pancreatic and periampullary carcinoma …chapter 5 • pancreatic and periampullary carcinoma...

C H A P T E R

5 Pancreatic and PeriampullaryCarcinoma (Nonendocrine)TAYLOR A. SOHN • CHARLES J. YEO

Ductal adenocarcinoma is the most common primarymalignant disease of the pancreas and periampullary re-gion. It accounts for more than 75% of all nonendocrinetumors arising in this region, which includes the pan-creas, the ampulla of Vater, the distal common bile duct,and the perivaterian duodenum. Pancreatic adenocarci-noma is the most common of the periampullary neo-plasms. In the United States, the annual incidence ofpancreatic cancer is 9 cases per 100,000 population;it ranks eleventh among all cancers and ninth amongnondermatologic cancers. It remains the most lethal can-cer, with an overall 5-year survival rate of less than 3% anda death-to-incidence ratio of approximately 0.99. Becausemore than 28,000 persons in the United States are ex-pected to die of pancreatic cancer in 2000, it is the fifthleading cause of cancer deaths in this country.1 Thischapter largely focuses on pancreatic adenocarcinoma.

Ampullary, distal common bile duct, and duodenaladenocarcinomas are less common than pancreatic tu-mors. They account for 15 to 20% of all periampullarymalignant diseases. Arising in the same region, they areassociated with similar clinical presentations and manage-ment algorithms, but these tumors have different survivalrates. These entities are discussed briefly in this chapter.

EPIDEMIOLOGY AND RISK FACTORS

Demographic Patterns

The risk factors for pancreatic cancer have been wellstudied and are summarized in Table 5–1. From 1920 to1978, the incidence rates of pancreatic cancer in theUnited States increased nearly threefold, and they subse-quently have plateaued. In nearly all European countries,a similar increase has been observed, with incidence ratesthat continue to rise. A portion of this apparent increasemay have resulted from misclassification of pancreaticcancers as other cancers, particularly gastric cancer, earlyin the 1900s. However, several subsequent analyses haveindicated that part of the increase is real, despite con-founding factors.2–4

Advancing age is a risk factor for pancreatic cancer,with 80% of cases occurring in patients 60 to 80 years ofage. The gender distribution of pancreatic cancer hasnearly equalized, and the incidence is slightly higher inmales. Blacks have the highest worldwide risk of pancre-

atic cancer, a risk approximately 30 to 40% higher thanthat observed in whites.2

In population studies in the United States, pancreaticcancer occurs more frequently among Jews than amongRoman Catholics or Protestants. A similar pattern is ob-served among Jews and non-Jews in Israel. Mormons inUtah have been reported to have a lower incidence ofpancreatic and other smoking-related cancers. However,this decrease is also seen in non-Mormons living in Utah,a finding suggesting that environmental factors may playa significant role. Some evidence indicates that migrantstatus is a risk factor. Immigrants from Japan have athreefold higher risk of developing pancreatic cancerthan do children born in the United States of Japaneseimmigrant parents and a 1.7-fold higher risk than whitesin the United States.2

From a worldwide perspective, pancreatic cancer ratesare highest in Western and industrialized countries andlowest in developing nations. An exception is noted inthe Maoris, a Polynesian people native to New Zealand,who have incidence rates similar to those seen in devel-oped countries.5

Host Factors

Host factors play an important role in the developmentof pancreatic cancer. The most striking examples are thesix genetic syndromes associated with an increased riskof developing pancreatic cancer. These syndromes arehereditary nonpolyposis colorectal cancer (HNPCC), fa-milial breast cancer associated with BRCA-2 mutations,Peutz-Jeghers syndrome, ataxia-telangiectasia syndrome,familial atypical multiple mole–melanoma syndrome(FAMMM), and hereditary pancreatitis. In addition to thegenetic syndromes, pancreatic cancer has been noted toaggregate in families. Evidence from the National FamilialPancreas Tumor Registry (NFPTR) at the Johns HopkinsHospital in Baltimore indicates that members of familieswith two or more first-degree relatives affected by pancre-atic cancer have at least a 16-fold increased risk of devel-oping pancreatic cancer. this finding could be accountedfor by a common nongenetic environmental exposure;however, evidence suggests that this observed familialaggregation has some genetic basis.6

Chronic pancreatitis, which is most commonly relatedto alcoholism, has been associated with an increased riskof developing pancreatic cancer. Although several studies

5-5002 Volume III • Pancreas

Table 5–1. Epidemiology and Risk Factors

Increased Risk Possible Risk Unproven Risk Decreased Risk

Demographic Factors: Advancing age Geography Socioeconomic statusBlack race Migrant statusMale genderJewish ethnicity

Host Factors: Hereditary nonpolyposis colorectal cancer Diabetes Peptic ulcer surgery TonsillectomyFamilial breast cancer Chronic pancreatitis Cholecystectomy Allergic disordersPeutz-Jeghers syndrome Endocrine tumorsAtaxia-telangiectasia Cystic fibrosisFamilial atypical multiple-mole melanoma Sex hormonesHereditary pancreatitis Pernicious anemia

Environmental Factors: Tobacco Diet AlcoholOccupation Coffee

Radiation

*From Gold, E.B., and Goldin, B.: Epidemiology of and risk factors for pancreatic cancer. Surg. Oncol. Clin. North Am., 7:67, 1998, with permission.

demonstrate such an increased risk,2,7–9 others suggestthat an increased risk is observed only when the diagno-sis of chronic pancreatitis precedes the diagnosis of can-cer by less than 10 years.10 These data imply either acommon risk factor for the two diseases or the suggestionthat chronic pancreatitis may represent an indolent pre-sentation of pancreatic cancer.

The data regarding the association of diabetes andpancreatic cancer are inconsistent. Most studies do notdemonstrate an association of diabetes with pancreaticcancer, except when cases are included in which diabeteswas diagnosed 1 to 5 years before the patient developedpancreatic cancer. Chow and colleagues11 demonstratedan increased risk only in patients developing diabetesafter age 40, whereas LaVecchia and colleagues12 showeda decreased risk with increasing time after the diagnosisof diabetes. These data suggest that diabetes is likely anearly symptom of pancreatic cancer rather than a caus-ative factor. These data are inconsistent with several otherstudies demonstrating an increased risk over time.13,14

Several other host factors have been associated withpancreatic cancer. These include thyroid tumors, otherbenign endocrine tumors, and cystic fibrosis.15 Equivocalresults have been obtained regarding the influence of sexhormones on the development of pancreatic cancer, butsome authors report an association.2,16 In Sweden, perni-cious anemia has been associated with an increased risk.2

Inconclusive data link previous peptic ulcer surgery andcholecystectomy to pancreatic cancer.17

Environmental Factors

A large body of evidence links cigarette smoking to pan-creatic cancer. Nitrosamines and tobacco smoke havebeen shown to be carcinogenic for the pancreas in animalstudies. In addition, human autopsy studies reveal hyper-plastic changes with atypical nuclear patterns in the pan-creatic ductal cells of smokers. Several prospective stud-ies evaluating death from pancreatic cancer in smokershave demonstrated increased risk ratios ranging from 2to 16.2 Some, but not all, studies demonstrated a dose-response relationship with either the number of ciga-rettes smoked or the duration of smoking.

Several reviews have examined the relationship of di-etary factors to the development of pancreatic can-cer.2,18,19 Despite conflicting data, some generalizationscan be made. Pancreatic cancer appears to be associatedwith increased total energy intake, as well as increasedintake of carbohydrate, cholesterol, meat, salt, dehydratedfood, fried food, refined sugar, soybeans, and nitrosa-mines. Fat, beta carotene, and coffee are of unprovenrisk, whereas dietary fiber, vitamin C, fruits, vegetables,absence of preservatives, raw foods, pressure cooking,and microwave cooking may have a protective effect.

Alcohol, coffee, and radiation exposure do not appearto be risk factors for the development of pancreaticcancer despite conflicting reports. When controlling forage, gender, smoking, socioeconomic status, and amountof alcohol consumed, three case-control studies fromEurope failed to demonstrate an association between al-cohol and pancreatic cancer.2 Despite past reports ofincreased risk of pancreatic cancer with coffee consump-tion,20,21 numerous subsequent reports have reported noassociation between the two. On the basis of these data,if an association exists, it is likely weak. The pancreasappears to be relatively insensitive to ionizing radiation,as demonstrated by studies evaluating the survivors ofthe bombings of Hiroshima and Nagasaki. These studieshave shown no increased risk of pancreatic cancer.23,24

Risk Factors for Other PeriampullaryCancers

Other periampullary cancers including distal commonbile duct, ampullary, and duodenal cancers are less com-mon and therefore are less well characterized in terms ofrisk factors. All are associated with increased age, withpeak incidences in the 60- to 80-year range. Distal com-mon bile duct cancers are associated with several knownhost factors in addition to advanced age. These includeinflammatory bowel disease, sclerosing cholangitis,choledochal cysts, and intrahepatic or common bile ductstones. In addition, a geographic association has beennoted for bile duct cancers, with clusters observed insome parts of the United States. Duodenal and ampullarycancers occur with increased frequency in patients with

Chapter 5 • Pancreatic and Periampullary Carcinoma (Nonendocrine) 5-5003

hereditary polyposis syndromes including HNPCC, Peutz-Jeghers syndrome, familial adenomatous polyposis, andGardner’s syndrome.

PATHOLOGY

Cancer of the pancreas and periampullary region canbe broadly classified as primary, metastatic, or systemic.Primary cancers arise in the pancreas or other periampul-lary sites and can demonstrate either endocrine or nonen-docrine differentiation. Ductal adenocarcinoma is by farthe most common periampullary malignant disease. Acareful analysis has yielded a large variety of histologicsubtypes.24,25

Primary Solid Nonendocrine EpithelialTumors

Ductal adenocarcinoma, the most common primarypancreatic malignant disease, accounts for approximately75% of all primary nonendocrine cancers. The head,neck, and uncinate process of the pancreas harbor 65%of all ductal carcinomas. In many cases, the tumor arisesin close proximity to the genu (or knee) of the mainpancreatic duct. An additional 15% of these tumors origi-nate in the body and tail of the pancreas, whereas another20% of lesions diffusely involve the gland. On gross sec-tion, ductal adenocarcinomas are white-yellow, poorlydefined, firm masses that often obstruct the main pancre-atic duct or common bile duct and lead to postobstruc-tive dilatation.26

Because of the tumor’s infiltrative nature, appreciatingthe true extent of neoplasm is often difficult intraopera-tively. Microscopic analysis often demonstrates tumor ex-tending beyond the grossly defined mass.26 On histologicanalysis, ductal adenocarcinomas contain infiltrativeglands of various shapes and sizes surrounded by anintense desmoplastic response (Fig. 5–1). The nuclei ofthe cells often show marked pleomorphism, hyperchro-masia, loss of polarity, and prominent nucleoli. The epi-thelial cells often contain mucin and may form papillaeand cribriform structures. These tumors frequently in-vade the vascular, lymphatic, and perineural spaces (Fig.5–2). Such invasion is associated with a reduction in sur-vival.

Ductal adenocarcinomas are typically aggressive tu-mors; most resected adenocarcinomas have already me-tastasized to regional lymph nodes. Moreover, these tu-mors may grow by direct extension to involve thecommon bile duct, duodenum, stomach, spleen, trans-verse mesocolon and colon, and adrenal glands. At thetime of death, up to 80% of patients have liver metastases,60% have peritoneal implants, 50 to 70% have metastasesto the lungs or pleura, and 25% have metastases to theadrenal glands.

