Alghamdi TH. When to operate pancreatic intraductal papillary mucinous neoplasm: Literature review. World J Clin Oncol 2026; 17(3): 114990 [DOI: 10.5306/wjco.v17.i3.114990]
Corresponding Author of This Article
Thamer H Alghamdi, Associate Professor, Consultant, Department of Surgery, Al-Baha University, King Fahad Street, Al Baha 65716, Saudi Arabia. tthaker@bu.edu.sa
Research Domain of This Article
Surgery
Article-Type of This Article
Minireviews
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Author contributions: Alghamdi TH was responsible for study design, collecting data, data analysis, and writing the paper.
Conflict-of-interest statement: Author declares no conflict of interest in publishing the manuscript.
Corresponding author: Thamer H Alghamdi, Associate Professor, Consultant, Department of Surgery, Al-Baha University, King Fahad Street, Al Baha 65716, Saudi Arabia. tthaker@bu.edu.sa
Received: October 11, 2025 Revised: December 6, 2025 Accepted: January 27, 2026 Published online: March 24, 2026 Processing time: 170 Days and 19.8 Hours
Abstract
Management of intraductal papillary mucinous neoplasms (IPMNs) is debated due to differing guidelines. The aim is to identify the timing of surgery and follow-up, as well as how to prioritize the imaging technique. We reviewed all IPMNs guidelines. Sendai guidelines recommended surgical resection for all main duct IPMNs and mixed-type IPMNs if the patient is healthy resulting in increased morbidity and mortality. International Association of Pancreatology Fukuoka guidelines introduced “worrisome feature” and “high-risk stigmata (HRS)”. International Consensus Guidelines recommended that surgery for all cases of main duct IPMNs with a main pancreatic diameter of more than 10 mm or associated with HRS. European Experts Consensus statement guidelines revealed absolute and relative indications for surgery of cases with high-risk IPMNs, considering the size of the cyst with a cut-off point of 4 cm. Fukuoka’s definitions of HRS and worrisome feature and planned the surgery for all mucinous type. American Gastroenterological Association guidelines restricted surgery for non-symptomatic patients. European guidelines recommend surgery in presence of jaundice, an enhanced mural nodule ≥ 5 mm, or have a solid component, positive malignancy and others. Although most of these guidelines showed agreement on the timing of surgery types of IPMNs, there are still debates about the timing of surveillance/follow-up and selection/prioritization of the imaging technique, despite new trials have emerged.
Core Tip: The importance of this literature review lies in clarifying the timing of surgery and surveillance across divergent consensus statements, highlighting areas of agreement and persistent controversy. Its value lies in distilling and juxtaposing guideline trajectories to expose an implicit hypothesis: That moving from the aggressive approach to the more restrictive, feature-based strategies that reduced unnecessary resections without increasing missed cancers.
Citation: Alghamdi TH. When to operate pancreatic intraductal papillary mucinous neoplasm: Literature review. World J Clin Oncol 2026; 17(3): 114990
Pancreatic cystic tumors accounted for 10%-13% of pancreatic cysts and represent as 1% of pancreatic cancer (PC)[1]. It is more common in men, with peak incidence at 60-70 years[2,3]. The definition of pancreatic intraductal papillary mucinous neoplasms (IPMNs) according to the World Health Organization is tumors that grow inside the pancreatic ducts and produce mucin-containing epithelial cells forming papillary projections[4]. The mortality rate of PC is high relative to other types of cancer and is considered one of the deadliest cancers worldwide. In United States, it is predicted to become the second cause of cancer-related deaths by the end of 2030[5].
CLASSIFICATION OF CYSTIC LESIONS
In general, cystic lesions of the pancreas are categorized into mucinous/non-mucinous neoplastic cysts and non-neoplastic lesions such as pseudocysts and retention cysts. Mucinous neoplastic cysts are identified macroscopically as precursor lesions of PC and include IPMNs and mucinous cystic neoplasms (MCNs). Non-mucinous neoplastic cysts have a low malignant potential and include solid pseudopapillary neoplasm, serous cystadenoma, cystic neuroendocrine tumor, and a group of epithelial cysts such as acinar cystic transformation, lymphoepithelial cysts, cystic teratomas, squamoid cysts, and others[6].
The initial categorization of the pancreatic mucinous tumors into intraductal papillary mucinous tumors and mucinous cystic tumors was introduced in 1996 by World Health Organization[7]. Afterward, in 2000, the two neoplasms were rechristened as IPMNs and MCNs, respectively[8]. Then, IPMNs were baptized and subclassified into benign, borderline, and malignant; adenoma, with moderate dysplasia, and noninvasive or invasive, respectively[9]. Lastly, the up-to-date pathological categorization divides IPMNs according to the presence or absence of dysplasia as well as its degree, in addition to the absence or presence of invasiveness into low and high-grade dysplasia, and finally invasive carcinoma[10,11].
