The collective phrase “cystic lesions of the pancreas,” typically described on cross-sectional imaging of the abdomen, refers to any cystic neoplasms of the pancreas and/or other cystic lesions, many of which cause “cyst-like” dilatations of the main or side branch pancreatic ducts. Specifically, the descriptor “cystic neoplasms of the pancreas” encompasses a wide variety of pathologic entities of the pancreas with variable malignant potential. The incidence of these cystic neoplasms seems to increase with age, with one autopsy study demonstrating that up to a quarter of elderly individuals harbor cystic lesions of the pancreas at their demise.1 As the use of abdominal computed tomography (CT) and magnetic resonance imaging (MRI) is increasing, cystic lesions of the pancreas are being defined more frequently, with the majority asymptomatic at discovery.2,3 Laffan and colleagues in 2008 estimated the incidence of asymptomatic discovered cysts on abdominal imaging for unrelated diagnoses at 2.6%.4 Some of these lesions will be malignant or have malignant potential at diagnosis, while others are clearly benign and may not warrant further surveillance. Resection of benign cystic pancreas lesions or those containing only high-grade dysplasia (premalignant) leads to nearly universal survival, while surgery for invasive carcinoma associated with cystic neoplasms generally has a more favorable prognosis than the results for resection of typical pancreatic ductal adenocarcinoma.5-7 Thus, careful consideration must be given to the diagnosis and prognostic implications of these lesions. As more becomes known about these neoplasms, the treatment and observation algorithm will continue to evolve to minimize unnecessary interventions, while maximizing the impact of surgical treatment.
An ideal diagnostic approach would allow for the resection of only those lesions with concurrent or near-future risk of malignancy, while excluding from surgery those individuals with either nonenlarging benign lesions or a prohibitive operative risk, thus minimizing the potential occurrence of mortality and morbidity associated with the surgical treatment of these cystic lesions. Recent advancements in imaging by CT, MRI, and endoscopic ultrasonography (EUS), linked with refinements in the pathological, molecular, and genetic understanding of cystic neoplasms of the pancreas, have furthered this effort. History and clinical criteria, such as age, gender, presence of symptoms, location of the neoplasm within the pancreas, as well as morphology by cross-sectional imaging and cyst fluid analysis by EUS with fine-needle aspiration (EUS-FNA), all may play a role in the diagnosis of pancreatic cystic neoplasms and assessment of the need for resection. While the phrase “cystic neoplasm of the pancreas” encompasses a large variety of pathologic entities, this review will focus on the most commonly encountered that may require surgical intervention.
The most common non-neoplastic cysts of pancreas are typically considered to be pancreatic pseudocysts (or early post-pancreatitis acute fluid collections). Their diagnosis is aided (and typically confirmed) by a history of acute or chronic pancreatitis.8 Congenital cysts are rare and include those associated with genetic diseases such as autosomal dominant polycystic disease,9 cystic fibrosis,10 and von Hippel–Lindau (VHL) disease.11,12 Lymphoepithelial cysts are rare benign lesions of the pancreas lined with squamous epithelium.13 Peripancreatic cystic lesions (such as esophageal or intestinal duplication cysts) may be mistaken for true pancreatic cystic lesions and need to be within the differential diagnosis in select situations.14 Finally, solid pseudopapillary neoplasms (which may have cystic components) are rare lesions occurring predominantly in young women, for which resection of the primary tumor results in an excellent opportunity for cure.
