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CONTROVERSIES IN CLINICAL PANCREATOLOGY

William M. Steinberg, MD, Chair,


Jamie S. Barkin, MD, FACP, MACG, Edward L. Bradley, III, MD,
Eugene DiMagno, MD, and Peter Layer, MD

Management of Pancreatic Masses


Daniel Wolfson, MD,* Jamie S. Barkin, MD, FACP, MACG,* Suresh T. Chari, MD,†
Jonathan E. Clain, MD,† Richard H. Bell, Jr., MD,‡ Nicholas Alexakis, MD,§
and John P. Neoptolemos, MA, MBBChir, MD, FRCSk

INTRODUCTION John P. Neoptolemos of the University of Liverpool presented


their forceful points for the positive.
Dr. William M. Steinberg
Traditionally, the approach to the patient presenting with
a resectable mass in the pancreas has been to take the patient to MEDICAL APPROACH
surgery without a preoperative biopsy. Because other entities
beside pancreatic adenocarcinoma may present with a mass Should a Patient With a Pancreatic Mass
not requiring surgical intervention, this approach was eval- Undergo Preoperative Biopsy?
uated at the November 2004 Controversies Section of the Drs. Daniel Wolfson and Jamie S. Barkin
American Pancreatic Association meeting. When a patient is found to have a pancreatic mass on
Under the direction of Dr. Jamie S. Barkin of the Uni- radiologic studies, one’s attention focuses on a neoplastic process.
versity of Miami, a panel of international experts was chosen However, there are many other causes of pancreatic masses,
to debate the merits of the preoperative biopsy of a patient including infectious, inflammatory, autoimmune, and neoplastic
presenting with a mass lesion. etiologies. We present a patient showing the difficulties of
First, Dr. Daniel Wolfson and Dr. Barkin presented evaluating a patient with a pancreatic mass (courtesy of Kamil
the differential diagnosis of pancreatic masses. This was fol- Obideen, Emory University School of Medicine, Atlanta, GA). A
lowed by the Mayo Clinic experience with non-neoplastic pancre- 49-year-old woman was referred for evaluation of a pancreatic
atic masses presented by Dr. Suresh T. Chari. Dr. Jonathan head mass that was incidentally discovered on an abdominal
E. Clain, also of the Mayo Clinic, discussed the pros and cons computed tomography (CT) scan performed after she had been in
of endoscopic ultrasound–guided biopsies of pancreatic mas- a motor vehicle accident. She had mild intermittent pruritus and
ses. Finally, 2 prominent surgeons with a con and pro approach intermittent epigastric discomfort radiating into her back. She was
to preoperative biopsy of pancreatic mass, Dr. Richard otherwise healthy, with no change in her appetite or weight loss.
H. Bell Jr., of Northwestern University, presented his cogent Her past medical history included a bilateral tubal ligation 15
arguments on the negative and Drs. Nicholas Alexakis and years ago. She did not take any medications, recreational drugs,
or alcohol. Her family history revealed that her mother had an
ovarian carcinoma and that her father had a prostate carcinoma.
Laboratory data included a white blood cell count of 7.6 3 109/L
(reference range, 5000–12,000 3 109/L), hemoglobin of 12.6
Received for publication June 8, 2005; accepted July 14, 2005.
g/dL, hematocrit (%) of 37.7 with a platelet count of 299,000 3
Discussants: From the *Department of Medicine, George Washington
University Medical Center, Washington, DC; †Division of Gastroenter- 109/L, and total protein of 8 g/dL, with an albumin of 3.4 mg/dL.
ology, University of Miami, School of Medicine/Mt. Sinai Medical Center, Her calcium was normal at 9.7 mg/dL. She had negative
Miami, FL; ‡Division of Gastroenterology and Hepatology, Mayo Clinic antinuclear antibodies (ANA), acute smooth muscle antibody
College of Medicine, Rochester, MN; §Department of Surgery, Feinberg (ASMA), antimitochondrial antibody (AMA), and human
School of Medicine, Northwestern University, Chicago, IL; kDivision
of Surgery and Oncology, University of Liverpool, Liverpool, United immunodeficiency virus (HIV). Her laboratory data revealed
Kingdom. abnormal liver function with a total bilirubin of 1.5 (reference
Editors: From the Department of Medicine (Steinberg), George Washington range, ,1.0 mg/dL) and alkaline phosphate of 1040 (reference
University Medical Center, Washington, DC; Division of Gastroenterol- range, ,129 U/L). A spartate amino transferase (AST) 237 U/L
ogy (Barkin), University of Miami, School of Medicine/Mt. Sinai Medical (reference range, ,40 U/L), ALT 206 U/L (reference range, ,40
Center, Miami, FL; Clinical Sciences (Surgery) (Bradley), Florida State
University College of Medicine, Tallahassee, FL; Department of Medicine U/L), and a cancer antigen (CA) 19-9 was 130 (reference range,
(DiMagno), Mayo Clinic, Rochester, MN; and Israelitisches Krankenhaus ,35 U/L). Her abdominal CT scan showed intrahepatic ductal
(Layer), Department of Internal Medicine, Hamburg, Germany. dilatation (Fig. 1), a mass at the head of the pancreas and celiac
Presented and discussed at the American Pancreatic Association Meeting, artery (Fig. 2), and a mass at the head of the pancreas and
November 4, 2004.
Reprints: Dr. Jamie S. Barkin. Mount Sinai Medical Center, 4300 Alton Road, calcified gallstones (Fig. 3). An endoscopic retrograde
Miami Beach, FL 33140 (e-mail: jbarkin@msmc.com). cholangio pancreatography (ERCP) showed dilated intra-
Copyright Ó 2005 by Lippincott Williams & Wilkins hepatic ducts and a distal common bile duct stricture (Fig. 4).

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Wolfson et al Pancreas  Volume 31, Number 3, October 2005

FIGURE 3. Abdominal CT scan revealing mass at the head of


the pancreas (white arrow) and calcified gallstones (black
FIGURE 1. Abdominal CT scan revealing intrahepatic ductal arrow).
dilatation (black arrow).

The pancreatic pathology revealed pancreatic granuloma and


Question 1 lymph node granuloma. Her chest X-ray, fungal cultures, and
The audience was surveyed as to whether this patient purified protein derivative (PPD) were negative. Bronchos-
should undergo (1) medical therapy, (2) preoperative biopsy, copy and transbronchial biopsies were also normal. A
(3) surgical exploration, or (4) biliary stent placement. diagnosis of sarcoid stage 0 was made. She was started on
prednisone, and a repeat ERCP with cholangiogram after 3
Answer months showed mild irregularity in the hilum. The biliary stent
(3). An overwhelming percentage of greater than 300 was subsequently removed. Clinically, she was asymptomatic
people suggested immediate surgical intervention. 8 months after diagnosis. Her liver tests were normal or were
Question 2 returning to normal values and included a normal total bilirubin
This patient underwent bile duct stent placement and (0.8 mg/dL; reference range, ,1.0 mg/dL), AST, ALT, and
a CT-guided fine needle aspiration (FNA) with 4 passes that alkaline phosphatase 293 mm/L (reference range, ,129
were negative for malignant cells and showed few fragments of mm/L).
benign pancreatic tissue. Regarding the next step, the choices Pancreatic mass lesions that are discovered on abdom-
were (1) repeat CT-guided pancreatic biopsy, (2) surgical inal imaging are most often caused by pancreatic
exploration, or (3) medical therapy, possibly with steroids.
Answer
(2). There was an overwhelming consensus that the
patient should undergo surgical exploration.
A laparoscopic exploration revealed 2 small lesions in
the left lateral segment of the liver and a very hard head of the
pancreas. There was bleeding from the head of the pancreas
after biopsy, and therefore an open procedure was performed.

