**7. Management**

detected in cyst fluid can separate IPMN from MCN, but similar to KRAS mutations, it does not predict malignancy. The absence of a GNAS mutation also does not correlate with a diagnosis of MCN because not all IPMNs will demonstrate a GNAS mutation [33–35]. A GNAS mutation was present in 66% of IPMNs." But a recent mutations study in GNAS at codon 201 has been identified in duodenal fluid samples even before the IPMN lesion, which was identified on radiologic imaging [36]. Moreover, one study reports that 33% of incipient IPMNs analyzed have a GNAS mutation, suggesting that a large proportion of incipient IPMNs are part of the IPMN pathway, and these mutations occur early in this

**Figure 5.** Use of EUS-FNA according to 2012 International Consensus Guidelines [28] and AGA Guidelines [29].

A recent study identified glucose and kynurenine to be differentially expressed between non-mucinous and mucinous pancreatic cysts [38]. Metabolic abundances for both were significantly lower in mucinous cysts compared with non-mucinous cysts. The clinical utility of

process [6, 37].

78 Challenges in Pancreatic Pathology

To date, three consensus guidelines have been proposed to manage pancreatic cystic lesions beginning with the original 2006 Sendai guideline, which was revised in 2012 by the International Association of Pancreatology (IAP) in Fukuoka, and the recent AGA guideline [43–45].

All guides agree that due to the higher risk of malignancy, all symptomatic cysts should be further evaluated or resected, depending on the clinical circumstances.

Invasive carcinoma in patients with asymptomatic cysts is very rare, especially in cysts <10 mm. In such cases, no further work-up will be needed; however, follow-up is still recommended [43–46]. For better characterization of the lesions, pancreatic protocol CT or gadolinium-enhanced MRI with magnetic resonance cholangiopancreatography (MRCP) is recommended for cysts >10 mm [47]. The most recent consensus among radiologists [10] suggests that MRI is preferable for evaluating cysts due to its high-contrast resolution, the identification of septum, nodules, and duct communications. Also, MRI is the preferable follow-up test because it avoids excessive exposure to radiation [47].

#### **According to Fukuoka guidelines (1), there are:**

	- Cyst of ≤3 cm.
	- Thickened enhanced cyst walls.
	- MPD of 5–9 mm.
	- Non-enhanced mural nodules.
	- Abrupt change in the MPD caliber with distal pancreatic atrophy.
	- Lymphadenopathy.
	- Obstructive jaundice in a patient with a cystic lesion of the pancreatic head.
	- Enhanced solid component, MPD size of 10 mm.

All patients with cysts of 3 cm in size without "worrisome features" should undergo surveillance according the size stratification. Patients with cysts of >3 cm and no "worrisome features" can also be considered for EUS to verify the absence of thickened walls or mural nodules, particularly if the patient is elderly. All smaller cysts with "worrisome features" should be evaluated by EUS to further risk stratify the lesion [48].

#### **7.1. Surgery**

If surgery is considered for a pancreatic cyst, patients are referred to a center with demonstrated expertise in pancreatic surgery. Surgery is the only treatment option in patients with IPMN of the pancreas with high-grade dysplasia or IPMNs that have progressed to invasive carcinoma (**Figure 6**).

#### *7.1.1. Indications*


Positive cytology on EUS-guided FNA has the highest specificity for diagnosing malignancy. If there is a combination of high-risk features on imaging, then this is likely to increase the

**Figure 6.** Proposed algorithm for surgery indications in IPMNs.

suggests that MRI is preferable for evaluating cysts due to its high-contrast resolution, the identification of septum, nodules, and duct communications. Also, MRI is the preferable

follow-up test because it avoids excessive exposure to radiation [47].

– Abrupt change in the MPD caliber with distal pancreatic atrophy.

– Enhanced solid component, MPD size of 10 mm.





should be evaluated by EUS to further risk stratify the lesion [48].

– Obstructive jaundice in a patient with a cystic lesion of the pancreatic head.

