The Current PBPath Journal Watch Articles

Wellcome to the PBPath Journal Watch!

This bi-monthly journal watch features exciting recently published pancreas and biliary pathology articles that will provide up to date medical knowledge in our field. These articles will be showcased in several convenient categories, including surgical pathology, molecular pathology and cytopathology among others. The articles in each category are in no particular order.

Previous months’ issues may be found in our archive.

We encourage members to actively participate by recommending new articles and providing feedback using the forms provided.

We hope that you will enjoy the new PBPath Journal Watch!

Surgical Pathology


Morphology, Diagnostics, IHC

- Comparison of Tumor Regression Grading of Residual Pancreatic Ductal Adenocarcinoma Following Neoadjuvant Chemotherapy Without Radiation: Would Fewer Tier-Stratification Be Favorable Toward Standardization?

The American journal of surgical pathology 2018 Sep;():

To assess whether the College of American Pathologists (CAP) and the Evans grading systems for neoadjuvant chemotherapy without radiation-treated pancreatectomy specimens are prognostic, and if a 3-tier stratification scheme preserves data granularity. Conducted retrospective review of 32 patients with ordinary pancreatic ductal adenocarcinoma treated with neoadjuvant therapy without radiation followed by surgical resection. Final pathologic tumor category (AJCC eighth edition) was 46.9% ypT1, 34.4% ypT2, and 18.7% ypT3. Median follow-up time was 29.8 months, median disease-free survival (DFS) was 19.6 months, and median overall survival (OS) was 34.2 months. CAP score 1, 2, 3 were present in 5 (15.6%), 18 (56.3%), and 9 (28.1%) patients, respectively. Evans grade III, IIb, IIa, and I were present in 10 (31.2%), 8 (25.0%), 7 (21.9%), and 7 (21.9%) patients, respectively. OS (CAP: P=0.005; Evans: P=0.001) and DFS (CAP: P=0.003; Evans: P=0.04) were statistically significant for both CAP and Evans. Stratified CAP scores 1 and 2 versus CAP score 3 was statistically significant for both OS (P=0.002) and DFS (P=0.002). Stratified Evans grades I, IIa, and IIb versus Evans grade III was statistically significant for both OS (P=0.04) and DFS (P=0.02). CAP, Evans, and 3-tier stratification are prognostic of OS and DFS.


- Residual Tumor Index: A Prognostically Significant Pathologic Parameter in Neoadjuvant-treated Pancreatic Ductal Adenocarcinoma

The American journal of surgical pathology 2018 Nov;42(11):1480-1487

In the setting of neoadjuvant therapy (NAT) for pancreatic ductual adenocarcinoma (PDAC), accurate measurement of tumor size, and consequently, staging based on AJCC eighth edition, is difficult. Attempts to address the limitations of tumor size in the NAT setting have included correlation of residual tumor percent with survival. However, only cases with complete pathologic response or minimal residual disease have shown better prognosis compared with all other groups. To date, no studies have simultaneously evaluated the prognostic value of tumor size and tumor regression in the setting of PDAC status post NAT (NAT-PDAC). Our aim was to study the prognostic value of residual tumor index (RTI), a metric combining residual tumor percent and tumor bed size as an interaction term (% residual tumor×tumor bed size [cm]). In a cohort of 105 cases of NAT-PDAC, we show that RTI supersedes the prognostic value of AJCC eighth edition T staging via multivariate cox regression. At a binary cutoff of 0.35 for RTI, the hazard ratio for recurrence-free survival is 3.26 (95% confidence interval, 1.51-7.04), P<0.01. We further identified cutoffs of ≤0.2, 0.2 to 2 and >2 that stratified our cases into 3 groups via RTI, which were statistically significant in Kaplan-Meier curve analysis of recurrence-free survival (P<0.01) and overall survival (P<0.01). RTI represents a novel metric for combining the prognostic value of tumor size and residual tumor in NAT-PDAC.


