**3. Diagnosis**

Early PC is often detected incidentally, with identification of a non-specific pancreatic lesion. The gold-standard treatment of early PC is with pancreaticoduodenectomy ('Whipple's' procedure); a major surgical undertaking with significant morbidity. Ensuring an accurate diagnosis of malignancy is crucial to preventing unnecessary surgeries and the complications thereof.

Diagnosing early PC noninvasively has been historically a difficult undertaking. Clinical suspicion of PC is often based on either non-specific clinical features (asthenia, weight loss, abdominal pain, anorexia, etc.), or features that are associated with advanced disease (jaundice, hepatomegaly, abdominal distension, signs of pancreatic insufficiency, etc.), but specific to pancreatic malignancy. Contributory evidence of malignancy has historically involved clinical history, including presence of risk factors for PC (discussed previously), serum level of cancer antigen 19-9 (CA19-9), and radiographical appearance on transabdominal ultrasound (US), computed tomography (CT), or magnetic resonance imaging (MRI). The advent of EUS and EUS-FNA has allowed for more accurate radiographical assessment of pancreatic lesions, as well as direct sampling to allow histological assessment of the lesion.

#### **3.1. Tumour markers**

CA19-9 is a useful biomarker for monitoring response to treatment, or disease progression or recurrence in patients with an established histological diagnosis of PC [8]. However, the specificity of CA19-9 (68–92%) and positive-predictive value (0.9% for serum concentrations >37 units/mL) negates the utility of CA19-9 in the diagnosis of PC [9].

#### **3.2. Imaging**

**2. History**

74 Advances in Pancreatic Cancer

**3. Diagnosis**

Endoscopy in its modern form began in 1806 with the invention of the Lichleiter, or 'light conductor', by Philipp Bozzini. This device consisted of two parts: the light container and viewing device, and the mechanical part (various speculae) that facilitated access to the subject's body. The fibre-optic endoscope was originally invented by the then medical student, Heinrich Lamm in 1930 [1]. Poor image quality limited the utility of this endoscope until scientific advances made by Harold Hopkins and Narinder Singh Kapany in 1954 [2] were

Ultrasound as an investigational modality was also being developed at this time, with Neurologist Dr. Karl Dussik publishing the first use of diagnostic ultrasound in 1941 [4]. The addition of radial ultrasound technology to endoscopy is credited to Dr. DiMagno in 1980, who felt that by internalising the ultrasound probe, problems with interfering gas patterns and nearby organs could be avoided, and the accuracy of ultrasound would be improved [4]. Although the intent at the time was to use this technique to image the pancreas, the coupling of endoscopy and ultrasonography also led to the development of transoesophageal echocar-

In 1991, Dr. Peter Vilmann and Søren Hancke utilised the curved linear array endoscope to facilitate minimally-invasive diagnostic and therapeutic interventions during endoscopic ultrasound [5]. The use of the linear array ultrasound probe enabled the use of instrument channels. These channels have facilitated the current utility of endoscopic ultrasound to perform fine needle aspirations (EUS-FNA) for diagnostic purposes, and for minimally-invasive therapeutic alternatives to radiologically-guided, or surgical drainage of collections, for bili-

Early PC is often detected incidentally, with identification of a non-specific pancreatic lesion. The gold-standard treatment of early PC is with pancreaticoduodenectomy ('Whipple's' procedure); a major surgical undertaking with significant morbidity. Ensuring an accurate diagnosis of malignancy is crucial to preventing unnecessary surgeries and the complications thereof.

Diagnosing early PC noninvasively has been historically a difficult undertaking. Clinical suspicion of PC is often based on either non-specific clinical features (asthenia, weight loss, abdominal pain, anorexia, etc.), or features that are associated with advanced disease (jaundice, hepatomegaly, abdominal distension, signs of pancreatic insufficiency, etc.), but specific to pancreatic malignancy. Contributory evidence of malignancy has historically involved clinical history, including presence of risk factors for PC (discussed previously), serum level of cancer antigen 19-9 (CA19-9), and radiographical appearance on transabdominal ultrasound (US), computed tomography (CT), or magnetic resonance imaging (MRI). The advent of EUS and EUS-FNA has allowed for more accurate radiographical assessment of pancreatic

lesions, as well as direct sampling to allow histological assessment of the lesion.

adapted by Dr. Basil Hirschowitz to create the flexible fiberscope [3].

diography, endoscopic bronchial ultrasound, and trans-rectal ultrasound.

ary drainage (EUS-BD), and to perform celiac plexus neurolysis (EUS-CPN) [6, 7].

