Pancreatic Ductal Adenocarcinoma is Spread to the Peripancreatic Soft Tissue in the Majority of Resected Cases, Rendering the AJCC T-Stage Protocol (7th Edition) Inapplicable and Insignificant: A Size-Based Staging System (pT1: ≤2, pT2: >2-≤4, pT3: >4 cm) is More Valid and Clinically Relevant.

BACKGROUND: Most studies have failed to identify any prognostic value of the current T-stage protocol for pancreatic ductal adenocarcinoma (PDAC) by the American Joint Committee on Cancer and the Union for International Cancer Control unless some grouping was performed. METHODS: To document the parameters included in this T-stage protocol, 223 consecutive pancreatoduodenectomy specimens with PDAC were processed by a uniform grossing protocol. RESULTS: Peripancreatic soft tissue (PST) involvement, the main pT3 parameter, was found to be inapplicable and irreproducible due to lack of a true capsule in the pancreas and variability in the amount and distribution of adipose tissue. Furthermore, 91 % of the cases showed carcinoma in the adipose tissue, presumably representing the PST, and thus were classified as pT3. An additional 4.5 % were qualified as pT3 due to extension into adjacent sites. The T-stage defined as such was not found to have any correlation with survival (p = 0.4). A revised T-stage protocol was devised that defined pT1 as 2 cm or smaller, pT2 as >2-4 cm, and pT3 as larger than 4 cm. This revised protocol was tested in 757 consecutive PDACs. The median and 3-year survival rates of this size-based protocol were 26, 18, 13 months, and 40 %, 26 %, 20 %, respectively (p < 0.0001). The association between higher T-stage and shorter survival persisted in N0 cases and in multivariate modeling. Analysis of the Surveillance, Epidemiology, and End Results database also confirmed the survival differences (p < 0.0001). CONCLUSIONS: This study showed that resected PDACs are already spread to various surfaces of the pancreas, leaving only about 4 % of PDACs to truly qualify as pT1/T2, and that the current T-stage protocol does not have any prognostic correlation. In contrast, as shown previously in many studies, size is an important prognosticator, and a size-based T-stage protocol is more applicable and has prognostic value in PDAC.

Multicenter evaluation of the role of UroVysion FISH assay in surveillance of patients with bladder cancer: does FISH positivity anticipate recurrence?

BACKGROUND: The significance of a positive UroVysion FISH assay is uncertain in patients with normal cystoscopy. This multicenter study evaluates the clinical significance of a positive FISH assay in patients with no visible tumor and excluding those with a positive cytology. METHODS: A multi-institutional, retrospective study of patients with a history of urothelial carcinoma of the bladder identified 664 patients with a FISH assay after excluding those with cystoscopic evidence of a tumor and/or positive cytology. Our primary end point was cancer recurrence, defined by biopsy. Progression was defined as recurrence with a tumor stage ≥T2. Statistical analyses were performed using Fisher's exact test as a one-tailed test and Chi-square test with significance at 0.05, using SPSS(®) version 19.0 (SPSS Inc., Chicago, IL, USA). RESULTS: Of the 664 patients in this study, tumor stage was Ta (363, 55 %), T1 (183, 28 %), and CIS (109, 16 %) and most were high grade (440 pts, 66 %). The median follow-up was 26 months (3-104 months), and 277 (41.7 %) patients were recurred. In patients who were FISH positive, mean time to recurrence was 12.6 months, compared to 17.9 months if FISH negative (p = 0.03). In univariate analysis, atypical cytology, positive FISH, cystoscopic findings (atypical vs. normal), and previous intravesical therapy were associated with recurrence (p < 0.05). On multivariate analysis, pathologic stage, cystoscopic findings, and cytology were independently associated with recurrence (p < 0.05). Progression to ≥T2 disease occurred in 34 (5.1 %) patients in this cohort. On multivariate analysis, only initial T stage and FISH result were found to be independent predictors of progression (p < 0.05). CONCLUSIONS: Patients with a positive FISH and atypical cytology are more likely to recur even in the absence of visible tumor. FISH positivity may portend a higher risk for progression. These findings require prospective validation.

