Endoscopic ultrasonography in the evaluation of pancreatic cysts

Key points

The differential diagnosis of pancreatic cystic lesions is wide: the majority of these lesions are benign, but detection of mucin-producing pancreatic cysts (IPMNs and MCNs) is important because these cysts have malignant potential and may harbor pancreatic adenocarcinoma.
The diagnostic accuracy of EUS based on morphology alone is limited.
A combination of EUS features, fluid cytology, CEA, and molecular markers is used to differentiate pancreatic cysts.
FNA of cystic lesions is safe, with low rates of bleeding, infection, and pancreatitis.
Accurate diagnosis and management of pancreatic cystic lesions require careful evaluation of the clinical setting, other imaging modalities, and multidisciplinary collaboration.

Introduction

Pancreatic cysts, once thought to be rare, are now detected more frequently as a result of the increased use of high-resolution imaging. Between 2% and 13% of patients undergoing CT or MRI with no history of pancreatic disease are found to have pancreatic cysts. These lesions represent a broad spectrum of pathologic changes from benign cysts to premalignant and malignant cysts. Pancreatic cysts thus represent an important and increasing disease burden which pose a difficult diagnostic and management problem: that is, how to accurately predict which cystic lesions are benign cysts and require no further follow-up, contain high-grade dysplasia or pancreatic adenocarcinoma (PDAC) and require surgical resection, or are mucin-producing cysts that can be followed safely with interval imaging.

Despite advances in CT and MRI, the ability of cross-sectional modalities to identify the exact nature of a cyst remains limited. EUS is ideally suited for the imaging of pancreatic lesions because of its high resolution and ability to sample cystic lesions. This chapter discusses the different types of pancreatic cysts, their endosonographic features, and the role of EUS-guided cyst sampling. A diagnostic approach to patients with pancreatic cysts is also described.

Types of pancreatic cysts

There are many different types of pancreatic cysts, including benign cysts with no malignant potential, intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) (henceforth referred to collectively as mucin-producing cysts), which are precursors to PDAC and a small number of whom will ultimately develop high-grade dysplasia or PDAC, and malignant cysts caused by cystic degeneration of PDAC or pancreatic neuroendocrine tumor (PanNET) ( Table 14.1 ).

TABLE 14.1

Classification of Pancreatic Cysts

No or Very Low Malignant Potential	Malignant Potential	Malignant
Pseudocyst	IPMN	Pancreatic ductal adenocarcinoma
Serous cystadenoma	MCN	Neuroendocrine tumor
Lymphoepithelial cyst		Solid pseudopapillary neoplasm
Retention cyst		Pancreatoblastoma
Congenital cyst		Acinar cell cystadenocarcinoma
Lymphangioma

IPMN , intraductal papillary mucinous neoplasm; MCN , mucinous cystic neoplasm.

Pseudocysts are common in general practice but account for less than 10% of resected pancreatic cysts. In modern surgical series, the most commonly resected pancreatic cysts are IPMNs, MCNs, and serous cystadenomas (SCAs), which account for 51%, 16%, and 13% of resected cysts, respectively. Solid neoplasms can also undergo cystic degeneration, with cystic degeneration of PanNETs, solid pseudopapillary neoplasms (SPNs), and PDACs accounting for up to 13% of resected cysts. The clinical presentation, endoscopic features, and management of these cysts are discussed below.

Diagnostic approach

Clinical history and imaging

Taking a good clinical history is important. Key questions are whether there is a history of acute pancreatitis, jaundice due to the cyst, or new onset of diabetes; is there any pancreatic type of abdominal or back pain, anorexia, or weight loss? The presence of any of these features is worrisome for the presence of high-grade dysplasia or PDAC, and these patients should undergo a careful EUS and be evaluated by a multidisciplinary team. Is there a personal or family history of related cancers to suggest multiple endocrine neoplasia (MEN) 1, von Hippel–Lindau (VHL) syndrome, hereditary nonpolyposis colorectal cancer (HNPCC), Peutz–Jeghers syndrome, BRCA1 / BRCA2 mutation, or familial atypical multiple mole melanoma (FAMMM) all of which are associated with a higher risk of developing IPMNs and PDAC ?

