Brain Metastases in Pancreatic Ductal Adenocarcinoma: Assessment of Molecular Genotype-Phenotype Features-An Entity With an Increasing Incidence?

PURPOSE: To assess clinical characteristics of patients with metastatic pancreas ductal adenocarcinoma (PDAC) and brain metastases (BM), and to assess somatic and germ-line molecular profiles where performed. PATIENTS AND METHODS: Patients with PDAC and BM between January 1990 and January 2016 were identified. Molecular characteristics of somatic and germ-line testing where performed in the subset of patients who had provided informed consent. Somatic alterations were assessed by either MSK-IMPACT testing (>340 key cancer genes) or Sequenom testing (8-gene panel). Overall survival was calculated from date of diagnosis to either date of last follow-up or death. Survival after BM was calculated from date of diagnosis of BM by radiology or pathology to either date of last follow-up or death. RESULTS: From a total of 5824 patients with PDAC identified from January 2000 to January 2016, twenty-five patients (0.4%) had BM. Median age at PDAC diagnosis was 58 years. Median time to the development of BM from initial PDAC diagnosis was 17 months (range, 0-79 months). Median overall survival after BM diagnosis was 1.5 months (range, 1-31 months). Overall survival for patients who had craniotomy (n = 4) was 11 months (range, 1-31 months), with 2 long-term survivors at 21 and 31 months, respectively. Four patients had leptomeningeal disease. Six of 25 patients had germ-line testing, and 3 had BRCA mutations (2 BRCA1 and 1 BRCA2). Somatic profiling identified KRAS mutations in 100% (4 G12D, 2 G12V, and 1 Q61K). CONCLUSION: BM from PDAC is a rare event. We identified a speculative association of germ-line BRCA1/2 alterations with BM in PDAC, which requires corroboration. Survival after BM development is poor; prolonged survival occurred in selected patients via a multidisciplinary approach.

A Comprehensive Assessment of Accurate Lymph Node Staging and Preoperative Detection in Resected Pancreatic Cancer.

BACKGROUND: The current (seventh edition) American Joint Commission on Cancer (AJCC) Staging System for pancreatic ductal adenocarcinoma (PDAC) dichotomizes pathologic lymph node (LN) involvement into absence (pN0) or presence (pN1) of disease. The recently announced eighth edition also includes stratification on the number of positive nodes. Furthermore, LNs detected on preoperative imaging (CT, MRI, or endoscopic ultrasound-EUS) are considered to be pathologically involved in other gastrointestinal cancers. However, this is less well defined for PDAC. Therefore, the three aims of this study were to determine (1) whether the new AJCC staging system led to more accurate staging, (2) the number of nodes needed to be examined to detect pathologic involvement, and (3) if pN disease could be reliably detected on preoperative imaging in PDAC. METHODS: A retrospective review of all patients undergoing pancreatectomy at a single US academic center from January 1990 to September 2015. Pathology reports of resected specimens were reviewed to determine the total number of LNs examined and those positive for metastasis. CT, MRI, and/or EUS reports were used to determine the presence or absence of preoperatively detectable LN enlargement. RESULTS: Of the 490 surgical resections for PDAC, pN1 disease was detected in 59.4% (n = 291) and was positively correlated with the number of LNs pathologically examined (P < 0.001). Patients with pN1 disease had a shorter overall survival (OS) than those without nodal involvement (25.1 vs. 44.0 months; P < 0.001); however, OS was not different when stratifying by the number of nodes as on the eighth AJCC system. Pathologic examination of > 20 LNs in treatment naïve patients was optimal to detect pN1 disease and predict longer OS for those without nodal involvement (median survival > 41.1 months, P = 0.03 when compared to < 15 or 15-19 LNs examined). LNs were detected by CT, MRI, or EUS in 30.7% (103/335) of patients. The positive predictive value (PPV) of preoperative LN detection for pathologic involvement was 77.3% for treatment naïve patients and 84.2% for those without biliary obstruction. CONCLUSIONS: Although the LN scoring in the seventh PDAC AJCC Staging System was sufficient to predict OS of our patients, more LNs than previously considered (20 vs. 15) were optimal to detect pathologic involvement. Preoperative LN detection was an accurate predictor of pN1 disease for treatment naïve patients without biliary obstruction.

