Primary cystic neoplasms of the pancreas constitute a rare entity and are composed of a variety of neoplasms with a wide range of malignant potential. Approximately 90% of these lesions are serous cystic neoplasms or mucin-producing neoplasms. In contrast to serous cystadenomas which are nearly always benign, the mucinous cystic neoplasms represent a more diverse, heterogenous spectrum of related neoplasms. Intraductal papillary mucinous neoplasms manifest a much greater latent or overt malignant potential than other cystic neoplasms of the pancreas. The various subgroups of cystic neoplasms of the pancreas are evaluated and compared through a review of current literature. No symptoms or signs are pathognomonic for the cystic pancreatic neoplasms. While identification of a cystic tumor is relatively easy, the identification of the specific tumor type may be difficult. Most investigators agree that accurate differentiation of benign from malignant neoplasms can be made only at histopathologic examination of the entire resected segment of the pancreas. Because of the low mortality and low postoperative morbidity, surgical resection is indicated in all patients with cystic tumors.
Primary cystic neoplasms of the pancreas are thought to be rare, perhaps accounting for 10–13% of pancreatic cysts and 1% of pancreatic cancers.1 They encompass a range of benign to malignant disease, and have received considerable interest in the last decade.
Primary cystic neoplasms of the pancreas are composed of a variety of neoplasms with a wide range of malignant potential.2 Approximately 90% of these lesions are serous cystic neoplasms (SCN) or mucin-producing neoplasms.2,3 The mucin-producing neoplasms consist of mucinous cystic neoplasms (MCN) and intraductal papillary nucinous neoplasms (IPMN). In 1978, Compagno and Oertel were the first to clearly characterize histopathologically both the features and the importance of differentiation of serous and mucinous cystic neoplasms.4 Currently the spectrum of cystic neoplasms of the pancreas includes the following subgroups: SCN, MCN, IPMN, and unusual cystic neoplasms/tumors, such as solid pseudopapillary5 (Table 1). Primary cystic neoplasms of the pancreas should be differentiated from both inflammatory pancreatic pseudocystic disease and from ductal cancer of the pancreas. Pancreatic pseudocysts are by far the most commonly recognized pancreatic/peripancreatic cystic lesion. Therefore, the main risk in managing the patient with a cystic neoplasm is the possibility of misdiagnosing the neoplasm as a pseudocyst. There are, however, general guidelines (according to age, sex, medical history, imaging findings, serum amylase, cyst fluid amylase, and gross appearance) (Fig. 1), that can render the preoperative differentiation obtained with reasonable assurance.6
Table 1. Classification of primary cystic neoplasms of pancreas
— intraductal papillary mucinous neoplasm with moderate dysplasia
— intraductal papillary mucinous carcinoma
3. Unusual cystic neoplasms
(a) cystic islet cell neoplasm
(b) acinar cell cystadenocarcinoma
(c) cystic choriocarcinoma
(d) cystic teratoma
(e) cystic lymphangiomatous neoplasm
(f) solid pseudopapillary neoplasm
— solid pseudopapillary neoplasm with borderline malignant potential
— solid pseudopapillary carcinoma
1. Serous cystic neoplasms
Serous cystic neoplasms (SCN) constitute the most common cystic tumors7 and an important group because of their special clinical presentation and biology. These tumors are nearly always benign, and there are only very few reports in the literature on patients with malignant serous cystadenocarcinoma.8 They represent about 30% of primary cystic neoplasms of the pancreas9 and affect predominantly women (65%), with an average age of 62 years.10 These neoplasms vary in size from a few centimeters to as large as 25 cm (mean: 6–10 cm), and tend to be located in the head of the pancreas. Currently, five subtypes of SCN can be distinguished: serous microcystic adenoma (SMA), which is the most common type, serous oligocystic ill-defined adenoma (SOIA), solid serous adenoma (SSA), serous cystadenocarcinoma (SCC), and the von Hippel-Lindau-associated cystic neoplasm (VHL-CN) (Table 1).