Three lesions make up approximately 90% of the cystic neoplasms seen in the pancreas: serous cystic neoplasms (SCNs), mucinous cystic neoplasms (MCNs), and intraductal papillary mucinous neoplasms (IPMNs). Overall, these three common pancreatic cystic neoplasms can be classified as either “mucinous” or “non-mucinous,” a distinction that has important clinical significance. SCNs (nonmucinous lesions) rarely demonstrate a progression to malignancy. Unequivocal proof of a SCN may permit nonoperative management of these lesions, provided symptoms do not mandate resection. Although the majority of non–mucin-producing lesions are benign in nature, cystic “degeneration” of other pancreatic tumors (ie, endocrine, solid pseudopapillary, or ductal adenocarcinoma) does occur and must be considered in the workup, as these may necessitate surgical resection. Mucin-producing lesions of the pancreas can be segregated into two types, which may differ significantly in natural history. Restriction of the definition of MCNs to include only those lesions with subendothelial ovarian-type stroma has permitted an improved distinction between MCNs and IPMNs.15 Consensus guidelines developed (and recently revised) by the International Association of Pancreatology16,17 (“Sendai” and “Fukuoka” guidelines) may assist in the management of cystic neoplasms of the pancreas. The premalignant nature of MCNs (and most IPMNs) prompts resection in patients who are acceptable operative risks, while observation of some branch duct IPMNs may be tenable, with an eventual risk of malignancy less than the operative mortality of pancreatic resection.18
The accurate pathological description of pancreatic cystic neoplasms has evolved significantly in the past several decades, influenced largely by an improved understanding of the malignant potential of MCNs in comparison to the largely benign nature of SCNs, and the emergence of an understanding of the pathogenesis and behavior of IPMNs. Current classification of these tumors follows the World Health Organization (WHO) International Classification of Tumors as published in 2010 (Table 72-1).15,19 While the diagnostic criteria and organizational schema for these tumors are likely to be adapted further in future editions, the current classification system provides a means to stratify these tumors in terms of prognosis and management. In this review, particular attention will be paid to the three most common lesions: SCNs, MCNs, and IPMNs (Table 72-2). Although this chapter is organized by pathologic diagnosis, the actual workup and treatment of these cystic lesions of the pancreas may have significant overlap, as at times the diagnosis may be challenging to delineate until definitive surgical resection.
Serous cystic neoplasms
Serous microcystic adenoma
Serous oligocystic adenoma
Mucinous cystic neoplasms
Mucinous cystic neoplasm with low- or intermediate grade of dysplasia
Mucinous cystic neoplasm with high-grade dysplasia
Mucinous cystic neoplasm with an associated invasive carcinoma
Intraductal papillary mucinous neoplasm
Intraductal papillary mucinous neoplasm with low- to intermediate-grade dysplasia
Intraductal papillary mucinous neoplasm with high-grade dysplasia (noninvasive)
Intraductal papillary mucinous neoplasm with an associated invasive carcinoma
SEROUS CYSTIC NEOPLASMS
SCNs, previously referred to either as serous cystadenomas, glycogen-rich adenomas, or microcystic adenomas, are almost always benign. Careful delineation of the radiological and clinical features that distinguish these lesions may support and facilitate nonoperative management of these lesions when appropriate (Table 72-2).
|Type of Neoplasm||Gender (Ratio F:M)||Age Range||Gross Feature||Microscopic Features||Imaging Features||Fluid Analysis||Malignant Potential||Suggested Treatment|
|Serous cystic neoplasm (SCN)|
|60-80 years||Typically polycystic “microcystic” with central stellate scar, may be oligocystic||Clear cytoplasm, single-layer cuboidal epithelium, glycogen-rich cells||Microcystic, honeycomb pattern with central stellate scar|
Low viscosity, clear glycogen rich cytoplasm
|Almost uniformly benign|
Stable size and asymptomatic: surveillance
Symptomatic or enlarging: consider resection
|Mucinous cystic neoplasm (MCN)|
|Large, macrocystic, solitary, thick-walled||Subendothelial ovarian-type stroma, tall columnar mucin producing epithelium||Macrocystic lesion in the body or tail without communication to ductal system, peripheral calcifications||High viscosity, elevated CEA, low amylase||Potentially malignant (exhibit spectrum from adenoma to carcinoma)|
Asymptomatic and size <3 cm: surveillance or resection (after patient education)
Asymptomatic and size >3 cm: resect
|Intraductal papillary mucinous neoplasm (IPMN)|
F = M
|60-70 years||Multilocular, involve main pancreatic duct and/or branch duct||Tall columnar mucin producing epithelium with variable degrees of dysplasia|
Main duct IPMN: diffuse or segmental main pancreatic duct dilation
Branch duct IPMN: pancreatic cyst with communication to ductal system
Mixed type IPMN: combination of cyst with communication to ductal system and main duct dilation
|Potentially malignant (exhibit spectrum from adenoma to carcinoma)|
Main duct IPMN: resect with use of intraoperative pancreatoscopy and careful inspection of remnant pancreas for synchronous neoplastic lesions
Branch duct IPMN: resect if symptomatic, tumor >3 cm, mural nodules, positive cytology, rapid growth, main duct dilation or young and healthy (age <55 years)
Observe, if asymptomatic, tumor <3 cm, no mural nodules, negative cytology, stable size, normal main duct, and advanced age (>75 years)
The majority of SCNs are polycystic or so-called “microcystic adenomas,” typically characterized by a well-circumscribed, soft mass which includes numerous small cysts filled with clear serous fluid arranged in a characteristic honeycomb-like pattern. Larger cysts may line the periphery of the lesion. The multiple small cystic loculations are well defined and are often accompanied by a central stellate scar with or without calcifications. These features may be highly suggestive of an SCN when seen on CT or MRI (Figs. 72-1 and 72-2). A small number of SCNs (≤10%) are oligocystic adenomas and present with one or more dominant cysts rather than multiple conjoined microcysts. Rarely, a single dominant cystic lesion may be identified. These unusual SCNs may be more difficult to distinguish radiographically from MCNs, IPMNs, pseudocysts, and other cystic lesions.
