Faculty Bibliography

OBJECTIVE:Solid pseudopapillary neoplasms (SPNs) are low-grade malignancies with an excellent prognosis, albeit with the potential for metastatic disease. This study details our institution's experience with the diagnosis and treatment of SPN, including clinical presentation, multimodality imaging findings, and potential predictors of aggressive tumor behavior. MATERIALS AND METHODS/METHODS:The institutional pathology database was searched through for all cases of SPN since 1988, yielding 51 patients. The electronic medical record was searched for clinical and demographic information regarding these patients, including age, sex, presenting symptoms, type of surgery, postoperative length of stay, tumor markers, and postsurgical follow-up. All available imaging data were reviewed, including those of 30 patients who underwent multidetector computed tomography, those of 9 patients who underwent magnetic resonance imaging (MRI), those of 3 patients who underwent conventional ultrasound, and those of 11 patients who underwent endoscopic ultrasound. RESULTS:A total of 84% of patients were females, with a mean age of only 33 years. Prognosis was excellent, with a mean follow-up of 3 years without recurrence. Only 1 of the 51 patients developed metastatic disease to the liver 8 years after the surgery. On computed tomography, lesions tended to be large (5.3 cm), well circumscribed (29/30), round/oval (20/30), and encapsulated (23/30). The lesions often demonstrated calcification (14/30) and typically resulted in no biliary or pancreatic ductal dilatation. The lesions ranged from completely cystic to completely solid. On MRI, the lesions often demonstrated a T2 hypointense or enhancing capsule (6/9) and demonstrated internal blood products (5/9). The lesions tended to be devoid of vascularity on conventional ultrasound. Ten patients were found to have "aggressive" histology at presentation (T3 tumor, nodal involvement, perineural invasion, or vascular invasion). No demographic, clinical, or multidetector computed tomographic imaging features were found to correlate with aggressive histology. CONCLUSIONS:Certain imaging features (eg, well-circumscribed mass with calcification, peripheral capsule, internal blood products, and lack of biliary/pancreatic ductal obstruction) on computed tomography and MRI are highly suggestive of the diagnosis of SPN, particularly when visualized in young female patients. However, it is not possible to predict aggressive histology on the basis of imaging findings, clinical presentation, or patient demographic features.

BACKGROUND:Assessment of patient performance status is often subjective. Sarcopenia--measurement of muscle wasting--may be a more objective means to assess performance status and therefore mortality risk following intra-arterial therapy (IAT). METHODS:Total psoas area (TPA) was measured on cross-sectional imaging in 216 patients undergoing IAT of hepatic malignancies between 2002 and 2012. Sarcopenia was defined as TPA in the lowest sex-specific quartile. Impact of sarcopenia was assessed relative to other clinicopathological factors. RESULTS:Indications for IAT included hepatocellular carcinoma (51 %), intrahepatic cholangiocarcinoma (13 %), colorectal liver metastasis (7 %), or other metastatic disease (30 %). Median TPA among men (568 mm(2)/m(2)) was greater than women (413 mm(2)/m(2)). IAT involved conventional chemoembolization (54 %), drug-eluting beads (40 %), or yttrium-90 (6 %). Median tumor size was 5.8 cm; most patients had multiple lesions (74 %). Ninety-day mortality was 9.3 %; 3-year survival was 39 %. Factors associated with risk of death were tumor size (HR = 1.84) and Child's score (HR = 2.15) (all P < 0.05). On multivariate analysis, sarcopenia remained independently associated with increased risk of death (lowest vs. highest TPA quartile, HR = 1.84; P = 0.04). Sarcopenic patients had a 3-year survival of 28 vs. 44 % for non-sarcopenic patients. CONCLUSIONS:Sarcopenia was an independent predictor of mortality following IAT with sarcopenic patients having a twofold increased risk of death. Sarcopenia is an objective measure of frailty that can help clinical decision-making regarding IAT for hepatic malignancies.

