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Abstract
Pancreatic incidentalomas [PIs] represent a clinical entity increasingly recognized due to advances in and easier access to imaging techniques. By definition, PIs should be detected during abdominal imaging performed for indications other than a pancreatic disease. They range from small cysts to invasive cancer. The incidental diagnosis of pancreatic cancer can contribute to early diagnosis and treatment. On the other hand, inadequate management of PIs may result in overtreatment and unneeded morbidity. Therefore, there is a strong need to evaluate the nature and clinical features of individual PIs. In this review, we summarize the major characteristics related to PIs and present suggestions for their management.
Keywords: cysts, early detection, incidentaloma, neoplasm, pancreas, pancreatic cancer, pancreatic tumor
1. Introduction
A pancreatic incidentaloma [PI] is defined as a lesion of the pancreas detected by imaging techniques performed for causes unrelated to the change itself or its implications. PIs may histologically correspond to a wide range of pathological conditions, from small cysts to large invading pancreatic tumors. The recent development of imaging techniques and their use contributed to the increase in the incidentaloma detection [1]. Incidental lesions are most often identified in organs, such as the thyroid gland, pituitary gland, kidney and lungs. In turn, the pancreas is characterized by lower spread of incidentalomas. However, PIs belong to the changes with higher rates of the potential malignancy compared to incidentalomas of other organs [2]. The random identification of PI may induce unnecessary anxiety in the patients and require useless diagnostics. In contrast, in cases of pre-malignant and malignant lesions, the detection of PI may be associated with the early diagnosis of treatable tumor and may prove to be lifesaving. Therefore, an assessment of PI is needed to implement adequate therapy, when medically indicated. Nevertheless, the discovery of PIs is a challenge for clinicians. It results from the fact that choice of appropriate investigations of PIs depends on a lot of factors, and management is not fully precise. Clinicians should consider numerous issues at diagnosis: how far its nature should be evaluated, lesion potential impact on the pancreas and adjacent structures, what follow-up is needed if at all, how the risk of missing a harmful diagnosis and a therapeutic opportunity against the risk of overdiagnosis can be balanced, as well as the patient stress. Hence, to gain a clearer understanding of the PIs and to help guide diagnosis and management, this review discusses the current state of knowledge on PIs, focusing on potential types of changes as PIs. We also emphasize the radiological and biochemical characteristics of individual PIs to facilitate proper, early diagnosis and pay attention to novel markers helpful for the diagnosis of PIs.
2. General Characteristics and Epidemiology
Initially, in 2009, the overall prevalence of PIs was estimated between 0.01–0.6% [3]. However, this rate may be considerably higher. An analysis of the pancreatic surgical resection series revealed that the frequency of asymptomatic neoplastic lesions is as high as 6–23% [4]. It is estimated that approximately 24 to 50% of them are malignant, and 24 to 47% are considered as potentially malignant or pre-malignant [5]. In turn, due to increasing abdominal imaging use and the general population aging, another study suggests that pancreatic cysts have been incidentally detected in up to 20% of patients in magnetic resonance imaging [MRI], and often even more in older subjects [6]. According to the most recent evidence, cystic lesions of the pancreas are widespread, often associated with incidental diagnosis, and their incidence may reach up to even 49% in the general population [7]. The vast majority of the detected pancreatic cysts are benign and only approximately 3% of them are malignant or potentially malignant [8].