Pathologic staging of pancreatic, ampullary, biliary, and gallbladder cancers: pitfalls and practical limitations of the current AJCC/UICC TNM staging system and opportunities for improvement.

Tumors of the ampulla-pancreatobiliary tract are encountered increasingly; however, their staging can be highly challenging due to lack of familiarity. In this review article, the various issues encountered in staging of these tumors at the pathologic level are evaluated and possible solutions for daily practice as well as potential improvements for future staging protocols are discussed. While N-stage parameters have now been well established (the number of lymph nodes required in pancreatoduodenectomies is 12), the T-staging has several issues: for the pancreas, the discovery of small cancers arising in intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) necessitates the creation of substages of T1 (as T1a, b, and c); lack of proper definition of "peripancreatic soft tissue" and "common bile duct involvement" (as to which part is meant) makes T3 highly subjective. Increasing resectability of main vessels (portal vein) brings the need to redefine a "T" for such cases. For the ampulla, due to factors like anatomic complexity of the region and the under-appreciation of three-dimensional spread of the tumors in this area (in particular, the frequent extension into periduodenal soft tissues and duodenal serosa, which are not addressed in the current system and which require specific grossing approaches to document), the current T-staging lacks reproducibility and clinical relevance, and therefore, major revisions are needed. Recently proposed refined definition and site-specific subclassification of ampullary tumors highlight the areas for improvement. For the extrahepatic bile ducts, the staging schemes that use the depth of invasion may be more practical to circumvent the inconsistencies in the histologic layering of the ducts; better definition of terms like "periductal spread" is needed. For the gallbladder, since many gallbladder cancers are "unapparent" (found in clinically and grossly unsuspected cholecystectomies), establishing proper grossing protocols and adequate sampling are crucial. Since the gallbladder does not have the distinct layering of the other gastrointestinal organs, the definitions of Tis/T1a/T1b lack practicality, and therefore, "early gallbladder carcinoma" category proposed in high-risk regions may have to be recognized instead. Involvement of the Rokitansky-Aschoff sinuses should be a part of the evaluation and management of these early gallbladder cancers; for advanced cancers, documentation of hepatic versus serosal involvement is necessary. In summary, T-staging of ampulla-pancreatobiliary tract tumors has many challenges. Proper grossing and appreciation of histo-anatomic subtleties of this region are crucial in addressing these issues and achieving more applicable and clinically relevant staging systems in the future.

Utility of p63 and high molecular weight cytokeratin in the distinction between urothelial carcinoma with prostatic stromal invasion and urothelial carcinoma with colonisation of prostatic ducts and acini.

AIMS: To evaluate the utility of p63 and high molecular weight cytokeratin in the distinction between urothelial carcinoma with prostatic stromal invasion and urothelial carcinoma with colonisation of prostatic ducts and acini which may be challenging on H&E, especially for general pathologists who may occasionally encounter these cases. METHODS: A search of surgical pathology and consultation files was made for cystoprostatectomy specimens with confirmed urothelial carcinoma with prostatic stromal invasion. Intensity for both p63 and high molecular weight cytokeratin within the tumour cells were scored as negative/weak or strong. RESULTS: A total of 34 cases were identified, 23 (68%) of which had associated foci of urothelial carcinoma with colonisation of prostatic ducts and acini. Mean patient age was 68.5 years (range 44-88 years). In all cases, basal cells of benign prostatic glands showed strong staining for both p63 and high molecular weight cytokeratin. Seventeen of 34 cases (50%) of urothelial carcinoma showed no or weak expression of high molecular weight cytokeratin in the tumour cells. The other 17 cases (50%) of urothelial carcinoma showed strong expression of high molecular weight cytokeratin in the tumour cells. Fourteen of 34 cases (41%) showed negative or weak expression of p63 in tumour cells. Twenty of 34 cases (59%) showed strong expression of p63 in tumour cells. In the 14 of 34 cases (41%) and 17 of 34 cases (50%) which showed negative/weak expression of p63 and high molecular weight cytokeratin, respectively, in the tumour cells, the positive staining of the basal cells by p63 and high molecular weight cytokeratin in the benign prostatic glands and acini or those colonised by urothelial carcinoma, aided in the distinction from urothelial carcinoma with prostatic stromal invasion. In the remaining 20 of 34 cases (59%) and 17 of 34 cases (50%) in which the tumour cells showed strong expression of p63 and high molecular weight cytokeratin, respectively, larger malignant tumour cells and smaller benign basal cells of the prostatic glands and acini were highlighted with these markers, and were easily distinguishable. CONCLUSION: Our study suggests that p63 and high molecular weight cytokeratin may be utilised in the distinction between urothelial carcinoma with prostatic stromal invasion and urothelial carcinoma with colonisation of prostatic ducts and acini.

