Radiology of pancreatic neoplasms: An update

Diagnostic imaging is an important tool to evaluate pancreatic neoplasms. We describe the imaging features of pancreatic malignancies and their benign mimics. Accurate detection and staging are essential for ensuring appropriate selection of patients who will benefit from surgery and for preventing unnecessary surgeries in patients with unresectable disease. Ultrasound, multidetector computed tomography with multiplanar reconstruction and magnetic resonance imaging can help to do a correct diagnosis. Radiologists should be aware of the wide variety of anatomic variants and pathologic conditions that may mimic pancreatic neoplasms. The knowledge of the most important characteristic key findings may facilitate the right diagnosis.     

In Defense of the Whipple: An Argument for Aggressive Surgical Management of Pancreatic Cancer

The authors argue that aggressive surgical management of patients with pancreatic cancer is warranted.     

Primary pancreatic cystic neoplasms revisited. Part III. Intraductal papillary mucinous neoplasms

Intraductal papillary mucinous neoplasms (IPMNs) represent about 25% of all primary pancreatic cystic neoplasms and are increasingly recognized during the last two decades. They are characterized by intraductal proliferation of neoplastic mucinous cells forming papillary projections into the pancreatic ductal system, which is typically dilated and contains globules of mucus. IPMNs may be multifocal and have malignant potential. Modern imaging is essential in establishing preoperative diagnosis and in differentiating different subtypes of IPMNs (i.e., main-duct vs. branch-type disease). Endoscopic retrograde or magnetic resonance cholangiopancreatography accurately delineate the morphologic changes of the pancreatic ductal system. Endoscopic ultrasonography (usually used in conjunction with image-guided FNA and analysis of the aspirated material) is commonly used for differential diagnosis of IPMNs from other pancreatic cystic lesions. Surgical resection (usually anatomic pancreatectomy, depending on the location of the disease) is the treatment of choice. Total pancreatectomy may occasionally be required in selected patients, but is associated with formidable long-term morbidity. A conservative approach has recently been proposed for carefully selected patients with branch-duct IPMNs. Recurrences following surgical resection can be observed, especially in patients with multifocal disease or in the presence of underlying malignancy.     

The impact of surgery delay on survival of resectable pancreatic cancer: A systematic review of observational studies

BackgroundPancreatic cancer is considered a lethal disease and the only potentially curative option is R0 excision. The aim of this study was to investigate whether the waiting time interval from diagnosis to surgical treatment affects overall survival in patients who undergo curative-intent surgery for pancreatic cancer.MethodsSearch in Medline, Scopus, Clinicaltrials.gov, EMBASE, Cochrane Central Register of Controlled Trials CENTRAL and Google Scholar databases was conducted from inception until April 2022.ResultsOverall, 10 studies were included that enrolled 181,344 patients. The dominating cut-off time point was 4 weeks in studies which utilized a biphasic waiting time pattern. In addition, prolonged waiting time interval was associated with decreased overall survival in 3 studies, whereas it demonstrated a favorable effect on overall survival in 2 studies and no impact on survival in 5 studies.ConclusionThe great diversity that was observed regarding the impact of surgery delay on survival underlines the lack of knowledge about biologic pathways of pancreatic cancer. Novel imaging studies and molecular “fingerprints” in combination to time-to-treatment standardization in the design of future randomized trials could lead to the recognition of patients that could benefit from a timely resection.     

Modified-FOLFIRINOX combined with deep regional hyperthermia in pancreatic cancer: a retrospective study in Chinese patients

Background: FOLFIRINOX chemotherapy displays significant survival improvements in patients with pancreatic cancer. However, toxicities have hampered enthusiasm for the use of FOLFIRINOX in full dose. In order to increase the tolerability, many researchers focused on the modification of FOLFIRINOX. On the other hand, hyperthermia (HT) has been considered as an effective ancillary treatment for cancer therapy. Up to now, there is no report evaluating combining deep regional hyperthermia (DRHT) with modified-FOLFIRINOX for pancreatic cancer patients.

