Pancreatoduodenectomy Specimens Research Articles

The radiological morphology of mesopancreas: A new variable to predict a positive vascular margin after pancreatoduodenectomy for pancreatic ductal adenocarcinoma?

615 Background: The most frequently invaded surgical margins on pancreatoduodenectomy (PD) specimens of pancreatic ductal adenocarcinoma (PDAC) are vascular margins, especially the superior mesenteric artery (SMA), also called mesopancreatic margin. Considering embryology, it may be hypothesized that PDAC cells tend to infiltrate the retroperitoneum through the contents of mesopancreas, justifying the frequent SMA positive margin. Because the radiological aspect of mesopancreas has been poorly studied, the aim of this original research was to assess the mesopancreatic infiltration on diagnostic imaging, corroborate with the corresponding margin pathology and evaluate the impact on survival in PDAC patients who underwent PD. Methods: From 2015 to 2021, all patients who underwent PD for PDAC with curative intent were reviewed, excluding patients lost to follow-up, who died postoperatively or within the first year for non-oncological reason, and those with unavailable preoperative imaging. Surgical margins of pathological specimens were reassessed. Blinded reviewing of preoperative radiographic images was conducted. According to qualitative assessment, the mesopancreas tissue was defined as normal fat (NF), fat stranding (FS) or solid infiltration (SI). Results: 133 patients were included in the study, including 51 (38%) who received neoadjuvant therapy. The tumor location was into the head or the uncinate process in 54% and 46%, respectively. At diagnosis, PDAC were classified as resectable (51%), borderline resectable (28%) and locally advanced (9%) according to the NCCN classification. FS or SI in the mesopancreas was present in 45 (34%) and 18 (14%) patients, respectively. Tumor size on imaging, tumor location, chronic obstructive pancreatitis, vascular contacts and NCCN resectability status were predictive factors of mesopancreas infiltration (p<0.001). Median overall and disease-free survivals were significantly lower in case of SI compared to NF and FS in the mesopancreas. When comparing patients with mesopancreatic FS at diagnosis who received neoadjuvant therapy (n=20) to those who underwent upfront surgery (n=25), no significant impact was observed in survivals. R0 resection was obtained in 36%; in all patients with R1 resection, a vascular margin was involved. Tumor size at pathology, SMA margin and resection status were factors that were significantly influenced by the radiological infiltration of the mesopancreas. Conclusions: The SI of mesopancreas on diagnostic imaging was associated with a poor prognosis, but not FS, in patients who underwent PD for PDAC. SMA margin and resection status were correlated with the radiological texture of the mesopancreas, which suggests to further explore underlying mechanisms related to tumoral invasion of vascular margin and mesopancreas.

Tumour origin, diagnostic accuracy and histopathological evaluation in patients with periampullary cancer: nationwide cohort study.

The prevalence of different periampullary cancers (pancreatic ductal adenocarcinoma, distal cholangiocarcinoma, ampullary cancer and duodenal cancer) is heterogeneous in the literature. During the 2010s, a standardized histopathological protocol for pancreatoduodenectomy specimens based on axial slicing was adopted in Sweden. The present study sought to provide information about periampullary cancers with regard to tumour types in curative and noncurative settings, preoperative diagnostic accuracy and the impact of a standardized evaluation of the surgical specimen on diagnosis, R status and lymph node assessment. Data from patients diagnosed with periampullary cancer from 2010 to 2019 were retrieved from the Swedish National Registry for Pancreatic and Periampullary Cancer. Among non-curative patients, 3704 (83.6 per cent) were diagnosed with pancreatic ductal adenocarcinoma. Among patients treated with pancreatoduodenectomy, diagnosis was pancreatic ductal adenocarcinoma in 1380 (50.0 per cent), distal cholangiocarcinoma in 284 (10.3 per cent), ampullary cancer in 376 (13.6 per cent), duodenal cancer in 160 (5.8 per cent) and other diagnoses in 560 (20.3 per cent) patients. The preoperative diagnosis corresponded to the postoperative in 1177 (67.5 per cent) patients for pancreatic ductal adenocarcinoma, 162 (37.4 per cent) patients for distal cholangiocarcinoma, 220 (61.3 per cent) patients for ampullary cancer and 120 (53.6 per cent) patients for duodenal cancer. A higher rate of pancreatic ductal adenocarcinoma was seen in surgical specimens who underwent standardized evaluation, from 56.8 per cent to 64.3 per cent (P = 0.003). After standardization, higher rates of R1 resection (31.7 per cent versus 44.6 per cent, P < 0.001) and N1 stage (62.1 per cent versus 77.0 per cent, P < 0.001) were found. The proportion of pancreatic ductal adenocarcinoma was higher in patients in a non-curative setting compared with patients who underwent surgery. The rate of misdiagnosis for periampullary cancers was confirmed to be high. Thus, it should be taken into account when preoperative oncological treatment is considered. Standardized evaluation of the surgical specimen has increased pancreatic ductal adenocarcinoma, R1 and N1 rates.

