCLUSIONS: At two and four weeks, both fat distribution in rabbit supraspinatus muscles and Goutallier grading scale mostly appeared as grade 2. Therefore, we can consider four weeks to be a suitable period for making a repairable RCT animal model for the human research, considering the early acute tissue reaction at 2 weeks after the tendon tears.

Metabolic Changes in Different Stages of Liver Fibrosis: In vivo Hyperpolarized 13C MR Spectroscopy and Metabolic Imaging.

PURPOSE: The objective was to assess metabolic changes in different stages of liver fibrosis using hyperpolarized C-13 magnetic resonance spectroscopy (MRS) and metabolic imaging. PROCEDURES: Mild and severe liver fibrosis were induced in C3H/HeN mice (n = 14) by injecting thioacetamide (TAA). Other C3H/HeN mice (n = 7) were injected with phosphate buffer saline (PBS) (7.4 pH) as normal controls. Hyperpolarized C-13 MRS was performed on the livers of the mice, which was accompanied by intravoxel incoherent motion (IVIM) diffusion-weighted imaging with 12 b values. The differential metabolite ratios, apparent diffusion coefficient values, and IVIM parameters among the three groups were analyzed by a one-way analysis of variance test. RESULTS: The ratios of [1-13C]lactate/pyruvate, [1-13C]lactate/total carbon (tC), [1-13C]alanine/pyruvate, and [1-13C] alanine/tC were significantly higher in both the mild and severe fibrosis groups than in the normal control group (p < 0.05). While the [1-13C]lactate/pyruvate and [1-13C]lactate/tC ratios were not significantly different between mild and severe fibrosis groups, the ratios of [1-13C]alanine/pyruvate and [1-13C]alanine/tC were significantly higher in the severe fibrosis group than in the mild fibrosis group (p < 0.05). In addition, D* showed a significantly lower value in the severe fibrosis group than in the normal or mild fibrosis groups and negatively correlated with the levels of [1-13C] lactate and [1-13C]alanine. CONCLUSIONS: Our findings suggest that it might be possible to differentiate mild from severe liver fibrosis using the cellular metabolic changes with hyperpolarized C-13 MRS and metabolic imaging.

Case of Primary Isolated Subconjunctival IgG4-Related Disease.

PURPOSE: To report a case of isolated subconjunctival ocular adnexal IgG4-related disease that met the diagnostic criteria according to the Japanese Ministry of Health, Labour and Welfare's 2011 guidelines. METHODS: We report a case of a 56-year-old woman with a left subconjunctival mass for 3 months. Excisional biopsy was performed. Postoperatively, the patient underwent systemic and radiologic evaluations for IgG4-related disease. RESULTS: The clinicopathologic study revealed storiform fibrosis and lymphoplasmacytic infiltration, with increased IgG4-positive plasma cells and an IgG4/IgG-positive plasma cell ratio of 40%. Serum IgG4 and IgG levels were slightly elevated. Systemic involvement was not detected. CONCLUSIONS: IgG4-related disease is well known in the orbit and ocular adnexa, particularly the lacrimal gland. However, subconjunctival involvement should be recognized as a possible presentation for this entity.

First report of palpebral conjunctival inflammatory nodule associated with Demodex species.

Demodex mite infestation of the palpebral conjunctiva as focal inflammatory nodule has been not reported. A 46-year-old man presented with lower palpebral conjunctival nodules in his left eye. Slit-lamp examination showed focal inflammatory nodules at the inferior palpebral conjunctiva accompanied by conjunctival hyperemia and purulent secretion. Excisional biopsy of this lesion was performed. Pathological evaluations revealed inflammatory granuloma associated with Demodex species in the palpebral conjunctiva. This is the first report of Demodex-related palpebral conjunctival inflammatory nodule and may be helpful in future Demodex-associated studies.

Metaplastic Carcinoma with Chondroid Differentiation Arising in Microglandular Adenosis.