- Significance of microcystic, elongated, and fragmented glandular-like features in intraductal papillary mucinous neoplasm of the pancreas

Human pathology 2018 Aug;78():18-27

Microcystic, elongated, and fragmented (MELF) glandular features are associated with epithelial-mesenchymal transition, invasion, and progression in endometrioid adenocarcinoma of the uterus. Similar histological features are also observed at the periphery of pancreatic intraductal papillary mucinous neoplasms (IPMNs). However, the clinicopathological significance of MELF-like features-particularly whether they represent regenerative or truly neoplastic conditions-in IPMNs remains unclear. We assessed a total of 152 surgically resected IPMNs. Fifty cases exhibited MELF-like features, including 26 cases of IPMNs with accompanying adenocarcinomas and 24 cases of IPMNs without accompanying adenocarcinomas. MELF-like features were more frequently observed in IPMN cases with accompanying adenocarcinomas, larger tumors, main-duct type, and non-gastric histologic subtype. A positive correlation between the presence of MELF-like features and high-grade dysplasia was observed in IPMNs without accompanying adenocarcinomas. Moreover, DPC4 loss and p53 overexpression in MELF-like glands were more commonly observed in IPMNs with high-grade dysplasia. IPMN patients with MELF-like features had worse overall and disease-specific survival by univariate analyses. Our observations suggest that MELF-like features in some IPMNs with high-grade dysplasia could be related to stromal invasion. Hence, when MELF-like features are observed in IPMNs, pathologists should carefully evaluate the results of microscopic examinations to identify the invasive components; and, immunohistochemical staining for DPC4 and p53 could help clarify its clinicopathological significance.


- Tumor-Infiltrating Platelets Predict Postsurgical Survival in Patients with Pancreatic Ductal Adenocarcinoma

Annals of surgical oncology 2018 Aug;():

BACKGROUND: Platelets are believed to promote tumor growth and metastasis in several tumor types. The prognostic role of blood platelets in pancreatic ductal adenocarcinoma (PDAC) remains controversial, and the prognostic value of tumor-infiltrating platelets (TIPs) remains unknown. METHODS: A total of 303 patients who underwent curative pancreatectomy for PDAC were enrolled from two independent centers in China and divided into three cohorts. Paired preoperative blood samples and surgical specimens from all patients were analyzed. The correlations between patient outcomes and preoperative blood platelet counts and the presence of TIPs, respectively, were analyzed. TIPs were identified by immunohistochemical staining of CD42b. Prognostic accuracy was estimated by concordance index (C-index) and Akaike information criterion (AIC). RESULTS: TIPs, but not preoperative blood platelet counts, were associated with overall survival (OS; all P < 0.001) and recurrence-free survival (RFS; all P < 0.001) in the training, testing, and validation sets. Positive CD42b expression predicted poor postsurgical survival. Incorporation of TIPs improved the predictive accuracy of the 8th edition American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system for OS in each of the three cohorts (C-index: 0.7164, 0.7569, and 0.7050, respectively; AIC: 472, 386, and 1019, respectively). The new predictor system was validated by incorporating TIPs with the 7th edition AJCC TNM staging system (C-index: 0.7052, 0.7623, and 0.7157; AIC: 476, 386, and 1015). CONCLUSION: TIPs were an independent prognostic factor that could be incorporated into the AJCC TNM staging system to refine risk stratification and predict surgical outcomes of patients with PDAC.


- Ki67 and P53 in Relation to Disease Progression in Metastatic Pancreatic Cancer: a Single Institution Analysis

Pathology oncology research : POR 2018 Sep;():

