Elsevier

The Lancet

Volume 388, Issue 10039, 2–8 July 2016, Pages 73-85
The Lancet

Seminar
Pancreatic cancer

https://doi.org/10.1016/S0140-6736(16)00141-0Get rights and content

Summary

Pancreatic cancer is a highly lethal disease, for which mortality closely parallels incidence. Most patients with pancreatic cancer remain asymptomatic until the disease reaches an advanced stage. There is no standard programme for screening patients at high risk of pancreatic cancer (eg, those with a family history of pancreatic cancer and chronic pancreatitis). Most pancreatic cancers arise from microscopic non-invasive epithelial proliferations within the pancreatic ducts, referred to as pancreatic intraepithelial neoplasias. There are four major driver genes for pancreatic cancer: KRAS, CDKN2A, TP53, and SMAD4. KRAS mutation and alterations in CDKN2A are early events in pancreatic tumorigenesis. Endoscopic ultrasonography and endoscopic ultrasonography-guided fine-needle aspiration offer high diagnostic ability for pancreatic cancer. Surgical resection is regarded as the only potentially curative treatment, and adjuvant chemotherapy with gemcitabine or S-1, an oral fluoropyrimidine derivative, is given after surgery. FOLFIRINOX (fluorouracil, folinic acid [leucovorin], irinotecan, and oxaliplatin) and gemcitabine plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) are the treatments of choice for patients who are not surgical candidates but have good performance status.

Introduction

Pancreatic cancer is associated with a very poor prognosis, highlighted by the close parallel between disease incidence and mortality.1 5-year survival in patients with pancreatic cancer remains as low as 6% in the USA.2 The low survival rate is attributed to several factors, of which perhaps the most important is the late stage at which most patients are diagnosed. Most patients with pancreatic cancer are asymptomatic until the disease develops to an advanced stage. Up to 20% of patients are eligible for initial resection.2 Even after potential curative resection, most patients will eventually have recurrence, and 5-year survival of completely resected patients is only up to 25%.1 Tumour biology of pancreatic cancer contributes to early recurrence and metastasis, and resistance to chemotherapy and radiotherapy. Autopsy series have shown that about 90% of cases of pancreatic cancer are complicated by distant metastasis.3

To improve prognosis, a screening programme for early diagnosis of pancreatic cancer is needed. Several risk factors for pancreatic cancer, such as a family history of pancreatic cancer,4 as well as personal history of cigarette smoking,5 chronic pancreatitis,6 and diabetes mellitus7, 8 have been identified, but there is currently no standard programme for screening patients at high risk. We review recent developments in the epidemiology, risk factors, pathology, diagnosis, and treatment of pancreatic cancer.

Section snippets

Epidemiology and risk factors

The American Cancer Society estimates that in 2015, about 49 000 people will be diagnosed with pancreatic cancer in the USA and 41 000 will die of the disease. Pancreatic cancer is the fourth leading cause of cancer death in the USA. Worldwide, pancreatic cancer accounts for more than 200 000 deaths every year. Total deaths from pancreatic cancer are currently increasing and are predicted to be the second leading cause of cancer death in the USA by 2030.9 Increases in pancreatic cancer

Histopathology and molecular pathology

Pancreatic ductal adenocarcinoma is by far the most common pancreatic neoplasm. It is an invasive mucin-producing gland-forming neoplasm that elicits an intense stromal desmoplastic reaction.11 Several histological features can help to diagnose pancreatic ductal adenocarcinoma: haphazard arrangement of glands, nuclear pleomorphism, incomplete glandular lumina, luminal necrosis, neoplastic glands immediately adjacent to muscular vessels, perineural invasion, and lymphovascular invasion (figure 1

