Antonio Pea

Differences between main-duct and branch-duct intraductal papillary mucinous neoplasms of the pancreas

In the last decade, intraductal papillary mucinous neoplasms (IPMNs) have become commonly diagnosed. From a morphological standpoint, they are classified in main-duct IPMNs (MD-IPMNs) and branch-duct IPMNs (BD-IPMNs), depending on the type of involvement of the pancreatic ductal system by the neoplasm. Despite the fact that our understanding of their natural history is still incomplete, recent data indicate that MD-IPMNs and BD-IPMNs show significant differences in terms of biological behaviour with MD-IPMNs at higher risk of malignant degeneration. In the present paper, clinical and epidemiological characteristics, rates of malignancy and the natural history of MD-IPMNs and BD-IPMNs are analyzed. The profile of IPMNs involving both the main pancreatic duct and its side branches (combined-IPMNs) are also discussed. Finally, general recommendations for management based on these differences are given.

Prognostic impact and implications of extracapsular lymph node involvement in colorectal cancer: a systematic review with meta-analysis

BACKGROUND The extranodal extension (ENE) of nodal metastasis (i.e. the extension of tumor cells through the nodal capsule into the perinodal adipose tissue) has recently emerged as an important prognostic factor in different types of malignancies. However, the tumor-node-metastasis (TNM) staging system for colorectal cancer does not consider it as a prognostic parameter. Therefore, we conducted a systematic review and meta-analysis to determine the prognostic role of ENE in patients with lymph node-positive colorectal cancer. MATERIALS AND METHODS Two independent authors searched PubMed and SCOPUS until 7 January 2015 without language restrictions. Prospective studies reporting data on prognostic parameters in subjects with colorectal cancer, comparing participants with the presence of ENE (ENE+) versus only intranodal extension (ENE-) were eligible. Data were summarized using risk ratios (RRs) for the number of deaths/recurrences and hazard ratios (HRs) together with 95% confidence intervals (CIs) for time-dependent risk related to ENE+, adjusted for potential confounders. RESULTS Thirteen studies including 1336 patients were identified with a median follow-up of 4.7 years. ENE was associated with a higher T stage and tumor grading. In addition, ENE was associated with a significantly increased risk of all-cause mortality (RR = 1.75; 95% CI 1.42-2.16, P < 0.0001, I(2) = 60%; HR = 1.69, 95% CI 1.32-2.17, P < 0.0001, I(2) = 46%) and of recurrence of disease (RR = 2.07, 95% CI 1.65-2.61, P < 0.0001, I(2) = 47%; HR = 2.31, 95% CI 1.54-3.44, P < 0.0001, I(2) = 48%). CONCLUSIONS Based of these results, in colorectal cancer, ENE should be considered from the gross sampling to the pathology report, as well as in future oncologic staging systems.

Targeted DNA Sequencing Reveals Patterns of Local Progression in the Pancreatic Remnant Following Resection of Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas

Objective: The aim of this study was to characterize patterns of local progression following resection for pancreatic intraductal papillary mucinous neoplasms (IPMN) using targeted next-generation sequencing (NGS). Background: Progression of neoplastic disease in the remnant pancreas following resection of IPMN may include development of a new IPMN or ductal adenocarcinoma (PDAC). However, it is not clear whether this progression represents recurrence of the same neoplasm or an independent second neoplasm. Methods: Targeted-NGS on genes commonly mutated in IPMN and PDAC was performed on tumors from (1) 13 patients who developed disease progression in the remnant pancreas following resection of IPMN; and (2) 10 patients who underwent a resection for PDAC and had a concomitant IPMN. Mutations in the tumors were compared in order to determine the relationship between neoplasms. In parallel, clinical and pathological characteristics of 260 patients who underwent resection of noninvasive IPMN were reviewed to identify risk factors associated with local progression. Results: We identified 3 mechanisms underlying local progression in the remnant pancreas: (1) residual microscopic disease at the resection margin, (2) intraparenchymal spread of neoplastic cells, leading to an anatomically separate but genetically related recurrence, and (3) multifocal disease with genetically distinct lesions. Analysis of the 260 patients with noninvasive IPMNs showed that family history of pancreatic cancer (P = 0.027) and high-grade dysplasia (HGD) (P = 0.003) were independent risk factors for the development of an IPMN with HGD or an invasive carcinoma in the remnant pancreas. Conclusions: Using NGS, we identify distinct mechanisms for development of metachronous or synchronous neoplasms in patients with IPMN. Patients with a primary IPMN with HGD or with positive family history are at an increased risk to develop subsequent high-risk neoplasms in the remnant pancreas.

