laparoscopic techniques allow synchronous pancreatic resections to be ..... pancreaticogastrostomy following pancreatectomy: results of a comparative study.
Textbook of Surgical Oncology
Pancreatic Cancer Narcis Octavian Zarnescu, Isam W Nasr, Mario Lora, A James Moser
Introduction Pancreatic cancer is the fourth leading cause of cancer death in the United States. Estimates of the American Cancer Society indicate that nearly 37,700 new cases of pancreatic cancer will be diagnosed in the United States in 2008, while almost 34,300 people will die of the disease. At the time of diagnosis, only 10-15% of patients have tumors confined to the pancreas, 35-40% have locally advanced disease and more than 50% have distant spread leaving only 10-20% as candidates for resection. Pancreatic cancer remains a diagnostic and therapeutic dilemma as early lesions cause few symptoms, strategies for screening remain unproven and current treatment modalities demonstrate poor response rates and 5-year actual survival.
Anatomy of the Pancreas
The pancreas is a retroperitoneal organ located in the lesser sac posterior to the greater curvature of the stomach. It is divided into four anatomic regions: the head, neck, body and tail. The pancreatic head lies medial to the C-loop of the duodenum posterior to the transverse mesocolon. It is anterior to the vena cava, the right renal artery and both renal veins. The neck of the pancreas lies directly over the portal vein. At the inferior border of the neck of the pancreas, the superior mesenteric vein joins the splenic vein, which eventually forms the portal vein. The body of the pancreas is anterior to the splenic artery and vein. The tail is the small segment that lies within the splenic hilum and is anterior to the left kidney. The posterior border of the pancreas lacks a peritoneal investment, exposing the pancreatic lymphatics to the retroperitoneum. Branches of the celiac and superior mesenteric arteries (SMA) give rise to the vasculature of the pancreas. The head is supplied by an arcade formed by the gastroduodenal artery (GDA) and the SMA: The GDA, which is the first branch of the common hepatic artery, gives rise to the superior pancreaticoduodenal artery, which divides
into anterior and posterior branches. The inferior pancreaticoduodenal artery is the first branch of the SMA and divides into anterior and posterior branches. These four arteries form an arcade which provides a blood supply shared by the pancreatic head as well as the second and third portions of the duodenum. The body and tail are supplied by branches of the splenic artery. The SMA branches into the inferior pancreatic artery that runs along the inferior border of the body and tail. The splenic artery and the inferior pancreatic artery, which run parallel to each other, are connected by the lateral, dorsal and the transverse pancreatic arteries. The venous drainage of the pancreas follows a pattern similar to the arterial supply, where the veins run anterior to the arteries. Lymphatic drainage is abundant and diffusely spread throughout the organ. The lymphatic vessels drain into five main nodal groups: The superior nodes drain the upper half of the head of the pancreas and are located along the superior border of the pancreas and celiac trunk. The anterior lymphatics drain to the prepyloric and infrapyloric nodes. The inferior group of nodes drain into the superior mesenteric and periaortic nodes and are along the inferior border of the pancreatic head and body. The posterior pancreaticoduodenal lymph nodes drain into right periaortic nodes and include the distal common bile duct and ampullary lymphatics. The splenic group of nodes drains the tail of the pancreas along the splenic vessels and into the interceliomesenteric lymph nodes (Figure 33-1).
Epidemiology Pancreatic cancer is ranked 13th in terms of incidence and represents the fourth leading cause of cancer death in the United States; 5-year survival is less than 5%. Most patients are between 65 and 80 years old at diagnosis and only 10% of all cases are under the age of 50; the risk increases sharply after age 50. Incidence is equal among men and women. African Americans appear to have a higher incidence of pancreatic cancer than white Americans.