Visible noninvasive mucinous epithelial neoplasm originating from the main pancreatic duct (MPD) or branch ducts, usually more than 5 mm in size, harboring numerous cell types exhibiting architectural and cytologic atypia[12]. Papillary lesion, according to the degree of dysplasia, is divided histologically as: (1) Low grade, which incorporates dysplasia of low or intermediate grade previously termed “intraductal papillary mucinous adenoma”; (2) High grade dysplasia previously termed “intraductal papillary mucinous carcinoma, noninvasive”; and (3) An associated invasive carcinoma previously termed “intraductal papillary mucinous carcinoma, invasive”[13].
There are many essential features for diagnosing the noninvasive mucinous epithelial neoplasm visible cystic lesion of more than 5 mm, mainly in the head of the pancreas, having more than 90% 5-year survival following complete resection, and a third of cases may be associated with invasive carcinoma. It is further subdivided into gastric, intestinal, and pancreaticobiliary types depending on epithelial types, despite the separation of the intraductal oncocytic papillary neoplasm (IOPN) as a separate subcategory[14]. Main duct IPMN (MD-IPMN) and branch-duct IPMNs (BD-IPMNs) mostly arise in the head of the pancreas (67%) and 33% in the body and tail[2].
No well-established factors are identified; one series reported cigarette smoking[15]. and others reported association with Peutz-Jeghers syndrome, which is an autosomal dominant inherited syndrome, mutations in STK11/LKB1I, and familial adenomatous polyposis[16].
CLINICAL DIVISION OF IPMNS
Clinically, IPMNs are divided into MD-IPMN, BD-IPMN, and mixed-type IPMN (MT-IPMN), which behave as MD IPMN type. MD-IPMN has symptoms and signs related to duct obstruction or pancreatitis, including weight loss, epigastric pain, jaundice, and diabetes[2,17]. In addition, BD-IPMN mainly appears to be asymptomatic and discovered incidentally on imaging[2]. IPMN is diagnosed radiographically or by endoscopic findings, fine needle aspiration (FNA), and surgical biopsy. Pancreatic cyst fluid analysis can help in identifying the type of cyst[18-20]. High levels of carcinoembryonic antigen and detection of KRAS/GNAS mutations support mucinous cyst diagnosis.
RADIOLOGIC WORK-UP OF IPMNS
Computerized tomography (CT) scan can assess macroscopic structures such as size of cysts and its anatomical position such as head, body, or tail, also either segmental or diffuse, MPD either dilated or of normal caliber, detection of thickened, enhanced walls or mural nodes, assess the presence or absence of lymphadenopathy, and pancreatic atrophy[10]. In addition, CT scan may be valuable to notice related signs of chronic pancreatitis such as ductal stenosis, calcifications, degenerative changes in mass lesions, or nodules. On the other hand, assessment of communication between the MPD and cystic lesion using CT alone is often difficult and needs further investigations[10,12].
CT revealed that the MD-IPMN causes distention of the MPD, while the BD-IPMN harbors multilocular grape-like cystic adventitia. Endoscopic retrograde cholangiopancreatography (ERCP) revealed the presence of pancreatic ductal filling defects, which may be associated with ductal dilation[21].
CT scans or ultrasound (US) are the first line of imaging procedures to make the diagnosis suspicious of IPMN. But they cannot be considered the best choice to catch an accurate diagnosis of IPMN. Accordingly, when a cystic lesion is suspected either by CT or US, additional high-resolution imaging procedures are required to confirm the diagnosis, such as endoscopic US (EUS) and magnetic resonance imaging (MRI)[22].
Magnetic resonance cholangiopancreatography (MRCP) revealed other imaging options that do not create radiation. FNA and cyst fluid analysis can be obtained through EUS[23,24]. It is widely used for high sensitivity and non-invasiveness and is considered the most important radiological investigation for IPMN. In contrast to CT, MRCP provides accurate information about Wirsung dilatation (segmental or diffuse) and permits screening of the communication between pancreatic cysts with the ductal system[22].
International guidelines put the range of 5-9 mm of the MPD size as a worrisome feature (WF) and indicative of the diagnosis of MD-IPMN. If MDP size is more than 10 mm, it is considered a high-risk stigmata (HRS), indicating MD-IPMN is highly suggestive of malignancy[10,12].
