RNA-binding protein LIN28 is a marker for primary extragonadal germ cell tumors: an immunohistochemical study of 131 cases.

LIN28 has been shown to have an important role in primordial germ cell development and malignant transformation of germ cells in mouse. In this study, we examined the immunohistochemical profile of LIN28 in 131 primary human extragonadal germ cell tumors (central nervous system (CNS) 76, mediastinum 17, sacrococcygeal region 30, pelvis 3, vagina 2, liver 1, omentum 1, and retroperitoneum 1), including the following tumors and/or components: 57 seminomas/germinomas, 10 embryonal carcinomas, 74 yolk sac tumors, 6 choriocarcinomas, 15 mature, and 13 immature teratomas. We compared LIN28 with SALL4 to assess its diagnostic value. To determine its specificity, we examined LIN28 in 406 extragonadal-non-germ cell tumors (103 carcinomas, 91 sarcomas, 9 melanomas, 12 mesotheliomas, 83 lymphomas, 9 plasmacytomas, 82 CNS tumors, and 17 thymic epithelial tumors). The staining was semi-quantitatively scored as 0 (no cell stained), 1+ (0-30%), 2+ (31-60%), 3+ (61-90%), and 4+ (>90%). LIN28 staining was seen in all seminomas/germinomas (3+ in 1 and 4+ in 56), embryonal carcinomas (4+ in all 10), and yolk sac tumors (3+ in 3 and 4+ in 71). Variable LIN28 staining was seen in 5 of 6 choriocarcinomas (1+ to 4+), 8 of 13 immature teratomas (1+ to 2+ in immature elements), and in 1 of 15 mature teratomas (1+). Only 11 of 406 non-germ cell tumors showed 1+ LIN28 staining. Therefore, LIN28 is a sensitive (100% sensitivity) marker for primary extragonadal seminomas/germinomas, embryonal carcinomas, and yolk sac tumors with high specificity. Compared with SALL4, LIN28 demonstrated a similar level of diagnostic sensitivity for seminomas/germinomas and embryonal carcinomas. For primary extragonadal yolk sac tumors, although SALL4 stained all tumors (1+ in 1, 2+ in 2, 3+ in 10, and 4+ in 61), LIN28 stained more tumor cells (mean 95 vs 90%, P = 0.03) and was therefore more sensitive. For primary extragonadal yolk sac tumors, combining LIN28 and SALL4 can achieve a higher diagnostic sensitivity than either alone.

The role of Movat pentachrome stain and immunoglobulin G4 immunostaining in the diagnosis of autoimmune pancreatitis.

Autoimmune pancreatitis is highly responsive to steroid therapy, but because it mimics pancreatic cancer, it often precipitates unnecessary surgery. Adequate diagnostic tests are needed to permit appropriate medical therapy. Lymphocytic and obliterative phlebitis are reported in the majority of cases, as are elevated IgG4-positive plasma cells, indicating their high sensitivity. Their specificities, especially when used in conjunction, however, remain largely unknown. Movat pentachrome vascular and IgG4 immunohistochemical stains were performed on a total of 15 autoimmune pancreatitis cases (11 pancreatic resections and 4 biopsies), 39 usual-type alcoholic or idiopathic chronic pancreatitis cases, 35 pancreatic ductal adenocarcinoma-associated chronic pancreatitis cases, and 29 normal pancreata. Marked and diffuse lymphocytic and obliterative venulitis were detected in all 15 cases of autoimmune pancreatitis on Movat staining (100% sensitivity). Only a single carcinoma-associated chronic pancreatitis case among all of the controls showed diffuse benign venulitis that was nonobliterative (99% specificity). Nine of 13, 9 autoimmune pancreatitis cases showed marked IgG4 immunopositivity at >or=10 positive plasma cells per x 400 field (69% sensitivity). No increased IgG4 plasma cells were found in any of 103 controls (100% specificity). In combination, all of the autoimmune pancreatitis cases had at least one (13/13) and most had both markers (9/13), whereas none of the controls had both markers. Overall, these combined stains show very promising diagnostic utility and should be considered in combination with clinical and serologic analyses in the evaluation of chronic pancreatitis suspicious for malignancy. Future validating studies on preoperative biopsies with outcome data following steroid therapy will be essential.

Diagnostic utility of SALL4 in primary germ cell tumors of the central nervous system: a study of 77 cases.