Figure 33-1: Lymph nodes for pancreatic drainage. (Reproduced with permission from Skandalakis JE, Gray SW, Rowe JS Jr, et al. Anatomical complications of pancreatic surgery. Contemp Surg 1979;15:17)
Risk Factors Both environmental and genetic factors contribute to the risk of pancreatic cancer. Smokers have a twofold increased risk of pancreatic cancer compared to nonsmokers. The risk increases with duration and intensity of smoking. Diets high in fat and low in fruits, vegetables and fiber were once thought to increase the risk of pancreatic cancer; however, a recent report on almost 125,000 patients did not validate this observation. Patients with chronic pancreatitis have a 20-fold increased risk of developing pancreatic cancer. There may be a link between chronic inflammation and the rate of genetic mutations required for oncogenesis. There is a positive
association between pancreatic cancer and diabetes mellitus. One meta-analysis identified a relative risk for pancreatic cancer of two (95% CI 1.2-3.2) in patients with longstanding diabetes (more than five years), similar to recent results of a prospective study (RR 1.49 for men and RR 1.51 for women). Approximately 1% of diabetics age 50 or older will develop PC within 3 years. Ten percent of cases have a familial genetic basis. Individuals with three first-degree relatives have a 32-fold increased risk. Numerous germ line mutations are associated with pancreatic cancer (Table 33-1). A strong family history of pancreatic cancer or hereditary pancreatitis requires screening in specialized centers with endoscopic ultrasound (EUS) and molecular analysis of
Genetic mutations associated with higher risk of pancreatic cancer
Risk by age 70
Familial breast and ovarian cancer syndromes
Breast, ovary, prostate
MLH1, MSH2, MSH6, HNPCC PMS1, PMS2
Colorectal, stomach, biliary tract, endometrial, ovarian, ureter, renal, brain
one half diameter)
Celiac axis/ Hepatic artery
Short-segment encasement/abutment of the common hepatic artery(typically at the gastroduodenalorigin); may require vascular resection
Encased and no technical option for reconstruction, extension to celiac axis
Short-segment occlusion with options for reconstruction; segmental venous occlusion alone without SMA involvement (rare)
Abbrevations: SMA, superior mesenteric artery; SMV/PV, superior mesenteric vein/portal vein
ultrasound. The typical appearance of pancreatic cancer on ultrasonography is a hypoechoic mass. Additional information that is provided by the ultrasound is the presence of peripancreatic lymphadenopathy as well as liver metastases and dilated bile ducts. Limitations of transabdominal ultrasonography include operator dependence, body habitus and bowel gas artifacts. Around 60-70% of patients with pancreatic cancer will have a discernable mass on ultrasound. Multidetector, pancreatic mass protocol computed tomography CT (MDCT) using oral water with arterialand venous-phase imaging of IV contrast is the imaging procedure of choice to assess resectability and detect distant metastases. Encasement of the portal or superior mesenteric veins as well as the involvement of the superior mesenteric, celiac or hepatic arteries with or without occlusion are ominous signs of unresectability (Table 32-2). Prior studies indicate that tumor involvement of more than half of the circumference of major vessels portends unresectability (Figure 33-3). Additional CT features include: involvement of the celiac plexus for body cancers anterolateral to the celiac trunk, dilation of the main pancreatic duct or bile duct or both (‘double duct sign’), lymph node involvement based on increased size and abnormal shape. The accuracy of CT for nodal staging has recently been questioned. In addition, hepatic metastatic deposits can be detected whereas peritoneal metastases cannot directly be visualized, but can be suspected from the presence of ascites or omental caking. Generally, a chest radiograph or CT scan (with or without intravenous contrast) is often performed during initial staging evaluation.
chemotherapy/radiation. The sensitivity of EUS is 88.8%, specificity 100%, PPV 100%, NVP 99%, with an accuracy of 99.1%. However, EUS is very operator dependent and may overestimate the degree of vascular involvement. EUS has superior resolution for small lesions of 2-3 mm and aids in defining the relationship between tumor and adjacent blood vessels (portal vein, mesenteric vessels). It also provides additional diagnostic information in patients with nonspecific CT/MRI findings such as dilatation of the pancreatic duct and enlargement of the head of the pancreas. One of the applications of EUS is injecting ethanol into the celiac plexus (neurolysis) for pain control.
Endoscopic Ultrasound (EUS) is used to stage patients with pancreatic tumors and provides a cytologic diagnosis as required for operative decision-making or to administer
Laparoscopy is an integral part of the diagnosis, staging and management of pancreatic cancer. The incidence of unsuspected metastases is 10-40% among patients
Figure 33-3: Diagnosis of pancreatic drainage
Textbook of Surgical Oncology undergoing exploratory laparotomy for potentially resectable lesions. Laparoscopic ultrasound raises the diagnostic accuracy of staging laparoscopy to that of laparotomy with less morbidity and mortality. Advanced laparoscopic techniques allow synchronous pancreatic resections to be performed as well as palliative procedures including choledocojejunostomy, gastrojejunostomy and celiac plexus neurolysis.
Peritoneal Cytology The prognostic significance and therapeutic implications of positive peritoneal washings remain controversial. The question of whether positive cytology correlates with prognosis remains unanswered, although a recent small prospective study has shown that patients with minute cancer cell dissemination detected by Real-time polymerase chain reaction (RT-PCR) in peritoneal washings have worse outcomes.
Pancreatic Intraepithelial Neoplasia Pancreatic intraepithelial neoplasia (PanINs) are lesions of the pancreatic duct that are identified microscopically and characterized by lack of invasion of the basement membrane. They are one of three preinvasive lesions of the pancreas that have been identified, the others being mucinous cystic neoplasms (MCN) and intraductal papillary mucinous neoplasms (IPMNs). PanINs are graded 1-3, with the grade of lesion based on nuclear anomalies, degree of necrosis, rate of mitoses and the presence of a papillary component. The incidence of PanINs increases with age. Grade 1 PanIN can be identified in up to 40% of patients who do not have pancreatic cancer, however, grade 3 PanIN has been found in up to 50% of patients with invasive carcinoma. The frequency and speed with which PanINs progress to invasive cancer is unknown. Most are small (less than 0.5 cm) and clinically silent. Kras proto-oncogene mutations have been described as leading to the development of these lesions and mouse models of PanINs are currently under investigation. PanINs have been described to produce lobulocentric atrophy of the pancreatic parenchyma which can at times be identified by EUS. An association with acinar-ductal metaplasia has been described, which suggests that PanINs may arise from acinar cell origin. Although not currently relevant as a screening tool, the identification of these precursor lesions may yield important advances in the management of high risk patients and continue to help to understand the progression of pancreatic cancer.