Increasing evidence suggests that pancreatic ductaladenocarcinoma has identifiable precursor lesions.26 Inpancreata resected for pancreatic cancer, the epithelialcells adjacent to the tumor often show high-grade dyspla-

Figure 5–1. A moderately differentiated ductal adenocarcinoma, whichcontains infiltrative glands of varous shapes and sizes surrounded bydense fibrous tissue. The duct forming cells are markedly atypical.(Original magnification, �100; from Wilentz, R.E., and Hruban, R.H.:Pathology of cancer of the pancreas. Surg. Oncol. Clin. North Am.,7:43, 1998, with permission.)

sia or atypia (Fig. 5–3).27 Investigators have shown thatpapillary ductal lesions are three times more common inpatients with pancreatic cancer than in normal pan-creata.25 In addition, three-dimensional mapping tech-niques have demonstrated a stepwise transformation frommild to severe dysplasia in pancreatic duct lesions,28 andseveral cases have been reported in which ductal adeno-carcinomas developed after the diagnosis of high-gradepancreatic intraepithelial neoplasia was made.29 Finally,ductal lesions display some of the same genetic changesas infiltrating carcinomas, specifically k-ras, p53, and p16mutations, findings further supporting the existence of aprecursor progression sequence.27

Ductal adenocarcinomas of the pancreas, ampulla ofVater, distal common bile duct, and duodenum may bedifficult to differentiate prior to microscopic evaluation.Histologically, the site of tumor origin is identified by (1)

Figure 5–2. Ductal adenocarcinoma with perineural invasion. (Originalmagnification, �200; from Wilentz, R.E., and Hruban, R.H.: Pathologyof cancer of the pancreas. Surg. Oncol. Clin. North Am., 7:43, 1998,with permission.)


Figure 5–3. Progression (left to right) from normal ductal epitheliumto low-grade pancreatic intraepithelial neoplasia, to high-grade intraepi-thelial neoplasia, and to infiltrating cancer. (From Wilentz, R.E., andHruban, R.H.: Pathology of cancer of the pancreas. Surg. Oncol. Clin.North Am., 7:43, 1998, with permission.)

looking for a component of carcinoma in situ in thepancreatic duct, ampulla of Vater, distal common bileduct, or duodenum and (2) determining where the tumoris centered (Fig. 5–4).30 It is important to differentiatethese tumors because they have varying prognoses.

Adenosquamous carcinoma is a variant of adenocarci-noma with both glandular and squamous differentiation.It occurs more frequently in patients with a history ofchemoradiation and has biologic behavior similar to thatof ductal adenocarcinoma.26

Giant cell carcinomas account for less than 5% ofsolid pancreatic malignant tumors. They arise with equalfrequency in the head, body, and tail of the gland andare characterized grossly as large, hemorrhagic tumors.Microscopically, these tumors contain large, uninucleatedor multinucleated tumor cells that are strikingly pleiomor-phic, with hyperchromatic, sharply angulated nuclei,

Figure 5–4. A histologic section including the duodenum (D), theampulla of Vater (AV), the distal bile duct (BD), the proximal pancreaticduct (PD), and the pancreatic parenchyma (PP). A distal bile ductcancer (CA) is shown. (From Yeo, C.J., Sohn, T.A., Cameron, J.L., et al.:Periampullary adenocarcinoma: Analysis of 5-year survivors. Ann. Surg.,227:821, 1998.

prominent nucleoli, and bizarre mitotic figures. Thesetumors appear to be associated with a poorer prognosisthan ductal cancers.

Acinar cell carcinomas have a distinct histologic ap-pearance, typically larger (often greater than 10 cm),fleshy, often hemorrhagic, forming acini, and lacking astrong desmoplastic response. Immunohistochemicalstains are often positive for trypsin, lipase, chymotrypsin,or amylase. In addition to biliary obstruction, up to 20%of patients with acinar cell cancers present with subcuta-neous fat necrosis, an erythema nodosum–like rash, pe-ripheral eosinophilia, and polyarthralgia. Patients withacinar cell cancers have a slightly better prognosis thando patients with the ductal counterparts of these tumors.

Pancreatoblastoma, or pancreatic cancer of infancy,occurs in children up to the age of 15 years. Thesetumors contain undifferentiated portions with back-to-back small cells in a syncytial growth pattern with eosino-philic cytoplasm and benign-appearing nuclei. The differ-entiated portions can demonstrate squamous, acinar, andendocrine differentiation. These tumors are uncommonand are associated with survival rates better than thoseseen in patients with ductal adenocarcinoma.

Primary Cystic Nonendocrine EpithelialTumors

Cystic neoplasms account for fewer than 15% of cysticpancreatic lesions. However, these entities are importantto recognize because their management is vastly differentfrom that of nonneoplastic pancreatic cystic lesions in-cluding pseudocysts, congenital cysts, and retentioncysts.

Serous cystic neoplasms, often called microcystic ade-nomas or glycogen-rich cystadenomas, vary in diameterand appear grossly as well-circumscribed, multiloculatedcysts with watery, clear, or brown fluid. Simple cuboidalcells line the cyst, separated from one another by dense,fibrous bands (Fig. 5–5). These lesions are more commonin women than in men. Most are benign, with only rarereports of metastases to lymph nodes.26

Figure 5–5. Serous cystadenoma. A layer of simple cuboidal cells linethe cysts, separated by fibrous bands. (Original magnification, �40;from Wilentz, R.E., and Hruban, R.H.: Pathology of cancer of the pan-creas. Surg. Oncol. Clin. North Am., 7:43, 1998, with permission.)


Figure 5–6. Mucinous cystadenoma. Tall, mucin-producing columnarcells line the cystic structure (top). Below the columnar cells is a dense‘‘ovarian’’ stroma, often seen in mucinous cystadenomas in women.(Original magnification, �100; from Wilentz, R.E., and Hruban, R.H.:Pathology of cancer of the pancreas. Surg. Oncol. Clin. North Am.,7:43, 1998, with permission.)

Mucinous cystic neoplasms range from benign tumorswith small cysts lined by a single layer of columnarepithelium to larger cysts associated with an infiltratingcomponent. They, too, are more common in women.These tumors often harbor a dense stroma beneath theepithelial cells, similar to that seen in the ovary (Fig.5–6). Microscopically, three different classes of mucinousneoplasms are seen: (1) mucinous cystadenomas, whichcontain a single layer of epithelium without atypia; (2)intermediate or borderline tumors, which may have cellu-lar atypia and more complex architecture including papil-lae; and (3) mucinous cystadenocarcinoma, with invasionof epithelial cells into surrounding stroma.26 In contrastto serous cystic neoplasms, mucinous cystic neoplasmsare precancerous lesions, and benign-appearing mu-cinous lesions may harbor small foci of invasive carci-noma. Therefore, all mucinous cystic neoplasms shouldbe resected completely. Patients with resected mucinouscystadenocarcinoma are observed to have 5-year survivalrates more than double those seen in patients with ductalpancreatic adenocarcinoma.

Intraductal papillary-mucinous neoplasms, alsoknown as intraductal mucin-hypersecreting neoplasms,mucinous duct ectasia, and intraductal papillary neo-plasms, contain columnar mucin-secreting cells with vary-ing degrees of atypia that line papillary projections. Theselesions reside within mucus-filled dilated pancreatic ductsand often diffusely involve the gland. They sometimesharbor k-ras mutations and may contain invasive carci-noma.31 Most patients have favorable outcomes after com-plete resection.

Solid and cystic papillary neoplasms, or Hamoudistumors, occur most commonly in women aged 30 to 50years. They are typically large tumors (5 to 15 cm) associ-ated with cysts, hemorrhage, and necrosis. Microscopi-cally, they contain solid, cystic, and papillary compo-nents. These lesions are typically benign, althoughmetastases have been reported.

Other Tumors

Beyond the scope of this chapter are other uncommontumors including malignant diseases metastatic to thepancreas, systemic malignancies, and mesenchymal tu-mors.26 The most common malignant diseases that metas-tasize to the pancreas are renal cell, breast, colorectal,small cell lung, and melanoma. Systemic malignant condi-tions involving the pancreas include leukemia and lym-phoma. The benign and malignant mesenchymal tumorsthat affect the pancreas include leiomyosarcoma, liposar-coma, schwannoma, and malignant fibrous histiocytoma.

MOLECULAR BIOLOGY OF PANCREATICCANCER

Pancreatic cancer, like many other malignancies, is adisease of acquired and inherited mutations in cancer-causing genes.32 These cancer-causing genes can be di-vided into three broad categories: tumor suppressorgenes, oncogenes, and DNA mismatch repair genes. Muta-tion in all three types of genes can accumulate to causepancreatic adenocarcinoma. Most pancreatic cancers aremultigenic. In an in-depth mutational analysis of 42 pan-creatic cancers by Rozenblum and colleagues,33 all 42tumors harbored k-ras mutations. Individual mutationalfrequencies of tumor suppressor genes p16, p53, DPC4,and BRCA2 were 82%, 76%, 53% and 10%, respectively.

Tumor Suppressor Genes

Tumor suppressor genes normally function to restraincell proliferation. Loss of function of these genes bymutation, deletion, chromosome rearrangement, or mi-totic recombination results in abnormally increased cellproliferation. At least five tumor suppressor genes areknown to play a role in the development of pancreaticcancer33,35 (Table 5–2). In order of decreasing frequencyof inactivation in pancreatic cancer, they are p16, p53,DPC4, BRCA2, and MKK4.

The p16 tumor suppressor gene, located on chromo-some 9p, is inactivated in approximately 95% of pancre-atic cancers.36,37 p16 is an important regulator of the cellcycle. The gene encodes for a protein that binds cyclinD-Cdk4 complexes. This subsequently inhibits the phos-phorylation of a number of growth and regulatory pro-

Table 5–2. Tumor Suppressor Genes in Pancreatic Cancer*

Gene Chromosome Location Frequency (%)

p53 17p 75p16 9p 80DPC4 18q 50BRCA2 13q 4–7MKK4 7p 4

*From Hruban, R.H., Peterson, G.M., Ha, P.K., et al.: Genetics of pancreaticcancer: From genes to families. Surg. Oncol. Clin. North Am., 7:1, 1998, with per-mission.


teins and leads to failure of cellular control and un-checked cellular proliferation.

The second most frequently inactivated tumor sup-pressor gene is p53, a well-characterized tumor suppres-sor that lies on chromosome 17p. It is inactivated inapproximately 75% of all pancreatic cancers.38 Like p16,the p53 gene encodes for an important regulator of thecell cycle. The p53 gene product is a nuclear DNA bind-ing protein that not only acts as a cell cycle check pointbut also serves to induce cell death (apoptosis). There-fore, mutations or deletions in the p53 gene lead to theloss of two important controls of cellular growth: theregulation of cellular proliferation and the induction ofcell death.

The DPC4 gene on chromosome 18q is inactivated inapproximately 50% of pancreatic cancers.39 The geneproduct of DPC4 appears to play a role in signal transduc-tion involving the transforming growth factor–beta recep-tor40. In contrast to p16 and p53, the inactivation of DPC4appears to be relatively specific for pancreatic cancer.41

The fourth major tumor suppressor gene known to beinactivated in pancreatic cancer is BRCA2, located onchromosome 13q.42 BRCA2 is inactivated in approxi-mately 7% of pancreatic cancers. The BRCA2 mutationappears to be an inherited germline mutation as opposedto the acquired mutations commonly seen in p16, p53,and DPC4.43

MKK4 (mitogen-activated protein kinase kinase 4), lo-cated on chromosome 17p, has been identified as a candi-date tumor suppressor gene in pancreatic cancer.44,45

MKK4 plays a central role in the stress- and cytokine-induced signal transduction pathway involving mitogen-activated protein kinase (MAPK) proteins. Approximately4% of pancreatic cancers appear to have mutations inMKK4.