Most patients have already undergone cross-sectional imaging before they are referred for EUS, but if not, an MRI or pancreatic protocol CT scan is helpful. From this scan and the clinical features, a diagnosis may be apparent. It may also be clear that the patient requires surgical resection. EUS is indicated when the diagnosis is unclear or where the patient has worrisome symptoms. A pragmatic algorithm for the differential diagnosis and management of pancreatic cysts is shown in Fig. 14.1 .

• Fig. 14.1, Endoscopic ultrasonography-based algorithmic approach to the management of pancreatic cystic lesions.

Endoscopic ultrasound

The EUS approach to examining the pancreas is described in detail in Chapter 11 , and FNA techniques are described in Chapter 19 . The general EUS approach to pancreatic cysts is described in this section; the appearances of specific cysts are described later.

When a cystic lesion has been identified, it is important to note the number of cysts; their location and size; and whether the cyst is within or outside of the pancreas. This information may influence management ( Table 14.3 ). The cyst should be examined to determine the presence of a thickened wall, mural nodule, or associated mass (see “Examination Checklist”). The size of the individual cyst compartments (microcystic, macrocystic [>1 cm], or a mixture of both), the presence and thickness of any septations ( Fig. 14.2 ), and the presence of echodense mucus or debris within the cyst should be documented. The size of the main pancreatic duct in the head, body, and tail, whether it communicates with the cyst, the presence of mucin or a mural nodule within the pancreatic duct, or any focal dilation should be noted.

TABLE 14.3

Comparison of Pancreatic Cyst Guidelines

	2017 Fukuoka Guidelines	2018 European Guidelines	2015 AGA Guidelines	2018 ACG Guidelines	2017 ACR Guidelines
Target cyst types	IPMNs	Neoplastic pancreatic cysts	Asymptomatic neoplastic pancreatic cysts	Pancreatic cysts ^a	Incidental pancreatic cysts
Target lesion	High-grade dysplasia or PDAC	High-grade dysplasia or PDAC	PDAC	High-grade dysplasia or PDAC	High-grade dysplasia or PDAC
Methodology	Scientific review, Expert consensus	Systematic review, GRADE methodology	Systematic review, GRADE methodology	Systematic review, GRADE methodology	Scientific review, Expert consensus
Indications for EUS	Worrisome features	Clinical or radiological features of concern AND results are expected to change clinical management	At least 2 high-risk features	When the diagnosis is unclear, and results are likely to alter management	Worrisome or high-risk features
Indications for surgery	High-risk features	Absolute indications vs relative indications	Positive cytology and dilated main pancreatic duct and/or concerning features on EUS FNA	N/A	N/A
Surveillance endpoint	Lifelong	Lifelong	5 years with no interval change	Review at 75	Stability over 9–10 years
Main pancreatic duct dilation	High risk: ≥10 mm Worrisome feature: 5.0 – 9.0 mm	Absolute indication: ≥ 10 mm Relative indication: 5.0 – 9.9 mm	High risk (no cutoff specified)	High risk: >5 mm	High risk: ≥10 mm Worrisome: ≥7 mm
Enhancing mural nodule	High risk: ≥5 mm Worrisome feature: <5 mm	Absolute indication: ≥5 mm Relative indication: <5 mm	High risk (no cutoff specified)	High risk (no cutoff specified)	High risk (Worrisome feature: nonenhancing nodule)
Solid mass	High risk	Absolute indication	High risk	High risk	High risk
Thickened/enhanced cyst walls	Worrisome feature	N/A	N/A	N/A	Worrisome feature
Cyst size	≥3 cm	≥4 cm	≥3 cm	≥3 cm	≥3 cm
Lymphadenopathy	Worrisome feature	N/A	N/A	N/A	N/A
Growth rate	≥5 mm/2 years	≥5 mm/year	N/A	≥3 mm/year	100% increase in longest axis diameter for cysts <5 mm, 50% increase for cysts ≥5 mm and <15 mm, 20% increase for cysts ≥15 mm
Acute pancreatitis	Worrisome feature	Relative indication	N/A	High risk	N/A
New onset diabetes	N/A	Relative indication	N/A	Relative indication: EUS FNA vs short interval MRI	N/A
Elevated serum CA 19-9	Worrisome feature	Relative indication	N/A	High risk	N/A

ACG , American College of Gastroenterology; ACR , American College of Radiology; AGA , American Gastroenterological Society; EUS , endoscopic ultrasound; FNA , fine-needle aspiration; GRADE , grading of recommendations assessment, development, and evaluation; PDAC , pancreatic ductal adenocarcinoma.

a Without strong family history of pancreatic cancer or genetic mutations known to predispose to pancreatic cancer.