We investigated the expression patterns of Ki67 and p53 in metastatic pancreatic adenocarcinomas and analyzed their relationship with disease progression-free survival (PFS) and overall survival (OS) in the overall study population and in patients treated with a gemcitabine-containing chemotherapy versus FOLFIRINOX chemotherapy. Patients with histologically confirmed stage IV adenocarcinoma of the pancreas treated at AUBMC were included after obtaining institutional review board approval (IRB ID: IM.ST.05). The ROC was plotted to identify the threshold Ki-67, p53 and CA19-9 value for disease progression, the identified value was further used in Kaplan Meier curves to compare PFS for both groups (gemcitabine versus FOLFIRINOX). A value of p < 0.05 was considered significant in all analyses. On univariate analysis, patients who had a Ki-67 > 12.5% or a p53 > 15% had significantly shorter PFS (p = 0.034 and p = 0.016, respectively). This effect was restricted to Gemcitabine or gemcitabine-combination treated patients. A decrease in CA19-9 levels 6-8 weeks after chemotherapy of >58% had significantly longer PFS (p = 0.027). On multivariate analysis after controlling for grade, age and P53, Ki-67 remained significant, for every one unit increase in Ki-67 the progression risk increases by 1.017 times. Our study highlights the negative impact of high P53 expression and Ki67 proliferation index on PFS in patients with metastatic pancreatic cancer.


- Overexpression of S100A4 protein may be associated with the development and progression of pancreatic cancer

Journal of cancer research and therapeutics 2018 ;14(Supplement):S159-S166

Aim: Accumulated evidence has suggested a relationship between S100A4 protein expression and the development and progression of pancreatic cancer (PC) while its role in diagnosis and prognosis of PC still keeps inconsistent. To obtain definitive associations between S100A4 and PC, a meta-analysis was conducted. Materials and Methods: The PubMed and Chinese National Knowledge Infrastructure databases were electronically searched to identify studies reporting an association between S100A4 protein and PC. Statistical analyses were undergone with the utilization of STATA version 12.0 software. Results: Nine clinical studies with a total of 545 tumor samples were included in the meta-analysis. Results revealed that increased S100A4 expression were associated with the tumor-node-metastasis stages of PC (III-IV vs. I-II: odds ratio [OR] =5.50, 95% confidence interval [95% CI] =3.13-9.67, P < 0.001). Also, compared with 1-2 histologic grade of PC samples, S100A4 protein was expressed more frequently in samples with 3-4 histologic grade (grades 1-2 vs. grades 3-4: OR = 2.57, 95% CI = 1.05-6.24, P = 0.038). Conclusion: This meta-analysis showed that overexpression of S100A4 seems to be associated with tumor progression and poor prognosis of PC patients.


- Prognostic stratification of resected pancreatic ductal adenocarcinoma: Past, present, and future

Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2018 Oct;50(10):979-990


Pancreatic ductal adenocarcinoma (PDAC) is the digestive cancer with the poorest prognosis, with a 5-year overall survival rate of 7%. Complete surgical resection followed by adjuvant chemotherapy is the only treatment with curative intent. However, many patients with an apparently localized disease who may undergo primary tumor resection already have micro-metastatic disease and will promptly develop metastases. Considering the significant rate of morbidity and mortality upon pancreatic surgery, the pre-operative identification of patients with an aggressive disease is therefore a major clinical issue. Although tumor size, differentiation, margins, and lymph node invasion are the main “classical” prognostic factors, they are not sufficient to fully predict early disease recurrence. In the last decade, multi-omics high-throughput analyses have provided a new insight into PDAC biology and have led to the description of multiple molecular subtypes, with a significant prognostic value for most of them, but that have not yet been transposed to routine clinical practice, mainly due to poor availability of tumor tissue material prior to surgical resection. In this review, we provide an overview of the current status of clinico-pathological and molecular biomarkers (tumor and blood) to predict early recurrence, and their implications for clinical practice and future research development.

