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Background: Biopsy Gleason score (bGS) remains an important prognostic indicator for adverse outcomes in Prostate Cancer (PCA). In the light of recent studies purporting difference in prognostic outcomes for the subgroups of GS7 group (primary Gleason pattern 4 vs. 3), upgrading of a bGS of 6 to a GS≥7 has serious implications. We sought to identify pre-operative factors associated with upgrading in a cohort of GS6 patients who underwent prostatectomy., Design: We identified 281 cases of GS6 PCA on biopsy with subsequent prostatectomies. Using data on pre-operative variables (age, PSA, biopsy pathology parameters), logistic regression models (LRM) were developed to identify factors that could be used to predict upgrading to GS≥7 on subsequent prostatectomy. A decision tree (DT) was constructed., Results: 92 of 281 cases (32.7%) were upgraded on subsequent prostatectomy. LRM identified a model with two variables with statistically significant ability to predict upgrading, including pre-biopsy PSA (Odds Ratio 8.66; 2.03-37.49, 95% CI) and highest percentage of cancer at any single biopsy site (Odds Ratio 1.03, 1.01-1.05, 95% CI). This two-parameter model yielded an area under curve of 0.67. The decision tree was constructed using only 3 leave nodes; with a test set classification accuracy of 70%., Conclusions: A simplistic model using clinical and biopsy data is able to predict the likelihood of upgrading of GS with an acceptable level of certainty. External validation of these findings along with development of a nomogram will aid in better stratifying the cohort of low risk patients as based on the GS.

The vast majority of urachal epithelial neoplasms are adenocarcinomas with several described morphologic subtypes that include both enteric and nonenteric histologies. Adenocarcinoma from several other primaries may mimic any of these urachal adenocarcinoma subtypes in the bladder or at distant sites. However, data regarding the immunohistochemical profile of urachal carcinoma are limited, let alone its correlation with the different histologic subtypes that may have implications in the differential diagnostic workup with their morphologic mimics. Herein, we performed an immunohistochemical analysis in a broad spectrum of 39 urachal epithelial neoplasms (34 adenocarcinomas, 1 urothelial carcinoma, and 4 noninvasive mucinous cystic tumors), 13 urachal remnants, and 6 secondary colonic adenocarcinomas of the bladder, using an antibody panel that included novel and traditional gastrointestinal tract-associated markers. Expression levels of p63, CK7, CK20, CDX2, nuclear β-catenin, claudin-18, and Reg IV in urachal adenocarcinoma were as follows: 3%, 50%, 100%, 85%, 6%, 53%, and 85%. In urachal adenocarcinoma subtypes, expression levels of CDX2, nuclear β-catenin, claudin-18, and Reg IV were as follows: mucinous (8/8, 0/8, 6/8, 8/8), enteric (10/11, 1/11, 3/11, 8/11), not otherwise specified (5/7, 0/7, 3/7, 5/7), and signet ring cell (4/6, 0/6, 4/6, 6/6) type. All urachal adenocarcinomas had membrano-cytoplasmic β-catenin staining and only 2 tumors had nuclear localization that were focal to moderate, in contrast to secondary colonic adenocarcinoma of the bladder, which mostly had both membrano-cytoplasmic and nuclear positivity. Claudin-18 positivity was observed only in frankly malignant tumors and not in noninvasive urachal tumors and urachal remnants. Reg IV expression seemed to be related to mucin production, which was often diffuse in mucinous and signet ring cell subtypes and focal in enteric subtype, with goblet cell-like reactivity similar to secondary colonic adenocarcinoma. p63 expression was present in urothelial urachal remnants (3/3) and contrasted with CDX2 expression seen in glandular (5/6) and mixed urothelial/glandular remnants (2/4). Thus, this study showed that CDX2 is expressed by urachal remnants of glandular type, noninvasive urachal mucinous cystic tumors and urachal adenocarcinomas, and can be diffuse in urachal adenocarcinomas, even without the classic enteric morphology. Nuclear localization of β-catenin can rarely occur in urachal adenocarcinoma; however, diffuse nuclear reactivity argues against its diagnosis. The novel gastrointestinal tract markers claudin-18 and Reg IV are both expressed in urachal adenocarcinoma, including in signet ring cell carcinoma, and thus refutes the suggested specificity for gastrointestinal tract signet ring cell carcinomas. An immunohistochemical panel that includes β-catenin and CK7 may have value in differentiating urachal adenocarcinoma of enteric morphology from colonic adenocarcinoma. Overall, this study suggests that the different morphologic presentations of urachal adenocarcinomas have a relatively similar or overlapping immunophenotype. Knowledge of the similarity in immunostaining to its different morphologic mimics may help avoid misdiagnosis in urachal adenocarcinoma.