This CT image depicts a cystic neoplasm in the head and neck of the pancreas (small arrow) detected incidentally in a 75-year-old man undergoing evaluation for nephrolithiasis. The patient underwent a pylorus-preserving pancreaticoduodenectomy without complications. Final pathology revealed a 6-cm serous cystic neoplasm without evidence of malignancy.
A. Abdominal CT (axial image) of a 61-year-old woman who presented with pruritus and jaundice and was found to have a large cystic lesion in the head of the pancreas (arrow). B. On coronal CT image, this polycystic mass with central calcifications (arrow) abuts the proximal superior mesenteric vein (SM) and portal vein (PV), and was resected via a pylorus-preserving pancreaticoduodenectomy for complete resection. Final pathology revealed a benign serous cystic neoplasm.
Beyond these gross distinctions, both microcystic and oligocystic adenomas are composed of a single layer of simple cuboidal epithelium with rounded nuclei and clear cytoplasm which is glycogen rich and stains periodic acid-Schiff-positive (Fig. 72-3). The cystic fluid is serous (clear) and typically has no mucin content, with a low carcinoembryonic antigen (CEA) level (< 5 ng/mL), factors that may provide diagnostic information upon cyst aspiration. Cytology diagnostic for SCN is present in less than 50% of cases; however, when positive the sensitivity is high.
Photomicrograph of a typical SCN of the pancreas. Characteristic features include the single layer of cuboidal epithelial cells lining the microcysts within the lesion, uniform round nuclear architecture, and clear cytoplasm. The cyst cavities contain serous fluid and little cellular debris.
The malignant potential of SCN is so low that most experienced centers recommend management of these lesions as benign entities. Certainly the argument can be made that a clearly documented classic-appearing SCN need not be resected unless symptomatic or enlarging. The incidence of serous cystadenocarcinoma is extremely low, and although the WHO has given serous cystadenocarcinoma a distinct definition, data on this extremely rare lesion are scarce. The WHO requires evidence of distant metastasis to verify the diagnosis. To date, there have been 42 cases of “invasive” or metastatic serous cystic neoplasms reported in the literature, with Reid et al. recently performing a critical analysis of these cases, finding that most would no longer be considered as serous “cystadenocarcinoma” based on the WHO 2010 classification.20 Khashab and colleagues reviewed the Johns Hopkins Hospital experience with 257 resected serous cystic neoplasms. Of these 257 cases, fourteen patients had “aggressive” tumors (defined as local extension or invasion), with two of these cases having liver metastases (considered malignant).21 The authors found that tumor size and location in the head of the pancreas are independent risk factors for aggressive behavior. Evidence of distant metastatic disease is considered necessary to confirm the rare diagnosis of serous cystadenocarcinoma according to the WHO, as both the primary and extrapancreatic disease may appear histologically indistinguishable from benign SCN.22,23 Importantly, vascular and perineural invasion, or local invasion of the stomach and duodenum, are not sufficient criteria for the diagnosis of malignancy of SCN.24,25 Hence, true histologic malignancy in the setting of serous cystic neoplasms is exceedingly rare.20
SCNs occur predominately in women in the sixth decade of life, while men tend to present at a later age. Bassi and colleagues described 100 patients with SCN, 87 of whom were female, with a mean age at presentation of 52 years.26 The average age of the 13 male patients was 54 years. In another study from the Massachusetts General Hospital, 75% patients were women, and the female patients were significantly younger at presentation than were the men (60 vs 67 years, p = .018).27 In the recent review of 257 cases from the Johns Hopkins Hospital, 179 patients were female, with a mean age of 61 years.21
