Table of Contents  

Skouras and Parks: Diagnosis and staging of pancreatic cancer

Introduction

Pancreatic cancer is one of the most lethal cancers, and continues to be a major health problem in the 21st century. In 2012, approximately 338 000 patients were diagnosed with pancreatic cancer, with indicative incidence rates of 6.8 patients per 100 000 of population in the Europe, 7.4 per 100 000 of population in North America and 3.2 per 100 000 of population in Asia.1 Despite recent advances in perioperative management, operative technique and neoadjuvant/adjuvant therapies, survival rates remain extremely poor. At the time of presentation, fewer than 20% of patients will be eligible for resection, which remains the only hope for long-term survival.2 In view of these challenges, diagnosis, staging and assessment of resectability are quintessential steps of the initial evaluation of patients with suspected pancreatic cancer, upon which appropriate management will depend.3

Clinical presentation

Early-stage pancreatic cancer is, usually, clinically silent, or manifests with non-specific symptoms that often go unrecognized. Disease usually becomes apparent only after invasion of surrounding structures or after the tumour has metastasised; therefore, most patients who present with symptoms attributable to pancreatic cancer have advanced disease.48 Typical presenting symptoms of pancreatic cancer include abdominal and/or mid-back pain, obstructive jaundice and weight loss.7,9,10 The presence of pain is associated with a higher incidence of unresectability and is a poor prognostic feature.4,8 Further presenting symptoms may be nausea and vomiting, anorexia or early satiety; associated signs include hepatomegaly, steatorrhea and malabsorption, new-onset type 2 diabetes mellitus or acute pancreatitis due to pancreatic duct obstruction.7,8,11 The classic Courvoisier’s sign (palpable gallbladder with concurrent painless jaundice) is present in less than 25% of patients, and Virchow’s node (enlarged left supraclavicular node) may occasionally be observed in the advanced stages of disease.8 In patients with tumours located in the pancreatic head or body, symptoms generally result from compression of surrounding structures, such as the bile or pancreatic duct, mesenteric and coeliac nerves and the duodenum. Pancreatic tail lesions may present with left upper quadrant or non-specific left-sided abdominal pain, but more commonly they manifest with symptoms attributable to metastatic disease.10 Cachexia is not uncommon in early and advanced disease.12

Imaging

Detection of pancreatic cancer is invariably dependent on imaging methods.13

Transabdominal ultrasound

Transabdominal ultrasound (TAUS) is frequently used as the first-line diagnostic approach for patients presenting with jaundice and/or upper abdominal pain. It is a non-invasive and cost-effective cross-sectional imaging modality which is widely available.1416 Although it is not always possible to visualize the pancreas with TAUS, various techniques have been developed to improve visualization of the gland, such as the use of different windows, various respiratory manoeuvres and different patient positions.16 Typical imaging features of cancer located in the pancreatic head are the presence of a hypoechoic, solid mass with ill-defined margins (Figure 1) and secondary dilatation of both the pancreatic duct and the common bile duct, resulting in the ‘double-duct sign’.17 In particularly aggressive forms of pancreatic ductal adenocarcinoma, necrosis or colliquation is a common finding, with the necrotic/liquid part of the tumour usually located centrally.17 Conversely, in cancers of the pancreatic body or tail, tumour detection is challenging because of the lack of biliary dilatation and the presence of obscuring gastric or colonic gas. In this situation, administration of water or oral contrast agents may help to delineate the entire organ.14

FIGURE 1

Abdominal ultrasound scan showing a 3.3 cm × 3.2 cm malignant lesion within the pancreatic head.

8-2-6-fig1.png

The reported diagnostic accuracy of TAUS varies widely and is highly dependent on operator experience, the stage of the disease and the patient’s body habitus.18 In most series, sensitivity and specificity range between 48% and 89% and 40% and 99%, respectively.15,18,19 Notably, sensitivity varies considerably in relation to tumour diameter and has been found to be particularly low for tumours smaller than 2 cm.19 Furthermore, differentiation of pancreatic cancer from other focal lesions, such as neuroendocrine tumours or chronic pancreatitis, is difficult on conventional unenhanced TAUS, because of similar imaging features.14 With regard to staging, the accuracy of conventional TAUS is much lower, and the potential for evaluation of lymph node and portal venous involvement is poor compared with other modalities [i.e. magnetic resonance imaging (MRI)], but can improve with the use of intravenous contrast.1923

Therefore, TAUS is not considered a reliable method for the confident diagnosis or exclusion of small pancreatic tumours; however, it remains useful for initial patient screening in those presenting with obstructive jaundice. In addition, more precise radiological modalities are necessary for a detailed examination of the pancreas and to assess resectability.8,13,24

