Introduction

Pancreatic cystic lesions (PCLs) are frequent incidental findings during transabdominal ultrasonography (US) or other abdominal imaging studies [1]. The prevalence of PCLs has been reported to vary from 0.2 to 45.9% (Table 1) [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16]. Depending on the imaging method used, the detection rates of cysts vary as described above, with the reported detection rates being 2.1–5.4% for computed tomography (CT) [2,3,4,5,6], 0.21–3.5% for US [7, 8], 10–45.9% for magnetic resonance imaging (MRI) [3, 9,10,11,12,13,14], and 9.4–21.5% for endoscopic ultrasonography (EUS) [15, 16].

Table 1 Previous studies on prevalence of pancreatic cystic lesions
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PCLs involve different entities, with each of them having a peculiar biological behavior, and they range from benign to premalignant or malignant neoplasms [17, 18]. Pancreatic cystic neoplasms account for approximately 9–10% of PCLs [19, 20]. Serous neoplasms (SNs) and pseudocysts are benign lesions, but mucinous pancreatic cystic lesions are associated with a risk of malignancy, and either aggressive treatment or surveillance is required. Mucinous pancreatic cystic lesions can be classified into mucinous cystic neoplasms (MCNs) and intraductal papillary mucinous neoplasms (IPMNs) [21]. IPMNs are the most common pancreatic cystic neoplasms, and they include a wide pathological spectrum of conditions, such as low-grade dysplasia, high-grade dysplasia, and invasive carcinoma. Therefore, the differential diagnosis of benign and malignant lesions is sometimes difficult. International consensus guidelines have been developed, and a flowchart of the treatment policy for branch duct-type IPMNs has been presented according to morphological features [22].

Risk factors for pancreatic cancer

In recent years, PCLs, particularly IPMNs, have been attracting attention as risk factors for pancreatic cancer. The risk of pancreatic cancer in people diagnosed with pancreatic cysts has been reported to be about 3–22.5 times higher than that in people without pancreatic cysts [13, 23,24,25,26]. Therefore, it is necessary to identify cases at risk of carcinogenesis from pancreatic cysts, and to closely observe these cases and intervene with early surgical treatment in cancerous cases. Additionally, pancreatic cysts have been shown to be associated with the presence of ductal adenocarcinoma elsewhere in the pancreas [13, 24]. Therefore, it should always be kept in mind that a pancreatic cyst might be an indirect finding of pancreatic cancer.

Transabdominal ultrasonography

As US is noninvasive, inexpensive, and widely available, it is considered to be the most appropriate imaging modality for the initial evaluation of pancreatic diseases including PCLs. The reported detection rate of PCLs is 0.21–3.5% for US [7, 8]. Additionally, the sensitivity of US for detecting pancreatic cysts has been reported to be 70.2–88.3% [27, 28]. The US detection rate was shown to be correlated with PCL location and size, as well as with patient sex, weight, and abdominal diameter [29, 30].

As the range to visualize the pancreatic area is reduced in obese individuals and in individuals with gastrointestinal gas, US might underestimate the existence of a PCL in these individuals. The pancreatic tail, in particular, is often difficult to assess by US [29, 30]. However, it becomes clearly observable on US after drinking 350 mL of liquid, as the liquid-filled stomach acts as an acoustic window. The sensitivity of this approach (92.2%) has been reported to be higher than that of routine upper abdominal US (70.2%) for the detection of PCLs [27].

PCLs have been shown to be associated with the presence of ductal adenocarcinoma elsewhere in the pancreas [13, 24]. If PCLs are found, the entire pancreas should be carefully observed using US to assess the presence of pancreatic cancer at other locations, and other abdominal imaging modalities might be necessary. Color Doppler US has been shown to contribute to the differential diagnosis of PCLs and vascular lesions [31,32,33]. On the other hand, it is difficult to show the normal intrapancreatic vessels with conventional Doppler imaging. However, superb microvascular imaging (SMI), a novel imaging modality that uses a special filtering technique, was developed to detect and visualize very slow blood flow not detected by conventional color Doppler imaging. Accordingly, SMI has recently been used to diagnose pancreatic diseases [33, 34].

Tissue harmonic imaging

Harmonic waves are generated by the non-linear propagation of ultrasound waves through body tissues. These beams have frequencies that are multiples of a fundamental transmitted frequency. In tissue harmonic imaging (THI) sonography, higher harmonic frequencies generated by propagation of an ultrasound beam through tissues are used instead of emitted US frequencies to produce a sonographic image. Presently, the second harmonic is being used to produce the sonographic image as the subsequent harmonics have decreasing amplitudes and are thus insufficient to generate a proper image. The following two methods have been developed for the generation of harmonic images: (1) a method involving harmonic band filtering of the fundamental component of the receiving signal and (2) a method involving phase inversion.

