Cystic neoplasms and IPMN

Introduction

Cystic neoplasms of the pancreas are being increasingly identified, due to the increased use of cross sectional imaging like CT or MRI. These neoplasms include intraductal papillary mucinous neoplasms (IPMNs) as well as mucinous cystic neoplasms (MCNs) and other more rare cystic tumors (e.g cystic islet cell tumors). The understanding of IPMN of the pancreas has evolved from the “mucin producing pancreatic tumor” with epithelial dysplasia to a new nomenclature with definitions encompassing specific clinical, radiologic, historical and genetic aspects of the disease.

Differentiating benign from malignant pancreatic cystic lesions remains a challenging task. Classifying these lesions is of paramount importance and ultimately determines when or if a lesion can be monitored or when surgery should be pursued. Parameters such as laboratory studies, cross-sectional imaging studies such as CT, MRI/MRCP as well as endoscopic investigations such as endoscopic ultrasound (EUS), fine needle aspiration (FNA) and endoscopic retrograde cholangiopancreatography (ERCP) are often needed. Frequently performed over the last 10 years, genetic testing and protein analysis are improving the diagnostic certainty of cystic neoplasms.

When a patient presents with symptoms of nonspecific or radiating abdominal pain, a workup is undertaken by gathering a history and performing a physical examination, initiating laboratory testing and obtaining cross-sectional imaging. On imaging, findings suggestive of a lesion identified in the pancreas often progresses to the consultation of a gastroenterologist, and not infrequently, a pancreatologist. In other cases, patients may present asymptomatically with abnormal laboratory tests or an incidental pancreatic lesion found on CT scan, MRI or abdominal ultrasound. Both types of patients have a lengthy list of differential diagnoses, of which cystic neoplasms including IPMN should be considered.

An IPMN is classified as either main duct type (MD-IPMN), branch duct type (BD-IPMN) or both, depending on the extent of involvement as well as the histomorphologic and immunohistochemical characteristics. The five variants of histologic subtypes are: gastric, intestinal, pancreaticobiliary, oncocytic and tubular. With the advent of protein analysis the mucin core protein expressed within a lesion can provide biologic information to assess the activity level of a given lesion within the pancreas.

DNA analysis also has shown a number of gene mutations associated with IPMN, with ongoing research still needed to identify the importance of these mutations. Further classification and therapy weighs heavily on combining all the available diagnostic tools of IPMN. EUS as an isolated modality remains insufficient to accurately evaluate malignant from benign IPMN but is a key component and a safe and effective way to obtain tissue and cytology when FNA is implemented.

The size of the lesion often has proven an unreliable guide for malignancy. Lesions smaller than 2 cm have been shown to have malignant potential in even asymptomatic patients. Fluid collected from an IPMN is typically viscous or stringy in consistency with a clear appearance. This fluid sample can be further analyzed by genetic testing to optimize the diagnostic potential for proper classification and treatment. The decision whether to monitor with careful surveillance a patient with BD-IPMN or guide a patient toward surgical resection for a more ominous diagnosis such as MD-IPMN is critical. The optimal surveillance protocol has yet to be defined but experts agree that close follow-up utilizing cross sectional imaging is necessary.

How can I be sure that the patient has cystic neoplasms and/or IPMN?

The main diagnostic issues revolve around differentiating a pseudocyst, a non-malignant cystic lesion (serous cystadenoma), a premalignant cystic lesion (MCN or IPMN), and frank malignancy. Pseudocysts occur after episodes of pancreatitis and are usually found outside the pancreas. In the absence of a history of pancreatitis, a cyst seen in or on the pancreas should be considered a cystic neoplasm until proven otherwise. Mucinous cystic lesions are considered premalignant, but not serous lesions. A combination of imaging features and analysis of cyst fluid contents is needed to differentiate these various cystic lesions.

Confirming the diagnosis of IPMN starts with a concise definition. The latest consensus guidelines were revised in 2012 during the International Association of Pancreatology (IAP) meeting in Fukuoka, Japan. Building on the previous consensus meeting regarding the clinical management of IPMN in Sendai, Japan, the international community has collaborated to define IPMN its utilizing clinical, radiological, histological, and genetic aspects. Clinical presentation alone is unreliable as patients can be either asymptomatic or symptomatic and may lend to an inaccurate diagnosis. Additionally, laboratory testing usually is not informative. The limited sensitivity of serum markers as well as cytology analysis do not preclude obtaining laboratory studies such as; amylase, lipase, and tumor makers including carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9, but these results vary widely.

