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BACKGROUND Spontaneous spinal epidural hematoma is a rare neurosurgical emergency. CASE SUMMARY A 53-year-old healthy woman suffered from complete paraplegia in both legs and loss of all sensation below the xiphoid process. She was diagnosed as acute spontaneous thoracic epidural hematoma caused by an intraspinal lymphangioma. The primary lab survey showed all within normal limits. Presence of a posteriorly epidural space-occupying lesion at the T4-T8 level of the spinal canal was confirmed on magnetic resonance imaging. A decompressive laminectomy was performed from the T4 to T7 levels at the sixth hour following abrupt onset of complete paraplegia. The lesion was confirmed as lymphangioma. This patient recovered well within one month. CONCLUSION This study reports a case of acute spontaneous thoracic epidural hematoma caused by an intraspinal lymphangioma with well recovery after surgical intervention.

Upper tract urothelial carcinoma (UTUC) is relatively rare in Western countries. The impact of programmed death-ligand 1 (PD-L1) expression on UTUC remains unclear because previous studies have focused on bladder UC. We investigated the association of PD-L1 expression with clinicopathological features and prognosis in patients with UTUC. We retrospectively reviewed the patients with UTUC that we treated at our institute from 2013 to 2018. In total, 105 patients with UTUC undergoing radical nephroureterectomy were analyzed to evaluate the PD-L1 expression on representative whole-tissue sections using the Combined Positive Score (CPS; Dako 22C3 pharmDx assay). A PD-L1 CPS ≥ 10 was considered positive. Among the 105 UTUC cases, 17.1% exhibited positive PD-L1 expression. A CPS ≥ 10 was significantly associated with higher tumor stage (≥ T2, p = 0.034) and lymph node invasion at diagnosis (p = 0.021). A multivariable analysis indicated that a CPS ≥ 10 was an independent prognostic predictor of shorter cancer-specific survival (hazard ratio [HR] = 4.59, 95% confidence interval [CI] = 1.66 − 12.7, p = 0.003) and overall survival (HR = 2.51, 95% CI = 1.19 − 5.27, p = 0.015). A PD-L1 CPS ≥ 10 in UTUC was associated with adverse pathological features and independently predicted worse cancer-specific and overall survival.

Objectives: Platinum-based chemotherapy is the standard treatment for metastatic urothelial carcinoma (mUC). However, considering elderly patients often experience comorbidities and frailty, the utility of cisplatin-based chemotherapy for elderly patients is still debatable. We conducted this study to compare the safety and efficacy of carboplatin and cisplatin in elderly patients with mUC. Methods: This retrospective study enrolled elderly patients with mUC (defined as aged ≥70 years) who underwent first-line platinum-based chemotherapy between September 2001 and October 2018. The primary endpoints were chemotherapy-related adverse events (AEs), including treatment-related hospitalization or death. The secondary outcomes were overall survival (OS) and progression-free survival calculated by Kaplan-Meier analysis. Results: In total, 108 elderly patients with mUC were enrolled and allocated into the cisplatin or carboplatin group. Patients treated with carboplatin-based chemotherapy had a significantly higher incidence of all grade ≥3 AEs (78.8 vs. 50.0%, p = 0.008) than those on cisplatin. AE-related hospitalization (47.5 vs. 19.1%, p = 0.002) and treatment-related death (17.5 vs. 4.4%, p = 0.02) were significantly increased in the carboplatin group. In the univariate analysis, the median OS in the cisplatin group was significantly increased compared with the carboplatin group (13.6 vs. 7.2 months, p = 0.045). The Cox multivariate regression model indicated that leukocytosis (HR 3.17, 95% CI 1.84–5.46, p < 0.001) and anemia (HR 2.02, 95% CI 1.11–3.65, p = 0.02) were independent prognostic factors. Conclusion: Elderly patients with mUC treated with cisplatin-based chemotherapy had better survival and safety profiles than those treated with carboplatin. Age itself was not a crucial factor in determining cisplatin eligibility.

Ribosome-binding protein 1 (RRBP1) is a potential oncogene in several cancer types. However, the correlation between RRBP1 expression and the prognosis of patients with upper tract urothelial carcinoma (UTUC) remains unclear. In this study, we identified that RRBP1 is associated with carcinogenesis and metastasis in UTUC using a methylation profiling microarray. High correlations between RRBP1 and cancer stages, nodal metastasis status, molecular subtypes, and prognosis in bladder urothelial cancer (BLCA) were found. Aberrant DNA methylation in the gene body region of RRBP1 was determined in UTUC tissues by methylation-specific PCR. RRBP1 expression was significantly increased in UTUC tissues and cell lines, as determined by real-time PCR and immunohistochemistry. RRBP1 depletion significantly reduced BFTC909 cell growth induced by specific shRNA. On the other hand, molecular subtype analysis showed that the expression of RRBP1 was associated with genes related to cell proliferation, epithelial–mesenchymal transition, and basal markers. A patient-derived organoid model was established to analyze patients’ responses to different drugs. The expression of RRBP1 was related to chemoresistance. Taken together, these results provide the first evidence that RRBP1 gene body hypomethylation predicts RRBP1 high expression in UTUC. The data highlight the importance of RRBP1 in UTUC malignancy and chemotherapeutic tolerance.

Galectin-1 (GAL1) is a &beta, galactoside-binding protein involved in multiple aspects of tumorigenesis. However, the biological role of GAL1 in upper tract urothelial carcinoma (UTUC) has not been entirely understood. Herein, we investigated the oncological effects of GAL1 expression in tumor specimens and identified related gene alterations through molecular analysis of GAL1. Clinical parameter data and tumor specimens were collected from 86 patients with pT3N0M0 UTUC who had undergone radical nephroureterectomy. We analyzed the difference in survival by using Kaplan&ndash, Meier analyses and Cox proportional regression models and in GAL1 expression by using immunohistochemical (IHC) methods. Public genomic data from the Cancer Genome Atlas (TCGA) and GSE32894 data sets were analyzed for comparison. Using four urothelial carcinoma (UC) cell lines (BFTC-909, T24, RT4, and J82) as in vitro models, we evaluated the functions of GAL1 in UC cell growth, invasiveness, and migration and its role in downstream signaling pathways. The study population was classified into two groups, GAL1-high (n = 35) and GAL1-low (GAL1 n = 51), according to IHC interpretation. Univariate analysis revealed that high GAL1 expression was significantly associated with poor recurrence-free survival (RFS, p = 0.028) and low cancer-specific survival (CSS, p = 0.025). Multivariate analysis revealed that GAL1-high was an independent predictive factor for RFS (hazard ratio (HR) 2.43, 95% confidence interval (CI) 1.17&ndash, 5.05, p = 0.018) and CSS (HR 4.04, 95% CI 1.25&ndash, 13.03, p = 0.019). In vitro studies revealed that GAL1 knockdown significantly reduced migration and invasiveness in UTUC (BFTC-909) and bladder cancer cells (T24). GAL1 knockdown significantly reduced protein levels of matrix metalloproteinase-2 (MMP-2) and MMP-9, which increased tissue inhibitor of metalloproteinase-1 (TIMP-1) and promoted epithelial&ndash, mesenchymal transition (EMT). Through gene expression microarray analysis of GAL1 vector and GAL1-KD cells, we identified multiple significant signaling pathways including p53, Forkhead box O (FOXO), and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT). We validated microarray results through immunoblotting, thus proving that downregulation of GAL1 reduced focal adhesion kinase (FAK), p-PI3K, p-AKT, and p-mTOR expression. We concluded that GAL1 expression was highly related to oncological survival in patients with locally advanced UTUC. GAL1 promoted UC invasion and metastasis by activating the FAK/PI3K/AKT/mTOR pathway.