- Pancreatic cancer: French clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, AFC)

Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2018 Aug;():


BACKGROUND: This document is a summary of the French intergroup guidelines regarding the management of pancreatic adenocarcinoma (PA), updated in July 2018. DESIGN: This collaborative work was produced under the auspices of all French medical and surgical societies involved in the management of PA. It is based on the previous guidelines, recent literature review and expert opinions. Recommendations were graded in three categories, according to the level of evidence. RESULTS: Over the last seven years, significant changes in PA management have been implemented in clinical practice. Imaging/staging: diffusion magnetic resonance imaging is useful before surgery to rule out small liver metastases. SURGERY: centralization of pancreatic surgery in expert centers is associated with a decreased postoperative mortality. Adjuvant chemotherapy: modified FOLFIRINOX in fit patients, or gemcitabine, or 5-FU, or gemcitabine plus capecitabine, to be discussed on a case-by-case basis. Locally advanced PA: no survival benefit of chemoradiotherapy. Metastatic PA: FOLFIRINOX and gemcitabine plus nab-paclitaxel combination are first-line standards in fit patients; second-line with 5FU/nal-IRI or 5FU/oxaliplatin combination after first-line gemcitabine. CONCLUSION: Guidelines for management of PA are continuously evolving and need to be regularly updated. This constant progress is made possible through clinical and translational research. However, as each individual case is particular, they cannot substitute to multidisciplinary tumor board discussion.

- Associations between autoimmune conditions and hepatobiliary cancer risk among elderly US adults

International journal of cancer 2018 Aug;():

Growing evidence suggests that people with autoimmune conditions may be at increased risk of hepatobiliary tumors. In the present study, we evaluated associations between autoimmune conditions and hepatobiliary cancers among adults aged ≥66 in the United States. We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data (1992-2013) to conduct a population-based, case-control study. Cases (n=32,443) had primary hepatobiliary cancer. Controls (n=200,000) were randomly selected, cancer-free adults frequency-matched to cases by sex, age, and year of selection. Using multivariate logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) for associations with 39 autoimmune conditions identified via Medicare claims. We also conducted separate analyses for diagnoses obtained via inpatient versus outpatient claims. Sixteen conditions were associated with at least one hepatobiliary cancer. The strongest risk estimates were for primary biliary cholangitis with hepatocellular carcinoma (OR: 31.33 [95% CI: 23.63-41.56]) and primary sclerosing cholangitis with intrahepatic cholangiocarcinoma (7.53 [5.73-10.57]), extrahepatic cholangiocarcinoma (5.59 [4.03-7.75]), gallbladder cancer (2.06 [1.27-3.33]), and ampulla of Vater cancer (6.29 [4.29-9.22]). Associations with hepatobiliary-related conditions as a group were observed across nearly all cancer sites (ORs ranging from 4.53 [95% CI: 3.30-6.21] for extrahepatic cholangiocarcinoma to 7.18 [5.94-8.67] for hepatocellular carcinoma). Restricting to autoimmune conditions diagnosed via inpatient claims, 6 conditions remained associated with at least one hepatobiliary cancer, and several risk estimates increased. In the outpatient restricted analysis, 12 conditions remained associated. Multiple autoimmune conditions are associated with hepatobiliary cancer risk in the US Medicare population, supporting a shared immuno-inflammatory etiology to these cancers. This article is protected by copyright. All rights reserved.


- Comparative outcomes of adenosquamous carcinoma of the pancreas: An analysis of the National Cancer Database

Journal of surgical oncology 2018 Jul;118(1):21-30


BACKGROUND: A paucity of data exists regarding the natural history and outcome measures of adenosquamous carcinoma of the pancreas (ASCP), a histology distinct from pancreatic adenocarcinoma (PDAC). The aim of this study is to characterize the clinicopathological features of ASCP in a large cohort of patients comparing outcome measures of surgically resected patients to PDAC. METHODS: We identified patients diagnosed with ASCP or PDAC from the National Cancer Database from 2004 to 2012. Patient demographics, tumor characteristics, treatment regimens, and overall survival were analyzed between the groups. RESULTS: We identified 207 073 patients: 205 328 (99%) in the PDAC group and 1745 (1%) in the ASCP group. ASCP tumors were larger, located more frequently in a body/tail location (36% vs 24%, P < 0.001), undifferentiated/anaplastic histology (41% vs 17%, P < 0.001), and early stage presentation, (39% vs 32%, P < 0.001). There was no significant difference in OS when comparing all patients with PDAC and ASCP (6.2 months and 5.7 months, P = 0.601). In surgical patients ASCP histology was associated with worse OS (14.8 months vs 20.5 months, P < 0.001) but had lower nodal involvement (55% vs 61%, P < 0.001). ASCP histology was independently associated with worse OS, after adjusting for tumor characteristics, treatment, and patient demographics. In patients with only resected ASCP histology, negative lymph node status, R0 surgical resection, and receipt of chemotherapy was independently associated with improved overall survival following surgical resection. CONCLUSION: Although patients with ASCP and PDAC tumors have similar survival when non-surgical and surgical patients are combined, ASCP is associated with worse survival in stage I/II resected patients.