A pancreatic protocol computed tomography (CT) scan or magnetic resonance imaging (MRI) of the abdomen allows characterization of a cystic neoplasm or IPMN. When displacement, dilation or stricture of the main pancreatic duct are identified by cross-sectional imaging, EUS or ERCP, cystic neoplasms should be considered in the differential diagnosis. Differentiation between MD-IPMN or BD-IPMN are important, as the natural history and therapy may vary. Although the more invasive testing of EUS presents some procedural risks, the benefits of a proper diagnosis outweigh the risks of anesthesia and the procedure itself.

The morphologic features of both MD-IPMN and BD-IPMN are better detected by EUS than cross-sectional imaging of the pancreas and abdomen, and EUS is routinely utilized in these patients for this purpose. Certain “high-risk stigmata” (obstructive jaundice, enhanced solid component of the wall, and main pancreatic duct size ≥ 10 mm) are more likely to be seen in those who have already developed malignancy (as presented in the Fukuoka 2012 guidelines) and are usually sufficient to recommend surgical resection as definitive treatment. Patients who present with evidence of other “concerning features” (cyst size ≥ 3 cm, thickened enhanced cyst walls, non-enhanced mural nodules, main pancreatic duct size 5-9 mm, abrupt change in main pancreatic duct caliber with distal pancreatic atrophy, lymphadenopathy, and clinical acute pancreatitis) should undergo characterization of their pancreatic lesion by EUS with cyst fluid aspiration first.

ERCP with duodenoscopy to inspect the duodenal papillas, sometimes along with pancreatography, and pancreatoscopy are often beneficial procedures for diagnosis of IPMN and cystic neoplasms of the pancreas. If mucus is observed extruding from the pancreatic orifice during duodenoscopy, this is said to be pathognomonic for IPMN. This “fish eye” appearance of mucin found on duodenoscopy often suggests malignant disease but is by no means diagnostic of cancer. A more ominous sign is a pancreaticoduodenal fistula with extruding mucus; however, this is uncommon with IPMN and typically not observed until malignant invasion is present. In almost all cases, EUS is utilized prior to ERCP in the evaluation of these patients.

As with most diagnoses, histological examination is the gold standard and in the case of pancreatic lesions, the ability to obtain tissue for cytology at EUS is useful. Unfortunately, cytology from cyst fluid is not highly accurate and even adding additional tools such as DNA analysis has not dramatically improved accuracy. EUS, however, remains a more sensitive test than computed tomography or MRI for the early detection of malignancy and differentiating benign from premalignant cysts.

Unusual signs and symptoms

Many patients have no symptoms. Diseases of the biliary tree, liver, abdominal viscera, abdominal wall, and abdominal vasculature produce similar symptoms to a cystic neoplasm of the pancreas. The majority of causes of abdominal pain can be elucidated through a careful history and physical and appropriate laboratory and imaging tests.

Cystic neoplasms of the pancreas often present asymptomatically. In these patients, pancreatic cystic lesions are incidentally found during a routine check-up or while undergoing a work-up for other medical conditions. This is actually the most common situation in which these cystic lesions are identified.

In symptomatic patients, recurrent abdominal pain, dyspepsia, weight loss, anorexia and/or jaundice may be present. Recurrent abdominal pain also may be present and may be the result of recurrent pancreatitis and ductal obstruction from the thick mucin. If biliary obstruction is significant it may result in jaundice. The presence of jaundice, or of significant pain or weight loss, is suggestive of malignancy.

In general, the severity of pancreatitis associated with IPMN is mild and resolves quickly with conservative medical therapy. Patients may be misdiagnosed as chronic pancreatitis. This diagnostic error is often attributed to nonspecific imaging modalities which may either miss small lesions, or a dilated pancreatic duct due to IPMN that is mistaken for chronic pancreatitis. In these cases patients may be inaccurately labeled as having pancreatitis until an appropriate imaging modality such as a pancreatic protocol CT, MRI of the abdomen or EUS identify the characteristic features of neoplastic cysts.

Pathognomonic or characteristic features

Cystic lesions of the pancreas encompass a wide range of diagnoses. The most common symptoms and signs are abdominal pain, weight loss, back pain, jaundice, pancreatitis, a palpable mass and postprandial fullness. As stated above, many patients also may be asymptomatic.