THI has several potential advantages [35]. First, the lateral resolution is improved. Second, reverberation artifacts and side-lobe artifacts are reduced. Third, the signal-to-noise ratio is improved. Fourth, the image quality is improved by better discrimination between liquid and solid structures, increasing spatial and contrast resolutions [36, 37]. Additionally, US images acquired by THI appear to be significantly clearer when compared with images acquired by fundamental B-mode imaging for PCLs (Fig. 1) [35, 38]. Therefore, THI is particularly useful for depicting PCLs [39]. THI should be considered in routine abdominal ultrasound examinations.

Fig. 1
figure 1

Intraductal papillary mucinous neoplasm (branch duct type). a Fundamental US shows a cystic mass with septa within the pancreatic tail. b THI shows septa within the mass more clearly because of marked clearing of noise

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Contrast-enhanced ultrasonography

Microbubble contrast agents can provide information on parenchymal vasculature, including its microvasculature. US contrast agents are confined to the blood pool, whereas CT or MRI contrast agents are rapidly cleared into the extravascular space. As microbubble contrast agents used in contrast-enhanced ultrasonography (CEUS) are approximately the size of red blood cells, they act as blood pool contrast agents. An advantage of CEUS is the ability to study the dynamics of lesions in real time. US contrast agents have very few allergic side effects, can be used in cases with liver and renal disorders, and have value with regard to safety. The excellent tolerance and safety profiles allow repeated examinations if needed [40]. Several studies have shown that transabdominal CEUS can be used to improve the identification, characterization, and staging of pancreatic diseases including PCLs [40,41,42,43,44,45,46,47,48]. A previous study reported that the diagnostic accuracy of CEUS is comparable to that of MRI for the detection of septa and mural nodules in PCLs (Fig. 2) [49]. The diagnostic accuracy of CEUS using a classification diagnostic criterion is superior to that of conventional US and shows substantial agreement with that of enhanced CT [50]. CEUS can be used for the differential diagnosis of PCLs and as a follow-up imaging technique.

Fig. 2
figure 2

Intraductal papillary mucinous neoplasm (branch duct type). a US shows a cystic mass within the pancreatic head. b CEUS shows enhanced septa and a mural nodule (arrow) within the mass

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Cystic diseases of the pancreas

In the following text, the morphological and sonographic characteristics of PCLs are outlined (Table 2). Additionally, a solid tumor with cystic degeneration is briefly described as an important differential diagnosis.

Table 2 Ultrasonographic characteristics of IPMN, MCN and SN
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Intraductal papillary mucinous neoplasm

IPMNs are the most common pancreatic cystic neoplasms. They can be classified into branch duct type, main duct type, and mixed type. Main duct-type IPMNs require surgery because of high malignancy rates when the main pancreatic duct diameter is 10 mm or more (Fig. 3). Branch duct-type IPMNs are conditions mostly suspected as pancreatic cysts on diagnostic imaging. They are depicted as lobed and septal cystic lesions, but in reality, they involve dilation of the branched pancreatic duct.

Fig. 3
figure 3

Intraductal papillary mucinous neoplasm (main duct type). The main pancreatic duct is dilated. There is an elevated lesion (arrow) in the dilated main pancreatic duct

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IPMNs include a wide pathological spectrum of conditions, such as low-grade dysplasia, high-grade dysplasia, and invasive carcinoma. Therefore, the differential diagnosis of benign and malignant lesions is sometimes difficult. International consensus guidelines have been developed, and a flowchart of the treatment policy for branch duct-type IPMNs has been presented according to the morphological features [22]. The presence of high-risk stigmata indicates malignancy, and a cystic lesion of the head of the pancreas with obstructive jaundice, an enhancing mural nodule measuring 5 mm or more, and a main pancreatic duct diameter of 10 mm or more are important findings. If any of these are recognized, surgery is strongly recommended. On the other hand, worrisome imaging findings include a lesion size of 3 cm or more in diameter, thickening or contrasting of the cystic wall, a main pancreatic duct diameter of 5–9 mm, an abrupt change in the caliber of the pancreatic duct with distal pancreatic atrophy, lymphadenopathy and a cyst growth rate of 5 mm or more per year, and if any of these are recognized, EUS should be performed. Visualization of nodules on US is often difficult [51], and THI allows better evaluation of walls, septa, and mural nodules [39, 52]. CEUS can be of considerable help in the identification of mural nodules and septa in IPMNs. Mural nodules and septa are enhanced because of their vascularization [53]. On the other hand, mucin is not enhanced. Therefore, CEUS can improve the differential diagnosis between mural nodules and mucin. In addition, it has been reported that quantitative evaluation of echogenicity after intravenous injection of IPMNs is closely related to the malignancy of IPMNs [47, 54].