The importance of the combination model of MRCP/MRI comes from the fourth dimension. First, it can assess static fluid with high accuracy owing to the presence of T2-weighted sequences, which are sensitive to signal from static fluid such as bile and pancreatic juices. Second, CPRM exploits more than 3000 ms echo time, thus allowing detecting and studying the widespread or segmental dilatation of MPD or secondary duct or both; main duct, branch-duct, mixed-type, along with studying the shape and communication between the ductal system and cystic lesions. Third, MRI can evaluate the morphological abnormalities, nodules, and solid parts of IPMN by T1-weighted sequences and intravenous paramagnetic/iodine contrast. Fourth, MRCP, in addition to using intravenous secretin, may be valuable in better imaging of the entire MPD and secondary branches[25-27].
EUS
The second line of imaging procedure applied for confirming the suspicion of IPMNs is the EUS. EUS provides complementary and integrated information with MRI. EUS is frequently executed after diagnosing a cystic lesion either by US or CT scan. EUS, in addition to MRI, has a high ability to display anatomical minutiae of cystic lesions and their contacts with nearby structures. Furthermore, EUS can reveal MPD and its branches, the diversity, and the ambiguous communications between ducts. Additionally, EUS can validate features indicative of malignancy, such as thickened septa between cysts, mural nodules, and the state of vasculature in these abnormal structures[28]. Also, EUS permits to practice of FNA to analyze the cystic fluid for cytological and biochemical assessment essential for the diagnosis of pancreatic cystic lesions. EUS can discover malignant deviations of IPMN. EUS and MRCP were alike at investigating pancreatic cyst and MPD communications as reported in one prospective study. EUS is praised in the FUKUOKA guidelines 2012 for IPMNs cases, for its greater sensitivity than CT scan or MRI[29].
Its role in evaluation of IPMNs is debated and not commonly used[30-32]. ERCP can be utilized in the management of IPMNs. It provides information about the anatomy of the pancreatic duct, pancreatic fluid analysis on the presence of mucus[10,12]. ERCP reveals the features of the papilla of Vater using a side-viewing endoscope. In IPMNs cases, duodenoscopy can reveal a papilla with excessive production of mucin (fish-eye appearance). In obscure segmental MPD dilatation, the squeezed mucin from the papilla after pancreatic sphincterotomy is indicative of IPMN diagnosis. Furthermore, ERCP may be used as a line of treatment in patients with IPMN. ERCP is an invasive technique, so it has been replaced by MRCP[10,12]. Endoscopic pancreatic sphincterotomy may be executed in patients who are not fit for surgery for cases suffering from recurrent attacks of acute pancreatitis due to MPD obstruction by mucus[10,12].
The use of per-oral pancreatoscopy is to discriminate between benign lesions from premalignant IPMN lesions. The incidence of pancreatitis as a sequela of this technique makes it very limited in clinical settings[33,34].
BIOCHEMICAL, MOLECULAR/CYTOGENETICS AND HISTOPATHOLOGICAL MORPHOLOGY OF IPMN
IPMNs do not cause any remarkable elevation in serum lipase and amylase levels, and these enzymes may show elevation due to compression on the MPD or biliary duct by enlarged IPMNs[10,12,22].
Serum carbohydrate antigen 19-9
Serum carbohydrate antigen 19-9 (CA19-9) has a major role in the follow-up of patients with IPMNs and is not one of the basic tests used for initial diagnosis of patients; its elevation in the follow-up period may be a relative indication for resection of IPMNs. Elevated serum CA19-9 levels may be valuable for the distinction between benign and invasive IPMNs. It is reported in 2013 by European experts’ consensus that elevated CA19-9 is a relative risk factor expecting malignancy in IPMNs patients. However, CA19-9 is not anticipated in the FUKUOKA 2012 guidelines for preliminary management of IPMNs[10,12,22].
Other markers, such as platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio, may be used to forecast malignant invasiveness of IPMN[35]. Though neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio are not applied in the usual biochemical investigation of IPMNs.
Molecular and cytogenetic analysis: The molecular and cytogenetic studies revealed that KRAS, GNAS, and RNF43 mutations have been discovered in decreasing order in most cases of noninvasive IPMNs and IPMNs with associated invasive carcinoma[36,37]. GNAS mutations are more frequently linked to cases of IPMNs that anchorage invasive colloid carcinoma. KRAS mutations are more frequent in cases of IPMNs that harbor an invasive tubular (ductal) adenocarcinoma. From low to high-grade dysplasia, the following mutations in KRAS, TP53, CDKN2A (p16) were detected. Also, mutations in KRAS2 and GNAS are detected on analysis of cystic fluid. Furthermore, hypermethylation and reduced BRG1 protein are confirmed in the pathogenesis of IPMNs. Also, loss of programmed cell death 4 and CD24 expression is seen to be associated with tumor progression and proliferation[38-40].