Risk of Pancreatic Cancer Recurrence after Surface/Margin Involvement on Pancreatoduodenectomy Specimens: Implications for Surgical Radicality

Risk of Pancreatic Cancer Recurrence after Surface/Margin Involvement on Pancreatoduodenectomy Specimens: Implications for Surgical Radicality

The Role of Pathological Method and Clearance Definition for the Evaluation of Margin Status after Pancreatoduodenectomy for Periampullary Cancer. Results of a Multicenter Prospective Randomized Trial.

Simple SummaryThere is no clear evidence on the most effective method of pathological analysis and clearance definition (0 vs. 1 mm) to define R1 resection after pancreatoduodenectomy (PD). However, several studies showed that the R1 resection is a poor prognostic factor in patients that have undergone PDs for periampullary cancers. In this randomized clinical trial, specimens were randomized with two pathological methods, the Leeds Pathology Protocol (LEEPP) or the conventional method adopted before the study. The 1 mm clearance is the most effective factor in determining R1 rate after PD but only when adopting the LEEP, the R1 resection represents a significant prognostic factor.Background: There is extreme heterogeneity in the available literature on the determination of R1 resection rate after pancreatoduodenectomy (PD); consequently, its prognostic role is still debated. The aims of this multicenter randomized study were to evaluate the effect of sampling and clearance definition in determining R1 rate after PD for periampullary cancer and to assess the prognostic role of R1 resection. Methods: PD specimens were randomized to Leeds Pathology Protocol (LEEPP) (group A) or the conventional method adopted before the study (group B). R1 rate was determined by adopting 0- and 1-mm clearance; the association between R1, local recurrence (LR) and overall survival (OS) was also evaluated. Results. One-hundred-sixty-eight PD specimens were included. With 0 mm clearance, R1 rate was 26.2% and 20.2% for groups A and B, respectively; with 1 mm, R1 rate was 60.7% and 57.1%, respectively (p > 0.05). Only in group A was R1 found to be a significant prognostic factor: at 0 mm, median OS was 36 and 20 months for R0 and R1, respectively, while at 1 mm, median OS was not reached and 30 months. At multivariate analysis, R1 resection was found to be a significant prognostic factor independent of clearance definition only in the case of the adoption of LEEPP. Conclusions. The 1 mm clearance is the most effective factor in determining the R1 rate after PD. However, the pathological method is crucial to accurately evaluate its prognostic role: only R1 resections obtained with the adoption of LEEPP seem to significantly affect prognosis.

Towards a More Standardized Approach to Pathologic Reporting of Pancreatoduodenectomy Specimens for Pancreatic Ductal Adenocarcinoma: Cross-continental and Cross-specialty Survey From the Pancreatobiliary Pathology Society Grossing Working Group.