Surgical Resection 492
Surgical resection is the only modality that increases 5-year actual survival and may lead to cure. There is good
evidence that the achievement of a negative surgical margin (R0 resection) is the surgeon’s major contribution to long-term survival. Preoperative Biliary Decompression For patients with obstructive jaundice, preoperative biliary decompression has been shown to increase overall morbidity and mortality rates after resection. A recent meta-analysis confirmed the absence of medical benefit following biliary stenting. A metal biliary stent may be required for patients with resectable pancreatic cancer undergoing neoadjuvant therapy. In our experience, metal biliary stents are associated with fewer stent-related complications than plastic and provide a longer duration of patency without increasing the risk of subsequent surgical resection. Strategies for Resection The type of resection is tailored to the anatomic location of the tumor and its adjacent vasculature. The majority of lesions is located in the pancreatic head and requires pancreaticoduodenectomy (Whipple operation). Lesions in the body and tail require distal pancreatectomy and occasionally central pancreatectomy. The search for distant metastases is the first stage of the operation. The liver, peritoneal surfaces and omentum are checked for cancer implants. Suspicious lesions are sent for frozen section. The presence of tumor in the periaortic lymph nodes of the celiac axis indicates metastatic disease and is a contraindication to resection. Local invasion into the inferior vena cava, aorta, superior mesenteric artery (SMA), superior mesenteric vein (SMV) and portal vein is then assessed after division of the attachments of the pancreatic head to surrounding structures (Kocher maneuver) (Figure 33.4). The standard Whipple operation (PD) requires resection of the pancreatic head, gallbladder, distal common bile duct, duodenum and distal stomach with extirpation of lymph nodes associated with the common bile duct, pylorus and anterior and posterior surfaces of the pancreatic head. The procedure is typically performed either through a midline incision or through bilateral subcostal incisions. The initial step involves a thorough assessment of the abdomen for metastatic disease. This includes inspection of all peritoneal surfaces as well as palpation of the liver, in conjunction with intraoperative ultrasound of the liver for suspicious lesions. Celiac, periportal and interaortocaval lymph nodes should also be inspected. All suspicious lesions should be biopsied and sent for frozen section. The next step consists of an extensive mobilization of the duodenum and the head of the pancreas from the underlying aorta and vena cava by performing a Kocher
Figures 33-4A and B: Whipple operation. (A) Resection of periampullary cancer. (B) Reconstruction after resection
maneuver. Involvement of the tumor with the superior mesenteric artery can then be assessed by palpating underneath the mobilized duodenum and head of pancreas. In order to gain access to the third and fourth portions of the duodenum, the hepatic flexure of the colon is mobilized. The mesocolon is separated from the head of the pancreas to expose the superior mesenteric vein. The SMV dissection is continued until it connects with the portal vein. After the stomach and the proximal duodenum are mobilized, the duodenum is transected 2 cm distal to the pylorus in the case of a pyloruspreserving pancreaticoduodenectomy, whereas in a classic Whipple, an antrectomy is performed. The next
step is dissection of the hepatoduodenal ligament. The GDA is then identified and ligated at its origin from the common hepatic artery. Care must be taken to make sure that there remains strong flow in the proper hepatic artery after occlusion of the GDA. If not, then there is likely to be a stenosis at the origin of the celiac artery or common hepatic artery that needs to be addressed prior to the Whipple procedure. The gallbladder is removed and the common hepatic duct is transected approximately 2 cm above its insertion into the head of the pancreas. Next, the proximal jejunum is mobilized and transected 10-20 cm from the ligament of Treitz. Its mesentery is divided and fourth portion of the duodenum is dissected off of
Textbook of Surgical Oncology the pancreas. The stump of the jejunum is reflected through the defect in the transverse mesocolon so that it is positioned laterally to the SMV. After that, the neck of the pancreas is transected and the specimen is dissected sharply off the SMV, portal vein and SMA. The distal stump of the jejunum is brought through the transverse mesocolon and a two-layer end-to-side pancreaticojejunostomy is performed first. Proximal to that, a single-layer hepaticojejunal anastomosis is performed. Finally, a duodenojejunostomy is performed distal to the choledochojejunostomy. It may be helpful to leave the afferent limb short enough so that an endoscopic cholangiogram or pancreatogram may be performed in the future as necessary. One close suction drain may be placed adjacent to the pancreatic anastomosis. Extended radical lymphadenectomy involves standard PD plus distal gastrectomy and retroperitoneal lymph node dissection extending from the right renal hilum to the left lateral border of the aorta and from the portal vein to the inferior mesenteric artery. Radical resection raises overall morbidity but does not convey a survival advantage. As mentioned above, an additional modification to the standard Whipple procedure is the pylorus-preserving Whipple. This operation was devised in an attempt to eliminate the morbidity associated with postgastrectomy syndromes and involves preservation of the right gastroepiploic arcade and/or the right gastric artery to protect the blood supply to the duodenum. Some studies have shown a reduction in operative time and blood loss using a pylorus preserving approach, however no significant differences in mortality have been noted when comparing the two procedures. Invasion of the portal vein (PV) or superior mesenteric vein (SMV) is often considered a contraindication to resection. However, resection of the portal vein and the superior mesenteric vein can achieve R0 resection with low morbidity and mortality in high volume centers. In a comprehensive review of synchronous PV/SMV resection for pancreatic cancer, 23 studies included 1646 patients from 52 centers without an adverse impact of PV/SMV invasion on 5-year survival rate. Resection is rarely justified in the presence of extensive portal vein encasement that precludes an R0 or R1 (microscopically positive) margin status.