Methods: In this study, we conducted a retrospective review of pancreatic cancer patients treated with the combination of new form modified-FOLFIRINOX and DRHT (BSD2000). Patients underwent chemotherapy that included low-dose irinotecan (70–130?mg/m²), oxaliplatin (65–70?mg/m²) on day 1 and 5-FU (2400?mg/m² as a 46?h continuous infusion, no bolus) or capecitabine (CAP) (1000?mg/m² twice daily on days 1–10) or tegafur, gimeracil and oteracil potassium (TS-1) (80–120?mg/d twice daily on days 1–10), 2-week schedule. Generally, DRHT treatment was performed weekly, 45?min for each time during chemotherapy.

Results: The patients receiving mFOLFIRINOX as the first line chemotherapy combining with DRHT, obtained an improvement in OS and PFS, 17 months (95% CI 1.97–32.03 months) and 4 months (95% CI 0–8.29 months) respectively. Overall, this combination regimen was safe; 17.6% patients suffered from grade 3/4 toxicities.

Conclusions: In conclusion, we conducted a retrospective study combining mFOLFIRINOX and DRHT, which was well tolerated. The efficacy in the treatment of pancreatic cancer was encouraging, but further studies would be required to prove its merit, compared with conventional treatment.     

Association between pancreatic intraductal papillary mucinous neoplasms and extrapancreatic malignancies: A systematic review with meta-analysis

BackgroundIt is unclear whether patients with intraductal papillary mucinous neoplasia harbor a higher risk of developing extrapancreatic malignancies.AimsWe performed a pooled estimate of the incidence of extrapancreatic malignancies in patients with intraductal papillary mucinous neoplasia, with a particular focus on the comparison to the general population.MethodsComputerized bibliographic search of main databases was performed through February 2021. The primary endpoint was the pooled incidence of extrapancreatic malignancies in patients with intraductal papillary mucinous neoplasms. Additional outcome was the comparison between intraductal papillary mucinous neoplasia patients and the general population, expressed in terms of standardized incidence ratio along with 95% confidence intervals.ResultsEighteen studies with 8709 patients were included. The pooled rate of metachronous extrapancreatic malignancies was 10 (6–13)/1000 persons-year. No difference was observed according to intraductal papillary mucinous neoplasia histology and sex, whereas a significantly superior incidence of extrapancreatic malignancies was observed in patients with main-duct (36.7%, 25.4%–48%) as compared to branch-duct intraductal papillary mucinous neoplasia (26.2%, 17.6%–34.8%; p = 0.03). Pooled standardized incidence ratio comparing expected rates in the general population was 1.01 (0.79–1.29); no difference was observed concerning rates of metachronous gastric cancer (standardized incidence ratio 1.60, 0.72–3.54) and colorectal cancer (1.29, 0.92–1.18), whereas biliary cancer was observed more frequently in intraductal papillary mucinous neoplasia patients (2.29, 1.07–4.93).ConclusionPatients with intraductal papillary mucinous neoplasia harbor an overall rate of extrapancreatic malignancies as high as 27.3%. The rate of metachronous extrapancreatic malignancies is not superior to the general population.     

Molecular markers associated with outcome and metastasis in human pancreatic cancer

