Pancreatic ductal adenocarcinoma (PDAC) carries one of the poorest overall prognosis of all human malignancies. The 5-year survival in patients with PDAC, for all stages, remains as low as 6–7%. The low survival rate is attributed to several factors, of which the two most important are aggressive tumor biology and late stage at which most patients are diagnosed. Only 10–20% of patients are eligible for resection at presentation, 30–40% are unresectable/locally advanced, and 50–60% are metastatic. Pancreatic cancer without distant metastasis can be divided into three categories: resectable, borderline resectable, and locally advanced. In absence of metastatic disease, the most important factor for improving survival and possibly offer cure is to achieve a margin-negative resection. Even after potential curative resection, most patients develop recurrences eventually, and 5-year survival of completely resected patients is only up to 25%. The aggressive tumor biology and its inherent resistance to chemotherapy and radiotherapy contributes to early recurrence and metastasis.
Pancreatic cancer surgery has evolved over the past few decades and remains the cornerstone of treatment of resectable and borderline resectable tumors. Advances in modern imaging give precise information on disease extension and vascular involvement that aids in surgical planning in order to achieve a margin-negative resection.
Surgical techniques for pancreatic cancer include pancreaticoduodenectomy, distal pancreatectomy with splenectomy, and total pancreatectomy. Standard lymphadenectomy for pancreatoduodenectomy should include removal of lymph node stations 5, 6, 8a, 12b1, 12b2, 12c, 13a, 13b, 14a, 14b, 17a, and 17b. Involvement of superior mesenteric vein (SMV)/portal vein(PV) was previously considered as a contraindication for resection. However, curative resection along with SMV/PV with vascular reconstruction has now become a standard practice in specialized high-volume centers. To improve margin-negative resections, specially in borderline resectable tumors with proximity to vascular structures, SMA first approach was proposed as a new modification of standard pancreatico-duodenectomy. In a systematic review, SMA first approach was shown to be associated with better perioperative outcomes, such as blood loss, transfusion requirements, pancreatic fistula, delayed gastric emptying, and reduced local and metastatic recurrence rates. In case of arterial involvement, there is no good evidence at present to justify arterial resections for right-sided pancreatic tumors. However, the modified Appleby procedure, which includes en bloc removal of celiac axis with or without arterial reconstruction, when used in appropriately selected patients, offers margin negative resection with survival benefit for locally advanced pancreatic body and tail tumors and should be performed in high-volume centers. Most evidence does not support advantage of more extended resections such as removal of the para-aortic lymph nodes and nerve plexus and multivisceral resections routinely. Such extended resections are associated with compromised quality of life because of associated higher perioperative morbidity and intractable diarrhea. However, in highly selected patients, with preserved performance status and stable or nonprogressive disease on neoadjuvant treatment, such extended resections can provide survival advantage over palliative treatments. Radical surgery in the presence of oligometastatic disease has also been reported to prolong survival in highly selected patients.
Neuroendocrine tumours (NETs) are neoplasia that can exhibit a range of features such as the production of neuropeptides, the presence of large dense-core secretory vesicles, and the lack of neural structures. NETs can be found in many body regions including the head, neck, lungs, and abdomen. Gastroenteropancreatic (GEP) NETs can be functioning or nonfunctioning, depending on whether hormones are secreted. While the majority of NETs are sporadic, a smaller portion can be related to genetic syndromes such as multiple endocrine neoplasia (MEN), von Hippel-Lindau (VHL), and neurofibromatosis (NF). Compared with their epithelial counterparts, NETs have usually better outcomes. Surgical resections, ranging from enucleation to standard pancreatectomy and lymphadenectomy, play a key role in the management of these lesions, even in advanced disease. Long-term outcomes are correlated with the grading of the disease. Among GEP-NETs, small intestinal NETs (Si-NETs) have a higher incidence than pancreatic neuroendocrine tumours (PanNETs).
Along with incidental diagnosis, tumour size and tumour grading are the most powerful predictors of long-term survival and recurrence. Based on this data, the ENETS guidelines suggested active surveillance rather than surgery for patients with incidental NF-PanNETs that are <2 cm. A recent systematic review demonstrated that surveillance of asymptomatic small NF-PanNETs is safe at least in selected patients although the quality of available studies is still too low to draw firm conclusions. Regardless the size of the primary tumour and the absence of symptoms, a G2 or G3 PanNET/Cs should be treated with resection. Surgery still remains the gold standard in patients with NF-PanNET >2 cm.