Postoperative Outcomes Mortality rates are in the range of 2-3%. Pancreatic fistula is one of the most frequent and serious complications, with an incidence ranging from 5% to 15%. It is defined as any measurable drain volume with an amylase content three times that of the serum level on or after postoperative day three. With adequate drainage and nutrition, pancreatic fistulas usually heal within 8 weeks. Delayed gastric
emptying occurs in 15-40% of cases; delayed gastric emptying is the most common indication of pancreatic fistula. Pancreatic exocrine insufficiency and steatorrhea are long-term complications treated with pancreatic enzymes at mealtime. Complications following pancreatic resection are classified into five grades of outcome, as reported by DeOliveira, et al in Annals of Surgery in 2006. The total incidence of complications in the study was 58.5%, and the specific incidence of complication per grade is noted in parentheses following the respective number below: • Grade I (10%): no need for specific intervention • Grade II (30%): need for drug therapy such as antibiotics • Grade III (13.5%): need for invasive therapy • Grade IV (3%): organ dysfunction with ICU stay • Grade V (2%): death Tumors in the body and tail of the pancreas usually present at an advanced stage having already metastasized or locally invaded adjacent structures, with only 10% of tumors being resectable at presentation. Resection usually involves distal pancreatectomy with or without splenectomy. Complications include subphrenic abscess in around 5-15% of cases, as well as pancreatic fistula in approximately 30% of patients. These can be managed with percutaneous drainage. Staging The current American Joint Committee on Cancer (AJCC) staging system for pancreatic cancer is reproduced in Table 33-3. Although staging may be implied preoperatively for the purposes of assignment to clinical trials, the true stage of a patient with pancreatic cancer can only be determined after resection and pathological analysis. At least ten regional lymph nodes should be included with the resected pancreatic specimen to allow for accurate staging. In addition to tumor size, lymph node status and distant metastasis, other factors that influence survival are: perineural invasion, angiolymphatic invasion, histologic grade, DNA content and genetic modifications.
Adjuvant Therapy for Resected Pancreatic Cancer Gemcitabine therapy alone was shown to be an effective adjuvant chemotherapy modality in the CONKO-001 trial, where gemcitabine was compared with observation. Median disease free survival in the gemcitabine group was 13.4 months versus 6.9 months in the control group. Disease free survival was also significantly improved in the gemcitabine group. At least five major trials have attempted to address the question of whether chemotherapy or chemoradiation are effective adjuvant therapies for resected pancreatic cancer.
Pancreatic Cancer TABLE 33-3
The sixth edition of the American Joint Commission on Cancer staging system for pancreatic adenocarcinoma
6th AJCC staging system
Primary tumor (T) Tis
No evidence of primary
Limited to pancreas,≤ 2 cm
Limited to pancreas,≥ 2 cm
Extends beyond pancreas, no involvement of CA or SMA
Involves CA or SMA
Regional lymph nodes (N) N0
No nodal metastasis
Regional lymph node metastasis
Distant metastasis (M) M0
No distant metastasis
Stage groupings Stage 0
In situ disease
Unresectable due to locally advanced disease
Unresectable due to distant metastasis
Reproduced with permission Abbreviations: CA, celiac axis; SMA, superior mesenteric artery
The data from these trials were pooled in a meta-analysis that showed 25% significant reduction in the risk of death with chemotherapy, with an increase in median survival from 13.5 to 19.0 months. As for chemoradiation, there appeared to be no significant difference in the risk of death, with a median survival of 15.8 months with chemoradiation and 15.2 months without. However, a subgroup analysis of patients with positive resection margins showed that chemoradiation was more effective than chemotherapy alone.