The role of colour Doppler ultrasound has been suggested as an auxiliary modality to assess for portal vein or superior mesenteric vein (SMV) involvement, and the use of echo-enhanced power Doppler sonography has provided promising results with regard to diagnostic accuracy.8,25

Computerized tomography

Computerized tomography (CT) is the most commonly used imaging modality for the diagnosis and staging of pancreatic cancer.16,26 The more sensitive, multiphase, multidetector helical CT (MDCT) with three-dimensional (3-D) reconstruction is currently the method of choice for the diagnosis and staging of pancreatic cancer.5,8,24,27,28 MDCT allows the acquisition of a larger volume of anatomy during any phase of intravenous contrast medium administration, in a much shorter duration of time and with no loss of image quality.29 Furthermore, even greater anatomical detail can be achieved by reconstructing raw CT data into thinner images, and various reprocessing protocols have been developed to provide a more comprehensive overview of the pertinent anatomy.3033

On CT imaging, pancreatic cancer is characterized by the presence of abundant fibrous stroma and hypovascularity, attributes responsible for poor tumour enhancement compared with that of the surrounding pancreatic parenchyma (Figures 2a to 2d).16,24 By offering greater parenchymal, arterial and portal venous enhancement, MDCT amplifies tumour-to-pancreatic parenchymal contrast differences and allows visualization of the primary lesion in relation to the superior mesenteric artery (SMA) and SMV, the portal vein and coeliac axis, as well as in relation to adjacent organs.3,34

FIGURE 2a

Axial CT showing a malignant multiloculated cystic lesion in the head of the pancreas and uncinate process (red arrows), measuring 3.9 cm × 3.1 cm × 5.7 cm, and causing a mass effect on the distal common bile duct (CBD). Multiple lymph nodes are also identified within the mesentery and anterior to the right renal vein.

8-2-6-fig2a.png
FIGURE 2b

Axial CT image of a 78-year-old patient presenting with a 2-week history of jaundice and pruritus, associated with weight loss and loss of appetite over the 6 months before her presentation. On examination, Courvoisier’s sign was positive. A 3.7-cm pancreatic head mass (red arrows) with marked dilatation of the gallbladder is visible.

8-2-6-fig2b.png
FIGURE 2c

Coronal CT image showing an 3.5-cm ill-defined soft-tissue density mass of the head of the pancreas (red arrows) with nearly complete attenuation of the portal vein confluence (white arrows) caused by tumour invasion.

8-2-6-fig2c.png
FIGURE 2d

Coronal CT view of a 3.5-cm poorly enhancing pancreatic head mass (red arrows). Almost complete atrophy of the pancreatic parenchyma is demonstrated, with gross pancreatic duct dilatation (white arrows). The fat plane between the mass and the SMV (blue asterisk) and the portal vein (red asterisk) is preserved.

8-2-6-fig2d.png

In general, contrast-enhanced CT is sufficient to confirm a suspected pancreatic lesion and to outline the initial management plan.3 A meta-analysis by Bipat et al.28 reported sensitivity and specificity of helical CT with regard to tumour detection of 91% and 85%, respectively, with slightly lower values of 81% and 82% for determining resectability. However, CT is not ideal for detecting small peritoneal and lymph node metastases in normal-sized nodes.16,3537 In addition, its diagnostic accuracy in the preoperative assessment of extraregional lymph node metastases was low in the meta-analysis by Tseng et al.26 mainly because of poor sensitivity.

Magnetic resonance imaging and magnetic resonance cholangiopancreatography

Magnetic resonance imaging and magnetic resonance cholangiopancreatography (MRCP) can also detect primary pancreatic tumours as well as regional and distant metastases. Pancreatic cancer appears hypointense on T1-weighted images (Figures 3a and 3b).27 No clear advantage of MRI over CT has been demonstrated, although MRCP is more sensitive and at least as specific in diagnosing pancreatic carcinoma in comparison with endoscopic retrograde cholangiopancreatography (ERCP).27,38 Sensitivity and specificity of MRI with regard to tumour detection (84% and 82%, respectively) and assessment of resectability (85% and 78%, respectively) are inferior to that of CT.26 Despite these findings, MRI can be used as a first-line modality and has an important role in patients with equivocal findings on other modalities.16 Promising results have recently been reported with gadolinium-enhanced dynamic MRI combined with MRCP that was comparable to those of MDCT.39

FIGURE 3a

Coronal view of MRI/MRCP on a 45-year-old patient presenting with painless jaundice and pruritus over several weeks, because of a poorly differentiated adenocarcinoma of the ampulla of Vater. Significant intra- and extrahepatic duct dilatation is evident; the CBD is dilated to 13 mm with an abrupt cut-off at the distal end and the pancreatic duct is concurrently dilated to 7 mm.