FIGURE 4. ERCP showing a dilated intrahepatic duct (black


FIGURE 2. Abdominal CT scan revealing mass at the head of arrow) and a distal CBD stricture in the helium (white arrow).
the pancreas (white arrow) and celiac artery (black arrow). Stent was placed, and negative brushing.

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adenocarcinoma. Pancreatic cancer is the fourth leading cause may be an isolated process to the pancreas or in association
of cancer-related deaths in men and women.1 Currently in the with other autoimmune diseases that include Sjögren syn-
United States, carcinoma of the pancreas is diagnosed in more drome, primary biliary cirrhosis, and primary sclerosing
than 29,000 people, and nearly all die of the disease. A variety cholangitis. Men are affected twice as often as women.10 It is
of benign or malignant masses of the pancreas with less estimated that AIP makes up about 2% of cases of CP. The
mortality than adenocarcinoma can mimic adenocarcinoma, pancreatic head is most commonly involved; however, focal
however.2 The differential diagnosis of a pancreatic mass swelling of the body or tail occurs.12 Horiuchi et al10 described
on radiologic imaging includes, but is not limited to, chronic several cases in which focal swelling was followed by more
pancreatitis, metastatic lesions, sarcoidosis, infections, neu- characteristic general pancreatic enlargement.
roendocrine tumors, cystic lesions, and pancreatic adenocar- CT scanning may reveal a capsule-like rim around
cinoma (Table 1). Below is a discussion of the more common the pancreas, corresponding to peripancreatic inflammation.
lesions that present as pancreatic masses. Delayed enhancement on CT is unique to this condition and
may help differentiate it from PC.13 Diffuse irregular narrow-
Inflammatory Masses (chronic pancreatitis) ing of the main pancreatic duct shown by ERCP occurs in
The differential diagnosis of chronic pancreatitis and approximately 75% of patients; segmental narrowing is less
pancreatic cancer is sometimes difficult because their clinical common.10 Several studies report antibodies to carbonic anhy-
presentation is similar, especially when obstruction of the bile drase II antigens on pancreatic duct epithelium or expres-
duct and the pancreatic duct exists. Despite the development sion of human leukocyte antigen (HLA-DR) on ductal cells.
of various diagnostic imaging modalities, such as surface US, Histologic changes include lymphoplasmacytic infiltration of
endoscopic US (EUS), intraductal US (IDUS), ERCP, CT, the pancreas, associated with pronounced acinar atrophy and
magnetic resonance imaging (MRI), and angiography, the dif- interstitial fibrosis. Similar processes may involve the bile
ferential diagnosis of pancreatic cancer (PC) and chronic ducts and gallbladder.14 Epithelioid cell granulomas, occa-
pancreatitis (CP) is difficult. This is because the findings of PC sionally containing multinucleated giant cells or foam cells,
and CP overlap and include dilation of main pancreatic duct may also occur in the pancreas.
parenchymal atrophy, fluid collections, focal pancreatic enlarge- Biopsy of the pancreas may show marked lymphocytic
ment, biliary ductal dilatation, and changes in attenuation in infiltrates and is helpful in differentiating AIP from adeno-
peripancreatic fat or fascia.3 carcinoma, but the histologic findings may be mistaken for
CP is a disease of prolonged pancreatic inflammation lymphoma. Serological findings include (1) antinuclear anti-
and is characterized by irreversible morphologic and bodies in the majority of patients15; (2) anticarbonic anhydrase
functional abnormalities.4 The histologic changes include II antibodies in approximately 30% to 60% of patients; and (3)
fibrosis and atrophy of the glandular elements.5 The main hypergammaglobulinemia in 75% to 80% of patients (pre-
cause of CP is alcohol abuse, possibly superimposed on dominantly an increase in IgG; elevation of IgE is less
a genetic predisposition. However, 30% of patients have no common).
identified cause and may result from ‘‘autoimmune pancre-
atitis’’ (AIP). The diagnosis of CP can be difficult because Pancreatic Metastasis
findings of laboratory evaluations are frequently normal. The A variety of primary malignancies metastasize to the
most pathognomonic feature of CP is the presence of pancreas. These are being diagnosed more frequently with the
parenchymal calcification on CT scans. Morphologic changes increasing use of CT modality for cancer staging. A pancreatic
frequently result in a shrunken and atrophic pancreas. metastasis usually develops late in the course of the primary
However, the pancreas is occasionally enlarged, and when disease and is often associated with widespread metastatic
this enlargement is focal, it is difficult to distinguish from disease. The majority of patients with pancreatic metastases
carcinoma or other tumors.6 A series from the Mayo Clinic do not have pancreatic symptoms, although abdominal pain,
reported that, over a 35-year period, 74 of 603 patients (12%) jaundice, weight loss, or symptoms of acute pancreatitis occur
who underwent pancreatoduodenectomy for a mass in the in some patients.16 The most common primary malignancies
pancreatic head had CP; 22 of these 74 patients (30%) were that spread to the pancreas are renal cell carcinoma followed
misdiagnosed as having malignant disease preoperatively.7 by bronchogenic carcinoma, breast and colon cancer, mela-
AIP is increasingly recognized as a cause of CP. The noma, and soft tissue sarcomas.17 The interval between initial
initial clinical presentation may include any presentation of diagnosis of the primary tumor and the detection of a pan-
pancreatic diseases, including acute pancreatitis with infre- creatic metastasis varies from a few months to several years. A
quent attacks of abdominal pain, CP with diffuse pancreatic renal cell carcinoma metastasis to the pancreas can present
parenchymal swelling and irregular narrowing of the main more than 10 years after the initial diagnosis of the primary
pancreatic duct, and focal pancreatitis with associated biliary tumor. Surgical resection of the isolated pancreatic metastasis
dilation,8,11 simulating pancreatic carcinoma. AIP is also re- prolongs survival.18
ferred to as sclerosing pancreatitis, lymphoplasmacytic scleros- Most metastatic lesions present as a large solitary mass
ing pancreatitis, CP with diffuse irregular narrowing of the with well-defined margins without a predilection for a specific
main pancreatic duct, primary inflammatory pancreatitis, and area of the pancreas.19 Other patterns include multifocal
sclerosing pancreatico-cholangitis. Sarles et al9 reported the lesions and diffuse infiltration of the gland. Dilatation of the
first case of primary inflammatory sclerosis of the pancreas in pancreatic duct by an obstructing metastasis occurs in up
1961 and suggested a possible autoimmune mechanism. AIP to one third of patients; obstruction of the biliary tree is less