In recent literature and international meetings held, it has become clear that there are significant differences regarding the definition of what constitutes as margins and how best to document the pathologic findings in pancreatic ductal adenocarcinoma. To capture the current practice, Pancreatobiliary Pathology Society (PBPS) Grossing Working Group conducted an international multispecialty survey encompassing 25 statements, regarding pathologic examination and reporting of pancreatic ductal adenocarcinoma, particularly in pancreatoduodenectomy specimens. The survey results highlighted several discordances; however, consensus/high concordance was reached for the following: (1) the pancreatic neck margin should be entirely submitted en face, and if tumor on the slide, then it is considered equivalent to R1; (2) uncinate margin should be submitted entirely and perpendicularly sectioned, and tumor distance from the uncinate margin should be reported; (3) all other surfaces (including vascular groove, posterior surface, and anterior surface) should be examined and documented; (4) carcinoma involving separately submitted celiac axis specimen should be staged as pT4. Although no consensus was achieved regarding what constitutes R1 versus R0, most participants agreed that ink on tumor or at and within 1 mm to the tumor is equivalent to R1 only in areas designated as a margin, not surface. In conclusion, this survey raises the awareness of the discordances and serves as a starting point towards further standardization of the pancreatoduodenectomy grossing and reporting protocols.

Axial slicing versus bivalving in the pathological examination of pancreatoduodenectomy specimens (APOLLO): a multicentre randomized controlled trial

BackgroundIn pancreatoduodenectomy specimens, dissection method may affect the assessment of primary tumour origin (i.e. pancreatic, distal bile duct or ampullary adenocarcinoma), which is primarily determined macroscopically. This is the first study to prospectively compare the two commonly used techniques, i.e. axial slicing and bivalving. MethodsIn four centres, a randomized controlled trial was performed in specimens of patients with a suspected (pre)malignant tumour in the pancreatic head. Primary outcome measure was the level of certainty (scale 0–100) regarding tumour origin by four independent gastrointestinal pathologists based on macroscopic assessment. Secondary outcomes were inter-observer agreement and R1 rate. ResultsIn total, 128 pancreatoduodenectomy specimens were randomized. The level of certainty in determining the primary tumour origin did not differ between axial slicing and bivalving (mean score 72 [sd 13] vs. 68 [sd 16], p = 0.21), nor did inter-observer agreement, both being moderate (kappa 0.45 vs. 0.47). In pancreatic cancer specimens, R1 rate (60% vs. 55%, p = 0.71) and the number of harvested lymph nodes (median 16 vs. 17, p = 0.58) were similar. ConclusionThis study demonstrated no differences in determining the tumour origin between axial slicing and bivalving. Both techniques performed similarly regarding inter-observer agreement, R1 rate, and lymph node harvest.

Axial slicing versus bivalving of the pancreatic head in the pathological examination of pancreatoduodenectomy specimens (apollo): A randomized controlled trial

Axial slicing versus bivalving of the pancreatic head in the pathological examination of pancreatoduodenectomy specimens (apollo): A randomized controlled trial

Does the Artery-first Approach Improve the Rate of R0 Resection in Pancreatoduodenectomy?: A Multicenter, Randomized, Controlled Trial.

To compare the rates of R0 resection in pancreatoduodenectomy (PD) for pancreatic and periampullary malignant tumors by means of standard (ST-PD) versus artery-first approach (AFA-PD). Standardized histological examination of PD specimens has shown that most pancreatic resections thought to be R0 resections are R1. "Artery-first approach" is a surgical technique characterized by meticulous dissection of arterial planes and clearing of retropancreatic tissue in an attempt to achieve a higher rate of R0. To date, studies comparing AFA-PD versus ST-PD are retrospective cohort or case-control studies. A multicenter, randomized, controlled trial was conducted in 10 University Hospitals (NCT02803814, ClinicalTrials.gov). Eligible patients were those who presented with pancreatic head adenocarcinoma and periampullary tumors (ampulloma, distal cholangiocarcinoma, duodenal adenocarcinoma). Assignment to each group (ST-PD or AFA-PD) was randomized by blocks and stratified by centers. The primary end-point was the rate of tumor-free resection margins (R0); secondary end-points were postoperative complications and mortality. One hundred seventy-nine patients were assessed for eligibility and 176 randomized. After exclusions, the final analysis included 75 ST-PD and 78 AFA-PD. R0 resection rates were 77.3% (95% CI: 68.4-87.4) with ST-PD and 67.9% (95% CI: 58.3-79.1) with AFA-PD, P=0.194. There were no significant differences in postoperative complication rates, overall 73.3% versus 67.9%, and perioperative mortality 4% versus 6.4%. Despite theoretical oncological advantages associated with AFA-PD and evidence coming from low-level studies, this multicenter, randomized, controlled trial has found no difference neither in R0 resection rates nor in postoperative complications in patients undergoing ST-PD versus AFA-PD for pancreatic head adenocarcinoma and other periampullary tumors.