Dorsal hood prepuce is a common congenital anomaly of the penis. Neoplasms of the prepuce are very rarely seen in children. We present an interesting case of a penile myofibroma encountered during circumcision of a dorsal hood foreskin in an 8-month-old infant., (Copyright © 2011 Elsevier Inc. All rights reserved.)

We previously developed a highly aggressive cell line from heart metastases of 4T1 breast carcinoma (designated 4THM), which produced liver metastases (designated 4TLM). In this study, gene array analysis (GAEA) compared gene expression profiles in 4TLM with profiles in 4T1 and 4THM primary tumors. GAEA demonstrated that 4T1 and 4THM tumors differed in about 250 genes. Over 1,000 genes, however, were expressed differently in 4TLM compared with primary tumors. A cohort of 16 genes showed significantly decreased expression in 4THM tumors, which decreased even further in 4TLM. Many of these genes have been implicated in breast cancer, and many are involved in cell adhesion and junctional complexes. Expression of multiple tight and adherence junction proteins was either downregulated or disappeared in 4TLM; downregulation of claudin 4, claudin 7 and gamma-catenin was confirmed by quantitative polymerase chain reaction, immunoblot, and immunocytochemical (ICC) analyses. At the protein level, intact ZO-1 was also observed in 4T1 tumors, but was not expressed in 4THM or 4TLM tumors. ICC demonstrated expression of gamma-catenin at the plasma membrane with 4T1 tumors, whereas staining appeared to be nuclear/perinuclear in 4THM tumors. Claudin 7 staining was also seen in monocyte/pmacrophage-like cells in liver around metastatic lesions by ICC, and it appeared that larger 4TLM tumors apparently reexpressed claudin 7 RNA and protein. Our results demonstrate that decreased or abnormal expression of a number of cell adhesion/junctional proteins, including claudin 4, 7, ZO-1 and gamma-catenin, correlates with liver metastases, and that cell adhesion molecules in the microenvironment are also altered.

Accurate recognition of urinary bladder muscularis propria (MP) invasion by urothelial carcinoma is crucial as it is the critical crossroad between conservative and aggressive management for the patient. It is now widely known that an inconsistent layer of muscularis mucosae (MM) muscle exists in the lamina propria, which can mimic the MP muscle, particularly when hyperplastic, making staging extremely challenging in some limited, unoriented, or highly cauterized specimens. Smoothelin is a novel smooth muscle-specific contractile protein expressed only by fully differentiated smooth muscle cells, and not by proliferative or noncontractile smooth muscle cells and myofibroblasts. We performed immunohistochemical staining in the bladder for smoothelin to: (a) evaluate its expression in MM and MP muscle in cystectomy specimens and by comparing the staining pattern with smooth muscle actin (SMA), (b) study MP variations in the bladder trigone and at the ureteric insertion in the bladder wall, and (c) assess the staining pattern of MM and MP in a representative group of transurethral resection of bladder tumor specimens. In contrast to SMA, which equitably stained both types of muscle fibers, smoothelin displayed striking differential immunoreactivity between MM and MP muscle. With smoothelin, the MM muscle (including hyperplastic forms) typically showed absent (19/42, 45%) or weak and focal (18/42, 43%) staining, whereas the MP muscle typically showed strong and diffuse staining (36/42, 86%). Smoothelin accentuated individual muscle fibers within groups of MP bundles only, a feature which was evident in both MM and MP stained by SMA. When only strong and diffuse immunoreactivity in muscle was set as a threshold for positivity, 100% specificity and positive predictive value of smoothelin for MP (vs. MM) was achieved in our study. Smoothelin staining confirmed the morphologic variations in MP muscle in the bladder wall of the trigone and at the ureteric insertion. In addition to the well-defined muscle layers of MM and MP, SMA staining revealed a continuous band of ill-defined haphazardly oriented compact spindle cells that were immediately subjacent to the urothelium in all cases. These spindle cells blended with the morphologically recognizable thin slender fascicles of the MM muscle. We designate this hitherto uncharacterized thin layer of SMA-positive [muscle-specific actin positive (6/6), Masson trichrome stain predominantly blue (5/6)] and smoothelin-negative cells as suburothelial band of myofibroblasts. In all 10 transurethral resection of bladder tumor sections, smoothelin staining was in agreement with the routine light microscopic presence and absence of MP muscle. In conclusion, the relatively distinct immunohistochemical staining pattern of smoothelin between MP and MM (including its hyperplastic forms) makes it a robust and attractive marker to be incorporated in the contemporary diagnostic armamentarium for the sometimes difficult area of staging bladder urothelial carcinoma.