8-2-6-fig3a.png
FIGURE 3b

Coronal view of MRI/MRCP demonstrating a 4.8 cm × 4.5 cm mixed signal mass (partly solid, partly cystic) in the pancreatic head (red arrows). Evidence of double-duct dilatation is also present, with beading of the pancreatic duct, which measures 5 mm in diameter, and stricturing of the distal CBD. There is also cystic duct and gallbladder dilatation with no evidence of calculi.

8-2-6-fig3b.png

Positron emission tomography

Positron emission tomography (PET) has been established as a useful non-invasive adjunct for the diagnosis of pancreatic cancer. The increased glycolytic activity of pancreatic cancer cells can be measured by PET with the use of 2[18F]-fluoro-2-deoxy-d-glucose (FDG), a radiolabelled analogue of glucose which enables 3-D visualization of regional glucose metabolism.40,41 FDG–PET has high detection sensitivity (82–100%) and specificity (75–100%), and has proven useful in the evaluation of recurrent or occult metastatic disease. It is of particular use in patients with suspected pancreatic cancer in whom CT fails to identify a discrete tumour mass,42 and may have a potential role in discerning pancreatic cancer from chronic pancreatitis.43,44 Although this functional imaging modality cannot replace CT in determining SMA and coeliac axis infiltration or in clarifying primary tumour resectability, its application as an addition to CT may alter clinical management in a proportion of patients.42,45 Notably, theoretical concerns have been raised regarding the limitations of this modality in patients with a significant degree of glucose intolerance, although these remain controversial.42,46

Recently, the combined use of FDG–PET and CT in a single modality (FDG–PET/CT) has been shown to provide further improvement in patient allocation to appropriate management pathways compared with stand-alone FDG–PET.45,47 It has been proposed for the evaluation of diagnostically challenging patients, especially those with biliary stricture(s) without evidence of malignancy on conventional imaging.48 Furthermore, when combined with standard staging CT, it has an increased specificity (87%) in detecting metastatic disease compared with standard CT imaging.49 As with stand-alone FDG–PET, the sensitivity of combined FDG–PET/CT in detecting local lymph node metastases is suboptimal, and therefore it is not the method of choice in assessing resectability of the primary lesion.48 High cost is another drawback, although those who advocate its use argue that it may prove cost-effective by reducing the number of futile laparotomies.45

Interventional methods

Endoscopic retrograde cholangiopancreatography

Endoscopic retrograde cholangiopancreatography as a diagnostic modality for the investigation of patients with suspected pancreatic cancer has been replaced by MRCP, mainly because it does not contribute sufficient information regarding the tumour stage, but also because of the high rate of associated complications.38 The role of ERCP remains important for patients who are deeply jaundiced or present with cholangitis and require stenting, and it can be used to obtain tissue biopsy for histology or ductal brushing for lavage cytology.3,50 Sensitivity rates are low (65–70%) but may improve with the use of techniques such as digital image analysis.51,52 Inadvertent post-ERCP pancreatitis can cause difficulties in the interpretation of subsequent imaging, and it can increase the risk of complications during fine-needle aspiration (FNA).53 Moreover, the presence of a biliary stent may reduce the accuracy of a subsequent endoscopic ultrasound (EUS).54 Therefore, undertaking ERCP immediately after EUS with FNA has been proposed and has been shown to be associated with acceptable complication rates.55

Endoscopic ultrasound

In modern times, EUS has gained popularity as one of the most promising modalities in pancreatic cancer staging.56 It currently has a complementary role to modern CT imaging for the evaluation of patients with pancreatic cancer. With its high resolution, it is able to detect focal lesions as small as 2–3 mm and reliably and accurately diagnose vascular invasion (Figures 4a and 4b).8,57,58 Furthermore, EUS has been shown to be very accurate in assessing tumour size and lymph node involvement, and generally has a high negative predictive value, although results vary between different groups.5961 It is useful in patients with suspected pancreatic cancer and equivocal CT findings, and is the preferred method for tissue sampling by FNA.3,56 Importantly, the combination of CT and EUS has been reported as more cost-effective and as having higher accuracy in predicting resectability than each of the two techniques independently.56,61 Drawbacks include interobserver variability, increased cost and variable availability accessibility.8,56

FIGURE 4a

EUS identification of a 2.1 cm × 2.3 cm pancreatic head cancer.