Background: Prognostic nutritional index (PNI) has been studied in various types of cancer which is significantly correlated with prognosis. The study aims to investigate the predictive role of PNI in patients with metastatic urothelial carcinoma (mUC) treated with systemic chemotherapy. Methods: We retrospectively reviewed 141 patients with mUC who received systemic chemotherapy. PNI was calculated as 10 × serum albumin concentration (g/dL) + 0.005 × lymphocyte count (number/mm2). The optimal cut-off value for PNI was estimated by using receiver operating curve analysis. Independent factors associated with progression-free survival (PFS) and overall survival (OS) were determined by Cox proportional regression models. Results: The recommended cut-off value for PNI was 40. Patients with a low PNI had more visceral metastases (p < 0.0001), leukocytosis (p = 0.006), and anemia (p < 0.0001). On univariate analysis, patients with a low PNI had poor OS than those with a high PNI (p < 0.0001). The multivariate analysis showed PNI was an independent factor to predict OS (p = 0.001). Conclusions: Our study showed PNI is an independent prognostic factor in patients with mUC. Our work is clinically useful for anticipation of outcomes, risks stratification in clinical studies as well as patients counseling.

We retrospectively enrolled 102 patients with upper tract urothelial carcinoma (UTUC) who underwent radical nephroureterectomy to examine the prognostic value of Ki-67 and programmed cell death ligand-1 (PD-L1). Then, we performed PD-L1 and Ki-67 immunohistochemical staining on whole tissue sections. The cut-off value of PD-L1 positivity was a combined positive score (CPS) ≥10 and the Ki-67 overexpression was 20%. Among the 102 patients, 16.7% and 48.0% showed positive PD-L1 expression and Ki-67 overexpression, respectively. A CPS ≥10 was significantly associated with a higher pathological T stage (p = 0.049). In addition, Ki-67 overexpression was significantly associated with a pathological T stage ≥ 2 (p = 0.027) and tumour necrosis (p = 0.016). In the multivariable analysis, a positive PD-L1 expression was significantly correlated with worse cancer-specific survival (HR = 3.66, 95% CI =1.37−9.77, p = 0.01). However, there was no predictive value using a combination of PD-L1 expression and Ki-67 overexpression as a prognostic predictor. Compared with Ki-67 overexpression, a positive PD-L1 expression with CPS ≥ 10 was a stronger independent prognostic factor for CSS in patients with UTUC.

// Yung-Che Chen 1, 6, * , Meng-Chih Lin 1, 6, * , Chang-Chun Hsiao 6, 7 , Yi-Xin Zheng 1 , Kuang-Den Chen 2 , Ming-Tse Sung 3 , Chung-Jen Chen 4 , Ting-Ya Wang 1 , Yong-Yong Lin 1 , Huang-Chih Chang 1, 6 , Yu-Mu Chen 1 and Jen-Chieh Chang 5 1 Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 2 Center of Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 3 Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 4 Division of Rheumatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 5 Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 6 Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan 7 Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan * These authors have contributed equally to this work Correspondence to: Yung-Che Chen, email: yungchechen@yahoo.com.tw Meng-Chih Lin, email: linmengchih@hotmail.com Chang-Chun Hsiao, email: cchsiao@mail.cgu.edu.tw Keywords: lung adenocarcinoma, S100A15, DNA methylation, next generation sequencing Received: November 02, 2016 Accepted: April 10, 2017 Published: April 24, 2017 ABSTRACT Purpose : This study aims to determine the functional role of S100A15 and its promoter DNA methylation patterns in lung cancer progression. Experimental Design : We analyzed 178 formalin-fixed paraffin embedded specimens from lung cancer patients, including 24 early stage and 91 advanced stage adenocarcinoma. S100A15 protein expression was evaluated by immunohistochemistry stain, and its DNA methylation levels were measured by pyrosequencing. Results : S100A15 nuclear staining was increased in lung adenocarcinoma patients with distant metastasis versus those without distant metastasis. There was reduced one/three-year overall survival in adenocarcinoma patients receiving first line target therapy and harboring high nuclear expressions of S100A15. Both DNA methylation levels over -423 and -248 CpG sites of the S100A15 gene promoter were decreased in adenocarcinoma patients with distant metastasis, and the former was associated with lower one-year overall survival. The highly invasive CL1-5 cell lines display decreased DNA methylation over –412/-248/-56 CpG sites of the S100A15 gene promoter and increased S100A15 gene/protein expressions as compared with the less invasive CL1-0 cell lines. Knockdown of S100A15 in CL1-5 cell line inhibited cell proliferation, migration, and invasion, while over-expression of S100A15 in CL1-0 cell line promoted cell proliferation, migration, and invasion. RNA sequencing analysis revealed potential biological effects of S100A15 over-expression and knock-down with CTNNB1, ZEB1, CDC42, HSP90AA1, BST2, and PCNA being the pivotal down-stream mediators. Conclusions : Increased S100A15 expression and decreased DNA methylation of its gene promoter region were associated with high metastasis potential and poor outcome in lung adenocarcinoma, probably through triggering CTNNB1 -centered pathways.

The prevalence of upper tract urothelial carcinoma (UTUC) in Taiwan is relatively higher than thatin Western countries. Aristolochic acid (AA), which is widely used in traditional Chinese herbology, is now recognized to be one of the carcinogens for UTUC. Numerous UTUC patients have chronic kidney diseases or end-stage renal diseases, however, little literature hasreported on theoncogenic pathway of AA-related UTUC. The aim of our study was to identify the potential target treatment for AA-related UTUC. Here, we established an AA pre-exposure followed bya 3-methylcholanthrene (MCA) stimulus tumorigenic cell model. We not only demonstrated that AA pre-exposure MCA stimulus tumorigenic cells have more behaviors of cell migration and invasion by enhancing the metalloproteinases (MMP) activity, which is compatible with clinical findings of AA-related UTUC, but we also validated that AA pre-exposure MCA stimulus tumorigeniccells could be activated through the mitogen-activated protein kinases (MAPK) pathway. We further dissected the route of the MAPK pathway and found that the p38 and extracellular signal regulated kinases (ERK) sub-pathways might play essential roles in AA pre-exposure urothelial cancer cell lines. This consequence was also corroborated with a tissue study in AA-exposed patients.

Tangeretin is one of the most abundant compounds in citrus peel, and studies have shown that it possesses anti-oxidant and anti-cancer properties. However, no study has been conducted on bladder cancer cells. Bladder cancer has the second highest mortality rate among urological cancers and is the fifth most common malignancy in the world. Currently, combination chemotherapy is the most common approach by which to treat patients with bladder cancer, and thus identifying more effective chemotherapeutic agents that can be safely administered to patients is a very important research issue. Therefore, this study investigated whether tangeretin can induce apoptosis and identified the signaling pathways of tangeretin-induced apoptosis in human bladder cancer cells using two-dimensional gel electrophoresis (2DGE). The results of the study demonstrated that 60 &mu, M tangeretin reduced the cell survival of a BFTC-905 bladder carcinoma cell line by 42%, and induced early and late apoptosis in the cells. In this study 2DGE proteomics technology identified 41 proteins that were differentially-expressed in tangeretin-treated cells, and subsequently LC&ndash, MS/MS analysis was performed to identify the proteins. Based on the functions of the differentially-expressed proteins, the results suggested that tangeretin caused mitochondrial dysfunction and further induced apoptosis in bladder cancer cells. Moreover, western blotting analysis demonstrated that tangeretin treatment disturbed calcium homeostasis in the mitochondria, triggered cytochrome C release, and activated caspase-3 and caspase-9, which led to apoptosis. In conclusion, our results showed that tangeretin-induced apoptosis in human bladder cancer cells is mediated by mitochondrial inactivation, suggesting that tangeretin has the potential to be developed as a new drug for the treatment of bladder cancer.

Upper urinary tract urothelial carcinoma (UT-UC) is rare and treatment options or prognostic markers are limited. There is increasing evidence indicating that urothelial carcinoma may be an endocrine-related cancer. The aim of this study was to analyze the prognostic effect of estrogen receptor beta (ERβ) on the outcome of UT-UC. From 2005 to 2012, this study included 105 patients with pT3 UT-UC. Perioperative factors, pathological features and ERβ immunostaining were reviewed and prognostic effects were examined by multivariate analysis. This study divided patients into either the ERβ-high (n = 52) or ERβ-low (n = 53) group and analyzed their oncologic outcomes. All pathological features except infiltrating tumor architecture (significantly higher incidence in ERβ-low group, p = 0.004) are symmetric in both groups. Low ERβ expression was significantly correlated with local recurrence and distant metastasis in univariate analysis (p = 0.035 and 0.004, respectively) and multivariate analysis (p = 0.05 and 0.008, respectively). Cell line study also proved that knock down of ERβ cause less UTUC proliferation and migration. In addition, ERβ agonist also enhanced the cytotoxic and migration inhibition effect of cisplatin and ERβ antagonist cause the UTUC cell more resistant to cisplatin. This result may help identify patients in need of adjuvant therapy or develop potential targeted therapy.

