Endoscopic Ultrasound and Fine-Needle Aspiration for Pancreatic and Biliary Disorders

Introduction

Endoscopic ultrasound (EUS) is a powerful technique that is integral to the management of many patients with biliary and pancreatic disease. EUS provides detailed images of the extrahepatic biliary tree and pancreas with very little risk to the patient, and is useful in the evaluation of obstructive jaundice, biliary or pancreatic ductal dilation, pancreatic masses, and pancreatitis. EUS and endoscopic retrograde cholangiopancreatography (ERCP) can be performed during the same sedation session, with EUS identifying patients likely to benefit from therapeutic ERCP. EUS-guided therapeutic interventions have an evolving role in selected patients, including celiac plexus block (CPB), fiducial placement, drainage of pancreas fluid collections, and EUS-guided drainage of inaccessible biliary and pancreatic ducts. EUS is an increasingly important tool for the biliary and pancreatic endoscopist. This chapter reviews the technique of pancreaticobiliary EUS and discusses its role in selected diagnoses. The role of EUS in patients with pancreatic malignancies, pancreatic cysts, and cholangiocarcinoma is discussed in other chapters.

Gallbladder Stones, Sludge, and Polyps

EUS is useful for diagnosis of gallbladder sludge or stones missed by transabdominal ultrasound, and is more sensitive than bile microscopy in patients with these conditions ( Fig. 51.1 ). It may be especially useful in obese patients and patients with stones in the gallbladder neck, settings in which transabdominal ultrasound is less sensitive for diagnosis. Sludge is visualized as echogenic, nonshadowing, layering material. It should not be confused with gain artifact or “ring-down artifact,” which appears as circular bright lines parallel to the transducer. A clear-cut sludge/bile interface is helpful for diagnosis of sludge. Cholesterol crystals have straight edges and are highly echogenic; they appear as bright flecks in bile, sometimes casting “comet tails.” Calcium bilirubinate granules are rounded and much less echogenic, and can be missed by EUS unless they are present in sufficient quantity to form layering sludge.

EUS has been used for differential diagnosis of gallbladder polyps. The best clinical studies have been reported from Asia, and their applicability to Western populations has not been well studied. Most gallbladder polyps are readily imaged, although the fundus and cap of the gallbladder may be difficult or impossible to visualize in some patients. Adherent sludge can mimic a gallbladder polyp, but sludge can usually be distinguished from polyp by gently shaking the patient's abdomen or turning the patient to the right decubitus position during EUS to determine whether the lesion moves ( Fig. 51.2 ).

The differential diagnosis of gallbladder polyps is listed in Table 51.1 . The size of gallbladder polyps is the single most important consideration in differential diagnosis. Neoplasm is unlikely in polyps with a diameter of 5 mm or less, but is usually present in polyps greater than 15 mm in diameter, at least in Asian populations. In patients with primary sclerosing cholangitis (PSC), neoplasia is likely in polyps of 8 mm diameter or greater, and cholecystectomy is recommended for gallbladder polyps in patients with PSC who have good liver function. Particular ultrasound echofeatures that predict the type of polyp have been identified. Doppler evidence of vascularity has been associated with neoplasia in gallbladder polyps when evaluated by transabdominal ultrasound. Neoplastic polyps may contain hypoechoic foci, whereas cholesterol polyps often contain bright, echogenic spots or demonstrate comet tail artifacts caused by cholesterol crystals in the lesion. Adenomyomatosis typically appears as multiple small cystic or anechoic spaces, and may also show evidence of cholesterol deposits in the lesion. However, these features lack high predictive accuracy, particularly in polyps less than 10 mm in diameter. When the distinctive findings of a non-neoplastic polyp are seen in a patient without risk factors for gallbladder cancer (such as stones or PSC), it may be reasonable to investigate larger gallbladder polyps, at least those that are less than 20 mm in diameter, although neoplastic polyps containing EUS features of cholesterolosis or adenomyomatosis have been reported. Neoplasm should be considered when the characteristic findings of a non-neoplastic lesion are absent and the lesion is greater than 5 mm, even in lesions confined to the mucosa. Loss of gallbladder wall architecture is suggestive of an invasive cancer.

Bile Duct Stones

EUS is highly accurate for the diagnosis of choledocholithiasis. EUS is especially useful in patients with a low or intermediate risk of bile duct stones, refining the use of ERCP and decreasing the overall risks of an endoscopic approach.

