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Review

Pancreatology 2005;5:330344

DOI: 10.1159/000086868

Pancreatitis Associated with Pancreatic

CarcinomaPreoperative Diagnosis: Role of CT Imaging in Detection and Evaluation

E.J. Balthazar

Department Radiology, New York University, Bellevue Medical Center, New York, N.Y., USA

The association of pancreatitis with carcinoma of thepancreas has been recognized and reported sporadicallyin the literature [19]. The combined occurrence of theserelatively common afflictions is occasionally seen in med-ical practice, having confusing clinical signs. Patients har-boring this association often present as perplexing diag-

nostic dilemmas with ambiguous clinical features butominous therapeutic and prognostic implications. Theclinical manifestations are nonspecific and overlapping,often leading to delays in the correct diagnosis. Moreover,the pathophysiologic relationship of these two distinctpancreatic entities is obscure and poorly understood. Dif-ficulties in establishing an initial accurate diagnosis per-tain not only to uncertain clinical and laboratory findings,but similarly, to equivocal imaging features and to diffi-cult surgical explorations often unable to depict carci-noma in the background of pancreatitis [19].

This review aims to summarize the controversial hy-

pothesis of the pathophysiologic connection of these con-ditions, address the pitfalls in the initial diagnosis andfocus on the evolving role of high resolution CT imagingin the evaluation of these patients. The differential diag-nostic features and the remaining limitations of CT imag-ing will be emphasized, together with the available stateof the art alternative or complementary diagnostic mo-dalities.

Key Words

Carcinoma of pancreas Pancreatitis, acute, chronic

Complications, pancreatic carcinomas

Abstract

The combined occurrence of pancreatic carcinoma withacute or chronic pancreatitis is seldom seen in medical

practice, but when present it is a challenging dilemma,

plagued by confusing overlapping clinical findings and

pitfalls in diagnostic imaging tests. This article reviews

the presumptive pathophysiological aspects of this rela-

tionship, the perplexing clinical presentations and the

advantages and limitations of the noninvasive imaging

examinations. The role of state-of-the-art CT imaging in

screening patients with acute and chronic pancreatitis is

emphasized and the impute of additional more invasive

tests in detecting pancreatic tumors in this cohort of pa-

tients is reviewed. The habitual use of CT imaging, fol-lowed when needed by complementary examinations,

can improve on previously reported low detection rates

and hopefully decrease the number of exploratory

laparatomies and unnecessary major pancreatic surgical

resections.

Copyright 2005 S. Karger AG, Basel and IAP

Published online: July 5, 2005

Dr. E.J. BalthazarNew York University, Bellevue Medical CenterRadiology Department, 3rd Floor, Room 3W-37-42, 462 First Avenue

New York, NY 10016 (USA)Tel. +1 212 263 6373, Fax +1 212 263 7666, E-Mail [email protected]

2005 S. Karger AG, Basel and IAP14243903/05/00550330$22.00/0

Accessible online at:www.karger.com/pan
http://dx.doi.org/10.1159%2F000086868http://dx.doi.org/10.1159%2F000086868


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Pancreatitis Associated with PancreaticCarcinoma

Pancreatology 2005;5:330344 331

Pathophysiologic Relationship

In clinical practice, the simultaneous appearance ofpancreatitis and pancreatic carcinoma is seen under twodistinct clinical settings. Some individuals without perti-nent histories that have occult pancreatic adenocarcino-

ma, suddenly exhibit signs of acute pancreatitis as theinitial manifestation with abdominal pain and elevatedserum amylase and/or serum lipase levels [15]. In otherindividuals with long histories of documented chronicpancreatitis, carcinoma develops later, but despite clini-cal suspicion, the correct diagnosis cannot be easily con-firmed because of overlapping clinical and morphologicabnormalities shared by both conditions [69].

Tentative and speculative hypothesis are suggested toexplain the association of these two pancreatic afflictions.In the majority of patients a random, coincidental occur-rence is very unlikely and thus a connecting or causal re-

lationship is probably present. The incidence of pancre-atitis associated with carcinoma of the pancreas is higherthan generally perceived and it cannot be explained bymere fortuity. Acute pancreatitis presenting as solitary ormultiple acute attacks, was reported to occur in about 3%of patients with pancreatic carcinoma [1]. Furthermore,pathologic stigmata of acute pancreatitis, such as fat ne-crosis and inflammatory reaction were found at surgeryand/or pathologic specimens in about 10% of patientswith carcinoma of the pancreas [1]. Conversely in a largeseries of patients with acute pancreatitis, 12% of thesubjects are reported to have carcinoma, without an al-

ternative known etiologic factor that could explain thecoincidental occurrence [10, 11]. Indeed, it appears thatcarcinoma of the pancreas, as well as other primary ormetastatic pancreatic tumors, can induce episodes ofacute pancreatitis, although the exact underlying mecha-nism, their capricious development and degree of second-ary inflammatory response produced by carcinoma isvariable and remains controversial [111].