Lymphadenectomy (LAD) is an important staging and treatment modality of oncologic surgery. LAD in genitourinary malignancies presents inherent difficulties to the urologist and pathologist because of the differences in anatomic sites and primary histologic type. This review focuses on pathologic evaluation and how communication between urologist and pathologist is necessary to provide optimal care. Recommendations covering general specimen submission and processing are discussed, as well as more specific recommendations concerning the kidney, upper urinary tract, urinary bladder, prostate, testes, and penis. Emerging areas of prognostic significance and the impact that improved molecular techniques are contributing to diagnostic interpretation are highlighted.

A 7-year-old girl presented to the emergency department with postprandial abdominal pain. An abdominal sonogram revealed a retroperitoneal septated cystic lesion. Magnetic resonance imaging showed a septated cystic lesion in the superior mesenteric artery (SMA) root with a vessel originating from the proximal SMA supplying the cyst wall and a deformed adjacent aortic contour. A laparotomy was performed and confirmed the presence of an isolated enteric duplication cyst with its own blood supply from the SMA and marked perilesional adhesions to the duodenal loop and aorta. Histopathologic study was consistent with a duplication. To our knowledge, this is the first report of isolated enteric duplication cyst in the superior mesenteric root with perilesional adhesion leading to postprandial abdominal pain, which was successfully relieved after surgery.

Rationale: Limbal dermoids are choristomas known as congenital benign tumors found in abnormal locations. Despite the benign nature, enlarging limbal dermoids may cause visual abnormalities by cornea infiltration with fat component, visual axis invasion, gradually induced corneal astigmatism, and finally result in anisometropic amblyopia. Here we report a rare case of progressive, large pediatric corneal limbal dermoid in a newborn, managed with tissue glue-assisted monolayer amniotic membrane transplantation. Patient concerns: A 1-day-old male baby (gestational age, 36 ± 6 weeks; birth body weight, 2785 gram) presented to our clinic with a whitish mass on his right eye since birth. Diagnosis: Ocular examination revealed a solid, whitish-yellow, and ovoid mass with central keratinized epithelium over the superior limbus; the lesion covered two-thirds of the cornea with rapid progression in size. The final pathological examination revealed that the lesion is composed of keratotic lining squamous epithelium resembling epidermis, underling dermal fibrotic connective tissue, and mature fat. Interventions: The patient underwent deep lamellar excision followed by mitomycin C (MMC) soaking (0.2 mg/mL, 3 minutes) and tissue glue-assisted monolayer amniotic membrane transplantation with the ring conformer at 2 months of age. Outcomes: The ring conformer was smoothly removed 2 weeks after the operation. The patient showed a smooth healing process with less pain and rapid corneal re-epithelization. The ocular surface was stable during the follow-up visits, and no complications were detected. Only mild post-operative scarring over the incision wound was observed. Lessons: Although a combination of excision, lamellar keratoplasty, and multilayer amniotic membrane and limbal stem cell transplantation is advocated for the treatment of grade II and III pediatric corneal limbal dermoids, the procedure used in this study offers an alternative surgical approach. However, because of the large size of the lesion and the young age of the patient, the management of amblyopia with visual rehabilitation and corneal transplantation is still needed in the future.

Aims: Patients who have undergone intestinal augmentation cystoplasty are at risk for developing latent vesicle malignancy. The aim was to evaluate the histological and immunohistochemical characteristics and molecular genetic alterations in these neoplasms. Methods and results: Four patients developing urothelial neoplasms after augmentation cystoplasty were included in the current study. The mean age of the patients, including two men and two women, was 37 years. The latency from bladder augmentation to developing malignancy ranged from 17 to 21 years (mean 19 years). All patients died of cancer shortly after diagnosis (mean 5 months). In the morphological evaluation, all tumours were high-grade (grade 3) invasive urothelial carcinoma comprising various architectural patterns with brisk mitoses and tumour necrosis. Three harboured glandular differentiation and the remaining one showed squamous differentiation. All cases revealed abnormal decreasing β-catenin expression. Two tumours showed nuclear expression of CDX2. On UroVysion fluorescence in situ hybridization (FISH) analysis, all tumours displayed characteristic chromosomal abnormalities. Point mutations of both FGFR3 and p53 genes were identified in one case. Conclusions: Urothelial carcinomas developed after augmentation cystoplasty are extremely aggressive and exhibit distinct morphological, immunohistochemical and genetic characteristics. UroVysion FISH analysis may offer a surveillance strategy in patients who undergo augmentation cystoplasty.

Urothelial papillomas and low-grade urothelial carcinomas have shown a high incidence of fibroblast growth factor receptor 3 (FGFR3) mutations and are associated with a favorable prognosis. The association of FGFR3 mutations with inverted papillomas is less known. We analyzed 20 cases of inverted papilloma in the urinary tract. Mutations of FGFR3 (exons 7, 10, and 15) and TP53 genes were evaluated by DNA sequencing in these cases. Point mutations of the FGFR3 gene were identified in 45% (9 of 20) of inverted papillomas with four cases exhibiting mutations at multiple exons. Seven cases had exon 7 mutations containing R248C, S249T, L259L, P260P, and V266M. Two cases had exon 10 and 15 mutations including A366D, H412H, E627D, D641N, and H643D; five cases had N653H. The most frequent mutation was identified at R248C. None of the inverted papillomas exhibited mutations in TP53. During a mean follow-up of 78 months, none had recurrence or developed urothelial carcinoma. These findings support the concept that low-grade and low-stage urothelial neoplasms arise in a background of molecular changes that are distinctly different from the molecular changes of high-grade and high-stage urothelial cancers.

Accurate diagnosis of mediastinal seminoma is critical because of its favorable response to radiation therapy and/or cisplatin-based chemotherapy. Immunohistochemical staining for OCT4 has recently been validated as a powerful tool for detecting gonadal seminoma. However, discrepancies between the genetic alterations and immunoprofiles of mediastinal and testicular seminomas have been reported, raising the question of whether techniques that are useful in the diagnosis of gonadal seminoma are applicable to its mediastinal counterpart. The present study was conducted to evaluate the morphologic and immunohistochemical characteristics and chromosomal abnormalities of 12p in 23 primary mediastinal seminomas and to compare their applicability as diagnostic tools. Dual-color fluorescence in situ hybridization (FISH) analyses for chromosome 12p and immunostains for OCT4, c-kit, placental-like alkaline phosphatase, CD30, and a panel of cytokeratins, including cytokeratin AE1/AE3 (AE1/3), high molecular weight cytokeratin (34betaE12, HMWCK), CAM5.2, cytokeratin 7 (CK7), cytokeratin 20 (CK20), and epithelial membrane antigen were performed. Lymphocytic infiltration was found in all 23 cases (100%). The incidence of other histologic characteristics were as follows: fibrous septa/stroma (21 cases, 91%), prominent tumor cell nucleoli (21 cases, 91%), clear tumor cell cytoplasm (20 cases, 87%), distinct tumor cell borders (20 cases, 87%), granulomatous inflammation (17 cases, 74%), cellular pleomorphism (10 cases, 43%), necrosis (8 cases, 35%), prominent cystic change (2 cases, 8%), intercellular edema (1 case, 4%), and syncytiotrophoblasts (1 case, 4%). The mean mitotic count was 4.4 (range 0 to 16) per 10 high-power fields. Moderate to strong nuclear OCT4 staining was identified in all 23 cases (100%). Seventeen tumors (74%) showed membranous expression of c-kit, with variable staining intensity and percentages. Weakly to moderately intense immunostaining for placental-like alkaline phosphatase was identified in 10 cases (43%) with occasional background staining artifact. The incidences of positive staining were 43% for AE1/3, 39% for HMWCK, 48% for CAM5.2, 39% for CK7, and 9% for epithelial membrane antigen, respectively. In most cases, these epithelial markers highlighted only a small proportion of tumor cells with variable intensities. Immunostaining for CD30 and CK20 was completely negative in all seminomas. Twenty-two seminomas (96%) revealed chromosome 12p abnormalities, including 12p amplification in 20 cases (87%) or i(12p) in 15 cases (65%). Lymphocytic infiltration is the most common histologic feature observed in primary mediastinal seminoma and both OCT4 immunostain and FISH for 12p abnormalities can be very helpful in diagnosing mediastinal seminoma. The intense staining pattern of OCT4 and the high sensitivity of FISH make them superior to other auxiliary diagnostic utilities for detecting seminoma. In addition, the incidences of cytokeratin expression of primary mediastinal seminoma are similar to those of its gonadal counterpart and pathologists must exercise caution in the interpretation of epithelial markers in mediastinal neoplasms.

