**6. Intraductal papillary mucinous neoplasms (IPMNs)**

stromal component of MCNs and ovarian tissue should be supported by morphological resemblance. This type is present almost exclusively in women of fifth–sixth decade and

There is another type of MCNs, more common, without ovarian stroma that can be located anywhere in the pancreas and occurs in both sexes. The malignant potential is very high in MCNs based on the possible evolution of mucinous transitional epithelium. Consequently, MCNs may be classified based on the degree of dysplasia: MCNs with low‐intermediate grade dysplasia, with high‐grade dysplasia, and finally with associated invasive carcinoma [14]. Histological heterogeneity of MCNs is in evidence with coexistence of benign appearance and

The macroscopic appearance of MCNs is cystic mass, unilocular or multilocular, containing thick mucine or sometimes mixed with hemorrhagic materials. The cystic wall is well defined,

Clinical appearance in the symptomatic patients presents abdominal pain, palpable mass, anorexia, fatigue, weight loss, and in some cases pancreatitis. The results of routine laboratory examinations are generally non‐specific. One‐third of patient can be asymptomatic [22]. Imaging examinations (CT and MRI) of MCNs show large cysts with septae and in some cases peripheral thin calcification of the walls. In some experiences, the presence of peripheral calcification, wall thickening, and thick septation has been highlighted as important for malignant evolution of MCNs [23]. Overlappable data can be detected by EUS: mass formed from fluid‐filled cysts with thin walls, septae, and diameter 1–2 cm without duct communica‐ tion. Malignancy suspicious can be based on wall thickening, irregularity, intracystic solid

EUS‐FNA can allow the evaluation of fluid content of cysts: CEA levels are high and can be useful in the diagnosis [6]. Pathological and evolutionary characteristic of MCNs affect treatment decisions. Malignant potential of these neoplasms is the cornerstone of the therapy. Relevant is the increase in the frequency of K‐ras and p53 mutations as in sequence adenoma– carcinoma of colon cancer. Consequently, there is high likelihood of evolution into cancer if untreated. In fact, there is age difference of 10 years longer between patients with cystadeno‐ carcinoma and patients with cystadenoma [24, 25]. Based on the pathological characteristics of histologic heterogeneity, extensive histologic sampling is necessary for certainty of diagnosis (from adenoma to carcinoma). The current and unanimous guidelines propose the surgical treatment for all MCNs. The contraindications for intervention are related to the patient's conditions. The pancreatic resection is connected with the location of lesion: head, body, and tail. Duodenopancreatectomy, middle pancreatectomy, and distal pancreatectomy with or without splenectomy should be performed. Less extensive resections, such as enucleations are not recommended also because usually followed by high complications rate. Laparoscopic

Cure rate of surgical resection for non‐invasive MCNs (carcinoma *in situ*) is 100%. The 5‐year survival rate for resected patients with invasive lesions is 40–50%; whereas the 2‐year survival

malignant epithelia. Malignancy, *in situ* or invasive, is found in 35–45% of cases [21].

predominantly is located in body and tail of pancreas.

fibrous, and sometimes (10%) calcified.

100 Challenges in Pancreatic Pathology

mass, and increased size of all lesion.

approaches are becoming more common and fully justified.

rate is 60–70%. Surveillance after surgery in these patients is required.

The incidence of IPMNs is not well defined. In the recent years, their detection is increased based on the technical improvement of imaging examinations and the better knowledge of pathological features. Some data from the literature report that incidence range from 20 to 50% of all pancreatic cystic neoplasms [6, 26, 27]. Tumor arises from epithelium of the main pancreatic duct or its side branches. The lesions are lined by the intraductal proliferations of ductal columnar mucin‐secreting epithelium with papillary projections that cause obstruction and dilatation of the duct. Tumors localized in the main pancreatic duct can spread in the rest of the duct. Men and women are equally affected. The neoplasm can be located anywhere in the pancreas. The most frequent localization of lesion is in the head of the gland and in 20– 30% of cases can be multifocal. In 5–10% of cases, the pancreas can be diffusely interested [26, 27]. There are two varieties of this neoplasm, following its localization: main duct type (MD‐ IPMNs), most frequent (57–92%), and side branches type (BD‐IPMNs), localized in the side branches of ductal system, less frequent (6–46%) [28]. In the combined type of IPMNs, main and branch ducts are both involved. IPMNs encompass epithelial changes from adenoma as premalignant lesions to carcinoma *in situ*, based on the progression of dysplasia, and finally invasive carcinoma. The degree of dysplasia allows the classification of IPMNs: IPMNs with low‐ or intermediate‐grade dysplasia, IPMNs with high grade, and IPMNs with invasive carcinoma.