The etiology of PIs is multiple, complex, and depends on the nature of the lesion. Pathological changes may comprise benign adenoma, malignant adenocarcinoma or borderline malignant tumor with moderate dysplasia. In addition, PIs can include the following: mesenchymal tumors, endocrine tumors, cysts, congenital changes [among them choledochocele], intrapancreatic accessory spleen, metastatic lesions, infectious masses induced by Ascaris lumbricoides, Candida albicans, Cytomegalovirus, Coxsackievirus, Cryptosporidium, Mumps virus, Mycobacterium or others, non-islet tumors, and inflammatory masses [3]. Morphologically, there are three different types of PIs: solid lesions, cystic lesions, and abnormal dilatation of the main pancreatic duct. In addition, all of them may be divided into three following categories: benign, pre-malignant, and malignant lesion [2]. The pancreatic cysts, known also as pancreatic cystic lesions [PCLs], include both non-neoplastic and neoplastic cysts. The first of these comprise pseudocysts caused mainly by pancreatic inflammation or traumatic injury. Therefore, an identification of the cyst with no history of pancreatitis or injury in asymptomatic subjects in particular, suggests the suspicion of neoplastic cyst, also known as pancreatic cystic neoplasm [PCN]. The classification of PCN is complex. There are two group of PCN: mucinous PCLs [MPCLs] and non-mucinous PCLs [n-MPCLs]. MPCLs are divided into intraductal papillary mucinous neoplasms [IPMNs] and mucinous cystic neoplasms [MCNs], and n-MPCLs include serous cystic neoplasms [SCNs], solid pseudopapillary neoplasms [SPNs], cystic neuroendocrine neoplasms [CNNs], and acinar-cell cystic neoplasms [ACNs] [9] [Figure 1]. IPMNs are the most representative group of PCN and constitute about 38% of PCLs. MCNs, SCNs and CNNs represent 23%, 16% and 7% of PCLs, respectively [10]. IPMNs are subdivided into main-duct IPMN, branch-duct IPMN and combined type of IPMN depending on an involvement of the pancreatic ductal system. Branch duct-IPMN is the most popular type of IPMN with the rate 46% of all IPMN, followed by combined type-IPMN [40%] and main duct-IPMN [14%] [9,11].
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Figure 1
Subgroups of PIs. It is worth emphasizing that abnormal dilatation of the MPD may coexist with other types of PIs. ACNs, acinar-cell cystic neoplasms; CNNs, cystic neuroendocrine neoplasms; FCP, focal chronic pancreatitis; IPMNs, intraductal papillary mucinous neoplasms; MCNs, mucinous cystic neoplasms; MPCLs, mucinous pancreatic cystic lesions; n-MPCLs, non-mucinous pancreatic lesions; PCLs, pancreatic cystic lesions; PCNs, pancreatic cystic neoplasms; PDAC, pancreatic ductal adenocarcinoma; PIs, pancreatic incidentalomas; pNET, pancreatic neuroendocrine tumor; SCNs, serous cystic neoplasms; SPNs, solid-pseudopapillary neoplasms.
In turn, the percentage of solid pancreatic incidental lesions varies in retrospective studies, however, this is calculated to be between 31–65% of all PIs. The spectrum of detected solid PIs is broad and comprises malignant changes, such as exocrine, endocrine, lymphoproliferative, pancreatic ductal adenocarcinoma [PDAC] or metastases, pre-malignant lesions, primarily solid pseudopapillary tumor and pancreatic neuroendocrine tumor [pNET], foci occurring in chronic inflammation of the pancreas, and others [Figure 1]. It is worth emphasizing that PDAC, pNET, solid pseudopapillary tumor and focal chronic pancreatitis are four most common solid incidental lesions with the incidence approximately ranging between 31–34%, 23–42%, 3–15%, 0–11% among solid PIs, respectively [12].
Abnormal dilatation of the main pancreatic duct [MPD] is associated with the various pancreatic diseases and may result from the existence of previously described solid or cystic lesions. However, it can also coexist with disorders of other organs, especially adjacent to the pancreas or occur in the patients with no pathology [13].
In the following chapter, we describe relevant features of pancreatic tumors, including their imaging, that may be of help in the differential diagnosis.