The majority of patients with SCN are asymptomatic. When symptoms exist, abdominal pain is the most common presenting symptom,24,26,27 weight loss is seen in 14 to 22% of patients,24,26 and fewer patients (10%)26 present with a mass or fullness. Symptoms typically associated with invasive disease, such as jaundice (6%) or pancreatitis, are uncommon (Fig. 72-2).24 Nausea and vomiting related to compression of the upper gastrointestinal tract may occur in 7% to 10% of patients.26 Traditionally, SCNs have been described as having a predilection for the pancreatic body and tail, although Le Borgne and coworkers described a relatively even distribution throughout the gland in 170 lesions (38% head, 41% body, 20% tail).28 Khashab et al. reported 39% of SCN in the pancreatic head, 21% in the body, 31% in the tail, and 9% were considered “extensive.”21 Large SCNs located in the head are surprisingly unlikely to cause biliary or duodenal obstruction, reflecting their slow pattern of growth, soft texture, and lack of invasive behavior. Rarely, extremely large tumors have been seen in elderly patients, with considerable symptoms of abdominal fullness and occasionally gastroduodenal obstruction or jaundice.
One clinical condition that has been clearly associated with SCNs of the pancreas is the VHL syndrome. Simple pancreatic cysts or SCNs occur in 17% to 56% of patients with this heritable multisystem neoplastic syndrome.29 The VHL tumor suppressor gene is located on chromosome 3p25. Vortmeyer et al. demonstrated deletion of 3p25 in 7 of 10 sporadic SCN cases studied, suggesting a role for the VHL gene in SCN tumorigenesis, even in the absence of the VHL syndrome.30 A recent review of 23 patients with VHL syndrome operated on for nonfunctioning pancreatic neuroendocrine tumors described that 13 (57%) of those patients had associated SCNs of the pancreas.31
SCNs often have a characteristic imaging phenotype (see Figs. 72-1 and 72-2). Most are well-demarcated solitary multicystic masses composed of innumerable small cysts. Up to one-third have a central, calcified starburst scar.28,32 SCNs may also present as oligocystic or unilocular cystic lesions, making differentiation from other cystic lesions of the pancreas difficult. Lee and colleagues reported on the preoperative diagnostic accuracy of CT in pathologically confirmed SCN.33 Radiological features led to a correct diagnosis in only 36% of unilocular SCNs, while honeycombed microcystic and multilocular macrocystic SCNs were appropriately defined in 81% and 88%, respectively (p = .005). Overall in their series, CT diagnosis was accurate in 71% of SCNs. In 164 patients with surgically verified pancreatic cystic lesions, 28 of whom had a SCN, Shah et al. suggested that the CT features predictive of the diagnosis of SCN are microcystic appearance (22/28, 78%), surface lobulations (25/28, 89%), and central scar (9/28, 32%).34 Stepwise logistic regression analysis showed that only a microcystic appearance was predictive for the CT diagnosis of SCN (p = .0001). MRI correctly predicted the pathological diagnosis of SCN with greater frequency than did CT in the study by Bassi and coworkers.26 CT allowed for the correct diagnosis in 54%, incorrect diagnosis in 34%, and was nondiagnostic in 12% of SCNs. The results with MRI were 74%, 26%, and 0%, respectively. A recent study by Chu and colleagues using pancreas protocol CT imaging in resected SCNs revealed that only 20% of cases had the “classic appearance” of multilocular masses with central stellate scars and calcifications. CT attenuation was helpful in distinguishing SCNs from MCNs, IPMNs, pseudocysts, and insulinomas, but not pancreatic ductal adenocarcinoma. The presence of external lobulations and the absence of “aggressive” features (such as pancreatic duct dilation, vascular invasion, lymphadenopathy, and liver metastasis) were helpful in distinguishing between SCN and classic pancreatic ductal adenocarcinoma.35
The limitations of the radiological diagnosis of SCN may call for additional analysis, which is frequently sought by EUS-FNA with cyst fluid cytology and biochemical analysis. The risk of complications with EUS-FNA is relatively low.36-38 Cyst fluid aspirates from SCN are frequently sparsely cellular and may be contaminated with columnar enterocytes and mucin from the scope and needle traversing the gastric or intestinal mucosa, potentially clouding the diagnostic accuracy of cytology. Cytology alone was found to be diagnostic of SCN in only 7 of 21 cases studied by Huang and others from MD Anderson Cancer Center.39,40 Detection of intracytoplasmic glycogen was noted to enhance the diagnostic confidence for the diagnosis of SCN. Cyst fluid analysis is an additional adjunct (beyond cytology) to improve the diagnostic accuracy of EUS-FNA. Fluid from within an SCN is typically low in viscosity and amylase due to a consistent lack of connection to the pancreatic ductal system.41 CEA levels less than 5 ng/mL have a sensitivity of 54% to 100%, and specificity of 77% to 86% in the differentiation of SCN from other pancreatic cystic lesions.42,43 The finding of a cyst fluid carbohydrate antigen (CA) 19-9 level less than 37 U/L and a CEA less than 5 ng/mL virtually excludes an MCN or IPMN.