Oncogenes

Oncogenes are derived from normal cellular genes calledproto-oncogenes that, when activated by a mutation oramplification, possess transforming properties. Activatingpoint mutations in codons 12, 13, and 61 of the k-ras gene are common genetic alterations in pancreaticcancer.46 Mutations in k-ras are present in 80 to 100% of

Table 5–3. Genetic Syndromes Associated with Pancreatic Cancer*

Syndrome Mode of Inheritance Gene Chromosome Locus

Hereditary pancreatitis AD Cationic trypsinogen 7q35HNPCC AD MSH2 2p

MLH1 3pPMS2 7pPMS1 2q

Familial breast cancer AD BRCA2 13qFAMMM AD p16 9pAtaxia-telangiectasia AR ATM 11q 22–23Peutz-Jeghers syndrome AD STK11 19p

AD � autosomal dominant, AR � autosomal recessive, FAMMM � familial atypical multiple-mole melanoma syndrome, HNPCC � hereditary nonpolyposiscolorectal cancer.

*From Hruban, R.H., Peterson, G.M., Ha, P.K., et al.: Genetics of pancreatic cancer: From genes to families. Surg. Oncol. Clin. North Am., 7:1, 1998, with permission.

pancreatic cancers, and most are located at codon 12. k-ras mutations impair the intrinsic guanosine triphospha-tase activity of its gene product and result in a proteinthat is constitutively active in signal transduction. Local-ization of these mutations to a single codon makes themrelatively easy to detect and makes k-ras a potential targetfor molecular-based screening tests for pancreatic cancer.

DNA Mismatch Repair Genes

DNA mismatch repair genes encode for proteins thatcorrect many errors that normally occur when DNA isreplicated. When these mismatch repair genes are dys-functional, errors in DNA replication are not repaired.Mutations in DNA mismatch repair genes can lead topancreatic cancer, as in the case of RER� (replicationerror–positive) tumors. In RER� tumors, mutations accu-mulate in normal simple repeated sequences locatedthroughout the genome, known as ‘‘CA’’ repeats. Thisleads to well-defined molecular phenotype called ‘‘micro-satellite instability.’’ An associated microscopic phenotypehas poor differentiation, pushing borders, and a syncytialgrowth pattern. Microsatellite instability occurs in ap-proximately 4% of pancreatic cancers.47

Familial Pancreatic Cancer

The familial aggregation of pancreatic cancer can be di-vided into two broad categories: those associated withknown clinical syndromes and those without such anassociation. Six genetic syndromes have been associatedwith pancreatic cancer: hereditary pancreatitis, HNPCC,familial breast cancer, FAMMM, ataxia-telangiectasia, andPeutz-Jeghers syndrome. The mode of inheritance, gene,and chromosomal location are summarized in Table 5–3.

Pancreatic cancers also aggregate in families withoutknown genetic syndromes. An analysis of the NFPTR atthe Johns Hopkins Hospital compared familial and spo-radic cases of pancreatic cancer. The results suggest thatfamilial aggregation has a genetic basis and is not duesolely to a nongenetic environmental factor.32 In contrastto other familial cancers, familial cases were found tooccur at a similar mean age as nonfamilial cases (65.8


years versus 65.2 years). In addition, familial cases had anincreased proportion of second primary cancers (23.8%versus 18.9%), first-degree relatives with any cancer(28.2% versus 14.9%), second-degree relative with anycancer (27.2% versus 12.1%), and second-degree relativeswith pancreatic cancer (3.7% versus 0.6%).32 Additionally,the NFPTR has gathered data concerning the prospectiverisk of pancreatic cancer in persons who have two orthree affected first-degree relatives with the tumor. Therisk is increased 16-fold with two affected first-degreerelatives, and it is 33-fold with three affected first-degreerelatives.48 Additional clinical and molecular data areneeded to characterize familial pancreatic cancer better.

GROWTH FACTORS

Increasing evidence suggests that the overexpression ofvarious polypeptide growth factors and their receptorsmay play a role in the development and biologic aggres-siveness of pancreatic cancers. These factors act in anautocrine or paracrine fashion at or near their site oforigin. They include epidermal growth factor, trans-forming growth factor–beta, fibroblast growth factors,and insulin and insulin-like growth factor.49

CLINICOPATHOLOGIC STAGING

The most commonly used staging system for pancreaticadenocarcinoma is the Union Internationale Contre leCancer (UICC) system, which is a tumor-node-metastasis(TNM)–based system (Table 5–4). The system allowsstage classification by primary tumor extent (T), regionallymph node involvement (N), and the presence or ab-sence of distant metastases (M), with determination offour stage groupings based on the TNM characteristics.50

A more complex staging system has been proposed by

Table 5–4. Union Internationale Contre le Cancer Staging of Pancreatic Cancer*

Stage Grouping T N M 5-Yr Survival

Stage I T1 or T2 N0 M0 20–40%Stage II T3 N0 M0 10–25%Stage III Any T N1 M0 10–15%Stage IV Any T Any N M1 0–8%

Tumor (T)

T1 � Limited to pancreasT2 � Extension directly to duodenum, bile duct, or peripancreatic tissuesT3 � Extension directly to stomach, spleen, colon, or adjacent large vessels

Lymph Nodes (N)

N0 � No lymph node metastasesN1 � Lymph node metastases

Distant Metastasis (M)

M0 � No distant metastasisM1 � Distant metastasis

*From Yeo, C.J., and Cameron, J.L.: Pancreatic cancer. Curr. Probl. Surg., 36:3, 1999, with permission.

the Japan Pancreas Society (Table 5–5), including addi-tional factors such as serosal invasion (S factor), retroperi-toneal invasion (RP factor), and portal venous invasion(PV factor). Because of its cumbersome nature, this sys-tem has not gained common use.51

DIAGNOSIS, IMAGING, AND STAGING

Clinical Presentation

Patients with pancreatic and other periampullary neo-plasms often have vague symptoms early in the course oftheir disease. These symptoms often go unrecognizedand lead to a delay in diagnosis.52 Approximately 65 to75% of patients with pancreatic cancer come to medicalattention when they develop obstructive jaundice sec-ondary to obstruction of the intrapancreatic portion ofthe common bile duct. The jaundice is often associatedwith pruritus, acholic stools and dark urine. Despite theteaching that pancreatic carcinoma classically presentswith painless jaundice, most patients experience pain aspart of their presenting symptoms. Early in the course,the pain is often described as a vague upper abdominal,epigastric, or back discomfort. The pain can progress tounremitting epigastric pain radiating to the back. Weightloss and other constitutional symptoms including an-orexia, fatigue, and change in bowel habits are seen inthe majority of patients. Nausea and vomiting, usually asa result of early gastric outlet or duodenal obstruction,can occur frequently in this patient population and maybe an ominous sign of locally advanced disease.

Occasionally, pancreatic cancer can present in an un-usual manner. Asymptomatic patients may be found tohave elevated liver function tests on routine laboratoryscreening. New-onset diabetes mellitus may be the firstsign in approximately 10% of patients.53 Anemia second-ary to gastrointestinal blood loss from erosion of thetumor into the duodenum is seen infrequently. Acute


Table 5–5. Japan Pancreas Society Stage Classification*

Stage Grouping T S RP PV N M 5-Yr Survival

Stage I T1 S0 RP0 PV0 N0 M0 35–45%Stage II T2 S1 RP1 PV1 N1 M0 15–25%Stage III T3 S2 RP2 PV2 N2 M0 5–15%Stage IV T4 S3 RP3 PV3 N3 M1 0–10%

Tumor (T)

T1 � 0 to 2 cmT2 � 2.1 to 4 cmT3 � 4.1 to 6 cmT4 � �6.1 cm

Serosal invasion (S); Retroperitoneal invasion (RP); Portal venous invasion (PV)

0 � Absence of invasion1 � Suspected invasion2 � Definite invasion3 � Severe invasion

Lymph nodes (N)

N0 � No metastasisN1 � Primary lymph node group metastasisN2 � Secondary lymph node group metastasisN3 � Tertiary lymph node group metastasis

Distant metastasis (M)

M0 � No distant metastasisM1 � Distant metastasis

*From Yeo, C.J., and Cameron, J.L.: Pancreatic cancer. Curr. Probl. Surg., 36:3, 1999, with permission.

pancreatitis resulting from partial or complete obstruc-tion of the pancreatic duct may be the first sign of apancreatic neoplasm. It is therefore important to enter-tain the diagnosis of periampullary cancer in older pa-tients presenting with acute pancreatitis and no obviouscause (i.e., no history of alcohol abuse and no biliarytract disease).

Although patients with pancreatic and distal commonbile duct lesions are more likely to present with obstruc-tive jaundice, those with ampullary and duodenal primarytumors are less likely to be jaundiced and are morelikely to have signs of gastric outlet obstruction. Further,patients with lesions in the body and tail of the pancreasare more likely to have weight loss and abdominal pain,without jaundice. For this reason, left-sided pancreaticneoplasms are often diagnosed at a later stage and areassociated with a poorer prognosis.

At the time of diagnosis, common findings on physicalexamination include jaundice, hepatomegaly, and a palpa-ble gallbladder (Courvoisier’s gallbladder). Many patientshave skin irritation resulting from the extreme pruritusand resultant scratching. Cachexia and muscle wastingare often signs of advanced disease. A search for meta-static disease should be undertaken during the physicalexamination. Such findings include a nodular liver, leftsupraclavicular adenopathy (Virchow’s node), periumbili-cal adenopathy (Sister Mary Joseph’s node), and pelvicmetastases encircling the perirectal region (Blumer’sshelf ).

In patients with cancers of the head of the pancreasor periampullary region, serum total and direct bilirubin,alkaline phosphatase, and gamma-glutamyl transpeptidase

values are often markedly elevated, with associated mildelevations in the hepatic transaminases. Patients withpancreatic body and tail lesions often have normal labora-tory values early in their course and only develop liverfunction test abnormalities later, a finding indicating dif-fuse metastatic disease with involvement of the portahepatis. In patients with markedly elevated bilirubin lev-els, coagulation parameters should be checked. De-creased enterohepatic circulation of bile salts leads tomalabsorption of fat-soluble vitamins and subsequent de-creased hepatic production of vitamin K–dependent clot-ting factors. Hypoalbuminemia and normochromic ane-mia are often seen, reflections of poor nutritional statusas a result of the underlying neoplastic process.

Considerable effort has been made to find serum mark-ers for pancreatic cancer to facilitate early diagnosis. Atpresent, the best available marker is the carbohydrateantigen 19-9 (CA 19-9). Serum levels of CA 19-9 areelevated to levels higher than normal (37 units/ml) inapproximately 75% of patients with pancreatic cancer.CA 19-9 is also elevated in 10% of patients with benignconditions of the pancreas, liver, and bile ducts. A CA 19-9 level higher than the upper limit of normal has anaccuracy of 80% in identifying patients with pancreaticcancer. Higher cutoff values increase the accuracy andspecificity of the test, at the expense of decreasing thesensitivity.54 CA 19-9 as an independent test is not suffi-ciently sensitive or specific to warrant its use in popula-tion screening. In addition to diagnosis, CA 19-9 has beenuseful in following patients after resection of disease orduring adjuvant and neoadjuvant regimens. Increasinglevels of CA 19-9 reflect progression of disease, whereas


steady or declining levels suggest a stable tumor bur-den.55,56 Results of studies looking at other potential tu-mor markers including SPAN-1, CA-50, DUPAN-2, elastaseI, tissue polypeptide antigen, and tissue polypeptide-spe-cific antigen have all been disappointing, with accuracyrates lower than those seen for CA 19-9. TIMP-1 (tissueinhibitor of metalloproteinase-1) has been shown by se-rial analysis of gene expression (SAGE) methodology tohold promise as an improved serum marker for pancreaticcancer.57

About 90% of pancreatic cancers contain mutationsin the k-ras proto-oncogene. k-ras mutations have beendetected from duodenal juice, pancreatic juice, stool andfine-needle aspirates of patients with proven pancreaticadenocarcinoma.58–60 Although this test is not commer-cially available, the use of such molecular genetic markersin the early diagnosis of pancreatic cancer may be crucialfor earlier detection strategies.