3. Types of Incidental Pancreatic Lesions
3.1. PCLs
Generally, PCLs are structures filled with fluid and may be found within or adjacent to the pancreas. In addition, some of them are characterized by a solid appearance, hindering proper diagnosis [14]. Higher incidence of PCLs is observed among elderly people, and is about 37% in adults aged over 80 [15]. Evaluation of pancreatic cysts should be performed in order to exclude or confirm its malignant nature. Various imaging methods are accessible to evaluate PCLs, including MRI, computed tomography [CT], and endoscopic ultrasound [EUS] with or without fine needle aspiration [FNA] [6,16]. Each of those techniques have advantages and disadvantages. For example, CT is widely available with short acquisition times, however, it is associated with exposure to ionizing radiation, as well as iodinated contrast media. MRI is characterized by high soft tissue contrast resolution and is also time-consuming. EUS may provide high spatial distribution imaging and enables FNA for an analysis of the PCLs fluid, but it is an invasive procedure [17]. The cystic fluid analysis is helpful in differentiating MPCLs from n-MCPLs. Nevertheless, it has limitations for distinguishing benign and malignant cystic lesions. Firstly, there are contradictory data on the cut-off value of markers, mainly carcino-embryonic antigen [CEA] and carcinoma antigen 19-9 [CA 19-9], differentiating benign and malignant lesions. Secondly, the molecular analysis of pancreatic cyst fluid, including genomic and epigenomic assay [genetic mutations, gene silencing, chromosomal deletions, heterozygosity loss] is still in progress [18,19]. Moreover, it was indicated that current imaging cannot accurately differentiate malignant from benign PCLs [20,21]. Despite the difficulties, there are some worrisome features suggesting the high risk of malignancy of PCLs, such as: the size of cyst [≥3 cm], dilatation of the main pancreatic duct [≥5 mm], the presence of a mural nodule, lymphadenopathy, thickened/enhancing walls of PCLs, sudden change in the format of the pancreatic duct concomitant with distal pancreatic atrophy, elevated serum level of CA 19-9, or rapid growth of lesion determined as ≥5 mm per two years rate [19,22,23].
3.1.1. Non-Neoplastic Pancreatic Cysts
True cysts, most of which are inborn, and pseudocysts, primarily formed as a result of inflammation or injury, belong to the benign, non-neoplastic pancreatic cysts. In the past, about 80% of PCLs were considered to be pseudocysts. The current consensus indicates that only approximately 30% of PCLs are pseudocysts. This change in tendency results primarily from the development of EUS-FNA and its increased use [24,25,26]. Pseudocysts contain fluid collection surrounded by a wall of fibrous tissue without epithelium lining and are connected with the pancreatic duct system, either as a direct communication or indirectly through the pancreatic parenchyma. The diagnosis of a pseudocyst is related to a patient history compatible with pancreatitis, with additional evidence from laboratory and imaging features. However, clinicians should remember that patients with PCNs may also have had pancreatitis, and that subjects with a pseudocyst can have no apparent history suggestive of inflammation of the pancreas. For example, some extrapancreatic disorders, such as peptic ulcer disease, gastric cancer, ovarian cancer, abdominal aortic aneurysm, intestinal ischemia, bowel obstruction, myocardial infarction and pneumonia, may mimic the clinical presentation of pancreatic pseudocysts [27]. In addition, it seems that male sex predisposes patients to the pseudocyst, and its location in the pancreas is distributed evenly [no pancreatic region typical for pseudocyst] [27]. The endosonographers developed the ”string sign” test, helpful in differentiating mucin containing cyst from other cystic lesions. In this test, an operator places a sample of the aspirated fluid from the PCL between the thumb and index finger and separates the fingers in order to measure the distance between the fingers before the string breaks. The formation of a long string due to a high concentration of mucus indicates mucinous cysts. Elevated levels of amylase and lipase in the cyst fluid with negative string sign and cystic fluid CEA concentration 8.5 cm], a large volume, and solid content inside or outside the MCNs on CT/MR belong to the main predictors of high-grade dysplasia or invasive cancer disease. Their average growth rate is very slow [approx. 4 mm/year] [52,53,54]. In MCN, similarly to IPMN, the cystic fluid is typically characterized by high density with cytology confirming the presence of mucinous cells. It is worth emphasizing that the levels of CEA may be used to differentiate between mucinous and non-mucinous lesions [55]. CEA level of >192 μg/L is the cut-off value for the cyst differentiation with the sensitivity and specificity of 52–78% and 63–91%, respectively [56,57]. In turn, the concentration of amylase is usually normal, however a high level does not exclude MCN [31]. Nevertheless, an identification of the presence of ovarian stroma in the histological assessment is key for the diagnosis of MCNs [49].