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TABLE 1. Etiologies of Pancreatic Mass Tumors TABLE 1. (continued ) Etiologies of Pancreatic Mass Tumors
1. Exocrine tumors Wagener’s disease
Benign Eosinophilic pancreatitis
 Serous cystadenoma Lymphoid hyperplasia
 Mucinous cystadenoma 6. Congenital
 Intraductal papillary mucinous adenoma  Congenital cyst
 Mature cystic teratoma  Choledochocele cyst
Borderline  Intrapancreatic accessory spleen
 Mucinous cystic tumor with moderate dysplasia 7. Metastatic lesions
 Intraductal papillary mucinous tumor with moderate dysplasia  Lung
 Solid pseudopapillary tumor  Breast
Malignant  Melanoma
 Ductal adenocarcinoma  Colon
 Osteoclast-like Giant Cell tumor  Renal cell carcinoma
 Serous cystadenocarcinoma  Lymphoma
 Mucinous cystadenocarcinoma 8. Cystic lesions
 Intraductal papillary mucinous carcinoma  Benign pancreatic cysts
 Acinar cell carcinoma  Retention pancreatic cysts
 Pancreatoblastoma  Parasitic cysts (echinococcus granulosis and
 Solid-pseudopapillary carcinoma  multilocularis cysts)
 Ampullary adenocarcinoma  Lymphoepithelial cysts (LECs)
2. Endocrine tumors  Pancreatic dermoid cysts
 Gastrinoma  Dysontogenic cysts
 Insulinoma  Hydatid cyst
 VIPoma 9. Infectious masses
 Glucagonoma  Mycobacterium tuberculosis
 Somatostatinoma  Mumps
 GRFoma  Mycobacterium avium complex
 ACTHoma  Candida albicans
 Carcinoid tumor  CMV
 PPoma  Cryptosporidiosis
3. Non–islet cell tumors  Ascaris lumbricoides
 Lymphoma  Coxsackievirus
 Anaplastic tumors
 Adenosquamous carcinoma
 Clear cell ‘‘sugar’’ tumor
common, and encasement of the major peripancreatic vessels
 Granulocytic sarcoma
is rare.
 Leukemia
The CT scan enhancement pattern of these metastases is
 Colloid carcinoma
variable and often mimics the enhancement characteristic of
 Primitive neuroectodermal tumor
the primary tumor.20 Many larger lesions tend to exhibit het-
erogeneous enhancement. Hypervascular pancreatic metasta-
4. Mesenchymal tumors
 Lymphangioma
ses, particularly renal cell carcinoma, display enhancement
 Lipoma
similar to the primary tumor and may mimic an islet cell
 Teratoma
tumor.21
 Schwannoma Islet Cell Tumors (neuroendocrine tumors)
 Plexiform neurofibroma Most of these tumors produce their symptoms through
 Pancreatic sarcoma excess secretion of a specific hormone. The neoplasms are
 Kaposi’s Sarcoma usually solitary, but in multiple endocrine neoplasia syndromes,
 Pancreatic hamartoma the pancreas may have more than 1 lesion. These tumors
 Pancreatic Castleman’s disease include the following:
5. Pancreatic inflammatory mass 1. Beta cell tumors (insulinomas) produce hypersecretion of
Focal pancreatitis insulin, leading to hypoglycemic episodes that are often
Phlegmon severe enough to produce coma, confusion, or behavioral
Pseudocyst changes. The highest incidence is found in patients between
Traumatic pancreatitis 30 and 60 years of age, with no predilection for either
Xanthogranulomatous pancreatitis sex. Most tumors are small (,2 cm) and are composed of
Inflammatory myofibroblastic tumor uniform cells that stain positively for insulin. More than 90%
of insulinomas are benign. The diagnostic procedure is EUS.

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2. G cell tumors (gastrinomas) are the second most frequent Sarcoidosis


functioning endocrine tumor of the pancreas. Gastrinomas Sarcoidosis is a systemic granulomatous disease of un-
may produce Zollinger Ellison syndrome (ZES), charac- known etiology that primarily affects the lung and lymphatic
terized by recurrent and multiple peptic ulcers in the stom- systems of the body, but any organ can be involved. The
ach and proximal small intestine, diarrhea, and/or gastro- characteristic lesion of sarcoidosis is a discrete, compact,
esophageal reflux. The mean age of onset of symptoms is noncaseating epithelioid cell granuloma. Epithelioid cell gran-
approximately 38 years. Seventy percent of patients with ulomas consist of highly differentiated mononuclear phagocytes
ZES are sporadic; the remaining patients have multi- (epithelioid cells and giant cells) and lymphocytes. The diagnosis
ple endocrine neoplasia type 1 syndrome. This autosomal- of sarcoidosis requires a histologic demonstration of noncaseat-
dominant inherited syndrome consists of tumors of para- ing granulomas, a compatible clinical picture, and exclusion of
thyroid glands, anterior pituitary, the endocrine pancreas, other diseases capable of producing a similar histologic or
and duodenum. Most of gastrinomas are malignant. The clinical picture.27 Our patient had this clinical presentation.
diagnostic procedure is an abdominal CT; otherwise, EUS Lung, lymph nodes, eyes, and skin are usually affected, but
should be used when suspicion is high. granulomas can present almost anywhere. When the gastro-
3. Alpha cell tumors (glucagonomas) are rare. The excess intestinal tract is involved, the liver is the most common site.
secretion of glucagon is often asymptomatic, although pa- Although sarcoidosis of the hollow gastrointestinal tract is
tients may be anemic, develop unexplained secondary dia- unusual, the stomach is most commonly involved. Pancreatic
betes, and have a bizarre characteristic skin rash called sarcoid was first reported in 1937.28 Its incidence ranges from 1%
necrolytic migratory erythema. Sixty percent of these tumors to 5% in necropsies of patients with sarcoidosis.29,30 Patients may
are malignant. have no symptoms or a broad array of abdominal and systemic
complaints. They may present with a pancreatic mass as in our
Infections patient. The symptoms of pancreatic sarcoid are likely to be
Up to 12% of patients with tuberculosis may have reversed by systemic corticosteroids. When the clinical pre-
involvement of abdominal organs.22 Tuberculosis of the hollow sentation is an isolated pancreatic mass suggestive of pancreatic
digestive tract may involve any part from the mouth to the anus. cancer, a histologic diagnosis and, in our opinion, a response to
The most common site is the ileo-cecal area. Intra-abdominal therapy, must be obtained before the surgeon chooses to operate.31
tuberculosis usually involves the liver, spleen, bowel, perito-
neum, and mesenteric lymph nodes. Atypical presentations of Cystic Lesions
gastrointestinal tuberculosis mostly occur in immunocompro- Cystic lesions of the pancreas include inflammatory
mised individuals. In isolated pancreatic/peripancreatic tuber- pseudocysts (70%–90%), cystic neoplasms (10%–15%), and
culosis, the most likely mechanism of spread is lymphohema- other true cysts that are rare.
togenous dissemination from an occult focus in the lungs.23 Pseudocysts may occur secondary to acute pancreatitis,
A similar proportion of men and women develop isolated pancreatic trauma, or CP. They occur in about 25% of patients
pancreatic tuberculosis, with a mean age of approximately with CP and are most commonly seen in patients with alco-
40 years.24 Most patients have lived in northeast Asia or holic CP.
have immigrated to Europe or the United States from countries
where tuberculosis is endemic. The number of reports of iso- Cystic Tumors
lated pancreatic tuberculosis has increased in recent years.24 In Cystic tumors of the pancreas account for 10% to 15%
the English literature, there are approximately 75 case reports of pancreatic cysts and 1% of pancreatic carcinomas and typi-
of isolated pancreatic tuberculosis in patients who did not cally occur in middle-aged women.32 The increased avail-
have documented or suspected immunodeficiency. The in- ability of high-resolution CT scans allows for more frequent
creased reporting is likely related to a worldwide increase in diagnosis. Mucinous and serous cystic tumors account for
tuberculosis,25 and a greater movement of persons from areas between 75% and 90% of cases.33 Two thirds of pancreatic
where tuberculosis is endemic to countries with more available cystic lesions are either malignant or premalignant. Mucinous
health care and testing. cystic tumors are the most frequently encountered cystic tumor
The main initial symptoms of pancreatic tuberculosis are and have the potential to become malignant. Conversely, serous
pain (81%), weight loss (55%), fever (36%), recurrent vomit- cystadenomas are almost always benign. Rare cystic tumors of
ing (19%), and jaundice (17%).26 Fever in a patient with the pancreas include intraductal papillary mucinous tumor
pancreatic mass suggests presence of tuberculosis or another and cystic islet cell tumors.34
infection such as candida. Most patients have a high erytroalyte It is important to distinguish between a pseudocyst and
sedimentation rate (ESR) and a positive tuberculin test a cystic tumor because they are frequently clinically and radio-
(70% of patients).26 logically difficult to distinguish, and management is entirely
However, the most frequent clinical scenario (.50% of different. A clinical feature that favors the diagnosis of a pseudo-
cases) is abdominal pain and a pancreatic mass, which mimics cyst is a history of pancreatitis or trauma. Conversely, absence of
carcinoma of the pancreas.22,24,26 When a diagnosis of isolated this history should raise the possibility of a cystic tumor.32
pancreatic tuberculosis is suspected on clinical and/or radio-
logic grounds, every effort should be made to preoperatively Adenocarcinoma
confirm the diagnosis to prevent an unnecessary laparotomy Adenocarcinoma of the pancreas accounts for about 5%
and/or pancreatic resection. of U.S. cancer deaths (2002) and is the fourth most common

