Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:Following resection of pancreatic adenocarcinoma, tumor size has been considered a key prognostic feature; however, this remains controversial. We sought to examine the association of size with outcomes following resection of pancreatic adenocarcinoma. METHODS:Between 1970 and 2010, 1,697 patients with pancreatic adenocarcinoma at the Johns Hopkins Hospital underwent curative intent pancreaticoduodenectomy. Prognostic factors were identified by univariate and multivariate analyses. RESULTS:Of 1,697 patients, tumor size was ≤ 2 cm in 418 (24.6%) patients, 2-5 cm in 1,070 (63.1%) patients, and ≥ 5 cm in 209 (12.3%) patients. On univariate analyses, 5-year survival was inversely proportional to tumor size (≤ 2 cm: 28.8% vs. 2-5 cm: 19.4% vs. ≥ 5 cm: 14.2%; P < 0.001). Size correlated with the risk of other adverse factors, with larger tumors being more likely to be associated with nodal disease and poor differentiation (both P < 0.05). On multivariate analysis, the 2 cm cut-off was not associated with survival, while nodal disease (HR = 1.59; P = 0.006) and poor differentiation (HR = 1.59; P = 0.04) remained predictive of outcome, regardless of size. CONCLUSION/CONCLUSIONS:The cut-off value of 2 cm is not independently associated with outcome, however, tumor size was strongly associated with the risk of other adverse prognostic factors. The effect of size on prognosis was largely attributable to these other biologic factors rather than tumor size itself.

BACKGROUND:The American Joint Committee on Cancer staging system for hilar cholangiocarcinoma may be inaccurate because the bile duct lacks discrete tissue boundaries. OBJECTIVES/OBJECTIVE:To examine the accuracy of the American Joint Committee on Cancer staging schemes and to determine the prognostic implications of tumor depth. DESIGN, SETTING, AND PATIENTS/METHODS:From January 1, 1987, through December 31, 2009, there were 106 patients who underwent resection of hilar cholangiocarcinoma who had pathologic slides available for re-review. MAIN OUTCOME MEASURES/METHODS:Tumor depth and overall survival. RESULTS:Overall median survival was 19.9 months. The 6th and 7th editions of the T-classification criteria were unable to discriminate among T1, T2, and T3 lesions (P > .05 for all). Median survival was associated with the invasion depth of the tumor (≥5 mm vs <5 mm): 18 months vs 30 months (P = .01). On multivariate analysis, tumor depth remained predictive of disease-specific death (hazard ratio, 1.70; P = .03). CONCLUSIONS:The American Joint Committee on Cancer T-classification criteria did not stratify patients with regard to prognosis. Depth of tumor invasion is a better predictor of long-term outcome.

BACKGROUND:The management of patients with liver metastasis from a gynecologic carcinoma remains controversial, as there is currently little data available. We sought to determine the safety and efficacy of liver-directed surgery for hepatic metastasis from gynecologic primaries. METHODS:Between 1990 and 2010, 87 patients with biopsy-proven liver metastasis from a gynecologic carcinoma were identified from an institutional hepatobiliary database. Fifty-two (60%) patients who underwent hepatic surgery for their liver disease and 35 (40%) patients who underwent biopsy only were matched for age, primary tumor characteristics, and hepatic tumor burden. Clinicopathologic, operative, and outcome data were collected and analyzed. RESULTS:Of the 87 patients, 30 (34%) presented with synchronous metastasis. The majority of patients had multiple hepatic tumors (63%), with a median size of the largest lesion being 2.5 cm. Of those patients who underwent liver surgery (n=52), most underwent a minor hepatic resection (n=44; 85%), while 29 (56%) patients underwent concurrent lymphadenectomy and 45 (87%) patients underwent simultaneous peritoneal debulking. Postoperative morbidity and mortality were 37% and 0%, respectively. Median survival from time of diagnosis was 53 months for patients who underwent liver-directed surgery compared with 21 months for patients who underwent biopsy alone (n=35) (p=0.01). Among those patients who underwent liver-directed surgery, 5-year survival following hepatic resection was 41%. CONCLUSIONS:Hepatic surgery for liver metastasis from gynecologic cancer can be performed safely. Liver surgery may be associated with prolonged survival in a subset of patients with hepatic metastasis from gynecologic primaries and therefore should be considered in carefully selected patients.