Diagnostic Imaging

Diagnostic imaging modalities for patients with suspectedperiampullary neoplasms include ultrasonography, com-puted tomography (CT) scanning, magnetic resonanceimaging (MRI) and magnetic resonance cholangiopan-creatography (MRCP), endoscopic retrograde cholangio-pancreatography (ERCP), percutaneous transhepatic cho-langiography (PTC), and positron emission tomography(PET). With appropriate use of these studies, one shouldbe able to arrive at the diagnosis of pancreatic cancer inmore than 90% of patients presenting with the disease.

Standard transcutaneous abdominal ultrasound re-mains the most sensitive test for the detection of gall-stones and is useful in demonstrating a dilated intrahe-patic and extrahepatic biliary tree in cases of obstructivejaundice. Ultrasound examination can provide informa-tion about liver metastases, pancreatic masses, peripan-creatic adenopathy, and ascites, but it depends on boththe operator and the patient’s body habitus. Ultrasoundscans reveal a pancreatic mass in 60 to 70% of patientswith pancreatic cancer. However, the absence of a pan-creatic mass on ultrasound scanning does not definitivelyrule out pancreatic cancer. If a pancreatic mass is identi-fied, spiral CT is often indicated, because CT providesmore complete and accurate imaging of the pancreatichead and surrounding structures. It has largely sup-planted ultrasound as the initial diagnostic procedureof choice.

At present, high-quality spiral or helical CT is the singlemost useful staging modality.61 Pancreatic cancer usuallyappears as an area of enlargement in the pancreas, gener-ally as a hypodense, focal lesion (Fig. 5–7). CT scanningprovides useful information not only about tumor sizebut also about the extent of disease. Spread to the liver,peripancreatic lymph nodes, or retroperitoneal structuresmay be demonstrated. In addition, the CT scan can beused to evaluate major vessels adjacent to the pancreas(superior mesenteric artery and vein, portal vein, splenicvein, hepatic artery) for tumor invasion, encasement, orthrombosis (Fig. 5–8), to give useful information regard-ing resectability. Tumors smaller than 1 cm can be

Figure 5–7. A spiral computed tomographic image demonstrates alarge hypodense mass at the head of the pancreas in a patient withobstructive jaundice. Associated findings include dilated intrahepaticducts and a distended gallbladder. (From Yeo, C.J., and Cameron, J.L.:Pancreatic cancer. Curr. Probl. Surg., 36:3, 1999, with permission.)

missed, and intrahepatic and extrahepatic ductal dilata-tion may be the only finding on spiral CT. Such a findingis suspicious for malignancy and should be followed upby cholangiography (ERCP, MRCP, or PTC).

Advances in MRI technology suggest that it may playan increasing role in pancreatic imaging. Ultrafast spin-echo MRI has been reported to be more sensitive thanclassic CT scanning, but because of motion artifacts, lackof bowel opacification, low spatial resolution, and lowsignal-to noise ratio, MRI has not been shown to have adefinitive advantage over modern CT scanning.61 MRCPholds promise as a noninvasive technique to image thebiliary and pancreatic ductal systems in a fashion similar

Figure 5–8. A spiral computed tomographic image in a patient whohad new onset diabetes and abdominal pain. A large hypodense tumormass is visualized in the head of the pancreas. The superior mesentericartery is identified (arrow), but the superior mesenteric vein is oc-cluded by tumor, indicating unresectability. (From Yeo, C.J., and Cam-eron, J.L.: Pancreatic cancer. Curr. Probl. Surg., 36:3, 1999, with permis-sion.)


to ERCP (Fig. 5–9). Likewise, magnetic resonance angiog-raphy (MRA) provides a noninvasive technique to evalu-ate major vascular involvement when CT is equivocal.Thus, MRI or MRCP has the potential to provide informa-tion about tumor size and extent, biliary and pancreaticductal anatomy, and vascular involvement through a sin-gle, noninvasive procedure.

ERCP is a sensitive diagnostic test for pancreatic can-cer, with sensitivities in the range of 90%. The finding ofa long, irregular stricture in an otherwise normal pancre-atic duct or a ‘‘double-duct sign’’ (cutoff of both thepancreatic and distal bile duct at the level of the genu ofthe pancreatic duct) with an appropriate history is nearlypathognomonic for pancreatic cancer (Fig. 5–10). How-ever, with the current advances in CT and MRI technol-ogy, diagnostic ERCP is rarely necessary. ERCP or otherforms of cholangiopancreatography should be consideredin patients with common bile duct or pancreatic ductobstruction without the finding of a pancreatic mass onCT or MRI. ERCP can also be useful in distinguishingchronic pancreatitis from pancreatic cancer. Chronic pan-creatitis is usually characterized by multiple focal steno-ses of the pancreatic duct, with involvement of secondaryand tertiary radicles, whereas pancreatic cancer is usuallycharacterized by an abrupt cutoff of the pancreatic ductat a single location. Beyond its use in diagnosis, ERCPcan be used therapeutically in patients with significantjaundice, because endoscopic stents (endoprostheses)can be placed for decompression of the biliary tree.

PTC is another means of delineating biliary anatomyand can be accompanied by percutaneous biliary drain-age (PBD) for relief of jaundice. When compared withERCP and endoscopic drainage, PTC has the potentialadvantage of better defining proximal biliary anatomyand the level of biliary obstruction. However, PTC has

Figure 5–9. A single shot, spin-echo magnetic resonance cholangiopan-creatogram in a patient with obstructive jaundice. Both the commonbile duct and the pancreatic duct are dilated, and a hypointense areaof tumor (arrow) is apparent in the periampullary region. (From Yeo,C.J., and Cameron, J.L.: Pancreatic cancer. Curr. Probl. Surg. 36:3, 1999,with permission.)

Figure 5–10. An endoscopic retrograde cholangiopancreatogram in apatient with obstructive jaundice reveals a classic ‘‘double-duct’’ sign.There is evidence of a tumor at the genu of the common bile duct andthe pancreatic duct. (From Yeo, C.J., and Cameron, J.L.: Pancreaticcancer. Curr. Probl. Surg., 36:3, 1999, with permission.)

several disadvantages, including its more invasive andtraumatic nature, the risk of hemobilia, and the inabilityto visualize the pancreatic duct. In most cases, PTC orPBD is used only occasionally for patients with pancreaticor periampullary neoplasms and typically only after anunsuccessful ERCP.

The foregoing tests remain the mainstays of imagingin patients with suspected periampullary neoplasms. PETscanning, which uses the increased glucose metabolismof pancreatic cancer cells as the basis of imaging, hasbeen evaluated as a tool for the diagnosis of periampul-lary neoplasms.62 At present, studies have failed to dem-onstrate a dramatic advantage over spiral CT scanning.PET scanning may be better able to distinguish betweenchronic pancreatitis and pancreatic cancer, and it mayhave some increased sensitivity for delineating meta-static disease.

Upper endoscopy is useful in the diagnosis of primaryduodenal and ampullary neoplasms, because access bythe endoscopic route allows for direct tumor visualizationand acquisition of tissue by biopsy. In addition, upperendoscopy can evaluate the degree of duodenal invasionor narrowing by a periampullary lesion.

Tissue Diagnosis

The use of percutaneous pancreatic biopsy in the diag-nostic evaluation of patients with suspected pancreatic


neoplasms remains controversial. Biopsy under CT orultrasonic guidance can be performed with nearly 100%specificity and 70 to 80% sensitivity in experiencedhands.63 Although a positive histologic diagnosis of malig-nancy is reliable, because of sampling error, malignancycannot be ruled out with certainty when no malignantcells are found in the aspirate. Percutaneous biopsy cangenerally be performed safely, but rare complications in-cluding pancreatic fistula, pancreatitis, hemorrhage, ab-scess, and death have been reported. In addition, con-cerns exist regarding tumor dissemination resulting fromcapsular puncture of the neoplasm. Tumor seeding of thebiopsy tract has been reported.64

Currently percutaneous biopsy has no role in patientsat low operative risk who are thought to have resectabledisease. A negative biopsy in this group should not pre-clude exploration and resection and leaves no reason toperform a biopsy in this setting. Percutaneous biopsyshould be performed in patients who are believed to beat prohibitively high operative risk and in patients whosetumors are believed to be unresectable because of locallyadvanced or metastatic disease. These patients may becandidates for palliative chemoradiation therapy, whichcannot be performed without a tissue diagnosis. Further,percutaneous biopsy should be considered in patientswhose presentation and workup are not suggestive ofadenocarcinoma, but rather suggest more uncommon le-sions including neuroendocrine tumors, pancreatic lym-phomas, or tumors metastatic from another primary site,when such a diagnosis would dictate further manage-ment. Endoscopic access with biopsy or fine-needle aspi-ration (FNA) appears to be a more attractive means ofobtaining a tissue diagnosis, when one is necessary. Sucha practice may supersede percutaneous biopsy in the fu-ture.

Preoperative Staging

After making the diagnosis of periampullary cancer, theclinician should stage the tumor. In clinical practice, sub-stantial overlap exists between diagnosis and staging. Thestudies used in the diagnostic workup of patients withperiampullary cancer also aid in the staging or determina-tion of resectability. Liver or peritoneal metastases andlocally advanced cancers involving major vascular struc-tures are the most common reasons precluding resection.

Spiral CT is not only the single most useful tool in thediagnosis of periampullary neoplasms, but it also servesas a major staging tool.61 CT accurately detects liver me-tastases larger than 2 cm, but it frequently misses thosesmaller than 1 cm. CT is not highly accurate in determin-ing retroperitoneal adenopathy or extension of tumor orin identifying peritoneal carcinomatosis in the absence ofascites. However, CT provides a great deal of informationregarding local resectability. The preservation of fatplanes around major peripancreatic vascular structuresincluding the celiac axis, superior mesenteric vessels, andportal vein suggests no invasion of these structures bythe tumor and is predictive of resectability.65 Occlusionof the portal vein or superior mesenteric vessels andevidence of periportal collateral vessels indicate unresect-

ability and preclude curative resection for lesions in thepancreatic head, neck, or uncinate process. For pancre-atic body and tail lesions, the splenic vein is often com-promised or occluded by tumor; however, this finding byitself is not a contraindication for resection.

Angiography was once the standard for the determina-tion of vascular involvement by periampullary cancers.This method is now controversial; some studies havedemonstrated that angiography enhances the reliabilityof CT, and other studies have shown that high-qualityspiral CT can predict resectability better than angiogra-phy. Angiography is useful in diagnosing vascular invasionby tumor (Fig. 5–11) as well as vascular anomalies thatmay be clinically relevant (i.e., replaced right hepaticartery, stenosis of the celiac trunk). However, the experi-enced pancreatic surgeon should be able to identify theseanomalies at the time of surgery. Pancreatic cancers,which infiltrate into surrounding tissues, are often associ-ated with a desmoplastic response. The finding of venousencasement on an angiogram, often believed to representtumor involvement of major venous structures, may in-stead be the result of this desmoplastic response. Angiog-raphy should be applied selectively when a question ofvascular involvement on spiral CT exists. In addition,angiography is useful for patients in whom intraoperativeassessment of major vessel involvement may be difficult,such as those who have undergone previous pancreaticor hepatobiliary surgery or those with a history of priorneoadjuvant chemoradiation therapy.