Treatment of Locally Advanced Pancreatic Cancer Vascular involvement often renders pancreatic cancer unresectable and unlike other cancers, pathologic downgrading is very difficult to achieve. Multiple trials involving chemoradiation have been performed. One French study compared gemcitabine vs chemoradiation using 5-FU and cisplatin. Overall survival was shorter in the chemoradiation arm (8.6 vs 13 months). One-year survival was also decreased (32% vs 53%).
A recent study (ECOG 4201) comparing gemcitabine in combination with radiation therapy versus gemcitabine alone had more promising results for locally advanced disease. Overall survival was increased in the chemoradiation group to 11 months versus 9.2 months in the control group. Another impressive result is that the 24-month survival was tripled (12% vs 4%).
Treatment of Metastatic Pancreatic Cancer An early study comparing gemcitabine to 5-FU showed that gemcitabine is more effective in alleviating the disease-related symptoms of patients with advanced and metastatic pancreatic cancer. The clinical benefit response was 23.8% for gemcitabine treated patients versus 4.8% for 5-FU treated patients. The survival rate at 12 months was 18% for gemcitabine and 2% for 5-FU. The median survival was also prolonged: 5.61 months for gemcitabine versus 4.41 months for 5-FU. To address the issue of patients with gemcitabine refractory pancreatic cancer, the CONKO-003 trial was
Textbook of Surgical Oncology designed. The patients were randomized to two chemotherapeutic regimens: the first was FF (5-FU plus folinic acid or leucovorin), the second was OFF (FF plus oxaliplatin). The results of the study indicated that alternating OFF/FF and continuous FF leads to significantly longer progression free survival (13 vs 9 weeks) and overall survival compared to FF (20 vs 13 weeks). Several other studies have been conducted whereby other chemotherapeutic agents have been added to gemcitabine, with no significant improvement in survival. Examples include molecular targeting agents such as cetuximab, bevacizumab, farnesyl transferase inhibitors and metalloproteinase inhibitors. One study showed a modest increase in overall survival by adding erlonitib to gemcitabine (6.24 months vs 5.91 months). There was also an increase in one-year survival with erlonitib plus gemcitabine (23% vs 17%). The AViTA study basically added bevacizumab to erlonitib and gemcitabine versus erlonitib and gemcitabine in patients with metastatic pancreatic cancer. The study showed that the triple combination significantly improved disease free survival (3.6 months vs 4.6 months), but not overall survival (6.0 months vs 7.1 months), compared to gemcitabine plus erlonitib.
Palliation of Symptoms
Most patients with pancreatic cancer present at an advanced stage of disease in which palliation is the most pressing medical need. The goals of palliative treatment are multiple, including reduction of symptoms, improvement of functional status, reduction in length of hospitalization, as well as improvement in overall quality of life. Surgery (open or laparoscopic) and endoscopic therapy can be used to relieve the symptoms of locally advanced pancreatic cancer causing obstructive jaundice, gastric outlet obstruction and intractable abdominal pain. Obstructive jaundice occurs in 70% of patients with pancreatic cancer. If untreated, obstructive jaundice causes progressive liver dysfunction, severe pruritus associated with cutaneous bile salt deposition, nausea and anorexia. For patients with metastatic cancer, endoscopic biliary decompression is associated with less procedural morbidity and a shorter hospital stay compared with surgical drainage. Metallic stents are the preferred method for patients with a life expectancy longer than 6 months, whereas less expensive plastic stents are adequate for patients with shorter survival. Complications of endoscopic stents include cholangitis, duodenal perforation, postsphincterotomy bleeding and post-ERCP-pancreatitis. Gastric outlet obstruction occurs in up to 20% of patients. The role of a prophylactic gastroenterostomy is still under discussion, but many authors argue that prophylactic bypass performed in a high volume specialty
center can be done with little morbidity and improve palliative outcomes. Techniques to relieve duodenal obstruction include laparoscopic gastrojejunostomy and endoscopic metal enteral stents. Recent analysis comparing these techniques showed better results with the endoscopic approach. Pain is best managed by combining a long-acting narcotic with acetaminophen. When pain relief requires doses of narcotic analgesics causing functional impairment or somnolence, the best method for permanent relief is celiac plexus neurolysis with ethanol under CT or EUS guidance.
Acinar Cell Carcinoma Although acinar cell carcinoma (ACC) represents less than 2% of all pancreatic malignancies, they are important to discuss due to some unique features from ductal adenocarcinoma of the pancreas. These aggressive tumors are capable of secreting lipase into the circulation, which results in systemic manifestations of this disease. Patients may present with erythema nodosum-like rashes, eosinophilia, subcutaneous fat necrosis and polyarthralgias. ACC can also produce alpha-fetoprotein (AFP), which serves as a useful marker for recurrence and therapeutic response following resection. Although clinical experience with these tumors is limited, the approach to surgical and adjuvant therapy is similar to ductal pancreatic cancer. A recent retrospective analysis suggests that these tumors carry a better prognoisis than the more common ductal type. In addition growing anecdotal experience at several high volume pancreatic center suggest that these tumors may highly be sensitive to platinum based regimens.