Primary germ cell tumors of the central nervous system (CNS) sometimes pose diagnostic difficulty. In this study we analyzed the diagnostic utility of a novel marker, SALL4, in 77 such tumors (59 pure and 18 mixed) consisting of the following tumors/tumor components: 49 germinomas, 7 embryonal carcinomas, 27 yolk sac tumors, 3 choriocarcinomas, and 14 teratomas. We also stained SALL4 in 99 primary non-germ cell tumors to test SALL4 specificity. We compared SALL4 with OCT4 in all germ cell tumors and compared SALL4 with alpha-fetoprotein and glypican-3 in all yolk sac tumors. The staining was semiquantitatively scored as 0 (no staining), 1+ (90%). Strong SALL4 staining was observed in all 49 germinomas (4+ in 48, 3+ in 1), 7 embryonal carcinomas (all 4+), and 27 yolk sac tumors (1+ in 1, 2+ in 2, 3+ in 7, 4+ in 17). SALL4 staining, 1+ weak to focally strong, was observed in 2 of 3 choriocarcinomas (in mononucleated trophoblasts) and in 9 of 14 teratomas (in primitive neuroepithelium and teratomatous glands). All germinomas and embryonal carcinomas showed strong OCT4 staining (4+ in all except 1 germinoma with 3+), whereas other germ cell tumors were negative. Out of 27 yolk sac tumors, 26 showed positive alpha-fetoprotein staining (1+ in 9, 2+ in 7, 3+ in 5, and 4+ in 5). All yolk sac tumors showed positive glypican-3 staining (1+ in 6, 2+ in 6, 3+ in 7, and 4+ in 8). The mean percentage of yolk sac tumor cells stained was 84% with SALL4, 45% with alpha-fetoprotein, and 63% with glypican-3 (P<0.01). No non-germ cell tumors showed SALL4 staining. Our results indicate that SALL4 is a novel sensitive diagnostic marker for primary germ cell tumors of the CNS with high specificity. SALL4 is a more sensitive marker than alpha-fetoprotein and glypican-3 for yolk sac tumors.

Quantitative proteomics investigation of pancreatic intraepithelial neoplasia.

Patients with pancreatic cancer are usually diagnosed at late stages, when the disease is incurable. Pancreatic intraepithelial neoplasia (PanIN) 3 is believed to be the immediate precursor lesion of pancreatic adenocarcinoma, and would be an ideal stage to diagnose patients, when intervention and cure are possible and patients are curable. In this study, we used quantitative proteomics to identify dysregulated proteins in PanIN 3 lesions. Altogether, over 200 dysregulated proteins were identified in the PanIN 3 tissues, with a minimum of a 1.75-fold change compared with the proteins in normal pancreas. These dysregulated PanIN 3 proteins play roles in cell motility, the inflammatory response, the blood clotting cascade, the cell cycle and its regulation, and protein degradation. Further network analysis of the proteins identified c-MYC as an important regulatory protein in PanIN 3 lesions. Finally, three of the overexpressed proteins, laminin beta-1, galectin-1, and actinin-4 were validated by immunohistochemistry analysis. All three of these proteins were overexpressed in the stroma or ductal epithelial cells of advanced PanIN lesions as well as in pancreatic cancer tissue. Our findings suggest that these three proteins may be useful as biomarkers for advanced PanIN and pancreatic cancer if further validated. The dysregulated proteins identified in this study may assist in the selection of candidates for future development of biomarkers for detecting early and curable pancreatic neoplasia.

Pseudocarcinomatous epithelial hyperplasia in the bladder unassociated with prior irradiation or chemotherapy.

Pseudocarcinomatous epithelial hyperplasia in the bladder is a little known phenomenon, recognized to be associated with prior irradiation and/or chemotherapy. Whether this process can occur outside of this setting has not been studied. We identified 8 of these cases mimicking invasive urothelial carcinoma from our consultation files from 07/04 to 07/06 with no prior history of radiation or chemotherapy. The mean age at diagnosis was 65 years (range, 42 to 81 y), with 5 of the 8 males. Seven patients had a potential etiology for these changes that could either have resulted in localized ischemia or injury to the urothelium. These included case 1: atrial fibrillation, hypertension, congestive heart failure, gastrointestinal bleeding, and coronary artery vascular disease; case 2: coronary angioplasty, atrial fibrillation, hyperlipidemia, and amputation of arm for ischemia; case 3: hypertension, uncontrolled diabetes, hyperlipidemia, and atrial fibrillation; case 4: underlying arteriovenous malformation of the bladder; cases 5 to 6: history of indwelling Foley catheter; and case 7: history of radical prostatectomy for prostate cancer but no radiation. One patient had no potential contributing factors. All 8 patients presented with gross hematuria. At cystoscopy, 7 patients had polypoid lesions with 1 appearing nonpolypoid. Histologically, all cases showed epithelial proliferation of urothelium with cells having prominent eosinophilic cytoplasm. This process that mimicked invasive cancer within the lamina propria was marked in 3 cases (38%). Moderate nuclear pleomorphism was seen in 6 cases (75%). Only 1 case revealed mitotic figures. Ulceration was seen in 1 case. All cases showed some degree of hemorrhage with hemosiderin deposition identified in 3 cases (38%). Fibrin deposition was present in 1 case within the stroma, 3 cases in the vessels, and 4 cases in both. Five cases show stromal fibrosis. Edema and vascular congestion were common features (90% and 100%, respectively). Six out of 8 cases were accompanied by moderate to marked acute and chronic inflammation. The original diagnosis included nested variant urothelial carcinoma (1 case), atypical suspicious for invasive carcinoma (5 cases), hemangioma (1 case), and eosinophilic cystitis (1 case). Patients were followed for a mean of 16.5 months (range, 10 to 34 mo), and none developed bladder cancer. As a rare response to ischemia and chronic irritation, pseudocarcinomatous epithelial proliferations in the bladder may be confused with invasive urothelial carcinoma. Pathologists must be aware of the histologic changes mimicking cancer, and recognize that it can occur outside of the setting of prior irradiation or chemotherapy.