All patients with cysts of 3 cm in size without "worrisome features" should undergo surveillance according the size stratification. Patients with cysts of >3 cm and no "worrisome features" can also be considered for EUS to verify the absence of thickened walls or mural nodules, particularly if the patient is elderly. All smaller cysts with "worrisome features"

If surgery is considered for a pancreatic cyst, patients are referred to a center with demonstrated expertise in pancreatic surgery. Surgery is the only treatment option in patients with IPMN of the pancreas with high-grade dysplasia or IPMNs that have progressed to invasive

Positive cytology on EUS-guided FNA has the highest specificity for diagnosing malignancy. If there is a combination of high-risk features on imaging, then this is likely to increase the

**According to Fukuoka guidelines (1), there are:**

– Thickened enhanced cyst walls.

– Non-enhanced mural nodules.

• **"Worrisome features"**:

– MPD of 5–9 mm.

– Lymphadenopathy.

• **"High-risk stigmata":**

**7.1. Surgery**

carcinoma (**Figure 6**).


*7.1.1. Indications*

– Cyst of ≤3 cm.

80 Challenges in Pancreatic Pathology

risk of malignancy. Even in the face of a negative cytology, if EUS and MRI confirm high-risk stigmata, the specificity is likely to be high. However, no currently available data can demonstrate the impact of multiple high-risk features. Molecular techniques to evaluate pancreatic cysts remain an emerging area of research [23, 49, 50], but had the benefits of surgery outweigh the risks in this selected population [51].

The most important aspect of resection is to achieve complete removal of a tumor with a negative margin. If a positive margin is found in a high-grade dysplasia, additional resection of the pancreas should be performed. However, there is no consensus regarding further resection in the case of a low- or moderate-grade dysplasia [51, 52].

Total pancreatectomy should be contemplated only in younger patients who can manage the comorbidities related to diabetes and exocrine insufficiency or in patients with a history of diabetes [53, 54]. The choice of surgery will be determined by the location of the tumor and the extent of involvement of the gland. It is not clearly established that multifocality corresponds to a higher risk of invasive cancer; in most cases with more than one lesion, the dominant or concerning lesions are resected; and the others are observed with follow-up imaging [1].

Regarding the BD-IPMN that occurs in elderly patients, the annual malignancy rate is only 2–3%. These factors support a conservative management with follow-up in patients who do not have risk factors predicting malignancy. Younger patients (<65 years) with a cyst size of >2 cm may be candidates for resection owing to the cumulative risk of malignancy [27]. BD-IPMN of >3 cm without these signs can be observed without immediate resection, particularly in elderly patients. The decision needs to be individualized and to depend not only on the risk of malignancy but also on the patient's conditions and cyst location [51].

#### **7.2. Adjuvant therapy**

It has not yet been determined whether or not to offer postresection adjuvant therapy to patients with IPMNs that have progressed to invasive carcinoma; it also undefined as to the optimal strategy for postoperative therapy (chemoradiotherapy versus chemotherapy alone) remains undefined [55]. A recent study by McMillan et al. [56] suggests that patients classified as AJCC stage II through IV, presenting with positive lymph nodes, positive resection margins or poorly differentiated tumors, may benefit from adjuvant chemoradiotherapy over chemotherapy alone in terms of overall survival, except for patients who had AJCC pathologic stage II disease.

#### **8. Follow-up**

The AGA recommends discussing the risks and benefits of a management strategy with the patient as a good clinical practice for nearly all diseases and interventions. Patients need to receive a full explanation of all therapeutical options so they can choose the best treatment in accordance with the most recent guidelines. Patients who have a limited life expectancy do not derive any benefit from surveillance, because it is inappropriate for patients who are not surgical candidates due to severe comorbidities.

The Fukuoka consensus has high sensitivity of the diagnosis of IPMN and prediction of malignancy [57], although the cyst size from the "high-risk stigmata" to "worrisome features" is still a matter of controversy [57–60]. A systematic review of the literature suggests that size >3 cm increased the risk of malignancy by approximately 3 times and the presence of a solid component increased the risk of malignancy approximately eight times [58].