#### *3.2.1. Transabdominal ultrasound (US)*

US can be used to assess pancreatic masses ≥3 cm in size with up to 95% sensitivity [10]. Specificity of US is reported between 94 and 98%, however sensitivity decreases substantially when assessing smaller lesions, and is highly operator-dependent [11]. In order to improve detection of PCs at a size where curative resection is achievable, more sensitive investigations are necessary.

#### *3.2.2. Computed tomography (CT)*

Abdominal CT scan (multidetector CT, MDCT) has a sensitivity nearing 100% for pancreatic lesions >2 cm, which reduces to 77% for tumours ≤2 cm [12]. Its utility in assessing local extension is demonstrated by an accuracy for predicting surgical resectability of 80–90% [13], however is limited by its ability to detect liver metastases and early lymph node metastases [11].

#### **3.3. Percutaneous biopsy**

Percutaneous, image-guided pancreatic mass biopsies using ultrasound or CT, are safe and effective at obtaining the diagnosis of PC. Due to the direct sampling nature of the procedure, specificity is close to 100%, with varying sensitivity between 80 and 90% [14]. Theoretic concerns with regards to percutaneous biopsies include the risk of tumour seeding along the biopsy tract, or the increased risk of peritoneal carcinomatosis in patients having undergone percutaneous biopsy, and is contraindicated in potentially-resectable cases [15].

#### **3.4. EUS-guided biopsy**

EUS-guided fine-needle aspiration (EUS-FNA) uses the instrument channel of the endoscopy to pass a biopsy needle in front of the linear-array ultrasound probe to obtain tissue from lesions under direct ultrasound visualisation. The angle of the needle can be modified to target more cellular-appearing aspects of the target lesion. Two to 10 passes are made into the lesion with the needle and the use of an on-site cytopathologist, or specialist nurse trained in assessment of samples for cellularity is recommended. EUS-FNA allows for tissue acquisition for diagnostic purposes with a low rate of morbidity and mortality, and allows for early genetic and molecular analysis for research and therapeutic decisions [16].

Eloubeidi et al. conducted a review of 100 patients who underwent EUS-FNA, and found 95% sensitivity, 95% specificity, 100% positive predictive value, and 85.2% negative predictive value [17]. These results have been replicated and shown to hold in multiple studies, including a meta-analysis and systematic review by Puli et al. , who identified 41 studies of EUS-FNA and found a pooled sensitivity of determining the correct nature of pancreatic masses of 86.8% (95% CI 85.5–87.9), a specificity of 95.8% (95% CI 94.6–96.7), a positive likelihood ratio of 15.2 (95% CI 8.5–27.3), and a negative likelihood ratio of 0.17 (95% CI 0.13–0.21) [18].

Chen et al. conducted a systematic review to determine the accuracy of EUS-FNA. They identified 15 studies, totalling 1860 patients and found 92% sensitivity (95% CI 91–93%, p < 0.001, I2 = 69.6%), 96% specificity (95% CI 93–98%, p = 0.006, I<sup>2</sup> = 54.9%) [19]. From a practical point of view, the additional benefit of EUS in the assessment of pancreatic lesions is that radiological characterisation of the lesion, local extension and nodal involvement, and histological sampling can all occur in the one procedure, as opposed to US assessment followed by a separate imaging-guided biopsy.