It has been assumed that similar to gallstones impact-ed at the ampula of Vater, obstruction of pancreatic ductby tumor leads to increased intraductal pressure maydamage duct membrane or may rupture secondary ducts

resulting in interstitial and retroperitoneal extravasationof activated pancreatic enzymes [1, 2, 4]. While this hy-pothesis is regarded as persuasive evidence to explain thedevelopment of pancreatitis in most patients with pan-creatic carcinoma, it unfortunately does not apply to allcases. It does not explain, for instance, why some docu-mented cases of pancreatic neoplasms that do not ob-struct the main pancreatic duct, can nevertheless induce

pancreatitis [4, 12], (fig. 1). More disturbing, most pa-tients with carcinoma of the head of the pancreas ob-structing and dilating the main pancreatic duct, exhibitsevere pancreatic atrophy but do not develop clinical ormorphologic evidence of acute pancreatitis. Further-

more, ligation of the pancreatic duct in most laboratoryanimals does not induce pancreatitis but results only inpancreatic atrophy [13]. A notable exception is the Amer-ican opossum which has a long common pancreatic bileduct similar to the common Opies channel present insome individuals [13]. Experimental ligation of this com-mon channel in opossum results in acinar cell necrosisand full fledged necrotizing pancreatitis possibly associ-ated with bile reflux into the pancreatic duct [13]. Thedevelopment of acute pancreatitis in the majority of pa-tients with carcinoma of pancreas however, does not re-produce this experimental model because in most pa-

tients pancreatitis is not induced by tumoral obstructionof a common pancreatico-biliary channel. Since the ductligation or other experimental models [13] do not applyto all cases of human pancreatitis combined with pancre-atic carcinoma, the mechanism for pancreatitis in someof these patients remains obscure. An attractive hypoth-esis, asserting that tumor cells may secrete plasminogen-activating enzymes which may in turn activate trypsino-

Fig. 1. Carcinoma of tail of pancreas presenting clinically as acutepancreatitis. 54-year-old male with a previous clinical episode ofacute pancreatitis presents 3 months earlier with abdominal pain

and elevated serum amylase and lipase levels. CT reveals a normalpancreatic body (small arrows) and a homogeneous lower attenua-tion infiltrating tumor in the tail of the pancreas invading the spleen(large arrows). S = Spleen; L = liver.


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gen-inducing autodigestion, which is the hallmark ofacute pancreatitis, has not been reliably confirmed [4, 14,15].

The insidious development of pancreatic carcinomain patients with long standing histories and typical mor-phologic features of chronic pancreatitis is more com-

monly seen in clinical practice, but the connection re-mains controversial. It is assumed that similar to otherchronic gastrointestinal conditions affecting the liver (cir-rhosis), colon (ulcerative colitis) or esophagus (Barrettsesophagitis), carcinoma of the pancreas will develop withan increased incidence in the background of a chroni-cally inflamed gland. Similar to other organs, the acceler-ated cell turnover induced by chronic inflammation hasbeen thought to be associated with a gradual but steadyincreased incidence of carcinoma in patients with chron-ic pancreatitis [16]. Indeed, while the general incidenceof pancreatic carcinoma in a cohort of patients of chron-

ic pancreatitis of over 2000 subjects, was 2.7%, the cumu-lative risk of pancreatic cancer was 2% after 10 years and5.9% after 20 years of documented chronic pancreatitis[16]. Furthermore, the risk of development of pancreaticcancer in this large cohort of patients was not dependenton the etiology of chronic pancreatitis. Whatever its caus-ative factors, patients with chronic pancreatitis have anexcess but similar risk to develop pancreatic cancer[16].

At this time it is fair to conclude that the pathophysi-ology of acute and chronic pancreatitis associated withcarcinoma is probably variable in different individuals

and its triggering mechanisms, mainly extravasation andactivation of pancreatic enzymes, not fully resolved.Based on empirical evidence, however, there is no doubtthat a reciprocal relationship between pancreatitis andcarcinoma of the pancreas should be acknowledged. Pan-creatic carcinoma, or other primary or metastatic pancre-atic tumors, can induce solitary or recurrent attacks ofacute pancreatitis and, conversely, a higher incidence ofcarcinoma of the pancreas should be expected in patientswith documented chronic pancreatitis.

Clinical Diagnostic Features and Pitfalls

Discrimination between acute pancreatitis and carci-noma of the pancreas is successfully achieved in mostpatients based on a characteristic history, symptoms andclinical signs. Sudden onset of severe upper abdominalpain, nausea and vomiting associated with elevated se-rum amylase and/or lipase levels are considered reliable

indicators of the occurrence of an acute attack of pancre-atitis. However, when the acute attack is triggered by anoccult pancreatic tumor, the clinical presentation domi-nated by symptoms and signs of acute pancreatitis willinevitably lead to errors in the initial clinical diagnosis.Indeed, historically in most reported cases, carcinoma

has not been suspected clinically [15], and symptoms ofacute pancreatitis with recurrent episodes have antedatedthe diagnosis of carcinoma for as long as 1824 months[15]. In one series of 26 cases of acute pancreatitis as-sociated with pancreatic carcinoma, the medium dura-tion of symptoms was 8 months and the diagnosis of car-cinoma was delayed for up to 12 months [1] (fig. 1). Fur-thermore, even in clinically suspected patients, thediagnosis of pancreatic carcinoma could be confirmedonly after repeated laparotomies or at postmortem ex-amination [1, 10].

Nevertheless, while in most patients specific discrimi-

nating parameters are lacking, certain clinical features arehelpful in at least suspecting a neoplastic etiology of acutepancreatitis. Individuals with unknown or uncertain eti-ologies classified as idiopathic pancreatitis, which ac-count for up to 30% of patients in some series [1719],should be viewed with suspicion and should undertake athorough work-up. State-of-the-art CT imaging, conven-tional and endoscopic ultrasound, MRCP and MR imag-ing and when indicated ERCP examinations can be per-formed. This approach is particularly useful in patientswith recurrent episodes of acute pancreatitis that have noidentifiable cause and in elderly individuals over 50 years

of age. In Trepnells series [10], long-term follow-up ofpatients with idiopathic pancreatitis revealed underlyingcarcinoma in 5% of cases. Moreover, in patients withacute pancreatitis, the development of jaundice or of se-rum bilirubin levels above 3 mg% should be viewed withcaution. Although benign etiologies such as common ductstones or inflammatory masses can produce it, tumors ofthe ampulla of Vater or head of pancreas should be con-sidered and a comprehensive imaging evaluation shouldbe instituted.