As mentioned earlier cystic neoplasms include serous cystadenomas, mucinous cystadenomas and cystadenocarcinomas, solid cystic pseudopapillary neoplasms, cystic endocrine tumors and IPMN. Cystic spaces also may be seen in pancreatic ductal adenocarcinoma, representing spaces proximal to a pancreatic tumor or regions of necrosis in the tumor. Identification of pathognomonic features of IPMN can differentiate it from other cystic neoplasms of the pancreas.

The highly specific finding of mucus extruding from a patulous pancreatic orifice on direct visualization by duodenoscopy is diagnostic of a main duct IPMN. The historical division of mucin-hypersecreting lesions was based on location within the pancreas; main duct, branch duct or peripheral type. Clarification of these parameters has defined mucinous cystic neoplasm (MCN), the peripheral type, into a separate lesion from IPMN.

Intraductal papillary proliferation of mucin-producing epithelial cells helps to define the IPMN lesions. The excessive secretion of mucin and broad range of dysplasia seen from these particular epithelial cells give the IPMN lesion a characteristic feature based on its dysplasia. The previous terminology classified the lesions as adenomas, borderline tumors, or carcinoma. Based on the Fukuoka consensus guidelines it now includes the degree of epithelial dysplasia and reports it as mild-, intermediate- and high-grade dysplasia to invasive carcinoma.

Although only invasive carcinoma is regarded as malignant, high-grade dysplasia has been shown to have the potential to progress to malignancy and is therefore recommended to be considered for surgical resection along with invasive carcinoma. Profuse secretion of mucin by IPMN results in cystic dilatation of the pancreatic ducts that is seen on cross sectional imaging and EUS examination.

Other features of an IPMN that warrant attention include BD-IPMN measuring more than 3 cm in diameter even without mural nodules, as there is higher prevalence of malignancy and invasive cancer in resected specimens of these lesions. The two layers of criteria for assessment of IPMN: “high-risk stigmata” considered being indicative of malignancy, and “worrisome features” of malignancy is a prominent point of the Fukuoka guidelines.

Patients presenting with obstructive jaundice, enhancing solid component, and main pancreatic duct size ≥ 10 mm should undergo resection without delay, as this defines high-risk stigmata. Patients in need of EUS for evaluation of worrisome features, such as acute pancreatitis, a cyst size 3 cm or larger, thickened and enhanced cyst walls, nonenhancing mural nodules, main pancreatic duct size 5-9 mm, an abrupt change in the main pancreatic duct caliber with distal pancreatic atrophy, and lymphadenopathy on imaging should be considered for surveillance.

The laboratory tests that have made the most advancement in diagnosis of IPMN have been at the level of DNA analysis. Molecular and genetic gene mutations allow for a target that correlates the oncogenesis of IPMN/IPM carcinoma (IPMC) with a “finger print” identifying genetic features.

Some less common clinical presentations

Cystic neoplasms are often only minimally symptomatic and are found at a higher incidence in the middle-aged or elderly. IPMN, a malignant or premalignant condition of the pancreatic duct, may produce ductal dilation, pancreatic gland atrophy and exocrine insufficiency, and can be mistaken for chronic pancreatitis. Because chronic pancreatitis is a risk factor for pancreatic adenocarcinoma and the two conditions may coexist, it is an important clinical distinction to separate from benign lesions.

Some forms of chronic pancreatitis are more prone to malignancy than others. Pancreatic cancer also may produce clinical symptoms and imaging features that are similar to chronic pancreatitis and the initial diagnostic approach emphasizing high-quality imaging studies is appropriate to help rule out the presence of pancreatic adenocarcinoma. Differentiation can often be made with EUS, although occasionally ERCP may be needed.

Exocrine and/or endocrine insufficiency is not an uncommon comorbidity of IPMN. Patients may not report diarrhea but usually note oily or greasy stools. Steatorrhea can be substantial but is not definitive of a specific pathology in the pancreas. IPMN has overlapping clinical features with chronic pancreatitis. Patients may develop fat-soluble vitamin deficiency (especially vitamin D) and are at high risk of osteopenia and osteoporosis. The presence of steatorrhea and exocrine insufficiency may be difficult to diagnose. Typically, the presence of excess fat on a qualitative stool stain (Sudan stain), coupled with the appropriate history and an abnormally low fecal elastase (<200 mcg/gm stool) or serum trypsin (<20 ng/mL) is sufficient evidence to support initiating pancreatic enzyme replacement therapy for exocrine insufficiency.