Residual tumor potentially left behind after local ablation therapy in prostate adenocarcinoma.

PURPOSE: We examined contralateral prostate cancer potentially left behind by focal therapy. MATERIALS AND METHODS: We investigated 100 completely embedded radical prostatectomy specimens in which needle biopsy predicted limited disease (less than 3 positive cores, 50% or less involvement of any positive core, Gleason score 6 or less) and all positive needle cores were unilateral. Clinical stage was T1c in 85 and T2a in 15 cases with the palpable lesion on the positive biopsy side. RESULTS: There was 1 positive core in 66 cases. On average 13.9% of each positive core was involved with tumor. The mean number of separate tumor nodules per radical prostatectomy was 2.9. In 65 radical prostatectomy specimens there was some tumor contralateral to the positive biopsy side. Total tumor volume in the radical prostatectomy contralateral to the positive biopsy side averaged 0.2 cm(3) (largest 1.3). In 23 cases contralateral tumor volume was greater than biopsy positive side tumor volume. There were 13 cases in which more than 0.5 cm(3) cancer was contralateral to the positive biopsy and 7 with predominantly anterior tumor. Volume contralateral to positive biopsy side could not be predicted by the number of positive cores (1 vs 2) or maximum percent of the core involved. Gleason pattern 4, extraprostatic extension or positive margins were seen contralateral to the positive biopsy side in 13, 1 and 2 cases, respectively. CONCLUSIONS: In a highly selected population with limited unilateral biopsy cancer, tumor contralateral to the positive biopsy side at radical prostatectomy is typically small. However, 20% of radical prostatectomy specimens had some contralateral adverse pathology in terms of size, extraprostatic extension, grade or margins.

Prostatic adenocarcinoma in colorectal biopsy: clinical and pathologic features.

Locally advanced prostate carcinoma (PCa) can involve adjacent colorectal tissue. In such cases, accurate assignment of primary source may prove difficult. Given the difference in treatment and prognosis between PCa and colorectal carcinoma (CRCa), an accurate diagnosis is crucial. Surgical pathology files were searched for all cases with a diagnosis of PCa on colorectal biopsy between 1987 and 2006. Histologic and clinical data were available in 23 of the 30 found cases. The diagnosis of PCa was made for the first time at the time of the colorectal presentation in 4 men. Three of the 4 underwent colectomy. Among the remaining 19 men with a previously documented diagnosis of PCa, the overall clinical and endoscopic impression still favored a second primary CRCa in 12 patients. The latter was due in part to the chronologically distant prior PCa diagnosis (mean, 6.9 years; range, 2-18 years). None of the colorectal biopsies demonstrated carcinoma in situ or dysplastic colonic mucosa. PCa architecture in the colonic biopsies was that of Gleason score of 9 to 10 in 20 cases and Gleason score of 8 in the remaining 3. Cribriform or microacinar architecture typical of PCa was seen in 6 cases. Immunostains were positive for prostate-specific antigen, P501S (prostein), prostate-specific membrane antigen, and prostate-specific acid phosphatase, in 16 of 20, 9 of 11, 10 of 11, and 10 of 20 cases, respectively. Three cases lacked immunohistochemical evidence of prostatic differentiation. Caudal-type homebox transcription factor 2 (CDX2) and beta-catenin were negative in all tested cases (0/11 for both). Although relatively rare, initial presentation of PCa as a rectal lesion may lead to an erroneous clinical and or histologic impression of CRCa. Because history of prostate cancer is often remote, clinical findings may be misleading. Pathologists should consider the possibility of prostatic origin in poorly differentiated carcinoma encountered on colorectal biopsy when features such as lack of an in situ component, extrinsic pattern of involvement, microacinar or solid architecture, and/or prominent nucleoli, are noted, especially in the absence of nuclear pleomorphism and mitotic activity. Immunohistochemical studies could help establish the diagnosis.