MORPHOLOGY OF IPMNS
The outline of main duct dilatation is contingent on the location of the tumor and the amount of mucus production, and accordingly, four models of ductal ectasia have been identified: (1) Diffuse; (2) Segmental; (3) Side branch ectasia; and (4) Multifocal cysts with duct communication. Each model has a specific prevalence of cancer and a definite clinical presentation and hence has more specific indications of resection. The occurrence of multifocal BD-IPMN does not predict bear high risk of malignancy[39]. BD-IPMNs are managed as premalignant lesions, but their risk of malignancy depends on the size, single or multiple, presence or absence of nodules, and epithelial type[40].
The malignant transformation, as defined by the presence of high-grade dysplasia and invasive carcinoma, varied according to reported data from previous literature. The range of occurrence of high-grade dysplasia is 6.3%-46.5%, with a mean of 25.5% and the range of invasiveness is 1.4%-36.7% with a mean of 17.7% for surgically resected BD-IPMNs, opposite to 40%-92% for MD-IPMNs and MT-IPMNs. Furthermore, in BD-IPMN patients, the risk of developing cancer has been investigated for about 10 years, and it is revealed that 20% of cases developed cancer[41-44]. In addition, the rate of cell progression from benign to malignant to the invasive state in MD-IPMNs has been assessed and revealed that the range of transformation was 5-7 years[10,12,22].
The gross appearance of IPMNs depends on their location. If the main duct is involved, it is usually dilated, irregular, tortuous, and filled with mucin. Classically, it arises in the head and progresses along the course of the main duct, may encompass the entire pancreas, or may implicate major or minor papillae, causing mucin to escape from the ampulla. The unaffected pancreatic tissue is frequently firm and pale, denoting prevalent chronic obstructive pancreatitis. On the other hand, if the branch duct is involved mainly in the uncinate process, it appears as grape-like multicystic structures, dilated duct forming cysts, filled distended by tenacious mucin. The wall of the cyst is thin and lined by flat or even papillary epithelial cells. Cyst walls are usually thin with a flat or papillary lining. Cysts are separated by areas of normal pancreatic tissue, signifying that cysts are disconnected on cut sections. 40% of cases show multicentricity[45]. Extensive sampling of cysts for microscopic examination is very important to detect any associated invasive carcinoma. Incipient IPMN is a term applied to lesions of 0.5-1.0 cm in size[46,47].
Frozen section
Frozen section is necessary for diagnosis; classically, resection margin status should be assessed to eliminate IPMN; extra margins will be acquired if invasive carcinoma exists or probably for the occurrence of high-grade dysplasia[13,48,49]. If low-grade dysplasia is present, classically, no extra resection is done; this may denote pancreatic intraepithelial neoplasia (PanIN) against IPMN[12,48].
Histological examination of IPMNs
The histology of IPMNS revealed presence of mucin-secreting epithelial cells with lake of mucin showing varied degrees of dysplasia ranged from low grade which is characterized by presence of a flat epithelial lining cells and basally located nuclei showing a little pleomorphism to intermediate dysplasia that has features between those of low and high grade dysplasia (low and intermediate is categorized as low grade dysplasia) to high grade identified by complex architectural features such as irregular branching, and cribiforming pattern along with loss of nuclear polarity, hyperchromatism and nuclear irregularities[48]. The epithelial cells are categorized morphologically as intestinal, gastric, and pancreaticobiliary types. The presence of oncocytic lining suggests the diagnosis of IOPN. It may be associated with chronic pancreatitis or PanIN[49]. It may be associated with foci of invasive carcinoma[2].
Cellular features of IPMNs
The cellular features range from gastric type IPMN, intestinal, and pancreaticobiliary type. In gastric type: Cells bear a resemblance to gastric foveolae and may be associated with intestinal metaplasia, usually with dysplasia of low-grade type, mainly occur as a BD-IPMN. If an associated invasive carcinoma is present, it is typically of ductal/tubular adenocarcinoma[47,50]. Intestinal type IPMN: Tall columnar epithelium, like intestinal villous adenomas, and may be associated with dysplasia that ranged from low to high-grade and MD-IPMN. If associated with invasive carcinoma, it is a mucinous/colloid carcinoma. Pancreaticobiliary type IPMN: Thin branching or complex papillae-like cholangio-papillary tumors. These papillae consist of cuboidal cells with prominent nucleoli associated with high-grade dysplasia, mainly seen in the MD-IPMN. If an associated invasive carcinoma is present, it is typically of ductal/tubular adenocarcinoma (Table 1).
Table 1 Histologic features of intraductal papillary mucinous neoplasms according to cell types.