Acinar cell cystadenoma (ACA) of the pancreas was initially described as a non-neoplastic cyst of the pancreas and, at that time, referred to as "acinar cystic transformation." In subsequent studies, these lesions were given the designation of "-oma," despite the relative lack of evidence supporting a neoplastic process. To characterize these lesions further, we examined the clinical, pathologic, and immunohistochemical features of 8 ACAs. The majority of patients were female (7 of 8, 88%) and ranged in age from 18 to 57 years (mean, 43 y). Grossly, the cysts involved the head (n=5), body (n=1), or the entire pancreas (n=2). ACAs were either multilocular (n=4) or unilocular (n=4) and ranged in size from 1.8 to 15 cm (mean, 6.8 cm). Histologically, multilocular ACAs were lined by patches of acinar and ductal epithelium. Immunolabeling, including double-labeling for cytokeratin 19 and chymotrypsin, highlighted the patchy pattern of the ductal and acinar cells lining the cysts. In some areas, the cysts with patches of acinar and ductal differentiation formed larger locules with incomplete septa as they appeared to fuse with other cysts. In contrast, the unilocular cases were lined by 1 to 2 cell layers of acinar cells with little intervening ductal epithelium. Nuclear atypia, mitotic figures, necrosis, infiltrative growth, and associated invasive carcinoma were absent in all cases. In addition, we assessed the clonal versus polyclonal nature of ACAs, occurring in women, using X-chromosome inactivation analysis of the human androgen receptor (AR) gene. Five of 7 cases were informative and demonstrated a random X-chromosome inactivation pattern. Clinical follow-up information was available for all patients, and follow-up ranged from 10 months to 7.8 years (mean, 3.6 y), with no evidence of recurrence or malignant transformation. We hypothesize that early lesions are marked by acinar dilatation that expands into and incorporates smaller ductules and later larger ducts. As the cysts increase in size, they fuse forming larger cysts. Later lesions demonstrate a unilocular cyst lined by predominantly acinar epithelium with scattered ductal cells. The term cystadenoma, with its neoplastic connotation, does not seem to accurately reflect the histologic, immunohistochemical, or molecular features of these lesions. We suggest readopting the term "acinar cystic transformation" until the non-neoplastic versus neoplastic origin of these lesions can be resolved.

INTRODUCTION/BACKGROUND:Pancreatoblastoma is an extremely rare pancreatic neoplasm in adults. The aim of this study is to report our experience with adult pancreatoblastoma as well as review the cases reported in the literature in order to provide guidelines for the management of patients with this rare neoplasm. METHODS:We have encountered three cases of pancreatoblastoma in adults at our institution in addition to the 30 cases reported to date in literature. RESULTS:The median age of pancreatoblastoma in adults is 37 years (range, 18-78 years); men and women are similarly affected (male/female = 16/17). The behavior of pancreatoblastoma is clearly that of a malignant neoplasm, with local invasion, recurrence, and metastasis. Among the adult reported cases, at diagnosis or operation, metastasis and/or local invasion was found in 14 of 31 adult patients (46 %) (2 patients had no data) The survival was significantly higher in patients with resected tumor (resection only and resection + adjuvant chemo/radiotherapy) when compared to unresected patients (palliative chemo/radiotherapy and no treatment), (p = 0.008, HR = 0.20). CONCLUSION/CONCLUSIONS:When disease is localized, the treatment of choice is a complete surgical resection. The role of adjuvant chemotherapy or radiotherapy is still unclear based on the very small number of patients treated.

PURPOSE/OBJECTIVE:Pancreatic cancer is the fourth leading cause of cancer deaths and there currently is no reliable modality for the early detection of this disease. Here, we identify cancer-specific promoter DNA methylation of BNC1 and ADAMTS1 as a promising biomarker detection strategy meriting investigation in pancreatic cancer. EXPERIMENTAL DESIGN/METHODS:We used a genome-wide pharmacologic transcriptome approach to identify novel cancer-specific DNA methylation alterations in pancreatic cancer cell lines. Of eight promising genes, we focused our studies on BNC1 and ADAMTS1 for further downstream analysis, including methylation and expression. We used a nanoparticle-enabled methylation on beads (MOB) technology to detect early-stage pancreatic cancers by analyzing DNA methylation in patient serum. RESULTS:We identified two novel genes, BNC1 (92%) and ADAMTS1 (68%), that showed a high frequency of methylation in pancreatic cancers (n = 143), up to 100% in PanIN-3 and 97% in stage I invasive cancers. Using the nanoparticle-enabled MOB technology, these alterations could be detected in serum samples (n = 42) from patients with pancreatic cancer, with a sensitivity for BNC1 of 79% [95% confidence interval (CI), 66%-91%] and for ADAMTS1 of 48% (95% CI, 33%-63%), whereas specificity was 89% for BNC1 (95% CI, 76%-100%) and 92% for ADAMTS1 (95% CI, 82%-100%). Overall sensitivity using both markers is 81% (95% CI, 69%-93%) and specificity is 85% (95% CI, 71%-99%). CONCLUSIONS:Promoter DNA methylation of BNC1 and ADAMTS1 is a potential biomarker to detect early-stage pancreatic cancers. Assaying the promoter methylation status of these genes in circulating DNA from serum is a promising strategy for early detection of pancreatic cancer and has the potential to improve mortality from this disease.