Purpose: Since clinically significant upgrading of the biopsy Gleason score has an adverse clinical impact, ancillary tools besides the visual determination of primary Gleason pattern are essential to aid in better risk stratification., Materials and Methods: A total of 61 prostate biopsies were selected in patients with a diagnosis of Gleason score 7 prostatic adenocarcinoma, including 41 with primary Gleason pattern 3 and 20 with primary Gleason pattern 4. Slides from these tissues were stained using Feulgen stain, a nuclear DNA stain. Areas of Gleason pattern in all cases were analyzed for 40 nuclear morphometric descriptors of size, shape and chromatin using a CAS-200 system (BD). The primary outcome analyzed was the ability of morphometric features to identify visually determined primary Gleason pattern 4 on the biopsy. Data were analyzed using logistic regression as well as a C4.5 decision tree with and without preselection., Results: Decision tree analysis yielded the best model. Automatic feature selection identified minimum nuclear diameter as the most discriminative feature in a 3-parameter model with 85% classification accuracy. Using a preselected 3-parameter model including minimum diameter, angularity and sum optical density the decision tree yielded a slightly lesser accuracy of around 79%. Bootstrap validation of logistic regression results revealed that there was no unique model that could significantly explain the variance in primary Gleason pattern status, although minimum nuclear diameter was the most frequently selected parameter., Conclusions: In this small cohort of patients with Gleason score 7 disease we report that Gleason pattern 4 nuclei from those with primary Gleason pattern 4 are generally larger with coarser chromatin compared with the Gleason pattern 4 in patients with primary Gleason pattern 3. These findings may aid in better risk stratification of the Gleason score 7 group by supplementing visual estimation of the percent of primary Gleason pattern 3 and 4 in the biopsy.

Background: Preneoplastic lung lesions and early-stage lung carcinomas are associated with molecular abnormalities. The authors performed a pilot study to evaluate the use of DNA fluorescence in situ hybridization (FISH) probes to ascertain whether these biomarkers can predict nonsmall cell lung carcinoma (NSCLC)., Methods: Fourteen bronchial brushings ipsilateral to the tumor (BB/Ts), tumor touch imprints, and touch imprints of the bronchus adjacent to the tumor obtained from 15 patients with early-stage NSCLC were analyzed. The LAVysion multicolor probe set consisting of probes to 5p15, 6, 7p12, and 8q2 and the in-house probes 3p22.1 and 10q22 was used. Using the LAVysion multicolor probe set, 25 epithelial cells were counted and considered positive if > 5 cells were abnormal. Using 3p22.1 and 10q22, > or = 100 nuclei per slide were scored. The results were tabulated as the percentage of cells with deletions compared with the centromeric probes 3 and 10. Greater than 2% of the deletions were positive for 3p22.1 and 10q22. Bronchial washings from patients without lung tumors were used as controls., Results: The BB/Ts were negative for malignant cells by cytologic evaluation and the LAVysion probe set; however, the combined in-house probes for 3p22.1 and 10q22 tested on BB/Ts predicted cancer in 100% of cancer patients. FISH positivity in the lung cancers was 100% for 3p22.1 deletions, 79% for 10q22 deletions, and 57% for LAVysion probes. When compared with the bronchial epithelium, tumor cells showed a 3.7-fold excess of 3p22.1 deletions, a 2-fold excess of 10q22 deletions, and a 12.6-fold excess of abnormal cells., Conclusions: The current study indicated that detection of molecular abnormalities in bronchial epithelial cells via FISH was very useful in identifying patients at high risk for developing lung carcinoma. The molecular abnormalities identified in the BB/Ts were detected at elevated levels in the tumor specimens., (2004 American Cancer Society)