Histologically, all five types share the same cell type, which is cuboidal and rich in glycogen. Serous cystadenomas are composed of a honeycomb of many small-diameter cysts lined by a glycogen-rich, low-cuboidal epithelium. This epithelium does not express mucin production and is without cellular features of atypia or dysplasia. The stroma separating these microcystic areas consists of a fibrous connective tissue and may even be calcified; this unique calcification gives rise to an almost pathognomonic central sunburst, radical or stellate scar pattern on computed tomography. All SCN are strongly positive for cytokeratins, but negative for vimentin, demonstrating clearly the epithelial nature of these tumors. In addition, recent molecular studies showed that SCN are clearly distinguished from MCN.11
No symptoms or signs are pathognomonic of primary cystic neoplasms of the pancreas. Up to 40–75% of patients are asymptomatic. Symptomatic complaints associated with cystic neoplasms of the pancreas are non-specific and usually secondary to effects of the pancreatic mass. Slow growth is a common feature. Signs of disease are the usual late symptoms and evidence of an increase in size and displacement. Although abdominal pain may occur, a complaint of abdominal fullness is most common. Jaundice is unusual.4,12 Unlike ductal cancers these lesions more commonly give rise to a vague fullness or poorly localized left upper quadrant discomfort and less commonly invade directly into other retroperitoneal structures.
The increasing recognition of cystic neoplasms of the pancreas, is due to the introduction in clinical practice and the wide availability of the newer, sophisticated abdominal imaging techniques.13 After discovery of a cystic lesion in the pancreatic region, there are three necessary diagnostic steps that aim to: (i) confirm the intrapancreatic origin of the cyst, (ii) exclude the diagnosis of a pseudocyst and (iii) differentiate the various types of lesions because of their vastly different biologic behavior and management.14 (Fig. 1). Finding the exact location of a tumor is possible in most cases by means of ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), or endoscopic retrograde cholangiopancreatography (ERCP). Uni- or multi-locular cysts with an inhomogeneous cystic solid structure, irregular surroundings and septae are radiological characteristics. Serous cystic neoplasms have three morphologic patterns: polycystic, oligocystic, and honeycomb. The polycystic pattern is the most common (70% of patients), and is characterized by a boss-elated collection of multiple, small (< 2 cm) cysts.15 A central fibrous scar with a characteristic stellate pattern of calcification—manifested as a central starburst calcification on imaging methods—occurs in up to 30% of these neoplasms and when present, is considered to be virtually pathognomonic of SCN. Calcification has not been detected in pseudocysts or in calcified chronic pancreatitis.1
Differentiation: serous versus mucinous cystic neoplasms
While identification of a cystic tumor is relatively easy, the identification of the specific tumor type may be difficult because of overlapping of characteristics: most occur in middle-aged women, have a mean diameter of 5 to 6 cm, and may present with pain, pancreatitis, or no signs. The ability to separate SCN from MCN might justify a non-operative management in the elderly or high-risk patient with an asymptomatic serous cystadenoma, especially if the cystic mass is in the head of the pancreas. Fine-needle aspiration has been used by several investigators to look for malignant cells and for the presence of mucin.16,17 Evaluation of cystic fluid obtained preoperatively may also be useful. Serous cystic neoplasms are characterized by the absence of mucin,12 lack of immunoreactivity for the cytokeratins AE1 and AE318 and positive staining for periodic acid-Schiff reaction for glycogen.12,18 A large concentration of amylase or other pancreatic enzymes suggests a pancreatic pseudocyst. On the contrary, amylase activities are a poor discriminator of the different types of cysts.19 Evaluation for mucin, increased viscosity, and increased concentrations of tumor markers such as CEA or CA19-9 have been found to be highly specific for mucinous (versus serous) cystadenomas and especially for mucinous cystadenocarcinomas.17,20,21 Other current imaging tests have little additional discriminating value.22–25
Due to the generally benign nature of SCN, conservative management is wholly justified for a well documented serous cystadenoma with no symptoms and without duct or vascular obstruction. However, various reports in the early 1990s advocated a more aggressive approach: curative resection for all cystic neoplasms.26–28 It has been estimated that 6.2% of serous cystic neoplasms of the pancreas are malignant. Because of the well-documented cases of serous cystadenocarcinoma and the diagnosis which can only be ascertained post-operatively, surgical resection is recommended for all cystic tumors. Moreover, the potential consequences of non-resectional therapy are significant, as rarely some SCN may develop complications.14 In addition, the perioperative morbidity and mortality of major pancreatic surgery has decreased markedly in experienced centers, and the prognosis with resection is good. In SCN complete resection is curative, and post-operative surveillance imaging is neither cost-effective nor necessary.3 Resection is, by all means, indicated when mass-related symptoms are presented, or when differentiation from MCN or side-branch IPMN can not be made confidently.27 (Table 2). When resection is planned, a conservative, non-radical resection is preferable. There is no need for lymphadenectomy or any extended resection. Although enucleation of serous cystadenomas is attractive in theory, Pyke et al. found a high incidence of local pancreatic complications after the procedure.27 Segmental ‘central’ pancreatectomy29–31 and spleen-preserving distal pancreatectomy32,33 constitute very reasonable procedures.