Summary Radical prostatectomy gives the most accurate and detailed information available for determining prognosis and deciding about adjuvant therapy for prostate cancer. The consistency and reproducibility of observations from these specimens requires a standardised protocol for tissue fixation, sampling, embedding and processing. Although the publication of processing protocols in recent years has led to a convergence of opinions, differences still exist in methods of handling, sampling and processing specimens. In this review article, we incorporate the processing methods for radical prostatectomy addressed in the previous reports and propose a comprehensively standardised approach to evaluate radical prostatectomy specimens.

Purpose: Although intestinal metaplasia is often found in association with adenocarcinoma of the urinary bladder, it is unclear whether intestinal metaplasia of the bladder is a premalignant lesion. Telomere shortening has recently been implicated in epithelial carcinogenesis. We used quantitative fluorescent in situ hybridization (FISH) to measure telomere length and UroVysion FISH to detect cytogenetic abnormalities in urinary bladder specimens with intestinal metaplasia.Experimental Design: Paraffin-embedded tissue blocks from 34 patients with intestinal metaplasia of the urinary bladder were evaluated. Twelve of the 34 patients had coexistent cystitis glandularis, and telomere length was measured in these lesions for comparison. Tissue sections were prepared and hybridized with a telomere-specific peptide nucleic acid probe. Quantitative FISH on interphase nuclei was used to assess telomere signal intensity. Additional sections were hybridized with centromeric probes for chromosomes 3, 7, and 17 and a locus-specific probe 9p21. Multicolor FISH was used to analyze for cytogenic abnormalities in the interphase nuclei of intestinal metaplasia.Results: In all 34 cases, reduced average telomere signal intensity was observed in the nuclei of intestinal metaplasia cells compared with adjacent control nuclei to produce a mean relative intensity of 48.5% (P < 0.0001). When cystitis glandularis was present, significant differences in the telomere-specific signal intensity existed between cystitis glandularis and normal cells (P = 0.0005) and between cystitis glandularis and intestinal metaplasia cells (P = 0.0015). Three of the 34 cases showed chromosomal gains in the UroVysion FISH assay.Conclusions: Our findings indicate that intestinal metaplasia in the urinary bladder is associated with significant telomere shortening relative to telomere length in adjacent normal urothelial cells. These lesions also occasionally showed cytogenetic abnormalities associated with telomere shortening. Our findings support the hypothesis that intestinal metaplasia of the urinary bladder is a precursor lesion to and could be a marker in the development of adenocarcinoma of the urinary bladder.

Alpha-methylacyl-CoA racemase (AMACR) has recently been shown to be a highly sensitive marker for the diagnosis of prostate cancer. However, there is limited information concerning its utility as a marker for prostate carcinoma after hormonal therapy. Our current investigation was conducted to evaluate the expression of AMACR in patients with prostate carcinoma after hormonal therapy and assess its diagnostic utility in combination with p63 and high molecular weight cytokeratin (34betaE12) staining. Prostate tissues from 49 patients who had been treated with hormonal therapy were immunohistochemically analyzed for AMACR, 34betaE12, and p63 expression by a triple antibody cocktail stain. The staining intensities and the percentages of positively staining tumor cells were recorded. The correlations between AMACR expression and metastatic status, associated hormonal therapy regimens, and the extent of hormone therapy effect were analyzed. All malignant acini were completely negative for both basal cell markers (34betaE12 and p63). Tumor cells failed to demonstrate expression of AMACR in 14 (29%) of 49 cases. In the remaining 35 cases (71%), positive immunostaining for AMACR was noted, but with variable intensities and percentages of cells stained. Positive staining for AMACR in benign glands was not seen in any case. In all cases, basal cells were strongly stained by p63 in benign acini with a mean positive percentage of 96%. Similarly, basal cells in benign acini displayed moderate staining intensities for 34betaE12 in 3 (7%) of 41 cases and strong immunostaining for this marker in the remaining 38 cases (93%); the mean percentage of positive cells was 92%. alpha-methylacyl-CoA racemase expression may be substantially diminished or entirely lost in prostate carcinoma after hormonal therapy. This variation in AMACR expression does not correlate with the metastatic status, the modality of hormonal therapy, or the extent of therapy-related effect. It is important that pathologists be aware that some hormonally treated prostate carcinomas do not express AMACR, and that immunostaining in such cases must be interpreted with caution. A triple cocktail stain using AMACR, 34betaE12, and p63 can be helpful in evaluating prostate specimens for the presence of residual or recurrent carcinoma after hormonal therapy for cancer.

The histogenesis of sarcomatoid urothelial carcinoma, a rare neoplasm with bidirectional epithelial and mesenchymal differentiation, has been a matter of controversy. To clarify its origin, we analysed the status of X-chromosome inactivation in sarcomatoid urothelial carcinomas from 10 female patients and examined losses of heterozygosity (LOH) in these specimens and in additional 20 tumours from male patients. Six polymorphic microsatellite markers where genetic alterations occur frequently in early or advanced stages of urothelial carcinomas, including D3S3050, D8S261, IFNA, D9S177, D11S569 and TP53, were investigated in the current study. The identical pattern of non-random X-chromosome inactivation in both carcinomatous and sarcomatous components was identified in five of eight informative female patients, and the remaining three informative cases showed a random, but concordant, pattern of X-chromosome inactivation. The concordant X-chromosome inactivation results in all eight informative cases support the concept of a monoclonal origin of both components of this biphasic neoplasm. Among the tumours demonstrating loss of heterozygosity, high incidences of an identical pattern of allelic loss between carcinomatous and sarcomatous components were identified in genetic alterations associated with early carcinogenesis: 86% at D8S261, 78% at D11S569, 75% at D9S177 and 57% at IFNA. In contrast, concordant LOH patterns were less frequently observed for microsatellites related to advanced carcinogenesis: only 40% at D3S3050 and 40% at TP53. The significant overlap of loss of heterozygosity supports a monoclonal cell origin and suggests that clonal divergence may occur during tumour progression and differentiation. Divergent patterns of discordant allelic loss of microsatellite markers imply that heterogeneous pathogenetic pathways may exist in the evolution of this enigmatic neoplasm.