However, a more recent Cochrane review highlighted the lack of quality studies in the area of comparative diagnostics with regards to PC; conclusions were unable to be drawn from the data as only three articles were identified that met the pre-defined quality parameters [20]. There is a paucity of good-quality head-to-head prospective, randomised controlled trials that compare the investigative modalities and heterogeneity in the inclusion criteria of many of the current studies within the literature. Coupled with variability in access and quality of EUS-FNA, interpreting the comparative efficacy and developing a standardised pathway for the investigation of pancreatic lesions remains open to debate.

Horwhat et al. reported an interesting randomised crossover trial comparing EUS-FNA with percutaneous biopsy. Patients with non-diagnostic first-line investigations were allowed to cross over to be investigated with the alternate modality. Fewer patients who received upfront EUS-FNA went on to have percutaneous biopsy (8/36 (22%) versus 16/36 (44%)). The comparative sensitivity of percutaneous biopsy and EUS-FNA was 62% (95% CI 0.41–0.80) and 84% (95% CI 0.64–0.95), respectively (p = 0.1164) [21]. In such a lethal disease, in a population where clinical deterioration often happens suddenly, accuracy in diagnosis is vital to facilitating early treatment. This study lends support to EUS-FNA over percutaneous biopsy for obtaining an early and accurate diagnosis.

Okasha et al. conducted a multicentre, prospective, controlled trial in a non-randomised population of EUS-FNA versus ultrasound-guided percutaneous biopsy (US-FNA) in the investigation of pancreatic head tumours. The investigative modality was dictated by accessibility and feasibility. One hundred and ninety seven patients underwent investigation and comparable accuracy (88.9% for EUS-FNA; 87.2% for US-FNA), sensitivity (84% EUS-FNA; 85.5% US-FNA), specificity (100% EUS-FNA; 90.4% US-FNA), positive predictive value (100% EUS-FNA; 94.7% US-FNA), and negative predictive value (73.3% EUS-FNA; 76% US-FNA) were found. Complications occurred in 1/72 patients (1.38%) in the EUS-FNA group (abdominal pain secondary to pancreatitis), compared with 7/125 (5.6%) in the US-FNA group (three cases of severe post-procedure epigastric pain, three cases of peritoneal seeding, and one case of pancreatic abscess requiring surgical debridement and drainage) [22].

with 1 case each of intraductal papillary mucinous neoplasia (IPMN), gastric cancer, malignant melanoma, and squamous cell cancer of unknown origin. All cases of needle tract seeding with relation to investigation of PC occurred with a transgastric approach and did not appear

**Figure 1.** CT and corresponding EUS image of a pancreatic mass that proved to be autoimmune pancreatitis.

Endoscopic Ultrasound in Pancreatic Cancer http://dx.doi.org/10.5772/intechopen.75211 77

EUS-FNA of solid masses is generally a safe procedure, with a reported overall complication rate of 0.5–2.54% [24, 25]. Complications include infection, bleeding, and acute pancreatitis. The mortality rate of the procedure has been quoted at 0.04% [25]. Several studies have not found significant benefit in diagnostic yield or complication rate relative to needle size used [26–28]. The use of core (trucut) biopsy (EUS-TCB) instead of, or in combination with FNA has not been investigated to an extent to definitively support its use [29]. EUS-TCB has the potential to provide information about tissue architecture, as well as allow for retrieval of a larger volume of tissue, which in an era of expanding availability of histological and molecular analyses, may become a more desirable methodology, however more information regard-

to be related to needle size (mostly 22G) or number of passes (range 1–5).

**Figure 2.** CT and corresponding EUS image of a pancreatic mass that proved to be pancreatic cancer.

ing the comparative efficacy and safety is required.