• Fig. 14.2, Pancreatic cystic lesion. Thin-walled internal septations (white arrow) and rounded, well-defined lesion with a hyperechoic wall and hypoechoic center (yellow arrow) are seen (these features are suggestive of mucin).

There are several features on EUS that are worrisome for malignant transformation of the cyst. These include the presence of a thick wall or septum, an associated solid mass, or a mural nodule ( Fig. 14.3 ). The presence of focal dilation of the main pancreatic duct, a pancreatic duct measuring ≥10 mm, or a main pancreatic duct measuring between 5 and 9 mm with a mural nodule are concerning and are associated with an increased risk of malignant transformation. One of the EUS features that can be difficult to differentiate is a mural nodule versus a “mucin ball.” Several features that are helpful in differentiating these two lesions are listed in Fig. 14.4 and shown in . Mucin typically has a round, hyperechoic, well-demarcated outer edge with a hypoechoic center. When these features are present on EUS it is associated with mucin in 90% of cases. In addition, mucin can be shown to move within the cyst either by moving the patient’s position or by targeting the lesion during endoscopic ultrasonography-guided fine-needle aspiration (EUS FNA), which is then shown to move with the needle (see ). One of the key questions when a mural nodule is found is whether there is a difference between a 2-mm and a 20-mm mural nodule. One Japanese group tried to answer this question by classifying mural nodules into four types; type I has 1- to 2-mm fine papillary protrusions; type II has a larger polypoid nodule; type III has a larger, protruding component with a thickened wall; and type IV is a papillary nodule associated with an ill-defined hypoechoic area within the parenchyma. This group found that mural nodules increased in size with a mean diameter of 5, 6, 11, and 20 mm for types I to IV, respectively. Furthermore, types III or IV were associated with invasive carcinoma in almost 90% of the patients. The take-home message is that large mural nodules or those associated with an ill-defined mass are highly concerning for the presence of high-grade dysplasia or PDAC. One technique that is very helpful is contrast-enhanced EUS (CE-EUS). Microbubbles are injected into a peripheral vein, which circulate through the pancreas 30 to 40 seconds later. The technique works on the hypothesis that a malignant tumor has a different vascular pattern than either normal pancreatic tissue or mucin. CE-EUS may demonstrate vascularity in mural nodules and is useful for differentiating a mural nodule from a mucin ball. ^, A large meta-analysis of 2297 resected IPMNs found a positive predictive value of 62% for the presence of high-grade dysplasia or PDAC when an enhancing nodule was seen on CE-EUS. The study also found the size of the enhancing mural nodule had a substantial effect on predicting high-grade dysplasia or PDAC, but no reliable cutoff could be identified as only a few case series had measured mural nodules prior to resection. The addition of tissue harmonic echo imaging optimizes real-time depiction of microvessels and parenchymal perfusion without Doppler-related artifacts. Studies have shown superior image visualization of mural nodules compared with normal B-mode imaging. Further information about CE-EUS can be found in Chapter 5 . Finally, it is important to inspect the entire parenchyma and not just the cyst, particularly in individuals with IPMNs, who can develop a PDAC in a region separate from the cyst, which is called a concomitant PDAC.

• Fig. 14.3, Main duct intraductal papillary mucinous neoplasia (MD-IPMN). (A) The main pancreatic duct is markedly dilated, and hypoechoic nodules can be seen arising from the duct wall. (B) Mural nodule arising from the pancreatic duct wall in a patient with an MD-IPMN.

• Fig. 14.4, (A) Mucin. There is a lesion in the 6-o’clock position adjacent to the wall. It is well defined, with a hyperechoic wall and hypoechoic center. These features are suggestive of mucin. (B) On endoscopic ultrasonography-guided fine-needle aspiration, the lesion was shown to move, confirming that it was mucin and not a mural nodule.