Preoperative evaluation of pancreatic ductal adenocarcinoma with synchronous liver metastasis: Diagnosis and assessment of unresectability.

AIM: To identify predictors for synchronous liver metastasis from resectable pancreatic ductal adenocarcinoma (PDAC) and assess unresectability of synchronous liver metastasis. METHODS: Retrospective records of PDAC patients with synchronous liver metastasis who underwent simultaneous resections of primary PDAC and synchronous liver metastasis, or palliative surgical bypass, were collected from 2007 to 2015. A series of pre-operative clinical parameters, including tumor markers and inflammation-based indices, were analyzed by logistic regression to figure out predictive factors and assess unresectability of synchronous liver metastasis. Cox regression was used to identify prognostic factors in liver-metastasized PDAC patients after surgery, with intention to validate their conformance to the indications of simultaneous resections and palliative surgical bypass. Survival of patients from different groups were analyzed by the Kaplan-Meier method. Intra- and post-operative courses were compared, including complications. PDAC patients with no distant metastases who underwent curative resection served as the control group. RESULTS: CA125 > 38 U/mL (OR = 12.397, 95%CI: 5.468-28.105, P < 0.001) and diabetes mellitus (OR = 3.343, 95%CI: 1.539-7.262, P = 0.002) independently predicted synchronous liver metastasis from resectable PDAC. CA125 > 62 U/mL (OR = 5.181, 95%CI: 1.612-16.665, P = 0.006) and age > 62 years (OR = 3.921, 95%CI: 1.217-12.632, P = 0.022) correlated with unresectability of synchronous liver metastasis, both of which also indicated a worse long-term outcome of liver-metastasized PDAC patients after surgery. After the simultaneous resections, patients with post-operatively elevated serum CA125 levels had shorter survival than those with post-operatively reduced serum CA125 levels (7.7 mo vs 16.3 mo, P = 0.013). The survival of liver-metastasized PDAC patients who underwent the simultaneous resections was similar to that of non-metastasized PDAC patients who underwent curative pancreatectomy alone (7.0 mo vs 16.9 mo, P < 0.001), with no higher rates of either pancreatic fistula (P = 0.072) or other complications (P = 0.230) and no greater impacts on length of hospital stay (P = 0.602) or post-operative diabetic control (P = 0.479). CONCLUSION: The criterion set up by CA125 levels could facilitate careful diagnosis of synchronous liver metastases from PDAC, and prudent selection of appropriate patients for the simultaneous resections.

Multidisciplinary approach and multimodal therapy in resected pancreatic cancer. Observational study.

OBJECTIVE: Analysis and evaluation of a multidisciplinary approach, postoperative results and survival of a group of patients with resected pancreatic cancer after a multimodal therapy. DESIGN: DESCRIPTIVE, prospective and observational study. PATIENTS: Between January 2004 and December 2004, 124 patients with pancreatic cancer were evaluated. In 30 patients pancreatic resection was performed, and they are the object of this study. Results of preoperative evaluation, postoperative morbidity and mortality, and long term survival were studied. RESULTS: Diagnostic evaluation was completed in ambulatory basis in 20% of the patients. In 63% of cases, admission was done in the same day of surgery. In 3 patients (9%), tumor resection was not achieved, therefore, concordance between radiological and surgical resectability rate was 91%. Resectability rate was 24.1%. Surgical Mortality was 3.3%, with a global morbidity rate of 56.6%. Survival at one, two, three and, four years was 76.2%, 56.3%, 43%, y 27.3% respectively. CONCLUSIONS: Technological development and coordination of efforts in multidisciplinary teams offer an accurate evaluation of tumor involvement, and may reduce the number of laparotomies without tumor resection. The application of a systematic and generalized multimodal treatment in pancreatic cancer is progressively showing a tendency of progressive increase in resectability and survival rates in pancreatic cancer.

Preoperative assessment of para-aortic lymph node metastasis in patients with pancreatic cancer.