It is important to recognise that peritoneal seeding after EUS-FNA has been reported [23], and is therefore not a delineating factor between choosing between percutaneous and EUS-guided biopsy. Of the 15 cases of needle tract seeding reported in this review of case studies of needletract seeding after EUS biopsy, 11 occurred during evaluation of pancreatic adenocarcinoma,

a meta-analysis and systematic review by Puli et al. , who identified 41 studies of EUS-FNA and found a pooled sensitivity of determining the correct nature of pancreatic masses of 86.8% (95% CI 85.5–87.9), a specificity of 95.8% (95% CI 94.6–96.7), a positive likelihood ratio of 15.2

Chen et al. conducted a systematic review to determine the accuracy of EUS-FNA. They identified 15 studies, totalling 1860 patients and found 92% sensitivity (95% CI 91–93%, p < 0.001, I2 = 69.6%), 96% specificity (95% CI 93–98%, p = 0.006, I<sup>2</sup> = 54.9%) [19]. From a practical point of view, the additional benefit of EUS in the assessment of pancreatic lesions is that radiological characterisation of the lesion, local extension and nodal involvement, and histological sampling can all occur in the one procedure, as opposed to US assessment followed by a separate

However, a more recent Cochrane review highlighted the lack of quality studies in the area of comparative diagnostics with regards to PC; conclusions were unable to be drawn from the data as only three articles were identified that met the pre-defined quality parameters [20]. There is a paucity of good-quality head-to-head prospective, randomised controlled trials that compare the investigative modalities and heterogeneity in the inclusion criteria of many of the current studies within the literature. Coupled with variability in access and quality of EUS-FNA, interpreting the comparative efficacy and developing a standardised pathway for

Horwhat et al. reported an interesting randomised crossover trial comparing EUS-FNA with percutaneous biopsy. Patients with non-diagnostic first-line investigations were allowed to cross over to be investigated with the alternate modality. Fewer patients who received upfront EUS-FNA went on to have percutaneous biopsy (8/36 (22%) versus 16/36 (44%)). The comparative sensitivity of percutaneous biopsy and EUS-FNA was 62% (95% CI 0.41–0.80) and 84% (95% CI 0.64–0.95), respectively (p = 0.1164) [21]. In such a lethal disease, in a population where clinical deterioration often happens suddenly, accuracy in diagnosis is vital to facilitating early treatment. This study lends support to EUS-FNA over percutaneous biopsy

Okasha et al. conducted a multicentre, prospective, controlled trial in a non-randomised population of EUS-FNA versus ultrasound-guided percutaneous biopsy (US-FNA) in the investigation of pancreatic head tumours. The investigative modality was dictated by accessibility and feasibility. One hundred and ninety seven patients underwent investigation and comparable accuracy (88.9% for EUS-FNA; 87.2% for US-FNA), sensitivity (84% EUS-FNA; 85.5% US-FNA), specificity (100% EUS-FNA; 90.4% US-FNA), positive predictive value (100% EUS-FNA; 94.7% US-FNA), and negative predictive value (73.3% EUS-FNA; 76% US-FNA) were found. Complications occurred in 1/72 patients (1.38%) in the EUS-FNA group (abdominal pain secondary to pancreatitis), compared with 7/125 (5.6%) in the US-FNA group (three cases of severe post-procedure epigastric pain, three cases of peritoneal seeding, and one case

It is important to recognise that peritoneal seeding after EUS-FNA has been reported [23], and is therefore not a delineating factor between choosing between percutaneous and EUS-guided biopsy. Of the 15 cases of needle tract seeding reported in this review of case studies of needletract seeding after EUS biopsy, 11 occurred during evaluation of pancreatic adenocarcinoma,

of pancreatic abscess requiring surgical debridement and drainage) [22].

(95% CI 8.5–27.3), and a negative likelihood ratio of 0.17 (95% CI 0.13–0.21) [18].

the investigation of pancreatic lesions remains open to debate.

for obtaining an early and accurate diagnosis.

imaging-guided biopsy.

76 Advances in Pancreatic Cancer

**Figure 1.** CT and corresponding EUS image of a pancreatic mass that proved to be autoimmune pancreatitis.

**Figure 2.** CT and corresponding EUS image of a pancreatic mass that proved to be pancreatic cancer.

with 1 case each of intraductal papillary mucinous neoplasia (IPMN), gastric cancer, malignant melanoma, and squamous cell cancer of unknown origin. All cases of needle tract seeding with relation to investigation of PC occurred with a transgastric approach and did not appear to be related to needle size (mostly 22G) or number of passes (range 1–5).