The insidious development of pancreatic carcinomain the background of chronic pancreatitis has been, and

to a lesser degree remains, a difficult diagnostic challengebecause of overlap in clinical findings and often confusingimaging features. Upper abdominal pain with or withoutassociated jaundice are symptoms seen in both condi-tions. Rapid deterioration of clinical parameters is suspi-cious for malignancy but it is not specific and it is usu-ally seen late in the evolution of the neoplastic process.In the past, in patients with chronic pancreatitis associ-


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ated with carcinoma an incorrect diagnosis has occurredin up to 25% of patients [20]. In recent years, the detec-tion rate has improved, but the differentiation betweenthese overlapping pancreatic afflictions remains uncer-tain in a disturbingly high number of cases [68]. Dis-crimination is unclear and false-positive and false-nega-

tive diagnoses are often rendered. In a more recent series[21], the diagnosis was uncertain in 7 of 40 cases of prov-en chronic pancreatitis (17%) and in 10 of 61 patients(16%) with chronic pancreatitis that have already devel-oped carcinoma of pancreas. Similar results have beenreported in other series. Furthermore, in the group of pa-tients with chronic pancreatitis, carcinoma can occur atany time, but frequent pitfalls lead to delays in securinga reliable diagnosis in most patients [68]. Thus far, atthe time of detection, the majority of patients with chron-ic pancreatitis and pancreatic carcinoma have revealedsurgically unresectable pancreatic lesions.

To avoid these shortcomings an aggressive surgical ap-proach has been advocated, based on suspicious clinicaland imaging findings, to eradicate incipient lesions whichmay be potentially curable [68]. This practice in addi-tion, will have the advantage of discovering histologicalvariants such as acinar cell carcinoma of the pancreaswhich may present as acute pancreatitis as well as otherless aggressive primary tumors, i.e. ampullary carcinoma,neuroendocrine tumors and intraductal papillary mucinproducing neoplasms (IPMN) or cystic adenocarcinoma,which have a significantly better prognosis comparedwith pancreatic duct adenocarcinoma, when resected in

time. The incidence of false negative diagnosis will de-crease, delays in securing a correct diagnosis will be re-duced and the number of potentially curable lesions inthis cohort of patients will probably increase.

Yet obviously, the downside of this aggressive surgicalapproach is the high incidence of inadvertent resectionsof suspicious lesions which turn out to be benign, with theattendant morbidity and mortality that ensues. Indeed,many series report a 510% rate of superfluous pancre-atic resections of benign inflammatory focal lesions inpatients with chronic pancreatitis suspected of harboringcarcinoma [22, 23]. In a more recent report, despite ad-

equate work-up, 6% of patients who underwent Wippleprocedures for presumed pancreatic carcinoma hadpathologically proven benign lesions [8]. In fact, the prac-tical consequences of this aggressive surgical approachmay not be very rewarding since the overall 5-year sur-vival rate for pancreatic ductal adenocarcinoma is only4.1% and the surgical resection in itself carries a morbid-ity rate 2030% and a mortality rate of as high as 5% [24,

25]. Hence, if one considers the financial implications,morbidity and mortality and the poor prognosis even ofthose few patients with resectable pancreatic cancer, onewonders whether or not an aggressive surgical policy is

justified.Evident pitfalls and frequent clinical errors in discrim-

inating pancreatitis from pancreatic carcinoma have re-sulted in an increased dependency and in the frequent useof noninvasive imaging modalities in the evaluation ofthese patients. Continuous improvements in image reso-lution, new protocols and acquired experience have nodoubt increased our ability to detect carcinoma in pa-tients with acute and chronic pancreatitis. While limita-tions remain, the judicial use of cutting edge CT imagingand other complementary or alternative modalities willreduce diagnostic errors and hopefully, will positively im-pact on the survival rates as well as on the number of in-advertent pancreatic resections of benign inflammatory

conditions.

CT Imaging

For more than 20 years, CT imaging has been acknowl-edged as the noninvasive examination of choice for thediagnosis of acute and chronic pancreatitis as well as forthe detection and evaluation of patients with pancreaticcarcinoma [2632]. CT imaging has been used to confirmthe clinical diagnosis of pancreatitis, to detect pancreati-tis in patients with equivocal clinical and laboratory find-

ings, and to depict other acute intra-abdominal condi-tions in individuals that present with misleading clinicaland laboratory abnormalities consistent with acute pan-creatitis. Moreover, the development of helical CT andrecently of multidetector computed tomography (MDCT)coupled with rapid intravenous administration (34 ml/s) of 150 ml of nonionic contrast material, has al-lowed detection of neoplasm as small as 12 cm in sizewith a reported CT sensitivity of 8997% for tumor de-tection [26, 27]. The fast acquisition of data has elimi-nated respiratory and streak artifacts, has improved reso-lution and has enabled the performance of dual phase

(pancreatic and portal phase) imaging with higher pan-creatic parenchymal contrast enhancement. Further-more, the computer acquired imaging data can be pro-cessed and thin (12 mm) collimation axial images ormultiplanar reconstructed displays can be rendered atvarious section intervals, including curved planar refor-mations [26, 3032].


