Risk Factors

As PC is relatively uncommon yet incredibly aggressive, numerous risk factors have been identified that aid in preventative measures (Table 81-1). Cigarette smoking is one of the most clearly proven and most preventable risk factors. The risk increases with longer duration and higher number of cigarettes smoked, but can return to normal after 10 years of cessation.^33,34 Cigarette smoke includes more than 50 carcinogens, the most important being nitrosamines, which promote tumor growth via various pathways, including activating the KRAS oncogene, and cause inflammation in the pancreas.^35–35 It is believed to cause 15% to 25% of PC, with a relative risk of 1.5- to threefold in smokers as compared to nonsmokers.^2,33–37 Chronic pancreatitis, often the result of chronic and heavy alcohol consumption or biliary duct blockages, leads to an increased risk of two- to 16-fold, although less than 5% of patients with chronic pancreatitis will develop PC. The chronic inflammation is thought to activate macrophages that produce cytokines that induce cell proliferation, angiogenesis, and inhibit apoptosis.^{34–36,38–42} Chronic pancreatitis may also be a manifesting symptom of PC from biliary obstruction caused by the tumor. Consequently, PC should be in the differential for a person who develops pancreatitis without any known risk factor.^32,42,43 Patients with hereditary pancreatitis, caused by a mutation in PRSS1 in the autosomal dominant form leading to premature activation of trypsin while still in the pancreas as opposed to in the duodenum, or by a mutation in SPINK1 or CFTR in the autosomal-recessive form, have a 40- to 85-fold increased risk and a cumulative risk of 30% to 55% of developing PC in their lifetime.^35,36,44,45 Alcohol is clearly a causative factor for cancers of the upper aerodigestive tract; however, it appears that only heavy alcohol use, defined as 3 or more alcoholic drinks per day, has a slightly increased relative risk of 1.2, whereas mild or moderate intake poses no increased risk.^33,35–37 Obesity, defined as body mass index equal to or greater than 30 and accounting for 33% of adults in the United States, may lead to an increased risk of 1.2- to 1.7-fold and possibly higher in the severely obese.^35,36,46 This link may result from increased circulating insulin and insulin growth factors, lower amounts of antiinflammatory cytokines, and a chronic low-grade inflammatory state throughout the bodies of obese people.⁴⁶

The relationship between diabetes mellitus and PC is difficult to ascertain as type 2 diabetes can be both an early sign of PC and a risk factor. PC is thought to lead to diabetes through destruction of glands causing decreased production of insulin; however, the presence of diabetes does not appear to correlate with the size or stage of the tumor as this theory would suggest,⁴⁷ so other mechanisms must be at play. Long-term diabetes is thought to increase the risk for PC because the increased secretion of insulin and insulin-like growth factors promote cell growth and the heightened state of inflammation leads to proinflammatory cytokines that contribute to angiogenesis and tumorigenesis.⁴⁸ Studies have demonstrated that 55% to 85% of PC patients were diagnosed with glucose intolerance or diabetes either concurrently or within the 2 years preceding their cancer diagnosis.^35,47,48 But, given the very high incidence of diabetes in the population, the relative risk of developing PC is still only 1.3- to 2.6-fold normal, when considered independently of obesity,^35,37,47,48 and does not imply that all newly diagnosed diabetic patients warrant screening. However it should be considered in the atypical patient with newly diagnosed diabetes who has a steady or decreased weight, no change in activity and no family history of diabetes.³⁶ Diets high in animal protein, history of gallstones, Helicobacter pylori infection, and some occupational exposures may lead to an increased risk.^{2,41,43,49,50} Allergies such as hay fever, increased vitamin D intake, blood type O, and diets high in fruits, vegetables, and citrus fruits may have a protective effect.^{2,35,36,44,51–54}