Oncologic outcomes at 10 years following robotic radical prostatectomy.

BACKGROUND: Reports on long-term oncologic outcomes for patients who undergo robot-assisted radical prostatectomy (RARP) are scant, as for radical prostatectomy covering only the contemporary prostate-specific antigen (PSA) era. OBJECTIVE: To evaluate cancer control in men who underwent RARP at least 10 yr ago. DESIGN, SETTING, AND PARTICIPANTS: From 2001 to 2003, we followed 483 consecutive men with localized prostate cancer who underwent RARP at a high-volume tertiary center. INTERVENTION: RARP as first-line therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We calculated biochemical recurrence -free survival (BCRFS), metastasis-free survival (MFS), and cancer-specific survival (CSS). Actuarial rates were estimated via Kaplan-Meier. Cox proportional hazards models were used to identify variables predictive of biochemical recurrence (BCR), receipt of salvage therapy, and metastases. RESULTS AND LIMITATIONS: There were 108 patients with BCR at a median follow-up of 121 mo (interquartile range: 97-132). Actuarial BCRFS, MFS, and CSS rates at 10 yr were 73.1%, 97.5%, and 98.8%, respectively. On multivariable analysis, D'Amico risk groups or pathologic Gleason grade, stage, and margins were the strongest predictors of BCR depending on whether preoperative or postoperative variables were considered. The value of the detectable PSAs together with disease severity were independent predictors of receipt of salvage therapy, together with a persistent PSA for metastases. CONCLUSIONS: In contemporary patients with localized prostate cancer, RARP confers effective 10-yr cancer control. Disease severity and PSA measurements can be used to guide more personalized and cost-effective postoperative surveillance regimens. PATIENT SUMMARY: Robot-assisted radical prostatectomy confers effective 10-yr cancer control for men with localized disease, similar to the open approach. Recurrence is best predicted by postoperative disease severity. Persistent disease signals the risk of progression likely requiring early salvage treatment; lower postoperative risk warrants protracted surveillance beyond 5 yr from surgery, and those with higher risk may require follow-up beyond 10 yr.

Prospective randomized phase 2 trial of intensity modulated radiation therapy with or without oncolytic adenovirus-mediated cytotoxic gene therapy in intermediate-risk prostate cancer.

PURPOSE: To assess the safety and efficacy of combining oncolytic adenovirus-mediated cytotoxic gene therapy (OAMCGT) with intensity modulated radiation therapy (IMRT) in intermediate-risk prostate cancer. METHODS AND MATERIALS: Forty-four men with intermediate-risk prostate cancer were randomly assigned to receive either OAMCGT plus IMRT (arm 1; n=21) or IMRT only (arm 2; n=23). The primary phase 2 endpoint was acute (≤90 days) toxicity. Secondary endpoints included quality of life (QOL), prostate biopsy (12-core) positivity at 2 years, freedom from biochemical/clinical failure (FFF), freedom from metastases, and survival. RESULTS: Men in arm 1 exhibited a greater incidence of low-grade influenza-like symptoms, transaminitis, neutropenia, and thrombocytopenia than men in arm 2. There were no significant differences in gastrointestinal or genitourinary events or QOL between the 2 arms. Two-year prostate biopsies were obtained from 37 men (84%). Thirty-three percent of men in arm 1 were biopsy-positive versus 58% in arm 2, representing a 42% relative reduction in biopsy positivity in the investigational arm (P=.13). There was a 60% relative reduction in biopsy positivity in the investigational arm in men with <50% positive biopsy cores at baseline (P=.07). To date, 1 patient in each arm exhibited biochemical failure (arm 1, 4.8%; arm 2, 4.3%). No patient developed hormone-refractory or metastatic disease, and none has died from prostate cancer. CONCLUSIONS: Combining OAMCGT with IMRT does not exacerbate the most common side effects of prostate radiation therapy and suggests a clinically meaningful reduction in positive biopsy results at 2 years in men with intermediate-risk prostate cancer.

Small cell-like change in prostatic intraepithelial neoplasia, intraductal carcinoma, and invasive prostatic carcinoma: a study of 7 cases.