A number of other complications may occur, including pancreatic pseudocysts, biliary obstruction, gastrointestinal bleeding and duodenal obstruction with the presence of a pancreatic cystic neoplasm. Cystic neoplasms often have a thick wall and have internal nodules or septations. Cystic neoplasms can usually be differentiated from pseudocyst by EUS with FNA as well. Cystic neoplasms may demonstrate high levels in the cyst fluid of CEA (carcinoembryonic antigen), low levels of amylase, and cytology demonstrating mucin or atypical cells. The therapy for a cystic neoplasm is resection, not drainage.

Other diseases and conditions that might mimic pancreatic cystic neoplasms

The pancreatic lesion with multiple small cysts smaller than 3 cm suggests a microcystic lesion such as a serous cystadenoma. These are benign lesions with little malignant potential. Pseudocysts are characterized by the absence of septation or solid components within the pancreas, and parenchymal abnormalities. More importantly, there is a history of pancreatitis preceding the development of the cyst. Although a hypoechoic mass with a cystic component is suggestive of an adenocarcinoma, a diffusely dilated pancreatic duct is commonly present in IPMN. Narrowing down the differential diagnosis is imperative for the correct diagnosis of IPMN.

MCNs are similar to IPMNs in that they both are considered to be mucin-hypersecreting neoplasms. MCN corresponds to the peripheral type, whereas IPMN corresponds to the main duct type and the branch duct type. Historically, these neoplasms have been divided based on the main location of the involvement, but recently MCN and IPMN have become separate classifications. The World Health Organization and Armed Forces Institute of Pathology clearly define IPMN and MCN differently. The mucin-producing columnar epithelium of MCN occurs in the body and tail of the pancreas in middle-aged women with higher frequency. Elderly men more commonly have lesions in the head of the pancreas identified as IPMN and do not have the ovarian type stroma of the MCN.

The signs, symptoms and clinical features of pancreatic cystic neoplasms can be mimicked by chronic pancreatitis and carries with them associated complications (e.g. pseudocyst, pancreatic stones) including pancreatic cancer. (See Figure 1 and Table I.) A similar work up and clinical management is required for these cystic neoplasms, with cross sectional imaging and histopathological examination by EUS-FNA for definitive diagnosis.

Figure 1.

Table I.

A tabular or chart listing of features and signs and symptoms

A summary of pancreatic cystic lesions is shown in Figure 1. Differentiation of pancreatic cystic neoplasms, pancreatitis and associated complications, and pancreatic cancer, according to clinical features, are listed in Table I.

How can I confirm the diagnosis?

Cystic neoplasms can be symptomatic or asymptomatic. The diagnosis can best be confirmed by utilizing imaging and aspiration of cyst contents. These may be detected or visualized by both cross-sectional imaging studies (CT, MRI), as well as by endoscopic evaluation by EUS or ERCP (endoscopic retrograde cholangiopancreatography). In cystic neoplasms, smaller lesions or non-obstructing disease, the diagnosis can be difficult to make as these patients may not have developed significant lesion size to be seen with cross-sectional imaging studies or analysis by EUS.

Diagnostic tests are usually divided into those that identify an abnormality of the structure of the pancreas (e.g. CT scans, EUS or ERCP) and those that identify an abnormality of function or secretory capacity of the pancreas. Each of these tests can be useful, but no one test accurately diagnoses IPMN. All vary in cost, risk, and availability.

Patients with BD-IPMN disease can be labeled as having pancreatic cysts with indeterminate significance. In these cases, the pancreatic duct is not dilated and the typical cross-sectional imaging features of IPMN have not developed. This is in contradistinction to MD-IPMN, in which the pancreatic duct is dilated and obvious changes of main duct communicating cyst(s) are visible on CT or MRI.

In most situations, a good-quality multidetector CT with pancreas protocol is the first test to order after basic laboratory evaluation. As an alternative, abdominal MRI with MRCP is comparable and perhaps superior to CT as the initial diagnostic test. MRI will demonstrate the same features as CT and MRCP provides better and more detailed imaging of the pancreatic duct.

While ultrasound imaging may allow reasonable imaging of the pancreas, the ability to image the pancreas by ultrasound is more limited as it is often obscured by bowel gas. In the early stages of BD-IPMN, there may not be sufficient accumulated structural damage to be easily visible on commonly used tests such as CT or MRI. Abdominal pain in BD-IPMN may be acutely episodic or chronic, sometimes even requiring hospitalization. In more advanced disease, structural changes have developed and diagnosis is more easily determined.