Table 2. Management of primary cystic pancreatic neoplasms
1. Conservative management:
is justified for a well documented serous cystadenoma with no symptoms and without duct or vascular obstruction and for elderly patients or patients with high operative risk.
2. Surgical management:
Curative conservative resection is recommended for all cystic neoplasms because of:
— unreliable preoperative differentiation of a benign versus a malignant cystic neoplasm
— low mortality, low postoperative morbidity, good prognosis with resection.
— significant potential consequences of non-resectional therapy
Cystic lesions of the pancreas should be resected if one of the following criteria is given:
— missing history of trauma or pancreatitis
— typical characteristics in CT, MRI, or ultrasound examination
— therapeutic failure of interventional methods
— elevated tumor markers in cystic fluid
— positive aspiration cytology
3. Adjuvant chemoradiation:
can be effective both in a preoperative and postoperative setting
— for rare malignant tumors
— if tissue invasion is present
— for en apparently unresectable tumor with no metastases
— for aneuploid neoplasms
Serous cystic neoplasms constitute neoplasms lacking tissue invasion and do not recur either locally or distally after complete surgical resection. A detailed, expensive, and emotionally trying, long term follow-up for such patients is probably unnecessary.10
2. Mucinous cystic neoplasms
In contrast to serous cystadenomas, the mucinous cystic neoplasms (MCN) represent a more diverse, heterogenous spectrum of related neoplasms. As originally delineated by Compagno and Oertel, MCN range from the overtly malignant cystadenocarcinoma to the ostensibly benign mucinous cystadenoma, considered to have a latent potential for malignant degeneration.4 Mucinous cystic neoplasms are also rare, representing 44–49% of primary cystic neoplasms of the pancreas.9 These lesions are thought to occur predominantly in women of 42–60 years of age.1 Although MCN are more common in the body/tail of the pancreas (75%), they do occur in the head region (25%) as well.34 The average size is greater than 5 cm (range: 3–20 cm).10 Recently, investigators from the Mayo Clinic proposed a new classification system for MCN,35 which includes three subgroups: (i) mucinous cystadenomas (65% of MCN), (ii) non-invasive proliferative MCN (30% of MCN) and (iii) mucinous cystadenocarcinomas (8% of MCN) (Table 1).