Allen et al. reported on the analysis of cyst fluid using a biomarker panel developed for pancreatic cancer.43 Assessment of protein expression within the cyst fluid led to an error rate in classification of lesions of 27% when all three types of cystic neoplasms were evaluated (SCN, MCN, and IPMN). When limiting the analysis to separating SCN from IPMN, this method had an error rate of only 8%, compared with a 14% error rate with the use of CEA levels alone. The greatest utility of protein expression analysis might be in the differentiation of cystic lesions of the head of the pancreas, as the vast majority of MCNs occur in the body and tail of the pancreas. However, the cost of this method may not be justified by the relatively small improvement in diagnostic accuracy. In addition, Cao and colleagues recently studied a three-marker panel of glycoforms of MUC5AC and endorepellian and showed 89% sensitivity and 100% specificity in distinguishing between mucinous (MCN, IPMN) and nonmucinous (SCN, pseudocysts) cystic neoplasms of the pancreas.44 Recently, Springer and colleagues examined a combination of molecular and clinical markers from a multi-institutional collaboration of resected cystic neoplasms of the pancreas and identified a combination of markers that approach 100% sensitivity and 98% specificity in diagnosing SCNs. The combination of the clinical characteristics of patients >25 years of age without abdominal pain or evidence of communication of the cyst with the pancreatic ductal system and the molecular presence of a VHL mutation and/or loss of heterozygosity of chromosome 3, as well as the absence of KRAS, GNAS, and RNF43 mutations, allowed for excellent diagnostic power.45
Observation of patients with SCN may be appropriate in asymptomatic patients. When a secure diagnosis of SCN is made, modern series demonstrate that a growing number of SCNs are being kept under surveillance by serial imaging (Table 72-2). Typically a pathological diagnosis is not required when classic imaging characteristics are observed. Bassi and colleagues followed 32 patients with the diagnosis of SCN for a median time of 69 months, without any observed development of malignancy or significant increase in diameter of the lesion.26 Rapid rate of growth of a lesion may heighten suspicion for the development of malignancy or increase the likelihood of developing symptoms. In a report from the Massachusetts General Hospital, Tseng and coworkers found a more rapid rate of growth in SCNs greater than or equal to 4 cm in size at presentation, compared with smaller tumors (1.98 cm/yr vs 0.12 cm/yr, p = .0002).27 Tumors less than 4 cm were less likely to be symptomatic than were those greater than or equal to 4 cm (22 vs 72%, p < .001). Resection was thus suggested by these authors, even for asymptomatic SCNs that were greater than or equal to 4 cm. A recent multinational review of over 2600 SCNs revealed that the average tumor size of patients who underwent surgical resection was 40 mm, with the most common indication being an “unclear diagnosis.” Only three serous cystadenocarcinomas were encountered in this entire cohort.46
When the diagnosis of SCN is uncertain, pancreatic resection is most often performed according to oncological principles, as if the lesion was malignant or had malignant potential (Fig. 72-2). Standard procedures include distal pancreatectomy for lesions of the body or tail, or pancreaticoduodenectomy for right-sided lesions. This practice avoids performance of an inadequate cancer operation in cases in which a malignancy is found on final pathological analysis. However, if the diagnosis of SCN is confirmed preoperatively, a less radical approach may be considered. Enucleation of SCNs has been shown to be technically feasible, although it can be challenging and is associated with a significant risk of pancreatic fistula.47-49 A central pancreatectomy, with remnant pancreatic reconstruction being performed via pancreaticogastrostomy or Roux-en-Y pancreaticojejunostomy (PJ), may be considered in select patients with lesions of the pancreatic neck.50 Distal pancreatectomy with splenic preservation may also be considered, particularly for small lesions in the tail, where the splenic hilum is more easily dissected. Lesions in the head of the pancreas that are not amenable to enucleation are best treated with pylorus-preserving pancreaticoduodenectomy. Many patients undergoing pancreaticoduodenectomy will have an otherwise normal pancreas, hence meticulous attention must be paid to the technique of PJ, since such patients have a significantly higher risk for developing a pancreatic fistula related to a failure of healing at the PJ. There has been some enthusiasm for duodenum-preserving pancreatic head resection as well, although this procedure has not had widespread application.51 The use of minimally invasive techniques is encouraged in institutions with experience and training in these complex procedures. Patients with pathologically proven, completely resected SCNs do not require serial imaging in follow-up. Recommendations for appropriate monitoring of unresected SCNs vary, but serial imaging with either CT or MRI every 6 months for 2 years and then annually or every other year thereafter seems reasonable.52