Histopathological study: a key point in pancreatic cancer

Introduction: R1 resection in pancreatoduodenectomy (PD) is a negative prognostic factor. Development of standardised pathologic protocols increased R1 rate and this can have implications in postoperative treatment strategy. Patients and methods: From 2000 we performed 243 PD. A total of 156 were due to pancreatic ductal adenocarcinoma. In May 2004 a new standardised anatomopathological protocol (SP) was introduced to evaluate resection's specimens (Verbeke Histopathology 2008). R1 was defined as presence of tumour cells at< 1mm from margin resection. Our series was divided in two groups: specimens studied with the old pathological protocol (NSP) with 93 cases) and SP group with72cases. There were no differences demographic data, tumour size, TNM staging, lymphadenectomy and positive lymph nodes. Results: There were no statistical differences in number of R1 pancreatic margins SP 7% vs NSP 3% or in R1 retroperitoneal margins (11% in both groups). More positive vascular margins were identified in SP group 25% vs 4% in NPS, P = 0.001. R1 circumferential margin was higher in SP group 32% vs 10% in NSP group, P = 0.001. 54% of patients in NSP received adjuvant chemotherapy vs 71% in SP group, P < 0.001 and 37% of patients in SP group received radiation as part of the adjuvant treatment vs 20% in NSP, P < 0.001. Survival rates at 2/ 5 years in SP were 91/39% respectively and in NSP group: 71/32% without statistical difference. Conclusions: Standardised pathologic study of PD specimens increased the rate of R1 margins and select patients suitable to more specific postoperative treatments.

Pathologic Evaluation of Surgical Margins in Pancreatic Cancer Specimens Using Color Coding With Tissue Marking Dyes.

Processing of pancreatoduodenectomy specimens is not standardized; the clinical impact of pathologic surgical margins remains controversial. We used the color-coding method using tissue-marking dyes to evaluate margin status of resected specimens to assess its association with postoperative recurrence. We developed a unified processing approach to assess pancreatoduodenectomy specimens. Five surgical margins of resected pancreatic specimens were marked with 5 colors. Microscopic resection margin distance (RMD) from margin closest to the tumor was evaluated for each surgical margin. Forty patients assessed using nonunified protocols, and 98 patients assessed using unified protocols were included. The frequency of tumors with RMD of 1 mm or less in posterior margin was significantly lower and that in portal vein/superior mesenteric vein margin was significantly higher in unified protocol group than in nonunified protocol group (P < 0.001). In unified protocol group, tumors with RMD of 1 mm or less correlated with locoregional recurrence (P = 0.025) and recurrence-free survival (P = 0.030). Multivariate analysis revealed that tumor size and lymph node metastasis were independent indicators for disease recurrence. Resection margin distance of 1 mm or less was a predictor for disease recurrence, particularly for locoregional recurrence. Early detection of small-sized tumors without lymph node metastasis is necessary for improved clinical outcomes in pancreas cancers.

The Role of Fibroblasts in Pancreatic Cancer: Extracellular Matrix Versus Paracrine Factors