Confocal laser endomicroscopy

Confocal laser endomicroscopy (CLE) is an imaging technique in which a low-power laser illuminates and scans a single plane of tissue, generating a real-time optical image of the tissue ( Fig. 14.5 , ). A needle-based CLE (nCLE) can be passed through a 19-gauge EUS FNA needle and image the epithelium to several hundred microns. To date, there have been seven prospective trials enrolling between 18 and 144 patients and reporting a sensitivity between 59% and 100% and a specificity between 94% and 100% in differentiating mucin–producing from non–mucin producing pancreatic cysts. However, there were notable limitations in earlier studies including that consecutive patients were not always enrolled, cysts <20 mm were often excluded, and that the nCLE diagnosis was confirmed by surgical pathology in only a small proportion of cases. The most recent INDEX study had the largest cohort of 144 patients, of which 65 (45%) had surgical pathology. They reported 98% sensitivity, 94% specificity, and 97% accuracy for diagnosing mucinous cysts. Further, they found nCLE to be more accurate than the combination of cyst fluid CEA and cytology.

Adverse events associated with nCLE include pancreatitis, with a recent systematic review reporting a pooled rate of 3%. Another potential technical limitation is the need to use a 19-gauge needle, which can be difficult for lesions accessed from the second part of the duodenum. In summary, there is growing evidence for nCLE; however, current guidelines do not recommend its routine use. We use nCLE in patients where the diagnosis remains unclear despite EUS FNA cytology, CEA and molecular markers and whose management would be altered depending on the diagnosis.

Endoscopic ultrasound-guided tissue sampling of pancreatic cysts

Fine-needle aspiration (FNA)

EUS morphology alone is imperfect at identifying the exact type of pancreatic cyst. A large prospective multicenter study found that the accuracy of EUS imaging features for diagnosing mucin-producing cysts was only 51%, although a more recent study from the Netherlands reported a sensitivity of 78%. Slightly worrying in the Dutch study, however, was the sensitivity for detecting PDAC in pancreatic cysts, which was only 25% for EUS. Hence, despite its high resolution, EUS has limitations.

EUS FNA is often performed in patients with pancreatic cysts, as it provides additional information that can be helpful in confirming the type of cyst or detecting the presence of high-grade dysplasia or PDAC. If possible, a single pass is made into the cyst and the fluid in that cyst compartment is aspirated ( Fig. 14.6 ). This technique is believed to decrease the risk of adverse events including infection, although the evidence for this is slim. Other helpful techniques include targeting the wall of the cyst with a gentle to-and-fro motion to aspirate cells from the wall itself rather than simply aspirating fluid from the center of the cyst. This has been shown to increase the cytologic diagnostic yield for mucin-producing and malignant cysts. Lesions that have a vascular component, such as cystic PanNETs, often yield bloody samples if large-bore needles are used; in such instances, a smaller-gauge needle (e.g., 25-gauge) may be helpful. Microcystic SCAs are particularly challenging to FNA. It is often difficult or impossible to obtain sufficient fluid for analysis from small cysts. In these cases, a 19-gauge needle can sometimes be used to obtain a core biopsy of the cyst, although we have not had great success with this approach in our hands. A further discussion on needle choice is included below and summarized in Fig. 14.7 .

• Fig. 14.6, Endoscopic ultrasound fine-needle aspiration. A 19-gauge, 22-gauge, or 25-gauge needle can be used. In this case, a 22-gauge needle was sufficient to aspirate the lesion completely. Aspiration should continue until the lesion collapses.

• Fig. 14.7, Algorithmic approach to needle choice when performing EUS-guided sampling. FNA, fine needle aspiration; FNB, fine needle biopsy; nCLE, needle confocal laser endomicroscopy; PD, pancreatic duct; TTNB, through-the-needle biopsy.

Through-the-needle biopsy forceps

A through-the-needle microbiopsy forceps (Moray microforceps; US Endoscopy, Mentor, Ohio) has been developed that is placed within a 19-gauge EUS FNA needle. The needle is inserted into the cyst and the biopsy forceps advanced under endoscopic guidance into the cyst. The forceps are then opened, advanced to the wall, and a biopsy obtained ( ). This approach offers the potential to obtain a larger biopsy sample than is possible with regular FNA.

To date, data mostly consists of retrospective studies. A single prospective multicenter trial of 114 patients found a diagnostic yield of 83% compared to 38% with FNA cytology. A systematic review and meta-analysis of 426 patients reported high technical success rate of 98% despite the 19-gauge needle and higher diagnostic yield of 73% when compared to 38% with FNA. The pooled sensitivity and specificity of microbiopsy forceps for differentiating mucin-producing cysts was 90.1% and 94%, respectively. However, the adverse event rate (intracystic bleeding and pancreatitis) was higher than what is normally seen with FNA, at 7%.