Clinical presentation, signs, and symptoms

Most pancreatic cancers have no symptoms in the early stage. A large case-control study comparing the incidence of early pancreatic cancer symptoms suggested that pancreatic cancer is associated with 12 alarm symptoms: weight loss, abdominal pain, nausea and vomiting, bloating, dyspepsia, new-onset diabetes, changes in bowel habit, pruritus, lethargy, back pain, shoulder pain, and jaundice.43 Back pain (odds ratio [OR] 1·33 [95% CI 1·18–1·49]), lethargy (OR 1·42 [1·25–1·62]), and new-onset

Serum tumour markers

The combination of serum carbohydrate antigen (CA) 19-9 and carcinoembryonic antigen (CEA)48, 49, 50 has been reported to decrease sensitivity to 37%, but increase specificity to 84% compared with CA19-9 alone, for diagnosis of pancreatic cancer.51 A recent study has shown that a serum protein biomarker panel consisting of CA125, CA19-9, and laminin γC (LAMC2) can significantly improve performance in detecting pancreatic cancer compared with CA19-9 alone under several conditions (ie, all

Differential diagnosis from autoimmune pancreatitis

Mass-forming pancreatitis and other pancreatic malignancies such as malignant lymphoma should be differentiated from pancreatic cancer. Most cases of mass-forming pancreatitis are autoimmune pancreatitis, which is divided into two subtypes. Type 1 autoimmune pancreatitis, the most common form, is characterised by the histological feature of lymphoplasmacytic sclerosing pancreatitis and is considered to be a pancreatic lesion of IgG4-related disease. Type 2 shows the histological feature of

Treatment

Treatment of pancreatic cancer includes surgery, chemotherapy, radiation therapy, and palliative care. The treatment options are selected depending on the stage of pancreatic cancer in a multidisciplinary approach (figure 5). Treatment of IPMN and MCN is reviewed elsewhere.85

Future perspectives

Screening programmes in high-risk individuals including familial pancreatic cancer kindreds are expected to yield more patients with pancreatic cancer at an early stage.111

There are several directions for future studies on pancreatic cancer. First, the correlation of genetic alterations with clinically important features, such as pattern of recurrence and response to chemotherapy, will facilitate the translation of these findings into clinically useful assays. The Individualized Molecular

Search strategy and selection criteria

We searched MEDLINE and PubMed databases for relevant randomised trials and other high-quality studies published from January, 1980, to July, 2015, with the keyword “pancreatic cancer”. We mainly selected publications from the past 5 years, but we did not exclude highly regarded and commonly referenced older publications. Additionally, we searched the reference lists of articles identified by this search strategy and selected those that we judged to be relevant. Review articles and book

References (116)

  • Y Zhang et al.

    Preoperative vascular evaluation with computed tomography and magnetic resonance imaging for pancreatic cancer: a meta-analysis

    Pancreatology

    (2012)
  • AP Rijkers et al.

    Usefulness of F-18-fluorodeoxyglucose positron emission tomography to confirm suspected pancreatic cancer: a meta-analysis

    Eur J Surg Oncol

    (2014)
  • S Tang et al.

    Usefulness of 18F-FDG PET, combined FDG-PET/CT and EUS in diagnosing primary pancreatic carcinoma: a meta-analysis

    Eur J Radiol

    (2011)
  • TT Gong et al.

    Contrast-enhanced EUS for differential diagnosis of pancreatic mass lesions: a meta-analysis

    Gastrointest Endosc

    (2012)
  • R Attam et al.

    “Wet suction technique (WEST)”: a novel way to enhance the quality of EUS-FNA aspirate. Results of a prospective, single-blind, randomized, controlled trial using a 22-gauge needle for EUS-FNA of solid lesions

    Gastrointest Endosc

    (2015)
  • RE Brand et al.

    A microRNA-based test improves endoscopic ultrasound-guided cytologic diagnosis of pancreatic cancer

    Clin Gastroenterol Hepatol

    (2014)
  • L Fuccio et al.

    The role of K-ras gene mutation analysis in EUS-guided FNA cytology specimens for the differential diagnosis of pancreatic solid masses: a meta-analysis of prospective studies

    Gastrointest Endosc

    (2013)
  • T Kamisawa et al.

