Drs. Gajdos, McCarter, Edil, Paniccia, and Schulick provide an extremely comprehensive chapter on the evaluation and treatment of patients with cancer of the periampullary region and especially the pancreatic head (Chapter 73). ­Importantly, there has been a tremendous advance in both the understanding of the molecular biology of pancreatic cancer as well as our ability to accurately image the pancreas and periampullary region prior to surgery. Advances in computed tomography (CT) and magnetic resonance imaging (MRI) have allowed for accurate assessment of critically important tumor-vessel relationships. Such accurate assessment of the relevant anatomy is important for both pretreatment staging and for planning the operation, especially if vascular resection and reconstruction may be indicated. The ability to preoperatively classify patients as having resectable, borderline resectable, or locally advanced pancreatic cancer (LAPC) allows for optimal treatment sequencing (often including neoadjuvant therapy), the evaluation of patients for investigator-­initiated and cooperative group clinical trials, and the referral of patients to higher volume centers.¹ Indeed, to the extent that outcome is improved for patients with localized disease at high-volume centers (by high-volume surgeons), patients will need to be accurately staged (CT imaging) and, when necessary, have biliary stents placed safely in order to facilitate referral to a specialty center. The ability to perform endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) biopsy will prevent diagnostic uncertainty and allow for medical oncology consultation and multidisciplinary care.

Fortunately, the past decade has witnessed the development of consensus for the CT staging of pancreatic cancer. In an attempt to clarify the anatomy of resectable, borderline resectable, and locally advanced disease, Varadhachary and colleagues from The University of Texas M.D. Anderson Cancer Center proposed an objectively defined, CT-based classification that distinguishes borderline resectable pancreatic cancer from both resectable pancreatic cancer and LAPC.² This definition was developed for the conduct of clinical trials of neoadjuvant treatment sequencing and was not intended to support a surgery-first strategy for patients who may require vascular resection and reconstruction. The Varadhachary definitions also assumed the technical capability to resect and reconstruct the superior mesenteric–­portal vein (SMPV) confluence (when necessary) and that the major determinants of margin status (R status) were the tumor-artery (celiac, hepatic, and superior mesenteric ­artery) relationships. In contrast to the management of resectable and borderline resectable pancreatic cancer, surgery has typically not been applied to patients with locally advanced or metastatic disease. Patients with LAPC were considered to have inoperable tumors; surgery was felt not to be technically possible. With recent improvements in response rates for systemic therapy, an increasing number of patients with LAPC are found to have stable or responding disease after a prolonged course of systemic therapy (4-6 months or more) with or without having received radiation therapy. Such patients have only 1 site of measurable disease—the primary tumor—and therefore are often sent for surgical consultation to consider removal of the only remaining abnormality seen on cross-sectional imaging. The patient is often confused: Surgery was initially thought not to be possible, and now there is a difference of opinion? In an effort to add clarity to the goals of treatment for patients with LAPC, we recently described a system for categorizing locally advanced disease based on the tumor-vessel anatomy^3,4; in LAPC type A, surgery may be considered after systemic therapy and chemoradiation, and in LAPC type B, surgery will likely never be possible (Table 75-1).

For surgeons who recommend a surgery-first strategy to patients with localized, potentially resectable pancreatic cancer, the CT definition of what should be considered ­“resectable,” and for which immediate surgery may be considered, is becoming more limited, which is a logical response to the clinical observation that almost all patients with apparent operable pancreatic cancer have radiographically occult micrometastatic disease. In general, there is an increasing trend for the management of localized pancreatic cancer with systemic therapy first.^5-7 Most clinical trials incorporate a period of induction systemic therapy, especially in those with arterial abutment, to include 2 to 4 months of chemotherapy, which may be followed by chemoradiation. Emerging clinical ­trials, as well as off-protocol therapy, include (as a backbone of therapy) what has been proven successful in metastatic ­disease, such as gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) and FOLFIRINOX (­fluorouracil, leucovorin, irinotecan, and oxaliplatin).⁸ Our management of localized, operable pancreatic cancer is evolving toward a total neoadjuvant approach (4-6 months) with surgery considered after all intended systemic therapy and chemoradiation. Restaging is performed after each 2 months of therapy; if there is significant treatment response (eg, clinical, radiographic, biochemical [cancer antigen 19-9]), then additional chemotherapy is prescribed with careful follow-up every 2 months. In the setting of stable or, hopefully, responding disease after 4 months of chemotherapy, a transition to chemoradiation is usually recommended. Importantly, our treatment algorithm incorporates a stepwise evolution of treatment that starts with accurate staging and proceeds to an extended course of chemotherapy, followed by chemoradiation and, finally, surgical resection. In the absence of disease response, the chemotherapy regimen can be changed (eg, FOLFIRINOX to gemcitabine plus nab-paclitaxel or vice versa). The length of induction systemic therapy, the timing and dose of radiation therapy, and the use of a variety of biomarkers to assess the presence or absence of response are areas of active investigation. Although chemotherapy and chemoradiation do not increase the risk for pancreatic leak or other known surgery-associated complications, it is likely that some patients of advanced age cannot tolerate multiple treatments in series and thus may not be suitable surgical candidates at the time of posttreatment/preoperative restaging; such patients likely receive a greater oncologic benefit from induction therapy than they would from a surgery-first/surgery-only approach.