The type of resection depends on the location of the lesion. In the presence of head lesions, Whipple’s procedure is the treatment of choice, while distal pancreatectomy and splenectomy is recommended in body-tail lesions. Regardless the type of surgery, a standard lymphadenectomy should be performed. The role of lymphadenectomy during surgical resection for PanNETs is still unclear; however, several authors have shown that the presence of lymph node metastases is associated with poor prognosis; therefore, lymphadenectomy is very helpful in the staging of the disease, but there is no evidence to support an extended lymphadenectomy. The risk of lymph node metastases increases with the increasing size of the primary lesion. Therefore, a standard lymphadenectomy which consists of peripancreatic lymph node dissection along major pancreatic vessels, should always be performed. Recent evidence on the role of conservative management of small PanNETs and the risk of node involvement in PanNETs >2 cm have now significantly limited the role of PSP in NF-PanNETs. These procedures that include enucleation and MP are now limited to patients with small, asymptomatic PanNETs in whom a conservative approach is contraindicated because of young age or for patient’s willingness. Despite a clear benefit in terms of long-term risk of developing pancreatic insufficiency, PSP has a similar morbidity and mortality to standard pancreatic resections.
For non-functioning pancreatic tumors, a surgical procedure is usually recommended. Exception occurs in patients with MEN-1 and who have tumors <2 cm, when the operation is not consensually recommended. For some authors and societies, observation and follow-up should be performed when the tumor is <1 cm, asymptomatic and incidental. The decision for surgical treatment should be made based on the estimated surgical risk, tumor location and comorbidities. The surgical choice may vary between enucleation, distal pancreatectomy and duodenopancreatectomy always associated with regional nodal resection due to the real chances of lymph node metastasis, even in tumors with a size between 1-2 cm. For patients with tumors >2 cm, the choice is tumor cell excision. The location is indicative for the choice of technique, which may range from duodenopancreatectomy to the distal pancreatectomy associated with splenectomy. Both should be accompanied by lymph node resection due to the risk of metastases. Complete resection R0 should always be the primary endpoint. Regardless of tumor size, there is no evidence to support adjuvant systemic therapy for pNET and optimal follow-up of patients undergoing surgical treatment remains unknown.
IPMNs were first recognized in 1982 by Ohashi, but the term IPMN was not officially used until 1993. IPMNs are defined in the WHO Classification of Tumors of the Digestive System as an intraductal, grossly visible epithelial neoplasm of mucin-producing cells. Using imaging and histology, IPMNs can be classified into three types based on duct involvement:
1. Main-duct IPMN (approximately 25% of IPMNs): Segmental or diffuse dilation of the main pancreatic duct (>5 mm) in the absence of other causes of ductal obstruction.
2. Branch-duct IPMN (approximately 57% of IPMNs): Pancreatic cysts (>5 mm) that communicate with the main pancreatic duct.
3. Mixed type IPMN (approximately 18% of IPMNs): Meets criteria for both main and branch duct.
Due to the asymptomatic nature of the disease, the overall incidence of IPMNs is difficult to define but is thought to account for approximately 3% to 5% of all pancreatic tumors. Most IPMNs are discovered as incidental lesions from the workup of an unrelated process by imaging or endoscopy. IPMNs are slightly more prevalent in males than in females, with a peak incidence of 60 to 70 years of age. Branch-duct IPMNs tend to occur in a slightly younger population and are less associated with malignancy compared with main-duct or mixed variants.
Because a majority of IPMNs are discovered incidentally, most are asymptomatic. When symptoms do occur, they tend to be nonspecific and include unexplained weight loss, anorexia, abdominal pain, and back pain. Jaundice can occur with mucin obstructing the ampulla or with an underlying invasive carcinoma. The obstruction of the pancreatic duct can also lead to pancreatitis. IPMNs may represent genomic instability of the entire pancreas. This concept, known as a “field defect,” has been described as a theoretical risk of developing a recurrent IPMN or pancreatic adenocarcinoma at a site remote from the original IPMN. The three different types of IPMNs, main duct, branch duct, and mixed duct, dictate different treatment algorithms.
MAIN DUCT IPMNs
Main-duct IPMNs should be resected in all patients unless the risks of existing comorbidities outweigh the benefits of resection. The goal of operative management of IPMNs is to remove all adenomatous or potentially malignant epithelium to minimize recurrence in the pancreas remnant. There are two theories on the pathophysiologic basis of IPMNs. The first groups IPMNs into a similar category as an adenocarcinoma, a localized process involving only a particular segment of the pancreas. The thought is that removal of the IPMN is the only treatment necessary. In contrast, some believe IPMNs to represent a field defect of the pancreas. All of the ductal epithelium remains at risk of malignant degeneration despite removal of the cyst. Ideally, a total pancreatectomy would eliminate all risk, but this is a radical procedure that is associated with metabolic derangements and exocrine insufficiency. Total pancreatectomy should be limited to the most fit patients, with a thorough preoperative assessment and proper risk stratification prior to undertaking this surgery.
