Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise tumor-specific molecular information difficult. Here, we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, which includes primary, metastatic, and normal samples. By digitally separating tumor, stroma, and normal gene expression, we have identified and validated two tumor-specific subtypes including a “basal-like” subtype which has worse outcome, and is molecularly similar to basal tumors in bladder and breast cancer. Furthermore, we define “normal” and “activated” stromal subtypes which are independently prognostic. Our results provide new insight into the molecular composition of PDAC which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies is critical.

Purpose: Molecular subtyping for pancreatic cancer has made substantial progress in recent years, facilitating the optimization of existing therapeutic approaches to improve clinical outcomes in pancreatic cancer. With advances in treatment combinations and choices, it is becoming increasingly important to determine ways to place patients on the best therapies upfront. While various molecular subtyping systems for pancreatic cancer have been proposed, consensus regarding proposed subtypes, as well as their relative clinical utility, remains largely unknown and presents a natural barrier to wider clinical adoption. Methods:We assess three major subtype classification schemas in the context of results from two clinical trials and by meta-analysis of publicly available expression data to assess statistical criteria of subtype robustness and overall clinical relevance. We then developed a Single Sample Classifier (SSC) using penalized logistic regression based on the most robust and replicable schema.

No abstract

No abstract

Purpose Desmoplastic stroma is a cardinal feature of primary pancreatic ductal adenocarcinoma (PDA), but its effects on the biology, prognosis, and therapeutic outcomes in the disease are not known. We developed an automated method to assess tumor stroma density (TSD) and investigated computed tomography (CT) correlates of stroma in PDA. Patients and Methods We collected PDA samples from rapid autopsy and resection series and digitally annotated samples to quantify TSD. A series of patients who had undergone resection also underwent preoperative multiphasic CT imaging. Results Automated and manual assessments of TSD were highly correlated (ρ = 0.65; P < .001). Solid organ metastases had a lower median TSD than primary tumors ( P < .001). Patients whose tumors had high TSD had prolonged recurrence-free survival (hazard ratio [HR] = 0.51; P = .003) and overall survival (HR = 0.57; P = .008). In another independent dataset, patients whose tumors had high TSD had decreased risk for recurrence (HR = 0.03; P = .003) and death (HR = 0.03; P = .003) at time of resection; however, the protective effect of high TSD diminished over time. Patients with a normalized portovenous phase CT tumor enhancement ratio ≥ 0.40 had a longer time to recurrence after resection ( P = .020). Normalized portovenous phase CT tumor enhancement ratio was significantly correlated with TSD ( P = .003). Conclusion Objective quantitative assessment of stroma in PDA revealed several clinically relevant observations. Stroma was less abundant in metastatic PDA, the primary cause of mortality associated with PDA. High stromal content correlated with favorable outcome in patients with resected tumors, implying a protective effect of stroma and suggesting careful consideration of active stromal depletion therapies. Standard, multiphase CT imaging correlated with stroma content and clinical outcome, indicating that noninvasive assessment of stroma is a feasible sensitivity enrichment approach in PDA.

Conflict of interest: KM is an employee of Foundation Medicine. MJP serves as a consultant for Perthera and holds stock in the company. EB is an employee of Perthera. BL is an employee of Bristol-Myers Squibb. ML is an employee and shareholder of Bristol-Myers Squibb. ZJW serves as a consultant for GE Healthcare. EC has Research Funding from Astra Zeneca, Ferro Therapeutics, Senti Biosciences, Merck KgA, and Bayer to UCSF; stock ownership in Tatara Therapeutics, Clara Health, BloodQ, Guardant Health, Illumina, Pacific Biosciences, and Exact Biosciences; and has received consulting income from Takeda and Merck.

We reviewed fine-needle aspiration (FNA) samples of metastatic tumor in the pancreas from nonhematologic neoplasms over a 5-year period. In 1,050 total procedures, 20 metastases were diagnosed: 9 renal-cell carcinomas (RCCs), 3 melanomas, 2 pulmonary small-cell carcinomas, 2 breast carcinomas, 1 prostate carcinoma, 1 colon adenocarcinoma, 1 pulmonary squamous-cell carcinoma, and 1 gastrointestinal stromal tumor. A wide range of latency from primary diagnosis was noted; the longest was RCC at 12.6 years (range, 5-28). Sites of involvement were: 13 heads, 4 bodies, and 3 tails. Eighteen cases presented as a solitary mass. The average size was 4.7 cm (range, 1.5-9.8), and a case of RCC (9.8 cm) was the largest. In seven cases, the clinical and radiographic impression was of a pancreatic primary. We conclude that metastases to the pancreas are rarely diagnosed by FNA and may clinically mimic a pancreatic primary.

BACKGROUND Duct brushing cytology is an important tool in evaluation of the extrahepatic biliary tract and large pancreatic ducts. The emergence of neoadjuvant therapies underscores the importance of accurate preoperative diagnosis by noninvasive means. Liquid‐based preparation methods, such as ThinPrep, have become popular for nongynecologic cytology specimens. METHODS Findings from bile and pancreatic duct brushings were reviewed over the 10‐year period of 1994‐2003. Cytologic material, imaging reports, and clinical data were reviewed and pathologic and clinical follow‐up data were obtained. The slides were prepared by direct smear only (18.8%), direct smear plus cytospin (14.4%), or direct smear plus ThinPrep (66.8%). RESULTS A total of 1118 specimens were identified (1008 bile duct, 110 pancreatic duct) from 864 patients. The cytologic findings were: 53.5% negative, 16.5% malignant, 18.2% suspicious for malignancy, 11% atypical/inconclusive, 0.8% inadequate. Follow‐up in the form of either histology or at least 6 months clinical observation was available for 82.2% of cases (n = 971). Overall operating characteristics were: 52.6% sensitivity, 99.4% specificity, 98.9% positive predictive value, 67.1% negative predictive value, and 75.7% accuracy. Diagnostic agreement between cytology and follow‐up was the main variable analyzed. Agreement was significantly affected by characteristics of the sampled lesion, with ductal narrowing having the lowest rate of malignancy. In addition, the ThinPrep method showed superior sensitivity and accuracy compared with other preparation methods (P = .02). Nonsignificant associations were noted for patient age and gender, site of lesion, and the presence of either stones or prior stent. CONCLUSION In a large dataset from a single institution, brushing cytology showed modest sensitivity and high specificity. Diagnostic agreement was considerably better for benign cases. The combination of direct smear and the ThinPrep method showed superior sensitivity and accuracy. Cancer (Cancer Cytopathol) 2006. © 2006 American Cancer Society.