The characteristic behavior of IPMNs progresses toward malignancy. There is, in the observa‐ tional studies, an age difference, 6 years longer, between patients with malignant tumors and patients with mucinous adenoma [29]. The communication with pancreatic duct system is characteristic. According to histological features (architecture and cytology), four types of IPMNs, such as gastric, intestinal, pancreatobiliary, and oncocystic, have been described. Gastric‐type epithelium is frequent in side branches type with better prognosis (malignant potential 28%); intestinal‐type and pancreatobiliary‐type epithelia are more frequent in main duct type with bad prognosis (malignant potential 60%) [30]. Several patients can be sympto‐ matic with non‐specific symptoms. Clinical appearances can be usually abdominal discomfort or pain, malaise, nausea, and vomiting. Frequently, first clinical appearance is acute pancrea‐ titis generally with benign evolution, due to mucous obstruction of the pancreatic ducts. Acute pancreatitis can be recurrent in 20% of cases. In most cases, IPMNs are asymptomatic. IPMNs with invasive carcinoma should be associated with more evident clinical data such as weight loss, jaundice, and diabetes.

IPMNs usually are diagnosed in elderly (sixth decade). Because high likelihood of malignant evolution of these lesions, there is an age difference, 6 years longer, between patients with malignant or benign lesions [29]. The results of blood examinations, as liver function tests, lipase, amylase, serum CA 19‐9, and CEA, and routine tests are non‐specific for these pancreatic cystic neoplasms.

Imaging examinations are decisive for diagnosis. They can be less invasive such as US, CT, MRI, and more invasive such as EUS, endoscopic retrograde cholangiopancreatography (ERCP).

Transabdominal US has limited diagnostic role. This examination can show dilatation of the main duct with cystic images around the ducts and thick mucinous content. Sometimes, US can detect the duct communications. CT and MRI are currently employed in the diagnostic assessment of IPMNs. These examinations can detect morphological features of the lesions: size and location, calcification, pancreatic duct dilatation, appearance of the cysts with septae, and thickening of wall. These morphological appearance detected by imaging examinations can identify IPMNs excluding other cystic pancreatic lesions and can distinguish the MD‐ IPMNs from BD‐IPMNs. MRI and CT can also demonstrate the communication between the duct and cyst.

In the past years, endoscopic retrograde cholangiopancreatography (ERCP) was crucial imaging examination in the diagnosis of IPMNs. ERCP may detect dilated main pancreatic duct with mucinous filling and/or intraductal proliferations. These features are characteristic of MD‐IPMNs. Whereas in the BD‐IPMNs, the examination shows cystic lesions due to dilatation of affected branch ducts that communicate with main pancreatic duct.

In some cases, the imaging studies show a dilated pancreatic duct but not the intraductal tumor. Moreover, the dilation can be proximal and distal to the tumor, because of overproduction of mucous. Classically, the endoscopic observation of open Vater's papilla and mucin extrusion has been reported.

Unfortunately, ERCP is invasive procedure and its diagnostic use has been limited. In the recent years, EUS plays an important role in the diagnostic program of pancreatic diseases. EUS should be useful in the differentiation of types of IPMNs. EUS findings in MD‐IPMNs can be a characteristic of morphological changes of these lesions such as various extension and degree of duct dilatation and, in some cases, the presence of intraductal tumor. The recurrent acute pancreatitis can show several parenchymal damages such as edema and enlargement of the gland or signs of parenchymal atrophy. Characteristics of BD‐IPMNs are the lesions formed by multiple little cysts (few millimeters) with internal septation, mucous, wall nodule, or thickening, intracystic papillary projections. The Wirsung's duct should be moderately dilated [31].