Pancreatic fibrosis or fibrosing reactions have been reported in IPMN [55, 56]. Ultrasound elastography is a possible method for noninvasively evaluating pancreatic fibrosis [57,58,59]. It was reported that elastography measurement of the background pancreatic parenchyma by US was useful for diagnosing the presence of BD-IPMN [60].

Current issues in the management of branch duct-type IPMNs include the selection of candidates for surgical resection and the development of intraductal papillary mucinous carcinoma during follow-up of an IPMN that was not resected [26, 61, 62]. Another issue is the occurrence of a ductal carcinoma of the pancreas concomitantly with an IPMN during follow-up of the IPMN [63,64,65].

EUS is useful for surveillance of patients with IPMNs to assess the potential development of concomitant ductal carcinoma of the pancreas [66, 67]. As IPMNs have a long clinical course, follow-up methods should be feasible and tolerable for patients and should have a reliable diagnostic ability. US is reasonable as a follow-up method from a clinical point of view, although it has obvious limitations with regard to diagnostic ability [62]. Ideally, a combination of US and EUS, CT, or MRI is recommended at present; however, there is no consensus on the best approach for combining US with EUS, CT, or MRI.

Future prospective studies are necessary to determine the optimal surveillance strategy (intervals and imaging modalities) for branch duct-type IPMNs.

Mucinous cystic neoplasm

MCNs have an estrogen or progesterone receptor-positive ovarian-like stroma and usually occur in women. They often occur in the body and tail of the pancreas. Although the malignancy grade is not high, these tumors can eventually become malignant, and surgery is the preferred approach if the procedure is tolerable [21]. MCNs are typically macrocystic tumors 2 cm or more in diameter. Although MCNs are usually unilocular cystic lesions, septa have been observed within the cyst in some cases, and the area partitioned by the septum is visualized as a cyst (cyst in cyst). A mural nodule might be found in the cyst. The cystic content can be nonhomogeneous owing to the presence of mucin or intralesional hemorrhage (independent cyst). Generally, there is no communication with the pancreatic duct and no dilation of the main pancreatic duct. Small MCNs with diameters of only a few millimeters have been noted. The definitive diagnosis of small MCNs from images alone is difficult, and they are often confused with IPMNs. In such cases, follow-up observation focused on worrisome features and high-risk stigmata should be selected; however, according to the American Gastroenterological Association Institute guidelines, the significance of discrimination between IPMN and MCN is low [68]. Evidence of malignancy includes the presence of cystic wall irregularity and thickening, a mural nodule, or an adjacent solid mass (Fig. 4).

Fig. 4
figure 4

Mucinous cystadenocarcinoma. a US shows a cystic mass with a thick wall and septum within the pancreatic tail. b CEUS shows thick septal enhancement

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Serous neoplasm

As few SNs are malignant, they often do not require surgical resection, and follow-up is selected in asymptomatic patients [69]. The most common appearance is an irregularly contoured sphere involving a multilocular tumor composed of many microcystic components inside (Fig. 5). This appearance was first described by Compagno and Oertel [70] as a “honeycomb.” There might be macrocysts (less than 2 cm) at the margin of the tumor. Additionally, central fibrosis or calcification might be seen [71]. In some SNs, US shows a solid mass owing to the presence of a large number of very small cysts delimited by septa [72, 73]. Additionally, uncommonly, SNs might have an oligolocular or macrocystic appearance and/or no central scar. In these cases, differentiation from other cystic or solid neoplasms of the pancreas can be difficult. Doppler signals might be observed in the solid component and septa on Doppler US. The CEUS findings of SNs include septal enhancement and massive enhancement (homogeneous enhancement within the solid component of the tumor and an irregular shape) [74].

Fig. 5
figure 5

Serous cystic adenoma. a US shows a mass with a microcystic feature within the pancreatic tail. Posterior acoustic enhancement is visible. b CEUS shows hyperenhancement within the solid component of the tumor

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Pseudocyst

Pseudocysts can arise as a complication of acute pancreatitis. These cysts are fibrous-walled anechoic structures without an epithelial lining. Inflammatory cysts have been referred to as so-called pseudocysts. Recently, the revised Atlanta classification has made it possible to divide cysts into pseudocysts and walled-off necrosis (WON) [75].

Pseudocysts vary in size and shape. They are often unilocular, but might have internal septa-like structures. Their walls are thick, and they might have high echoic debris internally. Pseudocysts can be difficult to distinguish from pancreatic cystic neoplasms, especially when they contain debris. CEUS has been reported to improve the characterization of pseudocysts [76, 77]. Pseudocysts appear anechoic because of the absence of vessels. Rices and Wermke [77] reported that the sensitivity and specificity of CEUS for the diagnosis of pseudocysts were both 100% among nine patients with pseudocysts.