BACKGROUND:The role of EUS for detection of pancreatic neuroendocrine tumors (PNETs) is not clearly defined in institutions that use multidetector CT for pancreatic imaging. OBJECTIVE:The aims of this study were to (1) compare the detection rates of EUS and CT by type and size of PNET and calculate the incremental benefit of EUS over CT, (2) evaluate the CT detection rate for PNETs adjusted for improved CT technology over time, and (3) determine the factors associated with CT-negative PNETs. DESIGN/METHODS:Retrospective single-center cohort study. SETTING/METHODS:Johns Hopkins Hospital. PATIENTS/METHODS:Patients with pathologically proven PNETs with preoperative CT. Incidentally found PNETs (resection specimens) and those without Johns Hopkins Hospital CT imaging were excluded. MAIN OUTCOME MEASUREMENT/METHODS:Detection rates of CT and EUS were compared by using pathology as the reference standard. RESULTS:In 217 patients (with 231 PNETs) studied, CT detected 84% of tumors (54.3% of insulinomas). The sensitivity of CT for the detection of PNETs significantly increased with improvement in CT technology (P = .02; χ(2) for trend). CT was more likely to miss lesions <2 cm (P = .005) and insulinomas (P < .0001). In 56 patients who had both CT and EUS, the sensitivity of EUS was greater than CT (91.7% vs 63.3%; P = .0002), particularly for insulinomas (84.2% vs 31.6%; P = .001). EUS detected 20 of 22 CT-negative tumors (91%). LIMITATIONS/CONCLUSIONS:Retrospective nonrandomized design and referral bias. CONCLUSIONS:The detection rate of CT has significantly improved over time. CT-negative tumors are small and more likely to be insulinomas. A sequential approach of CT followed by EUS can detect most PNETs. EUS is a more sensitive initial test for the detection of suspected insulinomas.

Pancreatic neuroendocrine tumors (PanNETs) are a rare but clinically important form of pancreatic neoplasia. To explore the genetic basis of PanNETs, we determined the exomic sequences of 10 nonfamilial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs. The most frequently mutated genes specify proteins implicated in chromatin remodeling: 44% of the tumors had somatic inactivating mutations in MEN1, which encodes menin, a component of a histone methyltransferase complex, and 43% had mutations in genes encoding either of the two subunits of a transcription/chromatin remodeling complex consisting of DAXX (death-domain-associated protein) and ATRX (α thalassemia/mental retardation syndrome X-linked). Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. We also found mutations in genes in the mTOR (mammalian target of rapamycin) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatment with mTOR inhibitors.

BACKGROUND:Margin status is one of the strongest prognosticators after resection of pancreatic ductal adenocarcinoma (PDAC). The clinical significance of pancreatic intraepithelial neoplasia (PanIN) at a surgical margin has not been established. METHODS:A total of 208 patients who underwent R0 resection for PDAC between 2004 and 2008 were selected. Intraoperative frozen section slides containing the final pancreatic parenchymal transection margin were evaluated for presence or absence, number, and grade of PanINs. Data were compared to clinicopathologic factors, including patient survival. RESULTS:PanIN lesions were present in margins in 107 of 208 patients (51.4%). Median number of PanINs per pancreatic resection margin was 1 (range, 1-11). A total of 72 patients had PanIN-1 (34.6%), 44 had PanIN-2 (21.1%), and 16 had PanIN-3 (7.2%) at their margin. Overall median survival was 17.9 (95% confidence interval, 14-21.9) months. Neither the presence nor absence of PanIN nor histological grade had any significant correlation with important clinicopathologic characteristics. There were no significant survival differences between patients with or without PanIN lesions at the resection margin or among patients with PanIN-3 (carcinoma in situ) versus lower PanIN grades. However, patients with R1 resection had a significantly worse outcome compared with patients without invasive cancer at a margin irrespective of the presence of PanIN (P = 0.02). CONCLUSIONS:The presence of PanINs at a resection margin does not affect survival in patients who undergo R0 resection for PDAC. These results have significant clinical implications for surgeons, because no additional resection seems to be indicated when intraoperative frozen sections reveal even high-grade PanIN lesions.