Microglandular adenosis (MGA) of the breast is a rare, benign proliferative lesion but with a significant rate of associated carcinoma. Herein, we report an unusual case of metaplastic carcinoma with chondroid differentiation associated with typical MGA. Histologically, MGA showed a direct transition to metaplastic carcinoma without an intervening atypical MGA or ductal carcinoma in situ component. The immunohistochemical profile of the metaplastic carcinoma was mostly similar to that of MGA. In both areas, all the epithelial cells were positive for S-100 protein, but negative for estrogen receptor, progesterone receptor, HER2/neu, and epidermal growth factor receptor. An increase in the Ki-67 and p53 labelling index was observed from MGA to invasive carcinoma. To the best of our knowledge, this is the first case of metaplastic carcinoma with chondroid differentiation arising in MGA in Korea. This case supports the hypothesis that a subset of MGA may be a non-obligate morphologic precursor of breast carcinoma, especially the triple-negative subtype.

Aggressively progressing primary undifferentiated pleomorphic sarcoma in the eyelid: A case report and review of the literature.

RATIONALE: Undifferentiated pleomorphic sarcoma is extremely rare in the head and neck area, and the aggressive nature of this tumor has not been previously described. PATIENT CONCERNS: Therefore, we report a unique case of a very rapidly growing primary undifferentiated pleomorphic sarcoma in the eyelid. A 67-year-old woman presented with a left lower lid mass. She had no previous history of surgery, skin malignancy, or radiation to the eyelid. On initial presentation, the patient showed a 2 × 1 × 1 cm firm, yellow nodule in the left lower eyelid. DIAGNOSES: We planned complete surgical removal of the mass; however, the patient was lost to follow-up. One month after the initial visit, the mass had markedly enlarged to 3 × 2.2 × 2.3 cm and a new 2 × 2 × 2 cm mass was observed in the left lower eyelid. INTERVENTIONS: Complete surgical resection of the tumor was performed with a myocutaneous free flap. At that time, two masses were emerged, which had grown to 8 × 8 × 5 cm. OUTCOMES: The patient died from sepsis caused by pneumonia 2 months after surgery without evidence of local recurrence. LESSONS: Primary undifferentiated pleomorphic sarcoma in the eyelid is extremely rare. Surgeons should be aware of this abruptly presenting, rapidly growing primary eyelid tumor and it is essential to excise the tumor completely as soon as possible.

In phyllodes tumors of the breast expression of SPARC (osteonectin/BM40) mRNA by in situ hybridization correlates with protein expression by immunohistochemistry and is associated with tumor progression.

Secreted protein acidic and rich in cysteine (SPARC) plays an essential role in tumor invasion and metastasis. The present work was undertaken to detect expression of SPARC mRNA in phyllodes tumors (PTs) and its association with SPARC protein expression. This study also evaluated expression of SPARC mRNA and its correlation between grade and clinical behavior of PTs. In addition, we assessed in PTs the association of expression of SPARC with that of matrix metalloproteinase (MMP)-2 and of MMP-9. SPARC mRNA expression was determined by RNAscope in situ hybridization (ISH) in 50 benign, 22 borderline, and 10 malignant PTs using a tissue microarray. Furthermore, we applied immunohistochemistry (IHC) to examine expression of SPARC, MMP-2, and MMP-9. SPARC mRNA appeared to be concentrated mainly in the stromal compartment of PTs. IHC staining patterns of SPARC protein showed concordance with SPARC mRNA ISH results. Stromal SPARC expression increased continuously as PTs progress from benign through borderline to malignant PTs, both at mRNA (using ISH) (P = 0.044) and protein level (using IHC) (P = 0.000). The recurrence percentage was higher in the stromal SPARC mRNA or protein-positive group than in the SPARC-negative group but this difference was not statistically significant. Stromal SPARC mRNA and protein expression was associated with PT grade and correlated with MMP-2 expression. These results indicate that SPARC-mediated degradation of the extracellular matrix, and its possible association with MMPs, might contribute to progression of PTs.