The accuracy of EUS for the diagnosis of bile duct stones and sludge relies on both endoscopic and patient factors. The common duct is best visualized from the duodenal bulb, where it can be followed from the common hepatic duct to the periampullary region. The biliary confluence is sometimes visualized from the bulb, more often with linear array echoendoscopes. The bile duct is distinguished from adjacent vessels by identifying its convergence with the pancreatic duct as both ducts taper into the duodenal wall ( Fig. 51.3 ). The cystic duct insertion is another useful landmark. In addition, the bile duct wall has an inner hypoechoic mucosal layer that is not present in adjacent vessels. Imaging should also be performed with the endoscope opposite the ampulla in the second duodenum for detection of stones in the ampulla or periampullary bile duct.

Stones are identified as echogenic structures casting dark acoustic shadows ( Fig. 51.4 ). Air bubbles in the duct also appear as echogenic, rounded structures, but cast hyperechoic acoustic reverberations instead of shadows. Sludge or cholesterol crystals can be visualized in the bile duct, much as they are visualized in the gallbladder (see Fig. 51.1 ).

Diagnosis of ductal stones is easiest when small stones are present in a dilated duct, the very situation in which cholangiography can miss stones. Conversely, sonographic diagnosis may be challenging when a diminutive duct is present or when the common duct is completely filled with stones, obliterating a visible ductal lumen. Care should be taken to visualize the entire bile duct, not skipping over portions. It is important to recognize a technically inadequate or incomplete EUS exam, and to consider other imaging tests rather than concluding that no stones are present.

EUS (either radial or linear) has similar or superior sensitivity and overall accuracy for the diagnosis of bile duct stones compared to ERCP or magnetic resonance cholangiopancreatography (MRCP). EUS appears to be more accurate for the diagnosis of stones less than 5 mm in diameter, and may also be preferable for the diagnosis of ampullary stones, whereas MRCP diagnoses intrahepatic duct stones not visualized by EUS.

EUS can be used as the sole imaging study to exclude choledocholithiasis prior to laparoscopic cholecystectomy. When EUS showed no bile duct stones, recurrent symptoms due to ductal stones did not occur during almost 3 years of follow-up in a European cohort. Several prospective randomized trials have compared clinical outcomes when either EUS or ERCP are used to evaluate the bile duct in patients at intermediate risk for bile duct stones, such as those with uncomplicated biliary pancreatitis or elevated serum liver tests. Taken together, these studies show higher diagnostic accuracy, fewer overall complications, and less resource utilization in patients evaluated with EUS. The majority of patients enrolled in the EUS arm of these studies did not have bile duct stones and did not require ERCP; those who did have ductal stones usually underwent ERCP immediately following EUS, under the same sedation. EUS has emerged as a preferred alternative to ERCP in patients at intermediate risk of bile duct stones, including many patients with a “positive” intraoperative cholangiogram.

Biliary intraductal ultrasound (IDUS) is also accurate for diagnosis of bile duct stones and sludge. IDUS requires deep cannulation of the bile duct with the intraductal probe, which can be passed over a guidewire without sphincterotomy. Most investigators have performed IDUS after obtaining a cholangiogram during ERCP. To minimize trauma to the probe and extend its useful life, the operator should use as little elevator as possible and image only during slow probe withdrawal.

Because IDUS utilizes a high-frequency probe placed directly in the duct, it is probably the best available imaging technique for the diagnosis of small stones and ductal sludge. In one direct comparison of cholangiography and IDUS, the sensitivity of IDUS for stones was 97%, compared to 81% for ERCP. Because it is performed during ERCP, IDUS is probably best used to clarify the diagnosis in patients with equivocal findings at cholangiography, such as small filling defects, possible air bubbles or polyps in the bile duct, or a dilated bile duct. The use of IDUS improves diagnostic accuracy in approximately one-third of these patients. The need to diagnose and treat small (< 5 mm) stones detected only with IDUS has been questioned, however, because such stones often pass spontaneously.

Direct cannulation of the papilla via a linear array echoendoscope with endosonographic confirmation of deep bile duct cannulation and subsequent sphincterotomy and stone extraction is technically feasible and appears to have similar efficacy and complications as standard ERCP for sphincterotomy and stone extraction in patients with small bile duct stones. This technique may be desirable in pregnant patients, as it avoids use of fluoroscopy.