Histological subtype
Histological features
Associated carcinoma
Prognosis
Gastric
Foveolar-like cells, may be associated with intestinal metaplasia, low-grade dysplasia. Mainly branch duct
Ductal/tubular adenocarcinoma
Slightly better prognosis than PDC not associated with IPMNs
Intestinal
Tall columnar epithelium (villous adenoma like), low to high-grade dysplasia. Often main duct affected
Mucinous/colloid carcinoma
Better than PDC
Pancreatobiliary
Cuboidal cells, thin branching or complex papillae (cholangio-papillary like tumors). High-grade dysplasia often main duct affected
Ductal/tubular adenocarcinoma
Slightly better prognosis than PDC not associated with IPMNs
Furthermore, quantitative histopathology was introduced and considered a well-organized way to differentiate chronic pancreatitis and pancreatic carcinoma from MD-IPMNs or BD-IPMNs. Its accuracy in categorizing pancreatic lesions is about 90% and 100% accurate in recognizing chronic pancreatitis. Quantitative histopathology can investigate nuclear features on biopsy specimen accuracy such as nuclear roundness, short and long run emphasis, run length matrix and percentage, and the total number of flippantly stained pixels, and combine these results with statistical analysis[51]. Therefore, quantitative histopathology is an innovative method beneficial in supporting pathologists to reach an accurate diagnosis, especially in cases with ambiguous histopathology.
DIFFERENTIAL DIAGNOSIS OF IPMNS
IOPN
It has a specific architectural pattern showing arborizing lined by oncocytic cells. It has a different molecular genetic alteration in one of the following genes: (1) ARHGAP26; (2) ASXL1; (3) EPHA8; and (4) ERBB4[52]. Immunohistochemistry revealed positivity for MUC1, MUC6, DNAJB1-PRKACA fusions[53].
Intraductal tubulopapillary neoplasm
Lately documented as a subtype originating from peribiliary cysts[54]. Its histological appearance in the form of tributary epithelial cells forming papillary and tubular patterns with signs of high-grade dysplasia is seen. In addition, solid growth with necrotic foci, little or invisible mucin, with intracytoplasmic mucin is present. No mutations in the KRAS2 gene are detected. immunohistochemically revealed positivity for MUC1+, MUC6+ and negativity for MUC2-.
MCN: This cyst is lined by an epithelial mucinous layer and stroma of ovarian type. Radiological investigations revealed no anatomical communication with the pancreatic duct or its branches.
PanIN: It differs from IMPNs as it has an occult mass that cannot be detected grossly and is only detected microscopically. Microscopically, it has differentiation towards gastric foveolar epithelium.
Simple mucinous cyst: Cyst is more than 1 cm, lined by flat epithelium with no papillary infoldings seen. The type of epithelial lining is differentiated towards a gastric mucinous type, with no or little significant atypia is seen[48,55].
Retention cyst: A Cyst is more than 1 cm with a simple flat epithelial lining, no papillary architecture is found, and little atypia in a contextual obstruction (Table 2)[48].
Table 2 It summarizes the differential diagnosis of intraductal papillary mucinous neoplasms.
Intraductal oncocytic papillary neoplasm
Intraductal tubulopapillary neoplasm
Mucinous cystic neoplasm
Pancreatic intraepithelial neoplasia
Simple mucinous cyst
Retention cyst
Variable sizes. Arborizing lined by oncocytic cells. It has a different molecular genetic alteration in one of the following genes, ARHGAP26, ASXL1, EPHA8 and ERBB4. DNAJB1-PRKACA fusions. MUC1 and MUC6 positivity
Variable sizes subtype originating from peribiliary cysts. Tributary epithelial cells forming papillary and tubular patterns. High-grade dysplasia solid growth with necrotic foci, little or invisible mucin with intracytoplasmic mucin is present. No mutations in KRAS2 positivity for MUC1+, MUC6+ and negativity for MUC2-
Variable sizes. This cyst is lined by epithelial mucinous layer and stroma of ovarian type. No anatomical communication with pancreatic duct or its branches radiologically
Occult mass. Detected microscopically. Epithelial differentiation towards gastric foveolar epithelium
> 1 cm. Flat epithelium (differentiated towards gastric mucinous type). No papillae. Little atypia
> 1 cm. Simple flat epithelial lining. No papillae. Little atypia
The prognosis depends on its type: MD-IPMN or BD-IPMN, or MT-IMPN, without or associated with invasive carcinoma. and those with associated invasive carcinoma, the prognosis depends on the histological pattern. Most of the MD-IPMN have high-grade dysplasia (60%) and are associated with an invasive carcinoma in 45% while the dysplasia in BD-IPMN is mostly of low grade, with nearly 25% of high grade, and 20% of cases are associated with an invasive carcinoma[2].
The tumor without invasive carcinoma has more than 90% 5-year survival, and those associated with invasive carcinoma have a worse prognosis; nearly 50% of the cases die of the disease. The histological pattern of invasive carcinoma is either tubular, colloid, or mixed. The colloid pattern bears a better prognosis than pancreatic ductal carcinoma (PDC). On the other hand, tubular (ductal) adenocarcinoma is seen in about 50% of cases and has a slightly better prognosis than non-IPMN-associated PDC[47].