Endoscopic ultrasound (EUS) produces images of thepancreas using the wall of the stomach and duodenum

Figure 5–11. Angiography. The venous phase of a superior mesentericartery injection demonstrates encasement (narrowing) at the conflu-ence of the superior mesenteric and portal veins. (From Yeo, C.J., andCameron, J.L.: Pancreatic cancer. Curr. Probl. Surg., 36:3, 1999, withpermission.)


as an acoustic window. The addition of EUS-guided FNAcan also provide a tissue diagnosis in cases when one isdesired.66 Although highly accurate in assessing the sizeand extent of the primary tumor (Fig. 5–12) and in de-tecting invasion of the portal and mesenteric vessels,EUS cannot reliably detect lymph node involvement ormetastatic disease in the liver and must be used in combi-nation with CT or MRI scans.

A further controversy in the management of patientswith pancreatic and periampullary tumors involves therole of staging laparoscopy. Staging laparoscopy can beperformed safely on an outpatient basis using a 30-degreeangled laparoscope to evaluate the peritoneal surfaces,the pericolic gutters, the hemidiaphragms, the pelvis,and the surface of the liver. Biopsies of peritoneal, liver,or omental nodules as well as enlarged lymph nodes canbe performed. Experienced laparoscopists can perform amore extensive exploration including examination of thehilum of liver and the use of laparoscopic ultrasoundto look for deep liver metastases and major vascularinvolvement.67–71 The rate of positive peritoneal findingsin all patients with pancreatic cancer is reported to ap-proach 20 to 25%. However, patients with lesions in thehead of the pancreas have positive findings only 15 to20% of the time, compared with those with body andtail lesions, in which the incidence of positive findingsapproaches 50%.72–74 Some clinicians are proponents ofroutine staging laparoscopy in all patients with poten-tially resectable pancreatic cancer. The rationale for rou-tine laparoscopy is based on data suggesting that 20 to

Figure 5–12. Endoscopic ultrasound image, with a linear array echoen-doscope, demonstrates a mass in the head of the pancreas with novascular invasion of the superior mesenteric artery (SMA), superiormesenteric vein (SMV), or portal vein (portal). (From Yeo, C.J., andCameron, J.L.: Pancreatic cancer. Curr. Probl. Surg., 36:3, 1999, withpermission.)

40% of patients staged by other modalities including CT,MRI, ERCP, and EUS will have unexpected, small perito-neal or liver implants at the time of exploration. Propo-nents of this approach believe that nonoperative pallia-tion in these patients is equivalent to operative palliation,and therefore, diagnostic laparoscopy spares many pa-tients an unnecessary laparotomy. In contrast, other sur-geons (including our group at Johns Hopkins) believe thatpatients with head of the pancreas lesions and resultingobstructive jaundice, gastric outlet obstruction, or tumor-related abdominal and back pain are best managed withsurgical palliation including biliary-enteric bypass, gastro-jejunostomy, and chemical splanchnicectomy of the ce-liac axis.75–80 Using this strategy, laparoscopy is unneces-sary. In patients with body and tail lesions, the strategydiffers. These patients have a high incidence of peritonealmetastases and do not usually require biliary or gastricbypass for relief of symptoms. Laparoscopy can sparethese patients an unnecessary laparotomy, when eitherbile duct or gastric bypass has no therapeutic benefit.

PALLIATIVE THERAPY

Nonoperative Palliation

Despite a greater awareness of the disease and advanceswith imaging and diagnostic techniques, most patientswith periampullary adenocarcinoma have unresectabletumors at presentation. Only 15 to 20% of patients withpancreatic cancer have tumors that are resectable forcure at the time of presentation, because either meta-static disease or extensive local involvement precludesresection. Therefore, palliation of symptoms remains animportant component in the management of this disease.Palliation of patients with periampullary cancer is aimedat three major symptoms: obstructive jaundice, duodenalor gastric outlet obstruction, and tumor-associated pain.Traditionally, surgery has offered the primary means forpalliation of periampullary carcinoma. Concomitant withadvances and improvements in surgical therapy, someadvances have been made in the nonoperative palliationof these symptoms.

Patients found to have distant metastases, unresectablelocal disease, or disseminated intra-abdominal tumors areappropriate candidates for nonoperative therapy. In addi-tion, patients with debilitating disease in whom anesthe-sia and surgery are unsafe should be managed nonopera-tively. Nonoperative palliation is not reliable for duodenalobstruction. Therefore, patients with symptomatic duo-denal obstruction should be managed operatively withgastrojejunostomy whenever possible.81 Age alone is nota contraindication to surgical resection or palliation.82 Inpatients who are to be managed nonoperatively, a tissuediagnosis can be obtained by CT- or US-guided liver orpancreas biopsy, ERCP brushings, PTC brushings, or EUS-guided FNA.

Biliary Obstruction

Jaundice is present in most patients who have right-sidedpancreatic cancer. If untreated, obstructive jaundice can


lead to progressive liver dysfunction, hepatic failure, andearlier death. In addition, the pruritus associated withbiliary obstruction can be debilitating and refractory tomedical therapy. Biliary decompression can be achievedby either endoscopic or percutaneous transhepatic tech-niques in nearly all patients who are not candidates forsurgical intervention. Percutaneous and endoscopic palli-ation of obstructive jaundice can provide biliary tractdecompression with lower early morbidity than openbiliary bypass.83–86

The use of PBD was first reported in 1974 as anextension of diagnostic PTC.87 The procedure is nowstandardized and commonly performed. It is generallydone using local anesthesia with intravenous sedation.Diagnostic cholangiography first defines the site of ob-struction and serves as a guide for subsequent biliarydrainage (Fig. 5–13). After accessing of the biliary tree,which is often easy to accomplish secondary to intrahe-patic biliary dilatation, a guidewire is placed down theextrahepatic biliary tree, through the obstruction andinto the duodenum. A small (normally No. 8 French)stent is then placed over the guidewire to stent theobstruction (Fig. 5–14). The small, stiff catheter can sub-sequently be exchanged for larger-diameter, softer tubes.A period of external drainage is usually allowed to mini-mize the risk of cholangitis. The stent can then be ‘‘inter-nalized,’’ meaning turned off at the outside to allow allbile to flow into the duodenum. The internal-external

Figure 5–13. A percutaneous transhepatic cholangiogram in a patientwith obstructive jaundice. A malignant obstruction of the biliary tree isseen at the level of the junction of the common hepatic duct and cysticduct. Staples are visible from a previous laparotomy for peptic ulcerdisease. (From Yeo, C.J., and Cameron, J.L.: Pancreatic cancer. Curr.Probl. Surg. 36:3, 1999, with permission.)

Figure 5–14. A cholangiogram obtained after placement of an internal-external percutaneous transhepatic biliary drainage catheter. The cathe-ter traverses the obstruction in the head of the pancreas. The tip of thecatheter resides in the duodenum, distal to the ampulla. (From Yeo,C.J., and Cameron, J.L.: Pancreatic cancer. Curr. Probl. Surg., 36:3, 1999,with permission.)

biliary stents require maintainence, with catheter ex-changes and upsizing every 3 months to prevent cholan-gitis and recurrent jaundice secondary to stent occlusion.The problem of late biliary obstruction resulting fromstent occlusion may be improved by percutaneouslyplaced self-expanding metallic endoprostheses, whichhave gained popularity because of their lower incidenceof late occlusion.88 Overall, percutaneous external biliarydrainage can be accomplished in nearly 100% of patients;however, the percentage of patients in whom completeinternal drainage can be accomplished is lower.76 Compli-cations of PTC or PBD include hemobilia, bile peritonitis,bile pleural effusion, cholangitis, pancreatitis, and acutecholecystitis.76,89

The endoscopic approach offers several distinct advan-tages over percutaneous methods.89 Endoscopic examina-tion may reveal a periampullary tumor mass and canallow biopsy to provide a tissue diagnosis. In addition, apancreatogram can be obtained, to provide informationabout the site of origin of the tumor. After endoscopicexamination, a limited sphincterotomy is typically per-formed, and biliary cannulation is attempted. A guidewireis then manipulated proximal to the stricture, and anendoprosthesis is placed through the obstruction (Fig.5–15). Endoprosthesis diameters typically are No. 7 to 10French. The overall morbidity rate for endoscopic stent-


Figure 5–15. Cholangiogram demonstrating a self-expanding metallicendoprosthesis placed for palliation of an unresectable pancreatic can-cer. (From Lillemoe, K.D.: Palliative therapy for pancreatic cancer. Surg.Oncol. Clin. North Am., 7:199, 1998, with permission.)

ing is less than 35%, but major procedure-related morbid-ity is seen in fewer than 10% of patients. Cholangitis,hyperamylasemia, and pancreatitis are the most commoncomplications associated with this technique. As withpercutaneous stents, endoscopic stents require plannedremoval and replacement every 3 to 6 months to preventrecurrent jaundice and cholangitis. Expandable metallicprostheses can also be placed by the endoscopic route.90

One prospective randomized trial and several other com-parisons summarized in a 1992 review showed compara-ble success rates for the percutaneous and endoscopicapproaches.78,91 However, the endoscopic approach haslower procedure-related morbidity and mortality, so it isthe method of choice.

Four prospective randomized trials in the 1980s com-pared surgical biliary bypass with nonoperative biliarystenting and found that nonoperative methods of palliat-ing obstructive jaundice had equal short-term efficacywith lower early morbidity and mortality.83–86 However,recurrent jaundice was seen in 17 to 38% of nonopera-tively stented patients before they died,83–86 comparedwith fewer than 10% of patients in most series of opera-tive biliary decompression.78,80

Pain

At the time of death, most patients with unresectedpancreatic cancer experience significant pain. Unfortu-nately, the pain associated with pancreatic cancer is unre-mitting and incapacitating and is often poorly managed.The postulated causes of tumor-associated pain includetumor infiltration into the celiac plexus, pain associatedwith early satiety, gastrodudenal obstruction and gallblad-

der or biliary obstruction, increased parenchymal pres-sure caused by pancreatic duct obstruction, and pancre-atic inflammation. The pain is not typically relieved byrelief of gastric or biliary obstruction. Tumor-associatedpain is best treated with long-acting oral or topical analge-sics in appropriate doses.92 Poor pain control is often theresult of inadequate dosing. Pain management specialistsmay be required to help manage this difficult problem.For pain intractable to typical narcotic regimens, severalnonoperative palliative treatment modalities are available.These include CT-guided percutaneous celiac nerveblock, external-beam radiation therapy, and thoraco-scopic or endoscopic chemical splanchnicectomy.

Duodenal Obstruction

At the time of diagnosis, 30 to 50% of patients withpancreatic cancer complain of nausea and vomiting.However, actual mechanical obstruction of the duode-num occurs much less commonly.93 If this problem is notaddressed at the time of initial palliation, between 10 and15% of patients require gastrojejunostomy before theydie, and an additional 15 to 20% die with symptoms ofduodenal obstruction.75,78,79,83 Until recently, patients withmalignant duodenal obstruction had few options besidessurgical gastrojejunostomy or feeding tubes. Endoluminalapproaches with biliary-type expandable metallic stentsare being tested.94 Early results are based on small num-bers of patients, and further assessment is necessary todetermine the role of endoluminal stenting for malignantduodenal obstruction.

Operative Palliation

With accurate preoperative staging (short of laparos-copy), many tertiary centers report resectability rates forperiampullary cancers ranging from 67 to 89%.74,80,95–97

The determination of resectability is one goal of surgicalexploration in patients with periampullary adenocarci-noma.80 Palliative surgery is indicated in patients whosetumors are found to be unresectable at the time of lapa-rotomy intended for curative resection and in patientsconsidered good operative risks whose symptoms are notamenable to or well managed by current nonoperativepalliative techniques.