As imaging studies such as CT and MRI are widely available and reasonably safe, these should be the initial tests to order. MRI will avoid undue radiation exposure, but, unfortunately, MRI may not be suitable for patients with cardiac pacemakers or other metallic hardware. If these tests are indeterminate or negative, the next step usually is an EUS with FNA.

The findings on EUS most consistent with cystic neoplasm IPMN include:

• 1. Cyst wall thickness greater than 3 mm.

• 2. Intracystic compartments (microseptation) larger than 10 mm.

• 3. Intramural mass in the cyst or main pancreatic duct.

• 4. Dilation of the main pancreatic duct.

EUS allows for a detailed image of the pancreatic parenchyma and duct. There are different systems used to classify the findings on EUS, based on specific ultrasonographic criteria. A word of caution as EUS is not perfect and many cystic conditions can cause similar appearing features.

If the EUS imaging characteristics are indeterminate or inconclusive, as is often the case, the cyst can be sampled with FNA. Another option is observation, as patients with BD-IPMN typically have a low malignancy potential and may be monitored with serial cross-sectional imaging. If a patient’s lesion continues to evolve, imaging studies will become abnormal enough to confidently reach a diagnosis.

An approach to diagnosis includes the following steps:

• Consider the disease in the appropriate patients, obtain history and physical exam.

• As an initial step, CT with pancreas protocol or MRI with MRCP is preferred.

• If the diagnosis is still in doubt, proceed with EUS.

• If the diagnosis is still in doubt, perform FNA for cyst fluid and cytology analysis.

Confocal endoscopy is a newer modality that is giving endoscopists the opportunity to characterize pancreatic lesions based on morphology. This technique of identifying IPMN-specific cellular changes offers another real-time imaging analysis to assist in the diagnosis. A confocal probe is passed through a needle which has been introduced in the cyst, and the cyst wall can be examined in microscopic detail.

The Paris classification with recent updates in the Miami criteria uses terminology such as “dark clumping, chicken wire appearance and thick bands” to describe the detail seen in the epithelial wall of a suspected pancreatic neoplasms or IPMN. Experts agree that more work is needed on confocal imaging technology as well as with biomarkers but both show a promising role in the future.

What tests should be ordered first?

The initial testing for suspected IPMN should be laboratory testing (complete blood count, serum chemistry, including liver function tests and amylase) and cross-sectional imaging such as a CT scan (pancreatic protocol) or even an MRI/MRCP if suspicion is high. Most patients will present with a cystic lesion already discovered on cross-sectional imaging, but repeating a CT with pancreas protocol can add additional information.

To confirm the diagnosis, additional tests of pancreatic imaging can be obtained. When BD-IPMN is suspected, the communication between the cystic lesion and the pancreatic ductal system can be documented. With advances in multidetector CT, the ductal communication may be demonstrated similar to MRI/MRCP. However, in cases in which the ductal communication is not demonstrated with CT, additional tests such as MRCP, ERCP and EUS should be considered. MRCP remains the least invasive test. Endoscopic testing would include ERCP and EUS, with EUS always being used first.

On MRI, the lesion is best visualized with T2-weighted images. On ERCP, the hallmark findings of the MD-IPMN are of the diffusely dilated main pancreatic duct with filling defects representing mucinous filling or papillary tumors. For BD-IPMN, the affected branch ducts are cystically dilated and communicate with the main pancreatic duct. In some occasions, mucus plugging prevents the lesion from filling with contrast. In some cases, duodenoscopy during ERCP reveals a patulous duodenal papilla and mucin extrusion.

What other tests are useful if the diagnosis is still in doubt?

Ultimately, the diagnosis of IPMN is often based on histology or cytology of the pancreatic duct or cysts. Cytology may be obtained with EUS-guided FNA.

Solidifying a diagnosis of IPMN requires the combination of many resources including laboratory, imaging, histopathology and endoscopic ultrasound, as well as ERCP expertise. The multidisciplinary approach is recommended for accurate diagnosis.

The previously mentioned five histological subtypes of IPMN (gastric, intestinal, pancreatobiliary, oncocytic and tubular) based on the histomorphological features of papillary proliferation and the immunohistochemical characteristics of mucin glycoproteins, can provide some information on prognosis. This information is usually only available after resection. Each subtype has a specific protein expression pattern, such as the finger-like papillary growths that are positive for MUC5AC and MUC6 in gastric type IPMN but negative for other protein expression MUC1 or MUC2.