Reflecting the inclusive prognosis, invasive carcinoma that emerges from IPMNs offers a better prognosis compared to primitive solid ductal adenocarcinoma. The reported data revealed that the invasive carcinoma consequent from IPMNs has a 5-year survival rate of 34.5% compared to 12.4% of PDC[56].
MANAGEMENT OF IPMNS
Many guidelines published about the management of IPMNs have been introduced. The main and common goals of these guidelines are to stress when to operate and when to do follow-up. So, the management of IPMNs is debated and controversial because of different guidelines offered by many associations, such as International Consensus Guidelines (ICG), American Gastroenterological Association (AGA), and European guidelines. Therefore, each guideline has specific indications for surgical treatment and postoperative surveillance for invasive IPMNs, as well as indications for follow-up for cases with low-risk IPMNs and in need for conservative treatment. In addition, most of these guidelines have agreement on the timing of follow-up, but the difference emerges from how to select and prioritize the imaging technique[57].
The three most widely validated guidelines developed are the Tanaka et al[10], European Experts’ Consensus[31], and Tanaka et al[58]. Additionally, other guidelines, such as 2014 Italian Association for the Study of the Pancreas guidelines, have been anticipated by the Italian Pancreas Group and (2015 AGA guidelines) by the AGA[59].
The ICG was the earliest Sendai guidelines and was very restrictive. Tanaka et al[58] recommended surgical resection of all MD-IPMNs and MT-IPMNs on the condition that the patient is healthy for surgery. The indication of surgery in BD-IPMNs patients, with no symptoms, is not only to relieve the signs but also to reduce the risk of malignant transformation.
Furthermore, affording these guidelines, BD-IPMNs of more than 30 mm or 3 cm in diameter and without MPD dilation or mural nodules, presence of atypia in the cystic fluid, and the patient has symptoms are recommended for immediate surgery. On the other hand, conservative treatment is recommended for those cases where the diameter of BD-IPMNs is less than 3 cm in an asymptomatic patient. These Sendai recommendations have resulted in a high rate of gratuitous pancreatic surgeries with increased morbidity and mortality rates[60]. However, the conservative management for BD-IPMNs was recommended by subsequent guidelines emerging over time.
The revised form of Sendai ICG was introduced and published in 2012 as International Association of Pancreatology Fukuoka guidelines 2012 (revised later in 2017), and introduced what is called WF and HRS. ICG recommended that surgery is strongly recommended for all cases of MD-IPMNs with a MPD of diameter of more than 10 mm or associated with HRS, which include enhanced solid component, obstructive jaundice, and MPD size is equal to or more than 10 mm[10,12]. The WFs comprise a set of the following signs: (1) Enhanced and thickened cyst walls; (2) The size of cyst ≥ 3 cm; (3) The size of MDP range from 5-9 mm; (4) Non-enhanced mural nodules; (5) A rapid change in the MPD caliber associated with distal pancreatic atrophy; (6) Contiguous lymphadenopathy on imaging investigations; and (7) Acute pancreatitis diagnosed clinically[12]. These WFs require further evaluation using EUS and should not be subjected to urgent resection[12,61]. The decision of surgical resection is strongly recommended when EUS results reveal definite mural nodules, the main duct is doubtful for malignant involvement, with suspicious or positive cytology for malignancy. On the contrary, if EUS is indecisive, close surveillance and periodic/alternating EUS/MRI every 3-6 months is highly recommended.
In the existence of IPMNs with no association with WFs and suspicious EUS report, the guidelines propose follow-up of short interval (3-6 months) to assess stability, then, imaging follow-up should be executed[10,12,22].
Consequently, the cyst size will determine the timing suggested for follow-up; CT/MRI should be done in 2-3 years for cysts less than 10 mm, CT/MRI in 12 months for 2 years for cysts of 10-20 mm, and the interval can be prolonged if no change appeared, EUS in 3-6 months for cysts of 20-30 mm, prolonged interval alternating MRI with EUS can be made, and surgery is indicated for young fit patient, with need for prolonged surveillance, and for cysts more than 30 mm, close surveillance is recommended, and alternating MRI/EUS every 3-6 months, and surgery is highly recommended for young, and fit patients[10,12,59]. For cases with MT-IPMNs, management is contingent on the patient’s fitness and the biology of the lesion. Frequently, they can be subjected to surgery like MD-IPMNs[12]. Conclusively, the Fukuoka guidelines 2012 recommended that patients with IPMNs in the presence of HRS should be referred to surgery resection without adjournment[10,12,59].