Different prognostic roles of tumor suppressor gene BAP1 in cancer: A systematic review with meta-analysis

Biallelic inactivation of the tumor suppressor gene BRCA1‐associated protein 1 (BAP1) has been demonstrated in several cancers, but its prognostic role has not been completely explained. We aimed to investigate the risk associated with loss of BAP1 (BAP1‐) for all‐cause mortality, cancer‐specific mortality and recurrence of disease in subjects with cancer. PubMed and SCOPUS were searched from database inception until 09/15/2015 without language restrictions. Prospective studies reporting data on prognostic parameters in subjects with cancer, comparing participants with presence of BAP1 (BAP1+) vs. BAP1‐ were included. Data were summarized using risk ratios (RR) for number of deaths/recurrences and hazard ratios (HR) for time‐dependent risk related to BAP1‐ adjusted for potential confounders. From 261 hits, 12 studies (including 13 cohorts) with 3,447 participants (BAP1‐: n = 697; BAP1+: n = 2,750), with a median follow‐up over 60 months, were meta‐analyzed. Compared to BAP1+, BAP1‐ significantly increased all‐cause mortality, cancer‐specific mortality and risk of recurrence in all the tumor types analyzed, except for mesothelioma, in which the presence of BAP1 mutations correlates with a better prognosis. Furthermore, we demonstrated that BAP1 mutated colorectal and renal carcinomas are associated with high‐tumor grading (P < 0.0001), and that BAP1 mutated is more common in women than in men (P < 0.0001). In conclusion, on the basis of our meta‐analysis, we have demonstrated a peculiar role of BAP1 in influencing the prognosis in cancer. Thus, BAP1 could be considered as an important potential target for personalized medicine.

Different prognostic roles of tumor suppressor gene BAP1 in cancer

Biallelic inactivation of the tumor suppressor gene BRCA1‐associated protein 1 (BAP1) has been demonstrated in several cancers, but its prognostic role has not been completely explained. We aimed to investigate the risk associated with loss of BAP1 (BAP1‐) for all‐cause mortality, cancer‐specific mortality and recurrence of disease in subjects with cancer. PubMed and SCOPUS were searched from database inception until 09/15/2015 without language restrictions. Prospective studies reporting data on prognostic parameters in subjects with cancer, comparing participants with presence of BAP1 (BAP1+) vs. BAP1‐ were included. Data were summarized using risk ratios (RR) for number of deaths/recurrences and hazard ratios (HR) for time‐dependent risk related to BAP1‐ adjusted for potential confounders. From 261 hits, 12 studies (including 13 cohorts) with 3,447 participants (BAP1‐: n = 697; BAP1+: n = 2,750), with a median follow‐up over 60 months, were meta‐analyzed. Compared to BAP1+, BAP1‐ significantly increased all‐cause mortality, cancer‐specific mortality and risk of recurrence in all the tumor types analyzed, except for mesothelioma, in which the presence of BAP1 mutations correlates with a better prognosis. Furthermore, we demonstrated that BAP1 mutated colorectal and renal carcinomas are associated with high‐tumor grading (P < 0.0001), and that BAP1 mutated is more common in women than in men (P < 0.0001). In conclusion, on the basis of our meta‐analysis, we have demonstrated a peculiar role of BAP1 in influencing the prognosis in cancer. Thus, BAP1 could be considered as an important potential target for personalized medicine.

Extranodal extension in N1-adenocarcinoma of the pancreas and papilla of Vater: a systematic review and meta-analysis of its prognostic significance.