Intestinal type IPMN has villous papillae that show immunohistochemical stain and expression of MUC2, MUC5and CDX2, but not MUC1; pancreatobiliary type IPMN enhances the papillary structure with protein expression positive for MUC5 and MUC1, but not MUC2; and oncocytic type IPMN has thick papillae with eosinophilic oncocytic cells that are prominent for MUC5AC and MUC1 as well as MUC2 at times, though this is inconsistent. The tubular type is more solid but because of its intraductal nature, it is included in the IPMN classification. In the last 10 years these subtypes are proving to have a clinical role for predicting the biological behavior and prognosis of IPMN. The tumor stage is the most significant predictor of survival, supported by prognostic analysis such as the histological subtype.

The laboratory tests that have resulted in the most significant advancement in diagnosis of IPMN have been at the level of DNA analysis. Molecular and genetic testing have progressed over recent years to include immunohistochemical mucin staining and genetic analysis. DNA analysis and flow cytometry shows specific characteristics of IPMN. Identifying cellular structures such as diploid or aneuploid helps to differentiate IPMN tumor cells of intermediate-grade dysplasia or high-grade dysplasia, respectively.

Specific mutations of the KRAS gene in IPMN are known to have point mutations at codon 12. The KRAS point mutations are seen with more frequency with higher-grade dysplasia but also in other pancreatic pathology such as chronic pancreatitis. Due to the wide variation of pancreatic disease that contain the mutations of the KRAS gene it has been a disappointing test for differentiation between carcinoma and adenoma.

Other mutations that show promise include the GNAS mutations at codon 201, which represent a highly specific genetic alteration in IPMNs, as well as BRAF mutations. The identification of these gene mutations will eventually identify targets that correlate the oncogenesis of IPMN/IPM carcinoma (IPMC) with a “finger print” identifying genetic features.

A tabular or chart listing of tests, radiographic studies, and endoscopic evaluations

Figure 2 and Figure 3 show a schematic and imaging, respectively, of IPMN. Table II lists radiological evaluation of pancreatic cystic neoplasm and IPMN.

Figure 2.

Figure 3.

Table II.

What other diseases, conditions, or complications should I look for in patients with cystic neoplasms and/or IPMN?

Major risk factors

The major risk factors for cystic neoplasms and IPMN is advanced age. Direct correlation between age and the development of cyst-related IPMNs has been noted. The presence of BD-IPMN may be an indicator of noninvasive pancreatic cancer as shown in some studies. Case reports of concomitant pancreatic cancer have occurred, albeit in low frequency, even in small pancreatic BD-IPMN lesions (≤1 cm diameter) seen during surveillance.

Malignant transformation of an IPMN is the main impetus for obtaining cross-sectional imaging and EUS. Identification of mural nodules in BD-IPMN warrants further investigation but is now being managed more conservatively without the need for surgical intervention. Although the Fukuoka guidelines recommend a 6-month surveillance schedule for these lesions, the international community still debates if this time interval is too long. The concern of missed lesions or early detection of treatable pancreatic cancer has prompted some pancreatologists to recommend closer surveillance.

Coexisting or postoperative pancreatic cancer may occur in patients with MD-IPMN or BD-IPMN. Specific subgroups of IPMN such as the gastric subtype may have a higher frequency of a concomitant pancreatic cancer. Patients with known IPMN also could be candidates for ERCP with cytological examination of pancreatic juice to detect concomitant cancer. A high-risk group of patients with IPMN includes patients with familial pancreatic cancer. These patients may present with BD-IPMN but a more ominous diagnosis of high-grade dysplasia may ultimately be present. A total pancreatectomy threshold should be lower but no agreed upon consensus has been reached.

Diseases that may occur with cystic neoplasms and IPMN

There are very few other diseases that are associated with IPMNs or cystic lesions of the pancreas. However, pancreatic cancer, diabetes (DM-II), pancreatic insufficiency, acute and chronic pancreatitis, IBS and functional abdominal pain are possible diseases that should be considered when faced with the diagnosis of an IPMN. These comorbidities can often lead to confusion at the time of initial diagnosis. Patients presenting with symptoms related to abdominal pain or change in bowel habits are tested for other diseases concurrently while utilizing modalities that help in diagnosing IPMN.