PurposeThis study investigated the prognostic role of histopathological variants in patients with advanced urothelial carcinoma (UC) who were treated with systemic chemotherapy.Materials and methodsWe conducted a retrospective analysis of patients with unresectable and/or metastatic UC who underwent systemic chemotherapy between January 1997 and December 2013 in Kaohsiung Chang Gung Memorial Hospital. Histopathological types were categorized as pure UC (PUC) and variants of UC (VUC). The overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier analyses and Cox proportional regression models.ResultsA total of 206 patients were enrolled; 53 of the patients (25.7%) had histopathological variants. The most common variant was squamous differentiation (68%). Compared with patients with PUC, patients with VUC significantly exhibited upper urinary tract origin (75% vs 52%, P = .008), chronic renal insufficiency (40% vs 23%, P = .03), and carboplatin-based chemotherapy (28% vs 10%, P = .003). According to univariate analysis, the median OS for PUC patients was significantly higher than that for VUC patients (15.9 vs 11.3 months, P = .007). The median PFS for patients who received first-line chemotherapy was 6.1 and 3.8 months for PUC patients and VUC patients, respectively (P = .004). Multivariate analysis revealed that VUC (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.16-2.40, P = .006), an age ≤ 60 years (HR 0.70, 95% CI 0.49-0.99, P = .045) and presence of visceral metastasis (HR 1.54, 95% CI 1.11-2.13, P = .009) were independent factors facilitating OS prediction.ConclusionsThe presence of histopathological variants indicates poor survival outcomes in patients with metastatic UC. Accordingly, VUC should be integrated into and considered an independent factor in a predictive model of survival.

Purpose: The distinction of epidermoid cyst of the testis from teratoma is of critical importance because the former is benign and the latter is a malignant tumor that may have associated metastasis of either teratomatous or non–teratomatous germ cell tumor types. Chromosome 12p abnormalities are seen in the vast majority of testicular germ cell tumors of adults and are present in all histologic subtypes. In this study, we investigated the clinical utility of interphase fluorescence in situ hybridization (FISH) analysis of chromosome 12p abnormalities for distinguishing epidermoid cysts of the testis from pure mature teratoma. Experimental Design: Sixteen testicular epidermoid cysts and 17 testicular teratomas were investigated for isochromosome 12p [i(12p)] and 12p overrepresentation using interphase FISH analysis. Results: Neither i(12p) nor 12p overrepresentation were observed in 16 epidermoid cyst cases, whereas i(12p) was detected in 76% of teratomas and 12p overrepresentation was identified in 29% of teratomas. Overall, 88% of testicular teratomas had chromosome 12p abnormalities. Conclusions: FISH identification of i(12p) and/or 12p overrepresentation in routinely processed surgical specimens is a useful ancillary diagnostic tool in distinguishing testicular epidermoid cysts from teratoma.

Purpose: Testicular teratomas in adult patients are histologically diverse tumors that frequently coexist with other germ cell tumor (GCT) components. These mixed GCTs often metastasize to retroperitoneal lymph nodes where multiple GCT elements are frequently present in the same metastatic lesion. Neither the genetic relationships among the different components in metastatic lesions nor the relationships between primary and metastatic GCT components have been elucidated. Experimental Design: We examined metastases from 31 patients who underwent primary retroperitoneal lymph node dissection for metastatic testicular GCT. All patients had metastatic mature teratoma with one or more other GCT components. This study included a total of 72 metastatic GCT components and 16 primary GCT components from 31 patients. Genomic DNA samples from each component were prepared from formalin-fixed, paraffin-embedded tissue sections using laser-assisted microdissection. Loss of heterozygosity (LOH) assays for seven microsatellite polymorphic markers on chromosomes 1p36 (D1S1646), 9p21 (D9S171 and IFNA), 9q21 (D9S303), 13q22-q31 (D13S317), 18q22 (D18S543), and 18q21 (D18S60) were done to assess clonality. Results: Twenty-nine of 31 (94%) cases showed allelic loss in one or more components of the metastatic GCTs. Twenty-nine of 31 mature teratomas showed allelic loss in at least one of seven microsatellite polymorphic markers analyzed. The frequency of allelic loss in informative cases of metastatic mature teratoma was 27% (8 of 30) with D1S1646, 34% (10 of 29) with D9S171, 37% (10 of 27) with IFNA, 27% (8 of 30) with D9S303, 46% (13 of 28) with D13S317, 26% (7 of 27) with D18S543, and 36% (10 of 28) with D18S60. Completely concordant allelic loss patterns between the mature teratoma and all of the other metastatic GCT components were seen in 26 of 29 cases in which the mature teratoma component showed LOH. Nearly identical allelic loss patterns were seen in the three remaining cases. In six cases analyzed, LOH patterns of each metastatic component were compared with each GCT component of the primary testicular tumor. In all six cases, each primary and metastatic component showed an identical pattern of allelic loss. Conclusion: Our data support the common clonal origin of metastatic mature teratomas with other components of metastatic testicular GCTs and with each component of the primary tumor.

Correctly diagnosing a metastatic germ cell tumor after chemotherapy may be challenging because of the diverse morphological manifestations of postchemotherapy tumors. Both OCT4 and CD30 are sensitive markers for the identification of primary embryonal carcinomas; however, loss of expression of CD30 (65%) has been reported in metastatic embryonal carcinomas after chemotherapy. The present study was conducted to evaluate the expression patterns of OCT4 and CD30 in postchemotherapy metastatic embryonal carcinomas and to compare their utility as diagnostic tools. Twenty-five cases of metastatic embryonal carcinoma after chemotherapy were immunohistochemically analyzed for CD30, OCT4, and cytokeratin AE1/AE3 expression. The staining intensities and the percentages of positively staining tumor cells were recorded. Nineteen (76%) of 25 cases revealed diffuse, moderate to strong nuclear OCT4 staining in postchemotherapy embryonal carcinomas. Among these 19 OCT4-positive cases, 8 also revealed diffuse and moderate to strong membranous CD30 staining. Seven of these OCT4-positive cases retained focal and weak CD30 expression. The remaining 4 OCT4-positive cases demonstrated a complete loss of CD30 expression. The 19 OCT4-positive cases showed a positive but variable cytokeratin AE1/AE3 expression pattern. Six (24%) of 25 cases were negative for both CD30 and OCT4 but demonstrated diffuse and strong cytokeratin AE1/AE3 staining. OCT4 is a useful diagnostic marker to identify metastatic embryonal carcinomas after chemotherapy, with a better sensitivity than CD30.

Germ cell tumours (GCTs) are a heterogeneous group of neoplasms, which develop in the gonads as well as in extragonadal sites, that share morphological patterns and an overall good prognosis, owing to their responsiveness to current surgical, chemotherapeutic, and radiotherapeutic measures. GCTs demonstrate extremely interesting biological features because of their close relationships with normal embryonal development as demonstrated by the pluripotentiality of some undifferentiated GCT variants. The similarities between GCTs and normal germ cell development have made it possible to identify possible pathogenetic pathways in neoplastic transformation and progression of GCTs. Genotypic and immunophenotypic profiles of these tumours are also useful in establishing and narrowing the differential diagnosis in cases of suspected GCTs. Recently, OCT4 (also known as OCT3 or POU5F1), a transcription factor that has been recognized as fundamental in the maintenance of pluripotency in embryonic stem cells and primordial germ cells, has been proposed as a useful marker for GCTs that exhibit features of pluripotentiality, specifically seminoma/dysgerminoma/germinoma and embryonal carcinoma. The development of commercially available OCT4-specific antibodies suitable for immunohistochemistry on paraffin-embedded specimens has generated increasing numbers of reports of OCT4 expression in a wide variety of gonadal and extragonadal GCTs. OCT4 immunostaining has been shown to be a sensitive and specific marker for seminomatous/(dys)germinomatous tumours and in embryonal carcinoma variants of non-seminomatous GCTs, whether in primary gonadal or extragonadal sites or in metastatic lesions. Therefore, OCT4 immunohistochemistry is an additional helpful marker both in the differential diagnosis of specific histological subtypes of GCTs and in establishing a germ cell origin for some metastatic tumours of uncertain primary. OCT4 expression has also been reported in pre-invasive conditions such as intratubular germ cell neoplasia, unclassified (IGCNU) and the germ cell component of gonadoblastoma. Additionally, OCT4 immunostaining shows promise as a useful tool in managing patients known to be at high risk for the development of invasive GCTs.