There is less uncertainty with treatment of main-duct IPMNs. The high incidence of underlying malignancy associated with the IPMNs warrants surgical resection. IPMNs localized to the body and tail (approximately 33%) can undergo a distal pancreatectomy with splenectomy. At the time of surgery, a frozen section of the proximal margin should be interpreted by a pathologist to rule out high-grade dysplasia. A prospective study identified a concordance rate of 94% between frozen section and final pathologic examination. If the margin is positive (high-grade dysplasia, invasion) additional margins may be resected from the pancreas until no evidence of disease is present. However, most surgeons will proceed to a total pancreatectomy after two subsequent margins demonstrate malignant changes. This more extensive procedure should be discussed with the patient prior to surgery, and the patient should be properly consented regarding the risks of a total pancreatectomy.
IPMNs localized to the head or uncinate process of the pancreas should undergo a pancreaticoduodenectomy. A frozen section of the distal margin should be analyzed by pathology for evidence of disease. As mentioned before, after two additional margins reveal malignant changes, a total pancreatectomy is usually indicated (approximately 5%). The absence of abnormal changes in frozen sections does not equate to negative disease throughout the pancreas remnant. Rather, skip lesions involving the remainder of the pancreas can exist and thus patients ultimately still require imaging surveillance after successful resection. A prophylactic total pancreatectomy is rarely performed because the subsequent pancreatic endocrine (diabetes mellitus) and exocrine deficits (malnutrition) carry an increased morbidity.
BRANCH DUCT IPMNs
Localized branch-duct IPMN can be treated with a formal anatomic pancreatectomy, pancreaticoduodenectomy, or distal pancreatectomy, depending on the location of the lesion. However, guidelines were established that allow for nonoperative management with certain branch- type IPMN characteristics.
These include asymptomatic patients with a cyst size less than 3 cm and lack of mural nodules. The data to support this demonstrate a very low incidence of malignancy (approximately 2%) in this patient group. Which nearly matches the anticipated mortality of undergoing a formal anatomic resection. In approximately 20% to 30% of patients with branch- duct IPMNs, there is evidence of multifocality. The additional IPMNs can be visualized on high-resolution CT or MRI imaging. Ideally, patients with multifocal branch-duct IPMNs should undergo a total pancreatectomy. However, as previously mentioned, the increased morbidity and lifestyle alterations associated with a total pancreatectomy allows for a more conservative approach. This would include removing the most suspicious or dominant of the lesions in an anatomic resection and follow-up imaging surveillance of the remaining pancreas remnant. If subsequent imaging demonstrates malignant charac- teristics, a completion pancreatectomy is usually indicated.
Recurrence rates with IPMNs are variable. An anatomic resection of a branch-duct IPMN with negative margins has been shown to be curative. The recurrence of a main- duct IPMN in the remnant gland is anywhere from 0% to 10% if the margins are negative and there is no evidence of invasion. Most case series cite a 5-year survival rate of at least 70% after resection of noninvasive IPMNs. In contrast, evidence of invasive disease, despite negative margins, decreases 5-year survival to 30% to 50%. The recurrence rate in either the pancreatic remnant or distant sites approaches 50% to 90% in these patients. Histopathologic subtype of the IPMN is correlated with survival. The aggressive tubular subtype has a 5-year survival ranging from 37% to 55% following surgical resection, whereas the colloid subtype has 5-year survival ranging from 61% to 87% post resection. Factors associated with decreased survival include tubular subtype, lymph node metastases, vascular invasion, and positive margins. IPMNs with evidence of invasion should be treated similar to pancreatic adenocarcinomas. Studies show that IPMNs tend to have better survival than pancreatic adenocarcinoma. This survival benefit may be secondary to the less aggressive tumor biology or the earlier diagnosis of IPMNs.
All patients who have a resected IPMN should undergo imaging surveillance. There is continual survival benefit with further resection if an IPMN does recur. International Consensus Guidelines published in 2017 offer recom- mendations for the frequency and modality of imaging surveillance after resection. Routine serum measurement of CEA and CA 19-9 has a limited role for detection of an IPMN recurrence. Of note, a new pancreatic lesion discovered on imaging after resection could represent a postoperative pseudocyst, a recurrence of the IPMN from inadequate resection, a new IPMN, or an unrelated new neoplastic process. IPMNs may also be associated with extrapancreatic neoplasms (stomach, colon, rectum, lung, breast) and pancreatic ductal adenocarcinoma. It is unclear if this represents a true genetic syndrome. However, patients with IPMNs should have a discussion about the implications of their disease with their physician and are encouraged to undergo colonoscopy to exclude a synchronous neoplastic process.