Complications

The complications associated with IPMN include pancreatitis, degeneration into pancreatic cancer, pancreatic insufficiency or jaundice from bile duct obstruction (not necessary as we do not drain IPMN). The risk of bleeding, perforation, infection, pancreatitis, aspiration, pancreatic-duct damage, complications related to sedation for the procedure, and even death are possible. Maintaining a multidisciplinary team that includes radiology, surgery and an experienced gastroenterology team is essential.

What is the right therapy for the patient with cystic neoplasms and/or IPMN?

What treatment options are effective?

Patients who have cystic neoplasm with symptoms or uncertain diagnosis after appropriate evaluation are candidates for surgical resection. For BD-IPMN, resection is advocated if one or more of the following criteria are met: (1) cystic lesion is larger than 30 mm in size; (2) presence of mural nodules; (3) dilated main pancreatic duct; (4) malignant pancreatic juice cytology; and (5) symptoms associated with the pancreatic cyst. A main duct IPMN has a much higher rate of malignancy and a surgical consultation is warranted. Solid pseudopapillary neoplasms (SPNs) are considered low-grade neoplasms with malignant potential and would also be recommended for surgical resection along with the extremely rare malignant serous cystic neoplasms.

Duodenal and/or biliary obstruction would warrant surgical intervention. A duodenal obstruction is rather uncommon, usually occurring in conjunction with biliary obstruction in patients with a large inflammatory mass in the head of the pancreas. In these patients, the presentation is quite similar to pancreatic cancer and it may be difficult to differentiate the two. In most centers, these patients are evaluated in conjunction with a pancreatic surgeon and usually undergo extensive testing with EUS and CT and tumor markers. Duodenal obstruction, with or without biliary obstruction, usually requires surgical therapy with either a traditional Whipple operation or one of the other operations (Frey or Beger), that aid in decompression of the duodenal and bile duct obstruction.

Isolated bile duct obstruction is more common than duodenal obstruction, and presents as cholestasis or jaundice. Remember that cholestasis or jaundice also can occur from intrinsic liver disease, such as alcoholic hepatitis. In some patients, the biliary obstruction is due to edema from an acute attack of pancreatitis superimposed on chronic pancreatitis. An IPMN lesion may only be identified incidentally with the symptoms from obstruction. In these patients, the biliary obstruction may resolve as the acute pancreatitis resolves. In most cases, however, the obstruction is more prolonged and more specific therapy is required.

Temporary biliary stenting with a plastic stent is appropriate as the first line of therapy. It also is appropriate to perform either biliary cytologic brushings at the time of the index ERCP, or to perform EUS with FNA, to determine if the biliary obstruction is due to secondary lesions of the pancreas developing in the setting of chronic pancreatitis. If after a period of temporary stenting (6-8 weeks) the distal bile duct stenosis persists, treatment with either multiple plastic stents (usually 4-6), a fully covered removable metal stent, or surgical biliary bypass is appropriate (if endoscopic therapy fails). If endoscopic therapy is performed, it is usually continued for 6-12 months.

Pancreatic cyst ablation techniques remain experimental but have shown promise in some small studies. The EUS guided injection of ethanol or ethanol plus paclitaxel in order to ablate pancreatic cysts is limited to a subset of patients. Patients who are high risk for surgical intervention or with significant comorbidities are prime candidates for a safe and effective procedure with minor complication rates and minimal risks. To date pancreatic cyst ablation is not available as a standard therapy for IPMN lesions and cyst ablation protocols are not well defined. There is supporting evidence that cystic neoplasms can be reduced with follow-up imaging but treatment cycles, longer term outcomes and malignant progression are still outstanding questions to be addressed.

What is the most effective initial therapy?

There is limited therapy of IPMN other than surgical resection; however, investigational therapies are on the horizon. Active surveillance is pursued with cross-sectional imaging for nonmalignant lesions. In most situations, a good-quality multidetector CT with pancreas protocol is the first test to order after basic laboratory evaluation. As an alternative, abdominal MRI with MRCP is comparable and perhaps superior to CT as the initial diagnostic test. MRI will demonstrate the same features as CT, and MRCP provides better and more detailed imaging of the pancreatic duct. There currently are no established endoscopic therapies for cystic neoplasms of the pancreas other than diagnostic measures.