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In patients with pancreatic carcinoma a relationshipbetween size of lesion, surgical resectability and even, ar-guably, long-term survival has been established [31, 32].At the time of presentation only 1020% of patients withpancreatic carcinoma are found resectable [33, 34]. How-ever, most small carcinomas, !2 cm are surgically resect-

able and among them, tumors confined to the pancreashave exhibited long term survival rates of up to 35% [35].Hence, the routine use of cutting edge CT imaging willhopefully be able to increase the detection of incipientsmall pancreatic neoplasms in patients with pancreatitis.Higher detection rates and recently reported improvedaccuracy values of up to 87% for tumor resectability [32],could on one hand potentially increase survival rates, andon the other, lower the number of unnecessary surgicalresections or exploratory laparatomies in patients withpancreatitis.

Tumor Detection in Acute Pancreatitis

The salient CT features of pancreatic carcinoma canbe divided into reliable primary diagnostic findings andsecondary imaging signs which are suspicious but notpathognomonic. Detection of an infiltrating soft tissueattenuated mass extending outside of the gland, distortingpancreatic contour, and invading adjacent organs and/orvascular structures is characteristic (fig. 1). These findingsas well as the presence of lymphadenopathy or liver me-tastases establishes the diagnosis and render these pa-

tients surgically unresectable (fig. 1, 2).Detection of a small (!3 cm) pancreatic carcinoma can

be made in addition, by the visualization of an enhancingbut slightly lower attenuated lesion which contrasts withthe higher density of normal pancreatic parenchyma dur-ing a bolus of intravenous contrast administration [27,3033] (fig. 3). Differences in attenuation values of morethan 30HU are visually perceptible allowing the detectionof small lesions. Discrimination becomes apparent main-ly in the late arterial (pancreatic) phase and to a lesserdegree in the portal phase of a biphasic helical or multi-detector row CT examination (fig. 1, 3). It has been re-

ported that about 90% of pancreatic adenocarcinoma dis-play obvious lower attenuated values with a mean tumor-pancreas contrast of about 75HU + 35 during the latearterial phase of CT imaging [36]. The remainder 10% ofpancreatic adenocarcinomas exhibit a mean tumor-pan-creas contrast of only about 9HU + 11, differences whichare not visually perceptible, impeding on the CT detec-tion of small lesions [36]. In these patients as well as in

individuals with other small intrapancreatic isoattenuat-ing primary or metastatic tumors, diagnosis is more dif-ficult and it is based mainly on the depiction of suspicioussecondary imaging findings.

Fig. 2. 51-year-old male with second episode of idiopathic pancre-atitis and unresectable carcinoma of pancreas. Presenting symp-toms were abdominal pain with high serum amylase (380 IU) andlipase (600 IU) levels. a CT reveals a slightly enlarged pancreaticbody and tail with extravasated fluid around pancreas (small ar-rows) indicative of pancreatitis. P = Pancreas. b More cranial axialimage shows a large irregular infiltrating tumor involving the celiacaxis (arrows) extending from carcinoma in the neck of pancreas.Biopsy proven.


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Secondary CT signs, although less specific, play a sig-nificant role in the detection of primary pancreatic tu-mors associated with acute pancreatitis. Presence of re-gional lymphadenopathy, venous or arterial neoplasticinvolvement or liver metastases makes the patient unre-sectable or surgically incurable (fig. 13). Furthermore,

the detection of a dilated pancreatic duct, of the doubleduct sign (dilated pancreatic and common duct) or aninterrupted or cutoff pancreatic duct are not compatiblewith acute pancreatitis of a benign etiology. These CTfindings when present in a patient with clinical and/orradiological evidence of acute pancreatitis should be con-sidered unusual and suspicious of a neoplastic etiology(fig. 3). The interrupted duct sign in the head or body ofthe pancreas with associated proximal parenchymal atro-phy or segmental pancreatitis affecting the tail of the pan-creas should particularly trigger a comprehensive work-up, since these findings often precede the appearance of

an imaging visible tumor [33]. In these patients, compli-mentary imaging examinations such as ERCP, MRCPand/or endoscopic sonography become very valuable indefining the morphology of the pancreatic duct, nature ofthe obstructive process and the presence of a small evolv-ing neoplastic lesion.

Additionally, when the parenchymal inflammatory re-action of acute pancreatitis and the peripancreatic het-erogeneous fluid collections obscure the proper visualiza-tion of the entire pancreatic gland, short-term follow-upCT examinations are indicated. Inability or failure to per-form high resolution CT examinations, to depict and

properly assess subtle CT signs, or to follow-up and work-up patients with equivocal findings may lead to unwar-ranted delays in the diagnosis. In some of these patients,complications following acute pancreatitis, such as ab-scesses or pseudocysts, maybe wrongly attributed to epi-sodes of pancreatitis when the initial triggering neoplasticlesion was missed (fig. 4).

Fig. 3. 50-year-old male with carcinoma of the pancreas presentingas acute pancreatitis. Sudden-onset abdominal pain and elevated

serum enzymes. a CT reveals mild peripancreatic inflammatorychanges and a cutoff of a distended pancreatic duct in the body ofpancreas (small arrows). There are peripancreatic fluid collections(curved arrow) and large metastatic nodes (long arrow). b Caudalimage shows a small 2 cm lower attenuated lesion in the neck ofpancreas (small arrow) indicative of carcinoma. h = Head of pan-creas. c Head of pancreas (h) is normal with collapsed, non-visual-ized pancreatic duct. Biopsy proven.