PURPOSE/OBJECTIVE:The choice between liver transplantation (LT), liver resection (LR), and radiofrequency ablation (RFA) as initial therapy for early hepatocellular carcinoma (HCC) is controversial, yet little is known about how surgeons choose therapy for individual patients. We sought to quantify the impact of both clinical factors and surgeon specialty on surgical decision making in early HCC by using conjoint analysis. METHODS:Surgeons with an interest in liver surgery were invited to complete a Web-based survey including 10 case scenarios. Choice of therapy was then analyzed by using regression models that included both clinical factors and surgeon specialty (non-LT v LT). RESULTS:When assessing early HCC occurrences, non-LT surgeons (50% LR; 41% LT; 9% RFA) made significantly different recommendations compared with LT surgeons (63% LT; 31% LR; 6% RFA; P < .001). Clinical factors, including tumor number and size, type of resection required, and platelet count, had significant effects on the choice between LR, LT, and RFA. After adjusting for clinical factors, non-LT surgeons remained more likely than LT surgeons to choose LR compared with LT (relative risk ratio [RRR], 2.67). When the weight of each clinical factor was allowed to vary by surgeon specialty, the residual independent effect of surgeon specialty on the decision between LR and LT was negligible (RRR, 0.93). CONCLUSION/CONCLUSIONS:The impact of surgeon specialty on choice of therapy for early HCC is stronger than that of some clinical factors. However, the influence of surgeon specialty does not merely reflect an across-the-board preference for one therapy over another. Rather, certain clinical factors are weighed differently by surgeons in different specialties.

Solid-pseudopapillary neoplasms of the pancreas are uncommon and usually occur in young women. They are generally large, encapsulated masses with mixture of solid, cystic, and hemorrhagic components. Some cases have atypical features; for example, they can form a small predominantly solid mass and produce dilatation of the main pancreatic duct. In this article we discuss and illustrate the spectrum of the appearances of this distinctive neoplasm on multidetector CT.

BACKGROUND:Biomarkers for the diagnostic classification of pancreatic cysts are urgently needed. Deregulated microRNA (miRNAs) expression is widespread in pancreatic cancer. We assessed whether aberrant miRNAs in pancreatic cyst fluid could be used as potential biomarkers for cystic precursor lesions of pancreatic cancer. METHODS:Cyst fluid specimens were prospectively collected from 40 surgically resected pancreatic cysts, and small RNAs were extracted. The 'mucinous' cohort included 14 intraductal papillary mucinous neoplasms (including 3 with an associated adenocarcinoma) and 10 mucinous cystic neoplasms; the 'nonmucinous' cohort included 11 serous cystadenomas and 5 other benign cysts. Quantitative reverse transcription PCR was performed for five miRNAs (miR-21, miR-155, miR-221, miR-17-3p, miR-191), which were previously reported as overexpressed in pancreatic adenocarcinomas. RESULTS:Significantly higher expression of miR-21, miR-221, and miR-17-3p was observed in the mucinous versus nonmucinous cysts (p < 0.01), with the mean relative fold differences being 7.0-, 7.9-, and 5.4-fold, respectively. Receiver operating characteristic curves demonstrated the highest median area under the curve for miR-21, with a median specificity of 76%, at a sensitivity of 80%. CONCLUSION/CONCLUSIONS:This pilot study demonstrates that profiling miRNAs in pancreatic cyst fluid samples is feasible and can yield potential biomarkers for the classification of cystic lesions of the pancreas. and IAP.