The optimal interval and modality for monitoring unresected IPMNs remain to be determined. The Sendai consensus has suggested that the follow-up intervals should be according to size of BD-IPMNs, without high-risk stigmata. For lesions less than 1 cm, annual follow-up was suggested; for lesions of 1-2 cm, follow-up every 6-12 months; and for lesions of 2-3 cm, every 3-6 months. It is also stated that the interval of follow-up may be lengthened after 2 years of no change (see Figure 4).

Figure 4.

The criteria have been updated in the latest consensus symposium held during the 14th meeting of the International Association of Pancreatology in Fukuoka, Japan, in 2010. These international guidelines suggest a 6-month surveillance protocol for a previously benign diagnosed IPMN. Malignant transformation of an IPMN is a concern and the main impetus for cross-sectional imaging as well as EUS intervention to prompt surgical resection. The essential role of EUS in the early detection of pancreatic cancer has been proven after small lesions failed to be detected on CT and MRI. A low suspicion of change in the IPMN warrants endoscopic intervention with EUS and a possible FNA for analysis.

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

Based on the diagnosis of BD-IPMN or MD-IPMN the guidelines provide different therapeutic options. Surgical resection is the only therapy available for neoplasms that are determined to have malignant potential, such as MD-IPMN, pancreatic lesions with mural nodules and ductal lesions 30 cm or larger. These cystic neoplasms showing invasive IPMN can be identified with high confidence and sensitivity using CT and MRI, EUS and ERCP. The challenge of differentiating premalignant, noninvasive and malignant IPMN remains to be the critical factor in assigning the appropriate initial therapy.

The 2010 Fukuoka consensus symposium generated new guidelines. The level of evidence for all items addressed in these guidelines are regarded as low due to lack of evidence. Therefore they are designated “consensus,” rather than “evidence-based,” guidelines.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

Second-line therapies might include treatment of pancreatic cancer arising from IPMN. These therapies encompass chemotherapy and radiation. For patients with unresectable pancreatic cancer arising from IPMN, chemotherapy and radiation therapy would be indicated. Experimental models of therapeutic treatment for IPMN have included cystic neoplasm ablation with ethanol or a combination of ethanol and paclitaxel to decrease the size of the pancreatic lesion.

The limits of this treatment include the possible need for serial ablation treatments, as there is a lack of long-term data. The current studies have shown cystic neoplasm size to decrease after one or two rounds of ablation with ethanol or a combination of ethanol and paclitaxel, but questions of efficacy are still present. The general consensus from experts in the field still stands that until we have better randomized, controlled trials, EUS-guided ethanol ablation of pancreatic cysts is best reserved for experimental protocols and for the subset of patients who cannot undergo surgical resection for treatment of their disease.

How should I monitor the patient with cystic neoplasms and/or IPMN?

Currently the Fukuoka guidelines suggest a 6-monthly surveillance protocol for a previously benign diagnosed IPMN (see Figure 4). Malignant change of an IPMN is always a concern and the main impetus for cross-sectional imaging as well as EUS intervention. The essential role of EUS in the early detection of pancreatic cancer has been proven after small lesions (<2 cm) failed to be detected on CT and MRI. A high suspicion of change in the IPMN warrants endoscopic intervention of EUS with a possible FNA for analysis.

Patients with IPMN are monitored with cross-sectional imaging that includes either a pancreatic protocol CT or MRCP, which will demonstrate the size and morphology of cysts, as well as of the main pancreatic duct. The rate of growth of the cysts should be calculated. Patients with enlarging cysts should undergo EUS and FNA for evidence of malignant cytology.

Patients can be monitored for the development of pancreatitis using routine clinical evaluations, as well as laboratory testing (amylase, lipase, liver function tests).

Listing of measures of progress of disease or monitoring recommendations, including timing and interpretation

The surveillance MRCP should provide a measure of the absolute size of the largest cyst as well as the rate of growth, based on previous examinations. There is a crude correlation between the size of an IPMN cyst and the presence of malignancy at the time of resection. There is no threshold for development of pancreatic malignancy but the larger the cyst, the greater the risk of cancer.

The size of the lesion is often an unreliable guide for malignancy as lesions smaller than 2 cm have been shown to have malignant potential in even asymptomatic patients. The presence of a nodule within the cyst also increases the risk of malignancy. The involvement of the main pancreatic duct also increases the risk of pancreatic cancer, with many of the patients shown to have malignancy at the time of resection when the main duct is involved.

What's the evidence?

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The original source for this chapter was William Brugge, MD. The chapter was revised for this program by Chris Forsmark, MD, Alexander Schlachterman, MD and Anand Gupte, MD.

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