Small cell carcinoma of the prostate is associated with poor prognosis and different treatment from conventional acinar adenocarcinoma. Given the important clinicopathologic implications of a diagnosis of small cell carcinoma, we report 7 cases showing unusual, extensive small cell-like change in intraductal carcinoma and invasive carcinoma. Prostatic biopsies from 3 patients and radical prostatectomy specimens from 4 patients showed variably extensive small cell-like high-grade prostatic intraepithelial neoplasia and intraductal carcinoma. Five cases were associated with conventional acinar adenocarcinoma (2 cases with Gleason score 4 + 3 = 7; 3 cases with Gleason 3 + 4 = 7). No small cell carcinoma was seen. Small and large ducts with small cell-like change showed solid and cribriform proliferations of atypical cells with abrupt transition between centrally located populations of small cells and more typical large dysplastic cells at the duct periphery. Rosette-like formations were noted within some involved ducts. Small cell-like change was characterized by crowded cells with uniformly bland vesicular nuclei and minimal cytoplasm and no significant mitotic or apoptotic activity. In 3 cases, similar small cell-like morphology was noted focally in invasive carcinoma. The small cell-like areas were negative for synaptophysin and chromogranin, focally positive for TTF-1, and weakly positive for racemase. Ki-67 labeled less than 5% with predominant labeling of the larger atypical cells and minimal reactivity in the small cell-like population. In summary, small cell-like change in prostatic intraepithelial neoplasia, intraductal carcinoma, and invasive carcinoma is not associated with small cell carcinoma; shows no immunohistochemical evidence of neuroendocrine differentiation; and likely is not an adverse prognostic feature.

Gleason score 7 adenocarcinoma of the prostate with lymph node metastases: analysis of 184 radical prostatectomy specimens.

CONTEXT: Prostate cancer (PC) with lymph node metastases (LN(+)) is relatively rare, whereas it is relatively common in disease with a Gleason score (GS) 8 to 10 and virtually never seen in PC with GS 6 or less. It is most variable in GS 7 PC. OBJECTIVE: To determine clinicopathologic features associated with GS 7 PC with LN(+) compared with a control group without lymph node metastases (LN(-)). DESIGN: We analyzed 184 GS 7 radical prostatectomies with LN(+) and the same number of LN(-) Gleason-matched controls. The LN(+) cases were GS 3 + 4 = 7 (n = 64; 34.8%), GS 4 + 3 = 7 (n = 66; 35.9%), GS 3 + 4 = 7 with tertiary 5 (n = 10; 5.4%), and GS 4 + 3 = 7 with tertiary 5 (n = 44; 23.9%). RESULTS: The LN(+) cases demonstrated higher average values in preoperative prostate-specific antigen (12.2 versus 8.1 ng/mL), percentage of positive biopsy cores (59.1% versus 42.9%), prostate weight (54.4 versus 49.4 g), number of LNs submitted (12.7 versus 9.4), incidence of nonfocal extraprostatic extension (82.6% versus 63.6%), tumor volume (28.9% versus 14.8%), frequency of lymphovascular invasion (78.3% versus 38.6%), intraductal spread of carcinoma (42.4% versus 20.7%), incidence of satellite tumor foci (16.4% versus 4.3%), incidence of pT3b disease (49.5% versus 14.7%), and lymphovascular invasion in the seminal vesicles (52% versus 30%). There were differences in GS 4 patterns and cytology between LN(+) and LN(-) cases, with the former having higher volumes of cribriform and poorly formed patterns, larger nuclei and nucleoli, and more-frequent macronucleoli. All P ≤ .05. CONCLUSION: Gleason score 7 PC with LN(+) has features highlighting a more-aggressive phenotype. These features can be assessed as prognostic markers in GS 7 disease on biopsy (eg, GS 4 pattern, intraductal spread, cytology) or at radical prostatectomies (all variables), even in men without LN dissection or LN(-) disease.

Stromal galectin-1 expression is associated with long-term survival in resectable pancreatic ductal adenocarcinoma.

The overall 5 year survival rate for pancreatic ductal adenocarcinoma (i.e., PDAC) is a dismal 5%, although patients that have undergone surgical resection have a somewhat better survival rate of up to 20%. Very long-term survivors of PDAC (defined as patients with ≥ 10 year survival following apparently curative resection), on the other hand, are considerably less frequent. The molecular characteristics of very long-term survivors (VLTS) are poorly understood, but might provide novel insights into prognostication for this disease. In this study, a panel of five VLTS and stage-matched short-term survivors (STS, defined as disease-specific mortality within 14 months of resection) were identified, and quantitative proteomics was applied to comparatively profile tumor tissues from both cohorts. Differentially expressed proteins were identified in cancers from VLTS vs. STS patients. Specifically, the expression of galectin-1 was 2-fold lower in VLTS compared with STS tumors. Validation studies were performed by immunohistochemistry (IHC) in two additional cohorts of resected PDAC, including: 1) an independent cohort of VLTS and 2) a panel of sporadic PDAC with a considerable range of overall survival following surgery. Immunolabeling analysis confirmed that significantly lower expression of stromal galectin-1 was associated with VLTS (p = 0.02) and also correlated with longer survival in sporadic, surgically-treated PDAC cases (hazard ratio = 4.9, p = 0.002). The results from this study provide new insights to better understand the role of galectin-1 in PDAC survival, and might be useful for rendering prognostic information, and developing more effective therapeutic strategies aimed at improving survival.