EUS-FNA of solid masses is generally a safe procedure, with a reported overall complication rate of 0.5–2.54% [24, 25]. Complications include infection, bleeding, and acute pancreatitis. The mortality rate of the procedure has been quoted at 0.04% [25]. Several studies have not found significant benefit in diagnostic yield or complication rate relative to needle size used [26–28]. The use of core (trucut) biopsy (EUS-TCB) instead of, or in combination with FNA has not been investigated to an extent to definitively support its use [29]. EUS-TCB has the potential to provide information about tissue architecture, as well as allow for retrieval of a larger volume of tissue, which in an era of expanding availability of histological and molecular analyses, may become a more desirable methodology, however more information regarding the comparative efficacy and safety is required.

**Figures 1** and **2** below show the abdominal CT scan and EUS images of two patients referred to our institution for investigation of painless jaundice and a pancreatic mass. The red arrows in the CT images indicate the pancreatic lesion; the red arrows in the ultrasound image indicted the EUS-FNA needle within the pancreatic mass. In the first case (**Figure 1**), the CT scan and US findings were suspicious for autoimmune pancreatitis. The patient was commenced on high-dose steroids and the lesion resolved and liver function tests returned to normal. In the second case (**Figure 2**) the EUS FNA confirmed the clinical and radiological suspicion of pancreatic cancer.

• Aortic involvement • Distant metastases

surgical resectability [35].

**5. Screening**

are not appreciated as unresectable.

• Presence of disease in lymph nodes beyond the field of resection

EUS provides high-resolution images of the primary mass, its relationship to local structures, and the appearance of regional lymph nodes. Conversely to CT, although EUS can detect some liver metastases, it provides insufficient information on distant disease. There have been few studies directly comparing the two modalities, however the combination of both modalities for their relative strengths seems to be the way forward. One study has shown an equivalent PPV of surgical resectability with regards to T-staging of either modality (63%), with a significant increase to 86% when used in combination [34]. While most studies have shown equivalence of EUS and CT with regards to N-staging, EUS has shown greater accuracy in assessing mesenteric vessel involvement, which often has a significant impact on determining

Endoscopic Ultrasound in Pancreatic Cancer http://dx.doi.org/10.5772/intechopen.75211 79

EUS has previously been thought to be superior to CT scanning for the detection and assessment of smaller pancreatic lesions, however comment has been made that the technological advances in radiology continually improving the resolution of CT images that contemporary CT scans may show more accurate results. EUS has however, been shown to lead to less overstaging than multidetector CT (MDCT) and MRI [35]. This is crucial so that resectable cases

The use of EUS in screening patients at increased risk (high-risk individuals [HRIs]) has been suggested due to the lethality of the disease, and the often late-onset of clinical features leading to a very low rate of patients diagnosed at a sufficiently-early stage to undergo curativeintent treatment (15–20%) [30]. In line with the Wilson and Jungner criteria for screening, PC is an important health problem with an acceptable treatment, with a 'latent' phase wherein curative treatment can be undertaken. EUS is a suitable test for early-stage disease that would be likely acceptable to an at-risk population. The questions remain as to whether EUS is yet an accessible test from a resource-availability perspective, and accurately defining HRIs to whom screening could be offered. Subsequent to this, EUS screening of HRIs is yet to be

Identifying HRIs should be based on risk factors for PC. Risk factors such as family history, presence of germline mutations (BRCA1, ATM, PALB2, CDKN2A, and MLH1), Peutz-Jeghers syndrome (PJS), cystic fibrosis, race, ABO blood group, chronic pancreatitis, diabetes mellitus, smoking history, and obesity, are all factors that could be combined to develop a pancreatic risk score. Wang et al. have developed PancPRO, a predictive model for PC using Bayesian modelling to provide risk stratification for developing PC based on family history. It was validated prospectively using the National Familial Pancreas Tumour Registry with an observed to predicted PC ratio of 0.83 (95% CI 0.52–1.20) [36]. The combination of risk stratification algorithms

proven to be efficacious, let alone cost-effective to offer as a screening tool.