Synovial sarcoma typically develops in the deep soft tissues of the extremities in adolescents and young adults. Uncommonly, these tumors may arise (9%) in the head and neck region (9%), especially at the cervical and parapharyngeal sites. Primary synovial sarcoma of the parotid gland is a rare occurrence that may not uncommonly cause differential diagnostic difficulties. In these cases, an origin from within the gland rather than a secondary involvement by tumor from a surrounding structure must be confirmed. We report a new case of biphasic synovial sarcoma arising in the parotid gland and review the previously documented cases.

Granular cell tumors (GCT) are uncommon benign neoplasms that have a predilection for the head and neck region. These tumors can frequently be associated with pseudoepitheliomatous hyperplasia (PEH), which in turn may be mistaken for squamous cell carcinoma. Although epidermal growth factors are overexpressed in squamous cell carcinomas of the head and neck, their presence in PEH, especially its relation to GCT, is unknown. We hypothesize that the expression of epidermal growth factor receptor (EGFR), epidermal growth factor (EGF), and transforming growth factor alpha (TGFalpha) in GCT have a role in the development of PEH overlying some GCT. Sections from 13 cases of GCT (five with overlying PEH) were examined histologically and evaluated immunohistochemically using monoclonal antibodies for EGFR, EGF, and TGFalpha. These were compared with nine cases of PEH independent of GCT. Two of five GCT with overlying PEH and two of six GCT without overlying PEH stained positively for TGFalpha. None of the GCT stained with EGFR or EGF. All cases of PEH, whether or not associated with GCT, were reactive for EGFR and EGF. Four of the five cases of PEH overlying GCT stained with TGFalpha. The staining pattern and intensity of all three antibodies were comparable to that of the adjacent normal squamous mucosa. Among the three antibodies, only TGFalpha in GCT appears to be related to the development of PEH. Epidermal growth factor receptor and EGF do not seem to be directly involved. The reason of PEH formation associated with GCT in the absence of growth factors is unknown., (Copyright 2003 Elsevier Inc. All rights reserved.)

The purpose of this study was to compare the cytologic features of melanoma fine-needle aspirates (FNAs) prepared by ThinPrep (TP) with those in conventional smears (CS) and to identify any diagnostic pitfalls. Fifty-one aspirates diagnosed as melanoma were obtained, 36 of which were prepared by both TP and CS. The preparations were evaluated for cellularity, cell aggregates, cellular appearance, melanin pigment, cytoplasmic, and nuclear features. Categorical data were analyzed by the chi-square test and continuous data by the Wilcoxin-signed rank test. Correlation was determined by Spearman's test for bivariate correlations (rho). Good correlation between the two methods was identified for the following features: cellularity, cell type, bi/multinucleated cells, cytoplasmic features, NC ratio, and presence of macronucleoli. TP exhibits coarser chromatin compared to CS (P = 0.005). Six of 36 CS contained large cellular groups; none of the TP contained them (P = 0.018). Twenty-five of 36 CS contained intranuclear inclusions as opposed to 12/36 TP (P < 0.001). The number of inclusions was significantly reduced on TP. The amount of intracellular melanin was the same with both techniques. Background melanin was markedly reduced on TP except when either trapped by fibrin or attached to cellular clusters (P = 0.006). Background blood was also markedly reduced on TP (P < 0.005). In summary, the cytological features of TP and CS for FNA evaluation of melanoma correlate well; however, one needs to be aware of the cytologic alterations introduced by TP. TP is a sufficient preparation method in the diagnosis of melanoma FNA aspirates when performed by clinicians. It is also a useful adjunct in bloody or low-cellular aspirates, where it tends to reduce the background blood and concentrate the cells., (Copyright 2002 Wiley-Liss, Inc.)