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous cancer in which differences in survival rates might be related to a variety in gene expression profiles. Although the molecular biology of PDAC begins to be revealed, genes or pathways that specifically drive tumour progression or metastasis are not well understood. METHODS: We performed microarray analyses on whole-tumour samples of 2 human PDAC subpopulations with similar clinicopathological features, but extremely distinct survival rates after potentially curative surgery, i.e. good outcome (OS and DFS > 50 months, n = 7) versus bad outcome (OS < 19 months and DFS < 7 months, n = 10). Additionally, liver- and peritoneal metastases were analysed and compared to primary cancer tissue (n = 11). RESULTS: The integrin and ephrin receptor families were upregulated in all PDAC samples, irrespective of outcome, supporting an important role of the interaction between pancreatic cancer cells and the surrounding desmoplastic reaction in tumorigenesis and cancer progression. Moreover, some components such as ITGB1 and EPHA2 were upregulated in PDAC samples with a poor outcome, Additionally, overexpression of the non-canonical Wnt/beta-catenin pathway and EMT genes in PDAC samples with bad versus good outcome suggests their contribution to the invasiveness of pancreatic cancer, with beta-catenin being also highly upregulated in metastatic tissue. CONCLUSIONS: Components of the integrin and ephrin pathways and EMT related genes, might serve as molecular markers in pancreatic cancer as their expression seems to be related with prognosis.     

Neoadjuvant FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer: An intention to treat analysis

Objective

To assess clinical and pathologic efficacy of neoadjuvant FOLFIRINOX for locally advanced (LAPC) and borderline resectable pancreatic cancer (BRPC).

Neoadjuvant preoperative chemoradiation in patients with pancreatic cancer

Purpose: To assess the toxicity and efficacy of preoperative chemoradiation in pancreatic cancer.

Methods and Materials: Between November 1996 and December 2001, 32 patients with biopsy-proven pancreatic adenocarcinoma (28 head; 4 body) were treated by chemoradiation consisting of either split-course therapy (two courses of 15 Gy separated by a 2-week break, n = 10) or standard-fractionation therapy (45 Gy during 5 weeks, n = 22). Concurrent chemotherapy included continuous infusion of 5-fluorouracil and a cisplatin bolus. Pancreatic resection was scheduled for 4–6 weeks after completion of chemoradiation treatment.

Results: All 32 patients completed the chemoradiation protocol. Only 2 cases of Grade 3 toxicity (weight loss, vomiting) and one fatal Grade 4 infection occurred. Of the 32 patients, 19 underwent curative resection. Two patients had a complete pathologic response. One patient died 36 months after diagnosis of late treatment-related toxicity (acute superior mesenteric artery thrombosis) with no evidence of disease. The 2-year overall survival rate for the entire group and the resected patients was 37.3% (95% confidence interval 18.2–56.4%) and 59.3% (95% confidence interval 34.1–84.9%), respectively.

Conclusion: Preoperative chemoradiation with 5-fluorouracil and cisplatin is feasible and promising.     

Presence of low-grade IPMN at the pancreatic transection margin does not have prognostic significance after resection of IPMN-associated pancreatic adenocarcinoma

IntroductionResection margin status is a well-established prognosticator in pancreatic cancer. The prognostic impact of IPMN dysplasia at the pancreatic transection margin in IPMN-associated carcinoma (IPMN-Ca) remains unclear, hence institutional practices on additional resections vary.MethodsPatients undergoing partial pancreatectomy or attempted partial pancreatectomy converted to total pancreatectomy for IPMN-Ca between 04/2002 and 12/2018 were identified. Final pathology of the definitive pancreatic transection margin was identified. The association between the presence of IPMN dysplasia at the margin and overall survival (OS) was assessed.ResultsOf 302 patients with IPMN-Ca, 181 (59.9%) patients received partial pancreatoduodenectomy, 61 (20.2%) distal pancreatectomy, and 60 (19.9%) were converted to total pancreatectomy. Median OS was 98.6 months in R0 (≥1 mm), 39.3 months in R1 (<1 mm), and 22.0 months in R1(direct) resected patients, respectively (p < 0.0001). No IPMN dysplasia at the definitive margin was present in 103 (34.1%), low-grade in 131 (43.4%), and high-grade/R1 in 8 (2.6%) patients. Low-grade dysplasia or total pancreatectomy were not associated with shorter OS compared to dysplasia-free margin across the entire cohort. Sensitivity analyses confirmed a lack of prognostic relevance of low-grade IPMN dysplasia at the pancreatic margin in R0 resected IPMN-Ca and in R0 resected UICC stage IA/IB IPMN-Ca.ConclusionsLow-grade IPMN at the transection margin is not associated with shorter overall survival after partial pancreatectomy for IPMN-Ca. Additional resections for low-grade dysplasia, up to total pancreatectomy do not result in a survival benefit and should be omitted. Due to limited sample size, high-grade dysplasia could not be analyzed.     