Small blue cells mimicking small cell carcinoma in spermatocele and hydrocele specimens: a report of 5 cases.

We identified 5 cases of hydrocele and spermatocele resections containing detached small cellular "blue" clusters, raising questions of small cell carcinoma by contributors to our consult service. Patients were 37, 39, 52, 67, and 70 years old. None of the 4 patients with follow-up developed small cell carcinoma. On routine stained sections, there were multiple clusters of detached hypercellular cells with focal streaming, high nuclear-to-cytoplasmic ratios, and hyperchromatic nuclei without prominent nuclei. There were no mitotic figures, apoptotic bodies, or necrosis. In 4 of 5 cases, there was sufficient tissue to perform immunohistochemistry along with 10 cases each of normal rete testis and epididymis. CD56 was positive in 4 of 4 cases of the "blue cells" and in 9 of 10 of normal rete testis; yet, it was positive in only 2 of 10 normal epididymis. Synaptophysin and chromogranin were negative in all cases of "blue cells." PAX2 was negative in all cases of "blue cells" similar to the 1 of 9 positive staining in rete testis and in contrast to the positivity seen in 9 of 9 cases of normal epididymis. Ki-67 was negative or showed only rare positive cells in all of the cases of the "blue cells." Clusters of blue cells suggestive of sloughed rete testis cells can mimic small cell carcinoma in hydrocele and spermatocele specimens based on their low power appearance and positive CD56 staining. Closer examination of the cells' bland morphology, low expression of Ki-67, and lack of chromogranin and synaptophysin, along with recognition of this entity, can prevent a misdiagnosis of malignancy.

Biochemical recurrence following robot-assisted radical prostatectomy: analysis of 1384 patients with a median 5-year follow-up.

BACKGROUND: There is a paucity of data on long-term oncologic outcomes for patients undergoing robot-assisted radical prostatectomy (RARP) for prostate cancer (PCa). OBJECTIVE: To evaluate oncologic outcomes in patients undergoing RARP at a high-volume tertiary center, with a focus on 5-yr biochemical recurrence-free survival (BCRFS). DESIGN, SETTING, AND PARTICIPANTS: The study cohort consisted of 1384 consecutive patients with localized PCa who underwent RARP between September 2001 and May 2005 and had a median follow-up of 60.2 mo. No patient had secondary therapy until documented biochemical recurrence (BCR). BCR was defined as a serum prostate-specific antigen ≥ 0.2 ng/ml with a confirmatory value. BCRFS was estimated using the Kaplan-Meier method. Event-time distributions for the time to failure were compared using the log-rank test. Univariable and multivariable Cox proportional hazards regression models were used to determine variables predictive of BCR. INTERVENTION: All patients underwent RARP. MEASUREMENTS: BCRFS rates were measured. RESULTS AND LIMITATIONS: This cohort of patients had moderately aggressive PCa: 49.0% were D'Amico intermediate or high risk on biopsy; however, 60.9% had Gleason 7-10 disease, and 25.5% had ≥ T3 disease on final pathology. There were 189 incidences of BCR (31 per 1,000 person years of follow-up) at a median follow-up of 60.2 mo (interquartile range [IQR]: 37.2-69.7). The actuarial BCRFS was 95.1%, 90.6%, 86.6%, and 81.0% at 1, 3, 5, and 7 yr, respectively. In the patients who recurred, median time to BCR was 20.4 mo; 65% of BCR incidences occurred within 3 yr and 86.2% within 5 yr. On multivariable analysis, the strongest predictors of BCR were pathologic Gleason grade 8-10 (hazard ratio [HR]: 5.37; 95% confidence interval [CI], 2.99-9.65; p < 0.0001) and pathologic stage T3b/T4 (HR: 2.71; 95% CI, 1.67-4.40; p < 0.0001). CONCLUSIONS: In a contemporary cohort of patients with localized PCa, RARP confers effective 5-yr biochemical control.

Polypoid/papillary cystitis: a series of 41 cases misdiagnosed as papillary urothelial neoplasia.