Mucinous cystic neoplasms contain a tall columnar epithelium that expresses mucin. These cells may also stain for CEA, serotonin, and somatostatin, which suggests an origin from ductal or stem cells.36 Papillary invaginations are common with multiple areas of atypia, dysplasia, carcinoma in situ, and overtly invasive carcinoma within the same neoplasm. Sometimes, mucin, accumulating within individual cysts, causes pressure necrosis of the epithelium, making the epithelial lining discontinuous.1
Latent malignant potential
Several reports have appeared to document the progression of apparently benign cystadenomas to overtly malignant cystadenocarcinomas.37 This malignant degeneration is relatively common and has been described, often after a long period of time (up to 17 years).4,9,38,39 The contention of malignant transformation is difficult or impossible to document objectively because of the well-known discontinuous changes in epithelial differentiation. Therefore, some investigators have even suggested that all MCN of the pancreas should be considered as at least grade I mucinous cystadenocarcinomas.18
In patients with MCN, the onset of symptoms can be insidious, developing over several months or even years.1 Symptoms are equally vague, as with SCN, but they are presented more frequently.10 Most symptoms from MCN seem related to a local mass effect, with surrounding tissue compression/displacement rather than invasion.10 The most frequent symptom is abdominal pain. The presence of symptoms increases the likelihood of a malignant MCN. In fact, nearly all patients with malignant MCN are symptomatic.40 Obstructive jaundice occurs in 25–54% of patients with MCN in the head of the pancreas.22,38,41 Symptoms such as bleeding related to gastric involvement, portal hypertension, hemobilia, or hemosuccus pancreaticus, indicate the existence of an aggressive lesion.42,43 A palpable mass is evident in approximately 25% of patients with malignant MCN.22,41
The overall size of the neoplasm is similar to that of SCN, so it is of no discriminating value.6 The complex internal architecture of the cysts is best depicted by US, CT, or MRI, which demonstrate the cysts to have thick, irregular walls with papillary excrescences or septae extending into the cysts. Approximately 20% of MCN exhibit some calcification, which usually tends to be patchy and more peripheral. When the calcification has en eggshell appearance, the likelihood that represents a mucinous cystadenocarcinoma increases.1
Preoperative differentiation of benign from malignant mucinous cystic neoplasms has been unreliable, and because of their latent malignant potential, probably all should be resected, whether in the proximal or distal pancreas and whether symptomatic or not. In experienced hands, the perioperative morbidity and mortality of pancreatic surgery is currently low.44,45 So, since cystic neoplasms are one of the few curable neoplasms of the pancreas with adequate surgical therapy, an aggressive surgical approach is indicated. For MCN in the head of the pancreas, a formal pylorus-preserving pancreatoduodenectomy is usually the procedure of choice. For MCN in the body or tail region, a segmental central resection or a spleen-preserving resection can be performed if there is no suspicion that the neoplasm has an invasive component. However, this type of management carries some risk.29–33,35 In some cases, a classic distal pancreatectomy with splenectomy may be the best treatment. Rarely, resection of involved adjacent structures/organs may be required.34 These extensive resections are justified as the 5-year survival rate may exceed 50%.46 Malignant MCN tend to push surrounding structures, rather than to invade them.41 Therefore, large size should not be a contraindication to exploration for resection. There is no benefit of an extended lymphadenectomy, and the majority of surgeons would not perform such an extended resection unless an invasive MCN was highly suspected. Given the limitations in preoperative and even intraoperative recognition of an underlying invasive malignancy, enucleation, duodenum-preserving subtotal pancreatic head resections, or even segmental resection of the neck or body of the pancreas, constitute suboptimal operative procedures. Several reports have suggested a response to adjuvant chemoradiation therapy47,48 both in a preoperative and postoperative setting.35,49 (Table 2).
Five-year survival rates of patients with MCN containing tissue invasion, appear to be somewhat better than those for typical ductal cancer of the pancreas ranging from 15% to 33%,35,50,51 but are not the 50–70% reported in the past. The prognosis for unresectable mucinous cystadenocarcinoma is as poor as that for unresectable pancreatic adenocarcinoma.9 A long term follow up for patients with completely resected non-invasive MCN is not necessary.