Other Periampullary Cancers Pancreatic cancer is by far the most common kind of periampullary cancer. Although rare, this region also harbors three other types of malignancies: Carcinoma of the ampulla of Vater, cholangiocarcinoma and duodenal cancer. Management of cholangiocarcinoma is discussed elsewhere within this text. The work-up and surgical approach to ampullary cancer and duodenal cancer are similar to that which has been presented above. It is important to note, however, that the survival rates of carcinoma of the ampulla of Vater and of duodenal cancer are better than pancreatic cancer. Five-year survival for ampullary carcinoma ranges 46-68% in some large series, while the survival for duodenal cancer can be up to 50% at 5 years. Furthermore, some authors advocate for resection of ampullary or duodenal cancers even in the setting of liver metastases to improve palliation and avoid the high risk of bleeding with these tumors. Both local and endoscopic resections have been described for benign lesions of the ampulla and for duodenal polyps in this
Pancreatic Cancer region, underscoring the role for endoscopy and EUS to biopsy these tumors.
Cystic and Intraductal Pancreatic Mucinous Neoplasms The identification of cystic pancreatic neoplasms has increased dramatically in recent years given advances in radiographic imaging. This has resulted in an increased referral of these patients for surgical evaluation. These cysts can be neoplastic or non-neoplastic and the neoplastic lesions encompass a spectrum of benign, premalignant and malignant. This section will focus only on the cystic neoplasms (discussion of non-neoplastic lesions, such as pseudocysts is outside of the scope of this chapter). The most common cystic neoplasms encountered by the pancreatic surgeon are serous cystadenomas (SCA), MCN and IPMNs. Additional, less common tumors of importance include solitary pseudopapillary neoplasm, cystic endocrine neoplasm, ductal adenocarcinoma with cystic degeneration, lymphoepithelial cysts and acinarcell cystadenomas. Each of these represents less than 10% of all cystic neoplasms. Table 33-4 lists a number of important characteristics that help to distinguish between the four most common types of pancreatic neoplasm. The following sections will discuss each of the more common cystic neoplasms in detail. TABLE 33-4
Serous Cystadenoma SCAs are small, microcystic tumors of the pancreas that are rarely malignant. The etiology of these lesions is unclear. Radiographically, they classically appear as a ‘honeycomb’ of multiple small cysts, although CT findings may vary from solid appearance to single cyst. Approximately 20% will have the hallmark finding of a central, stellate scar. These tumors are frequently confused with mucinous cystadenomas. EUS can be helpful in distinguishing SCAs and FNA aspirate yields high specificity in diagnosis. Histologically, these tumors are lined by cuboid epithelium and chromosomal alterations in the von Hippel-Lindau gene on chromosome 3p25 are quite common. Most SCAs are managed conservatively due to the low risk of malignancy. Symptomatic cysts should be resected, while asymptomatic lesions may be followed with serial CT scans every 1-2 years. Some authors have argued that larger lesions should be resected due to an increased incidence of rapid growth. A size cutoff of 4 cm has been proposed for resection, although this lacks the support of randomized-controlled data. Tumors that are unable to be confidently distinguished from other types of cystic neoplasia by radiographic or cytologic findings should be resected. Mucinous Cystic Neoplasms MCNs are large, multilocular or (rarely) unilocular cystic neoplasms lined by tall, mucin producing cells which may
Characteristics of common cystic and intraductal pancreatic mucinous neoplasms SCA
less than 10%
History of pancreatitis
Communication with pancreatic duct
Pancreatic duct on CT
Aspect of lesion on CT
microcysts (< 2 cm) fibrous central scar
macrocysts (> 2 cm) peripheral eggshell calcification
Solid component with cystic degeneration
cuboidal glycogenrich epithelial cells
dilated native ducts
uniform epithelium, solid sheets, nests and wellformed acinar structures, pseudo-papillae
10-15% in situ 8-30% invasive
5-20% in situ 10-40% invasive
Abbreviations: SCA: Serous cystadenoma; MCN: Mucinous cystic neoplasm; IPMN: Intraductal papillary mucinous neoplasm; F: female; M: male
Textbook of Surgical Oncology form papillae and they are found typically in the body and tail of the pancreas. These tumors frequently present in young women and are specifically characterized by the presence of ovarian-like stroma on histology. As with other tumors, they are frequently asymptomatic, however, when they are clinically evident, they frequently present with abdominal pain, early satiety, nausea and vomiting. MCNs occur in a spectrum ranging from benign (cystadenoma) to borderline to overtly malignant (cystadenocarcinoma), with approximately 20% harboring an in situ carcinoma. The diagnosis of malignant MCNs is based on the observation of invasion of the cyst wall. These tumors are frequently confused with IPMNs on initial radiographic assessment; however, MRCP or ERCP can be useful in identifying the lack of communication with the pancreatic duct present in MCNs. The presence of mural nodules identified on imaging is a predictor of malignancy. Again, EUS is useful for the characterization of these tumors as well as for sampling of fluid, which is likely to be more viscous than in SCAs and more likely to express high levels of CEA (Table 33-5). Given their malignant potential and risk of degradation of borderline lesions to become mucinous cystadenocarcinoma, MCNs should be resected. The prognosis for resected cystadenocarcinoma with negative margins (R0) is very good, with 5-year survival rates reported between 50% and 75%. Unresectable or metastatic lesions have a dismal prognosis, with rapid decline similar to adenocarcinoma and median survival of 4-6 months. TABLE 33-5