Solid pancreatic tumor with cystic degeneration

Solid pancreatic tumors, such as solid pseudopapillary neoplasms (SPNs), pancreatic neuroendocrine neoplasms (PNENs), and invasive ductal carcinomas (IDCs), might occasionally cause cystic degeneration and manifest as cystic lesions [78, 79]. Thus, solid tumors with cystic degeneration should be considered in the differential diagnosis of cystic lesions of the pancreas, although their prevalence is very low when compared with that of true pancreatic cystic neoplasms.

Solid pseudopapillary neoplasm

SPNs typically occur in young women (mean age of approximately 30 years). They usually start as solid tumors and cause cystic degeneration, resulting in a cystic appearance on US owing to hemorrhagic necrosis (Fig. 6) [80]. On US, SPNs typically appear as well-demarcated tumors with a combination of solid and cystic areas, and they might have eggshell-like or linear-like calcification. The atypical pure fluid forms are difficult to differentiate from MCNs.

Fig. 6
figure 6

Solid pseudopapillary neoplasm. a US shows a cystic mass with a thick wall and septum at the pancreatic tail. b The cut surface shows solid and cystic content surrounded by a fibrous capsule. c Low-magnification micrograph of hematoxylin and eosin staining shows pseudopapillae surrounded by non-cohesive neoplastic cells

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Pancreatic neuroendocrine neoplasm

Many PNENs are delineated as well-defined round lesions with a homogenous internal echo. However, cystic degeneration is sometimes noted with the unilocular form. In previous investigations of resected pancreatic neuroendocrine tumors, approximately 5–10% showed cystic degeneration [81, 82], and a high rate of 17% has also been reported [83]. A larger tumor size is considered to be associated with a higher rate of cystogenesis [83]. Additionally, it has been suggested that PNENs with cystic degeneration should be considered histologically different from PNENs without cystic degeneration and that they should be considered as low-grade independent subgroups [84, 85]. Although there is no clear mechanism of cystic degeneration, it is presumed to be associated with a tumor circulatory disorder and intratumoral hemorrhage. Cystic PNENs do not appear to have any typical US findings that can be used to distinguish them from other pancreatic cystic lesions (Fig. 7). Nevertheless, on US, cystic PNENs might show a pure cystic or mixed solid-cystic component, a more frequent unilocular form than multilocular form, and a thicker cystic wall (> 2 mm) when compared with MCNs [86].

Fig. 7
figure 7

Pancreatic neuroendocrine neoplasm. a US shows a cystic mass with a marked thick wall at the pancreatic head. b The cut surface shows a solid lesion and cystic degeneration with coagulation. c High-magnification micrograph of hematoxylin and eosin staining shows sheets of small round cells with rich fibrovascular stroma

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Invasive ductal carcinoma

It has been reported that IDCs can cause cystic degeneration [87,88,89,90]. A pancreatic ductal adenocarcinoma (PDAC) typically presents as an infiltrative hypoechoic solid mass. However, it has been reported that approximately 8% of PDACs have an intratumoral cystic appearance or show accompanying non-neoplastic cystic lesions in contact with the tumor [87]. The histopathologic findings of PDACs with cystic features are largely divided into neoplastic cystic and non-neoplastic cystic findings. Neoplastic cystic findings include large duct-type cysts, neoplastic mucin cysts, and colloid carcinomas formed by the neoplastic glands themselves and degenerative cystic changes usually associated with hemorrhagic tumor necrosis. Non-neoplastic cystic findings include retention cysts caused by ductal obstruction and pseudocysts caused by tumor-associated pancreatitis [88]. PDACs with degenerative cystic changes should be differentiated from SPNs and cystic PNENs. A combined retention cyst or pseudocyst might delay the diagnosis of PDACs as a small hypoechoic solid tumor can be masked by a large cystic lesion. PDACs should be considered in the differential diagnosis of PCLs.

Other IDCs, such as undifferentiated carcinomas with osteoclast-like giant cells [89] and adenosquamous carcinomas (Fig. 8) [90], might show bleeding and necrosis inside the tumor and cause cystic degeneration.

Fig. 8
figure 8

Adenosquamous carcinoma. a US shows a cystic mass at the pancreatic head with a marked thick wall. b The cut surface shows central cystic degeneration. c High-magnification micrograph of hematoxylin and eosin staining shows glandular and squamous components

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Conclusion

US is established as the most appropriate imaging modality for the initial evaluation of pancreatic diseases, including PCLs, as it is widely available, noninvasive, and inexpensive. In addition, new techniques, such as THI and CEUS, could contribute to the differential diagnosis of PCLs.