BACKGROUND. Inverted urothelial papilloma is an uncommon urothelial neoplasm. Although it is traditionally regarded as a benign tumor, conflicting data on multiplicity, recurrence rate, and association with urothelial carcinoma have left uncertainties concerning its biologic behavior. METHODS. The authors analyzed the clinicopathological characteristics of 75 cases of inverted papilloma in the urinary tract without prior or concurrent urothelial carcinoma to determine its biologic behavior and prognosis, and to correlate these findings with surveillance strategies. RESULTS. These patients ranged in age from 26 to 85 years (mean, 60 years). Of the 46 patients for whom tobacco use history was available, 28 gave a history of smoking. Inverted papillomas were located in the urinary bladder (67 cases), prostatic urethra (4 cases), and ureter (4 cases). The majority of vesical tumors arose from the trigone or near the bladder neck. Common presenting complaints included hematuria, dysuria, and irritative voiding symptoms. In 1 case of vesical inverted papilloma, there was a recurrence. All other patients were free of tumor recurrence or progression during a mean follow-up of 68 months (range, 2–240 months). CONCLUSIONS. Both the extremely low incidence of tumor recurrence (1%) and strikingly favorable prognosis suggest that inverted urothelial papilloma, when diagnosed according to strictly defined criteria, is a benign urothelial neoplasm not related to urothelial carcinoma. Therefore, complete transurethral resection of inverted papilloma is adequate surgical therapy, and surveillance protocols as rigorous as those employed in the management of urothelial carcinoma seem unnecessary. Cancer 2006. © 2006 American Cancer Society.

Intestinal metaplasia has been proposed to be a precursor lesion of adenocarcinoma in the urinary bladder. CDX2 is a transcription factor that is encoded by a homeotype gene that plays an essential role in the differentiation and proliferation of intestinal epithelial cells. Hepatocyte-specific antigen (Hep) has also been shown to be a useful marker of intestinal metaplasia. Tissues from 46 patients, including 22 cases of intestinal metaplasia of the urinary bladder, 11 cases of typical cystitis glandularis, and 13 cases containing both lesions, were selected and immunohistochemical stains for CDX2, Hep, cytokeratin 20 (CK20), and cytokeratin 7 (CK7) were performed. Nuclear staining for CDX2 was observed in 29 of 35 (83%) cases of intestinal metaplasia of the urinary bladder. In contrast, nuclear staining for CDX2 was not observed in any case of typical cystitis glandularis; however, seven of 24 (29%) cases showed aberrant cytoplasmic expression in a mean of 37% of cells. CK20 was expressed in 28 of 35 (80%) cases of intestinal metaplasia, but was observed in only one of 24 (4%) cases of cystitis glandularis in 15% of cells. CK7 was expressed in only six of 35 (17%) cases of intestinal metaplasia, whereas expression of CK7 was observed in all cases (100%) of typical cystitis glandularis with a mean percentage of positively staining cells of 63%. The mean percentages of positively staining cells in intestinal metaplasia with CDX2, CK20, and CK7 were 55, 49, and 53%, respectively. All examples of both intestinal metaplasia and typical cystitis glandularis were uniformly negative for Hep. In the urinary bladder, intestinal metaplasia and typical cystitis glandularis have sharply contrasting immunoprofiles. Additionally, the absence of Hep staining in intestinal metaplasia of the urinary bladder, despite its morphologic resemblance to normal colonic mucosa and intestinal metaplasia in other organs, may signify the presence of unique metaplastic pathways in the urinary bladder.

Inverted papilloma of urinary bladder is an uncommon urothelial neoplasm. Its relationship to urothelial carcinoma is controversial. Little is known of the genetic abnormalities of inverted papilloma. To better understand its genetics, we analyzed 39 inverted papillomas, including 36 from men and three from women, for loss of heterozygosity (LOH). We examined four polymorphic microsatellite markers located on chromosome 9q32-33(D9S177), chromosome 9p22 (IFNA), chromosome 3p14.2 (D3S1300) and chromosome 17p13.1 (TP53), where genetic alterations occur frequently in urothelial carcinomas. Additionally, the status of inactivation of X-chromosome was examined in three female patients. The frequency of LOH in informative cases was 8% (3 of 37) for D9S177, 10% (4 of 38) for TP53, 8% (3 of 37) for IFNA and 8% (3 of 36) for D3S1300. In the analysis of X-chromosome inactivation, all three cases yielded informative results and one had nonrandom inactivation of X-chromosomes. The monoclonal origin demonstrated in the study of X-chromosome inactivation indicates the clonal process of inverted papilloma; however, the low incidence of LOH supports the view that inverted papilloma in urinary bladder is a benign neoplasm with molecular genetic abnormalities different from those of urothelial carcinoma.

A 74-year-old woman presented with a one-week history of persistent cough. A chest x-ray and computed tomography images revealed features mimicking lung cancer, which included a large solitary consolidation and hilar lymphadenopathy. She had received low-dose amiodarone (200 mg/day) for treatment of atrial fibrillation for more than 2.5 years. The tumour-like abnormalities did not disappear until the discontinuation of amiodarone therapy. The finding of low-dose amiodarone causing tumour-like abnormalities on a chest x-ray is unique. Once amiodarone-induced tumour-like changes are diagnosed, therapeutic options are limited. In most cases, the tumour-like changes are reversible, if diagnosed early. An unusual case involving amiodarone-induced pulmonary abnormalities is reported, followed by a review of the relevant literature.

Summary Aims The detection of invasive cancer cells within the adipose tissue of needle biopsies has been regarded as bona fide evidence of extraprostatic tumour extension, and as a consequence may influence subsequent patient management. However, the identification of rare intraprostatic fat from recent reports involving series of autopsies has challenged this practice principle. We examined totally embedded, whole-mounted radical prostatectomy specimens in order to determine the occurrence of intraprostatic fat in prostatic tissue, and further, to assess the importance of the identification of fat infiltration by neoplastic cells in needle biopsy specimens as a marker of extraprostatic infiltration by tumour. Methods Between 2000 and 2003, 313 consecutive patients underwent radical prostatectomy for clinically localised prostate cancer in the Indiana University Hospital. All radical prostatectomy specimens were completely embedded and whole mounted for histological examination. All slides were reviewed and evaluated for the presence or absence of intraprostatic fat. Other pathological characteristics of prostate cancer were also assessed and clinical data were gathered by a review of patient charts. Results The mean age of patients was 60 years. None of these 313 radical prostatectomy specimens revealed any adipose tissue components within the most peripheral boundary of normal prostatic acini in the prostate. Conclusions We found no evidence of intraprostatic fat and our findings suggest that, at best, the occurrence of fat within the prostate is of extreme rarity. Accordingly, the finding of carcinoma invading adipose tissue in needle biopsies should continue to be considered as extraprostatic extension and stage pT3a assigned.

Xp11.2 translocation renal cell carcinoma (RCC) is rare and predominantly found in children and young adults. Because of the property of overexpressed transcription factor E3 (TFE3) fusion protein, immunohistochemical (IHC) staining with TFE3 antibody makes an excellent diagnostic tool. This study analyzed preliminary experiences of eight Xp11.2 translocation RCCs in our institution between 2007 and 2012. In four males and four females with a mean age of 28.4 years. Xp11.2 translocation RCCs were diagnosed. TFE3 IHC stain was positive in all tumor specimens. As the initial presentation, four patients suffered from abdominal pain, three cases had gross hematuria, and one case had hemoptysis caused by existing lung metastasis. The tumor was located in the right kidney (75%) with mean diameter of 5.85 ± 2.64 cm. Three cases (38%, 3/8) presented with lymph node metastasis at the time of diagnosis. In five cases (63%, 5/8), the initial diagnosis was Stage III and IV. Treatment included open surgery (one partial nephrectomy and five radical nephrectomies), cryoablation, immunotherapy, and target therapy. The mean follow-up time was 32 months. One patient died after 23.4 months of follow-up. The application of TFE3 IHC stain will improve the diagnostic accuracy for detecting XP11.2 translocation renal cell carcinoma. Surgery or cryoablation both had excellent prognosis in early stages. Although the disease is believed to be indolent, an increasingly aggressive clinical course should be kept in mind, especially for children and young adults.

Smooth muscle tumors are uncommon in the urinary bladder, and atypical leiomyoma of the urinary bladder is extremely rare. We report a case of atypical leiomyoma with a concurrent breast carcinoma and discuss the pathologic features, the possible etiology and clinical outcome of the tumor.