Epithelial periostin expression is correlated with poor survival in patients with invasive breast carcinoma.

Invasion and metastasis are direct causes of mortality in patients with breast cancer and require reciprocal interactions between cancer cells and the extracellular matrix (ECM). Periostin, a fasciclin-containing adhesive ECM glycoprotein, is frequently overexpressed in various types of human cancer, and its overexpression in cancer-associated stroma and/or cancer cells is usually associated with poor clinical outcomes. However, the expression of periostin in the successive steps of breast tumorigenesis and its association with outcome variables have not been well established in breast carcinoma. The present study aimed to assess the role of periostin alteration in breast tumorigenesis and evaluate the putative prognostic value of periostin as a function of its compartmentalization. Immunohistochemical staining with anti-periostin antibody was performed in a total of 300 patients (26 patients with normal breast tissues, 76 patients with ductal carcinoma in situ [DCIS], and 198 patients with invasive breast carcinoma [IBC]) using tissue microarray. Periostin immunoreactivity was assessed in both epithelial tissue and the surrounding stromal compartment. The mRNA and protein expression of periostin were analyzed in 10 paired normal/invasive cancer frozen specimens by quantitative real time-polymerase chain reaction and western blot analysis, respectively. In cancer tissues, periostin mRNA and protein expression were increased compared with adjacent normal tissues. Both epithelial and stromal periostin staining scores significantly increased in a stepwise manner with disease progression from normal breast tissue to DCIS and IBC (P = 0.000 and 0.000, respectively). High epithelial and stromal periostin expression was observed in 109/189 (57.7%) and 158/189 (83.6%) cases of IBC, respectively. High epithelial periostin expression was more frequently observed in the distant metastatic relapse-positive group than in the distant metastatic relapse-negative group (41/51 [80.4%] vs. 68/138 [49.3%] cases [P = 0.000]). Furthermore, high epithelial periostin expression was associated with reduced disease-free survival and overall survival in univariate and multivariate analysis. Periostin may play an important role in the progression of breast tumor, and epithelial periostin expression may serve as a new parameter for prediction of prognosis in patients with IBC. Further studies examining periostin expression and its potential as a target of IBC therapy are warranted.

Reduced RKIP Expression is Associated With Breast Neoplastic Progression and is Correlated With Poor Outcomes and Aberrant Methylation in Breast Carcinoma.

Raf kinase inhibitor protein's (RKIP) downregulation can predict poor outcome in patients with various types of malignancy. In this study, we aimed to assess the potential involvement of RKIP in breast carcinogenesis and to evaluate its association with outcome variables and aberrant promoter methylation in breast carcinoma (BC). Tissue microarray sections were immunostained for RKIP in 26 normal breasts, 25 usual ductal hyperplasia, 76 ductal carcinoma in situ, and 198 BC specimens. The methylation status of RKIP was also determined in BC. In addition, the mRNA and protein level of RKIP was analyzed in 8 pairs of BC tissues and surrounding normal tissues by quantitative real-time polymerase chain reaction and Western blot analysis, respectively. RKIP mRNA and protein expression was significantly downregulated in BC tissues compared with the surrounding normal tissues (P<0.05 and P<0.01, respectively). Reduced RKIP expression seemed to increase progressively from normal breast to BC (P<0.001). Reduced RKIP expression was significantly associated with metastatic relapse (P<0.001) and was identified as an independent adverse prognostic indicator for disease-free survival (P=0.003). Reduced RKIP expression in BC was significantly correlated with its aberrant promoter methylation (P<0.05). In conclusion, downregulation of RKIP plays an important role in the breast neoplastic progression and correlates with poor prognosis in patients with BC. Aberrant RKIP methylation is one of the mechanisms that lead to downregulation of RKIP in BC.