MUCINOUS CYSTIC NEOPLASMS
Progress in the diagnosis and management of pancreatic cystic neoplasms has been aided in large part by the recognition of distinct pathological features that distinguish MCNs from other cystic lesions.53,54 The distinction between MCN and SCN is critical, as the premalignant and malignant behavior of MCNs stand in stark contrast to the nearly universally benign nature of SCNs. Many of the same diagnostic challenges that exist for SCNs are true for MCNs, but the management decisions may be quite different, due to the differing clinical phenotype of these lesions.
While the true prevalence of MCNs is difficult to identify, more recent series suggest that approximately 15% to 30% of cystic neoplasms of the pancreas are MCNs.2,52,55,56 However, our experience at the Thomas Jefferson University Hospital reflects a lower percentage. Clinical series published prior to the establishment of the diagnostic criteria for IPMN in 1996 likely overestimated the relative prevalence of MCNs in comparison to other cystic lesions, since they included what are now categorized as IPMNs as various “mucinous tumors.”
MCNs (Table 72-2) are typically spherical, thick-walled, septated or unilocular cysts with a tall columnar mucin-producing epithelium accompanied by a subendothelial ovarian-type stroma that appears as a dense layer of spindle cells with sparse cytoplasm and uniform, elongated nuclei (Fig. 72-4). This stroma regularly expresses progesterone receptors, and less frequently estrogen receptors, and over 60% of these stroma stain for human chorionic gonadotropin.57 Both the WHO and the Armed Forces Institute of Pathology (AFIP) have defined the presence of this ovarian-like stroma as a requirement for the diagnosis of an MCN.4,53,54 The original and updated International Consensus Guidelines (“Sendai” and “Fukuoka”) for the management IPMN and MCN have also required the presence of ovarian-type stroma as a necessary criterion for the diagnosis of MCN, so as to prevent the misclassification of IPMN as MCN.16,17 In addition, MCNs typically do not communicate with the pancreatic ductal system, and this serves as another distinction between IPMNs.58 Given the similarity of the histology and immunohistochemistry between MCNs and ovarian mucinous cystadenomas, MCNs have been postulated to arise from ovarian rests (or ovarian-like stem cells) within the pancreas.59
MCNs exhibit characteristics of an adenoma-carcinoma sequence. Dependent on the degree of atypia, they are classified as mucinous cystadenomas, mucinous cystic tumors (borderline lesions), in situ lesions (high-grade dysplasia), or invasive cystadenocarcinomas (mucinous cystadenocarcinomas). Atypical changes within the lining epithelium may be patchy and sparse, with abrupt transitions to normal mucosa. Classification of MCN should be based upon the highest degree of atypia present, and the entire lesion should be examined pathologically.60,61 Invasive carcinomas arising within MCNs are usually tubular or ductal type, although some may be undifferentiated carcinoma with osteoclast-like giant cells,62 adenosquamous carcinoma,63 choriocarcinoma, or even high-grade sarcomas.64 Colloid carcinomas are extremely rare in MCN, but they occur commonly in IPMN.61 The molecular pathway of the pathogenesis of MCNs is not clearly understood. K-ras and p53 mutations have been implicated, as well as loss of DPC4.65,66 Interestingly, a recent study using a mouse model showed that APC haploinsufficiency coupled with p53 loss resulted in the development of MCN with invasive carcinoma with 100% penetrance.67