Probably the most important technical aspect of pancreaticoduodenectomy is the dissection of the superior mesenteric artery (SMA). In general, exposure of the SMA is facilitated by complete mobilization of the SMPV confluence to the patient’s left. This allows for careful separation of the uncinate process from the jejunal branch of the superior mesenteric vein and, ultimately, exposure of the SMA. Our current understanding of the pathophysiology of local recurrence after pancreaticoduodenectomy (with or without multimodality therapy) is microscopic infiltration of the autonomic neural sheath that surrounds the SMA (and celiac/hepatic arteries). Adenocarcinoma of the pancreas has a predisposition to spread along neural tissue, and this is likely responsible for the high frequency of local recurrence. As our systemic therapies become more effective, local recurrence may become a more dominant pattern of failure.

The chapter by Drs. Pucci and Yeo (Chapter 75) is equally comprehensive in their superb discussion of cystic neoplasms of the pancreas. They focus predominantly on serous cystadenoma, mucinous cystic neoplasm (MCN), and intraductal papillary mucinous neoplasm (IPMN). With regard to serous cystadenoma, this histology demonstrates fascinating tumor biology. As mentioned by the authors, it is generally felt that serous cystadenomas do not have the biologic ability to metastasize to distant organs or regional lymph nodes. However, they can be locally invasive and erode into adjacent bowel (duodenum, transverse colon, stomach) and occasionally can obstruct the splenic vein (resulting in sinistral portal hypertension) or the superior mesenteric and/or portal veins (resulting in extrahepatic portal hypertension). Importantly, the diagnosis of (microcystic) serous cystadenoma can usually be made on high-quality CT imaging with or without the additional benefit of EUS due to its characteristic imaging appearance (unless the serous cystadenoma is macrocystic). When referring a patient for EUS to confirm a diagnosis of serous cystadenoma (the EUS appearance is often diagnostic), we would recommend an FNA biopsy if the EUS is not consistent with this diagnosis or there appears to be discrepancy between CT or MRI imaging and the EUS appearance. A biopsy is often needed only when the imaging findings are not all congruent and inconsistent with a diagnosis of serous cystadenoma. Serous cystadenomas are characterized by a cyst fluid carcinoembryonic antigen (CEA) level that is usually undetectable or very low (<5 ng/mL). At present, the diagnosis of a serous cystadenoma is usually not difficult; however, knowing when to intervene with surgery is often challenging. As patients age and operative risk (medical comorbidities) increase, the benefit of surgery in an otherwise asymptomatic patient may be low. For example, it is relatively easy to understand a recommendation for surgery in an otherwise completely healthy 60-year-old patient with a serous cystadenoma of 6 cm or greater.⁹ However, the same pancreatic tumor in a ­75-year-old patient with 1 or 2 coronary stents and a relatively sedentary lifestyle is not the correct approach. In our practice, we try to carefully weigh risk versus benefit in asymptomatic patients. In addition, for serous cystadenomas that are less than 4 to 5 cm in size, we usually require that they demonstrate growth, over a period of observation, prior to proceeding with surgery; there simply is no down side to this approach. Our underlying philosophy is to completely avoid surgery-related mortality and major morbidity in patients who are asymptomatic with a tumor histology (such as serous cystadenoma) that poses no risk for distant metastases.