Faculty Bibliography

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.

Treatment of pancreatic ductal adenocarcinoma (PDAC) remains a challenge, given its propensity for early systemic spread and growth into the adjacent vital vascular structures. With the advent of newer surgical techniques and chemoradiation therapies, multidetector computed tomography (CT) plays a crucial role in the identification of patients with borderline resectable disease who may benefit from such treatments. Stage III PDAC is divided into two categories-locally advanced, defined by arterial encasement or nonreconstructible portovenous axis involvement; and borderline resectable, defined by limited arterial involvement and/or reconstructible portovenous involvement. A consensus definition for stage III borderline resectable PDAC has been proposed by the Americas Hepato-Pancreato-Biliary Association, the Society of Surgical Oncology, and the Society for Surgery of the Alimentary Tract and has gained widespread use. Evaluation of borderline resectable disease involves the identification of the circumferential and longitudinal relationship of the tumor with its neighboring vessels, markers of vascular invasion, and aberrant anatomic structures that alter the surgical approach. Furthermore, the use of template-based radiology reporting may increase the objectivity of the evaluation and mandate the provision of all of the key descriptors required for a comprehensive evaluation of the disease. In this review, the staging of PDAC at multidetector CT is described, with reference to the evaluation of the tumor-vessel interface as it guides treatment planning, along with a discussion of the key descriptors of PDAC at multidetector CT and their importance. Examples are provided of the imaging findings of borderline resectable disease and different surgical approaches, along with a discussion on the importance of standardized terminology and template-based reporting. ^©RSNA, 2016.

OBJECTIVE:The aim of this study was to evaluate and validate the proposed 8th edition American Joint Committee on Cancer (AJCC) system for T and N staging of pancreatic adenocarcinoma. SUMMARY OF BACKGROUND DATA:Investigators have questioned the clinical relevance and reproducibility of previous AJCC staging for pancreatic adenocarcinoma. METHODS:Prospective databases at Memorial Sloan Kettering (MSK), Massachusetts General Hospital (MGH), and Johns Hopkins Hospital (JHH) were queried for patients who had undergone resection for pancreatic adenocarcinoma. Patients who underwent a margin-negative (R0) resection, and who had previously undergone pathologic review, were included. Patients were staged according to 7th edition AJCC criteria, as well as the proposed 8th edition system that includes different definitions of tumor size (T) and nodal status (N). The dataset was randomly split into training and test sets. RESULTS:Two thousand three hundred eighteen patients were identified who met inclusion criteria. Recursive partitioning on the training set (n = 1551) identified statistically appropriate cutoffs for tumor size (<2.2 cm, ≥4.8 cm,) and nodal status (no positive nodes, 1 to 3 positive nodes, ≥4 positive nodes) that supported the proposed 8th edition changes. Median survival in patients staged as T3, N0 by the 7th edition definitions was different between institutions (median Center 1, 24 mo; Center 2, 37 mo; Center 3, 29 mo; P = 0.054). This difference was not observed when patients were staged as T3, N0 by 8th edition criteria. Stage, and stage-specific outcome (7th edition), on the test set revealed a predominance of patients (68%) within the IIB subgroup, and a concordance probability estimate (CPE) of 0.57 for stage-specific survival. When assessed with 8th edition criteria, no stage subgroup had a majority of patients, and the CPE was 0.58. CONCLUSIONS:The proposed 8th edition changes for T and N classification were statistically valid and may allow a more reproducible system of T staging. This system also stratifies patients more evenly across stages without sacrificing prognostic accuracy.

OBJECTIVE:Our objective was to develop an approach for selecting combinatorial markers of pathology from diverse clinical data types. We demonstrate this approach on the problem of pancreatic cyst classification. MATERIALS AND METHODS:We analyzed 1026 patients with surgically resected pancreatic cysts, comprising 584 intraductal papillary mucinous neoplasms, 332 serous cystadenomas, 78 mucinous cystic neoplasms, and 42 solid-pseudopapillary neoplasms. To derive optimal markers for cyst classification from the preoperative clinical and radiological data, we developed a statistical approach for combining any number of categorical, dichotomous, or continuous-valued clinical parameters into individual predictors of pathology. The approach is unbiased and statistically rigorous. Millions of feature combinations were tested using 10-fold cross-validation, and the most informative features were validated in an independent cohort of 130 patients with surgically resected pancreatic cysts. RESULTS:We identified combinatorial clinical markers that classified serous cystadenomas with 95% sensitivity and 83% specificity; solid-pseudopapillary neoplasms with 89% sensitivity and 86% specificity; mucinous cystic neoplasms with 91% sensitivity and 83% specificity; and intraductal papillary mucinous neoplasms with 94% sensitivity and 90% specificity. No individual features were as accurate as the combination markers. We further validated these combinatorial markers on an independent cohort of 130 pancreatic cysts, and achieved high and well-balanced accuracies. Overall sensitivity and specificity for identifying patients requiring surgical resection was 84% and 81%, respectively. CONCLUSIONS:Our approach identified combinatorial markers for pancreatic cyst classification that had improved performance relative to the individual features they comprise. In principle, this approach can be applied to any clinical dataset comprising dichotomous, categorical, and continuous-valued parameters.