Tumor markers in cyst fluid from common cystic neoplasms
Intraductal Papillary Mucinous Neoplasms IPMNs are by definition intraductal neoplasms that are characterized as benign, borderline or malignant based on a number of pathological features, including dysplasia and nuclear abnormalities. The presence of pancreatic ductal dilation is considered to be a hallmark of IPMNs. These tumors arise from a pancreatic duct and can be found in the main duct, branch ducts or both. Four patterns of pancreatic ductal dilation have been recognized: (1) diffuse main duct ectasia, (2) segmental main duct ectasia, (3) side branch ectasia, (4) multifocal
cysts with pancreatic duct communication. The rate of malignancy range from 5% and 40% in various studies (in situ 5-27%, carcinoma 15-40%) and is highly dependent upon the type of IPMN. Main duct IPMN has the highest rate of malignancy. Current recommendations are to resect all main duct IPMNs greater than 6 mm in patients who are otherwise fit for surgery. Diffuse main duct ectasia is frequently found in the head of the pancreas, requiring a Whipple operation, while segmental main duct ectasia is more frequently in the body and tail. Both diffuse main duct ectasia and the multifocal pattern can involve the entire pancreas, which may necessitate total pancreatectomy. Branch duct IPMNs are considered by most to be more favorable and less likely to be malignant than main duct. A number of large series have also concluded that size serves as a predictor of malignancy, with cysts > 3 cm harboring the highest risk of malignancy. In addition, the presence of mural nodules on imaging is also a marker of cancer. This has led to the development of a consensus paper published in Pancreatology in 2006 that recommends that branch chain IPMM with the following characteristics may safely be observed with repeat CT imaging on an annual basis: cyst < 3 cm, branch duct origin, asymptomatic and no additional radiographic markers of malignancy. For larger lesions and those with radiographic or cyst fluid suggestive of malignancy, aggressive surgical resection yields the best chance of cure. For cancers that are found to arise within IPMN, the prognosis is better than ductal adenocarcinoma of the pancreas. Five-year survival rates for in situ carcinoma in IPMN are > 80%, while overt carcinoma arising from IPMN has a 5-year survival of 30-40%. Multivariate analysis suggests that lymph node metastases is a predictor of poor prognosis. Frozen section is used by many to determine margins intraoperatively, which serves as a predictor of recurrence. Solid Pseudopapillary Tumors Solid pseudopapillary tumor, which is common in young females, is a rare pancreatic tumor with uncertain malignant potential. Also known as Frantz’s tumor, this lesion is characterized by dramatic overexpression of betacatenin and location in the body and tail of the pancreas. These tumors are often symptomatic owing to their large size. There is a low risk of malignant potential, however, even malignant and metastatic tumors of this subtype have a favorable prognosis. Aggressive surgical resection is indicated for these neoplasms, with overall 5-year survival rates of up to 97% reported in some series. The differential diagnosis for all cystic neoplasms of the pancreas found radiographically must include pancreatic pseudocysts. Although a complete discussion on the work-up and management of pseudocysts is
Pancreatic Cancer outside of the scope of this chapter, it is important to recognize a few common characteristics that distinguish pseudocysts from cystic neoplasms. A majority of patients with inflammatory pseudocysts will have a history of pancreatitis, alcohol abuse or complicated biliary disease. Although cystic neoplasms may cause pancreatitis from ductal obstruction, the incidence of significant pancreatitis is dramatically lower than for pseudocysts. Additionally, pseudocysts appear as large, single cysts without evidence of septations, distinguishing them from MCNs and SCNs. Aspiration of these lesions consistently reveals very high amylase levels (> 5000 U/ml) and frequently low levels of markers such as CEA, although these can falsely be elevated (although almost uniformly less than 400 ng/ml) in up to 50%. MRCP and EUS may be of diagnostic value to assess for the wall thickness and planning of drainage.
Future Directions Pancreatic cancer is an aggressive disease with a late presentation. Early detection and screening methods are urgently needed to improve the odds of survival. Surgical treatment at high volume centers for pancreatic surgery reduces the rate of postoperative complications and may improve cancer-specific survival. The standard of care for pancreatic cancer patients is enrolling them into a clinical trial. Molecular profiling may permit treatment decisions to be personalized in the future and identify new targets for cancer therapy.