Although the majority of PC are sporadic, 5% to 10% of patients have a family history.2,34,44 Familial PCc are defined as two or more first-degree relatives with the disease.³⁵ Having one first-degree relative with PC gives a person a threefold increased risk, two first-degree relatives has a 4- to 6.4-fold increase risk, and three or more first-degree relatives poses a 14- to 32-fold increased risk.^34,44,45 Although some patients with familial pancreatic cancer do not have identifiable genes, many syndromes have been described. Carriers of the BRCA2 gene (associated with breast, ovarian, and pancreatic cancers) have a 3.5- to 10-fold increased risk and account for 5% to 17% of families with familial PC. Mutations in PALB2 (binds to BRCA2) carry a sixfold increased risk,^2,44 whereas BRCA1 carriers may have a twofold increased risk.^{2,35,36,44,55,56} Germline mutations in STK11 cause the autosomal dominant Peutz-Jeghers syndrome, characterized by hamartomatous polyps, pigmented macules, and a more than 90% chance of developing some form of cancer including a 132-fold increased risk for PC.^{2,35,36,44,50} Familial atypical mole-multiple melanoma patients typically have a mutation in CDKN2A and carry a 13- to 47-fold increased risk of PC.^{2,35,36,44,45} Germline mutations in DNA mismatch repair genes causing Lynch syndrome carry a two- to eightfold increased risk.^35,36,44,57 Cystic fibrosis, characterized by a mutation in CFTR that produces viscous mucus that obstructs pancreatic ducts, carries an increased risk of 5.3-fold,^35,44 whereas familial adenomatous polyposis (germline mutation in APC gene) has a four fold increased risk.^44,45 Mutations in the tumor suppressor gene TP53 causing Li-Fraumeni syndrome results in a doubling of the risk.⁴⁴

Precursor Lesions

Approximately 85% of PC develops from the ductal epithelial, termed pancreatic ductal adenocarcinoma (PDAC). PDACs are thought to arise from precursor lesions: pancreatic intraepithelial neoplasms (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms (MCNs). PanINs, the most common precursor lesions, are defined as “microscopic papillary or flat noninvasive epithelial neoplasms [of <5 mm diameter, not visible by imaging] arising from the pancreatic ducts…characterized by mucin-containing cuboidal to columnar cells [with varying degrees of nuclear and architectural atypia].”45,62 PanINs, are classified from low-grade atypical lesions (PanIN-1A or -1B) to high-grade atypical lesions (PanIN-2 or -3) as molecular alterations accumulate and more dysplasia appears (Figs. 81-1 and 81-2).^{2,35,54,58,63,69,70,356} One reason for their identification as precursor lesions is the presence of similar mutations as compared with invasive carcinoma. Activating mutations of the KRAS oncogene are one of the earliest abnormalities in the development of PC, as they appear in 30% to 45% of PanIN-1 lesions and more than 90% of PanIN-3 lesions. BRAF mutations are also found in the early precursor lesions in the 5% of patients that are KRAS wild-type. Telomere shortening also occurs early and is present in 90% of PanIN-1 lesions and leads to chromosomal instability making further mutations more likely. Inactivating mutations of CDKN2A begin to occur in PanIN-2 lesions and inactivation of TP53, BRCA2, and SMAD4 are seen in PanIN-3 lesions.^{2,45,54,58–61,70} Low-grade PanIN lesions are common in older individuals; however, higher grade PanINs are typically seen in association with invasive cancer, especially in those with familial PC.^2,71,72 Although all precursor lesions have a risk of progressing to invasive carcinoma, the risk is very low for PanIN-1 lesions and very high for PanIN-3 lesions, as patients with PanIN-3 lesions at the margins of a resection virtually all recur with invasive carcinoma. Consequently, it is recommended that all margins should be clear of PanIN-3, even if this requires re-resection.^62,70

IPMNs and MCNs are two types of noninflammatory cysts in the pancreas that are diagnosed secondary to symptoms or from incidental findings on imaging. Cysts are found incidentally on 1.2% to 2.6% of the over 50 million computed tomography (CT) scans done annually in the United States. Given their malignant potential, recommendations have been developed for their management.⁷³ IPMNs are grossly visible, mucin-producing, epithelial neoplasms, typically with papillary architecture, that arise from either the main pancreatic duct or branch ducts and are graded according to degree of dysplasia. They range from 5 mm to 150 mm, are more commonly located in the pancreatic head, and can manifest with abdominal or back pain, weight loss, or anorexia from ductal obstruction from the mucin or the tumor itself. The average age at onset is 65 years and they have a 2 : 1 male-to-female predominance. Endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) can visualize the degree of dilation of the main pancreatic duct to help determine the place of origin. They are less frequent precursors to PC than PanINs, but they do share some of the same molecular aberrations. KRAS mutations are seen in 50% of low-grade IPMNs, whereas inactivating mutations of CDKN2A and TP53 are seen in high-grade lesions. Loss of SMAD4 is only rarely seen in even high-grade lesions, while mutations of GNAS are commonly seen. IPMNs arising from the branch ducts are less aggressive than those arising from the main duct with rates of malignancy and invasive malignancy (either mucinous noncystic carcinoma/colloid carcinoma or PDAC) of 25% and 15% for branch duct origin and 70% and 43% for main duct origin. Patients with main duct IPMNs should undergo resection. Their 5-year survival rate is 77% to 96% for the noninvasive neoplasms and 40% to 70% in the invasive lesions. Symptomatic patients with branch duct IPMNs have a higher risk of malignancy and should undergo resection. Asymptomatic branch duct IPMNs can be monitored with imaging (every 3 to 12 months depending on size) as they have a 0% to 5% chance of malignancy, especially if there is no main duct dilation, no mural nodules and the neoplasm is smaller than 30 mm. They should be removed if they become symptomatic or increase in size. Patients should be followed even after resection as well, yearly for benign IPMNs and twice yearly for invasive IPMNs, to catch any recurrence.^{2,45,70,74,75}