Bile Duct Strictures

Biliary strictures may be of indeterminate etiology, particularly when cross-sectional imaging and intraductal biopsies and brushings obtained during ERCP are nondiagnostic. The cholangiographic appearance of a stricture and the patient's clinical history traditionally determined whether unexplained bile duct strictures should be resected on suspicion of malignancy. EUS and IDUS may be used to evaluate biliary strictures, and may aid clinical decision-making by suggesting a benign or malignant process. Endosonography can also be used for local staging of malignant biliary strictures.

The bile duct wall appears to have two or three layers on EUS and IDUS ( Fig. 51.5 ). An internal, hyperechoic layer is sometimes seen, representing an interface echo. Deep to this layer is a hypoechoic layer corresponding to the mucosa, subepithelial connective tissue, muscularis propria, and the fibrous layer of the subserosa. The amount of muscularis varies, with little or no muscularis propria in the proximal bile duct. Deep to this hypoechoic layer is an outer hyperechoic layer formed by the adipose layer of the subserosa, the serosa, and the interface with surrounding tissue. The normal bile duct wall is less than 1 mm thick on EUS, although the presence of a stent or drain in the duct may lead to thickening of the wall up to 2.8 mm.

The bile duct wall layers can be identified with either EUS or IDUS. IDUS probes can be passed into the central intrahepatic ducts, visualizing portions of the biliary tree not usually accessible to transduodenal EUS, and IDUS also provides high resolution images of the bile duct wall and adjacent vessels and tissue. EUS with a dedicated echoendoscope can image the extrahepatic biliary tree, including Klatskin tumors, and its deeper penetration depth permits a thorough assessment of the gallbladder, pancreatic head, and regional nodes. The two techniques are complementary.

Endosonography has been used for differential diagnosis of indeterminate bile duct strictures. During IDUS, malignant strictures typically appear hypoechoic with a thickened wall and irregular margins, whereas postoperative strictures are usually relatively hyperechoic with smooth edges. Importantly, both PSC and IgG4-related sclerosing cholangitis (IgG4-SC) can mimic malignant strictures on IDUS. IgG4-SC typically presents with diffuse thickening of the wall of long segments of the bile duct, including regions with no cholangiographic stricture. Studies have shown IDUS and EUS to be more accurate than ERCP and intraductal tissue sampling for the diagnosis of malignant bile duct strictures, although these were retrospective studies that included few or no patients with PSC or IgG4-SC. In a large prospective study, IDUS was as useful as advanced cytology techniques (including fluorescent in-situ hybridization) for the diagnosis of indeterminate strictures. The combination of ERCP and IDUS is reported to have superior diagnostic accuracy for indeterminate bile duct strictures compared to EUS or CT. Indeterminate strictures are discussed in further detail in a later chapter of this book.

Both EUS and IDUS have been used to stage cholangiocarcinoma. The two techniques have a similar T stage diagnostic accuracy of approximately 80%, and can differentiate T1 lesions confined to the bile duct wall (involving the hypoechoic layer) from T2 lesions invading beyond the bile duct wall (with disruption of the outer hyperechoic layer) ( Fig. 51.6 ). IDUS is more useful than EUS for lesions of the proximal biliary tree. IDUS has also been used to estimate the longitudinal extent of cholangiocarcinoma because cholangiography often underestimates the longitudinal extent of ductal involvement. Unfortunately, nonspecific thickening of the bile duct wall due to the presence of a stent or drain limits the value of IDUS in previously drained patients. Intravenous ultrasound contrast may improve the specificity of IDUS for malignancy, demonstrating hyperperfusion of inflammatory lesions and hypoperfusion of tumor.

IDUS is probably a sensitive modality for the diagnosis of early cholangiocarcinoma in choledochal cysts. The technique should be considered in adult patients with choledochal cysts, especially if surgical resection of the cyst is not otherwise planned.

The diagnosis and staging of cholangiocarcinoma by EUS, IDUS, and EUS-FNA are discussed in detail in a later chapter.

Ampulla of Vater

EUS provides detailed images of the papilla of Vater. The papilla is best located during slow withdrawal of the echoendoscope from the third duodenum, using sonographic rather than endoscopic landmarks. The ventral pancreas is visualized, and the bile duct and/or pancreatic duct lumens identified. The ducts can then be traced to the duodenal wall and papilla. Administration of intravenous glucagon and instillation of water into the duodenum may improve visualization once the periampullary region has been located.