Based on EUS findings, some criteria of malignancy in IPMNs were defined: great dilatation (>10 mm) of the main pancreatic duct and evident, large intraductal tumor (>10 mm) in MD‐ IPMNs; large cystic lesions (>40 mm) with thick, irregular septation, wall thickening, mural nodule in BD‐IPMNs. We can also add to these criteria of malignancy the vascular invasion and lymph node metastases. The accuracy of EUS malignancy criteria ranges from 40 to 90% [32, 33]. Fine needle aspiration biopsy (FNAB) during EUS allows taking samples for bio‐ chemical, cytological, and DNA analyses. The first macroscopic finding is the mucinous fluid characteristic of MCNs and IPMNs. High concentration of CEA should be characteristic of mucinous lesions, such as high level of amylase because duct system communication. Brugge has emphasized the cutoff CEA level for differentiating mucinous from non‐mucinous pancreatic cystic lesions: the CEA level of 192 ng/ml has the sensitivity of 73% and specificity of 84% [34]. Unfortunately, this analysis not distinguish MCNs from IPMNs and benign from malignant lesions. Cytological study should be useful for the diagnosis of mucinous lesions with the presence of epithelial cells (different from glycogen‐rich clear cells of serous cysta‐

denoma). Moreover, the presence of high‐grade cytological atypia relevant to malignancy can be detected [35]. DNA analysis of pancreatic cyst fluid shows K‐ras mutation, characteristic for mucinous lesions, and GNAS mutation more present in IPMNs. The latter can differentiate IPMNs from MCNs [36].

Transabdominal US has limited diagnostic role. This examination can show dilatation of the main duct with cystic images around the ducts and thick mucinous content. Sometimes, US can detect the duct communications. CT and MRI are currently employed in the diagnostic assessment of IPMNs. These examinations can detect morphological features of the lesions: size and location, calcification, pancreatic duct dilatation, appearance of the cysts with septae, and thickening of wall. These morphological appearance detected by imaging examinations can identify IPMNs excluding other cystic pancreatic lesions and can distinguish the MD‐ IPMNs from BD‐IPMNs. MRI and CT can also demonstrate the communication between the

In the past years, endoscopic retrograde cholangiopancreatography (ERCP) was crucial imaging examination in the diagnosis of IPMNs. ERCP may detect dilated main pancreatic duct with mucinous filling and/or intraductal proliferations. These features are characteristic of MD‐IPMNs. Whereas in the BD‐IPMNs, the examination shows cystic lesions due to

In some cases, the imaging studies show a dilated pancreatic duct but not the intraductal tumor. Moreover, the dilation can be proximal and distal to the tumor, because of overproduction of mucous. Classically, the endoscopic observation of open Vater's papilla and mucin extrusion

Unfortunately, ERCP is invasive procedure and its diagnostic use has been limited. In the recent years, EUS plays an important role in the diagnostic program of pancreatic diseases. EUS should be useful in the differentiation of types of IPMNs. EUS findings in MD‐IPMNs can be a characteristic of morphological changes of these lesions such as various extension and degree of duct dilatation and, in some cases, the presence of intraductal tumor. The recurrent acute pancreatitis can show several parenchymal damages such as edema and enlargement of the gland or signs of parenchymal atrophy. Characteristics of BD‐IPMNs are the lesions formed by multiple little cysts (few millimeters) with internal septation, mucous, wall nodule, or thickening, intracystic papillary projections. The Wirsung's duct should be moderately

Based on EUS findings, some criteria of malignancy in IPMNs were defined: great dilatation (>10 mm) of the main pancreatic duct and evident, large intraductal tumor (>10 mm) in MD‐ IPMNs; large cystic lesions (>40 mm) with thick, irregular septation, wall thickening, mural nodule in BD‐IPMNs. We can also add to these criteria of malignancy the vascular invasion and lymph node metastases. The accuracy of EUS malignancy criteria ranges from 40 to 90% [32, 33]. Fine needle aspiration biopsy (FNAB) during EUS allows taking samples for bio‐ chemical, cytological, and DNA analyses. The first macroscopic finding is the mucinous fluid characteristic of MCNs and IPMNs. High concentration of CEA should be characteristic of mucinous lesions, such as high level of amylase because duct system communication. Brugge has emphasized the cutoff CEA level for differentiating mucinous from non‐mucinous pancreatic cystic lesions: the CEA level of 192 ng/ml has the sensitivity of 73% and specificity of 84% [34]. Unfortunately, this analysis not distinguish MCNs from IPMNs and benign from malignant lesions. Cytological study should be useful for the diagnosis of mucinous lesions with the presence of epithelial cells (different from glycogen‐rich clear cells of serous cysta‐