BACKGROUND AND AIM: Desmoplasia is a characteristic feature and a suspected mechanism of tumor progression in pancreatic ductal adenocarcinoma (PDAC). Main constituents of the stroma involve cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM). The aim of this study was to dissect the interaction of CAFs, ECM, and PDAC cells in both an in vitro setting and a large-scale clinical cohort study. METHODS AND MATERIAL: Patients operated for PDAC were identified from our prospectively maintained clinical database. A standard pathology protocol was applied for pancreatoduodenectomy specimens also assessing CAF activation as either CAF grade 0 or CAF grade +. Interaction between a spectrum of pancreatic cancer cell lines (PCCs) and mouse embryonic fibroblasts (NIH 3T3) was assessed in a conditioned medium experimental setup. RESULTS: One hundred eleven patients operated for PDAC from 2001 to 2011 were identified. Univariate analysis disclosed CAF grade + (P = .030), positive M status (P < .001), and lymph node ratio (LNR) > 0.1 (P = .045) to impair overall survival. Independent prognostic factors were CAF grade (P = .050) and positive M status (P = .002). CAF grade correlated with N status (CC = 0.206, P = .030), LNR (CC = 0.187, P = .049), tumor size (CC = −0.275, P = .003), and M status (CC = 0.190, P = .045). In the in vitro setting, paracrine effects of pancreatic cancer cell resulted in morphological activation of fibroblasts and tumor cell differentiation–dependent increase of fibroblast growth. Paracrine effects of poorly differentiated PCCs led to an upregulation of Vimentin in NIH 3T3 fibroblasts. Paracrine effects of fibroblasts on their part promoted cancer cell motility in all PCCs. As the second stromal component, fibroblast-derived ECM resulted in significantly decreased proliferation depending on density and led to upregulation of ZEB1 in poorly differentiated PCCs. CONCLUSION: In PDAC patients, positive CAF grading was identified as a negative prognostic parameter correlating with positive N status, high LNR, positive M status, and smaller tumor size. Whereas bilateral interaction of PCCs and CAFs promotes tumor progression, ECM poses PCC growth restrictions. In summary, our study discloses differential effects of stromal components and may help to interpret heterogeneous results of former studies.

Intrapancreatic distal common bile duct carcinoma: Analysis, staging considerations, and comparison with pancreatic ductal and ampullary adenocarcinomas

AbstractDistal common bile duct carcinoma is a poorly characterized entity for reasons such as variable terminology and difficulty in determining site of origin of intrapancreatic lesions. We compared clinicopathologic features of pancreatobiliary-type adenocarcinomas within the pancreas, but arising from the distal common bile duct, with those of pancreatic and ampullary origin. Upon careful review of 1017 pancreatoduodenectomy specimens with primary adenocarcinoma, 52 (5%) qualified as intrapancreatic distal common bile duct carcinoma. Five associated with an intraductal papillary neoplasm were excluded; the remaining 47 were compared to 109 pancreatic ductal adenocarcinomas and 133 ampullary carcinomas. Distal common bile duct carcinoma patients had a younger median age (58 years) than pancreatic ductal adenocarcinoma patients (65 years) and ampullary carcinoma patients (68 years). Distal common bile duct carcinoma was intermediate between pancreatic ductal adenocarcinoma and ampullary carcinoma with regard to tumor size and rates of node metastases and margin positivity. Median survival was better than for pancreatic ductal adenocarcinoma (P=0.0010) but worse than for ampullary carcinoma (P=0.0006). Distal common bile duct carcinoma often formed an even band around the common bile duct and commonly showed intraglandular neutrophil-rich debris and a small tubular pattern. Poor prognostic indicators included node metastasis (P=0.0010), lymphovascular invasion (P=0.0299), and margin positivity (P=0.0069). Categorizing the tumors based on size also had prognostic relevance (P=0.0096), unlike categorization based on anatomic structures invaded. Primary distal common bile duct carcinoma is seen in younger patients than pancreatic ductal adenocarcinoma or ampullary carcinoma. Its prognosis is significantly better than pancreatic ductal adenocarcinoma and worse than ampullary carcinoma, at least partly because of differences in clinical presentation. Use of size-based criteria for staging appears to improve its prognostic relevance. Invasive pancreatobiliary-type distal common bile duct carcinomas are uncommon in the West and have substantial clinicopathologic differences from carcinomas arising from the pancreas and ampulla.

Factors predicting adequate lymph node yield in patients undergoing pancreatoduodenectomy for malignancy.