    IgG4-related disease

    Lancet

    (2015)
  • M Tanaka et al.

    International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas

    Pancreatology

    (2012)
  • M Bockhorn et al.

    Borderline resectable pancreatic cancer: a consensus statement by the International Study Group of Pancreatic Surgery (ISGPS)

    Surgery

    (2014)
  • JL Van Laethem et al.

    New strategies and designs in pancreatic cancer research: consensus guidelines report from a European expert panel

    Ann Oncol

    (2012)
  • SH Shin et al.

    A comparative study of laparoscopic vs. open distal pancreatectomy for left-sided ductal adenocarcinoma: a propensity score-matched analysis

    J Am Coll Surg

    (2015)
  • A Vincent et al.

    Pancreatic cancer

    Lancet

    (2011)
  • R Siegel et al.

    Cancer statistics, 2014

    CA Cancer J Clin

    (2014)
  • S Gillen et al.

    Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages

    PLoS Med

    (2010)
  • T Kamisawa et al.

    Hematogenous metastases of pancreatic ductal carcinoma

    Pancreas

    (1995)
  • S Iodice et al.

    Tobacco and the risk of pancreatic cancer: a review and meta-analysis

    Langenbecks Arch Surg

    (2008)
  • RP Sah et al.

    New insights into pancreatic cancer-induced paraneoplastic diabetes

    Nat Rev Gastroenterol Hepatol

    (2013)
  • L Rahib et al.

    Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States

    Cancer Res

    (2014)
  • RH Hruban et al.

    Ductal adenocarcinoma of the pancreas

  • KJ Chang et al.

    Risk of pancreatic adenocarcinoma: disparity between African Americans and other race/ethnic groups

    Cancer

    (2005)
  • DT Silverman et al.

    Why do black Americans have a higher risk of pancreatic cancer than white Americans?

    Epidemiology

    (2003)
  • AP Klein et al.

    Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds

    Cancer Res

    (2004)
  • S Solomon et al.

    Inherited pancreatic cancer syndromes

    Cancer J

    (2012)
  • AK Rustgi

    Familial pancreatic cancer: genetic advances

    Genes Dev

    (2014)
  • FJ Couch et al.

    The prevalence of BRCA2 mutations in familial pancreatic cancer

    Cancer Epidemiol Biomarkers Prev

    (2007)
  • AM Goldstein et al.

    Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations

    N Engl J Med

    (1995)
  • FM Giardiello et al.

    Increased risk of cancer in the Peutz-Jeghers syndrome

    N Engl J Med

    (1987)
  • AB Lowenfels et al.

    Hereditary pancreatitis and the risk of pancreatic cancer

    J Natl Cancer Inst

    (1997)
  • RR McWilliams et al.

    Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and risk for pancreatic adenocarcinoma

    Cancer

    (2010)
  • F Kastrinos et al.

    Risk of pancreatic cancer in families with Lynch syndrome

    JAMA

    (2009)
  • S Jones et al.

    Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene

    Science

    (2009)
  • NJ Roberts et al.

    ATM mutations in patients with hereditary pancreatic cancer

    Cancer Discov

    (2012)
  • AA Arslan et al.

    Anthropometric measures, body mass index, and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan)

    Arch Intern Med

    (2010)
  • N Fukushima et al.

    Ductal adenocarcinoma variants and mixed neoplasms of the pancreas

  • JS Tomlinson et al.

    Accuracy of staging node-negative pancreas cancer: a potential quality measure

    Arch Surg

    (2007)
  • RH Hruban et al.

    Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions

    Am J Surg Pathol

    (2001)
  • O Basturk et al.

    A Revised classification system and recommendations from the Baltimore consensus meeting for neoplastic precursor lesions in the pancreas

    Am J Surg Pathol

    (2015)
  • NV Adsay et al.

    Intraductal neoplasms of the pancreas

  • T Furukawa et al.

    Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study

    Virchows Arch

    (2005)
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