影响胰腺癌根治术预后的围手术期相关因素的回顾性分析

背景与目的：胰腺癌是恶性程度极高的肿瘤,即使接受根治性切除手术,其预后也较差。为了更好地了解围手术期麻醉管理策略在改善患者预后中的作用,回顾性分析胰腺癌手术的相关资料以判明这些因素与预后的关系。方法：回顾性分析2011年12月—2016年1月在复旦大学附属肿瘤医院行胰腺癌根治性切除术的190例患者的围手术期临床和病理学资料,随访截至2019年1月。采用COX比例风险模型进行单因素和多因素分析。结果：COX比例风险模型单因素分析显示,术前CA19-9和中性粒细胞/淋巴细胞比值（neutrophil-lymphocyte ratio,NLR）、TNM分期、肿瘤分化程度和最大直径、淋巴结转移、术中失血量和输血与总生存期（overall survival,OS）均有显著相关性;术中应用地塞米松与OS之间也有一定的相关性（P=0.052,HR=0.73）。多因素回归分析显示,肿瘤分化程度（P=0.001,HR=0.59）、肿瘤最大直径（P=0.039,HR=1.51）、淋巴结转移（P=0.003,HR=1.61）、术中输血（P=0.046,HR=1.39）与OS都有显著相关性。术中输血组的中位生存期（15.7个月）比未输血组（23.3个月）明显缩短。结论：围手术期麻醉管理策略对保护患者免疫功能、降低复发转移风险、改善预后很重要。合理选择麻醉方式和麻醉药物,优化麻醉管理策略,建立个体化的输血管理方案,对于改善胰腺癌手术患者的远期生存具有重要意义。     

A multi-centre retrospective review of second-line therapy in advanced pancreatic adenocarcinoma

INTRODUCTION: Limited information on second-line treatment in patients with pancreatic adenocarcinoma is available. At time of first-line treatment failure, approximately half of the patients are candidates for further treatment. MATERIAL AND METHODS: A retrospective review of 183 patients submitted to second-line therapy has been performed to identify prognostic factors, provides useful information for patients counseling and generates hypotheses for future studies. Inclusion criteria were: cytological or histologic diagnosis of pancreatic adenocarcinoma and prior gemcitabine-including chemotherapy. Any age, performance status (PS) and chemotherapy regimen were considered. RESULTS: One hundred and eighty-three patients (106 males; 168 metastatic; median age 62 years; median PS 1; 63 submitted to prior curative surgery, 32 to prior radiotherapy) with a median previous progression-free survival (PFS) of 6.7 months were included. Median and 6-month PFS after initiation of salvage therapy were 3.0 months and 20%. Median, 1 and 2 years, overall survival after initiation of salvage therapy were 6.2 months, 17 and 4%, respectively. Previous PFS, CA19.9 levels and age independently predicted OS. CONCLUSION: Re-challenge with gemcitabine and 5-fluorouracil administration may have a role in selected patients.     