#### **8.1. MD-IPMN**

risk of malignancy. Even in the face of a negative cytology, if EUS and MRI confirm high-risk stigmata, the specificity is likely to be high. However, no currently available data can demonstrate the impact of multiple high-risk features. Molecular techniques to evaluate pancreatic cysts remain an emerging area of research [23, 49, 50], but had the benefits of surgery out-

The most important aspect of resection is to achieve complete removal of a tumor with a negative margin. If a positive margin is found in a high-grade dysplasia, additional resection of the pancreas should be performed. However, there is no consensus regarding further resection in

Total pancreatectomy should be contemplated only in younger patients who can manage the comorbidities related to diabetes and exocrine insufficiency or in patients with a history of diabetes [53, 54]. The choice of surgery will be determined by the location of the tumor and the extent of involvement of the gland. It is not clearly established that multifocality corresponds to a higher risk of invasive cancer; in most cases with more than one lesion, the dominant or concerning lesions are resected; and the others are observed with follow-up

Regarding the BD-IPMN that occurs in elderly patients, the annual malignancy rate is only 2–3%. These factors support a conservative management with follow-up in patients who do not have risk factors predicting malignancy. Younger patients (<65 years) with a cyst size of >2 cm may be candidates for resection owing to the cumulative risk of malignancy [27]. BD-IPMN of >3 cm without these signs can be observed without immediate resection, particularly in elderly patients. The decision needs to be individualized and to depend not only on

It has not yet been determined whether or not to offer postresection adjuvant therapy to patients with IPMNs that have progressed to invasive carcinoma; it also undefined as to the optimal strategy for postoperative therapy (chemoradiotherapy versus chemotherapy alone) remains undefined [55]. A recent study by McMillan et al. [56] suggests that patients classified as AJCC stage II through IV, presenting with positive lymph nodes, positive resection margins or poorly differentiated tumors, may benefit from adjuvant chemoradiotherapy over chemotherapy alone in terms of overall survival, except for patients who had AJCC patho-

The AGA recommends discussing the risks and benefits of a management strategy with the patient as a good clinical practice for nearly all diseases and interventions. Patients need to receive a full explanation of all therapeutical options so they can choose the best treatment in accordance with the most recent guidelines. Patients who have a limited life expectancy do not derive any benefit from surveillance, because it is inappropriate for patients who are not

the risk of malignancy but also on the patient's conditions and cyst location [51].

weigh the risks in this selected population [51].

82 Challenges in Pancreatic Pathology

imaging [1].

**7.2. Adjuvant therapy**

logic stage II disease.

surgical candidates due to severe comorbidities.

**8. Follow-up**

the case of a low- or moderate-grade dysplasia [51, 52].

The management depends on the degree of ductal dilation, ≥10 mm, if the duct is (**Figure 7**)


**Figure 7.** Follow-up for MD-IPMN <10 mm.

nancy with this degree of pancreatic duct dilation has not been well characterized. If the patient has a longer life expectancy, up to 10 years, he should be operated. For patients not undergoing surgery, we perform a magnetic retrograde cholangiopancreatography (MRCP) a year later. Surgery should be considered if the duct increases in size or if intramural nodules develop. If the duct is stable, we should repeat imaging every 2 years and continue it as long as the patient is a good surgical candidate.


#### **8.2. BD-IPMN**

Resection is generally indicated if there are high-risk stigmata and if patient has symptoms attributable to the IPMN. Besides, surgery is indicated if there is evidence of worrisome features or positive cytology. We must always take into account the patient's age, life expectancy, and performance status [28] (**Figure 8**)


Follow-up is made if the patient is a good surgical candidate. If, during surveillance, there are changes in the IPMN, a EUS-FNA should be performed.