- Well differentiated liposarcoma, sclerosing type, of the pancreas a case report

Experimental and molecular pathology 2016 12;101(3):320-322


- Clinical Features and Prognosis of Patients With the Bone Metastasis of Pancreatic Cancer: A Single-Institutional Cohort Study

Pancreas 2018 Aug;47(7):e43-e46


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Pancreas TNM staging, Margins, Survival

- Proposal of a modified American Joint Committee on Cancer staging scheme for resectable pancreatic ductal adenocarcinoma with a lymph node ratio-based N classification: A retrospective cohort study

Medicine 2018 Aug;97(34):e12094

The recently launched 8th edition of the American Joint Committee on Cancer (AJCC) staging scheme for pancreatic ductal adenocarcinoma (PDAC) did not account for the impact of the total examined lymph node count on prognostic accuracy. In this population-based cohort study, we proposed a modified AJCC staging scheme by incorporating a lymph node ratio (LNR)-based N classification for patients with resectable PDAC.We analyzed 8615 patients with resectable PDAC from the Surveillance, Epidemiology, and End Results database between 2004 and 2013. The optimal cut-off points for LNR were identified by recursive partitioning, and an LNR-based N classification was designed accordingly.The LNR-based N classification could further stratify patients with the 8th AJCC N1 and N2 disease into subgroups with significantly different overall survival (P < .001 for both). By replacing the 8th AJCC N classification with the corresponding LNR-based N classification, we further proposed a modified AJCC staging scheme. The modified AJCC staging outperformed the 8th AJCC staging in terms of the discriminatory capacity measured by the concordance index and Akaike information criterion, and the prognostic homogeneity assessed by using the likelihood ratio chi-squared test and stratified survival analysis.Replacing the 8th AJCC N classification with the LNR-based N classification can improve the prognostic performance of the 8th AJCC staging scheme for PDAC.


- Tumor grade as significant prognostic factor in pancreatic cancer: validation of a novel TNMG staging system

Neoplasma 2018 ;65(4):637-643

Aim of the study was to asses the tumor grade prognostic value in the Czech pancreatic cancer patients and to evaluate the accuracy of TNMG prognostic model. Retrospective analysis of 431 pancreatic cancer patients undergoing pancreatic resection in seven Czech oncological centers between 2003 and 2013 was performed. The impact of tumor grade and the accuracy of TNMG prognostic model were evaluated. Lymph node status, tumor size, tumor stage and grade were proved as statistically significant survival predictors. The lower tumor differentiation (grade 3 and 4) was associated with poorer prognosis in all stages (stage I: HR 2.23 [1.14; 4.36, CI 95%] p=0.019, stage II: HR 3.09 [2.01; 4.77, CI 95%] p=0.001, stage III and IV: HR 3.52 [1.73; 7.18, CI 95%] p=0.001). Kaplan-Meier analysis verified statistically significant impact of new TNMG stages on survival after resection for pancreatic cancer (p=0.001). In conclusion, we can state that the tumor grade was confirmed as statistically significant prognostic factor in pancreatic cancer. Its incorporation into the current TNM classification enables more accurate prognosis prediction within particular clinical stages. That is why an inclusion of the grade to the standard TNM classification should be discussed.


- The “T” now Matters: The Eighth Edition of the Union for International Cancer Control Classification of Pancreatic Adenocarcinoma

Annals of surgery 2018 Aug;268(2):e36-e37