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fistula and other complications after pancreaticoduodenectomy? Ann Surg 2001;234:262-3. DeOliveira ML, Winter JM, Schafer M, Cunningham SC, Cameron JL, Yeo CJ, Clavien PA. Assessment of complications after pancreatic surgery: a novel grading system applied to 633 patients undergoing pancreaticoduodenectomy. Ann Surg 2006;244:931-7; discussion 937-9. Farnell MB, Pearson RK, Sarr MG, DiMagno EP, Burgart LJ, Dahl TR, et al. A prospective randomized trial comparing standard pancreatoduodene-tomy with pancreatoduodenectomy with extended lymphadenectomy in resectable pancreatic head adenocarcinoma. Surgery 2005;138:618-28; discussion 628-30. Gouma DJ, van Geenen RC, van Gulik TM, de Haan RJ, de Wit LT, Busch OR, Obertop H. Rates of complications and death after pancreaticoduodenectomy: risk factors and the impact of hospital volume. Ann Surg 2000;232:786-95. Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res 2000;6:296972. Iacobuzio-Donahue CA, Maitra A, Shen-Ong GL, van Heek T, Ashfaq R, Meyer R, et al. Discovery of novel tumor markers of pancreatic cancer using global gene expression technology. Am J Pathol 2002;160:1239-49. Leach SD, Lee JE, Charnsangavej C, Cleary KR, Lowy AM, Fenoglio CJ, Pisters PW, Evans DB. Survival following pancreaticoduodenectomy with resection of the superior mesenteric-portal vein confluence for adenocarcinoma of the pancreatic head. Br J Surg 1998;85:611-7. Lillemoe KD, Kaushal S, Cameron JL, Sohn TA, Pitt HA, Yeo CJ. Distal pancreatectomy: Indications and outcomes in 235 patients. Ann Surg 1999;229:693-8; discussion 698700. Lowy AM. Neoadjuvant therapy for pancreatic cancer. J Gastrointest Surg 2008;12:1600-8. Michalski CW, Kleeff J, Wente MN, Diener MK, Buchler MW, Friess H. Systematic review and meta-analysis of standard and extended lymphadenectomy in pancreaticoduodenectomy for pancreatic cancer. Br J Surg 2007; 94:26573. Nathan H, Cameron JL, Goodwin CR, Seth AK, Edil BH, Wolfgang CL, et al. Risk factors for pancreatic leak after distal pancreatectomy. Ann Surg 2009;250:277-81. Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004;350:1200-10. Pawlik TM, Abdalla EK, Barnett CC, Ahmad SA, Cleary KR, Vauthey JN, et al. Feasibility of a randomized trial of extended lymphadenectomy for pancreatic cancer. Arch Surg 2005;140:584-9; discussion 589-91. Picozzi VJ, Pisters PW, Vickers SM, Strasberg SM. Strength of the evidence: Adjuvant therapy for resected pancreatic cancer. J Gastrointest Surg 2008;12:657-61. Pisters PW, Hudec WA, Hess KR, Lee JE, Vauthey JN, Lahoti S, Raijman I, Evans DB. Effect of preoperative biliary decompression on pancreaticoduodenectomy-associated morbidity in 300 consecutive patients. Ann Surg 2001; 234:47-55.
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Level of Evidence Table
Best level of evidence
Multidetector computed tomography (MDCT) with pancreas-protocol contrast is the minimum imaging modality required for evaluating pancreatic lesions. Endoscopic ultrasound (EUS) adds complementary diagnostic information regarding resectability and tumor histology.
EUS-guided FNA for analysis of pancreatic cyst fluid (amylase, CEA, CA19-9, cytology) may help diagnose the lesion to guide further therapy.
Serum CA 19-9 level is currently the most useful biomarker in the diagnosis and follow-up of pancreatic adenocarcinomas.
Routine preoperative biliary drainage of obstructive jaundice should not be performed (see Recommendations Table for Cholangiocarcinoma).
Neoadjuvant therapy for resectable pancreatic cancers has clear rationale but unproven benefits over adjuvant therapy.
Neoadjuvant therapy for borderline resectable pancreatic cancers may improve R0 resectability and thus survival.
Pylorus-preserving and standard pancreaticoduodenectomy are equivalent approaches to resection in terms of morbidity and survival. Pylorus-preservation is associated with lower blood loss and operative time.
Standard lymphadenectomy has equivalent survival with less morbidity compared to extended lymphadenectomy during pancreaticoduodenectomy for cancer.
No agents have been clearly demonstrated to reduce the rate of pancreatic fistula after operation. Somatostatin may be beneficial for small pancreatic ducts.
Pancreatic Cancer Contd... Adjuvant chemotherapy improves survival in resected pancreatic cancer. The benefit of adjuvant radiation for local control after resection is less clear.
Gemcitabine is the agent of choice in single- and combination chemotherapeutic regimens for pancreatic cancer.
Consensus guidelines regarding the management of main duct IPMN (resection), branch duct IPMN (selective resection) and mucinous cystic neoplasms (resection) have been at least retrospectively validated in different clinical centers.
Long-term surveillance for recurrence of IPMN is required for lesions treated by partial pancreatectomy.
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