BACKGROUND: Para-aortic lymph node (PALN) metastasis is an important prognostic factor in patients with pancreatic cancer, but accurate preoperative diagnosis is difficult. The objective of this study was to assess the accuracy of diagnosis of PALN by computed tomography (CT), magnetic resonance imaging (MRI), and (18)F-fluorodeoxyglucose positron-emission tomography (FDG-PET). METHODS: From August 2005 to July 2008, 119 patients with invasive ductal adenocarcinoma of the pancreas were included in this study. PALNs with a longer diameter >10 mm on CT or MRI were suspected of being involved by metastasis, whereas FDG uptake exceeding that of the adjacent normal tissue was considered to be positive for metastasis on FDG-PET studies. The imaging findings were compared with the pathological diagnosis of PALN metastasis. RESULTS: PALN dissection was performed in 71 patients (60.0%). Although histopathological examination revealed metastasis in 6 patients (8.5%), none of these patients was positive in any of the preoperative imaging studies. The longer diameter, the shorter diameter, the ratio of the two diameters, and the calculated lymph node volume showed no significant differences between patients with and without PALN metastasis. CONCLUSIONS: Preoperative detection of PALN metastasis in patients with pancreatic cancer is very difficult. Intraoperative histopathological examination of frozen sections is necessary if radical resection is contemplated.

Different approaches to assessment of lymph nodes and surgical margin status in patients with ductal adenocarcinoma of the pancreas treated with pancreaticoduodenectomy.

AIM: To develop a method of gross examination of pancreaticoduodenectomy specimens with pancreatic ductal adenocarcinoma, allowing adequate assessment of the entire pancreatic surface as a surgical margin, which would not affect the lymph node yield. METHODS: We retrospectively compared the R1 rates (i.e., proportions of patients with microscopic residual tumour at surgical margins) and lymph node yield in a series of 67 consecutive cases of pT3 ductal adenocarcinomas diagnosed in pancreaticoduodenectomy specimens during three different periods of time and sampled using three different approaches: (1) period 2006-2007, when the pancreatic surface (except for the transection margin and superior mesenteric artery margin) was not examined; (2) period January-September 2008, when the posterior pancreatic surface (posterior circumferential radial margin) was examined using an improved method based on sampling of 2.0-2.5 mm thick consecutive slices perpendicular to the duodenal axis; and (3) period October 2008 - June 2009, when the whole surface of the pancreatic head was sampled using the approach mentioned above. RESULTS: The R1 rates in three consecutive time periods were 23.5%, 40% and 53.8%, respectively. Median numbers of retrieved peripancreatic lymph nodes were 11.0, 12.0 and 14.0, respectively. CONCLUSIONS: The newly proposed approach allowed adequate assessment of the entire pancreatic head surface as a surgical margin and reduced the risk of under-detection of R1 status. Moreover, this approach did not affect the number of peripancreatic lymph nodes examined.

CT and pathologic assessment of prospective nodal staging in patients with ductal adenocarcinoma of the head of the pancreas.

OBJECTIVE: The aim of our study was to compare the assessment of peripancreatic lymph nodes using CT with the gold standard of detailed histopathologic assessment of resected specimens in patients with pancreatic ductal adenocarcinoma. SUBJECTS AND METHODS: Sixty-two patients with presumed pancreatic carcinoma were prospectively studied with dual-phase contrast-enhanced helical CT, and images were interpreted in consensus by three radiologists. Complete surgical resection was performed in 28 patients. A detailed nodal classification system was used for radiologic, surgical, and pathologic staging in the nine patients whose final diagnosis at histology was pancreatic ductal adenocarcinoma. RESULTS: Forty lymph nodes were prospectively identified on CT in these nine patients. Two of 23 nodes (9%) measuring less than 5 mm in the short-axis diameter were malignant, four of 11 nodes (36%) measuring 5-10 mm were malignant, and one of six nodes (17%) larger than 10 mm was malignant. Using a short-axis diameter of greater than 10 mm as the criterion for nodal involvement, we found a sensitivity of 14% (1/7) and a specificity of 85% (28/33), with a positive predictive value of 17% (1/6), a negative predictive value of 82% (28/34), and an overall accuracy of 73% (29/40). Ovoid nodal shape, clustering of nodes, and the absence of a fatty hilum were not useful predictors of malignancy on CT. CONCLUSION: In resectable pancreatic ductal adenocarcinoma, CT is not accurate overall for the prediction of nodal involvement. In a patient with presumed pancreatic carcinoma that is considered to be resectable, the depiction on CT of peripancreatic nodes should not prevent attempted curative resection.