The submucosal apparatus of the papilla can be visualized as a round hypoechoic structure in the duodenal submucosa, composed of the sphincter of Oddi and the intramural ducts. This normal submucosal structure is usually 4 to 7 mm in transverse cross-sectional diameter. The lumens of the bile duct and the pancreatic duct are usually not visible within the papilla; they generally taper and disappear from view as they reach the duodenal wall. The finding of a visible ductal lumen in the papilla suggests obstruction of the papilla by a stone (see Fig. 51.3 ), stenosis, or tumor, but can also be seen in choledochocele (type 3 choledochal cyst) and intraductal papillary mucinous neoplasm.

IDUS has been used to study the ampulla, and may aid in the local staging of some ampullary tumors. It identifies the sphincter mechanism and permits accurate measurement of its length. Sonographic features do not distinguish normal from hypertensive sphincters.

Ampullary Neoplasms

Adenomas of the papilla may occur on the duodenal surface of the papilla, within the papilla in the mucosa of the intraampullary ducts, or both. They may spread into or arise from the periampullary bile duct or pancreatic duct. EUS findings can include a mucosal mass on the duodenal surface of the papilla, enlargement of the submucosal ampullary apparatus due to intraampullary polyp, thickening of the periampullary duct walls, or the presence of an intraductal nonshadowing mass. These findings can be seen both in ampullary adenoma and in T1 ampullary cancer, and the two entities may be difficult or impossible to distinguish with EUS. We routinely perform EUS prior to ampullectomy to evaluate for intraductal extension.

The TNM staging of ampullary cancers is shown in Table 51.2 and illustrated in Fig. 51.7 . T1 carcinoma may be limited to the mucosal surfaces of the ampulla and intraampullary ducts, but may also involve the sphincter mechanism of the ampulla. The presence of an irregular outer edge of the submucosal ampullary apparatus suggests a T2 lesion invading the duodenal submucosa or muscularis propria. T3 cancers invade the pancreas, extending either through the duodenal wall or else directly from the periampullary ducts. A T4 tumor extends into peripancreatic soft tissue or other adjacent structures. Regional lymph nodes include not only those adjacent to the pancreatic head but also the portal hepatic and celiac nodes.

TABLE 51.2

Staging of Ampullary Carcinoma

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2009) published by Springer-Verlag New York, www.springer-ny.com .

TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ
T1	Tumor limited to ampulla of Vater or sphincter of Oddi
T2	Tumor invades duodenal wall
T3	Tumor invades pancreas
T4	Tumor invades peripancreatic soft tissues or other adjacent organs or structures other than the pancreas
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastases
N1	Regional lymph node metastases
M0	No distant metastases
M1	Distant metastases
Stage 0	Tis	N0	M0
Stage 1A	T1	N0	M0
Stage 1B	T2	N0	M0
Stage 2A	T3	N0	M0
Stage 2B	T1–3	N1	M0
Stage 3	T4	Any N	M0
Stage 4	Any T	Any N	M1

In one large series, EUS accuracy for T staging of ampullary malignancies was 78%. Adenomas were considered T1 lesions, highlighting the difficulty of distinguishing adenoma from T1 cancer with EUS. Most errors in staging involved overstaging of T2 lesions or understaging of T3 lesions, due to the difficulty of assessing the presence of invasion into the pancreas. The presence of peritumoral pancreatitis and edema, as well as shadowing and tissue thickening due to an indwelling biliary stent, were the major factors limiting the accuracy of EUS. Tumors may be difficult to distinguish from the normally hypoechoic ventral pancreas, and invasion of the duodenal muscularis propria may be difficult to detect because in normal anatomy the muscularis propria is interrupted by the ducts as they cross into the papilla. Despite these limitations, EUS is considerably more accurate than CT or magnetic resonance imaging (MRI). Combined data from two centers reported the accuracy of ampullary tumor staging with multiple imaging modalities in patients with and without endobiliary stents. Preoperative staging was performed in 50 consecutive patients with ampullary neoplasms by EUS plus CT (37 patients), MRI (13 patients), or angiography (10 patients) over a 3.5-year period. Of the 50 patients, 25 had a transpapillary endobiliary stent present at the time of EUS examination. EUS was shown to be more accurate than CT and MRI in the overall assessment of the T stage of ampullary neoplasms (EUS 78%, CT 24%, MRI 46%). No significant difference in N stage accuracy was noted between the three imaging modalities (EUS 68%, CT 59%, MRI 77%). EUS T stage accuracy was reduced from 84% to 72% in the presence of a transpapillary endobiliary stent. This was most prominent in the understaging of T2 and T3 carcinomas.