Urothelial carcinoma of the bladder with transmural and direct prostatic stromal invasion: does extent of stromal invasion significantly impact patient outcome?

Urothelial carcinoma of the bladder with prostatic stromal invasion is included in stage pT4a of the new 2010 American Joint Committee on Cancer/Tumor-Node-Metastasis classification. Despite being a strong indicator of poor prognosis, there have been few large studies investigating the impact of extent of prostatic stromal invasion on patient outcome. A search of the surgical pathology and expert consultation files at our institution was made for cystoprostatectomy specimens diagnosed as urothelial carcinoma with prostatic stromal invasion from 2002 to 2009. Cases were further stratified as follows: group 1--focal prostatic stromal invasion and group 2--extensive prostatic stromal invasion. Only patients who had surgery as monotherapy and those with available follow-up information were selected for this study. Thirty-five cases of urothelial carcinoma with prostatic stromal invasion and follow-up information were identified. Mean patient age was 70 years (range, 44-88 years). Of these 35 patients, 15 (43%) had focal prostatic stromal invasion and 20 (57%) had extensive prostatic stromal invasion. Angiolymphatic invasion was identified in 93% of group 1 cases and 79% of group 2 cases. Positive margins were identified in 50% of group 1 cases and 45% of group 2 cases. Incidence of nodal metastasis was 64% for group 1 and 60% for group 2. Four (27%) of 15 cases in group 1 and 6 (30%) of 20 cases in group 2 had various histologic variants identified. In group 1, there were 2 cases of urothelial carcinoma with micropapillary features and urothelial carcinoma with focal squamous differentiation. In group 2, there were 3 cases of urothelial carcinoma with focal squamous differentiation, 2 cases of urothelial carcinoma with focal sarcomatoid differentiation, and 1 case of urothelial carcinoma with focal micropapillary features. One- and 3-year overall survival for group 1 was 53% and 27%, respectively. One- and 3-year overall survival for group 2 was 47% and 12%, respectively. Mean survival was 17.4 and 16.3 months for groups 1 and 2, respectively. Overall survival curves did not show a statistically significant difference between the 2 groups from initial diagnosis (P = .889) and radical cystoprostatectomy (P = .369). Our study suggests that extent of prostatic stromal invasion by urothelial carcinoma of the bladder as an independent factor does not impact overall patient survival. Other well-known prognostic factors including positive margin status, presence of aggressive histologic variants of urothelial carcinoma, angiolymphatic invasion, and distant metastasis likely play more critical roles in predicting outcome in male patients who have urothelial carcinoma with prostatic stromal invasion.

An unusual presentation of a mixed epithelial and stromal tumor in an elderly male.

Mixed epithelial and stromal tumors (MESTs) of the kidney are rare renal neoplasms characterized by mixed cystic and solid components. These tumors are typically present in middle-aged women as a flank mass, or as a cause of flank pain or hematuria. We outline the case of an older male who presented with an enlarging abdominal mass causing symptoms that suggested a partial small bowel obstruction. Management of the patient and a brief review are discussed.