MCNs also produce mucin; however, they are characterized by ovarian-type stroma. They are found almost exclusively in women, typically in the fourth and fifth decades, and 95% are in the pancreatic body and tail. They tend to be slow growing, but the average size is 5 to 12.5 cm. They have an orangelike gross appearance and only rarely communicate with the pancreatic duct. All MCNs should be resected with a distal pancreatectomy and proper lymph node dissection as they may progress to mucinous cystadenocarcinomas which have a very poor prognosis. Patients with benign MCNs do not need to be followed after resection because they do not recur; however, patients with malignant MCNs (6% to 36%) should be followed by imaging every 6 months.2,45,70,74,75

Pathways of Spread

Invasive PC can spread through local invasion or through perineural, lymphatic, or vascular invasion, producing sites of distant metastasis. Given its location in the retroperitoneum, the most common sites of direct local invasion are to the stomach, duodenum, liver, common bile duct, gallbladder, spleen, superior mesenteric vein (SMV), superior mesenteric artery (SMA), and other surrounding arteries, veins, and lymph nodes. Perineural invasion is defined as the presence of cancer cells along nerves and/or within the neuronal sheath. Neurotrophins that are secreted by both the cancer cells and the nerve cells help support the survival and growth of these cells and promote neurogenesis, whereas chemokines like CX3CR1 appear to increase the cancer cells’ migration toward the nerve.99,100 The head of the pancreas is innervated by the superior mesenteric ganglion, the celiac plexus, and it branches which are the main routes for perineural invasion by the cancer cells. The main route of spread for cancers of the body and tail is through the celiac plexus and the splenic plexus. Intrapancreatic and/or extrapancreatic neural invasion is seen in virtually all advanced stage tumors, and even in more than 70% to 75% of stage I tumors, implying that this is an early event in the tumor’s progression. Given that some studies have reported worse prognosis for patients with perineural invasion, pathologists are now recommended to report the tumor’s perineural invasion status.^99–105 In a retrospective analysis of 193 patients with resected PDACs, those without nodal metastases or perineural invasion had a 5-year survival of 75% as compared with 29% of those with perineural invasion. In patients with nodal metastases, 5-year survival was 17% when there was no perineural invasion and only 10% when there was invasion.¹⁰³ Perineural invasion is one reason that many PC patients experience difficult to control abdominal and back pain.¹⁰⁰

Vascular invasion is critical for both resectability and prognosis. The head and neck of the pancreas are supplied from superior pancreaticoduodenal arteries arising from the celiac trunk, and the inferior pancreaticoduodenal arteries arising from the SMA. These areas drain into the SMV, inferior vena cava, portal vein, and inferior mesenteric vein. The body and tail are supplied by the splenic artery arising from the celiac trunk and from pancreatic branches off the SMA and mostly drain into the splenic vein. Given their proximity to the pancreas, the SMV and SMA are the most commonly involved artery and vein by the tumor. The celiac artery, splenic artery, portal vein, hepatic artery, and, more rarely, the inferior vena cava and aorta can also be involved.6,106,107 On pathological review of more than 1100 resections, 53% had evidence of vascular invasion.¹⁰⁸

Lymphatic invasion, and specifically nodal involvement, is the strongest predictor for survival. Lymphangiogenesis occurs during embryonic development and again during regeneration after a trauma and is thought to also occur during tumor growth. Tumor cells enter the lymphatic system by either migration through the interendothelial valves or by destroying the vessel walls. They will enter the smaller intralobular lymphatic vessels located within the pancreas and subsequently drain into the four main lymphatic branches of the pancreas: anterior, posterior, inferior, and superior pancreaticoduodenal lymphatic vessels. These then drain into regional lymph nodes that are typically located larger blood vessels: the celiac artery, common hepatic artery, SMA, and aorta for head/neck tumors and the splenic artery for body/tail tumors. At least 75% of all resections have positive lymph nodes.108–113