Obstructive Jaundice

The most commonly performed surgical procedures forthe relief of obstructive jaundice include hepaticojejunos-tomy or choledochojejunostomy, choledochoduodenos-tomy, and cholecystojejunostomy. Simple external drain-age through a T-tube is not an option because it createsa high-output biliary fistula that leads to electrolyte abnor-malities. Because of the proximity of the tumor to theanastomosis and the potential for duodenal obstruction,choledochoduodenostomy is associated with higher ratesof recurrent jaundice and is generally avoided in malig-nant biliary obstruction. Likewise, although cholecystoje-junostomy can be performed easily, it is not indicated inpatients with tumors located less than 2 to 3 cm from


the cystic duct–common hepatic duct junction, for fear ofcystic duct obstruction by tumor with resultant recurrentjaundice. Several studies comparing cholecystoentericwith choledochoenteric bypass suggested better long-term relief of jaundice with choledochoenteric by-pass.75,78

The favored technique is biliary-enteric bypass to thejejunum, performed as an end-to-side hepaticojejunos-tomy or choledochojejunostomy, with concomitant chole-cystectomy (Fig. 5–16). Although clinical studies havefailed to support an advantage with Roux-en-Y versusloop reconstruction, theoretic advantages exist to usinga Roux-en-Y limb. They include easier management ofbiliary-anastomotic leaks, a lower rate of cholangitis, andimproved mobility of the Roux limb to reach the hepatichilum.98 In a current series from the Johns Hopkins Hospi-tal using only choledochojejunostomy or hepaticojejunos-tomy, only 4% of operatively palliated patients had recur-rent jaundice before they died.80

Pain

At the time of operative palliation, chemical splanchni-cectomy can be performed to alleviate the debilitating

Liver

Gallbladder fossa

End-to-sidehepaticojejunostomy

Retrocolic jejunal loop

Ring catheter Transverse mesocolontacked to stomach

Duodenum Side-to-sideenteroenterosomy

Figure 5–16. The illustration depicts the anatomy after one method of palliative intervention. The biliary-enteric anastomosis is shown as aretrocolic end-to-side hepaticojejunostomy with a jejunal loop. A jejunojejunostomy was performed below the transverse mesocolon, to divert theenteric stream away from the biliary-enteric anastomosis. Also shown is a retrocolic gastrojejunostomy. (From Cameron, J.L.: Atlas of Surgery, vol.1. Toronto, B.C. Decker, 1990, p. 427, with permission.)

pain associated with pancreatic cancer. Intraoperativechemical splanchnicectomy was introduced by Coppingand colleagues in 1969.99 In 1993, the first and onlyprospective, randomized trial comparing introperativechemical splanchnicectomy with placebo was per-formed.100 The procedure was performed by injecting 20ml of 50% alcohol or saline placebo through a spinalneedle on either side of the aorta at the level of theceliac plexus (Fig. 5–17). The mean pain scores as deter-mined by a visual analog scale were lower in the groupreceiving the alcohol at all postoperative time points.These data support the use of chemical splanchnicec-tomy in all patients undergoing operative palliation forperiampullary neoplasms.

Duodenal Obstruction

Since the 1970s, the natural history of duodenal obstruc-tion in periampullary cancer has been extensively stud-ied. As previously mentioned, for those patients withoutduodenal obstruction at presentation, 10 to 15% requiregastrojejunostomy before they die, and an additional 15to 20% die with symptoms of gastroduodenal obstruc-tion.75,78,79,83 Despite these data, controversy remains re-


Bilateral injections of50% alcohol into

celiac ganglia

Celiacaxis

IVC

Ao

IVC

Ao

Figure 5–17. The technique of alcohol celiac nerve block; 20 ml of50% alcohol is injected on each side of the aorta (Ao) at the level ofthe celiac axis. IVC � inferior vena cava. (From Lillemoe, K.D., Cam-eron, J.L., Kaufman, H.S., et al.: Chemical splanchnicectomy in patientswith unresectable pancreatic cancer: A prospective, randomized trial.Ann. Surg., 217:447, 1993, with permission.)

garding the role of prophylactic gastrojejunostomy inpatients with unresectable disease. In a prospective, ran-domized trial from the Johns Hopkins Hospital, 87 pa-tients with unresectable periampullary adenocarcinomaand no signs of gastroduodenal obstruction were random-ized to receive either a retrocolic gastrojejunostomy or nogastrojejunostomy. In this series, no patients undergoingprophylactic gastrojejunostomy developed late gastricoutlet obstruction, whereas 19% of patients in the no-gastrojejunostomy group developed gastric outlet ob-struction requiring intervention.81 Although the operativetime was increased, the gastrojejunostomy did not in-crease morbidity, mortality, or length of stay, findingssuggesting that gastrojejunostomy should be performedroutinely in patients undergoing operative palliation. Wetypically perform a retrocolic, isoperistaltic gastrojejunos-tomy, using the jejunum 20 to 30 cm beyond the ligamentof Treitz. The horizontal gastrotomy is placed posteriorly,in the most dependent portion of the greater curve ofthe stomach. The incidence of delayed gastric emptyingwith this technique is reportedly low.81,99 Vagotomy is notroutinely performed because it may contribute to delayedgastric emptying. These patients have a limited life expec-tancy and are all managed with histamine (H2)-blockersor proton pump inhibitors to prevent marginal ulcerationat the gastrojejunal anastomosis.

RESECTIONAL THERAPY

Pancreaticoduodenectomy forPeriampullary Tumors

Halsted performed the first successful resection of a peri-ampullary tumor in 1898, and it involved local resectionof an ampullary cancer.100 Codivilla performed the firstunsuccessful en bloc resection of a periampullary can-cer,101 whereas Kausch performed the first successful enbloc resection using a two-stage approach.102 Whippleand colleagues popularized the procedure in the 1930sand 1940s.103,104 Although early reports described pancre-aticoduodenal resections that spared the pylorus, by themid-1970s, the procedure was routinely performed witha distal gastrectomy. The concept of pylorus preservationwas repopularized by Traverso and Longmire in 1978.105

Pylorus-preserving pancreaticoduodenectomy is now thefavored procedure because the gastric reservoir and thepyloric mechanism are kept intact. Some investigatorshave cautioned that pylorus preservation may compro-mise anticancer therapy, but this has not been supportedby our data.30,106 Distal gastrectomy is usually reservedfor tumors involving the first portion of the duodenum,pylorus, or distal stomach or for patients with ischemiaof the duodenal cuff after pylorus-preserving resection.

Operative Technique

The initial portion of the procedure is dedicated to thedetermination of resectability. The liver, visceral and peri-toneal surfaces, and omentum are examined thoroughlyfor metastases not detected in the preoperative workup.An extensive Kocher maneuver is then performed, byelevating the duodenum and head of the pancreas out ofthe retroperitoneum, assessing the superior mesentericvein and its branches, and palpating the superior mesen-teric artery pulse in its retropancreatic position. Thesuperior mesenteric vein is most easily identified duringthe extensive Kocher maneuver (Fig. 5–18). It can beseen running anterior to the third portion of the duode-num, often surrounded by adipose tissue with branchesfrom both the uncinate process and the transverse meso-colon.107 By mobilizing the gallbladder out of the gallblad-der fossa and following the cystic duct to its junctionwith the hepatic duct, the porta hepatis can be evaluatedfor tumor involvement. Early division of the common bileduct opens the plane to visualize the portal vein. If thetumor is localized to the periampullary region or head,neck, or uncinate process of the pancreas, with no evi-dence of distant metatstatic disease or major vascularinvolvement, the surgeon then proceeds with resection.With experience, many tumors that initially appear unre-sectable on the basis of local extension can be success-fully resected.108

Once the tumor is deemed resectable, the duodenumis divided approximately 2 cm distal to the pylorus byusing a linear stapling device. Likewise, the jejunum justbeyond the ligament of Treitz is cleared and divided. Thejejunum and duodenum are then brought to the patient’s


Figure 5–18. The superior mesen-teric vein (SMV) can be visualizedas an extended Kocher maneuver.At the level of the third portion ofthe duodenum (working laterallyto medially) the SMV is the firstand largest vascular structure run-ning anterior to the duodenum.The inset shows the gallbladder(GB). (From Cameron, J.L.: Rapidexposure of the portal and supe-rior mesenteric veins. Surg. Gyne-col. Obstet., 176:395, 1993, withpermission.)

right side, dorsal to the superior mesenteric vessels, tofacilitate dissection of the uncinate process from theright lateral aspect of the superior mesenteric vein. Thepancreatic neck is then divided with the electrocauteryunit, and the remainder of the head and uncinate processof the pancreas are dissected from the major vessels.

Many options for restoring gastrointestinal continuityexist. The most common reconstructive technique anas-tomoses the pancreas first, followed by the bile duct andthen the duodenum. The pancreatic anastomosis is mostfrequently performed as a pancreaticojejunostomy, in ei-ther an end-to-end or a end-to-side fashion. An alternativeform of reconstruction is by pancreaticogastrostomy,which has been reported to decrease the incidence ofpostoperative pancreatic fistula formation.108,109 However,in the only prospective, randomized trial of pancreatico-jejunostomy versus pancreaticogastrostomy, the pancre-atic fistula rate was equivalent.110 Controversy regardingthe optimal configuration of the pancreaticojejunostomy,the importance of duct-to-mucosa sutures, and the use ofpancreatic duct stents is ongoing. The biliary anastomosisis typically performed as an end-to-side hepaticojejunos-tomy, 10 cm distal to the pancreatic anastomosis. Finally,the duodenojejunostomy is performed 10 to 20 cm down-stream from the hepaticojejunostomy (Fig. 5–19).

Preoperative biliary stenting remains controversial.Multiple theoretic reasons to place preoperative biliarystents exist, including better definition of the level ofobstruction, relief of jaundice and pruritus, increasedease in performing the biliary anastomosis, and the pre-vention of biliary sepsis. Current data indicate that rou-tine preoperative biliary stenting is of no benefit andcarries potential risk, including an increased risk ofwound or infectious complications,111–113 as well as anincreased risk of pancreatic fistula formation.113 Stentingshould be used selectively in patients with obstructive

jaundice who will have a substantial delay between initialpresentation and definitive surgery, in patients with majorhepatic or hematologic abnormalities, in patients havingundergone previous biliary-bypass surgery, and in rarepatients with primary suppurative cholangitis. Themethod of stenting, endoscopic versus percutaneous,should be chosen based on local expertise.

Complications

The operative mortality rate for pancreaticoduodenec-tomy is currently less than 3% in centers specializing inpancreatic surgery.30,106,114–116 Despite low mortality rates,the incidence of postoperative complications remains ashigh as 40 to 50%.116 The two leading causes of morbidityare early delayed gastric emptying and disruption or leakat the pancreatic anastomosis (pancreatic fistula). Delayedgastric emptying is seen in up to 20% of patients.116

Although not life-threatening and usually self-limited, thiscondition can result in markedly prolonged lengths ofstay and increased hospital costs. The cause is likelymultifactorial, and the standard treatment involves paren-teral nutritional support and nasogastric decompression.Erythromycin, a motilin agonist, has been shown to im-prove gastric emptying after pancreaticoduodenec-tomy.117 Pancreatic fistula occurs in 10 to 15% of patientsafter pancreaticoduodenectomy.116 The morbidity re-sulting from a pancreatic leak is decreased by placingclosed-suction drains near the pancreatic anastomosis, tocreate a controlled fistula and to reduce the risk of intra-abdominal collections. By definition, a pancreatic fistulaoccurs 7 or more days postoperatively, when the drainoutput contains milky, amylase-rich fluid in excess of 50ml per day. In approximately 80% of patients, the pancre-atic leak seals with parenteral nutrition, nothing-by-month status, and maintainence of the pancreatic drains.