8-2-6-fig4a.png
FIGURE 4b

EUS view of pancreatic head and adjacent structures during assessment of resectability. GDA, gastroduodenal artery; HOP, head of pancreas; PD, pancreatic duct; PV, portal vein.

8-2-6-fig4b.png

Endoscopic ultrasound–fine-needle aspiration is well established as the method of choice in obtaining tissue diagnosis of solid pancreatic masses and is considered more useful, more cost effective and safer than other biopsy procedures.62 In a recent meta-analysis by Hewitt et al.,63 EUS–FNA was shown to have pooled sensitivity and specificity of approximately 85% and 98%, respectively, and had an excellent positive predictive value (99%) and a satisfactory negative predictive value (64%). EUS–FNA-induced complications include infection, pancreatitis, haemorrhage and biliary peritonitis, but it is a safe procedure with reported complication rates ranging between 0% and 2%, with major complications being very rare.62,64,65

Over the last decade, efforts have focused on increasing EUS accuracy in various settings. Digital image processing and computer-aided image differentiation technologies have been applied to improve differentiation between pancreatic cancer and chronic pancreatitis.66 EUS elastography is a novel technique that achieves high sensitivity but moderate specificity in differentiating between pancreatic cancer and pancreatic inflammatory masses, by assessing tissue elasticity in real time during conventional EUS.67 It has been proposed as a supplemental method to EUS–FNA, especially in patients with negative FNA results and those with coexisting pancreatitis.67,68 Finally, second-generation contrast-enhanced harmonic EUS reveals parenchymal perfusion and pancreatic microvasculature, aiding in the differential diagnosis of pancreatic cancer from other tumours with high sensitivity and specificity.69,70

Laparoscopy

The concept of laparoscopic staging in pancreatic cancer was popularised by Cushieri et al.,71 who published the first patient series in 1978, boosting interest in the procedure in an era when the accuracy of radiological imaging was inferior to that of modern modalities.71,72 However, over the past few years, advances in radiological imaging have substantially improved preoperative assessment of pancreatic cancer resectability, and as a consequence the indication for staging laparoscopy has significantly diminished.73 In combination with imaging modalities, laparoscopy has been shown to offer an improved assessment of resectability, mainly because of its strength in identifying peritoneal deposits and small liver metastases, rather than assessing locally advanced disease.73,74 Studies have shown that it can prevent futile laparotomies by identifying unsuspected metastases in a significant proportion (15–51%) of patients, therefore being a valuable adjunct in the staging of pancreatic cancer patients.72 In addition, staging laparoscopy may be used in patients with locally advanced disease to improve staging and patient selection for down-staging or enrolment to palliative therapies.75,76

In most centres, laparoscopy is reserved for patients with potentially resectable pancreatic cancer and an increased likelihood of metastatic disease.72,73,77 Features suspicious for metastatic disease may include large tumour size, tumour location in the pancreatic body or tail, back pain, weight loss, hypoalbuminaemia, elevated level of CA 19-9, ascites or equivocal CT findings.27,78,79 Its selective use is justified by the need to reduce additional costs, and to avoid scheduling conflicts and unnecessary exposure of patients to two procedures performed under a general anaesthetic,15,73,80 although in some centres it is commonly performed immediately before the main procedure and under the same anaesthetic.77,8183 Notably, proponents of a more generalized application of laparoscopy argue that costs from a prolonged hospital stay and associated morbidity after an unnecessary laparotomy will be avoided.27,84

The use of peritoneal cytology testing can enhance the sensitivity of staging laparoscopy by improving the detection of occult metastatic disease. Positive cytology results are an indicator of advanced disease and are associated with reduced survival.85,86 However, the exact role of this method in resectable disease is not yet fully deciphered, and positive cytology results do not constitute a contraindication for surgery in patients with otherwise resectable pancreatic cancer.8789

Laparoscopic ultrasound

Standard staging laparoscopy as a two-dimensional modality that lacks tactile sensation and cannot identify small intraparenchymal lesions in the liver or pancreatic head or deep-seated retropancreatic vascular and lymph node involvement.83 The use of laparoscopic ultrasound as a supplement to standard imaging and laparoscopic staging can improve resectability by offering a more accurate evaluation of the primary tumour in relation to the vasculature and peripancreatic lymphatic and soft tissues, and can identify small hepatic metastases in patients with resectable or equivocal disease on imaging.27,83,85,9092

In addition, laparoscopic ultrasound can be used as an aid in the selection of suitable palliative therapy in patients with radiologically occult distant spread or locally advanced disease.85,93