Polypoid cystitis and its more chronic phase papillary cystitis, which results as a reaction to injury to the bladder mucosa, is a benign lesion mimicking various papillary urothelial neoplasms. Analogous lesions occur throughout the urothelial tract and are referred to as polypoid urethritis, polypoid ureteritis, and polypoid pyelititis when present in the urethra, ureter, and renal pelvis, respectively. For simplicity, these lesions in different sites and papillary cystitis will typically be referred to as polypoid cystitis in this manuscript. A search of the consultation files from our institution from January 2000 to July 2007 was performed. Of 155 cases diagnosed as polypoid cystitis, we identified 41 cases that were diagnosed as papillary urothelial neoplasms by contributing pathologists and only sent to us, typically at the request of the urologist after the case had be signed out. For cases where information was available, clinical symptoms included bladder obstruction (n=7), gross hematuria (n=6), colovesicular fistula (n=4), follow-up status posttreatment of bladder and ureter carcinoma (n=4), bladder/urethral stones (n=2), benign prostate hyperplasia (n=2), follow-up after radiation for prostate cancer (n=2), long-standing urinary stents (n=2), and voiding dysfunction (n=1). Original diagnoses included noninvasive low grade papillary urothelial carcinoma (n=23), noninvasive high grade papillary urothelial carcinoma (n=6), papillary urothelial neoplasm of low malignant potential (n=5), papilloma (n=3), urothelial neoplasia (n=2), carcinoma in situ (n=1), and squamous carcinoma (n=1). The mean age at diagnosis was 63 years (range, 19 to 93 y; median 63 y). Male to female ratio was 3.1 to 1. Clinical symptoms varied with the most common manifestations, including gross hematuria, bladder/urethral stones, history of prostate cancer treated with radiation, follow-up after bladder/ureter carcinoma treatment, long-term urinary stents, and colovesicular fistulas. At cystoscopy, lesions were variably described as polypoid, trabeculations, bullous polyps, and diffuse erythema and edema. The locations of polypoid cystitis were bladder (n=34), ureteral orifice (n=2), urethra (n=2), renal pelvis (n=2), and undesignated (n=1). Architecturally, 31 cases had isolated papillary fronds with in 1 case branching papillary structures. The base of the papillary stalks were characterized as both broad and narrow (n=24), only broad (n=9), and only narrow (n=3). The overlying urothelium of polypoid cystitis was diffusely and focally thickened in 8 cases and 5 cases, respectively. Umbrella cells were identified in 32 cases. Acute and chronic inflammation was present in 28 cases, moderate in 15, and mild in 13 cases. Eleven cases showed chronic inflammation, mild in 10, and moderate in 1 case. Reactive urothelial atypia was noted in 26 cases with mitotic figures present in 22 cases, frequent in 3 and rare in 19 cases. Stroma edema was seen in 32 cases with fibrosis within the polypoid stalks seen in 16 cases. The key to correctly diagnosing polypoid/papillary cystitis is to recognize at low magnification the reactive nature of the process with an inflamed background that is edematous or densely fibrous with predominantly simple, non-branching, broad-based fronds of relatively normal thickness urothelium, and not focus at higher power on the exceptional frond that may more closely resemble a urothelial neoplasm either architecturally or cytologically. In cases where the diagnosis of papillary neoplasia is not straightforward and there is a question of polypoid cystitis, pathologists should seek clinical history that might suggest a reactive process. Because the urologist can more often better recognize the inflammatory nature of the lesion than the pathologist, the pathologist should hesitate diagnosing urothelial neoplasia when the cystoscopic impression is that of an inflammatory lesion.

Immunohistochemical expression of prostatic antigens in adenocarcinoma and villous adenoma of the urinary bladder.

Adenocarcinomas of the bladder are rare, with the diagnosis dependent on exclusion of secondary involvement by direct extension or metastatic spread from other sites. The recent description of an unusual form of urothelial-type mucinous prostatic adenocarcinoma raises a novel differential diagnosis between adenocarcinomas of the prostate and bladder, and investigation into the utility of classic prostatic immunohistochemical antigens in bladder adenocarcinoma is warranted. We identified 37 primary infiltrating adenocarcinomas of the bladder, which included signet ring cell carcinomas (n=11), urachal adenocarcinomas (n=5), and enteric adenocarcinoma (n=21). Also included for comparison were 3 cases, each of bladder villous adenomas and bladder adenocarcinoma in situ. Tissue microarrays were constructed from each case, with each specimen represented by multiple 1.0-mm cores to assess for tumor protein heterogeneity. Immunohistochemistry for prostate-specific antigen (PSA), prostate specific acid phosphatase (PSAP), P501S (prostein), and prostate specific membrane antigen (PSMA) was performed, and moderate to strong immunoreactivity was considered a positive result. Of the 37 adenocarcinomas, all were negative for PSA and PSAP (0/37; 0%). In contrast, a minority of bladder adenocarcinomas was labeled with the prostate antigens P501S and PSMA. P501S showed moderate diffuse cytoplasmic staining in 4/37 cases (11%), including 3 enteric-type adenocarcinomas and 1 mucinous adenocarcinoma. Additionally, 1 case of adenocarcinoma in situ demonstrated diffuse cytoplasmic staining for P501S. The granular perinuclear staining pattern of P501S typically seen in prostatic adenocarcinoma was absent in all cases of bladder adenocarcinoma. PSMA showed diffuse cytoplasmic staining in 4/37 (11%) infiltrating adenocarcinomas (including 1 signet ring carcinoma and 3 enteric-type adenocarcinomas), and in 1 case of adenocarcinoma in situ. Membranous PSMA staining was evident in an additional 3 tumors, 1 urachal mucinous adenocarcinoma, 1 nonurachal mucinous and signet ring cell adenocarcinoma, and 1 nonurachal villous adenoma. In conclusion, although all cases of bladder adenocarcinoma examined were negative for PSA and PSAP, the surprising finding that a subset of invasive and in situ adenocarcinomas of the bladder demonstrated immunoreactivity for P501S and PSMA should warrant caution when using these markers in differentiating prostatic from bladder adenocarcinomas. The lack of granular perinuclear staining for P501S and the absence of membranous PSMA staining both favor a bladder adenocarcinoma, although rare cases of villous adenoma and adenocarcinoma did show PSMA membranous staining indistinguishable from that seen in prostate cancer. Although the novel antigens P501S and PSMA are fairly specific and more sensitive in the differential diagnosis of prostate and urothelial carcinoma, care must be taken when adenocarcinomas of the bladder are considered within this differential diagnosis.