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Wolfson et al Pancreas  Volume 31, Number 3, October 2005

cause of cancer-related deaths and the 9th most common frequency of pancreatic resection for unsuspected benign pan-
malignancy in the United States. Its incidence has doubled in creatic disease.
the past 50 years, but it seems to have peaked in the 1990s at To determine the incidence of benign masses, we
8/100,000 people. The sex ratio is close to 1. PC is more com- reviewed 5 representative large series7,37,39,40,47 of pancreatic
mon in African Americans than in whites and has a peak resections done for suspected pancreatic cancer, representing
incidence in the seventh and eighth decades. Whereas the a total of more than 3000 pancreatic resections. Approximately
cause of PC is unknown, environmental factors associated 10% of the patients had benign, nonneoplastic conditions
with its occurrence include cigarette smoking and a high (Table 2). Whereas some of these operations may have been
dietary intake of fat, meat, or both. Other risk factors are CP warranted for symptomatic relief (eg, painful inflammatory
and diabetes mellitus existing more than 3 years before the mass caused by alcoholic pancreatitis), it is likely that most of
onset of PC. Fresh fruits and vegetables may protect against the resections in patients with benign pathology would not
developing PC.35 have been performed if the diagnosis had been ascertained
preoperatively.
Pancreatic Resection for Unsuspected Benign The histologic diagnoses of the resected lesions (Table 2)
Disease: How Often Does It Happen and revealed that CP, in its diverse forms, accounts for ;70%
Can We Avoid Surgery in of resections for unsuspected benign disease. Recently, 3
studies39,40,48 of pancreatic resections were published that dif-
Autoimmune Pancreatitis?
ferentiated ‘‘usual’’ CP from LPSP. Of 1808 resections for pre-
Dr. Suresh T. Chari sumed pancreatic malignancy, 2 published series39,40 and a third
The presenting features and imaging characteristics of in abstract form by Dr. Pearson,47 report 43 of 1808 (2.4%)
early pancreatic cancer can overlap with other less common had LPSP on histologic examination of the resected specimen.
pathologic entities so that differentiation is sometimes ex- LPSP accounted for 20% of resections for unsuspected
tremely difficult. This diagnostic uncertainty can lead to major benign disease in these 3 series.39,40,47
pancreatic resection for benign disease7 or rarely, avoidance of In 2003, we reported our experience with 45 patients
surgery for a potentially curable pancreatic cancer.36 In the who underwent pancreatic resection from January 1985 to
former situation, histologic examination of the resected pan- March 2001 for presumed cancer and were found to have CP
creas reveals a benign cause for the pancreatic mass,7,37–40 on histologic examination.48 Of these, 19 had ‘‘usual’’
which had it been diagnosed preoperatively, would not warrant alcoholic pancreatitis and 26 had AIP (14 had LPSP and 12
surgical resection. The aim of this commentary is to point out had idiopathic duct centric chronic pancreatitis). We carefully
how often unsuspected benign disease is found after pancre- correlated the clinical presentation of these patients with their
atic resection and to emphasize the preoperative clues to diag- histology. Since 1999, we diagnosed 26 patients with AIP, and
nosing AIP, a benign inflammatory mass that frequently of the 15 patients diagnosed since January 2003, only 1 patient
masquerades as PC. underwent resection at Mayo Clinic.
The causes of benign pancreatic masses have been What are the clues to the diagnosis of AIP? A high index
discussed previously and include tuberculosis,41,42 sarcoido- of suspicion is required, and AIP needs to be considered in the
sis,43 foreign body granuloma to a fish,44 Crohn’s disease– differential diagnosis of all pancreatic masses. The most
associated granulomas,45 AIP, and its histologic counterpart, pertinent and well-recognized clinical presentation of AIP is that
lymphoplasmacytic sclerosing pancreatitis (LPSP).46,49,50 of mimicking pancreatic ductal adenocarcinoma. The classic
However, these reports do not give us a clear sense of the presentation is that of an older man with generally painless

TABLE 2. Pancreatic Resection for Misdiagnosed Pancreatic Mass


Benign Disease Histology in Patients
Reference Institution Study Period N/Total N (%) With Benign Disease (N)
47 Mayo Clinic 1997–2003 5/79 (6) 3 had LPSP, 1 benign CBD stricture
40 Johns Hopkins 1999–2001 47/442 (11) 14 had alcohol/idiopathic ‘‘usual’’ chronic pancreatitis,
11 LPSP, 4 gallstone pancreatitis, 1 pancreas divisum
39 Memorial Sloan-Kettering 1985–2001 159/1287 (12) 28 had acute/‘‘usual’’ chronic pancreatitis, 29 LPSP
Cancer Center
37 Johns Hopkins 1987–1995 108/510 (21) 59 had chronic pancreatitis/fibrosis, 45 benign neoplasms
(19 benign cystic neoplasms, 9 benign islet cell tumors, and
12 benign ampullary or duodenal villous adenomas,
2 papillary cystic neoplasms of the pancreas (Hamoudi tumors),
1 single duodenal adenomyoma, 1 ampullary leiomyoma).
7 Mayo Clinic 1956–1990 29/603 (5) 22 had ‘‘chronic pancreatitis’’, 2 benign CBD stricture, and
1 each penetrating duodenal ulcer, metastatic melanoma,
ampullary adenoma, intrahepatic drug-induced cholestasis
and pseudocyst
Total 240/3014 (11.5) 166/240 (69%) had chronic pancreatitis (‘‘usual’’ or LPSP)