Tumor cells travel through the nerves, lymphatics, or vasculature to form distant metastases. The liver is the most common site of metastasis, possibly because tumor cells travel through the portal vein, followed by the peritoneal cavity. Lung metastases are the next most common, especially in long-term survivors.20,26,111,114–116 In a phase III trial for first-line metastatic PC, 88% of the patients had liver metastases, 24% had lung, 19% had peritoneal, and 14% had other sites.²⁶ In a second-line therapy trial, 70% had liver disease, 30% had peritoneal, and 17% had lung involvement.¹¹⁶ Brain^119–119 and skeletal metastases¹²⁰ are quite uncommon and there have only been case reports of metastases to the appendix,¹²¹ kidneys,¹²² skin,^123–126 prostate,¹²⁷ stomach,¹²⁸ heart,¹²⁹ thyroid,¹³⁰ and muscles.¹³¹

Diagnosis

When evaluating a patient for pancreatic cancer, it is recommended to involve a multidisciplinary team that includes medical oncology, surgical oncology, radiation oncology, pathology, and radiology.88,138 Figure 81-3 depicts a diagnostic algorithm. The goals of the imaging, labs, and biopsies are to help clarify the diagnosis, stage, resectability status, prognosis, and possible palliative options. As no patient should be denied a potentially curative surgery if the patient qualifies, the imaging of choice should emphasize specificity over sensitivity. Multiphase pancreatic protocol CT with IV contrast is typically the first study ordered (Fig. 81-4A-E). This should include a noncontrast phase as well as contrast-enhanced arterial (when tumor has poor enhancement as compared to pancreas parenchyma given its hypovascularity), pancreatic parenchymal, and portal venous phases, and include thin cuts of 3 mm or less to help detail the location of the tumor in relationship to the main vessels, find signs of mass effect or ductal obstruction, and detect small tumors and sites of metastasis.^{2,5,88,139–143} 3D reconstruction can add additional information for surgeons planning the operation.^88,142,144 CT has a 74% to 98% accuracy in detecting pancreatic cancer with sensitivities of 77% to 97% and specificities of 85% to 100%, with the lower numbers accounting for the smaller tumors that CT may miss because they have not caused any biliary or vasculature obstruction or impingement. Additionally, CTs have sensitivities of 55% to 97% and specificities of 91% to 100% for predicting vascular invasion, and sensitivities of 76% to 92% and specificities of 82% to 100% for predicting resectability. Typically, 10% to 30% of patients taken to surgery will have their surgery aborted or altered to a palliative only procedure because of more serious vascular involvement or metastatic disease that was not detected on CT scan.^{2,5,6,88,140–142,145–152} The technology has greatly improved and CTs have a higher accuracy now that the multiphase pancreatic protocols are being used. Chest CTs are also recommended to assess for pulmonary metastases prior to resection.² Multiphase pancreatic protocol MRI can be used when CT is contraindicated and may be able to detect smaller lesions and better differentiate between cancer and pancreatitis. However, it hasn’t been shown to be superior to multiphase CT. MRI can also detail the biliary and pancreatic ductal systems via magnetic resonance cholangiography. Its sensitivities and specificities for diagnosis are 84% to 98% and 82% to 88%, and for predicting resectability are 82% to 88% and 78%, respectively.^{2,88,139,142,143,150,153–155}

EUS is used in addition to either CT or MRI to obtain further information about nodal or vasculature involvement, to better identify suspected small lesions that were not seen on the prior imaging, and to help with staging (Fig. 81-4F). PDAC appears as a solid mass with irregular borders, is not homogeneous, and appears hypoechoic compared with the surrounding normal pancreatic parenchyma. Vascular invasion is determined when there is loss of the hyperechoic vessel wall and hypoechoic tumor interface, evidence of tumor within the vessel, irregularity of the vessel wall with tumor within 3 mm, inability to visualize a major vessel where collaterals are present, and vascular encasement. EUS may be superior to CT or MRI in differentiating cystic versus solid lesion, finding lesions smaller than 2 cm, noting pathological lymph nodes, and more accurately predicting the size of the tumor, but it is not very good at assessing SMA involvement. It does have the additional benefit of allowing a biopsy with fine-needle aspiration (FNA) or celiac plexus block to be performed at the same time. EUS has an accuracy of diagnosing PC of 86% to 96% with sensitivity of 85% to 100% and specificity of 98%.^{2,5,6,88,139,142,143,145,151,152,156–158} Although it is invasive, the complication rate is less than 2% and risk of major complications is 1 : 2500.¹⁵⁹ Therefore EUS can be used as an adjunct to CT or MRI. ERCP combines endoscopy and fluoroscopy to map out the biliary system and may be beneficial if there is a duct stricture with no obvious mass as it does allow for ductal brushings. It also enables the placement of a biliary stent to decompress an obstructed system for patients who are receiving chemotherapy or for surgical patients who have a delay before surgery or have cholangitis (Fig. 81-4G).^{2,88,139,142,160}