UNLABELLED:IMPORTANCE It is not known whether hospital and surgeon volumes have an association with readmission among patients undergoing pancreatoduodenectomy. OBJECTIVE:To evaluate patient-, surgeon-, and hospital-level factors associated with readmission. DESIGN, SETTING, AND PARTICIPANTS/METHODS:Retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare data with cases diagnosed from January 1, 1998, to December 31, 2005, and followed up until December 2007. Population-based cancer registry data were linked to Medicare data for the corresponding patients. A total of 1488 unique individuals who underwent a pancreatoduodenectomy were identified. INTERVENTIONS/METHODS:Undergoing pancreatoduodenectomy at hospitals classified by volume of pancreatoduodenectomy procedures performed at the facility were either very-low, low, medium, or high volume. Undergoing pancreatoduodenectomy by surgeons classified by volume of pancreatoduodenectomy procedures performed by the surgeon were either very-low, low, medium, or high volume. MAIN OUTCOMES AND MEASURES/METHODS:In-hospital morbidity, mortality, and 30-day readmission were examined. RESULTS:The median age was 74 years, and 1436 patients (96.5%) had a least 1 medical comorbidity. Patients were treated by 575 distinct surgeons at 298 distinct hospitals. Length of stay was longest (median, 17 days) and 90-day mortality highest (17.2%) at very-low-volume hospitals (P < .001). Among all pancreatoduodenectomy patients, 292 (21.3%) were readmitted within 30 days of discharge. There was no effect of surgeon volume and a modest effect of hospital volume (odds ratio for highest- vs lowest-volume quartiles, 1.85; 95% CI, 1.22-2.80; P = .02). The presence of significant preoperative medical comorbidities was associated with an increased risk for hospital readmission after pancreatoduodenectomy. A comorbidity score greater than 13 had a pronounced effect on the chance of readmission following pancreatoduodenectomy (odds ratio, 2.06; 95% CI, 1.56-2.71; P < .001). The source of variation in readmission was primarily attributable to patient-related factors (95.4%), while hospital factors accounted for 4.3% of the variability and physician factors for only 0.3%. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:Nearly 1 in 5 patients are readmitted following pancreatoduodenectomy. While variation in readmission is, in part, attributable to differences among hospitals, the largest share of variation was found at the patient level.

The grading system for pancreatic neuroendocrine tumors (PanNETs) adopted in 2010 by the World Health Organization (WHO) mandates the use of both mitotic rate and Ki67/MIB-1 index in defining the proliferative rate and assigning the grade. In cases when these measures are not concordant for grade, it is recommended to assign the higher grade, but specific data justifying this approach do not exist. Thus, we counted mitotic figures and immunolabeled, using the Ki67 antibody, 297 WHO mitotic grade 1 and 2 PanNETs surgically resected at a single institution. We quantified the Ki67 proliferative index by marking at least 500 cells in "hot spots" and by using digital image analysis software to count each marked positive/negative cell and then compared the results with histologic features and overall survival. Of 264 WHO mitotic grade 1 PanNETs, 33% were WHO grade 2 by Ki67 proliferative index. Compared with concordant grade 1 tumors, grade-discordant tumors were more likely to have metastases to lymph node (56% vs. 34%) (P<0.01) and to distant sites (46% vs. 12%) (P<0.01). Discordant mitotic grade 1 PanNETs also showed statistically significantly more infiltrative growth patterns, perineural invasion, and small vessel invasion. Overall survival was significantly different (P<0.01), with discordant mitotic grade 1 tumors showing a median survival of 12 years compared with 16.7 years for concordant grade 1 tumors. Conversely, mitotic grade 1/Ki67 grade 2 PanNETs showed few significant differences from tumors that were mitotic grade 2 and either Ki67 grade 1 or 2. Our data demonstrate that mitotic rate and Ki67-based grades of PanNETs are often discordant, and when the Ki67 grade is greater than the mitotic grade, clinical outcomes and histopathologic features are significantly worse than concordant grade 1 tumors. Patients with discordant mitotic grade 1/Ki67 grade 2 tumors have shorter overall survival and larger tumors with more metastases and more aggressive histologic features. These data strongly suggest that Ki67 labeling be performed on all PanNETs in addition to mitotic rate determination to define more accurately tumor grade and prognosis.