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obstructive jaundice and with a pancreatic mass on CT scan. How do patients who have undergone pancreatic resec-
Back pain may also be present. Weight loss may be significant, tion for AIP fare postoperatively? The morbidity and mortality
although anorexia is not a common feature. Diabetes mellitus, of pancreatic resection for AIP seems to be no higher than for
usually of recent onset, may be present 50% of the time. In PC.51 Whereas occasional recurrences have been noted after
addition, serum CA 19-9 levels may be no different from those surgical resection,12 for the most part, patients do well after
seen in pancreatic ductal adenocarcinoma.51 ERCP often shows pancreatic resection for AIP.48,51 In 37 patients with AIP fol-
a distal biliary stricture or double duct sign. It is therefore not lowed for a median of 33 months after resection, no patient had
surprising that, unless clinical suspicion is high for autoim- recurrent jaundice, and only 1 patient had clinically evident
mune pancreatitis, this constellation of symptoms and findings recurrent pancreatitis.51 Of patients in this study who were
frequently leads to pancreatic resection. interviewed by telephone after surgery, 68% subjectively rated
Whereas sometimes it can be very difficult to conclu- their quality of life as better, 18% reported no change, and 14%
sively prove the diagnosis of AIP or exclude the presence of reported diminished quality of life.51
pancreatic cancer, these clues can help:
1. Elevated serum IgG4 subclass of immunoglobulin. This EUS FNA and Tru-Cut Biopsy of the Pancreas:
substantiates the diagnosis of AIP. In our experience, lack Pros and Cons
of elevation of IgG4 does not exclude the diagnosis. Dr. Jonathan E. Clain
2. Diffuse enlargement of the gland (‘‘sausage-shaped’’ pan-
creas). AIP, however, can present with a focal mass. Delayed There are a number of issues that need to be considered
enhancement and rim enhancement are also features seen when addressing the pros and cons of EUS FNA or Tru-Cut
on MR.13 Biopsy (TCB). In this short review, I will discuss the methods,
3. Diffusely irregular and attenuated pancreatic duct. Pa- indications and contraindications, accuracy, complications, and the
tients may have a double-duct sign or focal pancreatic duct relative merits of EUS versus CT or US percutaneous approach.
stricture indistinguishable from that caused by PC. The operating characteristics of pancreatic masses are
4. Hilar or intrahepatic bile duct strictures. Whereas the ma- summarized in Table 3.
jority of AIP patients have distal bile duct strictures,
approximately 20% have more proximal strictures. The Technical Aspects of EUS FNA Versus EUS TCB
appearance of new strictures while patients are under When a pancreatic mass is suspected to be malignant,
observation, or fleeting strictures, may also be a clue to the a lymph node adjacent to or remote from the tumor is usually
diagnosis of AIP. easier to sample. In the past, with the instrument placed in the
5. Pancreatic core (trucut) biopsies. These biopsies can show postbulbar duodenum, angulation often made passage of the
diagnostic histology and need to be reviewed by a pathol- needle through the channel of the endoscope and insertion into
ogist familiar with the disease. the tumor difficult, but the newer disposable needles with a
Whereas the presence of AIP can be frustratingly spiral casing generally allow much easier passage. Never-
difficult to confirm in some patients, it is a very satisfying theless, lesions of the pancreatic body are usually easier to
diagnosis to make, because it leads to avoidance of potentially sample. It has only been possible in the past few years to
morbid surgery. However, despite awareness of the condition, perform a TCB through an echoendoscope. The hope has been
the uncertainty in the diagnosis and fear of missing resectable that it would require fewer passes to establish a diagnosis.
cancer may make pancreatic resection for presumed malig- Our initial experience has shown that it is possible to safely
nancy unavoidable in some patients.46 establish a histologic diagnosis using a TCB.52 The major

TABLE 3. Review of Literature: Operating Characteristics of EUS-FNA of Solid Pancreatic Masses


Year Number Length Sensitivity Specificity
Study Published of Patients of Study (years) (%) (%) PPV (%) NPV (%)
Chang 1997 44 2 83 80 100 96
Gress 1997 121 2 80 100 100 91
Faigel 1997 45 1.25 94 100 100 82
Bhutani 1997 47 ? 64 100 100 16
Wiersema 1997 124 4 86 94 100 86
Binmoeller 1998 45 1 70 100 100 37
Williams* 1999 144 3 72 100 100 38
Erickson 2000 95 4 98 ? 100 ?
Gress 2001 102 4 95 100 100 92
Harewood 2002 184 5 94 71 96 63
Current study 2003 156 2 84 97 99 64
Reprinted from The American Journal of Gastroenterology with permission pending.57
*Included 20 patients with cystic lesions of the pancreas.

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disadvantage is that the needle is stiff, so that if the tip of the How reliable is negative EUS examination in excluding
echoendoscope is angulated, the needle will not fire. Thus, it is pancreatic cancer? In a report of 80 patients with a variety
limited to biopsy of lesions accessible from the stomach and of symptoms or radiologic features, which raised the issue of
mediastinum and occasionally from the duodenal bulb. a pancreatic cause, no patient with a negative EUS was
The advantages of establishing a diagnosis of pancreatic later identified to develop a mass lesion over the following
cancer using the EUS TCB is not currently clear, because 24 months.55 Thus, EUS seems to be a reliable test to exclude
the number of patients studied is limited, as are the number pancreatic cancer.
of reports. Out initial experience suggests that for pancreatic The role of EUS when PC is suspect is as follows:
masses, FNA and TCB provide similar sensitivity, perhaps 1. Detecting small lesions not identified on CT.
with fewer passes for TCB when the lesion is accessible.53 2. Staging of lymph nodes.
3. Celiac plexus neurolysis for pain in patients with un-
Importance of on-site Cytopathology for Adequacy resectable cancer.
Assessment of the Sample 4. Tissue diagnosis.
In patients with PC, the average number of needle passes
for cytologic diagnosis has been reported to be between 3 and 4, However, before proceeding to EUS, a high-quality, fast
with a range of 1 to 10 passes.54 The degree of differentiation of CT with fine cut should be obtained even if a recent CT has
the tumor does not seem to be a factor influencing the number been performed and was not judged to be of optimal quality.
of passes required (Fig. 5). Thus, in contrast to malignant If advanced disease is shown, including hepatic metas-
lymph nodes where 3 passes almost invariably establish the tases, vascular encasement of superior mesenteric, celiac, or
diagnosis, in PC, this is not the case, and this underlines the hepatic artery, no further staging tests are required, because the
importance of on-site adequacy assessment that is conducted cancer is unresectable. However, histologic proof is required
by a cytotechnician in the endoscopy room using a ‘‘Diff for diagnosis, and the pros and cons of EUS-guided versus CT-
Quick’’ stain (Harleco, Gibbstown, NJ). This only takes 2 guided procurement of tissue as discussed below.
minutes to perform, providing the endosonographer with virtu- When EUS is felt to be indicated for staging purposes,
ally real time information as to when a satisfactory diagnostic the size and relationship of the tumor to the vascular structures
sample has been procured. is assessed, and a careful search for lymph nodes is made.
Lymph nodes outside the resection field are particularly im-
EUS Features and Role in Diagnosis and Staging portant, namely celiac or hepatogastric lymph nodes, because
The appearance of a pancreatic malignancy at EUS is their presence will make the cancer unresectable for cure.
that of a variably hypoechoic lesion, often with an indistinct EUS FNA confirmation of malignancy in these lymph nodes
border, indistinguishable from the appearances of focal pan- establishes the diagnosis and the futility of operative inter-
creatitis. Although spiral CT with fine cuts performed with vention. Examination of the liver for evidence of small hepatic
optimal contrast may detect small lesions, EUS is capable of metastases should be performed for lesions either not detected
detecting even smaller lesions. on CT or too small to easily sample.56 Examination of the
mediastinum for lymph nodes should be a part of the exami-
nation, but in our experience, will rarely be positive.
What are the indications for EUS FNA of a pancreatic
mass? Most clinicians would agree with the following indi-
cations, alone or in combination:
1. Unresectable mass for diagnosis.
2. Resectable mass only if the physician or surgeon, or pa-
tient, feels that a definitive diagnosis is required before
proceeding with surgery (eg, in a patient with significant
comorbidities).
3. Serious doubt as to the diagnosis: inflammatory versus
neoplastic.
4. Suspicious or indeterminate lymph nodes outside the field
of resection in a patient with an otherwise resectable lesion.
When a pancreatic mass appears resectable by CT and
EUS, and the clinical presentation and laboratory data sup-
port the diagnosis of PC, we do not recommend FNA because
FIGURE 5. Distribution of the number of EUS-guided FNA the result does not change management, ie, a negative FNA
passes in relation to tumor cytologic differentiation. The does not exclude malignancy, and FNA carries a small but
average number of passes required was 3.4, with a range of
definite risk of bleeding or pancreatitis (see below), which
1 to 10. Note that there was no endosonographic feature, which
predicted the number of passes necessary, emphasizing the could potentially delay surgery or increase the difficulty of
important role of on site cytology. More passes were required resection.
in well-differentiated tumors, explained by the fact that, for How accurate is EUS FNA for the diagnosis? A recent
confident cytologic diagnosis, additional tissue is needed. Re- paper citing studies from various centers (Table 3) shows
printed from Gastrointestinal Endoscopy with permission.54 variable sensitivity, perhaps in part because of different patient