A study by Muthusamy et al (2001) demonstrated the role of EUS-guided FNA in the diagnosis and staging of ampullary lesions. EUS-guided FNA was performed in 20 of 27 (74%) patients with suspected ampullary tumors, and made the initial ampullary tissue diagnosis in seven patients (adenocarcinoma in five patients, adenoma in one patient, neuroendocrine tumor in one patient). In addition, EUS-guided FNA resulted in a change of the diagnosis from adenoma to adenocarcinoma in one patient. In one patient, EUS-guided FNA detected a liver metastasis not seen on CT. Overall, EUS-guided FNA provided new histologic information in nine of 27 patients (33%). Another study of 35 patients who underwent EUS-guided FNA of ampullary lesions (with follow-up available in 27 patients) revealed 13 patients with adenocarcinoma, six with atypical cells (four suspicious for cancer and two consistent with reactive atypia), two with adenomas, one with carcinoid, and 13 with no evidence of malignancy. Three false-negative studies were identified, yielding a sensitivity of 82.4%, a specificity of 100%, a negative predictive value of 76.9%, and an overall accuracy of 88.8% for EUS-guided FNA in diagnosing ampullary lesions.

A recent study by Ridtitid et al (2015) retrospectively evaluated 119 patients who underwent EUS for an ampullary lesion, 99 of whom had an adenoma or adenocarcinoma. With surgical pathology used as the reference (n = 102), the sensitivity and specificity of EUS were 80% and 93%, respectively, and the sensitivity and specificity of ERCP were 83% and 93%, respectively; therefore they were comparable. The overall accuracy for EUS for local T and N staging was 90%.

IDUS is probably more accurate than transduodenal EUS for T staging of ampullary neoplasms. In one large series, IDUS had an overall accuracy of 89%. IDUS visualized small tumors missed by EUS and was more accurate than endoscopic biopsies for diagnosis of ampullary neoplasm. IDUS was also accurate for the differentiation of adenoma from T1 carcinoma. These results were achieved by experienced endosonographers, using IDUS at the patient's initial ERCP and before sphincterotomy, stent placement, or biopsy, which is an optimal algorithm for tumor imaging, but difficult to replicate in most EUS referral centers.

Acute Pancreatitis

Diagnostic EUS has two roles in patients with acute pancreatitis: the first is for timely diagnosis of common bile duct or ampullary stones in patients with acute gallstone pancreatitis, and the second is for differential diagnosis in patients with unexplained bouts of pancreatitis. In both cases, EUS can be used in place of diagnostic ERCP, and may identify those patients most likely to benefit from therapeutic ERCP.

The accuracy and cost effectiveness of EUS for the diagnosis of bile duct stones is discussed earlier in this chapter. When EUS is used to exclude ampullary stones, the ampulla must be examined from the second duodenum. A skilled examiner can perform a focused EUS of the extrahepatic bile duct in less than 10 minutes, and the patient can undergo therapeutic ERCP under the same sedation if a stone is demonstrated. This strategy allows patients with a suspected ductal stone to avoid the potential complications of ERCP if a stone is not present.

One prospective trial investigating EUS in gallstone pancreatitis reported that it was accurate for diagnosis of gallbladder and ductal stones, and predicted longer hospital stay in patients found to have peripancreatic fluid by EUS. In another large series in which ERCP was used selectively on the basis of EUS findings, patient outcomes were favorable, and recurrent biliary pancreatitis was uncommon.

EUS is also a useful tool in the evaluation of idiopathic pancreatitis, demonstrating abnormalities in the majority of patients. Findings include missed biliary stones or sludge (see Fig. 51.1 ), chronic pancreatitis (CP), pancreas divisum, pancreatic or ampullary malignancy, and pancreatic duct stones. EUS does not diagnose pancreatic sphincter stenosis, but may nevertheless supplant ERCP by diagnosing or excluding previously unsuspected gallbladder pathology, CP, or pancreatic malignancy. EUS and MRCP appeared to have similar utility in one study, whereas others have suggested that EUS may be superior. We feel it is best to wait until at least 4 weeks after an episode of acute pancreatitis, as acute inflammatory changes can make EUS interpretation and the detection of small tumors more challenging.