In 2013, absolute and relative indications for surgery of cases with high-risk IPMNs were introduced by the European Experts Consensus statement. The basis of absolute indications was elaborated from Sendai 2006 guidelines, considering the size of the cyst with a cut-off point of 4 cm. Relative indications comprised the rapid growth rate of the cyst with a cut-off point of at least 2 mm/year, and the increased serum level of CA19-9[31].
Fukuoka definitions of ‘HRS’ and ‘WFs’ were revised by the Italian Association of Hospital Gastroenterologists and Digestive Endoscopists-Italian Association for the Study of the Pancreas guidelines 2014, and planned the surgical treatment for all the pancreatic cysts that revealed a mucinous type, even if they exist as a solitary lesion in the WF after performing biochemical assay. All the experts of this committee approved the same follow-up timing and indication of surgery in ‘high-risk’ IPMN patients. However, disagreements were about the precise indication for the surgery, and imaging of follow-up[62].
AGA was introduced in 2012 and offered restrictions for surgical treatment for non-symptomatic patients and advocated it only in the existence of at least two out of three features: (1) Presence of nodule; (2) Diameter more than 30 mm; (3) Duct dilation; and (4) Malignant transformation approved by EUS-FNA[59].
Furthermore, in 2015, AGA proposed that pancreatic cyst patients devoid of any Fukuoka criteria or with negative EUS-FNA should be subjected to imaging follow-up with MRI for five years, once in the first year, then once every 2 years if there is no change either in character or size of the lesion. If no changes occur after 5 years, surveillance should be stopped. Alternatively, the presence of two or more Fukuoka criteria, or marked changes in the pancreatic cysts, should be inspected using EUS-FNA. Furthermore, these guidelines recommend that patients with a high-risk cyst should be subjected to surgery followed by doing MRI in the next postoperative follow-up every 2 years. So, these guidelines permit us to decrease the cost of surveillance[59]. In addition, AGA guidelines compared to the Japanese and European guidelines appear to employ a low follow-up surveillance, decrease the risk of stratification according to the cystic features, and finally, they don’t regularly deliberate the usage of EUS and its related investigations.
Other recommendations were offered by European surgeon and introduced what is called European guidelines[22] which recommended surgery in cases of IPMNs that presented with jaundice, enhanced mural nodule of at least or more than of 5 mm or has a solid component, positive cytology for malignant transformation, or MPD diameter of at least or more than 10 mm. in addition, surgery is recommended for IPMNs with MPD dilatation of 5-9.9 mm, increase cystic lesion of equal or more than 5 mm/year, high level of serum CA19-9 concentration more than cutoff point 37 U/mL, enhancement of mural nodules, and IPMNs more than 40 mm irrespective of the existence of other high-risk factors[31,63]. In addition, in BD-IPMNs, jaundice, presence of high-grade dysplasia or cancer in FNA cytology, a contrast-enhancing mural nodule of at least or more than ≥ 5 mm in diameter, or presence of a solid mass are considered absolute indications for surgery.
On the other hand, relative indications for surgery include growth rate of at least or more than 5 mm/year, high serum level of CA19-9 in the absence of jaundice, MPD diameter of 5-9.9 mm, IPMN size equal or more than 40 mm, presence of clinical manifestation such as new-onset diabetes mellitus, and contrast enhancing mural nodules[63]. From the guidelines offered, surgery is advocated in all IPMNs, including the MPD, but there is still some debate about MPD dilation. In the nonexistence of other HRS, MPD dilation alone is a pitfall for the risk of misdiagnosis and overtreatment. Hence, some surgeons proposed radiologic investigation for non-symptomatic patients with worrisome MPD dilatation between 5-9 mm[64].
Japanese guidelines have been the calibration of world management of IPMN patients. But these guidelines have sensibility and a lower specificity, and accordingly. These guidelines have a low predictive positive value (PPV) towards the assessment of all pancreatic cyst types, but on the other hand, they attain a higher PPV after IPMNs categorization into two main groups: (1) High-risk group; and (2) Worrisome risk group[65]. Another study was done on 138 surgically resected IPMN patients and found that Fukuoka guidelines have a better PPV, while Sendai guidelines have a better negative predictive value[65].
Recently, evidence-based guidelines were introduced in the form of a hierarchy of new algorithms to include in the assessment of HRS and WFs, and the imaging results from EUS and the results of cytological analysis from EUS-FNA, when this is performed. Another important component of the recent guidelines is to clarify whether lifetime surveillance for small IPMNs is obligatory and endorses two decisions: Either stop surveillance or continue surveillance for conceivable development of associated PDC[66-68]. All these guidelines are summarized in Table 3.
Table 3 It summarizes the indications of surgery and surveillance/follow-up for intraductal papillary mucinous neoplasms.