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Tumor Detection in Chronic Pancreatitis

While recent advances in technology have improved

the detection of pancreatic neoplasms, the CT ability todiscern an evolving carcinoma in the background ofchronic pancreatitis remains difficult. Several overlap-ping morphologic features of chronic pancreatitis andpancreatic carcinoma contribute and explain the limita-tions in the differential diagnosis.

Characteristic CT features are often seen in patientswith chronic pancreatitis with a spectrum and degree of

abnormalities related to type of morphologic involve-ment and probably to the severity and chronicity of theinflammatory process. In fact, in most patients with

proven chronic pancreatitis, CT imaging will show typ-ical morphologic changes with a relatively normal ap-pearing pancreatic gland seen in only 7% of patients[37]. A reliable CT feature is the dilatation of the entiremain pancreatic duct that can have a smooth or beadedconfiguration, seen in about 70% of cases. Diffuse pa-renchymal atrophy was described in 54%, intraductalcalcifications in 50% and biliary dilatation in 29% of

Fig. 4. 45-year-old male with 6 months history of acute pancreati-

tis and pancreatic pseudocysts secondary to carcinoma of pancreas.a, b CT reveals normal pancreatic body (thin arrows) and a largeinfiltrating tumor of lower attenuation replacing part of the bodyand tail of pancreas and extending posteriorly encasing the celiacaxis (thick arrows). Multiple encapsulated fluid collections consis-tent with pseudocysts are present in the left upper quadrant and inthe spleen. c = Pseudocysts; s = spleen; l = liver. Biopsy proven.

Fig. 5. 70-year-old male with carcinoma of the pancreas and long

history of chronic pancreatitis with acute exacerbations. a CTaxial image shows a slightly enlarged pancreas (small white ar-rows), distended pancreatic duct (small black arrows), peripancre-atic inflammatory changes and fluid collections (long arrows). b Alarge enhancing heterogeneous focal mass is seen in the head ofthe pancreas (thick arrows) and fluid is present in the left anteriorpararenal space (thin arrows).


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Fig. 6. Alcoholic male, 59 years old, with chronic pancreatitis anddevelopment of pancreatic carcinoma. a, b CT shows several small

ductal calcifications in the head of pancreas without focal mass(large arrows). Pancreatic duct is distended in the body of pancreas(small arrows). c, d Follow-up CT examination 3 months later re-veals a more distended pancreatic duct (small arrows) and the de-velopment of a focal mass in the head of pancreas (large arrows).e Percutaneous cholangiogram shows an obstructed common duct(large arrow) and a few calcifications in the head of the pancreas(small arrows). Carcinoma of pancreas confirmed by Whipple re-section, no metastases.


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patients with chronic pancreatitis [37]. The presence ofperipancreatic inflammatory changes and/or fluid col-lections is indicative of acute exacerbation of chronic

pancreatitis. With the development of MDCT and de-pending on the diagnostic parameters used, the CT ac-curacy to diagnose chronic pancreatitis will most likelyincrease.

In many of these patients, the depiction of a focal ho-mogeneous low attenuated soft tissue pancreatic mass inthe background of an atrophic gland is indicative of pan-creatic ductal carcinoma. Moreover, secondary signs such

as the cutoff of pancreatic duct or segmental rather thandiffuse atrophy of the pancreas are sign suggestive of adeveloping neoplasm. However, most of the limitations

on CT imaging are seen in patients that present with afocal mass or a focal enlargement of the pancreas, a fea-ture which occurs in up to 30% of cases of chronic pan-creatitis [37]. In these patients, differentiation from ad-enocarcinoma is challenging and wrought with frustra-tions. Secondary signs such as dilatation of the pan-creatic duct, ductal strictures and dilatation of thecommon duct with double duct sign may be seen in both

Fig. 7. Alcoholic male, 40 years old, with chronic pancreatitis anddevelopment of carcinoma of pancreas. a, b Initial CT examinationreveals an atrophic pancreatic gland with multiple large intraduc-tal calcifications (arrows). There are no focal masses. c, d Follow-upCT examination 15 months later reveals a massively distendedpancreatic duct in the body of the gland (thin arrows) and the de-

velopment of a focal homogeneous soft tissue mass in the head ofthe pancreas (large arrows). Gallbladder (G) and common duct inthe head of pancreas (small arrow) are distended. Extensive collat-eral circulation secondary to vascular invasion and occlusions isdetected around the pancreas. Biopsy-proven adenocarcinoma, un-resectable.


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conditions. Furthermore, the chronic inflammatory mass,depending on the amount of proliferating fibrotic tissue,has CT attenuation values (isoattenuating or hypoattenu-ating) similar to neoplastic tissue [27, 38] (fig. 5). Evenarterial encasement and peripancreatic venous obstruc-tions are findings that may be seen in both conditions.

Unless the CT imaging depicts metastatic disease, thediagnosis is uncertain and carcinoma can not be ruledout. When previous CT examinations are available orshort-term follow-up studies are performed, the detectionof a new developing mass is suggestive of carcinoma (fig.6). Similarly, the rapid increase in size of a homogeneousill-defined soft tissue mass that displaces pancreatic duc-tal calcifications and obliterates the previously seen di-lated secondary pancreatic ducts is consistent with pan-creatic adenocarcinoma (fig. 6, 7).

In patients with acute or chronic pancreatitis suspect-ed of harboring pancreatic carcinoma based on clinical

or CT imaging findings, alternative or complementaryexaminations should be attempted to secure an adequatediagnosis.