BackgroundMost pancreatoduodenectomy resections do not meet the minimum of 12 lymph nodes recommended by the American Joint Committee on Cancer for accurate staging of periampullary malignancies. The purpose of this study was to investigate factors affecting the likelihood of adequate nodal yield in pancreatoduodenectomy specimens subject to routine pathological assessment.MethodsSix hundred sixty-two patients subject to pancreatoduodenectomy between 1990 and 2013 for pancreatic, ampullary, and common bile duct cancers were reviewed. Predictors of yielding at least 12 lymph nodes were evaluated with a logistic regression model, and a survival analysis was carried out to verify the prognostic implications of nodal counts.ResultsThe median number of evaluated nodes was 17 (interquartile range 11 to 25), and less than 12 lymph nodes were reported in surgical specimens of 179 (27 %) patients. Tumor diameter ≥20 mm (odds ratio [OR] 2.547, 95 % confidence interval [CI] 1.225 to 5.329, P = 0.013), lymph node metastases (OR 2.642, 95 % CI 1.378 to 5.061, P = 0.004), and radical lymphadenectomy (OR 5.566, 95 % CI 2.041 to 15.148, P = 0.01) were significant predictors of retrieving 12 or more lymph nodes. Lymph node counts did not influence the overall prognosis of the patients. However, a subgroup analysis carried out for individual cancer sites demonstrated that removing at least 12 lymph nodes is associated with better prognosis for pancreatic cancer.ConclusionsFew variables affect adequate nodal yield in pancreatoduodenectomy specimens subject to routine pathological assessment. Considering the ambiguities related to the only modifiable factor identified, appropriate pathology training should be considered to increase nodal yield rather than more aggressive lymphatic dissection.

Pancreatic Ductal Adenocarcinoma is Spread to the Peripancreatic Soft Tissue in the Majority of Resected Cases, Rendering the AJCC T-Stage Protocol (7th Edition) Inapplicable and Insignificant: A Size-Based Staging System(pT1: ≤2, pT2: >2-≤4, pT3: >4 cm) is More Valid and Clinically Relevant.

Most studies have failed to identify any prognostic value of the current T-stage protocol for pancreatic ductal adenocarcinoma (PDAC) by the American Joint Committee on Cancer and the Union for International Cancer Control unless some grouping was performed. To document the parameters included in this T-stage protocol, 223 consecutive pancreatoduodenectomy specimens with PDAC were processed by a uniform grossing protocol. Peripancreatic soft tissue (PST) involvement, the main pT3 parameter, was found to be inapplicable and irreproducible due to lack of a true capsule in the pancreas and variability in the amount and distribution of adipose tissue. Furthermore, 91% of the cases showed carcinoma in the adipose tissue, presumably representing the PST, and thus were classified as pT3. An additional 4.5% were qualified as pT3 due to extension into adjacent sites. The T-stage defined as such was not found to have any correlation with survival (p=0.4). A revised T-stage protocol was devised that defined pT1 as 2cm or smaller, pT2 as >2-4cm, and pT3 as larger than 4cm. This revised protocol was tested in 757 consecutive PDACs. The median and 3-year survival rates of this size-based protocol were 26, 18, 13 months, and 40%, 26%, 20%, respectively (p<0.0001). The association between higher T-stage and shorter survival persisted in N0 cases and in multivariate modeling. Analysis of the Surveillance, Epidemiology, and End Results database also confirmed the survival differences (p<0.0001). This study showed that resected PDACs are already spread to various surfaces of the pancreas, leaving only about 4% of PDACs to truly qualify as pT1/T2, and that the current T-stage protocol does not have any prognostic correlation. In contrast, as shown previously in many studies, size is an important prognosticator, and a size-based T-stage protocol is more applicable and has prognostic value in PDAC.

The use of Ligasure® has no negative impact on histology of resection margins in pancreatoduodenectomy (PD) specimens

The use of Ligasure® has no negative impact on histology of resection margins in pancreatoduodenectomy (PD) specimens

Resection margins in pancreatic cancer

The R1 rate and prognostic significance of microscopic margin involvement differ consistently between published series. This divergence results from a lack of consensus regarding various aspects of margin status assessment. Central to the controversies is the lack of clarity about what 'R1' exactly stands for. The current UICC definition--residual microscopic tumor--is possibly too general and invites divergent interpretations. Adherence to different diagnostic criteria for microscopic margin involvement and divergent terminology for the various margins of pancreatoduodenectomy specimens add to the confusion. Furthermore, recent studies demonstrated that the dissection technique and extent of tissue sampling influence the accuracy of margin assessment. Axial specimen slicing, extensive tissue sampling, and multicolored margin inking result in a significantly higher, more accurate R1 rate than when using traditional grossing techniques. Only when international consensus on these various aspects is reached will pathology data on margin involvement be reliable and can multicenter clinical trials produce compelling evidence that allows improved pancreatic cancer treatment.