Items
IAP (2006)
American Gastroenterological Association (2015)
IAP (2017)
Indications for surgery
Size of the cyst is ≥ 3 cm. Mural nodule. Dilatation of MPD ≥ 5 mm. Positive fine needle aspiration cytology
High risk features: The size of cyst is ≥ 3 cm; solid part; dilated MPD. High-grade dysplasia or cancer on cytology
HRS include: Sign (jaundice); nodules enhancement ≥ 5 mm; MPD ≥ 10 mm. High-grade dysplasia or cancer on cytology WF: Cyst size is ≥ 3 cm; acute pancreatitis as a complication of IPMN. Thickened and enhancing cyst wall. Dilated MPD caliber 5-9 mm is associated with abrupt change of with distal pancreatic atrophy. Presence of lymphadenopathy. Elevated serum carbohydrate antigen 19-9. Cyst growth rate > 5 mm/2 years
Surveillance and follow-up
BD-IPMNs ≤ 30 mm without symptoms, or mural nodules, or positive cytology. MRI/MRCP or CT. Size ≤ 20 mm: Follow-up every 6-12 months. Size 20-30 mm: Follow-up every 3-6 months. The intermission can be prolonged if there are no changes after 2 years
BD-IPMNs ≤ 30 mm without solid component, or dilated MPD, or high-grade dysplasia/cancer. MRI. Years 1, 2, 5 from initial diagnosis; it can be considered to discontinue, if there are no changes after year
No HRS/WF: MRI/MRCP, CT size < 10 mm: The follow-up at 6 months from diagnosis every 2 years (if no change). No HRS/WF: MRI/MRCP, CT size 10-20 mm: The follow-up at 6 months from diagnosis yearly per 2 years. No HRS/WF: MRI/MRCP, EUS, size 20-30 mm, do EUS in 3-6 months, yearly EUS or MRI. No HRS, WF present: Size < 30 mm, MRI/MRCP EUS, every 3-6 months: EUS or MRI
When invasive cancer is assumed, pancreatectomy with lymphadenectomy is an essential procedure according to the guidelines of Sendai[59], and the type and extent of surgery vary according to location and extent of IPMN[31,63]. The head of the pancreas is the most common site for IPMN. Hence, pancreaticoduodenectomy (PD) is highly recommended for those located in the head, uncinate process, and neck of the pancreas. IPMNs located within the pancreatic body and tail, distal pancreatectomy should be performed.
Total pancreatectomy (TP) is achieved in extraordinary cases when IPMN verbosely includes the entire pancreas or when IPMN located in the pancreatic head/neck spreads to the distal pancreas, resulting in endocrine and exocrine pancreatic insufficiency that requires specific management, such as pancreatic enzyme supplementation and control of diabetes mellitus that will already appear.
For partial pancreatic resection, frozen section should be done to confirm the negative margin and confirm R0 state, and any cancer-positive margin should be managed by extended resection[30]. PD, distal pancreatectomy, or TP with lymphadenectomy (depending on the location and extent of IPMN) should be the standard surgical treatment according to the revised Fukuoka guidelines[8]. Focal nonanatomic resections such as excision, enucleation, uncinatectomy, or limited resections can be performed in BD-IPMN without invasiveness[61]. Furthermore, the nonanatomic resections may be associated with infrequent mucin leakage that would be complicated by the development of pseudomyxoma peritonei, a high incidence of postoperative pancreatic fistula, and a risk of recurrence.
Also, the European guidelines offered standard pancreatectomy and lymphadenectomy for cases with suspected cancer[31,59,63], in addition to PD with frozen section investigations of the resection margins for patients with MPD dilatation encompassing the entire pancreas. TP can be done for patients with mural nodules within the MPD and familial PC.
In addition, the tumor resection with standard lymphadenectomy should be advocated for BD-IPMNs, cases, as well as for those cases with an absolute indication for resection. In multifocal BD-IPMN, each tumor should be evaluated separately for the presence of malignant changes either grossly or histologically[64,66]. Surgical resection is suggested for elderly patients with MD-IPMN or MT-IPMN with a high level of CA19-9[67].
CONCLUSION
The management of IPMNs is debated and controversial because of different guidelines offered by many associations, such as ICG, AGA, and European guidelines. Therefore, each guideline has specific indications for surgical treatment and postoperative surveillance for invasive IPMNs, as well as indications for follow-up for cases with low-risk IPMNs and in need for conservative treatment. Although most of these guidelines showed agreement on the timing of surgery types of IPMNs, there are still some debates about the timing of surveillance/follow-up and selection/prioritization of the imaging technique, despite new trials that have emerged. The committees of these guidelines should give more unified agreement about the accurate timing of surgery and surveillance.
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