Autoimmune Pancreatitis

A form of pancreatitis caused by an autoimmunemechanism, variably called autoimmune pancreatitis,sclerosing pancreatitis or nonalcoholic duct-destructivechronic pancreatitis has been increasingly recognizedand reported [39]. This entity which may be associatedwith other autoimmune disorders, presents as a diffuseor a focal enlargement of the pancreas with strictures of

pancreatic and/or common duct that may be difficult todifferentiate from pancreatic carcinoma or lymphoma.On CT imaging, the diffuse or focal enlargement (pseu-dotumor) is homogeneous, with isoattenuation valuessimilar in the entire gland, sharp outer contour andsometimes a peripheral rim of hypoattenuation thatprobably represents inflammatory reaction. EndoscopicUS-guided biopsy shows a predominant lymphocytic in-filtrate, plasma cells, fibrosis and absence of malignantcells. When the imaging diagnosis is suspected, serummarkers of autoimmune disorders (elevated IgG and an-tinuclear antibody levels) are helpful to confirm the di-

agnosis. Good response to steroid therapy with resolu-tion of symptoms and return to a normal appearance ofthe pancreas has been documented in the literature[39].

Magnetic Resonance Imaging

When available, MRI can replace CT examination orit may be useful as a secondary noninvasive modality tocharacterize and better evaluate equivocal CT findings.MRI is particularly beneficial in patients in who intrave-

nous contrast enhanced CT studies are contraindicated(renal insufficiency, severe contrast allergy) and in preg-nant women to avoid radiation exposure.

MRI of the pancreas employ several pulse sequenceswhich usually are T1-weighted, T2-weighted, fat satura-tion and dynamic gadolinium-enhanced images. A com-prehensive examination includes MR cholangiopancrea-tography (MRCP) and when indicated vascular imaging[4042]. For optimal visualization of the pancreas anddepiction of gross morphologic abnormalities T1-weight-ed images are essential. T1-weighted, fat suppressed im-ages are useful for detecting focal or diffuse pancreatic

abnormalities. This pulse sequence will detect carcinomaas a focal lesion with diminished T1 signal compared tothe rest of the gland. Moreover, during the administrationof a dynamic intravenous bolus of gadolinium chelate,the normal pancreas enhances intensely while hypovas-cular pancreatic carcinoma, similar to CT imaging, showsdiminished signal intensity compared to the rest of thegland. Images can be reconstructed in any plane withoutloss of spatial resolution and MR angiograms are per-formed to better stage pancreatic carcinoma and detectunresectable tumors.

MRCP axial or projectional images use heavily 2D or

3D, T2 weighted sequences, very helpful in depictingmorphologic abnormalities of the common bile duct andpancreatic duct. The appearance of the pancreatic ducton MRCP can be useful in differentiating an inflamma-tory pancreatic mass from pancreatic carcinoma. Smoothtapering of the distal common duct and/or pancreaticduct, traversing the focal mass is seen in chronic pancre-atitis. Short irregular stricture or complete obstruction ofthe pancreatic duct or common duct within the confinesof the mass with proximal dilatation of the duct, is con-sistent with pancreatic carcinoma. Using these criteria,reported as the duct-penetrating sign, in 54 patients with

focal masses (43 carcinoma, 11 inflammatory), Ichikawaet al. [43] reported a characteristic benign pattern in 85%of patients with an inflammatory mass and a malignantmorphologic pattern in 96% of patients with pancreaticcarcinoma.

Because of MR fast acquisition of several sequencesand superior soft tissue contrast resolution, MRI hasbeen reported to have a higher sensitivity in depicting


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small pancreatic carcinoma compared to CT imaging[40, 41]. However, in the background of diffuse pancre-atic inflammation or focal inflammatory masses, MRIhas similar shortcomings with CT imaging, being unableto reliable differentiate inflammatory and fibrotic mass-es from carcinoma [38]. The enhancement pattern of fo-

cal inflammatory masses during dynamic gadolinium-enhanced MR imaging mimics that of pancreatic carci-noma [38].

Ultrasonography

Abdominal ultrasound is commonly used as the firstscreening test for patients suspected of pancreatic disease.The procedure is fast, noninvasive, widely available andaffordable and although operator dependent, it can depictgross pancreatic abnormalities as well as biliary stones

and dilatation of the common duct and pancreatic duct.Substandard imaging of the pancreas however occurs of-ten in obese individuals and because of overlying gas induodenum and transverse colon, which interferes withthe transmission of sound. Even under adequate condi-tions, subtle pancreatic inflammatory alterations or thedetection of small neoplastic lesions is questionable [44,45]. Despite advances made with the use of real-timehigh-resolution equipment and color and spectral Dopp-ler analysis, the differentiation of a focal inflammatorymass from carcinoma remains limited with disappointingaccuracy values [46, 47].

The discrimination between an inflammatory massfrom carcinoma was reported to significantly improve,with the use of contrast-enhanced sonography (CES) em-ploying carbon dioxide microbubbles. This technique de-picts chronic inflammatory lesions as isovascular andneoplastic lesions as hypovascular leading, in the initialreports, to a sensitivity of 98% in differentiating these twoconditions [48]. These preliminary observations have yetto be validated in a larger randomized clinical trial.