In light of the mandatory presence of the underlying ovarian-type stroma, not surprisingly MCNs are now diagnosed almost entirely in women.57,59,68-73 This requirement, combined with the usual lack of communication with the pancreatic duct, defines a unique phenotype separate from IPMN. In a combined report from the University of Verona and the Massachusetts General Hospital, Crippa and colleagues reviewed their experience with 163 MCNs that met the WHO criteria for diagnosis.72 Of the 163 patients, 95% (155 patients) were perimenopausal females. Only eight males were identified, and they were significantly older than the female patients (63 vs 44 years, p = .011). The location of MCN within the gland was almost entirely confined to the body and tail of the pancreas (97%), and only five lesions were found in the pancreatic head. In reviewing the literature regarding MCN, these researchers noted the importance of segregating studies according to whether or not the presence of ovarian-type stroma was required for inclusion of pathological specimens within collected reports. Goh et al. reviewed those studies where the presence of ovarian-type stroma was a mandatory criterion for the diagnosis of MCN and found that 99.7% of the patients were women, the mean age at presentation was 47 (range, 18-95) years, and 95% of MCNs occurred to the left of the pancreatic neck.74 By comparison, when this criterion was previously not a prerequisite to diagnose MCN, patients were older, more often male, and the lesions were located in the head with a frequency exceeding 30%.
Abdominal pain or discomfort is the most common presenting symptom, occurring in over 70% of patients.69–71 A history of acute pancreatitis may also be elicited in 9% to 13% of patients, although less commonly than in patients with IPMN.4,69,72 Patients with an MCN with an associated invasive carcinoma present 11 years later than those with noninvasive neoplasms, likely representing the longer time required to progress to overt malignancy within these neoplasms.72
In a female patient with a macrocystic lesion in the body or tail of the pancreas, MCN should be strongly considered. In addition, MCNs have some characteristic features that may be evident during imaging or preoperative evaluation. Classically, MCNs contain large septated cysts with thick irregular walls that may be well visualized on CT, MRI, or ultrasound evaluation. Papillary projections from the epithelium often extend into the cystic cavities and may be visible, particularly on high-quality axial or endoscopic ultrasound imaging. In a minority of cases, the wall of the MCN may contain calcifications, a characteristic associated with a higher likelihood of malignancy.75 MCNs may also present as large unilocular cysts that may appear similar on cross-sectional imaging to long-standing pseudocysts (Fig. 72-5). Two distinguishing characteristics in this scenario that suggest the diagnosis of MCN are the lack of surrounding inflammatory changes beyond the wall of the neoplasm in MCNs and the absence of pancreatitis.8 Demonstration of ductal communication with the cyst by MRI or magnetic resonance cholangiopancreatography (MRCP) may distinguish pseudocysts or IPMNs from MCNs, although MCNs can in rare instances exhibit a connection with the pancreatic duct.74
Abdominal CT performed on a 69-year-old healthy man who had a palpable abdominal mass detected on routine physical examination. The mass (arrow) was homogeneous in character and was initially presumed to be a pseudocyst. Pylorus-preserving pancreaticoduodenectomy was performed, revealing an 8.5-cm mucinous cystic neoplasm without malignancy.
Similar to SCN, determination of a treatment plan for MCN is predicated upon whether or not a given lesion is mucinous. Analysis of cyst fluid aspirated from MCNs typically show elevated levels of CEA and low amylase concentrations (as MCNs do not typically communicate with the pancreatic ductal system). The Cooperative Pancreatic Cyst Study demonstrated that a cyst fluid CEA value greater than 192 ng/mL achieved the greatest efficiency for differentiating mucinous from nonmucinous lesions.32 The accuracy of cyst fluid CEA (88/111, 79%) was greater than the accuracy of EUS morphology or cytology (p < .05). No combination of tests further improved diagnostic accuracy. A cyst fluid CEA level greater than 800 ng/mL has a specificity of 98% for predicting MCN, but a sensitivity of only 48%.76 Khalid and his coinvestigators tested the utility of DNA analysis of cyst fluid to diagnose mucinous and malignant cysts.77 The presence of a K–ras mutation was highly specific for a mucinous cyst (96%) but had a low sensitivity of only 45%. A considerable selection bias was introduced by the study design, which may have overestimated the ability of DNA analysis to define a mucinous cyst.78 Presence of a K–ras mutation in cyst fluid may provide additional information when CEA levels are not discriminative, particularly in lesions that appear to not have clear imaging patterns that allow separation of SCN versus MCN.