Management of borderline resectable pancreatic cancer

Pancreatic cancer is the fourth most common cause of cancer death in the United States. Surgery remains the only curative option; however only 20% of the patients have resectable disease at the time of initial presentation. The definition of borderline resectable pancreatic cancer is not uniform but generally denotes to regional vessel involvement that makes it unlikely to have negative surgical margins. The accurate staging of pancreatic cancer requires triple phase computed tomography or magnetic resonance imaging of the pancreas. Management of patients with borderline resectable pancreatic cancer remains unclear. The data for treatment of these patients is primarily derived from retrospective single institution experience. The prospective trials have been plagued by small numbers and poor accrual. Neoadjuvant therapy is recommended and typically consists of chemotherapy and radiation therapy. The chemotherapeutic regimens continue to evolve along with type and dose of radiation therapy. Gemcitabine or 5-fluorouracil based chemotherapeutic combinations are administered. The type and dose of radiation vary among different institutions. With neoadjuvant treatment, approximately 50% of the patients are able to undergo surgical resections with negative margins obtained in greater than 80% of the patients. Newer trials are attempting to standardize the definition of borderline resectable pancreatic cancer and treatment regimens. In this review, we outline the definition, imaging requirements and management of patients with borderline resectable pancreatic cancer.     

Observation or resection of pancreatic intraductal papillary mucinous neoplasm: An ongoing tug of war

An increasing number of patients are being referred to pancreatic centres around the world due to often incidentally discovered cystic neoplasms of the pancreas. The evaluation and management of pancreatic cystic neoplasms is a controversial topic and with existing guidelines based on a lack of strong evidence there is discordance between centres and guidelines with regard to when to offer surgery and when to favour surveillance. The frequency, duration and modality of surveillance is also controversial as this is resource-consuming and must be balanced against the perceived benefits and risks involved. While there is consensus that the risk of malignancy should be balanced against the life-expectancy and comorbidities, the indications for surgery and surveillance strategies vary among the guidelines. Thus, the tug of war between surveillance or resection continues. Here we discuss the recommendations from guidelines with further accumulating data and emerging reports on intraductal papillary mucinous neoplasm in the literature.     

Preoperative misdiagnosis of pancreatic and periampullary cancer in patients undergoing pancreatoduodenectomy: A multicentre retrospective cohort study

IntroductionWhereas neoadjuvant chemo(radio)therapy is increasingly used in pancreatic cancer, it is currently not recommended for other periampullary (non-pancreatic) cancers. This has important implications for the relevance of the preoperative diagnosis for pancreatoduodenectomy. This retrospective multicentre cohort study aimed to determine the frequency of clinically relevant misdiagnoses in patients undergoing pancreatoduodenectomy for pancreatic or other periampullary cancer.MethodsData from all consecutive patients who underwent a pancreatoduodenectomy between 2014 and 2018 were obtained from the prospective Dutch Pancreatic Cancer Audit. The preoperative diagnosis as concluded by the multidisciplinary team (MDT) meeting was compared with the final postoperative diagnosis at pathology to determine the rate of clinically relevant misdiagnosis (defined as missed pancreatic cancer or incorrect diagnosis of pancreatic cancer).ResultsIn total, 1244 patients underwent pancreatoduodenectomy of whom 203 (16%) had a clinically relevant misdiagnosis preoperatively. Of all patients with a final diagnosis of pancreatic cancer, 13% (87/679) were preoperatively misdiagnosed as distal cholangiocarcinoma (n = 41, 6.0%), ampullary cancer (n = 27, 4.0%) duodenal cancer (n = 16, 2.4%), or other (n = 3, 0.4%). Of all patients with a final diagnosis of periampullary (non-pancreatic) cancer, 21% (116/565) were preoperatively incorrectly diagnosed as pancreatic cancer. Accuracy of preoperative diagnosis was 84% for pancreatic cancer, 71% for distal cholangiocarcinoma, 73% for ampullary cancer and 73% for duodenal cancer. A prediction model for the preoperative likelihood of pancreatic cancer (versus other periampullary cancer) prior to pancreatoduodenectomy demonstrated an AUC of 0.88.DiscussionThis retrospective multicentre cohort study showed that 16% of patients have a clinically relevant misdiagnosis that could result in either missing the opportunity of neoadjuvant chemotherapy in patients with pancreatic cancer or inappropriate administration of neoadjuvant chemotherapy in patients with non-pancreatic periampullary cancer. A preoperative prediction model is available on www.pancreascalculator.com.     