Quantitative proteomics analysis reveals that proteins differentially expressed in chronic pancreatitis are also frequently involved in pancreatic cancer.

The effective treatment of pancreatic cancer relies on the diagnosis of the disease at an early stage, a difficult challenge. One major obstacle in the development of diagnostic biomarkers of early pancreatic cancer has been the dual expression of potential biomarkers in both chronic pancreatitis and cancer. To better understand the limitations of potential protein biomarkers, we used ICAT technology and tandem mass spectrometry-based proteomics to systematically study protein expression in chronic pancreatitis. Among the 116 differentially expressed proteins identified in chronic pancreatitis, most biological processes were responses to wounding and inflammation, a finding consistent with the underlining inflammation and tissue repair associated with chronic pancreatitis. Furthermore 40% of the differentially expressed proteins identified in chronic pancreatitis have been implicated previously in pancreatic cancer, suggesting some commonality in protein expression between these two diseases. Biological network analysis further identified c-MYC as a common prominent regulatory protein in pancreatic cancer and chronic pancreatitis. Lastly five proteins were selected for validation by Western blot and immunohistochemistry. Annexin A2 and insulin-like growth factor-binding protein 2 were overexpressed in cancer but not in chronic pancreatitis, making them promising biomarker candidates for pancreatic cancer. In addition, our study validated that cathepsin D, integrin beta1, and plasminogen were overexpressed in both pancreatic cancer and chronic pancreatitis. The positive involvement of these proteins in chronic pancreatitis and pancreatic cancer will potentially lower the specificity of these proteins as biomarker candidates for pancreatic cancer. Altogether our study provides some insights into the molecular events in chronic pancreatitis that may lead to diverse strategies for diagnosis and treatment of these diseases.

Pancreatic cancer proteome: the proteins that underlie invasion, metastasis, and immunologic escape.

BACKGROUND & AIMS: Pancreatic cancer is a highly lethal disease that has seen little headway in diagnosis and treatment for the past few decades. The effective treatment of pancreatic cancer is critically relying on the diagnosis of the disease at an early stage, which still remains challenging. New experimental approaches, such as quantitative proteomics, have shown great potential for the study of cancer and have opened new opportunities to investigate crucial events underlying pancreatic tumorigenesis and to exploit this knowledge for early detection and better intervention. METHODS: To systematically study protein expression in pancreatic cancer, we used isotope-coded affinity tag technology and tandem mass spectrometry to perform quantitative proteomic profiling of pancreatic cancer tissues and normal pancreas. RESULTS: A total of 656 proteins were identified and quantified in 2 pancreatic cancer samples, of which 151 were differentially expressed in cancer by at least 2-fold. This study revealed numerous proteins that are newly discovered to be associated with pancreatic cancer, providing candidates for future early diagnosis biomarkers and targets for therapy. Several differentially expressed proteins were further validated by tissue microarray immunohistochemistry. Many of the differentially expressed proteins identified are involved in protein-driven interactions between the ductal epithelium and the extracellular matrix that orchestrate tumor growth, migration, angiogenesis, invasion, metastasis, and immunologic escape. CONCLUSIONS: Our study is the first application of isotope-coded affinity tag technology for proteomic analysis of human cancer tissue and has shown the value of this technology in identifying differentially expressed proteins in cancer.