The incidence of PANCREATIC CYSTIC LESIONS will continue to increase as imaging technology improves. EUS, cytology, and molecular panels have made differentiating the type of PCN less problematic. The importance of an accurate preoperative diagnosis ensures that operative management is selectively offered to those with high-risk lesions. Management beyond surgery, including adjuvant therapy and surveillance, continue to be active areas of research.
Minimally invasive surgery, a widely adopted tool for most domains of gastrointestinal surgery, has been relatively slow to evolve in the field of pancreatic surgery. The reasons include proximity to the great vessels, retroperitoneal location, need for advanced intracorporeal suturing skills and increased risk of complications associated with these procedures. With enormous development in surgical technology coupled with improved anatomical knowledge and refined skills, minimally invasive pancreatic surgery has grown out of its infancy and is an established specialty in hepato-pancreato-biliary surgery today. As a result, the initial scepticism and reluctance associated with minimally invasive pancreatic resections has decreased and many surgeons are attempting to enter this difficult terrain. Recent publications highlight potential advantages of minimally invasive pancreatic resection (MIPR) over open pancreatic resection (OPR). These include reduced pain, decreased blood loss and need for transfusion, an earlier return of bowel function, decreased wound infection rates and shorter intensive care unit and overall hospital stays. Though the number of minimally invasive pancreatic resections performed for benign and malignant diseases of the pancreas has increased in recent years, cost considerations and financial implications of these new approaches need to be well defined. Clear guidelines and standardization of surgical technique are paramount for the safe and steady expansion of this novel surgical approach.
Minimally Invasive Pancreaticoduodenectomy
Gagner and Pomp reported the first LPD in 1994. They felt that laparoscopy was not useful for such a major resection and reconstruction. However, their initial patients included those with chronic pancreatitis, where LPD is considered difficult to do even at present. With this background, we began doing LPD after sufficient experience had been gained in other major laparoscopic procedures such as colectomy, gastrectomy and choledochal cyst excision. During the initial phase, LPD was attempted in only periampullary tumours or small pancreatic head masses. With increasing experience, the indications for LPD were expanded to include carcinoma head of the pancreas and larger tumours.
Over the years, numerous technical modifications in terms of surgeon comfort, use of energy source, radicality of surgery, type of reconstruction and specimen extraction were made. These refinements resulted in better outcomes as was evident in the next publication in 2009 which included 75 patients. Oncologically, the resection status and lymph nodal yield were comparable with the open approach and would translate to equal survival outcomes. Recently, Asbun et al. compared their open PDs and LPDs and found that LPD had better perioperative outcomes in terms of blood loss and ICU and hospital stays.
In 2015, Palanivelu reported that the pathological radicality of LPD was comparable to that of the open approach when performed by experienced minimal access surgeons. And analysed yours long-term outcomes following LPD in 130 patients with pancreatic and periampullary cancers. This study, one of the largest published series so far, showed excellent short-term results and acceptable long-term survival. The pancreatic fistula rate was 8.5%, mean (SD) operating time was 310 (34) min, and mean blood loss was 110 (22) ml with a mean hospital stay of 8 (2.6) days. The resected margins were positive in 9.2% with an overall 5-year actuarial survival of 29.4% and a median survival of 33 months.
Published outcomes of LPD have shown that it is feasible and safe when done in high-volume institutions by expert surgeons. In a recent systematic review of LPD, Boggi et al. identified 25 articles with 746 patients who had LPD for both malignant and benign indications. The mean operative time and estimated blood loss were 464 min and 321 ml, respectively. Conversion to open surgery was required in 9% of patients. The average hospital stay was 14 days. The overall morbidity, mortality and pancreatic fistula rates were 41.2, 1.9 and 22.3%, respectively. The majority of surgeons did a pancreaticojejunostomy (84%), whereas a small number did pancre- aticogastrostomy (9.8%) or duct occlusion (6.8%). A slight majority did pylorus preservation (55%) instead of hemigastrectomy (45%). No major differences in outcomes were seen for laparoscopic, robotic, laparoscopic-assisted or hand-assisted methods.
Similarly, no significant differences were seen between high-volume (>30 cases) and low-volume centres other than longer operative times and higher estimated blood loss in the low-volume ones. The average number of lymph nodes recovered was 14.4 and the negative margin rate was 95.6%. Although the data were heterogeneous with a high likelihood for selection bias, the results for LPD appear to be at least comparable to those in patients undergoing open PD.
In general, LPD was associated with reduced blood loss and hospital stay; however, operative times tend to be longer. The longer operative times associated with LPD tend to reduce with increasing experience. In a series by Kim et al., the median operative time for LPD was 7.9 h and decreased with accumulating experience of the surgeon doing this procedure from 9.8 h for the first 33 cases to 6.6 h for the last 34 cases.