Positron emission tomography (PET)-CT may also be used in addition to pancreatic protocol CT or MRI to help clarify the presence of metastatic disease if this distinction would change management. With sensitivities of 85% to 100% and specificities of 67% to 99%, there can still be false negatives when tumors are smaller than 1 cm.2,5,6,88,142,161–163 Abdominal ultrasound, on the other hand, may be one of the first tests that is ordered to evaluate jaundice or abdominal pain and can demonstrate a hypoechoic mass or biliary dilatation, but it cannot firmly differentiate between PC, neuroendocrine tumor, and chronic pancreatitis. The addition of color Doppler does aid in detecting vascular invasion, but its accuracy of diagnosis is around 75%. Consequently, this will always need to be followed by further imaging.^6,164–166 The use of staging laparoscopy has changed over time. It has been used in patients in whom unresectable disease is considered likely in order to prevent a larger laparotomy procedure that would need to be aborted. These higher-risk patients are those with CA19-9 higher than 100, head tumors larger than 3 cm, questionable findings on CT, or a body/tail lesion. Past studies did demonstrate that laparoscopy can prevent unnecessary laparotomies in 20% of patients, however these numbers are dropping to 5% to 8% as imaging studies have gotten better, making laparoscopy less likely to be helpful.^{6,88,139,167–169}

Although a biopsy is not required when a patient with a high suspicion for PC goes directly to surgery, it is required prior to any neoadjuvant treatment or treatment of locally advanced or metastatic disease. FNA via EUS or CT-guidance are the two most common approaches to obtain a tissue sample. EUS-FNA is preferred because of the higher diagnostic yield, lower chance of seeding the peritoneum causing carcinomatosis, and the benefit of additional staging information from EUS. EUS-FNA has a 92% accuracy of correctly diagnosing a pancreatic mass and a 84% accuracy when performed in patients with negative CT-guided biopsies. It also carries a low complication rate of 0.5% to 2%.2,88,139,145,148,160,170–173 CT-guided FNA may also be performed to biopsy a metastatic site. ERCP brushings may also be done and should be considered when there is a biliary stricture but no mass, but cytology from brushings has a low yield of positive results.^88,160 Although tumor-associated markers like CA19-9 can also assist in the diagnosis, as discussed previously, the sensitivity and specificity lead to a fair number of false positives and false negatives. The absolute value is often higher in more advanced stages, especially when there are liver metastases,⁸⁶ and the value can provide useful prognostic information.

Staging

Classically, PC has been staged according to the TNM (tumor–node–metastasis) staging system per the American Joint Committee on Cancer, as shown in Table 81-3.¹⁷⁴ The distinction of T1 and T2 tumors at 2 cm is secondary to the association of tumor size with survival in resected patients. Numerous reviews have demonstrated improved survival in patients with smaller tumors with 5-year survival improvements by 10% to 20% and increase in median survival by 5 to 20 months and hazard ratios around 1.6. Unfortunately, only a minority of patients (6% to 25%) present with tumors smaller than 2 cm.^{8,98,101,108,175–181} The classification of patients with nodal disease separately as stage IIB is because of the clear associated of nodal disease with worse survival, as described further below.¹⁷⁵

More recently, most centers and current clinical trials are classifying patients based on their resectability status (Table 81-4) because surgery is critical to achieve a cure in this disease. This characterizes stage I and II patients as resectable and divides stage III patients into those who are borderline resectable and may benefit from neoadjuvant therapy prior to surgery from those who are unresectable and are not surgical candidates. Tumors that encase the SMA or celiac artery would require technically difficult resections and reconstructions that carry a high perioperative mortality risk and are likely to leave some tumor behind and are therefore categorized as unresectable. In addition, there is a greater chance of perineural infiltration with SMA or celiac artery involvement because those arteries have a perineural sheath unlike the SMV or portal vein.^88,139,175 Tumors involving the SMV and portal vein are considered borderline resectable, on the other hand, because SMV and portal vein resection does not affect surgical outcome or overall survival when done at experienced centers and therefore is not an absolute contraindication to surgery.^19,175,182 Unfortunately, only 15% to 20% of patients present with resectable or borderline resectable disease.