The aim of the study was to investigate the prognostic role of extranodal extension (ENE) of lymph node metastasis in adenocarcinoma of the pancreas (PDAC) and papilla [cancer of the papilla of Vater (CPV)]. A PubMed and SCOPUS search from database inception until 5 January 2015 without language restrictions was conducted. Eligible were prospective studies reporting data on prognostic parameters in individuals with PDAC and/or CPV, comparing participants with the presence of ENE (ENE+) with those with intranodal extension (ENE−). Data were summarized using risk ratios for number of deaths/recurrences and hazard ratios for time-dependent risk related to ENE+, adjusted for potential confounders. ENE was found to be very common in these tumors (up to about 60% in both N1-PDAC and CPV), leading to a significant increased risk for all-cause mortality [risk ratio=1.20; 95% confidence interval (CI): 1.06–1.35, P=0.003, I2=44%; hazard ratio=1.415, 95% CI: 1.215–1.650, P<0.0001, I2=0%] and recurrence of disease (risk ratio=1.20, 95% CI: 1.03–1.40, P=0.02, I2=0%). On the basis of our results, in PDAC and CPV, ENE should be considered mandatorily from the gross sampling and pathology report to the oncologic staging and therapeutic approach.

Extranodal extension is an important prognostic parameter for both colonic and rectal cancer

We thank Qin and Huang [1] for their positive comments on our recent meta-analysis [2], in which we assessed the potential relationship between extranodal extension (ENE) of nodal metastasis and prognostic indexes in colorectal cancer. We found consistent evidence that ENE is associated with mortality and recurrence of disease, across multiple sensitivity analyses [2], which remained robust after adjustment for publication bias. Moreover, we conducted meta-regression analyses to explain the low-moderate heterogeneity we encountered (see supplementary Table S8, available at Annals of Oncology online) in line with best practice. Nonetheless, Qin and Huang [1] have proposed two new subgroup analyses using the same database on geographical location (Europe versus Japan) and site of tumor (colon, rectum, both colon and rectum cancer) to test the robustness of our results. Qin and Huang replicated all of our findings, except from the all-cause mortality in colon cancer [hazard ratio (HR) 1.396, 0.848–2.3] and colon and rectum cancer together (HR 1.513, 0.968–2.365). Although these additional analyses are of potential interest, we respectfully share a number of limitations. First, our initial analyses had low-moderate heterogeneity and our meta-regression analyses already significantly explained large portions of the heterogeneity we encountered. Second, Qin and Huang did not report any heterogeneity metric in their new analyses, so it is unclear to what extent their additional analyses addressed their own primary concern that our paper found low-moderate heterogeneity. Third, Qin and Huang included a limited number of studies in each subgroup (only five studies reported HR estimates: two studies for colon, two for rectum and one regarding colorectal cancer). Indeed, they only included 5 studies out of the 13 considered in our meta-analysis, thus type II error might be a factor in their null findings. Moreover, the P for the interaction for this subgroup analysis is 0.229, suggesting that this factor is not a probable moderator of our findings. Notably, the staging system does not separately consider colon and rectum cancer [2], further justifying our approach. Moreover, the meso-rectal adipose tissue, the main anatomical difference between a surgical specimen of colonic and of rectal cancer, contains very few lymph nodes: also from this point of view (i.e. number of lymph nodes and possible metastasis) colonic and rectal cancer can be studied together. Interestingly, the morphologic aspect most similar to ENE, that is represented by the free tumor deposits in adipose tissue (N1c category), is already considered in TNM staging system for both rectal and colonic cancer. Lastly, in other cancer types ENE appeared as a significant prognostic index [3, 4], and also of importance independently from specific anatomical subdistinction (e.g. carcinoma of pancreas versus of ampulla of Vater) [5]. In conclusion, we partly agree with the analyses of Qin and Huang and are grateful that they echo our calls for further research considering the prognostic role of ENE in colorectal cancer. However, we have a number of potential concerns that do not shift our stance, based on the data, that future research should consider colon and rectum cancer as only one entity.