Endoscopic Ultrasonography

Endoscopic ultrasonography (EUS) is a more recentand more accurate application of sonographic imaging,that has been used in the evaluation of the biliary ductsand of the pancreas [4952]. Examination is performedusing a specialized endoscope with a radial or linear ul-trasound transducer at the tip. The procedure requiresconscious sedation with images obtained transgastrically

or transduodenally utilizing a water filled balloon foracoustic coupling. The examination requires specialequipment, skillful manipulation and experience but hasthe advantage of being able to obtain high resolution im-ages and reliable cytology samplings of perceived pancre-atic neoplasms with fine-needle aspirations (FNA).

In patients with acute pancreatitis EUS is mainlyused for detecting small stones (!3 mm) and biliarysludge particularly in the common duct after negativeabdominal sonography prior to cholecystectomy. EUSand MRCP have similar accuracy rates of 8595% forthe diagnosis of choledocolithiasis [53, 54]. EUS can beused to evaluate patients with idiopathic pancreatitis.In a series of 31 patients with pancreatitis of unknownetiology, EUS was able to depict the cause of pancreati-tis in 21 patients (68%) and to detect 1 case (3.2%) ofpancreatic carcinoma [51]. Additionally, EUS is consid-ered both sensitive and specific to diagnose chronic pan-

creatitis, being able to image subtle morphologic chang-es not apparent on conventional sonography or ERCPstudies [52].

For patients with pancreatic carcinoma EUS canhave an important dual role: detection of pancreatic le-sions with FNA cytologic confirmation and preoperativestaging of malignant tumors. Tumor detection has beenreported to be equal or superior to CT, particularly withlesions smaller then 3 cm in diameter [55, 56]. However,the about 90% sensitivity for tumor detection has beenachieved by EUS in patients without associated acute orchronic pancreatitis and without uncertain focal inflam-

matory tumefactions. Furthermore, reported compari-son values of EUS versus CT were obtained with con-ventional helical (spiral) CT imaging and not with themore sensitive and now available MDCT technologyand the specialized pancreatic protocols.

Tumor sampling via the endoluminal approach (EUS-guided FNA) represents a major advantage of EUS overother imaging modalities. Biopsies of a primary pancre-atic lesion as well as of regional lymph nodes can be per-formed to confirm the diagnosis and help in staging. Ac-curacy rates of 8595% and sensitivity rates of 75 to 90%for FNA to diagnose malignant tumors have been

achieved [5760]. In expert hands the examination issafe with a complication rate of under 2% [61], and hasthe added advantage of avoiding metastatic seeding ofthe peritoneum. Staging is enhanced with EUS assess-ment of tumor extension and invasion of adjacent struc-tures including encasement and occlusions of major ves-sels. Accuracy rates for T-staging and lymph node in-volvement vary from 50 to 90%, with higher sensitivities


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in staging when CT or MR imaging is combined with EUSstaging [55, 62].

Endoscopic Retrograde Cholangio-

Pancreatography

Endoscopic retrograde cholangio-pancreatography(ERCP) is an invasive procedure associated with rela-tively small morbidity that has been extensively used todiagnose chronic pancreatitis as well as carcinoma of thepancreas [63, 64]. It has been reported to have 92% sen-sitivity and 95% specificity in diagnosing malignant pan-creatic lesions [63]. Visualization of a dilated and beadedpancreatic duct, secondary dilated ductules, and fillingdefects consistent with stones in the pancreatic ductalsystem is indicative of chronic pancreatitis. A completeobstruction of the pancreatic duct and/or common duct

or a severe irregular focal stricture with dilatation of theproximal pancreatic duct is indicative of a neoplastic pro-cess (fig. 6). However, isolated pancreatic strictures aswell as the double duct sign can be occasionally presentin patients with chronic pancreatitis [65]. Furthermore,10% of patients with pancreatic cancer may have a nor-mal pancreatogram and small peripheral tumors that canbe missed by ERCP [66].

ERCP should be used not as a primary diagnostic toolbut mainly as an additional complementary examinationperformed when a screening noninvasive imaging test(CT, sonography, MRI) detects an ambiguous morpho-

logic pancreatic abnormality. It has the advantage ofbrushing and collecting pancreatic secretions for cytolog-ic examination and forceps biopsies of suspicious lesions.Reported detection rates for brush cytology range from35 to 53% and for forceps biopsy from 43 to 81% in pa-tients with pancreatic carcinoma [6769]. Combiningthese techniques may increase sensitivity [67].

Serum Markers

Among a great number of serologic markers described

to detect malignances, CEA and CA 19-9 have receive thegreatest attention in the literature [63, 70, 71]. CEA ismainly used in patients with colon carcinoma, particu-larly for detecting recurrent disease, while CA 19-9 hasbeen used as a complementary test to detect pancreaticcarcinoma in patients with suspicious imaging findings.The CA 19-9 serologic test has a sensitivity and specific-ity of about 80% insufficient as a screening test but help-

ful to increase the accuracy of previously detected suspi-cious imaging findings [7274]. It has been reported thatthe combination of CA 19-9 and ultrasound may improvethe sensitivity of each test by 1015% [63] with similarresults to be expected when CT imaging is used as theinitial screening test. It should be emphasized that CA

19-9 is not specific for pancreatic cancer, it is not mean-ingful in the presence of biliary obstruction and that clin-ically significant elevations of serum levels are seen main-ly in large tumors but frequently they are normal in pa-tients with small incipient tumors [75].