The role of combining different modalities together has been evaluated in a retrospective study. When used alone, the diagnostic yield for cytology, microbiopsy forceps, and nCLE was 34.1%, 75.0%, and 84.1%, respectively. When cytology, microbiopsy forceps, and nCLE were combined, the diagnostic yield increased to 93.2%. Compared with the “composite standard” of clinical, morphological (based on cross-sectional imaging and EUS), cyst fluid chemistry and cytology, the addition of microbiopsy forceps and nCLE led to a change in management in 52.3% of cases. This did not seem to increase the rate of adverse events with one moderate adverse event (2.3%) of a pseudocyst requiring unplanned hospital admission and endoscopic drainage, one self-limited intraprocedural intracystic bleeding, and two self-limited postprocedural pain. These preliminary results are interesting but additional trials are required to evaluate prospectively the diagnostic yield, adverse event profile, and cost effectiveness of this approach. The routine use of microbiopsy forceps is not yet recommended by guidelines. ^, Like nCLE, we reserve the use of microbiopsy forceps for cases in which the diagnosis remains unclear despite cytology, CEA and molecular markers and where patient management would be altered by the results.

Through-the-needle cytology brush

A through-the-needle cytology brush (EchoBrush; Cook Endoscopy, Winston-Salem, NC, USA), designed for passage down a 19-gauge FNA needle, was developed for EUS-guided assessment of PCLs. Although some studies have shown that use of a cytologic brush was associated with a higher yield of epithelial cells and that this brush appeared to be superior in providing diagnostic cells and intracellular mucin compared with direct cyst fluid aspirate, other studies found no difference in the diagnostic yield between aspiration and brushing (55%). In addition, adverse events of up to 19% were reported, with major adverse events occurring in up to 8% to 10%, including one fatality. ^, A more recent randomized trial found no significant difference in the rate of adverse events compared with FNA, but also did not note any improvement in diagnostic yield. Accordingly, routine use of the through-the-needle cytology brush is not recommended by guidelines, and we do not use this in our practice. ^,

Needle choice for EUS-guided cyst sampling

There is limited comparative data on different needles for sampling pancreatic cystic lesions. A very recent trial randomized 250 patients with pancreatic cysts ≥13 mm to standard 19-gauge or 22-gauge needles and flexible 19-gauge needles. They noted complete cyst aspiration rate (final cyst diameter <5 mm) to be higher using the 19-gauge flexible (89%) and 22-gauge needles (82%) compared with the 19-gauge standard needle (75%). Repeated FNA due to failure of the first needle to reach, puncture, or fully drain the cyst was required in 7% using the 19-gauge needle, 12% using the 22-gauge, and 17% using the 19-gauge standard needle. This was more often in cysts located in the head/uncinate of the pancreas (19%) compared with the body and tail (4%). However, in patients whose cysts were successfully reached, the rate of sufficient cellular yield for cytology did not significantly differ between needle types. The overall rate of adverse events was low, with serious adverse events reported in three patients (1%, two acute pancreatitis and one aspiration pneumonia), although it was not detailed which needle was used in each case. A systematic review analyzing adverse events associated with EUS FNA of pancreatic cystic lesions including 5124 patients found an adverse event rate of 6% with 19-gauge needles versus 2% with 22-gauge needles, but this did not reach statistical significance. Core biopsy needles are available (discussed in detail in Chapter 19 ), and are helpful in solid pancreatic lesions; however, there is as yet no data to confirm their benefit for pancreatic cysts and we do not use them in our practice.

Hence, there is insufficient data to recommend a specific needle type or size, but rather the choice should be determined by cyst size, location, and the presence of adjacent vessels. If nCLE or microbiopsy forceps use is planned, the 19-gauge needle is required. Larger-gauge needles have the advantage of being able to aspirate the cyst more quickly; however, they can be more difficult to manipulate if the echoendoscope is torqued or in the second portion of the duodenum. Our preference is to use a 22-gauge needle for evaluation of pancreatic cysts, or a 25-gauge when sampling the main pancreatic duct or vascular lesions such as PanNET. A summary of needle choice is presented in Fig. 14.7 .

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