MRI is the preferred surveillance imaging modality over computed tomography. The length of surveillance for IPMN is another concern for every clinician. If there is no change in size or characteristics, the AGA suggests that patients without worrisome pancreatic features undergo MRI for surveillance in 1 year and then every 2 years after, for a total of 5 years. The review of the literature suggests that the risk of malignant transformation of pancreatic cysts is approximately 0.24% per year. The risk of cancer in cysts without a significant change over a 5-year period is lower but this recommendation has very low evidence quality. Therefore, more studies are needed [45]. In addition, the Fukuoka consensus suggests for BD-IPMN follow-up: yearly follow-up if lesion is <10 mm in size, 6–12 monthly follow-up for lesions between 10 and 20 mm, and 3–6 monthly follow-up for lesions >20 mm [28]. The optimal surveillance approach, however, remains unclear.

#### **8.3. Combined main duct and branch duct IPMN**

Each lesion is managed, as it would be if it were the only lesion.

Intraductal Papillary Mucinous Neoplasms of the Pancreas: Challenges and New Insights http://dx.doi.org/10.5772/66491 85

**Figure 8.** Follow-up algorithm for BD-IPMN.

nancy with this degree of pancreatic duct dilation has not been well characterized. If the patient has a longer life expectancy, up to 10 years, he should be operated. For patients not undergoing surgery, we perform a magnetic retrograde cholangiopancreatography (MRCP) a year later. Surgery should be considered if the duct increases in size or if intramural nodules develop. If the duct is stable, we should repeat imaging every 2 years and


Resection is generally indicated if there are high-risk stigmata and if patient has symptoms attributable to the IPMN. Besides, surgery is indicated if there is evidence of worrisome features or positive cytology. We must always take into account the patient's age, life expec-

• ≥**30 mm:** repeat MRCP in 1 year. If the IPMN is stable, continue surveillance with MRCP

• **10–30 mm:** repeat MRCP in 1 year. If the IPMN is stable, continue surveillance with MRCP every 2 years. After 5 years, the surveillance interval can be lengthened to every 3 years. • **<10 mm:** repeat in 1 year. If the IPMN is stable, continue surveillance with MRCP every 2

Follow-up is made if the patient is a good surgical candidate. If, during surveillance, there are

MRI is the preferred surveillance imaging modality over computed tomography. The length of surveillance for IPMN is another concern for every clinician. If there is no change in size or characteristics, the AGA suggests that patients without worrisome pancreatic features undergo MRI for surveillance in 1 year and then every 2 years after, for a total of 5 years. The review of the literature suggests that the risk of malignant transformation of pancreatic cysts is approximately 0.24% per year. The risk of cancer in cysts without a significant change over a 5-year period is lower but this recommendation has very low evidence quality. Therefore, more studies are needed [45]. In addition, the Fukuoka consensus suggests for BD-IPMN follow-up: yearly follow-up if lesion is <10 mm in size, 6–12 monthly follow-up for lesions between 10 and 20 mm, and 3–6 monthly follow-up for lesions >20 mm [28]. The optimal

continue it as long as the patient is a good surgical candidate.

lance as long as the patient remains a good surgical candidate.

tancy, and performance status [28] (**Figure 8**)

years. After 5 years, surveillance can be discontinued.

changes in the IPMN, a EUS-FNA should be performed.

surveillance approach, however, remains unclear.

**8.3. Combined main duct and branch duct IPMN**

Each lesion is managed, as it would be if it were the only lesion.

**8.2. BD-IPMN**

84 Challenges in Pancreatic Pathology

every 2 years.

#### *8.3.1. Surveillance following surgery*

• Noninvasive IPMN: the risk of developing a recurrence in the remaining pancreas is at least 5%. So we have to perform the follow-up with MRCP by including a lengthening in the surveillance interval if no changes are detected after several years. If there is another nonresected IPMN, follow-up should continue as stated above [23, 61].

• Invasive carcinoma: studies say that the risk of IPMN recurrence is 25–50% [62], and it recommended surveillance every 6 months [28]. If we diagnose patients, a recurrence of IPMN will need EUS for evaluation.