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populations.57 Based on this and other published studies, one masses is appropriate. The biopsy of some cystic neoplasms
should conclude that, in tertiary centers, a sensitivity of greater of the pancreas is appropriate if the radiologic differential
than 90% should be regarded as achievable. This compares diagnosis includes serous cystadenoma, because serous neo-
very favorably with percutaneous CT or US-guided biopsy, but plasms do not require operation if asymptomatic. Primary
there are no randomized trials comparing the 2 approaches. pancreatic lymphoma is a very rare cause of a pancreatic mass,
but if the radiologic appearance is suggestive of lymphoma,
Complications of EUS FNA percutaneous biopsy is appropriate because such neoplasms
Complications of EUS FNA or biopsy include bleeding, can be treated with chemotherapy alone. Patients with po-
pancreatitis, and infection, the latter if cyst aspiration is per- tentially resectable pancreatic adenocarcinoma by imaging
formed, and the remote possibility of complications of seda- must have a biopsy if they are going to receive neoadjuvant
tion or trauma resulting from passage of the echoendoscope. chemoradiation before operation.
The frequency of complications in the literature is 0.5% to 3% This debates focuses on whether there is a need to
in surveys in retrospective analyses, comparable with large CT perform a percutaneous or an endoscopically guided needle
FNA series.58–61 In all series, the proportion of patients with biopsy of a suspected pancreatic carcinoma when radiologic
serious complications is said to be small. For example, in imaging suggests that the tumor is resectable and immediate
a series of 158 patients where 30-day follow-up was obtained, operation is planned (no neoadjuvant therapy). Given the
immediate self-limited complications occurred in 6.3% of sensitivity of our current biopsy methods, requiring a tissue
the patients. Although 22% of patients reported at least 1 diagnosis before performing resection is not only unnecessary
symptom at 72 hours, all were minor except for 3 cases, 1 of but also medically inappropriate. My point of view is ‘‘patients
which had pancreatitis.57 In another series of 100 patients, the with potentially resectable pancreatic ductal adenocarcinoma
incidence of pancreatitis was 2%.62 do not need to undergo preoperative biopsy.’’
The proponents of mandatory biopsy argue that some
Percutaneous CT /US or EUS FNA Approach? patients suspected of harboring a pancreatic carcinoma by
When CT shows an unresectable lesion, what are the imaging actually do not have cancer, but rather CP mimicking
merits of an EUS versus a percutaneous approach for es- cancer. Requiring a tissue diagnosis of malignancy in such
tablishing a cytologic or histologic diagnosis? This can best be patients before resection would potentially avoid operation.
summarized as follows: Therefore, we should ask how many patients undergoing pan-
1. There are no controlled data comparing sensitivity, speci- creatic resection for suspected pancreatic cancer are actually
ficity, and complications of the 2 approaches. found to have CP or another benign diagnosis on pathologic
2. On-site adequacy assessment is performed routinely only examination of the operative specimen. Table 47,40,65 shows the
with EUS. frequency of benign findings in 3 large series of pancreati-
3. With a percutaneous approach, but not an EUS approach, coduodenectomy for suspected cancer. The studies suggest
access may be limited by intervening structures. that between 5% and 10% of patients undergoing resection for
4. Seeding of a head mass is a potential issue with the percu- suspected pancreatic cancer are found not to have cancer.
taneous approach, but not with the EUS transduodenal The next question of major importance is how many
approach, because the duodenum is removed as part of the patients die as a result of pancreatic resection for benign dis-
resection. There is only 1 case report63 of EUS FNA seeding ease. Two studies have addressed that question. Barens et al37
of PC into the gastric wall, so it is likely a very rare event. reported a mortality of 1% in 108 patients undergoing pan-
Percutaneous biopsy of a pancreatic mass presents greater creaticoduodenectomy for benign disease; Sakorafas and
theoretical risk of seeding, because the needle traverses the Sarr66 reported a 3% mortality in 105 patients.
peritoneal cavity. A report on the lower frequency of peri- In trying to assess the risk of surgery in patients with
toneal carcinomatosis in patients with PC diagnosed by EUS benign disease, it is important to recognize that most of such
FNA versus percutaneous FNA is in support of this idea.64 patients come to attention because of a clinical problem, usu-
5. EUS, because of sedation, is more pleasant for the patient, ally jaundice. Other possible presentations include weight loss
and this needs to be weighed against the increased cost. and abdominal pain. No doubt a few patients are found to have
6. In unresectable cancer with severe pain, EUS provides an a pancreatic mass while being evaluated for another condi-
opportunity for celiac plexus block at the same time as tion, but this is probably a distinct minority. This means that
procuring tissue for diagnosis. invasive therapies would be required in most of these patients

SURGICAL APPROACH TABLE 4. Percentage of Patients Undergoing


Pancreaticoduodenectomy (PD) for Suspected Cancer Who
Patients With Pancreatic Masses Should Not are Found to have Benign Disease Rather Than Cancer
Undergo Preoperative Biopsy Number Number of PDs Percent of PDs
of PDs for Found to Have Found to Have
Dr. Richard H. Bell, Jr. Reference Suspected PC Benign Disease Benign Disease
A more appropriate phrasing of the statement under 7 603 29 5%
debate would be ‘‘patients with pancreatic masses need not 65 220 14 6%
undergo preoperative biopsy.’’ Clearly there are circumstances 40 442 40 9%
in which percutaneous or EUS-guided biopsy of pancreatic

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Wolfson et al Pancreas  Volume 31, Number 3, October 2005

for palliation of jaundice or other symptoms. Any mortality


TABLE 5. Sensitivity of Preoperative Biopsy in Detecting
associated with other therapies such as operative biliary bypass
Carcinoma of the Pancreas
or endoscopic stenting have to be deducted from the estimated
Reference Method Sensitivity
risk of pancreatic resection.
In trying to understand how many lives of patients with 67 EUS-FNA 97%
benign disease are unnecessarily lost if we do not require a 68 EUS-FNA 78%
tissue diagnosis of cancer before resection, I propose the 69 CT-FNA 71%
model shown in Fig. 6. The assumptions in the model are listed
in the legend associated with the figure. The calculation sug- To understand how many patients might die of PC
gests that if 10,000 patients undergo pancreaticoduodenec- unnecessarily if we require a tissue diagnosis before resection,
tomy annually worldwide, 11 lives would be saved in the we need to know the sensitivity of percutaneous and EUS-
group of patients who have benign disease if a tissue diagnosis guided biopsies. Table 567–69 shows the sensitivity of biopsy in
of cancer was required before surgery. recent studies. There is variation from center to center, but I
Unfortunately, preventing unnecessary surgery in pa- believe that a sensitivity of 90% is a reasonable estimate for the
tients with benign disease comes at a price, and that price state of the art. This means that 10% of patients who actually
is failing to perform resection in patients who actually have have cancer will have a negative biopsy. If we use that figure to
cancer but whose biopsy is negative. To understand whether assess the impact of a policy that requires tissue biopsy in our
a policy of mandatory tissue diagnosis of cancer before 10,000 patients (Fig. 7), we find that 920 of the 9200 that
resection is rational, we must calculate the number of lives actually have cancer will have a negative biopsy and therefore
potentially lost because of false-negative biopsies in patients not undergo an indicated resection. If we assume that the
who actually have cancer and compare that with the number of 5-year survival of all patients undergoing pancreaticoduode-
lives potentially saved in patients with benign disease who are nectomy for pancreatic cancer is 5% (a conservative estimate),
spared surgery (the estimate we just completed). this means that 46 lives would be unnecessarily lost by a policy
of requiring a tissue diagnosis before resection.
In summary, if we compare the estimated number of
lives saved per year in patients with benign disease by re-
quiring a tissue diagnosis before resection (11) with the number
of lives lost in patients with cancer by requiring preoperative
tissue diagnosis (46), we must conclude that the policy of re-
quiring a biopsy positive for cancer before resection is a
policy that costs lives.
Obviously, this conclusion is based on current data about
the sensitivity of preoperative biopsy. The model I have used in
this discussion suggests that preoperative biopsy techniques
must improve to a sensitivity of approximately 98% before