Chronic Pancreatitis

The traditional endosonographic features of CP are listed in Table 51.3 and illustrated in Fig. 51.8 . This list of consensus criteria uses minimal standard terminology adopted by an international working group, and good interobserver agreement has been demonstrated for these criteria among experienced American endosonographers. Investigators have also described other features not included in this list, including honeycombing (in which contiguous lobularity of pancreatic parenchyma forms a honeycomb pattern), heterogeneous echotexture, focal areas of hypoechogenicity, tortuous pancreatic duct, thickened pancreatic duct wall, and narrowing of the main pancreatic duct. The traditional EUS approach to the diagnosis of CP gives each feature equal weight, and sums the number of features present. The Rosemont criteria, proposed in 2009, offer an alternative approach to diagnosis based on major and minor criteria ( Table 51.4 ). The Rosemont criteria likely have higher specificity and lower sensitivity than the traditional scoring system.

Definitions vary for some criteria. Hyperechoic foci have been defined greater than as g 3 mm by some investigators, but as 1 to 2 mm by others. Main pancreatic duct dilation has been variably defined, often as a diameter of greater than 2 mm in the body or greater than 1 mm in the tail. The Rosemont criteria offer semiquantitative definitions for many criteria (see Table 51.4 ). Criteria have been considered abnormal when visualized at either 12 or 7.5 MHz by some investigators, but at only 7.5 MHz by others. Findings must be interpreted with considerable caution when imaging the pancreatic head because some features (such as hyperechoic strands, lobularity, and visible branch ducts) are often seen in the normal pancreatic head, whereas others (such as cysts and stones) are not. Diagnosis is best made based on features seen in the pancreatic body and tail. Visible duct side branches have been seen in the normal pancreatic body by some investigators.

There are caveats regarding the specificity of EUS criteria for the diagnosis of pancreatitis. EUS features of CP have been reported in members of pancreatic cancer kindreds, in whom lobularity may correlate with the presence of pancreatic intraepithelial neoplasia (PanIN) in pancreatic branch ducts. Focal areas of pancreatic hypoechogenicity can be due to focal inflammation, but may also be due to neoplasm ( Fig. 51.9 ). Acute pancreatitis may cause decreased parenchymal echogenicity (due to edema), accentuating the echogenicity of the pancreatic duct wall and the interlobular septa of the pancreas. When performed for diagnosis of CP, EUS should therefore be done after an acute episode of pancreatitis has resolved. Finally, some degree of ductal dilation and pancreatic fibrosis is common, and often occurs without clinical pancreatic disease.

Some EUS findings may be attributable to the effects of age, cigarettes, alcohol, and comorbidities on the pancreas, rather than CP. Although studies in healthy volunteers have generally demonstrated no parenchymal EUS abnormalities in young, asymptomatic people who do not use alcohol, older patients with no history of pancreatic disease undergoing EUS for other indications had, on average, two EUS features of CP, and EUS findings tend to correlate with the extent of alcohol ingestion and cigarette use. Autopsy data show that pancreatic fibrosis is common in older persons, as well as in patients with diabetes, renal failure, or inflammatory bowel disease. These histologic changes, which were termed pancreatopathy in the 1980s, are commonly found at autopsy in persons with no clinical history of pancreatic disease. In one small autopsy study, EUS showed CP in 90% of persons with no clinical history of pancreatic disease, and EUS findings were associated with histologic pancreatopathy. A 2014 study of EUS elastography in persons with normal-appearing pancreases undergoing EUS for nonpancreatic indications found increasing pancreatic stiffness with increasing age, with overlap between age-related change and stiffness due to CP. Improved methods of distinguishing pancreatopathy from CP are needed.

The accuracy of EUS for diagnosis of “early” or “minimal change” CP is debated, and EUS has been compared to pancreatography, functional tests, and histology. Early studies comparing EUS to pancreatography concluded that the presence of three or more traditional criteria was the best threshold for EUS diagnosis of CP. These studies used pancreatography as a gold standard. However, the validity of pancreatography for the diagnosis of early CP is poorly established: the commonly used Cambridge criteria for pancreatogram interpretation are based on expert opinion, and autopsy studies have shown pancreatographic abnormalities in the majority of persons without a clinical history of pancreatic disease.