Figure 5–19. Pylorus-preserving pancreaticoduodenectomy. Top left,The structures resected include the following: the duodenum (exceptfor the initial 1 to 2 cm beyond the pylorus); the head, neck anduncinate process of the pancreas, with tumor (black); the gallbladder;and the distal extrahepatic biliary tree. Top right, The structures re-tained include the entire stomach, pylorus, proximal 1 to 2 cm of theduodenum, body and tail of the pancreas, proximal biliary tree, andjejunum distal to the ligament of Treitz. Bottom, The reconstruction isshown as a proximal end-to-end pancreaticojejunostomy, a hepaticojeju-nostomy decompressed with a percutaneous transhepatic catheter, anda distal duodenojejunostomy. (From Yeo, C.J., and Cameron, J.L.: Thepancreas. In Hardy, J.D. [ed.]: Hardy’s Textbook of Surgery, 2nd ed.Philadelphia, J.B. Lippincott, 1988, p. 718, with permission.)

An additional 15% will require radiologic intervention forimproved drainage. Five per cent may require reoperationfor intra-abdominal sepsis. Other complications are lesscommon and are summarized in Table 5–6.

Table 5–6. Complications in 650 ConsecutivePancreaticoduodenal Resections*

Percentage of Patients(%)

Overall complications 41Early delayed gastric emptying 19Pancreatic fistula 14Wound infection 10Intra-abdominal abscess 5Cholangitis 5Pneumonia 3Bile leak 3Pancreatitis 2

*From Yeo, C.J., Cameron, J.L., Sohn, T.A., et al.: Six hundred fifty consecutivepancreaticoduodenectomies in the 1990s: Pathology, complications and out-comes. Ann. Surg., 226:248, 1997, with permission.

Prognostic Factors for Head of thePancreas and Other Periampullary Cancers

The prognosis for patients with resected adenocarcinomaof the head, neck, or uncinate process of the pancreas isdetermined by multiple factors including tumor stage,biologic features, molecular genetics, perioperative fac-tors, and the use of adjuvant chemoradiation. Other peri-ampullary tumors including distal bile duct, ampullary,and duodenal adenocarcinomas are less common, andthe prognostic factors in these cancers are not as wellcharacterized as those for pancreatic cancers, but theoverall 5-year survival rate is better. In an analysis of long-term survivors with resected periampullary adenocarci-noma, the site-specific 5-year actual survival rates were15% for pancreatic cancer, 27% for distal bile duct cancer,39% for ampullary cancer, and 59% for duodenal cancer(Fig. 5–20). In this series, well-differentiated tumors, neg-ative resection margins, and negative nodal status wereindicators of a better prognosis for all periampullary can-cers.

For patients with pancreatic cancer, increasing clinico-pathologic stage has been associated with worseningprognosis. In addition, tumor biologic features and molec-ular genetics play a role in overall prognosis. Allisonand colleagues118 demonstrated that the DNA content ofpancreatic cancers can be segregated into diploid andaneuploid tumors, and patients with diploid tumors faredsignificantly better than those with aneuploid tumors.30,118

Accumulating evidence suggests that mutations in tumorsuppressor genes, oncogenes, and DNA mismatch repairgenes also influence prognosis. Patients with tumors har-boring p53 mutations have been shown to have a worseprognosis.27 As the number of tumor suppressor genemutations increases, the risk of death from cancer ap-pears to increase.33 In direct contrast, tumors with DNAmismatch repair mutations, so-called RER� tumors, have

Figure 5–20. The tumor-specific actual 5-year survival curves for thecohort of 242 patients treated by pancreaticoduodenectomy for periam-pullary adenocarcinoma. (From Yeo, C.J., Sohn, T.A., Cameron, J.L., etal.: Periampullary adenocarcinoma: Analysis of 5-year survivors. Ann.Surg., 227:821, 1998, with permission.)


Figure 5–21. The retroperitoneal dissection compo-nent of the extended lymphadenectomy. The retro-peritoneum is dissected from the hilum of the rightkidney (K) to the left lateral border of the aorta (Ao)in the horizontal axis, to expose the left renal vein. Inthe vertical axis, the dissection extends from the levelof the portal vein to below the level of the thirdportion of the duodenum (level of the inferior mesen-teric artery [IMA] origin). Here the gastric staple lineand pancreatic remnant (P) are being retracted towardthe upper right. The inferior vena cava (IVC) and aortaare fully exposed, and the right gonadal vein has beenpreserved. A curved vascular clamp gently occludesthe inferior aspect of the bile duct. The retroperito-neal fat and lymph nodes are being resected en bloc(bottom right). (From Yeo, C.J., Cameron J.L., Sohn,T.A., et al.: Pancreaticoduodenectomy with or withoutextended retroperitoneal lymphadenectomy for peri-ampullary adenocarcinoma: Comparison of morbidity,mortality and short-term outcome. Ann. Surg.,229:613, 1999, with permission.)

been associated with an improved prognosis.47 This find-ing is similar to the improved progress seen in patientswith HNPCC colorectal cancer, another group of tumorswith mutations in DNA mismatch repair genes. In ananalysis of 201 patients undergoing pancreaticoduodenec-tomy for pancreatic cancer, tumor diameter, lymph nodestatus, and resection margin status were found to beimportant predictors of survival by univariate and multi-variate analysis.30

Various intraoperative and technical factors have beenexamined in relation to overall prognosis. Some investiga-tors have suggested that extended retroperitoneal lymph-adenectomy may improve survival. For example, Pedraz-zoli and colleagues noted that patients with node-positivepancreatic cancer fared better after extended resection.119

The interim results of a prospective, randomized trialcomparing pancreaticoduodenectomy with or withoutextended retroperitoneal lymphadenectomy at JohnsHopkins (Fig. 5–21) suggested similar morbidity and mor-tality and no survival advantage for the extended lymph-adenectomy group (Fig. 5–22).120 However, the survivaldata are not yet mature enough to draw strong conclu-sions. In many analyses, factors such as the type of pan-createctomy performed (pylorus-preserving versus clas-sic), blood transfusions, and operative time wereevaluated, but none of these factors were independentpredictors of survival.30,121 Although single-institution ex-periences cannot consistently correlate intraoperative fac-tors with long-term outcome, published data from largestatewide registries have shown a relationship betweenhospital volume for pancreatic resection and periopera-tive mortality rates, length of hospital stay, hospital cost,

and long-term outcome.122–125 These important studiessuggest that regionalization of care will affect both thecost and the outcome for patients undergoing complexpancreatic procedures.

Another important prognostic factor for pancreatic

Figure 5–22. The actuarial survival curves for all patients who survivedthe immediate postoperative period, comparing the standard resection(n � 53) and the radical resection (n � 56) groups. The 1- and 2-yearsurvival rates were 77 and 47% for the standard group, respectively,compared with 83 and 56% for the radical group (P � .6, NS). (FromYeo, C.J., Cameron, J.L., Sohn, T.A., et al.: Pancreaticoduodenectomywith or without extended retroperitoneal lymphadenectomy for periam-pullary adenocarcinoma: Comparison of morbidity, mortality and short-term outcome. Ann. Surg., 229:613, 1999, with permission.)


cancer is the use of postoperative adjuvant chemotherapyand radiation therapy. Such therapy has been shown toimprove survival in most126–129 but not all analyses.130 In a1997 study, a multidisciplinary group at the Johns Hop-kins Hospital including surgeons, radiation oncologists,medical oncologists, and pathologists prospectively evalu-ated 174 patients with resected carcinoma of the head,neck, and uncinate process of the pancreas.121 This pro-spective study evaluated two different combined-modalityadjuvant chemoradiation therapy regimens and found thatadjuvant therapy significantly improved survival in amultivariate model. Based on these data and on earlierresults from the Gastrointestinal Tumor Study Group(GITSG),126,127 standard 5-fluorouracil (5-FU)–based che-motherapy and external-beam radiation therapy appearto be indicated after pancreaticoduodenectomy for pan-creatic adenocarcinoma.

Bile duct cancers or cholangiocarcinomas are best clas-sified as perihilar, distal, or intrahepatic. In a review of294 patients with cholangiocarcinoma, 27% were distal orperiampullary cholangiocarcinomas. The median survivalwas 22 months for distal bile duct tumors, with a 5-yearsurvival of 28%.131 Surgical resection, negative micro-scopic margins, preoperative nutritional status, and ab-sence of postoperative sepsis were the best predictorsof improved outcome. Adjuvant chemoradiation did notappear to prolong survival; however, the use of postoper-ative therapy has not been well studied for these tumors.

Adenocarcinoma of the ampulla of Vater is the secondmost common periampullary malignancy. Compared withpancreatic cancer, cancer of the ampulla of Vater has ahigher resectability rate and a better prognosis. In a seriesof 120 patients with resected ampullary cancer at theJohns Hopkins Hospital, the actuarial 5-year survival was38%.132 Factors favorably influencing long-term outcomeafter resection included no perioperative blood transfu-sions, negative lymph node status, and well-differentiatedor moderately differentiated tumors.

Of the periampullary neoplasms, adenocarcinoma ofthe duodenum is the least common, but it is associatedwith the best prognosis. In a series of 35 patients under-going pancreaticoduodenectomy for duodenal cancer, the5-year survival rate was 69%. Negative resection marginsand tumors located in the first and second portion of theduodenum appeared to influence survival favorably byunivariate analysis. Nodal status, tumor diameter, degreeof differentiation, and the use of adjuvant chemoradiationdid not influence survival.133

As the population of the United States ages, increasingnumbers of elderly patients may be considered for pan-creaticoduodenal resection. Data from the Johns HopkinsHospital demonstrate that pancreaticoduodenectomy forperiampullary adenocarcinoma can be performed safelyin selected octogenarians, with morbidity, mortality, andlong-term survival rates (Fig. 5–23) comparable withthose in younger patients. Age alone should not be acontraindication to potentially curative resection.82

Distal Pancreatectomy for Tumors of theBody and Tail

A few patients with pancreatic cancer have tumors aris-ing in the body and tail of the gland. Because these

Figure 5–23. Actuarial survival curves comparing patients 80 years ofage or older undergoing pancreaticoduodenectomy for periampullaryadenocarcinoma (n � 41; median survival, 32 months; 5-year survival,19%) to those younger than 80 years (n � 454; median survival, 20months; 5-year survival 27% P � 0.77). (From Sohn, T.A., Yeo, C.J.,Cameron, J.L., et al.: Should pancreaticoduodenectomy be performedin octogenarians? J. Gastrointest. Surg., 2:207, 1998, with permission.)

tumors do not obstruct the bile duct and cause earlyjaundice, the diagnosis of body and tail lesions is fre-quently delayed. As a result, tumors are often larger andmore likely to have local extension or metastatic spreadat the time of presentation, features that preclude resec-tion. In addition to routine staging including abdominalCT, staging laparoscopy appears to have an importantrole in patients with body and tail tumors, because occultmetastatic disease is present in the majority of thesepatients.

Should staging studies fail to reveal disseminated tu-mor or locally unresectable disease, curative resectionshould be attempted. The abdomen is first explored forevidence of metastatic disease as for pancreaticoduode-nectomy. The ligament of Treitz should be carefully evalu-ated, because tumors of the body and tail often invadethe fourth portion of the duodenum at the ligament. Thegastrocolic ligament should be opened to allow completeassessment of the tumor’s proximity to the ligament ofTreitz and the superior mesenteric vessels. Involvementof peripancreatic lymph nodes does not preclude resec-tion, but it diminishes the likelihood of long-term sur-vival.