Melanotic Xp11 translocation renal cancer is a recently recognized aggressive epithelioid neoplasm with features overlapping between PEComa, carcinoma, and melanoma. We describe morphologic and immunohistochemical characteristics of a melanotic Xp11 translocation renal cancer occurring in an 18-year-old girl and perform molecular genetic studies to analyze its genetic alterations and related melanogenetic activities. The tumor was composed of solid nests of epithelioid cells bearing abundant clear to finely granular eosinophilic cytoplasm and separated by delicate vascular septa. Finely granular and nonrefractile brown melanin pigments, highlighted by Fontana-Masson stain, were scattered through the tumor. By immunohistochemistry, the tumor was diffusely and strongly labeled by TFE3 and focally stained by HMB45 in a patchy pattern. In contrast, all other applied immunomarkers, including cytokeratins, epithelial membrane antigen, vimentin, CD10, S-100, smooth muscle actin, desmin, c-kit, CD68, and microphthalmia-associated transcription factor, were nonreactive to the tumor. Reverse transcription-polymerase chain reaction and validating sequencing demonstrated PSF-TFE3 gene fusion, a novel exon composition juxtaposing PSF exon 9 to TFE3 exon 5. Up-regulations of melanogenesis-associated regulators, including microphthalmia-associated transcription factor, tyrosinase (TYR), and tyrosinase-related protein 1 (TYRP1), were identified in the tumor by semiquantitative reverse transcription-polymerase chain reaction. The morphologic and immunohistochemical discrepancies between this intriguing melanotic tumor and other documented renal cell carcinomas bearing identical PSF-TFE3 gene fusion may suggest melanotic Xp11 translocation renal cancer is a distinct entity among the MiT/TFE family neoplasms.

Purpose: Clear cell adenocarcinoma in the urinary tract is a rare entity with an appearance resembling its counterpart in the female genital tract. Although several theories have been proposed about its origin, its exact histogenesis has remained uncertain. Experimental Design: We integrated molecular genetic evaluation by fluorescence in situ hybridization and X-chromosome inactivation with conventional morphologic and immunohistochemical analyses in 12 patients with clear cell adenocarcinomas in the urinary tract. Results: Concurrent urothelial carcinoma or urothelial carcinoma in situ was present in six cases (50%) and foci of cystitis glandularis were observed in four cases (33%). Neither intestinal metaplasia nor Müllerian component was identified in any case. Cytoplasmic expression of α-methylacyl-CoA racemase was demonstrable in 10 of 12 tumors (83%). Moderate to diffuse immunostaining for cytokeratin 7 was identified in all 12 tumors (100%), whereas only 3 of 12 (25%) tumors showed positive immunostaining for cytokeratin 20. Focal uroplakin III staining was seen in 6 of 12 tumors (50%). In five cases (42%), focal to moderate CD10 immunoreactivity was observed. Immunostains for OCT4 and CDX2 were completely negative in all tumors. In UroVysion fluorescence in situ hybridization assays, all tumors displayed chromosomal alterations similar to those commonly found in urothelial carcinoma. Identical patterns of nonrandom X-chromosome inactivation in concurrent clear cell adenocarcinoma and urothelial neoplasia were identified in two informative female cases. Conclusions: Our findings support an urothelial origin for most clear cell adenocarcinomas of the urinary tract, despite their morphologic resemblance to certain Müllerian-derived tumors of the female genital tract.

Inverted papilloma of the urinary bladder and urothelial carcinoma with an inverted (endophytic) growth pattern may be difficult to distinguish histologically, especially in small biopsies. The distinction is important as these lesions have very different biologic behaviors and are treated differently. We examined histologic features and undertook immunohistochemical staining and UroVysion fluorescence in situ hybridization (FISH) to determine whether these methods could aid in making this distinction. We examined histologic sections from 15 inverted papillomas and 29 urothelial carcinomas with an inverted growth pattern. Each tumor was stained with antibodies to Ki-67, p53, and cytokeratin 20. In addition, each tumor was examined with UroVysion FISH for gains of chromosomes 3, 7, and 17 and for loss of chromosome 9p21 signals. None of the inverted papillomas stained positively for Ki-67 or for cytokeratin 20. Only 1 of 15 inverted papillomas stained positively for p53. By contrast, 66%, 59%, and 59% of urothelial carcinomas with an inverted growth pattern stained positively for Ki-67, p53, and cytokeratin 20, respectively. Only 3 of the urothelial carcinomas stained negatively for all 3 immunohistochemical markers. UroVysion FISH produced normal results for all cases of inverted papilloma. By contrast, 21 of 29 cases (72%) of urothelial carcinoma with an inverted growth pattern demonstrated chromosomal abnormalities typical of urothelial cancer and were considered positive by UroVysion FISH criteria. Morphologic features, as well as immunohistochemical stains (including stains for Ki-67, p53, and cytokeratin 20) and/or UroVysion FISH can help to distinguish inverted papilloma from urothelial carcinoma with an inverted growth pattern.

Despite improvement in surgical techniques, prognosis of gallbladder carcinoma remains poor. It is desirable to identify prognostic biomarkers to aid in the development of targeted therapeutic strategies. Two SCF(Skp2) ubiquitin ligase-related proteins, Skp2 and cyclin-dependent kinase subunit 1 (Cks1), are involved in post-transcriptional degradation of p27(Kip1) tumor suppressor, which inhibits both cdk2/cyclin E and cdk2/cyclin A complexes and thus prevents transition to the S phase. However, the prognostic utility of p27(Kip1)-interacting cell cycle regulators has not been systematically assessed in gallbladder carcinoma. Immunohistochemistry was performed for p27(Kip1), Skp2, Cks1, cyclin E, cyclin A, and Ki-67 in tissue microarrays of 62 gallbladder carcinomas with follow-up. The data were correlated with clinicopathological features and overall survival (OS). The cumulative OS rate for all 62 cases was 42.9% at 3 years. Aberrant labeling indices (LIs) of p27(Kip1) (20%), cyclin E (or=5%), cyclin A (or=5%), Cks1 (or=40%), and Skp2 (or=10%) were identified in 29, 58, 66, 21, and 57% of gallbladder carcinomas, respectively. By log-rank tests, downregulation of p27(Kip1) (P=0.0319) and high LIs of Skp2 (P=0.0006), Cks1 (P=0.0460), cyclin E (P=0.0070), and Ki-67 (P=0.0037) were predictive of inferior OS. Furthermore, the combined expression status of Skp2 and Ki-67 robustly defined three prognostically different groups (P=0.0001). In multivariate comparison, Skp2 overexpression represented the strongest independent adverse prognosticator (P=0.004, risk ratio (RR): 5.538), followed by Ki-67 LIor=50% (P=0.016, RR: 3.254) and American Joint Committee on Cancer stages II-IV (P=0.013, RR: 3.163). In conclusion, aberrations of p27(Kip1)-interacting cell cycle regulators are common in gallbladder carcinomas. Skp2 overexpression is highly representative of biological aggressiveness and independently associated with poor OS, suggesting that it is a promising novel target for therapeutic intervention in aggressive cases. The combined assessment of Skp2 and Ki-67 LIs effectively risk-stratifies gallbladder carcinomas with different prognosis, which is worth being prospectively validated in future study.

Although focal myxoid change is a well-recognized feature of solitary fibrous tumor (SFT), predominantly myxoid SFT are exceedingly rare. Reported herein is the case of a 65-year-old man with SFT containing abundant myxoid matrix, arising from the capsule of the right seminal vesicle. To the authors' knowledge this is the first myxoid SFT involving the male genito-urinary system. Recognition of the myxoid variant of SFT is crucial, given possible confusion with a variety of myxoid spindle cell neoplasms with different biological potential in the pelvic cavity.