PURPOSE/OBJECTIVE:To generate a map of local recurrences after pancreaticoduodenectomy (PD) for patients with resectable pancreatic ductal adenocarcinoma (PDA) and to model an adjuvant radiation therapy planning treatment volume (PTV) that encompasses a majority of local recurrences. METHODS AND MATERIALS/METHODS:Consecutive patients with resectable PDA undergoing PD and 1 or more computed tomography (CT) scans more than 60 days after PD at our institution were reviewed. Patients were divided into 3 groups: no adjuvant treatment (NA), chemotherapy alone (CTA), or chemoradiation (CRT). Cross-sectional scans were centrally reviewed, and local recurrences were plotted to scale with respect to the celiac axis (CA), superior mesenteric artery (SMA), and renal veins on 1 CT scan of a template post-PD patient. An adjuvant clinical treatment volume comprising 90% of local failures based on standard expansions of the CA and SMA was created and simulated on 3 post-PD CT scans to assess the feasibility of this planning approach. RESULTS:Of the 202 patients in the study, 40 (20%), 34 (17%), and 128 (63%) received NA, CTA, and CRT adjuvant therapy, respectively. The rate of margin-positive resections was greater in CRT patients than in CTA patients (28% vs 9%, P=.023). Local recurrence occurred in 90 of the 202 patients overall (45%) and in 19 (48%), 22 (65%), and 49 (38%) in the NA, CTA, and CRT groups, respectively. Ninety percent of recurrences were within a 3.0-cm right-lateral, 2.0-cm left-lateral, 1.5-cm anterior, 1.0-cm posterior, 1.0-cm superior, and 2.0-cm inferior expansion of the combined CA and SMA contours. Three simulated radiation treatment plans using these expansions with adjustments to avoid nearby structures were created to demonstrate the use of this treatment volume. CONCLUSIONS:Modified PTVs targeting high-risk areas may improve local control while minimizing toxicities, allowing dose escalation with intensity-modulated or stereotactic body radiation therapy.

Limited treatment options exist for isolated local recurrence of pancreatic ductal adenocarcinoma (PDA) following surgical resection accompanied by neoadjuvant or adjuvant chemoradiation therapy (CRT). While select patients are eligible for re-resection, recurrent lesions are often unresectable. Stereotactic body radiation therapy (SBRT) represents a possible minimally invasive treatment option for these patients, although published data in this setting are currently lacking. This study examines the safety, efficacy, and palliative capacity of re-irradiation with SBRT for isolated local PDA recurrence. All patients undergoing SBRT at two academic centers from 2008-2012 were retrospectively reviewed to identify those who received re-irradiation with SBRT for isolated local recurrence or progression of PDA after previous conventionally fractionated CRT. Information regarding demographics, clinicopathologic characteristics, therapies received, survival, symptom palliation, and toxicity was obtained from patient charts. Kaplan-Meier statistics were used to analyze survival and the log-rank test was used to compare survival among patient subgroups. Eighteen patients were identified. Fifteen had previously undergone resection with neoadjuvant or adjuvant CRT, while 3 received definitive CRT for locally advanced disease. Median CRT dose was 50.4 Gy [interquartile range (IQR), 45.0-50.4 Gy] in 28 fractions. All patients subsequently received gemcitabine-based maintenance chemotherapy, but developed isolated local disease recurrence or progression without evidence of distant metastasis. Locally recurrent or progressive disease was treated with SBRT to a median dose of 25.0 Gy (range, 20.0-27.0 Gy) in 5 fractions. Median survival from SBRT was 8.8 months (95% CI, 1.2-16.4 months). Despite having similar clinicopathologic disease characteristics, patients who experienced local progression greater than vs. less than 9 months after surgery/definitive CRT demonstrated superior median survival (11.3 vs. 3.4 months; P=0.019) and progression-free survival (10.6 vs. 3.2 months; P=0.030) after SBRT. Rates of freedom from local progression at 6 and 12 months after SBRT were 78% (14 of 18 patients) and 62% (5 of 8 patients), respectively. Effective symptom palliation was achieved in 4 of 7 patients (57%) who reported symptoms of abdominal or back pain prior to SBRT. Five patients (28%) experienced grade 2 acute toxicity; none experienced grade ≥3 acute toxicity. One patient (6%) experienced grade 3 late toxicity in the form of small bowel obstruction. In conclusion, re-irradiation with hypofractionated SBRT in this salvage scenario appears to be a safe and reasonable option for palliation of isolated local PDA recurrence or progression following previous conventional CRT. Patients with a progression-free interval of greater than 9 months prior to isolated local recurrence or progression may be most suitable for re-irradiation with SBRT, as they appear to have a better prognosis with survival that is long enough for local control to be of potential benefit.