3. Intraductal papillary mucinous neoplasms
Intraductal papillary mucinous neoplasms have been diagnosed and managed with an increasing frequency, during the last decade. Some investigators question whether this entity existed before the early 1980s.52 They represent about 20–25% of primary cystic pancreatic neoplasms. These lesions occur most often in the head of the pancreas in elderly patients, with a slight male predominance. Patients generally present in their 60's, but several recent studies have shown that those patients with invasive IPMN are 5–6 years older than those patients with benign disease.53,54 Morphologically, IPMN of the pancreas can be classified as: main duct type (diffuse or segmental ectasia), branch duct type, or combined type.55 Based on the degree of cytoarchitectural dysplasia at microscopic examinations, IPMN can be classified (according to the current World Health Organization criteria) in three subgroups: intraductal papillary mucinous adenoma, IPMN with moderate dysplasia (borderline tumor) or intraductal papillary mucinous carcinoma (Table 1). The malignant subtype is further subdivided into in situ carcinoma and invasive carcinoma.56
Intraductal papillary mucinous neoplasms of the pancreas are defined as intraductal mucin-producing neoplasms with tall, columnar, mucin-containing epithelium with or without papillary projections. These lesions are characterized by intraductal proliferation of neoplastic mucinous cells, which usually form papillae and lead to cystic dilation of the main pancreatic duct and/or ductal side-branches. The regions of ductal dilation contain mucus and often form detectable ‘masses’.57 Frequently, normal epithelium, hyperplasia, dysplasia, carcinoma in situ, and invasive carcinoma are found in the same pancreas.58 Intraductal papillary mucinous neoplasms exhibit various histological patterns of papillae: intestinal (35%), pancreatobiliary (22%) and null (31%).59 The prognosis of these types differs.60 Recent research has shown that IPMN is associated with frequent point mutations in the K-ras gene, thereby establishing these mutations as a genetic marker in IPMN, just as in ductal pancreatic cancer.61
Intraductal papillary mucinous neoplasms manifest a much greater latent or overt malignant potential than other cystic neoplasms of the pancreas. About 35–45% of patients at the time of diagnosis will already have an established, invasive malignancy.62 The frequency of the presence of the invasive component in malignant IPMN has been reported to range from 25–70%.63 Data from literature show that branch duct-type IPMN constitutes an early stage of the disease with a better prognosis than main duct-type IPMN.64,65 On the contrary, main duct-type IPMN has not such a benign nature.
Approximately 20% of patients with IPMN appear asymptomatic, particularly those with only branch-type disease. The most frequent presenting symptoms constitute a vague abdominal pain and acute, recurrent, or more commonly chronic pancreatitis. Unexpected weight loss without abdominal pain is also commonly presented, and may be due to mucin hypersecretion which may lead to functional pancreatic ductal obstruction and finally to pancreatic exocrine insufficiency.6 When invasive carcinoma coexists in IPMN (up to 40% of patients), a clinical presentation similar to that of ductal carcinoma of the pancreas may be evident.3
Computed tomography scan is the radiological test of choice for IPMN, and if diagnostic uncertainty is present, endoscopic ultrasound with fine needle aspiration may be performed. Computed tomography is probably the most adequate technique to demonstrate the location and degree of pancreatic duct dilation and may be helpful to differentiate IPMN from other causes of duct dilation. Some CT parameters have been found to be helpful for differentiating malignant and benign IPMN of the pancreas.66–69 Endoscopic ultrasonography is more accurate than CT in identifying mural nodules and other signs of malignancy, but only in experienced hands.
Differentiation: mucinous cystic neoplasms versus intraductal papillary mucinous neoplasms
Mucinous cysts may coexist in patients with IPMN. Both entities are potentially or overtly malignant. Their epithelia are cytologically identical, so histologic examination of the cyst lining does not help distinguish between IPMN and MCN. However, gross and microscopic pathologic features usually allow one to distinguish between these two lesions. Firstly, tumor size can help in the process of differentiation. Mucinous cystic neoplasms in the vast majority of cases occur in the body or tail of the pancreas, while IPMN can involve any part of the pancreatic ductal system and most arise in the pancreatic head. Additionally, the gross contour of the two neoplasms differs. Moreover, the study of the subepithelial stroma can be extremely useful.3 Finally, pancreatic tissue adjacent to IPMN exhibit dysplastic changes of nuclear crowding, stratification, and hyperchromasia. Dysplasia of ducts distant from the main lesion is not considered a feature of MCN.
Preoperative discrimination of benign from malignant IPMN, as in case of MCN, is considered to be difficult, if not unfeasible. Most investigators agree that accurate differentiation of benign from malignant neoplasms can be made only at histopathologic examination of the entire resected segment of the pancreas.3 Because of the above reason and thus because IPMN manifest a much greater malignant potential compared with other cystic neoplasms of the pancreas, operative resection is usually considered mandatory. An extensive pancreatic resection is not indicated in branch duct type IPMN.65 When the IPMN involves branch duct disease, a localized but formal anatomic oncologic procedure is performed: pancreatoduodenectomy for head/uncinate neoplasms and classic distal pancreatectomy for body/tail regions.34 However, long-term follow up is indispensable to determine if there exists a localized disease or not.64 As far as main duct type disease is concerned, when dilation of the main pancreatic duct involves only the body and tail (10% of patients) a distal pancreatectomy with immediate frozen section analysis of the proximal pancreatic ductal margin is suggested.64,70 When the entire pancreatic duct is dilated, a pancreatoduodenectomy is performed with immediate frozen-section analysis of the distal margin.