The incidence of retroperitoneal seminoma is much less than that of its gonadal counterpart. Accurate diagnosis of retroperitoneal seminoma is critical, because it carries an excellent prognosis due to its favorable response to radiation therapy and/or cisplatin-based chemotherapy. However, correctly diagnosing a retroperitoneal seminoma may be challenging, especially when the biopsy material is limited. The present study was conducted to evaluate histologic findings and immunohistochemical staining patterns in biopsy specimens of retroperitoneal seminoma and to compare their utility as diagnostic tools. Thirty biopsy specimens of retroperitoneal seminoma were assessed for histologic characteristics and immunohistochemical expression of OCT4, c-kit, placental-like alkaline phosphatase, and cytokeratin AE1/AE3. The clinical information, morphologic features, and staining intensities and the percentages of positively staining tumor cells were analyzed. The mean age of patients was 38 years. Lymphocytic infiltration and nucleolar prominence in tumor cells were found in all 30 cases (100%). The incidence of other histologic characteristics were as follows: fibrous septa/stroma in 80% (24 cases), clear tumor cell cytoplasm in 70% (21 cases), tumor necrosis in 60% (18 cases), cellular pleomorphism in 53% (16 cases), granulomatous inflammation in 50% (15 cases), distinct cell borders in 46% (14 cases), intercellular edema in 23% (7 cases), and syncytiotrophoblasts in 3% (1 case). The mean mitotic count was 3 (range 0 to 15) per 10 high-power fields. All 30 cases (100%) of retroperitoneal seminoma revealed moderate to strong nuclear OCT4 staining in more than 50% of tumor cells. Twenty-one cases (70%) showed membranous expression of c-kit by tumor cells, with moderate to strong staining intensity in most cases. Variable degrees of staining for placental-like alkaline phosphatase were identified in 23 cases (77%) with occasional background staining artifact. Six cases (20%) displayed a positive cytokeratin AE1/AE3 staining pattern with weak to moderate intensity. In conclusion, the most common histologic findings in limited biopsy specimens of retroperitoneal seminoma were lymphocytic infiltration and nucleolar prominence in tumor cell nuclei. OCT4 immunostaining, with its superior sensitivity and easy interpretation compared with other markers, is a powerful tool for confirming the diagnosis of retroperitoneal seminoma.

A 42-year-old man presented with a two-year history of progressive dysphagia and hoarseness. Esophagogram and endoscopy revealed submucosal mass effect on the upper esophagus. Computed tomography and magnetic resonance imaging revealed an elongated mass in the retrotracheal region of the lower neck with extension to the posterior mediastinum. Partial tumor resection and histopathological evaluation revealed a WHO type B2 thymoma. Adjuvant radiation and chemotherapy were subsequently administered resulting in complete tumor regression. To our knowledge, this is the first report of ectopic retrotracheal thymoma with clinical and imaging manifestations mimicking those for esophageal submucosal tumor.

Tailgut cysts are rare congenital multicystic lesions preferentially occurring in the retrorectal space. They are assumed to arise from the remnant of embryonic tailgut and occasionally exhibit malignant transformation. The authors herein describe the clinical, radiologic, and pathologic features of an unusual perirenal tailgut cyst with an emphasis on its histogenesis and distinction from other intraabdominal cystic lesions.

Pure yolk sac tumor is the most common malignant gonadal tumor of infants and toddlers. However, the majority of extragonadal germ cell tumors in the midline are either seminomas (germinomas) or teratomas, and pure yolk sac tumors account for only a small fraction of these lesions. To date, only 1 primary urachal pure yolk sac tumor has been reported in the literature. We describe another case, occurring in a 7-month-old male infant who presented with a rapidly enlarging intra-abdominal tumor with marked engorgement of the superficial venous plexus around the umbilicus. With periodic follow-up for 3 years following surgical extirpation of the tumor and adjuvant chemotherapy, this patient is still alive without evidence of disease. Notably, the glandular elements predominating in the frozen sections resulted in the initial misdiagnosis of the tumor as a urachal adenocarcinoma, although the entirely resected specimen revealed typical histologic patterns and Schiller-Duval bodies. Immunohistochemistry showed that the tumor cells were diffusely reactive to α-fetoprotein, α1-antitrypsin, and cytokeratin. Tumor cells were negative for p53 protein, but revealed overexpression for MDM2 protein. Flow cytometry demonstrated a diploid DNA content with S-phase being as high as 55.36%. This case emphasizes that pure yolk sac tumor can occur primarily in the remnant of the urachus in young children.

This study evaluated the inhibitory activity of somatostatin 14 on the angiogenesis of cornea in vivo.Corneal neovascularization was induced with a pellet containing 90 ng of basic fibroblast growth factor (bFGF) in a rat corneal pocket model. Three kinds of pellets were made containing bFGF plus somatostatin (SST) 0 ng, 20 ng and 200 ng for the control group, group 1 and group 2, respectively. Neovascularization was observed biomicroscopically from day 4 to day 8, and the corneas were then examined for changes in histology. Quantitation of angiogenesis in the cornea was accomplished by caliper and image analysis.The 200-ng dose of SST showed significant inhibition of both length and area of neovascularization on day 7 (0.62+/-0.11 mm vs 1.29+/-0.16 mm, 0.50+/-0.16 mm2 vs 1.35+/-0.29mm2, group 2 vs control; P0.05). The 20 ng of somatostatin did not demonstrate any significant inhibition of neovascularization compared with the control group.Our study demonstrated that SST 14 can reduce bFGF-induced corneal angiogenesis. This shows the potential value of somatostatin in the treatment of corneal neovascularization.

Collagenous fibroma (desmoplastic fibroblastoma) is an extremely rare benign soft tissue tumor of fibroblastic origin. The majority of reported cases have been located in the deep subcutis, fascia, aponeurosis, or skeletal muscle of the extremities, limb girdles, or head and neck regions. There has been no mention of underlying diseases in patients who developed this tumor. We here report an additional three cases of superficial collagenous fibroma, one of which was a dermal lesion occurring in the abdomen of a 26-year-old male patient with a 5-year history of pemphigus vulgaris prior to development of the tumor. To the best of our knowledge, an association between collagenous fibroma and pemphigus vulgaris has not previously been reported. The remaining two tumors were located in the superficial subcutaneous tissue of the infrascapular area and right foot, respectively. There was no tumor recurrence or metastasis during follow up of 18, 25, and 47 months, respectively. All three tumors were well-circumscribed and unencapsulated without infiltrating borders. Histologically, the common denominator of all three cases was paucicellular proliferation of spindle or stellate fibroblasts enmeshed within an extensively collagenous background. Immunohistochemically, there was diffuse strong staining for vimentin and intense focal reaction for smooth muscle actin in two tumors tested. Electron microscopy revealed features consistent with a fibroblastic or myofibroblastic lineage. Flow cytometry in two cases demonstrated a diploid DNA content with low S-phase fractions, which correlated with minimal MIB-1 nuclear labeling (less than 1%) and benign behavior of this entity.

Solitary fibrous tumors have been described at many extrapleural sites in recent years. However, solitary fibrous tumors arising from somatic soft tissue occur only rarely and can pose problems in the differential diagnosis from other benign or malignant soft tissue tumors. The majority of solitary fibrous tumors occurring in the somatic soft tissue have been found in the extremities and limb girdles, and the head and neck regions. There have been only eight published cases located in the abdominal wall. We herein report two female patients who developed solitary fibrous tumors of the abdominal wall that were not in association with the underlying peritoneum. Histologically, both tumors were characterized by a variety of architectural patterns, alternating hypercellular and hypocellular areas, proliferation of plump spindle cells, thick keloid-like and/or amianthoid collagen bundles, and ectatic staghorn-like vessels. Both tumors showed a diffuse strong reaction for CD34 and vimentin as well as focal positivity for bcl-2 and smooth muscle actin. A striking predominance in females was found in a literature review of solitary fibrous tumors of the abdominal wall, contrasting with other somatic soft tissue sites which show an equal gender distribution. Interestingly, expression of estrogen but not progesterone receptor was observed in both tumors. Ultrastructurally, the tumor cells displayed features of fibroblasts with dilated branching rough endoplasmic reticulum (RER) and Golgi apparatus. Both tumors assayed by flow cytometry demonstrated a diploid DNA content with an S-phase fraction of 7.9% and 11.4%, respectively. At follow up, both patients were well without evidence of recurrence or metastasis after surgical excision.