A recent multi-institutional review of resected pancreatic cystic neoplasms showed promising results using a combination of a panel of molecular markers known to be implicated in pancreatic cysts and clinical features to predict lesions requiring resection versus observation. In reviewing MCNs, the authors approached 90% sensitivity and 97% specificity with the combination of certain molecular markers (including the absence of CTNNB1I and GNAS mutations, loss of heterozygosity on chromosome 3, and aneuploidy in chromosome 1q and 22q) and the following clinical markers: age <75 years old and the absence of all three of the following features: male sex, communication with the main pancreatic ductal system, and multiple cysts.45 In addition, as stated in the SCN section, additional biomarkers are being investigated to distinguish between mucinous and nonmucinous cysts.44
In their pooled review of the literature, including 10 studies of MCN defined by ovarian-type stroma, Goh and coworkers noted that in the 40 invasive carcinomas found in 344 patients, only one of the malignant MCNs was less than 4.5 cm in size at the time of resection.74 Crippa and colleagues noted that lesions containing either in situ or invasive carcinoma were larger (median size 80 vs 45 mm, p = .0001), and intracystic nodules or papillae were more frequently present (64% vs 4%, p = .0001), when compared with benign neoplasms.72 All lesions demonstrating cancer on pathology were either greater than 4 cm in diameter or contained nodules by preoperative imaging. Careful observation of asymptomatic lesions less than 3 cm in size, without the presence of nodules, appears to be a reasonable approach for MCN (see Table 72-2). However, a post-hoc analysis by Sawhney and associates has questioned whether size alone, based on the original Sendai Consensus criteria, is a sufficient predictor of malignancy in pancreatic cysts.16,79 Their data indicated that the original consensus guidelines should be applied with caution, and that more accurate diagnoses might be generated by the combination of cyst size and main pancreatic duct dilation greater than 3 mm. Crippa et al. reported a 73% rate of adenoma in their series of resected MCNs; however, this leaves approximately 27% of cases with at least borderline MCN pathology.
Biopsy of MCN should not be utilized to determine the presence of carcinoma, because the presence of invasion within a lesion may be patchy or discontiguous and a negative biopsy result may be obtained erroneously based on sampling error. Due to the significant rate of malignancy and the risk of progression to malignancy associated with MCN, symptomatic neoplasms, lesions greater than 3 cm, or those containing nodules or papillae should undergo resection. In addition, young, fit patients with MCNs should be considered for resection, as the cumulative risk of malignant transformation exceeds life expectancy. As with SCN, enucleation has been documented to be an effective strategy for resection in selected MCN cases.47,48,80 However, there is some risk of performing an inadequate oncologic resection for an MCN should it harbor an invasive component, while there is virtually no risk for SCN. Therefore, enucleation should only be applied to highly selected cases of small, peripherally located MCNs with confirmation of a noninvasive component by extensive frozen-section analysis. Likewise, segmental pancreatic resections for lesions in the pancreatic neck and body (central pancreatectomy) or tail (spleen-preserving distal pancreatectomy) should be performed cautiously in selected patients without any indication of invasive disease. Larger tumors in older patients (ie, patients fitting the characteristics of MCN with an associated invasive cancer) should be treated with formal pancreatic resection to include specimen-associated lymph node harvest. Lesions in the pancreatic head are best treated with pancreaticoduodenectomy, while left-sided lesions are treated via distal pancreatectomy with or without en bloc splenectomy. Extended lymphadenectomy, which has not been shown to definitively improve locoregional control or survival in patients with pancreatic ductal adenocarcinoma, has no role in the treatment of patients with cystic neoplasms.81,82 Minimally invasive resection techniques should be considered when appropriate at institutions with considerable experience and acceptable quality outcomes.