FIGURE 6. A model for estimating the number of deaths that


might be prevented in patients with benign disease if a policy
were adopted that required a tissue biopsy before performing
a resection for suspected PC. Currently, it is estimated that
10,000 pancreaticoduodenectomies are performed worldwide
annually for suspected pancreatic cancer. Eight percent (800
cases) result in a diagnosis of CP or other benign conditions. It
is estimated that 750 of the 800 patients present with jaundice
or another symptom that would still require an invasive
procedure for palliation if a pancreaticoduodenectomy was not FIGURE 7. A model for estimating the number of unnecessary
performed. If the operative mortality for a pancreaticoduode- deaths from cancer that occur if a policy is adopted that
nectomy is 2%, 15 of the 750 patients would die as a result of requires a tissue biopsy before performing a resection for
surgery. However, this figure must be corrected because some suspected PC. The model assumes that there is a 10% false-
deaths would occur from other invasive procedures other than negative rate for preoperative biopsy. This means that 920
pancreaticoduodenectomy that would be required to palliate patients with potentially resectable cancer would not undergo
symptoms. In the 50 patients who were asymptomatic, 1 death operation. If these patients had been operated, it is assumed
would occur as a result of surgery. Therefore, it would seem that 5% (46 patients) would have survived. In this model, none
that there are approximately 11 patients with benign disease of the patients who had benign disease underwent pancrea-
per year worldwide whose deaths would be prevented as ticoduodenectomy. Deaths in patients with benign disease are
a result of the policy of requiring tissue confirmation before restricted to mortality from procedures other than pancreati-
pancreaticoduodenectomy. coduodenectomy used to palliate symptoms.

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a policy of preoperative mandatory tissue diagnosis can be Nevertheless, there are now strong arguments for insist-
justified. If the long-term survival of patients undergoing ing that all patients undergo a histologic diagnosis before
pancreaticoduodenectomy for cancer improves, this of course proceeding to a treatment plan for the following reasons:
will require that preoperative biopsy techniques become even 1. The mortality rate from pancreatic resection is still
more sensitive. approximately 5%.
2. The morbidity is still high at approximately 30%.
3. Wider use of abdominal imaging means that more and more
All Patients With a Pancreatic Mass Should incidental lesions are being found.
Undergo Preoperative Biopsy 4. New technology has greatly increased the accuracy of tissue
Drs. Nicholas Alexakis and John P. Neoptolemos diagnosis: FNA or TCB under EUS guidance.
5. With tissue diagnosis, a more meaningful risk assessment
Are All Pancreatic Masses PC? of treatment can be given, enabling proper informed consent.
Not necessarily. A wide variety of benign and malignant 6. Tissue diagnosis is always needed and obtained in patients
diseases can produce a mass in the pancreas. The diagnosis with advanced PC—why not for early cancer?
of PC is usually straightforward, but not all patients with a
pancreatic mass have PC. The surgeon often comes with the Which Patients must have Preoperative Histology?
question: is this pancreatic head mass cancer or CP? Both may 1. Patients with unresectable tumors, because this enables
have the same symptoms, signs, and radiologic appearance. consideration of protocol-based therapies and also novel
Patients with CP can develop PC, and PC can induce an in- experimental treatments.
flammatory response. Approximately 10% to 15% of tumors 2. Patients who are not fit for any major operation.
in the head of the pancreas (periampullary cancers) are not 3. Patients with diffuse inflammation of the gland—some-
pancreatic ductal adenocarcinomas and have a different nat- times a feature of autoimmune pancreatitis or tuberculosis.
ural history, mostly with a more favorable prognosis, such as 4. Patients with small, smooth cystic lesions. The differen-
duodenal or ampullary cancers, and endocrine tumors and tial diagnosis of a cystic lesion of the pancreas includes a
mesenchymal tumors.70 pseudocyst and a cystic neoplasm (serous cystadenoma,
mucinous cystic tumors, intraductal papillary mucinous
What is the Incidence of a Benign Pathology in neoplasms, cystic endocrine tumor, and cystic pancreatic
Patients Presenting with a Pancreatic Mass? cancer). Premalignant or malignant cystic neoplasms need
Data from the Amsterdam Medical Center showed that to be resected. Analysis of the cyst fluid should include
14 (6.3%) of 220 patients underwent pancreatoduodenectomy the amylase level (high level indicates the presence of a
for presumed PC that histopathology proved to be CP.65 Also, pseudocyst) and carcino embryonic antigen (CEA) level
data from the Mayo Clinic-Rochester revealed that 29 (4.8%) (high levels indicate the presence of a mucinous cyst).74
of 603 patients in a 35-year period underwent pancreatoduo-
denectomy for misdiagnosed pancreatic mass.7 A study from What is the Diagnostic Yield from ERCP Brushings
the University of Mainz found 13 (7%) of 186 patients with and Biopsies?
suspected malignancy harbored benign pathology.71 Brushings obtained during endoscopic retrograde
cholangio pancreatography (ERCP) have high specificity
Is Pancreatic Resection Justified for All and until recently have tended to have rather poor sensitivity.75
Pancreatic Masses? The overall diagnostic sensitivity and specificity were 59.8%
There are good arguments for resecting all pancreatic and 98.1% in a series of 406 patients with pancreato-biliary
masses, including the following: strictures, and these improved from 44.3% and 96.4%, re-
1. Benign pathologies and notably CP have nonspecific spectively, in the initial one third to 70.7% and 97.1%, respec-
clinical symptoms (pain, jaundice, weight loss), which tively, in the final third of cases.76 A study from Chicago with
are often the same as for PC. 278 patients showed a sensitivity of 68% and a specificity of
2. Preoperative imaging is not always reliable in distinguish- 100% in the diagnosis of cancer using endoscopic retrograde
ing CP from PC. cholangio pancreatography (ERCP) brushings.77 The results of
3. There is a low perioperative mortality in specialist centers. ERCP brush cytology are summarized in Table 6.76–85 The
An aggressive approach toward any mass in the head of combination of stricture dilatation, endoscopic needle aspira-
the pancreas minimizes the risk of missing a small cancer, tion, and subsequent biliary brushing significantly increased
which may most benefit from resection. Also, negative pre- both the sensitivity (85%) and specificity (100%) of cytology in
operative histology may not reliably exclude the diagnosis a study with 46 patients from Boston.86
of cancer. In a retrospective study from the University of A team from the University of Münster combined
Nebraska, of 20 patients who underwent resection for sus- endoscopic transpapillary forceps biopsies (ETP) with IDUS
pected malignancy with nonconfirmatory biopsies, histopa- during ERCP and achieved a correct preoperative diagno-
thology revealed that 9 had malignant peripancreatic tumors, sis in 59 of 60 patients with bile duct strictures, resulting
including 6 pancreatic ductal adenocarcinomas.72 In a review in an accuracy rate of 98%.87 The results of studies using
of 224 pancreas cytologic reports from Seattle, 55% of those transpapillary biopsy techniques are shown in Table 7.87–90
reported as atypical and 49% of those reported negative were A study from Japan identified candidate genes for
confirmed malignant.73 pancreatic ductal adenocarcinoma-specific markers (AC133

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Wolfson et al Pancreas  Volume 31, Number 3, October 2005