Fine-Needle Aspiration Cytology

Since its introduction in clinical practice, percutane-ous fine-needle aspiration cytology (FNAC) performed byskilful interventional Radiologists under CT guidance

and interpreted by experienced cytologists, has become apowerful tool to diagnose pancreatic carcinoma. FNACis a useful test with a reported sensitivity of 8090% thatcan confirm a presumptive diagnosis of pancreatic carci-noma as well as other pancreatic neoplasms [76, 77]. Ithas an admirable positive predictive value of almost100% very useful in clinical practice, but a mediocre neg-ative predictive value since negative FNAC does not ruleout malignancy. Furthermore, in patients with a focal in-flammatory mass, the hard fibrotic reaction interfereswith the collection of an adequate tissue sample and duc-tal regenerative epithelium of chronic pancreatitis may

mimic neoplastic cells leading to false-positive patholog-ic errors [77]. Other potential drawbacks are the low mor-bidity associated with an invasive procedure, a few re-ported cases of needle tract seeding and apparently anincreased incidence of intraperitoneal malignant spreadfollowing FNAC for pancreatic carcinoma [78]. These re-ported limitations have been used to argue that percuta-neous FNAC should be employed mainly in patients withunresectable tumors for oncologic confirmation [6]. Be-cause of these limitations, percutaneous FNAC is beingreplaced by endoscopic FNAC in institutions where en-dosonography is available. In our practice, focal lesions

detected on CT or MR imaging and all unresectable tu-mors are biopsied, preferably by endosonographic FNAC,followed by attempted surgical resections of potentiallycurable tumors or by palliative procedures and/or sys-temic therapy reserved for patients with unresectable car-cinoma.


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Preoperative Diagnosis

Often, at the time of the initial presentation, pancre-atitis associated with carcinoma of the pancreas, displaysconfusing overlapping clinical and laboratory findingswithout distinguishing diagnostic features. While the in-

cidence of the combined occurrence is relatively low, ig-noring this latent possibility may lead to significant clin-ical consequences. To avoid this mishap, subsequent in-vestigations are required, which include screeningnoninvasive imaging tests as well as more invasive pre-operative modalities such as ERCP, endoscopic sonogra-phy, and percutaneous or endoscopic aspiration cytology.Diagnostic laparoscopies may be useful for staging to de-tect small liver metastases or peritoneal implants not seenby EUS or CT examinations. The timing and contribu-tion of these diagnostic tests is subject to some contro-versy and individual preferences but the clinical goals are

the same. First, to detect resectable and potentially cur-able lesions and second to eliminate or at least reduce thenumber of inadvertent major pancreatic resections forbenign disease.

In selecting the initial imaging examination of choiceand the required complementary tests, the strict adher-ence to an all comprehensive algorithm is of dubious andlimited help in clinical practice. Rather than relying onever shifting and conflicting data reported in the litera-ture, personal experience based on available equipment,acquired skills and institutional strength and weaknessesare used to decide on the appropriate work up of these

patients. With these considerations and qualificationsaside, the versatility of MDCT in detecting inflammatoryand neoplastic pancreatic abnormalities, makes it in myopinion an ideal first noninvasive test in screening pa-tients with acute and chronic pancreatitis.

In patients suspected of acute pancreatitis an associ-ated pancreatic tumor when present, can be usually de-tected by MDCT imaging (fig. 14). Furthermore, whenvascular invasion, regional or distant lymphadenopathy,peritoneal implants or liver metastases is present, lack ofresectability is established (fig. 35). In these patients per-cutaneous biopsy often of liver metastases confirms the

diagnosis. If small resectable-appearing tumors or equiv-ocal findings are detected by MDCT, complimentarystudies, i.e. EUS, MRI and/or ERCP followed by EUSaspiration biopsies, are advised (fig. 6). These importantsecondary diagnostic modalities will enhance the depic-tion rate and staging accuracy of small pancreatic tumors.When on the initial MDCT examination the pancreas isobscured by large inflammatory exudates of severe acute

pancreatitis, short interval (23 weeks) follow-up CTstudies to detect complications and better assess the in-tegrity of the pancreatic gland is indicated.

In patients with histories and morphologic stigmata ofchronic pancreatitis any focal mass when present, shouldbe considered suspicious for malignancy (fig. 57). Unless

metastatic deposits are evident (fig. 5), MRCP and/orERCP examinations should be performed to assess themorphology of the pancreatic and common bile duct tra-versing the focal mass. Smooth tapering is consistent withan inflammatory mass while a cutoff or an irregular stric-ture of pancreatic or common duct is suggestive of carci-noma of the pancreas (fig. 6). Because of the intense fi-brotic reaction induced by the chronic inflammatory pro-cess, we found EUS or percutaneous biopsies less helpfulin these circumstances. Increase in size of a focal pancre-atic mass in a patient with chronic pancreatitis, detectedat a follow-up examination, is strongly suggestive of pan-

creatic carcinoma (fig. 6, 7). Although pitfalls and excep-tions to these basic concepts of radiographic interpreta-tions are found in clinical practice, this custom will atleast reduce the previously reported 510% inadvertentresections of focal inflammatory masses in patients withchronic pancreatitis [22, 23].

In summary, helical CT and particularly MDCT arereliable noninvasive screening examinations able to de-tect carcinoma of the pancreas associated with pancreati-tis in the majority of patients. For this reason, I advise itsliberal use especially in cases of idiopathic acute pancre-atitis, in elderly individuals, and after unexplained re-

peated episodes of acute pancreatitis. Patients with chron-ic pancreatitis should be routinely monitored with CTimaging to detect a focal pancreatic mass. MRI and ERCPexaminations may be able to differentiate a focal inflam-matory mass from carcinoma. Short interval, increase insize of a focal mass in the background of chronic pancre-atitis is strongly suggestive of pancreatic carcinoma.


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