Intraductal papillary nucinous neoplasms have a similar aggressive behavior to that of pancreatic ductal cancer, but with a slightly better prognosis. For branch duct IPMN, several studies suggest that a local, anatomic resection is curative.65 On the contrary, in main duct type IPMN occurrence in the remnant gland has been found with variable rates. When there is invasion in the resection specimen, recurrent IPMN, occurs in 50–90% of patients and decreases the 5-year survival to less than 50%.3
4. Solid-pseudopapillary tumor
Solid pseudopapillary tumor (SPT) of the pancreas is a rare exocrine pancreatic tumor, which is well known for its indolent biologic behavior. These neoplasms only constitute 1–2% of all tumors of the pancreas, and affect predominantly women (82%) about 30 years of age.71 Solid pseudopapillary tumors can occur in every part of the pancreas but they are slightly more common in the tail.72 The size of the tumors ranges from as small as 1.5 to as large as 30 cm in diameter. Solid pseudopapillary tumors have been differentiated by the WHO classification into two subtypes: (i) solid-pseudopapillary neoplasms with borderline malignant potential and (ii) solid-pseudopapillary carcinomas (Table 1).
On gross examination, the tumor tissue is usually well demarcated from the normal pancreas by a fibrous capsule. On the cut surface, a variegated appearance is evident with variable combinations of solid hemorrhagic and cystic-necrotic areas. The microscopic features of SPT are solid areas which alternate with a pseudopapillary pattern composed of a fibrovascular stalk surrounded by several layers of epithelial cells. Solid pseudopapillary tumors are typically positive for vimentin, and antitrypsin and are negative for trypsin and chymotrypsin.
The neoplasm is usually asymptomatic, and hence its diagnosis is usually incidental during diagnostic tests or surgical explorations for other reasons. When symptomatic, complaints are nonspecific for a number of years, with diffuse pain in the epigastrium or left hypochondrium.
To the present, imaging studies or imaging-guided fine needle aspiration biopsy is the cardinal choice for preoperative diagnosis. Ultrasonographically, the tumor is well-encapsulated, homogeneous or heterogeneous, and composed of solid echogenic and hypoechogenic cystic components.73 Computed tomography defines these tumors as big, well-delimited growths with a thick capsule and a hyperdense cystic component showing bleeding areas that delimit cystic cavities with solid areas and calcifications.74 Magnetic resonance imaging is better than CT for distinguishing certain tissue characteristics, such as hemorrhage, cystic degeneration, or the presence of a capsule. Angio-CT may be useful to characterize these huge pancreatic masses.
Surgery is the only valid option with proven effectiveness and a high long-term survival rate even in rare malignant cases. Because the tumor is usually surrounded by a pseudo-capsule and exhibits benign or low-grade malignancy, conservative resection with preservation of as much pancreatic tissue as possible is the treatment of choice. Distal pancreatectomy with or without splenic preservation is feasible for tumors in the body or tail of the pancreas. For tumors of the pancreatic head, duodenopancreatectomy can be done.75
Cure following successful surgery occurs in 97% of patients. Long term mortality is attributed to rare cases of malignant disease with metastases. Recently, some histological features such as extensive necrosis, nuclear atypia, high mitotic rate and sarcomatoid areas have been suggested to be associated with aggressive behavior.
No symptoms or signs are pathognomonic of primary cystic neoplasms of the pancreas. Further prospective studies and incorporation of molecular markers could refine the diagnosis of these lesions. Because of the low mortality and low postoperative morbidity, surgical resection is indicated in all patients with cystic tumors. A borderline situation is given by older patients with serous cystadenoma, who must be treated on a more individualized basis. In the absence of invasive disease, prognosis is excellent, provided that an adequate resection has been performed. The existence of invasive features signifies a poor prognosis.