If after careful exploration the tumor is thought to beresectable, the inferior surface of the pancreas is mobi-lized to assess retroperitoneal involvement. Although ex-tensive involvement of the retroperitoneum precludesresection, involvement of the splenic vessels does not.Splenic preservation is not indicated in distal pancreatec-tomy for pancreatic cancer. The spleen is mobilized withearly ligation of the splenic artery and short gastric ves-sels, to facilitate subsequent dissection of the pancreaticbody and tail from the retroperitoneum (Fig. 5–24). Ifnecessary, the inferior mesenteric vein can be taken with-out additional morbidity. The pancreas is then divided, toleave a 1- to 2-cm gross margin of normal parenchymafrom the tumor. The pancreatic margin should be sentfor frozen section and should be resected further, if nec-essary. Closure of the pancreatic margin can be per-formed with mattress sutures or with a linear stapler. Aclosed-suction drain is left near the pancreatic remnant


Figure 5–24. Near the completion of adistal pancreatectomy and splenectomyfor a tumor in the body of the pancreas.The spleen and tail of the pancreas havebeen mobilized out of the retroperito-neum. The pancreatic parenchyma is be-ing divided with the electrocautery. (FromCameron, J.L.: Atlas of Surgery, vol. 1. To-ronto, B.C. Decker, 1990, p. 27, with per-mission.)

Spleen

Tail of pancreas

Retroperitonealbed

Superiormesenteric a.

Superiormesenteric v.

Inferiorpancreaticoduodenalv.and a.

Tumor

to control any leak from the oversewn pancreatic paren-chyma and the divided main pancreatic duct.

If resection is not possible, several palliative maneu-vers should be considered. Chemical splanchnicectomyusing alcohol has been shown to reduce or prevent theprogression of pain and to reduce narcotic requirementsfor patients with unresected pancreatic head, neck, oruncinate cancers.76 If the tumor involves the ligament ofTreitz, consideration should be given to palliative gastro-jejunostomy to prevent late duodenal obstruction. Like-wise, if the tumor appears to be extending toward theporta hepatis, hepaticojejunostomy to prevent biliary ob-struction should be considered. However, this procedurecan be difficult in a nondilated biliary system. For thisreason, cholecystectomy alone to prevent acute cholecys-titis is currently favored, with subsequent placement ofan endoprosthesis should obstructive jaundice occur.

The resectability rate for distal pancreatic adenocarci-noma was approximately 10% before routine laparos-copic staging. The routine use of staging laparoscopydetects metastatic disease and prevents unnecessary lapa-rotomy. Overall, patients with resectable disease have apoor prognosis, with a median survival of 7 to 13 monthsand a 5-year survival of less than 10%.134–138 Tumor size,lymph node involvement, and surgical margins all appearto affect long-term survival. Data on the role of adjuvanttherapy for these tumors are limited.

CHEMORADIATION THERAPY

The major obstacle to postresection cure of pancreaticadenocarcinoma appears to be the burden of remaining

subclinical regional disease. This finding is confirmed byfour observations: (1) the pattern of lymphatic involve-ment identified when regional staging is performed; (2)the patterns of failure observed after pancreaticoduode-nectomy; (3) the impact of positive nodal and resectionmargin status on long-term survival; and (4) the reportsof improved survival with radical or extended lymphnode dissection during pancreatectomy. Radiation ther-apy and chemotherapy are the two mainstays for themanagement of this subclinical tumor burden.

Ionizing radiation in the form of external-beam radia-tion therapy, intraoperative radiation therapy, or brachy-therapy is damaging to both normal tissue and tumor.Numerous studies of radiation therapy in pancreatic can-cer have been reviewed.139 Similarly, the principles re-garding the use of systemic chemotherapy are wellknown and include the delivery of the maximal tolerateddose in repeated cycles, at the time of least possibletumor burden, using combinations of maximally effectivedrugs. The combination of chemotherapy and radiationincorporates the benefits of each therapy alone. Radiationtherapy deals with the tumor burden in the region fromwhich the tumor was resected, whereas chemotherapydeals with microscopic systemic disease. The two alsoact synergistically, whereby the combined effects yieldenhanced tumor killing beyond what would be seen witheither modality alone.

Adjuvant Therapy

Early observations on combined-modality therapy with 5-FU and radiation for gastrointestinal malignant diseases


were first presented by Moertel and colleagues.140 Thebenefit of 5-FU and radiation for pancreatic cancer wassubsequently confirmed by the GITSG in 1985 and 1987.The first study was a prospective, randomized trial evalu-ating 5-FU–based chemotherapy and external-beam radia-tion after pancreatic resection for pancreatic cancer.126

The 22 patients in the control arm had a median survivalof 11 months, compared with 21 months in the treatmentarm (P � .03). This finding was confirmed in the secondstudy by comparing 30 patients with historical controlsand demonstrating a comparable 18-month median sur-vival.127 Unfortunately, the slow accrual rates, the smallsample sizes, and the lack of concurrent controls in thelatter series weakened the data.

Bosset and colleagues128 evaluated radiation therapyalone in a prospective, randomized trial, showing a me-dian survival of 23 months with external-beam radiationtherapy alone. Similary, Bakkevold and colleagues129 eval-uated chemotherapy alone (5-FU, doxorubicin, and mito-mycin C) and demonstrated improved survival. In a pro-spective trial at the Johns Hopkins Hospital, patients withpancreatic adenocarcinoma were offered three optionsafter resection: (1) standard therapy with radiation tothe tumor bed and intermittent bolus 5-FU therapy; (2)intensive therapy, with radiation to the tumor bed as wellas prophylactic hepatic irradiation and continuous 5-FUinfusion; and (3) no adjuvant therapy. By univariate analy-sis, patients who received either type of adjuvant therapyhad a median survival of 19.5 months and a 2-year sur-vival rate of 39% (Fig. 5–25), which was significantlyimproved compared with those receiving no therapy(13.5 months and 30%, P � .003). By multivariate analy-sis, both adjuvant protocols had a significant impact onsurvival.121 The more intensive regimen did not appear toimprove survival over standard therapy. Additional, well-designed trials of new chemoradiation protocols areneeded to evaluate the role of adjuvant therapy further.

Neoadjuvant Therapy

Neoadjuvant therapy involves the use of chemoradiationbefore surgical exploration and attempted resection. Ma-

Figure 5–25. The actuarial survival curves for pa-tients undergoing pancreaticoduodenectomy compar-ing patients receiving adjuvant therapy (n � 120) tothose declining adjuvant therapy (n � 53; P � .003).(From Yeo, C.J., Abrams, R.A., Grochow, L.B., et al.:Pancreaticoduodenectomy for pancreatic adenocarci-noma: Postoperative adjuvant chemoradiation im-proves survival. A prospective, single institution expe-rience. Ann. Surg., 225:621, 1997, with permission).

jor proponents of neoadjuvant therapy suggest that theadvantages include decreased locoregional tumor burden,the sterilization of tumor before surgical manipulation,and earlier administration of systemic therapy.141,142 Afteradministration of neoadjuvant therapy, restaging with achest radiograph and abdominal CT scan is performed.Laparotomy is avoided in patients with disseminated dis-ease evident at restaging. Early reports of neoadjuvanttherapy used standard fractionation with concomitantbolus 5-FU.143 Newer approaches involve rapid fraction-ation with a smaller total radiation dose and continuous5-FU infusion.142 Local tumor control and patient survivalare equal with the rapid and standard fractionation tech-niques. The group from the M.D. Anderson Cancer Cen-ter in Houston reported the results of multimodality ther-apy in 142 patients with pancreatic cancer. Forty-one ofthese patients received neoadjuvant therapy and pancre-aticoduodenectomy. They were compared with 19 pa-tients treated with pancreaticoduodenectomy and adju-vant therapy. No patients receiving neoadjuvant therapyexperienced a delay in surgery, whereas 24% of the eligi-ble postsurgical patients did not receive the intendedadjuvant therapy secondary to prolonged recovery. Inaddition, with the rapid fractionation technique used inthe neoadjuvant protocol, patients receiving preoperativetherapy had a 1-month shorter total duration of treat-ment.144 Although the overall survival was similar in thetwo groups, locoregional or peritoneal recurrence wasmore common in the adjuvant therapy group (21%) thanin the neoadjuvant therapy group (10%)

The controversy between neoadjuvant and adjuvantproponents continues. The two regimens are difficult tocompare because up to one third of the patients inneoadjuvant protocols do not undergo tumor resectionas a result of disseminated disease at the time of restaging.Our current policy is to attempt resection when possibleand to reserve neoadjuvant therapy for patients withlocally unresectable tumors.

Palliative Therapy

In patients with unresectable disease, many antitumortherapies have been studied with limited success, includ-


ing trials of chemotherapy and radiation both alone andin combination. Gemcitabine, an agent that inhibits DNAreplication and repair, has been used in several trials. Inphase I and II trials, patients with advanced diseaseshowed subjective symptomatic benefit, without a dra-matic objective tumor response after treatment with gem-citabine.145,146 Gemcitabine appears to be an improve-ment over 5-FU–based therapy in advanced disease, witha 1- to 2-month improvement in median survival and withimproved pain control, performance status, and weightgain observed with gemcitabine. Gemcitabine is a power-ful radiosensitizer and is being evaluated in combined-modality regimens worldwide. Other agents currently be-ing evaluated include paclitaxel (Taxol), matrix metallo-proteinase inhibitors (marimastat), perillyl alcohol, andangiogenesis inhibitors.143

HORMONE THERAPY

Hormonal therapy is routinely used in some tumors in-cluding prostate, breast, endometrial, and ovarian can-cers. Some data suggest that hormonal therapy may alsobe beneficial in pancreatic cancer. In vitro and in vivoevidence indicates that estrogen promotes pancreaticcancer growth. In addition, sex steroid biosynthetic en-zymes have been localized to pancreatic cancers. Andro-gen receptors have been found on pancreatic cancercells, and testosterone has been shown to stimulate pan-creatic cancer cell growth. Based on these data, severaltrials of the antiestrogen tamoxifen have been performed,showing no benefit.147,148 In a multicenter Norwegiantrial, tamoxifen was noted to improve survival in post-menopausal women.

Two gastrointestinal hormones, cholecystokinin andgastrin, have been studied in pancreatic cancer.149 Investi-gators demonstrated that cholecystokinin antagonists in-hibited pancreatic carcinogenesis, but clinical trials failedto demonstrate an impact on tumor growth and wereattended by significant side effects.150,151

GENE THERAPY

The term gene therapy has been used to describe severalapproaches involving recombinant DNA technology. Thetechnology of gene transfer was first made possible inthe 1980s. Although the concept of gene therapy wasinitially founded on the correction of a single gene defectas in thalassemia and severe combined immune defi-ciency, it has now been applied to cancer, in whichmultiple genetic defects occur. Currently, many phase Itrials are using an array of gene transfer systems in manycancers. Unfortunately, human pancreatic cancer has notbeen well studied, owing primarily to its aggressive na-ture.

A phase I clinical trial of a cytokine-secreting pancre-atic cancer vaccine made from primary tumors has beenundertaken at the Johns Hopkins Hospital.151 Tumor cellvaccines in murine models have been engineered to se-crete cytokines in a paracrine fashion, which can, in

turn, elicit an immune response capable of eliminatingestablished tumors.152,153 The impact of vaccine therapyon the survival of patients with pancreatic cancer iscurrently unknown, but perhaps such therapy, combinedwith surgical resection and chemoradiation, may be asso-ciated with improved long-term outcomes.

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