Extranodal extension of lymph node metastasis is a marker of poor prognosis in oesophageal cancer: a systematic review with meta-analysis

The extranodal extension (ENE) of nodal metastasis is the extension of neoplastic cells through the nodal capsule into the perinodal adipose tissue. This histological feature has recently been indicated as an important prognostic factor in different types of malignancies; in this manuscript, we aim at defining its role in the prognosis of oesophageal cancer with the tool of meta-analysis. Two independent authors searched SCOPUS and PubMed until 31 August 2015 without language restrictions. The studies with available data about prognostic parameters in subjects with oesophageal cancer, comparing patients with the presence of ENE (ENE+) versus only intranodal extension (ENE−), were considered as eligible. Data were summarised using risk ratios (RRs) for number of deaths/recurrences and HRs together with 95% CIs for time-dependent risk related to ENE+, adjusted for potential confounders. Fourteen studies were selected; they followed-up 1437 patients with oesophageal cancer for a median follow-up of 39.4 months. The presence of ENE was associated with a significantly increased risk of all-cause mortality (RR=1.33; 95% CI 1.18 to 1.50, p<0.0001, I2=49%; HR=2.72, 95% CI 2.03 to 3.64, p<0.0001, I2=0%), cancer-specific mortality (RR=1.35; 95% CI 1.14 to 1.59, p=0.001, I2=57%; HR=1.97, 95% CI 1.41 to 2.75, p<0.0001, I2=41%) and of risk of recurrence (RR=1.50, 95% CI 1.20 to 1.88, p<0.0001, I2=9%; HR=2.27, 95% CI 1.72 to 2.90, p<0.0001, I2=0%). On the basis of these results, in oesophageal cancer, ENE should be considered from the gross sampling to the pathology report, and in future oncological staging system.

Significance of the prognostic stratification of extranodal extension in colorectal cancer

We have to thank Huang and Yang for their very interesting letter [1], in which they comment a recent meta-analysis of our group of research [2], as well as a subsequent letter on the same topic [3]. We recognize as important points those highlighted by Huang et al., particularly when they pointed out that colon and rectal cancer are different in anatomic site, embryological origin, function and also in metastatic patterns. At the same time, we still consider of value the results of our manuscript, in which we present the analysis on the prognostic value of extranodal extension (ENE) of nodal metastasis considering colon and rectal cancer as one entity only. Notably, we have also presented the hazard ratios of a significant number of studies and, in the subsequent letter, we have indicated that the location has not been recognized as a probable moderator of our findings (P = 0.229). The approach to consider colon and rectal cancer together was further justified by the fact that the staging systems do not consider separately such neoplasms. Notably, the prognostic role of ENE has been shown in diverse other cancer types [4, 5] and its importance independently from specific anatomic subdistinctions is further suggested by the case of carcinoma of pancreas versus that of papilla of Vater [5]. In our meta-analysis and in our letter, we address the prognostic impact of ENE in both colon and rectal cancers, but without suggesting a unique staging system for these two neoplasms. Indeed, we recognize that the current TNM staging system needs improvements, and the inclusion of ENE might be one of these.

IPMNs with co-occurring invasive cancers: neighbours but not always relatives

Objective Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions that can give rise to invasive pancreatic carcinoma. Although approximately 8% of patients with resected pancreatic ductal adenocarcinoma have a co-occurring IPMN, the precise genetic relationship between these two lesions has not been systematically investigated. Design We analysed all available patients with co-occurring IPMN and invasive intrapancreatic carcinoma over a 10-year period at a single institution. For each patient, we separately isolated DNA from the carcinoma, adjacent IPMN and distant IPMN and performed targeted next generation sequencing of a panel of pancreatic cancer driver genes. We then used the identified mutations to infer the relatedness of the IPMN and co-occurring invasive carcinoma in each patient. Results We analysed co-occurring IPMN and invasive carcinoma from 61 patients with IPMN/ductal adenocarcinoma as well as 13 patients with IPMN/colloid carcinoma and 7 patients with IPMN/carcinoma of the ampullary region. Of the patients with co-occurring IPMN and ductal adenocarcinoma, 51% were likely related. Surprisingly, 18% of co-occurring IPMN and ductal adenocarcinomas were likely independent, suggesting that the carcinoma arose from an independent precursor. By contrast, all colloid carcinomas were likely related to their associated IPMNs. In addition, these analyses showed striking genetic heterogeneity in IPMNs, even with respect to well-characterised driver genes. Conclusion This study demonstrates a higher prevalence of likely independent co-occurring IPMN and ductal adenocarcinoma than previously appreciated. These findings have important implications for molecular risk stratification of patients with IPMN.