CD14 upregulation as a distinct feature of non-alcoholic fatty liver disease after pancreatoduodenectomy

To investigate the pathogenesis of non-alcoholic fatty liver disease (NAFLD) after pancreatoduodenectomy (PD). A cohort of 82 patients who underwent PD at Okayama University Hospital between 2003 and 2009 was enrolled and the clinicopathological features were compared between patients with and without NAFLD after PD. Computed tomography (CT) images were evaluated every 6 mo after PD for follow-up. Hepatic steatosis was diagnosed on CT when hepatic attenuation values were 40 Hounsfield units. Liver biopsy was performed for 4 of 30 patients with NAFLD after PD who consented to undergo biopsies. To compare NAFLD after PD with NAFLD associated with metabolic syndrome, liver samples were obtained from 10 patients with NAFLD associated with metabolic syndrome [fatty liver, n = 5; non-alcoholic steatohepatitis (NASH), n = 5] by percutaneous ultrasonography-guided liver biopsy. Double-fluorescence immunohistochemistry was applied to examine CD14 expression as a marker of lipopolysaccharide (LPS)-sensitized macrophage cells (Kupffer cells) in liver biopsy specimens. The incidence of postoperative NAFLD was 36.6% (30/82). Univariate analysis identified cancer of the pancreatic head, sex, diameter of the main pancreatic duct, and dissection of the nerve plexus as factors associated with the development of NAFLD after PD. Those patients who developed NAFLD after PD demonstrated significantly decreased levels of serum albumin, total protein, cholesterol and triglycerides compared to patients without NAFLD after PD, but no glucose intolerance or insulin resistance. Liver biopsy was performed in four patients with NAFLD after PD. All four patients showed moderate-to-severe steatosis and NASH was diagnosed in two. Numbers of cells positive for CD68 (a marker of Kupffer cells) and CD14 (a marker of LPS-sensitized Kupffer cells) were counted in all biopsy specimens. The number of CD68+ cells in specimens of NAFLD after PD was significantly increased from that in specimens of NAFLD associated with metabolic syndrome specimens, which indicated the presence of significantly more Kupffer cells in NAFLD after PD than in NAFLD associated with metabolic syndrome. Similarly, more CD14+ cells, namely, LPS-sensitized Kupffer cells, were observed in NAFLD after PD than in NAFLD associated with metabolic syndrome. Regarding NASH, more CD68+ cells and CD14+ cells were observed in NASH after PD specimens than in NASH associated with metabolic syndrome. This showed that more Kupffer cells and more LPS-sensitized Kupffer cells were present in NASH after PD than in NASH associated with metabolic syndrome. These observations suggest that after PD, Kupffer cells and LPS-sensitized Kupffer cells were significantly upregulated, not only in NASH, but also in simple fatty liver. NAFLD after PD is characterized by both malnutrition and the up-regulation of CD14 on Kupffer cells. Gut-derived endotoxin appears central to the development of NAFLD after PD.

Ampullary Region Carcinomas

Ampullary (AMP) carcinomas comprise a heterogeneous group of cancers lacking adequate subcategorization. In the present study, 249 strictly defined primary AMP carcinomas (ACs) identified in 1469 malignant pancreatoduodenectomy specimens were analyzed for defining features. Gross and microscopic findings were used to determine tumor epicenter and extent of preinvasive component. ACs were classified into 4 distinct subtypes based on location: (1) Intra-AMP (25%): Invasive carcinomas arising in intra-ampullary papillary-tubular neoplasms with zero to minimal, duodenal surface involvement (<25% of the tumor). These tumors were more commonly found in men, they had a relatively large overall size (mean, 2.9 cm) but had smaller invasive component (mean, 1.5 cm), and were predominantly of a lower TNM stage (85%, T1/2; and 72% N0). They carried the best prognosis among the 4 groups (3-y survival, 73%). (2) AMP-ductal (15%): These were tumors forming constrictive, sclerotic, plaque-like thickening of the walls of the common bile duct and/or pancreatic duct resulting in mucosa-covered, button-like elevations of the papilla into the duodenal lumen. There was no significant exophytic (preinvasive) growth. These were the smallest tumors (mean overall size, 1.9 cm; mean invasion size 1.7 cm), but carried the worst prognosis (3-y survival, 41%), presumably due to the pancreatobiliary histology/origin (in 86%); however, even this group had significantly better prognosis when compared with 113 ordinary pancreatic ductal adenocarcinomas (3 y, 11%; P<0.0001). (3) Peri-AMP-duodenal (5%): Massive exophytic, ulcero-fungating tumors growing into the duodenal lumen and eccentrically encasing the ampullary orifice with only minimal intra-ampullary luminal involvement. These were mostly of intestinal phenotype (75%) and some had mucinous features. Although these tumors were the largest (mean overall size 4.7 cm; and mean invasion size 3.4 cm), and had the highest incidence of lymph node metastasis (50%), they carried an intermediate prognosis (3-y survival, 69%) to that seen among a group of 55 nonampullary duodenal carcinoma controls. (4) AC-not otherwise specified ("papilla of Vater"; 55%): Ulcero-nodular tumors located at the papilla of Vater, which do not show the specific characteristics identified among the other 3 subtypes. In conclusion, ACs comprise 4 clinicopathologic subtypes that are prognostically distinct.