TABLE 6. Results of ERCP Aspiration and Brush Cytology


Reference Year Number Method Sensitivity Specificity Positive Predictive Value Negative Predictive Value
78 1990 53 Brush cytology 70% 100% 100% 44%
79 1993 47 Exfoliative cytology alone 33% 100% 100% 16%
79 1993 46 Exfoliative and brush cytology 69% 100% 100% 36%
80 1994 74 Brush cytology 56% 100% 100% 51%
81 1997 54 Brush/exfoliative 54% 100% 100% 8%
82 1998 15 Brush cytology 100% 100% 100% 100%
83 1999 101 Biliary cytology 50% 89% 89% 51%
83 1999 42 Pancreatic cytology 58% 100% 100% 64%
84 1999 78 Brush cytology 56% 91% 94% 43%
85 2000 106 Brush cytology 63% 96% 92% 64%
76 2001 246 Brush cytology 60% 98% 92% 61%
77 2002 278 Brush cytology 68% 100% 100% 76%

and carcinoembryonic antigen-related cell adhesion molecule With the application of newer technologies, the sensi-
7 or CEACAM7) in the pancreatic juice from patients with tivity is being steadily improved. In a study from University of
pancreatic ductal adenocarcinoma.91 In a study from the Tokyo, mutant K-ras was detected at high amounts in 20 of 26
University of Tubigen, 19 of 39 patients with PC showed specimens of EUS-FNA and in 12 of 19 of pancreatic juice in
p16INK4a promoter methylation, but none of the 16 patients cases with pancreatic carcinoma. Accurate diagnosis of the
with CP showed this.25 Methylation p14ARF was found in a carcinoma was 21 of 26 by combined cytology and molecular
lower percentage of PC specimens and in none of the samples method of EUS-FNA and increased to 23 of 26 by adding
of patients with CP.92 molecular analysis of pancreatic juice. In contrast, the mutant
Mutation analysis of K-ras in the pancreatic juice does gene was absent or in low level in patients with benign
not improve sensitivity, because it is mutated in both PC and pancreatic lesions.104
CP.93,94 In a study of bile from 118 patients with benign and
malignant diseases, the molecular analysis of p53 and ras
resulted in a sensitivity of 33% and specificity of 87% for the
diagnosis of a malignant condition.95 Conclusions
With a sensitivity of only 80% for the diagnostic test, we
What is the Diagnostic Yield from EUS can calculate the risk of cancer with negative cytology as 64%,
FNA guidance? assuming a specificity close to 100% and a 10% risk that the
EUS-FNA has sensitivity for malignancy of 90–94%, radiologic mass lesion is actually benign. As the sensitivity
a specificity for benign disease of 50–67%, and diagnostic increases to 90%, 95%, and 99%, the risk dramatically reduces
accuracy of 84–92%.61,96 The recent results reported from the to 47%, 29%, and 9%, respectively. These risks need to be
Anderson Cancer Center in Texas for the sensitivity, specificity counterbalanced against a mortality risk of approximately 5%
and accuracy of EUS-FNA for diagnosis of pancreatic malig- and a major morbidity of 30%.
nancy in 233 patients were 91%, 100% and 92% respec- There is considerable scope for improving the sensitivity
tively.31 The comparison of results between percutaneous of diagnostic FNA cytology. The current results are limited,
FNA and EUS-FNA are shown in Table 8.61,97–103 because they are based on the following:

TABLE 7. Results of Transpapillary Biopsy Techniques


Reference Year Number Method Sensitivity Specificity Positive Predictive Value Negative Predictive Value
88 1993 43 Forceps biopsy 71% (PC) 100% 100% 60%
89 1997 106 Forceps biopsy 64.9% 100% 100% 69.2%
89 1997 63 Brush cytology 46.7% 100% 100% 61.9%
89 1997 48 Forceps brush 70.4% 100% 100% 71.4%
90 1995 52 Forceps biopsy 53% 100% 100% 48%
90 1995 94 Brush cytology 54% 100% 100% 50%
90 1995 52 Forceps brush 61% 100% 100% 53%
87 2002 50 pancreatic Forceps 52% 100% 100% 29%
and biliary cancers
87 2002 30 pancreatic Intraductal ultrasound 90% 83% 84% 89%
cancers only

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TABLE 8. Comparative Results of Percutaneous FNA and EUS-FNA


Reference Year Number Modality Sensitivity Specificity Positive Predictive Value Negative Predictive Value
98 1988 79 Ultrasound-guided FNA 85% 100% 100% 55%
99 1989 62 Ultrasound-guided FNA 86% 100% 75% 62%
100 1998 510 Ultrasound-guided FNA 84% 100% 100% 61%
101 1997 47 EUS-guided FNA 64% 100% 100% 16%
102 1999 144 EUS-guided FNA 82% 100% 100% 51%
103 2001 102 EUS-guided FNA 93% 100% 100% 91%
61 2002 185 EUS-guided FNA 94% 71% 96% 60%
97 2003 233 EUS-guided FNA 91% 100% — —

 A single attempt at tissue sampling. 8. Ito T, Nakano I, Koyanagi S, et al. Autoimmune pancreatitis as a new
 No cytologist present during tissue sampling. clinical entity. Three cases of autoimmune pancreatitis with effective
steroid therapy. Dig Dis Sci. 1997.
 Test result is used in isolation. 9. Sarles H, Sarles JC, Muratore R, et al. Chronic inflammatory sclerosis of
The accuracy of preoperative histologic diagnosis could the pancreas—an autonomous pancreatic disease? Am J Dig Dis. 1961;6:
be dramatically increased by further practical developments, 688–698.
which include the following: 10. Horiuchi A, Kawa S, Akamatsu T, et al. Characteristic pancreatic duct
appearance in autoimmune chronic pancreatitis: a case report and review
 Ensuring a cytologist is present during tissue sampling. of the Japanese literature. Am J Gastroenterol. 1998;93:260–263.
 Repeating the procedure. 11. Ohana M, Okazaki K, Hajiro K, et al. Multiple pancreatic masses
 Combining diagnostic information. associated with autoimmunity. Am J Gastroenterol. 1998;93:99–
102.
Coupled with technological developments based on 12. Taniguchi T, et al. Autoimmune pancreatitis detected as a mass in the tail
molecular diagnostics,105 preoperative confirmation of pan- of the pancreas. J Gastroenterol Hepatol. 2000;15:461–464.
creatic malignancy should be routine. 13. Irie H, Honda H, Baba S, et al. Autoimmune pancreatitis: CT MR
Characteristics. AJR Am J Roentgenol. 1998;170:1323–1327.
14. Kawaguchi K, Koike M, Tsuruta K, et al. Lymphoplasmacytic sclerosing
SUMMARY AND CONCLUSION pancreatitis with cholangitis. Hum Pathol. 1991;22:387–395.
15. Okazaki K, Uchida K, Ohana M, et al. Autoimmune-related pancreatitis
is associated with autoantibodies and a Th1/Th2-type cellular immune
Dr. William M Steinberg response. Gastroenterology. 2000;118:573–581.
The 2 sides have been presented. We have read and 16. Merkle EM, Boaz T, Kolokythas O, et al. Metastases to the pancreas. Br J
relearned the differential diagnosis of pancreatic masses. Non- Radiol. 1998;71:1208–1214.
neoplastic masses caused by CP or AIP and certain neoplastic 17. Klein KA, Stephens DH, Welch TJ. CT characteristics of metastatic
disease of the pancreas. Radiographics. 1998;18:369–378.
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sitive and cannot always make the diagnosis. Would a negative Urology. 2000;56:211–215.
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curative but palliative? Furthermore, biopsy carries a small 20. Scatarige JC, Horton KM, Sheth S, et al. Pancreatic parenchymal
but definite risk, which may retard or occasionally complicate metastases: observations on helical CT. AJR Am J Roentgenol. 2001;176:
subsequent surgery. The reader must make his or her own 695–699.
decision based on the accumulated wisdom presented and 21. Ng CS, Loyer EM, Iyer RB, et al. Metastases to the pancreas from renal
discussed in this Controversies section. cell carcinoma: findings on three-phase contrast-enhanced helical CT.
AJR Am J Roentgenol. 1999;172:1555–1559.
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