3.1.3. N-MPCLs
In this subchapter, we focus on SCNs and SPNs. SCNs are benign lesions of the pancreatic exocrine glands and account for 16–33.3% of whole PCNs. Furthermore, these changes are characterized by very low risk of malignant transformation [58,59]. SCNs occur in patients in their late 50s and early 60s, usually developing in the body or tail of the pancreas. Interestingly, despite their benign nature, they slowly grow and can reach large diameters [60]. On the other hand, SCNs are representatively honeycombed microcystic tumors consisting of uniform, cuboidal, glycogen-rich epithelial cells. Thus far, there are four variants of serous cystadenoma, namely, macrocystic serous cystadenoma, solid serous adenoma, von Hippel–Lindau-related SCN, and mixed serous neuroendocrine neoplasm, in which the serous epithelial components are identical to those of serous cystadenoma [36]. It is known that CT is the preferable method as the first-line examination for SCNs. CT scans may reveal typical features such as a star-shaped central scar with calcification, or microcystic multiple small cyst, sometimes oligocytic. The diameter of a single capsule is usually smaller than 2 cm. In turn, EUS with FNA for SCNs is characterized with low specificity and sensitivity. Due to the vascularized fibrous septa of the SCN, biopsy may be complicated with hemorrhages. In addition, the cystic fluid level of CEA was found to be low [typical 3 cm, duct dilatation, vascular invasion, enlargement of peripancreatic lymph nodes, and calcification, suggest malignant character. Interestingly, a cut-off sizes of 2 and 3 cm result in a positive prospective value for malignancy of 44% and 61%, respectively [103]. Data indicate that intrapancreatic accessory spleen and serous cystadenoma should be primarily taken into account in the differential diagnosis of solid pNETs [104]. In the diagnostic process of pNETs, including their metastases, octreotide scintigraphy, single-photon emission computed tomography [SPECT] and positron emission tomography [PET]/CT with radioactively labelled somatostatin analogs should be considered and may be helpful when results of CT and MR are doubtful. It results from the fact that 50–90% of pNETs express the somatostatin receptors [105,106]. As mentioned above, it is important to determine whether a lesion is functioning. Therefore, biochemical diagnosis of pNETs is required. It is suggested that evaluation of the serum levels of chromogranin A, pancreatic polypeptide, glucose, insulin, gastrin, and glucagon could detect functional pNETs in asymptomatic patients. Both the North American [NANETS] and European [ENETS] Neuroendocrine Tumor Societies recommend measurement of chromogranin A in both non-functioning and functioning tumors, as well as evaluation of specific hormones, such as insulin, C-peptide, pro-insulin, gastrin, glucagon, vasoactive intestinal peptide, parathyroid hormone-related protein, adrenocorticotropic hormone, and somatostatin based on clinical manifestations [5]. However, recommendations according to small, asymptomatic, incidental pNETs are not clear. In the patients’ group, a measurement of chromogranin A, as well as pancreatic polypeptide and calcitonin, are recommended. Importantly, a thorough medical history is required to rule out multiple endocrine neoplasia [MEN] type 1. Currently, studies evaluating novel markers of pNETs are still in progress [107]. Nevertheless, there are some markers that deserve special attention. Circulating tumor cells [CTCs], the tumor cells in the peripheral blood, may be useful biomarkers for providing diagnostic and prognostic information, their presence is associated with higher tumor grade, tumor burden, an increased circulating chromogranin A concentration and higher Ki67 index [108]. Another novel biomarker of pNETs is a novel multianalyte biomarker, multiple transcript analysis PCR-based test [NETest] using blood-based quantitative real-time PCR to measure 51 different NET-related transcripts presented promising results in both the diagnosis and prognosis of the disease [109]. This method may be used in prognosis and response to treatment in follow-up. In addition, it seems that NETest is more informative than an evaluation of changes of chromogranin A in predicting alterations of the disease [110,111]. Moreover, microRNA seems to be valuable marker, and downregulation of serum microRNA-1290 may serve as discriminator pNET from PDAC [112].
Poorly differentiated PNETs generally present with metastases and are not generally subjected to resection. Well- or intermediately differentiated tumors ≥2 cm with imaging evidence of malignancy or with a Ki-67 >2% should be resected. It has been suggested that non-MEN related, non-functioning, and asymptomatic PNETs