Resection margin involvement and tumour origin in pancreatic head cancer

Assessment of the origin of adenocarcinoma in pancreatoduodenectomy specimens (pancreatic, ampullary or biliary) and resection margin status is not performed in a consistent manner in different centres. The aim of this review was to identify the impact of such variations on patient outcome. A systematic literature search for articles on pancreatic, ampullary, distal bile duct and periampullary cancer was performed, with special attention to data on resection margin status, pathological examination and outcome. The frequent reclassification of tumour origin following slide review, and the wide variation in published incidence of pancreatic (33-89 per cent), ampullary (5-42 per cent) and distal bile duct (5-38 per cent) cancers indicate that the histopathological distinction between the three cancer groups is less accurate than generally believed. Recent studies have shown that the wide range of rates of microscopic margin involvement (R1) in pancreatoduodenectomy specimens (18-85, 0-27 and 0-72 per cent respectively for pancreatic, ampullary and distal bile duct cancers) is mainly caused by differences in pathological assessment rather than surgical practice and patient selection. As a consequence of the existing inconsistency in reporting of these data items, the clinical significance of microscopic margin involvement in each of the three cancer groups remains unclear. Inaccurate and inconsistent distinction between pancreatic, ampullary and distal bile duct cancer, combined with inaccuracies in resection margin assessment, results in obfuscation of key clinicopathological data. Specimen dissection technique plays a key role in the quality of the assessment of both tumour origin and margin status. Unless the pathological examination is meticulous and standardized, comparison of results between centres and observations in multicentre trials will remain of limited value.

Survival estimates after pancreatoduodenectomy skewed by non-standardized histopathology reports

Survival estimates may be biased if quality control on histopathology is insufficient. We evaluated the effects of standardizing histopathology for pancreatoduodenectomy specimens and compared survival estimates based on standardized vs non-standardized histopathological evaluation. Microscopic slides and histopathological reports from 311 consecutive pancreatoduodenectomies (1980-2004) were reviewed, including 104 adenocarcinomas (1980-1997) resected before and 123 adenocarcinomas (1998-2004) resected after standardizing histopathology. Histopathological factors were re-evaluated for all primary adenocarcinomas (n = 227). The most frequent histological types were pancreatobiliary-type (n = 145) and intestinal-type (n = 73). Standardized histopathology was associated with sampling more blocks and nodes (p < 0.001), and with more frequent identification of non-pancreatic tumour origin, nodal and margin involvement, perineural infiltration, and poor differentiation (p < 0.05). Standardized evaluation was necessary to discriminate between prognostic groups with respect to perineural infiltration and tumour size, but not to identify disparate prognostic subgroups with respect to nodal and margin involvement. Nodal involvement (N1 vs N0, p < 0.001) and histological type (pancreatobiliary vs intestinal, p < 0.001) were independent prognostic factors after pancreatoduodenectomy. Histopathological evaluation should be standardized to provide reliable prognostic estimates and to discriminate between prognostic subgroups. Lymph node involvement and histological type are independent prognostic factors after pancreatoduodenectomy for adenocarcinoma.