白蛋白结合型紫杉醇联合吉西他滨动脉灌注治疗进展期胰腺癌的安全性和有效性回顾性研究

背景与目的：白蛋白结合型紫杉醇联合吉西他滨（nab-paclitaxel combined with gemcitabine,AG）方案静脉化疗是进展期胰腺癌有效治疗方案之一,动脉灌注化疗（transcatheter arterial chemotherapy,TAC）具有增强疗效并降低不良反应的优势,观察AG方案经TAC治疗进展期胰腺癌患者的有效性和安全性。方法：回顾性分析2016年1月—2019年6月复旦大学附属肿瘤医院收治的63例接受治疗的进展期胰腺癌患者,患者均经病理学检查确诊为胰腺导管腺癌,其中Ⅲ期15例,Ⅳ期48例,所有患者接受经动脉灌注化疗和（或）栓塞治疗,动脉灌注化疗用药方案为盐酸吉西他滨1 000 mg/m ² 联合白蛋白结合型紫杉醇125 mg/m ² ,灌注时间≥10 min,伴有肝转移者同时行供血动脉栓塞。结果：63例患者中,术中行数字减影血管造影（digital subtraction angiography,DSA）可见胰腺肿瘤和肝转移灶动脉供血比例分别为66.67%和35.29%;接受治疗1次4例,2次6例,3次6例,4次及以上47例,治疗次数最多为9次,间隔时间为21～45 d。1年生存率为36.51%,中位生存期（median overall survival,mOS）为9.2个月,6个月无进展生存（progression-free survival,PFS）率为44.44%,中位PFS（median PFS,mPFS）为4.7个月。多因素分析显示KPS≥80、Ⅲ期与较长的生存期相关,接受多次动脉灌注化疗和（或）栓塞是良好的生存预后相关因素。发生治疗相关的Ⅲ度及以上血液学不良反应包括中性粒细胞减少（3.17%）和血小板下降（4.76%）,非血液学不良反应包括乏力（6.35%）、恶心呕吐（9.52%）、腹泻（4.76%）和转氨酶升高（4.76%）;17.46%和22.22%的患者出现发热及肝区疼痛栓塞综合征,所有不良反应经治疗后均好转,无治疗相关性死亡病例。结论：白蛋白结合型紫杉醇联合吉西他滨经动脉灌注治疗进展期胰腺癌具有较好的安全性,不良反应与静脉给药相比有所减少,可有效地控制病情,使患者生存获益。     

Distribution and clinical significance of tumour-associated macrophages in pancreatic ductal adenocarcinoma: a retrospective analysis in China

Background

We aimed to characterize the localization and prognostic significance of tumour-associated macrophages (tams) in pancreatic ductal adenocarcinoma (pdac).

Methods

Tumour specimens from 70 patients with pdac and inflammatory specimens from 13 patients with chronic pancreatitis were collected and analyzed for tam and M2 macrophage counts by immunohistochemistry. Correlations between tam distributions and clinicopathologic features were determined.

Results

Immunohistochemical analysis showed that tam and M2 macrophage counts were higher in tissues from pdac than from chronic pancreatitis. The tams and M2 macrophages both infiltrated more into peritumour. Both macrophage types were positively associated with lymph node metastasis (p = 0.041 for tams in peritumour, p = 0.013 for M2 macrophages in introtumour, p = 0.006 for M2 macrophage in peritumour). In addition, abdominal pain was significantly more frequent in pdac patients with a greater tams count. The survival rate was much lower in patients having high infiltration by M2 macrophages than in those having low infiltration.

Conclusions

The tam count might be associated with neural invasion in pdac, and M2 macrophages might play an important role in lymph node metastasis. Higher counts of either macrophage type were associated with increased risk of lymph node metastasis, and the M2 macrophage count could potentially be a marker for evaluating prognosis.