Histologic comparisons have reached conflicting conclusions, with retrospective studies of surgical specimens concluding that three or four EUS criteria are the best threshold for diagnosis, and a prospective study of EUS fine-needle biopsy (FNB) concluding that histologic abnormalities were uncommon in persons with three or four traditional EUS criteria (see Fig. 51.9 ). This discrepancy is most likely due both to differences in tissue sampling methods and differences in patient populations: the surgical studies included patients with pancreatic disease of sufficient magnitude to require surgery, some of whom had calcifications or pancreatic malignancies, whereas the EUS-FNB study enrolled patients with chronic abdominal pain and a paucity of other objective findings. More recently, a 2016 study of patients with presumed noncalcific CP treated with total pancreatectomy and islet autotransplantation demonstrated a poor correlation between preoperative EUS features and histologic extent of pancreatic fibrosis in the resected organ. Many subjects in that study had mild fibrosis that might be termed pancreatopathy rather than CP.

EUS has also been compared to pancreatic function testing (PFT) and endoscopic PFT performed at the time of EUS. In populations of patients with either calcific CP or a low likelihood of CP, there is good overall correlation between the number of EUS features and the results of PFT; however, divergent results are common in patients with suspected minimal change CP. In those with divergent EUS and PFT results, it is unclear which test is more accurate.

We conclude that, in some cases, EUS findings should be deemed indeterminate for CP. This category, introduced by the Rosemont criteria (which rate the presence of three or four minor criteria as indeterminate), reflects clinical and histologic realities and our current state of knowledge. In such cases, PFT, pancreatic biopsy, or repeat evaluation over time may be useful.

Autoimmune Pancreatitis

Type 1 autoimmune pancreatitis (AIP) is a common manifestation of IgG4-related disease, and may have a variable EUS appearance. Type 1 AIP is often characterized by extensive parenchymal lymphoplasmacyctic infiltration, causing the pancreas to appear enlarged and hypoechoic on EUS, with loss of parenchymal lobulation and compression of the pancreatic duct. Long multifocal strictures of the pancreatic duct are common in Type I AIP, and may be apparent during EUS. In some cases, there is prominent infiltration around or within the main duct wall, causing a hypoechoic halo around the duct on EUS. Type 1 AIP may also present as solitary or multiple pancreatic mass lesions. Type 2 AIP, which is associated with inflammatory bowel disease and is often seen in younger patients than Type 1 AIP, may present as a focal pancreatic mass or as a diffusely abnormal pancreas, with hypoechoic enlargement of some regions and CP elsewhere. Diffuse bile duct wall thickening may suggest biliary involvement by IgG4-related disease, although this may be due to other processes, such as PSC, cholanogiocarcinoma, or the presence of a biliary stent.

EUS-guided tissue sampling is an important diagnostic tool for patients with suspected Type 1 AIP who do not otherwise meet clinical criteria for the diagnosis of IgG4-related disease. Although aspiration cytology has been deemed sufficient for diagnosis by some investigators, most favor core tissue biopsy, which allows histologic diagnosis using consensus pathologic criteria and includes quantitative analysis of tissue IgG and IgG4 immunostaining. EUS-FNB is also useful for the diagnosis of type 2 AIP, but the granulocyte epithelial lesion that is the pathognomonic histologic finding for this condition may be sparsely distributed in the lesion and missed by core biopsy samples.

EUS-Guided Fine-Needle Aspiration and Biopsy Technique

The technique of EUS-guided FNA has been well described in the literature. In general, the area of interest is visualized by EUS and placed within the center (or just slightly left of center on the monitor) of the imaging field. Doppler imaging is used as needed to identify vascularity of the lesion and to assess adjacent vascular structures. A standard FNA needle, with the stylet slightly withdrawn to provide a sharp tip, is advanced into the lesion under direct ultrasound visualization, avoiding any possible intervening vascular structures. The central stylet is advanced to remove any tissue that may be present in the needle tip as a result of the transluminal puncture. The following section covers specific aspects of the FNA and biopsy technique, with a focus on pancreatic and biliary lesions.