Biomarkers

The dismal prognosis and late presentation of patients with pancreatic cancer has rendered the discovery of suitable biomarkers that would enable early disease detection in high-risk patients and improve prognosis, the target of rigorous research in recent years. Several molecules have been identified as potential biomarkers for the diagnosis, staging and monitoring of pancreatic cancer therapy, but none of those identified so far is considered ideal.94,95

Carbohydrate antigen 19-9

Carbohydrate antigen (CA) 19-9 is a tumour-associated antigen, first described by Koprowski et al.96,97 CA 19-9 is the sialylated Lewis (Le)a blood group antigen98 and cannot be synthesized by individuals with a Lea–b– phenotype,99 and therefore cannot be used as a biomarker in these individuals (approximately 6% of Caucasians and up to 35% of the black population).100 It is not currently recommended as a routine diagnostic or screening test for pancreatic cancer,101 as its sensitivity, specificity and positive predictive value are considered inadequate for an accurate diagnosis.102104

Findings from several studies on the diagnostic value of CA 19-9 have been pooled by Goonetilleke and Siriwardena105 in a systematic review, resulting in a median sensitivity and specificity of approximately 79% and 82%, respectively, which is in keeping with reports from other scientific groups.106111 Notably, only 50% of patients with tumours smaller than 20 mm are associated with an elevated CA 19-9 level.112 On the other hand, serum CA 19-9 may be raised in a variety of unrelated conditions, resulting in false-positive findings. Such conditions may include benign hepatobiliary and pancreatic diseases (e.g. pancreatitis, cholangitis, hepatitis), gastrointestinal malignancies, hepatocellular and obstructive jaundice, as well as other miscellaneous conditions.102,104,111

Nevertheless, CA 19-9 remains a valuable marker and has been shown to have clinical applications in selecting patients for staging laparoscopy,113,114 monitoring therapeutic progress and in the early detection of recurrent disease after treatment in patients with known pancreatic cancer.3,104

Other tumour markers

A large number of tumour markers have been proposed, and examples include chromogranin A, carcinoembryonic antigen, CA50, CA242, K-Ras, p53, CAM-17.1, a number of mucins, Duke pancreatic monoclonal antigen type 2, elastase 1 and SPan-1, to name but a few.8,104,115 In recent years, various strategies for phenotype profiling have emerged.95,116,117 Attempts to identify a panel of biomarkers based on genetic, immunological and biochemical changes in pancreatic cancer may prove useful, since the discovery of a single biomarker with high diagnostic accuracy is likely to remain challenging.94,115 Notably, Harsha et al.94 have taken an important initial step towards the systematic development of a repository of pancreatic cancer biomarkers.

Staging

Accurate staging drives appropriate treatment of patients with pancreatic cancer, particularly when selecting those for surgical resection. Avoiding futile laparotomy remains a key goal as this facilitates enrolment into a suitable non-operative palliative care pathway, and, more importantly, it protects quality of life and improves end-of-life care.27,118 Pancreatic cancer staging is performed according to the most recent edition of the American Joint Committee on Cancer TNM (tumour, node, metastasis) classification, which is based on imaging findings.119 MDCT or MRI with MRCP should be used for staging, whereas EUS can provide complementary information on vessel invasion and potential lymph node involvement, in addition to facilitating biopsy of the pancreatic lesion.

Clinical staging classifies patients as resectable, borderline resectable, locally advanced or with metastatic disease; a scale which for localized tumours may be considered a continuum from resectable to non-resectable disease, according to Ryan et al.120 Nevertheless, determining resectability of the primary tumour is the most important objective of the initial evaluation.9 Specific imaging criteria that define resectability status have been published by the National Comprehensive Cancer Network in 2014121 – previously adopted by the European Society of Medical Oncology122 – with version 1.2015 being the latest available update. The absence of radiological evidence of peritoneal or hepatic metastases is a prerequisite for both resectable and borderline resectable disease. In addition, resectable tumours should demonstrate no radiographical evidence of SMV or portal vein distortion and clear fat planes around the coeliac axis, the hepatic artery and SMA. Conversely, borderline resectable disease includes, amongst others, tumours with resectable SMV or portal vein involvement or with SMA abutment less than 180°, although no perfect definition is currently possible for this stage.27,121

Future directions

Despite recent technological advancements in the diagnostic approach to pancreatic cancer and refinement of the clinical staging algorithm, early diagnosis remains a challenging task, and a substantial improvement in patient outcomes has not yet been observed. Accurate screening of high-risk populations by means of suitable biomarkers and/or imaging is a field of rigorous research that may hold the key to the long-awaited improvement in survival.

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