OBJECTIVES/OBJECTIVE:Pancreatic serous cystadenomas (SCAs) are benign tumors. Technological advances in imaging have led to increased recognition of asymptomatic pancreatic cysts, consequently increasing the demand for cytomorphologic evaluations of cyst fluid. STUDY DESIGN/METHODS:A retrospective search through the pathology archives over an 11-year period was performed to identify SCAs from pancreatectomy specimens with a presurgical pancreatic EUS-guided fine-needle aspiration (FNA). RESULTS:Fifty-one FNAs were identified. The average patient age was 59.9 years and 34 (67%) were female. Thirty-five (69%) of the SCAs were located in the body or tail of the pancreas. SCAs ranged in size from 1.3 to 8.0 cm (mean 4.9). On imaging, features suggestive of SCA were seen in 7 (14%) cases. The cytologic diagnoses were as follows: SCA in 5 (10%) cases, suspicious for mucin-producing neoplastic cyst in 4 (8%), pseudocyst in 4 (8%), and benign ductal and/or acinar epithelium, not otherwise specified in 24 (47%). Additionally, 14 (27%) cases were deemed nondiagnostic. CONCLUSIONS:A cytopathologic diagnosis of SCA on FNA is extremely difficult. The salient cytomorphologic features for identifying SCAs included scant cellularity, a mostly clear background, absence of extracellular mucin, hemosiderin-laden macrophages, and loose fragments of cuboidal cells with a notable absence of necrosis, atypia, and mitoses.

Cancer stem cells (CSCs) play an important role in the clonogenic growth and metastasis of pancreatic ductal adenocarcinoma (PDAC). A hallmark of PDAC is the desmoplastic reaction, but the impact of the tumor microenvironment (TME) on CSCs is unknown. In order to better understand the mechanisms, we examined the impact of extracellular matrix (ECM) proteins on PDAC CSCs. We quantified the effect of ECM proteins, β1-integrin, and focal adhesion kinase (FAK) on clonogenic PDAC growth and migration in vitro and tumor initiation, growth, and metastasis in vivo in nude mice using shRNA and overexpression constructs as well as small molecule FAK inhibitors. Type I collagen increased PDAC tumor initiating potential, self-renewal, and the frequency of CSCs through the activation of FAK. FAK overexpression increased tumor initiation, whereas a dominant negative FAK mutant or FAK kinase inhibitors reduced clonogenic PDAC growth in vitro and in vivo. Moreover, the FAK inhibitor VS-4718 extended the anti-tumor response to gemcitabine and nab-paclitaxel in patient-derived PDAC xenografts, and the loss of FAK expression limited metastatic dissemination of orthotopic xenografts. Type I collagen enhances PDAC CSCs, and both kinase-dependent and independent activities of FAK impact PDAC tumor initiation, self-renewal, and metastasis. The anti-tumor impact of FAK inhibitors in combination with standard chemotherapy support the clinical testing of this combination.

We previously developed a novel tumor subtype classification model for duodenal adenocarcinomas based on a combination of the CpG island methylator phenotype (CIMP) and MLH1 methylation status. Here, we tested the prognostic value of this model in stage II colorectal cancer (CRC) patients. Tumors were assigned to CIMP+/MLH1-unmethylated (MLH1-U), CIMP+/MLH1-methylated (MLH1-M), CIMP-/MLH1-U, or CIMP-/MLH1-M groups. Age, tumor location, lymphovascular invasion, and mucin production differed among the four patient subgroups, and CIMP+/MLH1-U tumors were more likely to have lymphovascular invasion and mucin production. Kaplan-Meier analyses revealed differences in both disease-free survival (DFS) and overall survival (OS) among the four groups. In a multivariate analysis, CIMP/MLH1 methylation status was predictive of both DFS and OS, and DFS and OS were shortest in CIMP+/MLH1-U stage II CRC patients. These results suggest that tumor subtype classification based on the combination of CIMP and MLH1 methylation status is informative in stage II CRC patients, and that CIMP+/MLH1-U tumors exhibit aggressive features and are associated with poor clinical outcomes.