dilatation of affected branch ducts that communicate with main pancreatic duct.

duct and cyst.

102 Challenges in Pancreatic Pathology

has been reported.

dilated [31].

The planned interventions for treatment of IPMNs are duodenopancreatectomy or distal/ middle pancreatectomy based on location of lesions. We need to take into account that the tumors localized in the main pancreatic duct can spread in the rest of the duct. Consequently, the surgical planification can have changes with possible extension of pancreatic resection to allow negative or low‐grade dysplasia at surgical margins. In fact, intraoperative frozen section diagnosis of the transection margin shows positive results in 20–50% of cases [28]. Surgical indications for IPMNs are based on risk of malignancy that is different for MD‐IPMNs and for BD‐IPMNs. The frequency of malignant potential in MD‐IPMNs is 61.6% and the frequency of invasive IPMNs is 43.1% [32]. The malignant potential in BD‐IPMNs reaches 28% and the frequency of the invasive lesions is 18%. Therefore, the indication for pancreatic resection is justified and recommended in the majority of the patients with MD‐IPMNs by international consensus guidelines [32]. On the contrary, surgical indications in the patients with BD‐IPMNs are more debatable. IPMNs, with some not negligible differences between main duct type and branch duct type, encompass epithelial changes from adenoma, carcinoma *in situ*, and invasive carcinoma. The lesions benign at the beginning progress toward malignancy. This character‐ istic of biological evolutivity makes difficult and complex the surgical indications or the timing of intervention after a possible observation period. Beside the positive and specific diagnosis of each type of cystic pancreatic neoplasm as IPMNs or MCNs, SCNs are crucial for the next diagnostic step, recognizing the malignancy of the neoplasm. In the difficult diagnosis of IPMN, the criteria based on CT imaging suggested by international consensus guidelines should be useful [32]. These criteria have been subdivided as "high‐risk stigmata" and "worrisome features." The first are obstructive jaundice in a patient with cystic lesion of the head of the pancreas, enhancing solid component within cyst, main pancreatic duct size of 5– 9 mm, or main pancreatic duct >10 mm in size. The "worrisome features" are cyst size >3 cm, thickened/enhancing cyst walls, non‐enhancing mural nodule, and lymphadenopathy [32]. Ablation therapies of cystic neoplasms have been proposed: EUS‐guided injection of cytotoxic agents (e.g., paclitaxel, ethanol) and radiofrequency ablation. These procedures are not widely employed and their results are not defined and can be evaluated with difficulty, also because these ablation therapies have been used for various PCNs [37–39]. The results of surgical treatment for non‐invasive disease are very positive with 5‐year overall survival of 100%; for invasive disease, 5‐year overall survival drops to 50–60% [28]. Recurrence rate of IPMNs can be evaluated after surgical resection. The mean recurrence rate is 15% in the remnant pancreas (ranges from 7 to 30%). The recurrence of IPMNs as invasive disease ranges from 3.4 to 44% [40, 41]. The differential diagnosis between IPMNs and chronic pancreatitis can be difficult in some cases. Usually, alcohol abuse is frequent in chronic pancreatitis. Several clinical and morphological features are common to both diseases: main duct and branch duct dilatation, intracystic and intraductal calcifications, and recurrent episodes of pancreatitis. Moderate and segmental dilatation of main pancreatic duct with intraductal lithiasic obstruction, moderate dilatation of the branch ducts communicating with main duct, and finally the widespread of the pancreatic ductal system are characteristic of chronic pancreatitis. On the contrary, segmental and marked dilatations of the branch ducts with little calcifications are character‐ istics of IPMNs.
